Lymph nodes & spleen, nonlymphoma

Present in 20 - 33% of autopsies
Usually small (up to 4 cm), resembles normal spleen macroscopically and microscopically
Near splenic hilum, gastrosplenic ligament, tail of pancreas (Pancreas 2011;40:956)
Important to document or find in patients with splenectomy for hematologic disease
Intrapancreatic accessory spleen may contain increased fibrous stroma, pancreatic islet tissue and indistinct border with adjacent pancreatic parenchyma
May contain epithelial cysts
Rare cases can result in torsion, sometimes presenting with either intermittent abdominal pain or acute abdomen

Case reports

3 year old girl with situs inversus and torsion of accessory spleen (J Med Invest 2012;59:220)
60 year old woman with 18 x 11 mm hypoechoic mass in tail of pancreas (Case of the Week #406)
Lymphoepithelial cyst and epidermoid cyst in accessory spleen located in pancreas (Mod Pathol 1998;11:1171)

Microscopic (histologic) images

Case of the Week #406

10x

40x

H&E

CD8

CD56

Chromogranin

Synaptophysin

Differential diagnosis

Acute nonspecific lymphadenitis

Table of Contents

Definition / general

Acute inflammation of lymph nodes

Essential features

Enlarged and painful, tender lymph nodes
Microscopic examination, if performed, will show sinus dilatation followed by accumulation of neutrophils, vascular dilatation and edema of the capsule

Terminology

Acute nonspecific lymphadenitis, nontuberculous lymphadenitis

ICD coding

Epidemiology

Common, mostly affects children

Sites

Cervical lymph nodes are commonly affected
Acute nonspecific mesenteric lymphadenitis is also a relatively common in children

Pathophysiology

Acute inflammation of the involved lymph node / nodes due to an infectious or inflammatory etiology

Etiology

Most commonly due to viral infections
Most common bacterial causes are Staphylococcus aureus and beta hemolytic Streptococcus
Inflammation of the draining sites or direct inflammation of the lymph nodes can be the cause

Clinical features

Enlarged painful / tender lymph nodes, redness of overlying skin, low grade fever, malaise

Diagnosis

Clinical examination, exclude specific causes

Laboratory

Depending on the cause, CBC may show leukocytosis with neutrophilia or lymphocytosis, elevated ESR and bacterial / viral confirmatory tests may be positive

Prognostic factors

Good prognosis

Treatment

Treat the underlying cause, supportive therapy

Gross description

Enlarged lymph node
If bacterial infection, there can be suppuration leading to necrosis and abscess formation

Microscopic (histologic) description

Biopsy is rarely performed
Microscopic examination, if performed, will show sinus dilatation followed by accumulation of neutrophils, vascular dilatation and edema of the capsule
If bacterial origin, suppurative inflammation is present
Necrotizing inflammation can be seen in bubonic plague and tularemia, Still disease and Kikuchi necrotizing lymphadenitis

Microscopic (histologic) images

Images hosted on other servers:

Acute lymphadenitis

Cytology description

Mixed small and large lymphocytes admixed with neutrophils

Positive stains

Varies by etiology
Gram stain highlights bacteria, if present

Differential diagnosis

Specific causes should be ruled out
Suppurative lymphadenitis caused by bacterial infections, mesenteric lymphadenitis, lymphogranuloma venereum, cat scratch disease, bubonic plague, tularemia, anthrax, typhoid fever, melioidosis

Additional references

Pediatr Surg Int 1997;12:108, Stomatologiia (Mosk) 1999;78:28, Br Med J 1945;2:680, Mod Pathol 2013;26:S88

Board review style question #1

23 year old woman presents with tender right cervical lymph node enlargement. She also complains of low grade fever and feeling tired. On examination she is found to have three 4 mm red papules on her right shoulder. On further enquiry she informs that she owns two cats. What is the best confirmatory test at this point?

A. Biopsy of the lymph node
B. Biopsy of the skin lesion
C. PCR
D. Serology

Board review style answer #1

D. Serology. Serology for IgG and IgM antibodies for Bartonella henslae is confirmatory for cat scratch disease. Biopsy is rarely indicated. If performed, a biopsy will show lymphoid hyperplasia, granuloma formation, stellate abscesses and vascular proliferation depending on the stage of the disease. PCR can be done on biopsy specimen to confirm the diagnosis.

Comment Here

Reference: Acute nonspecific lymphadenitis

Acute splenitis

Table of Contents

Definition / general | Gross description | Microscopic (histologic) description | Differential diagnosis

Definition / general

Also called acute splenic tumor or septic spleen
Although traditionally associated with bacteremia, only known study shows no correlation (Arch Pathol Lab Med 2001;125:888)

Gross description

Splenic parenchyma may "flow" from cut surface

Microscopic (histologic) description

Criteria are ill defined but traditionally are acute congestion of red pulp with numerous neutrophils in red and white pulp
Necrosis of follicles occurs with group A streptococcal infection
No capsular invasion by immunoblasts

Differential diagnosis

Infectious mononucleosis

Adipose tissue

Table of Contents

Definition / general

Pathological enlargement of lymph nodes caused by abnormal accumulation of fat, due to mature, benign adipocytes within lymph node capsules

Terminology

Lipo-lymph nodes
Lipoplastic lymphadenopathy

Epidemiology

Very common

Sites

Most commonly involved sites are external iliac and obturator groups

Pathophysiology

Accumulation of abnormal quantities of fat within lymph nodes in excess of normal aging changes
Benign process with good prognosis
Can cause mass effect depending on size
May mimic lymphoma or other neoplasms

Etiology

Unknown; postulated causes include exaggeration of normal fat deposition with aging, previous abdominal inflammatory disease, obesity

Clinical features

Enlarged lymph nodes; may lead to formation of large masses up to 10 cm

Diagnosis

Lymph node biopsy

Radiology description

Progressive enlargement and increased fatty infiltration
CAT scan and lymphangiography findings can be misleading towards neoplastic process

Case reports

47 year old man with abundant macroscopic fat in intra-abdominal lymph nodes (Br J Radiol 2012;85:e91)
49 year old woman with lipoplastic lymphadenopathy presenting as an ovarian mass (Gynecol Oncol 1987;28:345)
50 year old man with generalized lipomatosis of lymph nodes (Lymphology 1979;12:262)
Middle aged women with lipolymph nodes of mesentery (Am Surg 1985;51:596)
Lipoplastic lymphadenopathy simulating lymphoma and pelvic lipomatosis (J Urol 1975;114:788)
Pelvic and aortic lipolymph nodes (Acta Obstet Gynecol Scand 1982;61:383)

Treatment

Excision of involved lymph node in symptomatic cases serves both diagnostic and therapeutic purposes

Clinical images

Images hosted on other servers:

Progressively enlarging lymph node

Largest intra-abdominal adenopathy

Gross description

Enlarged lymph node with soft greasy yellow areas within capsule, or entirely replaced by similar cut surfaces

Gross images

Contributed by Jayalakshmi Balakrishna, M.D.

Lymph node replaced by adipose tissue

Microscopic (histologic) description

Benign mature adipocytes populate nodes whose capsules are thinly attenuated with fine vascular trabeculae dividing fat deposits

Microscopic (histologic) images

AFIP images

Lipomatosis

Contributed by Jayalakshmi Balakrishna, M.D.

Lymphoid tissue closely admixed with adipocytes

Lymph node with adipocytes within capsule

Differential diagnosis

Intranodal angiolipoma (Int J Surg Pathol 2005;13:99)
Other causes of lymphadenopathy: lymphoma, metastases, inflammatory / infectious causes
Retroperitoneal or pelvic lipomatosis

Additional references

Rosai and Ackerman's Surgical Pathology, 10th Edition, 2011

Adult onset Still disease

Table of Contents

Definition / general

Rare systemic inflammatory disease accompanied by a triad of spiking fever, maculopapular exanthema and arthralgia, accompanied frequently by lymphadenopathy

Essential features

Fever, skin rash, joint pains, lymphadenopathy with paracortical hyperplasia and immunoblastic reaction

ICD coding

M06.1

Epidemiology

Rare, shows female predilection and more common in young adults

Sites

Systemic disease
Generalized lymphadenopathy

Pathophysiology

Pathophysiology is yet to be clearly defined
Interleukins, macrophage colony stimulating factor, interferon gamma and tumor necrosis factor alpha may play a role
May also be due to genetic factors, immune dysfunction and infections

Clinical features

Systemic inflammatory disease manifesting with spiking fever, sore throat, arthralgia, skin rash and hepatosplenomegaly
Reactive hemophagocytic syndrome is also reported

Diagnosis

Clinical, laboratory and imaging results

Laboratory

Neutrophilic leukocytosis, anemia, elevated ferritin, C reactive protein (CRP), erythrocyte sedimentation rate (ESR) and abnormal liver function tests (AST and ALT)

Radiology description

Affected joints show progressive erosions and narrowing joint space
Commonly associated with hepatosplenomegaly

Prognostic factors

Disease can be self limiting and the prognosis depends on the specific disease pattern
Overall, patients with only localized disease have a better prognosis compared to those with more disseminated disabilities or severe complications
Disease can be monocyclic - self limiting, polycyclic - symptoms recur or have chronic articular pattern

Case reports

28 year old woman with AOSD (Acta Med Iran 2016;54:683)
53 year old woman diagnosed with AOSD based on Yamaguchi criteria (Am J Case Rep 2017;18:119)
Persistent pruritic lesions in adult onset Still disease (Am J Med Sci 2016;352:540)
Three Japanese women ages 22, 26 and 63 with lymph node lesions from AOSD (Int J Surg Pathol 2002;10:197)

Treatment

Mainly antiinflammatory medications, including steroids, NSAIDs and antirheumatic agents

Gross description

Nonspecific enlargement of lymph nodes, usually small size

Microscopic (histologic) description

Major histological findings limited to paracortical hyperplasia or a mixed pattern with paracortical and diffuse or paracortical, follicular and diffuse hyperplasia, with or without sinus histiocytosis
Vascular proliferation in the interfollicular areas, immunoblastic reaction and mixed inflammatory cell infiltrations are also described commonly
Rare findings described include pericapsular endarteritis and hemophagocytic features

Positive stains

CD20 and CD3 in the follicular and interfollicular areas
Interfollicular T cells show CD4 predominance over CD8
Immunoblasts are of B cell phenotype with CD30 expression
Plasma cells are polyclonal by light chain expression

Molecular / cytogenetics description

Polyclonal B and T cell gene rearrangement patterns

Differential diagnosis

Peripheral T cell lymphoma (PTCL) - angioimmunoblastic T cell lymphoma (AILT) and T zone variant of PTCL, NOS

Additional references

J Rheumatol 1989;16:349, Ann Hematol 1992;65:53, J Clin Pathol 2004;57:1052, J Rheumatol 1991;18:1418, Medicine (Baltimore) 2015;94:e787

Board review style question #1

CD20, CD3, CD45
CD3, CD4, CD8
CD30, CD15, OCT2
PD1, BCL6, CD10

Board review style answer #1

D. PD1, BCL6, CD10 - markers for follicular helper T cell phenotype. Angioimmunoblastic T cell lymphoma is of follicular helper T cell origin and is positive for PD1, BCL6 and CD10.

Comment Here

Reference: Adult onset Still disease

ALK+ histiocytosis

Table of Contents

Definition / general

ALK positive histiocytosis (APH) is a histiocytic neoplasm characterized by ALK (anaplastic lymphoma kinase) gene rearrangements and ALK immunoreactivity in the lesional histiocytes (Leukemia 2022;36:1703, Blood 2022;140:1229, Blood 2022;139:256)
Initially described in 2008 presenting as systemic histiocytosis in infants (Blood 2008;112:2965)

Essential features

Rare non-Langerhans cell histiocytic neoplasm with heterogeneous clinical features, presenting as single system disease, multisystem with systemic hematopoietic involvement (liver, spleen or marrow, skin, central nervous system [CNS]) or other multisystem disease (tumorous involvement of ≥ 2 organ systems)
ALK expression by immunohistochemistry, predominantly in a cytoplasmic pattern, rarely in a membranous or Golgi (dot-like) pattern and practically never in a nuclear pattern
Cytoplasmic ALK expression by immunohistochemistry with coexpression of histiocytic markers (CD68, CD163, CD4) is crucial to distinguish this entity from other histiocytic or spindle cell morphologic mimics
Characteristic ALK gene rearrangements allow for targeted therapy with ALK inhibitors

Terminology

ALK related histiocytosis
ALK rearranged histiocytosis

ICD coding

ICD-10: D76.3 - other histiocytosis syndromes

Epidemiology

Affects any age group, including children and young adults, with a female predilection (Blood 2022;139:256)

Sites

Multisystem with systemic hematopoietic involvement
- Systemic involvement of liver, spleen or bone marrow with or without involvement of additional sites (Blood 2022;139:256, Leukemia 2022;36:1720)
Multisystem disease, others
- ≥ 2 organs, most commonly central and peripheral nervous system, bone, lung and skin (Leukemia 2022;36:1720, Blood 2022;139:256)
Single system disease
- Tumorous involvement of a single organ with solitary or multiple lesions
- Most common sites include central and peripheral nervous system, skin, soft tissue and breast (Blood 2022;139:256)

Pathophysiology

Fusion of the receptor tyrosine kinase domain of the ALK gene, most commonly to exon 24 of KIF5B, results in constitutive activation of downstream signaling, including RAS-RAF-MEK-ERK (MAPK) and PI3K / AKT / mTOR signaling pathways
MAPK pathway activation leads to phosphorylation of downstream ERK, ultimately resulting in transcription of various effector genes, including the gene encoding for cyclin D1 (CCND1); translation of CCND1 messenger RNA to the cyclin D1 protein is mTOR dependent (Blood 2022;139:256)

Etiology

Unknown at this time

Diagrams / tables

Images hosted on other servers:

Reported sites of involvement

Clinical features

Diverse clinical presentations depending on site(s) of involvement
Infants with multisystem disease involving the hematopoietic system present with hepatomegaly, anemia and thrombocytopenia, often accompanied by splenomegaly and coagulopathy
Other multisystem and single system disease presents with varying mass effects depending on tumor size and location (Blood 2022;139:256)
- Neurologic involvement may present with headache, nausea / vomiting, ataxia, paresis, seizure, diplopia or trigeminal neuralgia
- Pulmonary involvement may present with dry cough or respiratory dysfunction requiring oxygen therapy
- Liver involvement may present with jaundice, coagulopathy or fever
- Cutaneous lesions present as slowly growing papules or nodules

Diagnosis

Comprehensive patient evaluation including clinical history, physical examination and imaging studies
Coexpression of histiocytic markers and ALK should prompt molecular confirmation of ALK gene rearrangement either by RNA sequencing or by FISH (fluorescence in situ hybridization) analysis
References: Mod Pathol 2019;32:598, Blood 2022;139:256

Laboratory

Variable, depending on organ system(s) involved
Liver involvement can be associated with elevated liver enzymes, elevated bilirubin and low fibrinogen (Blood 2022;139:256)
Hematopoietic involvement can be associated with anemia, thrombocytopenia and prolonged prothrombin time and activated partial thromboplastin time (Blood 2022;139:256)

Radiology description

Mass lesions can be identified by ultrasound, Xray, magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET) CT and other imaging modalities (Blood 2022;139:256)
- Liver, pancreas, long bone lesions appear hypermetabolic on PET CT imaging
- Liver and thyroid lesions appear hypoechoic on ultrasound
- Kidney tumors appear hypodense on CT imaging
- Tumors of the vertebral bodies and liver appear hyperintense by T2 weighted MRI
CNS tumors rarely can mimic meningioma on MRI (Radiol Case Rep 2023;18:2259)

Radiology images

Contributed by Keri Janowiak, M.D., M.Ed.

Screening mammography

Images hosted on other servers:

Nonneurologic disease manifestations

Left frontal lobe tumor

Prognostic factors

Prognosis depends on extent of disease and location(s) of tumor(s)
Typically favorable outcomes in cases with single system disease
Reports of death due to multisystem disease progression include every age group (Mod Pathol 2019;32:598, Blood 2022;139:256, JCO Precis Oncol 2021;5:PO.20.00383)

Case reports

17 month old boy with a 5.1 cm intracranial mass, multiple nodules in the liver and bilateral lungs, as well as multiple skin papules (Orphanet J Rare Dis 2023;18:53)
27 year old man with a 1.5 cm intradural extramedullary enhancing lesion (Turk Patoloji Derg 2021;37:172)
30 year old man with cavernous sinus lesion mimicking meningioma (Radiol Case Rep 2023;18:2259)
38 year old woman with multiple unilateral breast lesions (Int J Surg Case Rep 2022;97:107435)
50 year old woman with appendiceal nodule (Haematologica 2019;104:e534)
51 year old woman with lesions identified in the right lung, central nervous system and iliac lymph nodes (Ann Palliat Med 2021;10:10095)

Treatment

Management varies depending on extent of disease and site(s) of involvement
Surgical resection is often definitive treatment for single system disease (Blood 2022;139:256)
Systemic therapy for incompletely resected or unresectable tumors and for multisystem disease includes steroids, intravenous immune globulin (IVIG) or chemotherapy
Targeted therapy with ALK inhibitors has been used as first or second line treatment in a majority of cases (Blood 2022;139:256, JCO Precis Oncol 2021;5:PO.20.00383, Oncologist 2017;22:1444)
- ALK inhibitors include alectinib, loratinib, brigatinib, crizotinib, ceritinib and entrectinib
- Used as monotherapy or in combination with other treatment modalities
Rare cases have resulted in spontaneous regression (Blood 2022;139:256)

Clinical images

Images hosted on other servers:

Scalp lesion

Gross description

Tumors may be well circumscribed or ill defined with a tan, white or yellow cut surface

Gross images

Images hosted on other servers:

Breast APH lesion

Filum terminale

Microscopic (histologic) description

Large oval (epithelioid), foamy or spindle cells in varying proportions without significant nuclear atypia and abundant eosinophilic cytoplasm (Mod Pathol 2019;32:598, Blood 2022;139:256)
Large histiocytes may show irregular nuclear contours (indentation, folding, clefting, lobulation) with fine chromatin and small nucleoli (Mod Pathol 2019;32:598, Blood 2022;139:256)
Occasional multinucleated cells, including Touton giant cells, may be present (Mod Pathol 2019;32:598, Blood 2022;139:256)
Emperipolesis, characterized by engulfment of inflammatory cells (similar to Rosai-Dorfman disease), may be observed (Mod Pathol 2019;32:598, Blood 2022;139:256)
Hepatic involvement may show coalescing histiocytes indistinguishable from hepatocytes (Mod Pathol 2019;32:598)
Bone marrow infiltration may vary from focal to extensive involvement (Mod Pathol 2019;32:598)
Skin lesions are often noncircumscribed, nonepidermotropic infiltrates composed of sheets of histiocytes with varying degree of fibrosis (Mod Pathol 2019;32:598)
Fascicular and storiform growth patterns common in breast tumors (Am J Surg Pathol 2021;45:347)

Microscopic (histologic) images

Contributed by Keri Janowiak, M.D., M.Ed., Ekene Okoye, M.D. and Aishwarya Ravindran, M.D.

Storiform and fascicular growth

Infiltrative growth

Histiocyte morphology

Touton giant cells

CD68

CD163

Factor XIIIa

ALK

Cyclin D1

SMA

Peripheral smear description

In systemic cases with hematopoietic involvement, anemia, thrombocytopenia and leukocytosis are usually seen

Positive stains

ALK
- Cytoplasmic staining most common; occasionally membranous or dot-like Golgi pattern
- Lacks nuclear expression
- Can be weak or focal
CD163, CD68, CD14, CD4, lysozyme
Factor XIIIa, fascin, cyclin D1 (Am J Clin Pathol 2023;160:1)
Some cases show positivity for S100 and OCT2, mimicking Rosai-Dorfman disease (Blood 2008;112:2965, Am J Clin Pathol 2023;160:1)
pERK expression as a consequence of MAPK pathway activation

Negative stains

CD1a, langerin (Mod Pathol 2019;32:598, Am J Surg Pathol 2021;45:347)
CD23, CD21
Keratin
SMA, desmin (positivity seen in background stromal cells only) (Am J Surg Pathol 2021;45:347)
CD2, CD3, CD4, CD5, CD7, CD20, CD30 (positivity seen in background lymphocytes only)

Molecular / cytogenetics description

ALK rearrangements detected by FISH
ALK fusion partners identified via targeted RNA sequencing (Blood 2022;139:256)
- Most common: KIF5B::ALK fusion (~70 - 75% of cases)
- Other fusion partners reported: CLTC, TPM3, TFG, EML4, DCTN1, TRIM33, COL1A2

Molecular / cytogenetics images

Images hosted on other servers:

ALK FISH, breakapart probe

Sample pathology report

Left breast mass, lumpectomy:
- ALK positive histiocytosis, 9 mm in greatest dimension (see comment)
- Comment: Lesional histiocytes are characterized by cytoplasmic expression of ALK with coexpression of histiocytic markers (CD68, CD163) and cyclin D1. Molecular analysis by RNA sequencing was positive for KIF5B::ALK fusion. The overall immunophenotype in conjunction with the molecular analysis supports the above diagnosis.

Differential diagnosis

Reactive fibrohistiocytic proliferation:
- Observed in infectious or inflammatory conditions as well as fat necrosis
- Emperipolesis may be present (not pathognomonic for histiocytic neoplasms)
- IHC negative for S100, OCT2 and ALK
- Lacks ALK gene fusions
Rosai-Dorfman disease (RDD):
- Parenchymal effacement of nodal / extranodal tissue by large histiocytes with round / oval nuclei, pale chromatin, distinct nucleoli and abundant pale cytoplasm with frequent engulfment of inflammatory cells (emperipolesis)
- Abundant plasma cells and small lymphocytes; occasionally, neutrophils may also be present
- By immunohistochemistry, positive for S100, OCT2; uniformly negative for ALK
- ~10% of cases are negative for CD163 (Am J Clin Pathol 2023;160:1)
- Lacks ALK gene fusions
Juvenile xanthogranuloma (JXG):
- Usually affects pediatric population with ~33% of cases presenting within the first year of life
- Predominantly cutaneous involvement presenting as papulonodular lesions and usually asymptomatic / self resolving over months / years
- < 5% may be systemic JXG, including CNS that may present as seizures, hydrocephalus, diabetes insipidus; bone marrow involvement presents with cytopenias
- Nonencapsulated circumscribed lesions composed of large xanthomatous (foamy) histiocytes with bland nuclear features and Touton giant cells; occasionally lesions may be composed of spindled, epithelioid or oncocytic histiocytes
- Typically has an inflammatory background with a mixed population of lymphocytes, eosinophils, plasma cells, neutrophils and mast cells
- IHC negative for ALK
- Lacks ALK gene fusions
Erdheim-Chester disease:
- Heterogeneous clinical manifestations, most commonly presenting with bone pain, secondary to bilateral symmetric osteosclerosis of metadiaphysis of femur, tibia and fibula
- Bland appearing histiocytes characterized by abundant foamy (xanthomatous) cytoplasm with surrounding fibrosis (Mod Pathol 2018;31:581)
- Negative for OCT2 and ALK (Am J Surg Pathol 2021;45:35, Am J Clin Pathol 2023;160:1)
- Associated with MAPK pathway mutations, with BRAF V600E mutated in ~50 - 60% of cases
- Lacks ALK gene fusions
Langerhans cell histiocytosis:
- Langerhans cells characterized by irregular, grooved, folded or indented nuclei with fine chromatin, inconspicuous nucleoli and abundant pale eosinophilic cytoplasm
- Positive for S100, CD1a and langerin; negative for factor XIIIa and ALK (Am J Clin Pathol 2023;160:1)
- Lacks ALK gene fusions
Inflammatory myofibroblastic tumor (especially breast and soft tissue tumors):
- Proliferation of ALK positive spindle cells of myofibroblastic origin with variable prominent lymphoplasmacytic infiltrates
- Lesional cells are positive for vimentin (diffuse, strong), smooth muscle actin, muscle specific actin, calponin and desmin (variable)
- CD68 / CD163 positive histiocytes may be present in the background but are not the lesional cells

Additional references

WHO Classification of Tumours Editorial Board: Haematolymphoid Tumours, 5th Edition, 2024, BMJ Case Rep 2018;2018:bcr2018224506, Acta Neuropathol 2019;138:335, Neuropathol Appl Neurobiol 2021;47:878, Leuk Lymphoma 2021;62:1234, J Breast Imaging 2022;4:336, J Hematopathol 2021;14:89, Hum Pathol Case Rep 2021;24:200504, Hum Pathol Case Rep 2020;21:200404

Board review style question #1

A 41 year old woman underwent a core needle biopsy for a 3 cm breast mass discovered on her first screening mammogram. The lesional spindle cells show the CD68 immunostaining pattern seen above; they are also positive for ALK and negative for SMA and desmin. Which of the following is the most likely diagnosis?

ALK positive histiocytosis
Erdheim-Chester disease
Extranodal Rosai-Dorfman disease
Inflammatory myofibroblastic tumor
Juvenile xanthogranuloma

Board review style answer #1

A. ALK positive histiocytosis (APH) can occur as a localized mass in many anatomic locations or as multisystem disease. Morphologic features vary and may include spindled, epithelioid or foamy histiocytes with or without background lymphoplasmacytic infiltrate. Lesional histiocytes show positive immunostaining for at least 1 histiocytic marker (CD68, CD163, etc.) and for ALK. Answers B, C and E are incorrect because the lesional histiocytes in each of these lesions do not show positive immunostaining for ALK. Answer D is incorrect because the neoplastic spindle cells in inflammatory myofibroblastic tumor (IMT) are myofibroblastic in origin and are therefore positive for SMA and desmin and negative for CD68.

Comment Here

Reference: ALK+ histiocytosis

Amyloid

Table of Contents

Definition / general

Uncommon disease caused by the deposition of abnormal proteins within the soft tissues

Essential features

Extracellular deposition of amorphous, eosinophilic, hyaline substance
Amyloid is Congo red+

Terminology

Amyloid, amyloidosis, amyloid lymphadenopathy

Epidemiology

Rare

Sites

Cervical, supraclavicular and mediastinal lymph nodes
Any lymph node group can be affected

Pathophysiology

Results from abnormal folding of proteins
Proteins that form amyloid can be (a) normal proteins that have an inherent tendency to fold improperly, associate and form fibrils and do so when they are produced in increased amounts and (b) mutant proteins that are prone to misfolding and subsequent aggregation

Etiology

As part of primary systemic amyloidosis
As part of reactive systemic amyloidosis
In uremic patients
In non-Hodgkin lymphoma
As isolated primary deposits in lymph nodes

Clinical features

Lymph node enlargement
In secondary cases, depending on the primary condition

Diagnosis

Histologic demonstration of amyloid

Laboratory

If associated with monoclonal proteins of B cell lymphoma, serum and urine protein electrophoresis will demonstrate monoclonal proteins

Radiology description

None specific
Enlarged lymph nodes

Prognostic factors

Generalized amyloidosis tends to have poor prognosis

Case reports

46 year old man with localized lymph node light chain amyloidosis (Case Rep Hematol 2015;2015:816565)
77 year old woman with primary amyloidosis involving mediastinal lymph nodes diagnosed by EBUS TBNA (Respiratory Medicine CME 2009;2:51)
3 patients with AL amyloidosis manifesting as systemic lymphadenopathy (Amyloid 2008;15:117)
Massive cervical and abdominal lymphadenopathy caused by localized amyloidosis (J Clin Oncol 2007;25:343)

Treatment

Treatment of the associated condition
Treatments inhibiting protein misfolding and fibrillogenesis are under study

Gross description

Enlarged lymph node with firm waxy cut surfaces

Gross images

Contributed by Mark R. Wick, M.D.

Amyloidosis of lymph node

Microscopic (histologic) description

Hyaline-like amorphous eosinophilic depositions positive for Congo red staining
Polarizing microscope shows unique yellowish green birefringence

Microscopic (histologic) images

AFIP images

Amyloidosis of lymph node

Contributed by Mark R. Wick, M.D.

Amyloidosis of lymph node

Cytology description

Hyaline-like amorphous material on cytology smears
Acellular and associated with connective tissue
Eosinophilic to blue / green with Pap stain, deep blue with Diff-Quik

Positive stains

Congo red

Negative stains

PAS: pale staining
Elastic: stains negative

Electron microscopy description

Clusters of round / oval nodules, often enclosed with cytoplasmic processes of macrophages or reticulum cells
Fibrils are nonbranching, 7.5 nm in diameter, form parallel bundles close to cytoplasmic membranes

Differential diagnosis

Hyalinization

Additional references

Kumar: Robbins & Cotran Pathologic Basis of Disease, 9th Edition, 2014, Rosai: Rosai and Ackerman's Surgical Pathology, 10th Edition, 2011, Hum Pathol 1986;17:1245, Lab Invest 1962;11:585

Amyloidosis

Table of Contents

Definition / general

Usually secondary; rarely localized splenic nodules
Even with diffuse involvement, spleen may still retain "pitting" function that prevents appearance of Howell-Jolly bodies in peripheral blood smears (Arch Pathol Lab Med 1995;119:252)
Rarely can result in splenic rupture (Am J Hematol 2003;74:131)

Case reports

69 year old man with coexisting malignant GIST of stomach (Arch Pathol Lab Med 2003;127:470)
Amyloid tumor in lymphoma patient (Am J Surg Pathol 1987;11:723)

Gross description

Firm and waxy consistency

Microscopic (histologic) description

Deposition of pink amorphous material (amyloid) limited either to germinal follicles (sago spleen) or splenic sinusoids and surrounding connective tissue (lardaceous spleen)

Positive stains

Congo red with characteristic birefringence (apple green)

Differential diagnosis

Hyaline adventitial thickening of splenic vessels (normal, AIDS associated, Castleman disease)

Anatomy & histology-lymph nodes

Table of Contents

Definition / general

A secondary lymphoid organ, where B and T cells proliferate in response to exogenous antigen; primary lymphoid organs are bone marrow and thymus
Other secondary lymphoid organs are spleen and Peyer patches
Tertiary lymphoid organs are tissues with few lymphocytes that recruit more when inflammation is present
Lymph nodes are organized to detect and inactivate foreign antigens present in lymph fluid that drains skin, GI tract and respiratory tract, the major organs in contact with the environment

Terminology

Afferent lymph vessels:
- Penetrate capsule, enter marginal sinus, communicate with intranodal sinuses, then become efferent vessels, which lack an endothelial lining
- Intranodal vessels contain littoral cells or histiocytes with phagocytic properties
Capsule:
- Thin fibrous connective tissue covering of lymph node
- May be thicker at hilus
- Connected to fibrous trabeculae which penetrate the node
- Capsule may contain smooth muscle cells (Anat Rec 1975;183:517)
Cortex:
- Subcapsular portion of node with largest number of follicles (primary or secondary)
Primary follicle:
- Round aggregates of small, dark staining inactive (naïve) B lymphocytes, usually near the capsule, within a network of follicular dendritic cell processes
- No germinal center present
Secondary follicle:
- Arises from primary follicle that develops germinal centers (see below) due to antigenic stimulation of B cells and production of antibodies
- Contains pale staining germinal center which may be polarized towards site of antigen entry
- Surrounded by mantle zone and marginal zone lymphocytes
- Germinal center:
  - Contains predominantly B lymphocytes (including centroblasts and centrocytes) and scattered follicular T helper cells and T regs
  - Also tingible body macrophages and follicular dendritic cells
- Mantle zone:
  - Tightly packed small B lymphocytes of the primary follicles, pushed aside by the germinal centers
- Marginal zone:
  - Less packed small B lymphocytes with more cytoplasm
  - Light zone on outer rim of mantle zone
  - Contains a mix of post-follicular memory B cells derived after stimulation of recirculating cells from T cell dependent antigen and naïve B cells
  - Often not well developed in lymph nodes
Paracortex:
- Tissue between cortical follicles and medulla (see below)
- Contains predominantly dark staining mature T cells, B immunoblasts, interdigitating dendritic cells, plasmacytoid dendritic cells, histiocytes and high endothelial venules (postcapillary venules lined by plump endothelial cells that express leukocyte adhesion molecules and contain intraluminal lymphocytes)
- Expands during cell mediated immunological reactions
- Has coarse network of reticulin fibers
Medulla:
- Portion of node closest to hilum
- Contains the medullary cords, sinuses and vessels but minimal number of follicles
Medullary cords:
- Found in hilar region between the sinuses, composed mostly of small B and T lymphocytes, plasmacytoid lymphocytes, plasmablasts and plasma cells
Sinuses:
- Carry lymph from afferent to efferent lymphatics
- Subcapsular sinus is below capsule and partially lined by endothelium
- Becomes "medullary" as it approaches the hilum and is lined by macrophages
- Also contains mast cells and plasma cells
Vessels:
- Blood enters and leaves lymph node at hilus

Embryology

Develop from lateral plate mesoderm (on either side of intermediate mesoderm)
First, lymphatic sacs arise from endothelial outgrowths of large central veins at week 5
Second, lymphatic plexus develops from lymphatic sacs
Third, plexuses are invaded by mesenchymal cells that proliferate and aggregate to form lymph nodes
Small collections of lymphoblasts are present by first trimester
By second trimester, cortex is distinguishable from medulla and primary follicles are present
References: Martini: Human Anatomy, 9th Edition, 2017

Age related changes

Germinal centers are more common in infants and children, decrease in young adults, often absent in elderly (Am J Pathol 1975;78:7)
Germinal centers are more common in mesenteric and cervical lymph nodes ( J Clin Pathol 1980;33:454)
Hyaline deposits increased with age
Peripheral lymph nodes, with little antigenic stimulation, often have replacement by fat, particularly in axillary, cubital and popliteal nodes
Lymphocyte depletion, fibrosis and hyaline deposits are associated with chronic disease, particularly cancer

Diagrams / tables

Images hosted on other servers:

Lymph node structures

Lymph node architecture

Gross description

Ovoid with gray-tan cut surface

Microscopic (histologic) description

At low power, lymph node structures are capsule, cortex and medulla, follicles, paracortex, sinuses
Germinal center: round / oval zone containing pale staining cells, surrounded by darker cells
Mantle zone: small unchallenged B cells surrounding pale staining germinal centers
Marginal zone: light zone surrounding follicles; contains postfollicular memory B cells derived after stimulation of recirculating cells from T cell dependent antigen; named "marginal cells" due to location at interface of lymphoid white pulp and nonlymphoid red pulp in the spleen; however, marginal zone is rarely seen except in mesenteric nodes (APMIS 2002;110:325)
Sinuses: direct the flow of lymph from the afferent lymphatics, to the subcapsular sinus, to the trabecular sinus, to the medullary sinus, to the efferent lymphatics (see diagrams) (Toxicol Pathol 2006;34:409)

Centroblasts:
- Large noncleaved follicular center cells (B cells) with moderate amounts of basophilic cytoplasm, large round nuclei, open chromatin, multiple peripheral nucleoli
- Frequent mitotic figures
Centrocytes:
- Large and small cleaved follicular center cells (B cells) with scant cytoplasm and inconspicuous nucleoli
Immunoblasts:
- Large B cells scattered throughout the paracortex
- Intermediate between small B cell and a plasma cell
- Prominent single nucleoli
- Express B cell markers (CD20, CD79a, PAX5) and CD30
Macrophages:
- Process antigens via phagocytosis
- Related to circulatory monocytes
- Are present throughout the lymph node
- May contain thyroglobulin in lymph nodes draining thyroid tumors (J Clin Pathol 2001;54:314)
- Abundant cytoplasm with medium to large nuclei with vesicular chromatin
- Tingible body macrophages have clear cytoplasm and contain apoptotic bodies, which gives node a starry sky pattern
Mast cells:
- Present in T cell areas (World J Surg Oncol 2003;1:25)
- Difficult to detect
- Distinct cytoplasmic boundaries, faintly granular cytoplasm, large pale nuclei
- Some cells are elongated and resemble fibroblasts
NK cells:
- Distinct group of non T, non B lymphocytes (5 - 10% of peripheral blood lymphocytes) with large granular lymphocyte morphology on Wright-Giemsa stains
- NK cells derive from a common lymphoid progenitor with T cells
- First line of defense against various infections, by recognizing and killing target cells and producing cytokines, particularly interferon-gamma, which enhance the innate immune response
- Capable of lysing certain target cells (virally infected and tumor cells) without prior activation or major histocompatibility complex restriction (hence named "natural killers" that are part of "innate" immune system) (Wikipedia: Natural killer cell [Accessed 26 March 2021])
- Do not rearrange their receptor genes, as B / T cells do but rely on a fixed number of NK cell receptors (inhibitory and activating) that recognize MHC class I and class I-like molecules and other ligands
- Appear to have capability for memory-like responses (EMBO Rep 2009;10:1103)
- Important for immunomodulation and regulation of hematopoiesis
Plasma cells:
- Abundant basophilic cytoplasm (due to high content of rough endoplasmic reticulum) with paranuclear hof (highlighted by Giemsa stain, due to Golgi apparatus)
- Have eccentrically placed nucleus with spoke wheel (clock face) chromatin due to small clumps of chromatin on nuclear membrane in an otherwise round and clear nucleus
- May have Russell bodies (intracytoplasmic PAS+ globules)

Microscopic (histologic) images

Contributed by Nikhil Sangle, M.D.

Centroblasts

Centrocytes

AFIP images

Normal lymph node

Primary follicle

Lymph node

Secondary follicle

Paracortical T zone

Interdigitating dendritic cells

Smooth muscle proliferation in lymph node hilum

Sclerosis in an inguinal lymph node

Positive stains

B cells: CD19, CD20, CD22, CD79
- Germinal center B cells: strong and dense bcl6 and CD10
- B cells in primary follicules and mantle zones: IgD, IgM, CD21, CD23, occasionally CD5
- Antigen stimulated B cells with the capacity to differentiate toward plasma cells express MUM1 / IRF4 and CD138
T cells: CD2, CD3, variable CD4 and CD8
- Follicular helper T cells: C3, CD4, CD57, PD1 or CD279
- T regs: CD4, CD25 and FOXP3
- Premature B and T cells: TdT (terminal deoxynucleotidyl transferase)
Follicular dendritic cells: CD21, CD23, CD35
Macrophages: CD68, lysozyme
NK cells:
- CD56, CD57, CD16 (> 90% are CD16+ / CD56+)
- Also cytoplasmic (not surface) CD3, CD2, CD7, CD8 (up to 80%), perforin, granzyme B, TIA1
Germinal centers have strong dense BCL6 and CD10 expression

Negative stains

bcl2 (not expressed in germinal center B lymphocytes)

Electron microscopy images

Images hosted on other servers:

Plasma cells

Anatomy, histology & grossing-spleen

Table of Contents

Anatomy | Histology | Grossing | Drawings

Anatomy

Largest lymphoid tissue of human body, accounting for 25% of total lymphocytes
Lies between fundus of stomach and diaphragm
Normally 150 g with thin capsule
Pathophysiology:
- Filters foreign matter including old / damaged blood cells
- Participates in immune response to blood borne antigens
- Major repository of mononuclear phagocytic cells in red pulp, lymphoid cells in white pulp and platelets
- Produces new blood cells in infants / children or adults with severe anemia
Gross description: malpighian (splenic) follicles of white pulp are identifiable

Histology

Composed of red pulp (occupies 75% of splenic volume) and white pulp separated by marginal zone
Red pulp:
- Filters old / damaged red blood cells
- Traversed by thin walled venous sinusoids lined by littoral cells, a type of endothelial cell which also stains with histiocytic markers and has a discontinuous wall, allowing passing of red blood cells between sinus and cords
- Sinuses are separated by splenic cords (cords of Billroth) containing a labyrinth of splenic macrophages, which filter red blood cells and ingest old (normal lifespan is 120 days), damaged (seen in hereditary spherocytosis, sickle cell anemia) or antibody coated red blood cells
- Also remove Heinz bodies or other red blood cell inclusions (peripheral blood has Howell-Jolly bodies if no functional spleen is present)
White pulp:
- Forms sheaths of lymphoid cells around arteries (periarteriolar lymphatic sheath), composed of T cells and lymphoid follicles (B cells) with surrounding mantle zone (proliferating B cells) and outer marginal zone (memory B cells)
- Traps antigens for processing
- In young infants, immature marginal zone may contribute to increased susceptibility to bacterial infections or sudden infant death syndrome (Hum Pathol 2004;35:113)
Blood flow:
- Arteries terminate in fine penicilliary arterioles surrounded by lymphocytes, then enter red pulp sinusoids, then to splenic veins

Grossing

Fresh tissue preferable for special studies and flow cytometry
Section specimen every 3 - 5 mm
Obtain imprints after blotting with a towel to remove excess blood
Blocks should be thin for adequate fixation, since fixative penetrates spleen slowly
Describe apparent white pulp disorders (nodules), red pulp disorders (diffusely enlarged spleen without follicles or nodules) or other

Drawings

Images hosted on other servers:

Visceral surface

Transverse section highlighting veins

Transverse section highlighting arteries

Transverse section

Angiolipomatous hamartoma

Table of Contents

Definition / general

Benign mesenchymal proliferation with vascular and fatty components (Pathologica 2006;98:239)
Associated with Castleman lymphadenopathy, hyaline vascular variant (Arch Pathol Lab Med 1986;110:853)

Sites

Various nodal sites, including cervical, mediastinal and retroperitoneal lymph nodes
Occurs in nodal parenchyma or extracapsular soft tissue
Miscellaneous extranodal sites can be involved

Pathophysiology

Rare disorder of unknown etiology
Pseudotumor; not a true neoplasm

Clinical features

Innocuous and slow growing

Radiology images

Images hosted on other servers:

Mesenteric tumor with soft tissue parts

Case reports

16 year old boy with paraparesis caused by an angiolipomatous hamartoma with Proteus syndrome and scoliosis (J Neurosurg 2005;103:282)
60 year old man with a spindle cell sarcoma containing a focal angiolipomatous hamartoma component (J Pathol 2002;197:264)
70 year old man with angiolipomatous mesenchymal hamartoma (angiolipomatosis) of sigmoid mesocolon (Int J Clin Exp Pathol 2011;4:210)
Giant lymph node hyperplasia in an angiolipomatous mediastinal mass (Arch Pathol Lab Med 1986;110:853)
Vascular transformation of sinuses in bilateral cervical lymph nodes (Head Neck 1999;21:366)

Treatment

Surgical excision

Gross description

Unencapsulated single or multiple yellow and fatty nodules up to 15 cm
Tan nodules may represent accompanying hyaline vascular Castleman lymphadenopathy

Gross images

Images hosted on other servers:

Large smooth surfaced mass

Microscopic (histologic) description

Noncircumscribed intranodal or extranodal mass
Mature adipose tissue and haphazard thick walled muscular vessels of varying sizes
No thrombi within disorganized vascular channels
Lacks other mesenchymal tissue types, such as muscle
No necrosis, dense sclerosis, lipoblasts or marked cytologic atypia

Immunohistochemistry & special stains

Smooth muscle actin and desmin highlight muscular vessels

Differential diagnosis

Angiomyolipoma: contains myomatous component, common in kidney
Lipofibromatosis: pediatric soft tissue tumor with conspicuous fibrous component
Liposarcoma: malignant tumor with lipoblasts

Angiomyolipoma

Table of Contents

Definition / general

Benign tumor associated with renal angiomyolipoma
Proliferation of adipose tissue, smooth muscle and thick walled vessels in variable proportions
Rare nodal involvement of renal angiomyolipoma likely due to multicentric tumor rather than metastasis (Int J Urol 2000;7:386, Arch Pathol Lab Med 1990;114:65)

Sites

Retroperitoneal and periaortic lymph nodes draining the involved kidney

Pathophysiology

Clonal process, consistent with neoplasm rather than hamartoma
Common progenitor cell differentiating into the 3 cell types (adipose tissue, smooth muscle and blood vessels) (Semin Diagn Pathol 1998;15:21)

Clinical features

Presents as renal mass with regional lymphadenopathy
May be associated with tuberous sclerosis
Fat poor angiomyolipoma can mimic renal cell carcinoma with nodal metastasis on radiograph
Indolent clinical course and slow growth

Case reports

17 year old girl with angiomyolipoma of the kidney with lymph node involvement mimicking renal cell carcinoma (Int Urol Nephrol 2001;33:617)
28 year old man with angiomyolipoma with regional lymph node involvement (Hinyokika Kiyo 2003;49:81)
34 year old woman with retroperitoneal angiomyolipoma with rapidly progressing intracystic hemorrhage and lymph node involvement (Hinyokika Kiyo 2003;49:611)
37 year old woman with renal angiomyolipoma with lymph node involvement (Chang Gung Med J 2003;26:607)

Treatment

Observation
Embolization of renal mass or renal conserving surgery

Microscopic (histologic) description

Haphazard adipose tissue and smooth muscle cells radiating from thick walled blood vessels
Ranges from sinusoidal involvement to massive replacement of nodal parenchyma
Smooth muscle may be epithelioid or pleomorphic
Infrequent mitoses

Microscopic (histologic) images

AFIP images

Lymph node

Positive stains

Myoid cells: HMB45, MelanA / Mart1, smooth muscle actin, muscle specific actin
Fat cells: S100

Molecular / cytogenetics description

Diploid DNA, consistent with benign behavior

Differential diagnosis

Angiolipomatous hamartoma: may be associated with Castleman disease
Bacillary angiomatosis: vascular proliferation due to Bartonella infection
Kaposi sarcoma: malignant spindle cell neoplasm with vascular slits
Lymphangiomyomatosis: proliferation of lymphatics and smooth muscles

Additional references

Warnke: Tumors of the Lymph Nodes and Spleen, 3rd Series, 1996, Orazi: Knowles Neoplastic Hematopathology, 3rd Edition, 2013, Urol Ann 2012;4:126

Angiomyomatous hamartoma

Table of Contents

Definition / general

First described by Chan et al. in 1992 (Am J Surg Pathol 1992;16:335)
Rare and benign vascular disorder due to proliferation of blood vessels and smooth muscle in mostly the hilar region of lymph nodes, often of long duration

Essential features

Variably sized, thick walled blood vessels and haphazardly arranged smooth muscles in sclerotic nodal parenchyma
Benign lesion with no atypia
Uncommon process, usually asymptomatic and often solitary
Prominent smooth muscle infiltrate (SMA) with low proliferative fraction
HMB45 negative (to distinguish from angiomyolipoma)

ICD coding

ICD-11
- BD9Y - other specified disorders of lymphatic vessels or lymph nodes
- MA01.0 - localized lymph node enlargement

Epidemiology

M > F (Blood 2020;136:1794)
All ages, peaking at sixth decade (Hum Pathol 2017;68:175)

Sites

Mostly involves inguinal or femoral lymph nodes, usually solitary
May have associated limb edema; rare case report with a soft tissue mass (JAAD Case Rep 2022;27:117)
Rare reports of cervical lymph node and popliteal lymph node involvement (Histopathology 1996;29:80, Ann Diagn Pathol 2008;12:372)
Rarely presents as extensive lymphadenopathy (Blood 2020;136:1794)

Etiology

Unknown etiology; may represent reparative reaction to previous nodal inflammation or chronic blockage of nodal lymphatic flow (BMC Pediatr 2012;12:172)

Clinical features

Presents incidentally or as palpable nodule; rare report of lymphadenomegaly in different regions (Blood 2020;136:1794)
Typically asymptomatic; rarely lymphedema of ipsilateral limb (Fed Pract 2016;33:38)
Benign clinical course
No known recurrence or metastasis

Diagnosis

Excisional biopsy of lymph node usually diagnostic

Radiology description

Magnetic resonance imaging (MRI): well circumscribed solitary nodule with heterogeneous signal intensity (JAAD Case Rep 2022;27:117)

Case reports

33 year old man with postauricular lymph node, clinically masquerading as epidermal inclusion cyst (JAAD Case Rep 2020;7:131)
37 year old woman with weight loss and para-aortic lymph node (Prz Menopauzalny 2023;22:111)
53 year old woman with multiple neck lymph nodes showing angiomyomatous hamartoma (Int J Surg Pathol 2023 Nov 20 [Epub ahead of print])
60 year old man with several year history of lower leg edema (Case #118)
63 year old woman with right femoral subcutaneous mass and localized lymphedema (JAAD Case Rep 2022;27:117)
75 year old man with incidental extensive lymphadenopathy involving mediastinal, retroperitoneal, pelvic, inguinal and para-aortal lymph nodes (Blood 2020;136:1794)

Treatment

Surgical excision is curative

Gross description

Enlarged lymph node replaced by firm, white tissue

Gross images

AFIP images

Replacement by tan, firm tissue

Microscopic (histologic) description

Extensive and multifocal nodal involvement by thick walled hilar blood vessels, often with increased fibrous tissue
Nodal parenchyma has haphazard smooth muscle fibers in sclerotic stroma
Starts in nodal hilum and extends toward cortex
May have admixed adipose tissue
No cellular atypia, pleomorphism or necrosis; low mitotic rate (Hum Pathol 2017;68:175)

Microscopic (histologic) images

Contributed by Patricia Tsang, M.D., M.B.A., Vincent A. Graffeo, M.D. and AFIP

Disarrayed vascular proliferation

Angiomyomatous proliferation

Smooth muscle proliferation

Thick walled vasculature

Abnormal blood vessels

Angiomyomatous proliferation

Thick walled vessels

Disarrayed smooth muscles

Angiomyomatous hamartoma of lymph node

Smooth muscle actin

CD31

Positive stains

Smooth muscle actin, caldesmon and desmin stain smooth muscle fibers
CD31 and CD34 highlight endothelial cells (Int J Surg Pathol 2023 Nov 20 [Epub ahead of print])

Negative stains

HMB45 and cathepsin K, in contrast to angiomyolipoma and lymphangioleiomyomatosis
Ki67 is mostly negative (low proliferation) (Int J Surg Pathol 2023 Nov 20 [Epub ahead of print])

Sample pathology report

Inguinal lymph node, excision:
- Angiomyomatous hamartoma of lymph node (see comment)
- Comment: The nodal architecture is disrupted by a haphazard proliferation of thick walled vasculature and smooth muscle bundles. Occasional adipocytes are admixed. No cytologic atypia or mitoses are seen. Residual lymphoid tissue with reactive lymphoid follicles is present in the cortex. Immunohistochemistry shows CD31 and SMA highlighting the endothelial cells and smooth muscles, respectively. HMB45 is negative.

Differential diagnosis

Angiolipomatous hamartoma:
- Various nodal sites, including cervical, mediastinal and retroperitoneal lymph nodes
- Miscellaneous extranodal sites may be involved
- Associated with Castleman disease
Angiomyolipoma:
- HMB45+
- Typically involves retroperitoneal nodes
- Associated with renal angiomyolipoma
Lymphangiomatosis (Lymphat Res Biol 2011;9:191):
- Commonly in children and young adults, may be congenital
- Frequently involves lung with pleural effusion and other thoracic locations; also in bone, spleen and liver; primary nodal is rare
- Smooth muscle fascicles around anastomosing dilated vascular spaces lined by flat endothelial cells
Lymphangioleiomyomatosis:
- Female predominance
- Lungs and occasionally retroperitoneal lymph nodes
- HMB45+ and cathepsin K+
- Thin walled lymphatic channels and spindle cells in a fascicular pattern
Vascular transformation of lymph node sinuses (Am J Surg Pathol 1991;15:732):
- Small capillary vascular channels replacing nodal subcapsular sinuses
- Reactive process often accompanied by fibrosis; no cytologic atypia
- Involves single or multiple lymph nodes in a diffuse or segmental fashion

Board review style question #1

When differentiating angiomyomatous hamartoma from angiomyolipoma, which of the following immunohistochemical stains is the most helpful?

CD31
CD34
HMB45
SMA

Board review style answer #1

C. HMB45. Angiomyomatous hamartoma is negative for melanocytic markers (HMB45 and MelanA), while angiomyolipoma is positive for these stains. Answers A and B are incorrect because both lesions contain vascular proliferation which can be highlighted by the endothelial markers, CD31 and CD34. Answer D is incorrect because both lesions show positivity for SMA, which does not help differentiate these entities.

Comment Here

Reference: Angiomyomatous hamartoma

Board review style question #2

Which of the following statements is true of angiomyomatous hamartoma of the lymph node?

It can present as localized edema of the limb
It is associated with HHV8 infection
It is considered a premalignant lesion
It stains for HMB45

Board review style answer #2

A. It can present as localized edema of the limb. Angiomyomatous hamartoma may be found incidentally or may present with pain or localized edema. It can be present in any location but has a predilection for the inguinal and femoral lymph nodes. Answer C is incorrect because this entity is a benign hamartoma that consists of proliferation of smooth muscles and blood vessels. Answers B and D are incorrect because there is no known association with HHV8 or melanocytic immunostain markers.

Comment Here

Reference: Angiomyomatous hamartoma

Anthracosis

Table of Contents

Definition / general

Accumulation of carbon in lymph nodes, more commonly in intrapulmonary lymph nodes, due to coal dust, smoke or pollution
May be associated with storiform pattern of histiocytes that resembles a neoplasm (Hum Pathol 1998;29:851)
Associated with silica, although often no history of industrial exposure
Associated with hyalinization in nodes of elderly Japanese (Histol Histopathol 2003;18:1169)

Epidemiology

Very common

Sites

Common in hilar and bronchial lymph nodes

Clinical features

Enlargement of involved lymph nodes, prominent mediastinal lymphadenopathy is common

Radiology description

Enlarged lymph nodes, especially mediastinal and bronchial lymph nodes

Radiology images

Images hosted on other servers:

Apical lung lesion

Increased uptake in left upper lobe

FDG PET/CT scan shows
high-grade metabolic activity
in right hilar soft tissue lesion

Prognostic factors

Benign process with no significant clinical implications

Case reports

71 year old woman, with life-long exposure to soot from a wood cook stove, with anthracosis and large mediastinal mass with healed pulmonary tuberculosis (Clin Med Res 2010;8:99)
Women who cooked over wood fires, with primary nodal anthracosis identified as a cause of FDG PET/CT positive mediastinal lymphadenopathy (Respiratory Medicine Case Reports 2013;10:48)
A case of anthracosis presenting with mediastinal lymph nodes mimicking tuberculous lymphadenitis or malignancy (Eur J Intern Med 2003;14:444)

Treatment

If significant enlargement, excision biopsy

Gross description

Enlarged lymph nodes with firm dark brown to black cut surfaces

Microscopic (histologic) description

Anthracotic macrophages in clusters and singly dispersed
There may be storiform arrangement of spindle cells or granuloma like aggregates of macrophages
Fine anthracotic pigment
Also nodal hyaline scars and polarizable material suggestive of silica

Cytology description

Cellular smears with a population of anthracotic macrophages that are both singly dispersed and in variously sized aggregates
Variable foreign body type, multinucleated giant cells
No necrosis or atypical cells

Cytology images

Images hosted on other servers:

Abundant anthracotic pigment

Positive stains

CD68 (macrophages containing pigment)

Differential diagnosis

Clinically resembles malignancy: lymphoma, metastasis
Follicular dendritic cell tumor
Kaposi sarcoma
MFH
Sarcoidosis
Spindle cell melanoma
Tuberculosis

Additional references

J Korean Med Sci 2013;28:550, Ann Nucl Med Sci 2004;17:105, AJR Am J Roentgenol 2000;174:523

B & T cells

Table of Contents

Definition / general

B cells:

Progressive maturation of hematopoietic stem cells through several stages to ultimately give rise to mature B cell pool that has been selected for reactivity against non-self antigens (Expert Rev Clin Immunol 2010;6:765)
Develop from stem cells of yolk sac, fetal liver, spleen and bone marrow
B cells complete most of their development within the bone marrow, in contrast to T cells that mature within the thymus
In intersinusoidal bone marrow, hematopoietic stem cells mature to early lymphoid progenitors, the pro B, pre B stages
Developmental stages are in close contact with slender CD10+ stromal cells or their extensions, which allows tightly regulated signaling (J Pathol 2005;205:311)
Earliest stem cells are in subendosteum, adjacent to inner bone surface; with maturation, B lineage cells move towards central axis of marrow; final stages of development of immature B cells occur in peripheral lymphoid organs (spleen, lymph nodes)

T cells:

Develop from bone marrow, become prothymocytes, then migrate to thymus gland, where self recognizing T cells are eliminated

Pathophysiology

B cells:

B cells express surface immunoglobulin (Ig), composed of 2 heavy (H) and 2 light (L) chains (either kappa or lambda)
B cell antigen receptor loci may have 4 types of modification: (a) recombination of variable, diversity and joining regions (VDJ); (b) somatic hypermutation of V segments; (c) immunoglobulin heavy chain gene class switching; and (d) receptor editing
Early B cell precursor is TdT+, CD34+, HLA-DR+, then undergoes heavy (H) chain rearrangement and adds CD19, then adds CD10, then adds IgM heavy chain; then adds light (L) chain rearrangement and adds cytoplasmic IgM with heavy and light chains, then B cells express IgM and IgD with the same binding site, then adds CD20 (now called pre B cell); then adds surface Ig, then adds CD21 and CD22 and drops TdT (now called B cell)
If B cell encounters an antigen that interacts with its variable region, it becomes a plasma cell
Precursor B cells contain immunoglobulin related components but not immunoglobulin; express CD179a and CD179b (precursor to light chains) as part of their pre B cell receptor, which disappears when replaced with conventional light chains
B cells express surface immunoglobulin, consisting of 2 heavy chains and 2 light chains (kappa or lambda); immunoglobulin is associated with CD79a / CD79b complex to form a B cell antigen receptor complex
IgH gene (heavy chain of immunoglobulin) is at 14q32; variable portion is coded by VDJ regions
IgL gene (light chain of immunoglobulin): kappa is at 2p11, lambda is at 22q11; no diversity region is present
Heavy chain isotype switch: determines if immunoglobulin is IgM, IgD, IgG1-4, IgA1-2 or IgE (9 constant regions); mediated by switch genes

T cells:

T cell receptors (TCR) are either alpha / beta (95%) or gamma / delta (5%) heterodimers
T cell progenitors migrate to the thymus and undertake a highly ordered developmental program, regulated by signals derived from microenvironment
Most immature thymocytes are CD4- / CD8- ("double negative" / DN); DN is divided into 4 stages based on CD44 / CD25 expression: DN1 is CD44+, CD25-; DN2 is CD44+, CD25+; DN3 is CD44-, CD25+; DN4 is CD44-, CD25- (Immunol Res 2010;47:45)
Precursor cell is TdT+, CD34+, HLA-DR+, then drops HLA-DR, then adds CD2, CD5, CD7 (early thymocyte) while undergoing gamma / beta chain rearrangement, then adds CD1 and drops CD34, now a common thymocyte (CD4-, CD8-, "double negative"), then undergoes beta / alpha chain rearrangement (DN3 stage) and adds CD4 and CD8, then splits into helper (CD4) or cytotoxic (CD8) T cell ("single positive") with CD2 and CD3, and without TdT, CD1, CD5 and CD7
T alpha and delta genes are on 14q11; T beta gene is on 7q34; T gamma gene is on 7p15
Note: T cells and NK cells arise from common progenitor that expresses CD3 epsilon and cannot develop into B cells

Diagrams / tables

AFIP images

B cell biomarker expression during development

T cell biomarker expression during development

Images hosted on other servers:

B cell development

B cell response to antigen

B cell biomarker expression during development

Microenvironmental
niches in the bone
marrow required for
B cell development

T cell activation

T cell development

Clinical features

B cells:

B cell lymphomas: a clonal light chain rearrangement is usually specific for the presence of a B cell neoplasm
X linked agammaglobulinemia: no B cell development

T cells:

Defects in receiving T cell signals can cause hyper IgM syndrome (J Allergy Clin Immunol 2010;125:778)
90% of peripheral T cell lymphomas have rearrangements of T alpha, beta and gamma, including all cases of mycosis fungoides and Sezary syndrome
T cell lymphomas have no distinct marker of clonality, but cells may express an abnormal immunophenotype or TCR gene rearrangement
As there are only 10 V (variable) regions, a polyclonal population of cells can appear oligoclonal
T cell clonality is seen in AIDS and congenital immunodeficiency syndromes, but does NOT indicate malignancy
Rarely a clonal band may comigrate with the germline band; solution: use 2 - 3 restriction enzymes (HindIII, EcoRI, BamHI)

Positive stains

B cells: varies by developmental state, but typically CD19, CD20, CD79a
T cells: CD2, CD3, CD4 or CD8

Negative stains

B cells: CD2, CD3, CD4, CD8
T cells: CD19, CD20

Additional references

Wikipedia: B cell [Accessed 3 October 2018]

Castleman disease

Table of Contents

Definition / general

Unusual heterogeneous group of lymphoproliferative disorders with some common morphological features involving lymph nodes or extranodal sites
3 histological types: hyaline vascular variant (HVCD), plasma cell variant (PCCD) and mixed hyaline vascular and plasma cell variant
3 distinct clinical entities:
1. Unicentric Castleman disease (UCD): localized, stable and exhibiting hyaline vascular morphology (Cancer 1972;29:670)
2. Multicentric Castleman disease (MCD): a systemic progressive disease with lymphadenopathy of multiple sites (Cancer 1985;56:2446)
  - MCD is divided into idiopathic (iMCD) and human herpesvirus 8 associated (HHV8 MCD) (Blood 1995;86:1276)
  - Histologically, most cases show features of plasma cell variant
3. Oligocentric or regional Castleman disease: with involvement of 2 or 3 adjacent lymph node regions and clinical course like UCD (Blood Adv 2020;4:6039)

Essential features

Unusual heterogeneous group of lymphoproliferative disorders with some common morphological features involving lymph nodes or extranodal sites
3 distinct clinical entities: unicentric Castleman disease (UCD), multicentric Castleman disease (MCD) and oligocentric or regional Castleman disease
- MCD is divided into idiopathic (iMCD) and human herpesvirus 8 associated (HHV8 MCD)
3 histological types: hyaline vascular variant (HVCD), plasma cell variant (PCCD) and mixed hyaline vascular and plasma cell variant
Clinical syndromes associated with MCD POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein spike, skin changes) and MCD TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, organomegaly)
Castleman disease can show predisposition to certain neoplasms

Terminology

Angiofollicular hyperplasia
Giant lymph node hyperplasia
Unicentric Castleman disease (UCD)
Multicentric Castleman disease (MCD)
- Idiopathic (iMCD)
- Human herpesvirus 8 associated (HHV8 MCD)
  - Alternative / older terminology: Kaposi sarcoma herpesvirus associated (KSHV MCD)
Hyaline vascular type (HVCD)
Plasma cell type (PCCD)
MCD POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein spike, skin changes)
MCD TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, organomegaly)

ICD coding

ICD-10: D47. Z2 - Castleman disease

Epidemiology

UCD can affect all age groups and shows no gender difference with the median age of onset in the fourth decade (Hematol Oncol Clin North Am 2018;32:1)
MCD affects patients of all ages with a median age of onset in the fifth to seventh decades
HHV8 MCD affects mainly HIV positive individuals; however, individuals who are immunocompromised from other causes can also be affected (Leuk Lymphoma 2015;56:1252)
HHV8 MCD in individuals who are HIV negative accounts for 2 - 50% of cases and this variation depends on the prevalence of HHV8 in the region (Blood 2020;135:1353)
With the introduction of antiretroviral therapy (ART), the incidence of HHV8 MCD has increased
- Complex interplay between HIV and HHV8 and immune dysregulation of patients with HIV controlled by ART is thought to cause this increased incidence (Ann Oncol 2009;20:775)
UCD is more common in childhood (75%) than iMCD and only rare cases of HHV8 MCD are reported in children (Pediatrics 2012;129:e199, Pediatr Blood Cancer 2019;66:e27613)

Sites

UCD most commonly affects mediastinum; extrathoracic sites are also involved
- Presents as a solitary lymph node mass
MCD affects multiple lymph node sites, predominantly in the cervical region
Reference: Surg Pathol Clin 2019;12:849

Pathophysiology

Etiopathogenesis remains not well known
UCD
- Recent evidence suggests that UCD may be a neoplastic process involving follicular dendritic cells (Mod Pathol 2014;27:823)
- Among UCD patients, 17% have shown to harbor mutations in the gene PDGFRB encoding platelet receptor growth factor β (Leukemia 2019;33:1035)
iMCD
- iMCD is proposed to involve autoinflammatory or autoimmune diseases, paraneoplastic syndromes or an unidentified viral infection leading to polyclonal lymphoproliferation and hypercytokinemia (Blood 2014;123:2924)
- Current concept is that a cytokine storm due to increased production of IL6 is associated with Castleman disease since patients have elevated levels of IL6 and symptoms improve with IL6 suppression (N Engl J Med 2020;383:2255)
- VEGF, IL1, IL2, CXCL13 and TNF have also been shown to play a role in the pathogenesis of iMCD (Blood 1994;83:2587, Br J Haematol 1999;104:482, Am J Hematol 2018;93:902)
- T cell activation, and activation of mTOR, JAK / STAT3 and type I interferon signaling pathways also thought to be pathogenetic mechanisms (J Clin Invest 2019;129:4451, Blood 2020;135:1673)
HHV8 MCD
- HHV8 MCD occurs in HIV positive or negative individuals infected with HHV8 (Blood 2001;97:2130)
- HHV8 infected B cells in the mantle zones show expression of IgM lambda immunogobulins
  - This is by the loss of Ig kappa due to the upregulation of V(D)J recombination mediated by RAG protein and Ig lambda expression by B lymphocytes with HHV8 infection (PLoS Pathog 2018;14:e1006967)
- HHV8 encodes several viral genes; the resulting viral proteins and microRNAs stimulate cell growth, proliferation and cell survival among the infected cells, as well as among the neighboring cells by a paracrine mechanism (J Clin Invest 2016;126:3165)
- HHV8 viral lytic protein expression is proposed to be the contributing pathobiological factor of HHV8 MCD (Am J Pathol 2000;156:743)
- High viral load in patients with HHV8 MCD suggests active viral replication (Blood 2000;96:2069)
- HHV8 viral protein vIL6 is expressed in high levels in plasmablasts surrounding lymphoid follicles (J Virol 1999;73:4181)
- Additionally, human cytokines are elevated in patients with HHV8 MCD, which is thought to be driven by the virus (Blood 2013;122:4189)
- Inflammatory cytokines like hIL6 and vIL6 cause anemia, fever and hypoalbuminemia (Blood 2013;122:4189)

Etiology

UCD: etiology is unclear
iMCD: etiology is unclear
HHV8 MCD: HHV8 infected endothelial cell proliferation and vascularization

Clinical features

UCD: asymptomatic or an enlarging lymph node or mass; secondary symptoms related to the mass (compression or pain) (Blood 2020;135:1353)
MCD: all subtypes of MCD show systemic inflammatory manifestations including fever, weight loss, anasarca, generalized lymphadenopathy and hepatomegaly
- Anemia, hypoalbuminemia, cytopenias and elevated inflammatory markers are common (Blood Adv 2021;5:1660)
MCD POEMS: a syndrome characterized by peripheral neuropathy, organomegaly, skin changes and monoclonal paraproteins occurs in some patients with MCD (Blood 1994;83:2587)
MCD TAFRO: another syndrome characterized by thrombocytopenia, ascites, fever, reticulin fibrosis and organomegaly usually in patients with normal immunoglobulin levels and mixed or hyaline vascular histology (Sci Rep 2017;7:42316)
iMCD, NOS: shows elevated platelet counts and immunoglobulin levels and plasmacytic histology (Blood 2020;135:1353)

Diagnosis

Excisional biopsy of an affected lymph node with histopathological examination is the diagnostic modality of choice
18F fluorodeoxyglucose positron emission tomography (FDG PET) is used to exclude alternative diagnoses; also used to select the lymph node for biopsy (J Infect Dis 2015;212:1250)
HHV8 MCD requires the pathologic features and HHV8 positivity
iMCD is confirmed by integration of pathological findings and clinical syndrome; a diagnosis of iMCD requires exclusion of infectious, malignant and autoimmune disorders that can mimic iMCD (Blood 2017;129:1646)

Laboratory

UCD: usually no laboratory abnormalities
MCD subtypes: anemia, hypoalbuminemia, renal dysfunction and liver dysfunction, dysregulation of IL6 (increased) or other cytokines like VEGF, IL1 and TNFα (Nat Rev Dis Primers 2021;7:84)
MCD TAFRO: thrombocytopenia (Hematol Oncol Clin North Am 2018;32:37)

Radiology description

MCD: 18F FDG PET / CT shows increased uptake in the affected lymph nodes
- Lymph nodes are nonconfluent with a symmetric pattern and SUV ranging from 2 - 19
- Extramedullary involvement is demonstrated as pulmonary cysts, nodules and interstitial lung disease, hypermetabolic activity in spleen and bone marrow (Nucl Med Commun 2021;42:833)

Radiology images

Images hosted on other servers:

18F FDG PET / CT, HHV8 MCD

Prognostic factors

UCD: localized and excellent response to therapy
MCD: poorer prognosis, especially HIV positive patients and patients with MCD POEMS (Surg Pathol Clin 2019;12:849)
Predilection for association with neoplasms (Surg Pathol Clin 2019;12:849, Blood 2020;135:1353, Indian J Pathol Microbiol 2021;64:302, Infection 2021;49:945)
- HVCD
  - Follicular dendritic cell sarcoma
  - Vascular tumors
- HHV8 MCD
  - Kaposi sarcoma
  - HHV8+ large B cell lymphoma
  - Primary effusion lymphoma
- iMCD
  - Classic Hodgkin lymphoma
  - Diffuse large B cell lymphoma
  - Mantle cell lymphoma
  - Peripheral T cell lymphoma
Other
- HVCD can develop indolent T lymphoblastic proliferations

Case reports

26 year old woman with Castleman disease with AA amyloidosis (Medicine (Baltimore) 2020;99:e18978)
26 year old pregnant woman with Castleman disease and pemphigus (Medicine (Baltimore) 2021;100:e24990)
32 and 43 year old women with Castleman disease with spondyloarthritis treated with TNF alpha antagonist (Joint Bone Spine 2020;87:655)
35 year old woman with glycolytic hypermetabolism in Castleman disease by 18F FDG PET / CT (Clin Nucl Med 2020;45:868)
52 year old man with Castleman disease presenting as a chylous pleural effusion (Pathol Res Pract 2020;216:153209)
53 year old man with retroperitoneal mass (Int J Surg Case Rep 2020;70:24)
60 year old man with a hepatic mass and autoimmunity (Cancer Imaging 2019;19:53)
62 year old man with hypermetabolic mass of kidney (Clin Nucl Med 2021;46:510)
64 year old woman with multicentric Castleman disease and cryoglobulinemic vasculitis (J Dermatol 2021;48:e474)
82 year old woman with Castleman disease and eosinophilic dermatosis (Int J Dermatol 2020;59:e416)

Treatment

UCD
- Asymptomatic patients: expectant management and follow up for disease progression; resection
- Symptomatic patients: complete surgical resection (Br J Haematol 2021;195:328)
- Unresectable symptomatic UCD: volume reduction by debulking resection, embolization or cryoablation of feeding vessels, rituximab, steroids and radiation therapy and follow up evaluation is recommended to determine the possibility of complete resection (Br J Haematol 2021;195:328, Eur J Haematol 2021;107:484)
MCD
- Asymptomatic patients: no therapeutic intervention but follow up is needed to detect disease progression
- Symptomatic patients: depending on the presentation and disease driver (Br J Haematol 2021;195:328)
  - HHV8 MCD
    - Antiretroviral therapy with HHV8 MCD specific therapy
    - Cytotoxic chemotherapies are used: etoposide, vincristine, vinblastine, cyclophosphamide and liposomal doxorubicin
    - Chemotherapy is used in combination with rituximab
    - Antiherpesvirus therapy: gancyclovir, zidovudine, valganciclovir, pomalidomide
    - Anti-hIL6 therapy: siltuximab and tocilizumab are under trial (Br J Haematol 2021;195:328)
  - MCD POEMS
    - Therapy for the plasma cell dyscrasia: consolidation with autologous stem cell transplant
    - Patients without clonal plasmacytosis in bone marrow: radiation therapy
    - Patients with disseminated bone marrow involvement: systemic chemotherapy followed by adjuvant radiation; melphalan and dexamethasone, cyclophosphamide dexamethasone, lenalidomide, thalidomide and bortezomib
    - Daratumumab, BCMA CAR-T, bevacizumab (anti-VEGF), interferon alpha, tamoxifen, transretinoic acid, ticlopidine, argatroban and strontium 89 are also used in rare cases
  - iMCD
    - Surgery, steroids, rituximab, combination chemotherapy (CHOP [cyclophosphamide, doxorubicin, vincristine (Oncovin), prednisolone] or CVAD [cyclophosphamide, vincristine, adriamycin, etoposide]-like regimens and VDTPACE [Velcade (bortezomib), dexamethasone, thalidomide, cisplatinum, adriamycin, cyclophosphamide, etoposide]), autologous stem cell transplantation, anti-IL6 monoclonal antibodies (siltuximab and tocilizumab), bortezomib, thalidomide, anakinra (IL1 antagonist), interferon alpha and all transretinoic acid are used (Hematol Oncol Clin North Am 2018;32:89, Blood 2018;132:2115)
  - MCD TAFRO
    - Corticosteroids, rituximab, tocilizumab, cyclosporin A
    - Thrombocytopenia: romiplostim and eltrombopag
    - Other options: plasma exchange, high dose cyclophosphamide, thalidomide, lenalidomide, bortezomib rapamycin and combination chemotherapy such as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) (Ann Hematol 2022;101:485, Int J Hematol 2016;103:686)

Gross description

UCD: enlarged lymph node, firm and white cut surface with or without calcification

Microscopic (histologic) description

HVCD is characterized by prominent vascular proliferation and hyalinization of the vessel walls
- There are follicular changes and interfollicular / stromal changes described; based on the predominance of changes in each of these sites divided into follicular HVCD and stroma rich Castleman disease (Virchows Arch A Pathol Anat Histopathol 1993;423:369)
- Atretic germinal centers traversed by sclerotic penetrating vessels and hyalinization - lollipop follicles
- Mantle zones are thickened with lymphocytes arranged in layers - onion skin appearance
- Mantle zones may fuse and contain more than 1 germinal center - twinning
- Follicular dendritic cells may show proliferation and dysplastic features
- In the interfollicular areas, there is usually extensive vascular proliferation of high endothelial venules with perivascular hyalinization
- Clusters of plasmacytoid dendritic cells may be seen (Hum Pathol 2013;44:1003)
- Plasma cells, immunoblasts and eosinophils are seen in the interfollicular areas but no sheets of plasma cells
- Unapparent sinuses and obliteration of the subcapsular sinuses commonly seen
- Capsular thickening
UCD - plasma cell type: rare (< 10% of UCDs) and MCD needs to be excluded (Surg Pathol Clin 2019;12:849)
- Interfollicular areas and medulla containing sheets of small, mature plasma cells
- Hyperplastic follicles and a subset of the follicles with hyaline vascular features
MCD can be hyaline vascular (rare < 10%) or plasmacytic but usually shows a mix of histological features of both plasma cell and hyaline vascular Castleman disease (Blood 2017;129:1658, Blood 2017;129:1646)
- Hypervascular without dysplastic follicular dendritic cells or sclerotic vessels
- Diffuse plasma cell proliferation, germinal center hyperplasia, some follicles may show hyaline vascular changes and patent sinuses
HHV8 MCD (Am J Surg Pathol 2003;27:91)
- Plasmacytic
- HHV8 infected cells in the mantle zones show plasmablastic or immunoblastic morphology with large nuclei, vesicular chromatin and prominent nucleoli and lambda light chain restriction
- Polyclonal plasmacytosis
TAFRO (Hematol Oncol Clin North Am 2018;32:37)
- Mixed hyaline vascular and plasmacytic
- Lymph nodes: hypervascular
- Bone marrow: reticulin fibrosis, megakaryocytic hyperplasia and emperipolesis

Microscopic (histologic) images

Contributed by Jayalakshmi Balakrishna, M.D., Amy Duffield, M.D., Ph.D., Tapan Bhavsar, M.D., Ph.D.,
Carlos Murga-Zamalloa, M.D. and Jackie D. Sublett II, M.D.

