Histopathology 2021, 78, 644–657. DOI: 10.1111/his.

14265

REVIEW

Updates from the 2020 World Health Organization

Classification of Soft Tissue and Bone Tumours
William J Anderson & Leona A Doyle
Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

Date of submission 8 July 2020

Accepted for publication 24 September 2020
Published online Article Accepted 12 January 2021

Anderson W J & Doyle L A.

(2021) Histopathology 78, 644–657. https://doi.org/10.1111/his.14265
Updates from the 2020 World Health Organization classification of soft tissue and bone
tumours

The fifth edition of the World Health Organization
(WHO) classification of soft tissue and bone tumours was
published in May 2020. This ‘Blue Book’, which is also
available digitally for the first time, incorporates an array
of new information on these tumours, amassed in the
7 years since the previous edition. Major advances in
molecular characterisation have driven further
Keywords: bone, sarcoma, soft tissue, tumour, WHO
refinements in classification and the development of
ancillary diagnostic tests, and have improved our under-
standing of disease pathogenesis. Several new entities
are also included. This review summarises the main
changes introduced in the 2020 WHO classification for
each subcategory of soft tissue and bone tumours.

Introduction changes in each diagnostic category of the 2020

In the 7 years since the 2013 World Health Organi-
zation (WHO) classification of tumours of soft tissue
and bone, there have been considerable advances in
our understanding of this large and diverse group of
neoplasms.1 Many of these advances have been
underpinned by massively parallel sequencing, which
has become increasingly available during this period
in both clinical and research settings. The identifica-
tion of recurrent genetic events across the spectrum
of mesenchymal neoplasms has continued to drive
improvements in diagnoses using molecular methods
and novel immunohistochemical markers.2 There
have also been important refinements in classification
and the recognition of new entities. In this review,
we summarise the principal developments and
Address for correspondence: Leona A Doyle, MD, Department of
Pathology, Brigham and Women’s Hospital, 75 Francis Street, Bos-
ton, MA 02115, USA. e-mail: ladoyle@bwh.harvard.edu
WHO classification.3
Soft tissue
ADIPOCYTIC TUMOURS
The principal changes in this category are the addition
of two new entities: atypical spindle cell/pleomorphic
lipomatous tumour and myxoid pleomorphic liposar-
coma. Atypical spindle cell lipomatous tumour (ASLT)
and atypical pleomorphic lipomatous tumour (APLT)
are low-grade adipocytic neoplasms that are thought to
constitute a single entity, on the basis of their shared
clinicopathological and molecular features.4,5 They are
therefore classified together as ‘atypical spindle cell/pleo-
morphic lipomatous tumour’. These tumours are often
larger, have less well-defined margins and have a wider
anatomical distribution than spindle cell/pleomorphic
lipoma. Their variable proportions of adipocytes, spindle
cells (often with mild to moderate atypia), lipoblasts, flo-
ret-like giant cells and extracellular matrix (myxoid or

© 2020 John Wiley & Sons Ltd.


A characterised by MDM2 amplification.
B genesis.8
Figure 1. A, Atypical spindle cell lipomatous tumour is a benign
adipocytic neoplasm characterised by a prominent spindle cell com-
ponent in a collagenous or myxoid stroma. The spindle cells are
generally more numerous than in atypical lipomatous tumour/
well-differentiated liposarcoma, and show mild nuclear atypia. B,
Atypical pleomorphic lipomatous tumour has similar features, as
well as pleomorphic cells, floret-like multinucleated giant cells, and
lipoblasts, which are often numerous.
collagenous) result in a broad morphological spectrum
(Figure 1). Immunohistochemically, ASLT may be posi-
tive for CD34 (60%), S100 (~40%) and desmin (~20%).4
Retinoblastoma protein expression is often lost in both
ASLT and APLT, as these tumours commonly have dele-
tions of RB1 and its adjacent genes, i.e. RCBTB2,
DLEU1, and ITM2B. They may recur locally, but, in con-
trast to atypical lipomatous tumours, they have no
known potential to dedifferentiate or metastasise and are
classified as benign. Both ASLT and APLT lack MDM2
amplification, and molecular methods can therefore be
helpful in resolving the differential diagnosis with atypi-
cal lipomatous tumour/well-differentiated liposarcoma
© 2020 John Wiley & Sons Ltd, Histopathology, 78, 644–657.
WHO Classification 2020 645
and low-grade dedifferentiated liposarcoma, which are
Myxoid pleomorphic liposarcoma (pleomorphic
myxoid liposarcoma), which is also included for the
first time, is an extremely rare and aggressive tumour
of children, adolescents and young adults that has a
tendency to arise in the mediastinum.6 Histologically,
it contains areas resembling both myxoid liposarcoma
and conventional pleomorphic liposarcoma, but it
lacks the characteristic molecular alterations of other
genetically defined liposarcomas (e.g. FUS/EWSR1
rearrangement and MDM2 amplification), and is now
considered to be a distinct entity.7
Finally, angiolipomas are now known to have
recurrent low-level mutations in the protein kinase
D2 gene (PRKD2), which is thought to drive tumori-
FIBROBLASTIC AND MYOFIBROBLASTIC TUMOURS
This is the largest category of soft tissue tumours,
and it has grown even larger in the 2020 WHO
classification with the inclusion of several new enti-
ties. Among these is superficial CD34-positive fibrob-
lastic tumour, a low-grade tumour first described by
Carter et al. in 2014.9 It arises in the subcutis and
is typically well circumscribed. Histologically, it is
composed of spindled fibroblastic cells with ‘glassy’
cytoplasm admixed with scattered inflammatory cells
and foamy histiocytes (Figure 2).9,10 A key feature is
the presence of striking nuclear pleomorphism that
occurs in the absence of significant mitotic activity
or necrosis. In addition to diffuse positivity for CD34,
focal positivity for keratins (mostly AE1/AE3) or des-
min can be observed. Outcomes have so far been
very favourable, with only one reported metastasis
(to a regional lymph node) in the original series,
which included 13 patients with clinical follow-up
data - this tumor is therefore classified as intermedi-
ate with regards to biologic potential.9 Very recently,
a subset has been shown to harbour PRDM10 rear-
rangement.11
Angiofibroma of soft tissue is another new addition
to this category.12 This benign tumour arises most
commonly in the lower extremities of adults, close to
(and occasionally involving) large joints. It is well cir-
cumscribed and composed of bland spindled fibroblas-
tic cells in a fibromyxoid stroma with prominent
thin-walled branching blood vessels (Figure 3). The
latter have been likened to those of myxoid liposar-
coma.12 Immunohistochemically, almost half of cases
show some expression of epithelial membrane anti-
gen, and smaller subsets (~15%) show some degree of
646 W J Anderson and L A Doyle
Figure 2. Superficial CD34-positive fibroblastic tumour is a recently
described low-grade tumour comprising spindled and epithelioid
cells with variable amounts of eosinophilic ‘glassy’ cytoplasm.
Despite considerable nuclear atypia reminiscent of a pleomorphic
sarcoma, mitoses are very scarce and necrosis is absent.
Figure 3. Soft tissue angiofibroma is characterised by haphazardly
distributed bland spindle cells in a collagenous-to-myxoid stroma
with prominent thin-walled branching blood vessels. The majority
harbour AHRR–NCOA2 fusion gene.
CD34 or smooth muscle actin positivity. In the initial
series there was a recurrent t(5;8) rearrangement,
which has subsequently been shown to target
NCOA2, often resulting in AHRR–NCOA2 fusions.13
Also included for the first time is an emerging
entity provisionally termed EWSR1–SMAD3 fibrob-
lastic tumour. Two studies within the last year have
described this as a benign tumour that arises most
commonly in females at acral sites and appears to
Figure 4. EWSR1–SMAD3 fibroblastic tumour typically arises
superficially in the distal extremities. It is composed of intersecting
fascicles of bland fibroblastic spindle cells that infiltrate the sur-
rounding adipose tissue. Areas of stromal hyalinisation and calcifi-
cations are often present, either centrally, giving a zonation
architecture, or interspersed with the spindle cells, as in this
example.
be defined by EWSR1–SMAD3 fusion.14,15 Micro-
scopically, it often shows zonation by having a hya-
linised centre surrounded by cellular fascicles of
bland spindle cells (Figure 4). Immunohistochemi-
cally, ERG is consistently positive. Although only
small numbers of cases have been reported to date,
local recurrence after incomplete excision appears to
be common.
One of the chief molecular advances in this cate-
gory came in 2013, when NAB2–STAT6 fusion was
discovered as the defining molecular event in solitary
fibrous tumour (SFT).16 Immunohistochemistry for
signal transducer and activator of transcription 6
(STAT6) has since become an extremely reliable and
widely adopted means of establishing the diagnosis,
especially as the paracentric inversion of 12q that
produces the gene fusion is beyond the resolution of
fluorescence in-situ hybridisation (FISH).17 In more
recent years, TERT promoter mutations have been
characterised as secondary events associated with
aggressive behaviour and metastasis.18,19
Importantly, improved risk stratification criteria for
SFT are now included in the 2020 WHO classifica-
tion. In one widely adopted set of criteria—estab-
lished and later modified by Demicco et al.20—
tumours are assigned low-risk, intermediate-risk or
high-risk status (specifically for metastasis) based on
a combined assessment of clinical (patient age) and
pathological (tumour size, mitoses, and necrosis)
© 2020 John Wiley & Sons Ltd, Histopathology, 78, 644–657.

