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The 2020 WHO Classification of Tumors of Soft Tissue: Selected Changes and
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 REVIEW ARTICLE
The 2020 WHO Classification of Tumors of Soft Tissue:
Selected Changes and New Entities
Joon Hyuk Choi, MD, PhD* and Jae Y. Ro, MD, PhD†
Downloaded from http://journals.lww.com/anatomicpathology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 08/26/2021
Abstract: Soft tissue tumors are a relatively rare and diagnostically
challenging group of neoplasms that can have varying lines of dif-
ferentiation. Accurate diagnosis is important for appropriate
treatment and prognostication. In the 8 years since the publication
of the 4th Edition of World Health Organization (WHO) classi-
fication of soft tissue tumors, significant advances have been made
in our understanding of soft tissue tumor molecular biology and
diagnostic criteria. The 5th Edition of the 2020 WHO classification
of tumors of soft tissue and bone incorporated these changes.
Classification of tumors, in general, but particularly in soft tissue
tumors, is increasingly based on the molecular characteristics of
tumor types. Understanding tumor molecular genetics improves
diagnostic accuracy for tumors that have been difficult to classify on
the basis of morphology alone, or that have overlapping morpho-
logic features. In many large hospitals in the United States and
Europe, molecular tests on soft tissue tumors are a routine part of
diagnosis. Therefore, surgical pathologists should be familiar with
newly emerging molecular genetic techniques in clinical settings. In
the near future, molecular tests, particularly in soft tissue tumor
diagnosis, will become as routine during diagnosis as immunohis-
tochemistry is currently. This new edition provides an updated
classification scheme and essential diagnostic criteria for soft tissue
tumors. Newly recognized entities and subtypes of existing tumor
types, several reclassified tumors, and newly defined molecular and
genetic data have been incorporated. Herein, we summarize the
updates in the WHO 5th Edition, focusing on major changes in each
category of soft tissue tumor, and the newly described tumor entities
and subtypes.
Key Words: WHO classification, soft tissue, tumor, sarcoma,
genetics
(Adv Anat Pathol 2021;28:44–58)
T he 5th edition of the World Health Organization
(WHO) classification of soft tissue and bone was pub-
lished in April 2020.1 Since the publication of the 4th edition
in February 2013,2 considerable advances have been made
in our understanding of many soft tissue tumors, namely in
the form of newly recognized molecular and genetic alter-
ations, immunohistochemical markers, and biological
mechanisms. The new 2020 WHO classification follows the
same organization as the previous (4th) edition, describing
the following lineage groups: (1) adipocytic tumors, (2)
From the *Department of Pathology, Yeungnam University College of
Medicine, Daegu, South Korea; and †Department of Pathology and
Genomic Medicine, Houston Methodist Hospital, Weill Medical
College of Cornell University, Houston, TX.
The authors have no funding or conflicts of interest to disclose.
Reprints: Joon Hyuk Choi, MD, PhD, Department of Pathology,
Yeungnam University College of Medicine, 170 Hyeonchung-ro,
Namgu, Daegu 42415, South Korea (e-mail: joonhyukchoi@
ynu.ac.kr).
All figures can be viewed online in color at www.anatomicpathology.com.
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
44 | www.anatomicpathology.com Adv Anat Pathol  Volume 28, Number 1, January 2021
Copyright r 2020 Wolters Kluwer Health, Inc. All rights reserved.
fibroblastic and myofibroblastic tumors, (3) so-called fibro-
histiocytic tumors, (4) vascular tumors, (5) pericytic (peri-
vascular) tumors, (6) smooth muscle tumors, (7) skeletal
muscle tumors, (8) gastrointestinal stromal tumors (GISTs),
(9) chondro-osseous tumors, (10) peripheral nerve sheath
tumors, and (11) tumors of uncertain differentiation. A new
chapter describing undifferentiated small round cell sarco-
mas of bone and soft tissue has been introduced.
The WHO classification of soft tissue tumors serves as
a guide to clarify diagnoses among a multidisciplinary team
composed of pathologists, radiologists, and clinicians. In the
5th edition, the format of the book has been updated,
including a change from 3 to 2 columns and the inclusion of
larger, high-quality images. An updated section, including
pathogenesis, cytology, diagnostic molecular pathology,
essential diagnostic criteria, and staging, has been added for
each tumor type. Many new entities and subtypes have been
described in the 5th edition. Understanding the classification
of soft tissue tumors is necessary for accurate diagnosis,
correct patient management, and prognostication. Herein,
we review the major changes in each category of soft tissue
tumor and briefly explain newly described tumor entities
and subtypes on the basis of the 2020 WHO classification of
soft tissue tumors.
WHO CLASSIFICATION OF SOFT TISSUE TUMORS
Adipocytic Tumors
Selected Changes
In the 2020 WHO classification, atypical spindle cell/
pleomorphic lipomatous tumor (ASPLT) is newly described
in the category of adipocytic tumors. Myxoid pleomorphic
liposarcoma (MPLPS) is classified as a new distinct subtype
of LPS. Epithelioid LPS is classified as a distinctive variant
of pleomorphic LPS.3 Extrarenal angiomyolipoma was
deleted in this category and reclassified in the category of
tumors of uncertain differentiation and is now referred to by
“angiomyolipoma.” Extra-adrenal myelolipoma was remo-
ved in this edition. Newly described entities and subtypes,
reclassified tumors, and removed tumors are summarized in
Tables 1–3, respectively.
Atypical Spindle Cell/Pleomorphic Lipomatous Tumor
ASPLT is a benign adipocytic neoplasm, characterized
by ill-defined tumor margins and the presence of variable
proportions of mild to moderately atypical spindle cells,
adipocytes, lipoblasts, pleomorphic cells, multinucleated
giant cells, and a myxoid or collagenous extracellular
matrix.4 This tumor type has been previously referred to a
variety of terms, including spindle cell LPS. ASPLT occurs
predominantly in middle-aged adults but can affect patients
of any age. There is a slight male predominance. The
 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Adv Anat Pathol

TABLE 1. Selected New Tumor Entities and Subtypes in the 2020 WHO Classification of Soft Tissue Tumors
Biological New Entities and Immunohistochemical
Tumor Category Potential Subtypes Clinical Features Histologic Features Markers Molecular Features
Adipocytic tumors Benign Atypical spindle cell/ Middle-aged adults, slight male Atypical spindle cells, adipocytes, CD34 (+), S100 protein ( ± ), Deletions or losses of
pleomorphic predominance, wide anatomic lipoblasts, pleomorphic cells, loss of RB expression in 13q14, including


lipomatous tumor location, most common myxoid to collagenous 50%-70%, MDM2 (−) RB1, lack of MDM2

Volume 28, Number 1, January 2021

Copyright r 2020 Wolters Kluwer Health, Inc. All rights reserved.

