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Authors: Nadine Aguilera, M.D., Rabia Ahmed, M.B.B.S., Alnoor Akber, M.D., Borislav A. Alexiev, M.D., Rola H. Ali, M.D., Ahmad Alkashash, M.B.B.Ch., Alaaeddin Alrohaibani, M.D., Saba Anjum, M.B.B.S., Kshitij Arora, M.D., Tamanna Asghari, M.B.B.S., Anshu Bandhlish, M.D., Cecilia Belzarena, M.D, M.P.H., Dariusz Borys, M.D., Iva Brčić, M.D., Ph.D., Qurratulain Chundriger, M.B.B.S., Jiufa Cui, M.D., Ph.D., Jessica L. Davis, M.D., Gustavo de la Roza, M.D., Brent A. Enniss, D.O., Mark Girton, M.D., Raul S. Gonzalez, M.D., Akif K. Guney, M.D., Hans Magne Hamnvåg, M.D., Dana J. Hariri, M.D., Jesse Hart, D.O., Lawrence J. Jennings, M.D., Ph.D., Travis H. Johnson, D.O., M.S., Erica Kao, M.D., Hatem Kaseb, M.D., Ph.D., M.P.H., Kemal Kösemehmetoğlu, M.D., William B. Laskin, M.D., Bernadette Liegl-Atzwanger, M.D., Jose G. Mantilla, M.D., Aisha Memon, M.B.B.S., Mohammad Khurram Minhas, M.B.B.S., Sarosh Moeen, M.B.B.S., Elham Nasri, M.D., Farres Obeidin, M.D., Erdener Özer, M.D., Ph.D., Ashley Patton, D.O., Ph.D., Nat Pernick, M.D., Yelena Piazza, M.D., Olga Pozdnyakova, M.D., Ph.D., Shadi Qasem, M.D., M.B.A., Madiha Bilal Qureshi, M.B.B.S., Aishwarya Ravindran, M.D., Karen L. Rech, M.D., John D. Reith, M.D. , Robert Ricciotti, M.D., Serenella Serinelli, M.D., Ph.D., Nuha Shaker, M.D., M.S., Vijay Shankar, M.D., Vignesh Shanmugam, M.D., Charanjeet Singh, M.D., Sahar Suleman, M.B.B.S., Ummiya Tahir, M.B.B.S., Muhammad Usman Tariq, M.B.B.S., Nasir Ud Din, M.B.B.S., Jaylou M. Velez-Torres, M.D., Paul E. Wakely, Jr., M.D., Kristina Wakeman, M.D., Jigang Wang, M.D., Ph.D., Laura Warmke, M.D., Sheren Younes, M.D., Ph.D., Ghazi Zafar, M.B.B.S., Lingxin Zhang, M.D.
Resident / Fellow Advisory Boards: Josephine K. Dermawan, M.D., Ph.D., Erna Forgó, M.D., Farres Obeidin, M.D.
Editor-in-Chief: Debra L. Zynger, M.D.

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Soft Tissue & Bone related: Jobs, Fellowships, Conferences, Cases, CME, Board Review, What's New #1, What's New #2

Related chapters: Bone marrow nonneoplastic, Mandible & maxilla, Soft tissue

Editorial Board oversight: Farres Obeidin, M.D. (last reviewed November 2023), Josephine K. Dermawan, M.D., Ph.D. (last revised May 2023), Nasir Ud Din, M.B.B.S. (last reviewed January 2023), Borislav Alexiev, M.D. (last reviewed December 2022)
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Adamantinoma
Definition / general
  • Rare malignant primary bone tumor of uncertain histogenesis characterized by epithelial structures embedded in a mesenchymal (osteofibrous dysplasia-like) stroma
Essential features
  • Primary biphasic fibro-osseous tumor of bone
  • Almost exclusively involves the tibia or fibula
  • 3 clinicopathologic variants:
    • Osteofibrous dysplasia (OFD)-like (differentiated) adamantinoma: inconspicuous clusters of epithelial cells embedded in fibro-osseous stroma
    • Classic adamantinoma: obvious epithelial elements embedded in fibro-osseous stroma
    • Dedifferentiated adamantinoma: loss of epithelial differentiation, sarcomatoid change
Terminology
  • Not recommended: well differentiated adamantinoma
ICD coding
  • ICD-O:
    • 9261/1 - osteofibrous dysplasia-like adamantinoma
    • 9261/3 - adamantinoma of long bones
  • ICD-11:
    • 2B5J & XH1SV4 - malignant miscellaneous tumors of bone or articular cartilage of other or unspecified sites and ameloblastoma, NOS
Epidemiology
Sites
Etiology
Clinical features
  • Initial symptoms are often indolent and nonspecific and depend on location and extent of the disease (Diagn Pathol 2008;3:8)
  • Onset is insidious and its course shows a slow, progressive character (Diagn Pathol 2008;3:8)
Diagnosis
  • Despite advances in imaging techniques, the definitive diagnosis is mainly established by histopathological examination (StatPearls: Adamantinoma [Accessed 18 January 2021])
  • Open biopsy is better to obtain additional samples
  • Any difficult or nondiagnostic biopsies of solitary bone lesions should be referred to subspecialty expert for a second opinion
Radiology description
  • Single or multiple variably sized lytic lesions with sclerotic borders (soap bubble appearance) involving the diaphyseal and less commonly, the metaphyseal cortex; multifocality within the bone and invasion of the medullary cavity or extraosseous soft tissue invasion may occur (best visualized with MRI) (J Surg Oncol 2020;122:273, Pediatr Radiol 2006;36:1068)
  • Computed tomography of the primary site elucidates the cortical involvement and is important for detection of metastases (J Surg Oncol 2020;122:273)
  • Osteofibrous dysplasia-like adamantinoma is strictly intracortical (like osteofibrous dysplasia)
Radiology images

Contributed by Borislav A. Alexiev, M.D.
Tibia lesion, radiography

Tibia lesion, radiography

Tibia lesion, MRI

Tibia lesion, MRI

Prognostic factors
Case reports
Treatment
  • Typically, adamantinomas are treated surgically with wide local resection; intralesional or marginal excision carries an increased risk of local recurrence (J Surg Oncol 2020;122:273)
  • Long term follow up is necessary due to the possibility of late complications
Gross description
  • Most often the tumor is yellow-gray or grayish white and fleshy or firm in consistency (Diagn Pathol 2008;3:8)
  • Occasionally, tumors show macroscopic cysts containing a straw colored or blood-like fluid on gross examination (Cancer 1974;34:1796)
Gross images

Contributed by Mark R. Wick, M.D.
Tibial lesion

Tibial lesion

Microscopic (histologic) description
  • Biphasic tumor characterized by epithelial and osteofibrous components that may be intermingled with each other in various proportions and differentiating patterns (Diagn Pathol 2008;3:8, J Bone Joint Surg Am 1994;76:1482, J Surg Oncol 2020;122:273)
  • Fibrous component may be loose myxoid, hyalinized or sclerotic (Cancer 1989;64:730)
  • Mitotic figures are usually infrequent, most reporting 0 - 2 mitoses per 10 high power fields (Cancer 1989;64:730, J Bone Joint Surg Am 1994;76:1482)
  • Morphologic variants:
    • Classic adamantinoma
      • Prominent epithelial component composed of mildly atypical epithelial cells within an osteofibrous dysplasia-like stroma forming conspicuous solid basaloid nests with peripheral palisading or less often, tubular structures, keratinized squamous nests or spindled cell bundles (Am J Surg Pathol 2013;37:710)
    • Osteofibrous dysplasia-like adamantinoma
      • Characterized by small scattered epithelial clusters highlighted with keratin immunostaining within a prominent osteofibrous dysplasia-like stroma (Head Neck Pathol 2015;9:32)
    • Dedifferentiated adamantinoma
      • Exhibits sarcomatoid features including mitotically active, highly pleomorphic cells and oftentimes, osteoid and chondroid deposition or clear cell change
      • Keratin immunostaining may be negative in sarcomatous areas (Am J Surg Pathol 2013;37:710)
Microscopic (histologic) images

Contributed by Borislav A. Alexiev, M.D. and William B. Laskin, M.D.
Fibro-osseous lesion

Fibro-osseous lesion

Trabecular growth pattern

Trabecular growth pattern

Anastomosing trabeculae of epithelial cells

Anastomosing trabeculae of epithelial cells

Anastomosing trabeculae of epithelial cells

Epithelial cells


Classic adamantinoma

Classic adamantinoma

Osteofibrous dysplasia-like adamantinoma

Osteofibrous dysplasia-like adamantinoma

AE1 / AE3 expression

CK AE1 / AE3 expression

CK19 expression

CK19 expression

Cytology description
  • Biphasic admixture of epithelioid cells and cells with prominent spindling seen singly and in fragments (Diagn Cytopathol 2010;38:198)
  • Epithelioid cells with indistinct cytoplasm, bland round to oval nuclei with finely dispersed chromatic, occasional micronucleoli and well formed nuclear grooves (Diagn Cytopathol 1994;10:347)
  • Other population has more elongated nuclei, ample clear cytoplasm and spindled appearance (Diagn Cytopathol 2010;38:198)
Electron microscopy description
  • Epithelioid tumor cells possess epithelial ultrastructural features including tonofilaments, hemidesmosomes and desmosomes (Clin Orthop Relat Res 1984:299)
Molecular / cytogenetics description
Sample pathology report
  • Left tibia, bone biopsy:
    • Adamantinoma, classic variant (see comment)
    • Comment: MRI demonstrates a T1 isointense, T2 hyperintense, mildly enhancing lobulated lesion in the left distal tibia, not significantly different in appearance or number from the prior exam. The neoplasm is composed of basaloid cells with eosinophilic cytoplasm arranged in cords and nests. Nuclei are monomorphic, ovoid or round, with minimal atypia. Interspersed between the cells there is abundant fibrous stroma. No mitotic figures are identified (0 mitoses/10 high power fields). The tumor cells are positive for keratin AE1 / AE3 and p63 and negative for CD99, CAM5.2 and ERG. The findings support the above diagnosis. Adamantinomas are considered malignant neoplasms that frequently recur locally and can rarely metastasize.
Differential diagnosis
Additional references
Board review style question #1

The most common gene mutated in adamantinomas is

  1. KMT2D (MLL2)
  2. FUS
  3. SS18
  4. ZNF444
  5. FOS
Board review style answer #1
A. KMT2D (MLL2)

Comment Here

Reference: Adamantinoma
Board review style question #2
A 40 year old man presents with a left tibia mass. Radiography demonstrates a radiolucent lesion in mid / distal shaft with 2 satellite lesions proximally. Hematoxylin eosin stains show a nested and trabecular growth of basaloid and spindle cells with uniform, round to ovoid nuclei and eosinophilic or pale cytoplasm in fibrous background. Occasional mitotic figures are identified (1 mitosis/10 high power fields). Immunohistochemical stains for keratin AE1 / AE3, CK19 and vimentin are positive in tumor cells, while all of the following are negative: CAM5.2, MDM2, CD34, ERG, NKX2.2 and CD99.

Which of the following is most likely the correct diagnosis?

  1. Ewing sarcoma
  2. Low grade central osteosarcoma
  3. Metastatic carcinoma
  4. Pseudomyogenic hemangioendothelioma
  5. Adamantinoma
Board review style answer #2
E. Adamantinoma

Comment Here

Reference: Adamantinoma

Anatomy-bone & joints
Bone
  • Basic function of bone
    • Bone is the basic unit of the skeletal system and provides shape and support for the body, as well as protection for some organs
    • There are 206 bones in the human skeleton: 80 axial skeletal bones (e.g., skull, vertebral column and sacrum) and 120 appendicular skeletal bones (e.g., bones of extremities, scapula, pelvis)

  • Gross structure of bone
    • Epiphysis: region between the growth plate or growth plate scar and the extended end of bone, covered by articular cartilage
    • Metaphysis: region between the growth plate and diaphysis; contains abundant trabecular bone, but the cortical bone thins here comparing to diaphysis
    • Diaphysis or shaft: region between metaphyses, composed mainly of compact cortical bone
    • Physis (epiphyseal plate, growth plate): region of bone that separates the epiphysis from metaphysis
    • Zone of endochondral ossification in actively growing bone or the epiphyseal scar in a full grown bone
    • Cross section: periosteum, cortex (composed of cortical bone or compact bone), medullary space (composed of cancellous or spongy bone)
    • Bone composition: 35% organic (cells, proteins), 65% calcium hydroxyapatite (contains 99% of body's calcium, 85% of phosphorus, 65% of sodium, also magnesium)
    • Hydroxyapatite crystal is formed via phase transition; 12 day lag between matrix deposition and mineralization
    • Collagen resists tension, hydroxyapatite and proteoglycans in cartilage resist compression
    • Thicker cortex in middle of long bones resists bending; cancellous bone at ends of long bones resists compression
Joints
  • Junction between adjacent bones that provide painless range of motion and stability
  • Synovial or nonsynovial

  • Synovial joints:
    • Also called diarthroses
    • Contain joint space between ends of bones formed by endochondral ossification
    • Joints covered by hyaline cartilage, strengthened by dense fibrous capsule continuous with periosteum of bones and an inner synovial membrane
    • Joint is reinforced by ligaments and muscles
    • Presence of joint space allows wide range of motion and maintains stability during use

  • Nonsynovial joints:
    • Also called solid joint or synarthrosis
    • No joint space present
    • Provides structural integrity and minimal movement
    • May be fibrous / synarthrosis (cranial sutures, bonds between roots of teeth and jaw bones) or cartilaginous / amphiarthrosis (manubriosternalis and pubic)

  • Bursae:
    • Found when muscles, tendons and skin glide over bony prominences
    • Subject to same diseases as large joint spaces

  • Menisci:
    • Composed of collagen arranged circumferentially with some radial fibers
    • In young adults, are white, translucent and supple
    • Become more opaque, yellow, less supple in elderly
Classification
  • Bones are divided on the basis of their location, shape, size and structure

  • Based on location, bones can be classified as
    • Axial skeleton: bones of the skull, scapula, vertebral column
    • Appendicular skeleton: bones of the pectoral girdle, pelvis and limbs

  • Based on shape, bones can be classified as
    • Flat bone: bones of the skull, sternum, pelvis and ribs
    • Tubular bone: long tubular bones are bones of the extremities (e.g., femur, humerus); short tubular bones are bones of hands and feet
    • Irregular bone: bones of the face and vertebrae
    • Sesamoid bones: patella

  • Based on size, bones can be classified as
    • Long bone: tubular bones of extremities (e.g., femur, humerus)
    • Short bone: cuboidal in shape, in the foot (tarsal bones) and wrist (carpal bones)
Blood supply
  • The blood supply of bone varies with different types of bone, but vascular supply is especially rich in bones rich in red bone marrow

  • Long bones
    • Diaphyseal nutrient artery: most important arterial supply, passes obliquely through cortical bone
    • Metaphyseal and epiphyseal arteries: numerous small arteries supply the ends of bones; these blood vessels arise from arteries that supply adjacent joints, anastomose with the diaphyseal capillaries and terminate in bone marrow
    • Periosteal arterioles: these vessels supply the outer layers of cortical bone

  • Large irregular bones, short bones and flat bones
    • These bones are supplied by superficial periosteal arterioles

  • Venous and lymphatic drainage
    • Blood is drained from the bone via venous and lymphatic vessels that accompany arteries and frequently leave through foramina near the articular end of the bones

  • Nerve supply of bone
    • Nerves are most rich in articular extremities of long bones, vertebrae and larger flat bones
    • Nerves accompany the blood vessels to the interior of the bone and to the perivascular spaces of the haversian canals
    • The periosteal nerves are sensory, causing periosteum to be particularly sensitive to tearing or tension
Bone tissue types and structure
  • Bone tissue can be classified based on texture, matrix arrangement; also maturity and developmental origin (see Histology topic)

  • Based on texture, bone can be classified as
    • Compact bone (dense bone, cortical bone): dense bone that surrounds trabecular bone in the center, contains Haversian system and secondary osteons
    • Sponge bone (trabecular bone, cancellous bone): sponge-like with numerous cavities, located in the center of bone cavity, consists of connected bony trabeculae

  • Based on matrix arrangement bone can be classified as
    • Lamellar bone: mature bone with collagen fibers arranged in lamellae
      • Lamellae of sponge bone are arranged parallel to each other
      • In contrast, lamellae of compact bone are organized concentrically to around vascular canal (haversian canal)
    • Woven bone: immature bone; collagen fibers in woven bone are arranged in irregular random arrays and contain smaller amounts of mineral substance and a higher proportion of osteocytes to lamellar component
      • Woven bone is eventually converted to lamellar bone
Diagrams / tables

Images hosted on other servers:
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Femur


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Humerus

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Patella


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Pelvis: left-male, right-female

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Tibia and fibula


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Radius and ulna

Shoulder joint

Different types of synovial joints

Gross images

Images hosted on other servers:

Elbow joint; deep dissection; anterior view


Aneurysmal bone cyst
Definition / general
  • Benign, locally destructive multiloculated blood filled cystic lesion of bone
  • Classified as an osteoclastic giant cell rich tumor (WHO 2020)
  • Primary and secondary forms
  • High rate of local recurrence
Essential features
  • Imaging: multiloculated lesion with fluid-fluid levels, best appreciated on MRI
  • Histology: cyst walls composed of fibroblasts, woven bone and osteoclastic giant cells
  • Molecular: rearrangement of USP6 gene (primary form only)
Terminology
  • Related term: giant cell lesion of small bones
ICD coding
  • ICD-10: M85.50 - aneurysmal bone cyst, unspecified site
Epidemiology
  • Rare; 2.5% of all primary bone tumors
  • M = F
    • In mandible and maxilla, more common in young women
  • More common in skeletally immature patients
Sites
  • Broad skeletal distribution
    • Metaphyseal region of long tubular bones, most commonly the femur, tibia and humerus
    • Posterior elements of vertebrae
Etiology
Clinical features
  • Pain and swelling
  • Pathologic fracture
  • Nerve compression symptoms in cases of vertebral column involvement
  • May massively expand the mandible
Diagnosis
  • Requires correlation of clinical, radiographic and histologic findings to distinguish primary from secondary aneurysmal bone cyst
  • Lack of immunoreactivity for H3G34W (and other histone antibodies) is helpful in excluding giant cell tumor with cystic features
Radiology description
  • Xray:
  • CT scan:
    • Well delineated lytic lesion, usually with thin rim of reactive bone
    • Fluid-fluid levels occasionally visible
  • MRI:
    • Multiloculated cyst with characteristic fluid-fluid levels
  • Isotope scan:
    • Peripheral uptake with central photopenia imparts a donut-like appearances
Radiology images

Contributed by Elham Nasri, M.D.
Missing Image Missing Image Missing Image Missing Image

Aneurysmal bone cyst of proximal tibia

Missing Image Missing Image

Aneurysmal bone cyst of humerus


Missing Image Missing Image Missing Image

Aneurysmal bone cyst of distal tibia

Missing Image Missing Image

Aneurysmal bone cyst of calcaneus bone

Prognostic factors
Case reports
Treatment
  • Curettage or en bloc resection
  • Percutaneous sclerotherapy with doxycycline (Bone Joint J 2020;102-B:186)
  • Arterial embolization
  • Steroid or calcitonin injection
Clinical images

Images hosted on other servers:
Missing Image

Intraoral tumor

Gross description
  • Spongy, multiloculated, hemorrhagic lesion
  • Variable size
  • Irregular, sharply demarcated borders with thin shell of reactive bone
  • Variable amount of solid component
Gross images

Contributed by Elham Nasri, M.D.
Missing Image

Blood filled cysts

Missing Image

Multiloculated cyst

Frozen section description
  • Usually small fragments of cellular septa containing:
    • Fibroblast-like stromal cells lacking cytologic atypia
    • Osteoclast-like giant cells
    • Reactive woven bone
    • Mitotic activity typically present, no atypical mitoses
Frozen section images

Contributed by Elham Nasri, M.D.
Missing Image Missing Image

Cystic spaces and stromal giant cells

Microscopic (histologic) description
  • Multiloculated cystic lesion
    • Blood filled cystic spaces separated by cellular septa containing fibroblasts, giant cells and woven bone
    • Calcified, basophilic material (blue reticulated chondroid-like material)
    • Necrosis not common but mitotic activity is easily identified
    • No cytologic atypia (Am J Clin Pathol 2015;143:823)
  • Numerous giant cells in connective tissue that line large sinusoidal spaces
Microscopic (histologic) images

Contributed by Elham Nasri, M.D. and Kelly Magliocca, D.D.S., M.P.H.
Missing Image

Cysts and giant cells

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Blue chondroid like material

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Blood filled cystic spaces

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Solid area of cyst wall

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Reticulated chondroid-like material


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Multiple cystic spaces

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Blood filled cysts

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Reticulated chondroid-like material

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Cyst wall and giant cells

Aneurysmal bone cyst

Aneurysmal bone cyst

Positive stains
  • There is no specific immunohistochemical stain for aneurysmal bone cyst
Molecular / cytogenetics description
Sample pathology report
  • Mass, distal metaphysis, left tibia, curettage:
    • Aneurysmal bone cyst
Differential diagnosis
  • Telangiectatic osteosarcoma:
    • The most important differential diagnosis
    • Similar architecture but contains anaplastic stromal cells
    • Frequent atypical mitoses
    • No specific diagnostic immunohistochemical stain
    • Lacks USP6 gene rearrangement (Med Pregl 2015;68:127)
  • Central giant cell granuloma:
  • Secondary aneurysmal bone cyst:
    • Lacks USP6 gene rearrangement
    • Extensive sampling is critical to rule out an underlying primary lesion
    • More common in:
Board review style question #1
    Which of the following lesions does not have characteristic rearrangement of USP6 gene?

  1. Giant cell tumor of bone with secondary aneurysmal bone cyst
  2. Myositis ossificans
  3. Nodular fasciitis
  4. Primary aneurysmal bone cyst
Board review style answer #1
A. Secondary aneurysmal bone cyst lacks USP6 gene rearrangement.

Comment Here

Reference: Aneurysmal bone cyst (ABC)
Board review style question #2

    The H&E photo belongs to a well defined multiloculated cystic lesion of proximal tibia of a 17 year old boy. FISH analysis is positive for USP6 gene rearrangement. Which is the correct diagnosis?

  1. Aneurysmal bone cyst
  2. Giant cell tumor of bone
  3. Telangiectatic osteosarcoma
  4. Unicameral bone cyst
Board review style answer #2
A. Aneurysmal bone cyst. The H&E shows cystic spaces with stromal giant cells. Rearrangement of USP6 gene confirms the diagnosis in the above clinical and radiographic context.

Comment Here

Reference: Aneurysmal bone cyst (ABC)

Angiosarcoma
Definition / general
  • Also called hemangioendothelioma in bone, although angiosarcomas have more cytologic atypia
  • Rare; may be multicentric
  • 1/3 affect long tubular bones but any bone may be affected
  • 1/3 are multifocal, usually in one geographic area, such as an entire leg
  • After diagnosis, search for multicentricity
  • Distant metastases common, often to lungs
  • Graded 1 - 3 based on atypia of endothelial cells
  • Grade 1 have excellent prognosis versus poor prognosis for grade 3
Radiology description
  • Lytic areas of destruction, with minimal / no reactive new bone formation
Gross description
  • Red, hemorrhagic
Gross images

Contributed by Mark R. Wick, M.D.

Primary bone multifocal

Microscopic (histologic) description
  • Obvious atypia of tumor cells, solid areas alternating with irregular, anastomosing vascular channels
  • Necrosis and hemorrhage, brisk mitotic activity
  • Variable differentiation often within same tumor; may be epithelioid or histiocytic
  • May have benign giant cells, eosinophils, occasionally reactive bone formation
Microscopic (histologic) images

Contributed by Mark R. Wick, M.D. and AFIP images

Primary bone

Grade 3

Electron microscopy description
  • Endothelial cell features, may have pericytic features
Additional references
Epithelioid angiosarcoma
Definition / general
  • 80% male, mean age 62 years, range 26 - 83 years
  • 60% multifocal
  • Aggressive clinical course
  • > 90% of tumor cells have epithelioid features

Radiology images

Contributed by Mark R. Wick, M.D.

Primary bone Xray



Case reports

Gross description
  • Friable, hemorrhagic, destructive tumor, 2 - 12 cm
  • Poorly defined, infiltrates medullary canal, frequently erodes cortex and invades adjacent soft tissue

Microscopic (histologic) description
  • Solid and infiltrative sheets replacing the marrow and encasing bony trabeculae
  • No lobular growth pattern
  • Usually with prominent vascular channels or cystically dilated spaces
  • Tumor cells are large, polygonal with abundant eosinophilic cytoplasm, large nuclei with open chromatin, prominent eosinophilic nuclei
  • Frequent intratumoral hemorrhage, neutrophils, intracytoplasmic lumina
  • Frequent mitotic figures and necrosis
  • May have rhabdoid or spindled features

Microscopic (histologic) images

Contributed by Mark R. Wick, M.D.

Various images

Primary bone



Positive stains

Negative stains

Electron microscopy description
  • Long junctions, intracytoplasmic filaments, mitochondria, rough endoplasmic reticulum
  • May contain rare Weibel-Palade bodies

Differential diagnosis
  • Metastatic carcinoma: no well formed vascular channels, no neutrophils; negative for factor VIII, CD31 and CD34
  • Mucin+ cytoplasmic vacuoles

Additional references

Atypical cartilaginous tumor / chondrosarcoma, grade 1
Definition / general
  • Atypical cartilaginous tumor / chondrosarcoma, grade 1 (ACT / CS1) is a locally aggressive, hyaline cartilage producing neoplasm; tumors in the appendicular skeleton (long and short tubular bones) are termed ACTs, whereas tumors in the axial skeleton (flat bones, including the pelvis, scapula and skull base) should be called CS1
  • Primary conventional ACT / CS1 are tumors arising without a benign precursor; secondary conventional ACT / CS1 are tumors arising in association with a preexisting benign precursor.
Essential features
  • Abundance of cartilaginous matrix, often hyaline, sometimes with myxoid changes
  • Lobular growth pattern with entrapment of pre-existing lamellar bone trabeculae
  • Increased cellularity, with small condensed nuclei; binucleated cells are common
  • Absence of mitoses and severe nuclear atypia
Terminology
  • Primary central atypical cartilaginous tumors: arise in the medulla of bone without a benign precursor
  • Primary peripheral atypical cartilaginous tumors: arise on the bone surface without a benign precursor
  • Secondary central atypical cartilaginous tumors: arise in the medulla of bone in association with a pre-existing enchondroma
  • Secondary peripheral atypical cartilaginous tumors: arise within the cartilaginous cap of a pre-existing osteochondroma
  • Reference: Nosé: Diagnostic Pathology - Familial Cancer Syndromes, 2nd Edition, 2020
ICD coding
  • ICD-O:
    • 9222/1 - atypical cartilaginous tumor
    • 9222/3 - chondrosarcoma, grade 1
  • ICD-11: XH0FY0 - atypical cartilaginous tumor
Epidemiology
  • Third to sixth decades of life
  • M = F
  • Cumulative incidence of central atypical cartilaginous tumor / chondrosarcoma grade 1: 6.63 per 1 million person years (Surg Oncol 2018;27:402)
  • Central atypical cartilaginous tumor / chondrosarcoma grade 1 are more common (85 - 90%) than peripheral (10 - 15%)
  • Patients with secondary tumors are younger than those with primary tumors (Clin Orthop Relat Res 2003;411:193)
Sites
  • Bones that form by endochondral ossification (Arch Pathol Lab Med 2020;144:71)
  • Appendicular skeleton (long and short tubular bones)
  • Central atypical cartilaginous tumor:
    • Femur, humerus and tibia are most affected
    • 50% in metaphysis, 33% in the diaphysis and the rest in the epiphysis
    • Rare in the short tubular bones of hands and feet
  • Secondary peripheral atypical cartilaginous tumor:
    • Tibia and femur are most often involved
Etiology
Pathophysiology
  • Mechanisms involved in the transformation of benign cartilaginous lesions to malignant lesions have not been entirely elucidated
Clinical features
  • Pain, enlarging mass or pathologic fracture (Clin Orthop Relat Res 2003;411:193)
  • Worsening of clinical symptoms in pre-existing enchondromas / osteochondromas
  • Can be asymptomatic
Diagnosis
  • Imaging studies (Xrays, MRI, CT) and tissue biopsy
  • Because of high concordance of biopsy sample and presumed diagnosis on imaging studies alone, a diagnostic biopsy is often not necessary (J Am Acad Orthop Surg Glob Res Rev 2021;5:e21.00277)
  • The diagnostic distinction of ACT / CS1 from other cartilaginous lesions requires strict clinical and radiologic correlation combined with histologic examination, with the most important histologic feature being infiltration and encasement of preexisting trabecular bone (Arch Pathol Lab Med 2020;144:71)
Radiology description
  • Radiographically, it appears as an ill defined lytic lesion with geographical destruction, cortical scalloping and thickening of the cortex, often containing popcorn calcifications (Eur J Radiol 2015;84:2222)
  • MRI shows lesions > 2 cm with cortical remodeling, deep scalloping and enhancement
    • MRI is the best validated method to detect an atypical cartilaginous tumor arising in an osteochondroma
    • Cartilaginous cap thickness of > 2 cm in osteochondroma may raise concern for malignant transformation but is not entirely sufficient (Rofo 2021;193:262)
  • Presence of cortical expansion, followed by the presence of deep endosteal scalloping and a size > 6 cm, is the key imaging feature for differentiating enchondroma from atypical cartilaginous tumor, on both CT and MRI (Acta Radiol 2022;63:376)
Radiology images

Contributed by Serenella Serinelli, M.D., Ph.D. and Gustavo de la Roza, M.D.

Xray and MRI appearance



Images hosted on other servers:

Xray and MRI appearance

Cartilaginous cap MRI appearance

Prognostic factors
  • Atypical cartilaginous tumors show good prognosis, after curettage (J Bone Joint Surg Am 2016;98:303)
  • Locally aggressive behavior
  • Local recurrence in 7.5 - 11% of central atypical cartilaginous tumors and in 16 - 17.5% of secondary peripheral atypical cartilaginous tumors, due to incomplete excision in difficult locations (Eur J Orthop Surg Traumatol 2017;27:805, Clin Orthop Relat Res 2003;411:193)
  • In approximately 10% of recurring atypical cartilaginous tumors, progression to a higher grade is seen
  • Outcome is worse in tumors located in the axial skeleton (chondrosarcomas)
  • At present it is uncertain whether the presence of an IDH mutation is associated with prognosis (Clin Sarcoma Res 2017;7:8)
Case reports
Treatment
Gross description
  • Fragments from curettage are composed of glistening white-gray cartilage; yellow-white chalky areas of calcification are often present
  • In resection specimens, central atypical cartilaginous tumors are well defined, permeate the medullary cavity, scallop endosteal surface and produce cortical thickening
  • Secondary peripheral atypical cartilaginous tumors show a thick (> 2 cm), lobulated cartilaginous cap; the cap should be measured perpendicular to the bone / cartilage interface at its thickest portion (Clin Orthop Relat Res 2003;411:193, Mod Pathol 2012;25:1275)
Gross images

Contributed by Serenella Serinelli, M.D., Ph.D. and Gustavo de la Roza, M.D.

Humeral
central atypical
cartilaginous
tumor



Images hosted on other servers:

Femoral secondary
peripheral atypical
cartilaginous tumor

Microscopic (histologic) description
  • Lobulated growth pattern (J Dent Res Dent Clin Dent Prospects 2011;5:98)
  • Lobules have irregular shapes and sizes and may be separated by fibrous bands containing small vessels (Virchows Arch 2012;460:95)
  • Lobules are composed of abundant hyaline cartilage matrix (sometimes with mucoid / myxoid changes) and permeate and entrap lamellar bone trabeculae
  • Cellularity is slightly higher than in enchondroma
  • Cells show moderate eosinophilic to vacuolated cytoplasm
  • Nuclei are small and uniform with condensed chromatin (lymphocyte-like); sometimes they show open chromatin with visible nucleoli (Am J Surg Pathol 2009;33:50)
  • Mitoses and significant nuclear pleomorphism are absent
  • Binucleation can be observed
  • Necrosis can be seen
  • In cases arising from pre-existing enchondromas, areas of enchondroma with calcifications can be present
  • In cases arising from pre-existing osteochondroma, evidence of this tumor can be seen (Mod Pathol 2012;25:1275)
Microscopic (histologic) images

Contributed by Serenella Serinelli, M.D., Ph.D. and Gustavo de la Roza, M.D.

Lobulated architecture

Bone permeation

Scalloping of cortical bone

Bone scalloping

Lamellar bone scalloping


Myxoid changes

Necrosis

Cytology features

Arising from osteochondroma

Positive stains
Molecular / cytogenetics description
  • Primary peripheral and central atypical cartilaginous tumors show hotspot mutations at the IDH1 p.Arg132 and the IDH2 p.Arg172 positions (Histopathology 2012;60:363, Mol Oncol 2021;15:3679, Cells 2020;9:968)
    • IDH1 p.Arg132Cys mutation is the most frequently found
  • Secondary central atypical cartilaginous tumors arising from enchondromas, a finding that often occurs as part of the genetic syndromes (Ollier disease and Maffucci syndrome), are also characterized by IDH mutations
  • Secondary peripheral atypical cartilaginous tumors arising in association with osteochondromas show mutations in EXT1 and EXT2 (Clin Cases Miner Bone Metab 2016;13:110)
  • Reference: J Cancer Metastasis Treat 2021;7:8
Videos

Chondrosarcoma versus enchondroma: bone pathology with Dr. Andrew Rosenberg

Sample pathology report
  • Bone, left 5th and 4th metatarsals, excision:
    • Atypical cartilaginous tumor (see microscopic description)
    • Microscopic description: Examination of the histopathologic sections reveals mature trabecular bone with juxtaposed cartilaginous proliferation, characterized by low to moderate cellularity, chondrocytes with occasional binucleated cells and mild atypia in a hyaline cartilage matrix. Foci of necrosis, nonischemic type are seen. Given the presence of nonischemic type necrosis, the large size of the tumor and the cellular atypia, the tumor is most consistent with atypical cartilaginous tumor that may have arisen from an osteochondroma.
    • The specimen consists of multiple unoriented fragments and the surgical margins cannot be assessed.
Differential diagnosis
  • Enchondroma:
    • Lower cellularity
    • Regular distribution of cells
    • No atypia
    • No entrapment of pre-existing lamellar bone
    • < 20% myxoid changes in the matrix (Am J Surg Pathol 2009;33:50)
  • Grade 2 conventional chondrosarcoma:
    • Increased cellularity
    • Mitotic activity
    • Myxoid matrix degeneration
    • Spindle cell changes at the periphery of the lobules
    • Increased vascularization
    • Increased nuclear pleomorphism
  • Osteochondroma:
    • Differential for secondary peripheral atypical cartilaginous tumor
    • Cartilaginous cap < 2 cm in thickness
Board review style question #1

A 41 year old woman complained of an enlarging mass at her left proximal humerus. Xrays showed a lucent lesion with indistinct borders and endosteal scalloping. MRI showed an irregular, expansile, avidly enhancing mass. A biopsy of the lesion was performed and is shown above. What is the diagnosis?

  1. Atypical cartilaginous tumor
  2. Chondrosarcoma, grade 3
  3. Enchondroma
  4. Mesenchymal chondrosarcoma
  5. Osteochondroma
Board review style answer #1
A. Atypical cartilaginous tumor

Comment Here

Reference: Atypical cartilaginous tumor
Board review style question #2
Which gene is more frequently mutated in atypical cartilaginous tumors?

  1. BRAF
  2. EGFR
  3. H3-3A
  4. IDH1
  5. KRAS
Board review style answer #2

Avascular necrosis
Definition / general
  • Avascular necrosis (AVN) is a disease that results from temporary or permanent loss of blood supply to bone at watershed zones where collateral circulation is lacking
  • Pathologically, AVN is characterized by death of bone cells and marrow elements and manifests as a localized area of bone infarction, usually at subchondral locations
Essential features
  • Characterized by necrosis of bone and bone marrow cellular components due to ischemia
  • Preferentially involves subchondral / epiphyseal ends of bone, particularly the femoral head
  • Risk factors include traumatic and nontraumatic causes
  • Advanced disease results in cleavage of the subchondral bone from the overlying cartilage (crescent sign)
  • Eventually culminates in the collapse of the joint and secondary degenerative joint disease / osteoarthritis
Terminology
  • Synonyms: osteonecrosis (preferred term), aseptic necrosis, ischemic bone necrosis
  • Variants
    • Preiser disease: osteonecrosis of the scaphoid
    • Keinbock disease: osteonecrosis of the lunate
    • Legg-Calvé-Perthes disease: idiopathic osteonecrosis of femoral epiphysis in children
    • Dysbaric osteonecrosis / caisson disease: osteonecrosis in undersea divers
ICD coding
  • ICD-10: M87.00 - idiopathic aseptic necrosis of unspecified bone
Epidemiology
Sites
  • Femoral head is most common
  • Humeral head is second most common, usually with concurrent hip involvement (Orthop Surg 2020;12:1340)
  • Other: medial femoral condyle, talus, scaphoid and lunate
  • Traumatic AVN is typically unilateral while nontraumatic is commonly bilateral (Radiographics 2014;34:1003)
  • Multifocality (≥ 3 separate anatomic sites) also common in nontraumatic AVN (e.g., sickle cell disease, chronic corticosteroid use) but may be overlooked without radiological screening (Open Orthop J 2009;3:32, Sci Rep 2016:6:29576)
Pathophysiology
  • Disruption of blood supply is a key event
  • Subchondral microcirculation of the femoral head is particularly vulnerable (see Diagrams)
  • Mechanisms (Curr Rev Musculoskelet Med 2015;8:201)
    • Direct trauma to vessels: fractures, dislocation, surgery
    • Intravascular occlusion: thrombi, sickle cell aggregations, nitrogen and lipid emboli, venous outflow occlusion
    • Intraosseous compression of microcirculation: steroid induced adipogenesis and lipid deposition, Gaucher cells replacing bone marrow (Clin Orthop Relat Res 2000:370:295)
  • Sequence of events (Curr Rev Musculoskelet Med 2015;8:201)
    • Earliest: necrosis of hematopoietic marrow, interstitial marrow edema
    • Osteocyte necrosis occurs ~2 - 3 hours from the beginning of anoxia, though histological evidence may become evident 24 - 72 hours later
    • Reparative process begins at the periphery of the necrotic zone and involves bone resorption and production (yet the new bone is composed of weak woven bone)
    • Net result: ineffective repair, increased bone resorption relative to production and loss of structural integrity
  • Necrotic zone
    • Ischemia → loss of oxygen / nutrient supply → osteoblastic / osteoclastic activity is no longer supported → no bone remodeling → loss of bone compliance and structural integrity → fracturing occurs especially with weight bearing → articular collapse
  • Peripheral reparative zone
    • Growth of vascularized granulation tissue → osteoblastic / osteoclastic activity is supported → progressive yet ineffective remodeling at the interface between necrotic and viable bone (creeping substitution) with the formation of an outer sclerotic rim
Etiology
  • Frequently idiopathic: when no cause is apparent
  • Traumatic risk factors: femoral head fractures and dislocation, surgical interventions of bone
  • Nontraumatic risk factors: corticosteroids, alcohol abuse, sickle cell disease, systemic lupus erythematosus, antiphospholipid antibody syndrome, Gaucher disease, caisson disease (Clin J Sport Med 2015;25:153)
  • Other associations: pancreatitis, HIV, radiation therapy, renal transplantation, leukemia / lymphoma
  • Reference: Int J Environ Res Public Health 2022;19:7348
Diagrams / tables

Contributed by Rola H. Ali, M.D.
AVN of femoral head

AVN of femoral head

Clinical features
  • Slowly progressive groin pain, which may radiate to the buttock or knee and a limited range of motion
  • Asymptomatic cases can be found incidentally on imaging
Diagnosis
  • Diagnosis is based on careful history, physical exam and imaging studies
  • Bone pain in patients with known risk factors should prompt investigations for AVN
Laboratory
  • Only relevant to identify conditions that may predispose to AVN
Radiology description
  • Imaging appearances correspond to the underlying pathology
  • Plain Xray (insensitive in early stages)
    • Patchy areas of lucency (bone resorption) and sclerosis (partly due to saponification of fatty acids released from necrotic adipocytes in the marrow)
    • Sclerosis at the rim (new bone formation)
    • Curvilinear subchondral lucency (crescent sign) indicative of subchondral fracture and impending articular collapse
    • Secondary degenerative changes
  • MRI (most sensitive and specific): area of yellow marrow surrounded by a low signal intensity rim with all pulse sequences or a double line sign
  • CT: more sensitive than plain Xray particularly when assessing articular collapse
  • Reference: Radiographics 2014;34:1003
Radiology images

Images hosted on other servers:
Xray of femoral head AVN

Xray of femoral head AVN

MRI of bilateral AVN

MRI of bilateral AVN

Prognostic factors
  • Prognosis depends on the stage and location of the disease (Orthop Surg 2020;12:1340)
  • Clinical course is progressive with patients eventually requiring surgical intervention
Case reports
Treatment
Gross description
  • Wedge shaped infarct in the subchondral area that is dull yellow in color
  • Peripheral hyperemic border may be appreciated with or without osteosclerosis
  • Overlying articular cartilage may be buckled and separated from the infarcted bone
  • Gross pathological manifestations are not apparent in early stages
  • Reference: Rom J Morphol Embryol 2012;53:557
Gross images

Contributed by Rola H. Ali, M.D.
Wedge infarct

Wedge infarct

Subchondral collapse

Subchondral collapse

Microscopic (histologic) description
  • Microscopic changes depend on stage of the ischemia (see Pathophysiology and Diagrams)
  • Necrotic zone
    • Earliest histological sign: diffuse coagulative necrosis of marrow elements including hematopoietic cells, adipocytes and endothelial cells
    • Later, purplish aggregates of amorphous material appear in the marrow representing fat saponification (due to binding of released fatty acids with calcium)
      • This contributes to the radiodensity on radiographs
    • Osteocyte necrosis in cancellous bone trabeculae (Clin Cases Miner Bone Metab 2007;4:21)
      • Manifests initially as pyknotic nuclei and later as uniformly empty osteocyte lacunae
      • Loss of osteocytes may not be complete until 2 - 4 weeks after the onset of ischemia
      • Pitfall: occasional empty lacunae are expected in interstitial lamellae of normal cortical bone with increasing age
      • Another pitfall: overdecalcification of specimen results in artifactual loss of osteocytes
    • Osteoblastic / osteoclastic activity is absent in the death zone due to the lack of blood supply
  • Peripheral reparative zone
    • Hyperemic border develops at the periphery of the necrotic zone as vascularized granulation tissue grows around the infarct and progresses into a rim of reactive bone
      • Double line sign on MRI corresponds to the inner granulation tissue zone and outer rim of reactive bone
    • Increased osteoclastic activity is evident, supported by the neovascularization
    • Osteoblastic activity also evident with appositional bone formation seen over necrotic nonresorbed trabeculae (creeping substitution)
      • This contributes to increased radiodensity on imaging
  • Overlying articular cartilage
    • Usually intact and smooth in early stages (in contrast to primary degenerative joint disease with secondary subchondral osteonecrosis)
    • Later could be detached from the underlying necrotic bone (creating the crescent sign on radiology)
    • Secondary degenerative joint disease eventually develops in advanced stage
  • References: Radiographics 2014;34:1003, Clin Cases Miner Bone Metab 2007;4:21
Microscopic (histologic) images

Contributed by Rola H. Ali, M.D.
Subchondral infarct

Subchondral infarct

Necrotic zone

Necrotic zone

Empty lacunae

Empty lacunae

Reactive zone

Reactive zone

New bone

New bone

Creeping substitution

Creeping substitution

Positive stains
  • Immunostains are not required for diagnosis
  • Von Kossa stains the saponified fat black (may be compromised in decalcified sections)
Negative stains
  • Not required for diagnosis
Sample pathology report
  • Right head of femur, total hip replacement:
    • Osteonecrosis of the femoral head (see comment)
    • Subchondral fracture
    • Comment: The morphological features corroborate the radiological findings.
Differential diagnosis
  • Subchondral insufficiency fracture (Jpn J Radiol 2022;40:443):
    • Sudden onset of hip or knee pain since it is a fracture
    • Related to excessive stress to subchondral bone
    • Risk factors include osteoporosis and overweight status
    • Older term: spontaneous osteonecrosis of the knee (SONK)
    • Osteonecrosis occurs as a secondary finding
  • Degenerative joint disease:
    • Older patients
    • Progressive damage and loss of articular cartilage, subchondral bone thickening, osteophyte formation
    • Large subarticular cysts may cause collapse of articular plate and secondary focal osteonecrosis
  • Septic arthritis:
    • Usually young adults and children
    • Acute onset monoarticular joint pain with fever and swelling
    • Infectious etiology from hematogenous spread or direct inoculation
    • Neutrophilic collections within tissue and synovial fluid
  • Neuropathic joint (Charcot joint):
    • Destructive arthropathy in patients with peripheral neuropathies
    • Rapid joint erosion with destructive features of osteoarthritis
Board review style question #1

A 38 year old woman, who is on long term glucocorticoid therapy for systemic lupus erythematosus (SLE), has undergone a total hip replacement. The microscopic appearance of her femoral head is shown in the image above. What is the diagnosis?

  1. Avascular necrosis
  2. Enchondroma
  3. Fracture callus
  4. Osteomyelitis
  5. Tumoral calcinosis
Board review style answer #1
A. Avascular necrosis. Systemic lupus erythematosus (SLE) and long term steroid use are known risk factors for avascular necrosis. Histologically, the marrow space contains saponified necrotic fat and the bone shows empty lacunae. The clinical context and morphology are wrong for the other options. Answer B is incorrect because of the absence of hyaline cartilage within the medullary cavity. Answer C is incorrect because of the absence of granulation tissue and bone remodeling. Answer D is incorrect because of the absence of acute inflammation. Answer E is incorrect because it is deposition of granular material in periarticular subcutaneous tissue.

Comment Here

Reference: Avascular necrosis
Board review style question #2

What is the most common anatomical site of the bone lesion shown in the image above?

  1. Femoral head
  2. Humeral head
  3. Medial femoral condyle
  4. Scaphoid
  5. Talus
Board review style answer #2
A. Femoral head. The image shows features of avascular necrosis, which is most common in the head of femur. Answers B, C, D and E are incorrect because these sites are less common.

Comment Here

Reference: Avascular necrosis

BCOR::CCNB3 sarcoma
Definition / general
  • Undifferentiated round cell sarcoma characterized by BCOR::CCNB3 rearrangement (previously Ewing-like sarcoma)
Essential features
  • Predominantly arises from the bones of children and young adult males
  • Sheets or fascicles of round and spindle cells forming whorls and hemangiopericytic patterns, usually within a myxoid background
  • Nuclear CCNB3 and BCOR positivity as well as TLE1 and SATB2 coexpression
  • Molecular diagnosis is highly recommended: BCOR::CCNB3
  • Similar treatment and comparable prognosis with Ewing sarcoma
Terminology
  • BCOR::CCNB3 positive sarcoma
  • Undifferentiated round cell sarcoma with BCOR::CCNB3 fusion
Epidemiology
Sites
Pathophysiology
  • Both CCNB3 itself and BCOR::CCNB3 as a full fusion transcript seem to play a role in oncogenesis and phenotype (Nat Genet 2012;44:461)
Etiology
  • Unknown
Clinical features
  • Mainly metastasizes to the lung
Diagnosis
Radiology description
  • Permeative lytic / sclerotic tumor invariably associated with cortical thickening in the metadiaphyseal region of long bones
  • Wide zone of transition with periosteal reaction
  • MRI: iso or hypointense on T1 and heterogeneously hyperintense on T2 with postcontrast enhancement
  • PET CT: mean SUVmax = 6.3 (range: 5.7 - 6.9)
  • Reference: Skeletal Radiol 2021;50:521
Radiology images

Contributed by F. Bilge Ergen, M.D.

Plain Xray features

MRI of BCOR::CCNB3 sarcoma

Prognostic factors
Case reports
Treatment
Gross description
Gross images

Contributed by Kemal Kösemehmetoğlu, M.D.

BCOR::CCNB3 sarcoma of radius

Microscopic (histologic) description
Microscopic (histologic) images

Contributed by Kemal Kösemehmetoğlu, M.D.

Typical morphology of BCOR::CCNB3 sarcoma

High power cytological morphology

Various cellularity

Hemangiopericytic pattern


Whorling pattern

Subtle osteoid formation

Epithelioid balls and nests

Telangiectatic areas

CCNB3 expression

CD99


BCOR

SATB2

TLE1

Focal EMA expression

Diffuse cyclin D1 expression

Cytology description
Cytology images

Contributed by Kemal Kösemehmetoğlu, M.D.

Cytological features of BCOR::CCNB3

Molecular / cytogenetics description
  • Accounts for 60% of BCOR gene alterations (BCOR internal tandem duplication [ITD]); other partner genes are MAML3 and ZC3H7B
  • Paracentric inversion on chromosome X resulting in recurrent gene fusion of BCOR (encoding BCL6 interacting corepressor) on Xp11.4 and CCNB3 (cyclin B3) on Xp11.22
  • Gene profiling and single nucleotide polymorphism (SNP) analyses resulted in a distinct cluster from small round cell sarcomas, including Ewing sarcoma (Nat Genet 2012;44:461)
Molecular / cytogenetics images

Contributed by Kemal Kösemehmetoğlu, M.D.

Reverse transcription PCR for BCOR::CCNB3

Videos

BCOR::CCNB3 sarcoma of the proximal tibia

Sample pathology report
  • Proximal metadiaphyseal region of the right tibia, incisional biopsy:
    • BCOR::CCNB3 sarcoma (see comment)
    • Comment: Undifferentiated round and spindle neoplastic cells showed dot-like CD99 staining as well as TLE1 and SATB2 coexpression. BCOR and CCNB3 were diffusely positive. Breakapart FISH was negative for EWSR1 or SYT rearrangements. On reverse transcription PCR, BCOR::CCNB3 fusion product / band was observed at 140 bp.
Differential diagnosis
Additional references
Board review style question #1


Biopsy from a lytic mass located at the proximal part of the right tibia of a 15 year old boy is represented in the above figures. Immunohistochemically, tumor cells showed a dot-like CD99 expression as well as TLE1 and SATB2 coexpression. Desmin and AE1 / AE3 were negative. What is the expected molecular alteration of this tumor?

  1. BCOR::CCNB3
  2. CIC-DUX4
  3. EWSR1-FLI1
  4. EWSR1-NFATC2
  5. SYT-SSX
Board review style answer #1
A. BCOR::CCNB3

Comment Here

Reference: BCOR::CCNB3 fusion
Board review style question #2
Which following the clinicopathological settings is the most suitable for BCOR::CCNB3 sarcoma?

  1. CD99 and SATB2 positive bone producing sarcoma with prominent pleomorphism in the right distal femur
  2. Large and deep soft tissue mass in the lower leg of an elderly man
  3. Lytic bone tumor composed of small round to spindle cells with an abrupt transition in a 17 year old boy
  4. Lytic mass in the proximal humerus of a 65 year old woman
  5. NKX2.2 positive small round cell tumor in the vertebra of a 15 year old boy
Board review style answer #2
C. Lytic bone tumor composed of small round to spindle cells with an abrupt transition in a 17 year old boy

Comment Here

Reference: BCOR::CCNB3 fusion

Bacterial osteomyelitis (acute)
Definition / general
Essential features
Terminology
ICD coding
  • ICD-10: M86.9 - osteomyelitis, unspecified
Epidemiology
  • Hematogenous osteomyelitis
    • Occurs most commonly in children
      • More than half occurs in children younger than 5 years and one quarter in children younger than 2 years
      • M > F
    • Among adults:
  • Nonhematogenous osteomyelitis
    • Among younger adults: occurs most frequently in the setting of trauma and related surgery
    • Among older adults: occurs most frequently as a result of contiguous spread of infection to bone from adjacent soft tissues and joints (diabetic foot wounds or decubitus ulcers) (N Engl J Med 1970;282:198)
Sites
Pathophysiology
Etiology
Diagrams / tables

Images hosted on other servers:

Pathogenesis of osteomyelitis associated septic arthritis

Clinical features
  • Signs and symptoms:
    • Gradual onset of symptoms over several days
    • Dull pain at the involved site
    • Tenderness, warmth, erythema and swelling
    • Fever and rigors may also be present (N Engl J Med 1970;282:198)
Diagnosis
  • Diagnosis of osteomyelitis is established via culture obtained from biopsy of the involved bone
  • Histopathology consistent with osteomyelitis in the absence of positive culture data
  • Typical clinical and radiographic findings together with persistently elevated inflammatory markers in the absence of positive culture and no biopsy interpretation (Clin Infect Dis 2004;39:885)
Laboratory
Radiology description
Radiology images

Contributed by Mark R. Wick, M.D.
Bacterial osteomyelitis of tibia and vertebra in thoracic spine Bacterial osteomyelitis of tibia and vertebra in thoracic spine Bacterial osteomyelitis of tibia and vertebra in thoracic spine

Bacterial osteomyelitis of tibia and vertebra in thoracic spine



Images hosted on other servers:

Osteomyelitis of the distal fourth metatarsal

Abnormal T1 weighted signal

Localized increased radioactive tracer uptake

Prognostic factors
  • Chronic osteomyelitis develops in a subset of acute osteomyelitis due to:
    • Delayed treatment
    • Inadequate antibiotics
    • Incomplete surgical debridement of necrotic bone
    • Weakened host defenses (EFORT Open Rev 2017;1:128)
Case reports
Treatment
Gross description
  • Varies with patient age:
  • Acute disease has pus tracking through bone, periosteal elevation and shell of reactive periosteal bone around necrotic center
  • Neonates may have considerable subperiosteal spread
  • Chronic disease is accompanied by prominent periosteal bone formation
Microscopic (histologic) description

    Patterns of acute osteomyelitis
  • Osseous changes:
    • Osteonecrosis: bone trabeculae with visually empty osteocyte cavities are detectable as a criterion for necrotic bone tissue especially with EDTA decalcification
    • The bone trabeculae have irregular contours and are fragmented
    • They may be fractured and completely necrotic (so called bone sequester)
    • There are intramedullary granulocyte infiltrates and fibrin exudates
    • In bone tissue with a haemopoietic function (e.g. axial skeleton) there is a reduced or complete lack of haemopoiesis
  • Soft tissue changes:
    • Soft tissue necrosis: criteria for soft tissue necrosis are apoptoses, a tissue eosinophilia, fibrin exudations and a confining texture of the tissue
  • Inflammatory infiltrate pattern:
    • Neutrophilic granulocyte infiltrate: diffuse and grouped deposits (so called microabscesses, ≥ 5 granulocytes) of segmented neutrophilic granulocytes in the usually highly oedematous medullary spaces
    • The neutrophilic granulocytes are PAS cytoplasmic, coarsely granular positive and display a plumped, pyknotic chromatin texture (granulocyte apoptosis with pathogen phagocytosis and NETosis)
    • Immunohistochemically there is a specific intensive, coarsely granular, predominantly cytoplasmic CD15 positivity
    • Osteoclasts are also detectable alongside neutrophilic granulocytes on the irregular trabecular surface

    Patterns of chronic osteomyelitis
  • Osseous changes:
    • Bone neogenesis: spongy osseous tissue with reactive network bone neogenesis (POL detection of irregularly running fibrils), the bone surface is bordered by osteoblasts
    • Medullary space fibrosis with ectatic sinus
    • The medullary space tissue shows fibrosing with granulation tissue formation
    • The infiltrate consists of macrophages, lymphocytes, plasma cells and a few neutrophilic granulocytes
  • Soft tissue changes: there is fibrosing with granulation tissue formation, the infiltrate consists of macrophages, lymphocytes, plasma cells and a few neutrophilic granulocytes
  • Inflammatory infiltrate pattern:
    • Lymphocyte / macrophage / plasma cell infiltrate: in the highly fibrosed medullary spaces there is a lymphocyte and macrophage rich, sometimes also plasma cell rich, sometimes focal, sometimes inflammatory infiltration with a few neutrophilic granulocytes

  • Neutrophils (may persist for weeks), lymphocytes and plasma cells with bone necrosis and reactive new bone formation
  • Capillary proliferation and fibrosis
  • Subtypes include plasma cell osteomyelitis and xanthogranulomatous osteomyelitis (abundant foamy macrophages)
  • Bone marrow replaced by inflammatory tissue
  • Salmonella infection may produce tuberculoid granules with variable central necrosis (Am J Surg Pathol 1985;9:531)
  • Osteoblastic bone resorption
  • Bitten bone (chewed, scalloped bone)
  • Bone necrosis
  • Vessel damage
  • Vascular thrombosis
  • Marrow infarction
  • Dirty marrow (J Foot Ankle Surg 2020;59:75, GMS Interdiscip Plast Reconstr Surg DGPW 2014;3:Doc08)
Microscopic (histologic) images

Contributed by Dariusz Borys, M.D. and Mark R. Wick, M.D.
Acute osteomyelitis

Acute osteomyelitis

 Bacterial acute osteomyelitis  Bacterial acute osteomyelitis

Bacterial acute osteomyelitis

Positive stains
Sample pathology report
  • Femur, debridement (partial excision):
    • Fragments of scalloped viable and non-viable bone with surrounding acute inflammatory infiltrate, consistent with acute osteomyelitis
Differential diagnosis
Board review style question #1

Hematogenous osteomyelitis is usually

  1. Monomicrobial and most common organism involved is Staphylococcus aureus
  2. Monomicrobial and most common organism involved is Streptococcus pyogenes
  3. Polymicrobial and most common organism involved is Staphylococcus aureus
  4. Polymicrobial and most common organism involved is Streptococcus agalactiae
  5. Polymicrobial and most common organism involved is Streptococcus pyogenes
Board review style answer #1
B. Monomicrobial and most common organism involved is Streptococcus pyogenes

Comment Here

Reference: Bacterial osteomyelitis (acute)
Board review style question #2
Most common microbial etiology of bacterial osteomyelitis in neonatal age group is

  1. Salmonella typhi, Staphylococcus aureus, Streptococcus agalactiae
  2. Staphylococcus aureus, Klebsiella, Streptococcus pneumoniae
  3. Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli
  4. Staphylococcus aureus, Streptococcus agalactiae, Escherichia coli
Board review style answer #2
D. Staphylococcus aureus, Streptococcus agalactiae, Escherichia coli

Comment Here

Reference: Bacterial osteomyelitis (acute)

Benign notochordal cell tumor
Definition / general
  • Intraosseous tumors - not notochordal rest or hamartoma
  • At autopsy, found in 14% of spinal columns and 11.5% of clivi, usually ages 40+ years, often multiple
Treatment
  • Followup but no surgery
  • May undergo malignant transformation to classic chordomas
Gross description
  • Usually small within axial bones, rarely involve entire vertebrae
Microscopic (histologic) description
  • Well demarcated but unencapsulated
  • Sheets of adipocyte-like vacuolated or eosinophilic cells with fewer vacuoles
  • Often cytoplasmic eosinophilic hyaline globules
  • Bland round nuclei with mild pleomorphism
  • May contain colloid-like material
  • Bone trabeculae often sclerotic but no bony destruction
  • No intercellular myxoid matrix, no necrosis, no mitotic figures
Positive stains
  • PAS+ diastase resistant eosinophilic hyaline globules
Differential diagnosis
  • Chordoma: osteolytic, lobules are separate by thin fibrous septa, lobules contain cords, strands or sheets of physaliphorous cells with myxoid matrix, cells have mild to marked nuclear atypia
  • Notochordal vestiges: cords or strands of notochordal cells within myxoid background, cells have eosinophilic cytoplasm with small vacuoles, pyknotic round nuclei, CK18 negative, usually replaced by fibrocartilage by age 1 - 3 years
Additional references

Biopsy
Definition / general
  • Procedure in which bone samples are removed with a special biopsy needle or obtained during surgery to find out if cancer or other abnormal cells are present
  • Involves the outer layers of bone, unlike a bone marrow biopsy, which involves the innermost part of the bone
Essential features
  • Bone biopsies aim to facilitate definitive pathological diagnoses while minimizing complications, limiting potential tumor seeding and avoiding interference with subsequent therapies (Medicine (Baltimore) 2018;97:e11567)
  • There are 3 types of bone biopsies: open (surgical) biopsy, core needle biopsy and fine needle aspiration biopsy
  • Biopsy of a suspected primary bone neoplasm must yield enough tissue to permit complete histopathological evaluation, including grading
  • Core needle biopsy is the most common type of needle biopsy used for bone tumors
Indications for biopsy
  • Biopsy is the most critical first step in determining treatment strategy and outcomes in the management of musculoskeletal lesions (Medicine (Baltimore) 2018;97:e11567)
  • Bone biopsy is indicated in the following circumstances (Eur J Radiol 2013;82:2092, Oper Orthop Traumatol 2012;24:403):
    • Whenever there is significant doubt regarding the diagnosis of a benign or malignant lesion
    • When the histologic distinction among possible diagnoses could alter the planned course of treatment
    • Histopathologic evaluation of tumor entity and grading
    • Planning of definitive tumor resection and initiation of neoadjuvant therapeutic regimen
    • Obtaining unfixed, fresh frozen tumor samples for molecular / genetic analyses or tumor tissue bank
  • Bone biopsy is also important for diagnosis of nonneoplastic bone disease, including infection and bone turnover disorders, among others (the diagnostic yield may vary, however)
Contraindications
  • Bone biopsy is contraindicated in the following circumstances (Oper Orthop Traumatol 2012;24:403):
    • Hemorrhagic diathesis
    • Tumor is only accessible with a surgical approach leading to a significant damage of the surrounding tissue
    • High probability of tumor cell contamination with incisional biopsy
    • Poor physical status
    • Poor therapeutic compliance
ICD coding
  • Possible ICD-10 codes include but may not be limited to
    • M86.171 - other acute osteomyelitis, right ankle and foot
    • M86.172 - other acute osteomyelitis, left ankle and foot
    • M86.671 - other chronic osteomyelitis, right ankle and foot
    • M86.672 - other chronic osteomyelitis, left ankle and foot
    • C40.31 - malignant neoplasm of short bones of right lower limb
    • C40.32 - malignant neoplasm of short bones of left lower limb
    • D16.31 - benign neoplasm of short bones of right lower limb
    • D16.32 - benign neoplasm of short bones of left lower limb
    • D49.2 - neoplasm of unspecified behavior of bone, soft tissue and skin
Planning the biopsy
  • Biopsy must be carefully planned to ensure that adequate diagnostic tissue is obtained without compromising the oncologic outcome (Eur J Radiol 2013;82:2092)
  • Biopsies should take place after the completion of staging studies; the surgeon, radiologist and pathologist should review these studies in detail so that each member of the team is fully apprised of the diagnostic considerations
  • Site, approach and method selected for biopsy are intimately connected to the planned operative procedure; therefore, the biopsy should generally be performed at the hospital where definitive surgery will be carried out
  • Biopsy of a suspected primary neoplasm must yield enough tissue to permit complete histopathological evaluation, including grading
  • Biopsy must be performed such that the entire biopsy tract can be easily excised during later definitive surgery
  • Careful hemostasis is mandatory; a hematoma may permit the spread of tumor cells into adjacent compartments, compromise the possibility of limb salvage and increase the likelihood of a wound infection
Types of bone biopsy
  • Open (surgical) biopsy (Arch Orthop Trauma Surg 1979;94:71)
    • Can be categorized as either incisional (the tumor capsule is intentionally violated as part of the procedure and a portion of the mass or lesion is removed) or excisional (the entire tumor is removed)
    • Incisional biopsy is generally recommended for suspected benign lesions that can be treated definitively at the time of biopsy or in cases where greater volumes of tissue may be required than can be obtained with a needle biopsy in order to perform special staining or molecular diagnostics
    • Incisional biopsies are also often performed when a needle biopsy result is nondiagnostic; for incisional biopsies, the incision and dissection tract are planned such that they can be excised during the definitive limb salvage procedure
    • Excisional biopsy may be performed through the reactive zone that surrounds the tumor (termed marginal excision) or with a cuff of healthy tissue (primary wide excision)
  • Core needle biopsy (Clin Orthop Relat Res 2010;468:2992, Medicine (Baltimore) 2018;97:e11567, Eur J Surg Oncol 2001;27:668, Eur J Radiol 2013;82:2092)
    • Uses a large needle to remove a cylinder of tissue
    • The most common type of needle biopsy used for bone tumors
    • It is a safe, reliable and accurate procedure and yields diagnostic information in a high proportion of patients (Radiology 2008;248:962)
  • Fine needle aspiration (FNA) biopsy (Clin Orthop Relat Res 2010;468:2992, Medicine (Baltimore) 2018;97:e11567, Eur J Surg Oncol 2001;27:668, Eur J Radiol 2013;82:2092)
    • Uses a very thin needle on the end of a syringe to obtain a small amount of fluid and some cells from the tumor
    • It is a safe, reliable and accurate procedure and yields diagnostic information in a high proportion of patients (Radiology 2008;248:962)
Advantages and disadvantages
  • Open (surgical) biopsy has historically been the diagnostic standard (Medicine (Baltimore) 2018;97:e11567)
    • Provides large volumes of tissue sample, which facilitates accurate histological analyses and more precise estimates of patient prognoses
    • Biopsy associated complications involve hematoma, infection and neurapraxia
    • Biopsy procedure may spread tumor cells to surrounding tissue and therefore increase the risk of local recurrence
    • It is imperative that the biopsy tract be placed within the planned resection margins prior to planning of future treatment involving surgical resection and radiation
  • Core needle biopsy is increasingly accepted for the diagnosis of bone tumors (Clin Orthop Relat Res 2010;468:2992, Medicine (Baltimore) 2018;97:e11567)
    • Yields diagnostic results comparable to open biopsy when determining malignancy and grade in bone tumors
    • Advantages over open biopsy include time, cost and reduced morbidity
    • Higher diagnostic accuracy than FNA in all aspects, such as determining the nature of the tumor, establishing the histologic type and grade and achieving a specific diagnosis (Arch Pathol Lab Med 2004;128:759)
  • Fine needle aspiration (FNA) biopsy (Arch Pathol Lab Med 2004;128:759, Eur J Radiol 2013;82:2092, Clin Orthop Relat Res 2010;468:2992)
    • An excellent method to confirm metastatic disease in bone and to document tumor recurrence
    • It is also suitable for diagnosis of infection; although identification of a specific organism in chronic osteomyelitis may be difficult using any method
    • This type of biopsy is less likely to be helpful for bone tumors, as the smaller needle might not be able to penetrate the bone and may not remove enough of a sample for testing
    • FNA is usually insufficient for making a primary diagnosis of a bone tumor because it lacks tissue architecture and can only rarely provide information regarding tumor grade
Diagnosis
  • Correlation with clinical and radiologic characteristics is critical; therefore, to achieve an accurate diagnosis, it requires a high level of skill from both the radiologist and the pathologist
Radiology description
  • Prebiopsy imaging (EFORT Open Rev 2017;2:51)
    • Although initial referral imaging may be adequate for determining whether a biopsy is needed, imaging may have to be repeated if the whole lesion has not been imaged or in the case of malignant disease and the whole bone has not been imaged
    • For bone sarcomata, MRI is the technique of choice; this will provide additional information regarding the type of biopsy to consider (in order to supply sufficient tissue for the pathologist), the approach and the appropriate part of the lesion to target
    • MRI will also define areas which need to be avoided, such as the neurovascular bundle; the team will also be able to decide which imaging technique to use for guidance of the biopsy itself
    • In cases where an additional lesion is discovered within the bone that does not have the typical appearance of a skip metastasis, the second lesion may also require biopsy
    • MRI is also critical in defining whether there is local joint involvement
    • Growth dynamics are best assessed via PET CT for systemic screening and assessment of local metabolic activity of a tumor
  • Core biopsy with image guidance (i.e., fluoroscopy, ultrasound, CT or MRI) (EFORT Open Rev 2017;2:51)
    • Provides the opportunity to selectively biopsy specific areas of the tumor
    • CT is the most versatile of the imaging techniques, although relatively time consuming
    • Almost any part of the body can be biopsied safely with CT guidance and specific areas of tumor can be targeted for biopsy
    • Obtaining a minimum of 3 specimens in bone lesions optimizes diagnostic yield (Radiology 2008;248:962)
    • Multiple biopsies are often needed and even then, may not yield a definitive diagnosis
    • Diagnostic yield is lower for sclerotic bone lesions than for lytic lesions
    • Onsite adequacy assessment of touch preparations is an accurate, simple and fast method for obtaining sufficient material for a complete diagnostic workup
Radiology images

Contributed by Borislav A. Alexiev, M.D.
Left scapular neck mass

Left scapular neck mass

Clinical images

Contributed by Ajay R. Chapa, M.D.
Bone biopsy system

Bone biopsy system

Special specimen handling requirements
  • Smears are air dried for Diff-Quik stain or fixed in 95% acidified alcohol for Papanicolaou stain (Cancer Cytopathol 2014;122:851, J Am Soc Cytopathol 2020;9:322)
  • Tissue fragments retrieved from FNA biopsy are fixed in 10% buffered formalin and embedded in paraffin for cell blocks and hematoxylin eosin stained sections
  • Core biopsy specimens are immediately placed in 10% saline buffered formalin, embedded in paraffin and sectioned for hematoxylin eosin staining (Pathol Res Pract 2022;231:153777)
  • Decalcification to adequately process the biopsy
  • Specialized immunocytochemical studies for diagnosis
  • Molecular analysis on formalin fixed paraffin embedded (FFPE) or frozen tissue (cryopreserved at -70 °C)
  • Cytologic imprinting for fluorescence in situ hybridization (FISH) studies (alcohol fixed and air dried)
  • Tissue sample, fluid aspirate or swab should be sent for microbial culture if osteomyelitis is in the differential diagnosis
  • If lymphoma is suspected, the hematopathologist should be alerted ahead of time for proper tissue handling
    • Samples should be collected in saline and sent to the laboratory where they can be triaged to flow cytometry, cytogenetic and molecular studies
Board review style question #1

Which of the following is true about core needle biopsy (CNB)?

  1. CNB is usually insufficient for making a primary diagnosis of a bone tumor
  2. For each biopsy, a minimum of 1 core is obtained
  3. Lower diagnostic accuracy than FNA in all aspects, including determining the nature of the tumor, establishing the histologic type and grade and achieving a specific diagnosis
  4. Diagnostic yield is higher for sclerotic bone lesions than for lytic lesions
  5. Yields diagnostic results comparable to open biopsy for determining malignancy and grade in bone tumors
Board review style answer #1
E. Yields diagnostic results comparable to open biopsy for determining malignancy and grade in bone tumors. CNB is usually sufficient for making a primary diagnosis of a bone tumor. It has higher diagnostic accuracy than FNA in all aspects, including determining the nature of the tumor, establishing the histologic type and grade and achieving a specific diagnosis. For each biopsy, a minimum of 3 cores are obtained. The diagnostic yield is lower for sclerotic bone lesions than for lytic lesions.

Comment Here

Reference: Bone biopsy
Board review style question #2
Which of the following is true about open (surgical) biopsy?

  1. It is unimportant that the biopsy tract be placed within the planned resection margins prior to future treatment planning involving surgical resection and radiation
  2. Lower diagnostic accuracy than fine needle aspiration biopsy
  3. Open biopsy is not associated with increased risk for local recurrence
  4. Provides large volumes of tissue sample, which facilitates accurate histological analyses and more precise estimates of patient prognoses
  5. There are no contraindications for open biopsy
Board review style answer #2
D. Provides large volumes of tissue sample, which facilitates accurate histological analyses and more precise estimates of patient prognoses. Open biopsy is associated with increased risk for local recurrence. It has higher diagnostic accuracy than FNA in all aspects, including determining the nature of the tumor, establishing the histologic type and grade and achieving a specific diagnosis. Open biopsy is contraindicated in the following circumstances: hemorrhagic diathesis, high probability of tumor cell contamination, poor physical status and poor therapeutic compliance. It is imperative that the biopsy tract be placed within the planned resection margins prior to future treatment planning involving surgical resection and radiation.

Comment Here

Reference: Bone biopsy

Bizarre parosteal osteochondromatous proliferation
Definition / general
  • Also called Nora lesion
  • Rare form of myositis ossificans, resembles subungual (Dupuytren’s) exostosis, except for t(X;6) in the latter (Am J Surg Pathol 2004;28:1033)
  • 75% affect small tubular bones of hands and less commonly the feet; do not involve the nailbeds
  • 25% affect large bones
  • Usually ages 20 - 39 years
Radiology description
  • Hands: heavily calcified mass attached to underlying cortex / periosteum but not continuous with it (so not an osteochondroma)
  • Long bones: lesions may be destructive or in soft tissue
  • Benign but may recur locally (35 - 54%)
Radiology images

Contributed by Mark R. Wick, M.D.