criteria. A separate risk calculator to predict overall
survival, local recurrence and metastasis has also
been published by the French Sarcoma Group.21
Finally, for several fibroblastic/myofibroblastic
tumours there have been noteworthy advances in
our understanding of their genetics. Recurrent gene
fusions have been identified in calcifying aponeurotic
fibroma (FN1–EGF) and lipofibromatosis (involving
several genes encoding receptor tyrosine kinases),22
and insertion/duplication of EGFR exon 20 has been
identified as a consistent event in fibrous hamartoma
of infancy.23
VASCULAR TUMOURS
Epithelioid haemangioendothelioma (EHE) is now
recognised to comprise two distinct tumour subtypes.
A
Figure 5. A, Epithelioid haemangioendothelioma (EHE) with YAP1–
TFE3 accounts for a small subset of EHEs. It is composed of epithe-
lioid cells with abundant eosinophilic cytoplasm, and is typically
vasoformative, in contrast to conventional EHE (driven by
WWTR1–CAMTA1). B, Diffuse nuclear positivity for TFE3 is charac-
teristic.
© 2020 John Wiley & Sons Ltd, Histopathology, 78, 644–657.
WHO Classification 2020 647
In addition to those driven by WWTR1–CAMTA1
fusion (>90% of cases), a small subset with a some-
what different morphology has been found to harbour
an alternative YAP1–TFE3 fusion.24 In this variant,
the tumour cells have more voluminous eosinophilic
cytoplasm, and typically show a vasoformative
growth pattern as well as areas of solid growth (Fig-
ure 5A).24 Immunohistochemistry for TFE3 shows
strong and diffuse nuclear staining (Figure 5B). Given
that all EHEs are classified as malignant, the use of
the term ‘malignant EHE’, which has been used to
denote cases with higher-grade morphological fea-
tures, is no longer recommended. Pseudomyogenic
haemangioendothelioma, a vascular tumour of inter-
mediate biological potential, was included for the first
time in the 2013 classification; it is now understood
to be molecularly characterised by FOSB gene
rearrangements, as either SERPINE1–FOSB or
ACTB–FOSB fusions.25,26 Interestingly, FOSB activa-
tion—often via different fusions involving FOSB or
FOS—has also been identified in a subset of epithe-
lioid haemangiomas. FOSB immunohistochemistry
has therefore become a useful diagnostic marker for
both entities.25,27
Anastomosing haemangioma is included for the
first time, although it has been widely recognised
since 2009, when it was first described in the geni-
tourinary tract.28 This benign tumour most com-
monly occurs in the kidney and retroperitoneum.
Microscopically, it consists of delicately arborising
thin-walled vessels, whose architecture may resemble
Figure 6. Anastomosing haemangioma is composed of numerous
thin-walled branching vascular channels that are lined by a single
layer of endothelial cells with mildly protuberant nuclei. A charac-
teristic feature is the presence of extramedullary haematopoiesis, as
evidenced by a megakaryocyte in this case.
648 W J Anderson and L A Doyle

angiosarcoma at low power (Figure 6). In contrast,
however, the vessels are lined by a monolayer of uni-
form endothelial cells with only mildly protuberant
nuclei. When present, intracytoplasmic eosinophilic
globules, extramedullary haematopoiesis and minute
thrombi are helpful clues to the diagnosis. Most cases
have been shown to harbour activating mutations in
GNAQ or GNA14.29
Finally, tufted angioma and kaposiform haeman-
gioendothelioma are now classified together more
clearly, reflecting the fact that they are most likely
superficial and deep variants, respectively, of a single
entity. In addition to their shared clinical and mor-
phological features, recent work has also suggested
molecular overlap in a small number of cases.30
strong and diffuse desmin expression, and can be mis-
taken for a myogenic tumour such as leiomyosar-
coma. Interestingly, cellular myofibroma/
myopericytoma has a distinct SRF–RELA fusion (Fig-
ure 7).34 Glomus tumours that arise sporadically are
now known to commonly have MIR143–NOTCH1–3
fusions,36 and a small subset of those with intermedi-
ate or malignant behaviour have been shown to have
KRAS and BRAF (p.V600E) mutations.37,38
SMOOTH MUSCLE TUMOURS
In this section, Epstein–Barr virus (EBV)-associated
smooth muscle tumours (EBV-SMTs) are now classi-
fied separately from leiomyosarcoma. EBV-SMTs

PERICYTIC (PERIVASCULAR) TUMOURS A

In the 2013 WHO classification, myopericytoma and

myofibroma were classified together, as it had become
apparent that they represent a morphological contin-
uum. Since then, PDGFRB mutation has been identi-
fied as a key driver event in myopericytoma and
myofibroma, being present in both familial and spo-
radic cases,31–33 and providing additional support for
their classification as a single entity. More recently, a
distinct subtype of myofibroma/myopericytoma has
been recognised that is characterised by increased cel-
lularity and is thus termed ‘cellular myofibroma/my-
opericytoma’.34,35 This subtype frequently shows

Figure 8. A, Epstein–Barr virus (EBV)-associated smooth muscle

Figure 7. Cellular myofibroma/myopericytoma with SRF–RELA is a
recently recognised variant of myofibroma/myopericytoma. Micro-
scopically, there is a hypercellular population of uniform ovoid-to-
spindled cells arranged in a fascicular or slightly nested pattern, as
well as the typical vascular component of myopericytoma
tumour occurs in the setting of immunosuppression; histologically,
fascicles of spindle cells with eosinophilic cytoplasm are present,
often with areas that have a more rounded cytomorphology and
interspersed T lymphocytes. B, The tumour cells are positive for
EBV-encoded RNA by in-situ hybridisation.

