Pathology (February 2014) 46(2), pp.
95–104
SOFT TISSUE PATHOLOGY
WHO classification of soft tissue tumours: an update based on the 2013
(4th) edition
VICKIE Y. JO AND CHRISTOPHER D. M. FLETCHER
Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
Summary
The fourth edition of the World Health Organization (WHO)
Classification of Tumours of Soft Tissue and Bone was
published in February 2013, and serves to provide an updated
classification scheme and reproducible diagnostic criteria for
pathologists. Given the relative rarity of soft tissue tumours
and the rapid rate of immunohistochemical and genetic/mol-
ecular developments (not infrequently facilitating recognition
of new tumour entities), this updated text edited by a con-
sensus group is important for both practising pathologists and
oncologists. The 2013 WHO classification includes several
changes in soft tissue tumour classification, including several
new entities (e.g., pseudomyogenic haemangioendothe-
lioma, haemosiderotic fibrolipomatous tumour, and acral
fibromyxoma), three newly included sections for gastro-
intestinal stromal tumours, nerve sheath tumours, and
undifferentiated/unclassified soft tissue tumours, respect-
ively, various ‘reclassified’ tumours, and a plethora of new
genetic and molecular data for established tumour types that
facilitate better definition and are useful as diagnostic tools.
This article briefly outlines these updates based on the 2013
WHO classification of soft tissue tumours.
Key words: Sarcoma, soft tissue, tumour, WHO classification.
Received 28 October, accepted 13 November 2013
INTRODUCTION
The publication of the fourth edition of the World Health
Organization (WHO) Classification of Tumours of Soft Tissue
and Bone followed the meeting of an expert consensus group
that convened in Zurich, Switzerland, 18–20 April 2012. The
WHO texts, which are updated every 5–10 years for nearly all
organ systems, ideally provide pathologists with updated tumour
classification schemes based on currently available data (phe-
notypic, cytogenetic, and molecular) and propagate reproducible
diagnostic criteria. In the field of soft tissue pathology, this
consensus work is especially critical given the relative rarity
of soft tissue neoplasms and current rapid rate of immunohisto-
chemical and genetic/molecular developments and advances.
The WHO classification organises soft tissue neoplasms by
tumour type, as determined by morphological, immunohisto-
chemical and genetic features. The working group discussed
and edited each tumour type in detail, each authored by selected
contributors, to provide a consensus text on all diagnostic
entities. The 2002 classification organised tumours as
adipocytic, fibroblastic/myofibroblastic, so-called fibrohistio-
cytic, smooth muscle, pericytic/perivascular, skeletal muscle,
vascular, chondro-osseous, and the group labelled as ‘tumours
Print ISSN 0031-3025/Online ISSN 1465-3931 # 2014 Royal College of Pathologists of Australasia
DOI: 10.1097/PAT.0000000000000050
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
of uncertain differentiation’. This 2013 edition1 also now
includes chapters devoted to gastrointestinal stromal tumours
and nerve sheath tumours, which were formerly in other WHO
texts, and a newly introduced section for undifferentiated/
unclassified sarcomas.
Herein we discuss updates in the new 2013 WHO classifi-
cation,1 outlining changes from the 2002 WHO classification
scheme, with emphasis on newly described entities, novel
immunohistochemical markers, and new genetic/molecular data.
ADIPOCYTIC TUMOURS
There were no major changes for adipocytic tumours in the
fourth edition, with the exception of the removal of the terms
‘round cell liposarcoma’ and ‘mixed-type liposarcoma’. ‘Rou-
nd cell liposarcoma’ is no longer used, as the hypercellular and