Various images

Treatment
  • Surgical excision with wide margins
Case reports
Gross description
  • Resembles small osteochondroma
Microscopic (histologic) description
  • Irregular maturation of cartilage in bone produces chondro-osteoid with characteristic blue quality (“blue bone”)
  • Contains enlarged, bizarre, binucleated chondrocytes with maturation into bone
  • Spindle cell proliferation between bony trabeculae without atypia
Microscopic (histologic) images

Contributed by Mark R. Wick, M.D.
Missing Image

Various images

Missing Image

Nora lesion foot

Molecular / cytogenetics description

Bone formation and growth
Definition / general
  • Bone tissue is formed by intramembranous ossification or by endochondral ossification
  • The original or model tissue is gradually destroyed and replaced with bone tissue
  • Woven bone is primarily formed and later converted to lamellar bone by subsequent remodeling
Intramembranous ossification
  • Source of flat and less commonly short bones
  • Occurs through condensation of mesenchymal tissue
  • Process begins when multiple groups of cells differentiate into osteoblasts in a primary ossification center
  • Osteoid is synthesized, then mineralizes surrounding the osteoblasts, which mature to osteocytes
  • When ossification centers fuse, loose trabecular structures known as primary spongiosa are formed
  • Then blood vessels grow into the connective tissue between trabeculae

    Images hosted on other servers:
    Missing Image

    Intramembranous bone formation

Endochondral ossification
  • Responsible for formation of long and short bones
  • Hyaline cartilage model, which provides template of shape of the bone
  • May be divided into 2 phases:
  • 1st phase: chondrocytes are hypertrophic and degenerated, then calcified
  • 2nd phase: osteoprogenitor cells and blood capillaries invade the spaces left by degenerating cartilage; osteoblasts arise from osteoprogenitor cells and lay down a layer of rapidly mineralized osteoid on the surface of calcified cartilage, called primary spongiosa, which later is remodeled to lamellar bone (secondary spongiosa); calcified cartilage is resorbed by chondroblasts and replaced by bone and marrow cavities

    Images hosted on other servers:
    Missing Image

    Endochondral ossification

Histology of bone growth
  • Epiphyseal cartilage of long bone is located between epiphysis and metaphysis, is responsible for longitudinal growth; has 5 zones:
    (a) Resting zone – small chondrocytes
    (b) Proliferative zone – rapidly dividing chondrocytes in columns, parallel to the long axis of bone
    (c) Hypertrophic zone – large chondrocytes with clear cytoplasmic glycogen
    (d) Calcified cartilage zone (zone of provisional calcification) – chondrocyte graveyard, followed by blood vessel invasion and bone deposition
    (e) Ossification zone – formation of primary spongiosa by rapidly mineralized osteoid

    Images hosted on other servers:
    Missing Image

    Epiphyseal plate

Bone growth
  • Bone grows by either endochondral or intramembranous ossification
  • Endochondreal ossification of the epiphyseal plate is responsible for longitudinal growth of long bones
  • Periosteal deposition is responsible for length and thickness of long bones
  • Endosteal bone deposition is responsible for growth of trabecular bone and endosteal cortex, including the haversian system
Modeling and remodeling
  • Bone formation is an ongoing process that alters the size and shape of bone by partial resorption of preformed bone tissue and simultaneous deposition of new bone (modeling and remodeling)
  • Modeling is a process in which bone achieve its proper shape
  • Modeling is responsible for the circumferential growth of bone and expansion of marrow cavity
  • Remodeling is a continuous process, in which damaged bone is repaired, ion homeostasis is maintained, and bone is reinforced for increased stress; entire remodeling cycle requires ~ 6 months
  • In healthy adults, remodeling rate varies by type of bone: 25% per year in trabecular bone versus 3% in cortical bone
  • Resorption and deposition are normally balanced, and bone density is maintained
  • Resorptive activity exceeding deposition activity represents a pathologic state, may cause lytic lesions
  • The cement line (reversal line) is evidence of previous remodeling activity; is formed by filling of new bone in a previously resorbed cavity; is strongly basophilic due to high content of inorganic matrix and is normally found in the haversian and interstitial systems of adult bone
  • Cement line from normal remodeling is relatively long and straight; indented or mosaic pattern indicates a pathologically accelerated remodeling process

Bone island
Radiology images

Contributed by Mark R. Wick, M.D.
Missing Image

Femur Xray

Gross images

Contributed by Mark R. Wick, M.D.
Missing Image

Femur

Microscopic (histologic) images

Contributed by Mark R. Wick, M.D.
Missing Image

Femur


Brown tumor
Definition / general
  • Metabolic bone disease
  • Manifestation of hyperparathyroidism
  • Caused by increased osteoclastic activity and fibroblastic proliferation
  • The term brown tumor derives from the color, which is caused by the vascularity, hemorrhage and deposits of hemosiderin
Essential features
  • Elevated blood calcium or parathyroid hormone levels
  • Radiologically osteolytic lesion
  • Histologically giant cell rich lesion
Terminology
  • Osteitis fibrosa
  • Cystica generalisata
  • Von Recklinghausen disease of bone
ICD coding
  • ICD-10: E21.3 - hyperparathyroidism, unspecified
Epidemiology
Sites
  • Any part of the skeleton
  • Most frequently encountered in the ribs, clavicles, long bones, pelvic girdle, craniofacial bones (Case Rep Nephrol Dial 2016;6:46)
  • Rare in spine
Pathophysiology
  • Primary, secondary or tertiary hyperparathyroidism
  • Increased serum parathyroid hormone (PTH) concentrations
  • Detected by receptors on osteoblasts, which then release factors that stimulate osteoclast activity
  • Skeletal manifestations of hyperparathyroidism are caused by unabated osteoclastic bone resorption leading to mobilization of skeletal calcium
  • Rapid osteoclastic turnover of bone maintains normal serum calcium levels
  • In localized regions, bone loss is particularly rapid; hemorrhage and reparative granulation tissue with active, vascular, proliferating fibrous tissue may replace the normal marrow contents, resulting in a brown tumor
  • Hemosiderin imparts the brown color (hence the name of the lesions) (Kumar: Robbins & Cotran Pathologic Basis of Disease, 10th Edition, 2020)
Etiology
  • Primary hyperparathyroidism: adenoma (80 - 85%), hyperplasia (10 - 15%), carcinoma (1 - 5%) (J Med Case Rep 2018;12:176)
  • Secondary hyperparathyroidism: chronic renal disease, continual and excessive urinary calcium excretion (J Med Case Rep 2018;12:176)
  • Tertiary hyperparathyroidism: prolonged parathyroid stimulation from a secondary cause (e.g. paraneoplastic syndrome) (J Med Case Rep 2018;12:176)
Diagrams / tables

Images hosted on other servers:

Pathogenesis

Clinical features
Renal osteodystrophy
  • Collectively describes all the skeletal changes of chronic renal disease, including those associated with dialysis; the manifestations include:
    • Osteopenia / osteoporosis
    • Osteomalacia
    • Secondary hyperparathyroidism
    • Growth retardation
  • Various histologic bone changes in individuals with end stage renal failure can be divided into 3 major types of disorders:
    • High turnover osteodystrophy characterized by increased bone resorption and bone formation, with the former predominating
    • Low turnover or aplastic disease manifested by adynamic bone (little osteoclastic and osteoblastic activity) and less commonly, osteomalacia
    • Mixed pattern of disease
  • Pathophysiology:
    • Kidney disease causes skeletal abnormalities through 3 mechanisms:
      • Tubular dysfunction leading to renal tubular acidosis: the associated systemic acidosis dissolves hydroxyapatitie, resulting in matrix demineralization and osteomalacia
      • Secondary hyperparathyroidism due to reduced phosphate excretion, chronic hyperphosphatemia and hypocalcemia
      • Decreased production of vitamin D3 from damaged kidneys and reduced intestinal absorption of calcium because of low levels of vitamin D3
      • Resultant secondary hyperparathyroidism produces increased osteoclast activity
      • Other factors that are important in the genesis of adynamic renal osteodystrophy are diabetes mellitus, high dietary calcium ingestion, increasing age and iron accumulation in bone and aluminum deposition at the site of mineralization
  • Reference: Kumar: Robbins & Cotran Pathologic Basis of Disease, 10th Edition, 2020
Osteitis fibrosa cystica
  • Also called von Recklinghausen disease of bone
  • Rare nowadays because hyperparathyroidism is diagnosed and treated at an early stage
  • Increased number of osteoclasts erode bone matrix and mobilize calcium salts, particularly in the metaphysis of long tubular bones
  • Bone resorption is accompanied by increased osteoblastic activity and the formation of new bony trabeculae
  • Gross description: the cortex is thinned and the marrow contains increased amounts of fibrous tissue accompanied by foci of hemorrhage and cyst formation
  • Microscopic (histologic) description: increased bone cell activity, peritrabecular fibrosis, cystic brown tumors (Kumar: Robbins & Cotran Pathologic Basis of Disease, 10th Edition, 2020)
Diagnosis
  • Requires integration of laboratory investigations, radiological and histopathological findings
Laboratory
Radiology description
  • Plain radiograph: well defined, purely lytic lesions that provoke little reactive bone; the cortex may be thinned and expanded but will not be penetrated (AJR Am J Roentgenol 1993;160:752)
  • CT: attenuation values will be in the range of blood and fibrous tissue (Radiol Case Rep 2021;16:2482)
  • Angiography (DSA): lesions are usually hypervascular (AJR Am J Roentgenol 1993;160:752)
  • MRI: appearance depends on the relative proportion of its components; the lesions, therefore, may be solid, cystic or mixed (Skeletal Radiol 2011;40:205)
    • Solid components are intermediate to low intensity on T1 and T2 weighted images, while the cystic components are hyperintense on T2 weighted images and may have fluid-fluid levels
    • T1 C+ (Gd): there can be enhancement of the solid component and septa
  • Nuclear medicine: bone scan often shows intense uptake (AJR Am J Roentgenol 1993;160:752)
Radiology images

Contributed by Nasir Ud Din, M.B.B.S.
Multiple lytic lesions Multiple lytic lesions

Multiple lytic lesions

Multiple lytic lesions Multiple lytic lesions

Multiple lytic lesions

Prognostic factors
  • Brown tumors regress when the cause of hyperparathyroidism is removed
Case reports
Treatment
  • Normalizing PTH level with drugs, dialysis, parathyroidectomy or kidney transplantation will often cause the tumor to regress or resolve
  • Surgical resection of a brown tumor is generally not recommended and should only be considered if the patient wants quick resolution, if the lesion is compromising body functions or promoting facial deformation or if the lesion fails to regress after 1 - 2 years of follow up (Case Rep Nephrol Dial 2016;6:46)
Clinical images

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Mandibular lesion

Gross description
  • Spongy brown cystic hemorrhagic lesion
Gross images

Images hosted on other servers:

Multilocular, expansile, hemorrhagic mass in rib

Microscopic (histologic) description
  • Lobular pattern composed of groups and clusters of osteoclast-like multinucleated giant cells
  • Vascular fibroblastic stroma
  • Hemorrhage and hemosiderin deposits
  • Tunneling resorption of adjacent uninvolved bone (J Int Oral Health 2015;7:50)
Microscopic (histologic) images

Contributed by Nasir Ud Din, M.B.B.S.
Lobulated pattern

Lobulated pattern

Scattered nodular pattern

Scattered nodular pattern

Vague circumscription of nodule

Vague circumscription of nodule

Vague nodularity

Vague nodularity


Irregularly distributed giant cells

Irregularly distributed giant cells

Giant cells exhibiting tunneling resorption

Giant cells exhibiting tunneling resorption

Tunneling resorption

Tunneling resorption

Abundant hemosiderin deposition in the lesion

Abundant hemosiderin deposition in the lesion

Videos

Bone changes in hyperparathyroidism

Sample pathology report
  • Left femur lytic lesion, curettage:
    • Giant cell rich lesion (see comment)
    • Comment: The lesion is composed of clusters of giant cells in a hemorrhagic fibroblastic stroma. Focal tunneling bone resorption is seen. This feature, along with multiple lytic lesions on radiology, strongly favor brown tumor of hyperparathyroidism. Correlation with clinical history, radiological findings and serum PTH and calcium levels is recommended.
Differential diagnosis
  • Giant cell tumor:
    • Arises in epiphysis of long bones in adults
    • Uniform distribution of osteoclast type giant cells among mononuclear cells
    • Mononuclear cells are not as spindled as fibroblasts in brown tumor
    • Nuclei of mononuclear cells of giant cell tumor are similar to those of osteoclasts
    • Mononuclear cells are positive for H3G34W, p63 and CD68
    • Harbor H3F3A (G34W/V) mutations
    • Serum calcium and PTH levels are normal (Nielsen: Diagnostic Pathology - Bone, 3rd Edition, 2021)

  • Giant cell reparative granuloma:
    • Arises primarily in jaw, other craniofacial bones
    • Can have very similar morphologic features and may be impossible to distinguish from brown tumor by H&E alone
    • Brown tumor has much more lobulated growth pattern
    • Features of hyperparathyroidism in surrounding bone are not present
    • Nonuniform distribution of osteoclast type giant cells, mononuclear cells in a vascularized stroma
    • Serum calcium and PTH levels are normal (Nielsen: Diagnostic Pathology - Bone, 3rd Edition, 2021)

  • Solid aneurysmal bone cyst:
    • Most common during first 2 decades of life
    • Arises in the metaphysis of long bones
    • Does not demonstrate lobular growth pattern seen in brown tumor
    • Contains blood filled cystic spaces separated by fibrous septa
    • Fibrous septa are composed of a moderately dense cellular proliferation of bland fibroblasts, with scattered multinucleated, osteoclast type giant cells and reactive woven bone rimmed by osteoblasts
    • Solid subtype of aneurysmal bone cyst has the same components
    • USP6 gene rearrangement (Nielsen: Diagnostic Pathology - Bone, 3rd Edition, 2021)
Board review style question #1

A 50 year old woman presented with a swelling on the right side of her face that gradually increased in size over last 3 years. It was associated with pain, trismus and inability to open her right eye. She also had history of frequent headaches, abdominal pain and renal stones. Xray revealed a lytic lesion within the right mandible. Incisional biopsy was performed and microscopic examination revealed a lesion (shown above). The most likely diagnosis is

  1. Aneurysmal bone cyst
  2. Brown tumor of hyperparathyroidism
  3. Central giant cell granuloma
  4. Cherubism
  5. Giant cell tumor
Board review style answer #1
B. Brown tumor of hyperparathyroidism. The photomicrograph shows a lesion composed of bony trabeculae showing resorption along with scattered osteoclast-like giant cells in a vascularized spindled stroma. These microscopic findings with above mentioned clinical and radiological features are characteristic of brown tumor of hyperparathyroidism. Aneurysmal bone cyst affects young adults and shows large blood filled spaces with intervening septae containing fibroblasts and giant cells. Central giant cell granuloma produces radiolucent lesions in children and young women and shows osteoclast-like giant cells near hemorrhagic areas, cellular vascular and fibrous stroma and new bone formation at edge of lesion. Cherubism shows bilateral involvement of mandible and maxilla in young individuals and histology is similar to central giant cell granuloma. Giant cell tumor rarely affects mandible and shows uniform distribution of osteoclast type giant cells among mononuclear cells.

Comment Here

Reference: Brown tumor of hyperparathyroidism
Board review style question #2

A 49 year old hypertensive and diabetic man presents with a complaint of right mandibular pain, swelling and intraoral bleeding for a period of 12 months. There was a gradual increase in size and pain. Xray revealed a well defined multilocular lesion within the right mandible. Incisional biopsy was performed and microscopic examination revealed a lesion in the given photomicrograph. What is the most likely underlying etiology?

  1. Chronic adrenal insufficiency
  2. Chronic liver disease
  3. Chronic obstructive pulmonary disease
  4. End stage renal disease
  5. Ischemic heart disease
Board review style answer #2
D. End stage renal disease. The photomicrograph shows a lesion composed of scattered osteoclast-like giant cells in a vascularized spindled stroma characteristic of brown tumor of hyperparathyroidism. End stage renal disease causes decreased glomerular filtration due to reduced nephron function, which results in decreased synthesis of 1,25 dihydroxyvitamin D3 by the kidney. This leads to decreased absorption of calcium by the gut. Consequently, there is an increased level of serum phosphate. Increased serum phosphate causes serum calcium to be deposited in bone, also leading to a decreased serum calcium. In response to low serum calcium levels, the parathyroid glands secrete increased parathyroid hormone, which results in secondary hyperparathyroidism.

Comment Here

Reference: Brown tumor of hyperparathyroidism

Bursitis
Definition / general
  • Pain, erythema, swelling around bursae that lie between muscles, tendons and bony prominences
  • Usually due to chronic trauma (professional athletes in shoulders, pre and infrapatellar bursae of those who kneel); rheumatoid arthritis
  • Rarely associated with infection, gout
  • Associated with cysts, fluid and loose bodies
  • Chronically inflamed bursa may develop extensive calcification
  • Subdeltoid bursitis: degeneration of muscle / tendon in shoulder rotator cuff, followed by deposition of calcium in necrotic collagenous tissue, which stimulates inflammatory reaction
Clinical features
  • Common sites: shoulder, knee, elbow and hip
  • Infrequent sites: interspinous, ischio gluteal, retrocalcaneal
Case reports
Treatment
  • Varies based on cause of bursitis and changes in bursa
  • Includes aspiration, antibiotic irrigation, incision and drainage (for abscess), excision (for thickened bursa)
Clinical images

Images hosted on other servers:

Elbow

Gross description
  • Thickened, erythematous and shaggy bursal wall with fibrinous exudates
Microscopic (histologic) description
  • Chronic inflammation, scarring
Videos

Elbow: chronic fibrinous bursitis


CIC rearranged sarcoma

Calcium pyrophosphate crystal deposition disease
Definition / general
  • Calcium pyrophosphate crystal deposition (CPPD) is characterized by calcium pyrophosphate dihydrate crystal accumulation in extracellular cartilage matrix, synovium and joints
Essential features
  • Most common crystalline arthropathy
  • Different clinical presentations in the elderly
  • Diagnosis requires demonstration of calcium pyrophosphate crystals in synovial fluid or biopsy material
  • Classic rhomboid shaped crystals with positive birefringence under polarized light
Terminology
  • Calcium pyrophosphate dihydrate deposition disease
  • Pseudogout
  • Chondrocalcinosis polyarticularis
  • Articular chondrocalcinosis
  • Pyrophosphate arthropathy
  • Chondrocalsynovitis
ICD coding
  • ICD-10:
    • M11.20 - other chondrocalcinosis, unspecified site
    • M11.249 - other chondrocalcinosis, unspecified hand
  • ICD-11: FA26.0 - calcium pyrophosphate dehydrate deposition disease
Epidemiology
Sites
Pathophysiology
  • An imbalance between the production of pyrophosphate and the level of pyrophosphatases in diseased cartilage causes high levels of extracellular pyrophosphate, resulting in CPPD
  • Pyrophosphate is deposited in the synovium and adjacent tissues and combines with calcium to form calcium pyrophosphate (CPP)
  • CPP crystals mediate damage by eliciting inflammation or by inducing the production of destructive matrix metalloproteinases and prostaglandins (Best Pract Res Clin Rheumatol 2021;35:101718, N Engl J Med 2016;374:2575)
  • Crystals have a direct catabolic effect on chondrocytes and alter the mechanical properties of cartilage (Curr Rheumatol Rep 2001;3:17)
Etiology
Diagrams / tables

Images hosted on other servers:

Extracellular pyrophosphate mechanism

Pathogenesis

Clinical features
  • Clinical patterns:
    • Chondrocalcinosis:
      • Asymptomatic incidental finding in articular tissues
      • Commonly involves knee menisci and intervertebral discs
      • Often detected on radiology
    • Acute CPP deposition (acute pseudogout):
      • Symptomatic, painful swollen joints with warmth and erythema
      • Constitutional symptoms include fever, chills and malaise
      • Commonly involves knee
      • Acute episodes seen in the arms of elderly women
      • May last for weeks to months (Clin Exp Rheumatol 2019;37:254)
    • CPPD osteoarthritis:
      • CPPD crystal deposition frequently occurs in degenerated joints
      • Commonly affects the elderly
      • Radiology shows features of osteoarthritis, may detect crystals (Curr Opin Rheumatol 2007;19:158)
    • Chronic CPP deposition disease (pyrophosphate arthropathy):
      • Polyarticular form of arthritis that resembles osteoarthritis
      • Commonly affects women
      • Involvement of glenohumeral, wrist and metacarpophalanageal joints, in contrast to typical osteoarthritis
  • Tophaceous pseudogout and tumoral CPPD are solitary space occupying lesions, commonly seen in digits
  • Associated with crowned dens syndrome (Eur Radiol 2000;10:1003)
  • Associated with myelodysplastic syndrome (J Rheumatol 2017;44:1101)
  • Can be present as part of true neoplasms, such as calcified chondroid mesenchymal tumors with FN1 fusions (Mod Pathol 2021;34:1373)
Diagnosis
  • Arthrocentesis for synovial fluid analysis by light microscopy, compensated polarized light microscopy or phase contrast microscopy (Open Access Rheumatol 2014;6:39)
  • Can be identified in biopsy material, even in decalcified tissue
  • Radiography of the involved joints is helpful
Laboratory
  • Raised serum inflammatory markers like erythrocyte sedimentation rate (ESR), C reactive protein (CRP)
  • Screening for metabolic causes such as hyperthyroidism, hypothyroidism, hyperparathyroidism and hypomagnesemia (J Med Assoc Thai 1999;82:569)
Radiology description
  • Polyarticular chondrocalcinosis in fibro and hyaline cartilage (Curr Opin Rheumatol 2020;32:140)
  • Joint space narrowing and extensive subchondral sclerosis in pyrophosphate arthropathy
  • Knee, when involved, shows cartilage icing, large subchondral cysts, fragmentation of subchondral bone, intra-articular bodies and disproportionate narrowing of patellofemoral joint (PLoS One 2020;15:e0231508)
  • Soft tissue tophus-like opacities at the popliteus groove and gastrocnemius tendon calcification can be present
  • Hand, when involved, shows subchondral cysts and hook-like projections from second and third metacarpal heads; may show stepladder pattern of joint narrowing
  • Scapholunate advanced collapse (SLAC) (Insights Imaging 2014;5:407)
Radiology images

Contributed by Nasir Ud Din, M.B.B.S. and Jose G. Mantilla, M.D.

Right knee joint, AP

Right knee joint, lateral

Talonavicular joint, foot

Shoulder CPPD Xray

Shoulder CPPD CT

Shoulder CPPD T1 MRI gadolinium


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Pyrophosphate arthropathy

Meniscal
chondrocalcinosis

Prognostic factors
  • Acute calcium pyrophosphate arthritis is self limited; resolves within days to weeks of treatment
  • Chronic CPP arthritis is a waxing and waning disease, lasting for months
  • Osteoarthritis is exacerbated by CPPD (Clin Rheumatol 2001;20:428)
  • Immune checkpoint inhibitors exacerbate pseudogout (J Immunother Cancer 2019;7:126)
Case reports
Treatment
Clinical images

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Right index finger swelling

Calcified brittle intradural mass

Gross description
  • Gray to chalky white deposits in tissue
Gross images

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Chalky white depositions

Frozen section description
Microscopic (histologic) description
  • Distinct aggregates of basophilic to gray-brown material within tissue
  • Weakly anisotropic rhomboid to rod shaped crystals demonstrating positive birefringence under polarized light (Pathol Res Pract 2001;197:499)
  • Smaller and dimmer than gout crystals
  • Can be present within mononuclear cells as well
  • Surrounding tissue shows chronic inflammation and histiocytic reaction
  • Tophaceous pseudogout shows larger aggregates with granulomatous reaction
  • Foreign body giant cell reaction, chondroid metaplasia, hypertrophy of chondrocytes and myxoid degeneration may be seen
  • Focal amyloid deposition and lipid can be seen (Arthritis Rheum 1988;31:1057)
Microscopic (histologic) images

Contributed by Nasir Ud Din, M.B.B.S.

Basophilic deposits

Histiocytic reaction

Rhomboid crystals

Positive birefringence

Chondroid metaplasia

Cytology description
Cytology images

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Aggregates of birefringent crystals

Immunofluorescence description
Positive stains
  • VEGF and TGF beta (positive in hypertrophic chondrocytes), CD68 (in histiocytes) and CD34 (in vessels), although not required for diagnosis (Clin Rheumatol 2008;27:597)
Negative stains
Electron microscopy description
Molecular / cytogenetics description
Videos

Pseudogout

Sample pathology report
  • Finger, incisional biopsy:
    • Histologic features are consistent with calcium pyrophosphate crystal deposition disease (see comment)
    • Comment: Calcium pyrophosphate crystal deposition disease (CPPD) is a benign condition exhibiting aggregates of basophilic to gray-brown deposits of rhomboid crystals. These crystals show positive birefringence under polarized light. It can be primary (idiopathic or familial) or secondary due to metabolic disorders like hypothyroidism, hypophosphatasia, hyperparathyroidism, hypomagnesemia, hemochromatosis, Wilson disease and trauma. Clinical and serological correlation is recommended.
Differential diagnosis
  • Gout:
    • Early onset < 40 years, late onset disease > 40 years
    • M > F
    • Ultrasound examination: echogenic monosodium urate crystals line the surface of articular cartilage, in contrast to echogenic CPPD calcifications, located within the cartilage
    • Polarizable needle shaped urate crystals show negative birefringence (Arthritis Rheumatol 2020;72:1408)
    • May have hyperuricemia
    • Bone erosion may be seen
  • Rheumatoid arthritis:
    • Presence of skeletal erosive changes on radiology indicates a true rheumatoid arthritis process rather than CPPD (Radiology 1981;140:615)
    • Affects small bones of adult women
    • Proliferative synovitis with dense lymphoplasmacytic infiltrate
    • Necrobiotic nodules, fibrosis and organizing fibrin
  • Septic arthritis:
    • Usually affects young age adults and children
    • Involves single joint
    • Increased neutrophils and neutrophilic collections within tissue
  • Osteoarthritis:
    • Usually affects joints of weight bearing distribution
    • Manifests after 50
    • Necrotic chondrocytes with thinned and fragmented cartilage
  • Soft tissue chondroma:
    • Involves distal extremities including digits, hands and feet
    • Adults are commonly affected
    • Discrete lobulated mass in soft tissue
    • Hyaline cartilage is present with secondary dystrophic calcification
  • Ankylosing spondylitis:
    • Considered in differential when intervertebral discs are involved
    • Affects lumbar and thoracic spine
    • Mostly caused by pyogenic organisms
    • Necrosis of disc with acute or chronic osteomyelitis, can be granulomatous
Additional references
Board review style question #1


A 60 year old woman presented with painful knee swelling. Biopsy showed fibroadipose and fibrocollagenous tissue with a chalky white, firm lesion. Histology showed basophilic aggregates and clumps surrounded by macrophages. Chondroid metaplasia was also seen. The aggregates contained rhomboid shaped crystals with positive birefringence under polarization. What is the most likely diagnosis?

  1. Calcium pyrophosphate crystal deposition disease
  2. Chondroma
  3. Gout
  4. Synovial chondromatosis
  5. Tumoral calcinosis
Board review style answer #1
A. Calcium pyrophosphate crystal deposition disease

Comment Here

Reference: Calcium pyrophosphate crystal deposition disease
Board review style question #2
Which of the following is a cause of secondary calcium pyrophosphate crystal deposition disease?

  1. ABCG2 gene mutation
  2. ANKH gene mutation
  3. FGF23 gene mutation
  4. Hyperparathyroidism
  5. Idiopathic
Board review style answer #2

Cartilaginous rest
Definition / general
  • Also known as wattle, cervical auricle, persistent branchial cartilage and cervical tab
  • Represents abnormal development of embryonic branchial apparatus
  • Usually present at birth as asymptomatic skin colored subcutaneous nodules, typically located on lower third of neck
Case reports

Chondroblastoma
Definition / general
  • Benign neoplasm; rare (< 1% of primary bone neoplasms), arising in second to third decades of life, with slight male predilection
  • Treatment with surgical curettage is generally curative; recurrence varies with location
Essential features
  • Rare (< 1% of primary bone neoplasms)
  • Peaks in second decade of life, with slight male predilection
  • Common location includes epiphysis of long bones > metaphysis; may involve skull in older patients
  • Sheets of chondroblasts admixed with osteoclast-like giant cells and eosinophilic chondroid matrix; pericellular chicken wire type calcification may be present
  • K36M mutations commonly identified
ICD coding
  • ICD-O: 9230/0 - chondroblastoma, NOS
  • ICD-11: 2E82.Z - benign chondrogenic tumors, site unspecified
  • ICD-11: XH4NK2 - chondroblastoma, NOS
Epidemiology
Sites
Pathophysiology
Clinical features
Diagnosis
Radiology description
  • Xray: well defined lucent lesion with a thin sclerotic rim, with or without matrix calcifications, commonly arising eccentrically within the epiphysis of long bones; extension to the metaphysis can be seen (AJR Am J Roentgenol 1977;128:613)
  • CT scan: can show matrix calcification and solid periosteal reaction (J Comput Assist Tomogr 1984;8:907)
  • MRI: associated with bone marrow edema, periosteal and soft tissue reactions, varying signal intensity on T2 weighted sequences (Skeletal Radiol 2002;31:88)
Radiology images

Contributed by Mark R. Wick, M.D., Borislav A. Alexiev, M.D. and AFIP

Femur Xray

Foot talus Xray

Humerus Xray

Left acromion lesion

Radiograph of tibia

Prognostic factors
Case reports
Treatment
  • Excision or curettage, with or without bone grafting, is the mainstay of treatment (Acta Orthop Belg 2016;82:68)
  • En bloc resection or amputation is reserved for advanced cases
Gross description
  • When resected with bone: usually 3 - 6 cm, well circumscribed, white-blue-gray, firm
  • When resected as curetted material: reddish, friable material (Arch Pathol Lab Med 2017;141:867)
  • Variable calcification, necrosis, cystic areas
Microscopic (histologic) description
  • Composed of round or polyhedral chondroblasts with abundant eosinophilic cytoplasm and well defined cell borders; spindle shaped cells may be focal (Ann Diagn Pathol 2003;7:205, Cancer 1972;30:401)
  • Nuclei are oval, hyperlobulated with grooves
  • Pericellular lace-like or chicken wire type calcification among degenerative chondroblasts
  • Chondroid matrix almost always present (pink rather than blue matrix)
  • May have marked cellularity, intracytoplasmic glycogen granules, mitotic figures, necrosis and osteoclast type giant cells
  • No significant nuclear atypia as compared with malignant chondroblastoma (Mod Pathol 2020;33:2295)
  • Aneurysmal bone cyst-like change is common (Skeletal Radiol 2010;39:583)
Microscopic (histologic) images

Contributed by Ashley Patton, D.O., Ph.D., Nasir Ud Din, M.B.B.S. AFIP and @JMGardnerMD on Twitter

Chicken wire calcification and mature cartilage formation

Osteoclast-like giant cell

Sheets of chondroblasts

Chondroblastoma, H3K36M antibody

H3K36M antibody

Nuclei vary in size

Neoplastic cells with ovoid to spindled nuclei


Well formed chondroid matrix

Chicken wire appearance

Chondroblastoma

Chondroblastoma

Cytology description
  • FNA demonstrates clusters of uniformly round to oval cells with loose matrix and scattered multinucleated giant cells (Cancer Cytopathol 2018;126:552)
Cytology images

Contributed by Borislav A. Alexiev, M.D.

Giant cell rich lesion

Positive stains
Negative stains
Electron microscopy description
  • Resembles tissue culture epiphyseal cartilage cells with prominent fibrous lamina that causes microscopic well defined cell borders (Cancer 1972;30:401)
Molecular / cytogenetics description
Videos

Histological overview of chondrosarcoma

Sample pathology report
  • Left femur, resection:
    • Chondroblastoma
Differential diagnosis
  • Chondromyxoid fibroma:
    • Metaphyseal, myxoid with pseudolobular pattern with pleomorphic stellate cells
    • Negative for K36M
  • Giant cell tumor:
    • Metaphyseal or epiphyseal in patients with closed epiphysis (third decade of life), clustered giant cells that are larger and more numerous and uniformly distributed than chondroblastoma, no chondroid matrix or chicken wire matrix
    • Negative for K36M
  • Aneurysmal bone cyst:
  • Chondroblastoma-like osteosarcoma:
    • Histologically, chondroblastoma-like osteosarcoma is characterized by monotonous, minimally to moderately atypical rounded cells with ovoid nuclei resembling chondroblastoma and abnormal osteoid deposition with destruction of the bone (Arch Pathol Lab Med 2020;144:15, Orthopedics 1999;22:337)
    • Negative for H3K36M
Board review style question #1


An 18 year old man presents with a 3 cm, well defined lucent lesion within the epiphysis of the distal femur. Microscopic features of the surgical curettage specimen are represented by the H&E images. The best diagnosis is

  1. Chondroblastoma
  2. Chondroblastoma-like osteosarcoma
  3. Chondromyxoid fibroma
  4. Giant cell tumor of bone
Board review style answer #1
A. Chondroblastoma. Chondroblastomas commonly present in the second decade of life as a singular, well defined lucent lesion within skeletally immature long bones. Characteristic histopathological features include sheets of chondroblasts admixed with osteoclast-like giant cells in a chondroid matrix and focal chicken wire type calcification. Chondroid fibromas typically lack chicken wire type calcification. Chondroblastoma-like osteosarcomas generally display an infiltrative growth pattern with marked cytologic atypia. Chondroid matrix is not commonly seen in giant cell tumor of bone.

Comment Here

Reference: Chondroblastoma
Board review style question #2
Which of the following is a feature of chondroblastoma?

  1. Aggressive lesion with an infiltrative growth pattern
  2. Commonly arises in the epiphysis and metaphysis of long bones
  3. Generally shows a high degree of cytologic atypia
  4. Lacks a pericellular chicken wire calcification
Board review style answer #2
B. Commonly arises in the epiphysis and metaphysis of long bones. Chondroblastomas show pericellular chicken wire calcification and generally display well demarcated borders and a lesser degree cytologic atypia when compared with chondroblastoma-like osteosarcoma.

Comment Here

Reference: Chondroblastoma

Chondromyxoid fibroma
Definition / general
  • Benign cartilaginous tumor of young adults, arising in proximal or distal parts of long bones, showing zonal architecture
  • Local recurrence is common; malignant transformation is extremely rare
Essential features
  • Characteristic radiologic appearance; i.e. eccentric lytic lesion with sharp, sclerosed and scalloped intramedullary edges
  • Histologically, zonal architecture comprised of lobules of myxoid to chondroid tissue with intervening spindle and multinucleated giant cells, showing variable coarse calcifications
  • Complete surgical resection is the treatment of choice, with chances of recurrence following simple curettage but no potential for distant metastasis
ICD coding
  • ICD-O: 9241/0 - chondromyxoid fibroma
  • ICD-11: 2E82.Z & XH89S0 - benign chondrogenic tumors, site unspecified and chondromyxoid fibroma
Epidemiology
Sites
Pathophysiology
  • Upregulation of glutamate receptor gene GRM1 coding region of chromosome 6 through recombination with several partner genes in up to 90% of cases (Nat Genet 2014;46:474)
Etiology
  • Unknown
Diagrams / tables

Contributed by Qurratulain Chundriger, M.B.B.S.
Schematic presentation

Drawing showing histology

Clinical features
Diagnosis
  • Requires integration of radiological and histopathological findings
  • Diagnosis can be challenging on a small biopsy specimen (e.g. cytology or needle core)
Radiology description
Radiology images

Contributed by Mark R. Wick, M.D. and Nasir Ud Din, M.B.B.S.
Metatarsal Xray

Metatarsal Xray

Femur Xray

Femur Xray

Tibia Xray Tibia Xray

Tibia Xray

Proximal femur

Proximal femur


Distal tibia

Distal tibia

Proximal tibia

Proximal tibia

Distal tibia

Distal tibia

Metatarsal

Metatarsal



Images hosted on other servers:
Nasal mass

Nasal mass

Sternum

Sternum

Sellar lesion

Sellar lesion

Radius Radius

Radius


Rib Rib Rib

Rib

Sacrum

Sacrum

Metatarsal

Metatarsal

Prognostic factors
  • Around 15% cases may recur, mostly following simple curettage rather than total resection (World J Surg Oncol 2014;12:283)
  • Malignant transformation can occur after radiation therapy
Case reports
Treatment
Clinical images

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Lesion in mandible Lesion in mandible

Lesion in mandible

Orbital tumor with globe displacement

Orbital tumor with globe displacement

Gross description
  • Lobulated tumor mass with intact periosteum
  • Cut surface is firm, glistening with variable myxoid areas (J Clin Diagn Res 2015;9:XD04)
  • Calcifications may not be seen grossly
Gross images

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Orbital tumor resection specimen

Orbital tumor resection specimen

Resection of rib tumor

Resection of rib tumor

Microscopic (histologic) description
  • Lobulated architecture; lobules separated by mononuclear spindle cells and admixed multinucleated giant cells
  • Lobules have hypocellular centers and hypercellular periphery
  • Variably myxoid to chondroid stroma, representing various stages of cartilaginous development (Hum Pathol 1998;29:438)
  • Lobules have stellate cells in a myxoid background and reside in lacunae in chondroid areas (Am J Clin Pathol 2001;116:271)
  • Cells have variable pink cytoplasm, bipolar to multipolar cytoplasmic extensions and oval to spindled nuclei
  • Marked nuclear pleomorphism with nucleoli may be seen in some cases
  • Periphery of lobules show spindle shaped fibroblast-like cells and scattered multinucleated osteoclast-like giant cells
  • Low mitotic rate
  • Coarse calcifications may be seen in the stroma, particularly in tumors arising in older age group and unusual sites (Skeletal Radiol 1998;27:559)
  • Hemosiderin deposition and lymphocytes may be seen
  • Necrosis, cystic change or degenerative changes are rare
  • 10% of cases may show associated areas of aneurysmal bone cyst-like appearance (Hum Pathol 1998;29:438)
Microscopic (histologic) images

Contributed by Nasir Ud Din, M.B.B.S.
Confluent nodules with giant cells

Confluent nodules with giant cells

Well defined nodular growth

Well defined nodular growth

Fibroblastic population

Fibroblastic population

Peripheral giant cell proliferation

Peripheral giant cell proliferation

Stellate mesenchymal cells in nodules

Stellate mesenchymal cells in nodules

Adjacent ABC-like areas

Adjacent ABC-like areas


Chondroid differentiation Chondroid differentiation

Chondroid differentiation

Well developed chondroid areas

Well developed chondroid areas

Calcifications

Calcifications

Cytology description
  • Smears are moderately cellular, having fragments of fibrillary myxochondroid tissue, which stains metachromatically (Diagn Cytopathol 2013;41:904)
  • Fragments of spindle cells and variable numbers of osteoclast-like giant cells are seen (Iran J Pathol 2016;11:272)
  • Nuclear atypia may be variable and result in malignant interpretation
  • Calcification may not be seen in cytology smears
Cytology images

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FNA of metatarsal lesion

FNA of metatarsal lesion

FNA of lytic lesion in femur

FNA of lytic lesion in femur

FNA of metatarsal head lesion

FNA of metatarsal head lesion

Positive stains
  • Chondromyxoid fibroma does not require immunohistochemistry for diagnosis
  • S100 and SOX9: positive in the cells within chondroid lobules (Hum Pathol 1989;20:952)
  • SMA: spindle cells at the periphery of lobules may show some degree of positivity
Negative stains
Electron microscopy description
  • Cells show cytoplasmic processes, intracytoplasmic glycogen and thickening of the nuclear membrane
Molecular / cytogenetics description
  • Not required for reaching diagnosis
  • GRM1 upregulation is highly specific for chondromyxoid fibroma
Videos

Cartilage forming tumors

Sample pathology report
  • Left knee and proximal tibia, curettage:
    • Benign cartilaginous tumor with features favoring chondromyxoid fibroma (see comment)
    • Comment: Correlation with radiological findings is essential.
Differential diagnosis
  • Central chondrosarcoma:
    • Radiographically destructive, osteolytic lesion with invasion into adjacent bone and soft tissue, moth eaten appearance and foci of calcifications
    • Histologically infiltrative lobules of cartilage with variable degree of cellularity and nuclear atypia
    • Characterized by IDH mutations
  • Chondroblastoma:
    • Arises mostly in young patients with immature skeleton
    • Epiphyseal location is characteristic
    • Islands of mononuclear cells with distinct cell borders, characteristic grooved nuclei; scattered cells may appear epithelioid
    • Chicken wire-like calcifications are characteristic
    • Harbors mutations of H3.3 (H3F3B gene) on chromosome 17
  • Osteochondromyxoma:
    • Extremely rare chondroid and osteoid matrix producing benign myxoid tumor, occurring in association with Carney complex
    • Tumor arises in the diaphysis of radius and tibia and nasal bone
    • Variably cellular tumor of polygonal bipolar to stellate cells arranged in sheets and lobules along with osteoid and chondroid matrix present in myxoid stroma
    • Lacks GRM1 upregulation and other chromosome 6 aberrations; instead harbors mutations of PRKAR1A at chromosome 17
  • Aneurysmal bone cyst:
    • Lytic expansile lesion on radiology with variable fluid levels on MRI
    • Composed of cystic blood filled spaces lined by osteoclast-like giant cells
    • Solid areas show spindle cell proliferation with blue bone formation
    • May be associated morphological finding in a number of benign and malignant bone and cartilaginous tumors
  • Giant cell tumor:
    • Arises in epiphyses of long bones in adults
    • Uniform distribution of osteoclast type giant cells among mononuclear cells
    • Shows positive staining for RUNX2, SATB2, H3.3 (G34W)
    • Excellent response to denosumab (RUNX ligand inhibitor)
Board review style question #1

A 25 year old woman presented with painful swelling of the right knee. Radiology shows a lytic lesion with sclerotic intramedullary margins in the metaphysis of proximal fibula. En bloc resection of tumor was done and microscopy showed the above picture. Which of the statements regarding this entity is true?

  1. Denosumab is a newly developed drug for nonsurgical treatment
  2. Diagnosis does not require correlation with radiology
  3. Most cases of this tumor present clinically as painless masses
  4. Presence of adjacent aneurysmal bone cyst-like areas is unlikely
  5. This tumor shows various stages of cartilaginous development
Board review style answer #1
E. This tumor shows various stages of cartilaginous development. The photomicrograph shows a tumor comprised of lobules of myxoid to chondroid appearance with adjacent mononuclear cell population and some osteoclast-like giant cells. These findings are characteristic of chondromyxoid fibroma, which is also suggested by clinical and radiological appearances. The myxochondroid lobules of chondromyxoid fibroma represent various stages of cartilaginous development, from myxoid mesenchyme to well developed hyaline cartilage. Diagnosis always requires radiological correlation, which shows characteristic eccentric lytic lesion in the metaphyseal region of long bones. Painful mass is a common clinical presentation. Adjacent aneurysmal bone cyst-like areas may be seen in up to 10% of cases. Denosumab is a RUNX ligand inhibitor, recently developed for the treatment of giant cell tumor of bone.

Comment Here

Reference: Chondromyxoid fibroma
Board review style question #2

Which of the following genetic alterations is characteristic of chondromyxoid fibroma?

  1. GRM1 upregulation
  2. H3F3B mutation
  3. IDH1 mutation
  4. PRKAR1A mutation
  5. USP6 rearrangements
Board review style answer #2
A. GRM1 upregulation. USP6 rearrangements are seen in aneurysmal bone cysts. IDH1 mutations are characteristic of chondrosarcoma. H3F3B is mutated in chondroblastoma and PRKAR1A mutations are seen in osteochondromyxoma in the setting of Carney complex.

Comment Here

Reference: Chondromyxoid fibroma

Chondrosarcoma (primary, secondary, periosteal)
Definition / general
  • Locally aggressive or malignant group of tumors characterized by formation of cartilaginous matrix
  • Primary: arising without a benign precursor
  • Secondary:
    • Central: arising in preexisting enchondroma
    • Peripheral: arising in preexisting cartilaginous cap of an osteochondroma
  • Periosteal chondrosarcoma: occurs on the surface of the bone in association with the periosteum
Essential features
  • Locally aggressive or malignant group of tumors characterized by formation of cartilaginous matrix and chondrocytes embedded in lacunae
  • Histologic grade, extracompartmental spread and local recurrence are important prognostic factors
  • Radiology is essential, especially for low grade lesions
  • Change in the size or clinical symptoms might be an indicator of malignant transformation in enchondromas and osteochondromas
  • IDH1 and IDH2 mutations in approximately 50% of cases
Terminology
  • Atypical cartilaginous tumor = tumors resembling grade 1 chondrosarcoma arising in the appendicular skeleton
  • Periosteal chondrosarcoma = juxtacortical chondrosarcoma
  • Conventional chondrosarcoma = primary, secondary and periosteal chondrosarcomas
  • For low grade tumors, the term low grade cartilaginous neoplasm can be used
ICD coding
  • ICD-O: 9220/3 - chondrosarcoma, NOS
  • ICD-O: 9221/3 - periosteal chondrosarcoma
Epidemiology
  • Accounts for ~20% of all malignant bone tumors
  • Second most common primary malignant bone tumor after osteosarcoma (Cancer 1995;75:203)
  • Middle aged to older adults (secondary and periosteal chondrosarcoma are seen in younger patients)
  • M > F
Sites
  • Most common sites are the pelvic bones, femur and humerus (Cancer Imaging 2003;4:36)
  • Other sites are the trunk, skull and facial bones
  • Involvement of the hands and feet is rare
  • Periosteal chondrosarcoma involves the metaphysis of long bones, usually distal femur and humerus
  • Conventional type chondrosarcoma is also the most common sarcoma arising in the larynx (Am J Surg Pathol 2002;26:836, Head Neck Pathol 2020;14:707)
Etiology
  • Unknown etiology for primary chondrosarcoma
  • Malignant transformation from benign precursors in secondary chondrosarcomas (J Am Acad Orthop Surg 2010;18:608)
  • Increased risk of secondary chondrosarcoma in patients with Ollier disease and Maffucci syndrome (Oncologist 2011;16:1771)
Clinical features
Diagnosis
  • Diagnosis of chondrosarcoma can be made on imaging studies (Xray, CT scan, MRI) in combination with biopsy specimen (Skeletal Radiol 2013;42:611)
  • Radiology is essential, especially in low grade lesions
Radiology description
  • Xray: popcorn-like calcifications (punctate and ring-like opacities), lytic lesions, endosteal scalloping, thickened cortex, cortical erosion or destruction, soft tissue involvement (Curr Probl Diagn Radiol 2019;48:262)
  • Cortical destruction and soft tissue extension of pre-existing enchondromas might be indicators of secondary central chondrosarcoma
  • Thick cartilaginous cap > 1.5 - 2 cm in secondary peripheral chondrosarcoma (Radiologe 2016;56:476)
  • Multilobular appearance in periosteal chondrosarcoma
  • CT scan and MRI: helpful in showing the extent of the tumor
Radiology images

Contributed by Shadi Qasem, M.D.
Soft tissue extension

Soft tissue extension

Corresponding MRI for previous image

Corresponding MRI for previous image

Finger tumor

Finger tumor

Pelvic tumor

Pelvic tumor

Secondary tumor

Secondary tumor

Prognostic factors
  • Histologic grade, extracompartmental spread and local recurrence are important prognostic factors (J Bone Joint Surg Br 2002;84:93)
  • Atypical cartilaginous tumor / grade I chondrosarcomas are locally aggressive and have a good prognosis (~85% 5 year survival rate)
  • Grade II / III chondrosarcomas have a worse prognosis (~50% 5 year survival rate)
  • Local recurrence is related to tumor size and adequacy of surgical margins
Case reports
Treatment
  • Wide surgical resection is the mainstay of treatment
  • Low grade chondrosarcomas are often surgically cured
  • Chondrosarcomas are in general resistant to chemotherapy and radiotherapy (Curr Opin Oncol 2016;28:314)
  • Chondrogenic tumors require a high dose of radiation (Oncologist 2008;13:320)
  • Resection with adjuvant radiotherapy yields the best outcome for high grade chondrosarcomas (Neurosurgery 2017;81:520)
Gross description
  • Neoplastic hyaline cartilage has a lobular, gray-tan cut surface
  • Cystic changes with myxoid or mucoid material
  • Mineralization appears as chalky calcium deposits
  • Cortical erosion and soft tissue extension can be seen
  • Thick cartilage cap (1.5 - 2 cm) with cystic cavities in secondary peripheral chondrosarcoma
  • Periosteal chondrosarcoma appears as a large, lobular mass attached to the surface of bone (Am J Surg Pathol 1985;9:666)
Gross images

Contributed by Shadi Qasem, M.D.
Femoral tumor

Femoral tumor

Pelvic tumor

Pelvic tumor

Frozen section description
  • Nodules of hyaline cartilage with variable atypia (Sarcoma 2014;2014:902104)
  • For low grade tumors, the term low grade cartilaginous neoplasm can be used
Frozen section images

Contributed by Shadi Qasem, M.D.
Frozen section

Frozen section

Microscopic (histologic) description
  • Abundant cartilaginous matrix with chondrocytes embedded in lacunae
  • Lobular or diffuse growth (depending on grade)
  • Permeation of intertrabecular spaces
  • Varying degrees of increased cellularity, nuclear atypia and mitotic activity
    • Grade I: minimally increased cellularity, nodular growth and occasional binucleate nuclei
    • Grade II: moderate cellularity and diffuse growth
    • Grade III: high cellularity, marked atypical cells, pleomorphic appearance and easily identifiable mitotic figures
  • Myxoid changes, chondroid matrix liquefaction and necrosis can be seen
  • Formation of nodules and cystic cavities can be seen in secondary peripheral chondrosarcoma (generally low grade tumors)
  • Periosteal chondrosarcoma:
    • Grade I or II tumors seen on the external surface of the bone
    • Cortical invasion, soft tissue extension and size (> 5 cm) can be helpful in distinguishing from periosteal chondroma (AJR Am J Roentgenol 2001;177:1183)
Microscopic (histologic) images

Contributed by Shadi Qasem, M.D.
Grade I tumor

Grade I

Myxoid degeneration

Myxoid degeneration

Grade II tumor

Grade II

Grade III tumor

Grade III

Bone permeation

Bone permeation

Virtual slides

Images hosted on other servers:

Grade I

Grade II

Grade III

Cytology description
  • Abundance of extracellular matrix material, which is best appreciated on air dried, Giemsa based stained material
  • Recognizable lacunae, often containing binucleated or multinucleated chondrocytes
  • Atypical cartilaginous tumor / grade I chondrosarcoma is cytomorphologically indistinguishable from an enchondroma
  • Grade II / III chondrosarcomas are more cellular, more atypical with more myxoid matrix
  • Cytology is more reliable in metastatic than primary tumors (Diagn Cytopathol 2006;34:413)
Cytology images

Contributed by Shadi Qasem, M.D.
Magenta color matrix

Magenta color matrix

Multinucleation

Multinucleation



Contributed by @Elena_PradosMD on Twitter
Chondrosarcoma Chondrosarcoma Chondrosarcoma Chondrosarcoma

Chondrosarcoma

Positive stains
Negative stains
Molecular / cytogenetics description
  • IDH1 and IDH2 mutations in approximately 50% of cases
  • Aneuploidy is seen with increasing histologic grade
  • TP53 mutations and affected active signaling pathways (RB1, CDKN2A, CDK) are identified particularly in high grade chondrosarcomas (J Cell Mol Med 2009;13:2843)
Videos

Chondrosarcoma versus enchondroma

Sample pathology report
  • Tibia, biopsy:
    • Low grade cartilaginous neoplasm (see comment)
    • Comment: The differential diagnosis includes enchondroma and low grade chondrosarcoma. Clinical and radiologic correlation is recommended.
  • Femur, resection:
    • Chondrosarcoma, grade II (see comment)
    • Surgical margins are negative
    • See synoptic report below
    • Comment: The diagnosis is made in conjunction with radiologic findings.
Differential diagnosis
  • Chondroblastic osteosarcoma:
    • If there is significant osteoid formation, then it is osteosarcoma
    • Clinical and radiological correlation is helpful (typically younger patients)
  • Enchondroma:
    • No aggressive features radiologically
    • Cytologically almost indistinguishable from low grade chondrosarcoma
    • Less cellular, uniform hyaline, abundant matrix calcification
    • Small, uniform, round nuclei with homogenous chromatin
  • Fracture callus:
    • Sometimes can contain abundant proliferating cartilage looking like cartilaginous neoplasia
    • Chondroid matrix is less mineralized and dark blue in color
    • Clinical and radiological correlation is helpful
  • Chondromyxoid fibroma:
    • Clinically and radiologically not aggressive
    • Stellate cells
    • More myxoid and less chondroid background
    • SMA positive
Board review style question #1

A 54 year old man had an 8 cm mass in the femur, which was resected. Which of the following is the best assessment?

  1. Radiotherapy is the mainstay of treatment
  2. Skull is the most common site
  3. The most likely genetic abnormalities are IDH1 and IDH2 mutations
  4. The tumor is sensitive to chemotherapy
  5. There is a female predominance
Board review style answer #1
C. The most likely genetic abnormalities are IDH1 and IDH2 mutations

Comment Here

Reference: Chondrosarcoma (primary, secondary, periosteal)
Board review style question #2

A 45 year old man had a biopsy from a 7 cm mass in the proximal humerus demonstrating a low grade cartilaginous lesion. Which of the following is true?

  1. Correlation with radiologic findings is essential
  2. Fingers and toes are common sites for this neoplasm
  3. Molecular testing is important for diagnosis
  4. The tumor cells strongly stain with cytokeratin
  5. This tumor is common in pediatric population
Board review style answer #2
A. Correlation with radiologic findings is essential

Comment Here

Reference: Chondrosarcoma (primary, secondary, periosteal)

Chordoma
Definition / general
  • Malignant tumor with notochordal differentiation
  • 3 types:
    • Conventional chordoma: ~95% of cases; chondroid chordoma is a subtype of conventional chordoma (World Neurosurg 2017;104:346)
    • Poorly differentiated chordoma (very rare): cohesive sheets of epithelioid cells with eosinophilic cytoplasm and loss of INI1 staining; positive for brachyury
    • Dedifferentiated chordoma (< 1% of chordomas): a biphasic tumor composed of a conventional chordoma with high grade sarcomatous transformation (usually high grade undifferentiated pleomorphic sarcoma or osteosarcoma); poor prognosis
  • Chordoma periphericum is a primary soft tissue chordoma and is very rare
Essential features
  • Typically involves the clivus, sacrococcygeal bones or vertebrae
  • Chords, sheets and individual cells, including cells with bubbly cytoplasm (physaliphorous cells), arranged in lobules set in a myxoid matrix
  • Positive for cytokeratin, EMA, S100 protein and brachyury
  • Poorly differentiated chordoma demonstrates loss of INI1
ICD coding
  • ICD-10:
    • C41.2 - malignant neoplasm of the vertebral column
    • C41.4 - malignant neoplasm of pelvic bones, sacrum and coccyx
Epidemiology
  • 1 - 5% of primary malignant bone tumors (Orthop Clin North Am 1989;20:417)
  • Most commonly arises in the 40 - 60 year old age group (may occur at any age) (Cancer Causes Control 2001;12:1)
  • Male predominance (~2:1) in sacrococcygeal and vertebral body cases; no sex difference in tumors involving the skull base
  • Poorly differentiated chordoma usually affects children and young adults with a female (~2:1) predominance
Sites
  • Intraosseous: > 95% of cases (usually axial skeleton) (Cancer Causes Control 2001;12:1)
    • Base of skull / clivus of occipital bone
    • Vertebral bodies
    • Sacrococcygeal bones
    • Extra-axial skeleton (rare)
  • Soft tissue (chordoma periphericum): rare (Skeletal Radiol 2013;42:1451)
  • Children and young adults: usually cranial chordoma
  • Poorly differentiated chordoma: clivus or cervical spine (most cases); rare sacrococcygeal cases reported
Pathophysiology
  • Most cases are sporadic but rare cases may be associated with benign notochordal tumor (Br J Radiol 2010;83:e49)
  • T gene (brachyury) duplication (6q27)
    • T box transcription factor involved in mesodermal differentiation during gastrulation (formation of 3 germ layers), including notochordal development (Development 2014;141:3819)
    • 7% of sporadic chordomas
  • Familial associated tumors (autosomal dominant) are rare; they are associated with T gene duplication
  • Rare cases associated with tuberous sclerosis; biallelic inactivation of TSC1 or TSC2 identified in the cases analyzed (Neurosurg Clin N Am 2015;26:437, Nat Rev Mol Cell Biol 2009;10:307)
Diagnosis
  • Diagnosis is based on morphology, immunohistochemical findings and anatomic location of the tumor
Radiology description
Radiology images

Contributed by Jesse Hart, D.O. and Case #110
High signal intensity

High signal intensity

Destruction of cervical vertebrae

Destruction of cervical vertebrae

MRI with sacral mass

MRI with sacral mass

Prognostic factors
  • Median survival is 7 years
  • 5 year overall and disease free survival are 61% and 71%; 10 year overall and disease free survival are 41% and 57% (World Neurosurg 2017;104:346)
  • Worse prognosis in cranial cases
  • Approximately 40% of noncranial tumors metastasize (lung, bone, lymph nodes, subcutaneous tissue)
  • Poorly differentiated chordoma has a worse prognosis than conventional chordoma and dedifferentiated chordoma has a worse prognosis than conventional and poorly differentiated chordoma
Case reports
Treatment
  • Usually surgery followed by radiation or radiation alone in poor surgical candidates (J Orthop 2018;15:679, Int J Radiat Oncol Biol Phys 2006;65:1514)
  • Poor response to chemotherapy
  • Tyrosine kinase inhibitors have been used in advanced cases (Eur J Cancer 2017;79:119)
  • Ongoing clinical trials include CDK4/6 inhibitors, inhibitors of chromatin remodeling enzymes (in INI1 deficient tumors), PD1 / LAG3 inhibitors and brachyury therapeutic vaccines in combination with radiotherapy
Gross description
Gross images

Contributed by Jesse Hart, D.O.
Chordoma has fleshy cut surface

Chordoma has fleshy cut surface

Chordoma has invaded the soft tissue

Chordoma has invaded the soft tissue

Microscopic (histologic) description
  • Conventional chordoma:
    • Infiltrative border
    • Low power architecture is lobular, with fibrous bands separating lobules
    • Cytoarchitecture (within the lobules) consists of cells forming short chords, dense epithelioid sheets / nests and single cells within the matrix
    • Extracellular myxoid matrix
    • Cells are epithelioid with abundant clear (glycogen) to eosinophilic cytoplasm that may be have a bubbly / vacuolated appearance (physaliphorous cells)
    • Nuclear pleomorphism is heterogenous throughout the neoplasm, with low grade and higher grade areas; vesicular nucleus is common; nuclear pseudoinclusions may be seen
    • Mitoses usually identifiable (high grade areas)
    • Necrosis may be present
    • Occasionally, mitotically active spindle cells
  • Chondroid chordoma (a subtype of conventional chordoma):
    • Matrix mimics hyaline cartilage (may be focal or extensive)
    • Nearly all cases arise in the base of the skull
  • Dedifferentiated chordoma:
    • Biphasic tumor with 2 juxtaposed components (de novo):
      • Conventional chordoma component
      • High grade sarcomatous component (high grade undifferentiated pleomorphic sarcoma or osteosarcoma)
    • May only have sarcomatous component posttreatment at a site of previously treated chordoma
  • Poorly differentiated chordoma:
    • Sheets of nests of epithelioid cells with eosinophilic cytoplasm and scattered intracytoplasmic vacuoles (signet ring-like)
    • Focal rhabdoid morphology is often seen
    • Numerous mitotic figures
    • Necrosis is common
    • No physaliphorous cells and myxoid stroma is usually absent (occasional cases have focal myxoid stroma)
  • Reference: Arch Pathol Lab Med 2021 Jul 28 [Epub ahead of print]
Microscopic (histologic) images

Contributed by Jesse Hart, D.O. and Nasir Ud Din, M.B.B.S.

Lobular architecture

Vesicular chromatin

Abundant myxoid stroma

Epithelioid cells with eosinophilic chords

Tumor necrosis


Poorly differentiated chordoma in 2 year old

Poorly differentiated chordoma in 2 year old

Chondroid chordoma 1 Chondroid chordoma 2

Chondroid chordoma

Dedifferentiated chordoma 1 Dedifferentiated chordoma 2

Dedifferentiated chordoma


Brachyury

Cytokeratin cocktail

EMA

S100 protein

Positive stains
Negative stains
Molecular / cytogenetics description
  • T gene (brachyury) duplication (6q27) occurs in ~27% of sporadic chordomas; however, nearly all notochordal tumors over express brachyury (epigenetic mechanisms) (Nat Commun 2017;8:890)
  • Homozygous or heterozygous loss of CDKN2A (p16, p14ARF) or CDKN2B (p15) at 9p21 seen in ~70% of cases
  • EGFR amplification is common (7p12)
  • Commonly activated pathways:
    • EGFR
    • PDGFβ
    • IGFR1
    • IGF1
    • mTOR
    • MET
    • PI3K
    • Chromatin remodeling genes: ARID1A, PBRM1, SETD2
  • Somatic mutation in the following genes is not present:
    • Brachyury
    • IDH1 or IDH2
    • EGFR
    • KRAS
    • NRAS
    • HRAS
    • BRAF
    • FGFR1-4
  • Chromothripsis is seen in a subset of sporadic chordomas, which is a genetic mechanism in which hundreds of simultaneous gene rearrangements occur, secondary to a seminal event occurring when chromosomes are condensed in mitosis (ionizing radiation, aborted apoptosis in which chromosomes have already begun to fragment, telomere dysfunction), resulting in localized chromosomal fragmentation (involving 1 or a few chromosomes) and rejoining with incorrect orientations
  • Poorly differentiated chordoma: molecularly different from conventional chordoma and characterized for SMARCB1 deletion and subsequent loss of INI1 expression (Genes Chromosomes Cancer 2019;58:804)
  • Poorly differentiated chordoma: heterozygous or homozygous deletions involving SMARCB1
Sample pathology report
  • Cervicothoracic chordoma, en block resection including C7 - T3 laminectomies, ribs 1 - 3 and a wedge resection of the upper lobe of the left lung:
    • Conventional chordoma
      • Tumor size: 8.5 x 6.2 x 5.4 cm
      • Extent of disease: Tumor involves the T1 and T2 vertebrae, the intervertebral disk, the adjacent soft tissue and the parietal pleura of the resected lung; neither visceral pleural nor lung parenchymal invasion are seen.
      • Lymphovascular invasion: Not identified
      • Dedifferentiation: Not present
    • Surgical margins:
      • Soft tissue margins: < 1 mm from tumor (inferior)
      • Lung staple line: 5 mm from tumor
      • Vertebral bone margins: Negative for tumor
      • Rib margins: Negative for tumor
    • Stage (AJCC, 8th edition): pT1
Differential diagnosis
  • Chondrosarcoma:
    • May be confused with chondroid chordoma but will be negative for epithelial markers (cytokeratin / EMA) and brachyury
    • Unlike chordoma, chondrosarcoma may demonstrate IDH1 or IDH2 mutations
  • Metastatic carcinoma:
  • Myoepithelial tumors:
    • May occur in soft tissue (the differential would be with chordoma periphericum) or bone, coexpresses epithelial markers (cytokeratin / EMA) and S100 protein, may have epithelioid cells in a myxoid stroma
    • Will be negative for brachyury
    • May have an EWSR1 gene rearrangement (~50% of cases) (Genes Chromosomes Cancer 2010;49:1114)
  • Myxopapillary ependymoma:
    • Involves the sacral region but negative for epithelial markers
  • Ecchordosis physaliphora:
    • Hamartomatous extraskeletal lesion derived from notochordal remnants
    • Extraosseous
    • Polypoid mass arising on the clivus (ecchordosis physaliphora spheno-occipitalis) but may be found anywhere from the skull base to sacrum
    • No lobular architecture, necrosis, conspicuous mitoses or high grade nuclei
    • IHC identical to chordoma
  • Benign notochordal cell tumor:
    • Benign intraosseous neoplasm with notochordal differentiation
    • Confined to bone (no cortical permeation)
    • No lobular architecture, necrosis, conspicuous mitoses, high grade nuclei or myxoid matrix
    • IHC identical to chordoma
Board review style question #1

    A 56 year old man had a 6.2 cm sacral mass. The microscopic image is from the resection specimen. Which of the following is true about this entity?

  1. The tumor has a very low metastatic rate
  2. The tumor has the capacity to dedifferentiate
  3. The tumor is probably negative for EMA
  4. These tumors are very responsive to chemotherapy
  5. These tumors usually occur in the extremities
Board review style answer #1
B. This is a chordoma. The tumor has the capacity to dedifferentiate.

Comment Here

Reference: Chordoma
Board review style question #2

    A 65 year old man has a large vertebral tumor which was resected and found to express both EMA and S100 protein (image shown). His family history is negative for tumors of any type. The patient underwent adjuvant radiation therapy and is now disease free 1 year after surgery. Which of the following is most likely true?

  1. The patient is very unlikely to die of disease in the next 9 years
  2. The patient probably has hepatitis C
  3. The tumor has a duplication in the brachyury gene
  4. The tumor is positive for brachyury
  5. These tumors are benign and adjuvant radiation therapy was unnecessary
Board review style answer #2
D. This is a chordoma. The tumor is positive for brachyury.

Comment Here

Reference: Chordoma

Chronic osteomyelitis
Definition / general
  • Longstanding infection of bone lasting months to years; characterized by low grade inflammation and presence of dead bone or fistulous tract
Essential features
  • M:F = 4:1
  • Incidence is highest in adults, 41 - 50 years (29%)
  • Most common site: tarsal and metatarsal bones and toes (43%)
  • Most common organism: Staphylococcus aureus; responsible for 80 - 90% of cases
  • Contiguous spread osteomyelitis is most common
Terminology
ICD coding
  • ICD-10: M86 - osteomyelitis
Epidemiology
  • Overall age and sex adjusted annual incidence of osteomyelitis is 21.8 cases per 100,000 person years (J Bone Joint Surg Am 2015;97:837)
  • M:F = 4:1 (Sci Rep 2018;8:14895)
  • Incidence is highest in adults, 41 - 50 years (29%); attributed partly to higher frequency of traumatic injury in this population
  • Chronic nonbacterial osteomyelitis most commonly affects children
  • Diabetes is also associated with higher incidence (Sci Rep 2018;8:14895)
Sites
  • Unifocal disease (94%):
    • Tarsal and metatarsal bones and toes (43%)
    • Femur and tibiofibular (20%)
    • Spine, sternum and pelvis (19%)
    • Others: craniofacial, upper limb bones, jaw (J Bone Joint Surg Am 2015;97:837)
  • Localization within a bone:
    • Acute hematogenous osteomyelitis in infants and adults affects the epiphysis
    • In neonates and children, transphyseal blood vessels facilitate direct extension into the adjacent joint as the metaphysis is intra-articular in this age group
    • In children, the infection is usually limited to the metaphysis
    • In the spine, infection localizes to the subchondral regions of the vertebral body (Diagn Histopathol 2016;22:355)
Pathophysiology
  • Entry of the organism into bone occurs by 3 main mechanisms:
    • Osteomyelitis secondary to a contiguous focus of infection (after trauma, surgery or insertion of a joint prosthesis) is most common
    • Secondary to vascular insufficiency (e.g., diabetic foot)
    • Hematogenous seeding, least common
  • Acute suppurative inflammation and tissue necrosis
  • Vascular compromise leading to bone necrosis
  • Sequestration
  • Progression:
    • Spread toward an intracapsular location may lead to septic arthritis
    • Spread toward a subperiosteal location may lead to periosteal elevation
  • Extension of sequestrum and necrotic material through cortical bone may create a fistula and ultimately break through the skin (Lancet 2004;364:369)
Etiology
  • Contiguous spread osteomyelitis: single or multiple organisms including Staphylococcus aureus, Streptococcus species and Actinomyces; most common in adults
  • Secondary to vascular insufficiency: Staphylococcus aureus, Staphylococcus epidermidis, E. coli, Klebsiella pneumonia, Proteus spp. and Pseudomonas aeruginosa
  • Hematogenous osteomyelitis: Staphylococcus aureus is responsible for 80 - 90% of cases; most common in children (J Bone Joint Surg Am 2015;97:837, Diagn Histopathol 2016;22:355)
  • Mycobacterial infection
  • Treponemal infection, fungal infection, helminth infection (uncommon)
Clinical features
  • Patients with chronic osteomyelitis often have a protracted course
  • Fever, pain and swelling, depending on site involved
  • These patients may report interval acute episodes
  • Patient can also present with open wound that exposes fractured bone or an indolent draining fistula (Lancet 2004;364:369)
Diagnosis
  • Laboratory:
    • Bone biopsy is essential for diagnosis
    • Microbiological cultures for bacteria, mycobacteria and fungus are required for appropriate treatment (Lancet 2004;364:369)
  • Imaging studies:
    • Plain Xray: for initial diagnosis and follow up
    • Ultrasound: for initial diagnosis
    • CT scan and MRI: for initial diagnosis (Lancet 2004;364:369)
Radiology images

Contributed by Nasir Ud Din, M.B.B.S.
Epiphyseal osteomyelitis

Epiphyseal osteomyelitis

Sequestrum

Sequestrum

Periosteal reaction

Periosteal reaction

Cystic

Cystic

Prognostic factors
  • Diabetes is a poor prognostic factor in patients with chronic osteomyelitis; poor prognosis in patients with nutritional and systemic diseases
  • Complications: arthritis, pathological fractures, skeletal deformities, amyloidosis, malignant transformation (squamous cell carcinoma), pseudocarcinomatous squamous hyperplasia involving bone (rare)
  • Reference: Diagn Histopathol 2016;22:355
Case reports
Treatment
  • Antibiotic therapy
  • Surgical therapy (debridement, saucerization, sequestrectomy, continuous intramedullary irrigation)
  • May require myocutaneous flaps
  • Foreign material (e.g., infective implant) needs to be removed with temporary stabilization, occasionally with antibiotic beads or cement with subsequent reimplantation
  • Nonsteroidal anti-inflammatory drugs and bisphosphonates for chronic nonbacterial osteomyelitis
  • Reference: Lancet 2004;364:369
Clinical images

Images hosted on other servers:

Chronic osteomyelitis with wound infection

Microscopic (histologic) description
  • Necrotic bone
  • Inflammatory infiltrate rich in plasma cells
  • Fibrosis, variable
  • Granulomas, in cases of tuberculosis or fungal infection
  • Reference: Diagn Histopathol 2016;22:355
Microscopic (histologic) images

Contributed by Nasir Ud Din, M.B.B.S. and Mohammad Khurram Minhas, M.B.B.S.
Area of suppurative necrosis Area of suppurative necrosis

Area of suppurative necrosis

Chronic granulomatous osteomyelitis Chronic granulomatous osteomyelitis

Chronic granulomatous osteomyelitis

Sample pathology report
  • Tibial lesion, biopsy:
    • Features are consistent with chronic nonspecific osteomyelitis; clinical and radiological correlation is recommended (see comment)
    • Comment: Microscopy reveals fragments of necrotic bone and fibroconnective tissue exhibiting dense inflammation and abscess formation. Inflammatory infiltrate comprises of neutrophils, plasma cells, lymphocytes and some foamy histiocytes. Negative for malignancy.
Differential diagnosis
  • Langerhans cell histiocytosis:
    • Polymorphous inflammatory infiltrate, rich in eosinophils
    • Characteristic polygonal cells with vesicular nuclei with nuclear grooves
    • Neoplastic cells are immunoreactive for S100 and CD1a immunostains
  • Rosai-Dorfman disease:
    • Extranodal involvement is common and may also affect bones
    • Histologically, shows histiocyte proliferation
    • Histiocytes in Rosai-Dorfman disease exhibit emperipolesis, the nondestructive phagocytosis of lymphocytes and erythrocytes, which is the hallmark of the disease and required for diagnosis
    • These cells are positive for S100 immunostains and are negative for CD1a
  • Plasma cell neoplasia:
    • Bone based lytic lesions
    • Histologically composed of a monoclonal population of plasma cells with variable cytological differentiation
    • Absence of neutrophils
    • Monoclonal, as demonstrated by light chain restriction and serum immunoelectrophoresis
  • Hodgkin and non-Hodgkin lymphoma:
    • These lymphomas can secondarily involve bone
    • Non-Hodgkin lymphoma can be primary
    • Hodgkin lymphoma shows mixed inflammatory infiltrate, like in chronic osteomyelitis; however, there will be large atypical mononuclear and binucleated Reed-Sternberg cells, which will stain positive for CD30, CD15
    • Non-Hodgkin lymphomas histologically contain atypical lymphoid cells
  • Ewing sarcoma:
    • Tumor is composed of sheets of small round blue cells
    • Tumor cells are positive for MIC2 (CD99), FLI1 and NKX2.2 immunostains
Board review style question #1

A 25 year old man presented with pain around the knee joint. Xray studies were suggestive of a neoplastic lesion. The lesion was biopsied (image above) and it shows which of the following histologies?

  1. Chronic osteomyelitis
  2. Diffuse large B cell lymphoma
  3. Ewing sarcoma
  4. Metastatic carcinoma
  5. Plasma cell neoplasm
Board review style answer #1
A. Chronic osteomyelitis

Comment Here

Reference: Chronic osteomyelitis
Board review style question #2
The most common pathogen in chronic osteomyelitis is

  1. Escherichia coli
  2. Klebsiella pneumonia
  3. Mycobacterium tuberculous
  4. Staphylococcus aureus
  5. Staphylococcus epidermidis
Board review style answer #2
D. Staphylococcus aureus

Comment Here

Reference: Chronic osteomyelitis

Clear cell chondrosarcoma
Definition / general
  • Clear cell chondrosarcoma is a low grade malignant cartilaginous epiphyseal neoplasm characterized by lobules of cells with abundant clear cytoplasm
Essential features
  • Epiphyseal location
  • Clear cells with abundant cytoplasm and centrally placed nucleus
  • Presence of woven bone and osteoclast-like giant cells
ICD coding
  • ICD-O: 9242/3 - clear cell chondrosarcoma
  • ICD-11: 2B50.Z & XH7XB9 - chondrosarcoma of bone and articular cartilage of unspecified sites & clear cell chondrosarcoma
Epidemiology
Sites
  • Clear cell chondrosarcoma has a predilection for the epiphyses of long tubular bones (Pathologe 2000;21:449)
  • Proximal femur is the most frequent site of involvement (68%), followed by the proximal humerus (23%) (Skeletal Radiol 2003;32:687)
Etiology
  • Unknown
Diagrams / tables

Images hosted on other servers:

Gender and anatomical distribution

Clinical features
Diagnosis
  • Correlation of radiological and clinicopathological features is mandatory in the diagnosis of all bone tumors, including clear cell chondrosarcoma
Radiology description
  • Typical radiolographic manifestation of this tumor is a slow growing epiphyseal or epimetaphyseal osteolytic lesion with a sclerotic border (J Bone Oncol 2019;19:100267, Skeletal Radiol 2003;32:687)
  • Subtle cartilaginous calcifications are seen in > 50% of cases and a periosteal reaction may also be present
  • Lesions in the axial skeleton are typically expansile and destructive, often with soft tissue extension and a lack of mineralization (Skeletal Radiol 2003;32:687)
  • MR imaging is superior to conventional radiographs for demonstrating the intramedullary extent of a lesion as well as soft tissue extension (Skeletal Radiol 2003;32:687)
  • CT images better delineate the presence of cortical destruction and the character of matrix mineralization patterns (Skeletal Radiol 2003;32:687)
  • On T1 weighted sequences, the tumor is typically of low signal intensity (Skeletal Radiol 2002;31:88, Skeletal Radiol 2003;32:687)
  • On T2 weighted sequences, there is a heterogeneous pattern with overall low to intermediate signal intensity (Skeletal Radiol 2002;31:88)
  • Clear cell chondrosarcoma and chondroblastoma may have a very similar radiographic appearance, which prevents a reliable differentiation of the 2 tumors (Skeletal Radiol 2002;31:88)
Radiology images

Contributed by Borislav A. Alexiev, M.D.
Conventional radiography

Conventional radiography

T1 weighted MRI

T1 weighted MRI

MRI STIR sequence

MRI STIR sequence

T2 weighted MRI

T2 weighted MRI

Prognostic factors
  • Prognosis of clear cell chondrosarcoma is excellent when treated adequately with wide surgical resection, with 10 year disease survival approaching 90% (Radiol Case Rep 2015;8:848)
  • Clear cell chondrosarcoma has a tendency for very late recurrence and metastasis 20 years after initial diagnosis
  • Metastases in lungs and other skeletal sites develop in 15 - 20% of cases
  • Bone metastases are as common as pulmonary metastases (Clin Orthop Relat Res 2020;478:2537)
  • Dedifferentiation to high grade sarcoma has been reported (Am J Surg Pathol 2000;24:1079)
Case reports
Treatment
Gross description
Gross images

Contributed by Borislav A. Alexiev, M.D.
Femoral head mass

Femoral head mass

Microscopic (histologic) description
Microscopic (histologic) images

Contributed by Borislav A. Alexiev, M.D. and @JMGardnerMD on Twitter
Malignant bone neoplasm

Malignant bone neoplasm

Cells with pale cytoplasm

Cells with pale cytoplasm

Woven bone formation

Woven bone formation

Large round nuclei

Large round nuclei

Cartilaginous component

Cartilaginous component

S100

S100


D2-40

D2-40

AE1 / AE3

AE1 / AE3

H3K36M

H3K36M

Clear cell chondrosarcoma

Clear cell chondrosarcoma

Cytology description
  • Low to intermediate cellular smears of clusters and single round or oval tumor cells (Diagn Cytopathol 2021;49:46)
  • Tumor cells with rounded nuclei (sometimes binucleated) and rich vacuolated cytoplasm
  • Low grade cellular atypia
  • Chondroid background matrix
  • Occasional osteoclast-like giant cells in background
Negative stains
Molecular / cytogenetics description
  • Rb pathway is affected in 95% of clear cell chondrosarcomas (Genes Chromosomes Cancer 2012;51:899)
  • 1 of 15 clear cell chondrosarcomas investigated for histone 3.3 mutations (to date) has shown K36M mutations in H3F3B, a highly specific driver mutation for chondroblastoma, suggesting a pathogenetic relation in at least a small subset of tumors (Nat Genet 2013;45:1479)
  • Neither IDH1 nor IDH2 mutations are detected
Sample pathology report
  • Right femoral head, resection:
    • Clear cell chondrosarcoma, low grade (see comment)
    • Margins of resection are negative, with sarcoma closest at 2 cm from the lateral soft tissue margin
    • Comment: The tumor is composed of cells with abundant clear or slightly eosinophilic cytoplasm and large round nuclei with mild pleomorphism and small nucleoli. The cells are arranged in sheets and lobules, admixed with trabeculae of woven bone and scattered osteoclast-like giant cells. Mitotic figures are rare (1/10 high power fields). Areas with hyaline cartilaginous matrix with moderate cellularity and mild nuclear atypia are also present. There is entrapment of pre-existing lamellar bone and invasion of the subchondral bone plate. Immunohistochemically, the tumor cells are strongly positive for S100 and D2-40 and show focal immunoreactivity for keratin AE1 / AE3. Stains for H3K36M and PAX8 are negative.
    • This constellation of morphological and immunohistochemical features strongly supports the diagnosis of clear cell chondrosarcoma. The prognosis of clear cell chondrosarcoma is excellent when treated adequately with wide surgical resection. However, clear cell chondrosarcoma has a tendency for very late recurrence and metastasis 20 years after initial diagnosis.
Differential diagnosis
Board review style question #1

The following tumor is found in the femoral head epiphysis of a 39 year old man. Which is most likely the correct diagnosis?