locations are hand, foot, thigh extracellular matrix amplification

Malignant Myxoid pleomorphic Children and young adults, Admixture of areas resembling MDM2 (−), CDK4 (−), Absence of DDIT3
liposarcoma female predominance, a low-grade myxoid S100 protein ( ± ) rearrangement and
predilection for mediastinum liposarcoma and areas MDM2
resembling pleomorphic amplification,
liposarcoma inactivation of RB1
Fibroblastic and Benign EWSR1-SMAD3– A broad age range, female Distinctive zonation pattern ERG (+), SMA (−), EWSR1-SMAD3
myofibroblastic positive fibroblastic predominance, small with central acellular CD34 (−) fusion
tumors tumor (emerging) superficial nodule in hand hyalinized area and
and foot peripheral bland spindle cells’
proliferation
Benign Angiofibroma of soft Middle-aged adults, female Bland and uniform short spindle EMA ( ± ), CD34 ( ± ) AHRR-NCOA2 fusion
tissue predominance, lower cells, myxoid or collagenous
extremities, often adjacent to stroma, small thin-walled
large joint such as knee branching blood vessels
Intermediate Superficial Middle-aged adults, slight male Superficial location, large Diffuse CD34 expression, PRDM10
(rarely CD34-positive predominance, lower pleomorphic cells with cytokeratin (+) in ~70% rearrangements
metastasizing) fibroblastic tumor extremities, especially thigh, granular to glassy cytoplasm, (subset)
arm, buttock, shoulder but very low mitotic count
Vascular tumors Benign Anastomosing Predominantly adults, but can Anastomosing vessels lined by CD31 (+), CD34 (+), Mutation in GNAQ or
hemangioma arise in pediatric age, hobnail endothelial cells, ERG (+) GNA14
genitourinary tract, intracytoplasmic hyaline
retroperitoneum, globules, extramedullary
paravertebral soft tissue hematopoiesis
Smooth muscle Intermediate EBV-associated smooth Wide age range, arise in patients Fascicles of spindle cells with SMA (+) diffusely, desmin MYC overexpression,

The 2020 WHO Classification of Tumors of Soft Tissue

tumors muscle tumor with immunosuppression, elongated nuclei and (+), caldesmon (+), AKT/mTOR
visceral organs, soft tissue, eosinophilic cytoplasm, but EBER (+) by in situ pathway activation
skin more primitive-appearing hybridization
round cells in about 50%
www.anatomicpathology.com

Malignant Inflammatory Adults, with a male Eosinophilic spindle cells with SMA (+) diffusely, desmin Near-haploid genotype,
leiomyosarcoma predominance, lower limb, blunt-ended nuclei, diffuse (+), caldesmon (+) with or without
trunk, retroperitoneum, inflammatory cell infiltrate, subsequent whole-
visceral organs predominantly genome doubling(s)
lymphoplasmacytic cells
Skeletal muscle Malignant Congenital spindle cell Infants or below 3 y of age, Spindle cells with ovoid, Desmin (+) diffusely, Gene fusions involving
tumors RMS with VGLL2/ located in the soft tissues monomorphic nuclei and pale myogenin (+) variably VGLL2, SRF,
NCOA2/CITED2 eosinophilic cytoplasm, TEAD1, NCOA2,
rearrangement fibrous stroma, but more and CITED2
cellular (subset)
Malignant MYOD1-mutant spindle Any age, affect equally children Spindle cells with ovoid Desmin (+) diffusely, MYOD1 p.Leu122Arg
cell/sclerosing RMS and adults, female monomorphic nuclei and MYOD1 (+) diffusely, mutation
predominance, head and eosinophilic cytoplasm, myogenin (+) patchy
neck, extremities, trunk fascicular pattern, necrosis,
| 45

brisk mitotic activity

Choi and Ro Adv Anat Pathol  Volume 28, Number 1, January 2021

NTRK1 fusions with a

anatomic distribution is wide, with the most common

fused to the TFCP2

Molecular Features
EWSR1 or FUS gene

PRKAR1A mutation

variety of partners
locations being the hand, foot, and thigh. Deletion or loss of

NCOA2 fusion
13q14, including RB1 and its flanking genes RCBTB2,
gene, MEIS1- DLEU1, and ITM2B, has been identified in a substantial
subset of cases.5–8 Unlike conventional atypical lipomatous
tumors, there is no risk for dedifferentiation or metastasis.
Recently described dysplastic lipoma shows morphologic
similarity with ASPLT and is probably not a separate entity
but may be in the ASPLT morphologic spectrum.9,10
Middle-aged adults, associated Fascicles or sheets of spindle to S100 protein (+), SOX10 (+),
desmin (+), myogenin (+),

Pan-TRK (+), SOX10 (−)

Cytokeratin (AE1/AE3) (+),

S100 protein (+), CD34 (+),

Histologically, ASPLT shows a broad spectrum of
Immunohistochemical

PRKAR1A expression

morphology, with a nodular or multinodular growth pat-

HMB45 (+), Loss of

tern. It consists of variably mature adipocytes, spindle cells,

Markers

univacuolated or multivacuolated lipoblasts, and bizarre

pleomorphic multinucleated cells (Fig. 1A). The stroma is
MYOD1 (+)

− indicates negative staining; +, positive staining; ± , variable staining; EBER, Epstein-Barr virus-encoded RNA; RMS, rhabdomyosarcoma; RNA, ribonucleic acid.
collagenous and/or myxoid. Mitoses are rare and necrosis is
absent. A rare finding is heterologous differentiation,
including the presence of smooth muscle, cartilaginous, and/
or osseous elements.5,11 Immunohistochemically, tumor
cells show variable expression of CD34, S100 protein, and
desmin. Staining results for MDM2 (Fig. 1B) and CDK4
pigments, psammoma bodies

are negative, and loss of nuclear RB1 expression is observed

obvious rhabdomyoblastic

epithelioid Schwann cells,

Monomorphic spindle cells,

stromal and perivascular
Wide age range, mainly located Spindle cells with vesicular

hyalinization, infiltrative
nuclear groove, melanin

in about 50% to 70% of cases.