Hyaline vascular Castleman disease (HVCD)

Atretic follicles, interfollicular vascular proliferation

Atretic follicles, interfollicular vascular proliferation

Atretic germinal center

Twinning of germinal center

Twinning of germinal center, thickened mantle zones

Lollipop follicle, thickened mantle zones

Twinning of
germinal centers,
sclerosed
vessels

Thickened mantle zones

Sclerosed vessels

Vascular proliferation

Lollipop follicle

Atretic follicle

Proliferation of T lymphoblasts

Onion skin pattern

Twinning of germinal center, CD23

Interfollicular areas rich in T cells, CD3

Follicles and atretic germinal centers, CD20

Proliferation of TdT+ cells

Vascular proliferation, CD34

Interfollicular areas rich in T cells, CD5

Follicular dendritic cell meshworks, CD21

Low proliferation rate in interfollicular areas

Germinal centers, BCL6+

Plasma cells, CD138

Plasma cell Castleman disease (PCCD)

Aggregates of plasma cells

T cells in interfollicular areas, CD3

Atretic follicles, CD20

Aggregates of plasma cells, CD138

Vascular proliferation, ERG

Human herpesvirus 8 associated multicentric Castleman disease (HHV8 MCD)

Aggregates of plasma cells

Atretic follicle, interfollicular plasma cell proliferation

Kaposi sarcoma in a case of HHV8 MCD

Kaposi sarcoma in a case of HHV8 MCD, HHV8

Kaposi sarcoma in a case of HHV8 MCD, MUM1

HHV8+ cells

Lambda light chain predominance in plasma cells

Lambda light chain predominance in plasma cells

Increased proliferation in interfollicular areas, Ki67

Virtual slides

Contributed by Genevieve M. Crane, M.D., Ph.D.

Hyaline vascular Castleman

HHV8+ multicentric Castleman

Images hosted on other servers:

HVCD

Positive stains

HVCD (Surg Pathol Clin 2019;12:849)
- Concentric rings of follicular dendritic cells: CD21, CD23, CD35, EGFR, VCAM1 / CD106
- Germinal centers show remaining cells: CD10 and BCL6
- Expanded mantle zones: polytypic light chains, CD19, CD20, IgD and BCL2
- Plasmacytoid dendritic cells: CD68, CD123 and TCL1
PCCD (Histopathology 1989;14:333)
- Clusters of plasma cells in the interfollicular areas: CD138, polytypic light chains
HHV8 MCD (Hum Pathol 2001;32:95, PLoS Pathog 2018;14:e1006967)
- HHV8-LANA1, viral IL6, lambda light chain, cytoplasmic IgM, OCT2, BLIMP1 and IRF4 / MUM1

Negative stains

HVCD
- IL6, EBV, HHV8
- Germinal centers show remaining cells: BCL2
- Expanded mantle zones: CD10 and BCL6
HHV8 MCD
- HHV8 positive cells: PAX5, BCL6 and CD138
Reference: Surg Pathol Clin 2019;12:849

Flow cytometry description

Serum concentrations of IL2, IL4, IL6, IL10, TNFα and IFNγ cytokines can be evaluated by flow cytometry (J Med Virol 2021;93:4033)

Molecular / cytogenetics description

HVCD
- Subset of cases shows clonal cytogenetic abnormalities: t(1;16)(p11;p11), t(1;22)(p22;q13) and t(7;8)(qter;q12) (Am J Surg Pathol 2000;24:882)
- In about 75% of cases studied HUMARA gene assays show monoclonal pattern (loss of heterozygosity) (Mod Pathol 2014;27:823)
MCD
- Monoclonal IGH rearrangement in subset of cases (more common in HIV positive patients with HHV8 infection) (Am J Pathol 1988;131:84)
- B and T lymphocytes in Castleman disease are usually polyclonal (Histopathology 2006;48:233)

Sample pathology report

Lymph node, left axillary, excisional biopsy:
- Kaposi sarcoma and HHV8 positive multicentric Castleman disease (see comment and report)
- Comment: The patient has a history of HIV / AIDS and presents with generalized lymphadenopathy and fever. The lymph node shows morphologic features consistent with plasma cell type Castleman disease and focal involvement by Kaposi sarcoma. Flow cytometry shows no evidence of an immunophenotypically abnormal lymphocyte or plasma cell population and molecular analysis to evaluate presence of clonal B cell population is negative ruling out B cell lymphoma and plasma cell neoplasm.

Differential diagnosis

Systemic lupus erythematosus:
- Follicular hyperplasia, interfollicular expansion of lymphocytes and immunoblasts, and numerous plasma cells within germinal centers and medullary cords
- Coagulative necrosis with abundant karyorrhectic debris and histiocytes
- Hematoxylin bodies
- Serological diagnosis of systemic lupus erythematosus
Rheumatoid arthritis:
- Can resemble HVCD or PCCD
- Follicular hyperplasia, interfollicular and intrafollicular plasmacytosis and neutrophils within sinuses
- Lacks thickened mantle zones, twinning of germinal centers and piercing vessels
- Clinical and serological diagnosis of autoimmune disease
Hemophagocytic lymphohistiocytosis:
- Proliferation of benign histiocytes in the sinuses
- Lymphocyte depletion may be seen
- Phagocytosed red cells or white cells
Adult onset Still disease (Medicine (Baltimore) 2015;94:e787):
- Paracortical hyperplasia or mixed follicular and paracortical hyperplasia
- Vascular proliferation and immunoblasts
- Pericapsular endarteritis
- Clinical and serologic diagnosis of adult onset Still disease
IgG4 disease (Semin Diagn Pathol 2012;29:226):
- Fibroinflammatory disorder with dense lymphoplasmacytic infiltrates containing numerous IgG4+ plasma cells
- 5 different histological patterns - type resemble MCD
- Hyperplastic and regressed follicles, some with penetrating vessels
- Interfollicular areas with numerous plasma cells
- Serological diagnosis
Follicular dendritic cell sarcoma:
- Storiform or whorled bundles of spindle cells with interspersed small lymphocytes
- Positive for follicular dendritic cell markers: CD21, CD23 and CD35
Plasma cell neoplasm:
- Monoclonal plasma cells
HIV associated lymphadenitis:
- Clinical and serological diagnosis of HIV infection
Angioimmunoblastic T cell lymphoma, early stages:
- May resemble HVCD
- Loss of architecture and expanded follicular dendritic cell meshworks
- Atypical T cells: CD10, BCL6 and PD-1 positive
- Monoclonal T cell gene rearrangements
Follicular lymphoma:
- Atypical follicles of low grade follicular lymphoma can mimic HVCD
- Atypical lymphocytes CD10, BCL6 and BCL2 positive
- Clonal B cell population
- BCL2::IGH translocation
Mantle cell lymphoma:
- Mantle zone pattern may mimic HVCD
- Atypical lymphocytes, CD5 and cyclin D1 or SOX11 positive
- Clonal B cell population
- CCND1::IGH translocation
Reactive lymph node enlargement:
- Lack characteristic histological features of CD
- Can show different histological patterns: follicular hyperplasia, sinus histiocytosis, interfollicular / mixed and diffuse patterns

Additional references

Semin Diagn Pathol 2016;33:294, Cancer Control 2014;21:266, Med Oncol 2010;27:1171, Am J Hematol 2017;92:814, Jaffe: Hematopathology, 2nd Edition, 2017, Medeiros: Ioachim's Lymph Node Pathology, 5th Edition, 2021

Board review style question #1

What is the histopathological feature seen in this lymph node?

Dysplastic dendritic cells
Immunoblasts
Plasma cell infiltrates
Twinning of germinal centers

Board review style answer #1

D. Twinning of germinal centers. The features of hyaline vascular Castleman disease are atrophic follicles, penetrating vessels, onion skinning of mantle zones, twinning of germinal centers and hyalinized vessels.

Comment Here

Reference: Castleman disease

Board review style question #2

Which of these lymphomas occurs in the background of human herpesvirus 8 associated multicentric Castleman disease (HHV8 MCD)?

Burkitt lymphoma
EBV positive diffuse large B cell lymphoma, NOS
Follicular lymphoma
HHV8 positive large B cell lymphoma

Board review style answer #2

D. HHV8 positive large B cell lymphoma is known to occur in a background of HHV8 MCD. Other neoplasms occur in this setting are Kaposi sarcoma and primary effusion lymphoma.

Comment Here

Reference: Castleman disease

Cat scratch disease

Table of Contents

Definition / general

Majority of cases are caused by Bartonella henselae acquired via arthropod vector (cat flea) or inoculation by cat scratch (Pediatr Infect Dis J 2021;40:S11)
Cutaneous red papule 3 - 10 days after contact that may become crusted or pustular, with subsequent development of regional lymphadenopathy 1 - 2 weeks later
Histology is characterized by necrotizing stellate abscesses surrounded by palisading histiocytes
Usually resolves spontaneously; rare cases may require treatment with antimicrobial therapy

Essential features

Typically self limited lymphadenitis caused by Bartonella henselae and transmitted by cats
Cutaneous lesion followed by usually localized lymphadenopathy
Lymph node histopathology characterized by necrotizing stellate abscesses surrounded by palisading histiocytes
Organism stains with Warthin-Starry or specific immunohistochemistry; confirmation by serology or PCR

ICD coding

ICD-10: A28.1 - cat scratch disease

Epidemiology

Adults or children can be affected but the highest incidence is in children 14 and under (Emerg Infect Dis 2016;22:1741)
Considered the most common cause of benign lymphadenopathy in young people (Ocul Immunol Inflamm 2014;22:148)
Estimated annual incidence of 4.7/100,000 population (Emerg Infect Dis 2016;22:1741)
Incidence is higher in the southern United States and in the winter (thought to possibly be due to holiday adoption of kittens) (Emerg Infect Dis 2016;22:1741)

Sites

Skin: cutaneous red papule or wheal that may become crusted or pustular
Lymph nodes, most commonly upper extremity, followed by cervical and inguinal; patients may have involvement of 1 or multiple lymph node sites (Pediatr Infect Dis J 2021;40:S11)
Liver, spleen or bone
Rarely, CNS, eye, hematologic involvement / complications (Eur J Intern Med 2005;16:610)
Parinaud oculoglandular syndrome: follicular conjunctivitis and regional lymphadenopathy, possibly caused by direct conjunctival inoculation (Ocul Immunol Inflamm 2014;22:148)

Etiology

Majority of cases are caused by Bartonella henselae, harbored by kittens and young cats; transmitted between cats by the cat flea (Am J Clin Pathol 1994;101:607)
Up to 100% of cat fleas harbor Bartonella and it can also often be detected in cat saliva, blood, skin, claws and feces
Most important risk factors are owning a kitten and being bitten, scratched or licked by a kitten harboring fleas; however, up to 25% of patients with cat scratch disease do not report contact with cats

Diagrams / tables

Images hosted on other servers:

Algorithm for cat scratch disease diagnosis

Clinical features

Cutaneous nonpruritic red papule: 3 - 10 days after contact that may become crusted or pustular (Ocul Immunol Inflamm 2014;22:148)
Lymphadenopathy, often of cervical or axillary nodes, develops in 1 - 2 weeks; lymphadenopathy is essentially universal but 85% have involvement of only a single node
May have necrotizing granulomas in liver, spleen or bone
Fever and constitutional symptoms may be present (Am J Dis Child 1985;139:1124)
Rare complications in ~10%, including granulomatous conjunctivitis, thrombocytopenic purpura, CNS disease (Eur J Intern Med 2005;16:610, Infect Dis Clin North Am 1987;1:575, Am Fam Physician 2011;83:152)

Diagnosis

PCR (J Clin Microbiol 2005;43:3800)
Serology or immunofluorescence (Clin Diagn Lab Immunol 2003;10:686)
Culture is not practical, as Bartonella are fastidious organisms that are difficult to culture (Pediatr Infect Dis J 2021;40:S11)

Radiology description

Regional lymphadenopathy
Liver and spleen granulomas

Prognostic factors

Self limited disease in most; may take 2 - 6 months for lymphadenopathy to regress (Infect Dis Clin North Am 1987;1:575)
Immunocompromised patients may present with disseminated disease or other diseases / syndromes associated with Bartonella, such as bacillary angiomatosis (BMJ Case Rep 2021;14:e239932, Am J Clin Pathol 2004;121:S71, Eur J Clin Microbiol Infect Dis 2021 Apr 12 [Epub ahead of print])

Case reports

16 year old boy with tender cervical lymphadenopathy (Arch Pathol Lab Med 2005;129:1065)
32 year old HIV infected woman with B. quintana and M. tuberculosis coinfection (J Infect 2003;46:244)
53 year old man with cat scratch disease encephalopathy (BMJ Case Rep 2018;2018:bcr2017223647)
59 year old heart transplant patient with disseminated cat scratch disease (Transpl Infect Dis 2017;19)

Treatment

Treatment neither required nor recommended for immunocompetent patients / uncomplicated disease (Antimicrob Agents Chemother 2004;48:1921)
Antibiotics (doxycycline, rifampin) could be considered if disseminated or complicated disease (Antimicrob Agents Chemother 2004;48:1921, Pediatr Infect Dis J 2021;40:S11)

Clinical images

Images hosted on other servers:

Retroauricular lymph node enlargement

Cervical lymphadenopathy and primary lesion

Microscopic (histologic) description

Early: histiocytes and follicular hyperplasia, microabscesses localized adjacent to the thickened capsule (Am J Clin Pathol 2004;121:S71)
Intermediate: capsulitis and subcapsular granulomas
Late: necrosis and abscesses, often stellate, surrounded by palisading histiocytes (Int J Dermatol 1978;17:656)
Paracortical vascular proliferation (Am J Clin Pathol 2004;121:S71)
Sinuses are often packed with monocytoid B cells but no epithelioid cells are present (Am J Clin Pathol 2004;121:S71)
Small rods may be present with silver stain around small blood vessels and lymphatics; most readily identified early in disease (Science 1983;221:1403, Am J Clin Pathol 2004;121:S71)
Skin shows dermal necrosis surrounded by histiocytes
Also multinucleated giant cells, lymphocytes and eosinophils
References: Calif Med 1955;82:25, Am Fam Physician 2011;83:152

Microscopic (histologic) images

Contributed by Elizabeth Courville, M.D. and Mark R. Wick, M.D.

Suppurative granulomas

Palisading histiocytes

Lymph node biopsy

Steiner stain

Cytology description

Similar to histologic features (granulomas, epithelioid histiocytes, neutrophils, necrosis, polymorphous lymphocytes) (Acta Cytol 1985;29:542, Diagn Cytopathol 1996;15:108)

Positive stains

Warthin-Starry or other silver stains
B. henslae immunohistochemistry (Am J Clin Pathol 2009;131:250)
Combined use of Warthin-Starry and IHC may yield higher sensitivity than either alone (Appl Immunohistochem Mol Morphol 2020;28:781)

Negative stains

Gram stain has limited utility, as Bartonella usually does not stain well (Am J Clin Pathol 2009;131:250)

Electron microscopy description

Extracellular bacteria form small groups within bundles of collagen fibrils
Bacteria are gram negative pleomorphic rods, with thick and homogeneous cell walls (Am J Clin Pathol 1987;87:739)

Molecular / cytogenetics description

Causative organism may be detected by PCR (J Clin Microbiol 2005;43:3800)

Sample pathology report

Cervical lymph node, excision:
- Necrotizing granulomatous lymphadenitis (see comment)
- Comment: The lymph node architecture is distorted by frequent stellate necrotizing granulomas with occasional multinucleated giant cells. Bacterial structures are identified by both Warthin-Starry stain and immunohistochemistry for B. henselae. The overall features are in keeping with cat scratch lymphadenitis, a condition that is generally self limited in immunocompentent patients.

Differential diagnosis

Lymphoma, particularly classic Hodgkin lymphoma:
- May demonstrate granulomatous inflammation but will have Hodgkin / Reed-Sternberg cells and mixed inflammation, including eosinophils and plasma cells
Sarcoidosis:
- Granulomas usually small and tight without suppuration
Other infectious agents capable of causing granulomatous lymphadenitis:
- Mycobacteriaceae, Chlamydia trachomatis, Francisella tularensis, Treponema pallidum, fungi
Kikuchi syndrome:
- No neutrophils
Kimura disease:
- Eosinophils predominate, rather than neutrophils

Board review style question #1

A 10 year old girl presents with an enlarged, tender axillary lymph node. An excisional biopsy is performed with findings shown. Which of the following is a likely clinical history for this patient?

Asthma, peripheral blood eosinophilia and elevated serum IgE
Drenching night sweats, petechial rash and peripheral blood cytopenias
Fever, pharyngitis, splenomegaly and positive monospot (heterophile antibody) test
Low grade fever and fatigue, new kitten in the household

Board review style answer #1

D. Low grade fever and fatigue, new kitten in the household. The image shows multiple well formed suppurative granulomas. A relatively common cause of these morphologic findings is cat scratch disease, lymphadenitis transmitted by cats, almost always caused by B. henselae. Most patients with cat scratch disease are under the age of 18 and have recent exposure to a cat, with tender lymphadenopathy appearing in the draining lymph nodes from the site of a scratch. Fever, pharyngitis, splenomegaly and positive monospot (heterophile antibody) test (answer C) describes the classic presentation of infectious mononucleosis. Drenching night sweats, petechial rash and peripheral blood cytopenias (answer B) is more suggestive of a malignant process. Asthma, peripheral blood eosinophilia and elevated serum IgE (answer A) can be seen in Kimura disease.

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Reference: Cat scratch disease

Board review style question #2

Excisional lymph node biopsy from a 20 year old man shows the findings seen in the image. Which of the following is the most likely diagnosis?

Cat scratch lymphadenitis
Kimura disease
Progressive transformation of germinal centers
Treponema pallidum

Board review style answer #2

A. Cat scratch lymphadenitis. The image demonstrates lymphadenopathy with suppurative granulomas, a feature that can be seen in cat scratch lymphadenitis. Special stains (silver stain) or organism specific immunohistochemistry on tissue sections may be helpful. Clinical correlation (anatomic distribution of lymphadenopathy, presence of risk factors, such as contact with cats, etc.) and infectious disease workup (serologic studies and culture) are helpful. Kimura disease demonstrates prominent eosinophilic infiltration. Progressive transformation of germinal centers is characterized by indistinct germinal centers invaded by mantle zone cells. Treponema pallidum lymphadenopathy is characterized by plasmacytosis and capsular fibrosis.

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Reference: Cat scratch disease

Chronic lymphadenitis

Table of Contents

Definition / general

Common, chronic inflammatory process of lymph nodes in response to various pathogens
May be specific or nonspecific, known or unknown
Lymph nodes show variable amounts of necrosis, abscesses, granulomas and fibrosis

Essential features

Nonspecific etiology
General histological features are follicular hyperplasia, prominence of postcapillary venules, increased number of immunoblasts, plasma cells, histiocytes and fibrosis

Terminology

Also called chronic nonspecific lymphadenitis

Sites

Cervical or any other lymph node groups can be affected

Clinical features

Enlarged lymph nodes (by palpation or imaging)
Painless

Diagnosis

Biopsy and clinical history are necessary
Adjuvant diagnostic methods such as special stains, electron microscopy, immunohistochemistry, in situ hybridization analysis and polymerase chain reaction (PCR) techniques help delineate specific causative factors

Laboratory

Specific findings depend on the etiology

Prognostic factors

Good prognosis in general, although prognosis and treatment vary based on specific etiology

Clinical images

Images hosted on other servers:

Lymphadenopathy

Gross description

Enlarged lymph node
Capsule may be thickened

Microscopic (histologic) description

Follicular hyperplasia, prominence of postcapillary venules, increased number of immunoblasts, plasma cells and histiocytes and fibrosis
Capsule may be inflamed or fibrotic
Inflammation / fibrosis may extend into the immediate perinodal tissues
Terms such as xanthogranulomatous lymphadenitis and eosinophilic lymphadenitis are used to describe cases with undue prominence of eosinophils, foamy macrophages or mast cells

Cytology description

Smear derived from reactive follicle: centroblasts, centrocytes, small lymphocytes and tingible body macrophages with nuclear fragments
Paracortical hyperplasia: spectrum of basophilic cells, ranging from mature plasma cells to immunoblasts with a background of many small lymphocytes

Positive stains

T cell and B cell markers show reactive pattern

Negative stains

Special stains for microorganisms
Immunohistochemical stains / patterns for lymphoma

Flow cytometry description

Reactive pattern: mixed / polyclonal population

Differential diagnosis

Malignant: lymphoma, metastases
Specific infections: atypical mycobacteria, fungal infections, leprosy, parasites, syphilis, tuberculosis
Specific inflammatory lesions: Castleman disease, dermatopathic lymphadenitis, lupus erythematosus, rheumatoid arthritis, sarcoidosis

Additional references

Ioachim: Ioachim's Lymph Node Pathology, 4th Edition, 2008, Orell: Orell and Sterrett's Fine Needle Aspiration Cytology, 5th Edition, 2011, Jaffe: Hematopathology, 1st Edition, 2010

Common nonspecific abnormal features

Table of Contents

Foamy macrophages | Follicular hyperplasia | Hypersplenism | Infarction | Perisplenitis

Foamy macrophages

Definition / general

Increased foamy histiocytes / macrophages, typically in the red pulp

Essential features

Associated with a wide variety of conditions both benign and malignant
Conditions with high cell turnover may produce foamy histiocytes
Diagnosis typically requires clinicopathologic correlation

Terminology

Ceroid histiocytosis - histiocytes filled with phospholipids; not specific to a single disease entity

Case reports

7 year old boy diagnosed with Gaucher disease by FNA of spleen (J Clin Diagn Res 2016;10:ED13)
52 year old man with splenomegaly (BMJ Case Rep 2015 Feb 5;2015)

Microscopic (histologic) description

Red pulp expanded by histiocytes with abundant foamy cytoplasm
Histiocytes scattered without forming a discrete mass
May have basophilic cytoplasm from ingestion of platelets in idiopathic thrombocytopenic purpura (ITP)
Finely fibrillary cytoplasm suggests underlying storage disease
White pulp is normal in size

Microscopic (histologic) images

Contributed by David Lynch, M.D.

Foamy histiocytes

CD163

Positive stains

CD68, CD163, PAS, iron (in Gaucher disease)

Negative stains

S100, CD1a, langerin (CD207), GMS, AFB , keratin, kappa / lambda

Differential diagnosis

Autoimmune disease
Chronic myelogenous leukemia: extramedullary hematopoiesis with hypolobated megakaryocytes, foamy macrophages
Crystal storing histiocytosis: eosinophilic rhomboid crystals within histiocytes
Hemophagocytic lymphohistiocytosis: histiocytes have ingested RBCs
Hyperlipidemia
Idiopathic thrombocytopenic purpura: follicular hyperplasia, increased foamy histiocytes, increased plasma cells, lipogranulomas in some cases
Langerhans cell histiocytosis: cleaved nuclei; S100, CD1a and langerin are positive
Mycobacterial or fungal infections: positive AFB or GMS stains
Postchemotherapy histiocyte rich pseudotumor (Am J Clin Pathol 2009;132:342)
Rosai-Dorfman disease: emperipolesis is present; histiocytes are S100 positive
Storage disease (Gaucher, Niemann-Pick): histiocytes have fibrillary cytoplasm in Gaucher disease

Additional references

Am J Clin Pathol 1983;80:529, Hum Pathol 1985;16:1175, Histopathology 2013;63:19, Eur J Haematol 1988;40:58, Arch Pathol Lab Med 1995;119:533

Follicular hyperplasia

Definition / general

Also called reactive follicular hyperplasia
Focal or diffuse
Normal in children
In adults, due to systemic infection (malaria, measles, typhoid fever, virus, other), immune mediate disorders (hemolytic anemia, immune thrombocytopenic purpura, rheumatoid arthritis)
Often associated with congestion and plasmacytic proliferation
Associated with hypersplenism in Zaire, Nigeria and New Guinea, where spleens also show extramedullary hematopoiesis and marked sinusoidal dilation; may be related to malaria
Note: graft rejection and AIDS are associated with reactive nonfollicular hyperplasia, which may resemble lymphoma but has heterogeneous lymphocytic population without atypia and without clonality
Felty syndrome (rheumatoid arthritis): no granulocytic phagocytosis but expansion of red pulp cords and sinuses with macrophages

Gross description

May have enlarged spleen with multiple small, pale tan nodules or solitary large nodules resembling lymphoma (Am J Surg Pathol 1983;7:373)

Microscopic (histologic) description

Resemble nodal reactive follicles, with mixed follicular center population and tingible body macrophages
Usually mature lymphocytes and plasma cells in red pulp

Hypersplenism

Also called dysplenism
Enlarged spleen leads to removal of cellular blood components (some or all), causing thrombocytopenia, neutropenia, hemolytic anemia or pancytopenia
Due to disorders (congestive splenomegaly, Gaucher disease, hamartoma, hemangioma, Langerhans cell histiocytosis, leukemia / lymphoma, other conditions diffusely involving red pulp) causing widening of splenic cords with increase in macrophages or connective tissue, causing premature destruction of normal blood components
Reactive follicular hyperplasia of white pulp may be present in hypersplenism associated with cytopenias
Infectious causes include brucellosis, CMV, Echinococcus, histoplasmosis, infectious mononucleosis, leishmaniasis, malaria, schistosomiasis, syphilis, toxoplasmosis, trypanosomiasis, tuberculosis, typhoid
May be due to abnormal cellular blood components (hereditary spherocytosis)

Infarction

Definition / general

Due to thrombosis of splenic vein, usually secondary to cardiac emboli
Also associated with granulomatosis with polyangiitis (Wegener) (may cause splenic rupture), massive splenomegaly, idiopathic

Gross description

Wedge shaped white-gray infarct involving capsule; infarcts heal as large, depressed scars

Perisplenitis

Thick fibrous plaques coating splenic surface
Incidental finding at autopsy or associated with portal hypertension

Congestive splenomegaly

Table of Contents

Definition / general | Treatment | Gross description | Microscopic (histologic) description

Definition / general

Caused by portal hypertension, which may be due to Budd-Chiari syndrome (thrombosis of hepatic veins), cirrhosis, congestive heart failure, portal vein stenosis, thrombosis of splenic veins, other thrombosis
Portal vein thrombosis may be due to inflammation, inflammatory induced extrinsic pressure, trauma, tumor or idiopathic
Portal vein stenosis may be due to extension of obliterative process at birth in umbilical vein and ductus venosus into portal vein
Banti syndrome: idiopathic portal hypertension; controversial entity, cases in Japan and India, associated with fibroelastosis in portal tracts, dilated capillaries, phlebosclerosis; associated with hypersplenism and anemia, leukopenia and thrombocytopenia

Treatment

Splenectomy:
- No shunt needed if coronary vein joins portal system central to point of obstruction; otherwise shunt is needed
- Possible shunts include splenic vein to renal vein, portal vein to vena cava

Gross description

Large, firm, dark with fibrosis of capsule

Microscopic (histologic) description

Dilated veins and sinuses, fibrosis of red pulp, hemosiderin laden macrophages
Iron and calcium containing fibrotic nodules (Gamna-Gandy bodies) secondary to hemorrhage
No prominent lymphoid follicles

Decidual reaction

Table of Contents

Definition / general

Deposits of decidual tissue without accompanying glands in lymph nodes
Rare, incidental microscopic finding in para-aortic and pelvic lymph nodes in pregnancy
Decidual cell reaction in the absence of pregnancy is seen only with a corpus luteum present in the ovary
Ectopic decidual reaction in lymph nodes was first reported by Geipel in 1913
Ectopic decidual reaction can be located in the vagina, cervix, fallopian tubes, ovary, peritoneum; also appendix, diaphragm, liver (surface), lymph nodes, mesentery, small bowel, spleen

Epidemiology

Rare, but exact incidence unknown since it is detected as an incidental finding at autopsy or pelvic lymphadenectomy for a genital tract malignancy
A particular problem differentiating from squamous cell carcinoma during frozen section (Arch Pathol Lab Med 2005;129:e117)

Sites

Limited to para-aortic and pelvic lymph nodes including obturator and internal iliac lymph nodes

Etiology

Unclear
Theories postulated are:
- Decidual change of endometriotic sites in pregnant women
- Entrapment of or failure of migration of coelomic remanants during embryologic development and during pregnancy, these rests are sensitized by estrogen, progesterone and further stimuli inducing a decidual reaction
- Benign metastasis or lymphatic spread

Clinical features

May be enlargement of lymph nodes
May have associated peritoneal decidual reaction

Diagnosis

Biopsy of the involved lymph nodes

Prognostic factors

Typically no treatment needed
Although extremely rare, malignant change can occur in these inclusions

Case reports

33 year old woman with ectopic decidua suspicious of malignancy in pregnancy (The Internet Journal of Gynecology and Obstetrics 2004;5)
Decidual change in pelvic lymph nodes in the presence of cervical squamous cell carcinoma during pregnancy (Am J Obstet Gynecol 1977;127:674)
Decidua in pelvic lymph nodes (Obstet Gynecol 1967;29:824)
Ectopic decidua and metastatic squamous carcinoma (J Surg Oncol 1988;38:126)

Gross description

Rarely is grossly visible as tiny, gray, subcapsular nodules
Typically occupies the subcapsular sinus and superficial cortex, and less commonly, the central parts of the lymph node

Microscopic (histologic) description

Decidual cells arranged in well circumscribed round groups, solid nests and loosely cohesive aggregates in the subcapsular sinus, as well as deep within the lymphoid tissue
The individual large polygonal cells show abundant granular esosinophilic cytoplasm, sharply defined cell borders, small, round to oval bland nuclei with dispersed chromatin and single conspicuous nucleoli
Mitoses or atypical features are not present
The cells may be separated by an intervening amorphous pale staining myxoid stroma

Microscopic (histologic) images

AFIP images

Deciduosis

Negative stains

Cytokeratins such as CAM5.2 and AE1/AE3 are characteristically negative

Differential diagnosis

Metastatic squamous cell carcinoma: small, irregular nests with well circumscribed borders of tightly cohesive, polygonal cells with small, dark staining nuclei and pleomorphism

Additional references

Int J Gynecol Pathol 1983;2:209, Histopathology 1986;10:1089, J Surg Oncol 1984;26:6, J Surg Oncol 1982;19:81

Dermatopathic lymphadenopathy

Table of Contents

Definition / general

Reactive lymphadenopathy characterized by paracortical expansion with increased interdigitating dendritic cells, Langerhans cells and histiocytes / macrophages, typically including melanophages
Typically associated with chronic skin irritation, inflammation or infection

Essential features

T cell mediated immune response to persistent cutaneous antigenic stimulation
Paracortical expansion, often overall nodular in arrangement, with numerous interdigitating dendritic cells, Langerhans cells and histiocytes / macrophages
Macrophages containing melanin pigment are typically present but vary widely in extent
Classically associated with dermatologic disorders but can also present without any clinical evidence of skin disease

Terminology

Lipomelanotic reticular hyperplasia
Lipomelanotic reticulosis
Dermatopathic lymphadenitis
Pautrier-Woringer disease (Am J Dermatopathol 2004;26:499)

ICD coding

ICD-10: I88.9 - nonspecific lymphadenitis, unspecified

Epidemiology

Limited studies available
Sex: initial case series suggested predilection for males, while recent case series included more women than men (Calif Med 1967;106:170, Mod Pathol 2020;33:1104)
Age: any age, with peak in fifth to sixth decades (Calif Med 1967;106:170)

Sites

Most commonly affects superficial axillary or inguinal lymph nodes
Can be bilateral
Generalized lymphadenopathy can occur uncommonly
References: Medeiros: Ioachim's Lymph Node Pathology, 5th Edition, 2021, Medeiros: Diagnostic Pathology - Lymph Nodes and Extranodal Lymphomas, 2nd Edition, 2017

Pathophysiology

Persistent cutaneous antigenic stimulation leading to local cytokine release, which mediates migration of Langerhans cells to regional lymph nodes (J Exp Med 2002;196:417)
- Partially through tumor necrosis factor alpha mediated downregulation of epithelial adhesion molecules (e.g., E-cadherin) in skin
Antigen processing and presentation by dendritic cells and Langerhans cells, leading to a T cell mediated immune response
Presence of melanophages in part due to pigment incontinence, melanophagocytosis and migration from skin to lymph node (Mod Pathol 2020;33:1104, Int Immunol 2001;13:695)

Etiology

Dermatologic disorders
- Benign: atopic dermatitis, chronic contact dermatitis, erythrodermic drug reaction, psoriasis, stasis dermatitis
- Malignant: mycosis fungoides, melanoma, squamous cell carcinoma, Kaposi sarcoma
No underlying dermatologic disorder can be identified in a subset of cases (12 - 48%) (Calif Med 1967;106:170, Mod Pathol 2020;33:1104)

Clinical features

Moderately enlarged, firm, moveable and nontender lymph nodes
Typically associated with chronic dermatologic disorders (Mod Pathol 2020;33:1104)
Commonly found in patients with mycosis fungoides and Sézary syndrome
- Higher association with severe / florid dermatopathic lymphadenopathy (Mod Pathol 2020;33:1104)
Can be found in patients with autoimmune disease / presence of autoantibodies (Int J Surg Pathol 2004;12:127)

Diagnosis

Clinical, radiologic and histologic evaluation of lymph node biopsy

Laboratory

Peripheral eosinophilia (up to 35%)
Depending on the underlying condition, if any (e.g., autoimmune dermatitis could be associated with autoantibodies)
References: Medeiros: Ioachim's Lymph Node Pathology, 5th Edition, 2021, Medeiros: Diagnostic Pathology - Lymph Nodes and Extranodal Lymphomas, 2nd Edition, 2017

Radiology description

Moderately enlarged lymph node(s)
Can be FDG avid on ¹⁸F-FDG PET / CT (World J Nucl Med 2020;20:205, Chin Med J (Engl) 2015;128:3121)

Radiology images

Images hosted on other servers:

Moderately enlarged inguinal lymphadenopathy

¹⁸FDG avid lymphadenopathy

¹⁸FDG PET / CT, transaxial PET / CT

Prognostic factors

Usually self resolving, depending on underlying condition

Case reports

Newborn boy with chromosome 22q11.2 deletion syndrome and generalized skin rash (Am J Case Rep 2020;21:e924961)
21 year old man with fever, pruritis and nonblanching rash (Clin Case Rep 2018;6:1637)
50 year old woman without skin disease (J Cytol 2016;33:49)
56 year old woman with a history of breast carcinoma in remission (Am J Case Rep 2017;18:1330)

Treatment

Treatment of the underlying dermatologic disorder

Clinical images

Images hosted on other servers:

Cervical lymphadenopathy on examination

Gross description

Enlarged lymph node (usually > 1.5 cm in greatest dimension)
Yellow to tan with occasional brown pigmented foci

Microscopic (histologic) description

There is always preserved nodal architecture with intact capsule
Follicular hyperplasia may be present but it is usually minimal
Spectrum of changes from mild to severe, characterized by paracortical expansion with pale, irregularly shaped areas containing numerous pale staining histiocytes, interdigitating dendritic cells, Langerhans cells and occasional immunoblasts
- Predominance of interdigitating dendritic cells over Langerhans cells, which are indistinguishable on morphology alone
- Both cell types show ill defined cell borders with fine irregular reniform nuclear contours and occasional nuclear grooves
- Paracortical or sinusoidal histiocytes and macrophages often contain cytoplasmic melanin pigment but they also can contain hemosiderin or lipid
- Medullary plasmacytosis is variable
- Distended sinuses with histiocytes, plasma cells and eosinophils can be present
- Variable, usually mild capillary hyperplasia
Mild / early
- Increased interdigitating dendritic cells that do not form nodules or networks, admixed with Langerhans cells and histiocytes
- Hyperplastic lymphoid follicles
Severe / florid
- Large vague nodules or sheets of interdigitating dendritic cells that can compress lymphoid follicles
- Rarely, sinuses can be partially compressed
- Severe forms are more frequently seen in patients with mycosis fungoides
References: Medeiros: Ioachim's Lymph Node Pathology, 5th Edition, 2021, Medeiros: Diagnostic Pathology - Lymph Nodes and Extranodal Lymphomas, 2nd Edition, 2017

Microscopic (histologic) images

Contributed by Ingrid Tam, M.D., M.Sc., Emina Emilia Torlakovic, M.D., Ph.D. and Nikhil Sangle, M.D. (Case #396)

Vaguely nodular pattern

Polymorphous paracortical population

Cytological features, cytoplasmic pigment

Mild dermatopathic lymphadenitis

Paracortical expansion

Melanin pigment

Low Ki67 proliferative index

CD1a positive Langerhans cells

S100 positive dendritic cells

Peripheral smear description

Peripheral eosinophilia in up to 35% of cases

Positive stains

S100, CD1a, CD207 / langerin: Langerhans cells
CD4 and CD8: typically there is great predominance of CD4+ T cells over CD8
Fontana-Masson silver stain for melanin; melanin histochemical stain is often positive even when melanin is not readily identified on H&E sections
S100, MUM1 / IRF4: interdigitating dendritic cells (Am J Surg Pathol 2022;46:1514)
CD68: histiocytes and dendritic cells
Prussian blue for hemosiderin: this is less useful as it is not as specific as melanin for this diagnosis
Pan-T cell markers CD2, CD5 and especially CD7 may be useful if there is a suspicion of involvement by mycosis fungoides or other cutaneous T cell lymphoproliferative disease (e.g., CD7 is typically negative in mycosis fungoides)
CD30: immunoblasts; CD30+ immunoblasts are not required for diagnosis

Flow cytometry description

No evidence of aberrant B or T cell populations, except if involved by mycosis fungoides or other primary cutaneous lymphoproliferative disorder

Electron microscopy description

Predominance of interdigitating cells over Langerhans cells
Langerhans cells: cytoplasmic Birbeck granules are defining feature
Both interdigitating cells and Langerhans cells have fine irregular nuclear contours and finger-like cytoplasmic extensions
References: Medeiros: Ioachim's Lymph Node Pathology, 5th Edition, 2021, Medeiros: Diagnostic Pathology - Lymph Nodes and Extranodal Lymphomas, 2nd Edition, 2017

Molecular / cytogenetics description

No evidence of immunoglobulin or T cell receptor gene rearrangement when associated with benign skin disease
Monoclonal T cell receptor gene rearrangements when associated with mycosis fungoides / Sézary syndrome or other primary cutaneous lymphoproliferative disorder

Sample pathology report

Lymph node, left axilla, excision:
- Reactive changes consistent with dermatopathic lymphadenopathy (see comment)
- Comment: The lymphoid architecture is preserved. There is evidence of paracortical hyperplasia with dendritic cells, Langerhans cells and histiocytes. Melanin pigment is noted. There is also mild focal follicular hyperplasia. The overall features are consistent with dermatopathic lymphadenopathy.

Differential diagnosis

Mycosis fungoides:
- Neoplastic T lymphocytes with cerebriform nuclei that demonstrate partial loss of CD7
- Lymph node may be involved even if it is not possible to confirm the presence of atypical T cells by morphology or immunophenotyping; therefore, TCR clonality assay is always required in patients with primary cutaneous lymphoproliferative disorder where regional lymph nodes show dermatopathic changes (Am J Surg Pathol 1981;5:343)
- Flow cytometry: loss of CD7 is the most frequent finding; other pan-T cell markers including CD2, CD3, CD8 and CD5 may also be altered (low, high, negative, double positive CD4 / CD8, etc.); downregulated CD26 is often seen
- T cell receptor (TCR) clonality assay: monoclonal TCR gene rearrangement
Langerhans cell histiocytosis:
- Sinusoidal involvement with partial or total effacement of lymph node architecture
- Formation of aggregates and sheets of Langerhans cells is more typical of Langerhans cell histocytosis than dermatopathic lymphadenopathy, even when the latter is florid
- Predominance of large Langerhans cells with abundant eosinophilic cytoplasm
- Often with abundant eosinophils
- Molecular: BRAF V600E in up to 50% of cases; BRAF V600E IHC assay may also be used
Classic Hodgkin lymphoma:
- Reed-Sternberg or Hodgkin cells that are positive for CD30, PAX5, MUM1 and CD15 (variable)
- Typically there is no increase in interdigitating dendritic cells or Langerhans cells but this is variable and in rare cases, Langerhans cells could be abundant
Metastatic melanoma:
- Melanoma cells are positive for HMB45 (cytoplasmic), SOX10 (nuclear) or S100 (nuclear / cytoplasmic), MelanA / MART1 (cytoplasmic)
- Ki67 proliferative index often > 10% but this is a nonspecific finding
Reactive lymphadenopathy with paracortical hyperplasia due to viral infections:
- Positive serology, culture or in situ hybridization studies
- Usually no significant increase in interdigitating dendritic cells or Langerhans cells
- Melanophages are typically absent
Toxoplasma lymphadenitis:
- Sinuses with monocytoid B cells
- Interfollicular and paracortical epithelioid histiocytes
- Prominent follicular hyperplasia
- No significant increase in interdigitating dendritic cells or Langerhans cells
- Melanophages typically absent

Board review style question #1

Which of the following histologic patterns is characteristically seen in dermatopathic lymphadenopathy?

Florid reactive follicular hyperplasia
Nonnecrotizing granulomatous inflammation
Paracortical expansion with a predominance of interdigitating cells admixed with Langerhans cells and histiocytes
Reactive follicular hyperplasia, interfollicular epithelioid histiocytes and monocytoid B cell hyperplasia
Sinus expansion with histiocytes showing emperipolesis

Board review style answer #1

C. Dermatopathic lymphadenopathy is characterized by a paracortical expansion with increased interdigitating dendritic cells, Langerhans cells and histiocytes / macrophages. Florid reactive follicular hyperplasia (answer A) can be seen in a number of conditions, including HIV lymphadenitis, rheumatoid arthritis and syphilis. A variety of etiologies can lead to nonnecrotizing granulomatous inflammation (answer B), including sarcoidosis, infections and autoimmune conditions. Reactive follicular hyperplasia, interfollicular epithelioid histiocytes and monocytoid B cell hyperplasia describe the triad of Toxoplasma lymphadenitis (answer D). Sinus histiocytosis with emperipolesis (answer E), characterizes Rosai-Dorfman disease.

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Reference: Dermatopathic lymphadenopathy

Board review style question #2

What is the most common molecular finding in the entity pictured above?

BRAF V600E mutation
MAP2K1 mutation
Monoclonal B cell population
Monoclonal population by T cell receptor (TCR) assays
Polyclonal population by TCR assays

Board review style answer #2

E. Polyclonal population by TCR assays. In dermatopathic lymphadenopathy, T cell receptor gene rearrangement assays show a polyclonal population. There is no evidence of B or T cell clonality (answers C and D); however, dermatopathic lymphadenopathy detected in patients with mycosis fungoides may show T cell clonality. This may be the case even without morphologic evidence of involvement by mycosis fungoides (e.g., stage N1b, with histopathology Dutch grade 1). BRAF V600E mutation (answer A) is associated with several hematologic conditions, including Langerhans cell histiocytosis and hairy cell leukemia. MAP2K1 mutations (answer B) can be seen in a subset of Langerhans cell histiocytosis cases as well as in Rosai-Dorfman disease.

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Reference: Dermatopathic lymphadenopathy

Drug hypersensitivity

Table of Contents

Definition / general

Certain drugs may give rise to soft lymph node enlargement, predominantly in the neck (J Pathol Bacteriol 1968;95:314)
Lymphadenopathy may occur alone or be associated with involvement of other organs (Neurology 1979;29:1480)
May resemble lymphoma by morphology
When the drug is stopped, the lymphadenopathy usually disappears in 1 - 2 weeks
Can present with lymphadenopathy or with a rare systemic disorder, DIHS / DRESS (Drug Induced Hypersensitivity Syndrome / Drug Reaction with Eosinophilia and Systemic Symptoms (Rev Assoc Med Bras 2016;62:227)

Essential features

History of drug exposure
Polymorphous infiltrate composed of immunoblasts, small lymphocytes, plasma cells, eosinophils and histiocytes

Terminology

Drug induced lymphadenopathy
Hydantoin lymphadenopathy
Pseudolymphoma syndrome
Drug induced hypersensitivity syndrome (DIHS)
Drug reaction with eosinophilia and systemic symptoms (DRESS)

ICD coding

R59.9

Epidemiology

Uncommon
Pediatric population

Sites

Predominantly cervical but all lymph node groups can be affected
Can be generalized

Pathophysiology

Different theories have been proposed:
- Hapten: drug molecules become antigenic when bound to a carrier protein, creating an immune response (Curr Opin Immunol 2012;24:730)
- p-i concept: direct binding of drugs and their metabolites to HLA trigger T cell responses (Curr Opin Allergy Clin Immunol 2002;2:301)
- Very strong link between HLA-B*5701 in HIV positive Caucasians and the development of hypersensitivity to abacavir
  - Abacavir binds noncovalently and specifically to the peptide binding groove of HLA-B*5701 molecule (Nature 2012;486:554)
- Susceptibility to carbamazepine reactions in patients with HLA-B*1502 variant (Nature 2004;428:486)
- Drug reaction with eosinophilia and systemic symptoms (DRESS) is associated with reactivation of inactive Herpesviridae family viruses, including human herpesvirus 6 (HHV6), Epstein-Barr virus (EBV) and cytomegalovirus (CMV) (Arch Dermatol 2001;137:301, Br J Dermatol 2006;155:344, Arch Dermatol 2009;145:1030)

Etiology

Reaction to drug exposure, including (Am J Med 2011;124:588):
- Abacavir, allopurinol, antibiotics, carbamazepine, dapsone
- Lamotrigine, mexiletine, minocycline, nevirapine
- Oxcarbazepine, phenobarbital, phenytoin (J Pathol Bacteriol 1968;95:314, Neurology 1979;29:1480), salazosulfapyridine
- Sulfamethoxazole, sulfasalazine, strontium ranelate, vancomycin

Clinical features

Isolated lymph node enlargement OR
Drug Induced Hypersensitivity Syndrome (DIHS) / Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) (Allergol Int 2016;65:432):
- Fever, lymphadenopathy, facial edema, periorbital edema, conjunctival injection
- Abdominal pain, diarrhea, hepatomegaly, splenomegaly
- Skin rash (maculopapular rash, bullous, wheal and flare, plaque, patch, target lesion)
- Internal organ involvement (liver - elevated alanine aminotransferase levels, kidney, lung); also brain (Turk J Pediatr 2015;57:541), heart, muscle, pancreas, thyroid (Int J Mol Sci 2017 Jun 9;18(6) pii: E1243)
- Hematologic abnormalities (eosinophilia, atypical lymphocytes, lymphocytosis, lymphopenia, thrombocytopenia)

Diagnosis

Clinical history of drug exposure
Characteristic clinical and laboratory features
Biopsy of the affected lymph node (rarely done, not required for diagnosis)

Radiology description

Enlarged lymph nodes

Prognostic factors

Underlying disease conditions
Extent of drug exposure
Drug reaction with eosinophilia and systemic symptoms (DRESS) has 4% mortality (Acta Derm Venereol 2012;92:200)

Case reports

17 year old girl presenting with bilateral cervical neck lymphadenopathy (Int J Pediatr Otorhinolaryngol 2017;98:82)
20 year old woman with fever of 38°C, prostration and drowsiness (Rev Assoc Med Bras 2016;62:227)
24 year old woman with lamotrigine cervical pseudolymphoma (Epilepsy Behav Case Rep 2017;7:40)
37 year old woman with redness and edema of inguinal area (Drug Saf Case Rep 2017;4:1)
60 year old man with skin rash, fever, distended abdomen and severe pruritus for 10 days (Iran Red Crescent Med J 2016;18:e36825)

Treatment

Discontinuation of the offending drug
For severe cases, immunosuppressive drugs / corticosteroids, IV Ig, plasma exchange

Gross description

Enlarged lymph nodes

Microscopic (histologic) description

Polymorphous cellular infiltrate composed of lymphocytes, plasma cells, eosinophils and histiocytes, most often with architectural distortion
Focal hemorrhagic necrosis is usually seen without fibrosis or scarring
Typical multinucleated Reed-Sternberg cells are absent; however, cells resembling Hodgkin / Reed-Sternberg (HRS) cells may be seen
Blood vessels show endothelial hyperplasia
There is variable follicular and paracortical hyperplasia (Hum Pathol 1974;5:519)

Flow cytometry description

No aberrant immunophenotype

Molecular / cytogenetics description

No clonal cell populations

Differential diagnosis

For drug reaction with eosinophilia and systemic symptoms (DRESS) (Rev Assoc Med Bras 2016;62:227):
- Hypereosinophilic syndrome: manifests with urticaria and angioedema and can be a hematopoietic malignancy
- Kawasaki disease: presents with mucosal congestion and desquamation of extremities / skin and lacks eosinophilia and atypical lymphocytes
- Stevens-Johnson syndrome / toxic epidermal necrolysis: lacks eosinophilia, atypical lymphocytosis and lymphadenopathy
On lymph node biopsy (Hum Pathol 1974;5:519):
- Angioimmunoblastic T cell lymphoma (AITL):
  - Presence of vascular proliferation, immunoblasts and polymorphous infiltrate cause confusion with angioimmunoblastic T cell lymphoma
  - AITL has characteristic T cells of T follicular helper (TFH) phenotype in perisinusoidal areas and T cell clones, not seen in drug hypersensitivity
- Hodgkin lymphoma:
  - Presence of polymorphous inflammatory infiltrate and large Hodgkin / Reed-Sternberg-like cells may cause confusion
  - However, classic Hodgkin / Reed-Sternberg cells are not identified in drug hypersensitivity

Additional references

Am Fam Physician 2014;89:353, J Pathol Bacteriol 1968;95:314, Front Med (Lausanne) 2017;4:179, Neurology 1979;29:1480

Board review style question #1

All of the following are proposed pathogenetic mechanisms for drug hypersensitivity, except:

Direct toxicity
Drug interactions with specific HLA types
Hapten theory
p-i concept

Board review style answer #1

A. Direct toxicity. Drug molecules causing an immune reaction are proposed mechanisms of pathogenesis of drug hypersensitivity, including hapten theory (drug molecules bind to a protein and cause antigenicity), p-i concept (drug molecules bind to HLA and cause T cell response) and drug molecules interacting with certain HLA subtypes. Direct toxicity does not manifest as a drug reaction with eosinophilia and systemic symptoms (DRESS).

Comment Here

Reference: Drug hypersensitivity

EBV positive inflammatory follicular dendritic cell / fibroblastic reticular cell tumor

Table of Contents

Definition / general

Epstein-Barr virus (EBV) positive inflammatory follicular dendritic cell (FDC) / fibroblastic reticular cell (FRC) tumor (ICC, 2022) / EBV positive inflammatory follicular dendritic cell (FDC) sarcoma (WHO, 5th edition) is an EBV driven indolent malignancy of FDC / FRC phenotype with a prominent inflammatory background
Encompasses extranodal lesions previously referred to as EBV positive inflammatory pseudotumor (IPT); nodal EBV positive IPT as well as EBV negative FDC sarcoma are excluded

Essential features

Extranodal EBV positive mesenchymal neoplasm with a phenotypic spectrum ranging from FDCs to FRCs associated with a prominent polymorphic inflammatory background
Previously considered a variant of FDC sarcoma, it has now been recognized as a distinct entity by both the WHO, 5th edition and the ICC, 2022
Nodal cases reported as inflammatory pseudotumor are excluded
Usually involves middle aged women of Asian descent
Solitary, asymptomatic splenic mass is the most common finding but it can also affect the liver and rarely, the colon and pancreas

Terminology

Inflammatory pseudotumor of the spleen, EBV positive
Inflammatory pseudotumor-like follicular / fibroblastic dendritic cell sarcoma
Inflammatory pseudotumor-like follicular dendritic cell tumor

ICD coding

ICD-O: 9758/3 - follicular dendritic cell sarcoma
ICD-10: C96.7 - other specified malignant neoplasms of lymphoid, hematopoietic and related tissue
ICD-11: 2B31.Y - other specified histiocytic or dendritic cell neoplasms

Epidemiology

Lesion occurs predominantly in middle aged Asian women and is by definition associated with EBV infection
F:M = 10:1 to 7:2 (Am J Surg Pathol 2001;25:721, Am J Surg Pathol 2021;45:765)
Age distribution ranges between 19 and 67 years; mean age of 49 - 58 years (Am J Surg Pathol 2023;47:476, Am J Surg Pathol 2021;45:765, Am J Surg Pathol 2001;25:721)

Sites

Spleen is the most frequent site of involvement, followed by the liver (Am J Surg Pathol 2023;47:476, Am J Surg Pathol 2021;45:765, Am J Surg Pathol 2001;25:721)
Rare reports in the gastrointestinal (GI) tract and the lungs (Hum Pathol 2015;46:1956, Case Rep Pathol 2019:2019:2648123, Am J Surg Pathol 2023;47:476)
Nodal IPT cases are excluded; in these cases, EBV is consistently absent in the mesenchymal component (Hum Pathol 2015;46:1956)

Pathophysiology

Steps involved in the development of these neoplasms are poorly characterized
CD21 may allow entry of EBV in the FDCs (Proc Natl Acad Sci U S A 1984;81:4510, Virology 2016:494:23, Nat Rev Microbiol 2019;17:691)
- Mechanism of EBV infection in cases with an FRC phenotype is less clear
How EBV promotes neoplastic transformation in mesenchymal cells is not fully understood
Distinct from inflammatory myofibroblastic tumors in which ALK or other tyrosine kinase receptors are involved
- MAPK pathway alterations have not been reported (Am J Surg Pathol 2001;25:721)

Etiology

Neoplastic cells are positive for EBV encoded small RNA (EBER)
Frequent association with EBV genotype A, f variant and with a 30 base pair deletion in exon 3 of the LMP1 gene, demonstrating the presence of a clonal EBV genome (Histopathology 2016;69:883)
- This implies that EBV plays a role in the etiology of these lesions

Clinical features

Usually asymptomatic finding during imaging work up for other reasons
Systemic symptoms can be seen, including fever, fatigue and weight loss
Abdominal distension and pain with or without palpable abdominal mass
Colonic cases can present with positive fecal occult blood test (Am J Surg Pathol 2021;45:765)

Diagnosis

Clinical, laboratory and imaging findings are largely nonspecific
Endoscopy shows a polypoid mass in cases involving the GI tract (Hum Pathol 2015;46:1956)
Diagnosis requires histopathological demonstration of characteristic morphology, immunophenotype and EBER positivity by the WHO criteria; these are best evaluated on excisional specimens, including splenectomies

Laboratory

Nonspecific inflammatory reaction, including anemia, hypergammaglobulinemia, elevated C reactive protein

Radiology description

Solitary, well defined hypodense mass in the affected organ (J Comput Assist Tomogr 2018;42:399)

Radiology images

Images hosted on other servers:

Liver mass on MRI

Prognostic factors

EBV positive FDC / FRC is an indolent tumor with a propensity for local recurrences in later stages of the disease
Location seems to be important for the prognosis, with splenic cases showing fewer recurrences than cases in the liver (Int J Clin Exp Pathol 2014;7:2421, Am J Surg Pathol 2001;25:721)
Distant metastases are rare and have been reported in the lungs and the spine
Overall mortality rate is 10% for liver cases
Colonic cases do not seem to recur and can be cured by complete excision (Hum Pathol 2015;46:1956)

Case reports

42 year old woman with a polypoid mass in the ascending colon (Hum Pathol 2015;46:1956)
55 year old woman with a 20 cm liver mass (Front Med (Lausanne) 2023:10:1192998)
70 year old woman with a pancreatic mass (Case Rep Pathol 2019:2019:2648123)

Treatment

Surgical excision alone is the treatment of choice (Am J Surg Pathol 2023;47:476)

Gross description

Solitary, large and well circumscribed mass with a broad size range from 1.5 cm up to 20 cm (Am J Surg Pathol 2023;47:476, Front Med (Lausanne) 2023:10:1192998)
Cut surface is smooth, white to tan and often shows areas of hemorrhage and necrosis

Gross images

Contributed by Elaine S. Jaffe, M.D.

Splenic mass

Images hosted on other servers:

Solitary splenic nodule

Pancreatic nodule

Microscopic (histologic) description

Neoplastic cells are spindled to oval, with vesicular chromatin, a small, central nucleolus and indistinct cytoplasmic borders
Binucleate cells with a kissing nuclei appearance can be noted in cases with FDC differentiation
Neoplastic cells form loose fascicles with a storiform appearance
Rich inflammatory background composed of small lymphocytes, plasma cells and histiocytes; eosinophils can be present (Hum Pathol 1995;26:1093, Am J Surg Pathol 2001;25:721)
In some cases, the inflammatory component can obscure the sparsely distributed neoplastic cells
Cytologic atypia is variable; it can range from subtle, with cells showing delicate nuclear membranes, to prominent with Hodgkin / Reed-Sternberg (HRS)-like cells (Am J Surg Pathol 2001;25:721)
Necrosis can be seen and it has not been consistently associated with more aggressive behavior (Am J Surg Pathol 2001;25:721, Histopathology 2016;69:883, Am J Surg Pathol 2021;45:765)
Cases referred to as having a hemangioma-like appearance due to the prominence of blood vessel wall hyaline and fibrinoid degeneration have been reported (Am J Surg Pathol 2023;47:476)

Microscopic (histologic) images

Contributed by Elaine S. Jaffe, M.D., Shunyou Gong, M.D., Ph.D. and João Víctor Alves de Castro, M.D.

Spindle cells in an inflammatory background

Cytologic features and background

Fibrinoid necrosis

Colonic lesion

Interface between spleen and tumor

Vascular damage and granulomas

Inflammatory background obscuring neoplastic cells

SMA IHC

Double staining for SMA / EBER

Cytology description

Fine needle aspiration biopsy smears, touch imprints and scrape preparations show spindle cells with vesicular, atypical nuclei and delicate cytoplasmic processes distributed singly or in syncytial clusters (Diagn Cytopathol 2008;36:42)
Nuclear grooves and prominent nucleoli can be seen
Cellularity ranges from hypo to hypercellular smears
Background is polymorphic and is rich in lymphocytes, plasma cells and histiocytes; can be hemorrhagic or necrotic
Immunohistochemistry is mandatory for the diagnosis (see Positive stains)

Cytology images

Images hosted on other servers:

Syncytial group of tumor cells

Positive stains

FDC differentiation is demonstrated by at least a subset of cells positive for one or more markers
- CD21
- CD23
- CD35
- D2-40
- Clusterin
- CNA.42
- CXCL13
- SSTR2
FRC differentiation can be suggested by positivity for smooth muscle actin (SMA)
Cases with FRC differentiation may or may not be positive for FDC markers
EBER positivity in the spindle cells is required for the diagnosis
- EBV latency pattern is not consistently reported but latent membrane protein 1 (LMP1) is positive in 72 - 90% of cases evaluated (Int J Clin Exp Pathol 2014;7:2421, Histopathology 2016;69:883)
IgG4 positive plasma cells can be present (Am J Surg Pathol 2023;47:476)

Negative stains

ALK
CD30
Desmin
h-caldesmon
S100
References: Am J Surg Pathol 2001;25:721, Int J Clin Exp Pathol 2014;7:2421

Molecular / cytogenetics description

ALK and other tyrosine kinase gene rearrangements are negative by FISH and sequencing methods, including NGS

Molecular / cytogenetics images

Contributed by João Víctor Alves de Castro, M.D. and Elaine S. Jaffe, M.D.

EBER ISH

EBER positive spindle cells

Sample pathology report

Liver, left, partial hepatectomy:
- Epstein-Barr virus (EBV) positive inflammatory follicular dendritic cell / fibroblastic reticular cell tumor (ICC, 2022) / EBV positive inflammatory follicular dendritic cell sarcoma (see comment)
- Comment: Histologic sections reveal effacement of the liver architecture within the grossly described mass by an atypical lymphoplasmacytic infiltrate. The infiltrate is composed predominantly of small lymphocytes with mature chromatin and numerous plasma cells. There are rare scattered atypical cells with elongated nuclei. Fibrinoid deposition is present around several vessels in addition to areas of hyalinization. Within the areas of hyalinization, there are numerous large vessels. While scattered islands of hepatocytes are present, normal portal areas with bile ducts within the mass lesion are rare.
- Within the lesion, there are rare scattered atypical, spindled appearing cells that are positive for CD21 and more often SMA. Clusterin is focally positive. CD20 and CD3 highlight B and T cells in aggregates respectively, with a predominance of T cells. EBV ISH highlights numerous cells, some with a spindled morphology and others that are more rounded. CD34 and SMA highlight sinusoidal spaces while keratin 7 highlights bile ducts, which are decreased in amount.
- Given the patient's clinical presentation in conjunction with rare CD21, SMA and EBV positive spindled cells in the mass lesion, this case is best felt to represent an Epstein-Barr virus (EBV) positive inflammatory follicular dendritic cell / fibroblastic reticular cell tumor (ICC, 2022) / EBV positive inflammatory follicular dendritic cell sarcoma. The vessels and pattern of bile duct loss within the lesion are unusual. It is unclear whether the EBV positive spindle cell proliferation has distorted the underlying liver parenchyma, which then adapted to a predominantly arterial supply.
- Epstein-Barr virus (EBV) positive inflammatory follicular dendritic cell / fibroblastic reticular cell tumor is the terminology currently used for the lesion also known as inflammatory pseudotumor. These occur in extranodal locations, including spleen, liver and more rarely GI tract. While previously referred to as sarcoma, when localized, the process has a good prognosis without significant risk for dissemination. This is an EBV driven lesion, in which the EBV positive cells are thought to be either FDCs or fibroblastic reticular cells (SMA positive).