  1. Chondroblastoma
  2. Chordoma
  3. Clear cell chondrosarcoma
  4. Conventional osteosarcoma
  5. Giant cell tumor of bone
Board review style answer #1
C. Clear cell chondrosarcoma

Comment Here

Reference: Clear cell chondrosarcoma
Board review style question #2
Which of the following is true about clear cell chondrosarcoma?

  1. Clear cell chondrosarcoma has poor prognosis
  2. Clear cell chondrosarcoma is sensitive to radiation and chemotherapy
  3. Late recurrences and even distant metastases may occur
  4. Most clear cell chondrosarcomas have IDH1 or IDH2 mutations
  5. Most often affects the metaphysis of long bones
Board review style answer #2
C. Late recurrences and even distant metastases may occur

Comment Here

Reference: Clear cell chondrosarcoma

Cystic meniscus
Definition / general
  • Lesion similar to ganglion but in menisci of knee
  • Either at lateral or medial joint margin (AJR Am J Roentgenol 2001;177:409)
  • Either confined to meniscus or extends beyond capsule
  • Almost always associated with meniscal tears; may be due to trauma
  • Cyst caused by simple extrusion of synovial fluid through meniscal tear
  • Usually pain and swelling
Case reports
Clinical images

Images hosted on other servers:

Arthroscopic finding

External aspect of cyst

Cyst resection

Microscopic (histologic) description
  • Cyst lined by synovial epithelium with nonspecific inflammation and focal hemorrhage

Dedifferentiated chondrosarcoma
Definition / general
  • High grade malignant neoplasm defined by the presence of a conventional chondrosarcoma component juxtaposed to a high grade noncartilaginous sarcoma component
  • Poor prognosis with 5 year overall survival of 7 - 24% (Eur J Cancer 2007;43:2060)
Essential features
  • Development of a high grade sarcoma in association with a preexisting conventional chondrosarcoma; theoretically, may occur in approximately 1 of 10 - 20 untreated chondrosarcomas (Hum Pathol 1982;13:36, Rev Chir Orthop Reparatrice Appar Mot 1994;80:669)
  • Defined histologically by areas of lower grade chondrosarcoma adjacent to a high grade sarcoma
  • IDH mutations present
Terminology
  • Dedifferentiated chondrosarcoma
ICD coding
  • ICD-O: 9243/3 - dedifferentiated chondrosarcoma
  • ICD-11: 2B50.Z & XH6E77 - chondrosarcoma of bone or articular cartilage of unspecified sites & dedifferentiated chondrosarcoma
Epidemiology
Sites
  • Most common sites of involvement: femur, pelvis, humerus and scapula (Eur J Cancer 2007;43:2060)
  • Preferred site of involvement follows that of conventional chondrosarcoma
Pathophysiology
  • Common mutations with conventional chondrosarcoma (IDH and TP53) suggest similar pathogenesis with conventional type (J Pathol 2011;224:334)
Etiology
  • Unknown
Clinical features
  • Localized pain and palpable mass
  • Occasionally a clinical history of prolonged local discomfort with recent change of a rapidly enlarging mass
  • Pathological fractures can occur in 22% of the patients (Eur J Cancer 2007;43:2060)
Diagnosis
  • Histologic evaluation necessary, although it can be difficult to make the diagnosis on a limited amount of biopsy tissue if only the high grade sarcoma component is sampled and requires correlation with imaging findings for a cartilaginous component (Skeletal Radiol 1995;24:409)
  • Sample must show both components, conventional chondrosarcoma and high grade noncartilaginous sarcoma; otherwise, misdiagnosis can occur (Skeletal Radiol 1995;24:409)
  • IDH mutation helpful when present (J Pathol 2011;224:334)
Radiology description
  • Low grade component manifests as mineralized area with rings and arcs
  • High grade component is lytic and aggressive, with permeation and destruction of underlying bone
Radiology images

Contributed by Mark R. Wick, M.D. and AFIP images
Dedifferentiated chondrosarcoma

Pathological fracture

Cartilaginous matrix

Cartilaginous matrix

Prognostic factors
Case reports
Treatment
  • Surgical resection with adequate margins
  • Chemotherapy and radiotherapy can be used as adjuvants but have no effect on prognosis
Gross description
  • Cartilaginous and noncartilaginous components grossly evident in varying proportions (Skeletal Radiol 1995;24:409)
  • Blue-gray lobulated cartilage component usually located centrally and a fleshy, yellow or tan high grade sarcoma component is located near the site of pathologic fracture or is located extraosseously in the surrounding soft tissues (Hum Pathol 1982;13:36)
  • High grade sarcomatous component may show hemorrhage and necrosis (Skeletal Radiol 1995;24:409)
Gross images

Contributed by Mark R. Wick, M.D.
Gray-white cartilage next to tan sarcomatous component

Gray-white cartilage next to tan sarcomatous component

Microscopic (histologic) description
  • Conventional chondrosarcoma juxtaposed with an abrupt transition to high grade pleomorphic or spindle cell sarcoma
  • Cartilaginous component ranges from an enchondroma-like appearance to grade 1 or grade 2 chondrosarcoma
  • High grade dedifferentiated component usually has the appearance of high grade undifferentiated pleomorphic sarcoma or osteosarcoma
  • Less frequently, it may have features of angiosarcoma, leiomyosarcoma, rhabdomyosarcoma
  • Can even have epithelial differentiation to include squamous and adamantinoma-like morphologies (Oncol Res Treat 2018;41:456, Am J Surg Pathol 1996;20:293, Pathol Res Pract 2017;213:698)
  • Amount of dedifferentiation is highly variable and can range from 2 - 98% (Cancer 2006;106:2682)
Microscopic (histologic) images

Contributed by Erica Kao, M.D. and Mark R. Wick, M.D.
Abrupt demarcation

Abrupt demarcation

Low grade cartilage

Low grade cartilage

High grade component

High grade component

Dedifferentiated chondrosarcoma micro Dedifferentiated chondrosarcoma micro

Low grade cartilage juxtaposed with high grade sarcoma

Positive stains
  • IDH1 and IDH2 overexpression but of limited use
  • Only a small percentage of mutations can be captured using the mutation specific antibody (J Pathol 2011;224:334)
  • SOX9 and S100 may be expressed as markers of cartilage lineage differentiation in the low grade component
  • p53 overexpression, although not useful in practice
Molecular / cytogenetics description
Sample pathology report
  • Bone, left femur, core biopsy:
    • High grade malignant spindle cell neoplasm (see comment)
    • Comment: The patient's reported history of atypical cartilaginous tumor of the distal femur is noted. In that context, the morphologic findings in this biopsy could be consistent with dedifferentiated chondrosarcoma, although there is no cartilaginous component present in this biopsy.
Differential diagnosis
  • Chondroblastic osteosarcoma:
    • Younger patient population
    • Neoplastic bone formation
    • Gradual transition from high grade cartilaginous tumor to spindle cell sarcoma
  • High grade (grade 3) conventional chondrosarcoma:
    • May show spindling of tumor cells at the periphery of lobules
    • Gradual transition from chondrocytes to spindled cells without the sharp demarcation characteristic of dedifferentiated chondrosarcoma
  • Undifferentiated pleomorphic sarcoma of bone:
    • Especially problematic on small biopsies when only the high grade component is sampled
    • Requires clinical and radiographic correlation for a cartilage component
  • Metastatic sarcomatoid carcinoma:
    • Especially problematic on small biopsies when only the high grade component is sampled
    • Should express p63, at least focally
    • Clinical presentation (mass in lung or kidney) and imaging studies are important for the final diagnosis
Board review style question #1

What mutation can be frequently found in the tumor pictured above?

  1. EXT1
  2. IDH
  3. MDM2
  4. NF1
  5. RB
Board review style answer #1
B. IDH. 50 - 87% of dedifferentiated chondrosarcomas carry mutations in IDH1 or IDH2, which can be found in both the low grade and high grade components.

Comment Here

Reference: Dedifferentiated chondrosarcoma
Board review style question #2

What benign lesion can be associated with the tumor pictured above?

  1. Bone island
  2. Enchondroma
  3. Nonossifying fibroma
  4. Osteoblastoma
  5. Osteoid osteoma
Board review style answer #2
B. Enchondroma. As with conventional chondrosarcoma, dedifferentiated chondrosarcoma is associated with Ollier disease, multiple hereditary exostoses and enchondromas.

Comment Here

Reference: Dedifferentiated chondrosarcoma

Degenerative joint disease
Definition / general
  • Progressive arthropathy characterized by degenerative changes in articular cartilage, subchondral bone, synovium and ligaments, leading to joint stiffness, chronic pain and deranged joint movement (Nat Rev Drug Discov 2005;4:331)
Essential features
  • Degenerative arthropathy with multifactorial etiology
  • Most common cause of chronic joint pain in geriatric age group (Medicina (Kaunas) 2020;56:614)
  • Associated with joint stiffness and decreased range of motion
  • Classic radiologic features include loss of joint space, subchondral bone sclerosis and osteophyte formation
  • Diverse histologic features include progressive damage and ultimate loss of articular cartilage, subchondral bone thickening, osteophyte formation, mild chronic inflammation of synovium and degeneration of ligaments and menisci
Terminology
  • Osteoarthritis
  • Osteoarthrosis
  • Wear and tear disease
  • Joint degeneration
  • Degenerative arthritis
ICD coding
  • ICD-10: M19.90 - unspecified osteoarthritis, unspecified site
  • ICD-11:
    • FA00 - osteoarthritis of hip
    • FA01 - osteoarthritis of knee
    • FA02 - osteoarthritis of wrist or hand
    • FA03 - osteoarthritis of other specified joint
    • FA04 - oligoosteoarthritis
    • FA05 - polyosteoarthritis
    • FA0Z - osteoarthritis, unspecified
Epidemiology
  • Usually affects old age group
  • More common in women than men
  • More prevalent in the north (Osteoarthritis Cartilage 2011;19:1314, Curr Opin Rheumatol 2018;30:160)
  • Risk factors include personal and joint level factors
  • Personal factors with increased risk include African American race, female gender, genetic susceptibility, obesity, hyperlipidemia, increased systolic blood pressure, diet related factors (like vitamin D insufficiency) and high bone density / mass
  • Joint related factors include particular bone / joint shapes, joint malalignment, thigh flexor muscle weakness, engagement in certain occupational / sports activities and joint injury (Ann Phys Rehabil Med 2016;59:134)
  • Factors associated with decreased risk include weight loss, high fiber diet and Mediterranean diet
Sites
  • May affect any joint
  • Most commonly involves the large weight bearing joints like knees and hips along with hands, facet joints and feet (Br Med Bull 2013;105:185)
Pathophysiology
  • In general, the chondrocytes attain a catabolic phenotype while the underlying bone cells follow an anabolic phenotype
  • Chondrocytes fail to make normal amount and type of chondroid matrix
  • Increased degradation of matrix
  • Increased break down of cartilage attributed to deficiency of tissue inhibitors of metalloproteinase, aberrant production of matrix metalloproteinase (MMP) 13 and upregulation of cathepsin B (Biorheology 2002;39:237)
  • Production and repair of cartilage extracellular matrix is regulated by insulin-like growth factors 1 and 2 (IGF1 and IGF2), which themselves are modulated by IGF binding proteins
  • Reaction of differentiated chondrocytes to IGFs is enhanced by growth hormone
  • Osteoarthritic cartilage shows reduced response to IGFs (Curr Opin Rheumatol 2011;23:492)
  • Also, osteoarthritis is associated with aberrations of growth hormone, IGF and synthesis of IGF binding proteins
  • This dysfunction also affects function of osteoblasts increasing osteoblastic activity
  • Cytokines, specifically interleukin 1 (produced by the synoviocyte layer), upregulates MMPs production, increasing turnover of articular cartilage extracellular matrix (Aging Clin Exp Res 2003;15:364, Biorheology 2002;39:237)
  • Interleukin 1, tumor necrosis factor alpha and nitric oxide induce chondroapoptosis
  • Antiapoptotic molecule BCL2 production in decreased
  • Abnormal loading of cartilage causes interleukin 1 and MMP upregulation in joints
  • Chondrocyte senescence leads to decreased ability of chondrocytes to maintain the integrity of cartilage matrix, chondrocyte functional loss and propensity to undergo apoptosis (Ann Phys Rehabil Med 2016;59:333)
  • Damaged chondrocytes act as antigen presenting cells for T cells, initiating a cell mediated immune response
  • Humoral immunity mediated by antibodies against chondrocyte membrane proteins, proteoglycan link protein and cartilage proteins plays role in osteoarthritis (J Clin Med 2022;12:5)
  • Impaired balance between osteoblastic and osteoclastic activity causes marked osteoblastic bone deposition causing subchondral bone sclerosis and osteophyte formation
Etiology
Diagrams / tables

Images hosted on other servers:
Mechanism of osteoarthritis

Mechanism of osteoarthritis

Development of osteoarthritis

Development of osteoarthritis

Clinical features
  • Pain during or after movement of joint (SICOT J 2022;8:14)
  • Joint stiffness in the morning or after being inactive (Nurs Stand 2009;24:35)
  • Tenderness when light pressure is applied to or around joint
  • Decreased flexibility, limited range of motion
  • Grating sensation, popping or crackling sound on movement of joint
  • Bone spurs (extra bits of bone) around the affected joint
  • Swelling
  • Gradual loss of joint function
Diagnosis
  • Diagnosis is based on integration of history, physical examination, laboratory and radiologic findings (JAMA 2021;325:568)
  • Histopathologic findings help in diagnosis and assessment of severity of disease process
Laboratory
Radiology description
  • Narrowing of joint space: usually asymmetric
  • Subchondral sclerosis
  • Sclerosis involving joint margins
  • Osteophytosis
  • Joint erosions
  • Subchondral cysts
  • Bone marrow edema-like lesions, adjacent to regions of cartilage damage
  • Synovitis (50%)
  • Plain radiograph: most commonly used for assessment of bony changes (Best Pract Res Clin Rheumatol 2006;20:27)
  • Ultrasound: detects joint effusion and synovitis
  • CT: very efficient modality for detecting bony changes
  • MRI: accurate in assessing bony and soft tissue changes, detects cartilage loss and bone marrow changes; contrast helps reveal synovitis (Radiology 2020;296:5)
  • Technetium 99m methyl diphosphonate (99mTc MDP) / PET with 18FDG or 18F: used for multiple joint examination
Radiology images

Contributed by Nasir Ud Din, M.B.B.S.
Left knee joint Left knee joint

Left knee joint

Right hip joint

Right hip joint

Prognostic factors
  • Gradual progression
  • Articular cartilage is avascular and cannot rebuild, hence the degenerative changes cannot be reversed
  • Hip osteoarthritis: superolateral type of migration of the femoral head, subchondral sclerosis, high Kellgren Lawrence (KL) grade at baseline, high intensity sporting activities and being overweight (Arthritis Res Ther 2019;21:192)
  • Knee osteoarthritis: age, body mass index, ethnicity, comorbidity, infrapatellar synovitis, joint effusion, medial femorotibial cartilage loss, high serum level of hyaluronic acid and baseline severity of disease (Arthritis Res Ther 2015;17:152)
  • Physical workload is a prognostic factor for both types of osteoarthritis (Nat Clin Pract Rheumatol 2007;3:78)
Case reports
Treatment
  • Conservative treatment: physical therapy, oral NSAIDs and local steroid injection
  • Joint arthroplasty: unbearable pain, severely limited range of motion (PM R 2012;4:S97)
  • Systemic immune / inflammatory cause: specific treatment of cause may improve / slow down the degenerative process (F1000Res 2020;9:325)
Clinical images

Images hosted on other servers:
Hand osteoarthritis

Hand osteoarthritis

Knee osteoarthritis Knee osteoarthritis

Knee osteoarthritis

Hip joint osteoarthritis

Hip joint osteoarthritis

Gross description
  • Erosion and loss of articular cartilage (focal, segmental or diffuse)
  • Flattening of joint surface, concave deformity in tibial plateau
  • Bone erosions and deformities
  • Osteophytes: bony outgrowths usually seen at periphery of joint covered by fibro / hyaline cartilage; have reddish marrow as compared to marrow of medullary cavity
  • Eburnation of bone: loss of articular cartilage causes exposed bone to articulate on bone; the exposed bone forms a smooth hard surface owing to repeated abrasions (Radiol Technol 2011;83:37)
  • Subarticular pseudocysts called geodes
  • Large geodes may cause collapse of articular plate, microfractures and osteonecrosis
  • Intra-articular loose bodies (joint mice): fragmented pieces of articular cartilage / osteophytes
  • Synovium may appear finger-like
  • Sections should be taken from articular changes as well as soft tissue including synovium and menisci
Gross images

Contributed by Jian-Hua Qiao, M.D.
Advanced osteoarthritis of hip

Advanced osteoarthritis of hip

Microscopic (histologic) description
  • Articular cartilage changes
    • Begin with localized changes
    • First change is loss of proteoglycan from the superficial layers of articular cartilage
    • This loss damages the collagen network, leading to development of cracks, splits and fissures in the cartilage (Vet Pathol 2014;51:968)
    • They extend from the surface towards subchondral bone
    • Chondrocyte lacunae are reduced in number and appear empty due to chondrocyte apoptosis
    • Clones of chondrocytes (chondrocyte clusters) form adjacent to fissures and in deeper parts in order to repair the damaged cartilage but their functional ability is compromised (Curr Rheumatol Rep 2019;21:38)
    • Damaged cartilage thus appears more cellular due to unevenly distributed chondrocytes throughout the matrix
    • Pannus composed of fibroblasts and type I collagen forms at the periphery and in regions of matrix loss, bridging across fissures
    • Discrete hematoxyphilic lines (duplication of tide marks) form at the interface between mineralizing and nonmineralizing cartilage
    • Gradual progressive damage results in loss of articular cartilage from articular surface resulting in exposure of bone / calcified cartilage
    • Changes involve both opposing articular surfaces, causing bone to articulate on bone, followed by eburnation
    • Eburnated bone looks like cortical bone without periosteum in transverse sections
    • Eburnated bone is damaged and reparative fibrocartilage islands form and may grow to develop a complete fibrocartilaginous covering over the eburnated surface (Calcif Tissue Int 2021;109:303)
  • Subchondral bone changes
    • There is increased osteoblastic activity that results in subchondral bone sclerosis and osteophyte development (Microsc Res Tech 1997;37:333)
    • Mid zone chondrocytes near cartilage edge induce new bone formation via ingrowth of capillaries and endochondral ossification
    • With progression, the process of bone formation extends centrally
    • New bone formation within cartilage separates the cartilage into 2 layers; one above the surface of osteophyte and the other buried deep within bone in line of articular surface
    • At the junction of capsular and ligamentous insertions into bone osteophytes form via endochondral ossification from areas of chondroid metaplasia
    • Intra-articular osteophytes may break and form intra-articular loose bodies
    • Osteophytes have a shell of cortical bone continuous with the subchondral bone and cortical bone of the shaft
    • Eburnated bone may show small areas of necrosis (absence of osteocyte nuclei) secondary to damage
    • Necrosis is more common above cysts
    • Bone cysts (geodes) form in advanced osteoarthritis due to the permeation of synovial fluid through bone channels into marrow (Arthritis Res Ther 2013;15:223)
    • Cysts contain synovial fluid or fracture callus-like tissue (i.e., new cartilage, woven bone, fibrocartilage or fibrous tissue); they may also contain hypocellular myxoid material and inflammatory cells (lymphocytes and few plasma cells)
  • Synovium changes
    • Villous configuration
    • Synovial hypertrophy and hypervascularity (Arthritis Res Ther 2017;19:18)
    • Multinucleation of synoviocytes is often present
    • May appear inflamed initially with perivascular edema and mast cell infiltrate
    • Inflammation is usually not diffuse or subsynovial
    • Edema may become marked, specifically around dilated subintimal vessels; called serous synovitis
    • Progressive synovial fibrosis occurs in advanced arthropathy with associated subintimal perivascular chronic inflammatory cells (predominant lymphocytes and occasional plasma cells) (Clin Exp Rheumatol 1988;6:41)
    • Neutrophils are usually absent
    • Small fragments of cartilage and bone within and below the synoviocyte layer
    • Calcified debris within synovium may induce florid histiocytic response, which may have multinucleated cells; called dendritic synovitis
    • May have large bone particles when damage is marked and rapid
    • Calcium pyrophosphate dihydrate crystals may be present
Microscopic (histologic) description

Contributed by Nasir Ud Din, M.B.B.S.
Early osteoarthritic change in articular cartilage

Early osteo-
arthritic change
in articular
cartilage

Chondrocyte clusters

Chondrocyte clusters

Reduplication of tidemark

Reduplication of tidemark

Eburnated bone surface

Eburnated bone surface

Subchondral bone sclerosis

Subchondral bone sclerosis

Subchondral geode

Subchondral geode


Anabolic bone changes

Anabolic bone changes

Secondary encystification

Secondary encystification

Osteophyte formation

Osteophyte formation

Villous synovium

Villous synovium

Synovial osteophyte

Synovial osteophyte

Virtual slides

Images hosted on other servers:
Degenerative joint disease

Degenerative joint disease

Cytology description
  • Synovial fluid increases in volume and may lead to effusion
  • Viscid fluid contains debris of articular cartilage (chondrocyte clusters), calcium pyrophosphate crystals, hydroxyapatite crystals, bone, synovial villi or fibrils (Arthritis Rheum 1985;28:511)
  • Cell count is low (500 - 1,000 cells/mm3)
  • Cell types include macrophages, synoviocytes and lymphocytes
  • Blood / marrow / marrow derived lipid in cases of geode damage
Cytology images

Images hosted on other servers:
A: cartilage fragment in synovial fluid; B: chondrocytes

Cartilage fragment in synovial fluid; chondrocytes

Synoviocytes in synovial fluid

Synoviocytes in synovial fluid

Immunofluorescence description
Positive stains
Negative stains
  • Not required for diagnosis
Electron microscopy description
Electron microscopy images

Images hosted on other servers:
Morphological aspects of calcium containing crystals

Crystals in cartilage

Molecular / cytogenetics description
Videos

Osteoarthritis - causes, symptoms, diagnosis, treatment & pathology

Sample pathology report
  • Left head of femur, left knee replacement:
    • Features are consistent with degenerative joint disease (see comment)
    • Comment: Histology shows eburnated bone covered by fibrocartilaginous islands. There is loss of articular cartilage and subchondral bone sclerosis. Underlying subchondral cysts are present containing reactive woven bone, fibrous tissue and fibrocartilage. Peripheral osteophytes are present. Morphologic features and radiologic findings strongly support the diagnosis of degenerative joint disease.
Differential diagnosis
  • Superficial subarticular insufficiency fracture:
    • Type of stress fracture caused by repetitive and excessive stress to the subchondral bone (Jpn J Radiol 2022;40:443)
    • Usually affects osteoporotic females and overweight middle aged males
    • Acute onset of pain, may have pain for a few months
    • Not identified by conventional radiography; MRI is more efficient
    • Chronic fracture may show changes of osteoarthritis and osteonecrosis
  • Avascular necrosis:
    • Usually affects younger patients
    • Bilateral presentation if disease is associated with collagen vascular diseases, steroid therapy or inherited diseases, like Gaucher disease
    • Geographic subchondral bone and marrow necrosis (Am J Clin Pathol 2021;155:565)
    • Intact, partially separated / detached articular cartilage surface
    • Articular cartilage may appear smooth and fibrillated to folded and cracked
    • Necrosis more marked than small foci of osteonecrosis in osteoarthritis
    • Increased number of large bone particles in synovium
  • Neuropathic joint (Charcot joint):
    • Destructive arthropathy commonly associated with loss of proprioception
    • Rapid joint erosion, destructive features of osteoarthritis are present
    • Very little or no bone formation
    • Less stable joint, more prone to damage by secondary insult
    • Striking regional subarticular bone resorption
  • Rheumatoid arthritis:
    • Affects small bones of adult women
    • Proliferative synovitis (synovial hyperplasia) with dense florid lymphoplasmacytic infiltrate in contrast to mild inflammatory component in osteoarthritis
    • Necrobiotic nodules, fibrosis and organizing fibrin
  • Pseudogout (calcium pyrophosphate crystal deposition disease):
    • Calcium pyrophosphate dihydrate crystal accumulation in extracellular cartilage matrix, synovium and joints
    • Affects older adults and the elderly
    • Involves weight bearing joints, such as knees, hips, shoulders, wrists and ankles
    • Weakly polarizable rhomboid shaped calcium pyrophosphate crystals show positive birefringence
  • Septic arthritis:
    • Usually affects young adults and children
    • Involves a single joint
    • Increased neutrophils and neutrophilic collections within tissue
Board review style question #1

Which of the following is the osteoarthritic change that is indicated by the arrow in the image shown above?

  1. Cartilage fissuring
  2. Chondrocyte clusters
  3. Duplication of tidemarks
  4. Pannus formation
  5. Subchondral bone cyst
Board review style question #1
C. Duplication of tidemarks. The image shows duplication of tidemarks, which refers to discrete hematoxyphilic lines that form at the interface between mineralizing and nonmineralizing cartilage. Answer A is incorrect because cartilage fissuring is present at the upper edge. Articular cartilage osteoarthritic changes begin with loss of proteoglycan from the superficial layers of articular cartilage. This loss damages the collagen network leading to development of cracks, splits and fissures in the superficial cartilage. Answer B is incorrect because clones of chondrocytes (chondrocyte clusters) form adjacent to fissures and in deeper parts in order to repair the damaged cartilage. Answer D is incorrect because pannus is composed of fibroblasts and type I collagen that forms at the periphery and in regions of matrix loss, bridging across fissures. Answer E is incorrect because subchondral bone cysts are cysts that form below cartilage in advanced osteoarthritis due to the permeation of synovial fluid through bone channels into marrow.

Comment Here

Reference: Degenerative joint disease
Board review style question #2
Bone typically follows an anabolic phenotype in degenerative joint disease. What is the term used for bony outgrowths usually seen at the periphery of osteoarthritic joints?

  1. Eburnated bone
  2. Geodes
  3. Loose bodies
  4. Osteoma
  5. Osteophytes
Board review style answer #2
E. Osteophytes are bony outgrowths usually seen at periphery of joint covered by fibro / hyaline cartilage. Answer C is incorrect because intra-articular osteophytes may break and form intra-articular loose bodies. Answer A is incorrect because loss of articular cartilage causes exposed bone to articulate on bone and the exposed bone forms a smooth hard surface owing to repeated abrasions, referred to as eburnation. Answer B is incorrect because subchondral bone cysts (geodes) are cysts that form in advanced osteoarthritis due to the permeation of synovial fluid through bone channels into marrow. Cysts contain synovial fluid or fracture callus-like tissue (i.e., new cartilage, woven bone, fibrocartilage or fibrous tissue); they may also contain hypocellular myxoid material and inflammatory cells. Answer D is incorrect because osteoma is a benign bone forming tumor composed of mature cortical type or less frequently, trabecular bone, typically involving the craniofacial skeleton.

Comment Here

Reference: Degenerative joint disease

Desmoplastic fibroma of bone
Definition / general
  • Rare, benign / borderline behavior; bony counterpart of soft tissue fibromatosis
  • Intraosseous component of soft tissue fibromatosis
  • May be due to local trauma; may be part of Gardner syndrome
  • Benign but up to 35% recur, does not metastasize
Epidemiology
  • Mean 23 years, range 1 - 75 years
  • 75% younger than age 30 years, may be more common in males
Sites
  • Metaphysis of long bones (56%), mandible (26%), pelvis (14%)
Radiology description
  • Lytic and honeycombed (“soap bubble” appearance) metaphyseal lesions, cortical thinning with soft tissue extension
Case reports
Treatment
  • Wide local excision to prevent otherwise frequent recurrences
  • Causes local destruction, no metastases
Gross description
  • White-gray, nonencapsulated, fibrous rubbery mass with variable bony spicules and cysts
Microscopic (histologic) description
  • Poorly demarcated lesion with interlacing or fascicular pattern of mature fibrous tissue composed of small fibroblasts with no / minimal mitotic activity and abundant collagenous stroma
  • Mature, bland fibroblasts separated by abundant collagen with thin walled, dilated vascular channels
  • May infiltrate into soft tissue
  • No necrosis, no pleomorphism or atypia
Microscopic (histologic) images

Contributed by Kelly Magliocca, D.D.S., M.P.H.
Desmoplastic fibroma

Desmoplastic fibroma

Molecular / cytogenetics description
  • Trisomy 8, trisomy 20
Positive stains
Negative stains
Electron microscopy description
  • Predominantly myofibroblasts, also fibroblasts and primitive mesenchymal cells
Additional references

Disc material
Definition / general
  • Normal intervertebral disc contains central nucleus pulposus (water, proteoglycans) within an annulus of obliquely oriented collagen fibers and a cartilaginous end plate
  • Elderly have shrunken, yellowed and dehydrated nucleus pulposus
  • Common surgical specimen, obtained after intervertebral disc prolapse or herniation, which is most common in ages 20 - 39 years
  • Anterior herniation usually is asymptomatic; posterior herniation puts pressure on nerve roots or spinal canal and produces symptoms
  • Posterior herniation present in 50% of older individuals at autopsy, usually in lumbar spine
  • Herniation refers to either prolapse, protrusion or extrusion

  • Protrusion:
    • Bulging of nucleus pulposus through weakened annulus fibrosus, usually posterior or posteriolateral
    • Can rarely disappear spontaneously

  • Prolapse:
    • Rupture of nucleus pulposus through annulus but not the posterior or anterior longitudinal ligament
    • Associated with neovascularization at edges of fibrocartilaginous fragments (Hum Pathol 1988;19:406)
    • Usually in lumbar region
    • May occur in thoracic or cervical disc

  • Extrusion: rupture of nucleus pulposus through annulus and posterior or anterior longitudinal ligament

  • Sequestration:
    • Fragmentation of extruded segment, may extend into spinal canal or far from site of rupture
    • Clinical symptoms depend on severity of herniation and position of offending disc
    • Patient may develop cauda equina syndrome in severe cases
Case reports
Microscopic (histologic) description
  • Annular fibrosus: collagen (pink)
  • Nucleus pulposus: pure cartilage (blue)
  • Herniated disk: vascular ingrowth
  • Also chondrocyte proliferation, structural alterations in form of tears and clefts, granular changes and mucous degeneration (BMC Res Notes 2011;4:497)
Microscopic (histologic) images

Images hosted on other servers:

Intervertebral disc

Disc degeneration


Enchondroma
Definition / general
Essential features
  • Abundance of cartilaginous matrix (Skeletal Radiol 1997;26:325)
  • Histology with typical encasement pattern (deposition of bone surrounding the tumor lobules, a sign of indolent growth) (Clin Orthop Relat Res 1985;201:214)
  • Absence of cytological atypia, mitoses, cortical invasion and soft tissue extension
  • Tumors arising in the small bones or in patients with enchondromatosis may show more cellularity and atypia
Terminology
  • Not recommended: chondroma
ICD coding
  • ICD-O: 9220/0 - enchondroma
  • ICD-11: 2E83.Y & XH9SY5 - benign osteogenic tumor of other specified site & enchondroma
Epidemiology
  • 20% of all cartilaginous tumors, second only to osteochondroma (30%) (Skeletal Radiol 1997;26:325)
  • Most common in 20 - 50 year olds
  • M:F = 1:1
  • Enchondromatosis presents with multiple enchondromas; most common subtypes are Ollier disease and Maffucci syndrome (StatPearls: Enchondroma [Accessed 20 April 2023], Am J Med Genet A 2020;182:1093)
    • Ollier disease: multiple enchondromas in the appendicular skeleton in an asymmetric manner
      • Typically in short and long bones of the limbs; epiphyseal tumors can prevent normal bone growth in young patients
    • Maffucci syndrome
      • Multiple enchondromas in association with soft tissue and visceral hemangiomas and lymphangiomas
Sites
  • Enchondromas are usually solitary, central and metaphyseal lesions of tubular bones, favoring the small bones of the hand and feet followed by the femur and humerus (StatPearls: Enchondroma [Accessed 20 April 2023], Skeletal Radiol 1997;26:325)
  • Location in the flat bones is very uncommon
  • Most common primary bone tumors of the hand
  • In the hands, they most commonly involve the proximal phalanges
Pathophysiology
Etiology
  • Heterozygous somatic mutations in the IDH1 and IDH2 genes
  • Found in 40% of sporadic enchondromas and in ~80% of enchondromas in patients with Ollier disease and Maffucci syndrome (Nat Genet 2011;43:1256)
  • Mutant PTH / PTHrP type I receptor account for rare cases of enchondromatosis (Nat Genet 2002;30:306)
Clinical features
  • Most common presenting symptoms are pain, swelling and deformity
  • Pathologic fractures can be seen in 40 - 60% of patients at presentation (J Hand Surg Am 2012;37:1229, Hand (N Y) 2015;10:461)
  • Many are ultimately found incidentally on radiographic imaging
Diagnosis
  • Coordination between radiologists, oncologists, pathologists, surgeons and the primary medical team is needed to arrive at the diagnosis of an enchondroma (StatPearls: Enchondroma [Accessed 20 April 2023])
  • Decisive point of an enchondroma diagnosis is differentiating enchondroma from atypical cartilaginous tumor / chondrosarcoma grade 1 (ACT / CS1)
  • Combination of nonaggressive radiology and histology with indolent growth and no bone permeation
Radiology description
  • Enchondromas typically appear as well defined, solitary defects in the metaphyseal region of bones, especially in the long bones (StatPearls: Enchondroma [Accessed 20 April 2023])
  • Their appearance depends heavily on the location and extent of the calcification of the tumor
  • Radiographically visible calcifications appear as fine, punctate stippling
  • Larger lesions can cause endosteal scalloping along with expansion and thinning of the cortex
  • Heavily calcified lesions may resemble bone infarct or bone islands, while an uncalcified lesion may appear lytic
  • Computed tomography (CT) is useful for detecting matrix mineralization and cortex integrity, while magnetic resonance imaging (MRI) adds insight into the aggressive and destructive features of the tumor (Indian J Radiol Imaging 2021;31:582)
  • Progressive destruction of the chondrite matrix by an expanding, non mineralized component, an enlarging lesion associated with pain or an expansile soft tissue mass is strongly associated with the malignant transformation of an enchondroma (Indian J Radiol Imaging 2021;31:582)
Radiology images

Contributed by Borislav A. Alexiev, M.D. and Terrance D. Peabody, M.D.
Left thumb Xray

Left thumb Xray

Right index finger Xray

Right index finger Xray

Left thumb MRI

Left thumb MRI



Images hosted on other servers:

Ollier disease

Prognostic factors
  • Asymptomatic enchondromas can be followed clinically and do not need to be treated (StatPearls: Enchondroma [Accessed 20 April 2023])
  • Longstanding enchondromas identified radiologically have been shown to progress
  • Malignant transformation is rare in a nonsyndromic setting (< 1%)
  • Malignant transformation to chondrosarcoma is a major complication of enchondromatosis (Ollier disease and Maffucci syndrome) (J Clin Diagn Res 2016;10:TD01)
    • Risk of malignant transformation is up to 45.8% in patients with Ollier disease and 57% in patients with Maffucci syndrome, respectively (Neoplasma 2014;61:365)
Case reports
Treatment
Gross description
  • If treated with curettage, the specimen is usually received in fragments
  • Tissue fragments contain bluish white glistening cartilage tissue admixed with medullary bone
  • Resection specimens are uncommon and demonstrate a well marginated, often multinodular, whitish blue or whitish yellow tumor in the medullary cavity of the bone, with intact cortex (see Additional references section)
Gross images

Contributed by Borislav A. Alexiev, M.D. and Mark R. Wick, M.D.
First rib lesion

First rib lesion

Multifocal in Ollier disease

Multifocal in Ollier disease

Microscopic (histologic) description
  • Enchondromas are hypocellular, with an abundance of hyaline cartilage matrix (Clin Orthop Relat Res 1985;201:214, Semin Diagn Pathol 2014;31:10)
  • Tumor cells are embedded within lacunar spaces and evenly dispersed
  • Nuclei are small and round, with condensed chromatin (lymphocyte-like)
  • Cytoplasm is eosinophilic
  • Architecture can be multinodular or confluent
  • Separate cartilaginous nodules can be surrounded by bone, which is referred to as encasement (a sign of slow growth)
  • Normal bone marrow can be present between the cartilaginous nodules
  • Cytologic atypia and mitoses are absent
  • Degenerative changes, such as ischemic necrosis or calcification, can be prominent
  • In the small phalangeal bones and in patients with enchondromatosis, enchondromas can be much more cellular and the tumor cells occasionally have more open chromatin and small nucleoli; binucleated cells can seen
  • Enchondromas do not invade and destroy the cortex, entrap pre-existing lamellar bone or extend into soft tissue (see Additional references section)
Microscopic (histologic) images

Contributed by Borislav A. Alexiev, M.D.
Intramedullary lesion

Intramedullary lesion

Hypocellular lesion

Hypocellular lesion

Chondrocytes in lacunar spaces

Chondrocytes in lacunar spaces

Short tubular bone lesion

Short tubular bone lesion

Degenerative changes

Degenerative changes

Negative stains
Molecular / cytogenetics description
  • Molecular pathology is rarely used for diagnosis
  • Hotspot mutations are exclusively found at the IDH1 p.Arg132 and the IDH2 p.Arg172 positions (Nat Genet 2011;43:1256)
  • Mutation analysis cannot be used to distinguish enchondroma from ACT / CS1
Sample pathology report
  • Left fourth distal phalanx lesion, curettage:
    • Fragments of benign cartilaginous tissue consistent with enchondroma (see comment)
    • Comment: The patient is a 27 year old woman with left ring finger distal phalanx lesion with imaging characteristics suggestive of a chondroid lesion measuring 0.3 x 0.5 x 0.9 cm. The lesion is confined to the medullary space. Histologically, the lesion is hypocellular, with an abundance of hyaline cartilage matrix and is composed of separate cartilaginous nodules encased by thin mantles of bone. Normal bone marrow is seen between the nodules. The tumor cells are situated within sharped edged lacunar spaces and evenly distributed. The nuclei are small and round, with condensed chromatin (lymphocyte-like). The cytoplasm is clear or eosinophilic. Cytological atypia and mitoses are absent. There is no cortical destruction, entrapment of host lamellar bone and soft tissue extension. Overall, these findings are most consistent with enchondroma. Enchondroma is a benign cartilaginous neoplasm. Malignant transformation is rare (< 1%) in a nonsyndromic setting.
Differential diagnosis
Board review style question #1

A 40 year old man presented with a bubbly appearing lytic lesion involving most of the distal phalanx of the left thumb. The lesion is mildly expansile without evidence of frank cortical breakthrough or extraosseous soft tissue extension. Hematoxylin eosin stains demonstrate a lesion with multinodular architectural pattern characterized by islands of hyaline cartilage encased by thin mantles of bone that are separated by marrow. The tumor cells are situated within sharped edged lacunar spaces and are evenly distributed. The nuclei are small and round, with condensed chromatin (lymphocyte-like). The cytoplasm is eosinophilic. Cytological atypia and mitoses are absent. There is no cortical destruction, entrapment of host lamellar bone and soft tissue extension. Which of the following is most likely the correct diagnosis?

  1. Central atypical cartilaginous tumor / chondrosarcoma, grade 1
  2. Chondromyxoid fibroma
  3. Clear cell chondrosarcoma
  4. Enchondroma
  5. Osteochondroma
Board review style answer #1
D. Enchondroma. Enchondroma is located in the medullary cavity and is composed of separate nodules encased by thin mantels of bone, which is a sign of slow growth. Answer A is incorrect because there is no cortical destruction, soft tissue extension and entrapment of pre-existing lamellar bone (i.e., features of more aggressive behavior indicative of central atypical cartilaginous tumor / chondrosarcoma, grade 1). Answer B is incorrect because chondromyxoid fibroma demonstrates a zonal architecture and is composed of chondroid, myxoid and myofibroblastic areas. Answer C is incorrect because clear cell chondrosarcoma involves the epiphysis of a long bone and consists of tumor cells with abundant clear cytoplasm. Infiltrative growth can be seen. Answer E is incorrect because osteochondroma consists of a bony projection covered by a cartilaginous cap, arising at the external surface of bone and containing a marrow cavity that is continuous with that of the underlying bone.

Comment Here

Reference: Enchondroma
Board review style question #2
Which of the following is true about enchondroma?

  1. Deposition of bone surrounding the tumor nodules is a sign of indolent growth
  2. Enchondromas most commonly affect flat bones
  3. Immunohistochemistry is usually helpful in the diagnosis
  4. Malignant transformation is frequent in a nonsyndromic setting
  5. Mutation analysis can be used to distinguish enchondroma from ACT / CS1
Board review style answer #2
A. Deposition of bone surrounding the tumor nodules is a sign of indolent growth. Answer B is incorrect because location in the flat bones is very uncommon. Answer C is incorrect because Immunohistochemistry is not helpful in the diagnosis. Answer D is incorrect because malignant transformation is rare (< 1%) in nonsyndromic setting. Answer E is incorrect because mutation analysis cannot be used to distinguish enchondroma from ACT / CS1.

Comment Here

Reference: Enchondroma

Epidermoid inclusion cyst
Definition / general
  • Benign epithelial inclusion cyst in the bone lined with stratified squamous epithelium, identical to cutaneous counterpart
Essential features
  • Benign cystic lesion
  • Post traumatic squamous epithelium embedded in bone
  • Cyst wall lined by squamous epithelium, including granular layer
  • Cyst contents contain laminated keratin
Terminology
  • Epidermoid inclusion cyst, epidermal inclusion cyst, intraosseous epidermoid cyst
ICD coding
  • ICD-10: L72.0 - epidermal cyst
Epidemiology
  • Rare incidence
  • Young to middle aged
Sites
Pathophysiology
Clinical features
  • Asymptomatic / painless lump
  • Can become tender due to inflammation
Diagnosis
  • Clinical, radiological and pathological correlation is adequate for diagnosis
Radiology description
  • Xray
    • Round osteolytic lesion with sharply demarcated sclerotic borders and thin cortex
    • Expansion of bone
    • Pathologic fracture is uncommon
  • MRI (Clin Neurol Neurosurg 2021;200:106381):
    • Hypointense on T1
    • Hyperintense on T2
Radiology images

Contributed by Nasir Ud Din, M.B.B.S
Distal phalanx of thumb Distal phalanx of thumb

Distal phalanx of thumb

Distal phalanx of fourth finger

Distal phalanx of fourth finger

Skull bone

Skull bone

Prognostic factors
Case reports
Treatment
  • Simple curettage or excision
Gross description
  • Unilocular cyst filled with white to pale yellow, malodorous, cheesy material
Frozen section description
  • Seldom required
Microscopic (histologic) description
  • Cyst is lined by squamous epithelium, including a granular layer
  • Cyst wall is devoid of skin adnexal structures
  • Cyst contents contain laminated keratin flakes
  • Acute inflammation and foreign body type giant cell reaction may be present in the ruptured cyst
  • Reference: Eur J Orthop Surg Traumatol 2019;29:1355
Microscopic (histologic) images

Contributed by Nasir Ud Din, M.B.B.S.
Absence of adnexal structures

Absence of adnexal structures

Keratin flakes in cystic cavity

Keratin flakes in cystic cavity

Lamellated keratin

Lamellated keratin

Squamous epithelium with granular layer

Squamous epithelium with granular layer

Reactive bone around the cyst

Reactive bone around the cyst

Chronic inflammation

Chronic inflammation

Positive stains
  • H&E diagnosis
Sample pathology report
  • Bone, right fifth distal phalanx, excision:
    • Epidermoid inclusion cyst
Differential diagnosis
  • Dermoid cyst:
    • Presence of skin appendages in the cyst wall
    • Compact keratin
  • Enchondroma:
    • Included in the radiological differential diagnosis
    • Histologically composed of hypocellular cartilaginous nodules
  • Glomus tumor:
    • Rare in bone
    • Included in the radiological differential diagnosis
    • Histologically uniform small round cells with eosinophilic cytoplasm, distinct cell borders
  • Osteomyelitis:
    • Clinically mimics epidermal inclusion cyst
    • Infiltration of bone by inflammatory cells including neutrophils, lymphocytes, and plasma cells
    • Bone erosion and necrosis
    • Reactive bone formation
  • Squamous cell carcinoma:
    • Associated precursor lesions, such as actinic keratosis or squamous cell carcinoma in situ are often present
    • Invasion of dermis by tumor
    • Tumor is composed of dysplastic squamous cells and may show lack of normal maturation
    • Moderate and poorly differentiated carcinoma show focal or no keratinization
Board review style question #1

Which of the following is one of the morphological features of intraosseous epidermoid inclusion cyst?

  1. Cyst contents contain compact keratin
  2. Cyst wall lined by benign squamous epithelium including a granular layer
  3. It is a malignant neoplasm
  4. Presence of skin adnexal structures in the cyst wall
Board review style answer #1
B. Cyst wall lined by benign squamous epithelium including a granular layer. The presence of a granular layer in the squamous epithelium and lamellated keratin are the key features that differentiate the epidermoid inclusion cyst from the trichilemmal (pilar) cyst.

Comment Here

Reference: Epidermoid inclusion cyst
Board review style question #2

Which of the following morphological features differentiates dermoid cyst from epidermoid inclusion cyst?

  1. Benign squamous epithelium
  2. Chronic inflammation and fibrosis
  3. Overlying skin with dysplasia
  4. Presence of skin adnexal structures in the cyst wall
Board review style answer #2
D. Presence of skin adnexal structures in the cyst wall. Dermoid cyst differs from epidermoid inclusion cyst by the presence of skin appendages.

Comment Here

Reference: Epidermoid inclusion cyst

Epithelioid hemangioendothelioma
Definition / general
  • Malignant endothelial neoplasm that most commonly involves soft tissue, bone, lung, skin and liver; can be locally aggressive and has metastatic potential
  • 2 subtypes defined by WWTR1-CAMTA1 or YAP1-TFE3 rearrangement; former expressing CAMTA1 and latter TFE3 (less specific)
Essential features
  • Endothelial neoplasm that most commonly involves soft tissue, bone, lung, skin and liver
  • Locally aggressive tumor with metastatic potential
  • WWTR1-CAMTA1 rearranged tumors: composed of cords or small nests of large endothelial cells with abundant eosinophilic cytoplasm embedded in a myxohyaline stroma; CAMTA1 positive staining
  • YAP1-TFE3 rearranged tumors: composed of solid nests or pseudo alveolar formations of epithelioid cells enmeshed in a fibrous stroma; TFE3 positive staining
ICD coding
  • ICD-O: 9133/3 - epithelioid hemangioendothelioma, malignant
  • ICD-10: D18.0 - hemangioma
  • ICD-11: 2B5Y & XH9GF8 - epithelioid hemangioendothelioma, NOS
Epidemiology
Sites
Pathophysiology
Etiology
  • Unclear
Clinical features
  • Clinical presentation depends on the tumor location, most frequently pain
  • If arising from a vein, occurring symptoms caused by vascular occlusion, such as edema or thrombophlebitis
  • Recurs locally, may metastasize (usually to lymph nodes and lungs) (Diagn Pathol 2014;9:131, Am J Surg Pathol 1997;21:363)
Diagnosis
  • Diagnostic workup includes radiology, histology (biopsy, resection) with immunohistochemistry and molecular analysis
Radiology description
  • CT scan: poorly circumscribed lesion with ground glass appearance
Radiology images

Images hosted on other servers:

Multifocal liver lesions

Prognostic factors
  • 13% recur, 20 - 30% metastasize (lung, lymph nodes), 13% die of disease; for lung, mortality is 65% (Am J Surg Pathol 1997;21:363)
  • High risk (> 3 mitotic figures per 50 high power fields and size > 3 cm) have 5 year disease specific survival of 59% versus 100% for low risk (Am J Surg Pathol 2008;32:924)
Case reports
Treatment
  • Wide local excision
Gross description
Frozen section description
  • Hypercellular tumor composed of groups of epithelioid cells embedded in a myxohyaline stroma
Microscopic (histologic) description
  • WWTR1-CAMTA1 subtype (classic EHE):
    • Cords, strands or small nests of large endothelial cells with abundant eosinophilic cytoplasm embedded in a myxohyaline stroma
    • Tumor cells have vesicular, round to oval, sometimes indented nuclei
    • Some tumor cells have intracytoplasmic, round, clear vacuoles representing small vascular lumina, which may contain erythrocytes
  • YAP-TFE3 subtype:
    • Solid nests or pseudo alveolar arrangement of epithelioid cells enmeshed in a fibrous stroma
    • Tumor cells have abundant, densely eosinophilic cytoplasm and can form vascular spaces
    • Intracytoplasmic vacuoles are rare
  • Usually minimal mitotic activity, atypia or necrosis
  • Up to 10% of cases exhibit frank malignant features of prominent nuclear pleomorphism, increased mitotic activity, solid growth or necrosis; these tumors resemble epithelioid angiosarcoma and have a more aggressive behavior (Am J Surg Pathol 2008;32:924)
Microscopic (histologic) images

Contributed by Iva Brčić, M.D., Ph.D. and Bernadette Liegl-Atzwanger, M.D.
Poorly circumscribed

Poorly circumscribed

Cords and nests

Cords and nests

EHE in the bone

Tumor within bone

Erythrocytes in lumen

Erythrocytes in lumen

Cords in myxohyaline stroma

Cords in myxohyaline stroma

Cellular atypia

Cellular atypia


Mitosis and atypical cells

Mitosis and atypical cells

Nuclear CAMTA1 staining

Nuclear CAMTA1 staining

Diffuse CD31

Diffuse CD31

Diffuse ERG

Diffuse ERG

CAM5.2 focally positive

CAM5.2 focally positive

Cytology description
Positive stains
Negative stains
Molecular / cytogenetics description
Molecular / cytogenetics images

Images hosted on other servers:

YAP1-TFE3 fusion

Sample pathology report
  • Right thigh, excision:
    • WWTR1-CAMTA1 rearranged epithelioid hemangioendothelioma (see comment)
    • Comment: Tumor is composed of cords and small nests of large endothelial cells with abundant eosinophilic cytoplasm embedded in a myxohyaline stroma. Immunohistochemically, the tumor cells are positive for ERG, CD31, CAMTA1, focally positive for keratin and are negative for CD34 and TFE3. The morphology and immunoprofile strongly support the diagnosis of WWTR1-CAMTA1 rearranged epithelioid hemangioendothelioma.
Differential diagnosis
Additional references
Board review style question #1

Which of the following is true regarding epithelioid hemangioendothelioma?

  1. Cut surface is white with myxoid areas
  2. It is a benign neoplasm with vascular differentiation
  3. Most of the cases are negative for CAMTA1
  4. Tumor cells stain positive for ERG
  5. Tumor consists of spindle cells embedded in hyalinized stroma
Board review style answer #1
D. Tumor cells stain positive for ERG

Comment Here

Reference: Epithelioid hemangioendothelioma
Board review style question #2

A 30 year old woman presented with a mass of the trunk. Immunohistochemistry shows positive staining with CD31, CD34, ERG and CAMTA1 and focal positivity with keratin. Which of the following is most likely the correct diagnosis?

  1. Epithelioid angiosarcoma
  2. Epithelioid hemangioendothelioma
  3. Epithelioid hemangioma
  4. Malignant melanoma
  5. Myoepithelioma of soft tissue
Board review style answer #2
B. Epithelioid hemangioendothelioma

Comment Here

Reference: Epithelioid hemangioendothelioma

Epithelioid hemangioma of bone
Definition / general
  • Variant of hemangioma that is a benign neoplasm composed of plump, epithelioid cells of endothelial cell differentiation
  • Frequently arises in long tubular bones (40%) (Am J Surg Pathol 2009;33:270)
  • Can arise in skin, lymph nodes and soft tissue
Essential features
  • Most commonly arises in long tubular bones
  • Rearrangement of FOS is common
  • Symptomatic tumors treated with curettage
  • On imaging, lesions are well defined and lucent but can show aggressive features like soft tissue extension
  • Microscopically, lobulated growth pattern, composed of epithelioid endothelial cells, numerous inflammatory cells, including eosinophils and plasma cells
  • No hyalinized or myxoid matrix
Terminology
  • Angiolymphoid hyperplasia with eosinophilia
  • Not recommended to use: histiocytoid hemangioma, hemorrhagic epithelioid and spindle cell hemangioma
ICD coding
  • ICD-10: D18.09 - hemangioma of other sites
Epidemiology
Sites
  • Frequently arises in long tubular bones (40%), followed by flat bones (18%), vertebrae (16%) and small bones of hand and feet (8%) (Am J Surg Pathol 2009;33:270)
  • ~20% of cases involve multiple bones
  • Can involve bones of craniofacial skeleton
Pathophysiology
  • 70% of osseous hemangiomas harbor either FOS or FOSB gene fusion (Genes Chromosomes Cancer 2015;54:565)
  • Leads to truncation of FOS or FOSB protein, loss of transactivation domain and tumorigenesis
Etiology
  • Unclear
Clinical features
  • Patients usually present with pain localized to the involved bone
Diagnosis
  • Requires interpretation of clinical, radiological and histopathological findings
Laboratory
  • No specific abnormality
Radiology description
  • On plain radiograph, the lesions are lucent with well defined expansile margins but may show a mixed lytic and sclerotic appearance with cortical destruction and periosteal reactive bone formation (Skeletal Radiol 2000;29:63)
  • CT scan displays an expansile, lytic lesion with cortical destruction and bone expansion (Skeletal Radiol 2000;29:63)
  • On MRI, lesions are hypointense or isointense relative to muscle on T1 weighted images and hyperintense on T2 weighted images; markedly enhanced by gadolinium contrast (Skeletal Radiol 2000;29:63)
Radiology images

Contributed by Kshitij Arora, M.D.
CT of spine

CT of spine

T1 weighted MRI of foot

T1 weighted MRI of foot

Prognostic factors
  • Recurrences are uncommon
  • Spontaneous resolution has been reported
  • Multicentric disease may present as regional lymph node or other organ involvement
  • Reference: Am J Surg Pathol 2009;33:270
Case reports
Treatment
  • Asymptomatic patients can be followed
  • Curettage or en bloc excision for symptomatic tumors
Gross description
  • Soft, solid, red and hemorrhagic
  • Tumor is excised intact and is relatively well circumscribed, solid, red and frequently expands the cortex
  • Uncommonly, the tumor erodes the cortex and extends into the soft tissue with pushing margins (Am J Surg Pathol 2009;33:270)
Gross images

Contributed by Andrew E. Rosenberg, M.D.
Foot amputation

Foot amputation

Frozen section description
  • Irregular infiltrative neoplasm with nodular / lobular growth pattern
  • Cytologically, tumor cells are large polyhedral, have eosinophilic cytoplasm and frequently contain intracytoplasmic vacuoles
  • These tumors may appear very cellular and also can have a background of lymphocytes, eosinophils, fibrosis and hemorrhage, making it difficult to appreciate the lumen formation
  • Frozen section diagnosis can be challenging and can be misdiagnosed as metastatic carcinoma (Cureus 2021;13:e15371)
Microscopic (histologic) description
  • Lobulated growth pattern
  • Organoid architecture
  • Well demarcated or infiltrative
  • Nodules of the tumor cells are surrounded by loose connective tissue
  • Tumor cells are large polyhedral, have eosinophilic cytoplasm and frequently contain intracytoplasmic vacuoles
  • Mitoses may be present
  • Well formed vessels are present and tumor cell cytoplasm may bulge into lumen in a tombstone or hobnail-like pattern
  • Cells can grow in solid cords and sheets
  • Stroma may contain eosinophils and plasma cells
  • Background of hemorrhage, fibrosis and patchy woven bone formation may be present
  • No myxohyalinized stroma is present (Am J Surg Pathol 2009;33:270)
Microscopic (histologic) images

Contributed by Andrew E. Rosenberg, M.D. and Kshitij Arora, M.D.
Well demarcated nodule

Well demarcated

Nodular architecture

Nodular architecture

Arteriole type vessels

Arteriole type vessels

Well formed vascular spaces

Well formed vascular spaces

Epithelioid cells

Epithelioid cells


Sheets of cells

Sheets of cells

Epithelioid endothelial cells lining the lumen

Epithelioid endothelial cells lining the lumen

CD31 immunohistochemistry

CD31 IHC

FOS immunohistochemistry

FOS IHC

Cytology description
  • Cytology is not routinely used for diagnosis of epithelioid hemangioma of bone
Positive stains
Negative stains
Molecular / cytogenetics description
Sample pathology report
  • Left foot lesion, curettage:
    • Epithelioid hemangioma (see comment)
    • Comment: H&E stain slides show lobules and sheets of minimally atypical polyhedral cells with eosinophilic cytoplasm and intracytoplasmic vacuoles. The background stroma shows lymphoplasmacytic and eosinophilic infiltrates and peripheral reactive woven bone formation. Immunohistochemistry shows that tumor cells are positive for CD31, ERG and FOS, while negative for keratin AE1 / AE3. SATB2 stains background osteoblasts and is negative in the tumor cells.
Differential diagnosis
  • Metastatic carcinoma:
    • Greater cytological atypia
    • Atypical mitotic figures
    • Features associated with carcinoma like mucin formation, keratinization, etc.
    • Negative for CD31 and CD34
  • Epithelioid angiosarcoma:
    • Severe cytological atypia
    • Prominent nucleoli
    • Infiltrative borders
    • Atypical mitotic figures
    • Negative for FOS / FOSB
    • Different genetics
  • Epithelioid hemangioendothelioma:
    • Tumor cells grow in hyalinized / chondroid stroma
    • Degree of cytological atypia is high
    • Positive for CAMTA1 or TFE3 immunohistochemistry
    • Different genetics
Board review style question #1
Regarding epithelioid hemangioma, which of the following statements is true?

  1. Frequently associated with peripheral eosinophilia
  2. Myxohyaline stroma is characteristic
  3. Osseous epithelioid hemangioma can present as multiple bone involvement
  4. Rb expression is typically lost in the tumor
Board review style answer #1
C. Osseous epithelioid hemangioma can present as multiple bone involvement. ~20% of osseous epithelioid hemangiomas present as multiple bone lesions. Answer A is incorrect because epithelioid hemangioma is not associated with peripheral eosinophilia. Answer B is incorrect because myxohyaline stroma is characteristic of epithelioid hemangioendothelioma. Answer D is incorrect because Rb expression is generally not lost in the epithelioid hemangioma.

Comment Here

Reference: Epithelioid hemangioma
Board review style question #2

Which gene fusion is characteristic of epithelioid hemangioma?

  1. CAMTA1 gene fusion
  2. EWSR gene fusion
  3. Fusion of FOS or FOSB gene
  4. NR4A3 gene fusion
Board review style answer #2
C. Fusion of FOS or FOSB gene. ~70% of osseous epithelioid hemangioma cases show either FOS or FOSB gene fusion. Answer A is incorrect because CAMTA1 gene fusion is characteristic of epithelioid hemangioendothelioma. Answer B is incorrect because EWSR gene fusion is not characteristic of epithelioid hemangioma. Answer D is incorrect because NR4A3 gene fusion is characteristic of extraskeletal myxoid chondrosarcoma.

Comment Here

Reference: Epithelioid hemangioma

Erdheim-Chester disease
Definition / general
Essential features
  • Correlation of clinical features, histology and radiological findings are essential for diagnosis (Blood 2016;127:2672)
  • Systemic disease with frequent involvement of bone, retroperitoneum (hairy kidney, coated aorta), CNS and lung (Blood 2016;127:2672)
  • Clinical features and disease outcomes depend on the site(s) involved
  • BRAF V600E mutation in > 50% of cases (Blood 2012;120:2700)
Terminology
  • Previous known as lipoid (cholesterol) granulomatosis
  • Also known as polyostotic sclerosing histiocytosis
  • Classified in the ‘L’ group under the revised classification of histiocytic disorders (Blood 2016;127:2672)
ICD coding
  • ICD-10: E88.89 - Erdheim-Chester disease
Epidemiology
Sites
  • Skeletal involvement in almost all (> 95%) cases, most often in the long bones of the lower extremities
  • Extraskeletal disease frequent (50 - 60%) in the retroperitoneum, kidneys, cardiovascular system, lung (Blood 2016;127:2672)
  • Central nervous system and pituitary involvement (20 - 30%) (Blood 2016;127:2672)
  • Cutaneous involvement in 25%, orbit and testis involvement are rare (Br J Dermatol 2020;182:405)
Etiology
  • Activating mutations of the mitogen activated kinase (MAPK) pathway leads to tissue accumulation of histiocytes with increased expression of cytokines (Blood 2014;124:483, Arthritis Rheum 2006;54:4018, Rheumatology (Oxford) 2010;49:1203)
  • Sera of Erdheim-Chester disease patients demonstrate a unique inflammatory cytokine signature with elevated levels of interferon (IFN)-α, interleukin (IL)-12, monocyte chemotactic protein-1 and decreased IL-4 and IL-7, suggestive of a Th-1-mediated systemic immune response (Blood 2011;117:2783)
  • Increased prevalence of myeloid neoplasms among Erdheim-Chester disease patients that may be clonally related, suggestive of a clonal hematopoietic precursor (Br J Hematol 2019;187:e51, Hematologica 2020;105:e84)
Clinical features
  • Heterogeneous clinical course ranging from asymptomatic to progressive, lethal disease (Blood 2016;127:2672)
  • Skeletal involvement presents with bone pain predominantly in the distal extremities
  • Cardiovascular involvement is usually asymptomatic, diagnosed only on imaging (Arch Pathol Lab Med 2004; 128:682)
  • Retroperitoneal fibrosis may be complicated by bilateral hydronephrosis with sparing of the pelvic ureters and inferior vena cava (Rheum Dis Clin North Am 2013; 39:299)
  • Pulmonary involvement is often asymptomatic but may present with cough or dyspnea
  • Pituitary involvement most often presents with central diabetes insipidus and may predate diagnosis by a decade or more
  • Central nervous system involvement predominantly manifests as cerebellar and pyramidal syndromes (J Neurol 2006. 253:1267)
  • Cutaneous involvement may present with perioibital xanthelasma-like lesions (Br J Dermatol 2020;182:405)
  • Orbital involvement may produce pain, blindness, exophthalmos and oculomotor nerve dysfunction
Diagnosis
Radiology description
  • Bilateral and symmetrical cortical osteosclerosis of the diaphyseal and metaphyseal parts of the long bones, predominantly the distal femur and proximal tibia (Rheum Dis Clin North Am 2013; 39:299)
  • Symmetrical and abnormally intense labelling of the long bones of the legs and rarely arms on 99Tc bone scintigraphy (Rheum Dis Clin North Am 2013; 39:299)
  • PET-CT findings
    • Retroperitoneal involvement with perinephric soft tissue thickening producing the characteristic hairy kidney appearance
    • Cardiovascular involvement may be characterized by circumferential soft tissue thickening of the vasculature including the thoracic and abdominal aorta (coated aorta), infiltrating right atrium and atrioventricular groove (Rheum Dis Clin North Am 2013; 39:299)
  • Chest CT in pulmonary involvement demonstrates smooth interlobular septal thickening, micronodules, ground glass opacities, thickening of interlobular fissures and parenchymal condensation (Arthritis Rheum 2010;62:3504)
  • Cardiac and brain MRI may be useful in initial assessment in suspected Erdheim-Chester disease cases to capture asymptomatic lesions (Mayo Clin Proc 2019; 94:2054)
Radiology images

Images hosted on other servers:
Missing Image

Skeletal and lung involvement

Missing Image

Peirenal soft tissue thickening

Prognostic factors
  • Chronic disease with variable prognosis depending on the site(s) involved
  • 5 year overall survival of 68% among those treated with interferon therapy (Blood 2011;117:2778)
  • With targeted therapies, the 5 year overall survival has increased to 83% (Am J Hematol 2018;93:E114)
  • CNS involvement is an independent major prognostic factor and independent predictor of death in survival analysis (Blood 2011;117: 2783, Blood 2014;124:483)
Case reports
Treatment
Microscopic (histologic) description
  • Soft tissue infiltrate of bland appearing histiocytes characterized by abundant foamy (xanthomatous) cytoplasm with surrounding fibrosis (Mod Pathol 2018;31:581)
  • Touton giant cells are frequently present
  • Associated lymphoplasmacytic infiltrate is sparse
  • Erdheim-Chester disease may be a component of mixed histiocytosis with Langerhans cell histiocytosis or Rosai-Dorfman disease (Blood 2014;124:1119, Hematologica 2020;105:e5)
Microscopic (histologic) images

Contributed by Aishwarya Ravindran, M.B.B.S. and Karen L. Rech, M.D.

Excisional biopsy of perinephric soft tissue mass

CD163

Factor XIIIa

Core biopsy of soft tissue (buttock) mass

Positive stains
Negative stains
Molecular / cytogenetics description
  • Over 90% harbor mutations in the mitogen activated protein kinase (MAPK) pathway
Sample pathology report
  • Soft tissue, perinephric, biopsy:
    • Histiocytic neoplasm with BRAF V600E mutation by immunohistochemistry, consistent with Erdheim-Chester disease in the appropriate clinical context (see comment)
    • Comment: The histologic sections demonstrate adipose tissue with an infiltrate of foamy histiocytes admixed with scattered Touton giant cells. There is extensive fibrosis present. Immunoperoxidase studies were performed on paraffin embedded sections using antibodies directed against the following antigens: CD1a, CD68, CD163, Factor XIIIa, IgG, IgG4, langerin, S100 and BRAF V600E. The foamy histiocytes are positive for CD68, CD163 and Factor 13a and are negative for S100, CD1a and langerin. The lesional histiocytes are positive for BRAF V600E mutation by immunohistochemistry. There is no increase in number of IgG4 positive plasma cells or an abnormal IgG4/IgG ratio.
Differential diagnosis
  • Reactive histiocytic proliferations, such as those seen in fat necrosis and post chemotherapy:
    • Histologically may be indistinguishable
    • Clinical features important in distinguishing from histiocytic neoplasm
    • Immunostains for Factor XIIIa and BRAF V600E may be helpful
  • Langerhans cell histiocytosis:
    • Langerhans cells are characterized by their irregular, grooved, folded or indented nuclei with fine chromatin, inconspicuous nucleoli and abundant pale eosinophilic cytoplasm
    • CD1a and langerin
  • Juvenile xanthogranuloma:
    • Usually in infants and children
    • Histologically and phenotypically similar to Erdheim-Chester disease
    • Absence of BRAF or other MAPK pathway mutations
  • Rosai-Dorfman disease:
    • Lesional histiocytes are characterized by enlarged round nuclei with small distinct nucleoli, abundant cytoplasm and emperipolesis
    • More prominent plasma cell infiltrate and lymphoid aggregates
    • Positive for S100
Board review style question #1

H&E

CD163

Factor XIIIA


    A 37 year old man presented with abdominal pain. PET CT demonstrated soft tissue thickening around the kidneys with perinephric fat stranding, along with FDG avid metaphyseal lesions bilaterally in the distal femur and proximal tibia. Core biopsy of the perinephric soft tissue demonstrated the staining shown above. In conjunction with the histopathology and radiology, which of the following would be the best diagnosis?

  1. Erdheim-Chester disease
  2. Follicular dendritic cell sarcoma
  3. Juvenile xanthogranuloma
  4. Langerhans cell histiocytosis
  5. Reactive process
Board review style answer #1
A. Erdheim-Chester disease

Comment Here

Reference: Erdheim-Chester disease
Board review style question #2
    Which of the following genetic mutations is most commonly associated with Erdheim-Chester disease?

  1. APC
  2. BRAF V600E
  3. KIT D816V
  4. MET exon 14
  5. PTEN
Board review style answer #2
B. BRAF V600E

Comment Here

Reference: Erdheim-Chester disease

Ewing sarcoma
Definition / general
  • Small round cell sarcoma showing gene fusions involving one member of the FET family of genes (usually EWSR1) and a member of the E26 transformation specific (ETS) family of transcription factors
  • American pathologist James Ewing (1866 - 1943) first described the tumor as diffuse endothelioma of bone (CA Cancer J Clin 1972;22:95)
Essential features
  • Small round cell sarcoma
  • CD99 diffuse membranous expression
  • Gene fusion involving FET family of genes (usually EWSR1) and member of ETS family of transcription factors, most commonly EWSR1-FLI1 (~85 - 90%)
Terminology
  • Ewing sarcoma of bone
  • Extraskeletal Ewing sarcoma
  • Adamantinoma-like Ewing sarcoma
  • Primitive neuroectodermal tumor (PNET), term no longer recommended
  • Askin tumor (Ewing sarcoma arising in chest wall), term no longer recommended
ICD coding
  • ICD-O: 9260/3 - Ewing sarcoma
  • ICD-11: 2B52.3 - Ewing sarcoma of soft tissue
  • ICD-11: 2B52.Y - Ewing sarcoma of bone and articular cartilage of other specified sites
Epidemiology
Sites
  • Diaphyseal or metaphyseal - diaphyseal region of long bones (lower > upper extremity)
  • Pelvic bones and ribs common
  • Bone > soft tissue, approximately 12% extraskeletal (Nat Rev Dis Primers 2018;4:5)
Pathophysiology
Etiology
  • Chromosomal translocation commonly involving EWSR1 and ETS partner
  • Cell of origin possibly mesenchymal stem cell (Cancer Cell 2007;11:421)
Diagrams / tables

Images hosted on other servers:
Clinical features
  • Localized pain and swelling (J Bone Joint Surg Am 2000;82:667)
  • Painful enlarging mass
  • Associated pathologic fracture sometimes present
  • Systemic findings (fever, weight loss, anemia, leukocytosis and increased sedimentation rate) can occur
Diagnosis
  • Integration of clinical, radiographic, immunohistochemical and molecular information
  • Small round cell morphology
  • CD99 diffuse membranous expression
  • Genetic confirmation often required (all cases harbor FET-ETS fusion)
Laboratory
  • Anemia, leukocytosis and elevated sedimentation rate can occur
Radiology description
  • Plain radiograph
    • Osteolytic permeative lesion
    • Poorly defined margins
    • Moth eaten bone destruction
    • Aggressive periosteal reaction (onion skin appearance)
    • Sunburst periosteal reaction less common than osteosarcoma
    • Saucerization, extraosseous tumor erodes cortex
    • No evidence of tumor osteoid / matrix production
    • Often underestimates extent of tumor
  • CT / MRI / PET (Semin Musculoskelet Radiol 2019;23:36)
    • Fully define primary lesion
    • Evaluate soft tissue extension
    • Assess for metastatic disease (~25%)
    • T1 weighted MRI: low to intermediate signal intensity
    • T2 weighted MRI: heterogeneous but predominantly high signal
Radiology images

AFIP images
Saucerization

Saucerization



Images hosted on other servers:

Radiograph of humeral lesion

Radiograph of humeral lesion (close up)

CT of humeral lesion

Radiograph of humeral head lesion

MRI of humeral head lesion

Prognostic factors
  • Presence of metastases main prognostic factor
  • Localized, resectable disease with 5 year survival rate of 70%
  • Metastatic disease with 5 year survival rate of < 30%
  • Surgical removal of resectable lung metastases improves survival
  • Favorable: complete pathologic response to neoadjuvant chemotherapy, small tumor size, superficial location, easily resectable (Bone Joint J 2016;98-B:1138)
  • Unfavorable: early relapse, presence of metastases, anatomic location in trunk / pelvis
Case reports
Treatment
  • Neoadjuvant chemotherapy and surgery
  • Ewing specific protocol of alternating vincristine / doxorubicin / cyclophosphamide and ifosfamide / etoposide (VDC / IE)
  • Chemotherapy improved prognosis to 75% for 5 year survival
  • Radiotherapy for surgically inaccessible tumors, inadequate margins and palliation
  • Limited efficacy of immunotherapeutic approaches (J Immunother Cancer 2020;8:e000653)
Clinical images

Images hosted on other servers:

Extraosseus Ewing sarcoma of the forearm

Gross description
  • Gray-tan mass with infiltrative borders (Semin Diagn Pathol 2014;31:39)
  • Intramedullary mass with soft tissue involvement
  • Areas of hemorrhage and necrosis frequent
  • Assess chemotherapy induced necrosis (≥ 90% good) with mapping
Gross images

Contributed by Mark R. Wick, M.D.
Ewing sarcoma

Ewing sarcoma



Images hosted on other servers:

Ewing sarcoma of foot

Amputation for Ewing sarcoma

Frozen section description
  • Small round blue cell tumor
Frozen section images

Contributed by Laura Warmke, M.D.
Small round cells

Small round cells

Necrosis

Necrosis

Microscopic (histologic) description
  • Classical Ewing sarcoma (Virchows Arch 2009;455:397)
    • Uniform small round cells
    • Tumor cells 1 - 2x size of lymphocytes
    • Round nuclei
    • Finely stippled chromatin
    • Inconspicuous nucleoli
    • Scant clear to eosinophilic cytoplasm
    • Indistinct cytoplasmic membranes
    • Sheet-like growth pattern
    • Islands separated by dense fibrous tissue
    • Subset with neuroectodermal differentiation (Homer-Wright pseudorosettes)
  • Atypical Ewing sarcoma (Virchows Arch 2011;458:281)
    • Nuclear enlargement
    • Irregular nuclear contours
    • Vesicular or coarse chromatin
    • Prominent nucleoli
  • Adamantinoma-like Ewing sarcoma (Head Neck Pathol 2020;14:59, Am J Surg Pathol 1999;23:159, Am J Surg Pathol 2015;39:1267)
    • Nests of basaloid cells
    • Peripheral palisading and cording
    • Prominent myxoid, fibromyxoid or hyalinized stroma
    • Focal keratin pearl formation
    • High grade features with minimal pleomorphism
Microscopic (histologic) images

Contributed by Laura Warmke, M.D., Mark R. Wick, M.D. and Erdener Özer, M.D., Ph.D.
Small round cells

Small round cells

Clear cell change

Clear cell change

Apoptotic cells

Apoptotic cells

"Light" cell and "dark" cell appearance


Rosettes

Rosettes

CD99

CD99

FLI1

FLI1

Virtual slides

Images hosted on other servers:

Ewing sarcoma (H&E)

Cytology description
Cytology images

Contributed by Laura Warmke, M.D. and Erdener Özer, M.D., Ph.D.
Round cells

Round cells

Fine chromatin

Fine chromatin

Small nucleoli

Small nucleoli

Cytological appearance

Cytological appearance

Positive stains
Negative stains
Electron microscopy images

Images hosted on other servers:

Ultrastructure analysis of tumor

Molecular / cytogenetics description
Molecular / cytogenetics images

Images hosted on other servers:

Dual color break apart probe FISH test

Videos

Ewing family of tumors

Sample pathology report
  • Bone, right proximal humerus mass, core biopsy:
    • Ewing sarcoma (see comment)
    • Comment: This biopsy shows an undifferentiated small round cell sarcoma involving bone with focal areas of necrosis and scattered mitotic figures. Immunohistochemical studies show that the tumor cells are positive for CD99 (diffuse, membranous) and NKX2.2, while they are negative for cytokeratin cocktail, S100 protein, SMA, desmin and CD45. RT-PCR demonstrates the presence of an EWSR1-FLI1 fusion, confirming the above diagnosis.
Differential diagnosis
Board review style question #1

Ewing sarcoma characteristically shows strong, diffuse membranous staining with which of the following immunohistochemical stains?