© 2020 John Wiley & Sons Ltd, Histopathology, 78, 644–657.


occur in the setting of immunosuppression, being first
described in patients with human immunodeficiency
virus/acquired immunodeficiency syndrome and
organ transplants.39,40 Their behaviour varies from
benign to malignant, and is related to the degree of
immunosuppression. A proportion may be multifocal,
often because of separate localised EBV infections
rather than metastasis. Histologically, EBV-SMTs tend
to have low-grade cytological features (mild to mod-
erate atypia and pleomorphism; low mitotic activity)
and lymphocytic infiltrates (Figure 8A).41 Detection
of EBV-encoded RNA by in-situ hybridisation is useful
to confirm the diagnosis (Figure 8B). Inflammatory
leiomyosarcoma, first described in 1995, is included
for the first time as a distinct entity.42 In contrast to
conventional leiomyosarcoma, it has a prominent
infiltrate of lymphocytes and/or histiocytes (Figure 9).
Recent work has confirmed earlier reports of its
unique molecular profile, consisting of an unusual
haploid genome with few somatic mutations, thereby
supporting its separate classification.43,44
SKELETAL MUSCLE TUMOURS
Spindle cell/sclerosing rhabdomyosarcoma is now
known to comprise at least three subgroups of
tumours with quite distinct clinicopathological and
molecular features. This represents a substantial
advance over the previous classification, when its
molecular basis was largely unknown. First, there are
Figure 9. Inflammatory leiomyosarcoma comprises fascicles of spin-
dle cells with eosinophilic cytoplasm admixed with a prominent
infiltrate of lymphocytes and histiocytes. Its frequently haploid
genomic profile and favourable outcome support classification sepa-
rate from conventional leiomyosarcoma.
© 2020 John Wiley & Sons Ltd, Histopathology, 78, 644–657.
WHO Classification 2020 649
tumours with hotspot mutations in MYOD1
(p.L122R) that occur most often in adolescents and
young adults.45,46 Second, there are tumours har-
bouring gene fusions involving VGLL2, NCOA2 or
CITED2 that typically arise in paediatric patients and
that have a better prognosis.47,48 Third, there are
tumours that lack either of these alterations. Finally,
it is noteworthy that there are very recently charac-
terised variants of spindle cell/sclerosing rhab-
domyosarcoma with TFCP2 rearrangement or
MEIS–NCOA2 fusion that appear to have a predilec-
tion for bone.49–51 As a minor change, ectomes-
enchymoma is now assigned to this group, largely on
the basis of its genetic overlap with embryonal rhab-
domyosarcoma, having been previously classified as a
nerve sheath tumour.
CHONDRO-OSSEOUS TUMOURS
Soft tissue chondroma, which is a rare tumour that
arises mostly in the hands and feet, has been shown
to have recurrent FN1–FGFR2 and FN1–FGFR1
fusions in 50% of cases.52 Interestingly, those with
FN1 fusions all showed areas of so-called ‘grungy’
calcification (also referred to as the ‘chondroblas-
toma-like’ variant). This tumour therefore shows
morphological and molecular overlap with phospha-
turic mesenchymal tumour (PMT) (see below). Unlike
PMT, however, soft tissue chondroma has no associa-
tion with fibroblast growth factor 23 expression or
osteomalacia, possibly reflecting its distinct ‘cell of ori-
gin’ or epigenetic profile.52
PERIPHERAL NERVE SHEATH TUMOURS.
An important molecular advance in this category
came with the discovery that a large proportion of
malignant peripheral nerve sheath tumours
(MPNSTs), ~80%, show inactivation of SUZ12 or
EED, which are genes that encode members of poly-
comb repressive complex 2 (PRC2).53,54 PRC2 is an
epigenetic ‘writer’ that normally directs the trimethy-
lation of histone 3 on lysine 27. Loss of PRC2 func-
tion in MPNST therefore erases this methylation
mark. Immunohistochemistry for H3K27me3, (his-
tone H3 trimethylated on lysine 27) to demonstrate
loss of expression, has become a useful diagnostic
marker, particularly in tumours toward the higher-
grade end of the spectrum, with a few limitations,
such as patchy staining in synovial sarcoma and loss
of expression in a subset of radiation-associated sarco-
mas other than MPNST.55–59 Melanotic schwannoma
is now known as malignant melanotic nerve sheath
650 W J Anderson and L A Doyle
tumour, because large case series have better demon-
strated its aggressive behaviour.60 Inactivating muta-
tions in PRKAR1A have also been recognised in the
majority of cases, and loss of PRKAR1A immunohis-
tochemical expression can be used to support the
diagnosis.61 As a further advance, granular cell
tumour has been found to harbour mutations in
ATP6AP1/ATP6AP2 in ~70% of cases; these are not
only the probable inciting tumorigenic events, but
also result in the abnormal vesicle accumulation that
imparts the characteristic granular cytoplasm of this
tumour type.62
A
B SARCOMAS OF BONE AND SOFT TISSUE
Figure 10. A, NTRK-rearranged spindle cell neoplasm is an emerg-
ing entity with heterogeneous morphology. A characteristic feature
is the presence of stromal hyalinisation. There is often infiltrative
growth, as seen around a bronchiole in this pulmonary example
which harboured an NTRK3 rearrangement. B, Immunohistochem-
istry with a pan-TRK antibody usually shows cytoplasmic and/or
nuclear positivity.
TUMOURS OF UNCERTAIN DIFFERENTIATION
The principal change in this section is the inclusion
of NTRK-rearranged soft tissue neoplasms as an
‘emerging’ entity. These tumours occur most com-
monly in children and adolescents, but the age range
is wide, and they are defined molecularly by rear-
rangement of NTRK1, NTRK2, or NTRK3, which are
genes that encode tropomyosin receptor kinases
(although infantile fibrosarcoma, defined by ETV6–
NTRK3 fusion, remains in a separate category).63,64
They include the recently described lipofibromatosis-
like neural tumour.65 Microscopically, they are typi-
cally composed of bland spindle cells in a variably
hyalinised stroma, and they may have solid and infil-
trative growth patterns (Figure 10A). Although most
tumours, particularly those in children, are clinically
benign or intermediate in biological potential (be-
cause of local recurrence), some pursue a more
aggressive clinical course, and this is often associated
with the presence of hypercellularity and a high mito-
tic rate. Immunohistochemically, many are positive
for both S100 and CD34, and reasonably sensitive
(but not entirely specific) pan-TRK antibodies have
also become available (Figure 10B).66,67
PMT was included for the first time in the 2013
WHO classification, and since then two large studies
have characterised FN1–FGFR1 and FN1–FGF1
fusions in almost 50% of cases.68,69
UNDIFFERENTIATED SMALL ROUND CELL
Undifferentiated round cell sarcomas with CIC rear-
rangement, BCOR alterations or gene fusions involv-
ing non-ETS partner genes were each discussed only
briefly in the previous WHO classification. Our under-
standing of these tumours has grown considerably,
such that they are now classified individually in this
section separately from Ewing sarcoma, the tumour
for which many were mistaken in the past. CIC-rear-
ranged sarcomas are high-grade round cell sarcomas
that constitute the largest entity extracted from the
‘Ewing-like’ family of tumours. They are defined by
rearrangement of CIC (capicua), most commonly as a
gene fusion with DUX4, although rarer fusions with
non-DUX4 partner genes, such as FOXO4 and
NUTM1, have also been described.70,71 While this
tumour was originally identified in paediatric
patients, it is now recognised to occur over a wide
age range, and peaks in young adults.72,73 Histologi-
cally, it comprises mildly pleomorphic round cells
with vesicular nuclei, prominent nucleoli, and
© 2020 John Wiley & Sons Ltd, Histopathology, 78, 644–657.