high grade areas in myxoid liposarcoma are not exclusively
round cell in morphological appearance and, in fact, are more
often spindle-celled. Tumours previously classified as ‘mixed-
type liposarcoma’ are now thought mostly to be unusual
examples of dedifferentiated liposarcoma, based on currently
available immunohistochemical and molecular studies.
Chondroid lipomas are now known to be associated with the
recurrent translocation t(11;16)(q13;p13), resulting in
C11orf95-MKL2 fusion product,2 which has been validated
in a further study of eight cases since publication of the 2013
WHO classification.3
Since 2002, the immunohistochemical markers MDM2 and
CDK4 have come into widespread use for the diagnosis of
atypical lipomatous tumour/well-differentiated liposarcoma
and dedifferentiated liposarcoma. These nuclear markers are
antibodies against the gene products coded on 12q13-15 that are
amplified (in either supernumerary ring or giant marker
chromosomes) in atypical lipomatous tumour/well-differen-
tiated liposarcoma and dedifferentiated liposarcoma.4,5 For
negative or equivocal immunohistochemical results found in
clinically suspicious lesions, it is increasingly accepted that
molecular studies (usually FISH) are necessary. This is now
critical given the current understanding that lipomas can
(rarely) occur in the retroperitoneum, with a benign clinical
course.6,7 The diagnosis of retroperitoneal lipoma generally
requires confirmation of absent 12q13-15 amplification in
order to exclude the statistically more likely possibility of
well-differentiated liposarcoma.
The terminology ‘atypical lipomatous tumour’ and ‘well-
differentiated liposarcoma’ continues to need clarification.
While the section heading now lists only ‘atypical lipomatous
tumour’, the authors point out that retention of ‘well-differen-
tiated liposarcoma’ is still appropriate for tumours in sites
at which margin-negative resection is often impossible
 96 JO and FLETCHER
(e.g., retroperitoneum, mediastinum), since such tumours are
associated with substantial mortality.
Dedifferentiated liposarcoma is now known in some cases to
exhibit ‘homologous lipoblastic differentiation’, in which the
dedifferentiated component may exhibit lipoblasts and have
morphological features indistinguishable from pleomorphic
liposarcoma8 (see Fig. 1). Since publication of the 2013
WHO classification, a further series of 18 such cases has been
published, which included two cases that showed a homologous
lipoblastic component with low nuclear grade.9
FIBROBLASTIC/MYOFIBROBLASTIC TUMOURS
This category was updated to include major immunohistochem-
ical and genetic/molecular developments for several tumours,
including nodular fasciitis, myxoinflammatory fibroblastic sar-
coma, low grade fibromyxoid sarcoma, and sclerosing epithe-
lioid fibrosarcoma. Two tumour types formerly in the skin
volume are now included in the soft tissue volume: giant cell
fibroblastoma and dermatofibrosarcoma protuberans [both
defined by t(17;22)(q21;q13) resulting in PDGFB-COL1A1
fusion] and which occasionally occur together as hybrid tumours.
Two entities are no longer included in this category: (1) myofi-
broma/myofibromatosis, now classified as a ‘Pericytic (perivas-
cular) tumour’; and (2) giant cell angiofibroma which is now
listed as a synonym for extrapleural solitary fibrous tumour.
Nodular fasciitis, having the classical history of rapid growth
and spontaneous regression, was long considered by many to be a
A
B Low grade fibromyxoid sarcoma (LGFMS) harbours reci-
Fig. 1 Dedifferentiated liposarcoma showing homologous lipoblastic dedif-
ferentiation. This retroperitoneal tumour has morphological features closely
resembling pleomorphic liposarcoma with abundant lipoblasts (A) but was
strongly positive for MDM2 (B) and CDK4 (not shown).