  1. CD99
  2. Desmin
  3. FLI1
  4. S100 protein
Board review style answer #1
A. CD99

Comment Here

Reference: Ewing sarcoma
Board review style question #2

A 12 year old boy injured his left arm while playing football. Radiograph demonstrated an aggressive lesion in the mid diaphyseal region of his left humerus with permeative appearance and lamellated periosteal reaction (onion skin). Biopsy shows a small round blue cell tumor. What is the most likely diagnosis?

  1. Chondrosarcoma
  2. Ewing sarcoma
  3. Lymphoma
  4. Osteosarcoma
Board review style answer #2
B. Ewing sarcoma

Comment Here

Reference: Ewing sarcoma

Fibrodysplasia ossificans progressiva
Definition / general
  • Rare autosomal dominant disorder with congenital malformation of the great toes and progressive heterotopic ossification in defined anatomic patterns
  • Early preosseous lesions resemble aggressive juvenile fibromatosis

    Pathophysiology:
  • Spontaneous and post-traumatic flareups heralded by intense connective tissue edema with perivascular lymphocytic infiltration into skeletal muscle
  • Angiogenic fibroproliferative lesions that spread along muscle planes and evolve through endochondral ossification to form mature lamellar bone
  • Leads to immobilization of joints making movement impossible, later death due to starvation (ankylosis of jaw) or from restrictive disease of chest wall
  • May be mediated by mast cells (Hum Pathol 2001;32:842)
Treatment
  • None; surgical trauma induces further bone formation
Additional references

Fibrosarcoma of bone
Definition / general
  • Age 40 years or older, no gender preference
  • Sites: medulla of metaphysis of long bones, usually distal femur or proximal tibia, jaw
  • Often secondary to infarct, Paget disease, radiation
  • Occasionally is multicentric, but metastatic sarcomatoid carcinoma (kidney or other sites) is more likely
Radiology description
  • Osteolytic, soap bubble appearance
  • Invasive or well defined margins depending on differentiation of tumor
Radiology images

Contributed by Mark R. Wick, M.D. and AFIP images

Humerus Xray

Radius

Prognostic factors
  • High grade cytology (10 year survival 34% versus 83% for low grade)
Treatment
  • Amputation, wide local excision
Gross description
  • Fish flesh appearance of sarcomas
  • May destroy cortex and extend into soft tissue
Gross images

AFIP images

Well circumscribed tumor

Microscopic (histologic) description
  • Resembles soft tissue fibrosarcoma with herringbone pattern of spindle cells with variable anaplasia
  • No malignant osteoid
  • Classify as malignant fibrous histiocytoma if prominent pleomorphism
  • Well differentiated tumors are hypo- or hypercellular with mitotic figures and atypia
  • High grade tumors have more hyperchromasia and mitotic figures
  • May have small cells simulating Ewing / PNET
  • Other variants are sclerosing epithelioid and myofibroblastic
Microscopic (histologic) images

Contributed by Mark R. Wick, M.D. and AFIP images

Various images

Well differentiated

Grade 2

Grade 3


Fibrous dysplasia
Definition / general
  • Benign fibro-osseous lesion that may involve one (monostotic) or multiple (polyostotic) bones
  • Developmental disorder of bone resulting in the failure to form mature lamellar bone
  • Mass forming developmental defect composed of woven bone and fibroblast-like spindle cells
  • Caused by failure in bone maturation, with arrest as woven bone (see Pathophysiology)
  • Associated clinical or syndromic manifestations (see Clinical features)
Essential features
  • Slow growing expansion of bone, composed of a proliferation of irregular woven bone trabeculae lacking conspicuous osteoblastic rimming, within a background of fibrous tissue with cytologically bland spindle cells
  • Intramedullary lesions without cortical destruction
  • May be congenital or hereditary (but differs from cherubism)
Terminology
  • Historically, osteitis fibrosa or generalized fibrocystic disease of bone (both terms not conventionally used)
  • 2 basic clinical forms: monostotic and polyostotic
ICD coding
  • ICD-10:
    • M85.00 - fibrous dysplasia (monostotic), unspecified site
    • Q78.1 - polyostotic fibrous dysplasia of bone
  • ICD-11:
    • FB80.0 - fibrous dysplasia of bone
Epidemiology
Sites
  • Can affect any bone; however, involvement of the spine is very rare (J Orthop Case Rep 2014;4:73)
  • Monostotic forms are more common in ribs, craniofacial bones (maxilla > mandible) and femur
  • Polyostotic forms frequently affects lower extremities and pelvis
Pathophysiology
  • Arrest in development of cortical bone, leading to lesions composed of irregular woven bone and immature fibroblast-like spindle cells
  • Gain of function mutations in GNAS (guanine nucleotide-binding protein / α-subunit), located in 20q13.2-3, lead to overexpression of Gsα protein and increased downstream adenyl cyclase activity (Appl Immunohistochem Mol Morphol 2016;24:660)
  • Activation of c-jun, c-fos and Wnt/β-catenin are associated with activation of Gsα protein
  • Variable expression of GNAS mutations may explain the variability in clinical manifestations
Clinical features
  • Can be associated with McCune-Albright syndrome (endocrine abnormalities, café au lait spots) or Mazabraud syndrome (soft tissue myxomas)
  • Transformation into sarcoma is extremely rare but has been reported, typically decades after initial diagnosis (J Formos Med Assoc 2004;103:711)
  • Unilateral painless swelling of mandible or maxilla in men / women ages 25 - 35 years
Diagnosis
  • Radiologic imaging (plain Xray films, CT scan) and biopsy
  • Usually diagnosed by age 20 years
Laboratory
  • Alkaline phosphatase can be elevated in certain cases, especially when tumor is growing
  • Endocrine abnormalities (gonads, thyroid) can be seen in patients with McCune-Albright syndrome
Radiology description
  • Ill defined margins; diffusely radiopaque with ground glass image
  • Single or multiple well circumscribed intramedullary lesions with a sclerotic rim
  • May see cortical thinning as lesion expands
  • Centered in metaphysis or diaphysis
  • Radiolucent or ground glass appearance on Xray (Dorfman and Czerniak: Bone Tumors, 2nd Edition, 2015)
Radiology images

Contributed by Jose G. Mantilla, M.D., Mark R. Wick, M.D. and AFIP images
Femur

Femur

Missing Image

Femur coronal

Missing Image

Mandible

Missing Image

Femur

Missing Image

Ulna

Missing Image

Expanded rib

Prognostic factors
  • Unknown
Case reports
Treatment
  • No treatment since growth is self limited and responsive to pubertal hormonal changes
  • Usually conservative / symptomatic management
  • Surgery in cases with fracture or bony deformity
    • Surgical recontouring performed if facial deformity, although may regrow in 25%
Clinical images

Images hosted on other servers:
Missing Image

Craniofacial lesions

Missing Image

Buccal protrusion

Gross description
Gross images

Contributed by Jose G. Mantilla, M.D. and AFIP images
Missing Image

Bone lesion

Missing Image

Expanded rib

Missing Image

Expanded lesion of calvarium

Microscopic (histologic) description
  • Branching and anastomosing irregular trabeculae of woven bone ("C" and "S" shapes) with no conspicuous osteoblastic rimming
  • No / rare osteoclasts
  • Intervening fibrous stroma containing cytologically bland spindle cells, without prominent cytologic atypia
  • Mitotic figures rare
  • Stromal changes, including myxoid change and fatty metaplasia, may be seen in some cases (BMC Musculoskelet Disord 2003;4:20)
  • Secondary aneurysmal bone cyst-like changes may also be seen (Turk Patoloji Derg 2018;34:234)
  • Fibrocartilaginous dysplasia: uncommon variant containing variable proportions of cartilaginous differentiation and enchondral ossification (Am J Surg Pathol 1993;17:924)
  • Growing collagen (Sharpey's fibers) may form perpendicular to the sites of bone formation but are not essential for diagnosis (Oral Dis 2017;23:697)
Microscopic (histologic) images

Contributed by Jose G. Mantilla, M.D., Kelly Magliocca, D.D.S., M.P.H. and @JMGardnerMD on Twitter

Irregular trabeculae

Stromal cells

Aneurysmal bone cyst

Fibrous dysplasia

Fibrous dysplasia


Fibrous dysplasia Fibrous dysplasia

Fibrous dysplasia

Fibrous dysplasia Fibrous dysplasia

Fibrous dysplasia

Fibrous dysplasia

Fibrous dysplasia

Positive stains
Negative stains
Molecular / cytogenetics description
Sample pathology report
  • Right tibia, biopsy:
    • Benign fibro-osseous proliferation, consistent with fibrous dysplasia
Differential diagnosis
Board review style question #1
    What is the underlying genetic mutation in patients with McCune-Albright syndrome?

  1. GNAS1
  2. p53
  3. PTH1R
  4. SDH
Board review style answer #1
A. Mutations in GNAS1 are seen in patients with McCune-Albright and Mazabraud syndrome

Comment Here

Reference: Fibrous dysplasia
Board review style question #2

    Histologically, fibrous dysplasia frequently shows

  1. Lamellar bone trabeculae
  2. Numerous mitotic figures
  3. Osteoblastic rimming
  4. Woven bone trabeculae
Board review style answer #2
D. Woven bone trabeculae. The trabeculae in fibrous dysplasia are composed of woven bone with various phases of mineralization. Mature lamellar bone can be seen at the periphery but should not be part of the lesion itself.

Comment Here

Reference: Fibrous dysplasia

Fracture
Definition / general
  • Fracture is a partial or complete break in bone
Essential features
  • Fracture is a break in bone
  • There are many types of fracture, including complete, incomplete, open, closed, comminuted and avulsion, among others
  • Fracture healing occurs in multiple stages including hematoma formation, inflammation, soft callus formation, hard callus formation and remodeling
Terminology
  • Complete fracture occurs when the bone is broken into separate pieces
  • Open (or compound) fracture occurs when the bone breaks through the skin
  • Closed (or simple) fracture occurs when the bone is broken but the skin remains intact
  • Other descriptions or types of fracture include
    • Displaced (ends of bone are not aligned)
    • Greenstick (incomplete fracture where a portion of bone is broken, causing the other side to bend)
    • Transverse (break in a straight line across the bone), commonly associated with Paget disease and osteopetrosis
    • Spiral (break spirals around bone, common in twisting injury)
    • Oblique (break is diagonal across bone)
    • Compression (bone is crushed)
    • Comminuted (bone broken in 3 or more places with many fragments present)
    • Segmental (bone broken in 2 places with floating piece of bone)
    • Avulsion (fragment of bone breaks where ligament or tendon inserts)
ICD coding
  • ICD-10: M84.40XA - pathological fracture, unspecified site, initial encounter for fracture
Epidemiology
  • Osgood-Schlatter disease is an enthesopathy, which rarely results in an avulsion fracture at the tibial tubercle, that occurs in young children (age: 10 - 15 years) and represents the most common cause of knee pain in adolescents
  • Stress fractures involving the tibial shaft are common in long distance runners and ballet dancers, while those involving the second or third metatarsal bones often occur in military trainees
  • Osteogenesis imperfecta is a rare condition that predisposes bone to fracture
  • Women over the age of 50 with low bone mineral density are at increased risk for fracture (Injury 2006;37:691, Lancet Healthy Longev 2021;2:e580, Osteoporos Int 2005:16:S3)
  • Weight bearing exercise and a diet rich in calcium and vitamin D is protective and promotes bone health
  • Risk factors in female athletes include body mass index (BMI) < 19, late menarche (≥ 15 years) and participation in lean sports (Med Sci Sports Exerc 2013;45:1843)
Sites
  • Common fracture sites in children include the distal radius, supracondylar elbow and clavicle
  • Fractures involving the epiphyseal plate or physis represent between 15% and 18% of all pediatric fractures (Clin Orthop Relat Res 2016;474:2531)
  • Physeal fractures are classified using the Salter-Harris classification system (types I - V) based on the fracture pattern through the growth plate
  • Certain fracture types may raise concern for potential child abuse, including multiple fractures at different healing stages, femur fractures in nonwalking children, bucket handle fractures and fractures affecting the skull, ribs, scapula and ulna (Dtsch Arztebl Int 2018;115:769, BMJ 2008:337:a1518)
  • Avulsion fractures most commonly occur around the pelvis, particularly at the origin of the adductor muscles along the inferior pubic ramus and lower thigh where the adductor inserts
Pathophysiology
Etiology
  • Usually caused by trauma (e.g., falls, car accidents, sports injuries)
  • Most pediatric fractures result from falls during sports and play (Acta Orthop 2010;81:148)
  • Torus (or buckle) fracture is an incomplete fracture of the radius, ulna or both, commonly occurring due to a fall in a young child where the wrist absorbs the impact of the fall
  • Repetitive forces (e.g., long distance running, marching, ballet dancing) increase the risk of stress fracture
  • Pathologic fractures occur when bone is broken through an area weakened by preexisting disease by a degree of stress that would have left normal bone intact (e.g., osseous metastasis, multiple myeloma, osteoporosis)
  • Avulsion fractures occur from repeated trauma at sites of ligamentous and tendinous insertions
Diagrams / tables

Images hosted on other servers:
Types of bone fracture

Types of bone fracture

Fracture Healing

Fracture healing

Salter-Harris Classification System of Physeal Fractures

Salter-Harris classification of physeal fractures

Clinical features
  • Sudden and intense pain (Emerg Radiol 2016;23:365)
  • Visible bone deformity
  • Inability to move or put weight on limb
  • Swelling, bruising and bleeding
Diagnosis
  • Complete medical history (including description of injury)
  • Bone deformity may be evident on physical examination
  • Fracture confirmed on imaging studies (e.g., Xray, computerized tomography [CT], magnetic resonance imaging [MRI])
  • Careful correlation of all available clinical, radiologic and pathologic features of each case is essential (Am J Clin Pathol 1969;52:14)
Laboratory
  • In setting of delayed union, often check erythrocyte sedimentation rate (ESR), C reactive protein (CRP), vitamin D, calcium, thyroid and parathyroid hormone levels and HbA1c
  • In setting of pathologic fracture, often check CBC, BMP, serum protein electrophoresis (SPEP), PSA and other tumor markers (in addition to imaging with CT of chest / abdomen / pelvis)
Radiology description
  • Radiographs are first line modality (Emerg Radiol 2016;23:365)
  • Plain radiographs can show periosteal thickening, lucency and a discrete fracture line
  • CT can be useful in detecting occult fractures
  • MRI highlights periosteal edema, bone marrow and intracortical signal abnormality associated with fracture (Emerg Radiol 2016;23:365)
  • Radionuclide bone scans can detect stress injuries as soon as 2 - 8 days after symptoms (Radiology 1979;132:431)
  • Excessive callus formation with periosteal new bone formation may be mistaken for a bone forming tumor
Radiology images

Images hosted on other servers:
CT left ankle, sagittal view

CT of left ankle, sagittal view

Xray of distal femur

Xray of distal femur

CT of scaphoid, coronal view

CT of scaphoid, coronal view

Xray of mid tibia

Xray of mid tibia


Xray of mid leg fracture

Xray of mid leg fracture

Xray of femoral fracture

Xray of femoral fracture

Xray of humerus fracture

Xray of humerus fracture

Prognostic factors
  • Fracture takes several weeks to months to heal, depending on the severity and extent of the injury
  • Children’s thicker and more metabolically active periosteum accelerates healing and remodeling, requiring earlier treatment (StatPearls: Greenstick Fracture [Accessed 9 November 2023])
  • Physeal fractures may cause growth disturbances, limb length differences, angular deformities and occasionally delayed union or nonunion
  • Poor nutritional status can impede fracture healing
  • Caffeine, alcohol and tobacco negatively impact healing process (Am J Prev Med 2000;18:96)
  • Chronic nonunion of fracture site can lead to pseudoarthrosis
  • Increased callus formation occurs in unstable areas
  • Fractures may not heal due to improper immobilization, devascularization of bone fragments, persistent infection or interposition of soft tissue between ends of bone
Case reports
Treatment
  • Splint or cast to immobilize the injured area
  • Medication for pain control
  • Traction to align the broken bone
  • Debridement and lavage of open fracture (Chin J Traumatol 2018;21:187)
  • Surgery with internal (metal rods or pins inside the bone) or external (metal rods or pins outside the body) fixation (Radiographics 2003;23:1569)
  • Physical therapy to regain strength and mobility
Clinical images

Images hosted on other servers:
53 year old man with open fracture of tibia

53 year old man with open fracture of tibia

External fixation of fracture

External fixation of fracture

Segmental fracture of tibia

Segmental fracture of tibia

Open Fracture

Open fracture

Bruising in Broken Arm

Bruising in broken arm

Gross description
  • Visibly deformed or misshapen bone or joint
  • Exposed bone visible through skin in open fracture (Chin J Traumatol 2018;21:187)
  • Associated tumor may be present in pathologic fracture
  • Bone enlargement at the fracture site is evident during callus formation
Frozen section description
  • Fragments of reactive bone (may be difficult to cut)
  • Background of hemorrhage, fibrin and inflammatory cells
  • Lack of atypia
  • Fracture may impact the reliability of frozen section assessment of periprosthetic joint infection (Hip Int 2022;32:87)
Frozen section images

Contributed by Laura Warmke, M.D.
Reactive bone

Reactive bone

Fibrin

Fibrin

Hemorrhage

Hemorrhage

Inflammatory Cells

Inflammatory cells

Lack of atypia

Lack of atypia

Abundant hemorrhage

Abundant hemorrhage

Microscopic (histologic) description
  • First few days (< 3 days): organizing hemorrhage, edema, hematoma with neovascularization, acute inflammatory cells, necrotic bone (empty lacunae) adjacent to fracture site (Semin Diagn Pathol 2011;28:102)
  • 3 - 7 days: granulation tissue, reactive fibroblasts, tissue culture appearance (Semin Diagn Pathol 2011;28:102)
  • Fine wisps of bone present by 7 days and definite osteocartilaginous differentiation by 10 days (Semin Diagn Pathol 2011;28:102)
  • 1 - 2 weeks: proliferating fibrovascular tissue, increased cellularity, islands of immature bone and cartilage, disordered organization
  • 2 - 3 weeks onwards: anastomosing trabeculae of woven bone rimmed by prominent osteoblastic cells
  • Mixture of hyaline cartilage, woven and lamellar bone trabeculae in plexiform pattern with zoning
Microscopic (histologic) images

Contributed by Laura Warmke, M.D. and Mark R. Wick, M.D.
Hemorrhage

Hemorrhage

Fibrovascular stroma

Fibrovascular stroma

Fracture callus

Fracture callus

Endochondral ossification

Endochondral ossification

Hemorrhagic background

Hemorrhagic background


Woven bone Bone resorption

Woven bone

Devitalized bone

Devitalized bone

Bone resorption

Bone resorption

Bone resorption

Inflammatory cells


Fracture callus
Missing Image

Atypical cartilage component

Missing Image

Healing

Virtual slides

Images hosted on other servers:
Bone, healing fracture

Bone, healing fracture

Cytology description
  • Numerous uniform, benign looking osteoblasts and osteoclastic giant cells (Acta Cytol 2001;45:445)
  • Spindle cell clusters composed of fibroblasts
  • Small fragments of bony spicules
  • Lack of true cellular atypia
  • Hemorrhagic background
Videos

Common types of bone fracture

How do broken bones heal?

Sample pathology report
  • Bone and soft tissue, right tibia, biopsy:
    • Fracture callus (see comment)
    • Comment: This biopsy contains fragments of reactive bone admixed with benign hyaline cartilage and fibrovascular stroma with scattered inflammatory cells. Prominent osteoblastic rimming is present along the trabeculae of immature woven bone. No marked cytologic atypia and no evidence of malignancy is identified.
Differential diagnosis
  • Osteosarcoma:
    • Overt pleomorphism present
    • Frequent and atypical mitotic figures
    • Lace-like tumor osteoid production without osteoblastic rimming
    • Infiltrative borders that entrap preexisting bone
    • Lacks history of trauma or vigorous exercise
    • Lacks zonal distribution of fracture callus
  • Osteoid osteoma / osteoblastoma:
    • Composed of irregular woven bone
    • Cartilaginous matrix and fibrous component with granulation tissue missing
    • May mimic stress fracture on imaging; however, lucent nidus of osteoid osteoma is typically round instead of linear
  • Fibrosarcoma:
    • High grade sarcoma with fibroblastic differentiation
    • Fascicles of pleomorphic, spindle shaped cells with fascicular growth pattern
    • Atypical mitotic figures common
  • Fibrous dysplasia:
    • Woven bone trabeculae randomly arranged and curvilinear
    • Inconspicuous osteoblastic rimming
    • Spindle cells are arranged in storiform pattern
    • No / rare osteoclasts
  • Chondrosarcoma:
    • Infiltrating growth pattern encasing preexisting bone
    • Frequent myxoid change present (grade 2)
    • Neoplastic chondrocytes have varying degrees of cytologic atypia
  • Aseptic bone necrosis:
    • Usually occurs in younger patients
    • Wedge shaped infarction
    • Total necrosis of bone trabeculae and bone marrow
Board review style question #1

Fracture healing and repair occurs through multiple stages that mimic the natural development of the skeletal system. What is the appropriate chronological order of the different stages of fracture repair?

  1. Hard callus, soft callus, inflammation, remodeling, hematoma
  2. Hematoma, inflammation, soft callus, hard callus, remodeling
  3. Remodeling, hematoma, inflammation, hard callus, soft callus
  4. Soft callus, hematoma, remodeling, inflammation, hard callus
Board review style answer #1
B. Hematoma, inflammation, soft callus, hard callus, remodeling. Fracture healing starts when a hematoma forms between the 2 ends of bone, creating a fibrin mesh that seals the site. Next, tissue damage leads to inflammation and the activation of wound healing pathways. Chondroblasts and fibroblasts create a soft callus and new bone eventually replaces the soft callus with a hard callus. Lastly, remodeling leads to bone resorption and lamellar bone formation. Answers A, C and D are incorrect because the different stages of fracture repair are not listed in the appropriate chronological order as listed in answer B.

Comment Here

Reference: Fracture
Board review style question #2
Osgood-Schlatter disease may rarely result in which of the following types of fracture?

  1. Avulsion fracture
  2. Bucket handle fracture
  3. Greenstick fracture
  4. Open (compound) fracture
Board review style answer #2
A. Avulsion fracture. Osgood-Schlatter disease is an enthesopathy, which rarely results in an avulsion fracture of the tibial tubercle. It usually affects young, active adolescents experiencing growth spurts and frequently presents as anterior knee pain. Answer D is incorrect because an open (compound) fracture is associated with trauma and results in the fractured bone poking through the skin. Answer C is incorrect because a greenstick fracture is an incomplete fracture that frequently occurs in young children after a fall. Answer B is incorrect because a bucket handle fracture is a metaphyseal corner fracture that is associated with child abuse and nonaccidental injury.

Comment Here

Reference: Fracture

Ganglion cyst
Definition / general
Terminology
ICD coding
  • ICD-10: M67.40 - ganglion, unspecified site
Epidemiology
  • 60 - 70% of the soft tissue masses in the hand and wrist (StatPearls: Ganglion Cyst [Accessed 2 March 2021])
  • F:M = 3:1
  • Can occur at any age
  • Most common: 20 - 50 years
  • Risk factors:
    • Repetitive microinjuries due to overuse of the joint
    • Previous traumas
Sites
  • Dorsal aspect of the wrist, from the scapholunate ligament or scapholunate articulation → 70%
  • Volar aspect of the wrist, from the radiocarpal joint or scaphotrapezial joint → 20%
  • Distal interphalangeal joint, hip, knee, ankle, foot, others → 10%
  • Some studies found the volar location to be more common than the dorsal (J Ultrasound Med 2019;38:2155)
Pathophysiology
  • Cystic fluid analysis: gelatinous material containing mainly hyaluronic acid and lesser amounts of glucosamine, globulins and albumen (Curr Rev Musculoskelet Med 2008;1:205)
  • Since no epithelial lining exists in these structures, they should not be classified as true cysts
Etiology
  • Unclear
  • Numerous theories (Curr Rev Musculoskelet Med 2008;1:205):
    • Displacement of synovial tissue during embryogenesis
    • Herniation of synovial capsule / fluid from joints into the surrounding tissues → reaction between fluid and local tissue results in the creation of the cyst
    • Proliferation of pluripotential mesenchymal cells
    • Myxoid degeneration of connective tissue after trauma: repetitive injury to the capsular and ligamentous structures → production of hyaluronic acid from fibroblasts → accumulation of mucin jelly-like material to form the cyst (most likely)
    • Inflammatory etiology
Clinical features
Clinical images

Images hosted on other servers:

Dorsal wrist ganglion

Ganglion: intraoperative view

Volar wrist ganglion

Diagnosis
  • Clinical presentation is usually adequate for diagnosis
  • Cyst typically transilluminates on the exam
  • Ultrasound is used for a definitive diagnosis
  • MRI is useful to rule out a possible solid tumor or in case of occult dorsal ganglion cyst (which is not clinically observed or palpated but is found on imaging studies or intraoperatively) (J Wrist Surg 2019;8:276)
Radiology description
Radiology images

Images hosted on other servers:

Ultrasound: dorsal wrist ganglion

MRI: volar wrist ganglion

Prognostic factors
  • Benign condition
  • Prognosis for most patients is excellent
  • Ganglion cysts spontaneously recede in more than half of patients (ISRN Orthop 2013;2013:940615)
  • Recurrence rate is approximately 10 - 15% after surgery (Adv Clin Exp Med 2019;28:95)
    • Recurrence after surgery is unpredictable and independent of patient demographic factors or surgical techniques
  • Aspiration has higher rates of recurrence (ISRN Orthop 2013;2013:940615)
Case reports
Treatment
  • Indications for treatment include pain, stiffness, weakness and cosmetic appearance (J Hand Surg Am 2015;40:546)
  • Three general treatment approaches:
    • Observation
    • Aspiration: often combined with some form of injection, electrocautery or multiple puncture
    • Excision: open or arthroscopic
Gross description
Gross images

Images hosted on other servers:

Ganglion

Microscopic (histologic) description
  • Uni or multilocular cystic structure
  • Dense collagenous walls with foci of myxoid changes (Lindberg: Diagnostic Pathology - Soft Tissue Tumors, 2nd Edition, 2015)
  • No true epithelial lining
  • Lumen may contain myxoid fluid
  • There is no nuclear atypia or mitotic activity
  • Inflammation / hemorrhage may be observed if the cyst has previously been ruptured
Microscopic (histologic) images

Contributed by Serenella Serinelli, M.D., Ph.D.
Unilocular ganglion cyst

Unilocular ganglion cyst

Cyst wall and content

Cyst wall and content

Multilocular ganglion cyst

Multilocular ganglion cyst

Myxoid changes

Myxoid changes

Absence of synovial lining

Absence of synovial lining

Virtual slides

Images hosted on other servers:

Ganglion cyst

Cytology description
  • Aspiration of a ganglion can be used as a preoperative diagnostic tool or a therapeutic procedure
  • Paucicellular myxoid material that contains scattered / clustered histiocytes (Am J Clin Pathol 2005;123:858)
  • Myxoid material of the cyst usually forms thick folds on the slide
Cytology images

Images hosted on other servers:
Ganglion cyst mucoid material

Ganglion cyst mucoid material

Histiocytes in ganglion cyst

Histiocytes in ganglion cyst

Electron microscopy description
  • Wall is composed of randomly oriented sheets of collagen arranged in loose layers
  • Rare cells are present in the collagen sheets and appear to be fibroblasts or mesenchymal cells (Curr Rev Musculoskelet Med 2008;1:205)
Videos

Ganglion cyst features

Sample pathology report
  • Soft tissue, left dorsal wrist, excision:
    • Ganglion cyst
Differential diagnosis
  • Myxoma:
    • Lobulated, gelatinous cut surfaces
    • Most commonly occurring within large muscles (thigh, shoulder, upper arm)
  • Low grade myxofibrosarcoma:
    • Multinodular cut surfaces
    • At least focal nuclear atypia
    • Conspicuous, elongated, curvilinear, thin walled blood vessels are characteristic
    • Most common in subjects older than 50
  • Neurofibroma:
    • Absence of cystic spaces
    • S100+
Board review style question #1

40 year old woman presents with a superficial lesion over the dorsal wrist. The lesion is excised and displays a cystic appearance. The histology is shown above. What is one of the main features of this condition?

  1. Cyst shows no true epithelial lining
  2. Invariably consists of a unilocular cyst
  3. Marked cellular atypia is seen
  4. Mitoses are frequent
  5. Rare condition
Board review style answer #1
A. Cyst shows no true epithelial lining

Comment Here

Reference: Ganglion
Board review style question #2
Which of the following statements is true regarding ganglion cysts?

  1. More common among females
  2. More common in the pediatric population
  3. Myxoid changes in the cyst wall are never observed
  4. Nuclear atypia is required for the diagnosis
  5. Rarely found in the hand / wrist area
Board review style answer #2
A. More common among females

Comment Here

Reference: Ganglion

Giant cell tumor of bone, NOS
Definition / general
  • Giant cell tumor of bone (GCTB) is a locally aggressive and rarely metastasizing neoplasm composed of neoplastic mononuclear stromal cells admixed with macrophages and osteoclast-like giant cells
  • A small subset of cases are malignant
Essential features
  • Bone tumor with compatible imaging
  • Osteolytic circumscribed tumor involving the epiphysis and metaphysis, generally in skeletally mature individual
  • Mononuclear cell neoplastic component without atypia together with numerous osteoclasts
  • Detection of H3.3 pGly34 mutated cells / H3.3 pGly34Trp (G34W) immunoreactivity
Terminology
  • Not recommended: osteoclastoma
ICD coding
  • ICD-10: 9250/1 - giant cell tumor of bone NOS
  • ICD-11: 2F7B & XH4TC2 - neoplasms of uncertain behavior of bone or articular cartilage & giant cell tumor of bone NOS
Epidemiology
Sites
Pathophysiology
  • GCTB related clonal aberrations occur in a background of epigenetic histone modifications (especially the G34W mutation of H3F3A gene) (Hum Pathol 2018;81:1)
  • Neoplastic mononuclear stromal cells in GCTB express receptor activator of NFκβ ligands (RANKLs) and various chemokines and cytokines associated with monocyte recruitment and reactive multinucleated giant cells (osteoclastogenesis) (Hum Pathol 2018;81:1)
  • Activation of Wnt / beta catenin pathway in GCTB tumorigenesis (Pathol Res Pract 2009;205:626)
  • Clonal telomeric associations (tas) were found in GCTB (Genes Chromosomes Cancer 2009;48:583)
  • Transformation to malignancy may occur after therapeutic irradiation (Indian J Pathol Microbiol 2002;45:273)
  • TP53 and HRAS mutations have been identified in malignant GCTB not associated with prior radiation (Histopathology 2001;39:629)
Etiology
Diagrams / tables

Images hosted on other servers:

Anatomical distribution

Clinical features
Diagnosis
  • In many cases, the diagnosis of GCTB is suggested by the tumor location and appearance on Xray, computed tomography and magnetic resonance scans
  • A definitive diagnosis usually requires a biopsy
Radiology description
  • Typical appearance of GCTB is best demonstrated on conventional radiographs, which show a lytic lesion that has a well defined but nonsclerotic margin, is eccentric in location, extends to the subchondral bone and occurs in patients with closed physes (Radiographics 2013;33:197)
  • CT and MR imaging allow superior delineation of GCTB
  • Cortical thinning of bone is invariably apparent at radiography performed at clinical presentation (Radiographics 2001;21:1283)
  • Expansile remodeling of bone is also frequently seen (47 - 60% of cases)
  • Cortical penetration is seen in 33 - 50% of cases, often with an associated soft tissue mass (Radiographics 2001;21:1283)
  • Aneurysmal bone cyst components in GCTB are relatively common (14% of lesions)
  • Campanacci et al classified the GCTB into 3 grades, depending on their radiographic appearance:
    • Grade 1 lesion (latent) has a well defined margin and an intact cortex (J Bone Joint Surg Am 1987;69:106)
    • Grade 2 lesion (active) has a relatively well defined margin but no radiopaque rim and the cortex is thinned and moderately expanded
    • Grade 3 lesion (aggressive) has indistinct borders and cortical destruction
  • It has been suggested that the Campanacci classification scheme may more easily guide treatment; however, it is doubtful whether this classification accurately predicts the aggressiveness of GCTB (SICOT J 2017;3:54)
  • No correlation exists between the grading system and incidence of local recurrence and metastases (SICOT J 2017;3:54, Int Orthop 2012;36:2521)
Radiology images

Contributed by Borislav A. Alexiev, M.D.
Lytic lesion

Lytic lesion

Expansile solid lesion

Expansile solid lesion

Mass with extraosseous component

Mass with extraosseous component

Prognostic factors
  • Pulmonary metastasis in ~2% of cases; they are very slow growing (nonaggressive) and may spontaneously regress; metastases have same morphology as the bone lesion (Pathol Int 1998;48:723)
  • Local recurrence, a high Campanacci grade and curettage are possible high risk factors for pulmonary metastasis (J Bone Oncol 2017;7:23)
  • Secondary malignancy in giant cell tumor of bone (arising after treatment of a benign giant cell tumor) has a poor prognosis, akin to other high grade sarcomas and much worse than primary malignancy in giant cell tumor of bone (Cancer 2003;97:2520)
Case reports
Treatment
Clinical images

Images hosted on other servers:

Right proximal humerus tumor

Gross description
  • Typical gross lesion is a soft, friable, slightly brownish or red-tan, somewhat poorly defined neoplasm in the end of a long bone (AJR Am J Roentgenol 1985;144:955, Arch Bone Jt Surg 2016;4:2, Diagn Pathol 2014;9:111)
  • Yellow and firm white areas corresponding to xanthomatous change and fibrous tissue are common
  • Surrounding cortex is often thinned and may be destroyed completely
  • Destructive tumors may extend into soft tissue
  • Subchondral bone plate can be focally involved
  • Extensive cystic hemorrhagic areas corresponding to aneurysmal bone cyst-like changes may be seen
  • Cut surface of malignant GCTB is typically firm and fleshy
Gross images

Contributed by Borislav A. Alexiev, M.D. and Mark R. Wick, M.D.
Left distal femur lesion

Left distal femur lesion

Distal femur

Distal femur

Frozen section description
  • Highly cellular lesion composed of large number of osteoclast-like giant cells, between which mononuclear cells are embedded (Int Orthop 2006;30:484, Diagn Pathol 2014;9:111)
  • Due to the complex histological composition of GCTB, differential diagnosis is required to exclude the diagnosis of other lesions also containing giant cells, such as aneurysmal bone cyst, nonossifying fibroma, chondroblastoma, brown tumor of hyperparathyroidism and giant cell rich osteosarcoma (Int Orthop 2006;30:484)
  • In addition to the histological findings, precise details regarding age, localization and radiology findings within the framework of GCTB differential diagnosis is vital (Int Orthop 2006;30:484)
Microscopic (histologic) description
Microscopic (histologic) images

Contributed by Borislav A. Alexiev, M.D.
Osteoclasts-rich bone lesion

Osteoclasts-rich bone lesion

Typical features

Typical features

Reactive bone formation

Reactive bone formation

Aneurysmal change

Aneurysmal change

Neoplastic mononuclear cells

Neoplastic mononuclear cells

Residual tumor

Residual tumor


Depletion of giant cells

Depletion of giant cells

Reactive bone formation

Reactive bone formation

Complete response with hemorrhage

Complete response with hemorrhage

Spindle cell proliferation

Spindle cell proliferation

Complete response with fibrosis

Complete response with fibrosis

G34W IHC

G34W IHC


p63 IHC

p63 IHC

Cytology description
  • Smear preparations demonstrate oval to spindled mononuclear cells in cohesive clusters bordered by multiple multinucleated giant cells (Cancer Cytopathol 2018;126:552, Diagn Cytopathol 2004;30:14)
  • Mononuclear cells have spindled or plump cell bodies with moderate amounts of cytoplasm and well defined cytoplasmic membranes; oval nuclei demonstrate fine, evenly distributed chromatin and small nucleoli
  • Multinucleated cells are osteoclast-like and are associated with clusters of mononucleated cells or lying freely
  • They have a well demarcated cytoplasm and contain from a few to several dozen monomorphic nuclei (Diagn Cytopathol 1985;1:111)
Cytology images

Contributed by Lucy Jager, M.D.
Cellular smears

Cellular smears

Mononuclear and MGCs

Mononuclear and MGCs

Electron microscopy description
Molecular / cytogenetics description
Sample pathology report
  • Left distal femur, curettage:
    • Giant cell tumor of bone (see comment)
    • Comment: Radiology images of the left femur demonstrates a 5.2 x 5.9 x 5.2 cm expansile heterogeneous mass centered in the lateral femoral condyle. There is cortical breakthrough and an extraosseous component along the posterosuperior margin. Histologically, the neoplasm is cellular and composed of a large number of osteoclast-like giant cells, between which mononuclear round to oval cells and spindled cells with pale eosinophilic cytoplasm and nuclei with dispersed chromatin and small nucleoli are embedded. Scattered mitotic figures and no necrosis are seen (11 mitoses / 10 high power fields). There are aneurysmal change, clusters of hemosiderophages and fibrosis. The cortical bone is focally destroyed and replaced by a reactive rim of woven bone at the tumor periphery. Immunohistochemical stains for H3.3 G34W and p63 are positive in mononuclear cells. Overall, the appearance on computed tomography and magnetic resonance scans, morphological features and immunohistochemical profile support the diagnosis of giant cell tumor of bone.
    • Giant cell tumor of bone can be locally aggressive and it has a propensity to recur locally after curettage alone. Furthermore, in approximately 3 - 7% of cases, distant metastases occur, most often to the lungs.
Differential diagnosis
Board review style question #1

A 31 year old man presented with a left distal femur metadiaphyseal expansile, predominantly solid, enhancing lesion measuring 6.6 cm in greatest dimension. There is medial distal femur diffuse cortical thinning overlying the lesion and periosteal edema and enhancement. No convincing extraosseous component is seen.

Hematoxylin eosin stains demonstrate a cellular lesion composed of a large number osteoclast-like giant cells, between which mononuclear cells are embedded. The mononuclear cells exhibit a variety of morphological appearances, including round to oval cells and spindled cells with pale eosinophilic cytoplasm and nuclei with dispersed chromatin and small nucleoli. Scattered mitotic figures and no necrosis are seen (7 mitoses / 10 high power fields). There is reactive woven bone formation, aneurysmal changes with hemosiderin deposition and fibrosis. The cortical bone is eroded; however, there is no complete cortical bone destruction. Immunohistochemical stains for H3.3 G34W and p63 are positive in mononuclear cells. P53 expression is wild type (no mutation).

Which of the following is most likely the correct diagnosis?

  1. Aneurysmal bone cyst
  2. Chondroblastoma
  3. Giant cell tumor of bone
  4. Osteoblastoma
  5. Osteosarcoma
Board review style answer #1
C. Giant cell tumor of bone

Comment Here

Reference: Giant cell tumor of bone
Board review style question #2
Which of the following is true about giant cell tumor of bone (GCTB)?

  1. GCTB is composed of neoplastic osteoclast-like giant cells and nonneoplastic mononuclear stromal cells
  2. GCTB is positive for HG34W
  3. GCTB is positive for HK36M
  4. GCTB treated with denosumab shows a striking increase of osteoclast-like giant cells
  5. GCTB typically affects the diaphysis of long bones
Board review style answer #2
B. GCTB is positive for HG34W

Comment Here

Reference: Giant cell tumor of bone

Giant cell tumor of bone, malignant

Gout and gouty arthritis
Definition / general
  • Gout is a metabolic disorder that affects joints, bones, skin and soft tissues
  • Associated with hyperuricemia, which causes saturation of monosodium urate and eventual formation of crystals within tissue (Nat Rev Rheumatol 2020;16:380)
Essential features
  • Gout is the most common inflammatory arthritis
  • Monosodium urate crystals induce an acute neutrophil mediated inflammatory reaction in joint fluid, and a macrophage and giant cell reaction in other tissues
  • Crystal induced inflammation leads to acute, severe, self limiting joint pain
  • Can present as acute or chronic arthritis or tophaceous gout
  • Recurrent arthropathy becomes destructive
  • Risk of gout increases with age, obesity, hypertension and diuretic use (Arthritis Res Ther 2018;20:136)
Terminology
  • Acute gout
  • Gout attack
  • Gout flare
  • Podagra
  • Chronic gout with tophi
  • Chronic tophaceous gout
ICD coding
  • ICD-10:
    • M10.9 - gout, unspecified
    • M1A.9XX1 - chronic gout, unspecified, with tophus (tophi)
    • M1A.9XX0 - chronic gout, unspecified, without tophus (tophi)
Epidemiology
Sites
  • Involves lower extremities: first metatarsophalangeal joint (most common), midfoot, ankle and knee (Best Pract Res Clin Rheumatol 2010;24:811)
  • Late involvement of other joints including joints of upper extremities
  • Axial joint involvement is less common
  • Most common sites of deposition include periarticular soft tissue with involvement of bursae, tendons and ligaments
  • Tophi commonly involve olecranon bursa and Achilles tendon
  • Can affect other organs and viscera (BMC Musculoskelet Disord 2019;20:140)
  • Skin ulceration can be present
Pathophysiology
  • Core mechanism for pathogenesis of gout is an augmented serum level of uric acid following a reduced renal excretion (Int J Cardiol 2016;213:8)
  • Uric acid is the end product of exogenous and endogenous purine
  • Exogenous pool depends upon dietary intake, increased by foods like animal proteins
  • Endogenous production of uric acid is mainly from the liver, intestines and other tissues, like muscles, kidneys and the vascular endothelium (Cardiorenal Med 2013;3:208)
  • At physiologic pH, uric acid is a weak acid and exists mainly as urate, the salt of uric acid
  • As urate concentration increases in blood, uric acid crystal formation increases
  • When the level of uric acid becomes higher than 6.8 mg/dL, crystals of uric acid form as monosodium urate (MSU) (J Cardiol 2021;78:51)
  • MSU crystals are needle shaped crystals, targeted for consumption by neutrophils and monocytes
  • Inflammatory response is initiated via the release of interleukin 1 (IL1) and other cytokines, resulting in acute gout attack (RMD Open 2015;1:e000046)
  • Neutrophils with the ingested crystals grow closer and form a tight packing
  • This proceeds to cell death, presenting as tophaceous gout
  • High sodium content of the crystals increases intracellular sodium concentrations
  • To maintain iso-osmolarity, water enters the cell through aquaporins and induces cell swelling
  • Water also dilutes potassium, which falls below a critical level for the induction of the inflammasome
  • Activation of the inflammasome produces large amounts of interleukin 1β, resulting in chronic form
Etiology
  • Gout is caused by hyperuricemia
  • 10% of individuals with hyperuricemia develop gout
  • High intake of protein and alcohol increase risk of development
  • Hyperuricemia can be primary (90%), familial or sporadic, or secondary (10%)
  • 90% cases of primary hyperuricemia are sporadic: caused by reduced renal excretion of uric acid
  • Urate transporter dysfunctions cause urate transport disorders and hyperuricemia (Int J Mol Sci 2021;22:9221, Tohoku J Exp Med 2020;251:87)
  • Dysfunction of ABCG2 exporter causes hyperuricemia due to both renal urate underexcretion and renal urate overload (Sci Rep 2014;4:3755)
  • 10% of cases are familial: caused by inherited gene mutations like Lesch-Nyhan syndrome (J Cardiol 2021;78:51)
  • Secondary causes include pre-existing acquired or genetic disease
  • Hyperuricemia occurs due to increase in purine metabolism because of rapid cell turn over in diseases like psoriasis, myeloproliferative disorders and conditions like fasting, chemotherapy (Ann Rheum Dis 2015;74:1495, Clin Rheumatol 2001;20:288)
  • Hyperuricemia may also occur due to decreased secretion of uric acid, as in renal failure
  • Rare genetic disorders also cause high cell turn over and hyperuricemia, like certain glycogen storage diseases (Adv Skin Wound Care 2021;34:1)
Diagrams / tables

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Acute gout

Chronic tophaceous gout

Pathogenesis of gout

Clinical features
  • Presents in 3 ways: acute gout, tophaceous gout and chronic arthropathy
  • Acute gout:
    • Intermittent: presents with swelling, intense pain and soreness around joints
    • Asymptomatic period may occur between gout attacks (intercritical gout)
    • Acute flares are characterized by warmth, swelling, redness and severe pain
    • Pain tends to begin in the middle of the night or early morning
    • Fever and constitutional features such as malaise due to release of cytokines (Nature 2006;440:237)
  • Tophaceous gout:
    • Untreated cases result in soft tissue deposits, called tophi
    • Occurs almost 10 - 15 years after initial acute episode
  • Chronic arthropathy:
    • Recurrent gouty episodes result in chronic inflammatory arthropathy
    • Can cause secondary osteoarthritis
    • Phases of gout (progression):
      • Stage 1: asymptomatic hyperuricemia
        • Urate deposits directly contribute to organ damage
        • Does not occur in everyone
        • No evidence that treatment is warranted
      • Stages 2 and 3: acute gout and intercritical periods
        • Sufficient urate deposits develop around joints
        • Release of crystals is triggered into joint space by trauma, causing acute attack
        • During intercritical periods, crystals may be present at low level in the fluid
        • Crystals are also present in the periarticular and synovial tissue, providing a nidus for future attacks
      • Stage 4: advanced gout
        • Crystal deposits continue to accumulate
        • Patients develop chronically stiff and swollen joints
        • Uncommon stage, avoidable with therapy (Cleve Clin J Med 2008;75:S5)
Diagnosis
Laboratory
  • Blood tests: leukocytosis with neutrophilia, raised erythrocyte sedimentation rate (ESR), C reactive protein (CRP) and cytokines (Immunol Invest 2016;45:383)
  • Synovial fluid or bursal fluid analysis: tests include differential white cell count, examination of crystals under polarizing light microscopy
Radiology description
  • Plain radiography:
    • Joint effusion (earliest sign)
    • Subcortical bone cysts, chondrocalcinosis (5%)
    • Specific delicate bone erosions due to tophi occur with chronicity
    • Punched out erosions with sclerotic margins (rat bite erosions)
    • Punched out lytic lesions in bone
    • Osteonecrosis
    • Olecranon and prepatellar bursitis
    • Hyperdense periarticular soft tissue swelling (Eur Radiol 2008;18:621)
  • Ultrasonography:
    • Hyperechoic linear density (double contour sign) overlying the surface of joint cartilage
    • Tophaceous appearing deposits in joints or tendons, represented by an ovoid stippled signal (hyperechoic cloudy area) (Rheum Dis Clin North Am 2014;40:231, Ann Rheum Dis 2015;74:1868)
    • Synovial thickening with irregular bands opposed to articular cartilage
  • Computed tomography (CT): same as plain radiographic findings
  • Dual energy computed tomography (DECT):
    • Tissue characterization and detection of urate is based on different attenuation of Xrays of variable energy in different tissues
    • Only imaging technique that visualizes urate crystal depositions by their chemical composition
    • Able to detect presence of dense urate crystal deposits even in small volumes
    • Color coded images help in the clinical management of gout patients (Semin Arthritis Rheum 2014;43:662, Skeletal Radiol 2014;43:277)
  • Magnetic resonance imaging (MRI):
    • Tophi are isointense on T1
    • Characteristically heterogeneously hypointense on T2
Radiology images

Contributed by Nasir Ud Din, M.B.B.S.
Left foot

Left foot

Foot

Foot

Prognostic factors
  • Maori and Pacific ethnicity is recognized as a prognostic factor for more severe outcomes in gout (Clin Rheumatol 2013;32:247)
  • Optimal medical control of gout and its comorbidities may improve prognosis (J Rheumatol 2005;32:1923)
  • CRP levels > 30 mg/L and a lack of prophylaxis when starting urate lowering therapy (ULT) are prognostic factors for early gout flare reccurrence in patients starting ULT during an acute gout flare (Clin Rheumatol 2019;38:2233)
Case reports
Treatment
  • Acute gout: nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, prednisolone or cytokine blocking agents (e.g., IL1 blockers) if refractory disease
  • Long term treatment: urate lowering therapies include xanthine oxidase inhibitors (e.g., allopurinol or febuxostat), uricosuric drugs (e.g., probenecid) or uricase agents (e.g., pegloticase) (Lancet 2018;392:1403, Arthritis Rheumatol 2017;69:1903)
  • Risk reduction strategies that work on causes of hyperuricemia: lifestyle modification including dietary changes, weight loss, reduction in alcohol intake and substitutions for medications that can promote hyperuricemia (Arthritis Rheum 2005;52:283)
  • Prophylactic therapy includes use of colchicine prophylaxis for at least 3 - 6 months (Arthritis Rheumatol 2020;72:879)
  • Low dose NSAIDs in patients who do not tolerate low dose colchicine (Naunyn Schmiedebergs Arch Pharmacol 1986;334:138)
  • Symptomatic lesions of tophaceous gout may require surgical excision
Clinical images

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Bilateral tophi, hands

Bilateral tophi, feet

Gross description
  • Specimens of patients with history of gout / gross suspicion for crystals should not be processed in formalin
  • Uric acid crystals are water soluble and destroyed in routine formalin processing
  • They require alcohol fixation and anhydrous processing for microscopic visualization (The University of Chicago: Gross Pathology Manual [Accessed 12 August 2022])
  • If specimen is processed in formalin, chalky material should be removed from sample and scraped on slide for examination
  • Small white flecks to large deposits of crystals that may appear white or tan and chalky or crumbly
  • This appearance is associated with sugar icing, snow-like, powdery or toothpaste-like material
Gross images

Contributed by @Elena_PradosMD on Twitter
Gout and gouty arthritis

Gout and gouty arthritis



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Tan-white chalky, crumbly tophi

Frozen section description
Frozen section images

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Brown needle shaped crystals

Microscopic (histologic) description
  • Gout tophus:
    • Nodular aggregates / granuloma-like appearance consisting of acellular, amorphous, pale eosinophilic material surrounded by palisading arrangement of histiocytes and multinucleated giant cells (Dermatol Online J 2015;21:13030)
    • Feathery appearance in some deposits due to empty needle shaped spaces (Skeletal Radiol 2020;49:1325)
    • Presence of monosodium urate crystals (MSU) is diagnostic
    • Needle-like crystals that measure 5 - 25 micrometers in length
    • Brightly anisotropic under polarized light
    • Negative birefringence when examined with an interference plate in the light path (Otol Neurotol 2009;30:127)
    • Crystals appear yellowish when aligned parallel to the plate axis
    • Bluish appearance when alignment is across the direction of polarization
  • Synovium changes:
    • Affected synovium shows villous hyperplasia and synoviocyte hypertrophy and hyperplasia
    • Typical chronic synovitis with mononuclear leukocyte infiltrate
    • Urate crystals are also identified (Medicine (Baltimore) 1978;57:239)
  • Bone and cartilage changes:
    • MSU crystal deposition in bone is associated with cystic erosion, secondary cortical fracture, destruction of bony trabeculae, osteonecrosis and infiltration of trabecular spaces by chronic inflammatory cells
    • Other changes include fibrotic bone marrow with proliferation of dilated capillaries, osteoclastic and osteoblastic activity and new bone formation (BMC Musculoskelet Disord 2019;20:140)
    • Affected cartilage appears fibrillated, eroded and fissured
    • Granulation tissue formation, fibrous replacement and chondronecrosis may occur (BMC Musculoskelet Disord 2019;20:140)
  • Skin changes:
    • Skin changes include calcification, fat necrosis, granulomatous dermatitis and hemosiderin deposition
    • Thin epidermis, parakeratosis and hyperkeratosis
    • Increased melanin pigment and pigment laden melanophages in superficial dermis
    • Dermis shows dilated blood vessels, endothelial cell swelling and perivascular small mononuclear cell infiltrate (BMC Musculoskelet Disord 2019;20:140)
  • Kidney changes:
    • Light microscopy in gouty kidney shows diffuse thickening of glomerular capillary walls accompanied by spike formation and bubble-like appearance
    • Tophaceous granuloma in interstitium, tubular atrophy, chronic interstitial nephritis and benign nephrosclerosis (Nephron 1986;44:361)
Microscopic (histologic) images

Contributed by Nasir Ud Din, M.B.B.S. and @Elena_PradosMD on Twitter
Nodular aggregates

Nodular aggregates

Granulomatous appearance

Granulomatous appearance

Feathery appearance

Feathery appearance

Needle shaped crystals

Needle shaped crystals

Chronic inflammatory cells

Chronic inflammatory cells


Intersecting pattern of arrangement

Intersecting pattern of arrangement

Brightly anisotropic crystals

Brightly anisotropic crystals

Gout and gouty arthritis Gout and gouty arthritis

Gout and gouty arthritis

Cytology description
  • Fine needle aspiration cytology (FNAC) of tophi is easier and less painful than synovial biopsy and joint fluid analysis
  • Presence of MSU crystals in Papanicolaou stained smears is diagnostic
  • Crystals appear as a mass of fuzzy, amorphous, granular or crystalline material
  • Needle shaped crystals are arranged in sheaves and stacks, seen under polarized light
  • Foamy histiocytes, multinucleated giant cells and acute and chronic inflammatory cells can be variably present (Acta Cytol 2006;50:101)
  • Wet mount preparations from needle washings reveal long, thin, needle shaped crystals, singly and in clusters
  • These crystals show strong, yellow, negative birefringence (Acta Cytol 2000;44:433)
  • Synovial fluid wet preparation shows MSU crystals in tiny fragments of fibrin, cytoplasm of neutrophils and macrophages, or free in fluid
Cytology images

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Gouty tophus with crystalline material and inflammatory response

Immunofluorescence description
Positive stains
Negative stains
  • Not required for diagnosis
Electron microscopy description
  • Tophus: crystals are present in various arrangements: parallel to each other, interspersed with mature collagen fibers and thin fibrils, or haphazardly
  • Background amorphous matrix
  • Cells adjacent to the crystals have prominent rough endoplasmic reticulum and large lipid deposits
  • Crystals are seen occasionally in small phagosomes of the cells (Hum Pathol 1973;4:265)
  • Renal involvement: subepithelial dense deposits are observed
  • Membranous nephropathy should be considered in patients with gout having moderate to severe proteinuria (Nephron 1986;44:361)
Electron microscopy images

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Needle-like crystals

Molecular / cytogenetics description
Molecular / cytogenetics images

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Urate transporters

Uric acid transportasome

Videos

Brilliant polarizable birefringent monosodium urate crystals

Sample pathology report
  • Great toe, excisional biopsy:
    • Histologic features are consistent with gout (see comment)
    • Comment: Biopsy shows fibroadipose tissue exhibiting nodular aggregates and granulomatous appearance of acellular, amorphous, pale eosinophilic material surrounded by palisading arrangement of histiocytes and multinucleated giant cells. The eosinophilic material shows needle-like monosodium urate crystals, which exhibit negative birefringence under polarized light. Described features are consistent with gout. Gout is a metabolic condition associated with hyperuricemia. It can be primary (sporadic or familial) or secondary. Clinical and serological correlation with serum uric acid levels is recommended.
Differential diagnosis
  • Pseudogout (calcium pyrophosphate crystal deposition disease [CPPD]):
    • M = F
    • Polarizable rhomboid shaped calcium pyrophosphate crystals show positive birefringence (Mod Pathol 2001;14:806)
    • Response is more fibroblastic than histiocytic
  • Calcium apatite deposition disease (CADD):
    • Age range: 30 - 60 years
    • Usually involves shoulder joint (Milwaukee shoulder in elderly)
    • Radiology: fluffy, ill defined or well defined, homogenous calcifications
    • Calcium apatite stains purple with Wright-Giemsa stain and red with Alizarin stain (Radiol Res Pract 2016;2016:4801474)
  • Oxalate crystal disease:
    • Associated with primary or secondary hyperoxaluria
    • Typical joint involvement includes the proximal interphalangeal and metacarpophalangeal joints, knees, elbows and ankles
    • Radiology shows calcification around joints and within tendon sheaths and soft tissue
    • Calcium oxalate crystals occur in 2 forms: monohydrate (irregular squares or rods) and dihydrate (envelope-like shape)
    • Positive birefringence under polarized light (Curr Rheumatol Rep 2013;15:340)
  • Tumoral calcinosis:
    • Usually affects younger age group in the first and second decades of life
    • Most commonly occurs in elbows, hips and shoulders
    • Subcutaneous calcified masses in the periarticular soft tissues
    • Lobular to irregular deposits of amorphous calcium crystals (Arthritis Rheumatol 2020;72:1408)
  • Rheumatoid arthritis:
    • Affects small bones of adult women
    • Presence of periarticular osteopenia and joint space narrowing helps differentiate rheumatoid disease from gout
    • Proliferative synovitis with dense lymphoplasmacytic infiltrate
    • Necrobiotic nodules, fibrosis and organizing fibrin (Semin Arthritis Rheum 2017;46:e15)
  • Septic arthritis:
    • Usually affects young adults and children
    • Involves single joint
    • Increased neutrophils and neutrophilic collections within tissue
  • Osteoarthritis:
    • Usually affects joints of weight bearing distribution
    • Manifests after 50
    • Necrotic chondrocytes with thinned and fragmented cartilage
    • MSU crystals not seen
  • Necrotizing granulomatous inflammation:
    • Seen in mycobacterial and fungal infections
    • Central necrosis surrounded by epithelioid histiocytes and multinucleated giant cells
    • AFB and Fite special stains highlight bacilli in mycobacterial infection
    • GMS and PASD special stains highlight fungal organisms
  • Foreign body giant cell reaction:
    • Bone graft material mimics gout appearance
    • Eosinophilic material is more myxoid
    • More sharply angulated deposition than in gout
Board review style question #1

A 58 year old man presented with painful foot swelling. Biopsy showed skin covered fibroadipose and fibrocollagenous tissue with tan-white, chalky deposits. Histology showed nodular aggregates consisting of acellular, amorphous, pale eosinophilic material surrounded by palisading arrangement of histiocytes and multinucleated giant cells. The material showed needle-like crystals which appeared brightly anisotropic under polarized light. What is the most likely diagnosis?

  1. Calcium apatite deposition disease
  2. Calcium pyrophosphate crystal deposition disease
  3. Gout
  4. Rheumatoid arthritis
  5. Tumoral calcinosis
Board review style answer #1
Board review style question #2

Which type of crystals are seen in gout?

  1. Envelope-like crystals
  2. Needle shaped crystals
  3. Rhomboid crystals
  4. Spherical crystals
  5. Square shaped crystals
Board review style answer #2
B. Needle shaped crystals

Comment Here

Reference: Gout and gouty arthritis

Grossing, frozen section & features to report
Grossing
  • Orient specimen using identifiable landmarks
  • Measure specimen (each fragment)
  • Note gross characteristics including color (dead bone is yellow tan), localized lesions, sclerotic areas, calcification, cystic changes, necrosis
  • Radiographs or photographs of sliced bone specimens may be helpful (particularly for nidus of osteoid osteoma)
  • Use scalpel tip to tease out fleshy areas (except near tumors) for nondecalcified fixation
  • Histomorphometry may be helpful for metabolic bone disease
  • Submit fresh tissue for ancillary studies, as needed (Hum Pathol 2004;35:1173)

  • Decalcification:
    • 20% formic acid in 10% formalin (400 ml of formic acid in 1600 ml of 10% formalin)
    • Fix bone first; decalcify slices but not entire specimen in adequate amount of formic acid; change solution (dissolved calcium neutralizes the acid); wash thoroughly to remove acid
    • Small specimens may require only a few hours
    • Check specimen periodically to avoid excessive decalcification

  • Bone biopsy:
    • Divide needle biopsy longitudinally with a fine toothed saw if 5 mm or more in diameter
    • Dissect out soft tissue and process separately without decalcification

  • Open biopsy and curettage:
    • Separated calcified from noncalcified tissue and process separately

  • Femoral head:
    • Hold specimen with a clamp or vice and cut through center of articular surface with band saw
    • Then make another parallel cut 3 mm from the first cut
    • Submit abnormal areas, articular surface and synovium

  • Bone resection for tumor:
    • Review xrays
    • Check prior biopsy sites
    • Identify lymph node groups; dissect and place in separate containers
    • Ink and examine margins (scoop bone marrow from end margin)
    • Dissect away soft tissue, leaving bone and soft tissue extension of tumor (margins of soft tissue are examined at frozen section)
    • Examine major vessels and nerve trunks (limb specimens)
    • Determine position of tumor with respect to other landmarks present
    • Bivalve tumor with band saw (anterior - posterior or what exposes most of the bone tumor)
    • Describe status of cortex near tumor
    • Cut through joint if no apparent tumor
    • If joint contains apparent tumor, make cross section through adjacent noninvolved bone, then open and examine joints
    • Obtain 3 - 4 mm sections of tumor using band saw or handheld saw
    • Wash with running water, brush cut surfaces of bone with a nail brush to remove bone dust
    • Check for satellite lesions (examine under Wood's light if tetracycline was administered)
    • Calculate %necrosis in post chemotherapy specimens
      • For osteosarcoma and Ewing sarcoma, sample completely a slice of the tumor using a grid pattern diagram
      • Take additional blocks perpendicular to previous ones to evaluate tumor in 3 dimensions
      • Examine blocks from soft tissue, tumor / nodal interface, cortex, subcortical marrow, pericartilaginous regions, necrotic areas, ligaments
      • Necrosis is defined as follows:
        • Osteoblastic and chondroblastic osteosarcomas: empty lacunae or ghost cells
        • Fibroblastic and small cell osteosarcomas and Ewing's sarcoma: fibrous and granulation tissue replacing cellular tumor
        • Telangiectatic osteosarcoma: residual cystic spaces with blood or hemosiderin
        • Note: post chemotherapy atypia is NOT considered necrosis

  • Sections to submit:
    • 4 or more sections of tumor (representative, including dissimilar areas; tumor and cortex, medulla, articular cartilage, periosteum, soft tissue, epiphyseal line)
    • Tumor and margin
    • Osseous margin of resection
    • Prior biopsy sites
    • Other abnormal areas
    • Lymph nodes
Fine needle aspiration
  • Helpful for identifying metastatic disease (Arch Pathol Lab Med 2001;125:1463), recurrent tumor or unsuspected malignancy
  • Not helpful for cartilaginous lesions, cystic lesions or obviously benign lesions that require surgical management (chondromyxoid fibroma, giant cell tumor)
Frozen section
  • Click here for the frozen section procedure topic
  • Useful to document adequacy of tissue
  • Allows quicker definitive treatment (if diagnosis can be made)
  • Assessment of tumor margins
  • Useful to obtain culture for possible infectious lesions
  • Useful to differentiate between aseptic and infectious inflammation for implant replacement
Features to report
    • Organ
    • Site (include laterality if appropriate)
    • Procedure
    • Tumor diagnosis
    • Tumor size (1 dimension is mandatory, 2 - 3 dimensions if possible)
    • Histologic grade (low / high grade or I, II, III or IV)
    • Chemotherapy response:
      • I: no chemotherapy effect
      • IIA: some necrosis, more than 50% viable tumor
      • IIB: 3% - 50% viable tumor
      • III: less than 3% viable tumor but scattered foci present
      • IV: no viable tumor noted
    • Tumor extent:
      • surface only, cortex only, through cortex, into soft tissue, satellite lesions, invades or crosses joint spaces
    • Margins:
      • Proximal, distal, distance of tumor to closest surgical margin, involvement of neurovascular bundle at margin
      • Lymph nodes: number positive, number examined, extracapsular extension, largest nodal metastasis
      • Staging
      • Results of special studies
    • Optional features:
      • Name structures with gross involvement of tumor
      • Cystic change, hemorrhage, tumor necrosis (in non chemotherapy cases)
      • Large or small vessel invasion present / absent / indeterminate
      • Reference: Hum Pathol 2004;35:1173


Hemangioma
Definition / general
  • Most common vascular tumor of bone
  • Identified in vertebrae in 12% of autopsies, 34% are multiple
  • Usually incidental finding; ages 20 - 50 years, no definite gender preference
  • May actually be vascular malformations, not neoplasms
  • Multiple bony hemangiomas more common in children, associated with cutaneous, soft tissue or visceral hemangiomas
  • Sacral hemangiomas in infants associated with congenital anomalies
  • Sites for clinically significant hemangiomas: skull, vertebrae (causing spinal cord compression), jaw; occur in marrow
Radiology description
  • Sunburst appearance due to trabecular bone, particularly in spine and skull
  • Nonspecific in long bones
Gross description
  • Elevation of periosteum
  • Currant jelly cut surface
Microscopic (histologic) description
  • Thick walled lattice-like pattern of vessels
  • Either capillary or cavernous
  • Often with reactive new bone formation
  • No endothelial atypia
Differential diagnosis
Epithelioid hemangioma
Definition / general
  • Rare; usually affects long tubular and flat bones but may occur in any bone
  • Also occurs in skin and subcutis
  • Mean age 34 - 46 years, range teens to 70s
  • 25% multifocal

Radiology description
  • Lytic or blastic, well defined or poorly circumscribed margins

Treatment
  • Curettage, excellent prognosis

Gross description
  • 2 - 15 cm
  • Well circumscribed, soft, dark red, limited to medullary cavity

Microscopic (histologic) description
  • Replaces marrow, surrounds bony trabeculae, erodes cortex, may have soft tissue component
  • Lobular growth pattern
  • Epithelioid cells line well formed vessels, but may also grow in sheets and cords; nuclei are grooved, vesicular, may have prominent nucleoli
  • No severe nuclear atypia
  • Abundant eosinophilic cytoplasm, often with vacuoles
  • < 5 mitotic figures/10 high power fields
  • Stroma is loose connective tissue with lymphocytes, eosinophils, extravasated red blood cells

Positive stains
Differential diagnosis
Additional references

Hemangioma & variants
Definition / general
Essential features
  • Most cases arise in children, with equal gender distribution
  • Composed of small capillary sized blood vessels with a larger feeding vessel commonly present
  • Most cases are treated with topical or systemic beta blockers in isolation or in combination with other modalities like laser therapy, excision, etc.
  • Recurrence is uncommon and only exceptional examples show malignant transformation
Terminology
  • Hemangioma is commonly used with a qualifier (e.g. congenital hemangioma)
ICD coding
  • ICD-O: 9120/0 - hemangioma, NOS
  • ICD-11: 2E81.0Y - other specified neoplastic hemangioma
Epidemiology
Sites
Pathophysiology
  • Specific pathogenesis has not been fully understood
  • Currently regarded as a multifactorial condition, resulting in endothelial proliferation, with uncontrolled angiogenesis and abnormal function of downstream pathways (notably HIF1α, VEGF and PI3K / Akt) (Biomed Res Int 2021;2021:5695378)
Etiology
  • Not known
Clinical features
Diagnosis
  • Requires correlation of detailed history and physical examination with microscopic features, as the latter overlaps for various clinical presentations
Laboratory
  • Transient mild to moderate thrombocytopenia due to consumption may be seen in rapid growth phase (F1000Res 2019;8:F1000)
Radiology description
  • Mostly required for extracutaneous cases
  • Skeletal (bone) hemangiomas: radiology is highly nonspecific (BMC Musculoskelet Disord 2021;22:27)
  • Ultrasound: highly effective; shows well defined mass with high vascularity
  • Contrast enhanced ultrasonography (CEUS): gold standard for hepatic hemangiomas (Korean J Radiol 2000;1:191)
  • High flow in proliferative phase of infantile hemangioma; slow flow in involuted phase
  • Central high flow for NICH; slow flow for RICH
  • Fluttering sign: recently described feature for grayscale ultrasound in hepatic hemangiomas (Ultrasound Med Biol 2021;47:941)
  • MRI: useful in deep locations to estimate extent of tissue involvement
  • Infantile hemangioma: hyperintense on T2; isointense on T1 with postcontrast enhancement
  • Congenital hemangioma: heterogeneous appearance on MRI
  • CT scan: hypodense, with postcontrast enhancement of periphery (World J Gastroenterol 2020;26:11)
Radiology images

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Hepatic hemangioma Hepatic hemangioma

Hepatic hemangioma

Intrathoracic hemangioma

Intrathoracic hemangioma

Infantile thyroid hemangioma

Infantile thyroid hemangioma

Infantile hepatic hemangioma

Infantile hepatic hemangioma

Choroidal hemangioma (fundoscopy)

Choroidal hemangioma (fundoscopy)


Hemangioma in long bones Hemangioma in long bones

Hemangioma in long bones

Hemangioma in long bones Hemangioma in long bones Hemangioma in long bones

Hemangioma in long bones

Prognostic factors
Case reports
Treatment
Clinical images

Contributed by Nasir Ud Din, M.B.B.S.
Noninvoluting congenital hemangioma

Noninvoluting congenital hemangioma



Images hosted on other servers:
Infantile hemangioma

Infantile hemangioma

Caption

Infantile hemangioma with ulceration

Infantile hemangioma in beard distribution

Infantile hemangioma in beard distribution

Rapidly involuting congenital hemangioma

Rapidly involuting congenital hemangioma

Partially involuting congenital hemangioma

Partially involuting congenital hemangioma

Laryngeal hemangioma (laryngoscopic view)

Laryngeal hemangioma (laryngoscopic view)

Gross description
Gross images

Images hosted on other servers:
Atrial hemangioma

Atrial hemangioma

Hepatic hemangioma

Hepatic hemangioma

Pulmonary hemangioma

Pulmonary hemangioma

Microscopic (histologic) description
  • Lobules of capillary sized vascular channels, lined by single layer of flattened endothelial cells
  • Large feeding vessel is usually seen at the deeper aspect
  • Associated lymphocyte infiltrate may be seen (Cardiovasc Pathol 2017;28:59)
  • Anastomosing hemangioma: anastomosing vascular channels lined by flattened endothelium; deep occurrence
  • Angiomatosis: involvement of multiple tissue planes with irregular and poorly circumscribed edges
  • Cavernous hemangioma: shows predominantly ectatic channels
  • Congenital hemangioma:
    • Solid appearance in rapid growth phase with poorly canalized vessels and mitotically active endothelium
    • Surrounding pericyte layer is present
    • With maturation, the lumina become prominent and blood flow ensues
    • Combination of solid and vascular areas in varying proportions may be seen
    • Noninvoluting congenital hemangioma (NICH) shows well formed capillaries and vascular channels
    • Involuting examples show thickening of basement membranes and fibrosis in the background
  • Epithelioid hemangioma:
    • Well formed small vessels are lined by plump endothelial cells with abundant eosinophilic cytoplasm and round enlarged nuclei, accompanied by abundant eosinophils in the background
    • Lobulated, well demarcated with maturation of vascular lumina at the periphery
  • Glomeruloid hemangioma: resembles glomerular capillaries
  • Hobnail hemangioma: hobnail nuclei protruding into vascular lumina; circumscribed
  • Infantile hemangioma:
    • Proliferation of capillary lobules; has a distinct natural history involving three stages (i.e., proliferation, partial regression and complete regression):
      • Early proliferative stage: lobules of immature dendritic type cells with intervening stroma, large feeding vessels and occasional presence of perineural involvement
      • Early regression: capillaries dilate and eventually start disappearing; apoptotic debris in basement membrane with increased numbers of pericapillary mast cells.
      • Late regression / end stage: ghosts of capillaries, rings of basement membrane with rare endothelial cells having immunophenotype of placental capillaries (GLUT1, LeY, CD15, CCR6, IDO and IGF2 positive)
  • Intramuscular angioma:
    • Arises within skeletal muscle in association with variable amount of mature adipose tissue, phleboliths and metaplastic bone formation
    • Shows a combination of lymphatics, variable sized veins and arteriovenous component
  • Lobular capillary hemangioma / pyogenic granuloma: ulceration with dense mixed inflammation
  • Microvenular hemangioma:
    • Poorly defined, in superficial and deep dermis
    • Small venule-like channels lined by single layer of endothelial cells which lack mitotic activity, surrounded by single layer of pericytes; these venules appear to dissect hyalinized collagen bundles of the dermis but lack multilayering and HHV8 positivity
  • Sinusoidal hemangioma:
    • Well demarcated proliferation of dilated, congested and thin vascular channels anastomosing in a sinusoidal manner
    • Intervening stroma is scant and scant smooth muscle may be present in the wall
    • Mitotic activity is not seen
  • Spindle cell hemangioma: proliferating spindle cells with intraluminal phleboliths
  • Verrucous hemangioma: hyperkeratosis and involvement of several tissue planes
Microscopic (histologic) images

Contributed by Nasir Ud Din, M.B.B.S.
Anastomosing hemangioma Anastomosing hemangioma

Anastomosing hemangioma

Skeletal hemangioma Skeletal hemangioma Skeletal hemangioma

Skeletal hemangioma

Cavernous hemangioma

Cavernous hemangioma


Hobnail hemangioma Hobnail hemangioma

Hobnail hemangioma

Hepatic hemangioma Hepatic hemangioma

Hepatic hemangioma

Infantile hemangioma Infantile hemangioma

Infantile hemangioma


Infantile hemangioma

Infantile hemangioma

Lobular capillary hemangioma Lobular capillary hemangioma Lobular capillary hemangioma

Lobular capillary hemangioma

Spindle cell hemangioma Spindle cell hemangioma

Spindle cell hemangioma


Spindle cell hemangioma

Spindle cell hemangioma

Phleboliths in spindle cell hemangioma

Phleboliths in spindle cell hemangioma

Synovial hemangioma

Synovial hemangioma

Verrucous hemangioma

Verrucous hemangioma

Virtual slides

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Extensive evolution

Extensive evolution

Involuting infantile hemangioma

Involuting infantile hemangioma

Congenital hemangioma

Congenital hemangioma

Cytology description
  • Aspiration is not advised, as there is high risk of uncontrolled bleeding
Positive stains
Negative stains
Electron microscopy description
  • Not required for diagnosis in routine cases
  • Endothelial cells show cytoplasmic folds on luminal surface, junctional complexes and cytoplasmic pinocytic vesicles (Cancer Res 1990;50:4787)
Electron microscopy images

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Endothelial differentiation

Endothelial differentiation

Cutaneous hemangioma

Cutaneous hemangioma

Molecular / cytogenetics description
Molecular / cytogenetics images

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Sanger sequencing for <i>RASA1</i>

Sanger sequencing for RASA1

Videos

Spindle cell hemangioma

Cutaneous vascular tumors

Sample pathology report
  • Liver, lobectomy:
    • Benign vascular lesion, consistent with hemangioma (see comment)
    • Comment: The tumor is completely excised with free margins. Evidence of embolization is seen, with presence of acellular material within the lumina of large caliber vessels, accompanied by areas of infarction within the lesion.
Differential diagnosis
  • Granulation tissue:
    • Sites of trauma, commonly cutaneous or mucosal
    • Shows associated inflammatory infiltrate and edema
    • Feeding vessels are not seen commonly
    • Lobular capillary hemangioma is common mimicker
    • Correlation with clinical history is important
  • Hemangioendothelioma:
    • Mimics proliferating phase of congenital hemangioma
    • Retiform type mimics hobnailing seen in proliferating phase of congenital hemangioma
    • Not well circumscribed
    • Clinical presentation with consumptive coagulopathy is common in both
    • May be associated with other anomalies
    • Requires more aggressive treatment
  • Kaposi sarcoma:
    • Mimics proliferating phase of congenital hemangioma due to compact cellularity and slit-like spaces
    • Eosinophilic hyaline globules are not seen in hemangioma
    • HHV8 association is not seen in hemangioma
    • Requires aggressive treatment
  • Angiosarcoma:
    • Malignant vascular tumor with infiltrative growth
    • Marked nuclear pleomorphism and brisk mitotic activity
    • Visceral location is more common compared to hemangioma
Board review style question #1

A newborn shows a nodular growth on his scalp. Over the next couple of weeks, the lesion starts shrinking. Despite reassurances from the pediatrician, the parents insist on excision. Upon pathological examination, it shows a network of capillary sized vessels with large feeding vessels near the base, shown in the above photomicrograph. The diagnosis in this case is

  1. Infantile hemangioma
  2. Noninvoluting hemangioma
  3. Partially involuting hemangioma
  4. Rapidly involuting hemangioma
Board review style answer #1
A. Infantile hemangioma. This case is an example of infantile hemangioma, which typically shows regression after birth, unlike congenital hemangioma, which grows with the patient, at least to some extent. Within the umbrella of congenital hemangioma, there is partial involution over time with shrinkage and secondary changes. Noninvoluting examples grow with the baby and rapidly involuting ones regress at a much faster rate, ultimately disappearing completely.