A
B pression.76 Sarcomas with BCOR–CCNB3 occur most
C to be distinct from Ewing sarcoma. Sarcomas with
Figure 11. Round cell sarcomas. A, CIC-rearranged sarcoma typi-
cally has lobulated and sheet-like growth of round cells with mild
nuclear pleomorphism and prominent nucleoli. B, The tumour cells
of BCOR–CCNB3 sarcomas are usually small and round-to-ovoid
with inconspicuous nucleoli, and a delicate vascular network may
be seen. C, EWSR1–PATZ1 sarcomas have a broad range of mor-
phologies. This tumour shows small round cells with clear or
slightly amphophilic cytoplasm. The cells are in nests and trabecu-
lae separated by thin fibrous septae.
© 2020 John Wiley & Sons Ltd, Histopathology, 78, 644–657.
WHO Classification 2020 651
amphophilic cytoplasm, usually growing in a sheet-
like or lobular pattern (Figure 11A). In contrast to
Ewing sarcoma, it generally shows patchy CD99
expression. ETV4 and Wilms’ tumour 1 have emerged
as useful diagnostic markers, but are non-specific and
are best used as part of a panel of stains.74,75 These
tumours have a markedly worse prognosis than
Ewing sarcoma.73
It has also become apparent that a subgroup of
undifferentiated sarcomas with overlapping clinico-
pathological features harbour BCOR genetic alter-
ations. Such alterations, as either gene fusions (most
commonly BCOR–CCNB3) or internal tandem dupli-
cations (ITDs), result in BCOR activation or overex-
commonly in males in the first two decades of life,
and have a predilection for bone.77 However, sarco-
mas with BCOR ITD, in the form of infantile undiffer-
entiated round cell sarcoma or primitive myxoid
mesenchymal tumour of infancy, are more frequent
in soft tissues of the trunk and retroperitoneum. Mor-
phologically, sarcomas with BCOR alterations are
composed of primitive round to ovoid or occasionally
spindled cells (Figure 11B). Immunohistochemistry
for BCOR is sensitive but not specific, and SATB2 and
TLE1 are also often positive.78,79
Finally, rare sarcomas with EWSR1 fusions involv-
ing non-ETS partner genes have now also been
shown, by gene expression and methylation profiling,
EWSR1–NFATC2 (or FUS–NFATC2) arise mostly in
the metaphysis or diaphysis of long bones.80,81 They
show a slight male predominance and occur over a
wide age range, but are most frequent in middle-aged
adults.80,81 Microscopically, they consist of round or
spindled cells often arranged in nests and cords,82
and they may show foci of osseous or cartilaginous
differentiation.
In contrast, sarcomas with EWSR1–PATZ1 are
more common in the deep soft tissues of the trunk
and have a more equal sex distribution.83 The mor-
phological appearances are variable (Figure 11C),
and there is immunohistochemical coexpression of
muscle and neurogenic (S100 and SOX10) mark-
ers.84
Bone
CHONDROGENIC
In the 2013 WHO classification, the term ‘atypical
cartilaginous tumour’ (ACT) was introduced as a sub-
stitute for grade 1 chondrosarcoma, as it was felt that
652 W J Anderson and L A Doyle
A B
C D
such tumours, although locally aggressive, lacked
overtly malignant behaviour. In the 2020 classifica-
tion, it is proposed that ACT should be restricted to
tumours arising in the appendicular skeleton, which
are more amenable to complete surgical resection
than tumours located in the axial skeleton. Con-
versely, ‘chondrosarcoma, grade 1’ should be used for
axial tumours. The use of these two different terms
based on tumour resectability is similar to atypical
lipomatous tumour/well-differentiated liposarcoma.
An important molecular advance in this category
came in 2013, when Behjati et al. characterised recur-
rent p.K36M mutations of H3-3B (H3F3B), or rarely
H3-3A (H3F3A), in ~95% of chondroblastomas.85
Remarkably, the same study identified similar but dis-
tinct histone mutations in giant cell tumour of bone,
another giant cell-rich tumour of the epiphysis (see
below). This has led to the development of a sensitive
and specific immunohistochemical marker directed
against the mutant histone, K36M, facilitating the
diagnosis of chondroblastoma (Figure 12A,B).86 Given
its very low rate of metastasis (<1%), chondroblastoma
is also now classified as benign.
Synovial chondromatosis was previously considered
to be benign, but it is now classed as having interme-
diate (locally aggressive) biological potential. Further-
more, recurrent rearrangements of FN1 and/or
ACVR2A have been characterised in 57% of
cases.52,87,88 Synovial chondromatosis therefore joins
a growing list of mesenchymal tumours with
Figure 12. A,
Chondroblastoma is composed
of relatively uniform ovoid cells
with grooved nuclei and
distinct eosinophilic cytoplasm
within an eosinophilic
chondroid matrix. B, Histone
H3 with K36M mutation
(H3K36M) shows strong
nuclear positivity in tumour
cells. C, Giant cell tumour of
bone in a small biopsy
specimen. D, Histone H3 with
G34W mutation (H3G34W) is
diffusely positive in the
mononuclear cells, but not in
the osteoclast-like giant cells.
fibronectin gene (FN1) rearrangements outlined ear-
lier that show chondroid matrix production.52,87 It is
important to note that FN1/ACVR2A rearrangement
may also be detected in chondrosarcomas that can
rarely develop from synovial chondromatosis.88
Chondromyxoid fibroma is now classified as a
benign entity (with a local recurrence rate of approxi-
mately 10–15%).89 In addition, the majority of cases
are now known to be driven by fusions of the gluta-
mate receptor gene (GRM1). These fusions are formed
by complex genomic rearrangements, i.e. chromo-
plexy and chromothripsis, and result in GRM1 up-
regulation.90
OSTEOGENIC
The most common benign bone-forming neoplasms,
i.e. osteoid osteoma and osteoblastoma, have quite
recently been demonstrated to share FOS (and, less
commonly, FOSB) rearrangements.91 These molec-
ular findings, together with their identical histolog-
ical features, further support a very close
relationship between these tumours. Currently,
however, they are still classified separately, on the
basis of their distinct clinical and radiological pre-
sentations and an arbitrary size cut-off (20 mm).
FISH for FOS rearrangement and FOS immunohis-
tochemistry are emerging as valuable ancillary
tests with which to distinguish challenging cases
from osteosarcoma.91
© 2020 John Wiley & Sons Ltd, Histopathology, 78, 644–657.
 WHO Classification 2020 653

A B

C D

Figure 13. A, Poorly differentiated chordoma composed of sheets of epithelioid cells with moderate nuclear pleomorphism, vesicular chro-
matin, and occasional cells with a slightly rhabdoid appearance. B, Immunohistochemically, there is loss of expression of INI-1/SMARCB1.
C, Dedifferentiated chordoma is composed of highly pleomorphic atypical cells. D, There is loss of nuclear brachyury expression in the dedif-
ferentiated component.