Histologic Features

differentiation is absent
eosinophilic cytoplasm,
nuclei and abundant

growth, but variable

histologic features

Myxoid Pleomorphic Liposarcoma

MPLPS is an exceptionally rare, aggressive adipocytic
neoplasm, typically occurring in children and adolescents12
and first described by Alaggio et al.13 MPLPS presents a
mixture of histologic features from both conventional myxoid
LPS and pleomorphic LPS. It lacks the gene fusions and
amplifications of myxoid LPS, atypical lipomatous tumor/
well-differentiated LPS, and dedifferentiated LPS and usually
superficial and deep tumors in
(subset), arise from spinal or
invade soft tissue, aggressive

autonomic nerve, bone, soft

occurs in children and young adults13–15 with a female pre-

Children and young adults,

dominance. It has a predilection for the mediastinum, with a

craniofacial bones, may

the extremities or trunk

most tumors present as
Clinical Features

with Carney complex

wide anatomical location. MPLPSs lack MDM2 amplifica-

in bones, especially

tion and DDIT3 rearrangement but instead show more

complex genomic abnormalities and inactivation of RB1
tumor suppressor gene.16,17 Further clinical and molecular
cytogenetic study of these cases is needed.18
subtype

Histologically, MPLPS shows a distinctive mixture of

tissues

conventional myxoid LPS and pleomorphic LPS charac-

teristics. The myxoid LPS features show relatively bland
primitive round to oval cells, scattered lipoblasts, and a
Intraosseous spindle cell

delicate plexiform capillary network in an abundant myxoid

spindle cell neoplasm
RMS (with TFCP2/

nerve sheath tumor

New Entities and

matrix, with scattered pleomorphic spindle or ovoid cells.

Malignant melanotic

NTRK-rearranged
rearrangements)

Adjacent to these features is evidence of a transition to

Subtypes

pleomorphic LPS displaying increased cellularity, high-

(emerging)

grade cytologic atypia, atypical mitoses, and pleomorphic

NCOA2

lipoblasts. Necrosis is occasionally present. Immunohis-

tochemically, MPLPSs have a nonspecific immunoph-
enotype.

Fibroblastic and Myofibroblastic Tumors

Biological

Malignant

Malignant
Malignant
Potential

Selected Changes
In the fibroblastic and myofibroblastic tumors’ category,
the newly recognized entities are EWSR1-SMAD3-positive
fibroblastic tumor (ESPFT), angiofibroma of soft tissue
(AFST), and superficial CD34-positive fibroblastic tumor
TABLE 1. (continued)

(SCFT). Myxoid dermatofibrosarcoma protuberans (DFSP),

Tumor Category

DFSP with myoid differentiation, plaque-like DFSP, fat-

differentiation
Peripheral nerve
sheath tumor

forming (lipomatous) solitary fibrous tumor (SFT), giant cell-

uncertain

rich SFT, epithelioid inflammatory myofibroblastic sarcoma,

Tumors of

and epithelioid myxofibrosarcoma are classified as distinctive

variants of existing tumor types. SFT is now subdivided into
SFT benign [intermediate (locally aggressive) category], SFT

46 | www.anatomicpathology.com Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
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Adv Anat Pathol  Volume 28, Number 1, January 2021
TABLE 2. Tumors Reclassified in the 2020 WHO Classification of Soft Tissue Tumors
2013 WHO Classification
Extrarenal angiomyolipoma Adipocytic tumor
Acral fibromyxoma Tumor of uncertain differentiation
Ectomesenchymoma Peripheral nerve sheath tumor
Ewing sarcoma Miscellaneous tumor of bone
NOS [intermediate (rarely metastasizing) category], and SFT
malignant.19 The development of multivariate risk models
has resulted in improved prognostication over the traditional
benign/malignant distinction.19–21 Acral fibromyxoma (pre-
viously included in the category of tumors of uncertain dif-
ferentiation) has been reclassified as belonging to the category
of fibroblastic and myofibroblastic tumors. It is now appre-
ciated that acral fibromyxomas show deletion of RB1.22
Calcifying fibrous tumor was removed in this edition. The
term “mammary-type myofibroblastoma” has been changed
to “myofibroblastoma.”
EWSR1-SMAD3-positive Fibroblastic Tumor
(Emerging)
EWSR1-SMAD3-positive fibroblastic tumor (ESPFT) is
a benign neoplasm with a strong predilection for the hands and
feet.23 The tumor nomenclature is provisional. This tumor has
been described in recent studies.24,25 Tumors are superficially
located within the dermis and/or subcutaneous fat. There is a
broad age range (1 to 68 y), with a female predilection. It most
commonly arises in the dermis and subcutis of the distal
extremities (hands and feet). The tumor shows a fusion of exon
7 of EWSR1 (22q12.2) with exon 5 of SMAD3 (15q22.33).
The pathogenesis of ESPFTs is unclear, although they may be
related to calcifying aponeurotic tumor, lipofibromatosis, and
lipofibromatosis-like neural tumors.26
Histologically, ESPFT is well-demarcated and shows a
distinctive zonation pattern of peripheral hypercellular areas
and central hypocellular hyalinized areas. The peripheral
area consists of intersecting fascicles of uniform spindle
cells. These spindle cells have bland oval or fusiform nuclei
with open chromatin and pale eosinophilic cytoplasm. The
tumor lacks nuclear pleomorphism and mitosis. Most cases
are at least focally infiltrative. Dystrophic calcification can
be seen. The tumor cells consistently show diffuse ERG
immunoreactivity, but negative for SMA and CD34. ERG
expression is useful for diagnosing ESPFT.
Angiofibroma of Soft Tissue
AFST is a benign fibroblastic neoplasm composed of
uniform spindle cells with abundant fibromyxoid stroma
TABLE 3. Tumors Removed in the 2020 WHO Classification of
Soft Tissue Tumors
2013 WHO 2020 WHO
Classification Classification
Extra-adrenal myelolipoma Adipocytic tumor Removed
Calcifying fibrous tumor Fibroblastic/ Removed
myofibroblastic
tumor
Angiomatosis Vascular tumor Removed
Other intermediate vascular Vascular tumor Removed
neoplasms (polymorphous
hemangioendothelioma,
giant cell angioblastoma)
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
Copyright r 2020 Wolters Kluwer Health, Inc. All rights reserved.
The 2020 WHO Classification of Tumors of Soft Tissue
2020 WHO Classification
Tumor of uncertain differentiation
Fibroblastic and myofibroblastic tumor
Skeletal muscle tumor
Undifferentiated small round cell sarcoma of bone and soft tissue
and a prominent network of innumerable, thin-walled,
branching blood vessels.27 AFST affects predominantly
middle-aged adults, with a slight female predominance.
AFST usually arises in the extremities (mainly the legs),
frequently involving large joints, or adjacent to large joints
such as the knee.28–30 Unusual anatomic locations include
the back, abdominal wall, pelvic cavity, and breast. AFSTs
harbor a recurrent t(5;8)(p15;q13), resulting in an AHRR-
NCOA2 fusion gene in 60% to 80% of cases.31
Histologically, AFST is composed of uniform bland
spindle cells and a prominent vascular network (Fig. 2A).
The architecture is vaguely lobulated with alternating
myxoid and collagenous areas and regional variation in
cellularity. The neoplastic spindle cells have short ovoid or
tapering nuclei and inconspicuous, pale eosinophilic cyto-
plasm. Nuclear atypia and hyperchromasia are generally
absent. Innumerable small thin-walled branching blood
vessels are evenly distributed throughout the lesion
(Fig. 2B). Medium-sized or ectatic blood vessels with var-
iably thick walls are also usually present. No specific
immunohistochemical marker exists for AFST. The tumor
cells variably express EMA, CD34, SMA, and desmin.28,30
NCOA2 split signals on FISH may be useful for confirming
the diagnosis of AFST.32
Superficial CD34-positive Fibroblastic Tumor
SCFT is a distinctive low-grade neoplasm of the skin
and subcutis, characterized by a fascicular to sheet-like
proliferation of spindled cells with abundant, eosinophilic,
granular to glassy cytoplasm, marked nuclear pleo-
morphism, a low mitotic count, and diffuse CD34
expression.33 It occurs in middle-aged adults (median 37 y),
with a slight male predominance. This tumor typically
presents as a slow-growing, painless mass of the superficial
soft tissues. The tumor occurs most commonly in the deep
dermis and subcutaneous tissue of the lower extremities,
especially the thigh, followed by the arm, buttock, shoulder,
and rarely vulva.34,35 The recently identified “PRDM10-
rearranged soft tissue tumor” is characterized by pleomor-
phic morphology and a low mitotic count and shows
morphologic overlaps with SCFT.36
Histologically, SCFT grows as a relatively circum-
scribed mass but shows at least partially infiltrative growth
to adjacent adipose tissue. It is composed of highly cellular
fascicles and sheets of spindled to epithelioid cells with
abundant eosinophilic cytoplasm, often having a granular or
glassy appearance (Fig. 3A). The neoplastic cells show
moderate to marked nuclear pleomorphism, often with
bizarre hyperchromatic nuclei containing prominent nucle-
oli and intranuclear cytoplasmic pseudoinclusions. How-
ever, despite these alarming nuclear features, mitotic activity
is very low and necrosis is rarely seen. A mixed inflamma-
tory cell infiltrate is often present. Immunohistochemically,
the tumor cells show strong and diffuse CD34 expression
(Fig. 3B) and are focally positive for cytokeratins in ~70%
of cases.
www.anatomicpathology.com | 47
Choi and Ro Adv Anat Pathol  Volume 28, Number 1, January 2021