Comment Here

Reference: Hemangioma
Board review style question #2

A 9 year old boy presents with a purple nodular / bosselated lesion on the left leg, with involvement of the plantar and dorsal aspects of foot (as shown in the clinical photograph). He has had this lesion since birth and it has grown with him since then. The microscopic examination shows well formed vascular channels of variable size lined by a single layer of endothelial cells. The most likely diagnosis in this case is

  1. Birth mark
  2. Infantile hemangioma
  3. Kaposiform hemangioendothelioma
  4. Lobular capillary hemangioma
  5. Noninvoluting congenital hemangioma
Board review style answer #2
E. Noninvoluting congenital hemangioma. Noninvoluting congenital hemangioma is present at birth and grows with the child. As the name implies, there is no microscopic evidence of involution if a biopsy is performed. Birth marks commonly present with a flat, pigmented / reddish appearance of the skin rather than the appearance given in the clinical photograph, which shows prominent vascular marking, like the appearance of the lesion with some areas showing bosselation. Infantile hemangioma rapidly regresses after birth. Lobular capillary hemangioma presents as a nodular growth, commonly associated with ulceration of the skin or mucosa. Kaposiform hemangioendothelioma clinically presents commonly on the head and neck and trunk region, with a strong association with Kasabach-Merritt syndrome (consumptive coagulopathy). Microscopically, it shows glomeruloid proliferation and spindle cell morphology with slit-like spaces on microscopic examination.

Comment Here

Reference: Hemangioma

High grade surface osteosarcoma

Histology-bone
Definition / general
  • Bone is a type of mesenchymal connective tissue derived from common primitive mesenchymal precursors
  • Structure primarily consists of an extracellular matrix produced and modified by bone cells
  • It is a composite biphasic mix of organic and inorganic components
Essential features
  • Organic component (25%) includes type I fibrillar collagen (90%) and bone morphometric proteins and mucopolysaccharides (10%)
  • Inorganic component (75%) predominantly comprises the mineral complex calcium hydroxyapatite (J Musculoskelet Neuronal Interact 2020;20:347)
  • Organic portion provides tensile strength whereas the mineral portion gives stiffness to bone
Physiology
  • Provides structural and mechanical support for movement and protection of viscera
  • Helps in homeostatic mechanisms being the repository of calcium and phosphate in the body
  • Acts as an endocrine organ to regulate important biologic phenomena
  • Contains hematopoietic tissue
  • Bone cells: osteoblasts and osteoclasts are involved in bone modeling, remodeling and repair
  • Osteoblastic differentiation and maturation involve transcription factors such as runt related transcription factor 2 (RUNX2), osterix (OSX) and activating transcription factor 4 (ATF4) in addition to signaling pathways such as Wnt and Notch (Curr Opin Rheumatol 2018;30:59)
  • Osteoblasts secrete type I collagen, the main component in osteoid matrix (Histochem Cell Biol 2018;149:289)
    • Responsible for the production, transportation and arrangement of various components of the organic matrix (osteoid)
    • Commence and regulate matrix mineralization
    • Employ autocrine and paracrine mechanisms to organize the activity of adjacent osteoblasts, osteocytes and osteoclasts
  • Osteocytes function as sensor cells in bone, responding to mechanical forces
    • As mechanosensory cells, they convert mechanical stress into biologic activity
    • Stimulated osteocytes manufacture and liberate intercellular messengers that focus on precursor cells, osteoblasts and osteoclasts
    • These cells react by remodeling the bone
  • Mineral homeostasis is another function of osteocytes
    • Osteocytic osteolysis is a process through which osteocytes rapidly release calcium and phosphorus from mineralized matrix, which is histologically evident as distended lacunar spaces
  • Osteocytes produce fibroblast growth factor 23 (FGF23), which downregulates parathyroid hormone (PTH)
    • Controls osteoblastic activity by releasing sclerostin, which inhibits osteoblastic bone formation through Wnt / beta catenin pathway and osteoclastic activity through secretion of receptor activator of nuclear factor kappa beta ligand (RANKL) and osteoprotegerin (OPG) (Curr Opin Rheumatol 2018;30:59)
  • Osteoclasts resorb mineralized bone more efficiently than nonmineralized tissue
  • Osteoclastic development, maturation and activity involves diverse cytokines including interleukins (IL1, IL3, IL6, IL11), tumor necrosis factor (TNF), granulocyte macrophage colony stimulating factor (GM-CSF) and macrophage colony stimulating factor (M-CSF)
    • These factors work by either stimulating osteoclast progenitor cells or influencing other bone cells in a paracrine manner
    • This system is essential to bone metabolism and its mediators include the molecules RANK, RANKL and OPG
    • RANK / RANKL signaling is important in bone metabolism as a stimulator of osteoclast production, differentiation, activation and survival
    • RANKL can be blocked by another component of the TNF family of receptors, OPG, which is a soluble protein formed by various tissues including bone, hematopoietic marrow cells and immune cells
    • OPG inhibits osteoclastogenesis, acting as a decoy receptor that binds to RANKL and prevents the interaction of RANK with RANKL
    • The interplay permits osteoblasts and stromal cells to manage osteoclast development
    • This ensures the tight pairing of bone formation and resorption, which is vital to the success of the skeleton
Diagrams / tables

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Bone structure

Bone structure

Bone architecture

Bone architecture

Gross description
  • Firm and stiff with high tensile strength
  • Tan-white and smooth
  • All bones generally have a
    • Periosteum: fibrous connective tissue attached to the outer surface of the cortex (Eur J Radiol Open 2020:7:100249)
    • Cortex: made up of compact (cortical) bone with the endosteal surface forming border with the medullary canal
    • Medullary canal: contains variable amounts of cancellous (trabecular) bone with fatty tissue, hematopoietic elements, blood vessels and nerves
  • Shafts (diaphysis) of weight bearing bones (such as bones of extremities) have almost all of their mass near the surface with dense cortex (compact bone) and a medullary cavity nearly devoid of bone
  • There is a decrease in cortical thickness and increase in the content of cancellous bone towards the metaphysis
  • Epiphysis is almost completely made of cancellous bone
  • Less weight bearing bones of the trunk have thinner cortices and more hematopoietic marrow
Gross images

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Cancellous and compact bone

Cancellous and compact bone

Bone cell types
  • Bone cells belong to the osteoprogenitor series and osteoclast series
  • Osteoprogenitor series (primitive committed mesenchymal cells) is derivative of tissue bound mesenchymal stem cells
  • Mesenchymal stem cells are multipotential stromal precursor cells with potential to form adipocytes, chondrocytes, myocytes and fibroblasts
  • Present in the perianlage tissue of the fetus, periosteum, Haversian systems, Volkmann and medullary canals
  • Osteoprogenitor cells have the ability to fabricate osteoblasts only; they have basic spindle morphology
  • Osteoclast series is derived from monocyte granulocyte colony precursors in the bone marrow

Osteoblasts
  • Essential to the formation of bone tissue
  • Located on actively growing bone surfaces
  • Lifespan may range from months to many years
  • Metabolic state is intimately associated with their morphology
    • Active osteoblasts resemble plasma cells and range in size from 10 - 80 μm (average: 20 - 30 μm)
      • Large cuboidal to pear shaped, polyhedral mononuclear cells when rapidly forming bone
      • Contain copious amphophilic to basophilic cytoplasm that is in intimate contact with bone
      • Nuclear membranes are distinct with eccentric (polarized away from the matrix) vesicular nuclei that possess 1 or more prominent nucleoli
      • Visible perinuclear halo representing Golgi apparatus
    • Inactive osteoblasts / lining cells are spindle shaped to flattened
      • Present on the surface of bony trabeculae
      • Have flattened, nonreactive nuclei with scant cytoplasm
      • ~60 - 80% of osteoblasts go through apoptosis
      • Remaining osteoblasts either develop into osteocytes enveloped by matrix or flatten and stretch forming cellular coating on bone surfaces (J Bone Miner Res 2021;36:1432)

Osteocytes
  • Most abundant cell type of bone (> 90% of bone cells in adult bone)
  • Terminally differentiated osteoblasts that incorporate into bone matrix
  • Half life approaches 25 years
  • Appear as small blue dots within lacunar spaces in the bone matrix
  • Cell body, nucleus and surrounding scant cytoplasm dwell inside a lacunar space
  • Nuclei are small and not evident in every plane of section; therefore, in most slides of bone tissue, lacunae are empty
  • Part of osteocyte cytoplasm pinches off into long and delicate cytoplasmic processes resembling axons
  • These processes lie in canaliculi (channels traversing through the bone matrix)
  • The ends of osteocyte cell processes connect to those of adjoining osteocytes and to surface osteoblasts through gap junctions (Annu Rev Physiol 2020:82:485)
  • This creates a tremendous surface area of contact between the osteocyte and the matrix and extracellular fluid surrounding each cell
  • In this way, osteocytes communicate with one another forming intricate and integrated systems all over the bone tissue
  • Number, size, shape and position of osteocytes depend upon the type of bone they reside in
    • Woven bone
      • Abundant, big and plump
      • Appears disordered and random microscopically as their long axes are parallel to the direction of adjacent collagen fibers
    • Lamellar bone
      • Less in number, smaller, spindly
      • Seem to be organized as the cells are arranged in the same direction as the surrounding lamellae
      • Osteocyte apoptosis increases with aging, causing reduced osteocyte density

Osteoclasts
  • Osteoclasts are terminally differentiated cells
  • Lifespan of days to weeks
  • Present in scalloped, cup shaped depressions on bone surface called Howship lacunae
  • 40 - 100 μm in diameter
  • Polarized with one part of cell membrane closely adhered to bone (ruffled border) while the other pole is exposed to extracellular fluid
  • Have granular eosinophilic cytoplasm, may have 4 - 20 nuclei
  • Metabolic activation of osteoclasts is initiated by anchorage
  • Activated nuclei coordinate the complex and transitory cytoplasmic and cell membrane alterations necessary for bone digestion
  • After osteoclastic activity, macrophages mobilize to the base of the resorption pit and phagocytize the organic remnants (Connect Tissue Res 2018;59:99)
  • Osteoclast-like giant cells are multinucleated cells that were once osteoclasts but could not be defined at the moment because of absence of residual bone
Bone types
  • Based on matrix arrangement (orientation of collagen type I), bone can be classified as

    Woven bone / immature bone
    • Develops in utero and during phases of rapid bone formation
    • Coarsely and haphazardly oriented collagen with thick and loosely packed collagen fibers
    • Mineral content and osteocyte density are high
    • Osteocytes and lacunae are larger than those of mature bone
    • Calcification is irregular
    • Resembles particle board
    • Weaker, less rigid and more elastic than lamellar bone

    Lamellar bone / mature bone
    • Synthesized following birth
    • Collagen is present in successive layers with delicate and more closely packed fibers in the same direction to each other
    • Collagen bundles are organized in parallel layers or concentric layers / sheets called lamellae
    • Mineral content and osteocyte density are low and collagen density is high
    • Osteocytes and lacunae are smaller and organized
    • Resembles plywood
    • Firm with more tensile strength and less flexible than woven bone (Annu Rev Biomed Eng 2018:20:119)

  • Based on texture, bone can be classified as

    Cortical bone
    • Also known as compact bone
    • 90% bone and 10% space by volume
    • Found in diaphysis of long bones
    • Surrounds the cancellous compartment of epiphysis and metaphysis of long bones
    • Interior of bone consists of Haversian canals, Volkmann canals, osteocyte lacunae and osteocyte canaliculi
    • Bulk of compact bone is lamellar in type and comprises circumferential lamellae and secondary osteons
    • Haversian canals are tubes or tunnels in cortical bone that contain nerve fibers and a few capillaries
    • Circumferential lamellae encircle the entire bone
    • Earliest circumferential lamellae made during development lie on the inside of bony cortex (called inner circumferential lamellae), whereas the newest cortical lamellae deposited by periosteum lie on the outer surface of the cortex and are called outer circumferential lamellae
    • Secondary osteons are circumferential lamellae that encircle Haversian canals (Materials (Basel) 2019;12:913)
    • Osteon (Haversian units) are structural and functional elements of cortical bone
    • Osteons are cylinders with hollow centers oriented in the same axis as the long axis of bone
    • They branch and twist to connect with other osteons via lateral vascular channels called Volkmann canals
    • They replace circumferential lamellae in weight bearing bones
    • Osteocytes are present in spaces called osteocyte lacunae, which are ovoid spaces at the junctures of adjacent lamellae
    • Osteocyte canaliculi house the cell processes of osteocytes and are oriented radially to the Haversian canal between the osteocyte lacunae
    • Blood vessels and nerve fibers traverse Haversian canals
    • Osteoclasts and osteoblast progenitor cells pass through Haversian canals to initiate cortical bone remodeling
    • When parts of osteons or circumferential lamellae are remodeled by osteoclasts, the residual bone not supplied by previous blood supply becomes interstitial lamellae
    • Interstitial lamellae appear as randomly arranged pieces of bone in the cortex
    • Have necrotic bone matrix and lacunae devoid of osteocytes

    Trabecular bone
    • Also known as spongy or cancellous bone
    • 25% bone and 75% space by volume in long bone
    • Found in vertebrae, epiphysis and metaphysis of long bones (J Musculoskelet Neuronal Interact 2020;20:347)
    • Vertical plates of lamellar bone interconnected by short and thick lateral struts
    • Intertrabecular spaces contain bone marrow

    Cement lines
    • Basophilic lines produced by osteoblasts that separate osteons, interstitial lamellae and circumferential lamellae from one another (Bone 2018:110:187)
    • Have more calcium and mucopolysaccharides than surrounding bone
    • When bone is produced on a resorbed surface after osteoclastic activity, the cement lines produced by osteoblasts are called reversal cement lines
    • Cement lines produced by osteoblasts after prolonged inactivity are called arrest cement lines
    • Lamellae are oriented in different planes on the opposite sides of reversal cement lines, whereas lamellae in arrest cement lines are oriented in the same plane on opposite sides

    Periosteum
    • Slender, vascularized layer of tan-white fibrous connective tissue that immediately surrounds the outer surface of all cortices (Eur J Radiol Open 2020:7:100249)
    • Composed of an outer fibrous layer and an inner cellular (cambium) layer in children
    • Cambium layer is composed of spindle shaped fibroblasts, osteoprogenitor cells and mature osteoblasts
    • In adults, the periosteum is just a fibrous covering
    • Fibrous layer contains fibroblasts and type I collagen fibers that are in continuation with the joint capsule, tendons and muscle fascia
    • Periosteum is connected to bone by collagen fibers called Sharpey fibers
Microscopic (histologic) images

Contributed by Nasir Ud Din, M.B.B.S.
Active osteoblasts Active osteoblasts

Active osteoblasts

Inactive osteoblasts

Inactive osteoblasts

Osteoclasts Osteoclasts

Osteoclasts

Osteoclast type giant cells

Osteoclast type giant cells


Woven bone

Woven bone

Osteocytes in woven bone

Osteocytes in woven bone

Lamellar bone

Lamellar bone

Osteocytes in Lamellar bone

Osteocytes in Lamellar bone

Cortical bone Cortical bone

Cortical bone


Cortical bone Cortical bone

Cortical bone

Cortical bone

Cortical bone

Reversal cement lines Reversal cement lines

Reversal cement lines

Periosteum

Periosteum

Electron microscopy description
  • Osteoblasts
    • Cytoplasm of active osteoblasts contains widespread granular endoplasmic reticulum, a large, prominent Golgi apparatus, abundant mitochondria and lysosomes
    • In contrast, the cytoplasm of inactive osteoblasts resembles that of quiescent fibroblasts
  • Osteoclasts
    • In the cytoplasm, a network of interrelated actin filaments extends from the site where the osteoclast cell membrane attaches to the bone (clear zone) directly to the nuclei
  • Reference: StatPearls: Histology, Osteoblasts [Accessed 7 November 2023]
Electron microscopy images

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Osteoclast structure Osteoclast structure

Osteoclast structure

Videos

Normal bone histology & embryology 101 with Dr. Andrew Rosenberg

Bone cells and bone formation

Board review style question #1

Which of the following about this bone is true?

  1. Collagen bundles are organized in parallel or concentric layers
  2. Hypocellular with smaller lacunae than lamellar bone
  3. Low mineral content
  4. Synthesized slowly
  5. Weaker, less rigid and more flexible than lamellar bone
Board review style answer #1
E. Weaker, less rigid and more flexible than lamellar bone. The image depicts woven bone, which is weaker, less rigid and more flexible than lamellar bone. Answer C is incorrect because woven bone has a higher mineral content than lamellar bone. Answer B is incorrect because woven bone is more hypercellular than lamellar bone. Answer D is incorrect because woven bone is fabricated during rapid bone formation. Answer A is incorrect because collagen bundles are arranged haphazardly in woven bone.

Comment Here

Reference: Histology-bone
Board review style question #2

Which of the following corresponds to this structure?

  1. Does not go through apoptosis
  2. Has abundant cytoplasm and is multinucleated
  3. Most abundant cell type of bone tissue
  4. Resembles plasma cells, is polyhedral, with copious amphophilic cytoplasm and eccentrically placed nuclei with 1 or more nucleoli
  5. Spindle shaped
Board review style answer #2
D. Resembles plasma cells, is polyhedral, with copious amphophilic cytoplasm and eccentrically placed nuclei with 1 or more nucleoli. This is a description of activated osteoblasts, which resemble plasma cells in that they have an eccentrically placed nucleus with copious amphophilic cytoplasm. Answer E is incorrect because inactive osteoblasts are spindle shaped to flattened, not active osteoblasts as shown here. Answer B is incorrect because osteoclasts have abundant cytoplasm and multiple nuclei, not active osteoblasts. Answer A is incorrect because ~80% of active osteoblasts undergo apoptosis. Answer C is incorrect because osteocytes are the most abundant cell type in bone tissue, not active osteoblasts.

Comment Here

Reference: Histology-bone

Histology-joints
Definition / general
  • Articulations that allow bones to move relative to one another
Essential features
  • Various types of joints but the synovial joint (diarthrosis) is what mainly concerns pathologists
    • Synovial joint is composed of the articular cartilage (hyaline cartilage), articular capsule (synovial membrane and fibrous capsule) and in certain joints, other connective tissues (menisci, tendons and ligaments)
    • Normal synovial joint contains a scant amount of synovial fluid
  • Second most important type of joint is the amphiarthrosis, which consists of flattened attached disc of fibrocartilage between 2 subchondral plates of adjacent bones
  • Functional joint depends on the normal function of all of its components
Terminology
  • Classification based on degree of movement
    • Synarthroses: immovable joints (e.g., skull sutures, the distal tibial fibular joint)
    • Amphiarthroses: slightly movable joints (e.g., intervertebral joints, symphysis pubis)
    • Diarthroses: freely movable joints (e.g., hip, knee)
  • Classification based on type of connective tissue
    • Fibrous joints (e.g., skull sutures)
    • Cartilaginous joints (e.g., intervertebral joints, symphysis pubis)
    • Synovial joints (e.g., hip, knee: the type of joint that we usually have in mind when speaking of joints in general
  • Histologic varieties of cartilage
    • Hyaline cartilage: most common composition of articular cartilage; also seen in growth plates
    • Fibrocartilage: constitutes intraarticular structures (menisci, annuli fibrosis of the vertebrae) and occasionally articular cartilage and is also associated with entheses (tendinous and ligamentous insertions); compared with hyaline and elastic cartilage
    • Elastic cartilage: not directly associated with joints
  • Tidemark:
    • Interface between calcified and noncalcified cartilage layers in areas exposed to either loading (joint) or pulling (insertion) (Acta Biol Hung 1984;35:271)
    • In articular cartilage it appears with skeletal maturation; in other localizations it is age independent
Physiology
  • Articulates the tubular bones of the extremities; there are varieties of synovial joints in regard to the kind of motion (e.g., hinge joints, pivot joints, ball and socket joints, etc.)
  • Characterized by the presence of a joint space, which is closed off by a capsule that holds the bone ends together
    • Capsule is lined by synovium
    • Synovial recesses increase the joint space and allow a greater range of motion
    • Normal synovial joint contains a scant amount of synovial fluid which lubricates the cartilaginous surface
  • Articular cartilage, a specialized type of connective tissue, covers the area of functional contact between the opposed bone ends (within the joint capsule) and provides structural support, cushioning and gliding
    • At its periphery, the articular cartilage fuses with the joint capsule and with the periosteum
  • Normal articular cartilage is devoid of blood vessels, lymphatics and nerves; chondrocytes receive their nourishment by means of diffusion, mainly from the synovial fluid
  • In some synovial joints, the articular space is divided, completely or incompletely, by a disk or by menisci
    • Periphery of these intraarticular structures is continuous with the capsule
  • Functional synovial joint depends on the normal function of all of its components
Laboratory
  • Synovial fluid white blood cell (WBC) count and neutrophils percentages are used to aid in the diagnosis of joint infection
    • Septic arthritis (native joint): WBC > 50 x 109/L and neutrophils > 50%
    • Prosthetic joint infection: WBC > 1.7 x 109/L or neutrophils > 65%
  • Negative Gram stain and culture cannot rule out joint infection due to low sensitivity
  • Wet preparation and microscopy (in polarized light with an interference plate) is used to detect crystalline material:
    • Monosodium urate monohydrate: needle shaped, negative birefringent
    • Calcium pyrophosphate dehydrate: rod shaped, positive birefringent
Gross description
  • Most commonly encountered joint specimens are hips and knees (from arthroplasty)
    • Each component of the joint (including subarticular bone) should be described if possible
  • Hip joint (specimen consists of a femoral head with or without femoral neck and fragmented labrum):
    • Femoral head is round, the convex surface of which is lined by smooth and glistening hyaline cartilage
    • At the periphery of articular cartilage there is thin and smooth synovium
    • On cut section, the cartilage is yellow-white and ranges 2 - 3 mm in thickness
    • In a middle age individual, the subarticular bone contains yellow (fatty) marrow
  • Knee joint (specimen consists of fragments of soft tissue, articular, cortical and cancellous bone of the femoral condyles, tibial plateau and patella articular surfaces):
    • Articular surfaces of the medial, lateral and patella femoral compartments are lined by smooth, glistening hyaline cartilage
    • Synovium is thin and smooth
    • Medial and lateral menisci are preserved
Gross images

Contributed by Edward F. DiCarlo, M.D.

Tibial plateau

Microscopic (histologic) description
  • Articular cartilage
    • Hyaline: smooth, glistening; may be fibrous (e.g., temporomandibular and sternoclavicular joints)
    • Composed of chondrocytes (1% of volume), matrix water (70 - 80% wet weight) and a matrix macromolecular framework (collagen [chiefly type II collagen], hydrophilic proteoglycans, decoran, aggrecan and other noncollagenous proteins and glycoproteins) (J Physiol 2006;574:643)
    • Chondrocytes are dispersed within the extracellular matrix and reside in lacunae
      • Chondrocytes have pyknotic nulei and lack abundant nuclear detail
      • Clustering of chondrocytes (cloning) may be seen in degenerative and neoplastic conditions
    • 4 zones (from superficial to deep): gliding (superficial) zone, transitional zone, radial zone and calcified zone (Instr Course Lect 1998;47:477)
      • Chondrocytes are flattened near the surface and more rounded elsewhere
      • Calcified zone stands out by virtue of calcification of its matrix; delineated from the broad radial zone by a wavy line (tidemark), along which the calcareous material is concentrated
      • Calcified zone is anchored to a layer of dense osseous tissue (bony end plate), which seals off the marrow cavity
  • Synovium
    • Lines the remainder of the joint space
    • 2 layers: a thin intimal layer (1 - 3 synoviocytes in depth) and a deeper subintimal layer (vascular loose connective tissue with foci of fat)
  • Synovial fluid
    • Clear and slightly yellow, viscid mucoid
    • Chemical composition similar to plasma, supplemented with hyaluronans
    • 200 - 300 cells/mm2 (synoviocytes, fibrochondrocytes, lymphocytes)
  • Intraarticular and extracapsular structures
    • May be incorporated into the joint capsule or form independent structures, poorly vascularized
    • Ligament: bundles of collagen fibers (joined by proteoglycans) in an organized, hierarchical structure; connect bones to one another
    • Tendon: similar histology to ligaments; connect muscles to bone
    • Enthesis: the interface between bone and tendon / ligament
      • In polarized light, individual collagen fibers can be seen passing from the fibrous tissue at right angle to the bony endplate (Sharpey fibers)
      • Intermediary tissue may be fibrocartilage or hyaline cartilage
    • Disk and meniscus: circular or semilunar collagenous connective tissue in certain joints (e.g., temporomandibular, knee)
Microscopic (histologic) images

Contributed by Lingxin Zhang, M.D.

Articular cartilage

Normal articular cartilage

Ligament

Enthesis

Synovium

Videos

Histology of the joint

Embryology, history and pathology of articular cartilage

Board review style question #1
What are the articulating surfaces of the bone ends of synovial joints normally covered by?

  1. Elastic cartilage
  2. Fibrocartilage
  3. Hyaline cartilage
  4. No cartilage
Board review style answer #1
C. Hyaline cartilage

Comment Here

Reference: Histology-joints
Board review style question #2

Chondrocytes generally have a limited proliferating capacity. The phenomenon shown in the microphotograph is most commonly seen in which scenario?

  1. 30 year old man presents with right knee pain and founded to have numerous loose bodies in the joint
  2. 60 year old woman presents with progressive bilateral hip pain with limited range of motion
  3. 25 year old man presents with an expansile, radiolucent mass in his proximal phalanx of left long finger, with no frank destructive radiological features
  4. 55 year old woman has had increasing epigastric pain for 10 years; imaging reveals a 12 cm exophytic, partially calcified rib mass
Board review style answer #2
B. 60 year old woman presents with progressive bilateral hip pain with limited range of motion. The clinical scenario is degenerative joint disease (osteoarthritis). Chondrocyte cloning can be seen in the other scenarios (A: synovial chondromatosis, C: enchondroma, D: chondrosarcoma) but they are far less common than degenerative joint disease.

Comment Here

Reference: Histology-joints

Implant related changes
Definition / general
  • Tissue around failed implants is often submitted for examination
  • Causes of joint failure are infection (usually staphylococci, also inflammatory cells) and mechanical (granulomatous reaction to debris in joint)
  • Debris: due to metallic component of joint (gray black irregular fragments, often within histiocytes, particularly with titanium implants), polyethylene component of joint (thread-like particles up to 20 microns within histiocytes, visible only under polarized light), methyl methacrylate "grout" (dissolution during routine process reveals irregular holes from 1 - 100 microns), silicone rubber (bosselated, faintly yellow, refractile but not birefringent); all are associated with histiocytes and giant cells
  • Implants can result in aggressive metallosis eroding bone and causing joint failure (Acta Orthop 2010;81:402)
  • Frozen section: assessment of infected joint based on 5+ neutrophils/HPF (excluding surface fibrin and inflammatory exudates) in 5+ separate fields is 43% sensitive and 97% specific for infection compared to culture (Mod Pathol 1998;11:427)
Radiology images

Case #300


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Polyethylene liner wear

Case reports
  • 61 year old woman with loosening of her total hip replacement (THR) prosthesis after a fall (Case #300)
Clinical images

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Metallosis surrounding implant and cervical neck

Gross images

Case #300
Microscopic (histologic) images

Case #300

Polarizing light showed
crystal-like structures
consistent with polyethylene
particles



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Prosthetic synovitis:
hyperplastic synovial
membrane adjacent
to prosthesis

Methylmethacralate
debris (linear webs)
surrounded by
giant cells

Polyethylene flakes (shiny linear material) surrounded by foreign body giant cell reaction (polarized microscopy)

Calcium pyrophosphate crystals under polarized light


Infantile myofibromatosis
Definition / general
  • Also called congenital fibromatosis, solitary infantile myofibromatosis
  • Rare; median age 16 months, range 6 months to 16 years
  • Solitary lesion in craniofacial bone, single nodule in soft tissue, multiple nodules in bone and soft tissue or diffuse involvement of viscera
Radiology description
  • Well circumscribed bone lucency
  • Spontaneous resolution with good prognosis unless visceral involvement
Radiology images

Contributed by Mark R. Wick, M.D.

Multifocal congenital Xray

Case reports
Microscopic (histologic) description
  • Same as soft tissue myofibroma - proliferation of spindle cells with pink cytoplasm, myxoid background
  • Cells arranged in nodules with slit-like vascular spaces or hemangiopericytomatous pattern
Microscopic (histologic) images

Contributed by Mark R. Wick, M.D.

Multifocal congenital

Differential diagnosis
  • Sarcoma
Additional references

Infarct
Definition / general
  • Diaphysometaphyseal infarction: due to infection, vasculitis, sickle cell disease, pheochromocytoma, other vascular disease, Gaucher’s disease, pancreatitis, idiopathic, decompression sickness (historically)
  • Epiphysometaphyseal infarction: same as above, also fractures and dislocations, corticosteroids for collagen vascular diseases, thromboembolic disease, systemic lupus erythematosus, rheumatoid arthritis, Langerhans cell histiocytosis, osteochondrosis
  • Medullary infarcts: patchy necrosis involving cancellous bone and marrow; cortex has collateral blood flow
  • Subchondral infarcts: wedge shaped; cartilage remains viable since nutrients are present in synovial fluid
  • Sites: femoral head or other convex articular surfaces (see aseptic bone necrosis)
  • Complications: large infarcts are rarely associated with osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma; usually adult males in femur / tibia; poor prognosis (Arch Pathol Lab Med 1996;120:482)
  • Note: osteocytes may be lost even in normal bone due to decalcification
Radiology description
  • No changes until third week
  • Then reduced density in areas of dead bone and increased density due to new bone formation
  • Changes appear irregular / mottled
  • Thick, serpentine border
Case reports
Gross description
  • Early (identifiable at autopsy): elongated pale area with hyperemic border sharply demarcated from adjacent bones, radiologically normal
Microscopic (histologic) description
  • Early: ghost marrow cells with pyknotic basophilic nucleated red blood cells; irregular cystic spaces due to fat necrosis, focal calcification, dead trabeculae
  • Late: ingrowth of granulation tissue at periphery of lesion, “creeping substitution” of dead bone by layering of new bone on trabecular surfaces at periphery, rim of collagen forms around periphery, often with calcification
Differential diagnosis
  • Enchondroma: radiologically resembles infarct but lacks its sharp border, has diffuse calcification

Juvenile rheumatoid arthritis
Definition / general
  • Common connective tissue disease in children age 15 years or less - most common chronic rheumatic illness in children (Dermatology Online Journal 2001;7:19)
  • Worldwide incidence varies from 0.008 to 0.226 per 1,000 children
Sites
  • Knees, wrists, elbows, ankles
Pathophysiology
  • Pathogenesis: oligoarthritis and polyarthritis group are T helper 1 cell mediated disorders; precise mechanisms are unclear but proinflammatory cytokines are responsible for part of clinical symptoms (Korean J Pediatr 2010;53:921)
Diagrams / tables

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Cytokine signaling pathways

Clinical features
  • 65% male
  • Either oligoarticular (< 5 joints), polyarticular (5 or more joints) or systemic
  • Compared to classic rheumatoid arthritis, oligoarthritis is more common; systemic large joints are affected more than small joints
  • Associated with HLA-DRB1, infections by mycobacteria, bacteria, viruses
  • 70% recover, 10% have residual severe joint deformities
  • Usually seronegative for rheumatoid factor
  • Symptoms: systemic onset with fever, rash, hepatosplenomegaly, serositis; also warm and swollen joints; pericarditis, myocarditis, pulmonary fibrosis, glomerulonephritis, uveitis, growth retardation
Case reports
Treatment
Clinical images

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Various images

Swelling and flexion contracture

Polyarticular disease

Systemic onset disease

Microscopic (histologic) description
  • Similar morphologic changes as adult rheumatoid arthritis but less severe
Microscopic (histologic) images

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Various images


Juxta-articular myxoma
Definition / general
Epidemiology
  • Median age 43 years, range 16 - 83 years
  • 72% male
Sites
  • Knee (88%), also shoulder, elbow, ankle, hip
Case reports
Clinical images

Images hosted on other servers:

Arthroscopic image
of lesion within
suprapatellar pouch

Gross description
  • Myxoid, mucoid or slimy mass with pale white to yellow color
Gross images

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Glassy appearance

Microscopic (histologic) description
  • Loosely arranged spindle cells in hypovascular myxoid matrix; variable cystic spaces can be seen
Microscopic (histologic) images

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Myxoid stroma and spindle cells

Bland myxoid
neoplasm without
mesenchymal atypia
or hypercellularity


Langerhans cell histiocytosis
Definition / general
  • Langerhans cell histiocytosis (LCH) is a clonal proliferation of cells that morphologically and immunophenotypically resemble Langerhans cells
Essential features
  • Langerhans cell histiocytosis is a clonal proliferation of cells that morphologically and immunophenotypically resemble Langerhans cells
  • More common in childhood (1 - 3 years old) and involves nodal and extranodal sites (most common site is bone)
  • Lesional cells show prominent nuclear grooves with admixed eosinophils and are positive for CD1a, langerin (CD207) and S100
  • Most cases harbor BRAF V600E mutations and other RAS / MAPK pathway activating mutations (Blood 2010;116:1919)
  • Unifocal disease is generally associated with a good prognosis, whereas multisystem and multifocal disease is associated with poor prognosis
Terminology
  • Histiocytosis X
  • Eosinophilic granuloma (solitary bone lesion)
  • Hand-Schüller-Christian disease (multiple lesions)
  • Hashimoto-Pritzker disease
  • Letterer-Siwe disease (disseminated or visceral involvement)
ICD coding
  • ICD-10: C96.0 - multifocal and multisystemic (disseminated) Langerhans cell histiocytosis
  • ICD-10: C96.5 - multifocal and unisystemic Langerhans cell histiocytosis
  • ICD-10: C96.6 - unifocal Langerhans cell histiocytosis
  • ICD-O: 9751/3 - Langerhans cell histiocytosis, NOS
Epidemiology
  • More common in childhood (1 - 3 years old)
  • Incidence: 3 - 5 per million children, 1 - 2 per million adults (Blood 2015;126:26)
  • M > F
  • Pulmonary Langerhans cell histiocytosis strongly associated with smoking
Sites
  • Can be unifocal, multifocal but involving a single organ system or involve multiple organs (Blood 2015;126:26)
  • The most common sites involved are bone and adjacent soft tissue
  • The following sites can also be involved, particularly in multisystem disease (in order of decreasing frequency): bone, skin, bone marrow, lymph nodes, liver, spleen, oral mucosa, lung, central nervous system / pituitary and gastrointestinal tract
  • Brain involvement can result in a neurodegenerative syndrome; pituitary involvement can present with diabetes insipidus (Brain 2005;128:829)
Pathophysiology
  • The majority of cases are clonal and harbor driver mutations involving the RAS / MAPK pathway (Blood 2010;116:1919)
  • Misguided myeloid / dendritic cell model
    • Clinical severity and distribution of Langerhans cell histiocytosis lesion(s) may be defined by the cellular stage of myeloid differentiation during which the somatic BRAF V600E or other activating kinase mutation arises and results in pathological extracellular signal regulated kinases (ERK) activation (Br J Haematol 2015;169:3)
Etiology
  • Pulmonary Langerhans cell histiocytosis is strongly associated with smoking (N Engl J Med 2002;346:484)
  • Causes for other forms are unknown
Diagrams / tables

Contributed by Vignesh Shanmugam, M.D.

Misguided myeloid / dendritic cell model

Diagnosis
  • Imaging studies (Blood 2015;126:26):
    • Skeletal survey
    • PET-CT scan
    • MRI: most effective for brain lesions
  • Bone marrow biopsy / aspiration in patients with cytopenias
  • Endoscopy to rule out gastrointestinal involvement in patients with evidence of malabsorption
  • Biopsy of lesion(s): complete excision is not required, particularly for bone lesions
Laboratory
  • Complete blood count: cytopenias suggest bone marrow involvement (Blood 2015;126:26)
  • Liver function studies: abnormal if liver involved
Radiology description
Radiology images

Contributed by Vignesh Shanmugam, M.D.

Sagittal view

Coronal view



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LCH

Prognostic factors
  • Localized (single system) disease: good outcome
  • Multiorgan (2 or more organs) or multisystem disease including liver, spleen or bone marrow: poor outcome (Blood 2015;126:26)
Case reports
Treatment
  • Surgical resection may be sufficient for single system disease (Blood 2015;126:26)
    • Curettage may be sufficient for isolated bone lesions
  • Systemic chemotherapy (vinblastine, prednisone, mercaptopurine)
  • Smoking cessation for pulmonary Langerhans cell histiocytosis
Microscopic (histologic) description
  • Partial effacement of lymph node with preservation of follicular centers
  • Infiltration of sinuses by Langerhans cells: 12 - 15 microns in diameter with abundant, pale eosinophilic cytoplasm, irregular and elongated nuclei with prominent nuclear grooves and folds, fine chromatin and indistinct nucleoli (Arch Pathol Lab Med 2015;139:1211)
  • Occasionally multinucleated
  • Sinuses commonly have foci of necrosis, often surrounded by rim of eosinophils
  • Variable mitotic activity
Microscopic (histologic) images

Contributed by Vignesh Shanmugam, M.D.

Preservation of follicle centers

Sinusoidal infiltration

Infiltrate of subcapsular sinus

Frequent admixed eosinophils

Prominent nuclear grooves


Admixed multinucleated giant cells

Langerin

CD1a

S100

Cyclin D1



Contributed by Catherine Hagen, M.D.

Langerhans cell histiocytosis

CD1a positive LCH

S100 positive LCH



AFIP images


With Hodgkin lymphoma

Involving spleen

Malignant

S100

Nuclear and cytoplasmic staining S100



Case #314

Diffuse involvement

Sinusoidal and pericapsular involvement

Pericapsular involvement


Admixed eosinophils

Nuclear grooves

Mitotic activity


CD1a

CD5

CD20

CD23

Langerin

S100

Cytology images

Contributed by Vignesh Shanmugam, M.D.

Prominent nuclear grooves and admixed eosinophils

Scattered multinucleated giant cells

Negative stains
Electron microscopy description
  • Birbeck granules: tennis racquet shaped, 200 - 400 nm long and 33 nm wide, with a zipper-like appearance (Mol Biol Cell 2002;13:317)
Electron microscopy images

AFIP images

Birbeck granules



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Birbeck granules

Molecular / cytogenetics description
Sample pathology report
  • Lymph node, right inguinal, excisional biopsy:
    • Langerhans cell histiocytosis (see comment)
    • Comment: The sections show lymph node tissue with an infiltrate of epithelioid cells involving the interfollicular areas and sinuses. The infiltrate is composed of cells with irregular to folded nuclei with prominent nuclear grooves, vesicular chromatin, distinct nucleoli and moderate amounts of pale eosinophilic cytoplasm. Frequent admixed eosinophils are seen. Reactive appearing germinal centers are relatively preserved.
    • Immunohistochemical studies demonstrate that the lesional cells are strongly positive for CD1a, langerin, S100 and cyclin D1.
Differential diagnosis
Board review style question #1
Which of the following is the most frequently mutated gene in the entity pictured below?



  1. ARAF
  2. BRAF
  3. KRAS
  4. MAP2K1
  5. NRAS
Board review style answer #1
B. BRAF. The image shows histiocytoid cells in a background of eosinophils and multinucleated cells characteristic of Langerhans cell histiocytosis. The most frequent driver mutation in Langerhans cell histiocytosis is the BRAF V600E mutation (50% of cases).

Comment Here

Reference: Langerhans cell histiocytosis
Board review style question #2
A 2 year old boy presents with generalized lymphadenopathy, hepatosplenomegaly and lytic bone lesions. A diagnostic lymph node biopsy is performed which shows a sinusoidal infiltrate. Electron microscopy reveals club shaped structures in the lesional cells. Which of the following clinical findings can be seen in this entity?

  1. Bilateral sclerotic long bone lesions
  2. Elevated white blood cell count
  3. Hairy kidney
  4. Neurodegeneration
  5. Serum monoclonal paraprotein
Board review style answer #2
D. Neurodegeneration. The clinical scenario describes an aggressive presentation of multisystem Langerhans cell histiocytosis in a young patient. The histologic findings are characterized by sinusoidal involvement and electron microscopy shows Birbeck granules, i.e. club shaped or tennis racquet shaped structures in the neoplastic Langerhans cells. Brain involvement by Langerhans cell histiocytosis can result in neurodegenerative syndrome or diabetes insipidus secondary to involvement of the hypothalamic pituitary axis. Hairy kidney and sclerotic bone lesions are characteristic of Erdheim-Chester disease. Serum monoclonal paraproteins are typically seen in association with B cell lymphomas and plasma cell neoplasms.

Comment Here

Reference: Langerhans cell histiocytosis

Liposclerosing myxofibrous tumor
Definition / general
  • Also called polymorphic fibroosseous tumor of bone
  • Mixture of lipoma, fibroxanthoma, myxoma, myxofibroma, cyst formation, fat necrosis, ischemic ossification and fibrous dysplasia-like features
  • Mean age 40 years but also teens to 60’s
  • Usually incidental findings, but may gradually enlarge causing fracture, or occasionally undergo malignant transformation
  • Sites: 80% involve proximal femur; also ileum, humerus, rib
  • Some of these cases may be a variant of fibrous dysplasia with similar mutations (Hum Pathol 2003;34:1204)
  • 10% have malignant transformation
Radiology description
  • Well-defined, lytic lesion with sclerotic margin, resembling bone infarct
Microscopic (histologic) description
  • Fat, xanthoma cells, cementum-like ossicles, Paget-type bone, myxofibrous tissue with cystic change
  • Curvilinear trabeculae in fibrous tissue in some cases
Additional references

Low grade (central) osteosarcoma
Definition / general
  • Low grade central osteosarcoma (LGCOS) is a low grade malignant bone forming neoplasm that originates within the medullary cavity and consists of fibroblastic tumor cells with low grade nuclear atypia and well formed neoplastic bony trabeculae
Essential features
  • Predominantly fibroblastic osteosarcoma with mild nuclear atypia and well formed neoplastic bony trabeculae
  • Intramedullary location
  • MDM2 amplification
  • Good prognosis when widely resected
Terminology
  • Well differentiated intramedullary osteosarcoma
ICD coding
  • ICD-O: 9187/3 - Low grade central osteosarcoma
  • ICD-11: 2B51.Z & XH7N84 - Osteosarcoma of bone and articular cartilage of unspecified sites & low grade central osteosarcoma
Epidemiology
Sites
Pathophysiology
Etiology
  • Unknown
Clinical features
Diagnosis
  • Tissue sampling is the gold standard for a definitive diagnosis
  • When the radiologic diagnosis suggests a nontypical osseous lesion, clinicians should exercise caution during follow up of the lesion after the initial biopsy results in a benign diagnosis (Int J Clin Oncol 2014;19:731)
  • Open biopsy is better to obtain additional samples (Int J Clin Oncol 2014;19:731)
  • Lack of MDM2 amplification cannot exclude the diagnosis
  • Any difficult or nondiagnostic biopsies of solitary bone lesions should be referred to specialist tumor units for a second opinion (Sarcoma 2012;2012:764796)
Radiology description
Radiology images

Contributed by Borislav A. Alexiev, M.D.

MRI of tibia mass

Prognostic factors
Case reports
Treatment
  • Most important factor in adequate treatment is an accurate diagnosis
  • Should be treated by wide excision, even after intralesional excision, because intralesional excision alone leads to a poorer prognosis (Cancer 1993;71:338, Int J Clin Oncol 2014;19:731)
  • Dedifferentiated LGCOS patients are treated with chemotherapy largely according to regimens for conventional osteosarcoma (Bone Joint J 2019;101-B:745)
Gross description
  • Most often affects the metaphysis of a long bone
  • Usually poorly circumscribed, a feature reflecting infiltrative growth
  • Tumor sometimes has a well defined margin
  • White rubbery fibrous cut surface with gritty calcifications, located in the medullary cavity
  • Cortical destruction and soft tissue infiltration may be present
  • References: Clin Sarcoma Res 2018;8:16, Pathol Int 2003;53:115
Gross images

Contributed by Borislav A. Alexiev, M.D.

Bone mass

Frozen section description
  • Cellular fascicles of spindle cells with mild nuclear atypia admixed with neoplastic bone component
Microscopic (histologic) description
  • Mildly to moderately cellular fascicles of spindle (fibroblast-like) cells with mild nuclear atypia embedded in a fibrosclerotic stroma
  • Neoplastic bone component which typically consists of irregular anastomosing long and thick bony trabeculae, often in parallel arrangement
  • Bone is woven or lamellar
  • Pagetoid bone may be present (Mod Pathol 2004;17:288)
  • Invasive growth pattern (infiltration of the medullary spaces with encasement of preexisting trabeculae)
  • Cortical destruction and soft tissue infiltration may be present
  • Low mitotic activity (Cancer 1977;40:1337)
  • Cartilage formation may be focally present (Cancer 1990;65:1418)
  • Some tumors focally lack bone matrix
  • Can progress high grade sarcoma (dedifferentiation) (Hum Pathol 2000;31:615)
  • High grade areas often show high grade osteosarcoma histology
  • Variant morphology
Microscopic (histologic) images

Contributed by Borislav A. Alexiev, M.D.

Cortical destruction

Well formed neoplastic bone trabeculae

Fascicles of spindle cells

Lack of bone matrix

Mild nuclear atypia

Negative stains
Electron microscopy description
  • Predominant cells are fibroblasts with well developed rough endoplasmic reticulum
  • Few osteoblasts and myofibroblasts
  • Transition cells between fibroblasts and osteoblasts
  • Presence of osteoid matrix
  • Reference: Ultrastruct Pathol 2006;30:293
Molecular / cytogenetics description
Molecular / cytogenetics images

Contributed by Madina Sukhanova, Ph.D.

MDM2 FISH

Sample pathology report
  • Bone, left distal tibia, excision:
    • Low grade osteosarcoma (see comment)
    • Comment: Magnetic resonance imaging shows an enhancing lesion involving the distal tibial metadiaphysis with marked cortical scalloping. The lesion extends to the epiphysis. Hematoxylin eosin stained tissue sections show moderately cellular fascicles of spindle cells with mild nuclear atypia embedded in a fibrosclerotic stroma admixed with a neoplastic bone component, which consists of irregular anastomosing bony trabeculae. Permeation of host bone (infiltration of the medullary spaces with encasement of preexisting trabeculae) is present. Mitoses are extremely rare (1/10 high power fields). FISH shows MDM2 amplification in tumor cells. The findings support the diagnosis of low grade osteosarcoma. Low grade osteosarcoma has a good prognosis, when widely resected, with metastatic rate of < 5%.
Differential diagnosis
Board review style question #1

A 27 year old man presents with a left proximal femur mass. Hematoxylin eosin stained tissue sections show moderately cellular fascicles of spindle cells with mild nuclear atypia embedded in a fibrosclerotic stroma admixed with a neoplastic bone component. Infiltration of the medullary spaces with encasement of preexisting trabeculae and cortical destruction is present. Mitoses are extremely rare (1/10 high power fields). Immunohistochemical stain for MDM2 is positive in tumor cells while all of the following are negative: S100, AE1 / AE3, CD34, ERG and h-caldesmon. FISH studies demonstrate amplification of MDM2 (12q15).

Which of the following is most likely the correct diagnosis?

  1. Low grade osteosarcoma
  2. Ossifying fibromyxoid tumor
  3. Adamantinoma
  4. Fibrous dysplasia
  5. Desmoplastic fibroma
Board review style answer #1
Board review style question #2

Which of the following is true about low grade central osteosarcoma?

  1. Most often affects jaw bones
  2. Has a good prognosis with a metastatic rate of < 5%
  3. Is the most common primary sarcoma of the skeleton
  4. GNAS mutation is common
  5. Presence of cortical disruption and soft tissue infiltration rules out the diagnosis
Board review style answer #2
B. Has a good prognosis with a metastatic rate of < 5%

Comment Here

Reference: Low grade intraosseous (central) osteosarcoma

Lyme arthritis
Definition / general
  • Due to infection with Borrelia burgdorferi, a spirochete transmitted by Ixodes tick; joints affected weeks to years later
  • Causes chronic arthritis of large joints with pannus formation in 10%
  • Also affects skin, heart, nervous system
  • Precise pathophysiology of disease unknown but involves intricate network of vector, bacterial and host factors (Clin Vaccine Immunol 2008;15:21)
  • "Amber theory": disease due to infection of structures close to joint space, followed by entry of nonviable bacteria and debris into joint space, eliciting inflammatory response (Clin Rheumatol 2012;31:989)
Clinical images

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Erythema migrans skin lesion

Bullseye rash

Lyme arthritis of right knee

Microscopic (histologic) description
  • Chronic papillary synovitis with hyperplasia, fibrin deposition, mononuclear cell infiltrates, onion skin thickening of arterial walls; resembles rheumatoid arthritis
  • Perineuritis may be present
Microscopic (histologic) images

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Borrelia burgdorferi

Positive stains
  • Silver stain highlights bacteria
Electron microscopy description
  • Surface fibrin-like material, thickened synovial lining cell layer, evidence of vascular injury, Borrelia-like structures in synovial membranes and some synovial fluid cell samples (Hum Pathol 1996;27:1025)

Lymphoma
Definition / general
  • 40% of bone tumors are hematologic neoplasms, usually myeloma or lymphoma
  • Primary bone lymphoma (PBL): defined as lymphoma presenting in an osseous site with no evidence of disease elsewhere for at least 6 months
  • Presence of regional lymph nodes does not exclude the diagnosis of PBL (Joint Bone Spine 2000;67:446)
Epidemiology
  • PBL accounts for < 5% of extranodal lymphoma and < 1% of all non-Hodgkin lymphoma (Am J Surg Pathol 1990;14:329)
  • Slight male preponderance
  • Can occur at any age, common in adults, mean age 48 years (range 11 - 83 years)
  • 80% are diffuse large B cell lymphoma
  • PBL is classified into four groups:
    • Group 1: solitary bone lymphoma
    • Group 2: multifocal bony lesions
    • Group 3: cases with distant nodal disease
    • Group 4: cases with visceral disease
  • Secondary involvement of bone by lymphoma is more common than primary, considered to be stage IV
Sites
  • Any bone can be involved
  • Usually sites of bone marrow, axial skeleton (spine), femur
  • Common in metaphysis; presence in diaphysis or epiphysis probably means progressive disease
Pathophysiology
  • Unknown why bone marrow develops into PBL; may be due to osteoclast activating factor has been
  • Strong tendency to spread and relapse suggests homing properties of lymphoma
Clinical features
  • Most commonly bone pain
  • Also palpable mass, pathologic fracture, neurologic symptoms with spine involvement
  • LDH may be elevated
  • B symptoms are uncommon
  • May relapse and involve other bones, lymph nodes, adjacent soft tissue, lung, bone marrow, CNS
Diagnosis
  • Clinical, radiologic, and biopsy
Laboratory
  • Elevated LDH and B2 microglobulin
  • CBC, ESR and CRP
Radiology description
  • Most are permeative, mixed lytic sclerotic bone lesions
  • Usually large portion of bone is affected
  • May be unifocal, monostotic, or polystotic
  • Cortex is destroyed without reactive periosteal new bone formation
  • Variable sclerosis
  • Cystic, commonly mixed
  • Lymph node and soft tissue involvement is common
  • MRI shows signal abnormalities in bone marrow
Prognostic factors
  • Relatively good prognosis: 5 years survival > 80%
  • Factors associated with poor prognosis include: polystotic type, advanced disease, age > 60 years, site of mandible / maxilla
  • Also high IPI score, performance status < 2, normal LDH
  • Also combined modality therapy, higher radiation dose, > 3 cycles of chemotherapy, non germinal center phenotype of diffuse large B cell lymphoma
Case reports
Treatment
  • Combination of radiotherapy and chemotherapy (Clin Orthop Relat Res 2013;471:2684)
  • Surgery has limited role - may delay start of chemotherapy
  • In children, chemotherapy alone is treatment of choice - gives better response
  • Radiotherapy may cause bone sarcoma
Clinical images

AFIP images

Femur



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Imaging of sacral lymphoma

Gross description
  • Usually small biopsy to avoid pathologic fracture disabilities
  • Fish flesh appearance of lymphoma
  • Extraosseous extension and indistinct margins
Microscopic (histologic) description
  • Most common type is diffuse large B cell lymphoma (80%)
    • Similar to morphology at other sites: diffuse growth pattern, infiltrating between bone trabeculae
    • Large atypical cells, abundant cytoplasm
    • Centroblasts, immunoblasts, or large bizarre cells
    • Nuclei show clumped chromatin, prominent nucleoli
    • Component of small lymphocytes is admixed with large cells
    • May have marked spindling and fibrosis
  • Also Burkitt lymphoma, lymphoblastic lymphoma, follicular lymphoma, other low grade B cell lymphoma, Hodgkin lymphoma, T cell lymphomas
Microscopic (histologic) images

AFIP images

Dense nuclei and histiocyte-like cells



Images hosted on other servers:

Sacral diffuse large B cell lymphoma

Cytology description
  • Variable combination of centroblasts, immunoblasts
  • May show large bizarre cells
Peripheral smear description
  • Lymphoma cells are rarely present in peripheral blood; when centroblasts are present, cells are very large and pleomorphic with abundant cytoplasm, often lobulated nucleus containing one or more fairly prominent nucleoli
Positive stains
  • CD45, B cell and T cell markers vary with lymphoma type
  • Diffuse large B cell lymphoma can have germinal center phenotype (CD10+, BCL2+ ), post-germinal center phenotype (CD10−, BCL2− ), or undetermined
  • Often CD30, ALK
Negative stains
Flow cytometry description
  • Shows clonal rearrangement, helps determine phenotype
Electron microscopy description
  • Centroblasts have cleaved nuclei, immunoblasts have large, round nuclei with coarse chromatin and one to three prominent nucleoli
  • Rough endoplasmic reticulum with dilated cisternae and prominent Golgi apparatus are also apparent
  • The degree to which these features are present reflects the cellular degree of plasmacytoid differentiation
Molecular / cytogenetics description
  • Clonally rearranged immunoglobulin genes (BCL2, BCL6, MYC)
  • 80% of Non Hodgkin lymphoma have chromosomal abnormalities
  • Usually Epstein-Barr virus negative
Molecular / cytogenetics images

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FISH: diffuse
large B cell
lymphoma with
MYC translocation

Differential diagnosis
  • Sample size, fibrosis, crush artifacts, and admixed small cells can cause diagnostic problems
  • Metastatic carcinoma:
    • Cells may have cytoplasmic clearing or be arranged in Indian file pattern; keratin+ (other epithelial markers), negative for lymphoid markers
  • Osteosarcoma:
    • Due to reactive bone formation associated with lymphoma
  • Reactive inflammatory conditions:
    • Polymorphous infiltrate, no large neoplastic cells, mixed B and T cells, not clonal
  • Spindle cell sarcoma:
    • When neoplastic cells are spindled, or caused by fibrosis; are negative for CD45, lymphoid markers
  • Other hematopoietic neoplasms, including poorly differentiated plasmacytoma, myeloid sarcoma
  • Other round blue cell tumors of bone, all lack immunoreactivity to lymphoid markers
Staging / staging classifications
  • Ann Arbor staging system is preferred until a better system is available

Mazabraud syndrome
Definition / general
  • Mazabraud syndrome is a rare condition resulting from postzygotic activating somatic mutations in the GNAS gene
  • Typically codon 201 and rarely codon 227 (Histopathology 2007;50:691)
  • The exact presentation and severity depend on the extent of mosaicism and the involved tissues (Curr Osteoporos Rep 2015;13:146)
  • Most patients are diagnosed in adulthood
Essential features
  • Mazabraud syndrome is the dyad of:
    • Fibrous dysplasia of bone, either polyostotic or monostotic
    • One or more intramuscular myxomas
ICD coding
  • ICD-10: Q78.1 - polyostotic fibrous dysplasia
  • ICD-10: D21.9 - benign neoplasm of connective tissue and other soft tissue, unspecified
  • ICD-11: FB80.0 - fibrous dysplasia of bone
Epidemiology
  • Mazabraud syndrome is a very rare disorder identified with an estimated prevalence of < 1 in 1,000,000 and most data is drawn from a single large European cohort (J Bone Joint Surg Am 2019;101:160)
  • 2.2% of a multicenter European cohort of 1,446 patients with fibrous dysplasia eventually met criteria for Mazabraud syndrome (J Bone Joint Surg Am 2019;101:160)
  • F:M = 2.2:1 (J Bone Joint Surg Am 2019;101:160)
  • Women with right sided polyostotic fibrous dysplasia are statistically most likely to eventually be diagnosed
  • 15% have a preexisting diagnosis of McCune-Albright syndrome
  • Rare (< 1%) lifetime risk of sarcomatous transformation of fibrous dysplasia
Sites
  • There is an unexplained slight (60%) right sided predominance (J Bone Joint Surg Am 2019;101:160)
  • Fibrous dysplasia in Mazabraud syndrome is most commonly found in the proximal femur, pelvis and proximal tibia (J Bone Joint Surg Am 2019;101:160)
  • In contrast, nonsyndromic fibrous dysplasia is most commonly found in the ribs
  • Intramuscular myxomas are almost always adjacent to fibrous dysplasia lesions and are usually found in the quadriceps femoris or lower limb girdle muscles (J Bone Joint Surg Am 2019;101:160)
Pathophysiology
  • Constitutively active mutant GNAS results in increased cAMP
  • Increased cAMP:
    • Promotes proliferation and inhibits differentiation of fibroblasts, which replace normal bone producing fibrous dysplasia lesions
    • Promotes proliferation and inhibits differentiation of fibroblasts forming expansile, myxoid mass within muscle
  • Fibrous dysplasia elaborates fibroblast growth factor 23 (FGF23):
    • Inhibits renal resorption of phosphate
    • Causes hypophosphatemia
    • Causes hyperphosphaturia
Etiology
  • Results from de novo mutations in GNAS (J Bone Joint Surg Am 2019;101:160)
    • No inherited case has ever been reported
    • Germline GNAS mutation is presumed embryonic lethal
  • Has no risk factors
Clinical features
  • The two most common presentations are:
    • Fibrous dysplasia related pain / pathologic fracture
    • Intramuscular myxomas related pain
  • Fibrous dysplasia seen in Mazabraud syndrome:
    • Commonly polyostotic but may be monostotic
    • Is often unilateral, in keeping with postzygotic mutation and is more often right sided
  • Intramuscular myxomas seen in Mazabraud syndrome:
    • Are usually multiple
    • Are more likely to recur than their sporadic counterparts, although this observation may instead represent additional primary lesions
    • Often declare themselves up to 10 years after fibrous dysplasia
Diagnosis
  • Mazabraud syndrome is essentially a clinical diagnosis
  • Role of genetic testing:
    • Not routinely performed but available
    • False negatives are common due to mosaicism and sampling
    • Positive results merely confirm a clinical diagnosis
    • No genotype / phenotype correlation, therefore no prognostic value (Orphanet J Rare Dis 2008;3:12)
  • Up to 10 years temporal separation between diagnosis of fibrous dysplasia and clinically / radiologically apparent intramuscular myxomas is a significant barrier to diagnosis
Laboratory
  • Some patients with McCune-Albright syndrome have:
    • Depressed serum phosphate
    • Elevated urine phosphate
  • However, these are also seen in sporadic fibrous dysplasia
Radiology description
  • Fibrous dysplasia
    • On plain radiography and CT, fibrous dysplasia is usually well defined and homogeneous with endosteal scalloping and cortical thinning
    • Classic ground glass opacification is only sometimes present
    • MRI is not a recommended modality for assessing fibrous dysplasia (Insights Imaging 2018;9:1035)
  • Intramuscular myxoma
    • On US, intramuscular myxoma is a hypoechoic ovoid mass frequently with a hyperechoic rim (a so called bright rim sign) or hyperechoic pole(s)
    • Plain radiography is not recommended for assessing intramuscular myxoma
    • On CT, intramuscular myxoma is a well demarcated, hypodense, ovoid mass
    • On MRI, intramuscular myxoma has multiple patterns beyond the scope of this article (Radiographics 2014;34:964)
Prognostic factors
Case reports
Treatment
Microscopic (histologic) description
  • Fibrous dysplasia lesions seen in Mazabraud syndrome are histologically indistinguishable from nonsyndromic fibrous dysplasia, characterized by (Arch Pathol Lab Med 2013;137:134):
    • Woven bone with trabeculae that are:
      • Thin
      • Irregular
      • Curvilinear
    • Fibrous stroma
    • Absence of osteoblastic rimming
  • Intramuscular myxoma lesions seen in Mazabraud syndrome are histologically indistinguishable from nonsyndromic intramuscular myxomas, characterized by (Am J Surg Pathol 1998;22:1222):
    • Bland stellate and bipolar fibroblasts
    • Abundant myxoid matrix
    • Highly variable cellularity
Microscopic (histologic) images

Contributed by Jessica L. Davis, M.D.

Fibrous dysplasia

Intramuscular myxoma

Molecular / cytogenetics description
Sample pathology report
  • Bone, biopsy:
    • Fibrous dysplasia of bone (see comment)
    • Comment: Fibrous dysplasia is most commonly sporadic but is also a typical presenting feature of McCune-Albright syndrome and Mazabraud syndrome. Clinical correlation is advised.
  • Soft tissue, biopsy:
    • Intramuscular myxoma (see comment)
    • Comment: Intramuscular myxomas are most commonly sporadic but are also a common presenting feature of Mazabraud syndrome. Clinical correlation is advised.
Differential diagnosis
Board review style question #1

    A 54 year old woman is seen for 1 year of progressive radicular symptoms and on imaging is found to have a 2 cm lesion in her right piriformis muscle impinging upon her sciatic nerve. The resection specimen is signed out as intramuscular myxoma. She has no other significant medical history. Which of the following is true?

  1. The lesion is most likely sporadic
  2. The lesion most likely has an inactivating GNAS mutation
  3. The lesion most likely has wild type GNAS
  4. The patient most likely has Mazabraud syndrome
  5. The patient most likely has McCune-Albright syndrome
Board review style answer #1
A. Most intramuscular myxomas are sporadic. Although intramuscular myxomas are a feature of Mazabraud syndrome as in A, the patient does not meet diagnostic criteria which include polyostotic fibrous dysplasia and multiple intramuscular myxomas. McCune-Albright syndrome, as in C, does not include intramuscular myxomas. The genotype for sporadic intramuscular myxoma is an activating mutation in codon 201 of GNAS, not wild type as in B, and not an inactivating mutation as in E.

Comment Here

Reference: Mazabraud syndrome
Board review style question #2
    A 49 year old man presents to the ER after sudden onset of severe left hip pain while watering his garden. A plain radiograph reveals a fracture of the left femur involving a well circumscribed lesion with central ground glass matrix and an incomplete sclerotic rim. Similar lesions are noted in the left pubic ramus and left iliac wing. He undergoes hip replacement, and while being seen for possible revision 4 years later, a CT demonstrates well demarcated, hypodense, ovoid lesions in the gluteus minor and vastus medialis muscles. What is the etiology of these lesions?

  1. Chronic abscess formation
  2. Dysplastic ossification of soft tissue
  3. Migration of prosthetic hardware
  4. Natural progression of Mazabraud syndrome
  5. Sporadic mutation of a tyrosine kinase
Board review style answer #2
D. The patient's lesions are most consistent with polyostotic fibrous dysplasia and intramuscular myxomas, which together constitute Mazabraud syndrome.

Comment Here

Reference: Mazabraud syndrome

McCune-Albright syndrome
Definition / general
  • McCune-Albright syndrome (MAS) is a rare condition that results from postzygotic activating somatic mutations in the alpha subunit of the GNAS gene, leading to continued stimulation of endocrine glands
  • Exact presentation and severity depends on the extent of mosaicism and the involved tissues (Curr Osteoporos Rep 2015;13:146)
  • Most patients are diagnosed in childhood or adolescence
Essential features
  • Classically defined as the triad of
    • Polyostotic fibrous dysplasia of bone
    • Precocious puberty
    • > 3 café au lait macules
  • However, a more inclusive definition has been proposed, consisting of
    • Monostotic fibrous dysplasia of bone or polyostotic fibrous dysplasia of bone
    • Hyperfunctional endocrinopathy or café au lait macules (J Bone Miner Res 2006;21:P99)
Terminology
  • McCune-Albright syndrome (MAS) has no synonyms
ICD coding
  • ICD-10: Q78.1 - polyostotic fibrous dysplasia
  • ICD-11: FB80.0 - fibrous dysplasia of bone
Epidemiology
Sites
Pathophysiology
  • Constitutively active mutant GNAS results in increased cyclic adenosine monophosphate, which
    • Promotes proliferation and inhibits differentiation of fibroblasts, which replace normal bone and produce fibrous dysplasia lesions
    • Promotes proliferation and autonomous function of endocrine organs
  • Fibrous dysplasia elaborates fibroblast growth factor 23, which
    • Inhibits renal resorption of phosphate
    • Causes hypophosphatemia
    • Causes hyperphosphaturia
  • Examples:
Etiology
  • Results from de novo mutations in GNAS (Curr Osteoporos Rep 2015;13:146)
    • No inherited case has ever been reported
    • Germline GNAS mutation is presumed embryonic lethal
  • Has no risk factors
Clinical features
  • 2 most common presentations are fibrous dysplasia related pain and precocious puberty
  • Fibrous dysplasia
    • May be monostotic or polyostotic
    • When polyostotic, it may be unilateral, in keeping with postzygotic mutation
  • Classical and most common endocrinopathy is precocious puberty; however, other endocrinopathies include
  • Café au lait macules typically
    • Are light brown in color but can vary depending on patient's skin color
    • Are present at, or shortly after, birth
    • Are recognized after another feature of the disease has prompted a skin survey
    • Are near the midline
    • Respect the lines of Blaschko
    • Have jagged irregular borders, unlike the smooth borders that are characteristic of macules seen in neurofibromatosis
    • Are ipsilateral with fibrous dysplasia (Orphanet J Rare Dis 2008;3:12)
Diagnosis
  • Essentially a clinical diagnosis
  • Genetic testing:
    • Not routinely performed but available
    • False negatives are common due to mosaicism and sampling
    • Positive results merely confirm a clinical diagnosis
    • No genotype / phenotype correlation, therefore no prognostic value (Orphanet J Rare Dis 2008;3:12)
  • When there is clinical suspicion:
    • Skeletal survey to identify lesions suspicious for fibrous dysplasia
    • CT is more sensitive for craniofacial fibrous dysplasia
    • Biopsy can confirm fibrous dysplasia
    • Skin survey to identify café au lait macules
    • If not apparent at presentation, endocrinopathies may become apparent with laboratory studies and focused examinations
Laboratory
  • Some patients have multiple endocrinopathies; others have none
  • The following laboratory abnormalities may be present in any combination (Orphanet J Rare Dis 2008;3:12):
    • Depressed serum phosphate
    • Elevated urine phosphate
    • Elevated cortisol
    • Elevated sex steroid hormones
    • Elevated thyroid hormone
    • Depressed thyroid stimulating hormone
Radiology images

Images hosted on other servers:
Missing Image

Ulnar fracture

Missing Image

Lucency in long bones

Prognostic factors
Case reports
Treatment
Clinical images

Images hosted on other servers:

5 year old girl: jagged "coast of Maine" borders

Missing Image

Café au lait spots

Gross images

Images hosted on other servers:
Missing Image

Ovarian abnormalities

Microscopic (histologic) description
  • Fibrous dysplasia lesions are histologically indistinguishable from nonsyndromic fibrous dysplasia, characterized by (Arch Pathol Lab Med 2013;137:134)
    • Woven bone with trabeculae that are thin, irregular and curvilinear
    • Fibrous stroma
    • Absence of osteoblastic rimming
Microscopic (histologic) images

Contributed by Jessica L. Davis, M.D.

Fibrous dysplasia

Molecular / cytogenetics description
  • Mutation specific restriction enzyme digest (MSRED) method may identify mutations in codon 201 or 227 of the GNAS1 gene (Histopathology 2007;50:691)
Sample pathology report
  • Bone, biopsy:
    • Fibrous dysplasia of bone (see comment)
    • Comment: Fibrous dysplasia is most commonly sporadic but is also a typical presenting feature of McCune-Albright syndrome and Mazabraud syndrome. Clinical correlation is advised.
Differential diagnosis
  • Nonsyndromic fibrous dysplasia of bone:
    • Results from postzygotic GNAS mutations
    • Other features of McCune-Albright syndrome are absent or as yet undeclared
      • Endocrinopathies are absent
      • Café au lait macules are absent
  • Mazabraud syndrome:
    • Results from postzygotic GNAS mutations
    • Presents with polyostotic fibrous dysplasia and intramuscular myxomas
    • Typically diagnosed in adulthood
    • Patients may satisfy criteria for both McCune-Albright syndrome and Mazabraud syndrome
  • Hyperparathyroidism jaw tumor syndrome:
  • Ossifying fibromas of jaw may be confused with fibrous dysplasia:
    • Randomly distributed mature (lamellar) bone spicules rimmed by osteoblasts admixed with a fibrous stroma
Board review style question #1

A 23 year old man diagnosed at age 8 with McCune-Albright syndrome is considering starting a family and seeks genetic counseling. Which of the following best describes his likelihood of having an affected child?

  1. 0% chance of having an affected child
  2. 25% chance of having an affected female child
  3. 25% chance of having an affected male child
  4. 50% chance of having an affected child
  5. 100% chance of having an affected child
Board review style answer #1
A. 0% chance of having an affected child. McCune-Albright syndrome results from postzygotic mutations and an inherited case has never been reported. Germline mutation in GNAS is believed to be embryonic lethal. The likelihood that the patient will have an affected child is effectively 0% (Curr Osteoporos Rep 2015;13:146).

Comment Here

Reference: McCune-Albright syndrome
Board review style question #2
A 6 year old girl is brought to her pediatrician by her father who is concerned about her early breast development. On exam, the patient's breasts are Tanner stage 3 and the clinician also notes a large, irregularly contoured pigmented macule on her left flank. In addition to starting letrozole, which of the following is an appropriate next step?

  1. Diagnose the patient with McCune-Albright syndrome and order a skeletal survey
  2. Perform a complete skin survey in clinic and order a skeletal survey
  3. Perform a punch biopsy at the edge of the macule
  4. Send a blood sample for sequencing of GNAS
  5. Send a tissue sample for sequencing of GNAS
Board review style answer #2
B. Perform a complete skin survey in clinic and order a skeletal survey. A complete skin survey and skeletal survey would potentially reveal additional findings that would rule in or provisionally rule out McCune-Albright syndrome (MAS). As presented in the question, the patient has findings suggestive of but not diagnostic for MAS, making answer A wrong. A punch biopsy, as in answer C, would likely reveal melanocyte proliferation but would not aid in diagnosis or direct treatment. Sequencing studies, as in answers D and E, if negative, would not rule out MAS and if positive, would only confirm a clinical diagnosis; thus, neither is contributory (Curr Osteoporos Rep 2015;13:146).

Comment Here

Reference: McCune-Albright syndrome

Mesenchymal chondrosarcoma
Definition / general
  • Malignant biphasic mesenchymal neoplasm with a well differentiated hyaline cartilage component
  • Most cases have HEY-NCOA2 fusions; however IRF2BP2-CDX1 fusion has also been described (PLoS One 2012;7:e49705)
Essential features
  • Malignant biphasic neoplasm that most commonly involves soft tissue, bone and intracranial sites, with tendency for late local recurrences and distant metastases
ICD coding
  • ICD-O: 9240/3 - mesenchymal chondrosarcoma
  • ICD-10:
    • C40 - malignant neoplasm of bone and articular cartilage of limbs
    • C41 - malignant neoplasm of bone and articular cartilage of other and unspecified sites
  • ICD-11: 2B50.Z & XH8X47 - chondrosarcoma of bone and articular cartilage of unspecified sites and mesenchymal chondrosarcoma
Epidemiology
  • Usually adolescents and young adults
  • Slight female predominance
Sites
  • Most commonly bone, soft tissue (head and neck, thigh), intracranial sites (meninges) and visceral organs
  • Bone lesion: up to 50% in jaw (Arch Pathol Lab Med 2012;136:61)
Pathophysiology
  • Gene fusion driven
Etiology
  • HEY1-NCOA2 fusion evokes many different mechanisms, including direct DNA binding, protein - protein interaction and epigenetic modification
  • Combination of these pathway dysregulations (including Notch signaling pathway, chromatin remodeling, apoptosis and transforming growth factor beta [TGFβ] signaling) results in a chimeric fusion protein that drives the biology of mesenchymal chondrosarcoma (Curr Oncol Rep 2018;20:37)
Clinical features
  • Clinical symptoms depend on the tumor location and can last for years prior to diagnosis
  • Enlarging, usually painful mass
  • Neurologic symptoms If arising in spine / cranium (Arch Pathol Lab Med 2012;136:61)
Diagnosis
  • Diagnostic diagram includes radiology, histology (biopsy, resection specimen) with immunohistochemistry and molecular analysis
Radiology description
  • CT scan:
    • Lobulated, destructive lytic lesion with granular, ring and arc or irregularly shaped calcifications (Radiology 1993;186:819, Skeletal Radiol 2005;34:785)
    • Bone lesion: usually erodes / destroys the cortex and involves the surrounding soft tissue
  • MRI:
    • Lobulated, heterogeneous lesion with low signal intensity on T1 weighted images and high signal intensity on T2 (Skeletal Radiol 2005;34:785)
Radiology images

Contributed by Borislav A. Alexiev, M.D.
Anterior mediastinal mass

Anterior mediastinal mass

Prognostic factors
  • In one study, 5, 10 and 20 year overall survival was 55.0%, 43.5% and 15.7%, respectively (PLoS One 2015;10:e0122216)
  • With chemotherapy: 5 year and 10 year overall survival is 84% and 80%, respectively
  • Without chemotherapy, under surveillance: 5 year and 10 year overall survival is 73% and 46%, respectively (Eur J Cancer 2015;51:374)
Case reports
Treatment
Gross description
  • Lobulated, solid, firm, gray-tan, fleshy mass with scattered gritty white calcifications
  • Bone lesions arise in the medullary cavity or on the bone surface, causing cortical destruction and extension into the soft tissue (Arch Pathol Lab Med 2012;136:61)
Gross images

Contributed by Iva Brčić, M.D., Ph.D. and Bernadette Liegl-Atzwanger, M.D.
Lobulated mass

Lobulated mass

Calcifications

Calcifications

Frozen section description
  • Tumor composed of islands of well differentiated hyaline cartilage and primitive mesenchymal cells / undifferentiated small blue cells
Microscopic (histologic) description
Microscopic (histologic) images

Contributed by Iva Brčić, M.D., Ph.D. and Bernadette Liegl-Atzwanger, M.D.
Biphasic tumor

Biphasic tumor

Abrupt transition

Abrupt transition

2 components

2 components

Spindle cell morphology

Spindle cell morphology


Transition higher power

Transition higher power

Cellular atypia

Cellular atypia

CD99 staining

CD99 staining

Cytology description
  • Highly cellular smears composed of small round blue cells with high nuclear to cytoplasmic ratio infiltrating the fibrillary matrix (Arch Pathol Lab Med 2018;142:1421)
Positive stains
Molecular / cytogenetics description
Sample pathology report
  • Right thigh, excision:
    • Extraskeletal mesenchymal chondrosarcoma (see comment)
    • Comment: Tumor is composed of islands of well differentiated hyaline cartilage and primitive mesenchymal cells. Immunohistochemically, the tumor cells are positive for S100, focally positive for CD99 and SOX9 and are negative for CD20 and keratin. The morphology and immunoprofile strongly support the diagnosis of mesenchymal chondrosarcoma.
Differential diagnosis
  • Other small round cell neoplasms:
  • Ewing sarcoma:
    • Tumor composed of monotonous round blue cells
    • No hemangiopericytoma-like vascular pattern or cartilaginous component
    • NKX2.2+, CD99 diffuse membranous staining
    • Harbors EWSR1 negative and FUS rearrangements
  • Lymphoma:
    • Lack of cartilaginous component; lymphoid antibodies positive
  • Rhabdomyosarcoma:
  • Synovial sarcoma:
    • No cartilaginous component
    • Keratin+, EMA+, TLE1+, SSX+, SS18-SSX+
    • Harbors SSX rearrangements
  • Malignant solitary fibrous tumor:
    • No cartilaginous component, hemangiopericytoma-like vascular pattern present
    • CD34+, STAT6+
    • Harbors NAB2-STAT6 fusion
Board review style question #1
Which of the following is true about mesenchymal chondrosarcoma?