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
Pathology (2014), 46(2), February
reactive process, though sometimes misinterpreted as a sarcoma
when biopsied during the active growth phase owing to the
troubling clinical presentation and frequently high mitotic
activity. However, nodular fasciitis is now understood to be a
‘self-limiting’ clonal neoplasm with the discovery of
the recurrent translocation involving 17p13 and 22q13.1, result-
ing in MYH9-USP6 gene fusion.10 Notably, the USP6 gene is also
involved in the recurrent and consistent translocation in primary
aneurysmal bone cyst (but absent in secondary aneurysmal bone
cyst),11–13 most commonly being fused with CDH11.
Mammary-type myofibroblastoma, cellular angiofibroma,
and spindle cell lipoma/pleomorphic lipoma are closely related,
as first appreciated by shared morphological features and now
confirmed by cytogenetic studies. Spindle cell lipoma/pleo-
morphic lipoma has long been known to harbour consistent
rearrangements of 13q and 16q.14,15 While morphological
overlap has been recognised between spindle lipoma/pleo-
morphic lipoma, mammary-type myofibroblastoma and cellu-
lar angiofibroma, studies have demonstrated cytogenetic
similarities as well. Mammary-type myofibroblastoma, includ-
ing tumours occurring in extra-mammary sites, has been shown
to harbour both 13q and 16q abnormalities;16,17 more recently
cellular angiofibroma has been shown to have aberrations
involving the 13q14 locus.18,19 In spindle cell lipoma, re-
arrangement or deletion of 13q appears to affect the locus at
13q14, which includes the region encoding the tumour sup-
pressor Retinoblastoma (Rb);20 although not included in the
updated WHO classification, immunohistochemistry for Rb
may be helpful in diagnosing spindle cell lipoma/pleomorphic
lipoma, cellular angiofibroma, and mammary-type myofibro-
blastoma; Rb expression is absent in tumour cells secondary to
13q14 rearrangement21 (see Fig. 2). Lastly, the histological
spectrum of cellular angiofibroma now includes the rare occur-
rence of severe cytological atypia or ‘sarcomatous transform-
ation’, particularly in vulvovaginal sites, although this does not
seem to confer any increased tendency for recurrence when
compared to conventional cellular angiofibroma.22
Notably, for extrapleural solitary fibrous tumour, there is
now complete omission of the prior synonym ‘haemangioper-
icytoma’. Despite being published after the 2013 WHO classi-
fication, several significant recent studies warrant mention. It
has been demonstrated that solitary fibrous tumours are charac-
terised by a gene fusion resulting from inversion of two genes
located on chromosome 12q13, leading to a NAB2-STAT6
fusion product,23,24 and hence overexpression of STAT6
protein. Nuclear staining for STAT6 by immunohistochemistry
has very recently been shown to be a highly sensitive and
specific marker for solitary fibrous tumour,25,26 which is diag-
nostically very valuable as conventional cytogenetic methods
cannot detect the intrachromosomal NAB2-STAT6 fusion.
Myxoinflammatory fibroblastic sarcoma is now known to be
characterised by the translocation t(1;10)(p22–31;q24–25),
which has also been identified in haemosiderotic fibrolipoma-
tous tumour (a newly described entity classified under
‘Tumours of uncertain differentiation’).27,28 Interestingly,
hybrid tumours with features of both myxoinflammatory fibro-
blastic sarcoma and haemosiderotic fibrolipomatous tumour
are increasingly being recognised.28,29
procal translocations of the FUS gene (on chromosome 16p11),
most frequently with CREB3L2 (7q33) or CREB3L1 (11p11). A
newly described immunohistochemical marker, MUC4, has
had major diagnostic impact; gene expression studies identified
 WHO CLASSIFICATION OF SOFT TISSUE TUMOURS: AN UPDATE 97