Differential diagnosis

Inflammatory myofibroblastic tumor:
- Presence of ALK rearrangements
EBV associated smooth muscle tumor:
- Clinical setting of immunodeficiency (HIV, posttransplant or rarely primary immunodeficiency)
- Eosinophilic cytoplasm with myoid features
- Positive for desmin
IgG4 related disease:
- Clinical criteria, including increase in serum IgG4
Follicular dendritic cell sarcoma:
- EBER negative
- Can present as nodal disease
- Usually much more tumor cell rich, with only a sprinkling of small lymphocytes
Fibroblastic reticular cell tumor:
- EBER negative
- Positive for cytokeratin and desmin
Interdigitating dendritic cell sarcoma:
- EBER negative
- S100 positive
Hodgkin lymphoma:
- Positive for CD30 and weak PAX5
- Lacks FDC markers

Additional references

WHO Classification of Tumours Editorial Board: Haematolymphoid Tumours, 5th Edition, 2024

Board review style question #1

Epstein-Barr virus (EBV) positive inflammatory follicular dendritic cell / fibroblastic reticular cell tumor (ICC, 2022) / EBV positive inflammatory follicular dendritic cell sarcoma (WHO, 5th edition), previously referred to as EBV positive inflammatory pseudotumor (IPT), has been separated from EBV negative lesions that might also be termed IPT. Which of the following is compatible with the diagnosis of EBV positive FDC / FRC?

Inflammatory background usually lacks plasma cells
Lesion should be nodal in presentation, infrequently involving the spleen or liver
Negative results for LMP1
Neoplastic cells should have a distinct immunophenotype compatible with both follicular dendritic cell and fibroblastic reticular cell differentiation
This lesion has a good prognosis, differing from the aggressive FDC sarcoma (EBV negative)

Board review style answer #1

E. This lesion has a good prognosis, differing from the aggressive FDC sarcoma (EBV negative). EBV positive inflammatory FDC / FRC tumor (ICC, 2022) / sarcoma (WHO, 5th edition) is an indolent neoplasm, in contrast to the aggressive FDC sarcoma. Answer B is incorrect because the lesion should be extranodal. Answer C is incorrect because EBV positivity is an essential criterion usually detected by EBER, but LMP1 can also be detected in many cases. Answer D is incorrect because the immunophenotype is highly variable and can be of either FDC or FRC derivation. Answer A is incorrect because the inflammatory background is important for the diagnosis and usually has prominent plasma cells.

Comment Here

Reference: EBV positive inflammatory follicular dendritic cell / fibroblastic reticular cell tumor

Epithelial cyst

Table of Contents

Definition / general

Usually children or young adults
Solitary or multiple; may be associated with accessory spleen
May mimic mucinous cystic neoplasm if in intrapancreatic accessory spleen
Called "epithelioid" / "epidermoid" if squamous lining
Origin unknown; may derive from metaplasia in mesothelial cysts (Am J Surg Pathol 1988;12:275)
Often large and requires splenectomy

Case reports

62 year old man with epidermoid cyst in intrapancreatic accessory spleen (JOP 2011;12:279)

Gross description

Glistening inner surface with marked trabeculation

Gross images

Contributed by @Andrew_Fltv on Twitter

Epithelial cyst

Microscopic (histologic) description

Lined by squamous, columnar, cuboidal or mesothelial-like epithelium
No skin adnexae
Rarely mucinous and associated with pseudomyxoma peritonei

Microscopic (histologic) images

Contributed by @Andrew_Fltv on Twitter

Epithelial cyst

Positive stains

CEA, CA19-9 (Am J Surg Pathol 1998;22:704)

Differential diagnosis

Mucinous / cystic neoplasm
Pseudocyst

Epithelial inclusions

Table of Contents

Definition / general

Rare presence of benign, well differentiated epithelial cell clusters in lymph nodes
May coexist with breast micrometastases (Am J Surg Pathol 2003;27:513)
In axilla, may be due to pre-sentinel lymph node biopsy breast massage (Am J Surg Pathol 2004;28:1641, Arch Pathol Lab Med 2003;127:e25)

Terminology

Also called benign metastasis or heterotopia

Sites

Axillary, cervical, mediastinal, mesenteric, para-aortic, pelvic, renal lymph nodes

Pathophysiology

Different theories regarding the pathogenesis:
- Benign metastasis
- Developmental heterotopia
- Metaplasia of multipotent cells
- Iatrogenic displacement and transport (J Clin Oncol 2006;24:2013)

Clinical features

Asymptomatic, incidental finding

Prognostic factors

Benign with no significant clinical implications
Rarely may undergo disease processes and become cystic, a benign tumor or malignant

Case reports

44 year old woman with right breast carcinoma and benign Müllerian inclusions coexisting with breast metastatic carcinoma in an axillary lymph node (Virchows Arch 2005;446:467)
48 year old woman with axillary intranodal cysts associated with breast malignancy (Arch Pathol Lab Med 2004;128:361)
50 year old woman with unusual cystic epithelial choristoma in a celiac lymph node (Hum Pathol 1987;18:866)
52 year old woman with squamous inclusion cyst in a sentinel axillary lymph node associated with breast malignancy (J Coll Physicians Surg Pak 2012;22:50)
65, 66 and 75 year old women with endosalpingiosis in axillary sentinel lymph nodes obtained for staging of breast carcinoma (Am J Surg Pathol 2010;34:1211)
70 year old woman with invasive ductal carcinoma of the left breast and endosalpingiosis of axillary lymph nodes (Case Rep Pathol 2016;2016:2856358)
73 year old woman with ductal carcinoma in situ of the breast and epithelial inclusions in an ipsilateral axillary lymph node (Int J Surg Pathol 2018;26:564)
Epithelial inclusion in axillary lymph node associated with a breast carcinoma (Pathol Res Pract 1999;195:263)
Benign inclusion of axillary lymph nodes (Breast J 2009;15:664)

Treatment

No specific treatment needed, unless associated with another disease

Gross description

Normal unremarkable lymph nodes

Microscopic (histologic) description

Reactive follicular hyperplasia
Well formed epithelial formations, in or near the peripheral sinuses
Examples include salivary gland, thyroid follicles, breast tissue, respiratory type epithelium, fallopian tube lining or endometrium
Single or tubules of epithelial cells in subcapsular sinus of draining lymph node after surgical or needle manipulation (Am J Clin Pathol 2000;113:259)
Also hemosiderin laden macrophages and damaged erythrocytes

Microscopic (histologic) images

AFIP images

Mammary epithelial
inclusion in axillary
lymph node

Positive stains

Keratins and specific markers for the cell lineage

Differential diagnosis

Metastatic well differentiated carcinoma

Additional references

Am J Surg Pathol 2011;35:1123, Am J Surg Pathol 2010;34:1211, Ioachim's Lymph Node Pathology - Epithelial Inclusions in Lymphnodes (LWW, 2008), Rosai and Ackerman's Surgical Pathology - Lymph node inclusions (Mosby, 2011)

Fibroblastic reticulum cell sarcoma

Table of Contents

Definition / general

Rare malignant neoplasm of nodal stromal cells

Pathophysiology

Arises from fibroblastic reticular cells in the T cell zone of the nodal cortex
Fibroblastic reticular cells secrete chemokines (interleukin 7 and CCL19) responsible for naive T cell survival (Nat Immunol 2007;8:1255)

Case reports

25 year old man with reticulum cell sarcoma of lymph node with mixed dendritic and fibroblastic features (Mod Pathol 2001;14:1059)
71 year old woman with tumor of fibroblastic reticular cells of lymph node coincidental with an undifferentiated endometrial stromal sarcoma (APMIS 2011;119:216)

Treatment

Surgery

Microscopic (histologic) description

Storiform or fascicular pattern of oval to spindle cells in a collagenized background

Cytology images

Images hosted on other servers:

Wright stain

Positive stains

CD31, vimentin, desmin, smooth muscle actin
Cytokeratin variable

Negative stains

CD21, CD23, CD34, CD35, CD45, EBV, S100

Differential diagnosis

Additional references

Am J Surg Pathol 1998;22:1048, Hum Pathol 2003;34:954

Follicular dendritic cell sarcoma (FDCS)

Table of Contents

Definition / general

Rare mesenchymal neoplasm arising from follicular dendritic cells (FDC) of lymphoid follicles at nodal and extranodal sites
Nodal follicular dendritic cell sarcoma (FDCS) first characterized in 1986 (Am J Pathol 1986;122:562)
Extranodal follicular dendritic cell sarcoma first described in 1994 (Am J Surg Pathol 1994;18:148)

Essential features

Presents as a painless solid mass in nodal and extranodal sites
Behaves as a low grade sarcoma
Immunohistochemistry showing expression of ≥ 2 FDC markers is essential for diagnosis

Terminology

Previous designation: follicular dendritic cell tumor (in WHO classification prior to 2008)
Classified under histiocytic / dendritic cell neoplasms in the WHO Classification of Haematolymphoid Tumours (4th revised edition, 2017)
Classified under mesenchymal dendritic cell neoplasms in the category of stroma derived neoplasms of lymphoid tissues in the current WHO Classification of Haematolymphoid Tumours (5th edition, 2023)

ICD coding

ICD-10: C96.4 - sarcoma of dendritic cells (accessory cells)

Epidemiology

Wide age range; median age is 50 years (Crit Rev Oncol Hematol 2013;88:253)
M = F

Sites

Lymph nodes: cervical (most common); second most common is axillary or supraclavicular lymph nodes
Extranodal FDCS occurs in a wide variety of sites, including head and neck, gastrointestinal tract, retroperitoneum, tonsil and lung (Adv Anat Pathol 2021;28:21)

Pathophysiology

See Molecular / cytogenetics description

Etiology

May arise in the context of follicular dendritic cell proliferation in Castleman disease, hyaline vascular variant
Cases that show association with Epstein-Barr virus (EBV) and predominantly involve the liver or spleen are now considered a distinct entity: EBV positive inflammatory follicular dendritic cell sarcoma (Am J Surg Pathol 2001;25:721)

Clinical features

Nodal and extranodal involvement characterized by slow growing, painless solid mass
B symptoms (fever, night sweats, weight loss) are usually absent
Surgical resection results in complete remission in a majority of cases
- ~33% of cases recur locally
- May show late metastasis by hematologic spread to bone, lungs, liver
Rarely, may be associated with paraneoplastic autoimmune multiorgan syndrome (PAMS) (Am J Surg Pathol 2018;42:1647)

Diagnosis

Morphologic evaluation supplemented by immunophenotype of follicular dendritic cells is key to diagnosing FDCS
FDCS can coexist with Castleman disease (Pathologica 2021;113:316)

Radiology description

Nodal involvement presents as a homogeneous mass, slightly hypoattenuating on CT, hypointense or isointense on T1 weighted MRI and hyperintense on T2 weighted MRI (AJR Am J Roentgenol 2021;216:835)
Extranodal sites of involvement appear heterogeneous with hyperattenuation on unenhanced CT or hyperintense foci on T1 weighted MRI, with or without associated necrosis and calcifications, often accompanied by regional lymphadenopathy (AJR Am J Roentgenol 2021;216:835)

Radiology images

Images hosted on other servers:

Small bowel and liver tumor

Cystic neck lesion

Liver mass

Prognostic factors

Poor prognostic factors include size of tumor (> 6 cm), nuclear pleomorphism, increased mitoses (> 5/10 high power fields), necrosis and intra-abdominal location (Arch Pathol Lab Med 2017;141:596)
Association with paraneoplastic autoimmune multiorgan syndrome follows an aggressive course related to respiratory morbidity and mortality (Am J Surg Pathol 2018;42:1647)

Case reports

Man in his early 30s presented with jaundice, abdominal pain and weight loss (J Int Med Res 2022;50:3000605221142401)
34 year old man with Birt-Hogg-Dubé syndrome presented with mass at the ileocecal junction (Diagn Pathol 2022;17:64)
66 year old woman with intermittent right upper quadrant pain (World J Clin Cases 2019;7:785)
66 year old man with no significant medical history presented with right cervical mass (Mol Clin Oncol 2020;13:23)
72 year old man presented with enlarged mediastinal lymph nodes (Cureus 2023;15:e37715)

Treatment

Includes complete surgical resection with or without radiation therapy
Role of adjuvant chemotherapy or radiation is unclear (Cancers (Basel) 2014;6:2275)
Role of chemotherapy in advanced disease is not well established (Crit Rev Oncol Hematol 2013;88:253)

Clinical images

Images hosted on other servers:

Neck swelling

Paraneoplastic pemphigus

Gross description

Usually round to ovoid, well circumscribed fleshy solid mass (Arch Pathol Lab Med 2016;140:186)
Size ranges from 1 cm to 15 cm, largely dependent on the site of the tumor
May show areas of hemorrhage and necrosis

Gross images

Images hosted on other servers:

Mesentery tumor

Small bowel and liver tumor

Well circumscribed neck tumor

Liver tumor

Microscopic (histologic) description

Oval to spindled cells with dispersed chromatin, small nucleoli, eosinophilic and fibrillar cytoplasm with syncytial borders arranged in fascicles, whorls or storiform patterns
Often binucleate or occasional multinucleate forms, nuclear pseudoinclusions
Perivascular lymphocyte cuffs and admixed population of lymphocytes, eosinophils, plasma cells or neutrophils may be present (Am J Surg Pathol 2004;28:988)

Microscopic (histologic) images

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

Storiform growth

Ovoid cells mixed with lymphocytes

CD21

CD35

Clusterin

CXCL13

CD3

TdT

Virtual slides

Contributed by Genevieve M. Crane, M.D., Ph.D.

Aggressive B cell lymphoma

Positive stains

Most sensitive FDC markers: clusterin, CD21, CXCL13 (J Pathol 2008;216:356, Am J Surg Pathol 2004;28:988)
Most specific FDC markers: CXCL13, CD21, CD23, CD35
Other FDC markers: podoplanin / D2-40, SSTR2a, follicular dendritic cell secreted protein (FDCSP) and serglycin (SRGN) (Am J Clin Pathol 2007;128:776, Am J Surg Pathol 2019;43:374, Oncotarget 2017;8:16463)
Other positive stains: fascin, PDL1, desmoplakin, EGFR and vimentin (Mod Pathol 2005;18:260)
TdT highlights immature T cell lymphoblastic proliferation in 45% of cases; when abundant, this finding may be associated with paraneoplastic autoimmune multiorgan syndrome (Am J Surg Pathol 2018;42:1647)

Negative stains

Hematolymphoid markers: CD1a, CD43, CD45, CD163
Mesenchymal markers: actin, desmin, CD31, CD34
Epithelial markers: EMA, keratin (AE1 / AE3, CAM5.2)
Melanoma markers: HMB45, S100, MelanA, SOX10
References: Am J Surg Pathol 2004;28:988, J Exp Med 2021;218:e20210790

Molecular / cytogenetics description

Proposed molecular pathogenesis involves activation of nuclear factor κβ genes as a consequence of recurrent loss of function alterations in nuclear factor κβ regulatory genes (NFKBIA, CYLD, BIRC3, SOCS3, TRAF3, TNFAIP3), tumor suppressor genes (CDKN2A, RB1, TP53) and genes involved in immune evasion (CD274, PDCD1LG2) (Mod Pathol 2016;29:67)
Genetic alterations, including copy number variations, somatic mutations involving oncogenes / tumor suppressors (ZBTB7A, SETD2), chromatin remodeling genes (CABIN1, NCAPH) and other genes, have been reported (Blood Adv 2018;2:481)
BRAF V600E or other MAPK pathway mutations are uncommon (Histopathology 2014;65:261, Arch Pathol Lab Med 2023;147:896)
Chromosome analysis typically reveals a complex karyotype (In Vivo 2013;27:211)

Sample pathology report

Lymph node, left neck, excisional biopsy:
- Follicular dendritic cell sarcoma, completely excised (see comment)
- Comment: Lymph node architecture is partially effaced by an abnormal population of epithelioid to spindle shaped cells in a whorling pattern. The neoplastic cells have ovoid nuclei, delicate chromatin, small nucleoli and abundant eosinophilic cytoplasm. They are variably admixed with small lymphocytes. Immunohistochemical stains were performed on paraffin sections of the left neck lymph node (CD21, CD23, CD31, CD34, CD35, CD45, clusterin, CXCL13, epithelial membrane antigen, melanA, keratin [AE1 / AE3], HMB45, S100 and terminal deoxynucleotidyl transferase). The abnormal cells are positive for CD21, CD23, CD35, clusterin and CXCL13. There are small numbers of terminal deoxynucleotidyl transferase positive (TdT) cells mixed with the tumor. The neoplastic cells are negative for the other markers tested. Morphology and immunohistochemical stains support the diagnosis of follicular dendritic cell sarcoma.

Differential diagnosis

Interdigitating dendritic cell sarcoma:
- Histologically may be indistinguishable from follicular dendritic cell sarcoma and immunohistochemical studies are required for a definite diagnosis
- Positive for S100, CD45, CD68; negative for FDC markers (Am J Surg Pathol 2004;28:988)
Langerhans cell histiocytosis:
- Langerhans cells are oval and recognized by their grooved, folded or indented nuclei with fine chromatin, inconspicuous nucleoli and thin nuclear membrane with moderately abundant and slightly eosinophilic cytoplasm
- Positive for CD1a and langerin
Kaposi sarcoma:
- Atypical spindled cells form slit-like vascular spaces containing red blood cells
- Positive for HHV8
Spindle cell thymoma:
- Site involved is usually anterior mediastinum
- Bland spindled cells with fascicular to whorling growth pattern
- Positive for keratin (AE1 / AE3)
Metastatic carcinoma:
- Usually epithelioid cells in sheets, clusters or single cells with marked nuclear atypia
- Positive for keratin (AE1 / AE3)
Metastatic melanoma:
- Variable cytology including epithelioid or spindled cells with nuclear atypia and prominent nucleoli; cytoplasm may contain brown pigment (melanin)
- Positive for S100, MelanA, SOX10
Inflammatory myofibroblastic tumor:
- Spindled myofibroblasts and fibroblasts with bland nuclei
- Positive for ALK1
Pleomorphic sarcoma:
- Pleomorphic cells with a spectrum of cytology and may include spindled, plasmacytoid, epithelioid or multinucleated forms
- Negative for CXCL13, CD21, CD23, CD35

Additional references

Swerdlow: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition, 2017, WHO Classification of Tumours Editorial Board: Haematolymphoid Tumours, 5th Edition, 2024, Blood 2022;140:1229

Board review style question #1

An 88 year old man presented with significant snoring and increasing sleep apnea. Laryngoscopy revealed a pharyngeal mass. Computed tomography (CT) of the head and neck with intravenous (IV) contrast revealed a 6 cm enhancing mass in the right parapharyngeal space. An excisional biopsy was performed. Based on the immunophenotype (positive for CD21 and clusterin, negative for S100), what is the diagnosis?

Follicular dendritic cell sarcoma
Interdigitating dendritic cell sarcoma
Langerhans cell sarcoma
Pleomorphic sarcoma

Board review style answer #1

A. Follicular dendritic cell sarcoma. The immunophenotype indicated here is typical of follicular dendritic cells (FDC: CD21 positive, clusterin positive), supporting the diagnosis of follicular dendritic cell sarcoma. Answer B is incorrect because interdigitating dendritic cell sarcomas are characterized by positive expression of CD45, CD68 and S100, while they are negative for FDC markers. Answer C is incorrect because Langerhans cell sarcoma is positive for Langerhans cell markers (CD1a, Langerin) and negative for FDC markers. Answer D is incorrect because pleomorphic sarcoma is negative for FDC markers.

Comment here

Reference: Follicular dendritic cell sarcoma (FDCS)

Board review style question #2

Which of the following molecular pathways is most frequently associated with follicular dendritic cell sarcoma (FDCS)?

JAK-STAT
MAPK-ERK
NFκB
PI3K-Akt

Board review style answer #2

C. NFκB. Genetic alterations involving NFκB pathway are present in over 50% of FDCS cases. Answers B and D are incorrect because MAPK-ERK and PI3K-Akt pathways are frequently associated with histiocytic / dendritic cell neoplasms, such as Erdheim-Chester disease, Rosai-Dorfman disease and Langerhans cell histiocytosis. Answer A is incorrect because JAK-STAT pathway is associated with other hematologic malignancies (such as myeloproliferative neoplasms) and not FDCS.

Comment here

Reference: Follicular dendritic cell sarcoma (FDCS)

Follicular hyperplasia

Table of Contents

Definition / general

Follicular hyperplasia is a benign proliferation of lymphoid follicles, which can develop wherever lymphoid tissue is present (Surg Neurol 2008;70:514)

Essential features

Most common type of reactive lymphadenopathy (Mod Pathol 2013;26:S88)
Associated with varying degrees of paracortical or sinus hyperplasia (Mod Pathol 2013;26:S88)
A descriptive term that refers to an exaggerated response to antigenic stimulation, characterized by an increased number of germinal centers with variably sized mantle zones (Ann Diagn Pathol 2020;44:151421)
Follicular hyperplasia represents stimulation of the B cell compartment of the lymph node

Terminology

Follicular hyperplasia, reactive follicular hyperplasia (RFH), follicular lymphoid hyperplasia (FLH)

ICD coding

ICD-10: R59.9 - enlarged lymph nodes, unspecified

Epidemiology

Follicular hyperplasia is seen in pediatric and young adults but may also be encountered in all ages, including the elderly (Mod Pathol 1991;4:24)

Sites

Majority of cases with follicular hyperplasia occur in lymph nodes
However, it can affect extranodal organs
More than 75% of lymphadenopathies are generally localized but commonly involve head and neck regions (StatPearls: Adenopathy [Accessed 7 October 2022])

Pathophysiology

Reactive follicular hyperplasia is caused by stimulation of the B cell compartment and by abnormal cell growth of secondary follicles (Mod Pathol 2013;26:S88)

Etiology

Causes of reactive follicular hyperplasia are often unknown; however, it can be caused by bacterial and viral infections, as well as immune mediated disorders (Miranda: Atlas of Lymph Node Pathology, 1st Edition, 2013)

Diagrams / tables

Images hosted on other servers:

Normal lymph node

Clinical features

Lymphadenopathies such as follicular hyperplasia can present clinically as pain, swelling, warmth, tenderness, fever and chills (StatPearls: Adenopathy [Accessed 7 October 2022])
Nonspecific reactive follicular hyperplasia involving younger patients often resolves spontaneously (Mod Pathol 2013;26:S88)

Diagnosis

Morphologically, follicular hyperplasia can be diagnosed by observation of specific histological features such as expansion of germinal center, moderate to high mitotic rate, distinct mantle zone, polarization of the germinal center, variably shaped and sized follicles, tingible body macrophages and mixture of cell types in germinal center (Mod Pathol 2013;26:S88)
Lymph nodes with reactive follicular hyperplasia show a lower follicular density than is seen in follicular lymphoma

Laboratory

Leukocytosis, neutrophilia or lymphocytosis may be present in association with infections

Prognostic factors

Prognosis of follicular hyperplasia is mostly excellent

Case reports

51 year old woman with asymptomatic firm mass in the left posterior maxillary site (BMC Oral Health 2019;19:243)
55 year old Caucasian woman with swelling in her left posterior hard palate (J Craniomaxillofac Surg 2009;37:79)
74 year old edentulous woman with maxillary denture presenting with palatal swelling (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;96:172)
Reactive follicular hyperplasia in the lymph node lesions in 21 patients with systemic lupus erythematosus (Pathol Int 2000;50:304)

Treatment

Localized lymph node enlargement without any additional symptoms will usually spontaneously regress
Generalized lymphadenopathy usually requires additional investigation for etiology

Clinical images

Images hosted on other servers:

Lymphadenopathy

Gross description

Typically < 1 cm in size
Cut surface is tan-pink homogenous
No gross appearance of hemorrhage or necrosis
Reference: Mod Pathol 2013;26:S88

Gross images

Contributed by Mariah Ferrier, M.S., PA (ASCP)

Tan-pink homogenous surface

Microscopic (histologic) description

H&E sections of the lymph node show hyperplastic follicles with expanded germinal centers and paracortical regions
Follicles exhibit normal polarization
No significant cytologic atypia is identified
Immunostains reveal a normal staining pattern and distribution
Reference: Mod Pathol 2013;26:S88

Microscopic (histologic) images

Contributed by Jack Reid, M.D. and Sherif A. Rezk, M.D.

Hyperplastic lymphoid follicles

Polarization of germinal centers

Hyperplastic lymphoid follicles

HIV positive individual

Virtual slides

Images hosted on other servers:

Lymph node, follicular hyperplasia

Cytology description

Polymorphous lymphocytes and tingible body macrophages
Cytology to histopathology correlation is ~90%

Cytology images

Images hosted on other servers:

Polymorphous lymphocytes

Positive stains

BCL6 shows densely populated germinal centers with well defined and regular borders and strong staining of follicular center cells but only rare BCL6+ cells in the interfollicular areas (Hum Pathol 1999;30:403)
CD21, CD23 and CD35 highlight the enlargement of the dendritic meshwork (ScienceDirect: Follicular Hyperplasia [Accessed 29 September 2023])
Ki67 highlights a predominance of large transformed germinal center cells that have a high mitotic rate (ScienceDirect: Follicular Hyperplasia [Accessed 29 September 2023])
CD10 stains only follicular center cells and is typically much stronger in follicular lymphoma than in most follicular hyperplasias (Am J Surg Pathol 2000;24:846, ScienceDirect: Follicular Hyperplasia [Accessed 29 September 2023], Appl Immunohistochem Mol Morphol 2000;8:263)
HGAL also stains germinal center B cells, as does GCET1 (Nat Commun 2013;4:1338)

Negative stains

BCL2, helpful in distinguishing from follicular lymphoma (Weidner: Modern Surgical Pathology, 2nd Edition, 2009)

Flow cytometry description

Polytypic B cell population with positive CD10 and CD23; typically, it is a subset that is CD10 positive
Evaluation of CD38 by flow cytometry can be helpful in distinguishing follicular hyperplasia from follicular lymphoma (Cytometry B Clin Cytom 2009;76:315)
Clonal B cell populations may be present in the histologically reactive setting of follicular hyperplasia (Am J Clin Pathol 2004;121:464)
Combined analysis of CD20 and BCL2 by flow cytometry can distinguish follicular hyperplasia and follicular lymphoma; it may be particularly helpful if samples are limited or B cell clonality is questionable (Am J Clin Pathol 2000;114:258)

Flow cytometry images

Images hosted on other servers:

Analysis of CD38

Molecular / cytogenetics description

Unlike follicular lymphoma, there is no evidence of t(14;18)(q32;q21) or IGH::BCL2 fusion sequences found in cases with follicular hyperplasia
IgH rearrangement was not identified in follicular lymphoma and was mainly found in lymphoplasmacytoid and follicular lymphoma (Oncotarget 2017;8:77009)

Videos

Histopathology lymph node: follicular hyperplasia

Sample pathology report

Lymph node, excision:

Reactive follicular hyperplasia; no carcinoma or lymphoma (see comment)
Comment: The H&E sections of the lymph node show hyperplastic follicles with expanded germinal centers and paracortical region. The follicles exhibit normal polarization. No significant cytologic atypia is identified. The immunostains reveal a normal staining pattern and distribution. The histological and immunohistochemical features are consistent with a reactive follicular hyperplasia. Clinical and microbiological correlation is recommended for complete interpretation.

Immunohistochemical stain:

Block	Stain	Result
1	CD3	Positive in T cells
	CD20	Positive in B cells
	CD10	Positive in germinal center cells
	BCL6	Positive in germinal center cells
	BCL2	Positive in nongerminal center cells
	CD21	Highlight follicular dendritic meshwork

Interpretation: There is a reactive follicular hyperplasia with no evidence of a malignant lymphoma.

Differential diagnosis

Follicular lymphoma:
- Monoclonal
- B cell germinal centers typically express BCL2
- Cytogenetics usually shows t(14;18)(p32,q21) resulting in BCL2 gene rearrangement and BCL2 protein overexpression; however, aberrant BCL2 expression is not detected in all cases
- Germinal centers lack normal polarization
Progressive transformation of germinal centers (PTGCs):
- Morphologically, the nodules seen in PTGCs are 3 - 4 times larger than those of reactive follicular hyperplasia
- Germinal center B cells are BCL2 negative
Hyaline vascular Castleman disease:
- Regressed germinal centers
- Sclerotic vessels
- Prominent mantle zones with onion skin appearance
- Morphological features such as twinning (2 or more germinal centers inside each follicle) and lollipop sign (a radially penetrating sclerotic blood vessel in the germinal center)
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL):
- Immunophenotypically, NLPHL expresses CD45, EMA and 50% of the cases with MUM1
- Morphologically distinct NLPHL can be seen with neoplastic lymphocyte predominant (LP) cells in the background of small lymphocytes and epithelioid histiocytes
- Both follicular hyperplasia and NLPHL may show a nodular proliferation at low power; however, NLPHL nodules are more irregular and have a moth eaten appearance due to the presence of clusters of epithelioid histiocytes (Pediatr Blood Cancer 2018;65:10.1002/pbc.26753)
Follicular neoplasia in situ:
- Can be an incidental finding in a background of follicular hyperplasia (Blood 2011;118:2976)
Pediatric variant of follicular lymphoma (PFL):
- Biologically different from common follicular lymphoma (FL)
- PFL cases have been reported exclusively in male patients in both children and young adults
- Most common site of PFL cases is head / neck region
- Morphologically, PFL cases demonstrate blastoid cytologic features with a high proliferation rate by Ki67
- By immunohistochemistry, PFL is positive for germinal center markers (CD10, BCL6, LMO2, HGAL)
- BCL2 expression by immunohistochemistry varies depending on the anatomic site: testicles (negative), lymph nodes (18% weakly positive), tonsils (63% of cases are positive)
- Majority of PFL cases demonstrate clonal immunoglobulin gene rearrangement by PCR analysis
- Absence of BCL2::IGH translocation by FISH
- MAP kinase pathway involvement has been reported in 50% cases with PFL (Blood 2016;128:1093)
- TNFRSF14 mutations have been reported in cases of PFL (Blood 2016;128:1093)

Board review style question #1

When differentiating follicular hyperplasia from follicular lymphoma, which immunohistochemical stain is most helpful?

BCL2
BCL6
CD10
Ki67
MUM1

Board review style answer #1

A. BCL2. Follicular hyperplasia distinguishes itself from follicular lymphoma by lack of BCL2 expression whereas follicular lymphoma is classically positive for BCL2 expression.

Comment Here

Reference: Follicular hyperplasia

Board review style question #2

What morphologic finding is characteristic of follicular hyperplasia?

Polarization of the germinal center
Positive staining of BCL2 in the germinal center
Presence of multilobated popcorn cells
Reed-Sternberg (RS) cells
Twinning of the follicle

Board review style answer #2

A. Polarization of germinal centers is typically seen in follicular hyperplasia along with features such as low density of follicles, variably sized follicles, mixture of cell types in the germinal centers, tingible body macrophages, moderate to high mitotic rate, intact nodal architecture. Answer B is incorrect because positive staining of BCL2 in the germinal center is seen in follicular lymphoma. Answers C and D are incorrect because multilobated popcorn cells and Reed-Sternberg (RS) cells are seen in Hodgkin lymphoma. Answer E is incorrect because twinning of the follicle is seen in Castleman disease.

Comment Here

Reference: Follicular hyperplasia

Granulomatous inflammation

Table of Contents

Definition / general

Specialized immune response against various inflammatory insults, involving chronic activation and organization of mononuclear phagocytic cells (macrophages) (J Clin Tuberc Other Mycobact Dis 2017;7:1)
Histologically characterized by epithelioid histiocytes, with or without central necrosis, surrounded by acute or chronic inflammation

Essential features

Specialized inflammatory response against various offending entities, including (StatPearls: Granuloma [Accessed 13 June 2022]):
- Infectious (usually necrotic, suppurative)
- Autoimmune / inflammatory
- Malignancy
- Others (see below)
Histologically characterized by central epithelioid histiocytes surrounded by acute or chronic inflammation
Microbiologic cultures of fresh sample, special stains / immunohistochemistry for microorganisms are essential when clinical history includes suspicion of infection or an immunocompromised / suppressed state
Immunohistochemistry to evaluate for malignancies that arise as differential diagnoses (e.g., carcinoma [cytokeratin], melanoma [SOX10]) (O'Malley: Benign and Reactive Conditions of Lymph Node and Spleen, 1st Edition, 2009)

Terminology

Lymphadenitis (LA), infectious lymphadenitis, granulomatous lymphadenitis (GLA)

ICD coding

ICD-10:
- I88.1 - chronic or subacute lymphadenitis
- I88.8 - granuloma, gland (lymph)
- I88.9 - lymphadenitis
- L04.9 - acute lymphadenitis
- D86.1 - sarcoidosis of lymph nodes

Epidemiology

May be associated with infectious disease or noninfectious disease (J Clin Tuberc Other Mycobact Dis 2017;7:1)
No particular predilection for age / sex (StatPearls: Lymphadenopathy [Accessed 13 June 2022])

Sites

Any lymph node site in the body
Spleen (O'Malley: Benign and Reactive Conditions of Lymph Node and Spleen, 1st Edition, 2009)
Certain etiologies have strong association with anatomical site (J Clin Tuberc Other Mycobact Dis 2017;7:1)
- Inguinal nodes in lymphogranuloma venereum
- Cervical and axillary nodes in tularemia and cat scratch disease
- Mesenteric lymph nodes in Yersinia lymphadenitis
- Pulmonary hilar lymph nodes in environmental, fungal, tuberculous lymphadenitis

Pathophysiology

Dysregulation of immune response due to inability of macrophages to clear the offending agent (StatPearls: Granuloma [Accessed 13 June 2022])
Results in chronic active inflammation, histologically characterized by (StatPearls: Granuloma [Accessed 13 June 2022]):
- Central collection of epithelioid histiocytes
- Rim of plasma cells and lymphocytes
- Central necrosis or suppuration, depending on etiology
Can be conceptualized as consisting of 3 phases (J Clin Exp Hematop 2012;52:1):
- Initiation / accumulation, peak and late phase
- Initiation characterized by activation of T cells via MHC class II interactions with antigen presenting cells (APCs) (J Clin Tuberc Other Mycobact Dis 2017;7:1)
  - Activated T helper 1 (Th1) cells stimulate and recruit macrophages via secretion of TNF alpha, IFN gamma, IL2, IL12 and chemokines
- Precise mechanism of defective downregulation of active inflammation is poorly understood
- With ensuing active inflammation, peak phase is characterized by rim of chronic inflammatory infiltrate consisting of:
  - CD4+ T cells, CD8+ T cells, NK cells, plasma cells and occasional granulocytes
  - Certain infectious GLA features prominent monocytoid B cell infiltrates (Toxoplasma lymphadenitis, Bartonella) (J Clin Exp Hematop 2012;52:1)
    - Role poorly understood
- Late phase characterized by fibrosis and hyalinization
Resolution occurs after clearance of antigenic stimulus and is characterized by a fibrous scar

Etiology

Infectious:
- Suppurative (purulent):
  - Tularemia lymphadenitis (Francisella tularensis)
  - Cat scratch lymphadenitis (Bartonella henselae)
  - Yersinia lymphadenitis (Yersinia enterocolitica)
  - Various fungal infections
- Nonsuppurative:
  - Tuberculous lymphadenitis (Mycobacterium tuberculosis spp.)
  - Atypical mycobacterial infection
  - Bacillus Calmette-Guérin (BCG) lymphadenitis
  - Toxoplasma lymphadenitis
  - Hansen disease or leprosy (M. leprae)
  - Syphilis
  - Brucellosis
  - Fungal lymphadenitis (Coccidioides, Cryptococcus, Histoplasma, Pneumocystis)
Noninfectious:
- Systemic sarcoidosis
- Foreign body (berylliosis, silicosis)
- Malignancies (lymphoma, carcinoma, especially breast, uterus, lung, stomach)
- Systemic inflammatory / autoimmune conditions (lupus [SLE], rheumatoid arthritis [RA], granulomatosis with polyangiitis [GPA])
- Toxic (chemotherapy, heavy metals, beryllium, zirconium, silicon)
- Histiocytic inflammatory (Rosai-Dorfman disease, Castleman disease)
Reference: J Clin Tuberc Other Mycobact Dis 2017;7:1

Clinical features

Painful / painless lymphadenopathy (StatPearls: Lymphadenopathy [Accessed 13 June 2022])

Diagnosis

Clinical exam
Imaging:
- CT
- Ultrasound
Tissue biopsy:
- Excisional preferred over needle core biopsies, due to preservation of lymph node architecture; usually yields sufficient tissue to perform ancillary studies (microbiologic studies, special stains, immunostains)
Fine needle aspiration (FNA):
- Can be ultrasound guided
Reference: StatPearls: Lymphadenopathy [Accessed 13 June 2022]

Laboratory

Dependent on suspected etiology but generally includes:
- Microbiologic studies (e.g., cultures, serology)
  - Essential to obtain tissue cultures, as necrotic node usually contains high density of organisms
- Autoimmune / rheumatology workup
Reference: StatPearls: Lymphadenopathy [Accessed 13 June 2022]

Prognostic factors

Dependent on etiology (e.g., HIV, sarcoidosis, malignancy, infection)

Case reports

27 year old Greek man with suppurative necrotizing granulomatous lymphadenitis in adult onset Still disease (J Med Case Rep 2012;6:354)
29 year old man with necrotizing granulomatous sarcoidosis (Cureus 2020;12:e10220)
82 year old man with necrotizing granulomatous lymphadenitis (BMJ Case Rep 2011;2011:bcr1120103548)

Treatment

Management of underlying disease (e.g., infection, neoplasm, inflammatory / autoimmune)
Removal of offending agent (e.g., removal of foreign body)

Gross description

Pale tan circumscribed nodules
Fibrotic and firm compared to surrounding lymph node parenchyma
Can show central necrosis, which can be dry and crumbly (caseating) or soft with a gelatinous consistency
Can show gross suppuration
Reference: Foucar: Tumors of the Bone Marrow, 1st Edition, 2016

Gross images

Contributed by Ryan Hickey, PA (ASCP)

Inguinal lymph node with necrotizing granuloma

Frozen section description

See Gross description

Microscopic (histologic) description

Collection of epithelioid macrophages with abundant eosinophilic cytoplasm and indistinct cell borders (StatPearls: Granuloma [Accessed 13 June 2022])
Surrounded by a rim of inflammatory cells, including lymphocytes, plasma cells and macrophages (StatPearls: Granuloma [Accessed 13 June 2022])
Multinucleated giant cells are often present (StatPearls: Granuloma [Accessed 13 June 2022])
Certain etiologies may demonstrate characteristic features
- May present as a characteristic triad of florid follicular hyperplasia, interfollicular monocytoid B cells and cortical / subcortical, ill defined aggregates of epithelioid cells (Toxoplasma lymphadenitis)
Subtypes:
- Necrotizing granulomas (J Clin Exp Hematop 2012;52:1):
  - Necrotic focus surrounded by a rim of chronic inflammatory cells, including epithelioid macrophages
  - May show suppuration (acute inflammation) depending on etiology
  - Usually associated with infectious agents (e.g., tuberculosis, lymphogranuloma venereum, tularemia, cat scratch disease, fungal)
    - Important to look for organisms within granulomas
    - Use special stains to highlight
    - Often essential for diagnosis as serology may have low sensitivity / specificity
    - Obtain tissue culture
- Nonnecrotizing (sarcoid and sarcoid-like) granulomas (J Clin Exp Hematop 2012;52:1):
  - Well defined borders, cohesive solid appearance, no central necrosis
  - Various types of inclusions inside macrophages (e.g., asteroid bodies)
  - Etiology includes
    - Sarcoidosis containing Langhans type giant cells containing nuclei arranged in a horseshoe shape along cell periphery
    - Systemic / autoimmune entities
    - Foreign body type lymphadenitis containing giant cells with haphazardly arranged nuclei and engulfed foreign material
  - Lipogranuloma (O'Malley: Benign and Reactive Conditions of Lymph Node and Spleen, 1st Edition, 2009):
    - Frequently found in spleen; can be seen in lymph node
    - Focus of macrophages with ingested fat surrounded by a rim of lymphocytes and plasma cells
    - Etiology is unknown
    - Has been associated with excessive topical application / ingestion of mineral oils

Microscopic (histologic) images

Contributed by Simon A. Backer, M.D.

Necrotizing granuloma in a cervical lymph node

Infectious (suppurative) granulomatous lymphadenitis

Sarcoid granuloma

Sarcoid granuloma with asteroid body

Necrotizing granuloma with palisading histiocytes

GMS with fungal forms in necrotizing granuloma

Cytology description

Sarcoid granulomatous lymphadenitis:
- Tight collection of epithelioid histiocytes in syncytial arrangement with curved nuclei in horseshoe, C or V shape
Infectious type granulomatous lymphadenitis:
- Histiocyte cluster may be loose or tight
- Usually surrounded by abundant acute inflammation
- Can show suppuration or necrosis, depending on infectious etiology
Ultimately, findings are nonspecific and microbiologic, serologic studies are needed for a definitive etiology
Reference: Cibas: Cytology - Diagnostic Principles and Clinical Correlates, 5th Edition, 2020

Cytology images

Contributed by Simon A. Backer, M.D.

Epithelioid granuloma

Positive stains

CD68, CD163, lysozyme: highlights epithelioid histiocytes
CD3, CD20: highlights immunoarchitecture; rules out lymphoma

Negative stains

Acid fast bacilli (AFB): positive in mycobacterial etiology
Grocott methenamine silver (GMS) and periodic acid-Schiff (PAS): positive in fungal etiology
Cytokeratin: positive in carcinoma
SOX10: positive in melanoma
CD30: positive in Hodgkin lymphoma

Sample pathology report

R4 lymph node, excision:
- Nonnecrotizing granulomatous lymphadenitis (see comment)
- No evidence of malignancy identified
- Comment: The overall findings raise the possibility of sarcoidosis; infection remains in the differential diagnosis. AFB and GMS stains are negative for acid fast organisms and fungal forms. Clinical correlation with microbiologic studies is recommended.

Differential diagnosis

Necrotizing granulomatous inflammation:
- Suppurative:
- Nonsuppurative:
  - Syphilis
  - Brucellosis
  - Fungal infection (Cryptococcus, Histoplasma, coccidiomycosis, Pneumocystis, Aspergillus, Blastomyces, Mucorales)
  - Mycobacterium tuberculosis
  - Nontuberculous mycobacteria
  - Nocardia
  - Yersinia lymphadenitis
  - Cat scratch disease
Nonnecrotizing granulomatous inflammation:
- Mycobacterium tuberculosis
- Nontuberculous mycobacterium (including Hansen disease)
- Salmonella typhi
- Rickettsia spp.
- Coxiella
- C. albicans
- C. immitis
- Viral (cytomegalovirus, herpes, hepatitides)
- Parasitic (toxoplasmosis, schistosomiasis)
Noninfectious:
- Most noninfectious causes of granulomatous lymphadenitis present with nonnecrotizing granulomatous inflammation, including
  - Autoimmune:
    - Sarcoidosis
    - Vasculitides
    - Crohn's disease
    - Systemic lupus erythematosus
    - Rheumatoid arthritis
  - Drugs:
    - Bacillus Calmette-Guérin
    - NSAIDs
    - Antibiotics
    - Methotrexate
  - Malignancy associated:
    - Carcinoma
    - Melanoma
    - Lymphoma (e.g., classic Hodgkin lymphoma, T cell lymphoma)
Foreign body:
- Talc, starch, suture, hyaluronic acid (and other injectable fillers):
  - Foreign material may be visualized within granuloma
  - May be polarizable
Reactive conditions that present with granulomatous lymphadenitis:
- Kikuchi-Fujimoto disease:
  - Predominance of CD8+ T cells surrounding necrotic center
  - Histiocytes with C shaped nuclei
  - Plasmacytoid dendritic cells
- Kimura disease:
  - Hypereosinophilia and eosinophilic abscesses
  - Preservation of follicles, hyperplastic follicles
  - Stromal and perivascular sclerosis
Rosai-Dorfman disease (also known as sinus histiocytosis with massive lymphadenopathy):
- Histiocytes show abundant eosinophilic cytoplasm, central vesicular nucleus and prominent nucleolus
- Histiocytosis is accompanied by small lymphocytes and plasma cells
- Histiocytes are S100+, CD1a-
Histiocytic neoplasms:
- Histiocytic sarcoma:
  - Rarely affects lymph nodes (usually extranodal presentation)
  - Diffuse infiltration by malignant, variably pleomorphic, mature appearing histiocytes
  - Nodal architecture effacement, sparing of follicles
  - No well formed granulomas
- Langerhans cell histiocytosis:
  - Lesional cells show prominent nuclear grooves, admixed eosinophils
  - Positive for S100, CD99, CD1a, langerin
Reference: J Clin Tuberc Other Mycobact Dis 2017;7:1

Board review style question #1

A 30 year old pregnant woman presents to her general practitioner complaining of mild flu-like symptoms. On physical examination, there is small but palpable, tender cervical lymphadenopathy. She states that her allergies seem to be acting up lately, which may be due to her new cat. She reports a family history of lymphoma in a grandparent and would like the lymph node biopsied. Sections of the node reveal secondary follicles of varying shapes and sizes, clusters of monocytoid lymphoid cells and cortical, loose collections of epithelioid histiocytes. Based on the clinical presentation and histologic findings, what is the most likely etiology for this patient's presentation?

Cat scratch disease
Follicular lymphoma
Metastatic carcinoma
Toxoplasmosis
Tularemia

Board review style answer #1

D. Toxoplasmosis

Comment Here

Reference: Granulomatous inflammation

Board review style question #2

You receive an excisional biopsy of an enlarged superficial neck lymph node from a 55 year old homeless man who was found obtunded. He is a poor historian and is unable to provide the duration of the adenopathy but he reports feeling unwell for quite some time. On physical examination, he has somewhat tender cervical adenopathy, as well as axillary and inguinal adenopathy. In addition, imaging studies show mediastinal and intra-abdominal adenopathy. Biopsy sections of the superficial cervical node show follicular hyperplasia with scattered epithelioid granulomas that are nonnecrotizing. The expanded follicles show a monotonous proliferation of small to medium lymphocytes, with variably irregular nuclear contours, condensed chromatin and scant cytoplasm. Occasional larger lymphoid cells are seen. Interfollicular plasma cells, eosinophils and scattered epithelioid histiocytes are also seen. What additional studies could narrow your differential diagnosis?

AFB and GMS stains
Immunostains to evaluate for both non-Hodgkin and Hodgkin lymphomas
PCR studies for HIV
Serologic studies for infectious etiologies
Tissue culture of fresh tissue sent to the microbiology laboratory

Board review style answer #2

B. Immunostains to evaluate for both non-Hodgkin and Hodgkin lymphomas

Comment Here

Reference: Granulomatous inflammation

Granulomatous inflammation

Table of Contents

Definition / general | Treatment

Definition / general

Common in splenectomy specimens
Either:
1. Large active granulomas with epithelioid and Langhans giant cells, with or without central necrosis
2. Widespread small, sarcoid-like epithelioid granulomas with rare giant cells and no necrosis
3. Inactive granulomas with fibrosis and calcification
Granulomas usually associated with systemic disease involving liver, bone marrow and lymph nodes; also chronic uremia, IgA deficiency, infectious mononucleosis
Granulomas may be present in hairy cell leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, although granuloma itself does not mean spleen is involved by tumor (Arch Pathol Lab Med 1977;101:518)
Active granulomas: in adults, associated with fever, weight loss, hepatosplenomegaly and hypersplenism
Inactive granulomas: associated with histoplasmosis

Treatment

Splenectomy for symptoms of hypersplenism

Grossing & features to report-lymph nodes

Table of Contents

Grossing for diagnosis | Grossing for staging | Features to report by organization | Features to report

Grossing for diagnosis

Cut perpendicular to long axis if possible
Avoid squeezing nodes, which may alter histology
For culture (if clinically indicated) or for flow cytometry, use end of lymph node
For touch imprints, fix in ethanol, stain with H&E, Wright stain or use for immunocytochemistry
Use scrapes / cell suspension for flow cytometry, cytogenetics, molecular gene rearrangement studies, FISH
Sections for formalin or B5 fixation should be 3 - 4 mm thick to allow for proper fixation; B5 (mercury containing fixative) provides best morphologic details
Snap freezing is best for research, some immunohistochemistry, future molecular studies
Formalin fixation is best for PCR
EM is helpful only rarely to diagnose Langerhans histiocytosis or occasionally metastatic tumors
Include extranodal fat (infiltration implies malignant process)
Note: the most important slides to obtain are sufficient H&E for diagnosis
Frozen sections may confirm involvement of node by a disease process, but do not use to obtain a specific diagnosis because freezing artifacts may hinder diagnosis

Grossing for staging

Most lymph nodes are near the wall of the organ
Be aware of minimal number of nodes required for staging some carcinomas
May want to fix first overnight - lymph nodes stand out as white nodules
Carnoy solution helps clear the fat
Clearing solutions (such as ethanol, diethyl ether, glacial acetic acid and formalin) may help identify additional lymph nodes (Am J Surg Pathol 1997;21:1387, Arch Pathol Lab Med 2003;127:1552, Arch Pathol Lab Med 2001;125:642)
For each anatomic group, describe the number of nodes, the size of the largest node and any gross features
Submit all lymph nodes for histology; section node if 5 mm or greater in diameter
For large nodes grossly involved by tumor, only one section needs to be submitted to demonstrate tumor and possible extranodal extension but save remainder for resampling if necessary
For other large nodes, submission of entire node detects additional metastases in some cases (Am J Clin Pathol 1998;109:571)
Describe number of nodes in each cassette and whether whole or sectioned

Features to report by organization

Features to report

Clinical history: prior diagnoses of lymphoma, presence of lymphadenopathy or organomegaly, hematologic findings, constitutional symptoms, HIV status, prior immune abnormalities, autoimmune disorders, other relevant serology and other related conditions such as H. pylori infection
Anatomic site
Tumor type(s) (WHO classification), grade (if relevant)
Focal or complete involvement of lymph node or other structures
Specimen inadequacy
Results of ancillary studies
Diagnosis should incorporate all of the above findings or explain any inconsistencies
Checklist (2004)
References: Hum Pathol 2002;33:1064, Mod Pathol 2004;17:131

Hamartoma

Table of Contents

Definition / general

A rare, benign parenchymal lesion composed of disorganized red pulp without well formed white pulp

Essential features

Circumscribed nodule in spleen
Composed of disorganized red pulp and absent white pulp
CD8 confirms the presence of disorganized sinuses

Terminology

Also called splenoma

ICD coding

ICD-11: 3B81.0 - tumor-like conditions of spleen

Epidemiology

Uncommon
Occurs in all age groups and exhibits no sex predilection

Sites

Spleen

Pathophysiology

Postulated to represent a malformation, vascular neoplasm or posttraumatic reactive lesion
Debate exists if hamartoma is a true neoplasm (Mod Pathol 2011;24:108)
- Human androgen receptor assay (HUMARA) suggests a polyclonal lesion
- However, a single case showed dic(16;21)(p13.1;p11.2)del(16)(q11.1) with gains of several chromosomes and monosomy 21 (Cancer Genet Cytogenet 2005;157:160)

Etiology

Unknown

Clinical features

Usually an incidental finding in an asymptomatic individual
May infrequently present with symptoms related to mass effect, such as pain or a palpable mass
Can present with hematologic complications associated with hypersplenism, such as thrombocytopenia and anemia (Am J Case Rep 2022;23:e937195)
Splenic rupture is rare
Rare cases associated with tuberous sclerosis and Alagille syndrome (Fetal Pediatr Pathol 2014;33:216)

Diagnosis

Radiology (ultrasound, CT or MRI) demonstrates the presence of a solid mass
Splenic biopsy (FNA, needle biopsy)
Splenectomy
Reference: Am J Case Rep 2022;23:e937195

Laboratory

See Clinical features

Radiology description

Increased blood flow on color Doppler ultrasound in the splenic lesion
Most appear on MRI as isointense lesions on T1 weighted image and heterogeneously hyperintense on T2 weighted image

Radiology images

Images hosted on other servers:

Heterogenous enhancing splenic lesion on CT

Color Doppler showing dotted blood flow signals in mass

T1 and T2 weighted MRI of splenic mass

Isointense mass

Prognostic factors

Excellent prognosis

Case reports

19 year old man with upper abdominal pain (Am J Case Rep 2022;23:e937195)
21 year old man with an incidental splenic lesion on imaging (World J Clin Cases 2021;9:7231)
49 year old woman with a palpable painless mass on the left abdomen (Ann Med Surg (Lond) 2018;36:199)
65 year old man with pancytopenia (Hematol Transfus Cell Ther 2020;42:390)

Treatment

Splenectomy or partial splenectomy is curative

Gross description

Red circumscribed nodule, well demarcated from the uninvolved spleen (Semin Diagn Pathol 2019;36:16)
Usually single, rarely multiple
Median size of 50 mm (range: < 10 - 100 mm) (Semin Diagn Pathol 2021;38:159)
Can have a bulging appearance that compresses the adjacent normal spleen

Gross images

Contributed by Nadine S. Aguilera, M.D. and Emily Gardner, M.D.

Solitary well circumscribed mass

Hamartoma with similar texture and color as the spleen

Images hosted on other servers:

Nodule of increased stiffness

Resected spleen

Microscopic (histologic) description

Benign vascular proliferation composed of disorganized red pulp elements (sinuses and cords) only (Mod Pathol 2011;24:108)
Unencapsulated with borders that may be ill defined microscopically (Semin Diagn Pathol 2019;36:16)
Scant fibrous trabeculae
No well formed white pulp
Usually lacks cytologic atypia
CD8+ sinuses present
Additional features may include focal sclerosis, calcifications, hemorrhage, peliosis, plasmacytosis, extramedullary hematopoiesis, eosinophils and mast cells
Rarely, scattered bizarre cells featuring ill defined cytoplasm and irregular nuclei with vesicular chromatin that are likely dendritic or stromal myoid in nature are identified

Microscopic (histologic) images

Contributed by Nadine S. Aguilera, M.D.

Splenic hamartoma and uninvolved spleen

Red pulp

CD8 stain

CD34 stain

CD21 stain

CD68 stain

Cytology description

Nonspecific
- No atypia or mitosis
- Stromal cells can be bizarre

Positive stains

CD8+, CD31+, factor VIII+, vimentin+ and variable CD34: sinus lining cells (Arch Pathol Lab Med 2009;133:147)
- CD8 positivity is particularly helpful for distinguishing this lesion from other vascular lesions of the spleen
CD34+, CD31+ and CD8- : capillaries
CD31+, CD34- and CD8-: small veins

Negative stains

CD21: no white pulp
SMA

Molecular / cytogenetics description

See Pathophysiology

Sample pathology report

Spleen, splenectomy:
- Splenic hamartoma (see comment)
- Comment: Histopathologic examination of the [size] cm mass revealed a vaguely demarcated area showing red pulp without white pulp. Immunohistochemical staining was performed on block [X]. CD8 stains the endothelium of normal splenic sinuses in the normal splenic tissue as well as the disorganized sinuses in the hamartoma. CD20 and CD3 staining revealed a lack of B cells and rare T cells, respectively, within the hamartoma. Normal white pulp stains with CD20 with peripheral CD3 positive T cells. Kappa and lambda RNA staining revealed polytypic plasma cells throughout the tissue, without monotypic staining in the normal splenic white pulp. The findings support a diagnosis of splenic hamartoma. Extramedullary hematopoiesis is present and commonly found in splenic hamartomas.

Differential diagnosis

Splenic hemangioma:
- Cystically dilated and blood filled spaces, lined by a single layer of bland flat endothelial cells
- Does not contain cords and sinuses
- Vascular spaces are separated by thin fibrous septa
- Mitoses are absent
- CD34+, CD31+, factor VIII+, ERG +, CD8-, CD68- and D2-40-
Littoral cell angioma:
- Benign neoplasm unique to the spleen
- Pleomorphic vascular spaces ranging from slit-like to dilated cystic spaces
- Spaces commonly filled with papillary projections lined by tall / plump endothelial cells
- Tall lining cells: CD31+, CD68+, CD21 focal+, CD8- and CD34-
Sclerosing angiomatoid nodular transformation of the spleen (SANT):
- Benign vascular lesion of uncertain etiology, likely reactive
- Predominantly affects adults
- Typically presents as a single mass with a central stellate scar
- Multiple angiomatoid nodules containing a mixture of capillaries, sinusoids and veins
- Interspersed fibrosclerotic stroma
- Endothelial cells can be prominent
Peliosis:
- Can present as an isolated finding but most commonly presents in association with peliosis hepatis
- Multiple blood filled spaces that are haphazardly scattered in the red pulp
- Spaces are lined by inconspicuous endothelial cells; however, endothelial cells may be completely absent
- Key differentiating factor is the presence of white pulp
- If an endothelial lining is present: CD34+, factor VIII+ and CD31+

Additional references

Semin Diagn Pathol 2021;38:154

Board review style question #1

Which of the following features is seen in splenic hamartoma?

Anastomosing vessels
Dilated sinuses
Red pulp without white pulp
Sclerosing nodules and entrapped vessels

Board review style answer #1

C. Red pulp without white pulp. This is an essential feature of splenic hamartoma. Answer A is incorrect because anastomosing vessels are seen with splenic angiosarcoma. Answer B is incorrect because dilated sinuses are seen with congestive splenomegaly. Answer D is incorrect because sclerosing nodules and entrapped vessels are seen in sclerosing angiomatoid nodular transformation of the spleen (SANT).

Comment Here

Reference: Hamartoma

Hemangioma-lymph nodes

Table of Contents

Definition / general

Rare as primary lymph node tumor, usually an extension of soft tissue tumor
May represent a metastasis from epithelioid hemangioma of bone (Int J Surg Pathol 2006;14:9) or pulmonary sclerosing hemangioma (Arch Pathol Lab Med 2003;127:321, Ann Thorac Surg 2005;80:2351)

Case reports

4 year old boy with inguinal node hemangioma (Arch Pathol Lab Med 1989;113:804)
21 year old woman with hemangiomas of small bowel and local lymph nodes (J Clin Pathol 2000;53:552)

Microscopic (histologic) description

Resembles hemangiomas at other sites
Discrete mass lesion, either capillary or cavernous
May be highly cellular or epithelioid

Microscopic (histologic) images

AFIP images

Hemangioma

Capillary / cavernous hemangioma

Epithelioid hemangioma

Lobular capillary hemangioma

Cellular hemangioma

Differential diagnosis

Kimura disease: inflammatory process with prominent vessels
Other vascular tumors
Vascular transformation of sinuses: limited to sinuses

Additional references

Am J Surg Pathol 1992;16:335

Hemangioma-spleen

Table of Contents

Definition / general

Splenic hemangioma is a benign splenic lesion that is typified by the proliferation of variable sized blood vessels lined by bland endothelial cells
Most common benign splenic tumor

Essential features

Typically an asymptomatic, incidentally discovered splenic vascular lesion
Vascular channels are lined by a single layer of flat to plump endothelial cells without atypia or significant mitosis
Endothelial cells will stain positive for vascular markers and negative for histiocytic markers

Terminology

Hemangioma, splenic hemangioma, hemangioma of the spleen

ICD coding

ICD-10
- D18.03 - hemangioma of intra-abdominal structures
- D73.89 - other diseases of spleen

Epidemiology

Most are discovered in middle aged adults
No clear sex predilection (J Gastrointest Surg 2000;4:611)

Pathophysiology

Pathogenesis of splenic hemangiomas has not been well studied but may involve pathways that lead to increased expression of angiogenic factors such as VEGF (J Cancer Res Ther 2016;12:1323)

Etiology

Not known

Clinical features

Usually a small and solitary splenic lesion but can be large or diffuse
Majority are asymptomatic and incidentally discovered
Larger lesions may present as a palpable mass with abdominal discomfort
Can be associated with systemic angiomatosis syndromes, such as Klippel-Trenaunay syndrome (JBR-BTR 2013;96:357)
Larger hemangiomas may rarely precipitate Kasabach-Merritt syndrome, a consumptive coagulopathy caused by platelet sequestration within the hemangioma (Srp Arh Celok Lek 2012;140:777, Indian J Surg 2015;77:166)
Can rarely be associated with splenic rupture and massive hemorrhage (Front Cardiovasc Med 2022;9:925711)

Diagnosis

Hemangiomas have well described imaging characteristics but histologic analysis is necessary for definitive diagnosis (Semin Diagn Pathol 2003;20:128)
Histologically, the lesions should consist of vascular channels lined by endothelial cells that lack significant atypia or mitotic activity (Radiographics 2022;42:683)
Immunohistochemically, the lesion should stain positive for vascular markers CD31, CD34, ERG, D2-40 (variable) and negative for histiocytic markers CD68 and CD163 (Arch Pathol Lab Med 2019;143:1093)

Laboratory

Laboratory workup is typically noncontributory but anemia and thrombocytopenia may be appreciated in a subset of patients

Radiology description

Often a small, well circumscribed lesion on imaging
On ultrasound, it is typically a hyperechoic, homogenous lesion with posterior acoustic shadowing (Radiographics 2022;42:683)
On CT, it will appear as a hypoattenuating mass; centripetal enhancement is often appreciated following injection of contrast (Jpn J Radiol 2022;40:664)
On MRI, the lesion will be hypointense on T1 and hyperintense on T2 (AJR Am J Roentgenol 2006;186:1533)

Radiology images

Images hosted on other servers:

Giant splenic hemangioma

Cavernous splenic hemangioma

Splenomegaly and hemangiomas

Prognostic factors

Benign lesion with an excellent prognosis
Larger lesions are more likely to be associated with adverse events, such as splenic rupture

Case reports

11 year old girl who underwent successful splenic embolization for a 6 cm splenic hemangioma (BMC Pediatr 2018;18:354)
20 year old man with splenomegaly, abdominal pain, diarrhea and pancytopenia found to have a large splenic hemangioma and multiple hemangiomas in the vertebrae (BMC Res Notes 2016;9:76)
25 year old man with hypoglycemia and a 6 cm splenic lesion (Diagn Pathol 2019;14:135)
36 year old woman who successfully underwent preoperative partial splenic embolization followed by laparoscopic partial splenectomy for treatment of a splenic hemangioma (Medicine (Baltimore) 2018;97:e0498)
38 year old woman with anemia, thrombocytopenia and coagulopathy found to have a large splenic hemangioma (Indian J Surg 2015;77:166)
41 year old man with a 5 cm splenic spindle cell hemangioma (Medicine (Baltimore) 2019;98:e14555)

Treatment

Total splenectomy
- Typically reserved for large or multifocal lesions that cannot be safely treated by a partial splenectomy or emergent situations (J Minim Access Surg 2014;10:42, Radiographics 2022;42:683)
Partial splenectomy (Surg Laparosc Endosc Percutan Tech 2018;28:287)
- Due to the segmental blood supply of the spleen, a segmental artery can be ligated followed by resection of the demarcated, newly ischemic area (Surg Endosc 2015;29:94)
- Offers a safe alternative to total splenectomy in localized cases; preserves splenic function and reduced post operative complications (Surg Endosc 2014;28:3273, Ann Hepatobiliary Pancreat Surg 2018;22:116, Updates Surg 2022;74:1153)
Embolization
- Splenic artery embolization may be a safe and less invasive option compared to traditional splenectomy for large lesions or in emergent situations, such as spontaneous splenic rupture or Kasabach-Merrit Phenomenon (BMC Pediatr 2018;18:354, Vasc Endovascular Surg 2021;55:741, Front Cardiovasc Med 2022;9:925711)
Partial embolization
- Partial embolization with or without subsequent partial splenectomy may be an option for localized lesions (Langenbecks Arch Surg 2011;396:397, Int J Surg Case Rep 2022;92:106837)

Gross description

Solitary or multifocal unencapsulated lesion (Am J Surg Pathol 1997;21:827)
Typically, well demarcated from surrounding splenic tissue but can have irregular borders
Lesion is often dark red and spongy in appearance with cysts of varying size

Gross images

Contributed by @Andrew_Fltv on Twitter

Hemangioma

Microscopic (histologic) description

Vascular spaces lined by flat endothelial cells without significant atypia (Semin Diagn Pathol 2003;20:128)
Fibrous septa of variable width separating the vascular channels
Low mitotic rate without necrosis
Extramedullary hematopoiesis, thrombosis, infarction, cystic degeneration and fibrosis can occur (Srp Arh Celok Lek 2013;141:380, Auerbach: Diagnostic Pathology - Spleen, 2nd Edition, 2022)
Intermixed inflammation such as lymphocytes, histiocytes, plasma cells, neutrophils and even eosinophils can be present
Primary histologic variants
- Cavernous
  - Dilated, congested thin walled vessels
- Capillary
  - Small anastomosing vascular channels
Other described histologic variants
- Sclerosing
  - Increased sclerosis in bands of smaller amounts that can be morphologically similar / identical to sclerosing angiomatoid nodular transformation
- Spindle cell
  - Small, slit-like blood vessels with flat endothelial cells and a spindle cell stroma
  - Must be differentiated from Kaposi sarcoma (Medicine (Baltimore) 2019;98:e14555)
- Myoid
  - Small vascular channels with eosinophilic, spindled stroma that stains positive from smooth muscle markers (Iran J Med Sci 2017;42:89, Histopathology 1999;35:328)
- Splenic cord capillary
  - Nodules composed of small vascular channels surrounded by a fibrous stroma
  - Histologically will appear similar to sclerosing angiomatoid nodular transformation but will not contain trapped CD8+ sinuses (Diagn Pathol 2019;14:135)

Microscopic (histologic) images

Contributed by David Danielson, M.D., John Schmieg, M.D., Ph.D., Aaron Auerbach, M.D., M.P.H. and @Andrew_Fltv on Twitter

Architectural effacement by a vascular neoplasm

Variable sized blood vessels lined by bland endothelial cells

Typical proliferation of blood vessels

Open dilated vascular channels filled with blood

Cavernous hemangioma

Scattered megakaryocytes, erythroid islands

Hemangioma with extramedullary hematopoiesis

Hemangioma

Open dilated vessels lined by bland CD31+ endothelial cells

CD31 positive

CD34 positive

CD8

CD68 negative

D2-40 negative

Cytology description

Groups of bland, spindled endothelial cells with a background of erythrocytes

Positive stains

CD31, CD34, ERG, factor VIII

Negative stains

CD8, CD21, D2-40 (usually negative but can occasionally be expressed), CD68, CD163

Molecular / cytogenetics description

Molecular / cytogenetic aberrations in splenic hemangiomas have not been well studied with only one case report identified that describes a clonal cytogenetic abnormality (Int J Oncol 2016;48:1242)

Sample pathology report

Spleen, splenectomy:
- Hemangioma (see comment)
- Comment: The lesion consists of large dilated vascular spaces separated by fibrous bands. The vascular channels are lined by endothelial cells that range from flat to plump in appearance and have minimal cellular atypia. Mitotic figures and necrosis are not appreciated. Normal spleen can be appreciated on the periphery of the lesion. Immunohistochemical staining, with adequately reactive controls, is performed for CD31, CD34, ERG, factor VIII, CD68, CD163, D2-40 and CD8. The endothelial lining cells demonstrate positive staining for CD31, CD34, ERG and factor VIII with negative staining for CD68, CD163, D2-40 and CD8. Overall, the histologic and immunohistochemical findings are consistent with the diagnosis of a hemangioma.