  1. Cut surface is white with myxoid areas
  2. Cytology smears are paucicellular
  3. On imaging, calcifications are rare
  4. Tumor cells are typically negative for S100
  5. Tumor is composed of undifferentiated small blue cells mixed with islands of mature appearing, well differentiated hyaline cartilage
Board review style answer #1
E. Tumor is composed of undifferentiated small blue cells mixed with islands of mature appearing, well differentiated hyaline cartilage

Comment Here

Reference: Mesenchymal chondrosarcoma
Board review style question #2

A 24 year old man presented with an intracranial mass arising from the meninges. Histologically, tumor is composed of areas with small blue cells and islands of well differentiated hyaline cartilage. Which of the following is most likely the correct diagnosis?

  1. B cell lymphoma
  2. Ewing sarcoma
  3. Mesenchymal chondrosarcoma
  4. Rhabdomyosarcoma
  5. Synovial sarcoma
Board review style answer #2
C. Mesenchymal chondrosarcoma

Comment Here

Reference: Mesenchymal chondrosarcoma

Metastases
Definition / general
  • Most common malignant bone tumor is metastatic carcinoma
  • In adults, 80% from prostate, breast, kidney, lung or thyroid
  • In children, from neuroblastoma, Wilm tumor, osteosarcoma, Ewing / PNET or rhabdomyosarcoma
  • Intraspinal seeding may occur along Batson’s plexus of veins
  • Positive isotope bone scans (versus myeloma)
  • Sarcomatoid carcinoma: consider if patient 60+ years with spindling bone malignancy; cells usually plumper than bone sarcomas and accompanied by carcinoma; renal cell carcinoma is most common primary site
  • Common sites: axial skeleton, proximal femur, proximal humerus; usually marrow; very rare to be distal to elbow or knee
  • Solitary metastases: kidney, thyroid
  • Small bones of hands and feet: colon, lung, kidney
  • Blastic lesions: prostate, carcinoid tumor, neuroendocrine tumors
Radiology images

Contributed by Mark R. Wick, M.D. and AFIP images

Breast carcinoma

Lung carcinoma to metatarsal

Prostate adenocarcinoma

Thyroid carcinoma


Lung carcinoma metastasis

Prostate carcinoma - osteoblastic features

Thyroid carcinoma

Case reports
Treatment
  • Radiation therapy for pain relief and to prevent fracture of weight bearing bones
Gross images

Contributed by Mark R. Wick, M.D.

Lung carcinoma in humeral head

Lung squamous cell carcinoma

Microscopic (histologic) images

Contributed by Semir Vranić, M.D., Ph.D., Mark R. Wick, M.D. and AFIP images

Bone metastasis

Primary prostate adenocarcinoma

Lung carcinoma to metatarsal


Lung carcinoma to metatarsal

Lung carcinoma to metatarsal TTF1

Prostate adenocarcinoma

Renal cell carcinoma


Lung: metastatic carcinoma

Lung: metastatic carcinoma BerEp4

Prostate: metastatic carcinoma

Thyroid: metastatic carcinoma

Differential diagnosis
  • Myeloma:
    • Negative isotope bone scan, monoclonal protein in serum or urine

Myositis ossificans and fibro-osseous pseudotumor of digits
Definition / general
  • Myositis ossificans and fibro-osseous pseudotumor of digits are self limited, benign neoplasms composed of spindle cells and osteoblasts
  • Myositis ossificans, fibro-osseous psedotumor and soft tissue aneurysmal bone cyst belong to the same neoplastic spectrum
Essential features
  • Benign, reactive, ossifying soft tissue mass lesion, associated with trauma and characterized by zonal pattern
Terminology
  • Not recommended:
    • Pseudomalignant osseous tumor of soft tissue, myositis ossificans circumscripta, myositis ossificans traumatica
  • Related entities:
    • Panniculitis / fasciitis ossificans: similar histologic features but involves subcutis and tendons / fascia rather than muscle
ICD coding
  • ICD-10: M61.00 - myositis ossificans traumatica, unspecified site
Epidemiology
  • Usually physically active young males (second and third decade) with rapid growth of mass (Clin Case Rep 2021;9:e04608)
  • 60 - 75% have history of trauma in prior 4 - 6 weeks (J Med Case Rep 2010;4:270)
  • May also occur after elective surgery, severe burns, neurological injury
Sites
Pathophysiology
  • Pathogenesis is poorly understood
  • Thought to develop from differentiation of fibroblast to osteoblast secondary to inflammatory cytokine activity, particularly bone morphogenetic protein 1 (BMP1), BMP2 and transforming growth factor (TGF)
  • These cytokines promote differentiation of perivascular mesenchymal cells into osteoblasts and chondroblasts, which then undergo endochondral ossification (J Am Acad Orthop Surg 2015;23:612)
Etiology
Diagrams / tables

Images hosted on other servers:
Different stages of myositis ossificans

Different stages

Pathogenesis of myositis ossificans

Pathogenesis

Clinical features
Diagnosis
Laboratory
  • Usually not required for diagnosis
  • Early stage (0 - 4 weeks):
    • Serum alkaline phosphatase (SAP): normal
    • C reactive protein (CRP) and erythrocyte sedimentation rate (ESR): elevated
    • Creatinine phosphokinase (CPK): elevated
  • Intermediate stage (4 - 8 weeks):
    • SAP: elevated
    • CRP and ESR: normal to mildly elevated
    • CPK: elevated
  • Mature, late stage (> 8 weeks):
    • SAP: elevated
    • CRP and ESR: normal
    • CPK: normal to mildly elevated
  • Reference: Curr Sports Med Rep 2018;17:290
Radiology description
  • Early stage:
    • Xray: normal to faint calcification (flocculent radiopacities: dotted veil pattern)
    • CT scan: soft tissue edema
    • MRI: isodense on T1 and hyperintense on T2
  • Intermediate stage:
    • Xray: peripheral calcified rim with central lucency
    • CT scan: peripheral mineralization with central low attenuation (calcification proceeds from periphery to center)
    • MRI: isodense / hypodense to adjacent skeletal muscle on all images
  • Mature, late stage:
    • Xray: diffuse soft tissue calcification
    • CT scan: diffuse ossification pattern (even in late lesions, the central core may remain uncalcified)
    • MRI: well defined soft tissue mass and isodense to fat on all images
  • References: Curr Sports Med Rep 2018;17:290, J Clin Orthop Trauma 2021;17:123
Radiology images

Contributed by Nasir Ud Din, M.B.B.S.
Early stage

Xray of early stage

Xray of mid to late stage

Xray of mid to late stage

MRI buttock for soft tissue mass

MRI buttock for soft tissue mass



Images hosted on other servers:
Radiology of different stages

Different stages

Prognostic factors
Case reports
Treatment
Clinical images

Images hosted on other servers:
Clinical photograph (a) and chest radiograph (b)

Large right pectoral mass and chest radiograph

Gross description
Gross images

Images hosted on other servers:
Excised and bisected mass

Excised and bisected mass

Microscopic (histologic) description
  • Histologically, zonal pattern is characteristic with different degrees of cellular differentiation (inner zone, intermediate zone and peripheral zone)
    • Inner central zone:
      • Composed of fibroblastic / myofibroblastic proliferation, which is richly vascular, rich in inflammatory cells and resembles nodular fasciitis; some multinucleated giant cells may also be seen
      • Cells show mild degree of pleomorphism and brisk mitosis
      • Areas of hemorrhage, fibrin, endothelial proliferation and entrapped atrophic muscle fibers are noted
    • Intermediate zone:
      • There is a mixture of fibroblasts and osteoblasts along with erratic osteoid separated by small sized vessels
      • Scattered chondrocytes may be appreciated
    • Peripheral zone:
      • Osteoid undergoes calcification and leads to lamellar bone formation
      • Islands of mature or immature cartilage may be present
      • Extreme periphery / margin shows mature bone with osteoblastic rimming and little to no pleomorphism
      • Lesion is separated from the normal tissue (muscle) by a zone of loose, myxoid fibrous tissue
  • Early stage (0 - 4 weeks):
    • Mass shows central zone morphology with only rare foci showing osteoid
    • Zonal pattern is not very much appreciated
  • Intermediate stage (4 - 8 weeks):
    • Zonal pattern is appreciated with central zone, intermediate zone and peripheral zone
  • Late, mature stage (> 8 weeks):
    • Mass is mostly composed of mature bone
    • Very old lesions show only lamellar bone separated by fibrovascular stroma, mimicking osteoma
  • References: Curr Sports Med Rep 2018;17:290, Goldblum: Enzinger and Weiss's Soft Tissue Tumors, 7th Edition, 2019, Exp Ther Med 2021;21:531, Mol Clin Oncol 2018;8:749, Autops Case Rep 2021;11:e2021316
Microscopic (histologic) images

Contributed by Ghazi Zafar, M.B.B.S., Nasir Ud Din, M.B.B.S. and @JMGardnerMD on Twitter
Periphery

Periphery

Circumscription

Circumscription

Zonation

Zonation

Central zone

Central zone

Foci of cartilage

Foci of cartilage

Osteoid production

Osteoid production


Multinucleated giant cells

Multinucleated giant cells

Myositis ossificans and fibro-osseous pseudotumor of digits Myositis ossificans and fibro-osseous pseudotumor of digits Myositis ossificans and fibro-osseous pseudotumor of digits Myositis ossificans and fibro-osseous pseudotumor of digits

Myositis ossificans and fibro-osseous pseudotumor of digits

Cytology description
Cytology images

Images hosted on other servers:
Cytological features

Cytological features

Positive stains
Negative stains
Electron microscopy description
  • Fibroblasts and myofibroblasts have dilated rough endoplasmic reticulum and aggregates of cytoplasmic filaments variably associated with dense bodies; osteoblasts have numerous mitochondria and abundant, dilated rough endoplasmic reticulum
Molecular / cytogenetics description
Videos

Myositis ossificans (benign mimic of sarcoma) bone / soft tissue pathology & radiology correlation

Sample pathology report
  • Thigh mass, excision:
    • Myositis ossificans (see comment)
    • Comment: The sections from the mass show a circumscribed lesion with characteristic zonal pattern, with inner zone showing tissue culture-like background, against which are seen plump fibroblasts and myofibroblasts. This area is rimmed by immature bone in the middle and mature lamellar bone at the periphery.
Differential diagnosis
  • Extraskeletal osteosarcoma:
    • Usually occurs in sixth or seventh decade
    • No zoning pattern is seen (backward zonation is appreciated; that is, most mature bone in the center with woven bone at the periphery) (Czerniak: Dorfman and Czerniak's Bone Tumors, 2nd Edition, 2015, Clin Case Rep 2019;7:2260)
    • There is a mixture of atypical spindle cells with moderate to marked degree of pleomorphism and increased mitoses
    • Osteoid is seen directly produced by these atypical cells
  • Parosteal osteosarcoma:
    • Can cause diagnostic difficulty, especially when myositis ossificans is located near the surface of a major long tubular bone
    • Radiology shows central heavy mineralization as opposed to myositis ossificans
    • Connection with underlying bone is seen in parosteal osteosarcoma
    • Parosteal osteosarcoma shows well developed tumor bone, unlike zonal pattern of myositis ossificans
  • Periosteal osteosarcoma:
    • Connection with the bone surface is identifiable with periosteal reaction
    • Direct tumor bone formation identified
    • No zonal pattern
  • Fibrodysplasia ossificans progressiva:
    • Multifocality and specific hypoplasia of the first metacarpal and metatarsal bones
    • Rare genetic disorder that spreads along the muscle planes
  • Calcified / ossified synovial sarcoma:
    • Can become extensively calcified with secondary bone formation
    • Lacks zoning pattern
    • Highly hyperchromatic tumor cells express SS18::SSX and TLE1 immunostains
Board review style question #1

A 36 year old boxer presented with a painful mass in the right arm for the last 1.5 months. On radiology, an intramuscular mass was seen with peripheral mineralization and central latency. It was biopsied, which showed the morphology in the image above. What is the most likely diagnosis?

  1. Extraskeletal osteosarcoma
  2. Myositis ossificans
  3. Periosteal osteosarcoma
  4. Synovial sarcoma with bone formation
Board review style answer #1
B. Myositis ossificans. The given history in this case shows that the patient is physically active and provides short duration history of the lesion. The radiological findings suggest a lesion with maturation at periphery. The microscopic image shows characteristic zonation. These are all features of myositis ossificans.

Comment Here

Reference: Myositis ossificans
Board review style question #2
Biopsy from a thigh mass in a 31 year old man shows a circumscribed lesion rimmed entirely by skeletal muscle and comprised of a haphazard arrangement of spindle cells with mild nuclear pleomorphism, prominent nucleoli and increased mitotic figures. The background is highly fibrovascular and shows extravasated red blood cells, inflammatory cells and myxoid change. At the advancing edge of the lesion, there is focal, mature lamellar bone present. What is the likely diagnosis?

  1. Extraskeletal osteosarcoma
  2. Myositis ossificans
  3. Nodular fasciitis
  4. Ossified hemangioma
Board review style answer #2
B. Myositis ossificans. The question describes a detailed microscopic description of myositis ossificans. The lesion is not osteosarcoma because it is circumscribed and shows zonation in the form of mature periphery and immature center. This is contrary to osteosarcoma. Nodular fasciitis does not show heterotopic ossification and zonal pattern, although the center of myositis ossificans is reminiscent of nodular fasciitis.

Comment Here

Reference: Myositis ossificans

Nonossifying fibroma
Definition / general
  • Benign fibrohistiocytic tumor arising in the metaphysis of long bones of skeletally immature individuals, composed of bland fibroblastic proliferation admixed with osteoclast-like giant cells
  • Local recurrence and malignant transformation are extremely rare
Essential features
  • Characteristic radiologic appearance (i.e. radiolucent eccentric location within the metadiaphysis of long bones with lobulated, well demarcated, sclerotic rim and scalloped borders)
  • Histologically exhibits bland spindle shaped fibroblasts arranged in storiform pattern with interspersed osteoclast-like giant cells
Terminology
  • Metaphyseal fibrous defect
ICD coding
  • ICD-O: 8830/0 - benign fibrous histiocytoma
  • ICD-11
    • 2E85.Y & XH06N0 - benign fibrohistiocytic tumor of other specified sites & benign fibrous histiocytoma
    • 2E85.Y & XA5GG8 - benign fibrohistiocytic tumor of other specified sites and bones
Epidemiology
  • Accurate incidence is unknown because most of these lesions are asymptomatic and resolve spontaneously
  • Mostly arises in skeletally immature individuals, peaks in second decade of life
  • Up to 40% of children have an occult lesion (Chir Pediatr 1980;21:179)
Sites
Pathophysiology
Etiology
  • Germline mutations resulting in activation of KRAS-MAPK pathway
  • Unknown in sporadic cases
Diagrams / tables

Contributed by Qurratulain Chundriger, M.B.B.S.
Schematic presentation

Schematic presentation

Clinical features
Diagnosis
  • Requires integration of radiological and histopathological findings; diagnosis can be challenging on a small biopsy specimen (e.g. cytology or needle core)
Radiology description
Radiology images

Contributed by Nasir Ud Din, M.B.B.S. and AFIP images
Distal tibia

Distal tibia

Proximal tibia

Proximal tibia

Proximal fibula

Proximal fibula

Femur with fracture

Femur with fracture

Multifocal

Multifocal

Nonossifying fibroma

Nonossifying fibroma



Images hosted on other servers:
Radius (plain radiograph) Radius (plain radiograph)

Radius (plain radiograph)

Radius (MRI)

Radius (MRI)

Femur (plain radiograph)

Femur (plain radiograph)

Femur (CT scan)

Femur (CT scan)


Vertebral body

Vertebral body

Mandible Mandible

Mandible

Growth stages Growth stages

Growth stages

Prognostic factors
Case reports
Treatment
Clinical images

Images hosted on other servers:
Lesion in clavicle

Lesion in clavicle

Gross description
  • Well circumscribed, red-brown with areas of yellow discoloration and having sclerotic borders (Niger Postgrad Med J 2018;25:126)
  • Cut surface is firm, can exhibit cystic, hemorrhagic and necrotic areas
Gross images

Images hosted on other servers:
Lesion in clavicle

Lesion in clavicle

Lesion in mandible

Lesion in mandible

Microscopic (histologic) description
  • Bland, spindle shaped fibroblasts arranged in storiform pattern, interspersed with osteoclast-like multinucleated giant cells (Ear Nose Throat J 2015;94:E41)
  • Number of giant cells is much fewer than in giant cell tumor of bone
  • Some cases may resemble solid areas in aneurysmal bone cyst
  • Variable amount of foamy and hemosiderin laden macrophages (Head Neck Pathol 2013;7:203)
  • Cystic changes and areas of necrosis if associated with pathological fractures
  • Hemorrhage and inflammatory cells may also accompany necrosis associated with fracture
  • Areas of reactive woven bone formation may be seen (Spine (Phila Pa 1976) 2003;28:E359)
Microscopic (histologic) images

Contributed by Nasir Ud Din, M.B.B.S.

Circumscribed border on resection

Storiform arrangement

Interspersed giant cells

Few giant cells

Resembling ABC


Reactive woven bone

Aggregates of foamy macrophages

Hemorrhage and inflammatory cells

Necrosis after fracture

Cytology description
Cytology images

Images hosted on other servers:

Lesion in femur

Positive stains
Molecular / cytogenetics description
Videos

Bone and cartilage tumors

Sample pathology report
  • Left distal femur, curettage:
    • Benign spindle cell lesion with features consistent with nonossifying fibroma (see comment)
    • Comment: Correlation with radiological findings is essential.
Differential diagnosis
  • Giant cell tumor of bone:
    • Arises in epiphyses of long bones in adults
    • Uniform distribution of osteoclast type giant cells among mononuclear cells
    • Mononuclear cells in GCT are oval shaped and not spindled as seen in NOF
    • Giant cell nuclei are like mononuclear cell nuclei in GCT, which is not seen in NOF
    • Stromal mononuclear cells of GCT are positive for H3.3 G34W
    • GCT may have areas indistinguishable from NOF; positive staining of stromal cells for G34W will help resolve the issue
  • Benign fibrous histiocytoma:
    • Extremely rare, infiltrative lesion of soft tissue which causes destruction of adjacent bones, arising from primitive mesenchymal cells (Medicine (Baltimore) 2019;98:e17144)
    • Primary lesions of bone are even rarer, with cases reported to involve the spine and distal portions of long bones (J Bone Oncol 2018;12:78)
    • Fascicular and storiform growth of spindle cells with interspersed multinucleated giant cells resembles nonossifying fibroma microscopically
    • Extensive excision is required to prevent recurrence, which is common due to infiltrative growth (Medicine (Baltimore) 2019;98:e17144)
  • Solid aneurysmal bone cyst:
    • Arises in the metaphysis of long bones as expansile lytic lesion with circumscribed borders
    • Septal enhancement on contrast; fluid-fluid levels on MRI
    • Solid ABC often shows reactive woven bone formation within tumor and storiform pattern is not prominent
    • USP6 gene rearrangement by FISH, not detected in NOF
  • Fibrous dysplasia:
    • Common fibro-osseous lesion arises in long and craniofacial bones
    • Most cases are asymptomatic but may come to attention due to pain and fracture
    • Radiology shows diaphyseal or metadiaphyseal intramedullary sharply demarcated lesion with ground glass-like appearance, while NOF is eccentrically placed in metaphysis
    • Histology shows irregular curvilinear trabeculae of woven bone in a background of bland spindle cells
    • Multinucleated giant cells may be seen, along with myxoid change and foamy histiocytes but these are not a common feature
Board review style question #1


A 15 year old girl had a fall during marathon practice and sustained a fracture of the distal tibia. Radiological appearance is given in the picture above. Curettage was done and microscopic examination showed a lesion shown in the given photomicrograph. The most helpful feature for establishing the correct diagnosis in this case is

  1. Areas of chicken wire-like calcification surrounding the fibroblasts
  2. Curvilinear trabeculae of woven bone in background of spindle cells
  3. Linear trabeculae of woven bone surrounded by osteoblasts
  4. Pools of hemorrhage surrounded by multinucleated giant cells
  5. Storiform growth of bland spindle cells with scattered giant cells
Board review style answer #1
E. Storiform growth of bland spindle cells with scattered giant cells. The photomicrograph shows a tumor comprised of bland spindle cells growing in a storiform pattern. There are scattered multinucleated giant cells within the tumor. These findings are characteristic of nonossifying fibroma (NOF). The fact that the lesion was asymptomatic and caused pathological fracture due to trauma is another supportive feature in this case. Curvilinear trabeculae of woven bone are a feature of fibrous dysplasia of bone. Linear trabeculae of woven bone may be seen in some cases of NOF but they are not diagnostic of this lesion, per se. Similarly, pools of hemorrhage can be seen in cases of NOF secondary to an associated fracture. This feature, however, is a diagnostic primary finding of an aneurysmal bone cyst.

Comment Here

Reference: Nonossifying fibroma
Board review style question #2
Which of the following genetic mutations has been found to be common in nonossifying fibroma?

  1. BRAF
  2. GNAS
  3. H3F3B
  4. KRAS
  5. TBXT
Board review style answer #2
D. KRAS mutations are seen in up to 80% of nonossifying fibromas. GNAS mutations are a feature of fibrous dysplasia of bone. H3F3B is mutated in chondroblastoma and mutations involving TBXT are a feature of notochordal tumors. USP6 mutations are commonly seen in cases of aneurysmal bone cyst and nodular fasciitis in soft tissues.

Comment Here

Reference: Nonossifying fibroma

Osteoblastoma, NOS
Definition / general
  • Osteoblastoma is a locally aggressive bone forming tumor, morphologically similar to osteoid osteoma but with growth potential and generally > 2 cm in dimension
Essential features
  • Bone forming tumor composed of trabeculae of woven bone rimmed by plump osteoblasts in a vascularized stroma
  • Well defined tumor borders
  • Absence of host bone permeation
  • Radiology demonstration of a > 2 cm lesion
Terminology
  • Acceptable: epithelioid osteoblastoma
  • Not recommended: pseudomalignant osteoblastoma, aggressive osteoblastoma
ICD coding
  • ICD-O: 9200/1 - osteoblastoma, NOS
  • ICD-11: 2E83.Z & XH4316 - benign osteogenic tumors, unspecified & osteoblastoma, NOS
Epidemiology
Sites
Pathophysiology
  • Expresses Runx2 and Osterix, transcription factors involved in osteoblastic differentiation (Hum Pathol 2010;41:1788)
Etiology
  • Unknown
Diagrams / tables

Images hosted on other servers:
Epidemiology and localization

Epidemiology and localization

Clinical features
  • Earliest symptom in most patients is nonspecific pain, characterized as a dull ache that is less severe at night than during the day (Neurosurg Focus 2016;41:E4)
  • Pain is unlikely to be relieved by salicylates (PLoS One 2013;8:e74635)
  • Tumors located in the spine can press on nerves; when this happens, patients usually develop neurological symptoms in the legs, such as numbness, weakness or pain (PLoS One 2013;8:e74635)
  • Can produce beta hCG as a paraneoplastic manifestation (Skeletal Radiol 2017;46:1187)
Diagnosis
  • In many cases, the diagnosis is suggested by the tumor location, size and appearance on Xray, computed tomography and magnetic resonance scans
  • Definitive diagnosis usually requires a biopsy
Radiology description
  • Characteristic appearance on radiographs is a dense shell of bone surrounding the lesion, with some tumors resembling osteoid osteoma with a radiolucent nidus and surrounding sclerotic changes
  • In some cases, the bony shell tends to be very thin, with expansion into adjacent soft issues (Neurosurg Focus 2016;41:E4, Eur Spine J 2015;24:1778)
  • Cortical expansion and destruction are common radiographic findings (Hum Pathol 1994;25:117)
Radiology images

Contributed by Borislav A. Alexiev, M.D. and David R. Lucas, M.D.
Left frontal sinus mass

Left frontal sinus mass

Calcified mass

Calcified mass

T7 osteoblastoma with central nidus

T7 osteoblastoma with central nidus

Prognostic factors
Case reports
Treatment
Gross description
Gross images

Contributed by Borislav A. Alexiev, M.D. and David R. Lucas, M.D.
Bony mass with nidus

Bony mass with nidus

Osteoblastoma of clavicle

Osteoblastoma of clavicle

Spinal T7 osteoblastoma

Spinal T7 osteoblastoma

Microscopic (histologic) description
  • Expansile, surrounded by a sclerotic rim, may or may not have a central sclerotic nidus (Arch Pathol Lab Med 2010;134:1460)
  • Composed of interanastomosing trabeculae of woven bone, set within loose edematous fibrovascular stroma, often with extravasated erythrocytes (StatPearls: Osteoblastoma [Accessed 8 July 2021])
  • Tumors show a spectrum of bony maturational changes ranging from cords and clusters of activated osteoblasts associated with minimal osteoid to lace-like wispy osteoid to broad anastomosing trabeculae of woven bone to sclerotic sheets of woven bone (Arch Pathol Lab Med 2010;134:1460)
  • Osseous trabeculae are lined by a single layer of osteoblasts
  • Diffusely scattered osteoclast type, multinucleated giant cells are often present
  • Degenerative cytologic atypia characterized by cells with large degenerated nuclei and smudged chromatin may be present
  • Secondary aneurysmal bone cysts can occur, most commonly in large or expanded lesions
  • Rarely, one finds cartilage or chondro-osseous matrix within an osteoblastoma
  • Mitotic rate may be high but atypical mitoses are not present
  • Does not infiltrate or permeate pre-existing lamellar bone structures (StatPearls: Osteoblastoma [Accessed 8 July 2021])
  • Epithelioid osteoblastoma is a rare variant characterized histologically by epithelioid osteoblasts and clinically by local recurrences if not completely excised (J Foot Ankle Surg 2020;59:1279)
Microscopic (histologic) images

Contributed by Borislav A. Alexiev, M.D. and David R. Lucas, M.D.
Well marginated lesion

Well marginated lesion

Loose edematous fibrovascular stroma

Loose edematous fibrovascular stroma

Osseous trabeculae

Osseous trabeculae

Demarcated tumor

Demarcated tumor

Activated osteoblasts

Activated osteoblasts


Anastomosing trabeculae

Anastomosing trabeculae

Central nidus of sclerotic woven bone

Central nidus of sclerotic woven bone

Osteoblastoma high power

Woven bone trabeculae with osteoblastic rimming

Degenerative atypia

Degenerative atypia

Cytology description
  • Cellular smears with the presence of mononuclear and binucleated osteoblasts, along with scattered osteoclastic giant cells and uniform spindle cells entangled in myxoid stroma (Diagn Cytopathol 2015;43:218)
  • No necrosis and no atypical mitosis are observed (Cytojournal 2018;15:20)
Cytology images

Contributed by David R. Lucas, M.D.
Cytology smears

Cytology smears

Immunofluorescence description
  • Fluorescence in situ hybridization using split apart probes for FOS shows a segregated red and green signal (Virchows Arch 2020;476:455)
Negative stains
Electron microscopy description
  • Osteoblasts in osteoblastoma resemble normal osteoblasts with few exceptions: irregular, indented nuclei and occasional mitochondria with curved cristae and electron lucent areas (Cancer 1977;39:2127)
    • Ovoid or elongated osteoblasts with eccentric nuclei with irregular, indented nuclear membrane and condensed chromatin towards the periphery and abundant rough endoplasmic reticulum and well developed Golgi apparatus (Acta Pathol Jpn 1979;29:791)
  • Osteocytes and osteoclasts resemble their normal counterparts
    • Osteocytes with less prominent rough endoplasmic reticulum and well developed Golgi apparatus
    • Osteoclasts with sparse rough endoplasmic reticulum and numerous mitochondria
  • Osteoprogenitor cells in different stages of maturation
  • Calcified matrix and osteoid
  • Many blood vessels of varying caliber with osteoblasts in different stages of differentiation in the perivascular spaces
  • Large numbers of red blood cells and few monocytoid cells and histiocytes
Electron microscopy images

Images hosted on other servers:
Osteoblasts with eccentric nuclei

Osteoblasts with eccentric nuclei

Osteoblast with indented nucleus

Osteoblast with
indented nucleus

Molecular / cytogenetics description
  • Homo or hemizygous deletions in chromosome 22
  • Losses of ZNRF3, KREMEN1 and NF2 (inhibitors of the Wnt / beta catenin pathway) (PLoS One 2013;8:e80725)
Sample pathology report
  • Left frontal sinus mass, resection:
    • Osteoblastoma (see comment)
    • Comment: Radiology images demonstrate a calcified lobulated lesion centered in the mid left frontal sinus, 3.2 cm in greatest dimension. Histologically, the neoplasm is composed of interanastomosing trabeculae of woven bone, set within loose edematous fibrovascular stroma, with extravasated erythrocytes. The osseous trabeculae are lined by a single layer of osteoblasts. Diffusely scattered osteoclast type, multinucleated giant cells are present. The neoplasm is surrounded by a sclerotic rim. There is no infiltration of pre-existing lamellar bone structures. Rare mitotic figures and no necrosis are seen. Immunohistochemically, positive staining for FOS and nuclear beta catenin in lesional cells is present. Overall, the appearance on computed tomography and magnetic resonance scans, size (> 2 cm), morphological features and immunohistochemical profile support the diagnosis of osteoblastoma.
    • The prognosis of osteoblastoma is excellent, with most patients cured following the initial surgical treatment. Local recurrence is a relatively common complication, with rates ranging from 15% to 25%.
Differential diagnosis
Additional references
Board review style question #1

A 31 year old man presented with an aggressive appearing thoracic spine lesion measuring 2.8 cm in greatest dimension. Hematoxylin eosin stains demonstrate interanastomosing trabeculae of woven bone, set within loose edematous fibrovascular stroma, with extravasated erythrocytes. There is a spectrum of bony maturational changes ranging from cords and clusters of activated osteoblasts associated with minimal osteoid to lace-like wispy osteoid to broad anastomosing trabeculae of woven bone to sclerotic sheets of woven bone. The osseous trabeculae are lined by a single layer of osteoblasts. Diffusely scattered osteoclast type, multinucleated giant cells are present. The neoplasm is surrounded by a sclerotic rim. There is no infiltration of pre-existing lamellar bone structures. Rare mitotic figures and no necrosis are seen. Immunohistochemical stains for FOS and beta catenin (nuclear) are positive in tumor cells, while all of the following are negative: keratin AE1 / AE3, H3F3A (G34W) and p53. The tumor is negative for USP6 rearrangement.

Which of the following is most likely the correct diagnosis?

  1. Aneurysmal bone cyst
  2. Giant cell tumor of bone
  3. Osteoblastoma
  4. Osteoid osteoma
  5. Osteosarcoma
Board review style answer #1
C. Osteoblastoma

Comment Here

Reference: Osteoblastoma
Board review style question #2
Which of the following is true about osteoblastoma?

  1. Osteoblastoma is more common in females
  2. Predilection for the spine and the sacrum (40 - 55%)
  3. Tumor is positive for H3F3A (G34W)
  4. Tumor permeation of the surrounding host tissue structures is frequently identified
  5. Tumors of the mandible are associated with a poor prognosis
Board review style answer #2
B. Predilection for the spine and the sacrum (40 - 55%)

Comment Here

Reference: Osteoblastoma

Osteocartilaginous loose bodies (pending)
[Pending]

Osteochondritis dissecans
Definition / general
  • Benign noninflammatory condition affecting young adults, with necrosis of subchondral bone and adjacent articular cartilage causing separation from adjacent structures
  • Subchondral bone may remain attached to joint surface / synovium
    • If attached, both bone and cartilage remain viable
    • If detached, bone dies but cartilage remains viable through synovial fluid nutrients
  • Probably due to trauma although familial autosomal dominant (Clin Orthop Relat Res 1979;(140):131) and bilateral symmetric cases have been described
  • Symptoms include joint pain, joint effusions, locking of joint
Sites
  • Usually at lateral aspect of medial femoral condyle near intercondylar notch; also ankle and elbow joints
Radiology description
  • Well demarcated defect in articular surface of joint
Case reports
Treatment
  • Reattachment (if possible) or excision
Gross description
  • Flat, smooth nodule of avascular bone with overlying articular cartilage
  • Layer of fibrocartilage is usually present on bony surface
Gross images

Images hosted on other servers:

Head of femur

Osteochondritis of left humeral head
with secondary deformation of bone,
eighth to ninth century from Iona

Microscopic (histologic) description
  • Articular cartilage, often with calcification; 50% have subchondral bone
Microscopic (histologic) images

Images hosted on other servers:

Pathological specimen of Danish sow


Osteochondroma
Definition / general
  • Benign bone surface tumor composed of mature bone with a cartilage cap
  • May be solitary or occur as multiple hereditary exostoses (MHE)
Essential features
  • Exophytic lesion of bone surface composed of a stalk of mature bone with a cartilaginous cap; the marrow space / cancellous bone of the stalk communicates with that of the underlying bone
Terminology
  • Osteocartilaginous exostosis
ICD coding
  • ICD-O: 9210/0 - Osteochondroma
  • ICD-11: 2E83.Y & XH5Y87 - Other specified benign osteogenic tumors and osteochondroma
Epidemiology
  • Common, approximately 35% of benign bone tumors and 10% of all bone tumors
  • Predominance in men (M:F = 2:1)
  • Most cases diagnosed in the first 2 decades of life
Sites
  • Most common in the metaphysis of long bones: femur > humerus > tibia
  • Involvement of flat bones (ilium, scapula) may occur
  • Involvement of small bones of the hands and feet, ribs and vertebra is rare
Etiology
  • Both solitary sporadic tumors and multiple hereditary exostoses (MHE) are associated with loss of function mutations in EXT1 (8q24) and EXT2 (11p11) genes (J Genet 2015;94:749)
  • In solitary lesions, EXT gene inactivation is restricted to the cartilage cap and is somatic
  • MHE shows autosomal dominant inheritance (Am J Hum Genet 1998;62:346); patients have heterozygous germline EXT1/EXT2 mutation, while their tumors usually show homozygous EXT mutation
Clinical features
Diagnosis
  • Radiologic pathologic correlation is often specific
  • Secondary chondrosarcoma:
    • Histologic features alone are usually not definitive for diagnosis
    • Diagnosis of secondary chondrosarcoma arising in osteochondroma can be challenging and requires correlation with clinical and imaging findings (Mod Pathol 2012;25:1275, Radiology 2010;255:857, Oncogene 2012;31:1095)
    • Tumor growth and thickening of the cartilage cap (usually > 2 cm) are suggestive of malignant transformation in skeletally mature patients
Radiology description
  • Pedunculated or sessile
  • Mature bony stalk continuous with the cortex; cancellous bone of stalk communicates with that of underlying bone
  • Thin, lobulated cartilaginous cap, which may contain calcifications
  • Growth perpendicular to the long axis of the bone
Radiology images

Contributed by Jose G. Mantilla, M.D., Mark R. Wick, M.D. and AFIP images

Osteochondroma arising in the proximal femur

Osteochondroma arising in the distal femur

Missing Image

Distal portion of femur

Missing Image

Metatarsal Xray

Missing Image

Xray

Prognostic factors
Case reports
Treatment
  • Growth often stops after skeletal maturity and may spontaneously regress
  • Excision is typically curative in solitary lesions, with rare local recurrence
Gross description
  • Pedunculated or sessile bony lesion with hyaline cartilage cap
Gross images

Contributed by Jose G. Mantilla, M.D. and AFIP images

Hyaline cartilage cap

Missing Image

Outer and cut surfaces

Microscopic (histologic) description
  • Cap composed of mature hyaline cartilage with overlying fibrous perichondrium
  • In young patients, transition between bone and cartilage cap resembles growth plate, showing endochondral ossification into mature bone; cartilage cap diminishes and may essentially be absent in older adults
  • Marrow elements may be present within bony stalk; marrow space / cancellous bone contiguous with that of the native bone
Microscopic (histologic) images

Contributed by Jose G. Mantilla, M.D. and AFIP images

Whole slide

Cartilage cap

Missing Image

Whole mount section

Missing Image

Cellular cartilaginous foci

Missing Image

Junction of cartilage cap and underlying bone

Molecular / cytogenetics description
  • Solitary osteochondroma and MHE associated with EXT1 and EXT2 mutations
Sample pathology report
  • Knee mass, excision:
    • Osteochondroma
Differential diagnosis
  • Bizarre parosteal osteochondromatous proliferation (Nora lesion):
    • Disorganized growth of bone and cartilage with characteristic blue bone
    • Typically located in the distal extremities (J Orthop 2018;15:138)
  • Florid reactive periostitis:
    • Mixture of reactive woven bone and fibrous tissue without zonation
    • Typically arises in the periosteum of fingers
  • Parosteal osteosarcoma:
    • Similar location and age group
    • More aggressive growth areas of neoplastic woven bone formation and fibroblastic areas
    • Can have a cartilage cap in up to 25% of cases
  • Secondary chondrosarcoma:
    • Infiltrative growth with permeation of bone or extension into soft tissue
    • Usually well differentiated but with invasion into surrounding tissue
Board review style question #1
Which of the following is true about the epidemiology of osteochondromas?

  1. Congenital lesions are relatively common
  2. Female predominance
  3. Most lesions arise in long bones
  4. Most common in the elderly
  5. Multiple lesions are more common
Board review style answer #1
C. Most lesions arise in long bones

Comment Here

Reference: Osteochondroma
Board review style question #2
Which of the following is true regarding secondary chondrosarcoma?

  1. Most common subtype is clear cell chondrosarcoma
  2. Patients with multiple osteochondromas have a higher overall risk of developing chondrosarcoma
  3. Risk of malignancy in patients with multiple hereditary exostosis is near 50%
  4. Risk of malignancy in solitary osteochondromas is high
Board review style answer #2
B. Patients with multiple osteochondromas have a higher overall risk of developing chondrosarcoma

Comment Here

Reference: Osteochondroma

Osteochondromyxoma
Definition / general
  • Rare congenital bone tumor presenting with painless mass
  • Associated with Carney complex (familial lentinginous and multiorgan tumor syndrome, Am J Surg Pathol 2001;25:164)
  • Sites: nasal region, tibia, radius
Treatment
  • Resection, but recurs if incompletely excised
Gross description
  • Gelatinous, cartilaginous, bony
Microscopic (histologic) description
  • Sheets and lobules of bland cells in myxomatous, cartilaginous, osseous, and hyaline fibrous matrix
  • Low to moderate cellularity
  • Erodes bone and frequently extends into soft tissue

Osteofibrous dysplasia
Definition / general
  • Osteofibrous dysplasia (OFD) is a benign fibro-osseous tumor of the pediatric age group with strong predilection for the anterior tibial diaphysis
Essential features
  • Usually occurs in first 2 decades of life, without gender predilection and most commonly involves anterior diaphysis of tibia
  • Radiologically, tumor appears intracortical, multiloculated and radiolucent with well defined sclerotic margins
  • Microscopically, woven bone trabeculae with osteoblastic rimming are seen against bland fibroblastic stroma with storiform pattern
  • Maturation of bone trabeculae towards periphery (zonal architecture) and scattered keratin positive cells in the stroma are useful diagnostic features
  • Has the potential to recur; tumors may regress after skeletal maturity
Terminology
ICD coding
  • ICD-O: 9261/0 - osteofibrous dysplasia
  • ICD-11: 2E83.5 & XH6M86 - benign osteogenic tumors of bone or articular cartilage of limbs and ossifying fibroma
Epidemiology
Sites
Pathophysiology
Etiology
Clinical features
Diagnosis
Radiology description
  • Xray: typically intracortical, eccentric, multiloculated radiolucent / osteolytic lesion with internal septa and sharply defined sclerotic borders
  • Some lesions may show ground glass appearance, marked sclerosis and ill defined borders
  • Larger lesions cause cortical expansion, bowing deformity and fracture (Clin Radiol 2014;69:200, Surg Oncol 2021;38:101626)
  • On MRI scan, T1 weighted images show intermediate intensity signals while T2 weighted images show intermediate to hyperintense signals; with contrast, enhancement of homogenous or heterogenous patterns is observed (Korean J Radiol 2014;15:114)
  • MRI scan is useful for assessing medullary involvement and surgical staging but not useful in discrimination from the differentials (Clin Radiol 2014;69:200)
  • Involvement of the medullary cavity is uncommon; however, it has been reported in up to 40% of cases (Clin Radiol 2014;69:200)
  • In a single study, partial or complete medullary involvement was observed on MRI scan in all 24 cases (Korean J Radiol 2014;15:114)
  • CT scan is useful for assessing matrix mineralization, pathological fracture, lack of periosteal reaction and transitional zone; not superior to MRI scan (Clin Radiol 2014;69:200, Radiol Case Rep 2015;6:546)
Radiology images

Contributed by Nasir Ud Din, M.B.B.S., Mark R. Wick, M.D. and AFIP images
Multiloculated radiolucent lesion in tibia

Multiloculated radiolucent lesion in tibia

Multiloculation and sclerotic borders

Multiloculation and sclerotic borders

Thickened sclerotic areas

Thickened sclerotic areas

Marked bowing deformity Marked bowing deformity

Marked bowing deformity


Synchronous tumors in tibia and fibula

Synchronous tumors in tibia and fibula

Contrast enhancing lesion on CT scan

Contrast enhancing lesion on CT scan

Contrast enhancing lesion on MRI scan

Contrast enhancing lesion on MRI scan

Various images

Radiolucent and sclerotic areas

Ill defined lucencies and bowing deformity

Ill defined lucencies and bowing deformity



Images hosted on other servers:
Soft tissue and medullary cavity involvement

Soft tissue and medullary cavity involvement

Soap bubble appearance on CT scan

Soap bubble appearance on CT scan

Cortical lesion with sclerotic rim

Cortical lesion with sclerotic rim

Prognostic factors
Case reports
Treatment
  • Surgical excision (with or without grafting) or curettage for larger tumors and cases with tibial bowing
  • Some tumors are only observed, since the tumors regress after puberty (Surg Oncol 2021;38:101626)
  • Some authors recommend extraperiosteal excision for all cases due to the low recurrence rate (J Bone Joint Surg Br 2006;88:658)
Gross description
Gross images

Contributed by Mark R. Wick, M.D. and AFIP images
Solid tumor involving cortex and medulla

Solid tumor involving cortex and medulla

Focally eroded cortex

Focally eroded cortex

Microscopic (histologic) description
  • Tumor has 2 basic components: fibrous stroma and bone trabeculae
  • Zonation pattern is a characteristic feature
  • In the center, the lesion is more fibrous and the newly formed woven bone trabeculae are thin
  • Bone trabeculae become more numerous, thicker and mature (lamellar) and merge with the outer and inner cortices at the periphery
  • Bone trabeculae are rimmed by epithelioid / active osteoblasts
  • Fibrous stromal component is composed of spindle to stellate cells arranged in short fascicles and vague storiform pattern; background is myxoid
  • Rare epithelial cells in the stroma may be highlighted on cytokeratin
  • Scattered multinucleated giant cells, hemosiderin laden macrophages, hemosiderin and foamy macrophages may also be seen (Hum Pathol 1993;24:1339, Surg Oncol 2021;38:101626)
Microscopic (histologic) images

Contributed by Nasir Ud Din, M.B.B.S. and Mark R. Wick, M.D.
Fibro-osseous lesion with zonation pattern Fibro-osseous lesion with zonation pattern

Fibro-osseous lesion with zonation pattern

Thickened trabeculae at the periphery

Thickened trabeculae at the periphery

Bone trabeculae and storiform pattern

Bone trabeculae and storiform pattern

Osteoblastic rimming of bone trabeculae

Osteoblastic rimming of bone trabeculae

Osteoblastic rimming and storiform pattern

Osteoblastic rimming and storiform pattern


Osteoblastic rimming Osteoblastic rimming

Osteoblastic rimming

Multinucleated osteoclast-like giant cells Multinucleated osteoclast-like giant cells

Multinucleated osteoclast-like
giant cells

Keratin immunostain Keratin immunostain

Keratin immunostain

Positive stains
Electron microscopy description
  • Stromal cells show fibroblast-like cells with prominent rough endoplasmic reticulum; epithelial differentiation was not seen
  • Thickened woven bone trabeculae showed increased remodeling with osteoblastic and osteoclastic activity (Mod Pathol 2012;25:56)
Molecular / cytogenetics description
Videos

Osteofibrous dysplasia

Fibrous dysplasia and osteofibrous dysplasia: bone forming tumors,
part 4

Imaging osteofibrous dysplasia

Sample pathology report
  • Tibia, Tru-Cut / incisional biopsy:
    • Fibro-osseous tumor (see comment)
    • Comment: Morphological features are those of osteofibrous dysplasia (OFD); however, the possibility of classic adamantinoma and OFD-like adamantinoma cannot be entirely ruled out because these lesions also contain areas with morphological features of OFD. Correlation with clinical and radiological findings is recommended. A more definitive diagnosis would be possible on excision biopsy specimen.

  • Tibia, curettage / resection specimen:
    • Fibro-osseous tumor, consistent with osteofibrous dysplasia (see comment)
    • Comment: Histological examination showed a fibro-osseous tumor. The osseous component is composed of woven bone trabeculae rimmed by osteoblasts and fibroblastic stroma. CK AE1 / AE3 is positive in scattered stromal cells. No epithelial nests are seen. Correlation with clinical and radiological findings is recommended. OFD has the potential to recur locally; therefore, close follow up is advised.
Differential diagnosis
Board review style question #1

A 10 year old boy complained of pain in his right leg. Xray of right leg showed a intracortical multiloculated, osteolytic lesion with a well defined sclerotic margin involving the diaphysis of tibia. Microscopically, the tumor showed trabeculae of woven bone with osteoblastic rimming. The background showed fibroblastic stroma with storiform pattern. On immunohistochemistry, only rare stromal cells showed positivity for cytokeratin. What is the most likely diagnosis?

  1. Fibrous dysplasia
  2. Nonossifying fibroma
  3. Osteofibrous dysplasia
  4. Osteofibrous dysplasia-like adamantinoma
  5. Osteoid osteoma
Board review style answer #1
C. Osteofibrous dysplasia. Clinical, radiological, histological and immunohistochemical features are characteristic of osteofibrous dysplasia. Fibrous dysplasia is a fibroosseous lesion that usually lacks osteoid rimming of bone trabeculae. Nonossifying fibroma lacks bone trabeculae. Osteofibrous dysplasia-like adamantinoma closely resembles osteofibrous dysplasia. On IHC, small clusters and cords of cytokeratin positive epithelial cells are seen in the stroma rather than scattered epithelial cells seen in osteofibrous dysplasia. Osteoid osteoma shows loose fibrovascular stroma between bone trabeculae.

Comment Here

Reference: Osteofibrous dysplasia
Board review style question #2
Which of the following is the most helpful feature in differentiating osteofibrous dysplasia from osteofibrous dysplasia-like adamantinoma?

  1. Bone trabeculae without osteoblastic rimming
  2. Clusters and small nests of epithelial cells
  3. Patient's age
  4. Radiological findings
  5. Tumor location
Board review style answer #2
B. Clusters and small nests of epithelial cells. Osteofibrous dysplasia-like adamantinoma closely resembles osteofibrous dysplasia and the distinction is not possible clinically or radiologically. The differentiating feature on histology is the presence of cluster, cords and small nests of epithelial cells in the stroma of osteofibrous dysplasia-like adamantinoma, which are further highlighted on cytokeratin immunostains. Histologically, epithelial cells are not seen in the stroma of osteofibrous dysplasia and only scattered cytokeratin positive epithelial cells are highlighted on cytokeratin immunostains. Absence of osteoblastic rimming around bone trabeculae is a feature of fibrous dysplasia.

Comment Here

Reference: Osteofibrous dysplasia

Osteogenesis imperfecta
Definition / general
  • Also called brittle bone disease
  • One of the most common congenital connective tissue matrix diseases
  • Disease of type I collagen due to mutations in genes coding for alpha 1 - 2 collagen chains, usually autosomal dominant
  • A type of osteoporosis with marked cortical thinning and attenuation of trabeculae, plus other collagen related signs / symptoms
  • Skeletal abnormalities may be mild (reduced amounts of normal collagen) or severe/lethal (abnormal polypeptide chains cannot form collagen triple helix); associated with short stature and increased fractures (hundreds of minor / major fractures during childhood, usually in lower limb, often involving growth plate fragmentation around knees)
  • Blue sclera: due to translucent sclera and visualization of choroid
  • Hearing loss: sensorineural defect and impeded conduction due to abnormalities of middle ear bones
  • Dental imperfections: small, misshapen, blue - yellow teeth, due to dentin deficiency
  • Type I: usually acquired mutation, autosomal dominant, normal lifespan with increased fractures during childhood but decreasing after puberty
  • Type II: usually autosomal recessive, uniformly fatal due to extraordinary bone fragility with multiple intrauterine fractures; unstable triple helix
  • Type III: autosomal dominant or recessive, growth retardation, but otherwise like type I
  • Type IV: autosomal dominant, short stature, but otherwise like type I
Radiology description
  • Nodules of cartilage at growth plate resembling a bag of popcorn
  • Marked swelling of distal femur
Gross description
  • Cartilaginous nodules due to fragmentation of growth plate
Microscopic (histologic) description
  • Severe forms lack an organized trabecular pattern
  • Crowded osteocytes within bone (due to reduced collagen synthesis)
  • Large areas of woven bone
  • Less severe forms still have crowded osteocytes with thin lamellar bone

Osteoid osteoma
Definition / general
  • Benign, bone forming tumor
  • Usually small size (< 2 cm) and limited growth
Essential features
  • Imaging: well demarcated, small central nidus, usually surrounded by zone of sclerosis
  • Histology: bone forming tumor composed of woven bone with prominent osteoblastic rimming and a vascularized stroma
  • Molecular: FOSB gene locus rearrangement (not necessary for diagnosis)
ICD coding
  • ICD-10: D16.20 - benign neoplasm of long bones of unspecified lower limb
Epidemiology
  • 10 - 12% of all benign bone tumors; 2 - 3% of all primary bone tumors
  • M:F = 2:1
  • Rare familial occurrence reported (Skeletal Radiol 2003;32:416)
  • More common in children and adolescents
Sites
  • Broad skeletal distribution
    • 50% occur in the long bones of the lower extremities
      • Femoral neck is the single most frequent anatomic site
      • Usually near the end of the diaphysis of long bones
    • Less common in the long bones of upper extremities
      • Bones of elbow are the most common site in upper extremity
    • Small bones of hands and feet and posterior elements of vertebral body
    • Uncommon sites: flat bones, craniofacial bones
  • Preferential involvement of cortex (75%)
    • Subperiosteal and intramedullary lesions are less common
  • Reference: J Bone Oncol 2015;4:37
Etiology
  • Unknown
Clinical features
  • Nocturnal pain, relieved by aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) (J Am Acad Orthop Surg 2011;19:678)
  • Swelling and effusion of nearest joint in intracapsular osteoid osteomas
  • Painful scoliosis in osteoid osteomas of spine (Neurosurg Focus 2003;15:E5)
  • Osteoid osteomas in the small bones of the hands and feet may clinically mimic osteomyelitis
Diagnosis
  • Requires correlation of clinical, radiographic and histologic findings
Radiology description
  • Xray:
    • Intracortical lesions have a nidus with a variable degree of mineralization and surrounding reactive osteosclerosis
    • Intramedullary lesions may be more difficult to visualize on conventional radiography and often lack the surrounding sclerotic bone
  • CT scan:
    • Well defined oval to round nidus with low attenuation
    • Reactive cortical sclerosis
  • MRI:
    • Generally of limited value in the detection of a nidus, with the exception of intramedullary lesions
    • Characteristics of nidus tissue (depending on the degree of mineralization):
      • Low to intermediate signal intensity on T1 weighted images
      • Variable signal intensity on T2 weighted images
      • Target-like appearance of partially mineralized nidus
    • Bone marrow edema and joint effusion
    • Intracapsular lesions may be associated with marked synovitis, leading to an erroneous diagnosis of an inflammatory arthropathy
  • Isotope scan:
    • Zone of increased uptake corresponding to nidus and perilesional sclerosis
  • Reference: Radiographics 2010;30:737
Radiology images

Contributed by Elham Nasri, M.D. and John D. Reith, M.D.
Tibia

Tibia

Elbow Elbow

Elbow

Finger Finger

Finger


Distal femur Distal femur

Distal femur

Distal femur

Distal femur

Wrist Wrist

Wrist

Prognostic factors
Case reports
Treatment
  • NSAIDs
  • CT guided percutaneous radiofrequency ablation (Radiology 2003;229:171)
    • Symptomatic patients, nonresponsive to NSAIDs
    • Outpatient
    • Minimally invasive
  • Curettage and resection (Orthopade 2017;46:510)
    • Vertebral column
    • Small bone of hands and feet
    • Close relationship to peripheral nerves
    • Recurrent lesions
  • Reference: Acta Biomed 2018;89:175
Gross description
  • Oval red nidus is easily distinguishable from surrounding tissue
    • Soft and friable to sclerotic nidus
    • Surrounded by densely sclerotic reactive bone
Gross images

Contributed by John D. Reith, M.D.
Nidus tissue with surrounding bone

Nidus tissue with surrounding bone

Frozen section description
  • Not usually performed
Microscopic (histologic) description
  • Nidus:
    • Haphazard trabeculae of woven bone with prominent osteoblastic rimming
      • Different thickness and mineralization level
      • Disordered (Pagetic) cement lines in some cases
      • Sheet-like osteoid deposition in some cases
      • Densely sclerotic woven bone in some cases
  • Surrounding bone:
    • Thickened trabeculae of bone with adjacent loose fibrovascular stroma
  • Reference: Am J Surg Pathol 2019;43:1661
Microscopic (histologic) images

Contributed by Elham Nasri, M.D. and John D. Reith, M.D.
Well defined borders

Well defined borders

Osteoblastic rimming

Osteoblastic rimming

Sheet-like osteoid deposition

Sheet-like osteoid deposition

Sclerotic nidus

Sclerotic nidus

Peripheral transition to sclerotic bone

Peripheral transition to sclerotic bone

Bone trabeculae with variable mineralization

Bone trabeculae with variable mineralization

Positive stains
Molecular / cytogenetics description
Sample pathology report
  • Mass, distal metaphysis, left tibia, biopsy:
    • Osteoid osteoma
Differential diagnosis
Board review style question #1
Osteoid osteoma most likely shows rearrangement of which of the following genes?

  1. DDIT3
  2. EWSR1
  3. FOS / FOSB
  4. USP6
Board review style answer #1
C. FOS / FOSB

Comment Here

Reference: Osteoid osteoma
Board review style question #2

Provided H&E picture belongs to a well defined intracortical lesion of distal tibia of a 17 year old boy. Symptoms include nocturnal pain that is relieved by ibuprofen. What is the correct diagnosis?

  1. Aneurysmal bone cyst
  2. Giant cell tumor of bone
  3. Osteoid osteoma
  4. Osteomyelitis
Board review style answer #2
C. Osteoid osteoma

Comment Here

Reference: Osteoid osteoma

Osteoma, NOS
Definition / general
  • Benign, bone forming tumor composed of mature cortical type or less frequently, trabecular bone, typically involving the craniofacial skeleton
Essential features
  • Benign osteogenic tumor
  • Usually involves the surface of craniofacial bones
  • Admixture of mature lamellar and woven bone patterns, with Haversian-like canals
  • Cortical type bone architecture is typical
  • Lack of cellular atypia
Terminology
  • Torus palatinus (if palate is involved)
  • Torus mandibularis (if mandible is involved)
  • Parosteal osteoma
  • Button osteoma
  • Ivory exostosis
ICD coding
  • ICD-O: 9180/0 - osteoma, NOS
  • ICD-11:
    • XH4818 - osteoma, NOS
    • 2E83.Z - benign osteogenic tumor of unspecified site
Epidemiology
  • Incidence:
    • Accounts for 0.03% of biopsied primary bone tumors
    • Paranasal sinus osteoma: 3 - 6.4% of CT scans performed for sinus conditions (Acta Otolaryngol 2015;135:602)
    • Present in 80% with Gardner syndrome
  • Age: fourth through sixth decades
  • Sex: M = F
Sites
Pathophysiology
  • Controversy in the literature whether osteoma represents a true neoplasm or a developmental anomaly
Etiology
  • Still unclear
  • Theories: reactive bone hyperplasia triggered by trauma or infection; advanced ossification; end stage of fibrous dysplasia or subperiosteal hematomas (Imaging Sci Dent 2011;41:107)
  • Presence of multiple osteomas is suggestive of Gardner syndrome, a variant of familial adenomatous polyposis (FAP) that is characterized by colorectal adenomas, osteomas and benign skin tumors; it is caused by mutations in the APC gene (Imaging Sci Dent 2016;46:267)
Clinical features
Diagnosis
  • Radiology findings often helpful
Radiology description
  • In general, the lesion involves the surface of the bone and appears well delineated, ovoid or mushroom shaped, with broad base of attachment to cortex (Nielson: Diagnostic Pathology - Bone, 2nd Edition, 2017)
  • Xray: radiodense lesion with varying amounts of central lucency
  • CT: cortical density on bone window; no contrast enhancement (Clin Radiol 2000;55:435)
  • MRI: low signal intensity on T1 and T2 weighted images; no contrast enhancement
Radiology images

AFIP images
Dense lobular mass in frontal sinus

Dense lobular mass in frontal sinus



Images hosted on other servers:
CT bone window

CT bone window

Prognostic factors
  • Excellent prognosis
  • No recurrence if completely excised
Case reports
Treatment
  • Observation for asymptomatic cases
  • Surgical excision for symptomatic cases
Clinical images

Images hosted on other servers:
Osteoma of anterior maxilla

Osteoma of anterior maxilla

Forehead osteomas

Forehead osteomas

Nasal cavity osteoma with actinomycosis

Nasal cavity osteoma with actinomycosis

Gross description
Gross images

Contributed by David R. Lucas, M.D. and Mark R. Wick, M.D.
Osteoblastoma-like osteoma Osteoblastoma-like osteoma

Osteoblastoma-like osteoma

Skull osteoma

Skull osteoma



Images hosted on other servers:
Osteoma with smooth bosselated surface

Osteoma with smooth bosselated surface

Giant orbit osteoma

Giant orbit osteoma

Fronto-ethmoidal osteoma

Fronto-ethmoidal osteoma

Microscopic (histologic) description
  • Admixture of mature lamellar and woven bone patterns, with Haversian-like canals, which may have various sizes and shapes (Nielson: Diagnostic Pathology - Bone, 2nd Edition, 2017)
  • More frequent: cortical type bone architecture
  • Less frequent: trabecular bone architecture
  • Osteoblasts rimming bone are inconspicuous and small but can be prominent in growing lesions
  • Osteocytes in the matrix are small, not atypical and randomly distributed (Surg Pathol Clin 2012;5:101)
  • Intertrabecular marrow spaces are filled with moderately cellular, loose fibrous stroma (BMJ Case Rep 2013;2013:bcr2013009857)
  • Inflammatory infiltrates are typically absent
Microscopic (histologic) images

Contributed by Serenella Serinelli, M.D., Ph.D., Gustavo de la Roza, M.D. and Kelly Magliocca, D.D.S., M.P.H.
Cortical type bone architecture

Cortical type bone architecture

Trabecular bone architecture

Trabecular bone architecture

Lamellar bone

Lamellar bone

Osteoblasts and osteocytes

Osteoblasts and osteocytes

Fibrous stroma in marrow spaces

Fibrous stroma in marrow spaces

Osteoma

Osteoma

Videos

Osteoma of bone

Sample pathology report
  • Bone, left forehead, excision:
    • Osteoma
Differential diagnosis
Board review style question #1

A 40 year old woman seeks treatment for a slowly enlarging lesion over the left forehead. The mass is found to involve the external surface of the left frontal skull and is excised. The histology is shown above. What is the diagnosis?

  1. Osteoblastoma
  2. Osteochondroma
  3. Osteoid osteoma
  4. Osteoma
  5. Parosteal osteosarcoma
Board review style answer #1
D. Osteoma

Comment Here

Reference: Osteoma
Board review style question #2
Which of the following is a feature of osteoma?

  1. Atypia has to be present to make the diagnosis
  2. Involves mainly the long bones
  3. Most frequent architecture is cortical type bone
  4. Most frequent architecture is trabecular bone
  5. Typically does not involve the craniofacial skeleton
Board review style answer #2
C. Most frequent architecture is cortical type bone

Comment Here

Reference: Osteoma

Osteopetrosis
Definition / general
  • Also called marble bone disease, Albers-Schonberg disease
  • Rare, hereditary, diffuse and symmetric skeletal sclerosis (increased bone density) caused by osteoclast dysfunction
  • Bones have "stone-like" quality but are abnormality brittle and fracture like chalk
  • One cause is deficiency of carbonic anhydrase II, required by osteoclasts and renal tubular cells to excrete hydrogen ion; deficiency causes failure to solubilize and resorb matrix and failure to acidify urine
  • Associated with anemia and hepatosplenomegaly since reduced bone marrow
  • Types: "malignant" - autosomal recessive; detected in utero due to fractures, anemia, hydrocephaly, cranial nerve problems, infections, hepatosplenomegaly; "benign" - autosomal dominant; repeated fractures, mild cranial nerve deficits, anemia
Radiology description
  • Shortened long bones, loss of metaphyseal flare (Erlenmeyer flask deformity), uniform opacity of pelvis and peripheral bones alternating with normal bone causing a striped appearance
  • May cause spinal spondylolisthesis
Treatment
  • Bone marrow transplant (reverses many skeletal abnormalities), human interferon gamma
Gross description
  • Bones are solid and heavy with no medullary canal, long ends are bulbous, small neural foramina compress nerves
Microscopic (histologic) description
  • Primarily woven bone since bone is not remodeled
  • Central core of cartilage with dense and irregular bony trabeculae
  • Often abundant osteoclasts
  • Reduced marrow space
Electron microscopy description
  • Osteoclasts lack ruffled borders, lack features of actively resorbing osteoclasts
  • Surface of bone has massive smooth cartilaginous matrix with scattered rough areas of abnormal ossification but devoid of orderly lamellar haversian system of normal bone
  • Many irregular fracture lines present (Hum Pathol 1981;12:376)
Differential diagnosis
Additional references

Osteoporosis
Definition / general
  • Reduction in bone mass due to increased bone porosity, which predisposes bones to fracture
  • Usually refers to postmenopausal or senile loss of bone severe enough to cause fractures
  • Affects entire skeleton due to metabolic bone disease, but may be localized due to limb disuse
  • Usually due to increased bone resorption, with normal levels of bone formation
  • Osteopenia: defined as radiologic decrease in density of skeleton
  • Primary causes: due to postmenopausal condition, older age (15 million cases in US) or idiopathic
  • Secondary causes (due to identifiable conditions): endocrine (hyperparathyroidism, thyroid disorders, hypogonadism, pituitary tumors, type I diabetes, Addison’s disease), neoplasms (myeloma, carcinomatosis), gastrointestinal disturbances (malnutrition, deficiency of vitamins C or D), drugs (corticosteroids, chemotherapy), osteogenesis imperfecta, immobilization, homocystinuria, anemia
  • Menopause: postmenopausal women may lose 2% of cortical bone and 9% of cancellous bone / year; osteoporosis affects women more than men because estrogen deficiency leads to increased osteoclast activity, and osteoblasts cannot keep pace
  • Age related changes: osteoblasts have reduced reproductive and biosynthetic potential in elderly
  • Immobilization: important cause because mechanical forces stimulate bone remodeling; zero gravity (astronauts), immobilization cause reduced skeletal mass; athletes have higher bone density; weight training is more effective than jogging in increasing skeletal mass
  • Genetics: variation in Vitamin D receptor type accounts for 75% of maximal peak bone mass achieved; Vitamin D intake and parathyroid hormone levels are not significant causes, although low calcium intake in women is an important cause
  • Other risk factors: Whites / Asians, smoking, alcohol abuse
  • Bone mass: peak bone mass occurs in young adults, based on physical activity, muscle strength, diet, hormones; subsequent remodeling causes small deficit in bone formation with each resorption / ormation cycle, which causes bone loss of 0.7% per year
  • Sites: cancellous compartment of vertebral bone (with high surface area) affected first, causing loss of vertebral height in elderly, leading to dowager’s hump; also thinning of cortex; hip and wrist also affected
Radiology description
  • Flattening of vertebral bodies, widening and swelling of intervertebral discs, fish - mouth appearance
  • Usually thoracic and upper lumbar spine
Diagnosis
  • Radiographic measurement of bone density, iliac crest biopsy
Treatment
  • Calcium, Vitamin D and exercise to build up / maintain bone mass
  • Biphosphonates (inhibit post-menopausal bone loss)
Gross description
  • Loss of cancellous bone, accentuation of vertical trabeculae in spine
Microscopic (histologic) description
  • Thin trabeculae disconnected from each other
  • Increase in osteoclastic activity (may be uneven) or increased percentage of surface with resorptive pitting
Microscopic (histologic) images

Images hosted on other servers:
Missing Image

Osteoporosis


Osteosarcoma, NOS
Definition / general
Essential features
  • Malignant bone tumor with compatible imaging (Eur J Cancer 2002;38:1218)
  • Bone production by tumor cells (Am J Clin Pathol 2006;125:555)
  • Permeative and destructive growth pattern
  • Conventional central osteosarcoma:
    • Intramedullary sarcoma
    • Tumor cells with high grade atypia; atypical mitotic figures are frequently present
  • Low grade central osteosarcoma:
    • Intramedullary location
    • Predominantly fibroblastic osteosarcoma with mild nuclear atypia and well formed neoplastic bony trabeculae
    • MDM2 amplification
  • Paraosteal osteosarcoma:
    • Paraosteal location
    • Low grade spindle cell tumor with woven bone formation
    • MDM2 amplification
  • Periosteal osteosarcoma:
    • Surface location under the periosteum
    • Intermediate grade, often with chondroblastic features
  • High grade surface osteosarcoma:
    • Histologically high grade osteosarcoma
    • Arising on the surface of the bone without a substantial intraosseous component
    • No MDM2 amplification
  • Secondary osteosarcoma:
    • Known history of Paget disease of bone, previous radiation therapy, bone infarction, osteomyelitis, orthopedic implants
    • Osteosarcoma histology
Terminology
  • Primary osteosarcoma: a bone forming sarcoma arising in otherwise normal bone
    • Conventional central osteosarcoma: an intramedullary high grade bone forming sarcoma
    • Low grade central osteosarcoma: a low grade malignant bone forming sarcoma that originates within the medullary cavity
    • Parosteal osteosarcoma: a low grade malignant bone forming sarcoma that arises on the cortical surface of a bone
    • Periosteal osteosarcoma: an intermediate grade, predominantly chondroblastic, bone forming sarcoma arising on surface of the bone, typically underneath the periosteum
    • High grade surface osteosarcoma: a high grade malignant bone forming sarcoma arising on the cortical surface of a bone
    • Extraskeletal osteosarcoma: a bone forming sarcoma that arises without connection to the skeletal system
  • Secondary osteosarcoma: a bone forming sarcoma arising in abnormal bone (prior radiation therapy, coexisting Paget disease of bone, infarction, etc.)
  • See Diagrams / tables
ICD coding
  • ICD-O: 9180/3 - osteosarcoma, NOS
  • ICD-10: C41.9 - malignant neoplasm of bone and articular cartilage, unspecified
  • ICD-11: 2B51.Z & XH1XF3 - osteosarcoma of bone and articular cartilage of unspecified sites & osteosarcoma, NOS
Epidemiology
  • Incidence: most common high grade sarcoma of skeleton
  • Age (bimodal age distribution) (Cancer Treat Res 2009;152:3, Cancer 2009;115:1531):
    • Most cases: 10 - 14 years old
    • Second smaller peak: adults (> 40 year old); usually secondary osteosarcoma
  • M:F = 1.3:1
  • Paget disease of bone: ~1% (variable range among studies) of patients develop conventional osteosarcoma (55 - 70% arises in polyostotic Paget disease) (Bone 2009;44:431)
  • Parosteal osteosarcoma: most common surface osteosarcoma
  • Low grade central osteosarcoma: 1 - 2% of osteosarcoma
  • Periosteal osteosarcoma: rare (less common than parosteal osteosarcoma)
  • High grade surface osteosarcoma: rare (< 1% of osteosarcoma)
  • Extraskeletal osteosarcoma: rare; usually occurs in adults
Sites
  • See Diagrams / tables
  • Osteosarcoma may arise in any bone
  • Most common: long bones of extremities (near the most proliferative growth plates) (Cancer 2009;115:1531)
    • Distal femur
    • Proximal tibia
    • Proximal humerus
      • Metaphysis: 90%
      • Diaphysis: 9%
      • Epiphysis: 1%
  • Older patients: jaw, pelvis, spine (Cancer 2009;115:1531)
  • Multifocal osteosarcoma: may occur in the setting of Paget disease of the bone
  • Very rare: small bones of hands and feet
  • Parosteal osteosarcoma: arises on cortical surface, usually metaphysis
    • Most common: distal posterior femur
    • Other sites: proximal tibia, proximal humerus
    • Uncommon: flat bones
  • Low grade central osteosarcoma:
    • Long bones: distal femur, proximal tibia (metaphysis and diaphysis); may fill the medullary space of the entire bone
    • Uncommon: flat bones, small tubular bones of hands and feet
  • Periosteal osteosarcoma: arises from periosteum, usually metaphyseal or metadiaphyseal (often with an anterior or medial epicenter; often wraps around bone)
    • Common sites: long bones, pelvis
    • Other less common sites: clavicle, ribs, cranial bones, jaw
  • High grade surface osteosarcoma: arises on cortical surface (femur, tibia, humerus)
  • Extraskeletal osteosarcoma:
    • Most common: arises in the deep soft tissues (thigh, buttocks, shoulder girdle, trunk, retroperitoneum)
    • Skin and subcutaneous tissue: ~10%
Pathophysiology
  • Remains uncertain but a relationship seems to exist between rapid bone growth and the onset of this malignancy (JAAPA 2018;31:15)
Etiology
  • In most patients, the etiology of osteosarcoma remains obscure (Ann Oncol 2010;21:vii320)
  • The predilection of osteosarcoma for the age of pubertal growth spurt and the sites of maximum growth suggest a correlation with rapid bone proliferation (Ann Oncol 2010;21:vii320)
  • Association between Paget disease of bone and osteosarcoma (J Bone Miner Res 2006;21:P58)
  • A minority of osteosarcomas are caused by radiation exposure
  • Most common mutated genes in sporadic osteosarcoma are TP53 in > 90% and RB1 in 56% of cases
  • Osteosarcoma associated with genetic syndromes:
    • Li-Fraumeni syndrome (TP53)
    • Hereditary retinoblastoma syndrome (RB1)
    • Bloom syndrome (RECQL3)
    • Rothmund-Thompson syndrome (RECQL4)
    • Werner syndrome (RECQL4)
Diagrams / tables

Contributed by Jesse Hart, D.O.

