2
- Composed of variable proportions of atypical
spindle cells, adipocytes, univacuolated or
multivacuolated lipoblasts, pleomorphic to
multinucleated cells, and myxoid to collag-
enous stroma.
- Lack of MDM2 or CDK4 amplication.
- Rb expression is generally lost.
- Low rate of local recurrence (10%–15%); no
known risk of dedifferentiation.
• Myxoid pleomorphic liposarcoma
- Occurs predominantly in children and young
adults with a predilection for the mediastinum.
- Admixture of areas resembling myxoid
liposarcoma with more cellular areas contain-
ing overt nuclear pleomorphism, which resem-
bles pleomorphic liposarcoma.
- Lacks recurrent chromosomal changes, namely
MDM2 amplication and DDIT3 gene fusion.
- Clinical behavior akin to pleomorphic liposar-
coma.
Fibroblastic/myofibroblastic tumors
• EWSR1::SMAD4 positive broblastic tumor
- Small dermal and subcutaneous acral nodule,
with indolent biological behavior.
- Histologic zonation with acellular hyalinized
center and peripheral fascicular monomorphic
spindle cell growth.
- Diffuse ERG nuclear expression in the absence
of CD34 and SMA expression.
- EWSR1::SMAD4 fusion.
• Angiobroma of soft tissue
- Benign neoplasm with rare local recurrence.
- Uniformly bland short spindle cells in variably
myxoid to collagenous stroma, with promi-
nent vascular network of small thin-walled
branching blood vessels (Fig. 1).
- NCOA2 gene rearrangements in up to 80%.
• Supercial CD34-positive broblastic tumor
- Rare, slow-growing, indolent neoplasm.
- Supercial location, typically in the lower
extremities.
- Large eosinophilic cells with granular to glassy
cytoplasm; marked pleomorphism with low
mitotic count (Fig. 2).
- CD34 and frequent keratin expression.
Issue 20 || November 2022
WHAT’S NEW IN SOFT
TISSUE AND BONE
PATHOLOGY 2022–
UPDATES FROM THE
WHO CLASSIFICATION
5TH EDITION
Erica Y. Kao
1
, Jose G. Mantilla
2
1
Department of Pathology, Brooke Army Medical
Center, San Antonio, TX, USA
2
Department of Pathology, University of Washington,
Seattle, WA, USA
Corresponding Author: Erica Y. Kao, MD
Department of Pathology, Brooke Army Medical
Center, San Antonio, Texas, USA
E-mail: erica.kao.mil@health.mil
ORCID
Erica Y. Kao
https://orcid.org/0000-0001-6005-3559
Jose G. Mantilla
https://orcid.org/0000-0003-4752-6459
Abstract
The 2020 release of the WHO Classication of
Soft Tissue and Bone Tumors, 5th edition,
contains several changes driven by new knowl-
edge in the eld. These include reclassication of
some entities, renement of risk classication
systems, and the inclusion of novel disease
processes, many of which are driven by recurrent
gene fusions. The most notable changes are
described here.
SELECT NEW ENTITIES
Lipomatous tumors
• Atypical spindle cell/pleomoprhic lipomatous
tumor
Smooth muscle tumors
• Inammatory leiomyosarcoma
- Rare, and thought to be relatively indolent
compared to conventional leiomyosarcoma.
- Typically arise in the deep extremities.
- Variably atypical eosinophilic spindle cells in
fascicles, with mitotic activity and prominent,
usually diffuse, mixed (predominantly mono-
nuclear) inammatory inltrate.
- Near-haploid karyotype.
• EBV-associated smooth muscle tumor
- Associated with EBV infection, usually in the
setting of immunosuppression.
- Can arise in any anatomic location, most often
in visceral sites and CNS.
- Prognosis depends on the patient’s immune
condition. Most tumors do not metastasize.
- Cytologic atypia is highly variable. In half of
cases, a second population of more primitive
appearing round cells are seen. T-cell inam-
matory inltrates are common.
- Invariably positive expression of EBER.
PathologyOutlines.com
WHAT’S NEW
IN PATHOLOGY?
Sponsored by an unrestricted grant from Roche
Fig. 1. Angiofibroma of soft tissue.
Fig. 2. Superficial CD34-positive fibroblastic tumor.
3
to the ETS gene family, most commonly
NFATC2 or PATZ1 genes.
- Tumors with EWSR1::NFATC2 consist of
round or spindled cells arranged in cords, nests
and trabeculae in a myxohyaline background
(Fig. 3). They may have focal dot-like keratin
and CD138 expression. They may morpho-
logically mimic myoepithelial neoplasms or
ossifying bromyxoid tumor, among others.
- Sarcomas with EWSR1::PATZ1 fusion have a
broad morphologic spectrum. They may have
round to spindle cells within a brous stroma.
Co-expression of myogenic and nerve sheath
markers has been described.
• CIC-rearranged sarcoma
- Round cell sarcoma characterized by CIC gene
fusions, most commonly CIC::DUX4. Other
fusion partners include FOXO4, LEUTX,
NUTM1 and NUTM2A.