Differential diagnosis

Angiosarcoma (Int J Clin Exp Pathol 2015;8:14040):
- Cellular atypia, high mitotic rate, invasive / irregular border and necrosis
Littoral cell angioma (Int J Clin Exp Pathol 2015;8:14040):
- Anastomosing vascular channels lined by cuboidal to columnar cells that are often desquamated into the vascular channel
- Vascular lining cells are CD68+, CD163+, CD31+ and CD34-
Kaposi sarcoma (World J Clin Cases 2021;9:4765):
- Irregular vascular channels that are often slit-like with an atypical spindle component
- Atypical spindle cells are HHV8+ and CD34+
Lymphangioma (World J Gastroenterol 2009;15:5620, Front Oncol 2022;12:933777):
- Endothelial lined channels that are D2-40+
Sclerosing angiomatoid nodular transformation (SANT) (Arch Pathol Lab Med 2007;131:974):
- Multiple angiomatoid nodules consisting of capillaries, small veins and trapped sinusoids that are surrounded by a fibrous appearing stroma
- Can look very similar / identical to sclerosing hemangioma and may be easily separated by H&E
- Capillaries CD8-, CD31+, CD34+
- Veins CD8-, CD31+, CD34-
- Sinusoids CD8+, CD31+, CD34-
- By CD31 immunohistochemistry, SANT has sparse centrally located vessels within the nodular areas whereas sclerosing hemangioma has numerous blood vessels with a medusoid pattern
Splenic hamartoma (Am J Case Rep 2022;23:e937195, Acta Med Iran 2017;55:77):
- Unencapsulated lesion that often has a poorly defined border
- Composed entirely of disorganized red pulp elements (vascular sinusoids, splenic cords and capillaries)

Additional references

Auerbach: Diagnostic Pathology - Spleen, 2nd Edition, 2022

Board review style question #1

A splenic lesion was discovered during lung cancer screening. The image above demonstrates a section of the lesion on H&E. The cells of interest stain positive for CD31, CD34 and ERG. They are negative for CD68, CD163 and D2-40. CD8 staining is positive on sinusoids on the periphery of the lesion but negative within the lesion. What is the most likely diagnosis?

Angiosarcoma
Hemangioma
Littoral cell angioma
Lymphangioma
Splenic hamartoma

Board review style answer #1

B. Hemangioma. The prompt describes an incidentally discovered splenic vascular lesion. Answer A is incorrect because the description of flat endothelial cells without atypia makes the diagnosis of angiosarcoma less likely. Answer C is incorrect because histiocytic markers (CD68 and CD163) are typically positive in littoral cell angiomas. Answer D is incorrect because negative staining for D2-40 helps to rule out lymphangioma. Answer E is incorrect because splenic hamartomas typically consist of disorganized red pulp elements, which include CD8+ sinusoids.

Comment Here

Reference: Hemangioma - spleen

Board review style question #2

Which of the following statements about a splenic hemangioma is true?

Cellular atypia and increased mitosis are often present
Malignant transformation is common
Most are incidentally discovered and asymptomatic
Splenic hemangiomas have a known predilection for women on oral contraceptive pills
Splenic hemangiomas will stain positive for histiocytic markers (CD68 and CD163)

Board review style answer #2

C. Splenic hemangiomas are typically incidentally discovered and asymptomatic. Answer A is incorrect because splenic hemangiomas will have bland spindled to epithelioid cells that lack atypia or significant mitotic activity. Answer B is incorrect because malignant transformation to angiosarcoma has been reported in rare cases but is extremely uncommon. Answer D is incorrect because splenic hemangiomas do not have a known predilection for men or women. Answer E is incorrect because they will stain positive for vascular markers (ERG, CD31, CD34) and negative for histiocytic markers (CD68 and CD163).

Comment Here

Reference: Hemangioma - spleen

Hereditary spherocytosis

Table of Contents

Definition / general

Congenital hemolytic anemia due to genetically determined abnormal spectrin and ankyrin molecules, leading to defects in red blood cell membrane, causing spherical shape and lack of plasticity
Red blood cells become trapped within spleen and have less than usual 120 day lifespan
Splenic function is normal
Osmotic fragility: increased; basis for diagnostic testing

Diagrams / tables

Images hosted on other servers:

Scatter diagram of CBC

Treatment

Splenectomy (prolongs survival of red blood cells, although they still have membrane defects)

Gross description

Firm, deep red tissue, thin capsule, no grossly identifiable Malpighian follicles, 100 - 1000 g

Microscopic (histologic) description

Marked congestion in cords
Sinuses appear empty but actually contain ghost red blood cells
May have prominent endothelial lined sinuses, hemosiderin deposition, erythrophagocytosis

Peripheral smear images

Images hosted on other servers:

Small spherocytes

Histiocytic sarcoma

Table of Contents

Definition / general

Malignant proliferation of cells with morphologic and immunophenotypic features of mature histiocytes, excluding dendritic cell neoplasms, Langerhans cell neoplasms and myeloid sarcomas with monocytic differentiation
Mostly in extranodal locations, including skin, soft tissue, lung and central nervous system
- A small subset (~17%) in lymph nodes
Diagnosis requires histopathologic evidence of neoplasm and confirmation of cell origin by special studies

Essential features

Malignant neoplasm of mature histiocytes
May show highly pleomorphic or spindle cytology, mimicking pleomorphic or spindle cell sarcoma
Can be dedifferentiated from B cell lymphomas, myeloid neoplasms and rarely T cell lymphomas
Positive BRAF V600E mutation and clonal IGH or TRG rearrangements in a subset of cases

Terminology

Histiocytic medullary reticulosis, malignant histiocytosis, true histiocytic lymphoma, true histiocytic sarcoma

ICD coding

ICD-O: 9755/3 - Histiocytic sarcoma
ICD-10: C96.A - Histiocytic sarcoma

Epidemiology

< 1% of all hematolymphoid neoplasms (Leuk Lymphoma 2019;60:553)
Incidence: 0.17 cases per 1,000,000 individuals
Usually adults, median age ~61 years
Slight male predilection, M:F = 5:3

Sites

Mainly extranodal locations, including skin, soft tissue, lung and central nervous system (Leuk Lymphoma 2019;60:553)
~17% of cases in lymph nodes

Etiology

No specific etiologic agents discovered
~25% of cases transdifferentiated from B cell lymphomas, including small lymphocytic lymphoma / chronic lymphocytic leukemia, follicular lymphoma, mantle cell lymphoma, extranodal marginal zone lymphoma and diffuse large B cell lymphoma (Hum Pathol 2016;55:39, Eur J Haematol 2016;97:9)
Rare cases associated with B cell or T cell lymphoblastic lymphoma / acute lymphoblastic leukemia, myeloid neoplasms and mediastinal nonseminomatous germ cell tumors (Lancet Oncol 2004;5:248, Medicine (Baltimore) 2016;95:e2515)

Clinical features

Mostly advanced diseases with B symptoms (fever, fatigue and weight loss)
Physical examinations: lymphadenopathy, hepatosplenomegaly and skin lesions
Lytic bone lesions and rare central nervous system involvement
Median overall survival, 6 months (Leuk Lymphoma 2019;60:553)

Diagnosis

Presence of mature histiocytic cytology with variable degree of pleomorphism
Positive for histiocytic markers, particularly CD68, CD163 and lysozyme
Exclusion of myeloid sarcoma with monocytic differentiation, Langerhans cell neoplasm and other mimicries

Prognostic factors

Surgery alone or in combination with radiotherapy was associated with a prolonged overall survival in patients with skin and connective tissue disease (Leuk Lymphoma 2019;60:553)
Surgical treatment showed some statistically insignificant improvement in overall survival in patients with gastrointestinal and lung disease
Patients with hematopoietic and reticuloendothelial system involvement had a poor prognosis even with systemic chemotherapy
Compared with de novo cases, secondary histiocytic sarcomas have a more aggressive course and shorter overall survival (Clin Lymphoma Myeloma Leuk 2018;18:e427)

Case reports

47 year old woman with primary central nervous system histiocytic sarcoma with PDGFR mutation and PDL1 / PDL2 expression (Radiat Oncol 2018;13:167)
50 year old African American woman with clonally related histiocytic sarcoma and B lymphoblastic leukemia / lymphoma (Am J Clin Pathol 2019;152:486)
63 year old white woman with histiocytic sarcoma associated with splenic marginal zone lymphoma (J Med Case Rep 2017;11:92)
72 year old man with histiocytic sarcoma secondary to chronic myeloid leukemia (Eur J Haematol 2016;97:9)
74 year old man with histiocytic sarcoma arising from hairy cell leukemia (J Clin Oncol 2014;32:e117)
75 year old man with histiocytic sarcoma associated with follicular lymphoma (Clin Lymphoma Myeloma Leuk 2019;19:e1)

Treatment

Localized unifocal disease: surgical resection if possible, followed by adjuvant radiotherapy and chemotherapy
Disseminated disease: more intense chemotherapy regimens, including ifosfamide, carboplatin and etoposide; CHOP-like (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy; autologous hematopoietic stem cell transplantation (Clin Lymphoma Myeloma Leuk 2019;19:522)
Central nervous system cases: surgery, chemotherapy and focal radiation (Radiat Oncol 2018;13:167, Leuk Lymphoma 2016;57:1961)
Cases with activated RAS / MEK / ERK pathway: MEK inhibitor, trametinib (Int J Hematol 2019;109:228)

Microscopic (histologic) description

Diffuse infiltration in the soft tissue or characteristic sinusoidal infiltration in the lymph nodes, liver and spleen
Effacement of nodal architecture or commonly sinus expansion with sparing of follicles
Large tumor cells with variable pleomorphism but often resembling mature histiocytes
Oval or irregular and eccentrically placed nuclei with vesicular chromatin, large nucleoli and occasional grooves
Abundant eosinophilic cytoplasm, often foamy or vacuolated
Rarely with multinucleated giant tumor cells, erythrophagocytosis or focal spindling cytology
Increased mitotic figures and apoptotic cells and presence of tumor necrosis
Mixed inflammatory background with variable numbers of reactive lymphocytes, plasma cells, benign histiocytes and eosinophils
Reference: Surg Pathol Clin 2019;12:805

Microscopic (histologic) images

Contributed by Zenggang Pan, M.D., Ph.D.

Nodal histiocytic sarcoma

AFIP images

True histiocytic lymphoma

True histiocytic lymphoma with prominent erythrophagocytosis

CD45RB and CD68

S100

Positive stains

CD68, CD163, lysozyme, CD45, alpha-1-antitrypsin
CD4, HLA-DR, CD11c, CD14, CD15
Reference: Surg Pathol Clin 2019;12:805

Negative stains

B cell and T cell markers
Follicular dendritic markers: CD21, CD23 and CD35
Langerhans cell markers: CD1a and CD207
S100 typically negative albeit focal reactivity in some cases
CD34, CD30, HMB45, myeloperoxidase and cytokeratins
Reference: Surg Pathol Clin 2019;12:805

Electron microscopy description

Abundant surface activity, microfilaments, short segments of rough endoplasmic reticulum, scattered haloed granules
No Birbeck granules
Reference: Surg Pathol Clin 2019;12:805

Molecular / cytogenetics description

Clonal IGH and TRG rearrangements in a subset of bona fide cases and cases dedifferentiated from lymphomas (Oncotarget 2016;7:78355)
Cases transdifferentiated from B cell lymphomas retain the same genetic alterations in the prior B cell lymphoma, including t(14;18) in follicular lymphoma and del(13q) in small lymphocytic lymphoma / chronic lymphocytic leukemia (Diagn Cytopathol 2015;43:659)
BRAF V600E mutation detected in up to 63% of cases (Histopathology 2014;65:261)
Rare cases associated with mediastinal nonseminomatous germ cell tumors harbor isochromosome 12p (Medicine (Baltimore) 2016;95:e2515)

Sample pathology report

Lung, right upper lobe, wedge biopsy:
- Histiocytic sarcoma, dedifferentiated from follicular lymphoma (see comment)
- Comment: The patient had a history of follicular lymphoma (grade 1 - 2 of 3) 3 years ago, and the current pulmonary histiocytic sarcoma demonstrates IGH-BCL2 rearrangement by FISH studies and clonal IGH rearrangements by PCR assays. Therefore, this histiocytic sarcoma represents dedifferentiation from previous follicular lymphoma, which has been reported in the literature (Leukemia 2014;28:1937).
- Microscopic description: The wedge biopsy reveals a diffuse infiltrate of large, pleomorphic cells. The tumor cells have round or irregular nuclei, vesicular chromatin and prominent nucleoli. The cytoplasm is abundant and pale staining. Frequent mitotic figures and apoptotic cells are noted. No small lymphoma cells are present within the specimen.
- Immunohistochemical stains: The large tumor cells are diffusely positive for CD45, CD68, CD163 and lysozyme. S100 only stains a small subset of cells. All other markers studied are negative, including CD1a, CD3, CD20, cytokeratins (AE1 / AE3, CK7 and CK20) and melanocytic markers (SOX10, HMB45 and MelanA).
- Flow cytometric assays: No evidence of monotypic B cell or abnormal T cell population detected.
- FISH studies: Positive for IGH-BCL2 gene rearrangements in 47% of 200 cells analyzed.
- Molecular studies: Positive for clonal IGH gene rearrangement. Negative for clonal TRG gene rearrangement.

Differential diagnosis

Diffuse large cell lymphoma:
- Rarely shows prominent sinusoidal infiltrative pattern in lymph nodes
- Usually smaller than neoplastic histiocytes with less amounts of cytoplasm
- Positive for B cell markers: CD20, CD79a, PAX5
- Negative for histiocytic markers: CD68, CD163 and lysozyme
Anaplastic large cell lymphoma:
- Often sinusoidal infiltrative pattern in lymph node
- Uniformly CD30+
- Variable expression of T cell markers and ALK
- Negative for histiocytic markers
Rosai-Dorfman disease:
- Markedly expanded sinus in lymph node
- Large histiocytes with abundant cytoplasm and emperipolesis
- No significant cytologic atypia
- S100+, CD1a-, CD207-
Langerhans cell histiocytosis:
- Often sinusoidal infiltrative pattern in lymph node
- Prominent reactive eosinophils
- Positive CD1a, S100 and CD207
- CD68 variably positive
- Negative for CD163 and lysozyme
Metastatic carcinoma with anaplastic features:
- Clinical history of carcinoma
- Positive for cytokeratin
Metastatic melanoma:
- May show prominent sinus infiltrative pattern with histiocytic cytology
- Positive for S100, HMB45 and SOX10
- Negative for histiocytic markers
Myeloid sarcomas with monocytic differentiation:
- Blasts smaller than neoplastic histiocytes with a higher N/C ratio
- Current or subsequent involvement in peripheral blood and bone marrow
- High Ki67 proliferation index and often positive for CD56
Reactive histiocytosis and storage diseases:
- May present with a marked histiocytic infiltration in the sinuses
- Lack of significant cytologic atypia

Additional references

Arch Pathol Lab Med 2018;142:1322, Clin Lymphoma Myeloma Leuk 2018;18:e427, Blood 2018;131:265, Am J Surg Pathol 2009;33:863

Board review style question #1

Which of the following immunohistochemical stains are mostly positive in histiocytic sarcoma?

CD4, CD1a, S100
CD21, CD23, CD35
CD34, myeloperoxidase, CD117
CD45, CD68, CD163

Board review style answer #1

D. CD45, CD68, CD163

Comment Here

Reference: Histiocytic sarcoma

Board review style question #2

Which of the following statements is true regarding histiocytic sarcoma?

Cases dedifferentiated from B cell lymphomas usually retain the expression of B cell markers
Clonal IGH or TRG rearrangements detected in a subset of cases
Most cases initially occur in the lymph nodes
Typically expresses CD68, S100 and CD1a

Board review style answer #2

B. Clonal IGH or TRG rearrangements detected in a subset of cases

Comment Here

Reference: Histiocytic sarcoma

HIV

Table of Contents

Definition / general

Human immunodeficiency viruses (HIV) include HIV1 and HIV2, which belong to Lentivirus (a subgroup of retrovirus)
HIV1 causes acquired immunodeficiency syndrome (AIDS), a condition characterized by progressive failure of the immune system leading to opportunistic infections and cancers (PLoS One 2016;11:e0162704)
World Health Organization (WHO) defines advanced HIV disease as CD4 cell count < 0.2 x 10⁹/L or patient has disease manifestations of WHO stage 3 or 4 in adults and adolescents (WHO: HIV and AIDS [Accessed 29 February 2024])

Essential features

HIV infection is classified into different stages: 3 stages per The U.S. Centers for Disease Control and Prevention (CDC) and 4 stages per WHO
Viral load and CD4+ T cell count is useful for disease follow up
Per WHO, an estimated 39.0 million (33.1 - 45.7 million) people were living with HIV (LWH) at the end of 2022
In 2022, estimated that 630,000 (480,000 - 880,000) people died from HIV related causes and 1.3 million (1.0 - 1.7 million) people acquired HIV (WHO)

ICD coding

ICD-10: B20 - human immunodeficiency virus (HIV) disease
ICD-11: 1C62 - human immunodeficiency virus disease without mention of tuberculosis or malaria

Epidemiology

HIV1 is the most common subtype and the most common subtype associated with AIDS throughout most of the world
HIV2 is less common and is found mostly in Western Africa (J Gen Virol 2002;83:1253)
Clinical AIDS defining conditions include some of the following (refer to the complete list in MMWR Recomm Rep 2014;63:1)
- Kaposi sarcoma
- Lymphomas: Burkitt, immunoblastic, CNS
- Cervical carcinoma, invasive
- Encephalopathy, HIV related
- Wasting syndrome, HIV related
- Recurrent pneumonia
- Opportunistic infections caused by the following: Candida, Cryptococcus, Cryptosporidium, Histoplasma, herpes simplex virus, Mycobacterium, Pneumocystis, Toxoplasma, etc.

HIV infection has been classified into different stages per the CDC and WHO (MMWR Recomm Rep 2014;63:1, Virtual Mentor 2010;12:202)

CDC
Stage 0	Negative HIV test within 6 months of the first HIV diagnosis and remains 0 until 6 months after diagnosis
Stages	Age specific CD4+ T cell testing
	< 1 year		1 - 5 years		6 years - adult
	Cells/µL	%	Cells/µL	%	Cells/µL	%
1	≥ 1,500	≥ 34	≥ 1,000	≥ 30	≥ 500	≥ 26
2	750 - 1,499	26 - 33	500 - 999	22 - 29	200 - 499	14 - 25
3	< 750	> 26	< 500	< 22	< 200	< 14
Unknown stage	CD4 test results are missing

WHO
Stage 1	Asymptomatic or generalized lymphadenopathy of at least 2 sites for longer than 6 months
Stage 2	Unexplained weight loss of < 10% of body weight and recurrent respiratory / skin infections
Stage 3	Unexplained weight loss of > 10% of body weight, diarrhea (> 1 month), pulmonary tuberculosis (TB), mucocutaneous and systemic bacterial infections
Stage 4	AIDS defining illnesses, HIV wasting syndrome, pneumocystis pneumonia, recurrent severe bacterial pneumonia, extrapulmonary TB, Kaposi sarcoma, CNS toxoplasmosis, HIV encephalopathy, others

Pathophysiology

HIV is a spherical virus that attaches to the host cells with glycoproteins; the virus then integrates its chromosomal material into the host's cell, leading to generation of viral proteins and genetic material (StatPearls: Acquired Immune Deficiency Syndrome [Accessed 13 December 2023])
Cells in the lymph nodes that are infected include monocytes, macrophages and follicular dendritic cells
Progressive loss of CD4+ T cells occurs during the course of disease
B cell activation during early disease leads to hypergammaglobulinemia, autoimmune phenomenons and later decreased antibody production
Natural killer cell activity is also progressively decreased

Etiology

There are 4 modes of acquiring HIV infection
- Sexual contact with an infected partner
- Parenteral drug use
- Exposure to infected blood or blood products
- Perinatal exposure

Clinical features

Acute retroviral syndrome
- Headache, fever, rash, fatigue noted with initial HIV infection
- Occurs 1 - 3 weeks after infection and may last for 1 - 2 weeks
- Generalized lymphadenopathy
Early / asymptomatic HIV disease
- Latency period that may last for years
Advanced symptomatic HIV disease
- AIDS defining conditions
References: World Health Organization: WHO Case Definitions of HIV for Surveillance and Revised Clinical Staging and Immunological Classification of HIV Related Disease in Adults and Children [Accessed 5 January 2024], MMWR Recomm Rep 2014;63:1

Diagnosis

Screening test: performed on peripheral blood or body fluids
- Detection of antibodies to HIV glycoproteins by enzyme linked immunoassay (EIA) (J Infect Dis 2012;205:521, Curr Opin HIV AIDS 2012;7:125, J Infect Dis 2010;202:S270)
- Positive in about 2 - 4 weeks after infection
Confirmatory tests: antibodies to HIV through enzyme linked immunoassay fourth generation (15 - 20 days from infection) or HIV viral load test cutoff 50 copies/mL (10 - 15 days) or ultrasensitive cutoff 1 - 5 copies/mL (5 days from infection)
Latest recommendations: testing with immunoassay (both HIV1 and HIV2 antibodies) and p24 antigen
- Negative result: rules out infection within specific ranges of exposure and test sensitivity
- Positive result may have 4 scenarios
  - HIV1+ & HIV2-: HIV1 antibodies present
  - HIV1- & HIV2+: HIV2 antibodies present
  - HIV1+ & HIV2+: both HIV1 and HIV2 antibodies present
  - HIV1- or indeterminate & HIV2-: in this case nucleic acid test is done to identify the presence or absence of HIV1 acute infection
Once tested positive, viral load and CD4+ T cell counts are performed (Internist (Berl) 2016;57:773)

Laboratory

Anemia, neutropenia or thrombocytopenia
If the white blood cell and lymphocyte counts are within the reference ranges, then the CD4 count is most likely normal
If the absolute lymphocyte count is < 0.95 x 10⁹/L, then a CD4 count < 0.2 x 10⁹/L is likely (Acad Emerg Med 2011;18:385)
Based on the symptoms and organ involvement, different tests are performed
- Complete metabolic profile: baseline renal and hepatic function
- EKG, cardiac biomarkers and echocardiography
- Chest radiography, computed tomography of chest
- Arterial blood gas analysis
- Testing for tuberculosis (TB)
- Esophagogastroduodenoscopy, colonoscopy
- Testing for ova, parasites, bacteria and C. difficile toxins
- Computed tomography of the head and lumbar puncture with cerebrospinal fluid (CSF) analysis
- Positron emission tomography (PET)

Radiology description

Chest imaging: consolidation, ground glass opacity, cystic lesions, nodules and mass (AJR Am J Roentgenol 2012;198:1295)
Brain imaging: ring enhancing lesions, encephalitis and mass (Jpn J Radiol 2021;39:1023)
PET / CT: generalized lymphadenopathy, PET avid lesions in other organs

Prognostic factors

Prognosis of adults with HIV or AIDS is now approaching that of the general population; however, it depends on the effectiveness of combination antiretroviral therapy (cART) (J Hosp Med 2015;10:608, JAMA 2008;300:51)
Factors associated with poor prognosis from AIDS related conditions (Public Health Rep 2015;130:468, J Infect Dis 2009;199:991, J Int Assoc Physicians AIDS Care (Chic) 2011;10:5, HIV Clin Trials 2014;15:133)
- African American or mixed races
- Opportunistic infections
- Poor functional and nutritional status
- Anemia
- Substance abuse
- Low CD4+ count
- High HIV viral load
Type of malignancy also plays an important role in overall survival and progression free survival

Case reports

25 year old man presented with sudden onset of psychotic symptoms associated with fever, cough and general asthenia (Front Immunol 2021:12:669723)
40 year old man was diagnosed HIV positive in 2008 but his viral load estimation every year since then had always been below lower detection limit and he remained healthy without treatment (Case Rep Infect Dis 2018:2018:5279595)
40 year old man with a history of HIV on cART presented with dyspnea and hypertension (SAGE Open Med Case Rep 2020:8:2050313X20965423)
46 year old man with HIV infection on cART presented with fever off and on, splenomegaly, lymphadenopathy and severe thrombocytopenia (Int J STD AIDS 2021;32:286)
78 year old woman of African descent from Mtwara Region, south of Tanzania presented for evaluation of leukopenia and anemia (J Med Case Rep 2021;15:341)

Treatment

All individuals should be offered antiretroviral therapy (ART), regardless of the CD4 count or viral load
- Treatment results in sustained suppression of HIV RNA, improved cellular immunity (i.e., CD4 count), reduced HIV immune activation (e.g., proinflammatory cytokines, chronic inflammation and T cell activation) and decreased HIV transmission to others; however, access to care and treatment outcomes can differ depending upon demographic and psychosocial factors
cART / ART: includes reverse transcriptase inhibitors (RTIs), integrase inhibitors (IIs) and protease inhibitors (PIs) (Br J Haematol 2001;112:900, AIDS 2014;28:881, Cold Spring Harb Perspect Med 2012;2:a007161)
Latency reversing agents (LRAs): target the process of cell death via virus mediated cytolysis or immune associated clearance (Cell Host Microbe 2018;23:14, Nature 2012;487:482, PLoS Pathog 2014;10:e1004473)
Gene therapy: works by inserting a healthy gene into the cells, which acts by repressing the mutant RNA or correcting the mutant gene (Einstein (Sao Paulo) 2017;15:369)
Treatment of opportunistic infections and malignancies

Microscopic (histologic) description

Reactive and opportunistic infection

HIV patients with CD4+ cell counts < 0.2 x 10⁹/L, are prone to a wide variety of bacterial, viral, fungal and protozoal infections, which include
- Toxoplasma gondii, Pneumocystis jirovecii (previously Pneumocystis carinii), Cryptococcus neoformans, Mycobacterium avium, Mycobacterium tuberculosis, cytomegalovirus, herpes simplex viruses and Histoplasma capsulatum infections (StatPearls: HIV-1-Associated Opportunistic Infections [Accessed 13 December 2023])
Pathological findings depend on the organ involved and the type of infection
Most have lymphadenopathy, which includes florid follicular hyperplasia, paracortical hyperplasia, monocytoid B cell proliferation, granulomatous inflammation and necrosis
HIV lymphadenitis has 3 histologic patterns, which correspond to clinical stages: acute, chronic and burnout (Medeiros: Ioachim's Lymph Node Pathology, 5th Edition, 2021)
- Pattern A
  - Enlarged reactive follicles
  - Hyperplastic germinal centers
  - Diminished / absent mantle zones
  - Folliculolysis - disruption of germinal centers by small lymphocytes
  - Aggregates of monocytoid cells
- Pattern B
  - Disruption of follicular dendritic cell meshwork
  - Effacement of follicles
  - Involution of germinal centers
  - Increased plasma cells
  - Depletion of lymphocytes
  - Vascular proliferation
- Pattern C
  - Atrophic follicles
  - Hyalinized germinal centers
  - Excessive plasma cells
  - Marked loss of lymphocytes
  - Fibrosis

KSHV / HHV8 associated multicentric Castleman disease

Associated with 80% of HIV+ patients (Neth J Med 2015;73:202)
Seen in cases with low HIV viral load and median CD4 count (between 0.15 and 0.3 x 10⁹ cells) (J Clin Oncol 2011;29:2481, Blood 2011;118:3499, Blood 2013;122:4189)
Predominantly lymphadenopathy is noted with classic features
- Regressed follicles along with plasmacytosis
- Presence of plasmablasts in the mantle zones, which are medium to large cells with 1 - 2 nucleoli and a moderate amount of amphophilic cytoplasm
- Plasmablasts display negative to dim levels of CD20, positive expression for MUM1 and latency associated nuclear antigen (LANA) (a gene product of KSHV / HHV8 ORF73) and express cytoplasmic IgM lambda (Histopathology 2008;53:513, Blood 2001;97:2130)
Foci of Kaposi sarcoma may be seen (Blood 2000;95:1406, Am J Pathol 1997;151:1517, AIDS Rev 2008;10:25)
Increased risk of developing lymphoma

Polymorphic lymphoproliferative disorder arising in HIV

Incidence in HIV is < 5% (Am J Surg Pathol 2003;27:293, Virchows Arch 2012;461:93)
Architectural distortion by polymorphous infiltrate consisting of spectrum of B cells, including small lymphocytes, plasmacytoid cells, plasmablasts and immunoblasts along with T cells and histiocytes
May have Reed-Sternberg-like cells
Epstein-Barr virus (EBV) expression seen in both small and large cells
Responds well to cART

HIV associated lymphomas

Lymphomas arising in HIV+ patients now are classified under lymphomas arising in immune deficiency / dysregulation per 2022, WHO classification
HIV+ patients present with advanced clinical stage, bulky disease with a high tumor burden
Lymphomas arising in HIV+ patients include the following
- B cell lymphomas
  - Diffuse large B cell lymphoma (DLBCL)
  - Burkitt lymphoma
  - Extranodal marginal zone lymphoma
  - Primary effusion lymphoma
  - Plasmablastic lymphoma
  - KSHV / HHV8 positive diffuse large B cell lymphoma
- T cell lymphomas
  - Peripheral T cell lymphoma, not otherwise specified
  - Anaplastic large cell lymphoma
  - Nodal T follicular helper cell lymphoma, angioimmunoblastic type (nTFHL AI)
  - Hepatosplenic T cell lymphoma (HSTCL)
  - Mycosis fungoides
  - Extranodal NK / T cell lymphoma (ENKTCL)
- Classic Hodgkin lymphoma
Large B cell lymphoma in CNS (PCNS lymphoma) and diffuse large B cell lymphoma (DLBCL) are associated with low CD4+ T cell count
Burkitt lymphoma (BL) and classic Hodgkin lymphoma (CHL) noted in more immunocompetent patients (Adv Clin Path 1997;1:13, Blood 2001;98:2339, Lancet HIV 2020;7:e641)
Plasmablastic lymphoma, KSHV / HHV8 associated lymphomas such as primary effusion lymphomas (PEL) and KSHV / HHV8+ DLBCL occur predominantly in HIV+ patients
With the advent of cART, the incidence of PCNS lymphoma and DLBCL have declined, while CHL cases have increased and BL incidence has been stable (Blood 2001;98:2339, AIDS 2006;20:1645, J Natl Cancer Inst 2007;99:962, J Acquir Immune Defic Syndr 2016;72:177, AIDS Patient Care STDS 2013;27:259)

Most of the lymphomas are usually indistinguishable from their counterparts that arise in immunocompetent patients with some of the following differences

Lymphoma	Histologic features of lymphomas affecting HIV+ patients
BL	More variation in size and shape (pleomorphism) Plasmacytoid differentiation: eccentric nucleus, single central nucleolus and abundant cytoplasm (Ann Oncol 1991;2:289) Stronger EBV association (Semin Diagn Pathol 2017;34:352)
DLBCL	Extranodal or disseminated presentation Immunoblastic / plasmablastic morphology more common
CHL	Nodular sclerosis type comprises 50% of CHL cases in people living with HIV Lymphocyte depleted type specifically seen

Effective cART has negated the impact of HIV related prognostic factors and has led to better therapy for most of the aggressive lymphomas, contributing to better survival outcomes comparable to lymphoma occurring in the general population (Br J Haematol 2015;168:806, Blood 2015;125:1226, Ann Oncol 2015;26:958, Blood 2015;126:160, Blood Adv 2021;5:2852)

Microscopic (histologic) images

Contributed by Barina Aqil, M.D.

Florid follicular hyperplasia

Monocytoid cell hyperplasia

Follicular hyperplasia, EBV+ in HIV setting

Florid follicular hyperplasia in CMV lymphadenitis

Monocytoid cell hyperplasia in CMV lymphadenitis

Paracortical hyperplasia in CMV lymphadenitis

CMV lymphadenitis

Mycobacterium avium intracellulare (MAI)

Mycobacterium avium intracellulare (MAI)

Kaposi sarcoma

Burkitt lymphoma, EBV+ in HIV setting

Classic Hodgkin lymphoma, EBV+ in HIV setting

Classic Hodgkin lymphoma, EBV+ in HIV setting

Positive stains

p24 (Histopathology 2010;56:530)
- Antibody to HIV core protein
- Localized in reactive germinal centers along follicular dendritic cell processes
p15 and p17 (Am J Pathol 1988;133:516)
- Staining of follicular dendritic cells
Radiolabeled HIV RNA in situ hybridization (J Infect Dis 1991;164:1051)
- Found in high concentrations in germinal centers

Sample pathology report

Lymph node, left supraclavicular, needle core biopsy:
- Classic Hodgkin lymphoma, EBV+ arising in an HIV+ patient
- Flow cytometric analysis performed on the left supraclavicular lymph node biopsy reveals a polytypic B cell population and a T cell population without evidence of immunophenotypic abnormality based on the markers assayed
- Microscopic description: Histologic sections show cylindrical cores of lymphoid tissue with scattered large mononuclear cells with prominent macronucleoli in the background of histiocytes, small lymphocytes, plasma cells and eosinophils. Rare mummified cells are noted.
- Immunohistochemistry results: CD3- in large atypical cells (shows numerous small T cells), CD20- in large atypical cells (shows scattered small B cells), PAX5+ with strong staining in background B cells (dim in large atypical cells), CD30+ in large atypical cells, CD15+ in large atypical cells, MUM1+ in large atypical cells, EBER+ in scattered large atypical cells

Differential diagnosis

Infectious mononucleosis:
- Similarly reactive follicles as in HIV acute pattern
- Serologic testing positive for EBV
- Negative HIV antibodies
Cytomegalovirus, measles and varicella lymphadenitis:
- CMV inclusions seen in CMV infection
- Giant multinucleated cells (Warthin-Finkeldey) seen in both measles and HIV; so serologic testing is required
Toxoplasma lymphadenitis:
- Monocytoid hyperplasia noted in Toxoplasma as well as in HIV infection
- Perifollicular and intrafollicular clusters of epithelioid cells only noted in Toxoplasma
Castleman lymphadenopathy:
- Mimics pattern B and C of HIV lymphadenopathy
- Lacks depletion of lymphocytes
- Negative for HIV antibodies
Nodal TFH cell lymphoma, angioimmunoblastic type:
- Paracortical expansion with vascular proliferation and effaced follicles reminiscent to HIV chronic and burnout patterns
- No depletion of lymphocytes
- Proliferation of immunoblasts

Additional references

CDC: About HIV [Accessed 14 December 2023], CDC: PrEP (Pre-exposure Prophylaxis) [Accessed 14 December 2023], Bennett: Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 9th Edition, 2019, Goldman: Goldman-Cecil Medicine, 27th Edition, 2023, Clinicalinfo: Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV [Accessed 14 December 2023]

Board review style question #1

The patient is a 42 year old man who presented with fever, cough and weight loss. Imaging showed diffuse lymphadenopathy. An excisional lymph node biopsy was performed that showed the above morphology (H&E stains and LANA immunohistochemistry). What is the diagnosis?

Burnout pattern of HIV lymphadenitis
Diffuse large B cell lymphoma (DLBCL)
KSHV / HHV8 associated multicentric Castleman disease
Toxoplasma lymphadenitis

Board review style answer #1

C. KSHV / HHV8 associated multicentric Castleman disease. The lymph node showed regressed germinal centers with hyalinized arterioles, vascular proliferation and plasmablasts in the mantle zones. The plasmablasts are positive for CD138, MUM1, LANA and negative for B cell markers (CD20, PAX5, etc.).

Answer D is incorrect because toxoplasmosis has reactive follicles, monocytoid hyperplasia and perifollicular / intrafollicular clusters of epithelioid histiocytes. Answer A is incorrect because later stages of HIV lymphadenitis (patterns B and C) show markedly attenuated follicles with vascular proliferation and loss of lymphocytes. Answer B is incorrect because DLBCL has diffuse infiltrate of large neoplastic B cells, which can have variable cellular morphology, including centroblastic, immunoblastic or anaplastic. The neoplastic cells retain B cell markers and are LANA negative.

Comment Here

Reference: HIV

Board review style question #2

The patient is an adult who was found unresponsive at the bus stop and brought over to the emergency department by the paramedics. HIV serologies were positive. Imaging showed generalized lymphadenopathy, pulmonary infiltrates and bilateral pleural effusion. Lung sampling showed the above morphology (H&E stains and Gomori methenamine silver). What is the diagnosis?

Alveolar proteinosis
Blastomycosis
Mycobacterium avium intracellulare (MAI)
Pneumocystis jirovecii infection

Board review style answer #2

D. Pneumocystis jirovecii infection is a fungal infection seen in immunocompromised patients. Lung specimen shows pink foamy amorphous material within the alveolar spaces and the GMS (Grocott-Gomori methenamine silver) reveals thin walled, oval, round and crescentic yeast forms about the size of red blood cells (7 μm) with a small central dot.

Answer A is incorrect because intra-alveolar PAS (periodic acid Schiff) positive and GMS negative material is noted in alveolar proteinosis. Answer B is incorrect because blastomycosis is also a fungal infection characterized by granulomatous inflammation and GMS shows 12 μm spherical yeast forms with broad based buds. Answer C is incorrect because MAI is a bacterial infection that may have necrotizing granulomas or just foamy histiocytes with red stained acid fast bacilli seen on special stain (AFB).

Comment Here

Reference: HIV

IgG4 related lymphadenopathy

Table of Contents

Definition / general

Lymphadenopathy attributable to IgG4 related disease, with distinct clinicopathologic features

Essential features

Refers to lymphadenopathy that occurs in patients with established IgG4 related disease and is attributable to that disorder
Because increased IgG4 positive plasma cells are relatively nonspecific in lymph nodes, the term IgG4 related lymphadenopathy should not be used as a general descriptor for a lymph node with increased IgG4 positive plasma cells in a patient without established extranodal IgG4 related disease
Involved lymph nodes demonstrate both an absolute (> 100 IgG4 positive plasma cells per high power field [HPF]) and relative (IgG4:IgG plasma cell ratio > 40%) increase in IgG4 positive plasma cells
Various morphologic patterns are described, many of which are nonspecific: 1) Castleman disease-like, 2) follicular hyperplasia, 3) progressive transformation of germinal centers, 4) interfollicular expansion, 5) inflammatory pseudotumor-like as well as infrequent patterns, including infectious mononucleosis-like features
Features thought to be relatively specific for IgG4 related lymphadenopathy include increased IgG4 positive plasma cells (> 100 per HPF) and IgG4:IgG ratio (> 40%) within expanded interfollicular or fibrotic regions (i.e., interfollicular expansion and inflammatory pseudotumor-like patterns)

ICD coding

ICD-10
- D89.89 - other specified disorders involving the immune mechanism, not elsewhere classified
- D89.9 - disorder involving the immune mechanism, unspecified

Epidemiology

Most common in middle aged to older adults with a male predominance
Extremely rare in children
Lymphadenopathy occurs in at least 40 - 60% of patients with IgG4 related disease (Am J Surg Pathol 2010;34:1812, Arthritis Rheumatol 2015;67:2466)

Sites

Localized lymphadenopathy in anatomic regions near the site of extranodal IgG4 related disease is most common but distant lymphadenopathy and multifocal / generalized lymphadenopathy occurs in some cases

Pathophysiology

Pathophysiology of IgG4 related disease is poorly understood
Both aberrant B cell and T cell activity has been implicated
B cell depletion as a successful second line treatment for IgG4 related disease has implicated a role of activated B cells in IgG4 related disease; however, recent studies have favored abnormal T cells to be the underlying immunologic defect (N Engl J Med 2012;366:539, Haematologica 2019;104:444)
T follicular helper cells have been implicated in contributing to IgG4 related disease through cytokines IL21 and IL4, which are thought to contribute to lymphoid follicle formation, class switch to IgG4 and plasmablast induction (Arthritis Rheumatol 2015;67:2476, Arthritis Res Ther 2016;18:167)
- Circulating Tfh2 cells have been shown to be increased in IgG4 related disease and to correlate with serum IgG4 levels (Arthritis Rheumatol 2015;67:2476)
Treg cells also may contribute to IgG4 related disease through secretion of IL10 and TGF beta resulting in IgG4 class switching and fibrosis (Clin Nephrol 2010;73:385)
Oligoclonal expansions of CD4+ cytotoxic T cells have been found in blood and tissues of IgG4 related disease patients and have been implicated in contributing to fibrosis (Autoimmunity 2017;50:19)
Role of IgG4 positive plasma cells in the disease is uncertain
- Some have suggested that IgG4 positive plasma cells are a secondary phenomenon and may be produced in an attempt to dampen the inflammatory process (Clin Exp Allergy 2009;39:469, Gut 2018;67:728)
  - IgG4 is a relatively inactive immunoglobulin subclass that is nonprecipitating and behaves much like monovalent antibodies
  - IgG assay with the detection of labeled antigen fluid to solid phase cross linking showed that cross linking activity was usually absent in the presence of high serum levels of IgG4 (as measured by radioallergosorbent test [RAST])

Etiology

Lymph node involvement by IgG4 related disease

Clinical features

IgG4 related disease usually presents due to enlargement of an exocrine organ, most commonly submandibular glands, orbit / lacrimal glands or pancreaticobiliary tract, with systemic involvement in ~33% of cases
- Orbit is the most common site in children (Pediatr Rheumatol Online J 2016;14:18)
- Organ enlargement is detected by a visible mass in superficial sites (i.e., orbit or submandibular gland) or due to organ dysfunction from mass effect at deeper sites (i.e., pancreas)

Diagnosis

Physical exam and imaging play a central role in the diagnosis of IgG4 related disease through demonstration of mass-like lesions and for investigation of lymphadenopathy
In cases with characteristic organ involvement, physical exam or imaging may prompt consideration of IgG4 related disease and subsequent laboratory testing or biopsy
However, in many cases, the etiology of the tumefactive lesion of IgG4 related disease is not recognized and there may be clinical suspicion for a neoplastic process, prompting biopsy (Mod Pathol 2012;25:1181)

Laboratory

Elevated serum IgG4 levels are commonly touted (especially among pathologists) as defining IgG4 related disease; while useful, elevated serum IgG4 is neither sensitive nor specific for the diagnosis of IgG4 related disease
- Sensitivity of elevated serum IgG4 for the diagnosis of IgG4 related disease has been reported from ~50 to 90% and specificity ~60 - 80%, with higher IgG4 levels being more specific (Pediatr Rheumatol Online J 2016;14:18, Ann Rheum Dis 2015;74:14)
Serum IgG4 levels may also be elevated in other inflammatory and immune disorders and neoplasms, including IgG4 positive plasma cell neoplasms and IgG4 positive B cell neoplasms with plasmacytic differentiation; in the latter, the elevated IgG4 may be associated with a clonal M component on serum protein electrophoresis (SPEP) / immunofixation electrophoresis (IFE) (Mod Pathol 2014;27:375, Am J Clin Pathol 2017;148:215)
In contrast, the elevated serum IgG4 in IgG4 related disease is polyclonal
Other useful laboratory values often seen in IgG4 related disease include elevated serum IgE or CRP, decreased complement (C3, C4) levels and peripheral eosinophilia (Pediatr Rheumatol Online J 2016;14:18)

Radiology description

Imaging findings of mass-like enlargement or fibrosis plays a key role in diagnosis of IgG4 related disease

Prognostic factors

IgG4 related lymphadenopathy is generally treated in the context of IgG4 related disease in an attempt to prevent irreversible organ damage rather than as an attempt to correct the lymphadenopathy (Int J Clin Exp Pathol 2017;10:10153)
Natural history of IgG4 related disease is variable, ranging from spontaneous improvement in rare cases, a good and durable response to initial therapy in many cases, to progressive organ damage in some cases
Involvement of vital organs including the heart, aorta and kidneys may be associated with more severe outcomes
Flares of activity may result in complications such as exocrine dysfunction of various organs and diabetes mellitus in IgG4 related pancreatitis
Morbidities associated with treatment, such as long term steroid therapy, are also a consideration (Clin Chest Med 2019;40:583)

Case reports

48 year old woman with longstanding lymphadenopathy and development of pancreatitis and kidney disease (Mod Rheumatol Case Rep 2023;7:192)
58 year old man with jaundice, elevated transaminases and inguinal and axillary lymphadenopathy (Surg Exp Pathol 2020;3:30)
66 year old woman with a thyroid mass and lymphadenopathy (Diagn Pathol 2018;13:3)

Treatment

Treatment varies from watchful waiting in cases of IgG4 related disease with isolated lymphadenopathy or minimal salivary gland enlargement to prompt treatment of cases in which vital organs are involved
Most patients have good responses to glucocorticoids but may relapse after treatment
Rituximab is used as a second line agent in cases of recurrent or refractory disease (Arthritis Rheumatol 2015;67:1688)
Other agents have been used in combination with glucocorticoids including cyclophosphamide, azathioprine or methotrexate

Gross description

Lymph nodes are enlarged with variable cut surface ranging from fleshy to nodular and fibrotic

Microscopic (histologic) description

Enlarged lymph node with various reactive morphologic patterns (described below), increased plasma cells typically in extrafollicular locations (i.e., between follicles) and variable fibrosis that may be capsular, parenchymal or inflammatory pseudotumor-like (Am J Surg Pathol 2021;45:178)
Increased number (> 100 per HPF) of IgG4 positive plasma cells and increased ratio of IgG4:IgG positive plasma cells (> 40%) is required for the diagnosis of IgG4 related lymphadenopathy
- These parameters are increased in the lymph nodes of most patients with enlarged lymph nodes and established extranodal IgG4 related disease; however, in a subset of patients with known IgG4 related disease and enlarged lymph nodes, the lymph nodes will not show an increase of IgG4 positive plasma cells
Eosinophils are almost always present admixed with the plasma cells in IgG4 related disease and IgG4 related lymphadenopathy, a useful morphologic clue
Presence of increased IgG4 positive plasma cells and IgG4:IgG ratio in regions of nodal fibrosis or in extrafollicular regions appears more specific for true IgG4 related disease than an isolated increase in intrafollicular IgG4 positive plasma cells; increased IgG4 positive cells and IgG4:IgG ratio found only within follicles / germinal centers can be seen in many nonspecific causes of lymphadenopathy (Am J Surg Pathol 2021;45:178)
5 main morphologic patterns of IgG4 related lymphadenopathy are classically described
- These patterns are nonspecific in the absence of increased IgG4 immunostaining parameters as described above
- On H&E alone, none of these patterns are specific for IgG4 related disease but the presence of these patterns along with nodal plasmacytosis should prompt work up for IgG4 related lymphadenopathy
  - Multicentric Castleman disease-like pattern
    - Increased IgG4 positive cells outside of follicles
    - Lollipop follicles with a penetrating vessel and onion skin arrangement of mantle zone B cells
    - Variable fibrosis
    - In true Castleman disease follicles are atrophic, whereas in this pattern of IgG4 related disease follicles are more often normal sized or hyperplastic
  - Follicular hyperplasia pattern
    - Enlarged reactive follicles
    - Classically described with increased extrafollicular IgG4 positive plasma cells
  - Interfollicular expansion pattern
    - Markedly expanded interfollicular zones with few widely separated residual follicles
    - Interfollicular zones contain small lymphocytes, plasma cells, eosinophils, histiocytes and immunoblasts
    - Plasma cells are predominantly IgG4 positive
    - Morphologic features may be reminiscent of angioimmunoblastic T cell lymphoma
    - This pattern has been shown to be highly specific for IgG4 related disease (Am J Surg Pathol 2021;45:178)
  - Progressive transformation of germinal centers (PTGC) pattern
    - Follicular hyperplasia with frequent PTGC
    - This pattern is classically associated with increased intrafollicular IgG4 positive plasma cells
    - Some studies have suggested that when this pattern is present in submandibular / cervical lymph nodes it is associated with concurrent of subsequent development of submandibular IgG4 related sclerosing sialadenitis (Mod Pathol 2012;25:956)
  - Inflammatory pseudotumor-like pattern
    - Broad areas of fibrosis replacing lymph node parenchyma
    - Storiform fibrosis is common
    - Increased IgG4 positive plasma cells and IgG4:IgG ratio within the fibrosis
    - This pattern has been shown to be highly specific for IgG4 related disease (Am J Surg Pathol 2021;45:178)
Other uncommon patterns have been described, including infectious mononucleosis-like and rarely Rosai-Dorfman-like changes (Am J Surg Pathol 2018;42:977)
Other morphologic features that may be present include ring-like perifollicular granulomas or phlebitis
Significant neutrophilic inflammation is typically not present in IgG4 related disease or IgG4 related lymphadenopathy

Microscopic (histologic) description

Contributed by Jacob Bledsoe, M.D.

Capsular fibrosis

Interfollicular expansion pattern

Inflammatory pseudotumor-like pattern

IgG4 IHC

Positive stains

IgG4: the presence of > 100 IgG4 positive plasma per HPF in the regions with the highest number of IgG4 positive cells (site dependent; i.e., highest in skin)
IgG4:IgG: IgG4 positive plasma cells are > 40% of total IgG positive plasma cells in the regions with the highest number of IgG4 positive cells (regardless of site) (Haematologica 2019;104:444)
CD138: may be useful to aid in quantification if IgG stain shows high background staining
Kappa / lambda IHC or ISH: plasma cells are polytypic in IgG4 related disease; if monotypic, then consider an IgG4 positive plasma cell or B cell neoplasm with plasmacytic differentiation
Elastic stain may be useful to demonstrate obliterative phlebitis, a useful feature for extranodal IgG4 related disease but uncommonly present in lymph nodes

Negative stains

Spirochete / treponemal IHC and silver stains (syphilitic lymphadenitis may mimic IgG4 related lymphadenopathy) (Arch Pathol Lab Med 2024;148:633)
HHV8 (excludes HHV8 positive Castleman disease)
ALK1
ROS1

Flow cytometry description

Reactive pattern with polytypic B cells and plasma cells and immunophenotypically normal T cells

Molecular / cytogenetics description

IgG4 related disease and IgG4 related lymphadenopathy are nonneoplastic disorders and should not show molecular or cytogenetic abnormalities
When the differential diagnosis includes neoplastic entities, including IgG4 positive plasma cell neoplasms, IgG4 positive B cell lymphomas with plasmacytic differentiation, inflammatory myofibroblastic tumor or others, molecular / cytogenetic testing may be useful

Sample pathology report

Lymph node, excision:
- Enlarged lymph node with fibrosis and increased IgG4 positive plasma cells (see comment)
- Comment: The lymph node is enlarged with follicular hyperplasia, capsular fibrosis and foci of parenchymal fibrosis. There are frequent plasma cells with fewer admixed eosinophils within the regions of fibrosis and present between follicles. Immunohistochemistry for IgG4 and IgG show increased IgG4 positive plasma cells (up to 165 per HPF) and IgG4:IgG ratio of ~70% within interfollicular and fibrotic regions. Plasma cells demonstrate polytypic expression of kappa and lambda light chains by in situ hybridization. A spirochete (Treponema) immunostain is negative.
- Increased IgG4 positive plasma cells may be seen in lymph nodes in various conditions including IgG4 related disease, Castleman disease and other inflammatory and infectious processes. The presence of increased IgG4 staining parameters within fibrosis and interfollicular regions of enlarged lymph nodes, as seen in this case, has been described as a relatively specific finding for IgG4 related disease. Therefore, in this patient without a history of established extranodal IgG4 related disease, the findings are suspicious for IgG4 related lymphadenopathy; however, further investigation for an extranodal site of IgG4 related disease and laboratory testing including serum IgG4, IgE and complement (C3 / C4) levels may be useful for definitive diagnosis of IgG4 related disease.

Differential diagnosis

Increased IgG4 positive plasma cells can be seen in various reactive and neoplastic disorders involving lymph nodes
Rosai-Dorfman disease (RDD):
- May have increased IgG4 positive plasma cells and IgG4:IgG ratio
- Hallmark is enlarged histiocytes with atypical nuclei and emperipolesis
- RDD histiocytes are positive for S100, OCT2 and cyclin D1 (Am J Surg Pathol 2021;45:35, Br J Haematol 2019;186:837)
- Histiocyte emperipolesis may be seen extremely rarely in IgG4 related lymphadenitis as a focal finding and without cytologic atypia
Castleman disease:
- Lymph nodes in hyper-IL6 syndromes, including Castleman disease and rheumatoid arthritis, may contain increased IgG4 positive plasma cells, typically in the setting of interfollicular plasmacytosis
- Plasma cell type of Castleman disease typically contains regions with sheets of plasma cells without admixed eosinophils and with associated hemosiderin, a finding that would be uncommon in IgG4 related disease
- Neutrophils may be seen in lymph nodes of hyper-IL6 syndromes and are not seen in IgG4 related lymphadenopathy
- Castleman disease follicles are typically atrophic while follicles in the Castleman disease-like pattern of IgG4 are more often normal sized to hyperplastic
- HHV8 positive plasmablasts within Castleman disease type follicles supports the diagnosis of HHV8 associated Castleman disease
Plasma cell neoplasm expressing IgG4:
- IgG4 positive plasma cells are clonal by IHC / ISH for kappa and lambda light chains
- Serum IgG4 may be elevated
- SPEP / IFE may show M component
B cell lymphoma with plasmacytic differentiation expressing IgG4:
- Usually nodal or extranodal marginal zone lymphoma
- IgG4 positive plasma cells are clonal by IHC / ISH for kappa and lambda light chains
- Serum IgG4 may be elevated
- SPEP / IFE may show M component
Inflammatory myofibroblastic tumor (Am J Surg Pathol 2019;43:314):
- May demonstrate marked morphologic overlap with IgG4 related disease, including storiform fibrosis, plasmacytosis with increased IgG4 positive plasma cells and IgG4:IgG ratio and even obliterative phlebitis
- Stromal cells demonstrate cytologic atypia, a finding not seen in IgG4 related disease
- ALK1 and ROS1 immunohistochemistry or fusion analysis may be useful when inflammatory myofibroblastic tumor is suspected
Angioimmunoblastic T cell lymphoma (AITL):
- Morphologic overlap with interfollicular expansion pattern of IgG4 related lymphadenopathy
- IgG4 positive plasma cells are not typically increased in AITL
- T cells demonstrate a Tfh immunophenotype and clonal TCR gene rearrangement, may demonstrate aberrant loss of pan-T cell markers and are associated with expanded follicular dendritic cell meshworks
Syphilitic lymphadenitis:
- May closely mimic the morphology of IgG4 related disease and IgG4 related lymphadenopathy, including plasmacytosis, fibrosis and phlebitis
- Treponemal immunohistochemistry demonstrates spirochetes
- Laboratory for syphilis may be useful
- IgG4 positive plasma cells are usually not increased in syphilis but can be in some cases (Am J Surg Pathol 2018;42:472)
Chronic infections including mastoiditis, aortitis
Kimura disease:
- More extensive eosinophil infiltrates including eosinophilic microabscesses
- IgE deposition in follicles
- IgG4 positive plasma cells not typically increased in Kimura disease
Angiolymphoid hyperplasia with eosinophilia / epithelioid hemangioma:
- H&E morphology may be similar to IgG4 related disease, including plasmacytosis and eosinophilia
- Vascular proliferation not seen in IgG4 related disease
- IgG4 positive plasma cells not typically increased
- FOSB may be useful
Nonspecific inflammation adjacent to other tumors:
- Increased IgG4 positive plasma cells can be seen in soft tissue adjacent to other tumors; correlation with imaging and clinical suspicion is needed in such cases to avoid misdiagnosis as IgG4 related disease

Board review style question #1

A 65 year old man presents with bilateral enlargement of the submandibular glands and submandibular lymph nodes. An enlarged submandibular lymph node is excised. What stain is most likely to aid in rendering the correct diagnosis?

Cyclin D1
EBER in situ hybridization
HHV8
IgG and IgG4 immunostains
Toxoplasma immunostain

Board review style answer #1

D. IgG and IgG4 immunostains. The photomicrographs show marked fibrosis with a mixed inflammatory cell infiltrate including many plasma cells and eosinophils. Areas of storiform fibrosis are present. Along with the clinical history of bilateral submandibular gland enlargement, the morphologic findings should prompt consideration of the inflammatory pseudotumor-like pattern of IgG4 related lymphadenopathy. IgG4 and IgG immunostains are necessary for further evaluation.

Answer A is incorrect because cyclin D1 is positive in Rosai-Dorfman disease. Answer B is incorrect because while EBER positivity can occasionally be seen in IgG4 lymphadenopathy, it would not aid in diagnosis. Answer C is incorrect because HHV8 positive plasmablasts support the diagnosis of HHV8 associated Castleman disease. Answer E is incorrect because this positive immunostain would indicate Toxoplasma infection.

Comment Here

Reference: IgG4 related lymphadenopathy

Board review style question #2

A 60 year old woman presents with jaundice, a pancreatic mass and abdominal lymphadenopathy. Biopsy of the pancreas and peripancreatic lymph node demonstrates marked fibrosis with a storiform pattern, frequent plasma cells and obliterative phlebitis in the pancreas. What is the most likely diagnosis?

Desmoplastic small round cell tumor
IgG4 related disease and IgG4 related lymphadenopathy
Lymphoma
Pancreatic ductal adenocarcinoma
Pancreatic neuroendocrine tumor

Board review style answer #2

B. IgG4 related disease and IgG4 related lymphadenopathy. The morphologic description, including storiform fibrosis, obliterative phlebitis and plasmacytosis, is classic for IgG4 related disease. Immunohistochemistry for IgG4 and IgG will show increased IgG4 positive plasma cells and IgG4:IgG ratio.

Answers A and D are incorrect because although these entities show marked desmoplasia, desmoplastic small round cell tumor lacks plasma cells and has a characteristic EWSR1::WT1 gene fusion and pancreatic ductal adenocarcinoma is composed of infiltrating, well to poorly formed glandular / ductal structures. Answer C is incorrect due to the lack of lymphoma cells. If the plasma cells were atypical, a plasma cell neoplasm might be in the differential. Answer E is incorrect because pancreatic neuroendocrine tumors typically lack marked desmoplasia and are composed of small, round, monotonous cells that have coarse salt and pepper nuclear chromatin and minimal atypia but do not resemble plasma cells.

Comment Here

Reference: IgG4 related lymphadenopathy

Immune thrombocytopenia (ITP)

Table of Contents

Definition / general

Acquired autoimmune bleeding disorder characterized by isolated thrombocytopenia (peripheral blood platelet count < 100 × 10⁹/L) (Blood 2009;113:2386)
Mixed cell mediated and antibody mediated: abnormal T cell responses resulting in platelet destruction primarily in the spleen, mainly due to antiplatelet autoantibodies (J Clin Med 2017;6:16)

Essential features

Immune thrombocytopenia (ITP) is a diagnosis of exclusion with an isolated thrombocytopenia of < 100 × 10⁹/L (Blood 2009;113:2386)
Affected sites predominantly include skin and mucous membranes (petechiae, wet / dry purpura) and spleen (primary site of platelet clearance)
Impairment in CD4+ T regulatory cells and dendritic cells leads to the initiation and perpetuation of ITP (Curr Opin Hematol 2020;27:423)
Thrombocytopenia is due to IgG antiplatelet autoantibodies (principle mechanism of antibody mediated platelet phagocytosis), cytotoxic CD8+ T cells and impaired megakaryocyte function (J Clin Med 2017;6:16)
Primary diagnostic tests include complete blood counts, peripheral blood smear and testing to exclude HIV and hepatitis C virus; antiplatelet antibody testing is among the supportive tests that may be performed (UpToDate: Immune Thrombocytopenia (ITP) in Adults - Clinical Manifestations and Diagnosis [Accessed 16 February 2021])

Terminology

Formerly known as idiopathic thrombocytopenic purpura

ICD coding

ICD-10: D69.3 - Immune thrombocytopenic purpura

Epidemiology

Annual incidence: ~1 - 6 per 100,000 adults (Am J Hematol 2012;87:848)
Prevalence: ~12 per 100,000 in adults and 8 per 100,000 in children (Am J Hematol 2012;87:848)
Increased incidence with increasing age (Am J Hematol 2012;87:848, Br J Haematol 2009;145:235)
Incidence: M = F when > 60 years of age
Childhood ITP is a clinically distinct condition from adult ITP with a higher likelihood of spontaneous remission

Sites

Skin:
- Petechiae (flat, red, discrete lesions that do not blanch under pressure), often lower legs in ambulatory patients or sacral area in recumbent patients
- Dry purpura (coalescence of petechiae, nonpalpable)
Mucous membranes (such as oral mucosa):
- Wet purpura (hemorrhagic blisters)
Severe bleeding:
- Affects a minority of patients (J Thromb Haemost 2015;13:457)
- Associated with marked thrombocytopenia and new diagnosis of ITP
- Extensive mucosal bleeding often present
- Intracranial hemorrhage uncommon
Spleen: primary site of platelet clearance in most patients
Liver, bone marrow or lymph nodes: may also be sites of platelet clearance

Pathophysiology

Impairment in CD4+ T regulatory cells and dendritic cells leads to the initiation and perpetuation of ITP
- Decreased CD4+ CD25+ FOXP3+ T regulatory cell levels and function in patients with active disease (Curr Opin Hematol 2020;27:423)
- Also dendritic cells and myeloid derived suppressor cells have been described to be impaired in ITP (Curr Opin Hematol 2020;27:423, Blood 2016;127:1587)
Thrombocytopenia due to:
- IgG antiplatelet autoantibodies (principle mechanism) bind to platelet surface antigens (such as glycoprotein [GP] αIIbβ3 [GPIIbIIIA] and GPIb-IX-V)
- Platelets with bound autoantibodies are subsequently recognized by macrophages bearing Fcγ receptors (FcγRs), resulting in antibody mediated platelet phagocytosis and destruction primarily in the spleen (Haematologica 2021;106:250)
- Cytotoxic CD8+ T cells may directly lyse platelets (Nat Med 2003;9:1123)
- Impaired megakaryocyte function resulting in impaired platelet production due to targeting by antiplatelet autoantibodies or CD8+ T cells in the bone marrow (Haematologica 2015;100:623, Blood 2008;112:1078)

Diagnosis

ITP is a diagnosis of exclusion; an isolated thrombocytopenia is present (peripheral blood platelet count < 100 × 10⁹/L) without anemia or leukopenia and without another apparent cause of thrombocytopenia

Laboratory

Complete blood counts, peripheral blood smear: to confirm thrombocytopenia and to exclude platelet morphology abnormalities (e.g. lack of platelet granules or uniformly large or small platelets) suggestive of hereditary platelet disorders or myelodysplasia
HIV and hepatitis C virus testing: may explain the thrombocytopenia and treating the underlying infection might improve the platelet count
Additional testing for patients with suspected ITP may include:
- Helicobacter pylori testing: in case of gastrointestinal symptoms suggestive of infection due to association between ITP and H. pylori infection
- Bone marrow investigation: not required for typical presentation
  - Normal or increased number of megakaryocytes
  - In some patients, a shift towards younger megakaryocytes with hypolobation or lesser degrees of nuclear polyploidy and less evidence of platelet production
- Vitamin B12 and folate levels: required for hematopoiesis and their deficiency may present with mild thrombocytopenia
- Coagulation studies: to investigate and treat other potential causes of thrombocytopenia (e.g. liver disease) and bleeding (e.g. vitamin K deficiency)
- Immunologic studies (e.g. testing for antinuclear antibodies or quantitative immunoglobulin levels to identify underlying common variable immune deficiency)
- Antiplatelet antibody testing (not always detectable)
Reference: Curr Opin Hematol 2020;27:423, UpToDate: Immune Thrombocytopenia (ITP) in Adults - Clinical Manifestations and Diagnosis [Accessed 16 February 2021]

Prognostic factors

Adult ITP: majority stable, safe platelet count due to spontaneous remission (up to 10%) or therapy, often within first 6 months (Br J Haematol 2003;122:966)
Childhood ITP: spontaneous remission (up to 50%) after months or even years of chronic ITP

Case reports

3 year old boy and girl with intravenous immunoglobulin refractory ITP receiving chemotherapy for high risk neuroblastoma (J Pediatr Hematol Oncol 2019;41:e257)
41 year old woman with anti-GPVI mediated ITP (Res Pract Thromb Haemost 2017;1:291)
48 year old man critically ill with COVID-19 (Int J Infect Dis 2020;99:269)
65 and 71 year old men presenting with lethal diffuse alveolar hemorrhage (Case Rep Hematol 2019;2019:5170282)

Treatment

First line includes corticosteroids, intravenous immunoglobulin and anti-D immunoglobulin
Subsequent treatments include rituximab, splenectomy or thrombopoietin receptor agonists
Treatment goals: maintaining platelet counts > 20 - 30 × 10⁹/L for at least symptomatic patients (Blood Adv 2019;3:3780)

Clinical images

Images hosted on other servers:

Petechiae or small bruise-like markings

Microscopic (histologic) description

Splenic white pulp is prominent, with focal germinal centers and hyperplastic marginal zones
Red pulp is cellular with histiocytes, activated lymphocytes (immunoblasts) and neutrophils
Increased number of cordal macrophages, with phagocytosis of (apparent) antibody coated platelets
Cords of Billroth may have a dirty appearance due to granular platelet debris both within macrophages and extracellularly
Reference: HemaSphere: The spleen in immune thrombocytopenia [Accessed 22 February 2021]

Microscopic (histologic) images

Contributed by Julia Geyer, M.D.

Focal germinal centers, hyperplastic marginal zones

Histiocytes, immunoblasts, neutrophils, macrophages

Expanded red pulp, atrophic white pulp

Cordal macrophages, phagocytosing platelets

Sample pathology report

ITP is a clinical diagnosis of exclusion, typically not based primarily on a pathology specimen.

Differential diagnosis

ITP is a diagnosis of exclusion; an isolated thrombocytopenia is present (peripheral blood platelet count < 100 × 10⁹/L) without anemia or leukopenia and without another apparent cause of thrombocytopenia such as:
- Drug induced thrombocytopenia, including heparin induced thrombocytopenia
- Infections
- Liver disease
- Microangiopathic processes
- Hereditary thrombocytopenia
- Myelodysplastic syndromes and other acquired bone marrow disorders

Board review style question #1

A previously healthy 38 year old woman comes to the physician because of petechiae and bruising on her arms and legs for 3 weeks. CBC shows a platelet count of 15 × 10⁹/L as the sole abnormality. What should be the next step for the physician?

A bone marrow aspirate should be conducted to investigate megakaryocytes for confirmation of diagnosis of ITP
Other causes of thrombocytopenia should be excluded first to confirm the diagnosis of ITP
Patient should be started on corticosteroids for treatment of ITP
Patient should be tested for the presence of antiplatelet autoantibodies to confirm the diagnosis of ITP

Board review style answer #1

B. Other causes of thrombocytopenia should be ruled out first, which includes hereditary platelet disorders, HIV and hepatitis C virus infection.

Bone marrow investigation is not required in cases of typical presentation. It could be supportive as in some ITP patients a shift towards younger megakaryocytes with lesser degrees of nuclear polyploidy and less evidence of platelet production may be seen (answer A). Before considering any treatments for ITP, the diagnosis of ITP should be confirmed first. ITP is a diagnosis of exclusion. An isolated thrombocytopenia should be present (peripheral blood platelet count 9/L) without anemia or leukopenia and without another apparent cause of thrombocytopenia (answer C). The presence of antiplatelet autoantibodies could be supportive but is not required for the diagnosis of ITP. These autoantibodies are also not always detectable (answer D).

Comment Here

Reference: Immune thrombocytopenia

Board review style question #2

Which of the following is true regarding the bleeding disorder ITP?

Certain drugs can trigger the onset of ITP
Cytotoxic CD8+ T cells may play a pathogenetic role in platelet breakdown
Platelet breakdown occurs predominantly in the bone marrow
CD4+ CD25+ FOXP3+ T regulatory cells levels are increased in number and function in active disease

Board review style answer #2

B. Not only antiplatelet autoantibodies but also cytotoxic CD8+ T cells can be responsible for the platelet destruction.

When drugs trigger the onset of ITP, the diagnosis is drug induced thrombocytopenia, which should always be considered in the differential diagnosis of ITP (answer A). While the spleen is the primary site for platelet destruction, platelet clearance can also occur in liver, bone marrow or lymph nodes. ITP may still (re)occur after splenectomy (answer C). There is an impairment in CD4+ T regulatory cells which leads to the initiation and perpetuation of ITP, so CD4+ CD25+ FOXP3+ T regulatory cells are decreased in number and function in patients with active disease (answer D) (Curr Opin Hematol 2020;27:423).