Bone tumor of humerus

Clinical features
  • Patients typically present with a dull, aching pain of several months' duration that may suddenly become more severe (JAAPA 2018;31:15)
  • Night pain is common
  • Physical examination may reveal localized tenderness, swelling and restricted range of motion of the adjacent joint
  • Presence of a mass or pathologic fracture
  • Nearly 10 - 20% of patients are affected by measurable metastatic disease before actual onset, the most common site being the lungs (85%), followed by the bones (8 - 10%) and occasionally the lymph nodes
Diagnosis
  • Imaging features of a bone tumor:
    • For any suspected bone lesion, a preoperative imaging protocol should be followed, which includes taking at least 2 Xray views of the involved bone and the adjacent joints
    • Magnetic resonance imaging (MRI) is warranted to evaluate the lesion’s invasion into the soft tissue and neurovascular structures, level of bone marrow replacement, skip lesions and extension into the bordering joint (AJR Am J Roentgenol 1994;163:1171)
    • Computed tomography (CT) scans are useful in defining cortical irregularities, fracture sites, mineralization and neurovascular involvement
    • Positron emission tomography (PET) scans can be used to assess the primary lesion and to detect metastases in other organs
    • Some suggest using PET scans to assess the response of the disease to chemotherapy as well as to predict progression free survival (Clin Adv Hematol Oncol 2010;8:705)
  • Biopsy is essential in the diagnosis of osteosarcoma (SICOT J 2018;4:12)
  • Fine needle aspiration should not be used, as it does not provide a large enough sample for a precise diagnosis (Skeletal Radiol 2002;31:349)
Laboratory
Radiology description
  • Conventional central osteosarcoma (Radiographics 2010;30:1653):
    • Medullary and cortical bone destruction
    • Wide zone of transition, permeative appearance
    • Aggressive periosteal reaction
      • Sunburst type
      • Codman triangle
      • Lamellated (onion skin) reaction
    • Tumor matrix ossification / calcification
    • Soft tissue involvement
  • Low grade central osteosarcoma (Radiographics 2010;30:1653, Skeletal Radiol 2004;33:373):
    • Intracompartmental expansile lytic fibro-osseous lesion with varying amounts of septal ossification
    • Another less common pattern is as a dense sclerotic lesion
    • Cortical erosion and soft tissue extension are also common features
  • Parosteal osteosarcoma (Radiographics 2010;30:1653, Radiology 2004;233:129):
    • Usually located at the metaphysis, most commonly at the posterior aspect of the distal femur, followed by either end of the tibia and then the proximal humerus
    • Lobulated, cauliflower-like surface mass with central dense ossification adjacent to the bone
    • Tumor stalk
    • Cortical thickening without aggressive periosteal reaction is often seen
    • True marrow invasion is rare
  • Periosteal osteosarcoma (Radiographics 2010;30:1653, Skeletal Radiol 2021;50:9):
    • Lesions tend to be diaphyseal
    • Lucent, fusiform mass on the surface of the bone with variable mineralization, frequently accompanied by focal clumps of calcifications
    • Tumor incompletely encircles the bone
    • Although the thickened underlying cortex is eroded by the mass, the endosteal cortex typically remains intact
    • Periosteal reaction extending into the soft tissue component
    • Arises from the cortex, intramedullary extension is rare
    • Predominantly chondroid matrix
  • High grade surface osteosarcoma (Radiographics 2010;30:1653, Cancer 2008;112:1592):
    • Tumor arises from the bony surface
    • Dense ossification
    • Cortical erosions and medullary involvement (~50% of cases)
    • Relatively high circumferential involvement
    • Periosteal reaction uncommon
Radiology images

Contributed by Jesse Hart, D.O., Borislav A. Alexiev, M.D. and AFIP
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Soft tissue extension

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Proximal humerus mass

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Proximal femur mass

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Metadiaphyseal aspect of proximal tibia

Proximal fibula

Prognostic factors
  • Conventional (high grade) osteosarcoma:
    • Aggressive local growth and early hematogenous dissemination (lung metastasis, skeletal metastases)
    • Nonmetastatic disease: 60 - 70% 3 year event free survival with current treatment (neoadjuvant chemotherapy followed by resection) (Acta Orthop 2011;82:211)
    • Poor prognostic factors:
      • Metastatic tumor (lung, skeletal, pleura, heart) (J Clin Oncol 2002;20:776)
      • Axial tumor site (opposed to extremities)
      • Age < 14 years old, high serum alkaline phosphatase, tumor volume > 200 mL, older chemotherapy protocol, inadequate surgical margins and poor histologic response (good response: ≥ 90% treatment effect; poor response: < 90% treatment effect) (Cancer 2006;106:1154)
  • Parosteal and low grade central osteosarcoma:
  • Periosteal osteosarcoma:
  • High grade surface osteosarcoma: prognosis is similar to conventional (high grade, intramedullary) osteosarcoma
  • Extraskeletal osteosarcoma:
    • 5 year overall survival: ~25%
Case reports
Treatment
  • Conventional osteosarcoma treatment consists of a combination of neoadjuvant and adjuvant chemotherapy and surgery (J Clin Oncol 1987;5:21)
  • Chemotherapy regimens for osteosarcoma based on high dose methotrexate and cisplatin with doxorubicin and ifosfamide (Cancer 2006;106:1154)
  • Low grade osteosarcoma can typically be treated with excision alone and chemotherapy is avoided if final pathology confirms low grade (SICOT J 2018;4:12)
  • National Comprehensive Cancer Network (NCCN) guidelines (NCCN Guidelines: Bone Cancer [Accessed 2 December 2022]):
    • Low grade osteosarcomas (low grade central and parosteal osteosarcoma): wide excision
      • If high grade dedifferentiation is identified on the excisional specimen, adjuvant chemotherapy is administered
    • Periosteal osteosarcoma: wide excision
      • In some cases, neoadjuvant chemotherapy may be administered
    • High grade osteosarcoma (intramedullary and surface): neoadjuvant chemotherapy followed by wide excision
      • Adjuvant therapy includes chemotherapy and depending on the final margin status (or if the tumor is unresectable), may include radiation
    • Metastatic disease at presentation:
      • If the clinical team chooses to resect the metastases, then resection and chemotherapy
      • If the metastases are not resected, chemotherapy and radiation therapy are administered
    • Extraskeletal osteosarcoma: treated as a soft tissue sarcoma
      • Treatment depends on tumor location, stage and resectability
  • Assessment of preoperative chemotherapy:
    • Preoperative chemotherapy is commonly used with limb salvage procedures for treatment of high grade sarcomas, particularly osteosarcoma and Ewing sarcoma
    • It is generally required to quantify the extent of tumor necrosis as a percentage of the total tumor area
    • For osteosarcomas, chemotherapy induced necrosis of ≥ 90% has a > 90% disease free survival, compared with < 50% in patients with < 90% tumor necrosis
    • To determine the extent of necrosis in an osteosarcoma or Ewing sarcoma specimen, the slab specimen of the resected bone containing tumor provides the template for histologic analysis
    • Photograph of the slice is taken and the site of each numbered block is marked on a grid pattern diagram
Gross description
  • Conventional (high grade intramedullary) osteosarcoma:
    • Intramedullary mass: usually a metaphyseal epicenter with cortical permeation and a soft tissue component that raises the periosteum
    • Size (mean): 5 - 10 cm
    • Cut surface: gritty and mineralized (hard); may have cartilaginous areas (chondroblastic osteosarcoma), hemorrhage, necrosis and cystic change
  • Low grade central osteosarcoma:
    • Often fills entire metaphysis and diaphysis of involved bone
    • Firm, gritty cut surface
    • May demonstrate cortical destruction, periosteal reaction and soft tissue invasion
  • Parosteal osteosarcoma:
    • Hard lobulated mass: attached to cortex
    • Variable: nodules of cartilage partially capping tumor surface
    • Variable: dedifferentiated soft fleshy areas
  • Periosteal osteosarcoma:
    • Broad based (sessile) tumor arising from the cortical surface (may circumferentially involve bone)
    • Cortex is thickened with scalloping of external surface
    • Heavily ossified base of tumor
    • External aspect of tumor (often the majority of the tumor) is cartilaginous
    • Calcified spicules may extend perpendicularly from the cortex within the mass and intermix with the cartilage
    • Rare to see cortical permeation and medullary extension
  • High grade surface osteosarcoma:
    • Tumor arises from the cortical surface and erodes / invades the cortex
    • Cut surface may be osteoblastic, chondroblastic or fibroblastic; areas of necrosis are present
  • Status postneoadjuvant chemotherapy:
    • To gross: cut along long axis of tumor and map
  • References: Cancer 1982;49:1679, Onco Targets Ther 2013;6:593
Gross images

Contributed by Jesse Hart, D.O., Borislav A. Alexiev, M.D. and Mark R. Wick, M.D.
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Low grade central osteosarcoma of femur

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Osteosarcoma of the humerus

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Osteosarcoma of the femur

Telangiectatic osteosarcoma

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Grid pattern diagram

Microscopic (histologic) description
  • Conventional (high grade intramedullary) osteosarcoma (Eur J Cancer 2002;38:1218, Am J Clin Pathol 2006;125:555):
    • Permeative growth: intramedullary permeative growth (replacement of medullary space, surrounds and erodes native trabeculae, fills Haversian systems) and cortical destruction with soft tissue invasion
    • Neoplastic cells: marked atypia (pleomorphic, hyperchromatic)
      • Multiple cell morphologies often present in 1 tumor (epithelioid, plasmacytoid, spindled, small round cells, clear cells, giant tumor cells)
      • Mitotic figures are easily demonstrable and atypical mitotic figures may also be identified
    • Neoplastic bone (necessary for diagnosis): no minimum quantity necessary
      • Most common: filigree / lace-like disorganized woven bone (intimately associated with neoplastic cells)
      • Broad sheets of bone
    • Normalization: decreased cytologic atypia of neoplastic cells entrapped in the bone matrix
    • Scaffolding (appositional neoplastic osteoid deposition): deposition of neoplastic osteoid on native trabeculae
    • Nonneoplastic giant cells: ~25% of cases
  • Histologic subtypes of conventional osteosarcoma: no prognostic significance
    • Osteoblastic, chondroblastic and fibroblastic are based on the prominent matrix they secrete (often admixed in 1 tumor)
      • Osteoblastic osteosarcoma: the predominant matrix is neoplastic bone (as described above)
      • Chondroblastic osteosarcoma: the predominant matrix is high grade cartilage (never has low grade cartilage)
      • Fibroblastic osteosarcoma: spindled to epithelioid cells, often with severe atypia, which may secrete extracellular collagen (may be extensive)
      • Telangiectatic osteosarcoma: the tumor is multiloculated with large blood filled spaces; high grade malignant cells and neoplastic bone in septa (the imaging differential diagnosis is with aneurysmal bone cyst)
      • Other morphologic variants: giant cell rich variant (numerous osteoclast-like giant cells), epithelioid variant, osteoblastoma-like variant, chondroblastoma-like variant, chondromyxoid fibroma-like osteosarcoma, clear cell variant, small cell variant
  • Osteosarcoma secondary to Paget disease:
    • High grade intramedullary osteosarcoma
    • Any histologic variant
    • Often contains numerous osteoclast-like giant cells
  • Status postneoadjuvant chemotherapy:
    • Report treatment response as a percent tumor necrosis (really an assessment of tumor drop out)
      • Edematous scar: loose edematous to myxoid granulation tissue, fibrosis, mild chronic inflammation
      • Bony matrix remains
      • Residual tumor cells: nests of tumor cells in retraction clefts are common
    • Grading response to chemotherapy (same cutoffs as Ewing sarcoma) (Cancer 1993;72:3227, J Clin Oncol 1988;6:329):
      • Good response is > 90% tumor necrosis
  • Low grade central osteosarcoma:
    • Permeative growth:
      • Intramedullary (surrounds and erodes native trabeculae, fills Haversian systems)
      • Cortical destruction and soft tissue invasion
    • Neoplastic cells: fibroblast-like spindle cells (minimal atypia); hypocellular to moderately cellular
      • Scattered mitoses may be seen
      • Rare, scattered higher grade areas may be present
      • Arranged in fascicles or interlacing bundles
    • Neoplastic bone:
      • Bone trabeculae (fibrous dysplasia-like): curved, branching or interanastomosing
      • Longitudinal lamellar bone: like parosteal osteosarcoma
    • Benign multinucleated giant cells: present in 33% of cases
    • With or without scattered foci of atypical cartilage
    • Dedifferentiation / high grade transformation (10 - 35% of cases):
      • High grade osteosarcoma
      • High grade undifferentiated pleomorphic sarcoma
      • Fibrosarcoma
      • Most common in recurrent tumors (2 - 3 years after resection) but may be seen in the primary tumor
  • Parosteal osteosarcoma:
    • Invasion: tumor invades soft tissue; 25% invade bone (cortex / medullary)
    • Neoplastic cells: fibroblast-like spindle cells (minimal atypia); between bony trabeculae (may be hypocellular)
      • Scattered mitoses may be seen
    • Neoplastic bone: parallel bony trabeculae (osteoblastic rimming may be present)
    • Cartilage (present in ~50% of cases):
      • Nodules within lesion (hypercellular)
      • Cartilage cap: partially overlays tumor (moderate cellularity, chondrocytes are not arranged in columns, mild to moderate atypia)
    • Dedifferentiation (15 - 25% of cases): abrupt transition to high grade sarcoma
      • High grade osteosarcoma
      • High grade undifferentiated pleomorphic sarcoma
      • Fibrosarcoma
      • Most common in recurrent tumors but may be seen in the primary tumor
  • Periosteal osteosarcoma:
    • Ossified mass: intimately attached to native cortex (secondary to endochondral ossification)
      • Pericortical bone: dense, mature bone
      • Bony spicules: radiate from the dense pericortical bone peripherally and admix with the hyaline cartilage component
        • Large vascular cores in center of bony spicules
        • Periphery of spicules is calcified / osseous or chondro-osseous and merges with (atypical) hyaline cartilage
    • Periphery of mass (majority of the tumor’s volume):
      • Atypical hyaline cartilage (appearance of grade 1 - 3 chondrosarcoma); may have myxoid change
      • Osseous component (always present but not the dominant component): intermediate grade osteosarcoma intermixed with cartilaginous component; may have lace-like bone but large areas of conventional osteoblastic osteosarcoma are not present
      • May have an admixed fibroblastic component (fascicles of mitotically active spindle cells)
  • High grade surface osteosarcoma: same features as conventional (high grade, intramedullary) osteosarcoma
    • May have osteoblastic, chondroblastic or fibroblastic areas
    • Low grade areas are not present
  • Extraskeletal osteosarcoma: may be any type of osteosarcoma
    • Nearly all high grade (marked cytologic atypia, numerous mitoses)
    • Bone may be lacy / filigree or trabecular / sheet-like
Microscopic (histologic) images

Contributed by Jesse Hart, D.O., Borislav A. Alexiev, M.D. and AFIP
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Permeative growth pattern

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Lace-like bone

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Marked pleomorphism

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Soft tissue extension

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Chondroblastic osteosarcoma with focal bone


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Fibroblastic osteosarcoma

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Fibroblastic osteosarcoma spindle cells

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Postneoadjuvant resection

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Postneoadjuvant tumor cell drop out

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Postneoadjuvant loose, fibrous scar


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Low grade central osteosarcoma

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Low grade central osteosarcoma invasion

Small osteoblasts with indistinct cytoplasm

Lymphoma-like pattern

Small foci of osteoid


Telangiectatic osteosarcoma

Telangiectatic osteosarcoma

Positive stains
Molecular / cytogenetics description
Sample pathology report
  • Bone, right distal femur and proximal tibia, radical resection (status postneoadjuvant chemotherapy):
    • Residual high grade osteosarcoma (see synoptic report, key findings below)
      • Tumor size: 15.2 x 8.0 x 8.0 cm
      • Tumor location: Centered in the left distal femur, involving the metaphysis, adjacent diaphysis and epiphysis. Peripherally invades through the cortical bone into the soft tissue on the medial, posterior, anterior and lateral aspects of the distal femur.
      • Percent treatment response: ~60% (~40% residual viable tumor)
      • Discontinuous tumor foci: Not identified
      • Lymphovascular invasion: Not identified
      • Surgical margins: Negative for tumor
      • Lymph nodes: 1 benign lymph node (0/1)
      • Additional findings: Dermal scar / biopsy site
      • Stage (AJCC, 8th edition): ypT2 ypN0
Differential diagnosis
  • Chondrosarcoma:
    • Older age group (> 50 years old)
    • Often are low grade, predominantly cartilaginous; no production of osteoid matrix by malignant tumor cells
    • May have IDH1 or IDH2 mutations
  • Dedifferentiated chondrosarcoma with osteosarcomatous dedifferentiation:
    • Age: > 50 years old
    • Low grade cartilaginous component definitionally present (grade I or II chondrosarcomatous component)
    • IDH1 or IDH2 mutation: ~50%
  • Ewing sarcoma (may be in differential with small cell osteosarcoma):
    • No osteoid matrix production
    • Negative for SATB2
    • Contains a characteristic gene rearrangement (EWSR1::ETS transcription factor)
  • Osteochondroma (may be in differential with parosteal osteosarcoma):
    • Bone contiguous with native marrow
    • Intramedullary space filled with fat and hematopoietic elements (not spindle cells)
    • Cartilage cap completely covers lesion, chondrocytes arranged in small chords and nests
  • Bizarre parosteal osteochondromatous proliferation (may be in differential with parosteal osteosarcoma):
    • Usually involves small tubular bones (hands and feet)
    • Haphazard arrangement of hyaline cartilage (hypercellular and atypical chondrocytes), bone (disorganized blue bone and woven bone) and spindle cells
    • Negative for MDM2 gene amplification
  • Fibrous dysplasia (may be in differential with parosteal osteosarcoma):
    • No permeative growth
    • No MDM2 gene amplification
    • GNAS mutation
  • Osteoblastoma (Am J Clin Pathol 2006;125:555):
    • The most important histologic parameters for malignancy (not seen in osteoblastoma) include permeation of architecturally normal bone at its interface with tumor and increased and atypical mitotic figures
  • Chondroblastoma (Am J Clin Pathol 2006;125:555):
    • No osteoid or bone formation
    • No atypical mitotic figures
    • No infiltration of adjacent intertrabecular spaces
Board review style question #1
Missing Image Missing Image


A 12 year old girl has a 10.5 cm intramedullary mass in the distal femur, which was resected (see gross and microscopic images). High power views demonstrate bland spindle cells. Which of the following is most accurate regarding this tumor?

  1. Most likely, genetic abnormality is amplification of the MDM2 gene
  2. Most likely, genetic abnormality is a mutation in TP53
  3. Patient likely has lung metastases
  4. Tumor likely has a GNAS mutation
  5. Unusual tumor in the pediatric population
Board review style answer #1
A. Most likely, genetic abnormality is amplification of the MDM2 gene. The tumor is a low grade central osteosarcoma.

Comment Here

Reference: Conventional osteosarcoma and osteosarcoma overview
Board review style question #2

A 16 year old boy had a biopsy from a 16 cm mass in the proximal humerus (see image). Which of the following is true?

  1. Probability of metastasis is low
  2. Should recommend that the surgeon send intraoperative cultures upon resection
  3. Treatment will include neoadjuvant chemotherapy followed by resection
  4. Tumor likely has a mutation in the IDH1 or IDH2 gene
  5. Tumor is most often seen in older patients
Board review style answer #2
C. Treatment will include neoadjuvant chemotherapy followed by resection. This is a conventional high grade osteosarcoma.

Comment Here

Reference: Conventional osteosarcoma and osteosarcoma overview

Paget disease
Definition / general
Essential features
  • Essentially, accelerated bone turnover making disordered bone
  • Multiple phases are present, showing poorly formed bone, increased osteoclast activity (bites in the bone) and osteoblastic rimming
  • Diagnosis is usually made radiographically
  • Can be monostotic or polyostotic
Terminology
  • Also called osteitis deformans
ICD coding
  • ICD-10:
    • M88 - osteitis deformans
      • Multiple subdesignators based on location (i.e., M88.9 - osteitis deformans of unspecified bone)
    • M90.6 - osteitis deformans in neoplastic disease
Epidemiology
  • Most are over age 55; rare before age 40 (Am J Med 2018;131:1298)
  • Fairly common in older people with estimates ranging near 2.3% in that population (J Bone Miner Res 2000;15:461)
  • Most common in Western Europe and locations settled by those populations (U.S., Canada, Australia, etc.); rare in Africa and those of African descent, Scandinavia and Asia (Am J Med 2018;131:1298)
  • Slight male predominance (4:3)
Sites
  • Patients can present as polyostotic (multiple bones) or monostotic (one bone)
  • Most common sites:
    • Spine and pelvis (30 - 75%)
    • Sacrum (30 - 60%)
    • Skull (25 - 65%)
    • Femur (25 - 25%)
  • Rare in hands / feet, ribs, fibula (Wien Med Wochenschr 2017;167:9)
Pathophysiology
  • Believed to be a disease of osteoclasts
  • Genetic and environmental problems can lead to disruption in osteoclast differentiation and activation:
    • Receptor activator of nuclear factor kappa Β ligand (RANKL), osteoclast differentiation
    • Macrophage colony stimulating factor (MCSF), macrophage differentiation
    • Nuclear factor kappa B (NFκB), apoptosis regulation
    • Osteoprotegrin, bone remodeling (Curr Osteoporos Re 2021;19:327)
    • Abnormal osteoclast activity leads to exaggerated physiologic response
    • Not fully understood
Etiology
  • Not fully understood
  • May be due to slow virus infection of paramyxovirus, similar to subacute sclerosis leukoencephalitis (virus identified in osteoblasts)
  • Several gene mutations have been identified in familial and sporadic forms (Curr Osteoporos Re 2021;19:327)
Clinical features
  • Patients are generally asymptomatic or have mild symptoms
  • May show bone pain and deformities
  • Bone overgrowth or deformity can cause osteoarthritis and nerve impingement
  • Initial presentation is commonly after pathologic fracture
  • Incidental finding after imaging studies or serum alkaline phosphatase for other reasons
  • Also associated with high output congestive heart failure in polyostotic disease due to shunting of blood through highly vascular lesions (Am J Med 2018;131:1298)
  • While uncommon, osteitis deformans can progress to sarcoma, most of which are osteosarcoma; it has a very poor prognosis (Orthop Clin North Am 2015;46:577)
Diagnosis
  • Diagnosis is primarily radiologic
  • Serum alkaline phosphatase (ALP) can be helpful if positive and used to monitor disease progression
  • Biopsy is not needed in routine cases but can be useful if radiographically distinct lesions appear in an abnormal population or if there is concern that the lytic lesion is a metastasis; monostotic lesions that are not radiographically characteristic should be biopsied
Laboratory
  • Elevated serum ALP
    • ALP isoenzyme electrophoresis for bone type
    • Most patients with Paget have normal ALP, more so than those with monostotic disease
  • Other markers of increased bone turnover: procollagen type I N terminal propeptide (PINP), serum C telopeptide (CTx), urinary N telopeptide (NTx) and urinary hydroxyproline (Am J Med 2018;131:1298)
  • Serum calcium and phosphorus are generally normal
Radiology description
  • Early: radiolucency
  • Well defined lytic lesion is called osteoporosis circumscripta and is fairly specific for Paget disease when occurring in the frontal bone (Wien Med Wochenschr 2017;167:9)
  • Late: increased bone density, cortical thickening with marked tunneling, increased prominence of trabeculae, increased microfractures, loss of distinction between cortex and medulla; may have sharp demarcation between normal and affected bone; may extend into soft tissue if florid disease
  • Long bone can become bowed
  • Bone scintigraphy will show increased uptake in active lesions
Radiology images

Contributed by Jose G. Mantilla, M.D.
Paget COR CT Femur

Coronal CT of femur

Paget XR Femur

Xray of femur

Prognostic factors
  • Progression to sarcoma is a poor prognostic factor
Case reports
  • 60 year old man with JPD1 who described hardening of his external ears at age 45 years, after 4 years of treatment with bisphosphonates (Am J Med Genet A 2016;170A:978)
  • 74 year old African American man was referred for the investigation of symmetrical polyarthritis, left upper arm joint deformity and low back pain (Am J Case Rep 2019;20:764)
  • 75 year old man with a rapidly progressive cervical myelopathy on a background of a 3 year history of neck pain and a severely degenerative cervical spine (Ann R Coll Surg Engl 2019;101:e38)
Treatment
  • Bisphosphonates
  • Calcitonin
Frozen section description
  • Intraoperative evaluations of bone should not be performed
Microscopic (histologic) description
  • Major findings are haphazard layers of lamellar bone with woven bone, irregular cement lines between layers of lamellar bone, thickened trabeculae with osteoblastic rimming and areas of bone resorption (bite marks) with abnormal osteoclasts, peritrabecular fibrosis and increased vascularity of marrow
  • Early: primarily woven bone
    • Focal mosaic pattern of lamellar bone, resembles jigsaw puzzle with prominent irregular cement lines
    • Osteoclasts present at surface of bone with bite marks into the bone
    • In osteolytic phase, osteoclasts are increased and abnormal with up to 100 nuclei, peritrabecular fibrosis, increased vascularity
  • Middle phase: enlarged trabeculae with very irregular shapes and abnormal cement lines; prominent osteoblast activity
  • Late: significantly decreased osteoblast and osteoclast activity, thick trabeculae and thicker bones with mosaic pattern of cement lines; fine fibrosis of marrow
  • All phases may be identified within a single specimen
Microscopic (histologic) images

Contributed by Dana J. Hariri, M.D.
Osteoblastic rimming

Osteoblastic rimming

Jigsaw pattern

Jigsaw pattern

Haphazard Lamellar bone

Haphazard lamellar bone

Peritrabecular fibrosis

Peritrabecular fibrosis

Virtual slides

Images hosted on other servers:

Prominent mosaic pattern and marrow fibrosis

Cytology description
  • There is no utility for cytology
Positive stains
  • Reticulin (highlights disorganization of lamellar bone)
  • IHC has little utility
Molecular / cytogenetics description
  • SQSTM1 mutations are the most common in familial Paget disease of bone (Curr Osteoporos Re 2021;19:327)
  • TNFRSF11A gene encoding RANKL leads to increased osteoclast activity
Videos

Overview of diagnosis and management of Paget disease

Sample pathology report
  • Bone, distal femur, excision:
    • Osteitis deformans, Paget disease of bone
Differential diagnosis
  • Reactive bone formation adjacent to neoplasm:
    • Cement lines not as prominent
    • Clinical setting of adjacent neoplasm which can be seen on imaging
  • Chronic osteomyelitis:
    • Lack of mosaic pattern of bone formation
    • Can have fibrosis with new bone formation
    • Fibrosis usually accompanied by chronic inflammatory cells
  • Polyostotic fibrous dysplasia:
    • Branching and anastomosing irregular trabeculae of woven bone
    • Lacks prominent osteoblastic rimming
Board review style question #1

Which of the following is true of the lesion shown in the picture above?

  1. Heat stable alkaline phosphatase will be elevated
  2. It has a very poor prognosis and the patient will likely die within a year
  3. It will likely progress to a low grade sarcoma
  4. The lesion rarely has more than one site of involvement
  5. Pathologic fractures are a common initial presentation
Board review style answer #1
E. Pathologic fractures are a common initial presentation

Paget disease of bone most commonly presents with a pathologic fracture but can present as generic bone pain. It very rarely progresses to any form of sarcoma but it is a complication that presages a poor outcome; otherwise, the outcome is more benign. Alkaline phosphatase is sometimes elevated but the bone isoenzyme of ALP is heat labile (bone burns, liver lasts). It is important to note that while temperature stability is often mentioned for alkaline phosphatase isoenzymes, electrophoresis is the preferred way to subtype them. The lesions can be monostotic or polyostotic.

Comment Here

Reference: Paget disease
Board review style question #2
Of the following sites, which is the most likely to show Paget disease?

  1. Metatarsal of the hand
  2. Pelvis
  3. Ribs
  4. Tibia
Board review style answer #2
B. Pelvis. Common sites of involvement are pelvis, spine, skull, tibia, femur, skull, vertebrae and humerus. Hand, feet and ribs are very rare.

Comment Here

Reference: Paget disease

Parosteal osteosarcoma
Definition / general
  • Parosteal osteosarcoma (PO) is a rare malignant bone surface tumor
  • Most common surface osteosarcoma
Essential features
  • Most commonly occurs in third decade of life with slight female predominance; commonly involves metaphysis of long bones
  • Radiologically, tumor is a lobulated, ossified mass attached to bone surface with radiologic intact periosteum
  • Microscopically, tumor shows lamellar and woven bony trabeculae with intervening low grade spindle cell component; cartilage component is common and dedifferentiation is seen in some cases
  • MDM2 and CDK4 gene amplification and immunohistochemical expression are hallmark and useful for diagnostic purpose
  • Overall survival is excellent, with substantial risk of local recurrence and late distant metastasis
Terminology
  • Juxtacortical osteosarcoma (not recommended)
ICD coding
  • ICD-O: 9192/3 - parosteal osteosarcoma
  • ICD-10: C41.9 - malignant neoplasm of bone and articular cartilage, unspecified
  • ICD-11: 2B51.Z & XH8HG5 - osteosarcoma of bone and articular cartilage of unspecified sites & parosteal osteosarcoma
Epidemiology
  • Age range: 9 - 75 years with peak incidence in third decade of life; slight female predominance
  • Most common surface osteosarcoma; constitutes 4.5% of all osteosarcomas (Bone Joint J 2015;97:1698)
  • No causal connection or association
Sites
  • Commonly involves metaphysis of long bones
  • Posterior aspect of distal femur is the most common site (~70% of cases), followed by proximal tibia and proximal humerus
  • Less frequently involved sites include fibula, radius, ulna, scapula, ilium, ribs, metatarsals, metacarpals, maxilla, mandible, etc. (Hum Pathol 2019;91:11)
Pathophysiology
  • Characteristic molecular aberration in parosteal osteosarcoma is the presence of supernumerary ring chromosome(s) containing amplified material encoding MDM2 and CDK4 genes (Genes Chromosomes Cancer 2010;49:518)
Etiology
  • Unknown
Clinical features
  • Slow growing tumor; symptom duration is typically > 1 year and may remain undetected for 15 years
  • Usually painless swelling; can be painful in some cases
  • May be associated with restricted movements at associated joints
  • Dedifferentiated tumors present with shorter symptom duration
  • Tumor size range: 1.2 - 29 cm; mean: 7.6 cm (Hum Pathol 2019;91:11)
Diagnosis
  • Plain radiographs, CT scan and MRI scan confirm tumor location at bone surface
  • Incisional / open biopsy is done to histologically confirm the diagnosis before undergoing tumor excision
  • Reference: Int J Surg Oncol (N Y) 2017;2:e50
Radiology description
  • Plain radiograph: lobulated, sessile, mineralized mass attached to the bone surface through a pedicle with thin radiolucent cleavage plane of intact periosteum; no periosteal reaction is seen
  • CT scan findings: cortical changes and intramedullary extension
  • MRI scan findings: intramedullary extension, dedifferentiated component, cartilage component at tumor surface
  • MRI scan is more sensitive for detection of medullary involvement, while CT scan is more specific (Int J Biol Markers 2020;35:31)
Radiology images

Contributed by Nasir Ud Din, M.B.B.S., Mark R. Wick, M.D. and AFIP
Surface tumor with intact cortex

Surface tumor with intact cortex

Intact cortex and radiolucent cleavage of intact periosteum

Intact cortex

Intact cortex and radiolucent cleavage of intact periosteum

Radiolucent cleavage of intact periosteum

Lobulated tumor with cartilage component

Lobulated tumor with cartilage component

Parosteal osteosarcoma of rib

Parosteal osteosarcoma of rib


Distal femur Xray

Distal femur Xray

Proximal tibia Xra

Proximal tibia Xray

Mass behind knee

Mass behind knee

Femur

Femur

Prognostic factors
  • Overall 5 year survival rate is 91.8% and 10 year survival rate is 87.8% (Bone Joint J 2015;97:1698)
  • Prognosis of conventional parosteal osteosarcoma is better than conventional osteosarcoma, while the prognosis of dedifferentiated parosteal osteosarcoma is similar to conventional osteosarcoma
  • Recurrence rate up to 23% has been observed
    • Higher in incompletely or marginally resected tumors
    • Develops after a long term interval
  • Distant metastatic rate up to 19% has been observed
  • Female gender and young age are good prognostic factors (Bone Joint J 2015;97:1698)
  • Poor prognostic features include dedifferentiation, medullary involvement, distant metastasis and local recurrence
Case reports
Treatment
  • En bloc resection with clear margins is recommended for low grade, localized tumors
  • Amputation is performed in occasional cases
  • Adjuvant chemotherapy is usually administered in tumors with higher grade, dedifferentiation and local recurrence; no obvious benefit on survival (Bone Joint J 2015;97:1698)
Gross description
  • Lobulated mass attached to the outer surface of the bone by a broad pedicle; may invade into bone, involve medullary cavity or encircle the bone
  • Satellite nodules can be seen, especially in recurrent tumors
  • Cut surface may appear grey, white fibrous, cartilaginous or bony hard, depending on the different tumor components (Am J Clin Pathol 2000;114:S90)
  • Dedifferentiated areas may appear soft and fleshy
  • Cartilage cap may be grossly appreciable
Gross images

Contributed by Mark R. Wick, M.D. and AFIP
Distal femur

Distal femur

Proximal femur tumor

Proximal femur tumor

Cross section

Cross section



Images hosted on other servers:
Tumor encircling bone

Tumor encircling bone

Dedifferentiated parosteal osteosarcoma

Dedifferentiated parosteal osteosarcoma

Microscopic (histologic) description
  • Tumor has 2 basic components: bone trabeculae and spindle cells
  • Spindle cells are typically arranged as fascicles in intertrabecular spaces and show low cellularity, minimal atypia, low mitotic count and hyalinized background
  • Some tumors may show increased cellularity, higher nuclear grade and frequent mitotic activity
  • Spindle cell component is graded I - III (according to Broder's grading system) on the basis of cellularity, nuclear pleomorphism and mitoses; this grading system is not routinely practiced since its prognostic value is still not well established (J Bone Joint Surg Br 1984;66:313, Journal of Solid Tumors 2016;6:17, J Bone Joint Surg Am 1977;59:632)
  • At the periphery, spindle cells increase in cellularity and infiltrate into fat and muscle fibers; may take the form of spindle cell nodules
  • Bone trabeculae are commonly parallel streams of lamellar bone; interconnected trabeculae and woven bone may also be present and osteoblastic rimming may or may not be seen
  • Parallel streams of bone are seen in ~61% of cases
  • Medullary involvement in present in 35% of cases
  • Dedifferentiation is observed in 15 - 43% of cases; primary or recurrent tumors may show features of osteosarcoma, undifferentiated spindle cell sarcoma, chondroblastoma or rhabdomyosarcoma
  • Cartilaginous component is present in 25 - 50% of cases in the form of peripheral cartilage cap or cartilage nodules within tumor (Journal of Solid Tumors 2016;6:17)
Microscopic (histologic) images

Contributed by Nasir Ud Din, M.B.B.S.
Cartilage cap, bone and spindle cells Cartilage cap, bone and spindle cells

Cartilage cap, bone and spindle cells

Cartilage nodule, bone and spindle cells

Cartilage nodule, bone and spindle cells

Parallel bone trabeculae

Parallel bone trabeculae

Parallel and interconnected bone trabeculae Parallel and interconnected bone trabeculae

Parallel and interconnected bone trabeculae


Parallel and interconnected bone trabeculae

Parallel and interconnected bone trabeculae

Interconnected bone trabeculae Interconnected bone trabeculae

Interconnected bone trabeculae

Small islands of bone

Small islands of bone

Chinese letter-like bone trabeculae Chinese letter-like bone trabeculae

Chinese letter-like bone trabeculae


Low grade spindle cell component

Low grade spindle cell component

Intermediate grade spindle cell component

Intermediate grade spindle cell component

Dedifferentiated areas Dedifferentiated areas

Dedifferentiated areas

Fat and muscle entrapment

Fat and muscle entrapment

Skeletal muscle atrophy

Skeletal muscle atrophy

Positive stains
Electron microscopy description
  • Predominantly composed of myofibroblasts along with fibroblasts and some osteoblasts
  • Tumor cells are separated by abundant intercellular matrix and collagen fibers (Cancer 1982;50:949)
  • Cartilage component is normal
  • Desmosomes may be seen between undifferentiated cells (Hum Pathol 1980;11:373)
Molecular / cytogenetics description
  • Parosteal osteosarcoma is near diploid, cytogenetically characterized by one or more supernumerary ring chromosome(s), which contain(s) amplified material encoding MDM2 and CDK4 genes
  • MDM2 and CDK4 gene amplifications are detected by FISH in > 85% of cases (Genes Chromosomes Cancer 2010;49:518)
  • Activating GNAS mutations are also observed in 55% of cases (Am J Surg Pathol 2014;38:402)
Molecular / cytogenetics images

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<i>MDM2</i> gene amplification by FISH

MDM2 gene amplification by FISH

Videos

Parosteal osteosarcoma
by Lewis Hassell

Parosteal osteosarcoma made easy by Vikram Deshpande

Sample pathology report
  • Distal femur, wide local resection:
    • Parosteal osteosarcoma, grade 1 (see comment)
    • Tumor size: 7 x 5 x 3 cm
    • Dedifferentiated component: absent
    • Necrosis: absent
    • Involvement of medullary cavity: absent
    • Soft tissue and skeletal muscle invasion: present
    • Margins of resection are negative, with sarcoma closest at … cm from … bone margin and at … cm from … soft tissue margin
    • Pathologic TNM stage: pT1
    • Comment: Radiographs show a heterogeneous ossified mass attached to the posterior aspect of the distal femur at the metaphyseal region. The tumor is hypocellular and composed of well formed bone trabeculae with intervening fascicles of spindle cells with minimal atypia and low mitotic activity. At the periphery of the tumor, the spindle cell component invades into the adjacent skeletal muscle. Progression to high grade sarcoma is not identified. The findings support the above diagnosis.
    • The prognosis of parosteal osteosarcoma is excellent, with a 90% overall survival rate at 5 years. Wide local resection is curative for pure (low grade) parosteal osteosarcoma.
    • pN: Not assigned (no nodes submitted or found); pM: Not applicable - pM cannot be determined from the submitted specimen
Differential diagnosis
Board review style question #1


A 29 year old woman had a painless swelling at the posterior aspect to knee. Xray of the knee joint showed a sessile tumor at the posterior surface of femur with underlying intact cortex. Microscopically, tumor showed a cartilage cap and interconnected bone trabeculae with intervening low grade spindle cell population. What is the most likely diagnosis?

  1. Conventional osteosarcoma
  2. Myositis ossificans
  3. Osteochondroma
  4. Parosteal osteosarcoma
  5. Periosteal chondroma
Board review style answer #1
D. Parosteal osteosarcoma. The closest differential diagnosis is parosteal osteosarcoma and osteochondroma. In parosteal osteosarcoma, the intertrabecular spaces contain spindle cell component, while the intertrabecular spaces in osteochondroma contain hematopoietic precursors or adipocytes.

Comment Here

Reference: Parosteal osteosarcoma
Board review style question #2
Which of the following is the most important prognostic feature in parosteal osteosarcoma?

  1. Dedifferentiation
  2. Histologic grade
  3. Infiltration into adjacent soft tissue
  4. Necrosis
  5. Tumor size
Board review style answer #2
A. Dedifferentiation is the most important prognostic feature. The prognosis of conventional parosteal osteosarcoma is better than conventional osteosarcoma, while the prognosis of dedifferentiated parosteal osteosarcoma is similar to conventional osteosarcoma.

Comment Here

Reference: Parosteal osteosarcoma

Periosteal chondroma
Definition / general
  • Rare benign cartilaginous neoplasm that arises on the surface of cortical bone beneath periosteum
Essential features
  • Children and young adults
  • Well defined dome shaped lesion on the surface of the bone
  • Composed of benign hyaline cartilage
  • No connection with medullary cavity (radiologically)
Terminology
  • Juxtacortical chondroma, subperiosteal chondroma
ICD coding
  • ICD-O: 9221/0 - periosteal chondroma
  • ICD-11: 2E82 & XH3BC3 - benign chondrogenic tumors & periosteal chondroma
Epidemiology
  • < 2% of all chondromas
  • Affects children and young adults, predominantly < 30 years of age (Oncol Lett 2015;9:1637)
  • M:F = 1.5:1
Sites
  • Small bones of the hands and long bones of the skeleton, particularly proximal metaphyseal or diaphyseal regions of humerus and femur (Oncol Lett 2015;9:1637)
Pathophysiology
  • A subset of periosteal chondromas harbor mutations in one of the IDH genes (J Pathol 2011;224:334)
  • Other cytogenetic abnormalities have been reported
Etiology
  • Unknown
Clinical features
Diagnosis
  • Depends greatly on radiologic features
Radiology description
  • Sharply defined juxtacortical mass
  • Contains popcorn or ring-like calcifications, characteristic of cartilaginous tumors
  • Plain radiographs may show a discernible soft tissue mass with underlying cortical saucerization or scalloping, subjacent cortical sclerosis and overhanging margins
  • CT may be helpful in identifying the presence of scattered calcification and the lack of intramedullary extension (Case Rep Orthop 2014;2014:763480)
  • On MRI, periosteal chondroma typically appears as a well circumscribed juxtacortical mass with intermediate signal intensity on T1 weighted images and high signal intensity on T2 weighted images (Case Rep Orthop 2014;2014:763480)
Radiology images

Contributed by Shadi Qasem, M.D., M.B.A.
Xray of distal femur lesion

Xray of distal femur lesion

CT scan of distal femur lesion

CT scan of distal femur lesion

Proximal tibia lesion

Proximal tibia lesion

Prognostic factors
Case reports
Treatment
  • Surgical management in the form of intralesional, marginal or en bloc resection, is the mainstay of therapy
  • Marginal excision and curettage are preferable options if the diagnosis is certain prior to surgery (Oncol Lett 2015;9:1637)
Gross description
  • Well defined, waxy blue-gray
  • Size: < 5 cm
  • Focal calcification and lobulation (Am J Surg Pathol 1982;6:631)
  • Bone buttressing at the lateral edge but no medullary invasion
Gross images

Contributed by Shadi Qasem, M.D., M.B.A. and Mark R. Wick, M.D.
Marginal resection specimen

Marginal resection specimen

Wide resection specimen

Frozen section description
  • These lesions are typically sent for frozen section; frozen section would show mature hyaline cartilage
Microscopic (histologic) description
  • Well demarcated from the underlying sclerotic bone, which may be focally eroded but never permeated
  • Lobular architecture
  • Covered by a continuous layer of attenuated periosteum
  • Cellularity is variable but generally low
  • Chondrocytes do not show cytologic atypia
  • Occasionally, some tumors are more cellular and exhibit a greater degree of nuclear pleomorphism, including spindling and binucleation
  • Invasion of surrounding soft tissue or medullary canal is not seen
Microscopic (histologic) images

Contributed by Shadi Qasem, M.D., M.B.A.
Well defined margin

Well defined margin

Low cellularity

Low cellularity

No significant atypia

No significant atypia

Virtual slides

Images hosted on other servers:

Juxtacortical chondroma in Ollier disease

Molecular / cytogenetics description
  • IDH1 and IDH2 mutations have been identified in periosteal chondromas (Am J Surg Pathol 1982;6:631)
  • No consistent cytogenetic abnormality has been reported
Sample pathology report
  • Humerus, excision:
    • Periosteal chondroma (see comment)
    • Comment: The diagnosis is made in concert with radiologic findings.
Differential diagnosis
  • Periosteal chondrosarcoma:
    • Favored: if tumor size > 5 cm
    • Definitive diagnosis: presence of invasion into haversian system in addition to radiologic findings of a destructive bone lesion
  • Periosteal osteosarcoma:
    • Radiology: lucent, fusiform mass on the surface of bone, with variable mineralization; the cortex is thickened with periosteal reaction
    • Histology: poorly delineated lobules of atypical cartilage with intervening bands of primitive sarcomatous cells and neoplastic bone formation
  • Parosteal osteosarcoma:
    • Radiology: mineralized, lobular mass at the bone surface; the underlying cortex may be normal, thickened or destroyed
    • Histology: well formed bone trabeculae with intervening fascicles of spindle cells with minimal atypia and low mitotic activity
    • MDM2 amplification
  • Bizarre parosteal osteochondromatous proliferation:
    • Radiology: well circumscribed calcified mass on the cortical surface
    • Histology: disorganized cellular lesion composed of spindle cells, atypical chondrocytes and bone; the presence of blue bone is characteristic
  • Periosteal chondromyxoid fibroma:
    • Radiology: often multilobated with prominent calcifications
    • Histology: myxoid stroma with stellate cells
  • Soft tissue chondroma:
    • Radiology: well demarcated, separated from the bone and has calcifications
    • Histology: nodules of well delineated cartilage, matrix is hyaline or myxoid and may calcify; chondrocytes show limited atypia and little mitotic activity
Board review style question #1

A 17 year old boy had a distal femur lesion (see images above). Which of the following is true regarding this lesion?

  1. Connection with bone marrow is a key feature
  2. IDH mutation is diagnostic
  3. Often presents with intense localized pain, relieved by aspirin
  4. Radiology review is essential for diagnosis
Board review style answer #1
D. Radiology review is essential for diagnosis

Comment Here

Reference: Periosteal chondroma
Board review style question #2
Which of the following is true for periosteal chondroma?

  1. Bone buttressing is characteristic on gross examination
  2. En bloc resection is the preferred therapy
  3. Molecular testing is helpful for differentiating this lesion from chondrosarcoma
  4. Tumor size > 5 cm is not unusual
Board review style answer #2
A. Bone buttressing is characteristic on gross examination

Comment Here

Reference: Periosteal chondroma

Periosteal osteosarcoma

Pseudomyogenic hemangioendothelioma

Rheumatoid arthritis
Definition / general
  • Chronic systemic inflammatory disorder affecting synovial lining of joints, bursae and tendon sheaths; also skin, blood vessels, heart, lungs, muscles (Davidson College: Rheumatoid Arthritis [Accessed 26 January 2022])
  • Produces nonsuppurative proliferative synovitis, may progress to destruction of articular cartilage and joint ankylosis
Epidemiology
  • 1% of adults, 75% are women, peaks at ages 10 - 29 years; also menopausal women
Sites
  • Small bones of hand affected first (MCP, PIP joints of hands and feet), then wrist, elbow, knee
Pathophysiology
  • Triggered by exposure of immunogenetically susceptible host to arthitogenic microbial antigen; autoimmune reaction then occurs with T helper activation and release of inflammatory mediators and cytokines that destroys joints; circulating immune complexes deposit in cartilage, activate complement, cause cartilage damage
  • Parvovirus B19 may be important in pathogenesis (Mod Pathol 2003;16:811)
Clinical features
  • Clinical course: variable; malaise, fatigue, musculoskeletal pain, then joint involvement; joints are warm, swollen, painful, stiff in morning; 10% have acute onset of severe symptoms but usually joint involvement occurs over months to years; most damage occurs in first 5 years, joints are unstable with minimal range of motion; 50% have spinal involvement
  • Reduces life expectancy by 3 - 7 years, death due to amyloidosis, vasculitis, GI bleeds from NSAIDs, infections from steroids
Diagnosis
  • Morning stiffness, arthritis in 3+ joint areas, arthritis in hand joints, symmetric arthritis, rheumatoid nodules, rheumatoid factor, typical radiographic changes
Laboratory
  • 80% have IgM autoantibodies to Fc portion of IgG (rheumatoid factor), which is not sensitive or specific; synovial fluid has increased neutrophils (particularly in acute stage), increased protein, low mucin
  • Other antibodies include antikeratin antibody (specific, not sensitive), antiperinuclear factor, anti rheumatoid arthritis associated nuclear antigen (RANA)
Radiology description
  • Xray: joint effusions, juxta-articular osteopenia, erosions and narrowing of joint space; destruction of tendons, ligaments and joint capsules produce radial deviation of wrist, ulnar deviation of digits, swan neck finger abnormalities
Radiology images

Case #308

Bony lesion

MRI of bony lesion

Case reports
  • 30 year old woman with 7 year history of pain in lumbosacral area and 1 year history of pain in joints of both hands (Chin Med J (Engl) 2011;124:3430)
  • 49 year old woman with chief complaint of restricted mouth opening without pain, lasting approximately 4 months (Braz Dent J 2012;23:779)
  • 52 year old woman had pain in the right wrist joint for 6 months (Case #308)
  • 72 year old woman with 6 month history of progressive painful swelling of wrists (Int J Surg Case Rep 2011;2:208)
  • Woman with pain and edema in second, third and fourth proximal interphalangeal (PIP) joints of hands and wrists (Rev Bras Reumatol 2012;52:648)
Treatment
  • Nonsteroidal anti-inflammatory drugs (NSAIDs); immunosuppressive drugs; joint replacement (synovitis tends to lessen), synovectomy (inflamed synovium may recur and disease may continue to progress)
Clinical images

Images hosted on other servers:

Yellowish discharge of altered synovial fluid

Gross description
  • Joints have edematous, thick, hyperplastic synovium, covered by delicate and bulbous fronds
  • Osteophytes and new bone formation are not prominent
Microscopic (histologic) description
  • Dense perivascular inflammatory infiltrate of T lymphocytes, plasma cells (often with eosinophilic cytoplasmic inclusions called Russell bodies), macrophages; inflammation extends to subchondral bone (relatively specific for rheumatoid arthritis)
  • Proliferative synovitis with synovial cell hyperplasia and hypertrophy
  • Lymphoplasmacytic infiltrate with variable germinal centers, necrobiotic nodules and fibrosis
  • Increased vascularity with hemosiderin deposition
  • Organizing fibrin floating in joint space as rice bodies
  • Neutrophils present on synovial surface; osteoclasts present in bone forming cysts
  • Erosions, osteoporosis; pannus formation (synovium, synovial stroma with inflammatory cells, granulomatous tissue, fibroblasts), progressing to fibrous ankylosis (bridges joints), then ossifying to form bony ankylosis
  • Minimal evidence of repair (proliferative cartilage, sclerotic bone or osteophytes)
  • Weichselbaum's lacunae: enlarged chondrocyte lacunae within articular cartilage due to dead chondrocytes
  • Skin: rheumatoid nodules in 25%, usually those with severe disease in skin subject to pressure (ulnar forearm, elbows, occiput, lumbosacral area); also present in viscera; firm, nontender, with central fibrinoid necrosis surrounded by palisading epithelioid histiocytes, lymphocytes, plasma cells; obliterative endarteritis in vasa nervorum and digital arteries causes ulcers, neuropathy, gangrene
  • Blood vessels: small to medium size vessels in vital organs (not kidney) affected by severe erosive disease; rheumatoid nodules present, high titers of rheumatoid factor
Microscopic (histologic) images

Contributed by @MirunaPopescu13 on Twitter and Case #308
Rheumatoid arthritis

Rheumatoid arthritis

Various images



Images hosted on other servers:

Amorphous, pink, necrotic material

Cytology description
  • May have inflammatory exudate with neutrophils, suggesting an infectious arthritis
Molecular / cytogenetics description
Molecular / cytogenetics images

Images hosted on other servers:

HLA-DR4 molecule


Rickets / osteomalacia
Definition / general
  • Defect in matrix mineralization due to Vitamin D disturbance (deficiency, abnormal metabolism or calcium deficiency)
  • Causes accumulation of unmineralized bone matrix
  • Various causes related to decreased serum calcium or phosphorus, including rare inborn errors of metabolism or common chronic renal failure; also phosphaturic mesenchymal tumor
  • Associated with vague, generalized bone pain or muscle weakness (due to hypocalcemia)
  • Rickets: children with irregular, broadened, cup shaped epiphyseal growth plates around knee and wrist
  • Osteomalacia: adults, bone formed during remodeling is undermineralized, causes osteopenia and fractures
  • Hypophosphatemia: usually due to renal tubular defect, diuretics, hyperparathyroidism; rarely due to a vascular tumor
Diagnosis
  • Biopsy of long bone or iliac crest
Radiology description
  • Generalized osteopenia with multiple bilateral and symmetrical linear fractures (insufficiency or stress fractures)
Microscopic (histologic) description
  • Adults: wide, noncalcified matrix surrounding disorganized bone trabeculae; junction between osteoid and mineralized bone is irregular and granular; may be increased bone volume
  • Children: thickened, poorly defined growth plate, particularly on metaphyseal side; tongues of uncalcified cartilage may extend into metaphysis; wide osteoid seams

Round cell sarcoma with EWSR1 non-ETS fusions

Secondary osteosarcoma

Septic arthritis
Definition / general
  • Due to seeding of joint during bacteremia, most commonly Staphylococcus, Streptococcus, gram negative rods; rarely syphilis
  • Also due to postsurgical infection
  • Neonates: often due to osteomyelitis; hip more common than ankle or knee
  • Young women: usually gonorrhea, associated with multiple joint involvement, including knee
  • Sickle cell disease: Salmonella
  • Risk factors: immune deficiencies, severe illness, joint trauma, chronic arthritis, intravenous drug abuse
  • Symptoms: sudden development of acutely painful and swollen joint with restricted range of motion, systemic findings
Sites
  • Usually single joint (knee, hip, shoulder)
Diagnosis
  • Aspiration of joint under radiologic guidance
Case reports
Treatment
  • Immediate surgical incision and drainage, immobilization and antibiotics
Clinical images

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Ankle joint

Microscopic (histologic) description
  • Neutrophils (also Behcet disease, familial Mediterranean fever)

Simple bone cyst
Definition / general
  • A benign, intramedullary, mostly unilocular cystic lesion with a fibrous tissue wall containing serous or serosanguineous fluid
Essential features
  • Cystic bone lesion with compatible radiological features
  • Cyst lacks epithelial lining
  • Fibrin-like deposits in the cyst wall, which organize and mineralize, forming immature and mature bone as well as cementum-like structures
Terminology
  • Solitary bone cyst
  • Unicameral bone cyst (no longer recommended for use by WHO)
ICD coding
  • ICD-11: FB80.5 - solitary bone cyst
Epidemiology
Sites
  • Mostly involves appendicular skeleton, metaphysis of proximal humerus and proximal femur (Ann Diagn Pathol 2014;18:1)
  • Calcaneum, talus and pelvic bones (iliac wings) are less frequently involved and occur in older patients
  • May also involve radius, sacrum, spine and jaw bones
Pathophysiology
  • The exact pathogenesis is unknown; thought to be reactive or developmental in nature, probably related to a disturbance in growth at the epiphyseal plate
Etiology
  • Unknown
Clinical features
Diagnosis
  • Requires correlation of plain Xray findings with histological features
Radiology description
  • Xray
    • Intramedullary unilocular radiolucent lesion with symmetric expansion of cortex
    • When a pathological fracture occurs, cortical bone fragments float within cyst fluid (called fallen leaf sign); this phenomenon is pathognomonic of simple bone cyst (Skeletal Radiol 1989;18:261)
    • Another pathognomonic sign is presence of a gas bubble in most nondependent area of simple bone cyst called rising bubble sign (Skeletal Radiol 2009;38:597)
    • Multilocular appearance during healing of repeated fractures by multiple septation
  • CT and MRI
    • Cystic lesion with well circumscribed borders and homogenous fluid attenuation are CT findings
    • MRI shows high signal intensity on T2 weighted imaging, thus confirming increased fluid content and low signal intensity on T1 weighted images (Clin Orthop Relat Res 1999;366:186)
Radiology images

Contributed by Nasir Ud Din, M.B.B.S.

Proximal humerus

Humerus

Proximal femur

Proximal femur MRI

Calcaneus

Prognostic factors
Case reports
Treatment
  • Curettage with bone graft
  • Cyst fluid aspiration and then injecting steroids
Clinical images

Images hosted on other servers:

Mandible

Gross description
  • If an intact cyst is removed
    • Straw or clear fluid filled large intramedullary cavity
    • Usually unilocular but may be multilocular
    • Thin and smooth cyst membrane
  • In curettage specimens
    • Multiple thin greyish or reddish membranes admixed with blood clots and bony fragments
Gross images

Images hosted on other servers:

Humerus

Frozen section description
  • Frozen section is seldom done
  • Fragments of fibrous cyst wall, along with bony fragments with or without fibrin-like material in cyst wall
Microscopic (histologic) description
  • Thin fibrous cyst wall lacking an epithelial lining and composed of fibroblasts
  • Irregular bands of fibrin-like, often calcified material in cyst wall mimicking odontogenic cement (Histopathology 2011;59:390)
  • Osteoclast type giant cells, foamy histiocytes and hemosiderin pigment and cholesterol clefts in cyst wall
  • Reactive bone in case of fracture
Microscopic (histologic) images

Contributed by Nasir Ud Din, M.B.B.S.

Cyst fragments

Cyst wall

Fibrin-like deposits

Reactive bone

Cytology description
Positive stains
  • Immunohistochemical stains are of no diagnostic utility; in one study, the following IHC was performed (Histopathology 2011;59:390):
    • Elastic van Geison (EVG) stain, strong fuscinophilic appearance was noted
    • Procollagen I, collagen I, collagen III and bone proteoglycan (decorin) were positive
    • Transcription factors RUNX2 and osterix were positive in osteoblasts
Negative stains
Electron microscopy description
Sample pathology report
  • Right proximal humerus, cystic lesion, curettage:
    • Simple bone cyst (see comment)
    • Comment: Radiological and histological features are consistent with simple bone cyst.
Differential diagnosis
  • Aneurysmal bone cyst:
    • More expansile and eccentrically located
    • Septations are more pronounced than in simple bone cyst
    • Cystic spaces contain blood
    • More osteoclast type giant cells and reactive woven bone in cyst wall
    • Calcified, basophilic material (blue reticulated chondroid-like material)

  • Intraosseous ganglion cyst:
    • Usually found incidentally in the subchondral region
    • Found in skeletally mature individuals
    • Appears as a small radiolucent lesion
    • Histologically, like soft tissue ganglion cyst
    • No fibrin-like material or giant cells are seen
Board review style question #1

A 12 year old boy presented with pain and swelling of right upper arm. Xray and histology image of the cystic lesion are shown above. Which of the following is true regarding this lesion?

  1. Commonly involves small bones of hand and feet
  2. Commonly occurs in third to fourth decade of life
  3. Cyst frequently contains hemorrhagic fluid
  4. More common in females
  5. Proximal humerus is most common location
Board review style answer #1
E. Proximal humerus is most common location. This is a simple bone cyst.

Comment Here

Reference: Simple bone cyst
Board review style question #2
Which of the following is the most important diagnostic feature of simple bone cyst?

  1. Blood filled cystic spaces
  2. Calcified basophilic material
  3. Fibrin-like eosinophilic material
  4. Osteoclast like giant cells
  5. USP6 gene rearrangement
Board review style answer #2
C. Fibrin-like eosinophilic material

Comment Here

Reference: Simple bone cyst

Skeletal dysplasias
Definition / general
  • Skeletal dysplasias are a heterogeneous group of conditions associated with abnormalities of the skeleton, including abnormalities of bone shape, size and density, that manifest as abnormalities of the limbs, chest or skull
  • The latest classification lists 456 disorders under 40 group headings differentiated by specific clinical, radiographic and molecular criteria (J Back Musculoskelet Rehabil 2015;28:575)
  • The 4 most common conditions are thanatophoric dysplasia, achondroplasia, osteogenesis imperfecta and achondrogenesis
Essential features
  • Skeletal dysplasias differ in natural histories, prognoses, inheritance patterns and etiopathogenetic mechanisms
Terminology
  • Osteochondrodysplasias
Epidemiology
  • The prevalence of skeletal dysplasias (excluding limb amputations) is estimated at 2.14 per 10,000 births (Am J Med Genet 1996;61:49)
  • Males are primarily affected in X linked recessive disorders; otherwise, males and females are usually equally affected
Pathophysiology
  • Based on the underlying molecular genetic cause, the dysplasias can be broadly grouped by the function of the protein product of the causative gene
  • Many of the genes mutated in skeletal dysplasias encode proteins that play critical roles in the growth plate
  • Radiographics 2008;28:1061
Etiology
  • FGFR3 gene mutation causes achondroplasia, hypochondroplasia and thanatophoric dysplasia
  • Mutations in the procollagen I genes (COL1A1, COL1A2) cause various types of osteogenesis imperfecta
  • Mutations in the diastrophic dysplasia sulfate transporter gene (DTDST) cause diastrophic dysplasia, achondrogenesis type IB and atelosteogenesis type II
  • Mutations in the procollagen II gene (COL2A1) cause achondrogenesis type II
  • SOX9 gene mutation causes campomelic dysplasia
  • J Back Musculoskelet Rehabil 2015;28:575
Clinical features
  • Typically presents with disproportionate short stature in childhood or premature osteoarthritis in adulthood
  • In addition to the skeletal disorder, individuals frequently demonstrate abnormalities of hearing, vision, neurological, pulmonary, renal or cardiac function


Achondrogenesis
  • Type I:
    • Rare, lethal
    • Extreme limb shortening
    • Marked discrepancy between head and trunk size
    • Severely delayed ossification
  • Type IA:
    • Autosomal recessive
    • No ossification of vertebral pedicles
    • Rib fractures
    • Chondrocytes have inclusion bodies, but cartilage matrix is near normal
  • Type IB:
    • Distinctly abnormal cartilage matrix with rarefaction of ground substance and peculiar ringlike pericellular arrangement of collagen fibers
    • Lethal osteochondrodysplasia due to mutations in transporter gene for diastrophic dysplasia sulfate
    • Genetic defect causes complex derangement in cartilage matrix assembly
    • Impaired decorin deposition causes lack of development of normal interterritorial matrix, preventing necessary structural substrate for proper endochondral bone formation and severe skeletal phenotype
  • Reference: Emedicine: Achondrogenesis


Achondroplastic dwarfism
  • Major cause of dwarfism
  • Reduction in chondrocytes at growth plate is due to defect in fibroblastic growth factor receptor 3 gene (FGFR3)
  • FGFR3 inhibits cartilage proliferation, and is constitutively active in these patients
  • Autosomal dominant, but 80% of cases are new mutations
  • Clinical image
  • Clinical features:
    • Short proximal extremities, normal trunk, enlarged head (bulging forehead, depression of root of nose)
    • Normal intramembranous bone formation, so bone cortices seem thickened compared to short bone length
    • Normal life, IQ, reproductive status
  • Micro description: narrow / disorganized zones of proliferation and hypertrophy in growth plates; chondrocytes in clusters, not columns; base of growth plate has prematurely deposited struts of bone which seal the plate


Thanatophoric dwarfism
  • Also called thanatophoric dysplasia
  • “Thanato”: denoting death
  • Lethal form of dwarfism
  • Occurs in 1 per 20,000 live births
  • Case report: variant in 18 week male fetus (Arch Pathol Lab Med 1993;117:322)
  • Micro description: diminished proliferation of chondrocytes and poor columnization of zone of proliferation
Diagnosis
  • Prenatal evaluation of skeletal dysplasias includes a detailed ultrasound of the fetal skeleton in the second or third trimester of gestation and an extensive genetic family history work up
  • Low dose fetal CT is a powerful imaging tool that aids in diagnosing skeletal dysplasias (Radiographics 2008;28:1061, AJR Am J Roentgenol 2013;200:989)
Radiology description
  • No single unifying features exist; referring to the specific types of skeletal dysplasia for individual features is recommended (World J Radiol 2014;6:808, Radiographics 2008;28:1061)

  • Thanatophoric dysplasia is associated with:
    • Polyhydramnios
    • Thickened soft tissues
    • Micromelia
    • Extremities at 90° to trunk
    • Bowed femur (telephone receiver)
    • Platyspondyly
    • Frontal bossing, depressed nasal bridge
    • Cloverleaf skull (type II)

  • Achondrogenesis is associated with:
    • Polyhydramnios
    • Thickened soft tissues
    • Micromelia
    • Absent ossification of vertebral bodies
    • Normal calvarial ossification (type II)
    • Small thorax, some with rib fractures (type IA)

  • Osteogenesis imperfecta IIA is associated with:
    • Asymmetric micromelia
    • Irregular / thickened bones
    • Angulated bones
    • Beaded ribs, small thorax
    • Poorly ossified skull

  • Osteogenesis imperfecta IIB is associated with:
    • Lower extremities more affected
    • Less beading of ribs
    • Poorly ossified skeleton

  • Osteogenesis imperfecta IIC is associated with:
    • Thin bones, multiple fractures
    • Thin beaded ribs
    • Poorly ossified skull

  • Achondroplasia is associated with:
    • Rhizomelia, mild mesomelia
    • Stubby fingers
    • Frontal bossing
    • Narrowed interpediculate distance
Prognostic factors
  • The prognosis is widely variable, ranging from very mild cosmetic deficits to being lethal
  • Thanatophoric dysplasia and achondrogenesis account for 62% of all lethal skeletal dysplasias
  • Achondroplasia is the most common nonlethal skeletal dysplasia
Case reports
Treatment
  • Treatment is supportive
  • Mild cosmetic deficits can be treated surgically
Clinical images

Images hosted on other servers:

Osteogenesis imperfecta:
Postmortem photograph shows
deformed extremities, findings
that are consistent with fractures

Microscopic (histologic) description
Achondrogenesis
  • Abnormal endochondral bone formation with curved cartilage-bone junction at growth plates, periosteal bony spurs
  • Sponge-like cartilage matrix due to lack of interterritorial matrix
  • Epiphyseal cartilage composed of multiple discrete units of chondrocytes encased in territorial capsule and separated from each other by clefts containing fibroblast like cells
  • Mosaic of chondrocyte units (chondrons) due to breakdown of usual matrix continuity of epiphyseal cartilage
Differential diagnosis

Small cell osteosarcoma

Spondylodiskitis
Definition / general
  • Inflammation of intervertebral disk tissue and adjacent vertebrae, which are normally resistant to infection due to avascularity
  • Usually associated with back pain (since involves lumbar segments), ages 50+ years, male predominance
  • Spondylodiskitis commonly involves lumbar (45%), thoracic (35%), and cervical (10 - 20%) spine; causes secondary epidural abscess most commonly in cervical spine, also thoracic and lumbar spine
  • Increased frequency of diagnosis due to magnetic resonance imaging
  • Most cases are due to pyogenic organisms (Staph, Strep); also Candida, Aspergillus, Cryptococcus, Mycobacterium tuberculosis; rarely Enterococcus
Diagnosis
  • Culture usually positive (78%), special stains are usually negative
Case reports
Gross images

Images hosted on other servers:

Intervertebral disc
(top center) destroyed
by vertebral abscess

Spinal cord compressed by abscess

Microscopic (histologic) description
  • Vascularization, myxoid degeneration, necrosis of disk, chronic osteomyelitis
  • Variable acute osteomyelitis (25%), granulation tissue
  • Tuberculous infection has caseating granulomas
Microscopic (histologic) images

Images hosted on other servers:

C. tropicalis


Staging

Pathologic TNM staging of tumors of bone, AJCC 8th edition
Definition / general
  • Tumors arising in bone (including osteosarcoma, chondrosarcoma, Ewing sarcoma, spindle cell sarcoma, hemangioendothelioma, angiosarcoma, fibrosarcoma / myofibroid sarcoma, chordoma and adamantinoma) are covered by this staging system
  • Hematolymphoid tumors (primary malignant lymphoma, multiple myeloma) are not covered by this staging system
Essential features
  • AJCC 7th edition staging was sunset on December 31, 2017; as of January 1, 2018, use of the 8th edition is mandatory
ICD coding
  • ICD-10: C41.9 - malignant neoplasm of bone and articular cartilage, unspecified
Primary tumor (pT)
Categorization for appendicular skeleton, trunk, skull and facial bones:
  • pTX: primary tumor cannot be assessed
  • pT0: no evidence of primary tumor
  • pT1: tumor ≤ 8 cm in greatest dimension
  • pT2: tumor > 8 cm in greatest dimension
  • pT3: discontinuous tumors in the primary bone site

Categorization for spine:
  • pTX: primary tumor cannot be assessed
  • pT0: no evidence of primary tumor
  • pT1: tumor confined to one vertebral segment or two adjacent vertebral segments
  • pT2: tumor confined to three adjacent vertebral segments
  • pT3: tumor confined to four or more adjacent vertebral segments or any nonadjacent vertebral segments
  • pT4: extension into the spinal canal or great vessels
    • pT4a: extension into the spinal canal
    • pT4b: evidence of gross vascular invasion or tumor thrombus in the great vessels

Note:
  • Spine segments include right body, left body, right pedicle, left pedicle and posterior element

Categorization for pelvis:
  • pTX: primary tumor cannot be assessed
  • pT0: no evidence of primary tumor
  • pT1: tumor confined to one pelvic segment with no extraosseous extension
    • pT1a: tumor ≤ 8 cm in greatest dimension
    • pT1b: tumor > 8 cm in greatest dimension
  • pT2: tumor confined to one pelvic segment with extraosseous extension or two segments without extraosseous extension
    • pT2a: tumor ≤ 8 cm in greatest dimension
    • pT2b: tumor > 8 cm in greatest dimension
  • pT3: tumor spanning two pelvic segments with extraosseous extension
    • pT3a: tumor ≤ 8 cm in greatest dimension
    • pT3b: tumor > 8 cm in greatest dimension
  • pT4: tumor spanning three pelvic segments or crossing the sacroiliac joint
    • pT4a: tumor ≤ 8 cm in greatest dimension
    • pT4b: tumor > 8 cm in greatest dimension

Note:
  • Pelvic segments include sacrum, iliac wing, pubic rami / symphysis / ischium and acetabulum / periacetabulum
Regional lymph nodes (pN)
  • pNX: regional lymph nodes cannot be assessed
  • pN0: no regional lymph node metastases
  • pN1: regional lymph node metastases

Note:
  • Bone sarcomas very rarely involve lymph nodes and therefore NX can generally be assumed to represent N0 unless nodal involvement is evident clinically or pathologically
Distant metastasis (pM)
  • pM0: no distant metastasis
  • pM1: distant metastasis
    • pM1a: lung
    • pM1b: secondary bone or other distant sites (including distant lymph nodes)
Prefixes
  • y: preoperative radiotherapy or chemotherapy
  • r: recurrent tumor stage
Stage grouping for appendicular skeleton, trunk, skull and facial bones
  • Stage IA:T1 N0 M0 G1, GX
  • Stage IB:T2 - 3 N0 M0 G1, GX
  • Stage IIA:T1 N0 M0 G2, G3
  • Stage IIB:T2 N0 M0G2, G3
  • Stage III:T3 N0 M0G2, G3
  • Stage IVA:any T N0 M1a any G
  • Stage IVB:any T N1 any Many G
  • any T any NM1b any G


Note:
  • There is no stage grouping for bone tumors of the spine or pelvis
Registry data collection variables
  • Grade: G1, G2, G3
  • Three dimensions of tumor size
  • Percentage of necrosis after neoadjuvant systemic therapy, from pathology report
  • Number of resected pulmonary metastases, from pathology report
Histologic grade (generally tumor specific)
  • GX: grade cannot be assessed
  • G1: well differentiated, low grade
  • G2: moderately differentiated, high grade
  • G3: poorly differentiated, high grade
Histopathologic type
Board review style question #1
The 8th edition AJCC staging criteria incorporate a certain size cutoff for tumors of bone, with tumors smaller than or equal to the cutoff having a better prognosis than tumors larger than the cutoff. What is this cutoff?

  1. 2 cm
  2. 5 cm
  3. 8 cm
  4. 10 cm
Board review style answer #1
C. 8 cm

Comment Here

Reference: Bone staging
Board review style question #2
Combined TNM staging groups are used for primary bone tumors that arise in which of the following locations?

  1. Facial bones
  2. Pelvis
  3. Spine
Board review style answer #2
A. Facial bones. While all primary bone tumors should undergo TNM staging, an overall combined stage (e.g. Stage IIB) is determined for tumors of the appendicular skeleton, trunk, skull, and facial bones. Tumors of the pelvis or spine do not have combined stage groupings.

Comment Here

Reference: Bone staging

Subungual exostosis
Definition / general
  • Rare, benign osteocartilaginous lesion arising from the distal phalangeal bone below the nailbed
  • First described by Dupuytren in 1847
Essential features
  • Osteocartilaginous lesion involving the distal phalanx, lacking connection between the stalk of the lesion and medullary cavity of the native bone
Terminology
  • Dupuytren exostosis (not recommended)
ICD coding
  • ICD-O: 9213/0 - subungual exostosis (WHO Classification, page 345)
  • ICD-11: EE13.Y & XH1XL9 - certain disorders affecting the nails or perionychium & subungual exostosis
Epidemiology
Sites
Etiology
Clinical features
  • Most common clinical presentations include long standing pain (77%) followed by mass / swelling in the nail, nail changes such as erythema and deformity of the nailbed (Clin Orthop Relat Res 2014;472:1251)
  • Develops over a course of several months to years
Diagnosis
Radiology description
  • Pedunculated radiopaque mass on the dorsomedial aspect of the distal phalanx with nonaggressive growth
  • Lack of continuity between the lesion and the medullary cavity of the distal phalanx
  • Fibrocartilaginous cap appears hyperintense on T2 weighted images (Eur J Radiol 2019;112:93)
Radiology images

Contributed by Anshu Bandhlish, M.D. and AFIP images
Distal phalanx Xray Distal phalanx Xray Distal phalanx Xray

Distal phalanx Xray

Distal phalanx of great toe

Distal phalanx of great toe

Prognostic factors
  • Subungual exostoses are benign tumors
  • Local recurrence is seen in cases after incomplete excision in approximately 4% of cases (Clin Orthop Relat Res 2014;472:1251)
  • No malignant transformation or metastasis has been reported
Case reports
Treatment
Clinical images

Images hosted on other servers:
Subungual exostosis of index finger

Subungual exostosis of index finger

Subungual exostosis in an 8 year old child

Subungual exostosis in an 8 year old child

Subungual exostosis of right fifth toe

Subungual exostosis of right fifth toe

Gross description
  • Small bony and cartilaginous fragments
Microscopic (histologic) description
  • Peripheral fibrocartilaginous tissue with underlying stalk composed of trabecular bone, which is attached to the subjacent bone
  • Not continuous with the medullary cavity of the bone it arises from
  • Amount of cartilaginous tissue is determined by the age of the lesion
  • Early stage: cellular chondroid tissue with background proliferating fibrous tissue in the nailbed and may lack attachment to the underling phalangeal bone
  • Cartilaginous cap may show hypercellularity and atypia of the chondrocytes, with occasional mitoses; the cartilage matrix undergoes endochondral ossification over time
  • Late stage: eventually the lesion is composed of irregular trabecular bone with osteoblastic rimming with a thinned out or even absent cartilaginous cap (Czerniak: Dorfman and Czerniak's Bone Tumors, 2nd Edition, 2015)
Microscopic (histologic) images

Contributed by Robert Ricciotti, M.D. and AFIP images
Exophytic lesion of distal phalanx

Exophytic lesion of distal phalanx

Enchondral ossification

Enchondral ossification

Thin cartilaginous cap

Thin cartilaginous cap

Reactive bone Reactive bone

Reactive bone

Moderately cellular cartilage

Moderately cellular cartilage

Molecular / cytogenetics description
  • Consistently demonstrates t(X;6)(q24-26;q15-q25), associated with increased expression of IRS4 (insulin receptor substrate 4) gene
  • Fusion partners not fully characterized; however, COL12A1 is implicated in all cases described (Int J Cancer 2011;128:487, Int J Cancer 2006;118:1972)
Videos

What is a subungual exostosis?

Sample pathology report
  • Hallux, excision:
    • Subungual exostosis (see comment)
    • Comment: Osteocartilaginous lesion with a thin cartilaginous cap. Per imaging the lesion involves the distal phalanx of the great toe with lack of continuity with the medullary cavity of the underlying bone. Overall the morphology and the imaging findings are consistent with subungual exostosis.
Differential diagnosis
  • Osteochondroma:
    • Benign cartilaginous neoplasm with a cartilaginous cap
    • Medullary cavity of the stalk is continuous with that of the underlying bone
  • Florid reactive periostitis:
    • Mixture of reactive woven bone and fibrous tissue without zonation typically arising from the periosteum of fingers (commonly in the proximal phalanx)
  • Bizarre parosteal osteochondromatous proliferation ([BPOP] Nora lesion):
    • Surface osteocartilaginous lesion commonly develops in the proximal and middle phalanges of hands and feet
    • Long tubular bones can also be affected
    • Characteristic basophilic stroma at the interface of the bone and cartilage (blue bone) is identified
    • Balanced translocation t(X;6) seen in subungual exostosis is not reported in BPOP
    • Recurrent cytogenetic abnormalities described in BPOP include t(1;17)(q32;q21), inv(7) and inv(6) (Am J Surg Pathol 2004;28:1033, Virchows Arch 2005;447:99, Cancer Genet 2013;206:402)
Board review style question #1
Which bone is most commonly involved by subungual exostosis?

  1. Distal phalanx of the fingers
  2. Distal phalanx of the toes
  3. Middle phalanx of the toes
  4. Proximal phalanx of the fingers
Board review style answer #1
B. Distal phalanx of the toes

Comment Here

Reference: Subungual exostosis
Board review style question #2

Which of the following is true regarding subungual exostosis?

  1. Blue bone is a characteristic histologic finding
  2. Local recurrence may occur in approximately 30% of cases
  3. The marrow space of the stalk of the lesion communicates with the underlying bone
  4. There is no connection between the stalk of the lesion and medullary cavity of the native bone
Board review style answer #2
D. There is no connection between the stalk of the lesion and medullary cavity of the native bone

Comment Here

Reference: Subungual exostosis

Synovial & tenosynovial chondromatosis
Definition / general
  • Synovial chondromatosis is a locally aggressive neoplasm characterized by multiple hyaline cartilaginous nodules involving joint spaces, subsynovial tissue or tenosynovium
Essential features
  • Benign locally aggressive neoplasm characterized by formation of hyaline cartilaginous nodules within the synovium or free within joint spaces
  • Involves large joints, 60 - 70% of cases affecting the knee
  • Occurs in the third to fifth decade and is 2 - 4 times more common in men than women
  • Can recur in 15 - 20% of patients, more commonly in tenosynovial cases
  • Malignant transformation is uncommon; reported in 5 - 10% of cases
Terminology
ICD coding
  • ICD-O: 9220/1 - chondromatosis, NOS
  • ICD-11:
    • 2E82.Z - benign chondrogenic tumors, site unspecified
    • XH5BT0 - chondromatosis, NOS
Epidemiology
Sites
  • Involves the large joints; 60 - 70% of cases affecting the knee, followed by hip, shoulder, elbow, ankle and wrist
  • Can affect any joint, including temporomandibular and intervertebral joints (Am Fam Physician 1987;35:157)
  • May be extra-articular (tenosynovial chondromatosis or bursal chondromatosis), typically arising in hands and feet (Am J Surg Pathol 2003;27:1260)
Pathophysiology
  • Benign neoplastic, rather than metaplastic, lesion
  • Classified as primary and secondary synovial chondromatosis
  • Monoarticular in primary form and may be multiarticular in secondary form
  • Primary synovial chondromatosis is a self limited process that occurs in an otherwise normal joint
  • Secondary chondromatosis occurs in a joint previously afflicted with disease, often post traumatic or degenerative osteoarthritis
  • There are 3 phases of articular disease (J Bone Joint Surg Am 1977;59:792):
    • Initial phase: active intrasynovial disease only, with no loose bodies
    • Transitional phase: both active intrasynovial proliferation and free loose bodies
    • Inactive phase: resolution of synovial proliferation but loose bodies remain in the joint
  • Fusion between fibronectin 1 (FN1) and activin receptor 2A (ACVR2A) is found in at least 50% of cases of benign synovial chondromatosis, as well as in cases of malignant synovial chondromatosis (Mod Pathol 2019;32:1762)
  • Chromosome 6 abnormalities have also been observed (Cancer Genet Cytogenet 2003;140:18, Br J Cancer 1996;74:251, Virchows Arch 1998;433:189)
  • Possible role of fibroblast growth factor receptor 3 (FGFR3) and fibroblast growth factor 9 (FGF9) in primary synovial chondromatosis (Int J Exp Pathol 2000;81:183)
  • Small risk of malignant transformation to chondrosarcoma (Skeletal Radiol 1993;22:623)
Etiology
  • Although the etiology of primary synovial chondromatosis is unknown, a neoplastic etiology is supported by the identification of chromosomal abnormalities
  • Elevated levels of bone morphogenic protein, interleukin 6 and vascular endothelial growth factor A have been found in affected synovial joints but importance is uncertain (StatPearls: Synovial Chondromatosis [Accessed 15 August 2022])
  • Secondary synovial chondromatosis can occur due to mechanical changes in a joint due to degenerative arthropathy with formation of loose osteochondral bodies
Clinical features
  • May be asymptomatic
  • Pain and swelling, locking, crepitus and limited range of movement (JBJS Rev 2016;4:e2)
  • Palpable nodules on examination
  • Malignant change may be associated with persistent and increased pain
Diagnosis
  • Use of diagnostic radiographic imaging of involved joints
  • Histological evaluation of cartilaginous nodules
Laboratory
  • Serological tests for arthritis in cases of secondary synovial chondromatosis
Radiology description
  • Plain radiographs reveal multiple intra-articular calcifications of similar size and shape in 70 - 95% of cases (Radiographics 2007;27:1465)
  • Extrinsic erosion of bone is seen in 20 - 50% of cases
  • Computed tomography (CT) optimally depicts the calcified intra-articular fragments and extrinsic bone erosion
  • Magnetic resonance imaging (MRI) findings are more variable, depending on the degree of mineralization, although the most common pattern (77% of cases) reveals low to intermediate signal intensity with T1 weighting and very high signal intensity with T2 weighting with hypointense calcifications (Radiographics 2007;27:1465)
Radiology images

Contributed by Nasir Ud Din, M.B.B.S.