A A

B B

Fig. 2 Spindle cell lipoma (A) often shows immunohistochemical loss of Rb Fig. 3 Immunohistochemistry for MUC4 is highly sensitive and specific for
expression (B). low grade fibromyxoid sarcoma (A, H&E; B, MUC4).

MUC4 to be overexpressed in LGFMS30 and nuclear immu- terminology ‘malignant fibrous histiocytoma (MFH)’. Even
nostaining for MUC4 protein has high sensitivity and speci- at the time of the last WHO volume in 2002, it was recognised
ficity for LGFMS31 (Fig. 3). MUC4 is also positive in up to that most tumours previously labelled as MFH could be more
70% of sclerosing epithelioid fibrosarcomas (also a ‘Fibroblas- specifically classified with currently available immunohisto-
tic/myofibroblastic tumour’), a subset of which shares the same chemical and genetic/molecular markers.36,37 Tumours classi-
FUS-CREB3L1 translocation as LGFMS.32 Furthermore, fied as undifferentiated/unclassified pleomorphic sarcoma
tumours showing hybrid features of these two ‘entities’ are should only be labelled as such after exclusion of specific
now known to occur32,33 (Fig. 4). lines of differentiation (including epithelial and melanocytic)
Growing knowledge of the defining immunohistochemical (see ‘Undifferentiated/unclassified sarcomas’).
and molecular/genetic features of tumour entities has No other major changes were made in this tumour group, but
also facilitated recognition of new and important morphological additional genetic and molecular data are now available. Both
variants. A good example is the epithelioid variant of inflam-
matory myofibroblastic tumour, which shows consistently more
aggressive biological behaviour (it is considered by some to be
better named ‘epithelioid inflammatory myofibroblastic sar-
coma’) and its characteristic translocation confers a unique
staining pattern by ALK immunohistochemistry.34 The epithe-
lioid variant is associated with ALK-RANBP2 gene fusion; this
fusion results in characteristic nuclear membrane staining, as
RANBP2 localises ALK to the nuclear membrane (Fig. 5). The
epithelioid variant of myxofibrosarcoma, also recently
described, bears close morphological resemblance to carcinoma
or melanoma and shows more aggressive biological behaviour
than usual-type myxofibrosarcoma.35

SO-CALLED FIBROHISTIOCYTIC TUMOURS

This section is now updated with a significant change – the Fig. 4 ‘Hybrid’ tumour showing abrupt transition between low grade fibro-
abandonment of the outdated and largely meaningless myxoid sarcoma and sclerosing epithelioid fibrosarcoma.

Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
 98 JO and FLETCHER
A cell/sclerosing rhabdomyosarcoma as a separate category. Pre-
B within an extensively hyalinised stroma (thus sometimes appear-
Fig. 5 Epithelioid ‘inflammatory myofibroblastic sarcoma’ (A) shows epithe-
lioid morphology and a characteristic nuclear membrane staining pattern for
ALK (B).
localised and diffuse types of tenosynovial giant cell tumour are
characterised by reciprocal translocations involving the CSF
gene on chromosome 1p13, most frequently with the COL6A3
gene on chromosome 2q37.38–40
SMOOTH MUSCLE TUMOURS
The only notable change in this tumour group is that angio-
leiomyoma is now classified under ‘Pericytic (perivascular)
tumours’ (see next section).
PERICYTIC (PERIVASCULAR) TUMOURS
A few major changes were made in the classification scheme