Comment Here

Reference: Immune thrombocytopenia

Indeterminate cell histiocytosis / indeterminate dendritic cell tumor

Table of Contents

Definition / general

Indeterminate cell histiocytosis is an extremely rare neoplastic proliferation of cells of dendritic / histiocytic lineage that share immunophenotypic features of Langerhans cells but lack Birbeck granules and langerin expression

Essential features

Skin involvement can be solitary or multifocal
Usually restricted to skin, with rare organ or lymph node involvement
Indeterminate cells are histopathologically and antigenically similar to Langerhans cells but lack Birbeck granules and langerin (CD207) expression
Clinical course varies: spontaneous regression, stable disease, rapid progression or recurrence

Terminology

Indeterminate cell histiocytosis
Indeterminate cell tumor
Indeterminate dendritic cell tumor

ICD coding

ICD-10: D76.3 - other histiocytosis syndromes

Epidemiology

Rare neoplasm, with 85 cases reported between 1985 - 2016 (Am J Dermatopathol 2018;40:736)
Reported in all age groups, with a median age of 45
Near equal M:F

Sites

Cutaneous involvement (88%) is most common (Am J Dermatopathol 2018;40:736)
Lymph node (9%) and spleen (2.3%) involvement less common (Am J Dermatopathol 2018;40:736)

Etiology

Etiology remains uncertain
Multiple hypotheses on the relationship between indeterminate cells and Langerhans cells, including:
- Indeterminate cells are Langerhans cells that have lost their Birbeck granules
- Indeterminate cells are immature Langerhans cells
A subset of cases express dendritic cell marker ZBTB46, raising the possibility that a subset of cases arise directly from bone marrow progenitors as opposed to embryonic precursors that locally renew in the skin (Mod Pathol 2018;31:1479)
Association between other hematologic neoplasms has been reported (including B cell lymphoma, T cell lymphoma, acute myeloid leukemia and chronic myelomonocytic leukemia) (Am J Surg Pathol 2008;32:1868, J Cutan Pathol 2017;44:958, Am J Dermatopathol 2019;41:461, Dermatol Res Pract 2010;2010:569345)
Indeterminate cell histiocytosis can share clonal abnormality of associated lymphoma or leukemia (Am J Surg Pathol 2008;32:1868)

Clinical features

Reported in all age groups, with a median age of 45
Near equal M:F patients
Single cutaneous papulonodule or multiple lesions (few to innumerable)
Can have plaques and tumors with leonine facies (J Cutan Pathol 2016;43:158)
Usually restricted to skin with rare organ or lymph node involvement
Clinical course varies: spontaneous regression, stable disease, rapid progression or recurrence
Reference: Am J Dermatopathol 2018;40:736

Diagnosis

Skin biopsy for localized lesions
Systemic workup to exclude deep involvement
CT scans and bone marrow biopsy

Laboratory

Can have elevated lactate dehydrogenase, erythrocyte sedimentation rate and C reactive protein (Serbian J Dermatology Venereol 2018;10:18)

Radiology description

True cutaneous indeterminate cell histiocytosis typically lacks evidence of deep organ involvement on imaging

Prognostic factors

Cases restricted to the skin typically behave indolently
Involvement of deep or visceral tissues or bone marrow may portend worse prognosis

Case reports

6 year old girl with polypoid and verrucoid lesions of the vulva (Am J Dermatopathol 2018;40:736)
13 year old girl with pityriasis rosea type rash (Acta Derm Venereol 2002;82:288)
28 year old man presented after a mosquito bite (Medicine (Baltimore) 2015;94:e1443)
48 year old woman with a later diagnosis of mycosis fungoides (Am J Dermatopathol 2019;41:461)
55 year old woman with a history of burning and confluent erythematous papules on the face and arms (Cureus 2021;13:e12850)
55 year old woman presented with leonine facies (J Cutan Pathol 2016;43:158)
55 year old man with complete response to ultraviolet phototherapy (J Cutan Pathol 2017;44:958)
61 year old man with recurrence after excision (J Pathol Transl Med 2018;52:243)
72 year old man with chronic myelomonocytic leukemia (J Cutan Pathol 2017;44:958)
74 year old woman with a prior history of follicular lymphoma demonstrating t(14;18) translocation (Am J Surg Pathol 2008;32:1868)
90 year old man with aggressive case mimicking angiosarcoma (Ann Dermatol 2017;29:614)

Treatment

Surgical excision for isolated lesions
Psoralen and ultraviolet A therapy (PUVA) (J Cutan Pathol 2017;44:958, Autops Case Rep 2016;6:33, Kaohsiung J Med Sci 2004;20:24)
Chemotherapy can be considered for more aggressive disease or those cases associated with concurrent myeloid or lymphoid neoplasm

Clinical images

Images hosted on other servers:

Erythematous papules on face and neck

Ill defined, erythematous subcutaneous nodule

Microscopic (histologic) description

Dermal infiltration by pale eosinophilic histiocytic cells with reniform nuclei
Background reactive lymphocytes
Scant to absent eosinophils
Can have multinucleated cells
Spindled morphology is less common
References: Am J Dermatopathol 2018;40:736, Blood 2015;126:2344, Arch Pathol Lab Med 2003;127:748, Am J Surg Pathol 2008;32:1868, Cureus 2021;13:e12850

Microscopic (histologic) images

Contributed by Ryanne A. Brown, M.D., M.B.A.

Dermal histiocytoid cells

Histiocytoid cells

CD68

CD1a

S100

Langerin

BRAF V600E

Positive stains

Positive for S100, CD1a, CD68
Variably express CD4, CD45, CD56, lysozyme
References: Am J Dermatopathol 2018;40:736, Blood 2015;126:2344, Arch Pathol Lab Med 2003;127:748, Am J Surg Pathol 2008;32:1868

Negative stains

Negative for langerin (CD207)
Negative for histiocytic marker CD163
B cell and T cell markers, follicular dendritic cell markers (CD21, CD23 and CD35), CD30 and MPO
References: Am J Dermatopathol 2018;40:736, Blood 2015;126:2344, Arch Pathol Lab Med 2003;127:748, Am J Surg Pathol 2008;32:1868

Flow cytometry description

No known abnormalities in peripheral blood flow cytometry in true cutaneous indeterminate cell histiocytosis
For flow cytometry information for cases of chronic myelomonocytic leukemia with an indeterminate cell-like immunophenotype, please refer to chronic myelomonocytic leukemia

Electron microscopy description

Histiocytic cells show nuclear infoldings with peripheral villi (Rare Tumors 2013;5:e13)
Lamellated dense bodies but no Birbeck granules (Acta Derm Venereol 2002;82:288)

Electron microscopy images

Contributed by Ryanne A. Brown, M.D., M.B.A.

No Birbeck granules

Molecular / cytogenetics description

ETV3::NCOA2 in a subset (Blood 2015;126:2344, BMJ Case Rep 2017;2017:bcr2017221538)
BRAF V600E in rare cases (Ann Diagn Pathol 2015;19:113, Virchows Arch 2017;471:467)
Can share clonal abnormality of associated lymphoma or leukemia (Am J Surg Pathol 2008;32:1868)
TP53 in 1 case (Leukemia 2022;36:573)

Sample pathology report

Skin, left arm, biopsy:
- Compatible with indeterminate cell histiocytosis (see comment)
- Comment: The presence of histiocytes that express CD1a without langerin is compatible with a diagnosis of indeterminate cell histiocytosis (ICH). The definitive etiology of ICH is not known. ICH may represent a distinct entity, as suggested by the detection of ETV3::NCOA2 in a subset of cases or a variant of Langerhans cell histiocytosis (LCH) that has lost its Birbeck granules (Blood 2015;126:2344). Furthermore, chronic myelomonocytic leukemia (CMML) presenting with skin lesions rarely may mimic the immunohistochemical phenotype of ICH (J Cutan Pathol 2017;44:1075). If clinically indicated, correlation with genomic sequencing to assess for molecular aberrancies characteristic of ICH, LCH or CMML is recommended.
- Microscopic description: The histologic sections show skin with a nodular infiltrate of epithelioid cells with abundant eosinophilic cytoplasm, vesicular and variably reniform nuclei and prominent nucleoli present in sheets in the superficial and mid-dermis. On immunohistochemical staining, the lesional cells are positive for CD1a, S100 and CD68 and are negative for langerin, MPO and BRAF V600E.

Differential diagnosis

Langerhans cell histiocytosis:
- CD1a+, langerin (CD207)+ (100%), S100+, CD68+, BRAF VE1 (~50%)
Juvenile xanthogranuloma:
- CD1a-, langerin (CD207)-, S100 variable, CD68+
Multicentric reticulohistiocytosis:
- CD1a-, langerin (CD207)-, S100 variable, CD68+
Interdigitating dendritic cell sarcomas:
- CD1a-, langerin (CD207)-, S100+, SOX10+
Histiocytic sarcoma:
- Significant cytologic atypia, CD1a-
Chronic myelomonocytic leukemia secondarily involving the skin:
- Can have identical morphologic and immunohistochemical findings, correlate with molecular studies (J Cutan Pathol 2017;44:1075)
Reactive indeterminate cell infiltrates:
- Tick bite (Pediatr Dermatol 2017;34:e347)
- Scabies (J Dermatol 2000;27:181)

Board review style question #1

Which of the following electron microscopy findings is most consistent with a diagnosis of indeterminate cell histiocytosis (ICH)?

Lack of Birbeck granules
Presence of Birbeck granules
Presence of characteristic cytoplasmic inclusions
Proliferation of Langerhans cells

Board review style answer #1

A. Lack of Birbeck granules. Electron microscopy shows a lack of Birbeck granules in indeterminate cell histiocytosis.

Comment Here

Reference: Indeterminate cell histiocytosis / indeterminate dendritic cell tumor

Board review style question #2

Which of the following is the most useful immunohistochemical marker for differentiating between Langerhans cell histiocytosis and indeterminate dendritic cell tumor (image above)?

CD1a
CD45
CD68
CD207
S100

Board review style answer #2

D. CD207 (langerin) positivity in the Langerhans cells is specific for this disorder. Langerhans cells also typically stain for S100, CD1a and CD68 but CD1a is also expressed in indeterminate cell histiocytosis and CD68 and S100 can be seen in other histiocytic neoplasms. CD45 is a nonspecific leukocyte marker. CD20 is a B cell marker.

Comment Here

Reference: Indeterminate cell histiocytosis / indeterminate dendritic cell tumor

Indolent T lymphoblastic proliferations

Table of Contents

Definition / general

Benign expansion of immature terminal deoxynucleotidyl transferase (TdT) positive T cells in extramedullary and extrathymic tissues
Can be seen concurrently with other hematologic disorders or epithelial malignancies, such as Castleman disease, follicular dendritic cell sarcomas, angioimmunoblastic T cell lymphoma, hepatocellular carcinoma, acinic cell carcinoma, etc.

Essential features

Benign proliferation of extrathymic immature T cells that lack significant morphologic atypia but mimic malignant T lymphoblastic lymphoma / leukemia
Nonclonal process without evidence of TCR γ or β gene rearrangements
Lack of aberrant immunophenotypic or karyotypic abnormalities

Terminology

Immature T lymphoblastic proliferation
iT-LBP

Epidemiology

Age, gender, ethnicity, incidence / prevalence are undefined at this point

Sites

Typically presents with localized lymphadenopathy or a discrete mass
Common anatomical locations: mandible, cervical, supraclavicular, abdominal, retroperitoneal and oropharyngeal regions (Adv Anat Pathol 2013;20:137)
Rare cases have shown disseminated multinodal involvement (Am J Surg Pathol 2014;38:1298)
Does not involve mediastinum
Peripheral blood and bone marrow are not involved

Clinical features

Clinical presentation varies but patients are generally asymptomatic and healthy
Can be associated with other underlying neoplastic pathologic conditions, such as carcinomas, Castleman disease, follicular dendritic cell tumors and angioimmunoblastic T cell lymphoma (Am J Surg Pathol 2012;36:1619)

Diagnosis

Major criteria (Adv Anat Pathol 2013;20:137):
- No aberrant antigen expression (immunophenotype is of normal immature cortical thymocytes)
- Nonclonal TdT+ T cells
- No evidence of T cell gene rearrangements (TCR α and TCR β)
- Clinical evidence of indolence, > 6 months of follow up without progression in the absence of treatment

Prognostic factors

Clinically indolent
May persist in the involved tissue

Case reports

35 year old man with indolent T lymphoblastic proliferation associated with low grade follicular dendritic cell sarcoma and Castleman disease (Pathology 2018;50:351)
37 year old woman with an indolent T lymphoblastic proliferation involving the upper aerodigestive tract (Int J Clin Exp Pathol 2014;7:6350)
41 year old woman with pelvic pain found to have localized Castleman disease with concomitant iT-LBP (Ann Pathol 2019;39:29)

Treatment

Typical lesions show no signs of progression and require no treatment
Treatment for secondary disease (if present) may be needed

Gross description

Typically forms a tumor mass, varies in size from ≤ 1 cm to ≥ 9 cm in greatest dimension
External surface may be firm and fibrous or nonencapsulated
Displays pink-tan firm fleshy cut surfaces
Necrotic (yellow) areas may be seen in cases associated with hepatocellular carcinoma (HCC)
Reference: Adv Anat Pathol 2013;20:137

Microscopic (histologic) description

Preservation of overall tissue architecture (Adv Anat Pathol 2013;20:137)
Lymph nodes: benign lymphoblasts localize predominantly to interfollicular / paracortical regions
Carcinomas: lymphoblasts are interspersed or clustered between malignant epithelial cells without definitive evidence of lymphoepithelial lesions
Small to intermediate sized lymphoid cells with immature fine / blastoid chromatin lacking significant atypia
Inconspicuous nucleoli
Numerous mitotic figures may be present
Histiocytes are interspersed evenly throughout the proliferation

Microscopic (histologic) images

Contributed by Kunwar Singh, M.D. and Robert S. Ohgami, M.D., Ph.D.

Castleman disease

Follicular dendritic cell tumor

CD1a

CD3

CD4

CD8

CD99

TdT

Cytology description

Small to intermediate sized monotonous population with fine dispersed chromatin pattern and scant cytoplasm; occasional variably sized nucleoli may be present

Positive stains

Positive: TdT, CD3, CD43, CD45RO
Variable: CD10, CD99, CD1a, CD2, CD5, CD7, CD4+ / CD8+ or CD4- / CD8-
High Ki67 index

Negative stains

PAX5, CD20, CD79a, CD30
No thymic epithelium seen by immunostains

Flow cytometry description

Incidental benign TdT+ T cell populations may be detected by flow cytometry
Immunophenotype can show the entire range of T cell differentiation from the most immature dual CD4- / CD8- / CD7 bright+ / CD34+ / cytoplasmic CD3+ / surface CD3- forms to surface CD3+ forms with coexpression of CD4 and CD8 (Cytometry B Clin Cytom 2020;98:282)
Proportion of T lymphoblasts (identified by cytoplasmic CD3 and TdT expression) can vary from 50% of events

Molecular / cytogenetics description

iT-LBP have nonclonal T cell receptor (TCR) gene rearrangement studies (TCR γ or β)
No definitive chromosomal abnormalities
Initial reported case reported chromosome 9 inversion of uncertain significance (Am J Surg Pathol 1999;23:977)

Sample pathology report

Lymph node, inguinal, excision:
- Castleman disease, hyaline vascular variant
- Indolent T lymphoblastic proliferation (see comment)
- Comment: Sections from the inguinal node show predominantly preserved nodal architecture with atretic follicles and increased vascularity with a subset of hyalinized vessels penetrating regressed germinal centers. Interspersed within the paracortical areas are increased CD3+ / TdT+ positive T cells without aberrant antigen expression. The presence of immature T cells in association with hyaline vascular Castleman disease has been reported and typically shows indolent behavior. Clinical correlation is recommended. (Am J Surg Pathol 2012;36:1619)

Differential diagnosis

T lymphoblastic leukemia / lymphoma:
- Typically effaces nodal architecture or will infiltrate relatively nondiscriminately throughout entire node obliterating residual follicles
- Usually expresses LMO2 on malignant lymphoblasts (Histopathology 2020;77:984)
Ectopic thymic tissue:
- Residual thymic epithelium is also present and is highlighted by keratin stains: AE1 / AE3, CAM5.2, CK7
Thymoma:
- Lobulated architecture
- Presence of thymic epithelial meshworks
- No expression of LMO2 on lymphoblasts
- Presence in the mediastinum

Additional references

Am J Surg Pathol 2018;42:1647

Board review style question #1

Which of the following antigens do indolent T lymphoblastic proliferations lack?

CD3
CD20
CD33
CD45
TdT

Board review style answer #1

B. CD20. CD20 is a B cell marker which is not expressed by T lymphoblasts. CD3 is incorrect as it is a T cell marker expressed by indolent T lymphoblastic proliferations. CD33 is a myeloid associated marker which has been described as expressed by a subset of indolent T lymphoblastic proliferations. CD45 is a pan-hematopoietic cell marker which is expressed by indolent T lymphoblastic proliferations. TdT is incorrect as it is an immature marker expressed by indolent T lymphoblastic proliferations.

Comment Here

Reference: Indolent T lymphoblastic proliferations

Board review style question #2

Which of the following has been described to concomitantly occur in the disorder seen in the image above?

Chronic lymphadenitis
Indolent T lymphoblastic proliferation
Kikuchi-Fujimoto disease
Kimura disease
Rosai-Dorfman disease

Board review style answer #2

B. Indolent T lymphoblastic proliferation. This image shows a lymph node typical of Castleman disease. Indolent T lymphoblastic proliferations have been described in association with Castleman disease. Chronic lymphadenitis is incorrect as it is not a disease well known to occur in association with Castleman disease. Kikuchi-Fujimoto disease is incorrect as this is a necrotizing lymphadenitis of unknown etiology and association. Kimura disease is incorrect as it would show numerous eosinophils and eosinophilic granulomas and is not associated with Castleman disease. Rosai-Dorfman disease is incorrect as it shows large histiocytic cells with round to ovoid nuclei and distinct central nucleoli that exhibit emperipolesis.

Comment Here

Reference: Indolent T lymphoblastic proliferations

Infectious mononucleosis

Table of Contents

Definition / general

May cause spontaneous splenic rupture and death, often 10 - 21 days after disease onset
Rupture may be due to increased intrasplenic pressure due to congestion and weakening of splenic capsule from infiltration by immunoblasts

Case reports

16 year old girl with spontaneous splenic rupture (Int J Surg Case Rep 2012;3:97)

Clinical images

Images hosted on other servers:

Grossly enlarged with haematoma

Microscopic (histologic) description

Expansion of red pulp with immunoblastic proliferation
Immunoblasts may have strikingly atypical morphology, resemble Reed-Sternberg cells, infiltrate subintima of intratrabecular veins, occasionally exhibit hemophagocytosis

Positive stains

Immunoblasts are positive for B and T cell markers, EBV by in situ hybridization, variable CD30

Differential diagnosis

Interdigitating dendritic cell / reticulum cell sarcoma

Table of Contents

Definition / general

Rare malignant histiocytic neoplasm with morphologic and phenotypic features of interdigitating dendritic cells

Essential features

Most often involves lymph nodes, less commonly extranodal sites (Mod Pathol 2023;36:100268)
Characterized by epithelioid or spindled cells with diffuse expression of S100 and histiocytic markers, without expression of Langerhans cell markers (CD1a, langerin) (Mod Pathol 2023;36:100268)
Usually displays an aggressive clinical course, especially when multifocal (Ann Hematol 2019;98:2641, Am J Hematol 2024;99:871)
May be primary or secondary (i.e., associated with another hematologic neoplasm such as B cell lymphoma) (Mod Pathol 2023;36:100268)

Terminology

Also known as interdigitating dendritic cell tumor
Classified under histiocytic / dendritic cell neoplasms in the 2022 WHO Classification of Haematolymphoid Tumours and the International Consensus Classification (Leukemia 2022;36:1703, Blood 2022;140:1229)
Included as a subtype of malignant histiocytosis (M group) in the Histiocyte Society classification, along with histiocytic sarcoma and Langerhans cell sarcoma (Blood 2016;127:2672)

ICD coding

ICD-10: C96.4 - sarcoma of dendritic cells (accessory cells)

Epidemiology

Predominantly adults with median age of 58 years (Ann Hematol 2019;98:2641)
Slight male predominance (M:F = ~2:1) (Am J Hematol 2024;99:871, Ann Hematol 2019;98:2641)

Sites

Nodal (commonly cervical, axillary and mediastinal) and a wide variety of extranodal sites (skin, liver, gastrointestinal tract, lung, spleen, salivary glands, soft tissue, bone marrow) (Am J Hematol 2024;99:871, Ann Hematol 2019;98:2641)

Pathophysiology

Majority of cases show MAPK pathway activation (see Molecular / cytogenetics description)

Etiology

Etiology remains unknown
Secondary (associated with a hematologic neoplasm) in 10 - 20% of cases, most commonly secondary to B cell lymphoma, also may occur following T cell lymphoma or myeloid neoplasm (Mod Pathol 2023;36:100268, Ann Hematol 2019;98:2641, Crit Rev Oncol Hematol 2013;88:253)

Clinical features

Variable clinical signs / symptoms depending on the extent of disease, ranging from an asymptomatic solitary mass to systemic symptoms based on organ(s) involved (Am J Hematol 2024;99:871, Ann Hematol 2019;98:2641)
B symptoms (fever, night sweats, unintentional weight loss) may be present

Diagnosis

Morphologic evaluation supplemented by a panel of immunostains (diffuse S100 expression in conjunction with positive expression of at least 2 histiocytic lineage markers [i.e., CD4, CD68, CD163, PU.1]) is key to diagnosing IDCS
IDCS can demonstrate either a monocyte macrophage phenotype or a classical dendritic cell phenotype
Reference: Mod Pathol 2023;36:100268

Prognostic factors

Multifocal / disseminated disease with risk of organ involvement (bone marrow, liver, spleen) associated with poor prognosis (Am J Hematol 2024;99:871)
Median overall survival of multifocal / disseminated disease is < 1 year compared to unifocal / localized disease with median overall survival of > 2 years (Am J Hematol 2024;99:871, Ann Hematol 2019;98:2641)
Mortality rates are similar in isolated nodal or extranodal involvement with a 1 year mortality rate estimated at ~20 - 30%; however, combined nodal and extranodal sites have an estimated 1 year mortality rate at ~78% (Ann Hematol 2019;98:2641)
Surgically resectable disease has a 1 year mortality rate of ~18% compared to nonresectable disease with 63% (Ann Hematol 2019;98:2641)

Case reports

38 year old woman with painless right breast mass and bilateral neck masses (Virchow Arch 2005;446:546)
59 year old man with positron emission tomography (PET) avid left axillary lymphadenopathy (Cancer Biol Ther 2015;16:1128)
81 year old woman with asymptomatic skin papule in left temporal region (Pathol Res Pract 2023;247:154559)
81 year old man with history of gradually progressive painless mass in right submandibular region (Head Neck Pathol 2016;10:145)

Treatment

Unifocal / localized disease can be treated with surgical resection, with some cases achieving complete remission (Am J Hematol 2024;99:871)
Variable response to radiation therapy (Am J Hematol 2024;99:871, Ann Hematol 2019;98:2641)
Chemotherapy regimens or targeted therapy with MEK / BRAF inhibitors in those with MAPK alterations have shown limited efficacy without durable responses (Am J Hematol 2024;99:871)
Immune checkpoint inhibitors have been attempted in cases with high PDL1 expression (Am J Hematol 2024;99:871)

Gross description

Usually circumscribed with vaguely lobulated appearance and fleshy cut surface

Microscopic (histologic) description

Pleomorphic spindled or epithelioid cells arranged in fascicles, whorls or sheet-like patterns, often with indistinct cell borders and are characterized by large nuclei, vesicular chromatin, distinct nucleoli and abundant eosinophilic cytoplasm (Am J Clin Pathol 2001;115:589)
Paracortical distribution or diffuse effacement in lymph nodes
Occasional multinucleated forms may be present
Variable degree of admixed inflammatory cells, primarily lymphocytes and plasma cells

Microscopic (histologic) images

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

Epithelioid tumor cells with indistinct cell borders

CD68

CD163

CD14

S100

Cyclin D1

OCT2

Positive stains

2 lineage subsets (Mod Pathol 2023;36:100268)
- Macrophage - monocyte phenotype: S100 (diffuse), CD4, CD68, PU.1, CD163, CD14, OCT2
- Classical dendritic cell phenotype: S100 (diffuse), CD4, CD68 (majority show golgi / dot-like pattern of staining), CD11c, ZBTB46
  - This subset may be better classified as dendritic cell sarcoma, NOS
Cyclin D1 is expressed reflecting MAPK pathway activation

Negative stains

Follicular dendritic cell markers: CD21, CD23, CD35, clusterin, CXCL13
Langerhans cell markers: CD1a, langerin
Mesenchymal markers: actin, desmin, CD31, CD34
Epithelial markers: EMA, keratin (AE1 / AE3, CAM5.2)
Melanoma markers: HMB45, MelanA, SOX10
Lymphoma markers: CD3, CD20, CD30
References: Mod Pathol 2023;36:100268, Am J Surg Pathol 2004;28:988

Electron microscopy description

Interdigitating cytoplasmic processes but no desmosomes or other junctional complexes, no Birbeck granules

Molecular / cytogenetics description

MAPK pathway alterations, including mutations in BRAF V600E, KRAS and NRAS genes are frequent (Oncologist 2021;26:e1263, Mod Pathol 2023;36:100268)
In the setting of prior B / T cell neoplasms, shared genetic features between lymphoma and interdigitating dendritic cell sarcoma (IDCS) are present, such as IGH::BCL2 fusion in IDCS associated with follicular lymphoma (Mod Pathol 2023;36:100268)
Positive clonal B cell immunoglobulin gene rearrangement or T cell receptor gene rearrangement in secondary IDCS associated with prior B cell or T cell neoplasm

Sample pathology report

Lymph node, left neck, excisional biopsy:
- Interdigitating dendritic cell sarcoma (see comment)
- Comment: The submitted histologic sections show a portion of lymph node with a nodal architecture effaced by sheets of atypical epithelioid to spindled shaped cells. These neoplastic cells have large ovoid to folded nuclei with variable degrees of nuclear pleomorphism, vesicular chromatin, multiple small nucleoli and abundant pale eosinophilic cytoplasm.
- Immunostains were performed on formalin fixed and paraffin embedded tissue sections of the left neck lymph node (CD3, CD20, CD14, CD68, CD163, PU.1, CD1a, langerin, keratin (AE1 / AE3), SOX10, MelanA, HMB45, S100, OCT2, CD11c, CD21, CD23). The abnormal cells are positive for histiocytic markers (CD14, CD68, CD163, PU.1, OCT2), CD11c and S100 (diffuse and strong). The neoplastic cells are negative for melanocytic markers (SOX10, MelanA, HMB45), Langerhans cell markers (CD1a, langerin) and other markers tested. The overall morphologic and immunophenotypic findings support the diagnosis of interdigitating dendritic cell sarcoma.

Differential diagnosis

Histiocytic sarcoma (HS):
- Histologically indistinguishable from interdigitating dendritic cell sarcoma (IDCS)
- Macrophage phenotype; may show focal S100 expression, unlike the strong uniform expression in IDCS (Mod Pathol 2023;36:100268)
Langerhans cell sarcoma (LCS):
- Histologically indistinguishable from IDCS
- Positive for CD1a and langerin
Follicular dendritic cell sarcoma (FDCS):
- Histologically may have overlapping features with IDCS
- Positive for FDC markers (CD21, CD23, CD35, clusterin, CXCL13) (Am J Surg Pathol 2004;28:988)
- Negative for hematolymphoid markers (CD45, CD68, CD163, PU.1)
Metastatic melanoma:
- Histologically may have overlapping features with IDCS; cytoplasm may contain brown pigment (melanin)
- Positive for S100, Melan A, SOX10
- Negative for hematolymphoid markers (CD45, CD68, CD163, PU.1)
Diffuse large B cell lymphoma:
- Histologically may be similar with large discohesive cells
- Positive for CD20, CD45, PU.1
- Negative for S100, CD68, CD163
Anaplastic large cell lymphoma:
- Large anaplastic cells with abundant eosinophilic cytoplasm
- Positive for CD30; variable positivity for CD45, CD2, CD3, CD4, CD5, CD7
- Negative for S100, CD68, CD163, PU.1
Metastatic carcinoma:
- Usually epithelioid cells in sheets, clusters or single cells
- Positive for keratin (AE1 / AE3)
- Negative for hematolymphoid markers (CD45, CD68, CD163, PU.1)
Pleomorphic sarcoma:
- Pleomorphic cells with a spectrum of cytology and may include spindled, plasmacytoid, epithelioid or multinucleated forms
- Tumor cells are negative for histiocytic markers (CD4, CD68, CD163, PU.1); caution should be used to not misinterpret admixed reactive histiocytes

Additional references

WHO Classification of Tumours Editorial Board: Haematolymphoid Tumours, 5th Edition, 2024

Board review style question #1

A 79 year old man with a history of chronic lymphocytic leukemia (CLL) presented with a mesenteric mass. Core biopsy of the mesenteric mass revealed the images above (H&E, CD163, S100) and in addition, the tumor cells were positive for CD68, PU.1 and CD14. The tumor cells were negative for MelanA, SOX10, HMB45, CD3, CD20, PAX5, CD79a and CD19. Molecular studies were positive for clonal B cell immunoglobulin gene rearrangements and fluorescent in situ hybridization (FISH) analysis showed trisomy 12. Based on the morphology, immunophenotype and molecular studies, what is the most appropriate diagnosis?

Chronic lymphocytic leukemia
Diffuse large B cell lymphoma
Interdigitating dendritic cell sarcoma
Metastatic melanoma

Board review style answer #1

C. Interdigitating dendritic cell sarcoma (IDCS). H&E stained sections show sheets of atypical large cells with indistinct cell borders, characterized by epithelioid and occasionally spindled morphology, open chromatin, distinct nucleoli and abundant cytoplasm. Immunophenotypic studies (images) demonstrate a histiocyte / dendritic cell lineage with coexpression of CD163 and S100. Further, the presence of clonal B cell immunoglobulin gene rearrangements and trisomy 12 on FISH analysis suggest clonal relationship of the IDCS to patient's previously diagnosed CLL and therefore, this represents a secondary IDCS arising in the setting of transdifferentiation. The CLL component also harbored trisomy 12 on FISH analysis. Answers A and B are incorrect because of the morphology and immunophenotype (i.e., lack of all B cell markers: CD19, PAX5, CD79a, CD20). Answer D is incorrect because of the lack of other melanoma specific markers (SOX10, HMB45) and the presence of > 1 positive histiocytic lineage marker (CD68, CD163, PU.1, CD14).

Comment Here

Reference: Interdigitating dendritic cell / reticulum cell sarcoma

Board review style question #2

Which of the following molecular alterations is more common in interdigitating dendritic cell sarcoma (IDCS)?

JAK-STAT
MAPK
NFκB
Wnt

Board review style answer #2

B. MAPK alterations are present in > 50% of malignant histiocytosis, including IDCS cases. Answers A, C and D are incorrect because the other pathways are not typically associated with malignant histiocytosis.

Comment Here

Reference: Interdigitating dendritic cell / reticulum cell sarcoma

Interdigitating dendritic cell tumor

Table of Contents

Definition / general

Rare tumor of hematopoietic origin arising from interdigitating dendritic cells (IDCs), a type of immune accessory cell found in lymphoid and nonlymphoid organs
IDCs present antigens to T cells and regulate cellular immune responses (Crit Rev Oncol Hematol 2013;88:253)
Usually arises in lymph nodes (Am J Surg Pathol 1999;23:1141)

Epidemiology

IDC tumors have been reported in all age groups (median age 56 years)

Sites

Can be nodal or extranodal; have been described throughout the body
Only two reported cases of testicular involvement

Pathophysiology

Dysregulation of immune system may facilitate malignant transformation of IDCs (Crit Rev Oncol Hematol 2013;88:253)
Recent studies show a clonal relationship between IDC tumors and low grade B cell lymphomas in patients harboring both diseases synchronously or metachronously
A group of IDC tumors likely develops secondarily after the malignant transformation and trans differentiation of B cells, rather than transformation of IDCs themselves
IDC tumors have developed following the use of calcineurin inhibitors, tacrolimus and pimecrolimus; these drugs dampen the responses of T cells to which IDCs present antigens

Clinical features

Painless testicular mass

Laboratory

Serum tumor markers for testicular germ cell tumors (hCG and alpha fetoprotein) are normal

Radiology description

Testicular ultrasound is imaging modality of choice for a scrotal mass (Gordetsky: Gordo's Guide to GUPathology: A Resource for Urology and Pathology Residents, 2013)

Prognostic factors

Worse outcomes seen in younger patients and patients with intraabdominal involvement
Stage at presentation is most important prognostic factor (Crit Rev Oncol Hematol 2013;88:253)

Case reports

37 year old man with painless testicular mass (Int J Surg Pathol 2011;19:104)
74 year old man with a painless unilateral testicular mass (Am J Surg Pathol 1999;23:1141)

Treatment

Surgery with adjuvant chemotherapy

Gross description

Light tan, solid, may replace entire testis

Microscopic (histologic) description

Whorls and fascicles of spindle cells mixed with small lymphocytes

Microscopic (histologic) images

AFIP images

Various images from lymph node

Images hosted on other servers:

Axillary lymph node transformation from CLL / SLL

Positive stains

S100 (strong), vimentin (strong), CD68 (focal), CD4 (focal)

Negative stains

CD1a, CD3, CD20, CD21, CD23, CD34, CD35, CD45, actin, desmin, HMB45, cytokeratin, PLAP

Electron microscopy description

Complex interdigitating cytoplasmic dendritic processes, abundant rough endoplasmic reticulum, abundant mitochondria

Differential diagnosis

Germ cell tumors with a sarcomatous component
Sex cord stromal tumors
Infiltration by paratesticular spindle cell neoplasms
Metastasis

Kawasaki disease

Table of Contents

Definition / general | Treatment | Microscopic (histologic) description | Additional references

Definition / general

Also called mucocutaneous lymph node syndrome
Febrile disorder of unknown etiology usually affecting children
High incidence (39 per 100K children below age 5) in Hong Kong (Hong Kong Med J 2005;11:331)
Fever, pharyngitis and conjunctivitis, erythematous skin rashes, cervical adenopathy (25%); also arthritis (40%), coronary arteritis with persistent damage (15 - 25%) which may cause death

Treatment

IV gamma globulin, high dose aspirin

Microscopic (histologic) description

Fibrin thrombin in smaller vessels with patchy infarcts (Am J Surg Pathol 1982;6:493)

Additional references

eMedicine: Dermatologic Manifestations of Kawasaki Disease [Accessed 29 June 2018]

Kikuchi disease

Table of Contents

Definition / general

Benign, self limited lymphadenitis of unknown etiology with distinct histopathologic features

Essential features

Benign, self limited lymphadenitis of unknown etiology
Predominantly affects young adults, with cervical lymphadenopathy, fever and often leukopenia
Involved lymph nodes show histiocytes, plasmacytoid dendritic cells, immunoblasts and necrosis with karyorrhectic debris
Histologic features overlap with autoimmune disease associated lymphadenitis, especially systemic lupus erythematosus
Clinically and histologically may mimic lymphoma

Terminology

Kikuchi-Fujimoto disease
Kikuchi lymphadenitis
Histiocytic necrotizing lymphadenitis
Subacute necrotizing lymphadenitis

ICD coding

ICD-10: I88 - nonspecific lymphadenitis

Epidemiology

M:F = 1:1 - 4
Primarily young adults (average 20 - 30 years) but any age may be affected
Initially described in Asia; now known to occur worldwide
References: Semin Diagn Pathol 1988;5:329, Int J Infect Dis 2009;13:322, Acta Pathol Jpn 1993;43:635, Am J Surg Pathol 1995;19:798, Otolaryngol Head Neck Surg 2003;128:650, Clin Rheumatol 2007;26:50, Semin Arthritis Rheum 2012;41:900, Cureus 2020;12:e7383

Sites

Cervical lymph nodes, especially posterior
Other lymph nodes less commonly involved (axillary, mediastinal, abdominal, inguinal)
Rarely, extranodal sites, including skin

Pathophysiology

Necrosis is due to apoptotic cell death mediated by cytotoxic T cells (Acta Otolaryngol Suppl 1998;538:250, Mod Pathol 1997;10:231)

Etiology

Etiology unknown
May represent a T cell and histiocyte mediated immune reaction to an infectious agent; however, no definitive causal relationship with a specific infection established (Pathologica 2016;108:120, Cancer Control 2014;21:313, Clin Rheumatol 2007;26:50)
May represent a self limited autoimmune process (Semin Diagn Pathol 1988;5:329, Semin Arthritis Rheum 2012;41:900)
May be more likely in genetically predisposed individuals: HLA class II alleles DPA1*01 and DPB1*0202 more frequent among Japanese patients with Kikuchi disease than controls (Tissue Antigens 1999;54:246)

Clinical features

Acute or subacute onset
Lymphadenopathy (typically painful), usually cervical; may affect lymph nodes at other sites or be generalized
Fever is common
Additional symptoms may include weight loss, night sweats, fatigue, malaise, erythematous rash, headache, upper respiratory tract symptoms, joint pain, diarrhea, nausea, vomiting (J Microbiol Immunol Infect 2010;43:366, Pathologica 2016;108:120, Clin Rheumatol 2007;26:50, Semin Diagn Pathol 1988;5:329, Int J Infect Dis 2009;13:322)
May co-occur with or precede a diagnosis of systemic lupus erythematosus (2 - 23% of patients) or another autoimmune condition (Sjögren syndrome, polymyositis, rheumatoid arthritis, vasculitis, antiphospholipid syndrome, Still disease)
- If associated with systemic lupus erythematosus, may be best diagnosed as lymphadenitis associated with systemic lupus erythematosus (Semin Arthritis Rheum 2012;41:900, Case Rep Hematol 2018;2018:1791627, Int J Infect Dis 2009;13:322, Otolaryngol Head Neck Surg 2003;128:650)

Diagnosis

Lymph node excision with pathologic examination

Laboratory

No definitive diagnostic laboratory test
Leukopenia
Leukocytosis, especially in young children (Cureus 2020;12:e7383)
Anemia
Elevated lactate dehydrogenase
Elevated erythrocyte sedimentation rate; elevated C reactive protein
Antinuclear antibodies (ANA), anti-DNA antibodies and rheumatoid factor (RF) typically negative
Viral serologies typically negative
References: Otolaryngol Head Neck Surg 2003;128:650, Semin Diagn Pathol 1988;5:329, Semin Arthritis Rheum 2012;41:900, Clin Rheumatol 2007;26:50, Pathologica 2016;108:120, J Microbiol Immunol Infect 2010;43:366

Prognostic factors

Usually self limited; resolves within 1 - 6 months
May recur (3 - 21% of patients) (Am J Surg Pathol 1995;19:798, Am J Surg Pathol 1994;18:219, Int J Infect Dis 2009;13:322, Semin Diagn Pathol 1988;5:329, J Microbiol Immunol Infect 2010;43:366)
Rare fatalities reported (Pathologica 2016;108:120, Cancer 1989;63:1856, Clin Rheumatol 2007;26:50)

Case reports

20 month old boy with enlarged axillary lymph node and rash (Cureus 2020;12:e7383)
4 year old boy with Kikuchi disease and hemophagocytic lymphohistiocytosis (Medicine (Baltimore) 2020;99:e23500)
20 year old man with fevers and cervical adenopathy (Blood 2017;129:917)
38 year old woman with cervical lymphadenopathy (Head Neck Pathol 2020;14:272)

Treatment

Observation or supportive care (for example, nonsteroidal anti-inflammatory drugs) (Arch Pathol Lab Med 2010;134:289, Arch Pathol Lab Med 2018;142:1341)
May include corticosteroid therapy (J Laryngol Otol 2000;114:709, Medicine (Baltimore) 2014;93:372)
Followup is recommended, along with relevant laboratory studies, if indicated, to monitor for development of systemic lupus erythematosus

Microscopic (histologic) description

Partial or complete lymph node involvement by irregularly shaped, pale areas composed of histiocytes, plasmacytoid dendritic cells, eosinophilic granular material and abundant karyorrhectic debris (nuclear dust), often surrounding a central zone of overt necrosis
Karyorrhectic areas may extend beyond nodal capsule or involve residual germinal centers
Regions between pale areas include small lymphocytes admixed with immunoblasts and clusters of plasmacytoid dendritic cells, causing a mottled or starry sky appearance
Histiocytes include phagocytic cells with eosinophilic cytoplasm and crescent shaped nuclei (crescentic histiocytes) and nonphagocytic cells with twisted or reniform nuclei (Am J Surg Pathol 1994;18:219)
Plasmacytoid dendritic cells are intermediate in size with amphophilic cytoplasm, round nuclei, small nucleoli; difficult to recognize on H&E (Diagn Cytopathol 2010;38:521)
No neutrophils; rare to absent plasma cells (Clin Rheumatol 2007;26:50)
Overt necrosis not required for diagnosis (Am J Surg Pathol 1994;18:219)
3 stages described based on histology (Am J Surg Pathol 1995;19:798, Pathol Int 2004;54:237):
- Proliferative: proliferation of plasmacytoid dendritic cells, immunoblasts and histiocytes
- Necrotizing: areas of necrosis with karyorrhectic debris
- Xanthomatous: foamy histiocytes predominate; may represent histologic variant

Microscopic (histologic) images

Contributed by Elizabeth Courville, M.D. and Amy Beckman, M.D.

Lymph node from a 38 year old woman:

Distorted lymph node architecture

Pale staining areas

Karyorrhectic debris

Histiocytes and lymphocytes

CD3, CD4, CD8, CD20

CD3, CD4, CD8, CD68

CD30, CD123, MPO, EBV ISH

Cervical lymph node from a 40 year old woman:

Pale staining areas

Necrosis with mononuclear infiltrate

Karyorrhectic debris

Histiocytes

Lymph node

CD68

CD123

CD3

CD20

CD30

AFIP images

Kikuchi necrotizing lymphadenitis

Virtual slides

Images hosted on other servers:

Lymph node excision

Needle core biopsy

CD3 stain

CD30 stain

CD68 stain

CD123 stain

Cytology description

Phagocytic histiocytes with peripheral nuclei; plasmacytoid dendritic cells

Positive stains

CD3, CD4, CD8 highlight abundant T cells; CD8+ T cells > CD4+ T cells
Lysozyme, CD4 (weak) are positive in histiocytes
CD4 (weak), CD123 (bright) and TCL1 highlight plasmacytoid dendritic cells (Diagn Cytopathol 2010;38:521)
CD20 stains B cells present in uninvolved areas but absent from karyorrhectic areas
Myeloperoxidase: may stain histiocytes; emphasizes absence of granulocytes / neutrophils

Negative stains

Fite acid fast stain, Gomori methenamine silver (GMS)
HSV, CMV, in situ hybridization for EBV encoded RNA (EBER ISH)
Reference: Arch Pathol Lab Med 2018;142:1341

Electron microscopy description

Tubuloreticular structures present in cytoplasm of immunoblasts, endothelial cells and histiocytoid cells (Am J Pathol 1982;107:292)
Cells at various stages of apoptosis; histiocytes containing phagocytosed karyorrhectic debris / apoptotic bodies (Acta Otolaryngol Suppl 1998;538:250, Acta Pathol Jpn 1993;43:635)

Electron microscopy images

Images hosted on other servers:

Histiocytes with myelin figures

#2 with tubuloreticular structures

Sample pathology report

Lymph node, cervical, excision:
- Necrotizing lymphadenitis (see comment)
- Comment: The findings favor a diagnosis of Kikuchi disease, a benign and typically self limited lymphadenitis. There is no evidence of lymphoma. Histologically, changes associated with autoimmune disease may mimic those seen in Kikuchi disease. Clinical correlation, along with evaluation for a possible autoimmune disease, such as systemic lupus erythematosus, is recommended.
- Microscopic description: H&E stained sections show a lymph node with architecture distorted by pale areas composed of eosinophilic, granular material, karyorrhectic debris and interspersed lymphocytes and histiocytes. These areas are surrounded by histiocytic cells (some with twisted nuclei and others with so called crescentic nuclei) and cells with morphology suggestive of plasmacytoid dendritic cells. Outside the pale areas, there is an expansion of small lymphocytes admixed with immunoblasts. Residual primary and secondary follicles are present but neutrophils are not seen and plasma cells are rare to absent. Neither hematoxylin bodies nor aggregates of large atypical lymphocytes are identified. Immunohistochemical stains are performed with appropriate controls. CD3 highlights numerous T cells; CD8 positive cells outnumber CD4 positive cells. CD20 stains residual nodules of B cells. CD68 stains histiocytes within and adjacent to karyorrhectic areas. CD123 highlights plasmacytoid dendritic cells, which surround and form clusters outside of karyorrhectic areas. CD4 shows weak staining in both histiocytes and plasmacytoid dendritic cells.

Differential diagnosis

Lupus lymphadenitis:
- Hematoxylin bodies, Azzopardi phenomenon, plasma cells
- CD4+ T cells > CD8+ T cells
- Some cases may be histologically indistinguishable from Kikuchi disease
Infectious lymphadenitis:
- Neutrophils, granulomatous inflammation, viral cytopathic changes
Lymphoma (e.g., diffuse large B cell lymphoma, peripheral T cell lymphoma, NOS, Hodgkin lymphoma):
- Nodal effacement by monotonous or atypical lymphocytes or presence of Reed-Sternberg / Hodgkin cells
- Pattern of staining seen with a panel of immunohistochemical stains (for example, CD3, CD20, CD30, PAX5) and interpreted in the context of morphology on routine hematoxylin and eosin stain is important in making the distinction from Kikuchi disease

Additional references

eMedicine: Kikuchi Disease [Accessed 19 May 2021]

Board review style question #1

Which disease shows similar morphologic and immunohistochemical features to Kikuchi lymphadenitis?

Classic Hodgkin lymphoma
Rheumatoid arthritis
Systemic lupus erythematosus
Toxoplasmosis

Board review style answer #1

C. Systemic lupus erythematosus

Comment Here

Reference: Kikuchi disease

Board review style question #2

In this lymph node involved by Kikuchi disease, a proliferation of which cell type is illustrated by immunohistochemical stain for CD123?

Crescentic histiocytes
Immunoblasts
Monocytoid B cells
Plasmacytoid dendritic cells

Board review style answer #2

D. Plasmacytoid dendritic cells

Comment Here

Reference: Kikuchi disease

Kimura disease

Table of Contents

Definition / general

Benign chronic inflammatory disorder of unknown etiology (Am J Surg Pathol 2004;28:505)
Eosinophilic infiltrates forming microabscesses in a background of polymorphous inflammatory cells

Essential features

Benign disorder of unknown etiology with an indolent clinical course
Predominantly affects young Asian males
Involves nodal and extranodal sites, most commonly skin, head and neck
Commonly recurs postsurgical excision

Terminology

First described in 1937 by Kimm and Szeto as eosinophilic hyperplastic lymphogranuloma
In 1948, Kimura described it as "unusual granulation combined with hyperplastic changes in lymphoid tissue"; subsequently, this process was widely known as Kimura disease (Am J Otolaryngol 2017;38:626)

ICD coding

ICD-10: D21.9 - Kimura disease

Epidemiology

Predominantly affects males
Peak incidence between ages 20 - 40 years (Int J Oral Maxillofac Surg 2017;46:350)
Most common in Asians

Sites

Nodal and extranodal
Extranodal commonly includes skin and subcutaneous tissue, head and neck sites, including major salivary glands

Pathophysiology

Th1 / Th2 cytokine imbalance has been postulated as an underlying pathogenesis
Th2 cells may result in increased IgE production through interleukins (IL4 and IL5) and promote activation of eosinophils
Reference: Auris Nasus Larynx 2011;38:77

Etiology

Cause unknown
Presumed to be a consequence of an infection triggering an abnormal immune response

Clinical features

Insidious onset with an indolent clinical course
Slow growing nodules / masses, often painless and nontender
Systemic symptoms uncommon
Nephrotic syndrome may occur in a subset (Ren Fail 2019;41:126)
Recurrence is common after surgical excision

Diagnosis

Morphologic diagnosis characterized by hyperplastic reactive follicles surrounded by eosinophilic infiltrates in a background of polymorphous inflammatory cells

Laboratory

Elevated serum immunoglobulin IgE levels (Arch Pathol Lab Med 2007;131:650)
Peripheral blood eosinophilia (Am J Otolaryngol 2017;38:626)

Radiology description

Ultrasonography (US) and magnetic resonance imaging (MRI) studies are useful to detect extent of disease
CT findings may demonstrate the following findings (AJNR Am J Neuroradiol 1996;17:382)
- Enlarged lymph nodes with homogeneous enhancement
- Major salivary glands and soft tissue may show heterogeneous enhancement
US findings include the following findings (AJNR Am J Neuroradiol 2001;22:513)
- Enlarged lymph nodes appear as solid, hypoechoic and maintain hilar architecture
- Nodal involvement often exhibits hilar vascularity and occasionally a mixed hilar and capsular vascular pattern
- Soft tissue masses appear hypoechoic and predominantly solid but may occasionally have a cystic component with homogenous or heterogeneous internal architecture
MRI findings may demonstrate varying signal intensity proportionate to amount of fibrosis and vascular proliferation (AJNR Am J Neuroradiol 1996;17:382)

Radiology images

Images hosted on other servers:

Ultrasound findings

CT and MRI findings

Prognostic factors

Benign entity with an indolent course
Recurrence is common after surgical excision (Int J Oral Maxillofac Surg 2017;46:350)

Case reports

4 year old boy with bilateral upper eyelid swelling (Allergy Asthma Clin Immunol 2021;17:48)
7 year old boy with paralysis of bilateral lower extremities (BMC Surg 2020;20:209)
14 year old boy with submandibular swelling (Med Pharm Rep 2019;92:195)
18 year old man with nontender, mobile subcutaneous nodule below right ear (J Clin Diagn Res 2017;11:ME01)
28 year old man with multiple subcutaneous swellings of head and neck (Indian J Otolaryngol Head Neck Surg 2019;71:589)

Treatment

Conservative management in asymptomatic cases
Surgery followed by radiotherapy has been shown to result in longer period of remission (Int J Oral Maxillofac Surg 2017;46:350)
Other options include corticosteroids with or without immunosuppressants (e.g. cyclosporine)

Clinical images

Images hosted on other servers:

Lesion on buttock

Gross description

Enlarged lymph nodes
Soft tissue involvement presents as large, tumor-like masses

Frozen section description

Reactive lymphoid hyperplasia admixed with abundant eosinophils
Other entities need to be evaluated on permanent sections prior to classification as Kimura disease (see Differential diagnosis)

Microscopic (histologic) description

Hyperplastic follicles with germinal centers associated with expansion of interfollicular areas by abundant eosinophils, often forming eosinophilic microabscesses (Arch Pathol Lab Med 2007;131:650)
Disruption of follicles by increased eosinophils causing folliculolysis
Proteinaceous material may be present in germinal center due to increased IgE deposition
Admixed with polymorphous populations of lymphocytes, plasma cells, mast cells and histiocytes
Polykaryocytes of Warthin-Finkeldey type may be present (Am J Surg Pathol 1989;13:177)
Vascular proliferation in interfollicular areas
Necrosis may be present
Varying degree of sclerosis may be seen

Microscopic (histologic) images

Contributed by Aishwarya Ravindran, M.B.B.S. and Julie Teruya-Feldstein, M.D.

Excisional biopsy of lymph node

Eosinophilic infiltrates

Inflammatory milieu

Polykaryocytes of Warthin-Finkeldey type

Cytology description

Polymorphous population comprised of markedly increased eosinophils admixed with inflammatory cells (lymphocytes, plasma cells and occasionally histiocytes)
Cytologic findings are not sufficient to diagnose; biopsy is required for definitive characterization (Acta Cytol 2002;46:357)

Cytology images

Images hosted on other servers:

Eosinophils in a reactive background

Positive stains

Diagnosed on morphology; immunostains often not required
Involved tissue shows a reactive background with a mixture of CD3 positive T cells and CD20 positive B cells
IgE deposits in germinal centers (Am J Surg Pathol 1989;13:177)

Negative stains

CD1a, langerin, S100

Flow cytometry description

Absence of abnormal B cells, aberrant T cell population or increased blasts

Molecular / cytogenetics description

No known clonal gene rearrangements
Negative for gene translocations

Sample pathology report

Lymph node, right groin, excisional biopsy:
- Kimura disease (see comment)
- Comment: The right groin lymph node is involved by a proliferation of enlarged but well spaced secondary lymphoid follicles that maintain the normal zoning pattern of follicle center cells. The paracortex (interfollicular areas) is expanded by numerous eosinophils accompanied by small lymphocytes and occasional immunoblasts. Eosinophilic microabscesses are present and eosinophils also infiltrate some of the follicle centers. Additionally, the paracortex shows vascular proliferation. No malignant cells of any type are seen.

Differential diagnosis

Reactive follicular hyperplasia:
- Clinical history is important
- May occur in a variety of conditions, such as infections, medications, autoimmune diseases
Progressive transformation of germinal center:
- Hyperplastic germinal center follicles (4 - 5 times the normal) in a background of reactive follicular hyperplasia
- Eosinophilic microabscesses absent
Epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia):
- Benign vascular neoplasm, common in superficial dermis
- Morphology shows lobular proliferation of capillaries that are lined by plump, epithelioid endothelial cells, usually associated with eosinophilic and lymphocytic inflammatory infiltrate
- Subset shows FOSB gene rearrangements
Castleman disease, hyaline vascular variant:
- Large follicles with regressed germinal centers surrounded by concentric rings of mantle zone
- Interfollicular areas show increased vascular proliferation and plasmacytoid dendritic cells
- Eosinophilic microabscesses absent
Dermatopathic lymphadenopathy (Clin Case Rep 2018;6:1637):
- Commonly involves axillary and inguinal lymph nodes
- Paracortical expansion of lymph node parenchyma by mixed population of Langerhans cells, pigment laden histiocytes and small lymphocytes
- Eosinophilic microabscesses absent
Langerhans cell histiocytosis:
- Involves nodal and extranodal sites
- Langerhans cells characterized by grooved or reniform nuclei and abundant amount of eosinophilic cytoplasm, often admixed with eosinophils
- Positive for CD1a, langerin, S100
Hodgkin lymphoma, mixed cellularity type:
- Characterized by large Hodgkin / Reed-Sternberg (RS) cells in a mixed inflammatory background of eosinophils, lymphocytes, plasma cells and histiocytes
- RS cells are positive for CD15, CD30, PAX5 and negative for CD45 and CD20

Board review style question #1

A 30 year old previously healthy Asian man presented with enlarged cervical lymph node (see images above). Infectious and autoimmune workup were unrevealing. He was not taking any medications. Immunohistochemistry showed a mixture of CD3 positive T cells and CD20 positive B cells. Which of the following is the best diagnosis?

HIV lymphadenitis
Kikuchi-Fujimoto disease
Kimura disease
Langerhans cell histiocytosis
Rosai-Dorfman disease

Board review style answer #1

C. Kimura disease

Comment Here

Reference: Kimura disease

Board review style question #2

Microabscesses in Kimura disease are composed of which of the following inflammatory cells?

Eosinophils
Langerhans cells
Lymphocytes
Neutrophils
Plasma cells

Board review style answer #2

A. Eosinophils

Comment Here

Reference: Kimura disease

Langerhans cell histiocytic neoplasms

Table of Contents

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

Plain radiographs / CT: solitary or multiple punched out lytic lesions without sclerotic rim
 MRI: T1 hypointense to isointense, T2 hyperintense, T1 contrast enhancing (Dähnert: Radiology Review Manual, 6th Edition, 2007)

Radiology images

Contributed by Vignesh Shanmugam, M.D.

Sagittal view

Coronal view

Images hosted on other servers:

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

2 year old boy with generalized lymphadenopathy, hepatosplenomegaly and lytic lesions (J Cancer Res Ther 2015;11:1028)
7 year old girl with cervical lymphadenopathy (AABS 2016:3:C79)
41 year old woman with skin lesions and generalized lymphadenopathy (Postepy Dermatol Alergol 2015;32:225)
52 year old woman with inguinal lymphadenopathy (J Clin Pathol 2005;58:104)
68 year old woman with small lymphocytic lymphoma / chronic lymphocytic leukemia and rapidly expanding inguinal node (Case #314)

Langerhans cell sarcoma

Extremely rare (incidence of 0.2 cases per 10 million) with median overall survival of only 19 months (Clin Lymphoma Myeloma Leuk 2019;19:441)
May arise de novo or from Langerhans cell histiocytosis
Shows obliteration of nodal architecture, hypercellularity, nuclear atypia and increase in mitotic activity; some nuclear grooves, occasional multinucleation (J Clin Exp Hematop 2016;56:109)

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

CD21 (Histopathology 2002;41:1)
CD30 (Histopathology 2002;41:1)
B and T lineage markers (except CD4) (Histopathology 2002;41:1)

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

Images hosted on other servers:

Birbeck granules

Molecular / cytogenetics description

~50% of cases harbor BRAF V600E mutations (Blood 2010;116:1919)
~35% of BRAF wild type cases show other activating mutations involving the MAPK pathway in a mutually exclusive manner (MAP2K1 mutations, BRAF fusions, ARAF mutations, ERBB3 mutations) (Blood 2016;128:2533, Blood 2014;124:3007, Blood 2014;123:3152, Blood 2014;124:1655)
Most cases do not show any cytogenetic abnormalities (Genes Chromosom Cancer 2009;48:239)

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

Dermatopathic change:
- Pigment laden macrophages, lacks eosinophils, CD1a+ dendritic cells that are cyclin D1- (Am J Surg Pathol 2017;41:1390)
Cat scratch disease:
- Granulomas with necrosis
Kimura disease:
- Lacks a significant population of Langerhans cells
Juvenile xanthogranuloma:
- Benign proliferative disorder of histiocytic cells of the dermal dendrocyte phenotype (positive for factor XIIIa, a marker of interstitial dendrocytes, CD68, CD163, CD14 and fascin; negative for S100, CD1a and langerin)
Erdheim-Chester disease:
- CD1a-, langerin- histiocytes, including Touton type giant cells
Rosai-Dorfman disease:
- CD1a-, langerin-, S100+ histiocytes showing emperipolesis
Langerhans cell sarcoma:
- Pleomorphic and highly atypical Langerhans cells

Additional references

Swerdlow: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition, 2016

Board review style question #1

Which of the following is the most frequently mutated gene in the entity pictured below?

ARAF
BRAF
KRAS
MAP2K1
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?

Bilateral sclerotic long bone lesions
Elevated white blood cell count
Hairy kidney
Neurodegeneration
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

Lipofuscin

Table of Contents

Definition / general

Common incidental finding
Lipofuscin is a golden brown, finely granular pigment derived chiefly from the breakdown products of lipids, usually those derived from cell membranes
Ceroid is a variant of lipofuscin that is acid fast and autofluorescent

Sites

Portal lymph nodes and other nodes draining the liver
Also in other lymph node groups

Pathophysiology

Accumulation of lipofuscin in post mitotic cells by accretion of oxidized, cross linked proteins
Conspicuous in conditions associated with atrophy of an organ

Etiology

Various inflammatory, necrotic, neoplastic lesions, including chronic cholestatic lesions like primary biliary cirrhosis and primary sclerosing cholangitis

Clinical features

Enlarged lymph nodes

Prognostic factors

Although previously thought to have no significance, there is increasing evidence that lipofuscin may both cause and be due to increased oxidant stress in cells and may impair proteasomal and lysosomal functions

Gross description

Enlarged lymph nodes with brown pigment

Microscopic (histologic) description

Sinus histiocytosis with granular deposits of brown pigment in sinus macrophages
Varying degrees of follicular hyperplasia

Microscopic (histologic) images

Images hosted on other servers:

PAS

Black granules - Orcein

L: expansion of medullary sinuses; R: Long Ziehl-Neelsen stain

Positive stains

Sudan Black B, Schmorl reaction, oil red O, carbol lipofuscin stain, periodic acid-Schiff, Ziehl-Neelsen acid fast stain, autofluorescence or the lysosomal acid phosphatase and esterase stains

Negative stains

Electron microscopy description

Membrane limited, electron dense, spherical inclusions

Differential diagnosis

Additional references

Toxicol Pathol 2006;34:425, J Clin Pathol 1989;42:1160, Rubin's Pathology: Clinicopathologic Foundations of Medicine, 6th revised international ed edition, 2011, Invest Ophthalmol Vis Sci 1988;29:671

Littoral cell angioma

Table of Contents

Definition / general

Rare, typically benign splenic vascular tumor
Originates from littoral cells lining splenic red pulp sinuses

Essential features

Strong association with diverse immunologic and neoplastic disorders
Presentation varies from asymptomatic and incidental to fever, pain and cytopenias related to hypersplenism
Dual endothelial and histiocytic differentiation of tumor cells, similar to normal splenic littoral cells
CD34 is characteristically absent while other endothelial cell antigens are expressed

Terminology

Littoral cell angioma of the spleen

ICD coding

ICD-10: D73.89 - other diseases of spleen

Epidemiology

Mostly in middle aged adults
Median age: 50 years (range: 1 - 86 years)
M = F (Int J Clin Exp Pathol 2015;8:8516)

Sites

Unique to the spleen

Pathophysiology

Immunodysregulation is postulated to explain the clinical association with various malignancies or immune / autoimmune disorders (Histopathology 2016;69:762)

Etiology

Unknown etiology

Clinical features

Almost always benign with exceedingly rare malignant transformation
50% asymptomatic (World J Gastroenterol 2015;21:6660)
50% present with splenomegaly, hypersplenism associated thrombocytopenia and anemia, abdominal pain, fever or weight loss (Histopathology 2016;69:762, World J Gastroenterol 2015;21:6660)
36% associated with immune / autoimmune / metabolic disorders, such as Crohn's disease or immune thrombocytopenic purpura (Blood 2017;129:1564)
40 - 60% associated with malignancies, such as colonic adenocarcinoma, pancreatic tumor, lung carcinoma, renal cell carcinoma, lymphoma, myelodysplasia, aplastic anemia or testicular seminoma (Histopathology 2016;69:762)

Diagnostic criteria

Splenomegaly with nodules composed of benign tortuous vascular channels
Dual endothelial and histiocytic immunophenotype lacking CD34

Laboratory

Thrombocytopenia, anemia in subset of patients

Radiology description

Enlarged spleen
Ultrasound varies from heterogeneous echotexture without specific nodules to hyperechogenic, hypoechogenic or isoechogenic lesions
CT shows solitary or multiple hypoattenuating nodules (BMJ Case Rep 2015;2015:bcr2015212882)
MRI shows hypodense lesions on T1 and T2 weighted scans due to hemosiderin (Int J Clin Exp Pathol 2015;8:8516)

Radiology images

Contributed by Patricia Tsang, M.D., M.B.A. and Case #179

CT with contrast

CT scan

Prognostic factors

Typically benign with excellent prognosis postsplenectomy
Increased risk of malignant transformation with massive splenomegaly (> 1,500 g or > 20 cm long) (Minerva Chir 2014;69:229)
Rare reports of recurrence in accessory spleen or metastasis (Medicine (Baltimore) 2018;97:e0378)

Case reports

30 year old man presented with abdominal pain, fever and multiple splenic masses (Acta Chir Belg 2021;121:357)
38 year old man with splenic, renal and hepatic cysts (Arch Pathol Lab Med 2001;125:1505)
43 year old man with prior pulmonary sarcoidosis (World J Surg Oncol 2011;9:106)
45 year old man with obstructive jaundice (Indian J Pathol Microbiol 2012;55:109)
46 year old women and 52 year old man with littoral cell angioma detected during physical examination (Chin Med J (Engl) 2011;124:3423)
58 year old woman with large solitary littoral cell angioma (J Clin Imaging Sci 2012;2:69)
60 year old man with rapid increase in size of spleen (Rare Tumors 2010;2:e17)
61 year old woman with metastasis to the liver treated with chemotherapy (Medicine (Baltimore) 2018;97:e0378)

Treatment

Splenectomy
Management of any potential complications of asplenia (e.g., severe infection and thrombosis)
Clinical evaluation for any coexisting neoplastic or immune disorders (World J Gastroenterol 2015;21:6660)

Gross description

Solitary or multiple distinct splenic nodules (solitary to multiple ratio is ~0.3:1) (Front Oncol 2022;12:790332)
Minute to large nodules of variable consistency
Various colors (yellow / brown / red / black) depending on degree of necrosis, cyst formation, thrombi and fibrosis (Int J Clin Exp Pathol 2015;8:8516)
Spongy / cystic (J Cytol 2017;34:121)
Well demarcated but lacking a fibrous capsule

Gross images

Case #179

Cystic cut surface

Images hosted on other servers:

Multiple nodules

Microscopic (histologic) description

Proliferation of anastomosing, tortuous, blood filled vascular channels (Int J Clin Exp Pathol 2015;8:8516)
Irregular channel lumina, often with papillary projections and cystic spaces
Lined by tall endothelial cells with variable hemophagocytosis (BMJ Case Rep 2015;2015:bcr2015212882)
Sloughing of endothelial cells into vascular spaces
No sclerosis or cytologic atypia

Microscopic (histologic) images

Contributed by Patricia Tsang, M.D., M.B.A.

Tortuous vascular channels

Anastomosing vascular channels

Vascular channels appear papillary

CD31

CD34

CD68

Cytology description

3 dimensional, bland appearing, epithelioid foamy cells with low N:C ratio (J Cytol 2017;34:121)
May contain intracytoplasmic hemosiderin pigment

Positive stains

Dual endothelial (factor VIII, CD31, von Willebrand factor) and histiocytic (CD4, CD68, CD163, FLI1, MAC387, HAM56, lysozyme) differentiation (Histopathology 2016;69:762)
Langerin (CD207) (Hum Pathol 2019;83:43)
CD21
Vimentin
Cyclin D1
Low Ki67 proliferative index
S100 (variable; 20%) (Hum Pathol 2019;83:43)

Negative stains

CD34 (characteristically absent despite expression of other endothelial cell antigens)
ERG and WT1 vascular endothelial cell markers (Ann Diagn Pathol 2015;19:143)
CD45, CD8 (usually negative), CD117, HHV8, CD1a, cytokeratins

Molecular / cytogenetics description

No specific molecular findings

Sample pathology report

Spleen, splenectomy:
- Littoral cell angioma (see comment)
- Comment: The nodule in the splenic red pulp is composed of tortuous blood vessels lined by plump endothelial cells that form papillary projections into the lumina. No overt cytologic atypia or mitoses are seen. The white pulp is histologically unremarkable.
- Immunohistochemistry demonstrates dual endothelial and histiocytic differentiation of the vascular lining cells. The phenotypic profile is as follows: CD31+, factor VIII+, CD68+, lysozyme+, langerin+. Not expressed are CD34, CD117 and HHV8. The proliferative fraction based on Ki67 is low (about 15%).
- The overall findings are characteristic of splenic littoral cell angioma, which is benign in most cases. However, this lesion may be seen in association with a variety of neoplastic and immune / autoimmune conditions. Clinical correlation and follow up are suggested.

Differential diagnosis

Angiosarcoma:
- Atypical sarcomatous cells with hyperchromatic nuclei
- Frequent tumor necrosis, high mitotic rate and poor demarcation
- CD34+
Hamartoma:
- Disorganized blood vessels with entrapped adipocytes
- CD8+
Splenic littoral cell hemangioendothelioma:
- Typically mild to moderate cytologic atypia
- May have solid areas
- Potentially malignant or metastasizing
Kaposi sarcoma:
- Atypical spindle cells with HHV8 and CD34 positivity
- HIV related
Hemangioma:
- Usually asymptomatic, incidental finding
- Single layer of bland endothelial cells with CD34 positivity
- Lacks CD68 and other histiocytic markers
Hemangiopericytoma:
- Oval to spindle cells surrounding staghorn blood vessels
- CD34+, lysozyme-
- Relatively high malignant potential
Lymphangioma:
- Cystic, malformed lymphatic channels, often subcapsular
- Attenuated endothelial lining
- Lacks histiocytic markers and langerin

Additional references

J Clin Ultrasound 2014;42:308, World J Surg Oncol 2013;11:215, Arch Iran Med 2013;16:189

Board review style question #1

A 55 year old man presents with abdominal pain and multiple splenic nodules. The microscopic H&E image is shown above. The proliferative fraction is 20%. Which of the following immunostains is expected to be negative?

CD31
CD34
CD68
Factor VIII

Board review style answer #1

B. CD34. The photomicrograph shows anastomosing vascular channels in the spleen with sloughing of plump endothelial cells into the lumina, morphologically consistent with littoral cell angioma. The proliferative fraction is low. CD34 is characteristically negative in littoral cell angioma, while other vascular endothelial cell associated markers (CD31 and factor VIII) are positive. The histiocytic marker CD68 is also characteristically expressed.

Comment Here

Reference: Littoral cell angioma

Board review style question #2

Which of the following statements is true about littoral cell angioma of the spleen?