Multiple osteochondral bodies

Small
osteocartilaginous
bodies

Clumps of cartilaginous bodies

Multiple rounded to oval lesions

Prognostic factors
Case reports
Treatment
  • Arthroscopic or open removal of loose bodies with or without a synovectomy
Clinical images

Images hosted on other servers:

Right thumb: dorsal aspect, lateral aspect, palmar aspect

Intraoperative view and excised loose bodies

Gross description
  • Multiple, grayish white, smooth or irregular, uniform or variably sized nodules as intra-articular loose bodies or embedded within / attached to synovium
Gross images

Contributed by Nasir Ud Din, M.B.B.S.

Multiple osteochondral loose bodies

Chondral loose bodies

Microscopic (histologic) description
  • Multiple hyaline cartilaginous nodules embedded in synovium or loose in joint spaces
  • Clustering of chondrocytes
  • Minimal atypia and increased cellularity
  • Calcification or endochondral ossification may be seen in longstanding cases (JBJS Rev 2016;4:e2)
Microscopic (histologic) images

Contributed by Nasir Ud Din, M.B.B.S.

Loose chondral bodies

Subsynovial cartilaginous bodies

Clustering of chondrocytes

Mild cellularity


Subsynovial cartilaginous body

Mild atypia

Calcification

Cytology description
  • Micronodular clusters of chondrocytes with no significant cytologic atypia
  • Scant metachromatic chondroid matrix in background (Ann Diagn Pathol 2000;4:77)
Electron microscopy description
  • Cells in hyaline cartilaginous nodules show ultrastructural features of typical mature chondrocytes with abundant rough endoplasmic reticulum, prominent golgi complexes and peripheral aggregates of glycogen (Arch Pathol Lab Med 1982;106:688)
Molecular / cytogenetics description
  • FISH can be used to detect FN1::ACVR2A rearrangements
  • IDH1 and IDH2 mutations are absent
Videos

Synovial chondromatosis:
5 minute pathology pearls
by Dr. Jerad Gardner

Sample pathology report
  • Knee joint, incisional biopsy:
    • Histological features are consistent with synovial chondromatosis (see comment)
    • Comment: Light microscopy reveals multiple subsynovial mature hyaline cartilaginous nodules with no significant nuclear atypia, mitotic activity or infiltration of adjacent bone. Radiograph of knee joint shows multiple calcified densities with narrowing of joint spaces. Morphological and radiological features are characteristic of synovial chondromatosis. Synovial chondromatosis is a benign neoplasm but can be locally aggressive and can recur in 15 - 20% of patients with malignant transformation in 5 - 10% of cases. It can be primary (idiopathic) or secondary to degenerative joint diseases like osteoarthritis, rheumatoid arthritis or traumatic arthritis.
Differential diagnosis
Board review style question #1

A 45 year old man presented with pain and swelling with palpable nodules in the left knee. Biopsy showed multiple nodules of mature hyaline cartilage within the synovium. Which of the following genes is affected in the pathogenesis of this disease?

  1. ABCG2
  2. ANKH
  3. FGF23
  4. FN1
  5. IDH1
Board review style answer #1
Board review style question #2
Which of the following is true regarding synovial chondromatosis?

  1. It is a metaplastic process rather than neoplastic
  2. It is twice as common in females than in males
  3. Knee is the most common site of involvement
  4. Most commonly occurs in adolescence
  5. There is a high risk of malignant potential
Board review style answer #2
C. Knee is the most common site of involvement

Comment Here

Reference: Synovial & tenosynovial chondromatosis
Board review style question #3

A 30 year old woman presented with pain and swelling of right ankle with palpable nodules. Radiographs revealed multiple radiopaque masses located on the anterior aspect of the ankle joint. Biopsy showed multiple nodules of mature hyaline cartilage within the synovium. Which of the following is an additional characteristic histological feature seen in synovial chondromatosis?

  1. Clustering of chondrocytes
  2. Concentric layering of chondrocytes
  3. Multinucleation of chondrocytes
  4. Myxoid degeneration
  5. Permeation of bone
Board review style answer #3
A. Clustering of chondrocytes

Comment Here

Reference: Synovial & tenosynovial chondromatosis

Synovial cysts
Definition / general
  • Herniation of synovium through joint capsule, usually in joint of extremities
  • May bleed and become a mass-like lesion
Terminology
  • Baker cyst: also called popliteal cyst; synovial cyst in popliteal space
  • Cutaneous metaplastic synovial cyst: lined by metaplastic synovial tissue; may be due to local trauma
  • Spinal synovial cyst: cyst in spinal joint
Clinical features
  • Baker cyst: due to herniation of synovial membrane through posterior joint capsule or escape of joint fluid from bursae; associated with degenerative joint disease, neuropathic arthropathy, rheumatoid arthritis
  • Spinal synovial cyst:
    • Soft tissue mass located extradurally along medial border of degenerated facet joint
    • Usually at L4-5, rarely in cervical or thoracic spine
    • Filled with clear or xanthochromic fluid
    • Causes back and radicular pain
    • Rarely results in cauda equina syndrome (Pain Physician 2012;15:435)
Diagrams / tables

Images hosted on other servers:

Baker cysts

Radiology images

Images hosted on other servers:

Spinal synovial cyst

Case reports
Treatment
  • Baker cyst: treat cause of excess fluid, sclerotherapy (Pain Physician 2008;11:375)
  • Cutaneous metaplastic synovial cyst: surgical excision; recurrence is rare
Clinical images

Images hosted on other servers:

Baker cysts

Cutaneous metaplastic synovial cyst

Radiology images

Images hosted on other servers:

MRI of Baker cyst

Microscopic (histologic) description
  • Baker cyst: lined by synovium, may have cartilage in cyst wall; palisading histiocytes and fibrinoid necrosis, similar to rheumatoid pericarditis and rheumatoid nodules
  • Cutaneous metaplastic synovial cyst: cystic structure with papillary projections lined by epithelium resembling synovium
Microscopic (histologic) images

Images hosted on other servers:

Cutaneous metaplastic synovial cyst with numerous villous-like structures; vimentin+ CD34- CD68-

Hemorrhagic spinal synovial cyst with thin fibrous wall


Synovial lipomatosis
Definition / general
  • Pseudotumor of synovium with distinct histomorphology, possibly due to inappropriate fat deposition and degenerative articular diseases of joints (J Lab Physicians 2011;3:84)
Terminology
  • Also called Hoffa disease, villous lipomatous proliferation of synovial membrane, diffuse lipoma of joint, lipoma arborescens
  • Not a WHO diagnosis
Epidemiology
  • Rare
  • Older patients, usually male, associated with joint trauma, degenerative joint disease and chronic arthritis
Clinical features
  • Rare; usually knee but may occur in any joint
  • Unknown etiology
  • Men are commonly affected with pain and swelling of joint
  • MRI is useful in diagnosis (Radiol Med 2005;109:540)
Case reports
Treatment
  • Arthroscopy and excision
  • May recur since often is a reactive process
Gross description
  • Enlargement of infrapatellar fat pad with pain in anterior compartment of knee; synovium is papillary, yellow and fatty
Gross images

Contributed by Mark R. Wick, M.D.
Microscopic (histologic) description
  • Synovial hyperplasia with unremarkable fat extending to synovial lining; occasional chronic inflammatory infiltrate
Microscopic (histologic) images

Images hosted on other servers:

Villi-like structures

Papillary architecture

Mature adipocytes

Focal hyperplasia

Few mature lipocytes


Systemic lupus erythematosus
Definition / general
  • Autoimmune disease that usually presents with mild arthritis or joint effusions
  • Destructive joint disease is rare except for those on steroid therapy who rarely can develop aseptic necrosis
  • Occasionally there is a progression to rheumatoid-like nonerosive hand deformities (Jaccoud syndrome) (Rheum Dis Clin North Am 1988;14:99, Ann Rheum Dis 1974;33:204)
  • Synovial fluid shows less inflammation than rheumatoid arthritis
Clinical images

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Correctable swan neck deformities and ulnar deviation

Readily correctable swan neck deformities and subluxation of right fifth MCP

Metacarpal heads - no cartilage damage seen

Noncorrectable deformities of PIP joints

Mild ulnar deviation, especially on right

Microscopic (histologic) description
  • Changes resemble rheumatoid arthritis but with more intense surface fibrin deposition and less synovial proliferation and less intense inflammation
  • Occasional vasculitis can be seen (Ann Intern Med 1971;74:911)
Microscopic (histologic) images

Images hosted on other servers:

Synovial membrane


Systemic mastocytosis
Definition / general
  • Mastocytoses are a heterogeneous group of disorders characterized by abnormal growth and accumulation of mast cells in 1 or more organ systems
  • Mast cells are cytologically and immunophenotypically abnormal in neoplastic mast cell proliferations
Essential features
  • Systemic mastocytosis is a neoplastic condition in which histomorphologically atypical mast cells involve tissue sites including bone marrow, skin and other tissues
  • Occurs primarily in adults and is strongly associated with c-KIT mutations with the majority being KIT D816V
  • Also associated with myeloid neoplasms
  • Major or minor criteria are required for diagnosis and include identification of atypical spindled mast cell clusters, aberrant expression of CD25, CD2 or CD30, the presence of a KIT mutation or elevated serum tryptase
  • Categories of disease are based upon sites of involvement, related symptoms and laboratory findings
Terminology
  • According to the 2017 WHO classification, mastocytosis is classified into the following categories
    • Cutaneous mastocytosis
      • Urticaria pigmentosa / maculopapular cutaneous mastocytosis
      • Diffuse cutaneous mastocytosis
      • Mastocytoma of skin
    • Systemic mastocytosis
      • Indolent systemic mastocytosis
      • Bone marrow mastocytosis
      • Smoldering systemic mastocytosis
      • Systemic mastocytosis with an associated hematological neoplasm
      • Aggressive systemic mastocytosis
      • Mast cell leukemia
    • Diagnosis of these entities requires correlation with burden of disease (B findings) and cytoreduction requiring (C findings), which indicate organ involvement with and without organ dysfunction, respectively (see Clinical features)
ICD coding
  • ICD-10:
    • D47.02 - systemic mastocytosis
    • C96.21 - aggressive systemic mastocytosis
    • C94.3 - mast cell leukemia
  • ICD-11:
    • 2A21.00 - mast cell leukemia
    • 2A21.0Y - other specified systemic mastocytosis
    • 2A21.0Z - systemic mastocytosis, unspecified
Epidemiology
  • Prevalence estimate of 10 - 13 per 100,000 (Transl Res 2016;174:86, Cancers (Basel) 2021;13:6380)
  • Indolent / smoldering types present at median age of ~50 years; more aggressive types present at older age with a median of ~70 years
  • Pediatric systemic mastocytosis is extremely rare
    • Mastocytoses in pediatric patients are predominantly cutaneous limited (not systemic) with a bimodal incidence of birth to 2 years and over 15 years
    • ~50% of cases are self limited, resolving after onset of puberty
  • M ≈ F; most studies show no significant difference or only slight differences in incidence among men and women (Transl Res 2016;174:86)
  • Familial disease is rare, accounting for ~1 - 2% of all cases (Br J Haematol 2021;193:845)
  • Bone marrow or bone involvement is present in up to 90% of systemic mastocytosis cases
Sites
Pathophysiology
  • Clonal expansion of cells with mast cell differentiation having c-KIT mutation
  • Mast cell proliferation and degranulation results in destructive lesions
Etiology
  • Generally thought to differentiate from a CD34+, CD117 / KIT+, CD13+ hematopoietic progenitor cells or a mast cell committed precursor
  • Proto-oncogene c-KIT (Leukemia 2015;29:1223)
    • Chromosome 4
    • Codes for tyrosine protein kinase KIT, CD117 or mast / stem cell growth factor receptor (SCFR)
    • KIT is dimerized by stem cell growth factor, ultimately inducing cell survival, proliferation and differentiation
    • In mastocytosis, c-KIT mutation leads to stem cell growth factor independent activation of KIT
    • The most common c-KIT mutation is KIT D816V, while cutaneous mastocytosis has more frequent non-D816V codon 816 mutations
    • Mast cell release of mediators including histamine may contribute to increased osteoblast activity, activation of osteoclasts and formation of sclerotic lesions
Clinical features
  • Course is variable from benign and self limited to aggressive with a variety of symptoms which differ based on disease subtype (Am J Hematol 2021;96:508)
  • Most commonly affected sites are skin (urticaria pigmentosa) and bone marrow
  • 4 categories of systemic mastocytosis presenting symptoms
    • Constitutional: weight loss, fever and diaphoresis, fatigue
    • Skin manifestations: urticaria and pruritus, flushing, dermatographism
    • Mediator related systemic events: abdominal pain, headache, hypotension, syncope
    • Musculoskeletal symptoms: osteoporosis, osteopenia, bone pain and fracture, arthralgia and myalgia
  • Other presentation findings may include organ impairment associated with infiltration, especially in aggressive systemic mastocytosis and mast cell leukemia
  • Symptoms related to mast cell degranulation with associated increased serum tryptase may be diagnosed as mast cell activation syndrome
    • Mast cell activation syndrome is not considered a subtype of systemic mastocytosis and may be diagnosed in the absence of mastocytosis if criteria are not fulfilled
    • In the absence of all required diagnostic criteria, a clonal mast cell population with KIT D816V mutation or aberrant surface CD25 warrants a diagnosis of monoclonal mast cell activation syndrome
  • Patients with mediator related symptoms and systemic mastocytosis are designated as having primary (clonal) mast cell activation syndrome, which has diagnostic and therapeutic implications
  • Systemic mastocytosis with an associated hematological neoplasm (AHN): associated and often clonally related secondary myeloid neoplasm, most commonly chronic myelomonocytic leukemia
  • C (cytoreduction requiring) findings:
    • Neoplastic mast cell infiltration impacting bone marrow function is defined as ≤ 1 cytopenia, absolute neutrophil count < 1.0 x 109/L, hemoglobin < 10 g/dL or platelet count < 1.0 x 109/L
    • Abnormal liver function with ascites and elevated liver enzymes with or without hepatomegaly, cirrhosis, portal hypertension
    • Large osteolytic lesions (≥ 20 mm) with or without bone pain, pathologic fractures (excepting osteoporosis related fractures)
    • Palpable splenomegaly with hypersplenism with or without weight loss, hypalbuminemia
    • Gastrointestinal mast cell infiltrates causing malabsorption with or without weight loss
  • B (burden of disease) findings:
    • > 30% of mast cells on bone marrow biopsy and serum total tryptase > 200 ng/mL or KIT D816V mutation with VAF ≥ 10% in bone marrow cells or peripheral blood leukocytes (Leukemia 2022;36:1703)
      • International Consensus Classification (ICC): high mast cell burden, > 30% of bone marrow cellularity by mast cell aggregates (assessed on bone marrow biopsy) and serum tryptase > 200 ng/mL)
    • Dysplastic changes or myeloproliferation in nonmast cell lineages, without meeting criteria for associated hematological neoplasm, with normal or only slightly abnormal blood counts
      • ICC: cytopenia (not meeting criteria for C findings) or cytosis excluding reactive causes and other myeloid neoplasm criteria are not met
    • Hepatomegaly without liver dysfunction, palpable splenomegaly without hypersplenism or lymphadenopathy
    • Additional provisional B finding proposed for the upcoming WHO fifth edition update
      • KIT D816V mutation with variant allele fraction ≥ 10% in bone marrow cells or peripheral blood leukocytes (Leukemia 2022;36:1703)
Diagnosis
  • 2017 WHO classification diagnostic criteria for systemic mastocytosis; must demonstrate major criterion and at least 1 minor criterion or ≥ 3 minor criteria
  • ICC diagnostic criteria are very similar to the WHO 5th edition criteria; variation from WHO 5th edition are noted
    • Major criterion
      • Multifocal dense mast cell infiltrates detected in sections of bone marrow or extracutaneous organs; infiltrate is defined as ≥ 15 mast cells in aggregate (ICC specifies that the mast cells must express tryptase or CD117)
    • Minor criteria
      • > 25% of mast cells in bone marrow biopsy are spindled, have abnormal morphology of bone marrow aspirate / tissue infiltrate mast cells are immature or atypical
      • Detection of KIT mutation in blood, bone marrow or other nonskin tissue (activating point mutation at codon 816 or any KIT mutation conferring ligand independent activation (Leukemia 2022;36:1703)
      • Expression of one or more of the following antigens in the mast cell population in addition to normal mast cell markers (by flow cytometry or IHC): CD25, CD2, CD30 (Leukemia 2022;36:1703)
      • Persistent serum total tryptase > 20 ng/mL (except in context of associated myeloid neoplasm)
  • Diagnostic criteria for variants of systemic mastocytosis (in addition to general criteria above)
    • Indolent systemic mastocytosis
      • No C findings indicative of organ involvement
      • No evidence of associated hematological neoplasm
      • Low mast cell burden
      • Skin lesions are almost always present
    • Bone marrow mastocytosis
      • Similar criteria as indolent variant with bone marrow involvement
      • No skin lesions
      • Proposed fifth edition WHO criteria refinement includes tryptase < 125 ng/mL (Leukemia 2022;36:1703)
    • Smoldering systemic mastocytosis
      • ≥ 2 B findings in absence of C findings
      • No evidence of associated hematological neoplasm
      • High mast cell burden
      • Does not meet mast cell leukemia criteria
    • Systemic mastocytosis with an associated hematological neoplasm
      • Associated hematological neoplasm including myelodysplastic syndrome, myeloproliferative neoplasm, acute myeloid leukemia, lymphoma or other WHO classified distinct hematological neoplasm
    • Aggressive systemic mastocytosis
      • ≥ 1 C finding
      • Does not meet mast cell leukemia criteria
      • Skin lesions are usually absent
    • Mast cell leukemia
      • Diffuse infiltration of bone marrow by dense aggregates of atypical, immature mast cells
      • ≥ 20% mast cells in bone marrow aspirate
      • Classic: ≥ 10% white blood cell count is mast cells in peripheral blood
      • Aleukemic: < 10% peripheral blood mast cells (more common than classic)
        • Skin lesions are usually absent
  • Additional morphologic pattern proposed for the upcoming WHO fifth edition update:
    • Well differentiated systemic mastocytosis (Leukemia 2022;36:1703)
      • May occur in any subtype with mast cells lacking atypical histomorphologic characteristics, may not have expression of CD25, CD2 or CD30, predominantly lacking KIT D816V mutation (J Allergy Clin Immunol 2016;137:168)
      • High percentage of bone marrow mast cells
      • Predominantly in women, childhood onset and familial aggregation
Laboratory
  • Complete blood count (CBC) may demonstrate anemia, thrombocytopenia, thrombocytosis, leukocytosis or eosinophilia
  • Serum tryptase > 20 ng/mL (fluoro immunoenzymatic assay [Pharmacia, Uppsala, Sweden]) is a minor diagnostic criterion (Arch Pathol Lab Med 2007;131:784)
  • Elevated histamine metabolites in 24 hour urine sample may be present in patients with cutaneous lesions
Radiology description
  • Skeletal involvement reported in 70 - 90% of patients (Annu Rev Med 2004;55:419)
  • Osteoporosis reported in up to 40% of patients; dual energy Xray absorptiometry (DEXA) of hip and spine should be performed (Cancers (Basel) 2021;13:6380)
  • Most common skeletal findings:
    • Multiple focal sclerotic axial and appendicular bone lesions
    • Diffuse, circumscribed, sclerotic foci with alternating zones having normal or reduced density in axial skeleton, ribs, humerus, femur
Prognostic factors
  • Prognosis is linked to disease subclassification (Am J Hematol 2021;96:508)
    • Favorable prognosis
      • Indolent / smoldering systemic mastocytosis
        • 3% progression to more aggressive forms in study with median follow up of > 10 years; life expectancy is approximately normal
    • Poor prognosis
      • Aggressive systemic mastocytosis
        • Overall median survival of ~40 months
      • Systemic mastocytosis with an associated hematological neoplasm
        • Overall median survival of ~24 months (longer in patients with myeloproliferative neoplasms, shorter in those with chronic myelomonocytic leukemia, myelodysplastic syndrome or acute leukemia)
      • Mast cell leukemia
        • ~2 year overall median survival
  • Prognosis is linked to independent risk factors
    • Age: > 60 years
    • Platelet count: < 150 x 109/L
    • Serum alkaline phosphatase above reference interval
    • Presence of adverse mutation in ASXL1, RUNX1, SRSF2 or NRAS
    • Increased plasma IL2Rɑ / CD25 confers worse prognosis in indolent SM
Case reports
  • 33 year old man with abdominal pain and blood per rectum (Ann Gastroenterol 2019;32:208)
  • 50 year old man with foamy mastocytosis who presented with flushing, fever, intestinal disorder, skin lesions and splenomegaly (Blood 2018;131:586)
  • 62 year old man with systemic mastocytosis and essential thrombocythemia who presented with thrombocytosis and hepatosplenomegaly with cutaneous papules (Medicina (Kaunas) 2019;55:528)
  • 83 year old man with systemic mastocytosis and multiple myeloma who presented with hematuria and bone pain (Blood 2018;132:1545)
Treatment
  • Indolent disease may not require treatment or treatment may be aimed at symptomatic management, including antihistamines, leukotrienes, mast cell stabilizers, proton pump inhibitors, calcium vitamin D, bisphosphonates; epinephrine may be needed for patients having risk of anaphylaxis (Am J Hematol 2021;96:508)
  • Avoidance of exposures that aggravate mast cell degranulation including temperature extremes, mechanical irritation, medications and alcohol
  • Aggressive disease requiring cytoreductive therapy may be treated with the following agents
    • Interferon alpha is often paired with prednisone; may have severe side effects including myelosuppression
    • 2-chlorodeoxyadenosine issued as a second line therapy for interferon alpha refractory disease; may have severe side effects including myelosuppression, lymphopenia and risk of opportunistic infection
    • Cladribine purine analog with mechanism independent of tyrosine kinase inhibition
    • Tyrosine kinase inhibitors
      • Avapritinib targets PDFRɑ and KIT (Int J Mol Sci 2021;22:2983)
      • Midostaurin targets FLT3, KIT D816V mutation (Blood 2020;135:1365)
      • Imatinib targets BCR::ABL, wild type KIT
      • Nilotinib targets BCR::ABL, wild type KIT
      • Dasatinib dual SRC / ABL inhibitor
    • Chemotherapy regimens employed in acute myeloid leukemia
    • Allogeneic stem cell transplantation in rare cases
Microscopic (histologic) description
  • Neoplastic mast cells may be spindled to round / oval (similar to normal mast cells) with variable cytoplasmic granularity
  • Spindled mast cell aggregates may invoke a streaming-like appearance
  • Bone marrow aspirate sampling of mast cells may be limited due to associated reticulin or collagen fibrosis
  • Characteristically, mast cells have a light blue-gray cytoplasm; granules may be inconspicuous on H&E sections but are more prominent with regional distribution on Wright-Giemsa stained bone marrow aspirate and peripheral blood smears
  • Basophilic to amphipathic cytoplasmic granules may obscure mast cell nuclei on Wright-Giemsa stain
  • On H&E sections, round mast cells with central nuclei may give a fried egg-like appearance at low power, raising a differential that includes hairy cell leukemia (Arch Pathol Lab Med 2007;131:784)
  • Mast cell nuclei may have 1 to a few prominent nucleoli and relatively smooth nuclear chromatin
  • Mast cell aggregates may be intermixed with lymphohistiocytic proliferations, often with interspersed eosinophils and plasma cells
  • Atypical mast cell features include spindle morphology, hypogranulation and atypical nuclear borders
  • Bone may demonstrate osteosclerosis, increased trabeculation volume, increased cortical thickness and narrowing of marrow spaces
Microscopic (histologic) images

Contributed by Mark Girton, M.D. and AFIP
Marrow mast cell cluster

Marrow mast cell cluster

Intermixed with lymphoid aggregate

Intermixed with lymphoid aggregate

Aspirate with mast cells Aspirate with mast cells Aspirate with mast cells

Aspirate with mast cells

Mast cell cluster

Mast cell cluster


Hypercellular bone marrow biopsy

Hypercellular bone marrow biopsy

Bone marrow biopsy with marrow replacement

Bone marrow biopsy with marrow replacement

Cytologic spectrum

Cytologic spectrum

CD117 positive mast cells

CD117 positive mast cells

CD25 positive mast cells

CD25 positive mast cells


CD2 positive mast cells

CD2 positive mast cells

CD30 positive mast cells

CD30 positive mast cells

CD117 positive mast cells

CD117 positive mast cells

Mast cell tryptase positive

Mast cell tryptase positive

CD25 positive mast cells

CD25 positive mast cells


Perifollicular distribution

Perifollicular distribution

Characteristic sclerosis

Characteristic sclerosis

Mast cell infiltrate

Mast cell infiltrate

Delicate collagen fibrils and eosinophils

Delicate collagen fibrils and eosinophils

Mast cell staining

Mast cell staining


Interfollicular pattern

Interfollicular pattern

Diffuse involvement

Diffuse involvement

Ovoid nuclei with eosinophilic cytoplasm

Ovoid nuclei with eosinophilic cytoplasm

Spindle shaped mast cells

Spindle shaped mast cells

Spindly configuration

Spindly configuration

Peripheral smear images

Contributed by Mark Girton, M.D.
Peripheral blood mast cell Peripheral blood mast cell Peripheral blood mast cell

Peripheral blood mast cell

Positive stains
Negative stains
Flow cytometry description
  • Neoplastic mast cell populations may be difficult to sample because of associated reticulin or collagen fibrosis; therefore, the population of interest may be underrepresented in flow cytometry assays
  • Antibodies against CD45, CD13, CD33, CD117, CD25 and CD2 are typically positive in neoplastic mast cells, while CD34 is generally expected to be negative, except in mast cell precursors
  • Nonneoplastic mast cells lack expression of CD25 and CD2
  • CD38 expression may be seen in normal mast cell precursors
Molecular / cytogenetics description
Sample pathology report
  • Blood, peripheral smear:
    • Unremarkable peripheral blood smear (see comment)
    • Comment: Microscopic examination of the peripheral blood smear demonstrates a normal red blood cell count with erythrocytes, which are morphologically unremarkable. The white blood cell count is normal and leukocytes are morphologically unremarkable. Platelets are normal in number and morphology.

  • Bone marrow, left, aspirate smear:
    • Trilineage hematopoiesis with occasional mast cells present (see comment)
    • Comment: Microscopic examination of the bone marrow aspirate demonstrates a spicular and cellular specimen which is adequate for evaluation. There is trilineage hematopoiesis. Erythroid precursors demonstrate normoblastic maturation. Myeloid precursors demonstrate the full spectrum of maturation. The myeloid to erythroid (M:E) ratio is normal at 2.3:1. Megakaryocytes are present and appear normal in number and morphology. There are occasional mast cells present, some of which demonstrate a spindled morphology. There is no increase in blasts. An iron stain demonstrates the presence of storage iron and no significant increase in ring sideroblasts.

  • Bone marrow, left, core biopsy:
    • Limited subcortical specimen showing trilineage hematopoiesis with involvement by systemic mastocytosis (see comment)
    • Comment: Microscopic examination of the core biopsy demonstrates a subcortical bone marrow specimen limited sampling, which precludes evaluation of the cellularity. There is trilineage hematopoiesis and small, ill defined lymphoid aggregates. Immunohistochemical staining for CD117 and mast cell tryptase demonstrate clusters of spindle shaped mast cells. Staining for CD25 is positive and staining for CD2 is negative. The lymphoid aggregates are composed of a mixture of B cells and T cells as demonstrated by CD20 and CD3 positivity, respectively. The myeloid to erythroid ratio appears normal. Megakaryocytes are present and appear normal in number and morphology. A PAS stain highlights the myeloid elements and megakaryocytes. An iron stain shows the presence of storage iron. A reticulin stain is not evaluable due to the limited specimen size.

  • Bone marrow, left, clot section:
    • Normocellular bone marrow with trilineage hematopoiesis and involvement by systemic mastocytosis (see comment)
    • Comment: Microscopic examination of the clot preparation demonstrates a cellular specimen that is adequate for evaluation. The clot section appears normocellular. There is trilineage hematopoiesis. The myeloid to erythroid ratio appears normal. Megakaryocytes are present and appear normal in number with unremarkable morphology. There are multiple lymphoid aggregates present with mast cell clusters having focal areas of scattered eosinophils. Immunohistochemical staining for CD117 and mast cell tryptase demonstrate clusters of spindle shaped mast cells. Staining for CD25 is positive and staining for CD2 is negative. The lymphoid aggregates are a mixture of B cells and T cells as demonstrated by CD20 and CD3 positivity, respectively. There is no increase in blasts. An iron stain shows the presence of storage iron and no ring sideroblasts.
    • In summary, the patient's specimen demonstrates an overall normocellular bone marrow with trilineage hematopoiesis and involvement by systemic mastocytosis. Correlation with molecular and genetic studies is recommended.
Differential diagnosis
Board review style question #1
Regarding systemic mastocytosis, which of the following is the most commonly associated hematological neoplasm (AHN)?

  1. Acute myeloid leukemia (AML)
  2. Chronic myelomonocytic leukemia (CMML)
  3. Chronic myelocytic leukemia (CML)
  4. Plasma cell myeloma
  5. Polycythemia vera (PV)
Board review style answer #1
B. Chronic myelomonocytic leukemia (CMML). Associated hematological neoplasms are reported to include CMML, non-Hodgkin lymphoma, refractory anemia with ring sideroblasts and thrombocytosis, essential thrombocythemia, multiple myeloma, monoclonal gammopathy of undetermined significance, myelodysplastic syndrome, myelofibrosis and acute myeloid leukemia. CMML is the most commonly reported associated hematological neoplasm (Am J Hematol 2016;91:692).

Comment Here

Reference: Systemic mastocytosis
Board review style question #2
Which of the following features fulfills a fifth edition WHO classification minor diagnostic criterion for systemic mastocytosis?

  1. Identification of a BRAF V600E mutation in blood, bone marrow aspirate or nonskin tissue
  2. Mast cell expression of CD25, with or without CD2, in combination with normal mast cell markers
  3. Mast cells expressing CD117 or tryptase by immunohistochemical staining
  4. Multiple dense mast cell groups as defined by ≥ 15 mast cells per aggregate in bone marrow or other extracutaneous organ
Board review style answer #2
B. Mast cell expression of CD25, with or without CD2, in combination with normal mast cell markers. The fifth edition WHO’s diagnostic criteria for systemic mastocytosis must demonstrate major criterion and at least 1 minor criterion or ≥ 3 minor criteria. Major criterion includes: multifocal dense mast cell infiltrates detected in sections of bone marrow or extracutaneous organs (infiltrate is defined as ≥ 15 mast cells in aggregate). International Consensus Classification (ICC) specifies that the mast cells must express tryptase or CD117. Minor criteria include: > 25% of mast cells in bone marrow biopsy are spindled, have abnormal morphology of bone marrow aspirate / tissue infiltrate mast cells are immature or atypical; detection of KIT mutation in blood, bone marrow or other nonskin tissue (activating point mutation at codon 816); expression of one or more of the following antigens in the mast cell population in addition to normal mast cell markers (by flow cytometry or IHC): CD25, CD2, CD30; and persistent serum total tryptase > 20 ng/mL (except in context of associated myeloid neoplasm; may be adjusted in this context according to ICC). Additional provisional minor criteria proposed for the fifth edition WHO include CD30 expression and any KIT mutation conferring ligand independent activation (Leukemia 2022;36:1703).

Comment Here

Reference: Systemic mastocytosis

Telangiectatic osteosarcoma

Tenosynovial giant cell tumor
Definition / general
  • Tenosynovial giant cell tumor encompasses a group of lesions that most often arise from the synovium of joints, bursae and tendon sheaths and show synovial differentiation
  • Malignant tenosynovial giant cell tumor is very uncommon and is defined by the coexistence of a benign tenosynovial giant cell tumor with overtly malignant areas or by recurrence of a typical giant cell tumor as a sarcoma
Essential features
  • Localized type
    • Second most common tumor of the hand (after ganglion cyst)
    • Well circumscribed and lobulated, usually in close association with a tendon
    • Composed of variable proportions of large epithelioid mononuclear cells, macrophages and osteoclast-like giant cells
  • Diffuse type
    • Intra-articular tumors within large joints
    • Extra-articular invasive tumors of tendon sheath, bursa or soft tissue origin
  • Malignant
    • Only ~50 cases were reported
    • Contains definite sarcomatous area
    • Arises de novo or occurs after multiple recurrences of a conventional tenosynovial giant cell tumor
Terminology
  • Acceptable: giant cell tumor of tendon sheath
  • Not recommended: pigmented villonodular synovitis
ICD coding
  • ICD-O: 9252/0 - tenosynovial giant cell tumor, NOS
  • ICD-10: D48.1 - neoplasm of uncertain behavior of connective and other soft tissue
  • ICD-11:
    • 2F7Z & XH6911 - neoplasms of uncertain behavior of unspecified site & tenosynovial giant cell tumor, localized
    • 2F7Z & XH52J9 - neoplasms of uncertain behavior of unspecified site & tenosynovial giant cell tumor, diffuse
    • 2D4Y & XH5AQ9 - other specified malignant neoplasms of ill defined or unspecified primary sites & malignant tenosynovial giant cell tumor
Epidemiology
  • Localized type
    • 40 patients/1 million
    • Fourth or fifth decade of life (most frequently)
    • F:M = 2:1
  • Diffuse type (NIH: SEER Cancer Statistics Review, 1975-2010 [Accessed 24 November 2021])
    • Annual incidence rate: 1.8 patients/1 million in United States
    • Peaks in the third and fourth decades of life with an average of 35 years
    • Female predominance
  • Malignant
    • Uncommon
    • Middle aged to older adults (most are 50 - 60 years)
Sites
  • Localized type
    • Predominantly occurs in the digits (85%), especially fingers (75%)
    • Uncommon around large joints (10%)
      • Intra-articular localized tenosynovial giant cell tumors are most frequent in the knee
  • Diffuse type (Lancet Oncol 2019;20:877)
    • Intra-articular
      • Knee (65%)
      • Hip and ankle (25%)
      • Elbow, shoulder, temporomandibular joint, spine
    • Extra-articular extension
      • Knee
      • Foot, wrist, inguinal, elbow region, digits
  • Malignant
    • Often occurs in the lower extremities
Pathophysiology
  • Translocation of the CSF gene that encodes colony stimulating factor 1 (CSF1) was frequently involved in this tumor
  • It is reported that tumor cells with CSF1 translocation synthesize large amounts of the CSF1 protein
  • Actually, only a small subset of cells harbor the translocation
Etiology
  • Unknown
Clinical features
  • Localized type (Orthop Traumatol Surg Res 2017;103:S91)
    • Skin colored nodule without specific features
    • Most are slow growing and painless
  • Diffuse type (J Rheumatol 2017;44:1476)
    • Painful mass, long duration
    • Hemorrhagic joint effusion
    • Decreased range of motion
  • Malignant (Mod Pathol 2019;32:242)
    • Similar to their benign counterparts in tumor location
    • Recurrence or metastasis to regional lymph nodes and distant locations
Diagnosis
Laboratory
  • Nonspecific
Radiology description
Radiology images

Contributed by Jigang Wang, M.D., Ph.D. and Jiufa Cui, M.D., Ph.D.

Diffuse type
Bone erosion on CT Bone erosion on CT

Bone erosion on CT

Low signal on MR Low signal on MR

Low signal on MR


Low signal on MR

Low signal on MR

Low signal on MR Low signal on MR

Low signal on MR



Images hosted on other servers:

Localized type
Mass on the tendon

Mass on the tendon

Missing Image

Ultrasound of finger lesion

Missing Image

Hand MRI


Diffuse type

MRI of the ankle


Malignant
Progressive increasing mass

Progressive increasing mass

Prognostic factors
  • Localized type
    • Benign but recurs locally (10 - 20%)
    • Risk factors for recurrence include degenerative joint disease and osseous erosion
  • Diffuse type (Eur J Cancer 2015;51:210)
    • High recurrence rate
    • Risk factors for recurrence are still unknown
    • It is very rare that tumors progress to malignancy or metastasize
  • Malignant
    • Risk factors for recurrence are still unknown
Case reports
Treatment
  • Localized type
    • Complete local excision
  • Diffuse type (Eur J Cancer 2016;63:34)
    • Surgical excision
      • Wide local excision
      • Total synovectomy
      • Prosthetic joint replacement
      • Amputation in advanced cases
    • External beam radiotherapy
    • Radiosynovectomy
    • New therapeutic strategies
      • Immunotherapy: anti-TNF-α drugs
      • Targeted therapy: tyrosine kinase inhibitors, CSF inhibitors
  • Malignant
    • Local treatment
      • Radical resection
    • Systemic therapy
      • Tyrosine kinase inhibitors (TKIs) had very limited activity in malignant tenosynovial giant cell tumor (BMC Cancer 2018;18:1296)
      • CSF1R inhibitors
      • Cytotoxic chemotherapy
Clinical images

Contributed by Mark R. Wick, M.D.

Localized type

Digit lesion



Images hosted on other servers:

Localized type
Missing Image

Mass over lateral right foot

Missing Image

Tumor at surgery

Neurovascular bundle involvement

Neurovascular bundle involvement

Swelling appearance

Swelling appearance

Lateral route

Lateral route


Diffuse type
Brownish mass

Brownish mass

Gross description
  • Localized type
    • Well circumscribed and partially encapsulated with a lobulated appearance
    • Variegated cut surface (yellow, tan, red-brown)
  • Diffuse type
    • Brown-yellow spongy tissue, firm and nodular, often 5 cm or larger
    • Diffusely covers most of synovial surface
    • Villous, nodular or villonodular
    • Poorly demarcated from adjacent tissues
  • Malignant
    • Similar to benign but may be larger
    • Sarcomatous area showed a solid growth pattern with whitish color, massive hemorrhage and necrosis (Pathol Int 2012;62:559)
Gross images

Contributed by Mark R. Wick, M.D.

Localized type
Missing Image

Cut surface



Images hosted on other servers:

Diffuse type
Tumor mass

Tumor mass

Microscopic (histologic) description
  • Composed of mononuclear cells, multinucleated giant cells, foamy macrophages, inflammatory cells and hemosiderin
  • 2 principal cell types of the mononuclear components:
    • Small histiocyte-like cells: pale cytoplasm and round or reniform nuclei
    • Large epithelioid cells: amphophilic cytoplasm and rounded vesicular nuclei, often containing a peripheral rim of hemosiderin granules
  • Mitotic activity may be brisk
  • Necrosis can be present
  • Localized type (J Surg Oncol 1998;68:100)
    • Lobulated and well circumscribed
    • Osteoclast-like giant cells are usually readily apparent
    • Xanthoma cells are frequent, tend to aggregate locally near the periphery of nodules, and may be associated with cholesterol clefts
    • Hemosiderin deposits
    • Stroma showed variable degrees of hyalinization
  • Diffuse type (J Surg Oncol 1998;68:100, J Oral Maxillofac Surg 2019;77:1022.e1)
    • Infiltrative, and grow as diffuse, expansile sheets
    • Osteoclast-like giant cells are less common in the diffuse form than the localized form and may be absent or extremely rare in as many as 20% of cases
    • Cleft-like spaces are common and appear either as artifactual tears or as synovial lined spaces
    • Stromal hyalinization is common and may mimic osteoid
    • Blood filled pseudoalveolar spaces are seen in approximately 10% of cases
  • Malignant (Hum Pathol 2017;63:144, Am J Surg Pathol 1997;21:153)
    • Composed of sheets and nodules of enlarged mononuclear cells
    • Significantly increased mitotic count, including atypical mitoses, necrosis, enlarged nuclei with nucleoli, spindling of mononucleated cells and myxoid changes
    • May contain areas that resemble undifferentiated pleomorphic sarcoma or myxofibrosarcoma
Microscopic (histologic) images

Contributed by Jigang Wang, M.D., Ph.D., Jiufa Cui, M.D., Ph.D. and Michella Whisman, M.D.

Localized type
Missing Image

Fibrous bands

Missing Image

Lobular appearance

Large epithelioid cells Large epithelioid cells

Large epithelioid cells

Missing Image

Multinucleated giant cells

Missing Image

Pigment laden histiocytes


Missing Image

Foamy histiocytes

Foamy histiocytes Missing Image

Foamy histiocytes

Missing Image Missing Image

Mononuclear component



Diffuse type
Foamy histiocytes (xanthoma cells)

Foamy histiocytes (xanthoma cells)

Mononuclear cells

Mononuclear cells

Large mononuclear cells

Large mononuclear cells

Chondroid metaplasia

Chondroid metaplasia

Papillary growth pattern

Papillary growth pattern

Numerous mononuclear cells

Numerous mononuclear cells

Cytology description
  • Localized type (Rare Tumors 2015;7:5814)
    • Moderately cellular smears with a variable admixture of cell populations:
      • Polygonal to spindled mononuclear cells in loose clusters or individually dispersed with moderate cytoplasm and round to oval nuclei
      • Scattered osteoclast-like multinucleated giant cells
      • Foamy histiocytes
      • Hemosiderin laden histiocytes
    • Relatively scant background inflammation in most cases
  • Diffuse type (Acta Cytol 2017;61:160)
    • Heterogeneous cell populations:
      • Large epithelioid mononuclear cells
        • Abundant eosinophilic cytoplasm, usually containing ring-like hemosiderin pigment
        • Vesicular, round to oval, eccentric nuclei with prominent nucleoli
      • Macrophages with smaller, oval or reniform nuclei
      • Osteoclast-like giant cells
    • Frequent mitotic figures
    • Chondroid metaplasia is common in the temporomandibular joint
  • Malignant (J Cytol 2017;34:174)
Cytology images

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Localized type

Mononuclear stromal cells, osteoclast giant cells


Malignant
Mitosis

Mitosis

Immunofluorescence description
  • Unknown at this time
Positive stains
Negative stains
Electron microscopy description
Molecular / cytogenetics description
Molecular / cytogenetics images

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Diffuse type
Structural chromosomal aberration

Structural chromosomal aberration

Sample pathology report
  • Right finger, index, excision:
    • Tenosynovial giant cell tumor, localized type (giant cell tumor of tendon sheath), 1.6 cm (see comment)
    • Comment: Surgery is the main treatment. Localized type rarely recurs after complete removal while diffuse type often recurs.

  • Right hip, index, excision:
    • Tenosynovial giant cell tumor, diffuse type (pigmented villonodular synovitis)

  • Right hip, excision:
    • Malignant diffuse tenosynovial giant cell tumor
Differential diagnosis
  • Localized type
    • Diffuse type tenosynovial giant cell tumor:
      • Essentially identical appearance to localized form at high magnification
      • Distinguished from localized form by large size, infiltrative growth or anatomic site (often intra-articular and in larger joints)
      • Villonodular architecture when intra-articular
    • Giant cell tumor of soft tissue:
      • More uniform background of mononuclear cells
      • Typically have sheets of osteoclastic giant cells similar to giant cell tumor of bone
      • Less association with a tendon
    • Fibroma of tendon sheath:
      • Slit-like vascular spaces at the periphery
      • Cracking artifact in collagenous background
      • Spindled to stellate fibroblasts / myofibroblasts
      • Lacks giant cells, large histiocytoid cells with eccentric nucleus, hemosiderin laden histiocytes and foamy histiocytes
  • Diffuse type
    • Localized type tenosynovial giant cell tumor:
      • Well circumscribed and encapsulated
      • Lacks villi
      • Localized to digits, uncommon in large joint
    • Hemarthrosis:
      • Villiform synovial hyperplasia with hemosiderosis
      • Solid cellular areas are rare
      • History is important: repetitive hemarthrosis (e.g., trauma or hemophilia)
    • Malignant tenosynovial giant cell tumor:
      • Often with past history of radiation therapy
      • Pleomorphic spindle cells and high mitotic rate and necrosis
      • Epithelioid cells with prominent nucleoli
  • Malignant
    • Benign diffuse tenosynovial giant cell tumor:
      • Lacks sarcomatous area
    • Other soft tissue sarcoma:
      • Lacks typical area of diffuse tenosynovial giant cell tumor
      • Lacks medical history of diffuse tenosynovial giant cell tumor
  • Dermatofibroma:
    • Dermal lesions
    • Rare in digits
    • Lacks large epithelioid cells and osteoclast-like giant cells
    • Lacks CSF1 rearrangement
  • Plexiform fibrohistiocytic tumor:
    • Usually involves dermis and subcutis
    • Nodules or clusters are interconnected in characteristic plexiform arrangement
    • Plump fibroblastic cells and histiocyte-like cells within a finely granular myxoid background
    • Large epithelioid mononulear cells are absent
Board review style question #1
Which of the following features must be identified to the make the diagnosis of tenosynovial giant cell tumor?

  1. Epithelioid mononuclear cells
  2. Foamy macrophages
  3. Hemosiderin laden macrophages
  4. Inflammatory cells
  5. Multinucleated giant cells
Board review style answer #1
A. Epithelioid mononuclear cells. The lesion is a tenosynovial giant cell tumor, localized type (also called giant cell tumor of tendon sheath). Although all the listed cell types can be seen in varying proportions within the tumor, the histiocytoid mononuclear cells are the neoplastic component and should always be present.

Comment Here

Reference: Tenosynovial giant cell tumor
Board review style question #2
Which of the following is true regarding tenosynovial giant cell tumor, localized type?

  1. Both genders are affected equally
  2. Diagnosis can be made even in the absence of osteoclast-like giant cells
  3. Highly infiltrative lesion, which leads to recurrence in the majority of cases
  4. It is the most common tumor of the hand
  5. The patient always reports a history of trauma
Board review style answer #2
B. The diagnosis can be made even in the absence of osteoclast-like giant cells. Some cases show a paucity of giant cells, which is why it is best to know the constellation of histologic features aside from the presence of giant cells in order to make the diagnosis in giant cell poor cases. Tenosynovial giant cell tumor, localized type, is the second most common tumor of the hand (ganglion cyst is most common). It shows a predilection for females (F:M = 2:1). The tumors are usually well circumscribed. They may recur but simple excision is curative most of the time. Some patients report a history of trauma but not all.

Comment Here

Reference: Tenosynovial giant cell tumor
Board review style question #3
Which of the following is true regarding the location of diffuse tenosynovial giant cell tumor?

  1. Knee is the most frequent, followed by hip and ankle
  2. Often in foot and hand
  3. Often occurs in small joint
  4. Only intra-articular
Board review style answer #3
A. Knee is the most frequent, followed by hip and ankle. Diffuse tenosynovial giant cell tumor often involves large joint and can be extra-articular. Localized tenosynovial giant cell tumor often occurs in small joint, such as foot and hand.

Comment Here

Reference: Tenosynovial giant cell tumor
Board review style question #4
BRQ image BRQ image BRQ image


A 15 year old girl presented with finger mass for 1 year. The tumor (shown above) was well defined, attached to the tendon and was approximately 1 cm in diameter. What is your diagnosis?

  1. Chondroblastoma
  2. Dermatofibroma
  3. Fibroma of tendon sheath
  4. Giant cell tumor
  5. Tenosynovial giant cell tumor
Board review style answer #4
E. Tenosynovial giant cell tumor. The pictured lesion is a tenosynovial giant cell tumor, localized type (also called giant cell tumor of tendon sheath). The tumor usually occurs in small joint and is attached to tendon sheath. Microscopically, the tumor was a giant cell rich tumor with prominent epithelioid mononuclear cells that can be observed.

Comment Here

Reference: Tenosynovial giant cell tumor
Board review style question #5
Which of the following is true regarding malignant tenosynovial giant cell tumor?

  1. Malignant tumor from the location around large joint
  2. May have a previous history or typical morphological area of tenosynovial giant cell tumor
  3. Often occurs in upper extremities
  4. Usually affects young people
Board review style answer #5
B. May have a previous history or typical morphological area of tenosynovial giant cell tumor

Comment Here

Reference: Tenosynovial giant cell tumor

Translocation negative (pending)
[Pending]

Tuberculous arthritis
Definition / general
  • Insidious onset of chronic progressive arthritis, usually monoarticular in knee and hip; usually after osteomyelitis
  • More common in children
  • First, synovial membrane secretes excessive fluid; then proliferation, thickening, studding of its inner surface with tubercles; finally fibrosis of outer surface
  • Leads to fibrous ankylosis of joint with obliteration of joint space
  • Can detect from culture, examination of synovial fluid, PCR (apparent false positives in clinically negative patients may represent early disease, Arch Pathol Lab Med 2004;128:205)
Radiology description
  • Marginal erosion of hip and knee joints, with destruction of subchondral bone on both sides of joint and loss of joint space
Case reports
Clinical images

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Arthroscopic view of elbow joint

Microscopic (histologic) description
  • Granulomas with caseous necrosis; AIDS patients often have histiocytes with numerous acid fast organisms but no granulomas
Microscopic (histologic) images

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Synovial tissue


Tuberculous osteomyelitis
Definition / general
    Osteomyelitis - general
    • Infection of bone (osteitis) or bone marrow space (myelitis) = osteomyelitis
    • Usually pyogenic, fungal or tubercular
    • HIV+ patients may be infected by unusual organisms (eg. Mycobacterium avium)
    • Radiographically may resemble a neoplasm, particularly after antibiotic treatment
    • Severe osteomyelitis is not associated with grade IV sacral decubitus ulcers in non-septic patients; imaging may be misleading (Arch Pathol Lab Med 2003;127:1599)
    • May cause secondary AA amyloidosis

    Osteomyelitis - tuberculous
    • Usually young adults or children

    Pott's disease:
    • Involvement of spine (thoracic / lumbar)
    • Extensive necrosis of intervertebral discs with extension into soft tissue
    • May produce significant deformities or neurologic deficits
    • Difficult to treat
Clinical features
  • In US, due to immigrants and immunosuppression
  • 1 - 3% with tuberculosis have bone infection, usually from focus of acute visceral disease, direct extension or lymphatics
  • Rarely causes inguinal mass with fluctuant psoas abscess
  • In AIDS patients, bone infection usually multifocal
  • Advanced cases are associated with cutaneous sinuses, which cause secondary bacterial infections
  • Associated with fusion of joint, denudation of cartilage, sequestra of medullary cavity
  • Can detect in synovial fluid by culture and examination
Sites
  • Vertebrae, hip, knee, ankle, elbow, wrist
  • Usually involves synovium, epiphysis or metaphysis
Radiology images

Contributed by Mark R. Wick, M.D.
Missing Image

Paraspinal tuberculous abscess MRI

Gross images

Contributed by Mark R. Wick, M.D.
Missing Image

Tubeculous vertebral osteomyelitis

Microscopic (histologic) images

Contributed by Mark R. Wick, M.D.
Missing Image

Various images

Differential diagnosis

Tumoral calcinosis
Definition / general
  • Tumor-like deposits of calcium hydroxyapatite in soft tissue surrounding major joints
Essential features
  • Nonneoplastic condition, mimics osteocartilaginous tumors
  • Can be primary (familial or sporadic) or secondary (tumoral calcinosis-like lesions) (World J Clin Cases 2014;2:409)
  • Painless periarticular subcutaneous masses involving large joints and occurring in the first 2 decades
  • Characterized by lobular deposits of amorphous granular material (hydroxyapatite crystals) with basophilic calcifications
  • Histiocytic granulomatous response to crystals
  • Treated with surgical excision, secondary form requires treatment of underlying cause
Terminology
  • Coined by Inclan in 1943
  • Synonyms: lipid calcinosis, tumoral lipocalcinosis, calcifying collagenolysis, calcifying bursitis, hip stone disease, Kikuyu bursa
ICD coding
  • ICD-10:
    • L94.2 - calcinosis cutis
    • E83.59 - other disorders of calcium metabolism
Epidemiology
  • Usually affects younger age groups in the first and second decades of life (Acta Orthop Belg 2008;74:837)
  • Rare after 50 years
  • Familial form has predilection for young black males (African Americans) (Genet Couns 2008;19:183)
  • Secondary form is associated with trauma, scleroderma, osteoarthritis and diseases affecting calcium phosphate metabolism, including chronic renal failure, milk alkali syndrome, hypervitaminosis D, etc.
Sites
  • Involves periarticular subcutaneous tissue of large joints
  • Attached to the underlying fascia, muscle or tendon, unrelated to bone and joint
  • Most commonly occurs in elbows, hips and shoulders (J Dermatol 1996;23:545)
  • Solitary lesion in sporadic type
  • Often multicentric and bilateral lesions in familial type
Pathophysiology
  • Familial tumoral calcinosis has 2 types:
    • Autosomal recessive hyperphosphatemic type:
      • Characterized by germline mutations in the FGF23, GALNT3 or KL gene (J Invest Dermatol 2010;130:652)
      • These mutations prevent degradation of fibroblast growth factor 23 (FGF23), which is involved in phosphate homeostasis
    • Autosomal recessive normophosphatemic type:
      • Characterized by SAMD9 genetic mutation
      • Mutation results in deficiency of the associated interferon γ and tumor necrosis factor α responsive protein
  • Sporadic tumoral calcinosis is idiopathic (most common form)
  • Secondary tumoral calcinosis is caused by underlying disorder (Am J Surg Pathol 2007;31:15)
Etiology
  • Secondary form is associated with various predisposing conditions, including chronic renal failure (typically associated with secondary hyperparathyroidism), primary hyperparathyroidism, systemic sclerosis, scleroderma, dermatomyositis, sarcoidosis, osteoarthritis and congenital deformities (Rheumatol Int 2005;25:55)
Diagrams / tables

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Schematics of tumoral calcinosis

Approach for tumoral calcinosis

Clinical features
  • Painless, firm, subcutaneous calcified masses in the periarticular soft tissues, especially along extensor surfaces (J Bone Joint Surg Am 1967;49:721)
  • Subcutaneous deposits tend to be large and dense
  • May be associated with papular and nodular skin lesions
  • Dermal deposits are multiple, small and globular in type
  • Both familial forms of tumoral calcinosis may be associated with bony abnormalities, including calcifications in long bones and cranium, ocular and dental abnormalities
Diagnosis
  • Plain Xray, CT scan and MRI are helpful imaging modalities in combination with clinical findings
Laboratory
  • Normal / elevated serum phosphate levels in sporadic type
  • Serum calcium levels are usually normal in sporadic type (J Endocrinol Invest 2020;43:173)
  • Elevated serum phosphate and vitamin D levels in familial, hyperphosphatemic type
  • Normal serum phosphate and vitamin D levels in familial, normophosphatemic (NFTC) type
  • Secondary form has impaired calcium and phosphate levels depending on the type and extent of underlying metabolic disease
Radiology description
  • Plain radiographs show rounded, multilobulated cloud-like calcifications in periarticular area (Skeletal Radiol 1995;24:573)
  • CT scan reveals solid or cystic appearance with rounded opacities separated by radiolucent lines (fibrous septa) and multiple fluid calcium levels due to calcium layering (sedimentation sign) in some nodules (Acta Biomed 2019;90:587)
  • MRI shows more prominent sedimentation sign and variable signal intensity (Br J Radiol 1974;47:734)
  • Low intensity signal in more calcified portions and high intensity signal in cystic areas in T2 weighted sequences
  • Mild contrast enhancement in areas of septation
  • Radionuclide bone scan may show intense uptake in the calcific masses
Radiology images

Contributed by Nasir Ud Din, M.B.B.S.
Right finger, distal phalanx

Right finger, distal phalanx

Calcified lesion, foot

Calcified lesion, foot

Prognostic factors
  • Benign condition with good prognosis (Arch Craniofac Surg 2018;19:287)
  • Recurrence may occur in familial forms
  • Prognosis in secondary type depends on the treatment of causative systemic condition
Case reports
Treatment
  • Surgical excision is the primary treatment for sporadic and familial forms (Am J Orthop (Belle Mead NJ) 2011;40:E170)
  • Medical treatment to control the hyperphosphatemia (e.g., a low phosphate diet and oral administration of phosphate binders) is an important adjunct to surgical excision (Front Endocrinol (Lausanne) 2020;11:293)
  • Targeted therapies to decrease intestinal absorption and increase renal excretion of phosphate are helpful in familial type (JBMR Plus 2019;3:e10185)
  • Secondary form also requires medical treatment of underlying disease
Clinical images

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Nodules on patient’s hands

Metastatic
calcifications
presenting as
firm solid masses

NFTC and dermatomyositis

Gross description
  • Firm, rubbery, unencapsulated, multinodular to multicystic mass
  • Size varies from 5 - 30 cm
  • Cut surface shows cystic spaces filled with chalky, milky liquid or semisolid gritty material
  • Fibrous tissue separates cavities
Gross images

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Cystic spaces filled with yellowish material

Frozen section description
  • Can be diagnosed on frozen section in correlation with complete clinical, radiological and serological information (Neurosurgery 2005;57:E596)
Microscopic (histologic) description
  • Histology is same regardless of the type, primary or secondary (Am J Surg Pathol 1993;17:788)
  • Lobular to irregular deposits of amorphous calcium crystals (hydroxyapatite crystals) within cystic spaces, surrounded by foreign body giant cell reaction
  • Deposits of calcium are present within collagen fibrils and ground substance
  • Calcification may be chunky basophilic or may form psammoma body-like calcospherites
  • Foreign body giant cell reaction comprises of histiocytes, multinucleated foreign body giant cells, osteoclast-like giant cells and chronic inflammatory cells
  • Foreign body giant cell reaction may show granulomatous appearance
  • Histological features depend upon the stage of evolution of the lesion (Int J Surg Pathol 2012;20:462)
    • In early stage, cystic spaces contain eosinophilic debris undergoing calcification with histiocytic reaction
    • In advanced stage, heavily calcified material is surrounded by densely hyalinized connective tissue
  • 3 stage classification scheme:
    • Early (proliferative) phase: fibrohistiocytic nodules composed of fibroblast-like cells, foamy histiocytes, mononuclear macrophages and hemosiderin laden macrophages
    • Active (cellular) phase: amorphous or granular calcified material surrounded by exuberant proliferation of macrophages, fibroblasts, osteoclast-like giant cells and chronic inflammatory cells
    • Inactive phase: heavily calcified material, bordered by dense fibrosis or a cystic space, enclosed by calcium deposits
Microscopic (histologic) images

Contributed by Nasir Ud Din, M.B.B.S. and John Irlam, D.O.
Irregular basophilic deposits

Irregular basophilic deposits

Foreign body giant cell reaction

Foreign body giant cell reaction

Amorphous granular pink deposits

Amorphous granular pink deposits

Chunky basophilic deposits

Chunky basophilic deposits


Psammoma body-like calcospherites

Psammoma body-like calcospherites

Calcinosis

Virtual slides

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Idiopathic scrotal calcinosis

Cytology description
  • Diagnosis can be made on cytology with clinical, serological and radiological correlation
  • Cytology smears show coarse to fine calcific debris (Diagn Cytopathol 1995;13:339, Turk Patoloji Derg 2015;31:145)
  • Clumps of dark, basophilic, amorphous calcium deposits are present
  • Few ill defined granulomas may be seen
Cytology images

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Amorphous pink deposits

Basophilic, amorphous calcium deposits

Electron microscopy description
Molecular / cytogenetics description
Videos

Scrotal calcinosis - pathology mini tutorial

Sample pathology report
  • Elbow, excision:
    • Histologic features are consistent with tumoral calcinosis (see comment)
    • Comment: Histology of the lesion shows nodular to irregular aggregates of amorphous to basophilic calcium deposits surrounded by foreign body giant cell reaction, features classic of tumoral calcinosis. It is a benign condition that can be primary (idiopathic or familial) or secondary due to metabolic disorders and systemic conditions like chronic renal insufficiency, hyperparathyroidism, milk alkali syndrome, hypervitaminosis D, systemic sclerosis, scleroderma, dermatomyositis, sarcoidosis, osteoarthritis, congenital deformities and trauma. Clinical and serological correlation is recommended.
Differential diagnosis
  • Soft tissue chondroma:
    • Occurs in middle age group with male predominance
    • Involves distal extremities including digits, hands and feet
    • Hyaline cartilage is present with secondary dystrophic calcification
  • Gout:
    • More commonly affects men between the ages of 30 - 50
    • Women usually affected after menopause
    • Polarizable needle shaped urate crystals show negative birefringence (Arthritis Rheumatol 2020;72:1408)
    • Less calcification
    • May have hyperuricemia
    • Bone erosion may be seen
  • Pseudogout (calcium pyrophosphate dihydrate crystal deposition disease):
    • Affects older adults and the elderly
    • Involves weight bearing joints, such as knees, hips, shoulders, wrists and ankles
    • Polarizable rhomboid shaped calcium pyrophosphate crystals show positive birefringence (Mod Pathol 2001;14:806)
    • Response is more fibroblastic than histiocytic
  • Calcific tendinitis:
    • Age range is between 30 - 60 years
    • Women are more affected than men
    • Shoulder > hip > elbow > wrist > knee
    • Deposition of calcium hydroxyapatite crystals in tendons
    • No sedimentation of calcium
  • Calcifying synovial sarcoma:
    • Arises in deep soft tissue of extremities of young adults
    • Knee is most commonly affected
    • Distinct tumor fascicles of plump spindle cells
    • Less calcification
    • Cytokeratin, EMA: focal / patchy positive
    • TLE1: diffuse nuclear positive
Board review style question #1

A 20 year old woman presented with painless bilateral hip swellings. Gross specimen was comprised of skin covered fibroadipose and fibromuscular tissue with an unencapsulated multicystic lesion in subcutaneum. Microscopy revealed large basophilic calcium deposits surrounded by foreign body giant cell reaction with intervening areas of fibrosis. No atypical cells were seen. What is the most likely diagnosis?

  1. Chondroma
  2. Gout
  3. Osteolipoma
  4. Pseudogout
  5. Tumoral calcinosis
Board review style answer #1
E. Tumoral calcinosis

Comment Here

Reference: Tumoral calcinosis
Board review style question #2
Which of the following is a cause of secondary tumoral calcinosis?

  1. Chronic renal failure
  2. FGF23 gene mutation
  3. GALNT3 gene mutation
  4. Idiopathic
  5. SAMD9 gene mutation
Board review style answer #2
A. Chronic renal failure

Comment Here

Reference: Tumoral calcinosis

Undifferentiated pleomorphic sarcoma
Definition / general
  • Undifferentiated pleomorphic sarcoma (UPS) is a pleomorphic malignant neoplasm of bone lacking a distinct line of differentiation
Essential features
  • Distinct clinicopathologic entity in the WHO Soft Tissue and Bone Tumours classification (5th edition)
  • Mesenchymal tumor of bone
  • Pleomorphic spindle shaped and epithelioid cells in a storiform or fascicular growth pattern
  • No osteoid or cartilage matrix production
  • No identifiable line of differentiation; diagnosis of exclusion
  • Diagnosis requires correlation with clinical, radiological and pathologic findings
Terminology
  • Malignant fibrous histiocytoma of bone, pleomorphic fibrosarcoma of bone
    • This terminology is currently not recommended
ICD coding
  • ICD-O: 8802/3 - pleomorphic cell sarcoma
  • ICD-11: 2B54 & XH0947 - unclassified pleomorphic sarcoma, primary site & malignant fibrous histiocytoma
Epidemiology
Sites
  • Usually unicentric (Cancer 1997;79:482)
  • Long tubular bones, particularly around the knee (Cancer 1997;79:482)
  • Femur is most commonly involved, followed by tibia and humerus
  • Among the bones of the trunk, pelvic bones are most commonly affected
Pathophysiology
  • Shows many diverse genetic alterations and chromosomal structural aberrations
  • Chromosomal losses of 8p, 9p, 10, 13q and 18q and gains of 4q, 5p, 6p, 7p, 8q, 12p, 14q, 17q, 19p, 20q, 22q and X have been reported
  • Loss of heterozygosity in multiple genes has been reported, including
  • Mutations in TP53 (~30%) or chromatin remodeling genes (~40%) including ATRX, DOT1L and H3F3A are most frequent (J Pathol 2019;247:166)
Etiology
  • Largely unclear and unknown
  • First described in 1972 by Frieda Feldman and David Norman (Radiology 1972;104:497)
  • Most cases are de novo (primary) (Semin Diagn Pathol 2021;38:163, Cancer 1997;79:482)
  • Secondary (nearly 30% of cases)
    • Some cases arise from preexisting bone disease
      • Bone infarct, Paget disease
    • Prior irradiation in the field of the affected bone
    • Rare cases were associated with metallic prosthesis or hardware
    • Some cases associated with hereditary diaphyseal medullary stenosis (Hardcastle syndrome)
Clinical features
Diagnosis
  • Diagnosis requires correlation with clinical, radiological and pathologic findings
  • Pathologic findings
    • Pleomorphic spindle shaped and epithelioid cells in a storiform or fascicular growth pattern
    • No osteoid or cartilage matrix production
    • No identifiable line of differentiation; diagnosis of exclusion
Radiology description
  • Radiological features are nonspecific but the majority of cases demonstrate an aggressive osteolytic neoplasm with ill defined margins, cortical destruction, an associated soft tissue mass and pathologic fracture (Skeletal Radiol 2021;50:1491)
  • On magnetic resonance imaging (MRI), the tumor is heterogeneous on T1 and T2 weighted images (Semin Diagn Pathol 2021;38:163)
  • Tumors are usually centered in the metadiaphyseal region of long bones and occasionally extend into the epiphysis
Radiology images

Contributed by AFIP and Mark R. Wick, M.D.
Radiograph of tibial tumor

Radiograph of tibial tumor

Primary, distal femur

Primary, distal femur

Prognostic factors
  • Depends on staging
  • Overall, 5 year and 10 year survival rates of 38.3% and 30.5%, respectively (J Surg Oncol 2020;121:1097)
  • Localized disease tends to have a favorable prognosis
  • Secondary undifferentiated pleomorphic sarcoma and metastatic disease are associated with a poorer prognosis
Case reports
Treatment
  • Radical surgery with adjuvant chemotherapy
  • Radiotherapy for unresectable tumors
Gross description
  • Tumor is usually centered in the medullary cavity (Semin Diagn Pathol 2021;38:163)
  • Tumor grows with a permeative pattern, encasing preexisting bony trabecula (Semin Diagn Pathol 2021;38:163)
  • Variable color (white-gray, tan-yellow and tan-brown)
  • Typically shows cortical bone destruction and soft tissue mass
  • Areas of necrosis and hemorrhage
Gross images

Contributed by Mark R. Wick, M.D.
Primary

Primary

Microscopic (histologic) description
  • Usually hypercellular and composed of spindle shaped, epithelioid or polygonal cells with marked pleomorphism arranged in a haphazard, storiform and fascicular growth pattern
  • Background could be hyalinized with some inflammatory cells
  • No osteoid or cartilaginous matrix
  • Usually atypical mitotic figures and necrosis is present
  • Considered a grade 3 sarcoma and is distinguished from grade 2 adult type fibrosarcoma by the significantly greater degree of atypia and architectural arrangement (Semin Diagn Pathol 2021;38:163)
Microscopic (histologic) images

Contributed by Hatem Kaseb, M.D., Ph.D., M.P.H., Mark R. Wick, M.D. and AFIP
Significant pleomorphism Significant pleomorphism

Significant pleomorphism

Significant pleomorphism Significant pleomorphism

Significant pleomorphism


Significant pleomorphism

Significant pleomorphism

Fascicles of fibroblasts

Fascicles of fibroblasts

Irregular deposits of noncalcified collagen

Noncalcified collagen

Negative stains
Sample pathology report
  • Bone, right distal femur, radical resection (status postneoadjuvant chemotherapy):
    • Residual undifferentiated pleomorphic sarcoma of bone (see synoptic report)
    • Synoptic report
      • Tumor size: 11.3 x 8.0 x 8.0 cm
      • Tumor location: right distal femur
      • Percent treatment response: ~80% (~20% residual viable tumor)
      • Discontinuous tumor foci: not identified
      • Lymphovascular invasion: not identified
      • Surgical margins: negative for tumor
      • Lymph nodes: 1 benign lymph node (0/1)
      • Additional findings: biopsy site
      • Stage (AJCC, 8th edition): ypT2 ypN0
Differential diagnosis
  • High grade sarcomas:
    • Osteosarcoma:
      • Typically shows osteoid matrix and positive SATB2
    • Leiomyosarcoma:
      • Some areas could show fascicles of spindled cells
      • SMA positivity with an additional myogenic marker
    • Rhabdomyosarcoma:
      • Shows distinct morphological features of types, such as alveolar or embryonal
      • Typically positive for desmin, myogenin and MyoD1
    • Synovial sarcoma:
      • Morphology consistent with monophasisc or biphasic could be helpful for differentiation
      • Harbors t(X;18)(p11;q11) SYT::SSX fusion
  • Metastatic sarcomatoid carcinoma:
    • Typically has a different clinical presentation
    • Usually partially / diffusely CK positive
  • Metastatic carcinoma:
    • Typically has a different clinical presentation
    • Usually positive for CK7 or CK20 or both, depending on the primary tumor site
  • Metastatic melanoma:
    • Typically has a different clinical presentation
    • On morphology, pigment seen in the cytoplasm or cells with prominent eosinophilic nucleoli could be helpful for differentiation
    • Usually positive for S100, SOX10, MelanA or HMB45
  • Dedifferentiated chondrosarcoma:
    • Usually shows IDH1 or IDH2 mutations (Hum Pathol 2017:65:239)
    • Usually shows a well differentiated cartilaginous component
    • Shows some distinct clinical, radiologic and pathologic features
  • Fibrous dysplasia:
    • Caused by mutations in GNAS gene
Board review style question #1

Which of the following stains is usually positive in undifferentiated pleomorphic sarcoma of bone?

  1. CD31
  2. Desmin
  3. Myogenin
  4. SATB2
  5. Vimentin
Board review style answer #1
E. Vimentin. The only stain that is usually positive in undifferentiated pleomorphic sarcoma of bone is vimentin. Answers A - D are incorrect because CD31, desmin, myogenin and SATB2 are usually negative or show focal positivity in this tumor.

Comment Here

Reference: Undifferentiated pleomorphic sarcoma
Board review style question #2
Which of the following risk factors has been associated with undifferentiated pleomorphic sarcoma of bone?

  1. Diaphyseal medullary stenosis
  2. Ethnic origin
  3. Increased alcohol consumption
  4. Nonmetallic prosthesis or hardware
  5. Smoking
Board review style answer #2
A. Diaphyseal medullary stenosis. Diaphyseal medullary stenosis has been shown to be associated with undifferentiated pleomorphic sarcoma of bone. Answers B - E are incorrect because all of these other risk factors have not been shown to be associated with undifferentiated pleomorphic sarcoma of bone.

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Reference: Undifferentiated pleomorphic sarcoma

WHO classification
Definition / general
  • WHO classification of bone tumors is regarded as the gold standard reference for diagnosis of bone tumors and provides an indispensable international resource for those involved in the care of patients with bone cancer or in cancer research, including pathologists, oncologists and surgeons (Adv Anat Pathol 2021;28:119)
Major updates
  • Selected tumors removed in the 2020 WHO classification of bone tumors:
    • Benign fibrous histiocytoma
    • Giant cell lesion of the small bones
    • Leiomyoma
    • Liposarcoma
  • Selected tumors reclassified in the categorization of 2020 WHO classification of bone tumors:
    • Aneurysmal bone cyst (tumor categorization: osteoclastic giant cell rich tumor)
    • Nonossifying fibroma (tumor categorization: osteoclastic giant cell rich tumor)
    • Chondromesenchymal hamartoma of chest wall (tumor categorization: other mesenchymal tumor of bone)
    • Simple bone cyst (tumor categorization: other mesenchymal tumor of bone)
    • Fibrous dysplasia (tumor categorization: other mesenchymal tumor of bone)
    • Osteofibrous dysplasia (tumor categorization: other mesenchymal tumor of bone)
    • Adamantinoma (tumor categorization: other mesenchymal tumor of bone)
    • Pleomorphic sarcoma, undifferentiated (tumor categorization: other mesenchymal tumor of bone)
    • Langerhans cell histiocytosis (tumor categorization: hematopoietic neoplasm of bone)
    • Erdheim-Chester disease (tumor categorization: hematopoietic neoplasm of bone)
    • Rosai-Dorfman disease (tumor categorization: hematopoietic neoplasm of bone)
    • Ewing sarcoma (tumor categorization: undifferentiated small round cell sarcoma of bone and soft tissue)
  • Selected new tumor entities and subtypes in the 2020 WHO classification of bone tumors:
WHO (2020)







Microscopic (histologic) images

Contributed by Borislav A. Alexiev, M.D.
Enchondroma

Enchondroma

Chondrosarcoma

Chondrosarcoma

Dedifferentiated chondrosarcoma

Dedifferentiated chondrosarcoma

Mesenchymal chondrosarcoma

Mesenchymal chondrosarcoma

Low grade osteosarcoma

Low grade osteosarcoma

Osteosarcoma

Osteosarcoma


Aneurysmal bone cyst

Aneurysmal bone cyst

Chondroblastoma

Chondroblastoma

Giant cell tumor of bone

Giant cell tumor of bone

Nonossifying fibroma

Nonossifying fibroma

Conventional chordoma

Conventional chordoma

Board review style question #1
Central atypical cartilaginous tumor / chondrosarcoma grade 1 is a locally aggressive, hyaline cartilage producing neoplasm arising in the medulla of bone. The term atypical cartilaginous tumor should be reserved for tumors arising in which of the following anatomical sites?

  1. Chest wall
  2. Long and short tubular bones
  3. Pelvis
  4. Scapula
  5. Skull base
Board review style answer #1
B. Long and short tubular bones. Cartilaginous tumors in the appendicular skeletons (long and short tubular bones) should be termed atypical cartilaginous tumors, while the term chondrosarcoma grade 1 should be reserved for tumors of the axial skeleton, including the pelvis, scapula and skull base (flat bones), reflecting the poorer clinical outcome of these tumors at these sites.

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Reference: Bone tumors - WHO classification
Board review style question #2

The histologic pattern shown above would be most commonly expected in which of the following bone tumors listed in WHO 2020?

  1. Chondrosarcoma, grade 1
  2. Chordoma
  3. Low grade osteosarcoma
  4. Mesenchymal chondrosarcoma
  5. Osteosarcoma
Board review style answer #2
E. Osteosarcoma. Note highly atypical spindle cells producing lace-like unmineralized matrix (osteoid).

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Reference: Bone tumors - WHO classification

Xanthoma
Definition / general
  • 65% male, age 20+ years
  • Usually solitary; affects pelvis, ribs, skull
Radiology description
  • Well defined, expansile lytic lesion, often with sclerotic margin
Microscopic (histologic) description
  • Foam cells, multinucleated giant cells, cholesterol clefts, fibrosis
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Recent Bone & joints Pathology books

Bocklage: 2014

Czerniak: 2015

Deyrup: 2015

Dodd: 2014

Folpe: 2022

Forest: 1998

Greenspan: 2015

Horvai: 2012

IARC: 2020

Jo: 2015

Klein: 2011

Montgomery: 2020

Nielsen: 2021

Nielsen: 2021

Picci: 2019

Santini-Araujo: 2020

Unni: 2009

Wei: 2013



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