for this tumour group, based on the observation of a continuous
morphological spectrum between entities in this category.
Lesions previously classified as ‘myofibroma’ are now classi-
fied under ‘myopericytoma, including myofibroma’ based on
the morphological continuum between these tumours. Further-
more, because angioleiomyoma shares morphological features
with myopericytoma, by showing perivascular concentric
arrangement of smooth muscle cells, this entity is now classi-
fied in this section.
For glomus tumour, there are differences in the recommen-
dation for designation of tumours as ‘malignant’ and ‘uncertain
malignant potential’ compared to the third edition. The current
designation of ‘malignant’ glomus tumours applies to tumours
having marked nuclear atypia and any level of mitotic activity,
or having atypical mitotic figures. In 2002, tumour size greater
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
Pathology (2014), 46(2), February
than 2.0 cm and location in a deep site were considered to be
features of malignancy; tumours with these features (in the
absence of nuclear atypia) are now classified as glomus tumours
of ‘uncertain malignant potential’. Glomus tumours may be
associated with neurofibromatosis-1,41,42 and a subset of spora-
dic cases have been associated with BRAF (V600E) or KRAS
(G12A) mutations.43 After publication of the WHO classifi-
cation, NOTCH mutations (of either NOTCH2 or NOTCH3)
have also been demonstrated to be present in some glomus
tumours.44
SKELETAL MUSCLE TUMOURS
The major change in this tumour group is the listing of spindle
viously, in 2002, spindle cell rhabdomysoarcoma was listed as a
variant of embryonal rhabdomyosarcoma. Spindle cell rhabdo-
myosarcoma in the paediatric population occurs most frequently
in paratesticular sites and is associated with a more favourable
outcome compared to other rhabdomyosarcoma subtypes. How-
ever, the clinicopathological features of spindle cell rhabdomyo-
sarcoma are different in adults: tumours most frequently occur in
head and neck sites and are associated with a significantly poorer
outcome than in children, with up to a 50% rate of recurrence and
metastasis.45 Furthermore, spindle cell rhabdomyosarcomas in
young children are associated with rearrangements of NCOA2,46
although this appears to be absent in tumours in adults. Scleros-
ing rhabdomyosarcoma most frequently occurs in the limbs in
both adults and children. These tumours show mostly spindled
cells with nested, microalveolar, or trabecular growth patterns
ing ‘pseudovascular’)47,48 (Fig. 6). Some spindle cell rhabdo-
myosarcomas show sclerosing morphology in proportions
ranging from focal to subtotal, helping to underscore the morpho-
logical continuum. In adults these tumours are also associated
with a high rate of recurrence and metastasis.
VASCULAR TUMOURS
This section includes numerous updates from the 2002 edition,
including the addition of the entity of pseudomyogenic hae-
mangioendothelioma and genetic characterisation of epithe-
lioid haemangioendothelioma and secondary angiosarcomas.
The entity pseudomyogenic (epithelioid sarcoma-like) hae-
mangioendothelioma49,50 was introduced in the 2013 WHO
Fig. 6 Sclerosing rhabdomyosarcoma. Tumour cells are embedded in a densely
hyaline stroma.
 WHO CLASSIFICATION OF SOFT TISSUE TUMOURS: AN UPDATE 99