FIGURE 1. Atypical spindle cell lipomatous tumor. A, Atypical hyperchromatic stromal spindle cells are present. B, Immunostaining for
MDM2 is negative.

So-called Fibrohistiocytic Tumors
There were no significant changes in this category. The
concept of fibrohistiocytic differentiation has been challenged
and is regarded as a poorly defined morphologic description of
histiocytic differentiation.37 It is generally accepted that vir-
tually none of the lesions in this category show true histiocytic
differentiation. The term “fibrohistiocytic” is a misnomer and
falsely brings together a group of heterogenous lesions, many
of which are likely unrelated. However, the term has been
retained, at least for the time being, to facilitate a degree of
diagnostic uniformity.38 In the 2020 WHO classification, the
term “tenosynovial giant cell tumor” encompasses a group of
lesions most often arising from the synovium of joints, bursae,
and tendon sheaths, which show synovial differentiation.39 It
most often involves translocation of the CSF1 gene, which
encodes colony-stimulating factor 1 (CSF1).40,41
Vascular Tumors
Selected Changes
Anastomosing hemangioma is newly described in the
category of vascular tumors. Tufted angioma (TA) is now
classified under kaposiform hemangioendothelioma (KHE), as
these tumors have identical morphologic features. Cellular
epithelioid hemangioma, atypical epithelioid hemangioma,
neuroendocrine composite hemangioendothelioma (CHE),
epithelioid hemangioendothelioma (EHE) with WWTR1-
CAMTA1 fusion, and EHE with YAP1-TFE3 fusion have
been classified as distinctive variants of existing tumor types.
Angiomatosis was removed from this edition. Other inter-
mediate vascular neoplasms, such as polymorphous heman-
gioendothelioma and giant cell angioblastoma, were also
removed because available data were insufficient. No clear
diagnostic criteria for these tumors yet exist.
Anastomosing Hemangioma
Anastomosing hemangioma is a benign vascular neo-
plasm that usually presents with poorly defined margins and
consists of thin-walled anastomosing vessels lined by a
monolayer of endothelial cells with somewhat protuberant
nuclei.42 The most common sites of occurrence are the
genitourinary tract and retroperitoneal soft tissue,43–45 but
this type of hemangioma has also been reported in multiple
sites, including the female genital tract, gastrointestinal
tract, liver, paraspinal soft tissue, and skin.46–49 It occurs
predominantly in adults, but lesions in the pediatric age

FIGURE 2. Angiofibroma of soft tissue. A, The tumor is composed of uniform, spindle-shaped tumor cells and prominent thin-walled
branching blood vessels. B, Immunostaining for CD34 highlights thin-walled, branching blood vessels. Please see this image in color
online.