- Composed of sheets of large round cells with
mild nuclear pleomorphism, lightly eosino-
philic cytoplasm, geographic necrosis and
brisk mitotic activity (Fig. 4).
- Immunohistochemically, they show variable
CD99 expression, nuclear WT1 and DUX4
reactivity.
- Response to chemotherapy is poor compared
to Ewing sarcoma and BCOR fusion sarcomas.
• Sarcoma with BCOR alterations
- Primitive round cell sarcoma with BCOR gene
fusions, most commonly BCOR::CCNB3,
followed by BCOR internal tandem duplication.
- Composed of primitive round to spindled cells
in nests, sheets or fascicles in variably myxoid
stroma, which may morphologically resemble
synovial sarcoma. Their clinical response to
chemotherapy is favorable when compared to
Ewing sarcoma and CIC-fusion sarcomas.
- Sarcomas with BCOR fusion are slightly more
common in bone and tend to arise in patients
younger than 20 years. On the other hand,
sarcomas with BCOR internal tandem duplica-
tion tend to arise in the soft tissues of the
trunk, retroperitoneum, and head and neck.
These usually occur within the rst year of life
or may present at birth.
Fig. 3. Round cell sarcoma with EWSR1::non-ETS
fusions.
Fig. 4. CIC-rearranged sarcoma.
Vascular tumors
• Anastomosing hemangioma
- Benign vascular neoplasm. Often arises in
viscera and can be multifocal.
- Thin-walled anastomosing vessels lined by
hobnail endothelial cells. Vascular thrombi are
typical. Loosely lobulated architecture with
focal inltration into adjoining tissue. May be
associated with a medium-caliber vessel.
- Activating mutations in GNAQ or GNA14.
• Epithelioid hemangioendotehlioma with
YAP1::TFE3 gene fusion
- Considered to have a generally more aggressive
behavior.
- Tends to have more solid growth and be
vasoformative, compared to cases harboring
WWTR::CAMTA1 fusion.
Tumors of uncertain differentiation
• Kinase gene-rearranged spindle cell neoplasms
- Outside of infantile brosarcoma, this repre-
sents an emerging group of tumors with a
wide morphologic spectrum.
- Most tumors have co-expression of S100 and
CD34 in the absence of SOX10.
- They can resemble lipobromatosis or can be
composed of monomorphic spindle cells with
prominent collagen deposition and hyaliniza-
tion; amianthoid-like bers and inltrative
growth may also be present.
- Harbor gene fusions involving kinase genes,
such as NTRK, ALK, RAF1 and BRAF.
Undifferentiated round cell sarcomas
Due to the recent expansion in molecular studies,
multiple recurrent gene fusions have been
described in previously unclassied round cell
sarcomas. These lesions have been shown to have
particular clinical and morphologic features.
These include:
• Round cell sarcoma with EWSR1::non-ETS
fusions
- Round and spindle cell sarcomas with fusions
in EWSR1 or FUS with partners unrelated
Dr. Kao has been an author for
PathologyOutlines since 2020. She is currently
a staff pathologist at Brooke Army Medical
Center in San Antonio, TX in where she
practices Bone and Soft Tissue pathology and
is an Assistant Professor for the Uniformed
Services University of the Health Sciences. She
obtained her M.D. at the Uniformed Services
University of the Health Sciences in Bethesda,
MD, completed her residency in AP/CP
Pathology at Brooke Army Medical Center,
and fellowship in Bone and Soft Tissue
Pathology at the University of Washington.
Dr. Mantilla has been an author for
PathologyOutlines since 2019 and part of the
PathologyOutlines editorial board since
December 2020. He is an Assistant Professor
of Laboratory Medicine and Pathology and
Program Director of the Surgical Pathology
fellowship at the University of Washington in
Seattle. He obtained his M.D. at the Ponticia
Universidad Javeriana (Bogotá, Colombia),
followed by a residency in Anatomic and
Clinical Pathology at Monteore Medical
Center in New York and fellowships in
Surgical Pathology and Bone and Soft Tissue
Pathology at the University of Washington.
Meet the Author
CHANGES IN NOMENCLATURE
• Mammary-type myobroblastoma has been
renamed as myobroblastoma.
• Melanotic schwannoma has been renamed to
malignant melanotic nerve sheath tumor. This
change better reects its aggressive clinical
behavior.
OTHER CHANGES
• Solitary brous tumor
- Risk stratication based on age, tumor size,
mitotic activity, and necrosis is recommended
(Mod Pathol 2017;30:1433-1442).
• Spindle cell/sclerosing rhabdomyosarcoma
- Subclassication depends on the presence of
genetic alterations associated with prognosis.
- Tumors with VGL2L, NCOA2 and CITED2
gene rearrangements typically arise in infants
and have favorable prognosis.
- Tumors with MYOD1 mutations usually arise
in adolescents and adults, and have unfavorable
prognosis.
- Tumors with TFCP2/NCOA2 gene rearrange-
ments can be intraosseous.