It is of note that small-cell and telangiectatic
osteosarcoma are now described as variants of
osteosarcoma rather than as separate entities.
OSTEOCLASTIC GIANT CELL-RICH
Giant cell tumour of bone has been shown to harbour
H3-3A (H3F3A) mutations in ~95% of cases, the
most common being p.G34W (~90%).85 Immunohis-
tochemically, G34W is positive in the mononuclear
cells, and it has become a very helpful diagnostic
marker (Figure 12C,D). However, G34W positivity is
not synonymous with benignity, as malignant giant
cell tumour of bone can harbour the same mutation.
Non-ossifying fibroma is another benign osteoclast-
rich lesion whose molecular basis has now been
determined. In a recent series of 59 cases, mutually
exclusive mutations of mitogen-activated protein
kinase pathway genes were identified, including
mutations of KRAS (64%), FGFR1 (14%), and NF1
(two cases).92 These intriguing results highlight non-
ossifying fibroma as another example of a ‘self-limit-
ing’ neoplasm, analogous to nodular fasciitis of soft
tissues, as it has long been recognised to undergo
spontaneous regression.92,93
Aneurysmal bone cyst, the third tumour in this
section, was previously in the intermediate (locally
aggressive) category but is now classified as benign.
The designation ‘benign fibrous histiocytoma of
bone’ is no longer recommended. Tumours with such
morphology are now generally considered to be
examples of non-ossifying fibroma when arising in
the metaphysis, or giant cell tumour of bone (with
regressive changes) when located in the epiphysis.
‘Giant cell lesion of the small bones’ is also no longer
regarded as a distinct entity.
NOTOCHORDAL TUMOURS
Poorly differentiated chordoma and dedifferentiated
chordoma are discussed in more detail in the 2020
WHO classification. Poorly differentiated chordoma
was first described in 2010 as an aggressive chor-
doma variant that typically occurs in the base of the
skull or the upper cervical spine of children.94 Mor-
phologically, it is composed of epithelioid cells with
eosinophilic cytoplasm and prominent nucleoli,
arranged in a solid or nested growth pattern with
areas of necrosis (Figure 13A).95 Although it is histo-
logically distinct from conventional chordoma, it is

© 2020 John Wiley & Sons Ltd, Histopathology, 78, 644–657.

654 W J Anderson and L A Doyle
similarly positive for keratins and brachyury. In addi-
tion, this variant is characterised by homozygous
deletions of SMARCB1, and, immunohistochemically,
shows loss of INI-1 (SMARCB1) expression (Fig-
ure 13B).96 Dedifferentiated chordoma, in contrast, is
a high-grade sarcoma that derives from conventional
chordoma and was first described in 1987.97 Progres-
sion to dedifferentiated chordoma is often histologi-
cally abrupt, imparting a biphasic appearance, and is
associated with loss of brachyury expression (Fig-
ure 13C,D).98
OTHER MESENCHYMAL TUMOURS OF BONE
Fibrocartilaginous mesenchymoma is included as a
new entity in this category, having been originally
described by Dahlin et al. in 1984.99 This very rare
tumour of adolescents and young adults tends to
arise in the metaphysis of long bones and is locally
aggressive. Histologically, it is composed of mildly
atypical spindle cells admixed with nodules of hyaline
cartilage that have a ‘growth plate-like’ appearance
and undergo endochondral ossification. In a recent
small series, GNAS and IDH1/2 mutations were
absent, as was MDM2 amplification, providing molec-
ular support for fibrocartilaginous mesenchymoma
being distinct from several other entities that show
overlapping morphology (fibrocartilaginous dysplasia,
chondrosarcoma, and low-grade osteosarcoma,
respectively).100
Adamantinoma, a biphasic fibro-osseous tumour
that almost always arises in the tibia and/or fibula,
has a variety of histological patterns that, in the past,
were all regarded as malignant. However, the osteofi-
brous dysplasia (OFD)-like variant has now been clas-
sified as an intermediate-category (locally aggressive)
neoplasm. In contrast to the classic variant, which
recurs very frequently and can metastasise in approx-
imately 10–30% of cases, the OFD-like variant has a
low local recurrence rate (20%), and metastases are
rare.101–103 Histologically, apart from resembling
OFD, this variant also differs from classic adamanti-
noma by having less prominent epithelial nests.
Finally, very rare examples of dedifferentiated
adamantinoma are also now recognised; these show
transition to a high-grade malignancy with pleomor-
phism and loss of the typical epithelial elements.
Final comments and conclusions
Some terms introduced in the 2020 WHO classifica-
tion for the purpose of International Classification of
Diseases for Oncology (ICD-O) coding (in the tables of
tumour classifications), and for which there is no
clear or corresponding diagnostic category, should be
used with caution or avoided, e.g. ‘epithelioid liposar-
coma’. Epithelioid liposarcoma refers only to a mor-
phological variant of pleomorphic liposarcoma with
predominantly epithelioid cytomorphology rather
than a distinct subtype of liposarcoma. Similarly,
‘clear cell sarcoma NOS’, ‘rhabdoid tumour NOS’ and
‘mesenchymoma NOS’ refer only to clear cell sar-
coma, malignant rhabdoid tumour and fibrocartilagi-
nous mesenchymoma, as there are no other defined
types of these tumours in soft tissue or bone.
In summary, the 2020 WHO classification of soft
tissue and bone tumours incorporates an array of
new information that has been amassed in the
7 years since the previous edition, including major
advances in the molecular characterisation of soft tis-
sue and bone tumours, refinements in tumour classi-
fication, and novel ancillary diagnostic tests, all of
which are helping to improve our understanding of
disease pathogenesis.
Conflicts of interest
The authors have no conflicts of interest to disclose.
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no
new data were created or analyzed in this study.
References
1. Fletcher CDM, Bridge JA, Hogendoorn PCW et al. eds. World
Health Organization classification of tumours of soft tissue and
bone. 4th ed. Lyon: IARC Press, 2013.
2. Anderson WJ, Hornick JL. Immunohistochemical correlates of
recurrent genetic alterations in sarcomas. Genes Chromosomes
Cancer 2019; 58; 111–123.
3. WHO Classification of Tumours Editorial Board eds. World
Health Organization classification of soft tissue and bone tumours.
5th ed. Lyon: IARC Press, 2020.
4. Marino-Enriquez A, Nascimento AF, Ligon AH et al. Atypical
spindle cell lipomatous tumor: clinicopathologic characteriza-
tion of 232 cases demonstrating a morphologic spectrum. Am.
J. Surg. Pathol. 2017; 41; 234–244.
5. Creytens D, Mentzel T, Ferdinande L et al. ‘Atypical’ pleomor-
phic lipomatous tumor: a clinicopathologic, immunohisto-
chemical and molecular study of 21 cases, emphasizing its
relationship to atypical spindle cell lipomatous tumor and sug-
gesting a morphologic spectrum (atypical spindle cell/pleomor-
phic lipomatous tumor). Am. J. Surg. Pathol. 2017; 41; 1443–
1455.
6. Alaggio R, Coffin CM, Weiss SW et al. Liposarcomas in young
patients: a study of 82 cases occurring in patients younger
© 2020 John Wiley & Sons Ltd, Histopathology, 78, 644–657.