Hypersplenism related anemia or thrombocytopenia is a well recognized manifestation
It is pathogenetically linked to human herpesvirus 8 (HHV8)
It originates from the white pulp vascular lining cells of the spleen
Malignant transformation is common among middle aged and elderly patients

Board review style answer #2

A. Hypersplenism related anemia or thrombocytopenia is a well recognized manifestation. Hypersplenism in patients with littoral cell angioma can cause entrapment of RBCs and platelets in the spleen, leading to anemia and thrombocytopenia.

Comment Here

Reference: Littoral cell angioma

Luetic lymphadenitis

Table of Contents

Definition / general

Lymph node pathology caused by Treponema pallidum (syphilis) infection

Essential features

Lymphadenitis caused by Treponema pallidum
Characteristic histologic features include extensive capsular fibrosis with pericapsular chronic inflammation, follicular hyperplasia with numerous plasma cells, phlebitis with endarteritis and occasional poorly formed granulomas
Organisms stain with Warthin-Starry or specific immunohistochemical stains; confirmation by serology or PCR

Terminology

Syphilitic lymphadenitis

ICD coding

ICD-10: A52.79 - other symptomatic late syphilis

Epidemiology

In 2021 there were > 171,000 cases of all stages of syphilis, representing a 68% increase from 2017 (Infect Dis Clin North Am 2023;37:195)
Sexually transmitted infection or congenital syphilis acquired from infected mothers
Screening recommended for men who have sex with men, in the setting of HIV and in pregnant patients

Sites

Lymphadenitis associated with secondary syphilis (see Clinical features)
Inguinal (most common), axillae, cervical and occipital (Br Med J 1970;4:67)

Pathophysiology

Spread of T. pallidum organisms from the primary site of inoculation (chancre, painless ulcer with indurated margins) to regional or distant lymph nodes resulting in lymphadenopathy
Modes of transmission include sexual contact and infection passed from mother to child
T. pallidum infection normally triggers a robust humoral and cellular immune response but may take weeks or months to gain control of infection which is often incomplete with common infectious relapses (PLoS Negl Trop Dis 2012;6:e1717)
Macrophages appear to be the primary means of bacterial killing in the skin (PLoS Negl Trop Dis 2012;6:e1717)
Spirochetal membrane, including lipoproteins, is key in interacting with the host immune system, first triggering an innate immune response
Spirochetal lipoproteins, such as outer surface protein B (OspB), may inhibit neutrophil function and prevent oxidative burst; others may activate neutrophils, induce neutrophil extracellular traps and activate monocytes / macrophages and dentritic cells through CD14 and Toll-like receptor signaling pathways resulting in a proinflammatory response and cytokine production (Front Immunol 2017:8:364, PLoS Negl Trop Dis 2012;6:e1717)
However, the outer membrane of T. pallidum is unique with limited exposed lipoproteins and antigenic variation within the population in lipoprotein expression, resulting in overall poor reaction with antibodies present in syphilitic sera and enabling T. pallidum to evade the immune system (Infect Immun 2010;78:5178)
Secondary syphilis occurs as a result of T. pallidum’s ability to escape immune recognition while causing inflammation (PLoS Negl Trop Dis 2012;6:e1717)
T. pallidum may also trigger systemic immunologic abnormalities (PLoS Negl Trop Dis 2012;6:e1717)
Syphilis infection increases the likelihood of HIV infection; may increase HIV viral load and decrease CD4 count in HIV infected patients (Neurol Clin Pract 2014;4:114)

Etiology

Treponema pallidum (gram negative spirochete) infection

Clinical features

Primary syphilis
- Painless chancre with or without regional lymphadenopathy typically within 3 - 6 weeks of inoculation of spirochete in the site of infection (Sex Transm Dis 1997;24:185, CMAJ 2011;183:2015)
Secondary syphilis
- Disseminated skin rash (maculopapular or with pustular scales) or localized to the palms and soles of the feet, typically within 4 - 10 weeks after the appearance of the chancre (Genitourin Med 1989;65:1)
- Cutaneous well demarcated hypertrophic papules or plaques (condyloma lata) (JAAD Case Rep 2021;10:18)
- May also be associated with diffuse lymphadenopathy, hepatosplenomegaly, hepatitis or nephrotic syndrome (Am J Case Rep 2018;19:238)
Tertiary syphilis
- Occurs 10 - 20 years post infections in untreated patients
- Cardiovascular syphilis (aneurysm or aortic insufficiency), granulomatous lesions invading and causing tissue destruction (gummas) and neurosyphilis (Infect Dis Clin North Am 2023;37:195)
Latent syphilis
- Lack of clinical symptoms

Diagnosis

Darkfield examinations and molecular tests for detecting T. pallidum directly from lesion exudate or tissue are the definitive methods for diagnosing early syphilis and congenital syphilis (CDC: Syphilis [Accessed 11 October 2023])
2 types of serologic test for syphilis are classified based on the type of antigen to which they are directed and are required for presumptive diagnosis (Neurol Clin Pract 2014;4:114, CDC: Syphilis [Accessed 11 October 2023])
- Treponemal tests detect antibody to T. pallidum proteins (reactive versus nonreactive); may show false positive in inflammatory diseases
  - Treponemal tests include microhemagglutination assay, particle agglutination, hemagglutination assay, fluorescent treponemal antibody absorbed (FTA ABS) test, chemoluminescence immunoassays and enzyme immunoassays
- Nontreponemal tests detect antibodies (IgM or IgG) against lipoidal antigens, damaged host cells and possibly from treponemes and are semiquantitative, reflecting disease activity (Neurol Clin Pract 2014;4:114)
  - Nontreponemal tests include rapid plasma reagin (RPR), the venereal disease research laboratory (VDRL) test and the toluidine red unheated serum test
- No single test is sufficient with both tests being used to confirm infection or determine disease activity

Laboratory

Histology and immunohistochemical staining (J Biol Chem 1988;263:6363, J Invest Dermatol 2007;127:2345)
- Silver stain (Warthin-Starry) or antibodies to identify spirochetes in formalin fixed paraffin
- Embedded tissues from primary or secondary syphilis infections
PCR (J Biol Chem 1988;263:6363)
- Complimentary test to serology in the diagnosis of early syphilis or congenital syphilis
Dark field microscopy (Toxicol Sci 2004;81:3)
- Immunofluorescence is required for diagnosis but has the ability to distinguish between Treponema pallidum from nonpathogenic treponemes
Culture (Can J Infect Dis Med Microbiol 2005;16:45)
- Technically impractical for routine diagnosis

Radiology description

Lymphadenopathy, regional or distant sites

Prognostic factors

Favorable prognosis with appropriate antibiotic treatment

Case reports

23 year old man with painless enlarged inguinal lymph node (Hum Pathol 2018;13:9)
27 year old man with right sided neck mass (Am J Case Rep 2018;19:238)
29 year old woman with painful unilateral neck swelling (Cureus 2023;15:e36065)
35 year old man with cervical syphilis with Pringer-Kuchinka-like lymphadenitis (Br J Oral Maxillofac Surg 2014;52:e141)
40 year old man with syphilitic cervical lymphadenitis with abscess formation (Blood 2018;131:707)
48 year old woman with acute onset of bilateral inguinal enlargement (Histopathology 2010;56:656)
48 and 72 year old men with nontender, progressively enlarging neck masses (J Int Med Res 2012;40:1988)
56 year old man with a firm enlarged inguinal lymph node and histologic features mimicking lymphogranuloma venereum (S Afr Med J 2016;106:49)
71 year old with primary syphilis and painful inguinal lymphadenopathy without cutaneous manifestations (Radiol Case Rep 2022;18:280)
2 brothers presented with isolated unilateral cervical lymphadenitis (J Infect 2009;58:76)

Frozen section description

Similar findings to microscopic with reactive follicles and increased plasma cells
Organisms can be seen on Giemsa stains (Intern Med 2017;56:2083)

Frozen section images

Contributed by Genevieve M. Crane, M.D., Ph.D.

Touch imprint syphilitic lymphadenitis

Microscopic (histologic) description

Preserved or partial architectural distortion of lymphoid architecture (Pathol Int 2016;66:142)
Thickened capsule with pericapsular chronic inflammation, plasma cells and extensive fibrosis (Histopathology 2010;56:656)
Marked follicular hyperplasia with interfollicular, sinusoidal, perinodal and perivascular plasmacytosis (Arch Otolaryngol Head Neck Surg 1992;118:757)
Phlebitis with endarteritis in the capsule and nodular tissue
Variable histiocytes, noncaseating granulomas may be present (Pathol Int 2016;66:142, Am J Clin Pathol 1970;53:304)
Unusual formation of abscess containing spirochetes may occur (Blood 2018;131:707, Am J Clin Pathol 1970;53:304)

Microscopic (histologic) images

Contributed by Genevieve M. Crane, M.D., Ph.D.

Thickened capsule

Thickened fibrotic capsule

Inflammatory cells in capsule

T. pallidum organisms

Plasma cells in capsule

T. pallidum organisms

Ki67

Virtual slides

Images hosted on other servers:

Syphilitic lymphadenitis

Syphilitic lymphadenitis, T. pallidum IHC

Cytology description

Branching / arborizing vessels with perivascular plasma cell cuffing, presence of neutrophils and granulomas (Diagn Cytopathol 2023;51:E199)

Cytology images

Images hosted on other servers:

Spiral shaped bacteria

Peripheral smear description

Leukocytosis, anemia and thrombocytopenia especially in neonates in the setting of congenital acquired syphilis (AJP Rep 2017;7:e167)

Positive stains

Warthin-Starry silver stain or modified Steiner stain highlights spirochetes (Hum Pathol 2018;13:9)
T. pallidum IHC (Hum Pathol 2018;13:9)
Giemsa stain (Intern Med 2017;56:2083)

Negative stains

Difficult to visualize with Gram stain (Intern Med 2017;56:2083)
Acid fast stain (Medeiros: Ioachim's Lymph Node Pathology, 5th Edition, 2021)

Electron microscopy description

Complex structure with 2 layered outer wall (Bull World Health Organ 1966;35:223)

Sample pathology report

Inguinal lymph node, excisional biopsy:
- Reactive follicular hyperplasia with increased plasma cells, capsular thickening and fibrosis (see comment)
- Positive for T. pallidum consistent with syphilitic lymphadenitis
- Comment: The patient is a 60 year old man presenting with an indurated inguinal mass. Concurrent flow cytometry demonstrates no evidence of a monoclonal B cell or aberrant T cell population. The morphologic findings together with the organisms visualized by a special stain for T. pallidum are consistent with syphilitic (luetic) lymphadenitis. Correlation with clinical presentation and history are recommended. Confirmation with serologic or molecular studies can be considered if clinically indicated.

Differential diagnosis

Lymphogranuloma venereum:
- Sexually transmitted disease caused by Chlamydia trachomatis
- Diagnosis may be complicated by coinfection with T. pallidum
- Hyperplastic lymphoid follicles with increased plasma cell infiltrates and suppurative lymphadenitis which often involves the lymph node capsule and surrounding tissues
- Stellate abscesses are characteristic but not specific (S Afr Med J 2016;106:49)
- PCR for chlamydial DNA or complement fixation with titers > 1:256
- No commonly available stain for the tissue identification of C. trachomatis (Histopathology 2021;78:392)
Necrotizing granulomatous lymphadenitis:
- Lymphadenitis characterized by acute inflammatory cells and necrosis with giant cells and granulomas
- Clinical conditions include tuberculosis, cat scratch disease, histoplasmosis and leprosy
- Etiologic agents can be determined through serology, specific antibodies or identification of specific antigens using PCR
Inflammatory pseudotumor:
- Etiology unknown
- Prominent benign lymphadenopathy affecting 1 or several nodes
- Reactive node with mixed inflammation, vascular proliferation with phlebitis and varying degrees of storiform sclerosis
- Negative stains: Warthin-Starry or anti-Treponema pallidum antibodies, ALK and HHV8
Cat scratch lymphadenitis:
- Caused by Bartonella henselae acquired from arthropod vector or inoculation by scratch from infected cat
- Lymph nodes show follicular hyperplasia with deposition of amorphous intercellular proteinaceous material in follicles and characteristic stellate necrotizing granulomas (Am J Clin Pathol 1962;38:513)
- Positive stain with Warthin-Starry (rod shape rather than spiral)
- Monoclonal anti-B. henselae on paraffin fixed tissue or PCR analysis of bacterial DNA
Toxoplasma lymphadenitis:
- Lymphadenitis caused by Toxoplasma gondii
- Preserved lymph node architecture, with no capsular involvement
- Characteristic triad of florid follicular hyperplasia, monocytoid B cell hyperplasia and epithelioid histiocytes and microgranulomas
- Difficult to identify organisms in nodes but infection can be confirmed by serology for IgM and IgG antibodies against T. gondii cell wall antigens
- Highly sensitive and specific Sabin-Feldman dye test (mainly used by reference laboratories)
HIV lymphadenitis:
- Similar patient population and may co-occur
- Prominent follicular hyperplasia
- Capsular fibrosis is not a characteristic feature
- Distinguished by a lack of detectable organisms, serology
Reference: Medeiros: Ioachim's Lymph Node Pathology, 5th Edition, 2021

Board review style question #1

A 40 year old man presents with a right sided inguinal lymphadenopathy several weeks after a new sexual encounter. No monoclonal B cell or aberrant T cell populations are detected by flow cytometry. Histologic sections of a lymph node and an IHC stain are shown. Which of the following is most consistent with the timing, region and morphologic features of this process?

Lymphogranuloma venereum
New HIV infection
Primary syphilis
Secondary syphilis
Tertiary syphilis

Board review style answer #1

D. Secondary syphilis. The findings are most suggestive of syphilitic lymphadenitis, which is associated with secondary syphilis. Answer B is incorrect because while this may overlap with an HIV infection, acute HIV will typically show robust follicular hyperplasia without increased capsular fibrosis and without identifiable organisms. Answer A is incorrect because lymphogranuloma venereum may show some overlapping features but typically shows more suppurative features. Overlapping conditions may occur and so clinical correlation and serologic studies are recommended. Answers C and E are incorrect because timing and clinical features described are not consistent with primary or tertiary syphilis.

Comment Here

Reference: Luetic lymphadenitis

Board review style question #2

Which morphologic feature is least characteristic of syphilitic (luetic) lymphadenitis?

Ability to visualize organisms by special stains
Acute inflammation with necrotizing granulomas
Increased plasma cells
Reactive follicular hyperplasia
Thickened, fibrotic capsule

Board review style answer #2

B. Acute inflammation with necrotizing granulomas. Answers A and C - E are incorrect because syphilitic lymphadenitis is characterized by follicular hyperplasia, increased plasma cells, thickened fibrotic capsule and the ability to visualize organisms by silver stain or IHC for T. pallidum. Granulomatous inflammation can also be seen but necrotizing granulomas with acute inflammation are more characteristic of cat scratch lymphadenitis. Toxoplasma lymphadenitis may show follicular hyperplasia, epithelioid granulomas and increased monocytoid cells along vessels. Toxoplasma organisms are not usually well visualized by special stains in affected lymph nodes.

Comment Here

Reference: Luetic lymphadenitis

Lymphangioma

Table of Contents

Definition / general

Usually an extension of a soft tissue tumor
Rare as primary of lymph node

Case reports

12 year old girl with growing neck mass (Kulak Burun Bogaz Ihtis Derg 2013;23:187)
60 year old man with slow growing, upper laterocervical, painless enlargement (Acta Cytol 1999;43:442)

Microscopic (histologic) description

Dilated, thin walled lymphatic vessels, lined by attenuated endothelial cells
Lumina are empty or filled with proteinaceous material, lymphocytes or erythrocytes
Surrounding stroma shows lymphocytic infiltrate

Microscopic (histologic) images

AFIP images

Lymph node

Cytology description

Uniform population of small and round nonatypical lymphocytes with occasional histiocytes, centrocytes, centroblasts and plasma cells
No mitotic figures, no atypia (Acta Cytol 1999;43:442)

Positive stains

D2-40

Lymphangiomyomatosis

Table of Contents

Definition / general

Multisystem disorder affecting mainly middle age females, causing pulmonary and extrapulmonary disease
Its pathologic features result from the proliferation of neoplastic cells (LAM cells), which have characteristics of both smooth muscle cells and melanocytes
It was originally classified as benign but now is considered a "low grade, destructive metastasizing neoplasm" (Am J Respir Crit Care Med 2012;186:1210)

Terminology

Also called lymphangioleiomyomatosis

Epidemiology

Estimated median transplant free survival time for LAM patients in the U.S. is 29 years from onset of symptoms and 23 years from diagnosis
- Estimated 10 year survival transplant free is 86% (Lung 2013;191:35)
About 80% of women with TSC develop cystic disease in lungs (Chest 2013;144:578), compared to 13% of male patients (Clin Radiol 2011;66:625)
Relationship between pulmonary and extrapulmonary LAM needs further investigation

Etiology

Associated with tuberous sclerosis complex (TSC), an autosomal dominant disorder caused by mutations in the TSC1 or TSC2 genes, characterized by intellectual disability, autism, seizures, facial angiofibroma, cortical tubers, cardiac rhabdomyoma, asrocytoma

Diagrams / tables

Images hosted on other servers:

Diagnostic criteria

Case reports

47, 59 and 71 year old women with extrapulmonary lymphangioleiomyomatosis in pelvic and paraaortic lymph nodes (Int J Gynecol Pathol 2011;30:470)
55 year old woman with extrapulmonary lymphangioleiomyomatosis (Case of the Month #522)
59 year old woman with "malignant" uterine perivascular epithelioid cell tumor, pelvic lymph node lymphangioleiomyomatosis and gynecological pecomatosis (Int J Gynecol Pathol 2008;27:86)
Extrapulmonary lymphangioleiomyomatosis in pelvic lymph nodes associated with uterine cancer (Zhonghua Bing Li Xue Za Zhi 2015;44:527)
Incidental pelvic and paraaortic lymph node lymphangioleiomyomatosis (Am J Surg Pathol 2015;39:1015)

Microscopic (histologic) description

Single or multiple lymph nodes, median size is 3.5 cm
Mostly affecting nodal parenchyma but can be seen in hilum, subcapsular sinuses or extranodal extension
LAM cells are either spindle or epitheliod
Epithelioid cells are arranged in nests or swirls, separated by clefts which resemble lymphatic spaces
Spindled cells show fascicular growth with some nesting and less prominent lymphatic channels
No atypia, no necrosis, no mitosis

Microscopic (histologic) images

Contributed by Anna Sarah Erem, M.D. and Gulisa Turashvili, M.D., Ph.D. (Case #522), @katcollmd on Twitter and AFIP

Extrapulmonary lymphangioleiomyomatosis

Lymphangiomyomatosis

Lymph node

Involving pelvic lymph node

Cytology description

Relatively large monomorphic spindle cells (Acta Cytol 1997;41:877)

Positive stains

SMA and desmin
HMB45: patchy or diffuse, cytoplasmic or membranous
B catenin: positive, strong and diffuse
MelanA / A103: positive in 39% of cases
D2-40: highlights lymphatic endothelium

Differential diagnosis

Metastatic well differentiated leiomyosarcoma: no prominent vascular channels, more atypia and mitotic figures, HMB45-

Additional references

eMedicine: Lymphangioleiomyomatosis Imaging [Accessed 25 June 2018]

Massive splenomegaly

Table of Contents

Definition / general

Spleen > 1000 g
Due to chronic myeloid leukemia, Gaucher disease, hairy cell leukemia, marginal zone B cell lymphoma, myelofibrosis, plasmacytoma, prolymphocytic leukemia

Mesothelial inclusions

Table of Contents

Definition / general

Inclusions of benign mesothelial cells in lymph nodes
Often missed on routine H&E sections (Am J Surg Pathol 1999;23:1264)
Hyperplastic mesothelial cells in nodal tissue may derive from reactive serosal mesothelium that is dislodged into draining lymphatics (Arch Pathol Lab Med 2000;124:609)
Often associated with serosal fluid collection (pericardial, pleural, abdominal) at time of nodal biopsy (Hum Pathol 1998;29:339), including episodes of intraperitoneal hemorrhage and ascites (Pathology 2001;33:239), perhaps because effusion allows for mesothelial cell migration into lymphatics (Diagn Cytopathol 2003;29:163)

Terminology

Benign mesothelial inclusions
Benign metastasizing mesothelial cells

Epidemiology

Very rare occurrence

Sites

Mediastinal and abdominal lymph nodes
Rare - cervical lymph nodes

Etiology

Transportation of these cells through the lymphatics to the lymph node during injury or manipulation at the primary site of the origin
They undergo a degeneration, and thus it becomes difficult to find them

Clinical features

Incidental finding
Enlarged lymph nodes
Site specific symptoms

Diagnosis

Biopsy plus immunohistochemistry

Radiology images

Contributed by Kristin Dittmar, M.D.

Enlarged lymph node due to mesothelial inclusion

Prognostic factors

Benign process with no significant clinical implications

Case reports

12 year old boy with diffuse hyperplastic mesothelial cells in multiple lymph nodes (Int J Clin Exp Pathol 2013;6:926)
16 year old boy with mesothelial cell inclusions mimicking adenocarcinoma (Indian J Med Paediatr Oncol 2010;31:62)
18 year old woman with benign metastasizing mesothelial cells (J Clin Oncol 2011;29:e546)
52 year old woman with mesothelial pelvic lymph node inclusions mimicking metastatic thyroid carcinoma (Gynecol Oncol 1998;68:210)
Mesothelial cell inclusions in mediastinal lymph nodes mimicking metastatic carcinoma (Am J Clin Pathol 1990;93:741)
Mesothelial cell inclusions within mediastinal lymph nodes (Histopathology 1994;25:483)
Mesothelial pelvic lymph node inclusion in a patient with ovarian microinvasive borderline mucinous tumor (Int J Gynecol Cancer 2007;17:917)
Benign hyperplastic mesothelial cells in lymph node (Int J Surg Pathol 2007;15:297)

Treatment

Depends upon the clinical presentation / underlying cause
In incidental findings, none necessary

Gross description

Enlarged lymph nodes with yellowish tan to gray white, smooth to mottled surface

Microscopic (histologic) description

Small clusters and singly scattered, round to polygonal cells, seen in the subcapsular and interfollicular sinuses of the nodes
These cells show a round, vesicular nucleus with small nucleolus
The nuclear - cytoplasmic ratio is low
No mitotic activity is detected
There is no extranodal or parenchymal infiltration of the cells
Tiny spaces are seen in between the cells of the clusters (mesothelial windows)

Microscopic (histologic) images

Contributed by Debra L. Zynger, M.D.

Core biopsy

High power

CK7

CK5 / 6

Calretinin

Positive stains

Cytokeratin AE1 / AE3, cytokeratin 7 (CK7)
Calretinin (nuclear and cytoplasmic), WT1, CK5 / 6, CAIX (membranous)
EMA (weak and cytoplasmic)

Negative stains

Differential diagnosis

Lymphangioma: multicystic, has smooth muscle and lymphocytes in cyst wall and lumen, keratin+
Metastatic adenocarcinoma
Metastatic mesothelioma
Mucinous cystadenoma: ovarian-like stroma, mucin+, CEA+, negative for hyaluronic acid
Müllerian inclusions: ER+; negative for calretinin, CK5 / 6; PAX8 can be positive in both
Simple hemorrhagic cyst: keratin-
Sinus histiocytosis

Additional references

Ioachim's Lymph Node Pathology, 4th Edition, 2008, Dunphy: Frozen Section Library: Lymph Node, 2012, Jaffe: Hematopathology, 1st Edition, 2010

Metastases

Table of Contents

Definition / general

Splenic metastasis is usually associated with extensive metastases - isolated splenic metastasis is rare

Sites

Usually from lung, breast, melanoma, colon, ovary (Arch Pathol Lab Med 2000;124:526)
Rarely from endometrium, brain, liver or salivary glands

Pathophysiology

Metastasis may be rare due to spleen's immunological function
Metastases developed by hematogenous, lymphatic or abdominal cavity implantation routes; also direct invasion from lesions in adjacent organs
Hematogenous or direct seeding is more common

Clinical features

No specific clinical presentation
Rarely present with splenic rupture

Diagnosis

By radiological examination followed by histopathological confirmation

Radiology description

In ultrasonographic examination, the metastatic foci in the spleen may be hyperechoic, hypoechoic or nonechoic
In CT, hypodense lesions are seen

Radiology images

Images hosted on other servers:

F-FDG PET images of splenic metastasis

CT images of splenic metastasis

Case reports

47 year old woman with metastatic glioblastoma (Neurol Med Chir (Tokyo) 2003;43:452)
54 year old woman with solitary spleen metastasis of endometrial carcinoma (Chin J Cancer 2010;29:30)
61 year old man with atraumatic splenic rupture secondary to metastatic non small cell lung cancer (J Surg Case Rep 2013;2013:rjt051)
66 year old man with splenic metastasis from carcinoma ex pleomorphic adenoma of parotid gland (World J Surg Oncol 2014;12:18)

Treatment

Splenectomy and chemotherapy depending on the primary tumor

Gross description

Splenic metastasis can be seen as solitary nodule, multiple nodules or diffuse infiltration or cyst
Rarely resembles follicular lymphoma grossly with multiple nodules

Microscopic (histologic) description

Histology is similar to primary tumor
Red pulp may show nodular transformation similar to sclerosing angiomatoid nodular transformation

Microscopic (histologic) images

Images hosted on other servers:

Parotid gland: carcinoma ex pleomorphic adenoma

Metastases

Table of Contents

Definition / general

Lymph nodes are common site of metastatic disease
Presence of metastases is important for TNM staging
Must determine when examining lymph nodes: tumor present or not; tumor primary or metastatic; possible sites of primary; number of metastatic nodes; size of largest metastatic deposit often helpful; presence of extranodal or vascular involvement
Nodal metastases are common with carcinoma, melanoma or germ cell tumors; rare with CNS tumors and sarcoma (except for angiosarcoma, clear cell sarcoma, epithelioid sarcoma, MFH, rhabdomyosarcoma or synovial sarcoma)
Must also rule out lymphoma; compared to metastatic disease, lymphomas are more likely multifocal with diffuse penetration of vessel wall, minimal necrosis, no nesting, not limited to sinuses, not limited to intravascular invasion; differentiate based on special stains / immunostains (see below), touch preparations (clumping favors carcinoma), EM for epithelial features
Rarely, there is passive transport of benign neoplastic cells to lymph nodes (Arch Pathol Lab Med 2005;129:1317)
Carcinomas usually have cohesive tumor cells, sinus involvement, clearly defined margins with lymphoid tissue; may resemble Hodgkin lymphoma due to prominent nucleoli and mixed inflammatory infiltrate
Tumors misinterpreted as lymphoma: nasopharyngeal carcinoma - undifferentiated (tumor cells mix with lymphocytes and tumor does not appear cohesive), melanoma (tumor cells separate from each other within clusters), breast lobular carcinoma (may appear noncohesive), seminoma (inguinal and abdominal nodes)
Recommended stains (by Rosai) - first round: CD45 / LCA, pankeratin, S100; second round: (as necessary) CD3 (T cells), CD20 (B cell), EMA, CEA, vimentin, possibly GCDFP15 or lactalbumin (for breast), chromogranin (for neuroendocrine), PSA / PAP (for prostate)
Note: TdT+ lymphoid precursors are present in benign pediatric lymph nodes (Am J Clin Pathol 2002;118:248) and tonsils (Am J Clin Pathol 2001;116:12), causing possible confusion in ALL patients
Site of metastases:
- Upper cervical nodes: associated with upper aerodigestive tract
- Midcervical nodes: thyroid carcinoma, salivary gland, upper aerodigestive tract; also thymus or ovary
- Supraclavicular nodes: breast or lung, also stomach, pancreas, prostate, testis
- Axillary nodes: breast (women), melanoma, lung
- Inguinal nodes: external genitalia, melanoma
- Undetectable primaries with nodal metastases: nasopharynx, retrotonsillar pillars
Posttreatment changes: foamy histiocytes, fibrosis, mucin, atypical residual tumor cells

Microscopic (histologic) images

AFIP images

Metastatic Merkel cell carcinoma from skin

Metastatic Merkel cell carcinoma

Metastatic neuroblastoma

Metastatic seminoma

Metastatic carcinoma
simulating Hodgkin
lymphoma

Adenocarcinoma

Definition / general

Signet ring cells may actual be muciphages (Am J Surg Pathol 1998;22:545)

Gross images

Contributed by Dr. Mark R. Wick

Adenocarcinoma of
lung, mediastinal
lymph node biopsy

Microscopic (histologic) images

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

EMA stain

Mucicarmine stain

PAS stain

GEJ primary with signet ring features

Metastatic prostatic adenocarcinoma

Cytology images

AFIP images

Cytology of metastatic adenocarcinoma

Breast adenocarcinoma

Definition / general

Lobular carcinoma may resemble lymphoma, particularly if signet ring cells are present

Microscopic (histologic) description

Ductal: large apocrine-like pleomorphic cells with pink, granular cytoplasm, large nuclei and prominent nucleoli
Often cytoplasmic mucin
Comedo, trabecular and papillary patterns

Microscopic (histologic) images

Contributed by Dr. Mark R. Wick, Case #4 and AFIP images

CK stain

Micropapillary carcinoma

Metastatic lobular carcinoma of breast

Metastatic
mammary carcinoma
in axillary
lymph node

Metastatic mammary carcinoma

Images hosted on other servers:

Micropapillary carcinoma

Hepatocellular carcinoma

Microscopic (histologic) description

May produce bile

Microscopic (histologic) images

AFIP images

Metastatic hepatocellular carcinoma

Melanoma

Gross images

Images hosted on other servers:

Black staining tissue

Microscopic (histologic) description

Often melanin pigment in some tumor cells
Balloon cell variant resembles histiocytes, although nuclei are atypical

Microscopic (histologic) images

AFIP images

Metastatic melanoma in lymph node

Cytology images

AFIP images

Metastatic melanoma

Mesothelioma

Definition / general

Nodal involvement may be initial presentation (Am J Surg Pathol 1990;14:819)

Microscopic (histologic) description

May expand sinuses
Cuboidal cells with eosinophilic cytoplasm and central nucleus

Cytology description

Large dyscohesive cells with abundant pale cytoplasm, ruffled cytoplasmic borders, prominent central nucleoli (Am J Clin Pathol 1992;97:493)

Nasopharyngeal carcinoma

Definition / general

Also called lymphoepithelial carcinoma

Microscopic (histologic) description

Syncytium of cells with ill defined cytoplasm, vesicular nuclei and prominent nucleoli

Microscopic (histologic) images

AFIP images

Metastatic nasopharyngeal carcinoma

Metastatic undifferentiated nasopharyngeal carcinoma

Metastatic undifferentiated carcinoma from nasopharynx

Metastatic nasopharyngeal carcinoma

EBV+

Cytology images

AFIP images

Cytology of metastatic
undifferentiated carcinoma
from nasopharynx

Pancreatic adenocarcinoma

Microscopic (histologic) images

Images hosted on other servers:

Ductal adenocarcinoma

Papillary thyroid carcinoma

Microscopic (histologic) description

May appear as unilocular or multilocular cyst with attenuated lining cells and lack of distinct nuclear features of papillary carcinoma

Microscopic (histologic) images

Contributed by Dr. Marino Leon and AFIP images

Enlarged upper mediastinal node

Cystic metastatic papillary thyroid carcinoma

Positive stains

Thyroglobulin

Paraganglia

Microscopic (histologic) images

Images hosted on other servers:

Subcapsular invasion
with pleomorphic cells
with abundant granular
eosinophilic cytoplasm

Plexiform fibrohistiocytic tumor

Definition / general

Uncommonly metastasizes to lymph nodes (Am J Surg Pathol 1999;23:662)

Microscopic (histologic) description

Multiple plexiform nodules within and external to node
Nodules composed of plump fibrohistiocytic cells with multinucleated giant cells

Rhabdomyosarcoma

Definition / general

Alveolar subtype may first present with nodal involvement

Microscopic (histologic) description

Alveolar subtype: large packets of cells with central dehiscence, cells have moderate eosinophilic cytoplasm, with some rhabdomyoblasts present

Microscopic (histologic) images

AFIP images

Metastatic alveolar rhabdomyosarcoma

Serous borderline tumor

Case reports

Nodal metastases may be metastatic ovarian serous borderline tumor (Am J Surg Pathol 2006;30:739)
58 year old woman with high grade urothelial carcinoma of bladder and unknown ovary tumor 33 years prior (Arch Pathol Lab Med 2005;129:537)

Small cell neuroendocrine carcinoma

Definition / general

May resemble lymphoma

Microscopic (histologic) description

Minimal cytoplasm, dense chromatin with nuclear molding
Often focal necrosis and crush artifact
Azzopardi phenomena (dense hematoxylin staining of vessel walls)

Microscopic (histologic) images

Contributed by Dr. Mark R. Wick and AFIP images

Metastatic neuroendocrine lung carcinoma

Synaptophysin

Chromogranin

Metastatic small cell carcinoma from lung

Squamous cell carcinoma

Definition / general

Squamous cyst within cervical lymph node should be considered metastatic carcinoma until proven otherwise

Microscopic (histologic) description

Cystic change is common, particularly from head and neck region
Often bland looking squamous cells with only focal atypia

Microscopic (histologic) images

Contributed by Dr. Mark R. Wick and AFIP images

Squamous carcinoma
of lung, mediastinal
lymph node biopsy

Cystic metastatic squamous cell carcinoma

Mycobacteria-atypical / other than TB or leprosy

Table of Contents

Definition / general

Common cause of granulomatous lymphadenitis in immunocompetent children (1 - 5 years) and immunocompromised adults (Pediatr Int 2018;60:1062)
Clinical definite diagnosis of nontuberculous (non-TB) mycobacterial lymphadenitis requires a positive mycobacterial culture or positive PCR test of the purulent discharge or fine needle aspirate (FNA; based on the International Pediatric Otolaryngology Group [IPOG] 2023 Consensus guidelines) (Int J Pediatr Otorhinolaryngol 2023;166:111469)

Essential features

Unilateral anterior neck lymph nodes in children (1 - 5 years) and immunocompromised adults (e.g., HIV+)
Granulomatous inflammation with or without necrosis or partial or total nodal effacement by sheets of foamy histiocytes
Diagnosis is by positive culture for atypical mycobacteria or by excluding Mycobacterium tuberculosis in the presence of suggestive histology (Adv Exp Med Biol 2017;944:19)
Diagnosis can be established by positive PCR on excisional tissue biopsy or FNA, although performing an FNA on a suspected lymph node to confirm MTB lymphadenitis is controversial due to possible complications (i.e., iatrogenic needle track fistula formation) (J Clin Tuberc Other Mycobact Dis 2021;24:100244)

Terminology

Atypical mycobacterial lymphadenitis
Non-TB mycobacterial lymphadenitis (NTML)

ICD coding

ICD-10: A31.8 - other mycobacterial infections

Epidemiology

Children ages 1 - 5 are most susceptible
Immunocompromised adults, HIV+

Sites

Head and neck, usually unilateral anterior cervical chain lymph nodes

Pathophysiology

Mycobacterial, intracellular organisms, replicate within macrophages
Macrophages antagonize bacterial growth via TNF dependent mechanisms
Mycobacteria induce infected macrophage apoptosis
Newly recruited macrophages engulf cellular debris, contributing to granuloma expansion
Newly infected macrophages can exit the primary granuloma and establish secondary granuloma in distal tissue (Cold Spring Harb Perspect Med 2014;5:a018499)

Etiology

Most common causes are M. avium intracellulare complex, M. marinum, M. fortuitum, M. scrofulaceum, M. kansasii (Clin Infect Dis 1995;20:954)

Clinical features

Chronic, slow growing, painless, lymphadenopathy
Head and neck, unilateral

Diagnosis

Culture: sensitivity 41%, specificity 100% (gold standard) (Int J Pediatr Otorhinolaryngol 2018;112:48)
PCR: sensitivity 71.6%, specificity 100%
Immunoassay: sensitivity 87.5 - 100%, specificity 81 - 100%
Skin tests (PPD-S): sensitivity 70%, specificity 94%
Higher sensitivity of skin test by using multiple species coverage (e.g., PPD-A and PPD-K) (Eur J Pediatr 2021;180:1279)

Laboratory

PCR can identify Mycobacterium tuberculosis and 6 dominant nontuberculous mycobacterial species with a sensitivity of ~40% and 98% specificity (Microbiol Spectr 2023;11:e0160623)
Nucleic acid amplification (NAAT) only for Mycobacterium tuberculosis complex; M. tuberculosis and M. bovis: 90% sensitivity
- Good for diagnosis but not follow up; could detect RNA 6 months after starting therapy

Radiology description

Ultrasound: markedly decreased echogenicity, intranodal liquefactive / cystic necrosis, nodal matting and adjacent soft tissue edema (Pediatr Radiol 2006;36:1063)

Case reports

19 month old girl with the first reported case of human infection with Mycobacterium stomatepiae (JMM Case Rep 2018;5:e005146)
7 year old healthy girl with a rare case of Mycobacterium simiae cervical lymphadenitis (Aust J Otolaryngol 2022;5:31)
44 year old HIV+ man with diffuse large B cell lymphoma stage IV and on chemotherapy treatment presented with mycobacterial pseudotumor showing as an FDG avid mass on interim PET / CT (IDCases 2023;32:e01757)
46 year old man with necrotizing lymphadenitis during therapy for acute myeloid leukemia (Infect Chemother 2017;49:78)
67 year old man without immunodeficiency with right axillary lymphadenitis and lung right upper lobe nodule (Respir Med Case Rep 2019;28:100947)

Treatment

Complete excision: highest cure rate and highest risk of facial nerve palsy
Macrolides and rifampin for 6 months is the most commonly used regimen (Int J Pediatr Otorhinolaryngol 2023;166:111469)
Decision on excision versus longterm antibiotics versus no treatment should be based on location and number of lymph nodes (J Infect 2015;71:9)
Spontaneous regression may occur after 4 - 6 months

Clinical images

Images hosted on other servers:

Submandibular lymphadenopathy

Gross description

Enlarged rubbery lymph node, tan glistening surface with multifocal irregular necrotic soft tissue

Gross images

Images hosted on other servers:

Central caseation
in node involved
by M. avium
intracellulare

Frozen section description

Identical to microscopic

Microscopic (histologic) description

Granulomatous inflammation with or without necrosis, the presence of microabscesses, ill defined granulomas, noncaseating granulomas and a small number of giant cells favor nontuberculous mycobacteria over tuberculosis (Histopathology 1999;35:534)
Can present as bland appearing foamy histiocytes in sinuses or diffuse sheets occupying part or entire lymph node (mycobacterial pseudotumor) (IDCases 2023;32:e01757)

Microscopic (histologic) images

Contributed by Ahmed Alrajjal, M.D.

Sheets of foamy histiocytes

Nonnecrotizing granuloma

Reactive histiocytes

Sheets of histiocytes

Lymph node, AFB stain

Cytology description

Suppurative granulomas
Necrotizing granulomas are typical in M. tuberculosis infection but are also seen in atypical mycobacterial infection
Granulomas without necrosis can be suggestive of sarcoidosis
Multiple passes for cultures or PCR testing are recommended
Reference: BMC Infect Dis 2020;20:224

Cytology images

Contributed by Ahmed Alrajjal, M.D.

Touch imprint, lymph node granuloma

Images hosted on other servers:

Mycobacterium avium complex (MAC), Ziehl-Neelsen stain

Positive stains

Ziehl-Neelsen
- Acid fast bacteria are red
- Growth only (hot stain [i.e., requires dry heat for fixation])
- Identifies TB and all non-TB mycobacteria
Kinyoun stain
- Acid fast bacteria are red
- Growth and susceptibility (cold stain [i.e., no dry heat fixation required])
- Limited non-TB identification
Fite stain
- Acid fast bacteria are red
Auramine O
- Bright yellow luminous rods against a dark background with fluorescent microscope
- Identifies TB and all non-TB mycobacteria
- Increased sensitivity
References: Ann Clin Lab Sci Spring 2014;44:131, J Clin Tuberc Other Mycobact Dis 2021;24:100244

Negative stains

Gram stain

Molecular / cytogenetics description

16S rRNA sequencing (New Microbes New Infect 2017;22:24, J Clin Microbiol 2000;38:246)
PCR restriction fragment length polymorphism (PCR RFLP) procedure capable of rapidly identifying 28 species of clinically encountered mycobacteria (J Clin Microbiol 1997;35:79)

Molecular / cytogenetics images

Images hosted on other servers:

PCR for 7 different strains

Sample pathology report

Lymph node, left neck, excision:
- Nonnecrotizing granulomatous lymphadenitis (see comment)
- Comment: The lymph node architecture is partially affected by sheets of foamy histiocytes and multifocal granulomas. The granulomas are ill defined and composed of epithelioid histiocytes, lymphocytes and occasional plasma cells. No evidence of necrosis is noted. Acid fast bacteria (AFB) Fite special stain is positive for mycobacterial organisms. Paraffin embedded block was sent for PCR analysis for strain identification and subspeciation and the results will be reported in an addendum.

Differential diagnosis

Tuberculous mycobacterial infection:
- Usually necrotizing granulomas
- Few organisms seen by AFB stain
- Nucleic acid amplification and culture are positive for Mycobacterium tuberculosis
Fungal infection:
- Acute: suppurative inflammation; neutrophils, eosinophils and histiocytes
- Chronic: granulomatous inflammation; can be necrotizing
- Negative for AFB stain and positive for GMS or PAS
Foreign body reaction:
- Polarizable material may be present in tissue
Sarcoidosis:
- Diagnosis of exclusion by definition
- Negative for cultures and stains
- Naked type granuloma with very few lymphocytes

Board review style question #1

What is the most common histologic finding in immunocompromised patients with nontuberculous mycobacterial lymphadenitis caused by Mycobacterium avium complex (MAC) infection?

Follicular hyperplasia
Necrotizing granulomatous inflammation
Nonnecrotizing granulomatous inflammation with sheets of foamy histiocytes
Parafollicular hyperplasia
Suppurative inflammation

Board review style answer #1

C. Nonnecrotizing granulomatous inflammation with sheets of foamy histiocytes is the correct answer because atypical mycobacterial infection typically shows nonnecrotizing granuloma. Sheets of foamy histocytes morphology is also not uncommon, especially in MAC infection. Answer A is incorrect because this morphology is typical of other bacterial and some viral infections. Answer B is incorrect because necrotizing granuloma is seen in typical mycobacterial tuberculosis. Answer D is incorrect because parafollicular hyperplasia is associated with viral lymphadenitis. Answer E is incorrect because suppurative lymphadenitis is associated with bacterial infection.

Comment Here

Reference: Mycobacteria-atypical / other than TB or leprosy

Board review style question #2

An HIV positive 34 year old man has an enlarged painless lymph node. Nucleic acid amplification and culture are negative for M. tuberculosis organisms. What is the most common mycobacterial infection in immunocompromised patients such as this one?

M. aortuitum
M. avium intracellulare
M. gordonae
M. scrufulaceum

Board review style answer #2

B. M. avium intracellulare is the most common nontuberculous mycobacterial infection in immunocompromised patients. Answers A, C and D are incorrect because they are isolated less frequently compared to M. avium intracellulare. Those organisms can be seen in immunocompetent children.

Comment Here

Reference: Mycobacteria-atypical / other than TB or leprosy

Other ectopic tissue / inclusions

Table of Contents

Extramedullary hematopoiesis

Definition / general

Rarely associated with myeloproliferative disorders but also in healthy patients (Diagn Cytopathol 1993;9:522, Arch Otolaryngol 1982;108:523)

Case reports

26 year old woman presented with modified Bloom Richardson grade 2 invasive ductal carcinoma and ipsilateral axillary lymph node metastasis at diagnosis; her cancer was hormone receptor positive, HER2 equivocal (2+) on IHC (Case of the month #537)

Microscopic (histologic) images

Contributed by Nikhil Sangle, M.D., Sherif Shabaan, M.D. and Julie M. Jorns, M.D. (Case #537)

Liver with extramedullary hematopoiesis

H&E SLN capsule and parenchyma

H&E Another region of the SLN

Metastatic carcinoma

Cytokeratin AE1 / AE3

Differential diagnosis

Hodgkin lymphoma

Megakaryocytes

Definition / general

Often associated with extramedullary hematopoiesis when present in lymph nodes

Case reports

35 year old woman with megakaryocytes mimicking metastatic breast carcinoma (Arch Pathol Lab Med 2002;126:618)

Microscopic (histologic) images

Images hosted on other servers:

Megakaryocytes in bone marrow

Positive stains

CD31, CD61, vWF

Negative stains

Keratin, CD68

Differential diagnosis

Multinucleated histiocytes:
- Larger, more cytoplasm, vesicular nuclei that are not multilobated
- CD68+

Müllerian inclusions

Definition / general

Benign glandular inclusions lined by salpingeal or ovarian epithelium with no endometrial stroma or hemosiderophages

Terminology

Also called endosalpingiosis

Sites

Predominantly pelvic and paraaortic lymph nodes
Present in 5 - 41% of intra-abdominal nodes of women, 20% of women with gynecologic malignancies in paraaortic / pelvic nodes (Am J Obstet Gynecol 1978;130:813, Gynecol Oncol 2000;78:242)

Pathophysiology

Theories include:
- Passage of epithelial cells through the tubal ostium for implantation in the peritoneum following peeling, followed by transportation by the lymphatic route to reach the pelvic lymph node
- Metaplastic origin from the peritoneum
- Foci of endometriosis
- Vestiges of paramesonephricus ducts
- Metastases from ovarian serous borderline tumors (Am J Surg Pathol 2000;24:710)

Clinical features

Incidental finding / enlarged lymph nodes

Case reports

64 year old woman with endosalpingiosis with psammoma bodies within an intramammary lymph node presented as microcalcifications on mammography (Arch Pathol Lab Med 1995;119:841)
Coexisting with breast metastatic carcinoma in an axillary lymph node (Virchows Arch 2005;446:467)

Treatment

Benign process, with no clinical significance

Gross description

Enlarged lymph nodes

Microscopic (histologic) description

Glandular / cystic inclusions lined by cuboidal / columnar cells with a Müllerian or coelomic appearance commonly found in the capsule
Psammoma bodies are common
May undergo squamous metaplasia
No / rare mitotic figures, no / mild atypia, no desmoplastic stroma, no endometrial stroma

Microscopic (histologic) images

AFIP images

In pelvic lymph node

Positive stains

Keratin, mucin

Differential diagnosis

Metastasis from borderline / malignant ovarian tumors or uterine carcinomas

Additional references

J Clin Oncol 2006;24:2013, Ioachim: Ioachim's Lymph Node Pathology, 4th Edition, 2008, Rosai: Rosai and Ackerman's Surgical Pathology, 10th Edition, 2011, Robboy: Robboy's Pathology of the Female Reproductive Tract, 2nd Edition, 2008, Dunphy: Frozen Section Library - Lymph Nodes, 2012, Weiss: Lymph Nodes, 1st Edition, 2008, University of Pittsburgh: Endometriosis and Bland Glandular Inclusions [Accessed 12 April 2023]

Nevus cells

Definition / general

Incidence in axillary nodes is 7% per patient and 0.5% per node in one study (Am J Clin Pathol 1994;102:102)
Presence in sentinel nodes in melanoma patients is associated with
- Cutaneous nevi (Am J Clin Pathol 2004;121:58)
- Congenital cutaneous nevi (Am J Dermatopathol 2002;24:1)
May represent benign metastases from intradermal nevus in area of lymphatic drainage (Am J Clin Pathol 1985;84:220)

Microscopic (histologic) description

Single cells, linear arrangements or aggregates of small, round / oval nevus cells with moderate pale / clear cytoplasm, round nuclei with fine chromatin, no prominent nucleoli or pleomorphism, usually within fibrous capsule and trabeculae but also within nodal parenchyma or surrounding a small vessel (Am J Surg Pathol 2003;27:673, Am J Surg Pathol 1996;20:834)

Microscopic (histologic) images

Contributed by Debra L. Zynger, M.D.

Nests within capsule

Bland cells

SOX10

S100

AE1/3

Positive stains

S100, MART1, tyrosinase, p16 (Virchows Arch 2003;443:745)

Negative stains

HMB45 (occasionally is very focal), Ki-67 (Am J Surg Pathol 2002;26:1351)

Differential diagnosis

Blue nevus:
- Also spindled / dendritic cells with heavy pigmentation
Metastatic carcinoma or melanoma:
- Usually not confined to capsule, atypia, mitotic figures, different immunostaining
Spitz nevus:
- Larger cells with abundant eosinophilic cytoplasm
- Vesicular nuclei with prominent nucleoli

Salivary gland

Definition / general

Benign salivary gland structures in lymph nodes
Includes ducts and acini

Terminology

Salivary gland inclusions
Ectopic salivary tissue
Heterotropic salivary gland tissue

Epidemiology

Common incidental finding

Sites

Most common in upper cervical lymph nodes
Rarely - thoracic, mediastinal lymph nodes

Pathophysiology

Considered a normal event related to the embryology of the region

Clinical features

None - incidental finding
Enlarged lymph nodes

Prognostic factors

Benign with no significance
May undergo diseases of salivary glands including neoplastic processes - Warthin tumor is most common tumor

Case reports

55 year old woman with sialometaplasia arising in ectopic salivary gland ductal inclusions (J Clin Pathol 2004;57:1335)
60 year old man with salivary gland tissue in cervical lymph nodes (Laryngorhinootologie 2007;86:44)
68 year old woman with benign salivary gland tissue inclusion in a pulmonary hilar lymph node (Int J Surg Pathol 2011;19:382)
Proliferative sialometaplasia arising in an intraparotid lymph node (Am J Clin Pathol 1986;86:116)

Treatment

Usually none but may be indicated based on clinical situation

Clinical images

Images hosted on other servers:

Circumscribed mass lesions due to
sialometaplasia arising in ectopic
salivary gland ductal inclusions

Gross description

Normal / enlarged lymph nodes

Microscopic (histologic) description

Both ducts and acini are usually present
Benign ducts are lined by double layer of epithelium and myoepithelium
Benign acini have zymogen granules

Microscopic (histologic) images

AFIP images

Salivary gland inclusion in lymph node

Images hosted on other servers:

Inclusions undergoing sialometaplasia show extensive squamous metaplasia

Inclusions with sialometaplasia: SMA

Differential diagnosis

Metastatic adenocarcinoma

Additional references

Arch Pathol Lab Med 2003;127:e25, Jaffe: Hematopathology, 1st Edition, 2010, Rosai: Rosai and Ackerman's Surgical Pathology, 10th Edition, 2011

Smooth muscle

Definition / general

Topic discusses the presence of smooth muscle within the capsule and hilum of normal lymph nodes
Common, incidental finding in lymph nodes of hilar smooth muscle proliferation, more commonly in males than females (Virchows Arch A Pathol Anat Histopathol 1985;406:261)

Sites

Superficial, inguinal and axillary lymph nodes are most commonly involved

Etiology

Suggested etiological factors include back pressure in efferent lymphatics, local inflammation

Clinical features

Asymptomatic, with no apparent clinical significance, but may have enlarged lymph nodes

Diagnosis

Biopsy
Immunohistochemistry for smooth muscle to confirm

Case reports

6 year old boy with intranodal leiomyoma (Pediatr Dev Pathol 2014;17:118)

Gross description

Enlarged lymph nodes with firm, tan cut surface

Microscopic (histologic) description

Nodal architecture is well preserved
Muscle fibers run parallel to capsule or hilar blood vessels
Varied patterns of hilar changes:
- Smooth muscle fibers may be densely interwoven within fibrous tissue and hug the hilar nodal capsule
- Smooth muscle fibers may form a loose network extending in all directions within hilar adipose tissue
- Smooth muscle may surround individual islands of fat cells

Microscopic (histologic) images

Images hosted on other servers:

Angiomyomatous hamartoma of lymph node

Positive stains

Smooth muscle actin, desmin, muscle specific actin

Negative stains

CD34

Differential diagnosis

Additional references

Anat Rec 1975;183:517, J Cell Biol 2012;197:837, Ioachim: Ioachim's Lymph Node Pathology, 4th Edition, 2008

Squamous epithelium

Definition / general

Also called lymphoepithelial cyst
Most common in upper cervical nodes
Depending on location, may be a branchial pouch derivative or derive from metaplastic calyceal urothelium (Hum Pathol 1990;21:1239)

Case reports

33 and 64 year old women with benign heterotopic epithelial inclusions in axillary lymph nodes (Arch Pathol Lab Med 2003;127:e25)
48 year old woman with axillary intranodal cysts associated with breast malignancy (Arch Pathol Lab Med 2004;128:361)
57 and 75 year old women with cystic lymphoepithelial lesions of peripancreatic nodes (Surg Today 1999;29:467)
Epithelial inclusion in axillary lymph node associated with a breast carcinoma (Pathol Res Pract 1999;195:263)

Microscopic (histologic) description

Small cystic structures lined by well differentiated squamous epithelium

Differential diagnosis

Metastatic well differentiated squamous cell carcinoma:
- Often undergoes cystic change

Thymus

Definition / general

Ectopic thymus may be present in supraclavicular nodes

Microscopic (histologic) description

Lymphoid stroma with Hassall corpuscles

Differential diagnosis

Metastatic squamous cell carcinoma

Other infections

Table of Contents

Actinomyces

Definition / general

Rare
Associated with poor dental hygiene (is a normal inhabitant of the oral cavity)
Causes lymphadenopathy

Gram stain

Gram positive, filamentous branching bacteria

Treatment

Appropriate dental care and antibiotics

Case reports

12 year old girl with retroperitoneal tumor with rib involvement (Eur J Pediatr Surg 2005;15:38)

Gross description

Tan-white cut surface, multiple pinpoint white spots

Microscopic (histologic) description

Marked capsular fibrotic thickening with thick fibrous bands dividing nodes into nodules
Also follicular hyperplasia, marked interfollicular fibrosis and multiple interfollicular microabscesses containing focal Actinomyces colonies with classic sulfur granules (may require deeper levels to identify)
No palisading of histiocytes around the abscesses
Numerous macrophages are present in germinal centers

Cytology images

Images hosted on other servers:

Cervical cytology

Differential diagnosis

Cat-scratch disease
Lymphogranuloma venereum:
- Palisading histiocytes present
Syphilis:
- Fibrotic capsule but also prominent plasma cells

Additional references

Arch Pathol Lab Med 2000;124:1502

Bacillary angiomatosis

Definition / general

Caused by Bartonella (formerly Rochalimaea) henselae, which also causes cat-scratch disease
May also be caused by Bartonella quintana (Ann N Y Acad Sci 2005;1063:302)
Almost all patients are HIV+ or otherwise immunosuppressed
May have multiple red / violet skin lesions resembling Kaposi sarcoma but also involves lymph nodes and spleen
Bacterial reservoir is domestic cats (transmit to humans) and cat fleas (transmit to other cats)
May appear neoplastic but is reactive

Gram stain

Small, curved, motile, gram negative rod that is difficult to culture

Diagnosis

Case reports

17 year old renal transplant patient with persistent fever, pancytopenia and axillary lymphadenopathy (Arch Pathol Lab Med 2004;128:e12)

Treatment

Erythromycin, other macrolides or doxycycline are very effective

Microscopic (histologic) description

Focal nodal effacement by multiple coalescing intranodal clusters of small blood vessels, lined by epithelioid endothelial cells with pale cytoplasm
May have focal nuclear atypia
Interstitium contains abundant eosinophilic to amphophilic, amorphous or granular material containing aggregates of bacteria (highlighted by Warthin-Starry stain)
Also neutrophils

Microscopic (histologic) images

AFIP images

Multinodular; confluent nodules

Ectatic vessels

Barely canalized proliferated blood vessels

Eosinophilic material

Foamy histiocytes

Warthin-Starry stain

Differential diagnosis

Epithelioid hemangioma or hemangioendothelioma:
- Eosinophilic and vacuolated cytoplasm
- No amorphous / granular material
Kaposi sarcoma:
- Cleft-like vessels, spindled endothelial cells, no bacteria

Additional references

Am J Surg Pathol 1991;15:430, eMedicine: Bacillary Angiomatosis [Accessed 29 June 2018]

bCG

Definition / general

Post vaccination bacille Calmette-Guerin infection occurs in 1% of infants, although swelling usually subsides (Braz J Med Biol Res 2004;37:697)BACILLARY ANGIOMATOSIS Left: Proliferated blood vessels are separated by abundant eosinophilic, vaguely fibrillary material. Some neutrophils are also seen. Right: Barely canalized blood vessels separated by eosinophilic interstitial materials in the absence of neutrophils.
Patients with normal immunity have complete recovery after postvaccination bCG infection after excision of infected lymph node; immunosuppressed patients may require antiTB therapy to avoid fatal disseminated infection (Am J Clin Pathol 2000;113:703)

Case reports

3 month old Chinese baby with post bcg vaccination lymphadenitis (Arch Dis Child 2004;89:812)
68 year old man with cervical lymphadenitis post-bCG for bladder cancer (Respiration 2001;68:420)

Treatment

Surgery for large (3 cm) nodes, anti-TB therapy for small (1 cm) nodes (J Ayub Med Coll Abbottabad 2005;17:16)

Microscopic (histologic) description

Patients with normal immunity:
- Multiple epithelioid granulomas and Langhans giant cells
- Variable suppuration, minimal caseous necrosis
- Few acid fast bacteria identified with Ziehl-Neelsen stain
Immunosuppressed patients:
- Histiocytes with abundant gray cytoplasm containing numerous acid fast bacilli, plump nuclei

Cytology description

Poorly to moderately cellular smears of epithelioid histiocytes in a granuloma pattern with occasional multinucleated Langerhans type giant cells, lymphocytes and neutrophils
Background is finely granular with necrotic debris
Isolated calcified spherules (Diagn Cytopathol 2001;25:134)
May be heavy involvement of acid fast bacilli (World J Surg Oncol 2003;1:25)

Additional references

Postgrad Med J 2002;78:327

Brucellosis

Definition / general

Due to Brucella abortus, melitensis or suis
Either occupational or food related (milk and cheese)
Fever, hepatosplenomegaly, rarely lymphadenopathy

Case reports

22 year old woman with Kikuchi-Fujimoto necrotizing lymphadenitis associated with brucellosis (Sangre (Barc) 1992;37:201)
43 year old man with B. melitensis and subsequent Kikuchi-Fujimoto disease (In Vivo 2003;17:51)

Diagnosis

Culture, PCR, serology

Microscopic (histologic) description

Follicular hyperplasia, clusters of epithelioid histiocytes that may form large noncaseating granulomas
Eosinophils, plasma cells, immunoblasts

Differential diagnosis

Hodgkin lymphoma

Coccidioides

Definition / general

Also called San Jaquin Valley Fever
Dimorphic fungus with distinct yeast and mold stages
Endemic to Lower Sonoran Desert (southwest US, Central and South America)
Usually self limiting but more severe disease in immunocompromised hosts

Case reports

27 year old man on steroids for clinical pneumonia with enlarged paratracheal lymph node (Arch Pathol Lab Med 2005;129:699)

Diagnosis

Culture (grows on all media)
Has enteroarthric conidia (alternating segments of hyphae undergo autolysis, while surviving segments form infective barrel shaped multinucleate arthroconidia)

Microscopic (histologic) description

Thick walled spherules 20 - 150 microns containing 3 - 5 micron endospores, surrounded by a giant cell granulomatous reaction

Additional references

eMedicine: Coccidioidomycosis and Valley Fever [Accessed 2 July 2018]

Herpes simplex

Definition / general

HSV lymphadenitis is very uncommon
Usually inguinal nodes (Am J Clin Pathol 1991;95:709)
Often associated with hematopoietic malignancies

Case reports

23 year old woman with lymphadenitis before appearance of cutaneous vulvar lesions (Arch Pathol Lab Med 1985;109:1043)
43 year old man with immunodeficiency (Clin Infect Dis 2002;34:1)
43 year old woman with mantle cell lymphoma (Arch Pathol Lab Med 2006;130:536)
59 year old man with HSV infection resembling Richter transformation (Am J Hematol 2001;68:287)

Microscopic (histologic) description

Well circumscribed necrosis, follicular and paracortical hyperplasia (Histopathology 1991;19:355)
Cells have intranuclear inclusions, particularly at edge of necrotic areas
Also marked immunoblasts, T cell hyperplasia

Microscopic (histologic) images

Contributed by Mark R. Wick, M.D.

Herpes simplex lymphadenitis

Positive stains

HSV

Electron microscopy description

Intranuclear and cytoplasmic virus particles (Am J Surg Pathol 1990;14:571)

Histoplasmosis

Definition / general

May clinically mimic tuberculosis

Microscopic (histologic) description

Chronic suppurative lesion
Granulomatous process or widespread nodal necrosis with diffuse sinus histiocytosis (Centers for Disease Control and Prevention: Histoplasmosis [Accessed 3 July 2018])

Microscopic (histologic) images

Contributed by Mark R. Wick, M.D.

H&E and GMS stain

Positive stains

GMS or PAS

Leishmania

Definition / general

Parasites may continue in lymph nodes after clinical cure (J Infect 2003;47:77)

Case reports

8 year old boy with atypical presentation with hepatitis and adenopathy in disseminated disease (Trans R Soc Trop Med Hyg 2006;100:79)

Microscopic (histologic) description

Granulomas with abundant plasma cells, focal fibrosis, variable necrosis, leishmanian amastigotes (by immunostain, Am J Clin Pathol 1994;102:11)

Cytology description

Polymorphous lymphocytes, histiocytes, plasma cells, giant cells and tingible body macrophages
Amastigote forms within histiocytes and multinucleated giant cells and extracellularly (Acta Cytol 2005;49:286)

Leprosy

Diagnosis

PCR, immunofluorescence

Case reports

25 year old man with coexisting tuberculosis (Lepr Rev 1999;70:345)

Microscopic (histologic) description

Lepromatous leprosy exhibits large, pale, round histiocytes without granulomas and with no / rare necrosis

Microscopic (histologic) images

Images hosted on other servers:

Well developed germinal centers

Foamy histiocytes
contain M. leprae

Positive stains

Acid fast (modified Ziehl-Neelsen)

Differential diagnosis

Lymphoma:
- Clinically (Lepr Rev 2005;76:87)

Lymphogranuloma venereum

Definition / general

Sexually transmitted disease caused by Chlamydia trachomatis serotypes L1, L2 and L3 (Mod Pathol 1995;8:924, MedlinePlus: Lymphogranuloma venereum [Accessed 3 July 2018], eMedicine: Lymphogranuloma Venereum (LGV) in Emergency Medicine [Accessed 3 July 2018], Wikipedia: Lymphogranuloma venereum [Accessed 3 July 2018])
Endemic in tropical areas, rare in industrialized countries
Outbreaks in Western Europe
- Among male homosexuals (Rev Prat 2005;55:1747)
- In Bahamas associated with crack cocaine and HIV (Sex Transm Dis 2002;29:253)
Three clinical stages

Diagnosis

PCR
Previously Frei test (delayed hypersensitivity skin test using "lygranum" chlamydial antigen)

Treatment

Doxycycline for 21 days

Microscopic (histologic) description

Early: tiny necrotic foci with neutrophils
Late: stellate abscesses surrounded by pale epithelioid cells
Abscesses may merge and sinus tracts may develop
Macrophages may have organisms within vacuoles

Microscopic (histologic) images

Contributed by Mark R. Wick, M.D.

Lymphogranuloma
venereum

Electron microscopy description

Elementary and reticulate bodies

Differential diagnosis

Measles

Definition / general

Live attenuated vaccine may cause regional lymphadenopathy
Measles associated lymphopenia may be due to apoptosis of uninfected lymphocytes (Arch Virol 2000;145:905)
Fatal measles cases in South African in 1976-1982 were associated with malnutrition; caused depletion of T cell zones (S Afr Med J 1985;68:858)

Case reports

14 month old boy with familial immunodeficiency and necrotizing lymphadenitis with Warthin-Finkeldey type giant cells after measles vaccination (Ultrastruct Pathol 1980;1:243)

Microscopic (histologic) description

Polykaryocytes
In germinal centers, Warthin-Finkeldey giant cells have large nuclei and B cell markers
In interfollicular areas they have small hyperchromatic nuclei and T cell markers (Pathol Int 1994;44:442)

Microscopic (histologic) images

Images hosted on other servers:

Measles lymphadenitis

Microfilaria

See also related Breast topic

Definition / general

Filariasis is due to infection by threadlike nematodes of the family Filarioidea
Filarial infection can cause lymphedema of the limbs (elephantiasis), genital disease (hydrocele, chylocele and swelling of the scrotum and penis) and recurrent painful acute attacks (WHO: Lymphatic filariasis [Accessed 29 March 2021])

Essential features

Wuchereria bancrofti accounts for up to 90% of cases
Diagnosis is typically made by identifying microfilariae in peripheral blood smears
Rarely, microfilariae are coincidentally detected in FNAC in association with various inflammatory and neoplastic lesions
Wuchereria bancrofti can be identified by its sheath and multiple, coarse, discrete nuclei extending from head to tail except in the small terminal portion of the caudal end

Epidemiology

Major public health problem in India, China, Indonesia, Africa and the Far East

Pathophysiology

Wuchereria bancrofti accounts for up to 90% of cases
Adult worms lodge in the lymphatics, where females release larvae (microfilaria) which periodically circulate in the blood and are occasionally ingested by feeding mosquitoes
Microfilaria mature in the mosquitoes before becoming infective and are spread to new humans during mosquito feeding

Clinical features

Humans are the exclusive host of infection with W. bancrofti
Many infected individuals remain asymptomatic and serve as potential sources of infection
Virtually all infected people have subclinical lymphatic damage and up to 40% have kidney damage with proteinuria and hematuria

Diagnosis

Diagnosis is typically made by identifying microfilariae in peripheral blood smears
Rarely, microfilariae are coincidentally detected in FNAC in association with various inflammatory and neoplastic lesions (J Cytol 2010;27:78, J Cytol 2017;34:43)
Finding microfilaria in cytosmears is rare

Treatment

Treatment consists of multiple doses of albendazole and ivermectin to the entire at risk population, in addition to mosquito control

Microscopic (histologic) description

Wuchereria bancrofti can be identified by its sheath and multiple, coarse, discrete nuclei extending from head to tail except in the small terminal portion of the caudal end

Microscopic (histologic) images

Contributed by Sajna V.M. Kutty, M.D.

Case #446

Board review style question

Mycobacterial spindle cell pseudotumor

Definition / general

HIV+ patients, often involvement of many sites
Also infants after
- bCG vaccination (Zhonghua Bing Li Xue Za Zhi 2001;30:89)
- Posttransplant (Am J Clin Pathol 1985;83:524)
Spindle cells are macrophages with large amounts of mycobacteria (Am J Surg Pathol 1992;16:276)
Intraoperative touch imprints may demonstrate numerous intracellular organisms (Arch Pathol Lab Med 1995;119:811)

Radiology images

Contributed by Chunyu Cai, M.D., Ph.D. (Case #532)

MRI T1 post contrast

Case reports

35 year old HIV+ man with diffuse lymphadenopathy (Case of the Week #218)
52 year old man with a history of HIV infection and Kaposi sarcoma 5 years prior, presented with lower extremity weakness (Case of the month #532)

Treatment

Antiretroviral therapy for HIV
Antibiotics

Microscopic (histologic) description

Nodes show partial / complete effacement by storiform pattern of bland spindle cells, some with vacuoles
Numerous vessels lined by plump endothelial cells, plasma cells and lymphocytes
No multinucleated tumor cells, no foamy histiocytes

Microscopic (histologic) images

Contributed by AFIP and Chunyu Cai, M.D., Ph.D. (Case #532)

Mycobacterial spindle cell pseudotumor of lymph node

CD68

PAS

AFB

Cytology description

Spindle cell proliferation resembling Kaposi sarcoma; no foamy histiocytes (Acta Cytol 1995;39:125)

Positive stains

Spindle cells: CD45, CD68, HLA-DR, S100, desmin
Ziehl-Neelsen: numerous bacteria identified

Differential diagnosis

Kaposi sarcoma:
- Fascicular spindle cells, slit-like spaces, mitotic figures, no granular or acidophilic cytoplasm
- Spindle cells are CD31+ and CD34+
- S100- and CD68- (Am J Surg Pathol 1999;23:656)
Smooth muscle tumor

Board review style question

Parvovirus B19

Definition / general

In adults, parvovirus B19 infection is associated with fever (81%), arthralgia / myalgia (62%), skin rash (48%), general fatigue (43%), lymphadenopathy (38%) and edema (38%) (Intern Med 2002;41:295)
May be associated with hemophagocytic syndrome (Br J Haematol 1997;96:868)

Diagnosis

PCR
Immunohistochemistry

Case reports

16 year old girl with cervical lymphadenopathy, fever and fatigue (J Clin Pathol 2005;58:872)

Microscopic (histologic) description

Massive nodular histiocytic proliferation resembling Kikuchi disease with prominent apoptosis but no necrosis
One case showed florid reactive hyperplasia with paracortical expansion, neutrophils and hemophagocytosis (Pathol Int 1998;48:829)

Microscopic (histologic) images

Images hosted on other servers:

Prominent nodules of histiocytes

Tuberculosis

See also: Lung - nontumor chapter

Definition / general

Usually nodal involvement of cervical region (scrofula), often with draining sinus to skin
Generalized TB in AIDS cases at autopsy show thoracic or abdominal nodal involvement in almost all cases, although TB often not diagnosed prior to death (Arch Pathol Lab Med 2000;124:1267)
Needle biopsy of enlarged nodes may be helpful in smear negative, HIV+ patients with suspected TB (Int J Tuberc Lung Dis 2005;9:220)

Diagnosis

PCR (preferred, J Clin Pathol 2000;53:355)
Ligase chain reaction (Scand J Infect Dis 2004;36:724)
Immunostains
Culture

Case reports

8 year old boy with chronic renal failure and mediastinal nodal TB (Clin Exp Nephrol 2006;10:152)
52 year old woman with TB and metastatic breast carcinoma in axillary node (World J Surg Oncol 2003;1:3)
63 year old woman with Hodgkin lymphoma (Med Klin (Munich) 2006;101:500)
82 year old woman with coinfection with Trichomonad tenax (Hum Pathol 2000;31:1317)

Gross description

Large multinodular mass that resembles carcinoma with multiple foci of caseous necrosis

Gross images

Contributed by Mark R. Wick, M.D.