analysis of the fusion protein in so-called ‘multifocal’ liver

tumours demonstrated that the multiple foci are in fact mono-
clonal,54 which suggests that multifocal disease represents
locoregional metastasis rather than independent primary
tumours. Since publication of the new WHO classification,
it has been reported that YAP1-TFE3 translocation defines a
further distinct subset of epithelioid haemangioendotheliomas
which tend to affect younger adults and focally show well-
formed vascular channels.55 Risk stratification according to
size and mitotic activity has been proposed, based on a large
series of conventional epithelioid haemangioendothelioma, that
reported 59% 5-year survival rate when patients had tumours
A larger than 3.0 cm and more than 3 mitoses per 50 high power
fields, in contrast to patients with tumours lacking these features
that had a 5-year disease-specific survival rate of 100%.56
Genetic data which help characterise angiosarcomas in more
detail are emerging. Notably, the majority of angiosarcomas
associated with radiation or pre-existing lymphoedema are
associated with MYC gene amplification with co-amplification
of FLT4 in a quarter of cases,57–59 which can be demonstrated
by fluorescence in situ hybridisation or immunohistochemistry
(Fig. 8). This may be helpful in challenging cases where
atypical post-radiation vascular proliferation (which does not
show MYC amplification) is in the differential diagnosis. A
subset of primary angiosarcoma is also now known to be
B associated with MYC amplification.60 Both primary and sec-
ondary mammary angiosarcomas show KDR mutations in up to
10% of tumours.61 Lastly, while mammary angiosarcoma dis-
plays a wide histological range, the histological grade is not
predictive of biological behaviour,62 as is already recognised at
other anatomical locations.

Fig. 7 Pseudomyogenic haemangioendothelioma (A). Tumour cells express

the endothelial marker ERG (B) and cytokeratin AE1/AE3 (C).