than 22 years of age. Am. J. Surg. Pathol. 2009; 33; 645–
658.
7. Hofvander J, Jo VY, Ghanei I et al. Comprehensive genetic
analysis of a paediatric pleomorphic myxoid liposarcoma
reveals near-haploidization and loss of the RB1 gene.
Histopathology 2016; 69; 141–147.
8. Hofvander J, Arbajian E, Stenkula KG et al. Frequent low-level
mutations of protein kinase D2 in angiolipoma. J. Pathol.
2017; 241; 578–582.
9. Carter JM, Weiss SW, Linos K et al. Superficial CD34-positive
fibroblastic tumor: report of 18 cases of a distinctive low-grade
mesenchymal neoplasm of intermediate (borderline) malig-
nancy. Mod. Pathol. 2014; 27; 294–302.
10. Lao IW, Yu L, Wang J. Superficial CD34-positive fibroblastic
tumour: a clinicopathological and immunohistochemical study
of an additional series. Histopathology 2017; 70; 394–401.
11. Puls F, Pillay N, Fagman H et al. PRDM10-rearranged soft tis-
sue tumor: a clinicopathologic study of 9 cases. Am. J. Surg.
Pathol. 2019; 43; 504–513.
12. Marino-Enriquez A, Fletcher CD. Angiofibroma of soft tissue:
clinicopathologic characterization of a distinctive benign
fibrovascular neoplasm in a series of 37 cases. Am. J. Surg.
Pathol. 2012; 36; 500–508.
13. Jin Y, Moller E, Nord KH et al. Fusion of the AHRR and
NCOA2 genes through a recurrent translocation t(5;8)(p15;
q13) in soft tissue angiofibroma results in upregulation of aryl
hydrocarbon receptor target genes. Genes Chromosomes Cancer
2012; 51; 510–520.
14. Kao YC, Flucke U, Eijkelenboom A et al. Novel EWSR1-
SMAD3 gene fusions in a group of acral fibroblastic spindle
cell neoplasms. Am. J. Surg. Pathol. 2018; 42; 522–528.
15. Michal M, Kazakov DV, Michalova K, Michal M. Atypical
multivacuolated lipoblasts and atypical mitoses are not com-
patible with the diagnosis of spindle cell/pleomorphic lipoma
—reply. Hum. Pathol. 2018; 74; 189.
16. Robinson DR, Wu YM, Kalyana-Sundaram S et al. Identifica-
tion of recurrent NAB2-STAT6 gene fusions in solitary fibrous
tumor by integrative sequencing. Nat. Genet. 2013; 45; 180–
185.
17. Doyle LA, Vivero M, Fletcher CD et al. Nuclear expression of
STAT6 distinguishes solitary fibrous tumor from histologic
mimics. Mod. Pathol. 2014; 27; 390–395.
18. Bahrami A, Lee S, Schaefer IM et al. TERT promoter muta-
tions and prognosis in solitary fibrous tumor. Mod. Pathol.
2016; 29; 1511–1522.
19. Demicco EG, Wani K, Ingram D et al. TERT promoter muta-
tions in solitary fibrous tumour. Histopathology 2018; 73;
843–851.
20. Demicco EG, Wagner MJ, Maki RG et al. Risk assessment in
solitary fibrous tumors: validation and refinement of a risk
stratification model. Mod. Pathol. 2017; 30; 1433–1442.
21. Salas S, Resseguier N, Blay JY et al. Prediction of local and
metastatic recurrence in solitary fibrous tumor: construction
of a risk calculator in a multicenter cohort from the French
Sarcoma Group (FSG) database. Ann. Oncol. 2017; 28; 1979–
1987.
22. Al-Ibraheemi A, Folpe AL, Perez-Atayde AR et al. Aberrant
receptor tyrosine kinase signaling in lipofibromatosis: a clini-
copathological and molecular genetic study of 20 cases. Mod.
Pathol. 2019; 32; 423–434.
23. Park JY, Cohen C, Lopez D et al. EGFR exon 20 insertion/du-
plication mutations characterize fibrous hamartoma of
infancy. Am. J. Surg. Pathol. 2016; 40; 1713–1718.
© 2020 John Wiley & Sons Ltd, Histopathology, 78, 644–657.
WHO Classification 2020 655
24. Antonescu CR, Le Loarer F, Mosquera JM et al. Novel YAP1-
TFE3 fusion defines a distinct subset of epithelioid heman-
gioendothelioma. Genes Chromosomes Cancer 2013; 52; 775–
784.
25. Walther C, Tayebwa J, Lilljebjorn H et al. A novel SERPINE1–
FOSB fusion gene results in transcriptional up-regulation of
FOSB in pseudomyogenic haemangioendothelioma. J. Pathol.
2014; 232; 534–540.
26. Agaram NP, Zhang L, Cotzia P, Antonescu CR. Expanding
the spectrum of genetic alterations in pseudomyogenic
hemangioendothelioma with recurrent novel ACTB-FOSB
gene fusions. Am. J. Surg. Pathol. 2018; 42; 1653–1661.
27. Hung YP, Fletcher CD, Hornick JL. FOSB is a useful diagnostic
marker for pseudomyogenic hemangioendothelioma. Am. J.
Surg. Pathol. 2017; 41; 596–606.
28. Montgomery E, Epstein JI. Anastomosing hemangioma of the
genitourinary tract: a lesion mimicking angiosarcoma. Am. J.
Surg. Pathol. 2009; 33; 1364–1369.
29. Bean GR, Joseph NM, Gill RM et al. Recurrent GNAQ muta-
tions in anastomosing hemangiomas. Mod. Pathol. 2017; 30;
722–727.
30. Lim YH, Bacchiocchi A, Qiu J et al. GNA14 somatic mutation
causes congenital and sporadic vascular tumors by MAPK
activation. Am. J. Hum. Genet. 2016; 99; 443–450.
31. Agaimy A, Bieg M, Michal M et al. Recurrent somatic
PDGFRB mutations in sporadic infantile/solitary adult myofi-
bromas but not in angioleiomyomas and myopericytomas.
Am. J. Surg. Pathol. 2017; 41; 195–203.
32. Hung YP, Fletcher CDM. Myopericytomatosis: clinicopatho-
logic analysis of 11 cases with molecular identification of
recurrent PDGFRB alterations in myopericytomatosis and
myopericytoma. Am. J. Surg. Pathol. 2017; 41; 1034–1044.
33. Martignetti JA, Tian L, Li D et al. Mutations in PDGFRB cause
autosomal-dominant infantile myofibromatosis. Am. J. Hum.
Genet. 2013; 92; 1001–1007.
34. Antonescu CR, Sung YS, Zhang L et al. Recurrent SRF-RELA
fusions define a novel subset of cellular myofibroma/myopericy-
toma: a potential diagnostic pitfall with sarcomas with myo-
genic differentiation. Am. J. Surg. Pathol. 2017; 41; 677–684.
35. Linos K, Carter JM, Gardner JM et al. Myofibromas with atypi-
cal features: expanding the morphologic spectrum of a benign
entity. Am. J. Surg. Pathol. 2014; 38; 1649–1654.
36. Mosquera JM, Sboner A, Zhang L et al. Novel MIR143-
NOTCH fusions in benign and malignant glomus tumors.
Genes Chromosomes Cancer 2013; 52; 1075–1087.
37. Chakrapani A, Warrick A, Nelson D et al. BRAF and KRAS
mutations in sporadic glomus tumors. Am. J. Dermatopathol.
2012; 34; 533–535.
38. Karamzadeh Dashti N, Bahrami A, Lee SJ et al. BRAF V600E
mutations occur in a subset of glomus tumors, and are asso-
ciated with malignant histologic characteristics. Am. J. Surg.
Pathol. 2017; 41; 1532–1541.
39. Lee ES, Locker J, Nalesnik M et al. The association of Epstein-
Barr virus with smooth-muscle tumors occurring after organ
transplantation. N. Engl. J. Med. 1995; 332; 19–25.
40. McClain KL, Leach CT, Jenson HB et al. Association of
Epstein-Barr virus with leiomyosarcomas in young people
with AIDS. N. Engl. J. Med. 1995; 332; 12–18.
41. Deyrup AT, Lee VK, Hill CE et al. Epstein-Barr virus-associated
smooth muscle tumors are distinctive mesenchymal tumors
reflecting multiple infection events: a clinicopathologic and