Tuberculous lymphadenitis

Images hosted on other servers:

Multinodular mass

Microscopic (histologic) description

Either multiple small epithelioid granulomas or huge epithelioid granulomas with prominent Langhans giant cells and central necrosis (J Clin Pathol 1988;41:93)

Microscopic (histologic) images

Contributed by Mark R. Wick, M.D.

Tuberculous lymphadenitis

Ziehl-Neelsen stain

Images hosted on other servers:

Granulomatous reaction

Noncaseous necrosis with prominent nuclear debris

Macrophages around foci of necrosis

With metastatic adenocarcinoma

Ziehl-Neelsen stain in HIV+ patient with TB

Tularemia

Definition / general

Caused by Francisella tularensis, a gram negative coccobacilli found in rodents, rabbits and hares, transmitted by ticks and deer flies
Commonly due to food and water contamination by rodents, hunting hares and mosquito bites (Med Clin (Barc) 2002;119:455, Emerg Infect Dis 2002;8:956)
Also a virulent, potential biowarfare agent (Centers for Disease Control and Prevention: Tularemia [Accessed 2 July 2018], eMedicine: Tularemia [Accessed 2 July 2018])
Symptoms: sudden fever, chills, headaches, diarrhea, muscle aches, joint pain, dry cough, progressive weakness; also pneumonia, skin / mouth ulcers, lymphadenopathy, eye involvement
Ulceroglandular form: prominent lymphadenopathy of either axilla (mammalian vectors, such as handling rabbits) or cervical / inguinal regions (arthropod vectors)

Diagnosis

Rise in titers
PCR (Mod Pathol 2004;17:489)
Immunofluorescence (Scand J Infect Dis 2004;36:785)

Microscopic (histologic) description

Early: reactive changes
Second week: abscess with variable epithelioid cell reaction
Fourth week: caseous necrosis, diffuse lymphadenitis
Late: granulomatous reactions that may resemble TB
Often extracapsular inflammation (Arch Pathol Lab Med 1986;110:42)

Differential diagnosis

Whipple disease

Definition / general

Rare; due to infection by Tropheryma whipplei, present in soil and sewage but not animals
Typically affects farmers and outdoor workers
Symptoms include diarrhea, malabsorption, weight loss, fever, arthralgias; also occasional CNS and cardiac involvement
May cause marked enlargement of mesenteric and periaortic lymph nodes; enlargement of peripheral lymph nodes may occur early
Diagnosis requires massive involvement of node plus intense PAS+ staining (small aggregates of PAS+ macrophages are nonspecific) or PCR
Gram stain: gram+ bacteria

Case reports

55 year old woman with mesenteric lymphadenopathy and a monoclonal B cell proliferation (Arch Pathol Lab Med 2003;127:1619)

Treatment

IV penicillin and streptomycin or third generalization cephalosporin for 10 - 14 days, plus cotrimoxazone for 1 year

Microscopic (histologic) description

Nodal architecture obscured by ill defined lipogranulomas
Involvement of sinuses by macrophages with foamy cytoplasm

Microscopic (histologic) images

Contributed by Mark R. Wick, M.D.

Various images

PAS stain

Warthin-Starry stain

Positive stains

PAS+ diastase resistant bacilli within histiocytes
Immunostains for bacteria (Am J Clin Pathol 2002;118:742)

Negative stains

Ziehl-Neelsen

Electron microscopy description

Rod-like organisms

Electron microscopy images

Images hosted on other servers:

Trilaminar cell wall

Molecular / cytogenetics description

PCR to confirm diagnosis; difficult to culture (Am J Clin Pathol 2001;116:898)

Differential diagnosis

Fabry disease

Yersinia pestis

Definition / general

Similar to Y. pseudotuberculosis

Clinical features

Infection is usually limited to lymph nodes ("bubo" as in bubonic plague) and is self limited
Clinical picture may resemble acute appendicitis but laparotomy often shows mesenteric lymphadenitis (Pediatr Surg Int 1998;13:2)
Pneumonic plague occurs if bacterial are aerosolized (eMedicine: Plague [Accessed 2 July 2018], Wikipedia: Bubonic Plague [Accessed 2 July 2018])

Diagnosis

Gram stain: gram negative, polymorphic, coccoid or ovoid mobile bacteria
PCR
Cultures

Case reports

46 year old woman with weight loss and abdominal lymphadenopathy (Radiologe 1998;38:37)

Microscopic (histologic) description

Capsular thickening and edema
Immunoblasts and plasma cells in cortical and paracortical region
Large lymphocytes within sinuses, germinal center hyperplasia
No granulomas (unlike Y. pseudotuberculosis)
Depletion of lymphocytes, edema, necrosis, foamy macrophages
Bacteria may involve blood vessels

Positive stains

Yersinia immunostain (Am J Clin Pathol 2002;117:205)

Yersinia pseudotuberculosis

Definition / general

Clinical picture usually resembles acute appendicitis with possible abdominal mass but laparotomy often shows mesenteric lymphadenitis (Eur J Pediatr Surg 1997;7:180)
Usually self limited but may be associated with Kawasaki disease (Kansenshogaku Zasshi 2005;79:895, Acta Paediatr 1997;86:661)
Ampicillin reduces fetal excretion of bacteria but provides no clinical benefit (Pediatr Infect Dis J 1988;7:686)
Gram stain: gram negative, polymorphic, coccoid or ovoid mobile bacteria

Diagnosis

PCR
Cultures

Gross description

Inflammation of terminal ileum and cecum

Microscopic (histologic) description

Capsular thickening and edema
Granulomas with central necrosis and microabscesses
Immunoblasts and plasma cells in cortical and paracortical region, large lymphocytes within sinuses, germinal center hyperplasia

Additional references

Am J Clin Pathol 1979;71:631, eMedicine: Pseudotuberculosis (Yersinia pseudotuberculosis Infection) [Accessed 2 July 2018]

Board review style question #1

Which statement regarding microfilarial infection is true

Diagnosis is made by culture
Infections are associated with exposure to animals
Most patients have nonspecific symptoms
Mosquito control is an important part of treatment
Quarantine is an important component of treatment

Board review style answer #1

D. Mosquito control is an important part of treatment

Comment Here

Reference: Other infections

Board review style question #2

A 52 year old AIDS patient with low CD4 count presented with multiple enhancing brain nodules. Infectious workup revealed disseminated mycobacterium avium intracellulare complex. Biopsy of the brain nodule showed a tumor with mixed spindle and epithelioid cells. What is the mostly likely immunohistochemical profile of this tumor?

CD31+, CD68-, SMA-,EBER-, HHV8+
CD31-, CD68+, SMA-, EBER-, HHV8-
CD31-, CD68-, SMA+, EBER+, HHV8-
CD31-, CD68-, S100+, EBER-, HHV8-

Board review style answer #2

B. CD31-, CD68+, SMA-, EBER-, HHV8-. This describes mycobacteria pseudotumor. Answer A is incorrect because it describes Kaposi sarcoma. Answer C is incorrect because it describes leiomyosarcoma. Answer D is incorrect because it describes schwannoma. See Case #532 for more information.

Comment Here

Reference: Other infections

Other nonspecific findings

Table of Contents

Clofazimine induced changes

Definition / general

Clofazimine induced crystal storing histiocytosis

ICD coding

ICD-10: R59.9 - enlarged lymph nodes, unspecified

Epidemiology

Rare condition in patients taking clofazimine, an antileprosy medication

Sites

Most commonly subcutaneous tissue, spleen, lymph nodes, liver, lung and gastrointestinal tract

Clinical features

Red discoloration of skin and other tissues, mass formation, lymphadenopathy

Diagnosis

History of clofazimine intake, biopsy

Radiology description

Enlarged lymph nodes, particularly intra-abdominal lymph nodes

Prognostic factors

Extent of involvement

Case reports

32 year old man with chronic abdominal pain (Am J Surg Pathol 2000;24:129)
41 year old leprosy patient with abdominal pain (Pathology 1993;25:24)
44 year old woman with adenocarcinoma of colon and crystal storing histiocytosis (Lepr Rev 2004;75:171)

Treatment

Excision of affected lymph node
Cessation of treatment apparently does not reverse the process

Gross description

Enlarged lymph node with light brown to dark red discoloration
Fixative and solutions used for processing the specimen turn red with the crystals dissolving in them

Microscopic (histologic) description

Marked interfollicular plasmacytosis and histiocytes containing crystals in their cytoplasm, which are elongated with irregular edges, some forming bundles
Crystals are typically deep red, but depending on the fixative and processing can be clear and colorless (crystals dissolve in alcohol)
Crystals show bright red birefringence if polarized
They can be seen in extra and intracellular locations

Positive stains

Plasma cells are highlighted by CD138 and are polyclonal by kappa and lambda light chain stains
Lymphocytes are mixed B and T cells and histiocytes show positive staining with CD68 and CD163

Negative stains

Crystals are negative for PAS and immunoglobulin heavy and light chains

Electron microscopy description

Transmission electron microscopy shows the empty spaces which crystals have been occupying
Crystals show some osmiophilic material which appear to be granular or multivesicular bodies
Upon higher magnification, these crystals show a multilamellar core or a lattice with elements spaced periodically

Electron microscopy images

Images hosted on other servers:

Elongated and rhomboid shaped dense crystals

Molecular / cytogenetics description

No clonal populations of cells

Differential diagnosis

Crystal storing histiocytosis with immunoglobulin crystals:
- Usually associated with a lymphoid or plasma cell neoplasm
Fungi
Parasites

Additional references

PLoS One 2012;7:e47494, Head Neck Pathol 2012;6:111, Antimicrob Agents Chemother 2016;60:3470, Antimicrob Agents Chemother 2011;55;4000, J Pharmac Sciences 2017;106:1162

Board review style question #1

Hyaline deposits

Definition / general

Also called proteinaceous lymphadenopathy
Often present in stroma of pelvic or abdominal nodes
Nonspecific finding
Increases with age (Am J Pathol 1975;78:7, Histol Histopathol 2003;18:1169)
- May reduce nodal function
Associated with
- Rheumatoid arthritis and systemic sclerosis (J Clin Pathol 1994;47:138, Br J Rheumatol 1995;34:1087)
- Hypergammaglobulinemia (Arch Pathol Lab Med 1990;114:34, Am J Surg Pathol 1979;3:137)
- Posttreatment changes for carcinoma (Histopathology 1996;29:63)
May calcify

Microscopic (histologic) description

Extracellular eosinophilic material resembling amyloid but Congo Red negative
Hyaline sclerosis of small and midsized vessels of lymph nodes and organs (Blood 1995;86:1159)

Positive stains

Immunoglobulins

Negative stains

Congo Red

Differential diagnosis

Infarction

Definition / general

Uncommon
Associated with fever, pain and lymphadenopathy (Am J Clin Pathol 1980;74:687)
Causes:
- Lymphoma
- Melanoma or granulocytic sarcoma (APMIS 2003;111:1133)
- Venous thrombosis
- Arterial occlusion in vasculitis (polyarteritis nodosa)
- Emboli (cholesterol) (Hum Pathol 1978;9:597)
- Heart lung transplantation (J Thorac Cardiovasc Surg 1990;99:861)
- Fine needle aspiration (J Clin Pathol 1982;35:855, Diagn Cytopathol 2001;25:104)
- Mediastinoscopy (Ann Thorac Surg 1989;48:247)
- Gold injection (J Clin Pathol 2001;54:562)
- Dengue fever with DIC (BMC Clin Pathol 2005;5:11)
- Infectious mononucleosis (Int J Surg Pathol 2002;10:223)
- Parvovirus B19
- Intestinal volvulus
Examine node carefully (possibly with levels or immunohistochemistry) and follow patient to rule out lymphoma or other malignancies (Histopathology 1986;10:571, Indian J Pathol Microbiol 2005;48:510)

Microscopic (histologic) description

Extensive necrosis with perinodal inflammation and granulation tissue
May retain a rim of viable lymphatic tissue
Reticulin architecture is retained

Microscopic (histologic) images

Images hosted on other servers:

Coagulative necrosis

Marked congestion and fibrin thrombi

CD20+

Post gold injection

Loss of follicles, few lymphocytes and distended sinuses

Superficial lymph nodes:

Early infarction with
small thrombosed
veins and perinodal
neutrophils

Thrombosed vein next to node

Organizing thrombus of hilar vein

Recanalizing thrombus of hilar vein

Lymphocytes
beneath sinus,
perinodal infiltrate
is present

Retention of reticulin

Immunohistochemistry

Tumor cells may stain with traditional markers (keratin, S100), even if remaining node is necrotic but be cautious (Arch Pathol Lab Med 2003;127:60, Arch Pathol Lab Med 2003;127:922)

Differential diagnosis

Additional references

J Clin Pathol 1972;25:689

Lymphedema

Definition / general

Either congenital, infectious, obstructive, traumatic or idiopathic
Congenital: also called Milroy disease (primary hereditary lymphedema), autosomal dominant (OMIM: Lymphedema, Hereditary, IA; LMPH1A [Accessed 28 June 2018], OMIM: Lymphedema, Hereditary, II; LMPH2 [Accessed 28 June 2018], OMIM: Yellow Nail Syndrome [Accessed 28 June 2018], OMIM: Lymphedema-Distichiasis Syndrome [Accessed 28 June 2018])
Infectious: due to schistosomiasis in endemic areas; occasionally due to minor infection such as furuncle
Obstructive: associated with malignancy or nodal dissection (axilla or groin most common)
Traumatic: may be as minor as sprained ankle
Idiopathic: called lymphedema praecox (if before age 35 years) or tarda
All causes are associated with lymphangitis, cellulitis and recurrent infections
Postmastectomy lymphedema may lead to angiosarcoma

Treatment

Elevation of extremity, compression and massage; if necessary, excise thickened skin and replace with skin grafts

Microscopic (histologic) description

Markedly dilated dermal lymphatics, including in lymph nodes
Fibrous tissue deposition in overlying skin, subcutaneous tissue and fascia

Microscopic (histologic) images

Images hosted on other servers:

Dilated lymphatic spaces lined by endothelium

Additional references

eMedicine: Lymphedema [Accessed 28 June 2018]

Mantle cell / marginal zone hyperplasia

Definition / general

Gene rearrangement studies and followup recommended to rule out occult lymphoma in cases with clear cells (Am J Clin Pathol 2001;116:550)
Marginal zone hyperplasia is rare (except in mesenteric nodes) but does occur in reactive nodes (APMIS 2002;110:325)

Microscopic (histologic) description

Monomorphic proliferation of small lymphocytes with clear cytoplasm and round nuclei
No pericapsular infiltration, sinuses are identifiable, scattered reactive follicles

Microscopic (histologic) images

Contributed by Mark R. Wick, M.D.

Cortical hyperplasia

Positive stains

BCL2 (by marginal zone B cells) (Am J Surg Pathol 2003;27:888)

Negative stains

No light chain restriction

Molecular / cytogenetics description

Usually negative

Monocytoid B cell hyperplasia

Definition / general

Benign disorders are toxoplasmosis, cat scratch disease, EBV, HIV, autoimmune disorders, zoonotic Brugia (Am J Surg Pathol 2005;29:595, Hum Pathol 1985;16:979, Am J Clin Pathol 1996;105:384)
Also associated with mantle cell / marginal zone hyperplasia

Microscopic (histologic) description

Sinuses distended by small lymphoid cells with clear cytoplasm and central, round / oval nuclei
Variable neutrophils

Differential diagnosis

Additional references

Pathol Res Pract 1998;194:559

Plasmacytosis

Definition / general

Common in paracolic lymph nodes draining tumor (Virchows Arch A Pathol Anat Histopathol 1987;411:239)
Associated with idiopathic plasmacytic lymphadenopathy, which resembles Castleman disease (Int J Surg Pathol 2004;12:25)

Case reports

72 year old woman with Sjögren syndrome and plasmacytosis resembling myeloma (J Korean Med Sci 2005;20:506)

Microscopic (histologic) description

Well preserved nodal architecture with plasma cells and plasma cell precursors in medullary cords
Sinuses are patent

Negative stains

No light chain restriction

Molecular / cytogenetics description

Not clonal

Differential diagnosis

Plasmacytic SLL / CLL:
- Diffuse, not just involvement of medullary cords

Polykaryocytes

Definition / general

Warthin-Finkeldey polykaryocytes are associated with various benign and malignant lymphoid conditions
Initially identified in tonsils of patients with measles
Also present in HIV patients

Case reports

65 year old woman with systemic lupus erythematosus (Hum Pathol 1988;19:1358)

Microscopic (histologic) description

Multinucleated giant cells from 25 - 150 microns, with minimal cytoplasm and up to 60 nuclei

Microscopic (histologic) images

Images hosted on other servers:

Warthin-Finkeldey giant cells with numerous closely packed nuclei

Positive stains

CD3, CD43 (T cells)

Additional references

Am J Clin Pathol 1992;97:179

Sinus histiocytosis

Definition / general

Also called sinus hyperplasia
Nonspecific finding associated with various etiologies (benign or malignant), including postprosthesis
May represent pregranulomatous phase of sarcoidosis (Am J Surg Pathol Acta Histochem 2006;107:473)
Rarely occurs in pelvic nodes of prostate cancer and axillary nodes of breast cancer patients (Cancer 1997;80:277)

Case reports

16 year old girl with parvovirus (J Clin Pathol 2005;58:872)
68 year old woman with postarthroplasty histiocytic lymphadenopathy (Arch Gynecol Obstet 2004;269:217, J Urol 1997;158:128)
70 year old diabetic patient with signet ring cell sinus histiocytosis resembling carcinoma (Am J Clin Pathol 1989;92:509, Int J Clin Oncol 2003;8:184)

Microscopic (histologic) description

Dilated and prominent sinuses, often containing increased macrophages or sinus lining cells
May resemble signet ring cell carcinoma cells but lack atypia and are mucin negative

Microscopic (histologic) images

Images hosted on other servers:

Sinus histiocytosis

Cytology description

Polygonal histiocytes with rounded nuclei (Acta Cytol 1998;42:1347)

Board review style question #1

In crystal storing histiocytosis, the cell type which accumulates crystals is

Histiocytes
Lymphocytes
Neutrophils
Plasma cells

Board review style answer #1

A. The crystals in CSH in tissues get phagocytosed by histiocytes where they form collections. When these cells accumulate, they form a mass lesion.

Comment Here

Reference: Other nonspecific findings

Other pigment / foreign material

Table of Contents

Asbestos

Terminology

Also called Ferruginous bodies

Epidemiology

Usually due to industrial / occupational exposure

Sites

Most common in thoracic / hilar lymph nodes
Concentration of asbestos fibers in lymph nodes is 2 - 3x higher than in lung

Clinical features

Inhaled asbestos fibers have iron protein mucopolysaccharide coating
Enlarged lymph nodes are common
Associated symptoms / signs of pulmonary asbestosis

Diagnosis

Biopsy of affected lymph node
Bleach digestion for confirmation

Radiology description

Mediastinal / hilar lymphadenopathy

Prognostic factors

Pulmonary asbestosis is a risk factor for lung carcinoma and mesothelioma

Case reports

26 year old man with mesothelioma due to asbestos exposure (Case Rep Med 2011;2011:951732)

Clinical images

Images hosted on other servers:

Asbestos with mesothelioma:

Enlarged supraclavicular node

Epiphrenic node on right

Node inside lesion

Gross description

Lymph nodes may be enlarged but show no significant abnormalities on cut surface

Microscopic (histologic) description

Asbestos bodies are golden-brown, beaded or dumbbell shaped structures with a thin, translucent core

Differential diagnosis

Pseudoasbestos bodies
Other ferruginous bodies

Additional references

Am Rev Respir Dis 1990;142:843, Environ Health Perspect 1994;102 Suppl 5:253, Arch Pathol Lab Med 2010;134:462, Thorax 1985;40:948, Environ Health 2008;7:4, Mod Pathol 1990;3:513, Am J Ind Med 2000;37:169, Clin Radiol 1992;45:340, Am J Physiol Lung Cell Mol Physiol 2014;306:L170

Gold

Definition / general

Colloidal gold is used for anti-tumor therapy, to treat autoimmune diseases and for drug delivery (Wikipedia: Colloidal gold [Accessed 22 June 2018])
Lymphadenopathy and lymph node infarction are uncommon complications of gold injections; occur via accumulation of gold particles in macrophages

Sites

Cervical, axillary, mesenteric lymph nodes, depending on route of administration

Clinical features

Tender enlarged lymph nodes
Benign process with resolution of symptoms on withdrawal of gold treatment

Diagnosis

Biopsy
Darkfield microscopy and autometallography methods demonstrate gold nanoparticles 15 to 50 nm

Laboratory

Polymorphonuclear neutrophilia, leukopenia, thrombocytopenia
Hepatic toxicity

Radiology description

Gold deposits can mimic intranodal axillary calcific deposits on mammography in patients with rheumatoid arthritis (Proc (Bayl Univ Med Cent) 2013;26:28)

Case reports

34 year old woman with lymphadenopathy and lymph node infarction (J Clin Pathol 2001;54:562)
Intramammary lymph node gold deposits simulating microcalcifications on mammogram (Hum Pathol 1988;19:992)
Lymphadenopathy and lymph node infarction (Am J Med 1986;80:537)

Gross description

Extensive necrosis of lymph node

Microscopic (histologic) description

Subtotal or complete infarction with peripheral rim of organizing granulation tissue in region of subcapsular sinus
Small focus of residual viable lymphoid tissue has features of follicular hyperplasia
Center of node has ghost outlines of necrotic cells

Microscopic (histologic) images

Images hosted on other servers:

Infarcted tissue

Reticulin: preservation of nodal architecture

Positive stains

Immunohistochemical stains confirm the reactive nature of the process

Differential diagnosis

Lymphoma
Vascular thrombosis, infections and mechanical pressure can also cause infarction of lymph nodes

Additional references

Russian Open Medical Journal 2013;2:1

Iron

Definition / general

Iron deposition in lymph nodes is rare
Also called hemosiderosis
May be associated with hemochromatosis

Sites

Portal, splenic, mesenteric or axillary, depending on the primary cause

Pathophysiology

Parenteral iron administration
Multiple transfusions: red blood cells are lysed and iron is deposited in macrophages in the liver and spleen followed by drainage to adjacent lymph nodes
Hereditary hemosiderosis: abnormalities in iron transport - most common is HFE1 gene mutation; also mutations in TfR2, HJV, HAMP, ferroportin-V162del (Hepatology 2005;42:466)
Anemia of inflammation: associated with rheumatoid arthritis, gout (Ann Rheum Dis 1970;29:81)

Clinical features

Depends on the primary cause
Enlarged lymph nodes

Diagnosis

Biopsy with Perls Prussian blue stain

Radiology description

CT: enlarged and hyperdense lymph nodes (AJR Am J Roentgenol 1981;136:1191)

Prognostic factors

Depends on the primary cause, severity and extent of the disease

Case reports

Women, 19 to 49 years, with lymphadenopathy after single infusion of iron dextran (J Clin Pathol 1968;21:492)

Treatment

Reduce iron overload, treat the primary cause

Gross description

Enlarged lymph nodes

Gross images

Images hosted on other servers:

Lymph nodes at bottom right

Microscopic (histologic) description

Follicular hyperplasia, sinus histiocytosis, golden brown pigment deposition

Microscopic (histologic) images

Contributed by Mark R. Wick, M.D.

In sickle cell disease

Positive stains

Perls prussian blue

Negative stains

Melanin stains

Electron microscopy description

Prominent phagocytic reticulum cells containing vacuoles, myelin figures, lipid droplets and very large lysosomal bodies with fine electron dense granules concentrated in these lysosomal bodies and in the cytoplasm, which show molecular structure of ferritin

Differential diagnosis

Charcoal laden macrophages
Hemazoin pigment: seen in malaria
Melanin pigment deposition: melanoma, dermatopathic lymphadenitis
Tattoo pigment

Additional references

Histopathology 2013;62:481, Gastrointest Radiol 1989;14:59

Lipogranuloma

Definition / general

Also called lipophagic granuloma
Secondary to various inflammatory and neoplastic conditions or primary lesion of lymph node
In West, commonly due to mineral oil ingestion or total parenteral nutrition

Case reports

27 year old woman with prior giant cell tumor (Acta Cytol 2002;46:772)

Microscopic (histologic) description

Giant cells (mono or multinuclear) with foamy and vacuolated cytoplasm

Melanosis

Definition / general

A rare manifestation of a completely regressed melanoma

Terminology

Tumoral melanosis
Nodular melanosis
Nodal melanosis

Epidemiology

Very rare in lymph nodes

Sites

Sentinel lymph nodes of regressed melanoma
Mesenteric lymph nodes

Pathophysiology

Possibilities include:
- A regressed focus of metastatic melanoma
- Melanophages migrating to the lymph node from the primary lesion

Clinical features

Enlarged lymph nodes
Yellow brown spindle bodies in mesenteric nodes may be due to melanosis coli (Histopathology 1978;2:47)
The paucity of cases precludes adequate evaluation of long term implications and treatment outcomes

Case reports

36 year old man with lymph node melanosis and metastatic melanoma of unknown primary (Arch Pathol Lab Med 2009;133:1332)
83 year old man with melanosis coli involving pericolonic lymph nodes associated with the herbal laxative Swiss Kriss (Arch Pathol Lab Med 2004;128:565)
Tumoral melanosis involving the sentinel lymph nodes (J Cutan Pathol 2007;34:284)
Lymph node melanosis from a primary cutaneous lesion combining a nodular (tumoral) melanosis and a congenital dermal melanocytic nevus (Am J Dermatopathol 2012;34:653)

Gross description

Enlarged lymph nodes with or without brown pigment deposition

Microscopic (histologic) description

Subcapsular and sinusoidal accumulation of pigmented cells with vesicular chromatin and inconspicuous nucleoli
Cells may be spindle shaped or epithelioid

Microscopic (histologic) images

Images hosted on other servers:

Melanosis coli in a pericolonic lymph node

Positive stains

CD68

Negative stains

S100, HMB45 and MelanA

Differential diagnosis

Metastatic melanoma

Additional references

Ioachim: Ioachim's Lymph Node Pathology, 4th Edition, 2008

Prosthesis related

Definition / general

See also silicone
May be an incidental finding at radical prostatectomy (J Clin Pathol 2002;55:623)

Case reports

76 year old woman with histiocytic lymphadenitis post shoulder joint replacement (Am J Clin Pathol 1993;99:314)
78 year old woman with right pelvic cystic mass due to chromium in hip prosthesis (Acta Cytol 2003;47:270)
Post hip replacement with coexisting metastatic prostate adenocarcinoma to same lymph node (Hum Pathol 1998;29:95)

Microscopic (histologic) description

Sinuses distended by large macrophages with abundant granular PAS+ eosinophilic cytoplasm representing polyethylene (Am J Surg Pathol 1989;13:1050)
May contain black specks which resemble "dirt"
Pelvic lymph nodes in patients with cobalt chromium or titanium hip implants may have heavy metal microparticles or polyethylene particles with associated florid sinus histiocytosis (Am J Surg Pathol 1994;18:83)

Microscopic (histologic) images

Images hosted on other servers:

Sinus histiocytosis

Positive stains

PAS+ polyethylene particles

Electron microscopy images

Images hosted on other servers:

Particles are 1 micron

Differential diagnosis

Metastatic melanoma (J Surg Oncol 1995;60:128)

Peliosis

Table of Contents

Definition / general

Also called peliosis lienis
Multiple blood filled cystic spaces
Usually associated with peliosis hepatis but may be independent
Multiple pathogenetic mechanisms possible - may be caused by infection with Bartonella henselae in HIV patients with bacillary angiomatosis
May cause splenic rupture and death, particularly in patients with carcinomatosis, chronic leukemia, post liver transplantation, recipients of anabolic androgenic steroids, tuberculosis

Case reports

56 year old woman with abdominal pain and anorexia (Br J Radiol 2010;83:e126)
62 year old man with peliosis and splenic rupture secondary to untreated chronic myelomonocytic leukemia (Am J Surg Pathol 1983;7:197)

Microscopic (histologic) description

Blood filled sinuses with reduced lining cells, similar to hairy cell leukemia

Microscopic (histologic) images

Images hosted on other servers:

Splenic peliosis

Differential diagnosis

Cavernous hemangioma

Additional references

Forensic Sci Int 2005;149:25

Plasmacytoma

Table of Contents

Definition / general | Case reports | Microscopic (histologic) images | Differential diagnosis

Definition / general

This topic only discusses features of plasmacytoma in lymph nodes different from plasmacytoma and myeloma
Very rare (< 50 reported cases)
Diagnosis of primary plasmacytoma of lymph node requires exclusion of extramedullary plasmacytoma (15% of upper respiratory tract plasmacytomas metastasize to cervical nodes) and myeloma (40% of high stage myelomas metastasize to nodes)
2/3 male; median age 59 years (range 39 - 76 years)
Often involves cervical nodes
Similar survival to other extramedullary plasmacytomas, although does not progress to myeloma (Am J Clin Pathol 2001;115:119, Hum Pathol 1997;28:1083)

Case reports

65 year old man with cervical and submandibular node involvement (Korean J Intern Med 2005;20:183)
71 year old man with diffuse hypermetabolic lymphadenopathy of chest, abdomen and pelvis (J Med Case Rep 2019;13:153)
81 year old man with Sjögren syndrome (Pathol Int 1999;49:577)
Patient with Castleman disease (Arch Pathol Lab Med 1986;110:157, Am J Clin Pathol 1982;78:541)

Microscopic (histologic) images

AFIP images

Plasmacytoma

With crystalloids

With amyloid deposition

With blood lakes

With myxoid stroma

Plasmablastic plasmacytoma of nasopharynx

Anaplastic plasmacytoma

Immunohistochemistry

Differential diagnosis

Castleman disease, plasma cell variant
Lymphoplasmacytic lymphoma:
- Also has neoplastic small lymphocytes
- Often shows IgM restriction and MYD88 gene mutation
Marginal zone lymphoma:
- May have plasmacytoid features but more extensive sampling may reveal B cell component
- CD20 expression by neoplastic B cells and plasmacytoid cells
- Clonal B cell population by flow; molecular or cytogenetic features of marginal zone lymphoma
Large cell lymphoma:
- May have immunoblastic or plasmablastic features
Plasma cell myeloma with nodal involvement:
- Must be excluded by radiographs, bone marrow biopsy
Plasmablastic lymphoma:
- Mostly extranodal; less frequent nodal involvement
- Associated with HIV or other immunosuppressive states and EBV
Reactive plasmacytosis:
- Often follicular hyperplasia
- No light chain restriction

Progressive transformation of germinal centers

Table of Contents

Definition / general

Progressive transformation of germinal centers (PTGC) is a clinicopathologic entity characterized by chronic lymphadenopathy with a wide age distribution
Characterized by enlarged nodal lymphoid follicles with ingress of mantle zone B cells into the germinal centers (Arch Otolaryngol Head Neck Surg 2006;132:797)
Nonspecific manifestation of a variety of associated conditions, including immune and autoimmune disorders
Associated with previous, concurrent or subsequent lymphoma, particularly nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), in a small proportion of patients; less frequently with classic Hodgkin lymphoma (J Clin Exp Hematop 2014;54:205)

Essential features

Common differential diagnosis of persistent reactive lymphadenopathy, especially in adolescent boys (Pediatr Blood Cancer 2022;69:e29638)
Expansile lymphoid follicles with mantle zone B cells expanding into and disrupting the germinal centers in a hyperplastic lymph node (Pediatr Blood Cancer 2022;69:e29638)
Not a premalignant condition; may occur prior to, concurrent with or following Hodgkin lymphoma, most commonly NLPHL (Int J Pediatr Otorhinolaryngol 2002;65:195)
Associated with immune and autoimmune conditions in some patients

Terminology

Progressive transformation of germinal centers
Follicle lysis: follicle centers fractured by ingrowth of mantle cells

ICD coding

ICD-10: R59.9 - enlarged lymph nodes, unspecified

Epidemiology

M:F = 3:1 (Int J Pediatr Otorhinolaryngol 2002;65:195)
Occurs in both adult and pediatric populations (Int J Pediatr Otorhinolaryngol 2002;65:195)

Sites

Cervical lymph nodes: most commonly affected site (50%) (Pediatr Blood Cancer 2022;69:e29638)
Inguinal (25%) and axillary (22%) lymph nodes also common (Pediatr Blood Cancer 2022;69:e29638)
Abdominal lymph nodes infrequent (Int J Pediatr Otorhinolaryngol 2002;65:195)

Pathophysiology

Nonspecific, likely multifactorial, representing a state of follicular hyperplasia following reactive stimuli (Case Rep Otolaryngol 2017;2017:5982168)
Does not follow the typical progression of lymphoid follicular reaction (whereby germinal center reaction comes to an end, follicle regresses, reaction dissipates)
However, there is somatic hypermutation, clonal expansion and selection, similar to usual hyperplastic germinal centers (Blood 2001;97:714)
Instead, germinal center proceeds through morphologically distinct stages
- Germinal center becomes enlarged and mantle zone thickens
- Mantle zone B cells migrate into the germinal center, disrupting the follicular dendritic meshwork and fracturing the germinal center into irregular clusters of centrocytes and centroblasts (follicle lysis)
- Stromal microenvironment is distorted and the follicle becomes entirely overrun by mantle cells (Ann Diagn Pathol 2020;44:151421)

Etiology

Unknown etiology; probably a nonspecific lymphoid reaction
May represent an abnormal or unusual immune response to a variety of stimuli (Am J Surg Pathol 1992;16:252)

Clinical features

Can present as an isolated lesion or as part of the presentation of systemic conditions (Pediatr Blood Cancer 2022;69:e29638)
More commonly presents as slow growing lymphadenopathy with no constitutional symptoms (Semin Diagn Pathol 2023;40:371)
May involve numerous lymph nodes in one region (Pediatr Blood Cancer 2022;69:e29638)
Lymphadenopathy with constitutional symptoms should raise the suspicion of concurrent malignancy or other systemic disorders (Pediatr Blood Cancer 2022;69:e29638)
Associated noncausally, most commonly with NLPHL, which may precede, follow or coincide with the diagnosis of PTGC (Leuk Lymphoma 2011;52:2041)
May also be associated with immune and autoimmune disorders, such as Castleman disease and lupus (Pediatr Blood Cancer 2013;60:26)
Rare case associated with papillary thyroid carcinoma (Case Rep Otolaryngol 2016;2016:6469073)

Diagnosis

Excisional biopsy is needed to establish the diagnosis, usually evident at low magnification
Careful microscopic examination for the possibility of potential concurrent Hodgkin lymphoma
Evaluation for possible associated conditions should be tailored for patients with constitutional symptoms (Pediatr Blood Cancer 2022;69:e29638)

Laboratory

Not usually associated with elevated lactate dehydrogenase (LDH), as seen in lymphoma

Radiology description

Hypoechoic lymph node on ultrasound (Ann Hematol 2018;97:1081)

Prognostic factors

PTGC follows a clinically indolent course (Semin Diagn Pathol 2023;40:371)
Increased risk of recurrence seen in pediatric patients (Pediatr Blood Cancer 2022;69:e29638)
Not a premalignant condition but there is a noncausal association with NLPHL in a small number of patients (Leuk Lymphoma 2011;52:2041)
May also be seen in association with immune and autoimmune conditions

Case reports

2 year old boy with a lump in the right axilla (Children (Basel) 2022;9:214)
32 year old woman with palpable lymph nodes in the left axilla (Taehan Yongsang Uihakhoe Chi 2021;82:423)
39 year old woman with right neck lymphadenopathy (Case Rep Otolaryngol 2017;2017:5982168)

Treatment

Standard of care: active surveillance (Leuk Lymphoma 2011;52:2041)
- Ongoing follow up and annual examination, including biopsy of any subsequent enlarged lymph nodes to assess for possibility of reactive follicular hyperplasia, PTGC or Hodgkin lymphoma (Int J Pediatr Otorhinolaryngol 2002;65:195)

Gross description

Well encapsulated, enlarged lymph node
Pale gray to tan lobulated cut surface; typically not fish flesh as seen in lymphoma

Microscopic (histologic) description

Occurs in a background of follicular hyperplasia of lymph node
Preserved nodal architecture with PTGC follicles diameter being 3 - 5 times larger than usual reactive follicles (Am J Clin Pathol 1990;93:219)
Background lymphoid follicles appear as primary follicles when PTGC is associated with NLPHL (Hum Pathol 2015;46:1655)
PTGC nodules may appear in different morphologic stages
- Multifocal migration of small lymphocytes from the thickened mantle zone into the germinal center, disrupting the germinal center and breaking up the germinal center into variegated clusters of follicle center cells (follicle lysis)
- Loss of demarcation between germinal center and mantle zone
- Normal germinal center cells (centrocytes, centroblasts, follicular dendritic cells) may be lost (Acta Haematol 2002;108:33)

Microscopic (histologic) images

Contributed by Roaa Aljuaid, M.B.B.S.

Follicular hyperplasia

Nodules at different stages

Macronodules

Expansile lymphoid follicles

Reactive follicles

Ingrowth of mantle zone B cells

IgD in PTGC

BCL2 in PTGC nodules

BCL6 in PTGC nodules

CD10 in PTGC nodules

Atypical lymphocytes versus immunoblasts

CD15

EMA

PAX5

Virtual slides

Images hosted on other servers:

Follicular hyperplasia with PTGC

Positive stains

Mantle zone B cells: express pan-B cell markers (CD19, CD20, PAX5 and CD79a) and IgD
Germinal center cells: express pan-B cell markers as well as germinal center markers (BCL6, CD10, HGAL and GCET1)
CD21 shows disruption of the follicular dendritic cell meshwork
Reference: Pediatr Blood Cancer 2022;69:e29638

Negative stains

EBV (EBER, LMP) negative; no large neoplastic cells on EMA, CD15 or CD30
Mantle zone B cells: negative for BCL1, SOX11, CD5 and CD43
Germinal center B cells: negative for BCL2
Reference: Int J Pediatr Otorhinolaryngol 2002;65:195

Flow cytometry description

Polytypic B cells
No T cell immunophenotypic aberrancy

Molecular / cytogenetics description

No evidence of B cell (IGH and IGK) or T cell receptor (TRB and TRG) gene rearrangement
No BCL2 or BCL6 gene alterations

Sample pathology report

Right cervical lymph node, excisional biopsy:
- Reactive lymphoid hyperplasia with progressive transformation of germinal centers (PTGC) (see comment)
- Negative for malignancy
- Comment: PTGC may precede, follow or coincide with nodular lymphocyte predominant Hodgkin lymphoma in certain patients.

Differential diagnosis

Nodular lymphocyte predominant Hodgkin lymphoma:
- Nodular lymphocyte predominant Hodgkin lymphoma (WHO HAEM5), also known as nodular lymphocyte predominant B cell lymphoma (Blood 2022;140:1229)
- Lymph node architecture is partially or completely effaced
- Nodules contain lymphocytic and histiocytic (popcorn) neoplastic B cells
- Large lymphocytes express pan-B cell markers, BCL6, EMA (variable) and strong OCT2
- T cells rosette around lymphocytic and histiocytic cells and often express CD3, PD-1 and CD57
Follicular lymphoma, floral variant:
- Partial or complete effacement of the lymph node architecture
- Follicles are fused, fragmented and back to back
- Neoplastic germinal centers may appear monotonous with various proportions of centrocytes and centroblasts and diminished tingible body macrophages and mitoses
- Monoclonal B cells typically express BCL6, CD10, HGAL, GCET1 and BCL2
Lymphocyte rich Hodgkin lymphoma, nodular variant:
- Lymphoid nodules replace large areas or the entirety of lymph node
- Small number of Hodgkin / Reed-Sternberg cells intermingled in a background of small benign B cells
- Hodgkin / Reed-Sternberg cells express CD30, CD15 (variable), PAX5 (weak), MUM1
Human immunodeficiency virus (HIV) associated lymphadenopathy:
- Affected lymph node in acute HIV infection can resemble PTGC
- Follicle lysis: small mantle zone B cells penetrate and disrupt the germinal centers
- Affected follicles are not as large as the PTGC follicles
- Hemorrhage with large monocytoid cell proliferation is common
IgG4 related lymphadenopathy (Semin Diagn Pathol 2024;41:108, Am J Surg Pathol 2018;42:977):
- 5 distinct histologic patterns
- Progressive transformation of germinal centers is a hallmark of one of the variants
- Increased number of IgG4 positive plasma cells in affected nodes
- Epithelioid granulomas around PTGC is a rare and specific finding (Semin Diagn Pathol 2018;35:61)
Pediatric nodal marginal zone lymphoma:
- Marginal zone expansion with interfollicular infiltration of lymphoma cells (Virchows Arch 2023;483:317)
- Follicular changes similar to PTGC
- Peripheral rims of the follicles are disrupted by the proliferation of the marginal zone (Adv Anat Pathol 2017;24:128)

Board review style question #1

Which of the following markers is expressed in the expanded mantle zone B cells of progressive transformation of germinal centers (PTGC)?

BCL1
BCL6
CD5
CD43
CD79a

Board review style answer #1

E. CD79a. The mantle cells express pan-B cell antigens, including CD79a. Answers A, C and D are incorrect because these markers are characteristically positive in mantle cell lymphoma but not in the nonneoplastic mantle cells of PTGC. Answer B is incorrect because BCL6 is immunoreactive on follicle center cells and not on mantle cells.

Comment Here

Reference: Progressive transformation of germinal centers

Board review style question #2

Which of the following lymphoid neoplasms is more commonly associated with progressive transformation of germinal centers (PTGC)?

Follicular lymphoma
Mantle cell lymphoma
Mycosis fungoides
Nodular lymphocyte predominant Hodgkin lymphoma
Plasma cell neoplasm

Board review style answer #2

D. Nodular lymphocyte predominant Hodgkin lymphoma has been found to have the highest risk of being seen in association with PTGC. Answer C is incorrect because mycosis fungoides is associated with dermatopathic lymphadenopathy and not PTGC. Answers A, B and E are incorrect because these hematopoietic neoplasms are not known to occur with increased incidence in patients with PTGC.

Comment Here

Reference: Progressive transformation of germinal centers

Pseudocyst

Table of Contents

Definition / general

75% of nonparasitic splenic cysts
Usually due to trauma; some may be epithelial cysts with denuded epithelial lining
Usually solitary, asymptomatic
Wall composed of dense fibrous tissue without an epithelial lining, often calcified
Often contains blood and necrotic debris
Rupture may cause massive hemoperitoneum

Reactive B cell rich lymphoid proliferations that can mimic lymphoma

Table of Contents

Definition / general

Heterogeneous group of nonneoplastic proliferations that mimic B cell lymphomas and affect lymphoid tissue in nodal or extranodal sites

Essential features

Heterogeneous group of nonneoplastic proliferations that mimic B cell lymphomas and affect lymphoid tissue in nodal or extranodal sites
3 different main patterns
- Nodal and extranodal follicular proliferations
- Nodal and extranodal nodular proliferations
- Nodal and extranodal immunoblastic proliferations

Nodal follicular / nodular proliferations

Florid follicular hyperplasia (Hematol Oncol Clin North Am 2009;23:729)

Increased number of widely spaced primary and secondary follicles
- Florid cases usually involve medulla
Follicles show uneven size and shape
Hyperplastic germinal centers (GC) comprise a mixture of centroblasts and centrocytes with brisk mitoses, reactive T cells, follicular dendritic cells (FDCs) and tingible body macrophages (Ann Diagn Pathol 2020;44:151421)
- B lymphocytes
  - Centroblasts
    - Mainly in the dark zone of GC
    - 3 - 4x size of small lymphocytes
    - Large vesicular nuclei, 1 - 3 peripheral nucleoli
  - Centrocytes
    - Mainly in the light zone of GC
    - Small to intermediate sized cells with cleaved, hyperchromatic nuclei and small or absent nucleolus
  - Both centroblasts and centrocytes are BCL6+, CD10+, LMO2+, HGAL / GCET+, OCT2+
- T lymphocytes
  - Small and round
  - CD3+ and BCL2+
  - Subset of T helper cells (TFH): polarized CD4+, PD-1 / CD279+, BCL6+, CD10+, CXCL13+, ICOS+
- Follicular dendritic cells (FDCs)
  - Few (usually ~1%)
  - 2 square shaped and adjacent nuclei (kissing cells) with vesicular chromatin
    - May display small nucleolus
  - Long cytoplasmic processes
  - CD21+, CD23+ or CD35+
- Tingible body macrophages
  - Display oval or twisted vesicular nuclei
  - Abundant pale cytoplasm containing karyorrhectic nuclei
  - Impart a starry sky pattern when prominent
  - CD4+, CD68+ or CD163+
Well developed mantle zones
Distinction from germinal centers
- Composed predominantly of small lymphocytes and IgD+
No or limited extension outside the capsule into perinodal soft tissue
Location can suggest underlying disease and additional workup is necessary to confirm the diagnosis (Pediatr Clin North Am 2002;49:1009)
- Cervical: infectious mononucleosis
- Posterior cervical: toxoplasmosis
- Parotid, submaxillary, epitrochlear: HIV infection
- Cervical and axillary: cat scratch disease, dermatopathic lymphadenitis
- Inguinal: sexually transmitted diseases
Immunoarchitecture (Ann Diagn Pathol 2020;44:151421, Clin Lab Med 2021;41:433)
- Lymphoid follicles express B cell antigens
- Primary follicles
  - Small lymphocytes
  - BCL2+, Ki67 (usually < 10%), BCL6- and CD10-
- Secondary follicles
  - GCs are BCL2-
    - TFH cells: subset of T cells in germinal centers are BCL2 positive and occasionally are increased
      - May mimic follicular lymphoma
    - Pediatric type follicular lymphoma (FL) is BCL2 negative
      - FOXP1 is positive in GC cells of pediatric FL (Virchows Arch 2019;475:771)
  - High proliferation Ki67
    - Polarization (centroblast rich dark zone and a centrocyte rich pale zone)
    - Low Ki67 proliferation rate within a germinal center should always be considered atypical and suspicious for follicular lymphoma
  - BCL6+ and CD10+ are restricted to GCs, minimal in interfollicular areas
Flow cytometry
- Polytypic B cells; CD10+, T cell antigens-
Polymerase chain reaction (PCR)
- Polyclonal immunoglobulin heavy chain gene rearrangement
- No evidence of t(14;18)(q32;q21) or IGH::BCL2 fusion

Progressive transformation of germinal centers (PTGC) (Virchows Arch 2019;475:771)

Single or few large (4 - 5x normal) lymphoid follicles with mantle cells extensively indenting into GCs
Background lymph node exhibits reactive follicular hyperplasia (RFH)
Negative for rosetting by PD-1+ cells (TFH) around large B cells
GCs remnants rarely show tingible body macrophages
Morphological changes seem to proceed gradually
- Early stages show hyperplastic GCs
- Fusion of GCs within one single follicle (usually 2 - 3x size)
- Inward migration of mantle zone small B cells into the germinal center
- Later stages: dissolution of GCs results in islands or scattered centrocytes and centroblasts with follicular dendritic cells among small mantle zone B cells
Immunoarchitecture
- Preserved B and T cell compartments of lymph node and prominent follicular pattern
- Both GC and mantle zone cells express pan-B cell antigens
- Mantle cells: BCL2+, IgD+, BCL6- and CD10-
- Disrupted GCs: BCL6+, CD10+, BCL2- and IgD-
- CD21, CD23 or CD35 show disruption of FDCs meshwork
- IgG4+ plasma cells: ~40 - 50% of cases
Flow cytometry
- Polytypic B cells
Genetic testing
- Polyclonal IGH rearrangements

Hyaline vascular Castleman disease (HVCD)

Young adults (Blood 2017;129:1658)
- Usually < 30 years old
- Can also affect children
Numerous follicles in cortex and medulla of lymph node or extramedullary sites
Obliteration of subcapsular and interfollicular sinuses
≥ 2 germinal centers in follicle (also known as twinning)
Follicles typically large with regressed (or involuted) germinal centers
- Mostly composed of FDCs with few lymphocytes
- Mantle zones prominent
- FDCs often hyperplastic and can show dysplasia
Many follicles show so called lollipop features
- Concentric rings of mantle zone lymphocytes (onion skin appearance)
- Sclerotic blood vessels radially traversing into germinal center
Interfollicular or stromal component is also important (J Clin Exp Hematop 2022;62:60)
- Increased number of high endothelial venules with hyalinized walls
- Stromal component can predominate with only a few hyaline vascular follicles
Clusters of plasmacytoid dendritic cells can occur
Plasma cells and immunoblasts are not abundant in HVCD
- More common and abundant in plasma cell Castleman disease (PCCD)
Immunohistochemistry
- HHV8 is absent
- Polytypic B, T cells and plasma cells
- Increased FDCs in involuted germinal centers
  - CD21+, CD23+, CD35+ or EGFR+
- Dysplastic FDCs often stain variably for FDC markers
Differential diagnosis
- Classic Hodgkin lymphoma concurrent with Castleman disease (Virchows Arch 2020;477:437)
  - Diagnosis is established upon identification of Hodgkin Reed-Sternberg (HRS) cells with usual phenotype
- Castleman-like follicles in infectious lymphadenopathies
  - Changes are focal and sinuses are open

Table 1. Differential diagnosis between florid follicular hyperplasia and B cell lymphomas with follicular formation
Feature	Florid follicular hyperplasia	Follicular lymphoma	Marginal zone lymphoma	Mantle cell lymphoma, mantle zone pattern
Follicles	Enlarged, with prominent GCs and distinct mantle zones	Variably sized surrounded by faint mantle zones	Nodules with remnants of GCs surrounded by monocytoid cells	Thickened mantle zones
Density	Low, widely spaced	Back to back	Variable; may be confluent	Variable
Size	Uneven	Uniform	Variable	Uniform
Borders of GC	Sharp, well defined	Fainted, crack artifact	Blurry	Sharp, well defined
Distribution	Cortical predominance; florid cases involve medulla	Cortex and medulla	Cortex and medulla	Even distribution throughout cortex and medulla
Extension to perinodal fat	Absent or unusual	Often present	Often present	Uncommon
Mantle zone	Present, well developed	Attenuated to absent	Generally absent	Expanded in mantle zone pattern
Marginal zone	Can be hyperplastic	Absent	Expanded, may coalesce	Absent
Germinal center cells			Colonized by monocytoid cells	Absent
Tingible body macrophages	Present and common	Decreased or absent	Decreased or absent	Variable
Polarization	Present	Absent	Absent	Variable
Cytologic features	Centroblasts, centrocytes and macrophages	Centroblasts and centrocytes in various proportions	Monocytoid and plasmacytoid; scattered large cells	Small and intermediate centrocyte-like cells; few large cells
Immunoarchitecture
BCL2	Negative in GCs	Positive in germinal centers of FL grades 1 - 2; 50% in FL grade 3	Positive in neoplastic cells; GC remnants are negative	Positive in mantle zones
BCL6, CD10	Positive, restricted to GCs	Positive in GCs and interfollicular areas	Negative, GC remnants positive	Positive, restricted to GCs
Ki67	High proliferation rate; polarized in GCs	Low, nonpolarized	Low, nonpolarized	Variable in mantle zones
CD21, CD23, CD35	FDC meshworks preserved	FDC meshworks preserved	Distorted FDC meshworks	FDC meshworks preserved
Common positive markers	BCL6, LMO2, OCT2, HGAL	CD10, BCL2, BCL6, LMO2	CD43, MNDA, CD5-/+	Cyclin D1, SOX11, CD5
Common negative markers	CD3, BCL2	CD5, cyclin D1	CD10, cyclin D1, SOX11	CD10-, CD23- in mantle zones
Flow cytometry	Polytypic	Monotypic surface Ig; CD10 positive	Monotypic surface Ig; CD10 neg; CD5 neg or weak	Monotypic surface Ig; CD5 positive

Table 2. Differential diagnosis between progressive transformation of germinal centers and lymphomas with large nodules
Feature	Progressive transformation of germinal center	Nodular predominant Hodgkin lymphoma (patterns A / B)	Lymphocyte rich classic Hodgkin lymphoma, nodular variant
Follicles
Size	Scattered large nodules	Nodules larger than PTGC	Moderately enlarged
Germinal centers	Variably disrupted or involuted	Absent	Present within neoplastic nodules
Centrocytes and centroblasts	Decreased; scattered, BCL2-	Absent	In residual GCs
Mantle zone cells	Inward growth into GCs, BCL2+ and IgD+	Absent	Expanded
Reactive follicular hyperplasia	Present at background	Absent or focal	Absent or focal
Immunoarchitecture
T follicular helper cells rosettes (PD-1+)	Absent	Present	May be present
IgG4+ plasma cells	In 40 - 50% of cases	Absent	Absent
Large B cells	Rare immunoblasts	LP cells (popcorn cells)	Present, HRS cells
Immunophenotype	IgG+	CD20+, CD45+, OCT2+, EMA+/-, PAX5+ strong, IgD-/+	CD30+, CD45-, CD15+, PAX5+ dim, OCT2-, EMA-, CD20-

Nodal immunoblastic proliferations

Infectious mononucleosis (Semin Diagn Pathol 2018;35:54, Virchows Arch 2019;475:771)

Caused by acute Epstein-Barr virus (EBV) infection
Histologic changes are variable and depend on disease duration
- Early stage: reactive follicles, with mild paracortical expansion
- Progression: follicles sparse due to interfollicular expansion
- Advanced stage: follicles may become effaced, with interfollicular expansion
Interfollicular areas with numerous immunoblasts or mixed infiltrate
- Immunoblasts can be dispersed or abundant
- Lymphocytes range from small to intermediate and large in size
- Plasma cells, plasmacytoid cells and histiocytes are variably present, less frequently accompanied by eosinophils
- Sinuses are regularly occupied by immunoblasts, monocytoid B cells and histiocytes
Immunoblasts can be binucleated, mimicking HRS
- Intact nodal architecture admixed with B and T immunoblasts are indicative of a reactive process
Focal necrosis may be present
Immunohistochemistry
- HRS-like cells are CD45+, CD15-, CD30+ (weak) admixed with B and T immunoblasts
- EBV latency type 3 (Semin Diagn Pathol 2018;35:54)
  - EBV encoded RNA (EBER) present in numerous infected cells, ranging from small and intermediate lymphocytes to HRS-like immunoblasts
  - EBNA1+, EBNA2 variable and EBNA3+
  - LMP1+ and LMP2+
- Most lymphocytes in the background are CD8+, TIA1+

Herpesvirus lymphadenitis (Virchows Arch 2019;475:771)

Uncommon complication from either primary exposure or reactivation (more common)
Prominent immunoblastic paracortical hyperplasia
- Similar to infectious mononucleosis
Sharply circumscribed areas of necrosis and sinus histiocytosis
Adjacent to areas of necrosis
- Multinucleated cells with ground glass chromatin and intranuclear viral inclusions (halo)
Herpes simplex virus (HSV) immunohistochemistry confirms the diagnosis

Cytomegalovirus lymphadenitis (Virchows Arch 2019;475:771)

Morphologic features overlapping with those described in other viral infections
Monocytoid B cell hyperplasia is frequent
Characteristic owl eye central intranuclear inclusions with a halo
Cells infected with cytomegalovirus (CMV) often are T cells or endothelial cells
Diagnosis can be established utilizing CMV immunohistochemical stain

Table 3. Differential diagnosis between nodal B cell immunoblastic proliferation and lymphomas
Feature	Infectious mononucleosis	Classic Hodgkin lymphoma	Diffuse large B cell lymphoma, EBV+
Nodal compartment	Paracortical	Diffuse effacement	Diffuse effacement
Neoplastic cells	Not present	Scattered large cells; confluent in nodular sclerosis syncytial variant	Abundant large cells; diffuse pattern
Background lymphocytes
B cells	Small to intermediate	Small	Small
T cells	CD8+, small to intermediate	CD4+, small	CD8+, small
Monocytoid B cells hyperplasia	Often present	Absent	Absent
Plasma cells	Variably present	Few	Not frequent
Histiocytes	Variably present	Variable	Variable
Eosinophils	Rare	Present, often abundant	May be present
Necrosis	Focally present	Often present in nodular sclerosis subtype	May be present
Immunoarchitecture
EBV latency type	Type III	Type II	Type I
EBER	Positive in most cells	Positive in HRS cells	Positive in large cells
LMP1	Positive, fewer small and large cells (less sensitive)	Restricted to HRS cells in positive cases	If positive, restricted to large neoplastic cells
EBNA2	Mostly positive	Negative	Negative
EBNA3	Positive	Negative	Negative
CD20	Positive in large cells	Faint reactivity in HRS cells in ~20% of cases	Positive in large cells
CD3	Positive in small lymphocytes	Negative in HRS cells	Negative in large cells
CD30	Positive in HRS-like cells, usually dim	Positive in HRS cells, strong	May be positive in neoplastic cells
CD45	Positive in most cells	Negative in HRS cells	Positive in neoplastic cells
CD4, PD-1, ICOS, CXCL13	Negative in immunoblasts	Negative in HRS cells	Negative in neoplastic cells
CD21	Present only in GCs	Present only in residual GCs	Absent
Diagnostic molecular testing	Polyclonal B and T cells	Polyclonal B and T cells	Monoclonal IGH gene rearrangements

Extranodal follicular proliferations

Florid reactive lymphoid hyperplasia

Most cases represent reactive tertiary lymphoid tissue and may be associated either with an infectious agent, autoimmune phenomena or chronic repetitive trauma; these processes may lead to extranodal marginal zone lymphoma (Pathology 2020;52:15)
- Stomach: Helicobacter pylori
- Skin: Borrelia burgdorferi
- Conjunctiva: Chlamydia psittaci
- Cervix: Chlamydia trachomatis
- Small intestine: Campylobacter jejuni
- Lung: Achromobacter xylosoxidans
- Gallbladder: extrahepatic biliary obstruction
- Thyroid: Hashimoto thyroiditis
- Salivary gland: Sjögren syndrome
Differential diagnosis with marginal zone lymphoma can be challenging in some cases
- Cutaneous reactive lymphoid hyperplasia must be also distinguished from primary cutaneous follicular center lymphoma (see table) (Arch Pathol Lab Med 2018;142:1313)
- Florid reactive lymphoid hyperplasia of the female reproductive tract
  - Cervix is the most frequent affected site, followed by endometrium and vulva (Int J Gynecol Pathol 2022;41:459)
Most cases show lymphoid infiltrate with superficial distribution, with or without ulceration
Architecture varies from patchy and nodular to diffuse, with secondary follicles in most cases
- Tends to imitate lymph nodes organization, with a B follicular and T interfollicular compartments
Cytologically composed by small lymphocytes and polytypic plasma cells, with variable number of granulocytes and histiocytes in the background
Scattered large CD30+ immunoblasts are present in the majority of cases
Clonal IGH rearrangement is not uncommon, although patients are free of lymphoma on follow up (Arch Pathol Lab Med 2018;142:1313)

Table 4. Differential diagnosis between cutaneous follicular hyperplasia and B cell lymphomas
Feature	Reactive follicular hyperplasia	Primary cutaneous follicular center lymphoma	Primary cutaneous marginal zone lymphoma
Infiltrate	Denser in superficial dermis, wedge shaped	Denser in deep dermis, Grenz zone	Vertical orientation around follicles
Follicular architecture	Present, uneven shapes and size	Follicular or diffuse pattern	Pale nodules, some residual germinal centers
Mantle zone	Present, well developed	Attenuated to absent	Absent
Marginal zone	Generally absent	Absent	Expanded, may coalesce
Germinal center cells			Colonized by monocytoid cells
Tingible body macrophages	Present	Absent	Present in GC remnants
Polarization	Present	Absent	Absent
Cytologic features	Centrocytes and centroblasts	Centroblasts and centrocytes	Monocytoid cells, few large cells; plasma cells
Immunoarchitecture	B and T compartments preserved	Effaced, B cell predominant	Effaced, B cell predominant
BCL2	Negative in germinal centers	Negative in germinal centers	Positive in neoplastic cells; GC remnants are negative
BCL6	Positive, restricted to GCs	Positive in both GCs and interfollicular areas	Negative, GC remnants positive
Ki67	High and polarized in GCs	Low, nonpolarized	Low, nonpolarized
CD21, CD23, CD35	FDC meshworks preserved	FDC meshworks preserved	Distorted FDC meshworks
Light chain restriction	Absent	May be present	Present in plasmacytoid lymphocytes or mature plasma cells
Positive IgH / IgK clonality assays	No	Yes	Yes

Extranodal immunoblastic proliferations

EBV positive mucocutaneous ulcer (Surg Pathol Clin 2023;16:213)

Lymphoproliferative disorder characterized by EBV+ large B cells / Reed-Sternberg-like cells (RS-like cells) cells
Oral mucosa is most common site, followed by skin
- Multiple small lesions within same anatomic region can occur
No systemic symptoms, lymphadenopathy, hepatosplenomegaly or bone marrow involvement
Well circumscribed superficial ulcer with a subjacent polymorphous infiltrate
Deep base shows a sharp demarcation by a dense rim of small lymphocytes
Angioinvasion and high proliferation index may be present
Monoclonal IGH or TCR gene rearrangements can occur in up to a third of cases
Immunohistochemistry
- HRS-like cells: CD45+, CD15- and CD30+ (usually weak)
- Background: B and T cells
- EBV latency type 3 (Semin Diagn Pathol 2018;35:54)
  - EBV encoded RNA (EBER) present in numerous infected cells, ranging from small and intermediate lymphocytes to HRS-like immunoblasts
  - LMP1+, EBNA2+
- Basal rim of T cells are CD8+

Case reports

24 year old man with follicular lymphoid hyperplasia with aggressive behavior in maxilla (Oral Maxillofac Surg 2017;21:475)
40 year old man with infectious mononucleosis that presented as a lymphadenopathy with geographic necrosis (Pathol Res Pract 2004;200:53)
57 year old woman with idiopathic multicentric Castleman disease (TAFRO subtype) (Br J Haematol 2022;196:461)
70 year old woman with atypical follicular hyperplasia after COVID-19 booster (Virchows Arch 2023;482:905)

Microscopic (histologic) images

Contributed by Roberto N. Miranda, M.D. and Roman Segura-Rivera, M.D.

Reactive follicular hyperplasia

Polarized Ki67

Follicular lymphoma

Nonpolarized Ki67

Nodal marginal zone lymphoma

Monocytoid cytology

Mantle cell lymphoma (MCL) with mantle zone pattern

Cyclin D1 (mantle pattern) in MCL

Progressive transformation of germinal centers

CD20 in PTGC

NLPHL

LP cells

Rosetting CD3+ lymphocytes

Castleman disease, hyaline vascular variant

Germinal center in HVCD

Interfollicular expansion

Immunoblasts

Infectious mononucleosis, EBER

EBV positive diffuse large B cell lymphoma

EBER positivity in EBV positive diffuse large B cell lymphoma

Mixed cellularity classic Hodgkin lymphoma (MCCHL)

EBER positivity in mixed cellularity classic Hodgkin lymphoma

EBER positivity in MCCHL

Board review style question #1

Which of the following statements is true about progressive transformation of germinal center (PTGC)?

Centrocytes are increased and have a BCL2+ phenotype
IgG4+ plasma cells are usually absent
Reactive follicular hyperplasia is usually absent in the background
Rosettes of T follicular helper (TFH) cells are usually absent

Board review style answer #1

D. Rosettes of TFH cells are usually absent. Answer B is incorrect because PTGC cases usually present with IgG4+ plasma cells in up to 50% of cases. Answers A and C are incorrect because there is a decrease of centrocytes and reactive follicular hyperplasia in the background.

Comment Here

Reference: Reactive B cell rich lymphoid proliferations that can mimic lymphoma

Board review style question #2

What latency pattern is more common in infectious mononucleosis?

Type 0: EBER+, LMP1-, EBNA2-
Type I: EBER+, LMP1-, EBNA2-
Type II: EBER+, LMP1+, EBNA2-
Type III: EBER+, LMP1+, EBNA2+

Board review style answer #2

D. Type III: EBER+, LMP1+, EBNA2+. Answers A, B and C are incorrect because the most common latency pattern in infectious mononucleosis is the pattern III, which is characterized by the positivity of EBER, LMP1 and EBNA2.