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Adv Anat Pathol  Volume 28, Number 1, January 2021
FIGURE 3. Superficial CD34-positive fibroblastic tumor. A, At low magnification, the tumor is in the dermis and subcutaneous tissue. B,
The tumor cells show nuclear pleomorphism, with inflammatory cell infiltrate, hemosiderin deposition (left), and diffuse CD34 expression
(right). Please see this image in color online.
group have been reported.50 The majority of cases contain
an activating hotspot mutation in GNAQ or GNA14.51
Histologically, anastomosing hemangioma consists of
anastomosing, sinusoidal, capillary-sized vessels lined by
plump endothelial cells with a hobnail-like appearance and
fibrin thrombi. The tumor has a loosely lobulated archi-
tecture. Intracytoplasmic hyaline globules may be seen.
Hyalinized septa containing nonendothelial supporting cells
are present. Focal infiltration into adjacent tissue is often
seen. Mitoses are absent or rare. Mild cytologic atypia can
be seen, but no multilayering of endothelial cells is present.
Zones of sclerosis and infarction are frequently seen.
Extramedullary hematopoiesis can be a prominent feature.
Immunohistochemically, the endothelial cells are positive
for CD34, CD31, and ERG.
Tufted Angioma and Kaposiform
Hemangioendothelioma
TA and KHE are widely believed to be variants of a
single tumor type. KHE is a rare (often deep-seated) vas-
cular neoplasm, usually presenting in children, characterized
by lobular infiltrates of capillaries and spindled endothelial
cells associated with lymphatic vessels.52 TA, a more
superficial lesion, is otherwise almost identical to KHE.
Both lesions may induce Kasabach-Merritt syndrome.53–55
Somatic activating mutations in GNA14 gene have been
reported in 1 TA case and 1 KHE case.56
Histologically, the TA pattern shows superficial dis-
crete lobules of capillaries in a cannonball-like pattern
within dermal collagen. The KHE pattern shows infiltrative,
ill-defined, variably sized lobules and sheets of spindled
endothelial cells. Within the lobules, spindle cells are
arranged in short fascicles, with slit-like lumina containing
erythrocytes.52 Dilated lymphatic vessels are seen in the
periphery. Immunohistochemically, tumor endothelial cells
are positive for CD31, CD34, ERG, and lymphatic endo-
thelial markers (eg, podoplanin, PROX1, LYVE1).57
Epithelioid Hemangioma
Epithelioid hemangioma is a benign vascular neoplasm
composed of well-formed blood vessels lined by plump, epi-
thelioid (histiocytoid) endothelial cells, with abundant
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The 2020 WHO Classification of Tumors of Soft Tissue
eosinophilic cytoplasm and a variable eosinophilic infiltrate.58
Recurrent fusion involving the FOS and FOSB genes is
present in up to half of the cases. Newly recognized subtypes
include cellular epithelioid hemangioma and atypical epi-
thelioid hemangioma. Cellular epithelioid hemangioma
exhibits > 50% sheet-like growth of tumor cells. Atypical
epithelioid hemangioma displays more nuclear pleo-
morphism, solid growth, focal necrosis, and infiltrative
growth, and often has FOSB fusions.59 Angiolymphoid
hyperplasia with eosinophilia subtype of epithelioid heman-
gioma may be non-neoplastic due to a lack of the FOS or
FOSB gene rearrangement.60 Immunohistochemically, the
tumor cells are positive for FOSB in ~50% of epithelioid
hemangioma (including angiolymphoid hyperplasia with
eosinophilia subtype).61
Neuroendocrine Composite Hemangioendothelioma
Classic CHE is a locally aggressive, rarely metastasizing
vascular neoplasm, containing a mixture of histologically
distinct components.62 Neuroendocrine CHE has recently
been described as a rare, distinctive variant of CHE, which is
composed of an admixture of retiform and EHE-like areas,
and areas resembling neuroendocrine tumors characterized
by nests of epithelioid cells and expression of neuroendocrine
markers.63 Neuroendocrine CHE seems to be more aggres-
sive with distant metastases. Tumor cells are positive for
synaptophysin in all cases and negative for chromogranin in
most cases (90%).63 Synaptophysin immunoreactivity likely
represents aberrant expression rather than genuine neuro-
endocrine differentiation.64 Further studies are needed to
elucidate neuroendocrine CHE.
Epithelioid Hemangioendothelioma
EHE is a malignant vascular neoplasm composed of
epithelioid endothelial cells within a distinctive myxohyaline
stroma.65 Most cases ( > 90%) show WWTR1-CAMTA1
fusion. EHE with WWTR1-CAMTA1 fusion shows diffuse
and strong nuclear expression of CAMTA1.66 EHE with
YAP1-TFE3 fusion is a newly identified variant of EHE. It
accounts for ~5% of tumors traditionally classified as EHE65
and shows distinct histologic features, including solid
growth or more well-formed vessels, large epithelioid tumor
www.anatomicpathology.com | 49
Choi and Ro
cells with abundant eosinophilic cytoplasm, and diffuse
nuclear TFE3 overexpression.67 EHE with YAP1-TFE3
fusion affects younger adults more than EHE with
WWTR1-CAMTA1 fusion and, despite a high propensity
for metastasis, follows an indolent course clinically.
Pericytic (Perivascular) Tumors
No significant changes or newly described entities were
introduced in the pericytic (perivascular) tumors’ category.
Recently, several novel molecular findings have been reported
in pericytic tumors. Mutations in the PDGFRB gene seem to
represent a common pathogenesis for myopericytoma, myo-
pericytomatosis, and myofibroma.68,69 Cellular/atypical myo-
fibromas are associated with SRF-RELA gene fusions.70
Sporadic benign and malignant glomus tumors of soft tissue or
visceral origin have been shown to harbor recurrent NOTCH
gene family rearrangements with MIR143-NOTCH1/2/3
fusion genes present in more than half of the cases.71 BRAF
V600E mutations occur in a subset of glomus tumors and are
associated with malignant histologic characteristics.72,73
Smooth Muscle Tumors
Selected Changes
EBV-associated smooth muscle tumor (EBV-SMT)
and inflammatory leiomyosarcoma (LMS) are newly
described in the category of smooth muscle tumors. Reliable
prediction of smooth muscle tumor progression has been
especially problematic at many anatomic locations.74,75 The
criteria for malignancy vary by anatomical site and sex and
are not yet clearly defined. In the 2020 WHO classification,
the term “smooth muscle tumor of uncertain malignant
potential” has been designated and classified as an inter-
mediate tumor category. The term “leiomyoma of deep soft
tissue” has been changed to “leiomyoma NOS.”
EBV-associated Smooth Muscle Tumor
EBV-SMT is a smooth muscle tumor of uncertain
malignant potential associated with EBV infection, usually
in the setting of immunosuppression.76 The majority of cases
develop in 1 of 3 main settings: (1) immunodeficiency caused
by HIV/AIDS infection, (2) immunosuppressive treatment
after organ transplantation, and (3) congenital or primary
immunodeficiency disorders.77–79 EBV-SMTs can occur
anywhere in the body, but they commonly arise in the vis-
ceral organs (eg, gastrointestinal tract, liver, lung, spleen,
adrenal gland), brain, skin, and soft tissues. These tumors
are often multicentric. EBV-SMT occurs over a wide age
range, with a slight female predominance. Most primary
immunodeficiency patients with EBV-SMT have been chil-
dren, whereas 68% of posttransplant and 72% of HIV/AIDS
patients have been adults.76 Prognosis is determined by the
patient’s immune condition. Compared with conventional
LMS, EBV-SMT may exhibit a more favorable prognosis.80
Histologically, the tumor is composed of intersecting
fascicles of spindle cells with ample eosinophilic cytoplasm
and elongated nuclei. In about 50% of cases, more primitive-
appearing round cells are seen. Cytologic atypia is usually
mild to moderate. In HIV-positive patients, higher mitotic
activity and necrosis can be seen. Prominent intratumoral
T-lymphocytic infiltrate is present. Immunohistochemically,
tumor cells usually show diffuse positivity for SMA and
focal positivity for desmin and caldesmon. The diagnosis of
EBV-SMT can be confirmed by diffuse nuclear positivity for
EBV-encoded ribonucleic acid by in situ hybridization.
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Adv Anat Pathol  Volume 28, Number 1, January 2021
Inflammatory Leiomyosarcoma
Inflammatory LMS is a rare, malignant neoplasm
showing smooth muscle differentiation, a prominent inflam-
matory infiltrate, and near-haploidization.81 Most inflam-
matory LMSs arise in deep soft tissue, most commonly in the
lower limb, followed by the trunk and retroperitoneum.82,83 It
occurs most commonly in adults, with a median age of 35 to
40 years. The near-haploidization is an important pathoge-
netic characteristic.83,84 Gene expression profiling has
revealed differentially expressed genes involved in muscle
development and function, including ITGA7, MYF5, MYF6,
MYOD1, MYOG, and PAX7.83 These tumors have a
favorable clinical outcome.
Histologically, inflammatory LMS consists of eosino-
philic spindle cells with blunt-ended elongated nuclei,
arranged in fascicles or a storiform pattern. Nuclear atypia,