molecular analysis of 29 tumors from 19 patients. Am. J.
Surg. Pathol. 2006; 30; 75–82.
656 W J Anderson and L A Doyle
42. Merchant W, Calonje E, Fletcher CD. Inflammatory
leiomyosarcoma: a morphological subgroup within the
heterogeneous family of so-called inflammatory malignant
fibrous histiocytoma. Histopathology 1995; 27; 525–532.
43. Dal Cin P, Sciot R, Fletcher CD et al. Inflammatory
leiomyosarcoma may be characterized by specific near-haploid
chromosome changes. J. Pathol. 1998; 185; 112–115.
44. Arbajian E, Koster J, Vult von Steyern F, Mertens F. Inflam-
matory leiomyosarcoma is a distinct tumor characterized by
near-haploidization, few somatic mutations, and a primitive
myogenic gene expression signature. Mod. Pathol. 2018; 31;
93–100.
45. Kohsaka S, Shukla N, Ameur N et al. A recurrent neomorphic
mutation in MYOD1 defines a clinically aggressive subset of
embryonal rhabdomyosarcoma associated with PI3K-AKT
pathway mutations. Nat. Genet. 2014; 46; 595–600.
46. Szuhai K, de Jong D, Leung WY et al. Transactivating muta-
tion of the MYOD1 gene is a frequent event in adult spindle
cell rhabdomyosarcoma. J. Pathol. 2014; 232; 300–307.
47. Alaggio R, Zhang L, Sung YS et al. A molecular study of pedi-
atric spindle and sclerosing rhabdomyosarcoma: identification
of novel and recurrent VGLL2-related fusions in infantile
cases. Am. J. Surg. Pathol. 2016; 40; 224–235.
48. Mosquera JM, Sboner A, Zhang L et al. Recurrent NCOA2
gene rearrangements in congenital/infantile spindle cell rhab-
domyosarcoma. Genes Chromosomes Cancer 2013; 52; 538–
550.
49. Watson S, Perrin V, Guillemot D et al. Transcriptomic defini-
tion of molecular subgroups of small round cell sarcomas. J.
Pathol. 2018; 245; 29–40.
50. Dashti NK, Wehrs RN, Thomas BC et al. Spindle cell rhab-
domyosarcoma of bone with FUS–TFCP2 fusion: confirmation
of a very recently described rhabdomyosarcoma subtype.
Histopathology 2018; 73; 514–520.
51. Agaram NP, Zhang L, Sung YS et al. Expanding the spectrum
of intraosseous rhabdomyosarcoma: correlation between 2
distinct gene fusions and phenotype. Am. J. Surg. Pathol.
2019; 43; 695–702.
52. Amary F, Perez-Casanova L, Ye H et al. Synovial chondro-
matosis and soft tissue chondroma: extraosseous cartilaginous
tumor defined by FN1 gene rearrangement. Mod. Pathol.
2019; 32; 1762–1771.
53. Lee W, Teckie S, Wiesner T et al. PRC2 is recurrently inacti-
vated through EED or SUZ12 loss in malignant peripheral
nerve sheath tumors. Nat. Genet. 2014; 46; 1227–1232.
54. Zhang M, Wang Y, Jones S et al. Somatic mutations of SUZ12
in malignant peripheral nerve sheath tumors. Nat. Genet.
2014; 46; 1170–1172.
55. Schaefer IM, Fletcher CD, Hornick JL. Loss of H3K27
trimethylation distinguishes malignant peripheral nerve
sheath tumors from histologic mimics. Mod. Pathol. 2016; 29;
4–13.
56. Prieto-Granada CN, Wiesner T, Messina JL et al. Loss of
H3K27me3 expression is a highly sensitive marker for spo-
radic and radiation-induced MPNST. Am. J. Surg. Pathol.
2016; 40; 479–489.
57. Cleven AH, Sannaa GA, Briaire-de Bruijn I et al. Loss of
H3K27 tri-methylation is a diagnostic marker for malignant
peripheral nerve sheath tumors and an indicator for an infe-
rior survival. Mod. Pathol. 2016; 29; 582–590.
58. Mentzel T, Kiss K. Reduced H3K27me3 expression in radia-
tion-associated angiosarcoma of the breast. Virchows Arch.
2018; 472; 361–368.
59. Panse G, Mito JK, Ingram DRet al.Radiation-associated sarco-
mas other than malignant peripheral nerve sheath tumors
demonstrate loss of histone H3K27 trimethylation.
Histopathology 2020. E-pub ahead of print, 31 July.
60. Khoo M, Pressney I, Hargunani R, Tirabosco R. Melanotic
schwannoma: an 11-year case series. Skeletal Radiol. 2016;
45; 29–34.
61. Wang L, Zehir A, Sadowska J et al. Consistent copy number
changes and recurrent PRKAR1A mutations distinguish
melanotic schwannomas from melanomas: SNP-array and
next generation sequencing analysis. Genes Chromosomes Can-
cer 2015; 54; 463–471.
62. Pareja F, Brandes AH, Basili T et al. Loss-of-function muta-
tions in ATP6AP1 and ATP6AP2 in granular cell tumors.
Nat. Commun. 2018; 9; 3533.
63. Suurmeijer AJH, Dickson BC, Swanson D et al. A novel group
of spindle cell tumors defined by S100 and CD34 co-expres-
sion shows recurrent fusions involving RAF1, BRAF, and
NTRK1/2 genes. Genes Chromosomes Cancer 2018; 57; 611–
621.
64. Yamazaki F, Nakatani F, Asano N et al. Novel NTRK3 fusions
in fibrosarcomas of adults. Am. J. Surg. Pathol. 2019; 43;
523–530.
65. Agaram NP, Zhang L, Sung YS et al. Recurrent NTRK1 gene
fusions define a novel subset of locally aggressive lipofibro-
matosis-like neural tumors. Am. J. Surg. Pathol. 2016; 40;
1407–1416.
66. Hechtman JF, Benayed R, Hyman DM et al. Pan-Trk immuno-
histochemistry is an efficient and reliable screen for the detec-
tion of NTRK fusions. Am. J. Surg. Pathol. 2017; 41; 1547–
1551.
67. Hung YP, Fletcher CDM, Hornick JL. Evaluation of pan-TRK
immunohistochemistry in infantile fibrosarcoma, lipofibro-
matosis-like neural tumour and histological mimics.
Histopathology 2018; 73; 634–644.
68. Lee JC, Jeng YM, Su SY et al. Identification of a novel FN1–
FGFR1 genetic fusion as a frequent event in phosphaturic
mesenchymal tumour. J. Pathol. 2015; 235; 539–545.
69. Lee JC, Su SY, Changou CA et al. Characterization of FN1–
FGFR1 and novel FN1–FGF1 fusion genes in a large series of
phosphaturic mesenchymal tumors. Mod. Pathol. 2016; 29;
1335–1346.
70. Le Loarer F, Pissaloux D, Watson S et al. Clinicopathologic
features of CIC-NUTM1 sarcomas, a new molecular variant of
the family of CIC-fused sarcomas. Am. J. Surg. Pathol. 2019;
43; 268–276.
71. Sugita S, Arai Y, Tonooka A et al. A novel CIC-FOXO4 gene
fusion in undifferentiated small round cell sarcoma: a geneti-
cally distinct variant of Ewing-like sarcoma. Am. J. Surg.
Pathol. 2014; 38; 1571–1576.
72. Richkind KE, Romansky SG, Finklestein JZ. t(4;19)(q35;
q13.1): a recurrent change in primitive mesenchymal
tumors? Cancer Genet. Cytogenet. 1996; 87; 71–74.
73. Antonescu CR, Owosho AA, Zhang L et al. Sarcomas
with CIC-rearrangements are a distinct pathologic entity
with aggressive outcome: a clinicopathologic and molecu-
lar study of 115 cases. Am. J. Surg. Pathol. 2017; 41; 941–
949.
74. Hung YP, Fletcher CD, Hornick JL. Evaluation of ETV4 and
WT1 expression in CIC-rearranged sarcomas and histologic
mimics. Mod. Pathol. 2016; 29; 1324–1334.
75. Le Guellec S, Velasco V, Perot G et al. ETV4 is a useful mar-
ker for the diagnosis of CIC-rearranged undifferentiated
© 2020 John Wiley & Sons Ltd, Histopathology, 78, 644–657.