Comment Here

Reference: Reactive B cell rich lymphoid proliferations that can mimic lymphoma

Reactive lymphadenopathy

Table of Contents

Definition / general

Lymph node enlargement due to proliferation of some or all compartments or cellular components of lymph nodes, reflecting antigenic stimulation
Can be acute or chronic depending on the pathogenic agents

Essential features

Lymph node enlargement
Acute: painful or tender; chronic: nontender
4 architectural patterns: follicular hyperplasia, sinus histiocytosis, interfollicular / mixed and diffuse
No clonal B or T cell proliferations
No cytologic or architectural atypia

Terminology

Reactive lymphoid hyperplasia
Reactive follicular hyperplasia
Diffuse paracortical hyperplasia
Sinus histiocytosis
Acute nonspecific lymphadenitis
Chronic lymphadenitis

ICD coding

ICD-10: R59.9 - enlarged lymph nodes, unspecified

Epidemiology

Represents the reaction of lymphoid tissue to intrinsic or environmental antigens
Most lymph node enlargements are reactive
Can occur in any age group and gender
In children, most lymphadenopathies are benign; in adults, chance of malignancy increases with age (Mayo Clin Proc 2000;75:723)

Sites

Any lymph node group can be affected depending on the etiology and area of drainage (Clin Pediatr (Phila) 2011;50:683)

Pathophysiology

Lymph nodes filter lymph drained from tributary regions
Antigenic substances reaching the lymph nodes evokes an immune reaction (Semin Diagn Pathol 2018;35:4)
Bacteria and fungi cause predominantly inflammatory reactions; viruses and drugs cause predominantly immune reactions
Acute nonspecific lymphadenitis: acute inflammation of the lymph node due to an infectious or inflammatory etiology
Chronic nonspecific lymphadenitis: chronic inflammation of the lymph node in response to a pathogen / antigen, known or unknown

Etiology

Infections: virus, bacteria, fungi and protozoa
Chemicals: environmental pollution
Drugs: phenytoin, allopurinol, gold, penicillin, quinidine
Altered tissue components: inflammation, tissue necrosis
Other antigens or allergens including vaccines (Mayo Clin Proc 2000;75:723, Iran J Med Sci 2014;39:158, Pediatr Clin North Am 2002;49:1009)

Diagrams / tables

N/A

Clinical features

Clinical features reflect the underlying cause
Enlarged lymph nodes (Am Fam Physician 2016;94:896)
In acute lymphadenitis, can be painful or tender and nodes may be soft or fluctuant, with or without associated fever, weight loss, malaise, loss of appetite and redness of overlying skin
In chronic lymphadenitis, enlarged lymph nodes are commonly painless (Mayo Clin Proc 2000;75:723)

Diagnosis

Clinical examination
Histopathology: biopsy is rarely performed if reactive nature is clinically obvious
In chronic lymphadenitis, biopsy and histopathology evaluation are necessary
Exclusion of specific causes: clinical, laboratory and imaging findings
If suspicious, exclude lymphoid neoplasia by immunohistochemistry, flow cytometry and required genetic studies

Laboratory

Laboratory findings depend on the etiology and nature of the process (acute versus chronic)
Complete blood count (CBC) may show leukocytosis with neutrophilia or lymphocytosis and erythrocyte sedimentation rate (ESR) may be elevated
Confirmatory tests for specific etiologic agents (infectious agents) may be positive

Radiology description

Enlarged lymph node(s)
Advanced imaging techniques may help to distinguish reactive lymph node enlargement from tumor metastases or other specific lymph node enlargements (Mol Imaging Biol 2013;15:40, Indian J Gastroenterol 2016;35:55)

Radiology images

N/A

Prognostic factors

Benign, usually self limiting process with good prognosis
Prognosis depends on the etiology and appropriate and timely management of the cause

Case reports

40 year old man who received dasatinib for chronic myeloid leukemia presented with a large axillary mass (Medicine (Baltimore) 2020;99:e22791)
41 year old woman with a history of nasopharyngeal carcinoma and enlarged cervical lymph nodes (Clin Nucl Med 2022;47:367)
68 year old man with right cheek melanoma and multiple FDG avid lymph nodes in the left axilla (Clin Nucl Med 2021;46:433)

Treatment

Treat the underlying cause

Clinical images

N/A

Gross description

Enlarged, soft lymph nodes with tan, homogenous cut surfaces
Acute lymphadenitis: suppuration may lead to necrosis and abscess formation
Chronic lymphadenitis: thickened capsule and fibrosis may be obvious (Walker: Clinical Methods - The History, Physical, and Laboratory Examinations, 3rd Edition, 1990)

Gross images

Contributed by Kathy Smith, PA

Enlarged lymph node

Tan, homogenous appearance

Frozen section description

N/A

Frozen section images

N/A

Microscopic (histologic) description

4 architectural patterns of reactive hyperplasia are described, depending on the etiology: follicular / nodular, sinus histiocytosis, interfollicular / mixed and diffuse
Follicular hyperplasia (most common reactive pattern)
- Enlarged follicles, varying in size and shape, may coalesce and display different configurations
- Prominent germinal center and mantle zone
- Germinal centers show mixed small and large lymphocytes, centrocytes and centroblasts
- Centroblasts polarize to the medial pole / medullary side forming the darker zone and centrocytes accumulate at the peripheral pole / capsular side forming the lighter zone (Immunity 2016;45:471)
- Centroblasts are 3 - 4 times larger than the inactivated lymphocytes and show a narrow rim of basophilic cytoplasm and large, round to oval vesicular nuclei with 1 - 3 prominent peripheral nucleoli
- Mitotic figures are frequent
- Centrocytes are smaller lymphocytes with scant cytoplasm, cleaved nuclei, clumped chromatin and small or absent nucleoli
- Numerous tingible body macrophages are a characteristic feature of follicular hyperplasia (Semin Diagn Pathol 2018;35:4, Am J Surg Pathol 1987;11:866)
- Other cells: plasma cells, T cells and follicular dendritic cells
- PD-1+ T cells (T follicular helper cells) are seen predominantly at the periphery of the germinal center (Ann Diagn Pathol 2020;44:151421)
- Mantle zone: around the light zone, small lymphocytes
- Interfollicular areas may show rare transformed cells (immunoblasts), small lymphocytes, plasma cells and high endothelial venules
- Monocytoid B cell proliferation may be seen in follicular hyperplasia around cortical sinuses (Pathol Res Pract 1998;194:559)
Sinus histiocytosis
- Expansion of sinuses by histiocytes
- Common pattern in lymph nodes draining tumor (Br J Surg 1983;70:317)
Interfollicular / mixed patterns
- Paracortical hyperplasia: seen usually in viral infections, nodes draining tumors and autoimmune disorders (Pathol Res Pract 2001;197:230, Hum Pathol. 1975;6:3, APMIS 2001;109:419)
- Mixed small lymphocytes and immunoblasts, with increased vascularity and interdigitating dendritic cells
- Granulomatous lymphadenitis: necrotizing, nonnecrotizing or suppurative granulomas depending on the etiology (Rev Infect Dis 1986;8:322)
Diffuse
- Architecture may be effaced
- Diffuse proliferation of mixed small lymphocytes, immunoblasts and plasma cells (APMIS 2001;109:419)
- Immunoblasts may rarely mimic Hodgkin-Reed / Sternberg cells
Acute lymphadenitis
- Sinus dilatation followed by accumulation of neutrophils, vascular dilatation and edema of the capsule
- Suppurative or necrotizing inflammation may be seen depending on the etiology (Semin Pediatr Surg 2006;15:99)
Chronic lymphadenitis
- Follicular hyperplasia, prominence of postcapillary venules, increased number of immunoblasts, fibrosis, plasma cells and histiocytes
- Capsule may be inflamed or fibrotic (Semin Pediatr Surg 2006;15:99)

Microscopic (histologic) images

Contributed by Jayalakshmi Balakrishna, M.D.

Follicular hyperplasia

Interfollicular area

Germinal center dark zone

Sinus histiocytosis

Granulomatous lymphadenitis

Necrosis

Chronic lymphadenitis

Primary follicle

CD20

Germinal center

CD3

Plasma cells

Immunoblasts

Polarization of germinal center

Reactive germinal center

Virtual slides

N/A

Cytology description

Cellular smears with mixed small and large lymphocytes, tingible body macrophages and other cell types including histiocytes and follicular dendritic cells
In acute lymphadenitis a prominence of neutrophils may be seen

Cytology images

N/A

Peripheral smear description

If there is leukocytosis with lymphocytosis or neutrophilia depending on the cause, the same may be observed

Peripheral smear images

Contributed by Jayalakshmi Balakrishna, M.D.

Lymphocytosis

Neutrophilic leukocytosis

Positive stains

Follicles: positive for pan B cell markers, such as CD19, CD20, CD22, CD79a, PAX5
Germinal centers: positive for germinal center markers, such as CD10 and BCL6
Follicular dendritic cells: positive for CD21, CD23
T cells: CD3, CD4, PD-1
Plasma cells: CD138
Paracortex (T cells): positive for pan T cell markers, such as CD3, CD2, CD5 and CD7, mixed CD4 and CD8 positive T cells
Immunoblasts: positive for CD30 (StatPearls: Histology, Lymph Nodes [Accessed 4 December 2024])
Ki67: high proliferation rate in the germinal centers with polarization (dark zone with higher rate of proliferation and light zone with lower rate)

Negative stains

Germinal centers: negative for BCL2

Flow cytometry description

No immunophenotypic aberrancies
Mixed B and T cell populations
B cells polytypic based on light chain pattern
T cells mixed CD4 and CD8 positive cells (Cytopathology 2022;33:505, J BUON 2013;18:739)

Flow cytometry images

Contributed by Jayalakshmi Balakrishna, M.D.

B cells

T cells

Electron microscopy description

N/A

Electron microscopy images

N/A

Molecular / cytogenetics description

Polyclonal pattern of B and T cell gene rearrangements
Negative for cytogenetic or molecular abnormalities

Molecular / cytogenetics images

N/A

Videos

N/A

Sample pathology report

Lymph node, left cervical, needle core biopsy:
- Reactive lymphoid hyperplasia and no morphologic or immunophenotypic evidence of a lymphoproliferative disorder

Differential diagnosis

Follicular hyperplasia
- Classic follicular lymphoma:
  - Effaced architecture, back to back follicles, invasion of capsule or adjacent structures, no polarization of the follicle, no tingible body macrophages, no well defined mantle zones
  - Positive for CD10, BCL6 and BCL2, monotypic light chain expression, monoclonal B cell gene rearrangement and presence of t(14;18)
- In situ follicular neoplasia:
  - No polarization and bright expression of CD10 and BCL2 in involved germinal centers, monotypic light chain expression, monoclonal B cell gene rearrangement and presence of t(14;18)
Sinus histiocytosis
- Expansion of the sinuses with tumor cells
  - Melanoma:
    - Positive for S100 and melanocytic markers
  - Mesothelioma:
    - Positive for WT1 and other mesothelial markers
  - Anaplastic large cell lymphoma:
    - Positive for T cell markers, CD30 and may be positive for ALK1
Specific causes of lymphadenopathy need to be ruled out
- Acute:
  - Lymphogranuloma venereum, cat scratch disease, bubonic plague, tularemia, anthrax, typhoid fever, melioidosis
- Chronic:
  - Tuberculosis, leprosy, atypical mycobacteria, syphilis, fungal or parasitic infections:
    - Special stains for the causative microorganisms will be positive

Additional references

Medeiros: Ioachim's Lymph Node Pathology, 5th Edition, 2021, Jaffe: Hematopathology, 3rd Edition, 2024

Board review style question #1

A 23 year old woman presents with tender right cervical lymph node enlargement. She also complains of low grade fever and feeling tired. On examination, she is found to have 3 red papules (4 mm) on her right shoulder. On further inquiry, she informs that she owns 2 cats. What is the best confirmatory test at this point?

Biopsy of the lymph node
Biopsy of the skin lesion
Polymerase chain reaction (PCR)
Serology

Board review style answer #1

D. Serology for IgG and IgM antibodies for Bartonella henslae is confirmatory for cat scratch disease. Answers A and B are incorrect because biopsy is rarely indicated. If performed, a biopsy will show lymphoid hyperplasia, granuloma formation, stellate abscesses and vascular proliferation depending on the stage of the disease. Answer C is incorrect because PCR can be done on a biopsy specimen to confirm the diagnosis.

Comment Here

Reference: Reactive lymphadenopathy

Board review style question #2

A 10 year old girl presents with bilateral cervical lymph node enlargement. Her parents state that she has had a fever and throat pain for the past few days. On examination, she is found to have multiple enlarged bilateral cervical lymph nodes. The above image shows a low power view of the cervical lymph node biopsy (H&E, 10x). What is your diagnosis?

Burkitt lymphoma
Follicular hyperplasia
Follicular lymphoma
Paracortical expansion

Board review style answer #2

B. Follicular hyperplasia. The presence of hyperplastic secondary follicles with prominent germinal centers, which show polarization and tingible body macrophages and mantle zone, is favorable for reactive follicular hyperplasia. Answer C is incorrect because follicular lymphoma shows effaced architecture with back to back follicles, absence of polarization and tingible body macrophages; it also lacks well defined mantle zones. Answer A is incorrect because Burkitt lymphoma is a diffuse proliferation of medium sized atypical lymphoid cells with blastoid morphology and conspicuous 1 - 3 nucleoli. Answer D is incorrect because paracortical hyperplasia is the expansion of interfollicular areas with mixed small lymphocytes, immunoblasts, vessels and interdigitating dendritic cells.

Comment Here

Reference: Reactive lymphadenopathy

Reactive lymphadenopathy

Table of Contents

Definition / general

Lymph node enlargement due to hyperplasia of cellular components reflecting antigenic stimulation
Benign and reversible process.

Essential features

Clinically manifests as lymph node enlargement
No clonal process
No cytologic or architectural atypia

Terminology

Reactive lymphoid hyperplasia
Reactive follicular hyperplasia
Diffuse paracortical hyperplasia
Sinus histiocytosis

ICD coding

R59.9

Epidemiology

Represents the reaction of lymphoid tissue to intrinsic or environmental antigens
Most lymph node enlargements are reactive
In children, most lymphadenopathies are benign; in adults, chance of malignancy increases with age

Sites

Any lymph node group can be affected depending on the stimulation

Pathophysiology

Lymph nodes filter lymph drained from tributary regions
Substances carried by lymph reach the nodes; these may be antigenic and cause an immune reaction
Bacteria and fungi cause predominantly inflammatory reactions; viruses and drugs cause predominantly immune reactions
4 patterns of reactive hyperplasia have been described, depending on the etiology: follicular, paracortical / diffuse, sinus and mixed

Etiology

Multiple etiologic factors, including:
- Bacteria
- Fungi
- Viruses
- Chemicals
- Environmental pollutants
- Drugs: phenytoin, allopurinol, atenolol, gold, penicillin, quinidine
- Altered tissue components
- Other antigens or allergens
Definitive identification of etiologic agent is possible only in a small subset of cases

Clinical features

Clinical syndrome usually reflects the underlying disorder
Generally, of short duration but may be prolonged
Enlargement of lymph node(s) may be painful or tender
Associated symptoms include fever, weight loss, malaise, loss of appetite
Nodes are soft or fluctuant in inflammation and suppuration

Diagnosis

Histopathology
Exclude specific causes by clinical, laboratory and imaging studies

Laboratory

Depends on the etiologic agent

Radiology description

Enlarged lymph node(s)

Prognostic factors

Benign, self limiting process
Prognosis depends on the etiology

Treatment

Treatment of the underlying disorder

Gross description

Enlarged, soft, lymph node with tan homogenous cut surfaces

Microscopic (histologic) description

Reactive follicular hyperplasia
- B cell response pattern
- Enlarged follicles, varying in size and shape, may coalesce and display different configurations
- Prominent germinal center and mantle zone
- Germinal centers show mixed small and large lymphocytes - centrocytes and centroblasts
- Centroblasts polarize to the medial pole forming the darker zone and centrocytes accumulate at the peripheral pole forming the lighter zone
- Centroblasts are 3 - 4 times larger than the inactivated lymphocytes and show narrow rim of basophilic cytoplasm and large, round to oval vesicular nuclei with 1 - 3 prominent peripheral nucleoli
- Mitotic figures are frequent
- Centrocytes are smaller lymphocytes with scant cytoplasm, cleaved nuclei, clumped chromatin and small or absent nucleoli
- Numerous tingible body macrophages are a characteristic feature of follicular hyperplasia
Diffuse paracortical hyperplasia
- T cell response pattern
- T cell zones, paracortical or interfollicular are expanded with a heterogeneous population of cells, including numerous small lymphocytes and admixed immunoblasts resulting in a starry sky or moth eaten appearance
- Immunoblasts in some cases may resemble Reed-Sternberg cells
- Proliferation of high endothelial venules is another characteristic finding
Sinus histiocytosis
- Sinuses are prominent and are lined by hyperplastic sinus histiocytes
Mixed
- Follicular, diffuse and sinus patterns coexist in one lymph node

Microscopic (histologic) images

Images hosted on other servers:

Reactive lymphoid hyperplasia

Cytology description

Cellular smears with mixed small and large lymphocytes and numerous tingible body macrophages
No cytologic atypia

Positive stains

B cell zones are positive for pan B cell markers (CD19, CD20) and T cell zones for pan T cell markers (CD3, CD4, CD8)
Immunoblasts are positive for CD20 and CD30

Negative stains

BCL2 is negative in reactive follicular centers (in contrast to follicular lymphoma, in which neoplastic follicles are BCL2+)

Flow cytometry description

No aberrant immunophenotype

Molecular / cytogenetics description

Gene rearrangement - polyclonal pattern

Differential diagnosis

Atypical lymphoid hyperplasia: cellular atypia
Follicular lymphoma: effaced architecture, back to back nodules which invade surrounding tissues and capsule; no tingible body macrophages, no mantle zones; germinal center is BCL2+; follicular cells are monoclonal, t(14;18) present
Hodgkin lymphoma: Reed-Sternberg cells and variants are present
Other non-Hodgkin lymphomas: monotonous population of atypical lymphoid cells, invasion of capsule and surrounding tissues, monoclonal nature and specific surface markers

Additional references

Ioachim: Ioachim's lymph node pathology, 4th Edition, 2009, Jaffe: Hematopathology, 2nd Edition, 2016, J Surg Oncol 1980;14:53

Rheumatoid arthritis

Table of Contents

Definition / general | Microscopic (histologic) description | Microscopic (histologic) images | Negative stains

Definition / general

Associated with lymphadenopathy during course of disease in 82%, usually axillary (J Int Med Res 2003;31:345)
Lymphadenopathy usually disappears during disease remission
May also have fever, weight loss, anemia
Modestly increased risk of lymphoma, may be due to methotrexate treatment

Microscopic (histologic) description

Follicular hyperplasia with sparse (J Clin Pathol 1990;43:106) vs. active (Acta Pathol Jpn 1990;40:249) proliferative activity, interfollicular plasma cells with Russell bodies, vascular proliferation
Capsular lymphocytic infiltrate
May resemble plasma cell variant of Castleman disease
Often PAS+ extracellular hyaline material
Occasionally focal necrosis and microabscesses
May have sarcoid-like granulomas

Microscopic (histologic) images

AFIP images

Reactive lymphadenopathy of rheumatoid arthritis

Images hosted on other servers:

Follicular hyperplasia
with eosinophilic
material in
interfollicular areas

Extensive replacement
by focally calcified
eosinophilic material

Rounded, well
separated follicles
with expanded
paracortex

Follicular center composed
primarily of centrocytes,
with no / rare tingible body
macrophages or mitotic figures

Interdigitating dendritic
cells (CD1+) are associated
with small lymphocytes

Negative stains

Polyclonal plasma cells (no light chain restriction)

Rosai-Dorfman disease (RDD)

Table of Contents

Definition / general

Rare, non-Langerhans cell histiocytosis with heterogeneous clinical features
Described in 1960s as a self limiting condition involving the lymph nodes (Arch Pathol 1969;87:63)
Extranodal involvement in approximately 40% of cases; may be limited or disseminated disease (Blood 2018;131:2877)
May be familial or associated with neoplasia or immune disease (Blood 2016;127:2672)

Essential features

Clinical features depend on the site(s) involved and disease associations
Classic (nodal) Rosai-Dorfman disease (RDD) and cutaneous RDD often self limited and benign
Disseminated RDD may have an aggressive clinical course necessitating systemic therapies (Haematologica 2020;105:348, Blood 2018;131:2877)
Approximately 33% of cases harbor clonal mitogen activated protein kinase / extracellular signal regulated kinase (MAPK / ERK) pathway alterations (Mod Pathol 2017;30:1367, Haematologica 2020;105:e5)

Terminology

Initially described by Destombes as adenitis with lipid excess (Bull Soc Pathol Exot Filiales 1965;58:1169)
Rosai and Dorfman described as sinus histiocytosis with massive lymphadenopathy (Arch Pathol 1969;87:63)
Classified in the R group (nodal and extranodal disease) and the C group (cutaneous disease only) under the revised classification of histiocytic disorders (Blood 2016;127:2672)

ICD coding

ICD-10: D76.3 - Rosai-Dorfman disease

Epidemiology

Mean age at diagnosis: 50 years (range 2 - 79) (Haematologica 2020;105:348)
F:M = 1.5:1

Sites

Lymph node involvement common (30 - 50%) (Am J Surg Pathol 2021;45:35, Blood 2018;131:2877)
Skin is the most common extranodal site (50%)
Other extranodal sites include bone, upper respiratory tract (sinus), central nervous system including dura and parenchymal lesions, orbit, retroperitoneum (Mayo Clin Proc 2019;94:2054)

Etiology

Pathogenesis unclear and likely multifactorial
Association with immune disease suggests that immune dysregulation may play a role in pathogenesis
Subset harbor MAPK / ERK pathway alterations, suggesting a pathogenesis similar to Langerhans cell histiocytosis and Erdheim-Chester disease (Mod Pathol 2017;30:1367, Cancer Discov 2016;6:154)

Clinical features

Heterogeneous clinical course, depending on the site of involvement
Associated conditions include autoimmune disorders (systemic lupus erythematosus, idiopathic juvenile arthritis, autoimmune hemolytic anemia), neoplasia such as lymphomas and myeloid neoplasms and IgG4 related RDD characterized by increased IgG4 positive plasma cells (Blood 2018;131:2877, Haematologica 2020;105:348)
Classic (nodal) RDD presents as enlarged lymph nodes, most commonly involving bilateral cervical nodes in young males
Extranodal RDD manifests with diverse clinical presentations (Blood 2018;131:2877)
- Cutaneous lesions present as slow growing, painless nodules, papules or plaques
- Neurologic involvement may present with headache, seizures, motor / sensory abnormalities and gait disturbances
- Orbital involvement may present with exophthalmos or visual disturbance
- Sinus involvement may display nasal congestion or obstruction
- Pulmonary RDD can present with dry cough, dyspnea and may mimic primary lung cancer, interstitial lung disease and other inflammatory / infectious conditions
- Retroperitoneal involvement may present as diffuse infiltration and less commonly a discrete mass with or without hydronephrosis and ureteral obstruction
Multisystem involvement in approximately 20% cases and prognosis related to the number of extranodal sites
Rosai-Dorfman disease may be a component of mixed histiocytosis with Langerhans cell histiocytosis or Erdheim-Chester disease (Mod Pathol 2010;23:1616, Haematologica 2020;105:e5)

Diagnosis

Comprehensive evaluation, including clinical history, physical examination and imaging studies in conjunction with morphologic features
RDD may be associated with other histiocytic neoplasms, including Langerhans cell histiocytosis and Erdheim-Chester disease, which should be confirmed by biopsy in the setting of atypical clinical manifestations (Mod Pathol 2010;23:1616, Haematologica 2020;105:e5)

Radiology description

Nodal involvement on PET CT harboring RDD shows increased central intake with a photopenic halo (Mayo Clin Proc 2019;94:2054)
Extranodal involvement may show the following findings:
- CNS involvement often presents as hyperattenuating meningeal based mass showing contrast enhancement on CT (Asian J Neurosurg 2010;5:19)
  - Skeletal RDD lesions are usually lytic and centered in medullary space (Mayo Clin Proc 2019;94:2054)
  - Pulmonary involvement may present as cystic change, interstitial lung disease, nodules, focal pulmonary infiltrate or airway disease
  - Sinus involvement may present with maxillary wall thickening
  - Retroperitoneum involvement may present as renal hilar masses, subcapsular hypodense infiltration or renal cortical hypodense nodules

Radiology images

Images hosted on other servers:

Imaging findings in RDD

Prognostic factors

Optimal duration of treatment with systemic therapy is individualized, depending on the extent of involvement
Usually favorable outcomes in cases with nodal and cutaneous involvement
Subset may demonstrate aggressive clinical course usually associated with multifocal involvement (Haematologica 2020;105:348)

Case reports

10 year old boy with polyuria and polydipsia (Front Med (Lausanne) 2020;7:613756)
12 year old boy with dyspnea and left sided chest pain presented with interatrial septal mass (J Radiol Case Rep 2012;6:1)
29 year old woman with arthralgias in the hands and knees and lytic lesions of the left distal radius (Curr Rheumatol Rep 2017;19:29)
41 year old man with paravertebral mass (J Int Med Res 2017;45:875)
53 year old man with diminished vision of right eye associated with a palpable mass (J Microsc Ultrastruct 2019;7:50)
57 year old woman with progressive vision loss (Head Neck Pathol 2016;10:414)

Treatment

Management varies, depending on the site of involvement and the presence / absence of symptoms (Blood 2018;131:2877)
Nodal / cutaneous involvement usually self limited and requires only observation
Surgical resection may be considered in symptomatic cases with single site of involvement
Multifocal and refractory cases may require systemic therapy (first line therapy with cladribine, cytarabine, methotrexate or prednisone)
Targeted therapy with MEK inhibitors is under investigation in those with MAPK / ERK pathway alterations (Haematologica 2020;105:348)

Microscopic (histologic) description

Characterized by the accumulation of histiocytes with enlarged, round to oval hypochromatic nuclei and abundant eosinophilic cytoplasm, often containing engulfed intact inflammatory cells known as emperipolesis (Am J Surg Pathol 2021;45:35)
Lesional histiocytes usually associated with fibrosis and prominent inflammatory infiltrate comprised of plasma cells and lymphocytes
Occasional neutrophilic infiltrates are present
Nodal involvement is characterized by distended sinuses with lesional histiocytes
Rosai-Dorfman disease is rarely detected as an incidental finding concomitantly with lymphoma in the same biopsy specimen (Mod Pathol 2019;32:16)

Microscopic (histologic) images

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

Excisional biopsy of
subcutaneous mass

CD163

S100

OCT2

Cyclin D1

Positive stains

Monocyte / macrophage markers: CD68, CD163, OCT2
S100, cyclin D1 / BCL1
Reference: Am J Surg Pathol 2021;45:35

Negative stains

Molecular / cytogenetics description

Approximately 33% of cases harbor mutually exclusive recurrent KRAS and MAP2K1 mutations (Mod Pathol 2017;30:1367)
Germline mutations in SLC29A3 gene may be present in familial cases of RDD (Blood 2016;127:2672)

Sample pathology report

Lymph node, right axillary, excisional biopsy:
Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy) (see comment)
- Comment: Histologic examination shows distended lymph node sinuses containing a prominent population of histiocytes characterized by large, round nuclei and voluminous cytoplasm showing emperipolesis with engulfment of lymphocytes. The lymphoplasmacytic infiltrate within the lymph node parenchyma is cytologically unremarkable. Immunohistochemistry shows that the atypical histiocytes within the lymph node sinuses are positive for CD68, CD163 with coexpression of S100, OCT2 and cyclin D1. They are negative for BRAF V600E by immunohistochemistry. There is no increase in the number of IgG4 positive plasma cells or an abnormal IgG4/IgG ratio. CD3 and CD20 reveal an appropriate mixture of T cells and B cells, respectively. Kappa and lambda immunoglobulin light chains reveal polytypic plasma cells. CD1a and langerin are negative.

Differential diagnosis

Sinus histiocytosis:
- Reactive process characterized by prominent sinuses in lymph nodes containing normal histiocytes
- Immunostains for S100, cyclin D1 and OCT2 are negative
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
- Positive for CD1a and langerin
Erdheim-Chester disease:
- Bland appearing histiocytes characterized by abundant foamy (xanthomatous) cytoplasm with surrounding fibrosis (Mod Pathol 2018;31:581)
- Touton giant cells are frequently present
- Positive for CD68, CD163, factor XIIIa and negative for OCT2 expression by immunohistochemistry (Am J Surg Pathol 2021;45:35)
- Clinical, radiologic and morphologic correlation required (Mayo Clin Proc 2019;94:2054)
Juvenile xanthogranuloma:
- Usually in infants and young children
- Histologically and phenotypically similar to Erdheim-Chester disease
Low grade B cell lymphoma:
- Lymphoplasmacytic infiltrate with monotypic expression of immunoglobulin light chains
- Absence of S100, OCT2 positive histiocytes

Board review style question #1

A 47 year old woman presented with multiple skin nodules on bilateral arms that were gradually increasing in size over 6 months. Based on the morphology, which of the following is the most likely diagnosis?

Follicular dendritic cell sarcoma
Juvenile xanthogranuloma
Langerhans cell histiocytosis
Reactive process
Rosai-Dorfman disease

Board review style answer #1

E. Rosai-Dorfman disease

Comment Here

Reference: Rosai-Dorfman disease (RDD)

Board review style question #2

Lesional cells in sinus histiocytosis with massive lymphadenopathy show positive expression of which of the following immunostains?

AE1 / AE3, CAM5.2, CK34βE12
CD117, DOG1, muscle specific actin
Cyclin D1, S100 and OCT2
Desmin, MyoD1, myogenin
SMA, p63, p40

Board review style answer #2

C. Cyclin D1, S100 and OCT2 (Am J Surg Pathol 2021;45:35)

Comment Here

Reference: Rosai-Dorfman disease (RDD)

Sclerosing angiomatoid nodular transformation

Table of Contents

Definition / general

Rare, benign splenic lesion of unknown etiology, characterized by confluent angiomatoid nodules surrounded by concentric collagen fibers

Essential features

Nonneoplastic condition that affects the spleen only; not described in other sites
Microscopically characterized by multiple angiomatoid nodules in a fibrosclerotic stroma
Surgery is curative in all the cases and recurrence has not been reported

Terminology

Multinodular hemangioma (obsolete)

ICD coding

ICD-10: D18.03 - hemangioma of intra-abdominal structures

Epidemiology

Female predilection (F:M = 2:1)
Mean age of 48 years
Range is 30 - 60 years (Int J Surg Case Rep 2012;3:492)

Sites

Only described in the spleen
Confined to the splenic parenchyma, with no extrasplenic involvement

Etiology

Etiology and pathogenesis unknown
Exaggerated sclerotic and neoangiogenic splenic reaction could be secondary to different pre-existing conditions, including vascular lesions undergoing thrombosis, infarcts and even hamartoma (Int J Surg Case Rep 2012;3:492, Am J Surg Pathol 2004;28:1268)

Clinical features

Asymptomatic in the majority of the cases; incidentally discovered by imaging studies or at time of surgery for unrelated processes (Am J Surg Pathol 2004;28:1268)
Symptomatic patients may experience nonspecific symptoms, including abdominal discomfort, abdominal fullness, nausea, vomiting and undesired weight loss

Diagnosis

Clinically and radiologically indistinguishable from other lesions of the spleen, including hemangioma, hamartoma and rarely, malignancies
Final diagnosis is achieved only with histopathologic examination and immunohistochemistry of resected spleen specimens
Splenectomy serves both diagnostic and treatment functions
References: Am J Surg Pathol 2004;28:1268, Semin Diagn Pathol 2021;38:159

Laboratory

Laboratory values are mostly unaltered
Occasional reports of nonspecific findings, including raised erythrocyte sedimentation rate, leukocytosis and polyclonal hypergammaglobulinemia (Am J Surg Pathol 2004;28:1268)

Radiology description

No characteristic and unique radiologic findings of this entity
Abdominal ultrasound, CT scan and MRI studies usually reveal an isolated, multinodular solid splenic mass
References: J Comput Assist Tomogr 2019;43:863, Diagn Interv Imaging 2021;102:389

Radiology images

Images hosted on other servers:

CT findings

Expansible low density mass

5 cm tumor in hilus

Hypointensity of tumor

Splenic lesion at medial aspect

Lesion in lower spleen

Hypoenhancing mass

Prognostic factors

Benign clinical behavior with favorable prognosis and no reported recurrences after splenectomy (Am J Surg Pathol 2004;28:1268)

Case reports

21 year old woman with mild thrombocytopenia and a hypervascular splenic mass (Radiol Case Rep 2018;14:521)
26 year old man and 65 year old woman presenting with undesired weight loss and a lasting feeling of abdominal fullness (World J Clin Cases 2020;8:103)
37 year old woman with a 5 cm hypoechoic mass in the spleen with low standardized uptake value (SUV) at FDG PET / CT scan (Acta Radiol Open 2016;5:2058460116649799)
49 year old woman with a newly diagnosed invasive clear cell carcinoma of the uterus and a 4 cm isolated splenic nodule suspicious for metastatic involvement (J Med Case Rep 2018;12:377)
67 year old man with an isolated 55 mm splenic lesion suspicious for an abscess (Int J Surg Case Rep 2019;56:1)

Treatment

Splenectomy performed at discovery of the splenic mass is curative in all the cases

Clinical images

Images hosted on other servers:

Macroscopic findings

Laparoscopic view

Gross description

Single unencapsulated, well circumscribed solid mass with a striking multinodular quality and variable fibrotic strands (Semin Diagn Pathol 2021;38:159)

Gross images

Contributed by Shafinaz Hussein, M.D. and Huifei Liu, M.D., Ph.D. (Case #364)

Circumscribed, bosselated, firm, tan colored mass

Images hosted on other servers:

Well demarcated, unencapsulated lesion

Splenic resection

Well defined, nonencapsulated lesion

Red-brown, multinodular lesions

Microscopic (histologic) description

Multiple, well circumscribed and confluent angiomatoid nodules surrounded by a variable fibrosclerotic stroma and occasionally, by a fibrinoid rim imparting a granuloma-like appearance at low magnification (Arch Pathol Lab Med 2007;131:974, Semin Diagn Pathol 2021;38:159)
Nodules contain a mixture of slit-like, round or irregular vascular spaces lined by cytologically bland, sometimes plump endothelial cells; lacking atypia, necrosis and mitotic figures
3 different types of vessels within the nodules can be highlighted by immunohistochemistry (see Positive stains), which recapitulate the normal red pulp composition: capillaries, sinusoids and small veins
Stroma separating the nodules is fibrous to fibromyxoid with bland fibroblasts and myofibroblasts; contains abundant inflammatory cells, including lymphocytes, hemosiderin laden macrophages and polytypic plasma cells (Semin Diagn Pathol 2021;38:159)
IgG4 positive plasma cells occasionally numerous with IgG4:IgG ratio increased; however, serum IgG4 concentration not elevated (Pathol Int 2009;59:844)
Adjacent splenic tissue is unremarkable

Microscopic (histologic) images

Contributed by Valentina Sangiorgio, M.D., Shafinaz Hussein, M.D. and Huifei Liu, M.D., Ph.D. (Case #364)

Multiple vascular nodules

Predominantly small capillaries

Bland endothelial cells

CD8

CD31

CD34

Positive stains

3 types of vessels (as seen in the normal splenic red pulp):
- Capillaries: CD34+ / CD8- / CD31+
- Sinusoids: CD34- / CD8+ / CD31+
- Small veins: CD34- / CD8- / CD31+
SMA positive in myofibroblasts in the nodules
CD68 positive in histiocytes / macrophages
Polytypic expression of kappa and lambda light chains within plasma cells
References: Am J Surg Pathol 2004;28:1268, Arch Pathol Lab Med 2013;137:1309

Negative stains

D2-40
Epstein Barr virus (EBV) in situ hybridization

Electron microscopy description

Small vascular spaces lined by endothelial cells with pinocytotic vesicles but no Weibel-Palade bodies (Am J Surg Pathol 2004;28:1268)

Sample pathology report

Spleen, splenectomy:
- Sclerosing angiomatoid nodular transformation (SANT) of the spleen

Differential diagnosis

Hemangioma:
- Often of cavernous type
- Cystically dilated, blood filled spaces lined by a layer of bland endothelial cells
- Vascular spaces separated by thin fibrous septa, without the striking angiomatoid nodular appearance of sclerosing angiomatoid nodular transformation (Semin Diagn Pathol 2021;38:154)
Littoral cell angioma:
- Macroscopically enlarged spleen overrun by multiple hemorrhagic nodules with a vague lobular configuration and a spongy appearance; uncommonly solitary nodules
- Nodules composed of pleomorphic vascular spaces filled with papillary projections
- Papillary stalks lined by plump endothelial cells
- Characteristic immunophenotype of splenic littoral cells with dual histiocytic and endothelial differentiation lacking CD34
Hemangioendothelioma and angiosarcoma:
- Ill defined vascular spaces lined by variably atypical, malignant endothelial cells, with necrosis and increased mitotic activity (Semin Diagn Pathol 2021;38:154)
Hamartoma:
- Structurally disorganized red pulp tissue, with no Malpighian follicles and only occasional fibrous trabeculae
- Compared with sclerosing angiomatoid nodular transformation, the borders are poorly defined and it lacks the angiomatoid nodular appearance (Semin Diagn Pathol 2021;38:154)

Board review style question #1

What does this image from a sclerosing angiomatoid nodular transformation of the spleen show?

Areas of geographic necrosis
Atypical endothelial cells with prominent nucleoli
Easily identifiable mitotic figures (≥ 1 per 10 high power fields)
Small capillaries admixed with scattered inflammatory cells, including small lymphocytes, histiocytes and plasma cells

Board review style answer #1

D. Small capillaries admixed with scattered inflammatory cells, including small lymphocytes, histiocytes and plasma cells. Necrosis, atypia and increased mitotic activity (≥ 1 per 10 high power fields) are not seen in this image. They are not seen in otherwise conventional sclerosing angiomatoid nodular transformation and their identification should prompt alternative diagnoses, including hemangioendothelioma or angiosarcoma.

Comment Here

Reference: Sclerosing angiomatoid nodular transformation

Board review style question #2

Which of the following statements best describes sclerosing angiomatoid nodular transformation of the spleen?

Benign condition that affects the spleen only, is cured with splenectomy and does not manifest any metastatic potential
Benign neoplasm that can affect parenchymatous organs (mostly spleen, liver and lung) and does not manifest any metastatic potential
Neoplasm of uncertain malignant potential as it can recur after resection in sites other than spleen
Neoplasm of uncertain malignant potential as occasional cases transform into overt angiosarcoma

Board review style answer #2

A. Benign condition that affects the spleen only, is cured with splenectomy and does not manifest any metastatic potential. Sclerosing angiomatoid nodular transformation is a nonneoplastic lesion which affects the spleen only, with no description in other anatomic sites. It is cured by splenectomy and never recurs thereafter.

Comment Here

Reference: Sclerosing angiomatoid nodular transformation

Silicone

Table of Contents

Definition / general

Rare enlargement of regional lymph nodes caused by the presence of silicone carried from tributary organs
Either an incidental finding or causes painful / enlarged lymph node
May be associated with granulomatous inflammation (Histol Histopathol 1997;12:1003)

Terminology

Silicone lymphadenopathy

Sites

Draining lymph nodes of the implant site, commonly axillary lymph nodes (Respiratory Medicine CME 2011;4:126)

Pathophysiology

Silicone is widely used in implants, especially augmentation mammoplasty and joint prostheses (Hum Pathol 1980;11:240)
Once released into tissue, silicone migrates to distant sites through lymphatic channels and bloodstream
Once it reaches lymph nodes, it elicits a reaction and cause silicone lymphadenopathy

Etiology

Rupture / leak of the implant, or implant 'bleeds', or releases microparticles into blood / lymphatics

Clinical features

Enlarged lymph nodes
Asymptomatic or with pain

Diagnosis

Biopsy

Radiology description

Ultrasonogram: hyperechoeic (increased echogenicity of the lymph node mediastinum with dirty acoustic shadowing), beginning in the hilum and progressing outward through the cortex with time and amount of silicone
In severe cases, snowstorm appearance

Prognostic factors

Depends upon the amount of silicone and severity of the reaction

Case reports

35 year old woman with axillary silicone lymphadenopathy (J Med Case Rep 2009;3:6442)
40 year old woman with silicone lymphadenopathy involving intramammary lymph nodes (AJR Am J Roentgenol 1994;162:1089)
45 year old woman with axillary silicone lymphadenopathy secondary to augmentation mammaplasty (Indian J Plast Surg 2010;43:206)
47 year old woman with silicone lymphadenopathy mimicking lymphoma (J Clin Pathol 2000;53:549)
49 year old woman with lymphadenopathy associated with total joint prostheses (J Bone Joint Surg Am 1996;78:588)
59 year old woman with silicone migration to the contralateral axillary lymph nodes and breast after highly cohesive silicone gel implant failure (Cases J 2009;2:6420)
71 year old woman with siliconoma in internal mammary lymph node (Radiology Case Reports 2011;6(4))

Treatment

Removal of lymph nodes

Clinical images

Images hosted on other servers:

Rupture of implant

Various images

Gross description

No specific gross features
Enlarged and firmer than normal
Extreme cases show distorted architecture and fibrosis

Microscopic (histologic) description

Diffuse follicular hyperplasia
Histiocytes with vacuolated cytoplasm especially inside the sinusoids
Histiocytes cause foreign body granulomatous reaction, giant cells and empty vacuoles
Giant cells have refractile and non-birefringent particles
Asteroid bodies may be seen
Silicone from orthopedic devices: prominent granulomatous reaction with clumps of granular yellowish refractile material
Silicone from mammary prostheses: finer vacuolated deposits

Microscopic (histologic) images

Contributed by Dr. Mark R. Wick

Silicone in axillary lymph node

Images hosted on other servers:

Material consistent with silicone

Liquid silicone droplets

Various images

Subcapsular sinus diffusely expanded

Vacuoles which contain refractile material

Foreign body granuloma

Germinal centers surrounded by sinuses

Silicone leakage

Silicone particles in cystic spaces

Cytology description

Numerous multi-vacuolated histiocytic cells both scattered individually as well as in aggregates
Contain clear, refractile but non-polarizable material
Background may show scattered lymphocytes

Positive stains

Histiocytes: CD68 and CD44

Negative stains

Silicone is negative for PAS, mucin, trichrome, oil red O

Electron microscopy description

Electron opaque fragmented spicules or flakes

Differential diagnosis

Fat necrosis
Lipogranuloma
Metastatic lobular carcinoma
Metastatic renal cell carcinoma
Metastatic signet ring cell carcinoma
Signet ring cell type lymphoma
Sinus histiocytosis with massive lymphadenopathy

Additional references

Ioachim's Lymph Node Pathology, 4th Edition, 2008, Stavros: Breast Ultrasound, 1st Edition, 2004, Am J Surg Pathol 2005;29:506

Splendore-Hoeppli phenomenon

Table of Contents

Definition / general | Case reports

Definition / general

Abscess containing brightly eosinophilic, pseudomycotic structures composed of necrotic debris and immunoglobulin in starburst pattern
In U.S., usually due to Staphylococcus aureus or Pseudomonas aeruginosa; in tropics, due to schistosomiasis, microfilariae, various fungi

Case reports

61 year old woman with CLL for 10 years with Nocardia asteroides in spleen (Arch Pathol Lab Med 2001;125:1515)

Splenectomy, rupture & splenosis

Table of Contents

Splenectomy | Rupture | Splenosis

Splenectomy

Definition / general

Usually performed for traumatic rupture
Usually no clinical consequence in adults but elevated risk of infection is present, especially in elderly and those with malignancy (Med J Aust 2012;196:582)
In children, associated with increased incidence and severity of infections, particularly encapsulated bacteria such as Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae; overwhelming infections (OPSI: overwhelming postsplenectomy infection) may begin days to years after splenectomy, without an identifiable focus and have 50 - 80% mortality despite antibiotics
Increased susceptibility to severe infections with intraerythrocytic parasites Babesia and Plasmodium (Clin Microbiol Rev 2010;23:740)
In children, splenectomy is avoided in favor of splenic repair, partial splenectomy or splenic autotransplant
Must consider possibility of accessory spleen(s) if splenectomy is performed for hematologic disorders

Laboratory

Howell-Jolly bodies are evidence of no splenic function

Case reports

2 cases of postsplenectomy pneumococcemia (Arch Pathol Lab Med 1980;104:258)

Peripheral smear images

Images hosted on other servers:

Howell-Jolly bodies

Rupture

Definition / general

Due to blunt trauma or abdominal surgery, causing hemoperitoneum and emergency splenectomy
Only rarely ruptures spontaneously (associated with acute splenitis, amyloidosis [rare], infectious mononucleosis, inflammatory disorders, leukemia / lymphoma, malaria, other tumors, peliosis lienis, pregnancy, subacute bacterial endocarditis, typhoid fever)
Splenic rupture may be delayed after trivial / minor trauma

Case reports

16 year old girl with infectious mononucleosis (Int J Surg Case Rep 2012;3:97)
29 year old woman with splenic pregnancy (Arch Pathol Lab Med 2004;128:e146)
54 year old woman with systemic lupus erythematosus (Clin Rheumatol 2012;31:1019)
2 patients with pancreatic cancer presenting with splenic rupture (Arch Pathol Lab Med 2004;128:1146)

Clinical images

Images hosted on other servers:

Grossly enlarged with hematoma

Gross description

Rupture may be a very small capsular tear, often in superior pole or hilum

Microscopic (histologic) description

Neutrophils below capsular tear with intraparenchymal hemorrhage; also lymphoid hyperplasia with prominent marginal zone

Additional references

Mod Pathol 1997;10:1214

Splenosis

Definition / general

Autotransplantation of splenic tissue on peritoneal surface, abdominal wall or elsewhere after rupture or splenectomy
Usually affects young men
Common; may affect 67% of those with trauma to spleen
May also implant within pleural cavity, lung parenchyma or brain

Case reports

20 year old man with cerebral splenosis 15 years after posttraumatic splenectomy (Am J Surg Pathol 1998;22:894)
49 year old woman with abdominal splenosis mimicking colon and liver tumors (Int J Med Sci 2012;9:174)

Clinical images

Images hosted on other servers:

Autotransplantation
spleen tissues

Microscopic (histologic) description

Red and white pulp, resembling accessory spleen

Differential diagnosis

Splenic malformations

Table of Contents

Asplenia

Rare, associated with cardiac malformations (80%, usually involving atrioventricular endocardial cushion and ventricular outflow tract), situs inversus, anomalies of blood vessels, lung, abdominal viscera
Can present with pneumococcal sepsis (OPSI)

Hepatolienal fusion

Fusion of liver and spleen (Hum Pathol 1978;9:234)
Very rare

Hyposplenism

Atrophy of spleen with concomitant compromised splenic function (Lancet 2011;378:86)
Usually acquired but rare congenital forms exist (isolated congenital hyposplenia, Ivemark syndrome, hypoparathyroidism syndrome, autoimmune polyendocrinopathy candidiasis ectodermal dystrophy [APECED] syndrome, Stormorken syndrome)

Polysplenia

Multiple spleens, found as part of heterotaxy syndromes (malpositioning of organs on opposite side of body, e.g. situs inversus)
Associated with extrahepatic biliary atresia (Arch Pathol Lab Med 1980;104:212), cardiac abnormalities and developmental anomalies of pancreas, portal vein, inferior vena cava

Splenic gonadal fusion

Rare congenital anomaly in which ectopic splenic tissue unites with a gonad (< 200 cases reported)
Continuous: spleen connected to ectopic splenic mass by cord of splenic and fibrous tissue
Discontinuous: no connection between spleen and ectopic splenic mass
20% of continuous types associated with other congenital defects, including peromelus (fetus with malformed limbs) and micrognathia; also testicular ectopia, inguinal hernia
90% in males; usually left sided; usually less than 20 years old
Diagnosis: Technetium Tc 99m sulfur colloid scan
Treatment: Surgical excision of ectopic splenic tissue to prevent testicular atrophy, torsion or infarction and preserve fertility

Splenorenal fusion

May be due to splenosis after splenic trauma or splenectomy; less commonly is developmental anomaly resulting in fusion of splenic and renal tissue
May present as a renal mass or with symptoms of hypersplenism

Wandering spleen

Due to congenital loss, weakness of splenic ligaments or abnormal length of splenic vessels
Susceptible to torsion
May rarely be associated with polysplenia

Case reports

16 year old boy with chronic, painless testicular mass (Case #309)
22 year old woman with intermittent hypochondrial pain for over a year (Int J Surg Case Rep 2012;3:151)
27 year old man with bilateral cryptorchidism and nonseminomatous germ cell tumor in intra-abdominal splenic gonadal mass (Arch Pathol Lab Med 2002;126:1222)
51 year old woman with renal mass (Arch Pathol Lab Med 2003;127:e1)
56 year old man with asymptomatic testicular mass (Arch Pathol Lab Med 2003;127:e277)
62 year old woman with polysplenia with agenesis of dorsal pancreas and preduodenal portal vein presenting with obstructive jaundice (Br J Radiol 2011;84:e217)
Familial congenital asplenia (Eur J Pediatr 2010;169:315)
Woman with discontinuous type (Hum Pathol 1989;20:486)

Gross description

Splenic gonadal fusion: ectopic splenic tissue is well demarcated from gonad, only rarely is intermingling of tissue

Microscopic (histologic) description

Splenic gonadal fusion:
- Normal splenic parenchyma but may have thrombosis, calcification, fibrosis, fat degeneration, hemosiderin deposits
- Testicular tissue may be normal but may have atrophy or fibrosis of seminiferous tubules, increased Leydig cells, thrombosis of spermatic vessels or testicular tumors

Microscopic (histologic) images

Case #309

Splenic gonadal fusion

Systemic lupus erythematosus

Table of Contents

Definition / general

Most SLE patients have cervical lymphadenopathy

Case reports

32 year old woman with coexisting Kukuchi disease (Int J Dermatol 2006;45:454)
Patient with coexisting Castleman disease (J Rheumatol 1999;26:1400)

Microscopic (histologic) description

Architectural preservation but follicular hyperplasia with variable sized follicles, increased vascularity, interfollicular immunoblasts and plasma cells
Often well circumscribed areas of paracortical necrosis with necrosis of small vessels (APMIS 2001;109:141)
Occasionally DNA deposition / hematoxylin bodies (hematoxyphilic material) in stroma, sinuses and blood vessel walls
May have giant follicles (APMIS 2005;113:558), often disarray of follicular dendritic cell network (Pathol Int 2000;50:304), no / rare granulomas, no / rare neutrophils

Microscopic (histologic) images

Images hosted on other servers:

Necrotizing lymphadenopathy

Cytology description

Typical and atypical immunoblasts, plasma cells, occasional Reed-Sternberg-like cells and dispersed hematoxylin bodies (Acta Cytol 2000;44:67)

Positive stains

CD11b+ and CD15+ histiocytes
CD8+ T cells, EBV (up to 20%, Int J Surg Pathol 2005;13:273)

Differential diagnosis

Castleman disease (Pathol Res Pract 1997;193:565)
Cat scratch disease: has neutrophils
Kikuchi disease: less prominent follicular hyperplasia and interfollicular plasma cells, more prominent immunoblasts resembling lymphoma
Lymphogranuloma venereum: has granulomas
Polykaryocytes

Toxoplasmosis

Table of Contents

Definition / general

Lymphadenitis caused by infection with the protozoan Toxoplasma gondii

Essential features

Worldwide distribution:
- Toxoplasma infection is seroprevalent in approximately 33% of the world's population
- 10 - 20% of patients with acute infection may develop cervical lymphadenopathy (Centers for Disease Control DPDx: Toxoplasmosis [Accessed 6 January 2022])
- Most common parasite infection in the U.S.
Cats are the only known definitive host (Centers for Disease Control DPDx: Toxoplasmosis [Accessed 6 January 2022])
Humans infected through contaminated soil, pet litter boxes and ingesting undercooked meat
Primary infection is subclinical
- Unilateral posterior cervical lymphadenopathy is classic presentation
Infection during pregnancy can be detrimental to the fetus: congenital toxoplasmosis
Histologic triad on microscopy (Ioachim: Ioachim’s Lymph Node Pathology, 4th Edition, 2008):
- Reactive germinal centers
- Perifollicular / interfollicular epithelioid histiocytes
- Patches of monocytoid B cells

Terminology

Toxoplasma lymphadenitis
Glandular toxoplasmosis
Piringer-Kuchinka lymphadenopathy

ICD coding

ICD-10:
- B58.8 - toxoplasmosis with other organ involvement
- B58.89 - toxoplasmosis with other organ involvement

Epidemiology

Common parasite worldwide (Centers for Disease Control DPDx: Toxoplasmosis [Accessed 6 January 2022])
- Prevalent in warm and humid climates
- Affects children and young adults most commonly
- No gender predilection
- 1.9% IgM and 32.9% IgG seroprevalence globally (Sci Rep 2020;10:12102)
Most common parasitic infection in the U.S.
- 11% of U.S. population greater than 6 years have been infected with T. gondii (Centers for Disease Control DPDx: Toxoplasmosis [Accessed 6 January 2022])
- Humans can become infected by (Centers for Disease Control DPDx: Toxoplasmosis [Accessed 6 January 2022]):
  - Eating undercooked meat of animals harboring tissue cysts
  - Consuming food or water contaminated with cat feces
  - Exposure to environmental samples
    - Fecal contaminated soil
    - Changing pet cat litter box
  - Blood transfusion or organ transplantation
  - Transplacental transmission from mother to fetus
    - Greatest risk of infection in first trimester
    - Risk of stillbirth in seropositive mothers
    - Every year about 400 - 4,000 children are infected at birth in the U.S. (Am Fam Physician 2003;67:2131)
  - Often an opportunistic infection of immunocompromised patients
    - Infection may result from reactivation in patients with cancer or diabetes
  - Asymptomatic infection of immunocompetent individuals

Sites

Toxoplasma gondii is a protozoan which can invade many cell types (Ioachim: Ioachim’s Lymph Node Pathology, 4th Edition, 2008)
- Lymph nodes are commonly affected: unilateral posterior cervical node is characteristic
- Other lymph nodes can often be involved
- Generalized lymphadenopathy or hepatosplenomegaly unusually occurs
In the human host, the parasites form tissue cysts in skeletal muscle, myocardium, brain and eyes; these cysts may remain throughout the life of the host

Pathophysiology

Cats are the only known definitive host for sexual stage of reproduction (Centers for Disease Control DPDx: Toxoplasmosis [Accessed 6 January 2022])
Cats become infected after consuming intermediate hosts harboring tissue cysts or by ingestion of sporulated oocysts
Trophozoites multiply in intestine and produce oocytes
Unsporulated oocysts are shed in the cat's feces
- Oocysts are usually shed for 1 - 3 weeks and in large numbers, up to several million (Lancet 2004;363:1965)
- Oocysts take 1 - 5 days to sporulate in the environment and become infective
Intermediate hosts in nature (including humans, birds and rodents) become infected after ingesting soil, water or plant material contaminated with oocysts
- Through ingestion of contaminated soil or water
- Ingestion of infected, undercooked meat
Oocysts are degraded by digestive enzymes and transform into trophozoites
- Tachyzoites are the crescentic / oval shaped, rapidly multiplying stage of the parasite (Lancet 2004;363:1965)
- Tachyzoites are released into the intestine
- Enter all nucleated cells, form cytoplasmic vacuoles, replicate, where finally host cells are disrupted, releasing tachyzoites (Lancet 2004;363:1965)
- Carried by macrophages and spread by lymphatics and blood vessels to infect tissues
- Tachyzoite form leads to the strong inflammatory response and tissue destruction, causing the clinical manifestations of the infection (Lancet 2004;363:1965)
- Tachyzoites are transformed into bradyzoites under the pressure of the immune response to form cysts (thousands of bradyzoites per cyst) and survive the lifetime of the host

Etiology

Toxoplasmosis gondii infection

Diagrams / tables

Images hosted on other servers:

Life cycle

Clinical features

Immunocompetent individuals:
- Asymptomatic infection with or without nontender, nonsuppurative lymphadenopathy (Lancet 2004;363:1965)
- Mild illness in the form of malaise, fever, myalgia (10 - 20%) (Medeiros: Diagnostic Pathology - Lymph Nodes and Extranodal Lymphomas, 2nd Edition, 2017)
- Disease is usually benign and self limited with resolution in weeks or months
Immunocompromised patients (Centers for Disease Control DPDx: Toxoplasmosis [Accessed 6 January 2022]):
- Caused by reactivation of chronic infection
- Often have central nervous system (CNS) disease
- Systemic disease occurs in severe immunodeficiency
  - Myocarditis, pneumonitis, chorioretinitis, encephalitis
  - In AIDS, toxoplasmic encephalitis is the most common cause of intracerebral mass lesions
Congenital toxoplasmosis:
- In the U.S., the age adjusted seroprevalence among women of childbearing age (15 - 44 years) was 9% in 2009 to 2010 (Am J Trop Med Hyg 2014;90:1135)
- Third trimester has the highest risk of transmission
- First trimester poses greatest damage to fetus
- Neonatal clinical manifestations vary widely:
  - Hydrocephalus, microcephaly, intracranial calcifications, chorioretinitis, strabismus, blindness, epilepsy, psychomotor or mental retardation, petechia due to thrombocytopenia and anemia (Lancet 2004;363:1965)
- In congenital infection, patients are often asymptomatic until the second or third decade of life, when lesions develop in the eye
Rarely, ocular infection may lead to visual loss
Ocular Toxoplasma infection, an important cause of retinochoroiditis in the U.S., can be the result of congenital infection or infection after birth
- T. gondii chorioretinitis develops in ~21,000 persons each year in the U.S. (Am J Trop Med Hyg 2014;90:794)

Diagnosis

Diagnosis is usually achieved by serology, although tissue cysts may be observed in stained biopsy specimens
Diagnosis of congenital infections can be achieved by detecting T. gondii DNA in amniotic fluid using molecular methods such as PCR (Centers for Disease Control DPDx: Toxoplasmosis [Accessed 6 January 2022])

Laboratory

Sabin-Feldman dye test
Highly sensitive and specific
Requires live organisms so has been replaced with indirect immunofluorescence (IF)
IF and enzyme immunoassays measure antibodies to T. gondii
Can measure immunoglobulin M (IgM) and IgG antibodies to cell wall antigens
IgM antibodies detected within a few days after infection
IgG antibodies detected at 6 - 8 weeks
Latex agglutination test and enzyme linked immunosorbent assay (ELISA)
PCR can be used to amplify T. gondii DNA
References: Ioachim: Ioachim’s Lymph Node Pathology, 4th Edition, 2008, Medeiros: Diagnostic Pathology - Lymph Nodes and Extranodal Lymphomas, 2nd Edition, 2017

Prognostic factors

Immunocompetent individuals (Lancet 2004;363:1965):
- Self limiting infection
Immunodeficient patients:
- Risk of disseminating infection
- Almost always due to reactivation of chronic infection (Lancet 2004;363:1965)
  - Encephalitis, chorioretinitis, pneumonia, multiple organ involvement or death

Case reports

11 month old HIV / AIDS girl with cerebellar toxoplasmosis (Neurol Sci 2012;33:1423)
29 year old man with disseminated toxoplasmosis associated with hemophagocytic lymphohistiocystosis after kidney transplant (Transpl Infect Dis 2019;21:e13154)
33 year old pregnant woman with axillary lymphadenopathy (Ann R Coll Surg Engl 2020;102:e167)
Squash preparation of a brain biopsy (Creepy Dreadful Wonderful Parasites: Case of the Week 519 [Accessed 6 January 2022])

Treatment

Combination therapy of pyrimethamine and sulfadiazime with folinic acid (Centers for Disease Control DPDx: Toxoplasmosis [Accessed 6 January 2022], Lancet 2004;363:1965)

Microscopic (histologic) description

Lymph node
- Preserved architecture
- Capsule / pericapsule: with minimal involvement
- Sinuses with distended monocytoid B cells
  - Large cells with sharp cell boarders, clear cytoplasm and darkly stained nuclei
- Follicles with florid reactive follicular hyperplasia
  - Numerous tingible body macrophages
  - Germinal centers with ragged, indistinct margins
- Interfollicular and paracortical areas with epithelioid histiocytes
  - Invade germinal centers
  - Form collections of
  - Medullary cords with plasma cells and immunoblasts
  - Toxoplasma cysts and bradyzoites are rare (1% of cases)
- References: Ioachim: Ioachim’s Lymph Node Pathology, 4th Edition, 2008, Medeiros: Diagnostic Pathology - Lymph Nodes and Extranodal Lymphomas, 2nd Edition, 2017

Microscopic (histologic) images

Contributed by Tayler A. van den Akker, M.D.

Histologic triad

Follicular hyperplasia

Reactive follicles, monocytoid cells

Epithelioid histiocytes

Epithelioid histiocytes, monocytoid B cells

Toxoplasma special stain

AFIP images

Toxoplasmic lymphadenitis

Monocytoid B cells

Virtual slides

Images hosted on other servers:

Brain, toxoplasmosis

Cytology description

Cytologic features based on fine needle aspiration biopsy:
- Polymorphous cell population
  - Small and large lymphocytes
  - Clusters of epithelioid histiocytes (microgranulomas)
- Parasitic cysts can be detected, rarely
References: Ioachim: Ioachim’s Lymph Node Pathology, 4th Edition, 2008, Medeiros: Diagnostic Pathology - Lymph Nodes and Extranodal Lymphomas, 2nd Edition, 2017

Cytology images

Contributed by Bobbi Pritt, M.D.

Tachyzoites of Toxoplasma gondii

Positive stains

Anti-T. gondii antibodies can detect parasites in tissue

Negative stains

Periodic acid Schiff

Electron microscopy description

Distinctive features on electron microscopy:
- Paired organelles, dense bodies
- Concoid nuclei at rounded posterior end
- Double layered pellicles
References: Ioachim: Ioachim’s Lymph Node Pathology, 4th Edition, 2008, Medeiros: Diagnostic Pathology - Lymph Nodes and Extranodal Lymphomas, 2nd Edition, 2017

Electron microscopy images

Images hosted on other servers:

Toxoplasma tissue cyst within an intact neurone

Molecular / cytogenetics description

Polymerase chain reaction (PCR)
- Toxoplasma genomes are detected by conventional and nested PCR

Videos

Classic histomorphology of toxoplasma lymphadenitis

Great teaching case of cerebral toxoplasmosis

Sample pathology report

Lymph node, right inguinal, excisional biopsy:
- Reactive lymphoid follicular hyperplasia, monocytoid B cell hyperplasia and aggregates of epithelioid histiocytes, suggestive of toxoplasma lymphadenitis (see comment)
- Comment: The classic triad present in this case (follicular hyperplasia, intrafollicular clusters of epithelioid cells and aggregates of monocytes) is reported to have a 91% specificity for toxoplasma lymphadenitis. There is no evidence of lymphoma. The morphologic findings are very suggestive of toxoplasmosis. Serologic studies are recommended to confirm the diagnosis.
- Microscopic description:
  - Right cervical lymph node: The lymph node is enlarged and has a preserved architecture with a thin capsule and open sinuses. There is evidence of reactive lymphoid follicular hyperplasia. In addition, numerous small, well defined aggregates of epithelioid histiocytes are noted, including within the germinal centers. Focally, monocytoid B cell hyperplasia is present. There is no morphologic evidence of lymphoma.
  - Special stains for AFB and GMS are negative for microorganisms.
  - Immunohistochemical staining performed on block A1 shows that the CD20+ B cells are confined to the germinal centers, while the CD3+ T cells are interfollicular. Monocytoid B cells also express CD20. Immunohistochemical stain for toxoplasma is positive. There is no staining for cytomegalovirus. In situ hybridization for EBV encoded RNA (EBER) is negative.
  - Note: Control slides show appropriate reactivity.
  - Left inguinal lymph node for flow cytometry:
    - The following analytes were tested: Kappa, Lambda, CD5, CD23, CD10, CD20, CD19, CD45, sCD3, CD57, CD4, CD7, CD8, CD2 (total of 14)
- Flow cytometry interpretation:
  - Cytospin: Morphologic evaluation of Diff-Quik stained cytospin shows no increase in atypical lymphocytes.
  - Flow cytometry: Analysis was performed with the above antigens. The T cells show no loss of pan T cell antigens. The B cells are polytypic. The findings provide no evidence of a non-Hodgkin lymphoma.

Differential diagnosis

Sarcoid lymphadenopathy:
- Well formed granulomas with multinucleated giant cells
- Usually lacks monocytoid B cells (Medeiros: Diagnostic Pathology - Lymph Nodes and Extranodal Lymphomas, 2nd Edition, 2017)
HIV lymphadenitis:
- Early stages of HIV lymphadenitis may mimic toxoplasmosis
- Pattern A: aggregates of monocytoid cells and florid follicular hyperplasia
- May lack clusters of epithelioid cells or may be present
- HIV p24 stains positive
Leishmaniasis lymphadenitis:
- Histomorphologically very similar
- Multinucleated giant cells present
- Necrosis and fibrosis present with Leishmania infection
- Histiocytes contain Leishman-Donovan bodies within the cytoplasm (Medeiros: Diagnostic Pathology - Lymph Nodes and Extranodal Lymphomas, 2nd Edition, 2017)
- Electron microscopy demonstrates presence of rod shaped kinetoplast and target shaped basal body
Dermatopathic lymphadenopathy:
- Paracortical distribution of of histiocyte collections, pigment and lipids
- Histiocytes with twisted nuclei
- S100+, CD1a (+ in a subset) (Medeiros: Diagnostic Pathology - Lymph Nodes and Extranodal Lymphomas, 2nd Edition, 2017)

Board review style question #1

Which feature is included in the the classic histologic pattern of toxoplasmosis lymphadenitis?

Fibrosis with necrosis
Florid follicular hyperplasia, perifollicular epithelioid histiocytes and patches of monocytoid B cells
Necrosis without neutrophils
Reactive follicular hyperplasia, T cells and a lack of histiocytes
Well formed granulomas with multinucleated giant cells

Board review style answer #1

B. The histologic triad of Toxoplasma lymphadenitis includes reactive follicular hyperplasia, perifollicular / interfollicular epithelioid histiocytes and aggregates of monocytoid B cells.

Comment Here

Reference: Toxoplasmosis

Board review style question #2

Which of the following statements is correct regarding the life cycle of Toxoplasma gondii?

Although prevalent worldwide, T. gondii is relatively uncommon in the U.S.
Cysts containing tachyzoites localize in tissues (skeletal muscle, brain and eyes)
Oocysts are shed, unsporulated, in the feces of cats and sporulate in the environment to become infective
Rodents, cats and birds are definitive hosts, while humans are intermediate hosts

Board review style answer #2

C. Oocysts are shed, unsporulated, in the feces of cats and sporulate in the environment to become infective. Cats are the only definitive host, while birds, rodents and humans are intermediate hosts. T. gondii is the most common parasite in the U.S. Oocysts transform into tachyzoites after ingestion. Tachyzoites localize in tissues and develop into tissue cysts containing bradyzoites.

Comment Here

Reference: Toxoplasmosis

Uncommon infections

Table of Contents

AIDS

Prior to highly active antiretroviral therapy (HAART), typical findings were white pulp depletion, hemosiderin deposition, spindle cell proliferation and perivascular hyalinization; also infectious and malignant infiltrates (Mod Pathol 2002;15:406)
Post-HAART findings include less frequent white pulp depletion but similar rates of splenic involvement by atypical mycobacteria and CMV in those with systemic disease

Hantavirus

Rare but deadly disease transmitted to humans through aerosolized virus from rodent urine, droppings or saliva
Usually causes pulmonary syndrome with acute respiratory distress syndrome
Gross description: dense, rubbery and heavy lungs floating within yellow serous fluid within pleural cavity; no specific splenic findings
Micro description: generalized capillary dilation and edema, immunoblasts in red pulp and periarteriolar sheaths of spleen, occasional prominent and swollen endothelial cells

Mycobacteria

Small, weakly gram positive bacteria that are acid fast (due to mycolic acid in cell wall) and slow growers (3 - 4 weeks to develop a visible colony)
Mycobacterium avium complex (MAC) consists of M. avium and M. intracellulare, which cause disseminated disease associated with advanced HIV; cause pulmonary disease and cervical lymphadenitis in immunocompetent individuals
Disseminated MAC is most common systemic bacterial infection in HIV+ patients
Spleen may show presence of pseudo-Gaucher cells (J Clin Pathol 2005;58:1113)
Treatment: clarithromycin or azithromycin plus ethambutol, for life

Parvovirus

Causes "fifth" disease in children, a mild illness with a "slapped cheek" facial rash
Pregnant women may pass virus to fetus, where it causes marked fetal anemia and hydrops
Attacks erythroblasts, affecting those with minimal reserve (sickle cell patients, fetuses)

Typhoid fever

Due to Salmonella typhi infection
Causes inflammatory destruction of GI tract mucosa
Bacteremic phase may cause splenomegaly with destruction of splenic vessels

Case reports

37 year old white man with advanced HIV and splenomegaly (Arch Pathol Lab Med 2001;125:697)

Vascular transformation of sinuses

Table of Contents

Definition / general | Case reports | Microscopic (histologic) description | Microscopic (histologic) images | Differential diagnosis

Definition / general

Also called nodal angiomatosis
Usually found incidentally after resection of a nearby tumor
Benign; all ages
Due to obstruction of lymphatic efferent vessels or venous obstruction (Arch Pathol Lab Med 1990;114:656) or perhaps other angiogenic factors

Case reports

57 year old man with gastric cancer; lymph nodes removed during surgery (Case of the Week #405)
Man with congestive heart failure (G Ital Nefrol 2002;19:60)

Microscopic (histologic) description

Subcapsular and medullary sinuses contain complex network of anastomosing blood vessels of variable sizes with fibrosis
May have irregularly branching vascular slits accompanied by pericytes with maturation towards well formed vascular channels, may have extravasated red blood cells and interstitial fibrin deposits
Reactive, not neoplastic
May also have spindle cell nodules confined to sinus (associated with retroperitoneal nodes removed for renal cell carcinoma)
Lymphoid parenchyma may show atrophy
No atypia, no PAS+ hyaline globules, no capsular involvement

Microscopic (histologic) images

Case #405

AFIP images

Vascular transformation of sinuses

Intra-abdominal lymph node

Nodular spindle cell vascular transformation

Differential diagnosis

Kaposi sarcoma: involvement throughout lymph node including capsule, not just sinuses; well formed and curved spindle cell fascicles, vascular slits are nonbranching; atypia and PAS+ hyaline globules, no fibrosis, patients are HIV+ or African children (Am J Surg Pathol 1991;15:732)

WHO system for reporting lymph node cytopathology (pending)

[Pending]

Recent Lymph nodes & spleen, nonlymphoma Pathology books

Ashton-Key: 2016

Auerbach: 2022

Crane: 2021

Duffield: 2020

Hsi: 2017

Hudnall: 2019

Jaffe: 2016

Jiang: 2023

King: 2023

Medeiros: 2017

Medeiros: 2021

Medeiros: 2023

Naeim: 2018

Wang: 2020

Find related Pathology books: hematopathology, cytopathology

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