pleomorphism, and mitotic rate vary according to the
degree of histologic grade. Most cases seem to be low-grade.
There is a diffuse inflammatory cell infiltrate, which often
obscures neoplastic cells. The inflammatory component is
usually dominated by small lymphocytes, sometimes mixed
with plasma cells but often dominated by histiocytes,
including aggregates of foam cells. Psammomatous calcifi-
cations may be seen. Immunohistochemically, tumor cells
are diffusely positive for SMA and variably positive for
desmin and caldesmon.
Skeletal Muscle Tumors
Selected Changes
In the 2020 WHO classification, rhabdomyosarcoma
(RMS) has been subdivided into 4 types, including
embryonal, alveolar, pleomorphic, and spindle cell/scle-
rosing RMS. Spindle cell/sclerosing RMS has been newly
classified into three subtypes on the basis of genetic
abnormalities: (1) congenital spindle cell RMS with
VGLL2/NCOA2/CITED2 rearrangements, (2) MYOD1-
mutant spindle cell/sclerosing RMS, and (3) intraosseous
spindle cell RMS (with TFCP2/NCOA2 rearrangements).85
Although all these tumors share the terminology “spindle
cell/sclerosing RMS,” their morphology, clinical behavior,
and underlying molecular alterations are different.86
Patients with congenital spindle cell RMS with VGLL2/
NCOA2 rearrangements have a favorable prognosis,87
while those with MYOD1-mutant spindle cell/sclerosing
RMSs display an aggressive clinical course.88 Intraosseous
spindle cell RMSs (with TFCP2/NCOA2 rearrangements)
show areas of epithelioid cells arranged in sheets and
fascicles.89 Ectomesenchymoma is an exceedingly rare
multiphenotypic sarcoma consisting of both mesenchymal
and neuroectodermal lines of differentiation.90 Trisomies
of chromosomes 2, 8, and 11, and frequent HRAS muta-
tions suggest that ectomesenchymoma is more closely
related to RMS than to a neural crest neoplasm.91 There-
fore, ectomesenchymoma (previously classified within
the category of peripheral nerve sheath tumors) has now
been reclassified within the category of skeletal muscle
tumors.
Gastrointestinal Stromal Tumors
There were no significant changes in the category of
GISTs. The best-documented prognostic parameters for
GIST are mitotic activity, tumor size, and anatomic site.92
An important change in the 5th edition of the WHO Clas-
sification of Tumors Series is the conversion of the
Adv Anat Pathol  Volume 28, Number 1, January 2021
traditional mitotic count denominator of ten high-power
fields to a defined area expressed in mm2.93 This serves to
standardize the true area over which mitoses are counted, as
different microscopes have high-power fields of different
sizes. The mitotic rate of GIST is best expressed as the
number of mitoses per 5 mm2, which in most modern
microscopes corresponds to 20 to 25 fields using a ×40
objective and standard eyepiece diameter.94
Chondro-osseous Tumors
There were no significant changes in the category of
chondro-osseous tumors. Extraskeletal osteosarcoma (EOS)
is a rare malignant soft tissue tumor characterized by
production of osteoid and bone matrix by neoplastic cells.
EOS shows highly complex chromosomal aberrations.95
While EOS and conventional pediatric osteosarcoma share
histologic and genetic similarities, there are notable dissim-
ilarities and mechanistic differences in the molecular
pathways involved in EOS.96 The title “extraskeletal mes-
enchymal chondrosarcoma” has been deleted in the cat-
egory of chondro-osseous tumors.
Peripheral Nerve Sheath Tumors
Selected Changes
Melanotic schwannoma was previously classified as a
benign tumor category in the 2013 WHO classification.97 In
the 2020 WHO classification, the term “melanotic schwan-
noma” has been changed to “malignant melanotic nerve
sheath tumor (MMNST),” which is now reclassified as a
malignant tumor because of its aggressive clinical behavior.
The term “atypical neurofibromatous neoplasm of uncertain
biological potential (ANNUBP)” has been newly proposed
specifically for neurofibromatosis type 1 patients and is not
applied in sporadic lesions.98 ANNUBP displays at least 2
of the following 4 features: cytologic atypia, loss of neuro-
fibroma architecture, hypercellularity, and mitotic rate > 1/
50 HPFs but <3/10 HPFs.99
Malignant Melanotic Nerve Sheath Tumor
MMNST is a rare aggressive peripheral nerve sheath
tumor uniformly composed of Schwann cells showing
melanocytic differentiation, usually arising in association
with spinal or visceral autonomic nerves.100 Approximately
50% of cases are associated with Carney complex.101
MMNST occurs chiefly in middle-aged adults and most
often arises from the spinal or autonomic nerves near the
midline.102,103 However, MMNST has been reported in the
bone, soft tissues, heart, bronchus, liver, skin, and gastro-
intestinal tract.104,105 PRKAR1A mutations and loss of
PRKAR1A protein expression are seen in the majority
of cases.
Histologically, MMNST exhibits fascicles or sheets of
atypical spindled and epithelioid Schwann cells. The tumor
cells have vesicular, grooved nuclei, often with pseudoin-
clusions, and eosinophilic to amphophilic cytoplasm.
Marked nuclear hyperchromatism with prominent macro-
nucleoli, mitoses, and necrosis can be seen. Melanin pigment
may be coarsely clumped or finely granular with variable
degrees of pigmentation from area to area. Psammoma
bodies are present in about 50% of cases. Ultrastructurally,
the tumor cells show typical Schwann cell features con-
taining melanosomes. Immunohistochemically, tumor cells
strongly and diffusely express S100 protein and SOX10.
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
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The 2020 WHO Classification of Tumors of Soft Tissue
Tumor cells are also positive for melanocytic markers (eg,
HMB45, melan-A, tyrosinase), although PRKAR1A
expression is typically lost.102
Tumors of Uncertain Differentiation
Selected Changes
In the 2020 WHO classification, NTRK-rearranged
spindle cell neoplasm (emerging) has been described for the
first time in the category of tumors of uncertain differ-
entiation. The group of undifferentiated/unclassified
sarcomas [previously classified as a separate group of
undifferentiated/unclassified sarcomas (US)] has been
included in the category of tumors of uncertain differ-
entiation and newly termed “unclassified sarcoma (US).”
Approximately 10% to 20% of soft tissue sarcomas lack an
identifiable line of differentiation and cannot be classified.
USs can be broadly divided into pleomorphic, spindle cell,
round cell, and epithelioid subsets.106 Undifferentiated
pleomorphic sarcomas represent the largest group of these
tumors and are associated with complex karyotypes with
chromosome numbers ranging from near haploid to
hyperoctaploid.107 Many round cell US cases can now be
more precisely classified within specific molecular subsets.
There are only a few studies with regard to USs with epi-
thelioid morphology.108 Angiomyolipoma (previously clas-
sified in the category of adipocytic tumors) is now included
in the category of tumors of uncertain differentiation and
has been divided into 2 groups: an angiomyolipoma (benign
tumor) and an angiomyolipoma, epithelioid [intermediate
(locally aggressive) tumor] category.
NTRK-rearranged Spindle Cell Neoplasm (Emerging)
NTRK-rearranged spindle cell neoplasms (outside
infantile fibrosarcoma) represent an emerging group of
molecularly defined, rare soft tissue tumors, spanning a wide
spectrum of morphologies and histologic grades and showing
frequent coexpression of S100 protein and CD34 in immu-
nohistochemical analyses.109 This provisional category
includes the recently described lipofibromatosis-like neural
tumors and tumors that closely resemble peripheral nerve
sheath tumors.110–112 Most tumors occur in children and
young adults and present as superficial or deep tumors in the
extremities or trunk.109 Most tumors also harbor NTRK1
fusions with a variety of gene partners, resulting mostly from
intrachromosomal interstitial deletions (LMNA) or inver-
sions (TPR, TPM3). One of the best-characterized entities in
the NTRK-rearranged sarcomas’ group is infantile
fibrosarcoma, which harbors an ETV6-NTRK3 fusion.113
Identification of the NTRK rearrangement is important, as
treatment of patients with NTRK fusion-positive neoplasms
using NTRK inhibitors has been associated with a high
response rate ( > 75%), regardless of tumor histology.114
Histologically, NTRK-rearranged spindle cell neo-
plasms shows a wide morphologic spectrum. Most tumors
of this category are of low-grade characterized by a mono-
morphic spindle cell morphology with an infiltrative growth
(Fig. 4A), but some display a higher-grade phenotype, with
markedly increased cellularity arranged in intersecting fas-
cicles and a high mitotic count. Necrosis may be present.
Keloid-like stromal collagen and perivascular hyalinization
are seen in a subset of cases. Immunohistochemically, tumor
cells show patchy expression of S100 protein and CD34,
without SOX expression.116 Immunohistochemistry for pan-
TRK shows diffuse expression (Fig. 4B).117,118 However,
www.anatomicpathology.com | 51
Choi and Ro Adv Anat Pathol  Volume 28, Number 1, January 2021