round-cell sarcomas: a study of 127 cases including mimick-
ing lesions. Mod. Pathol. 2016; 29; 1523–1531.
76. Pierron G, Tirode F, Lucchesi C et al. A new subtype of bone
sarcoma defined by BCOR-CCNB3 gene fusion. Nat. Genet.
2012; 44; 461–466.
77. Puls F, Niblett A, Marland G et al. BCOR-CCNB3 (Ewing-like)
sarcoma: a clinicopathologic analysis of 10 cases, in compar-
ison with conventional Ewing sarcoma. Am. J. Surg. Pathol.
2014; 38; 1307–1318.
78. Li WS, Liao IC, Wen MC et al. BCOR–CCNB3-positive soft tissue
sarcoma with round-cell and spindle-cell histology: a series of
four cases highlighting the pitfall of mimicking poorly differen-
tiated synovial sarcoma. Histopathology 2016; 69; 792–801.
79. Kao YC, Owosho AA, Sung YS et al. BCOR-CCNB3 fusion pos-
itive sarcomas: a clinicopathologic and molecular analysis of
36 cases with comparison to morphologic spectrum and clini-
cal behavior of other round cell sarcomas. Am. J. Surg. Pathol.
2018; 42; 604–615.
80. Diaz-Perez JA, Nielsen GP, Antonescu C et al. EWSR1/FUS-
NFATc2 rearranged round cell sarcoma: clinicopathological
series of 4 cases and literature review. Hum. Pathol. 2019;
90; 45–53.
81. Perret R, Escuriol J, Velasco V et al. NFATc2-rearranged sar-
comas: clinicopathologic, molecular, and cytogenetic study of
7 cases with evidence of AGGRECAN as a novel diagnostic
marker. Mod. Pathol. 2020; 33; 1930–1944.
82. Wang GY, Thomas DG, Davis JL et al. EWSR1-NFATC2
translocation-associated sarcoma clinicopathologic findings in
a rare aggressive primary bone or soft tissue tumor. Am. J.
Surg. Pathol. 2019; 43; 1112–1122.
83. Bridge JA, Sumegi J, Druta M et al. Clinical, pathological, and
genomic features of EWSR1-PATZ1 fusion sarcoma. Mod.
Pathol. 2019; 32; 1593–1604.
84. Chougule A, Taylor MS, Nardi V et al. Spindle and round cell
sarcoma with EWSR1-PATZ1 gene fusion: a sarcoma with
polyphenotypic differentiation. Am. J. Surg. Pathol. 2019; 43;
220–228.
85. Behjati S, Tarpey PS, Presneau N et al. Distinct H3F3A and
H3F3B driver mutations define chondroblastoma and giant
cell tumor of bone. Nat. Genet. 2013; 45; 1479–1482.
86. Amary MF, Berisha F, Mozela R et al. The H3F3 K36M mutant
antibody is a sensitive and specific marker for the diagnosis of
chondroblastoma. Histopathology 2016; 69; 121–127.
87. Agaram NP, Zhang L, Dickson BC et al. A molecular study of
synovial chondromatosis. Genes Chromosomes Cancer 2020;
59; 144–151.
88. Totoki Y, Yoshida A, Hosoda F et al. Unique mutation por-
traits and frequent COL2A1 gene alteration in chondrosar-
coma. Genome Res. 2014; 24; 1411–1420.
© 2020 John Wiley & Sons Ltd, Histopathology, 78, 644–657.
WHO Classification 2020 657
89. Bhamra JS, Al-Khateeb H, Dhinsa BS et al. Chondromyxoid
fibroma management: a single institution experience of 22
cases. World J. Surg. Oncol. 2014; 12; 283.
90. Nord KH, Lilljebjorn H, Vezzi F et al. GRM1 is upregulated
through gene fusion and promoter swapping in chondromyx-
oid fibroma. Nat. Genet. 2014; 46; 474–477.
91. Fittall MW, Mifsud W, Pillay N et al. Recurrent rearrange-
ments of FOS and FOSB define osteoblastoma. Nat. Commun.
2018; 9; 2150.
92. Baumhoer D, Kovac M, Sperveslage J et al. Activating muta-
tions in the MAP-kinase pathway define non-ossifying
fibroma of bone. J. Pathol. 2019; 248; 116–122.
93. Bovee JV, Hogendoorn PC. Non-ossifying fibroma: a RAS-
MAPK driven benign bone neoplasm. J. Pathol. 2019; 248;
127–130.
94. Mobley BC, McKenney JK, Bangs CD et al. Loss of SMARCB1/
INI1 expression in poorly differentiated chordomas. Acta Neu-
ropathol. 2010; 120; 745–753.
95. Shih AR, Cote GM, Chebib I et al. Clinicopathologic character-
istics of poorly differentiated chordoma. Mod. Pathol. 2018;
31; 1237–1245.
96. Hasselblatt M, Thomas C, Hovestadt V et al. Poorly differenti-
ated chordoma with SMARCB1/INI1 loss: a distinct molecular
entity with dismal prognosis. Acta Neuropathol. 2016; 132;
149–151.
97. Meis JM, Raymond AK, Evans HL et al. ‘Dedifferentiated’
chordoma. A clinicopathologic and immunohistochemical
study of three cases. Am. J. Surg. Pathol. 1987; 11; 516–
525.
98. Vujovic S, Henderson S, Presneau N et al. Brachyury, a cru-
cial regulator of notochordal development, is a novel biomar-
ker for chordomas. J. Pathol. 2006; 209; 157–165.
99. Dahlin DC, Bertoni F, Beabout JW, Campanacci M. Fibrocarti-
laginous mesenchymoma with low-grade malignancy. Skeletal
Radiol. 1984; 12; 263–269.
100. Gambarotti M, Righi A, Vanel D et al. Fibrocartilaginous mes-
enchymoma of bone: a single-institution experience with
molecular investigations and a review of the literature.
Histopathology 2017; 71; 134–142.
101. Scholfield DW, Sadozai Z, Ghali C et al. Does osteofibrous dys-
plasia progress to adamantinoma and how should they be
treated? Bone Joint J. 2017; 99-b; 409–416.
102. Keeney GL, Unni KK, Beabout JW, Pritchard DJ. Adamanti-
noma of long bones. A clinicopathologic study of 85 cases.
Cancer 1989; 64; 730–737.
103. Houdek MT, Sherman CE, Inwards CY et al. Adamantinoma
of bone: long-term follow-up of 46 consecutive patients. J.
Surg. Oncol. 2018; 118; 1150–1154.