FIGURE 4. NTRK-rearranged spindle cell neoplasm. A, Tumor cells are monomorphic, spindle-shaped, and arranged in a patternless
pattern, with distinctive stromal collagen deposition. B, Tumor cells show diffuse cytoplasmic expression of TRK protein. Reprinted from
Thway and Folpe,115 with permission from Springer Nature. Copyright Springer Nature, New York, NY. All permission requests for this
image should be made to the copyright holder. Please see this image in color online.

diffuse pan-TRK immunoreactivity is a highly sensitive but
not entirely specific diagnostic marker, and molecular
studies are recommended for a conclusive diagnosis of
NTRK-rearranged neoplasms.110
UNDIFFERENTIATED SMALL ROUND CELL
SARCOMAS OF BONE AND SOFT TISSUE
Selected Changes
Ewing sarcoma and Ewing-like sarcoma family are
highly aggressive round cell mesenchymal neoplasms, most
often occurring in children and young adults.119,120
Recently, new discrete sarcoma types have been emerging
among sarcomas previously classified in the category of
“undifferentiated round cell sarcoma” on the basis of the
gene fusion type. In the 2020 WHO classification, a new
chapter covering “undifferentiated small round cell sarco-
mas of bone and soft tissue tumors” has been introduced.119
The new chapter includes Ewing sarcoma and 3 main cat-
egories, including round cell sarcomas with EWSR1–non-
ETS fusions, CIC-rearranged sarcoma, and sarcomas with
BCOR genetic alterations. Although these entities show
considerable morphologic overlap, most exhibit character-
istic morphologic and clinical features predictive of the
underlying molecular alterations.120 A combination of his-
tologic, immunohistochemical, and molecular findings,
including next-generation sequencing–based approaches,
allows accurate classification in most cases. The undiffer-
entiated small round cell sarcomas of bone and soft tissue
are summarized in Table 4.
Round Cell Sarcoma With EWSR1–Non-ETS
Fusions
Round cell sarcomas with EWSR1–non-ETS fusions
are rare, round and spindle cell sarcomas with EWSR1 or
FUS fusions involving partners unrelated to the ETS gene
family.121 The genes most commonly fused with EWSR1 or
FUS include NFATC2 and PATZ1. Compared with Ewing
sarcoma, these tumors tend to occur in older patients with a
broad age range. EWSR1-NFATC2 sarcomas predom-
inantly arise in the metaphysis or diaphysis of the long
bones, with a 4:1 ratio over soft tissues.122 Soft tissue cases
involve the extremities, head, neck, and chest wall.123,124
FUS-NFATC2 tumors have been reported exclusively in
long bones.89,125 EWSR1-PATZ1 sarcomas arise in the deep
soft tissue of the chest wall and abdomen, extremities, head,
and neck.126,127
Histologically, compared with conventional Ewing
Sarcoma, EWSR1-NFATC2 and FUS-NFATC2 sarcomas
are heterogenous and composed of small to medium-sized
round and/or spindled cells predominantly arranged in
cords, small nests, trabeculae, and pseudoacinar structures
in a fibrohyaline or myxohyaline stromal background.121
Atypical features such as nuclear pleomorphism, prominent
nucleoli, and cytoplasmic clearing can be seen. Immuno-
histochemically, the tumor cells diffusely express CD99 in
half of the cases; PAX7 and NKX2-2 may also be
expressed.128 Focal dot-like staining for cytokeratin (AE1/
AE3) can be seen. The histopathologic and immunopheno-
typic features of EWSR1-PATZ1 sarcomas are also
heterogenous.89,126 The tumor cells are small, round, and/or
spindled and are often accompanied by a fibrous stroma.
Coexpression of myogenic markers (eg, desmin, myogenin,
MYOD1) and neurogenic markers (eg, S100 protein,
SOX10, GFAP) is seen at variable levels. CD34 can be
expressed, and CD99 is not consistently expressed.
CIC-rearranged Sarcoma
CIC-rearranged sarcoma is a high-grade round cell
undifferentiated sarcoma defined by CIC-related gene
fusions, most often CIC-DUX4.129 It is most frequently
occurring and best characterized subgroup of the Ewing-like
sarcoma family. There is a wide age range at presentation,
from children to elderly adults, with a slight male
predominance.130,131 Most CIC sarcomas occur in the deep
soft tissues of the limbs or trunk, and less commonly in the
head and neck, retroperitoneum, or pelvis. Primary osseous
involvement is rare (< 5%).130–132 CIC-DUX4 fusion is
present in the vast majority of cases, resulting from either a t
(4;19)(q35;q13) or a t(10;19)(q26;q13) translocation.133,134
Approximately 5% of cases are associated with non-DUX4
gene fusions, including FOXO4, LEUTX, NUTM1, and
NUTM2A.135–137 CIC-rearranged sarcomas are more
aggressive than Ewing sarcomas.130

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Adv Anat Pathol  Volume 28, Number 1, January 2021 The 2020 WHO Classification of Tumors of Soft Tissue

Gene fusions involving one member

(usually EWSR1) and a member

EWSR1-NFATC2, FUS-NFATC2,
Histologically, CIC-rearranged sarcomas appear less

BCOR-CCNB3, BCOR-MAML3,
CIC-DUX4 (95%), CIC-FOXO4,
monotonous than Ewing sarcoma and are composed of

CIC-LEUTX, CIC-NUTM1,
of the FET family of genes
diffuse sheets of undifferentiated round cells, with a lobu-
Molecular Features

lated growth pattern (Fig. 5A). Spindled or epithelioid

tumor cells may be partially seen. The tumor cells often
of the ETS family

BCOR3-ZC3H7B
EWSR1-PATZ1 reveal a mild degree of nuclear pleomorphism, with vesic-

CIC-NUTM2A
ular chromatin and prominent nucleoli, and a moderate
amount of lightly eosinophilic or clear cytoplasm. Necrosis
is common, and the mitotic rate is usually high. In one third
of the cases, focal myxoid stromal changes are present.
Immunohistochemically, tumor cells often express CD99
(mostly in a patchy pattern, and less commonly in a diffuse
and membranous pattern). Tumor cells frequently express
Children and young adults, long bones, pelvis, Classic ES; uniform, small round cells and scant clear CD99 (+) diffusely membranous

NKX2.2 (−), CD99 (+) patchy

coexpression of myogenic and
Immunohistochemical Marker

BCOR (+), SATB2 (+), TLE1

(+), CD99 (+) heterogenous
diffusely nuclear expression,

WT1 and ETV4 (Fig. 5B), which represent useful ancillary

sarcoma; CD99 (+) in 50%,

markers.137 Sarcomas with CIC-NUTM1 fusions have been

expression, NKX2.2 (+)

PAX7 (+), NKX2.2 (+)

EWSR1-PATZ1 sarcoma;

staining in about 50% shown to express the NUT protein.138

EWSR1/FUS-NFATC2

neurogenic markers
FLI1 (+), ERG (+)

ETV4 (+), WT1 (+),

Sarcoma With BCOR Genetic Alterations

Sarcomas with BCOR genetic alterations are uncom-
mon, with a much lower incidence than Ewing sarcoma and
are divided into 2 groups: BCOR-CCNB3 sarcomas and
sarcomas with BCOR internal tandem duplication (BCOR-
ITD).139 BCOR-CCNB3 sarcomas occur slightly more often
in the bone than in soft tissue, with a predilection for the
regions, including extremities, paravertebral Atypical ES; larger, prominent nucleoli, and irregular

pseudoacinar, cords, or sheet pattern, fibrohyaline

pelvis, lower extremities, and paraspinal region.140,141

stromal changes, mostly low-grade features, but

Primitive round to spindle cells arranged in nests,

BCOR-CCNB3 sarcomas have a striking predilection for

CIC-rearranged Young adults, but a wide age distribution, deep Predominant round cell phenotype, mild nuclear
TABLE 4. Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue in the 2020 WHO Classification

sheets, or fascicular pattern, variably myxoid

pleomorphism, epithelioid and/or spindle cell

children, with > 90% of patients aged below 20 years, and

EWSR1/FUS-NFATC2 sarcoma; children and Spindled to rounded cells arranged in nests,

show a male predominance.142 Sarcomas with BCOR-ITD

occur mainly in the soft tissues of the trunk, retro-
components, variably myxoid stroma

peritoneum, head, and neck, typically sparing the extrem-

Histologic Features

ities, and within the first year of life or may be present at

stroma with delicate vasculature

birth.143
high-grade cases are reported

Histologically, BCOR family tumors show substantial

or eosinophilic cytoplasm

morphologic overlap. BCOR-CCNB3 sarcomas are typi-

cally composed of a uniform proliferation of primitive small
round to ovoid cells arranged in solid sheets or a vague
nesting pattern surrounded by a rich capillary netwo-
rk.141,144 Sarcomas with BCOR-ITD abnormalities show
contours

variable degrees of cellularity, ranging from solid sheets of

small primitive cells to hypocellular areas of dispersed
spindle cells, within a myxoid matrix and an association
with delicate vessels.142,145 Immunohistochemically, almost
all tumors show BCOR and CCNB3 expression. However,
adults, with a male predominance, long bones
EWSR1-PATZ1 sarcoma; wide age range, chest

soft tissues of the limbs or trunk, about 10%

because CCNB3 and BCOR immunohistochemistry lack

Children, male predominance, more often in
and ribs, about 12% arise in extraskeletal

wall, abdomen, extremities, head and neck

adequate sensitivity and specificity, a molecular genetic

bone than in soft tissue, pelvis, lower

approach remains essential for diagnosis.144 CD99 expres-

extremities, paraspinal region, trunk

sion is present in 42% to 80% of cases, with more hetero-

arise in visceral organs (kidney,

genous staining pattern compared with Ewing

Clinical Features

sarcoma.142,143 The tumor cells also show TLE1 and SATB2

expression in most of the cases.144,146,147
gastrointestinal tract)
region, mediastinum

CONCLUSIONS
This review summarizes the major changes and selected
new entities and subtypes in the 2020 WHO classification of
ES indicates Ewing sarcoma.

soft tissue tumors. The 2020 WHO classification details

recent advances in the classification of soft tissue tumors and
our understanding of pathogenetic mechanisms on the basis
of a combination of histologic and molecular genetic find-
ings. Soft tissue classification will continue to evolve as we
EWSR1–non-
sarcoma with
Ewing sarcoma

ETS fusions

Sarcoma with

accumulate new histologic, molecular, genetic, and clinical

alterations

findings in unclassified and uncommon soft tissue lesions.

Round cell

sarcoma

genetic
BCOR

Further studies are required to understand the pathogenetic

mechanisms and behavior of soft tissue tumors and improve
accurate diagnosis.

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Choi and Ro
FIGURE 5. CIC-rearranged sarcoma. A, Tumor cells are round-shaped, with a lobular growth pattern. There is more pleomorphism
compared with Ewing sarcoma. B, Tumor cells show strong nuclear expression of ETV4. Reprinted from Thway and Folpe,115 with
permission from Springer Nature. Copyright Springer Nature, New York, NY. All permission requests for this image should be made to the
copyright holder. Please see this image in color online.
ACKNOWLEDGMENTS
The authors thank Drs Heather McConnell and Sasha
Pejerrey for their excellent editorial help.
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