classification. This tumour most frequently occurs in young adult A

males on the limbs, and two-thirds of cases have the distinctive
presentation as multifocal nodules involving multiple tissue
planes (dermal, subcutaneous, subfascial, and even intraoss-
eous). Microscopically, the nodules are comprised of relatively
uniform plump spindle cells distributed in a discohesive fashion
or in loose fascicles or sometimes sheets, with eosinophilic
cytoplasm and vesicular nuclei with small nucleoli (Fig. 7).
Admixed neutrophils are quite common. Tumour cells are
positive for AE1/AE3 and ERG, and CD31 is frequently positive
(50% of tumours). Pan-keratin, EMA, S-100, CD34, and desmin
are negative. Furthermore, this tumour is characterised by a
t(7;19) translocation.51 Despite the often worrisome clinical
presentation, true metastasis seems to be very infrequent.
Epithelioid haemangioendothelioma is characterised by the
translocation t(1;3)(p36;q23–25), resulting in the fusion gene B
WWTR1-CAMTA1.52,53 This translocation is present in these Fig. 8 Radiation-associated angiosarcoma (A) showing MYC amplification by
tumours at all anatomical sites. Furthermore, breakpoint immunohistochemistry (B).

Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
 100 JO and FLETCHER Pathology (2014), 46(2), February

CHONDRO-OSSEOUS TUMOURS
No major changes were effected in the category of chondro-
osseous lesions.

GASTROINTESTINAL STROMAL TUMOURS

Gastrointestinal stromal tumours (GISTs) are now included in
this volume, having previously been included in the volume on
gastrointestinal tumours. The immunohistochemical marker
DOG-1 has emerged as a highly sensitive and specific marker
for GIST,63,64 and appears to be positive in approximately one-
third of KIT-immunonegative GISTs.65 The risk stratification
scheme recommended by the National Comprehensive Cancer
Network (NCCN) guidelines, first established in 2006 and A
modified in 2010,66 is now widely used for reporting GIST.
This risk stratification scheme is based on anatomical site,
tumour size, and mitotic count, which have been shown in the
several large retrospective series of Miettinen et al. to be highly
predictive of malignant behaviour.67,68
Much has been learned about GIST from a genetic standpoint
that has important clinical implications. The majority of GISTs
(90%) harbour mutations in c-kit or PDGFRA; those c-kit
with mutations in exon 9 or 11 are the most responsive to the
tyrosine kinase inhibitor agent imatinib, albeit exon 9 tumours
often require a higher dose. It has been increasingly recognised
that many wild-type GISTs are characterised by succinate
dehydrogenase (SDH) ‘deficiency’, secondary to inactivation
of SDHA, B, C, or D genes. This group of tumours were first
described as ‘paediatric-type’ or ‘wild-type’ GISTs (in adults B
and children), being distinct for lacking c-kit or PDGFR-alpha Fig. 9 Multinodular growth through muscularis propria and epithelioid
mutations, strikingly epithelioid morphology, multinodular morphology (A) is characteristic of succinate dehydrogenase B deficient gastro-
growth pattern within the gastric wall and frequent lymph node intestinal stromal tumours (B).
metastases69 (Fig. 9). The behaviour of these lesions cannot be
predicted using conventional NCCN risk stratification. SDH areas of Schwann cells and perineurial cells73 (Fig. 10). Hybrid
deficiency can be identified by immunohistochemistry: loss of neurofibroma/schwannomas are more common in neurofibro-
SDHB staining occurs in tumours with a mutation in any one of matosis-1 patients, and display a biphasic appearance in which
the SDH genes, whereas loss of both SDHB and SDHA seemingly hypercellular nests of schwannian cells are inter-
expression is seen only in the context of an SDHA mutation.70 spersed within a typical or plexiform neurofibroma.74 The
The small proportion of patients in this group that have germ- components in a hybrid nerve sheath tumour can be highlighted
line mutations (Carney–Stratakis syndrome, characterised by using immunohistochemistry: EMA and Claudin-1 for peri-
GIST and paraganglioma) can thus be identified and referred neurial cells and S-100 for Schwann cells and neurofibroma
for genetic counselling. Interestingly, the spectrum of SDH cells, and less specifically, CD34 and NFP to highlight a
deficient tumours and familial syndromes has been expanding, neurofibromatous component.
including familial phaeochromocytoma-paraganglioma and
SDHB deficient renal tumours.71,72
TUMOURS OF UNCERTAIN DIFFERENTIATION
Four tumour types are included for the first time in this section
NERVE SHEATH TUMOURS in the 2013 WHO classification: acral fibromyxoma, atypical
This group of tumours is now included in the 2013 WHO soft fibroxanthoma, haemosiderotic fibrolipomatous tumour, and
tissue volume and includes nerve sheath neoplasms occurring phosphaturic mesenchymal tumour. Numerous immunohisto-
in both cutaneous and deep-seated locations, many of which chemical and molecular developments have been made to
have previously been included in other volumes. This section further define existing entities, as described below.
describes the new category of hybrid nerve sheath tumours, Acral fibromyxoma (also known as digital fibromyxoma) is a
which bear hybrid features of more than one type of conven- benign lesion that typically occurs in subungual/periungual
tional nerve sheath tumour. Hybrid nerve sheath tumours occur sites on the hands or feet.75,76 These lesions show a population
most frequently in dermal or subcutaneous sites over a wide of benign spindle and stellate fibroblastic-type cells typically
anatomical distribution, and show a similar benign clinical arranged in alternating fibrous and myxoid areas, having
course to their component counterparts. By far the most com- minimal atypia and extremely low (if any) mitotic activity
mon is hybrid schwannoma/perineurioma, which occurs (Fig. 11). These lesions are positive for CD34 and have a low
sporadically and most frequently occurs on the distal extremi- rate of recurrence (particularly if incompletely excised), but no
ties in adults (although the age and anatomical site distributions risk of metastasis has been reported.
are wide). These tumours are well-circumscribed and charac- Atypical fibroxanthoma is now included in this volume. This
terised by a storiform or fascicular architecture with alternating dermal tumour, when strictly defined, is a benign lesion with

Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.

Fig. 10 Hybrid schwannoma/perineurioma with storiform architecture.
essentially no risk for recurrence or metastasis. These lesions
are rapidly growing, nodular/polypoid and usually associated
with solar elastosis. Atypical fibroxanthoma is completely
confined to the dermis, usually shows smooth demarcation
from normal dermis, and often ‘pushes down’ normal skin
adnexal structures. The tumour cells are typically pleomorphic
with frequent mitotic activity. Spindle cell squamous cell
carcinoma and malignant melanoma must always be excluded,
usually by immunohistochemistry.
Haemosiderotic fibrolipomatous tumour is a locally aggres-
sive tumour that most frequently occurs on the distal lower
extremity in adult females,77,78 and as mentioned above, shares
the same t(1;10) translocation as myxoinflammatory fibroblas-
tic sarcoma (with which it occasionally occurs in hybrid
tumours).28,29 Microscopically, tumours are comprised of
fibroblastic spindle cells lacking significant atypia or mitotic
activity, arranged in fascicles with associated haemosiderin
deposition, haemosiderin-laden macrophages, osteoclastic-like
giant cells, and interdigitating in a complex fashion with a
mature adipocytic component (Fig. 12). CD34 is frequently
positive. Tumours have a recurrence rate of 30–50% when
incompletely excised.
Phosphaturic mesenchymal tumour, which had inadvertently
been omitted from prior editions, typically affects adults in a
wide anatomical distribution, and is notable for its association
with osteomalacia, related to over-expression of FGF23 (which
is also elevated in serum).79 These tumours are comprised of
bland spindle to stellate cells growing in sheets with haeman-
giopericytoma-like vessels and stromal calcifications often
described as ‘grungy’ (Fig. 13). Most tumours lack features
Fig. 11 Acral fibromyxoma showing uniform spindle cell morphology with
vaguely fascicular or whorled growth patterns within a collagenous stroma.
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
WHO CLASSIFICATION OF SOFT TISSUE TUMOURS: AN UPDATE 101
Fig. 12 Haemosiderotic fibrolipomatous tumour showing an admixture of
bland fibroblastic cells and adiopocytes with associated haemosiderin depo-
sition.
of malignancy and follow a benign clinical course; osteoma-
lacia typically resolves after resection. Malignant examples
are infrequent.
Since the last WHO edition, myoepithelial neoplasms have
been further characterised by morphological, immunohisto-
chemical, and genetic means. These tumours are now known
to occur over a wide age range in a broad anatomical distri-
bution (including visceral locations). Mixed tumours show
ductal differentiation, while myoepithelioma is comprised
of purely myoepithelial cells. Myoepithelial carcinoma of
skin and soft tissue is defined strictly by cytological atypia
(although often associated with high mitotic rate and necro-
sis) and often shows an aggressive clinical course in both
children and adults80,81 (Fig. 14), in contrast to salivary gland
counterparts in which malignancy is largely based on architec-
tural features (i.e., invasive growth). Mixed tumours and myoe-
pitheliomas typically show a benign clinical course, with a low
risk of recurrence (20%) usually following incomplete excision.
Notably, mixed tumours show PLAG1 gene rearrangement (also
observed by immunohistochemistry),82,83 supporting a relation-
ship with the salivary counterpart. In contrast, a subset of
myoepitheliomas and myoepithelial carcinomas of soft tissue
are associated with EWSR1 translocations.84–88 Likely owing to
functional loss of material on chromosome 22q, SMARCB1/
INI1 expression is lost in a subset of myoepitheliomas and
myoepithelial carcinomas.89
Ossifying fibromyxoid tumours are now known to be associ-
ated with recurrent rearrangement of PHF1, located on 6p21.90,91
Fig. 13 Phosphaturic mesenchymal tumour with bland myoid-appearing spin-
dle cells and ‘grungy’ calcification.
 102 JO and FLETCHER
Fig. 14 Myoepithelial carcinoma in soft tissue showing cytological atypia and
mitoses.
The designation of tumours as ‘atypical’ or ‘malignant’ remains
in discussion, but features such as high nuclear grade, high
cellularity, mitotic activity >2 per 50 high power fields, and
atypical ossification within tumour nodules have been suggested
as features of malignancy. Since publication of the WHO
classification, a large series of conventional, atypical, and malig-
nant tumours have been shown to have PHF1 gene rearrange-
ment by FISH,92 confirming that genetically-defined ossifying
fibromyxoid tumour shows a wide range of morphology and
behaviour.
For PEComa, malignant criteria remain to be clearly defined
and validated, but certain histological features appear predic-
tive of malignant behaviour: mitotic activity, necrosis, marked
nuclear atypia, pleomorphism, large size, and infiltrative
growth.93 A sclerosing variant is also now recognised, charac-
terised by densely collagenous stroma in which cords of tumour
cells are embedded; this variant is reported to occur most
frequently in the retroperitoneum (often perirenal).94 While
PEComas have long been known to express both myoid and
melanocytic immunohistochemical markers, a small percen-
tage of tumours are negative for MiTF, Mart-1, and HMB-45;
these lesions often harbour a TFE3 gene fusion and are in turn
immunopositive for TFE3.93,95
UNDIFFERENTIATED/UNCLASSIFIED
SARCOMAS
This new category, which may comprise up to 20% of all
pleomorphic soft tissue sarcomas37 (and 25% of radiation-
associated sarcomas96,97), encompasses tumours in which all
recognisable lines of differentiation have been excluded. Many
of these tumours, at least when pleomorphic, would have been
called ‘malignant fibrous histiocytoma’ in the past. These
tumours are typically high grade, show a wide range of
morphological features, and are often associated with a poor
prognosis. These tumours can be subclassified according to
predominant morphological patterns: round cell, spindle cell,
pleomorphic, and epithelioid. In younger patients, genetic
subsets seem to be emerging. These include round cell sarco-
mas with EWSR1 translocations with non-ETS fusion partners
(including SP398 and POU5F199), CIC-DUX4 transloca-
tion100,101 (Fig. 15) and BCOR-CCNB3 fusion.102 It has yet
to be determined with certainty whether these morphological or
genetic subgroups represent distinct clinicopathological enti-
ties, but this seems likely.
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
Pathology (2014), 46(2), February
Fig. 15 Undifferentiated round cell sarcoma with CIC-DUX4 translocation
typically shows vesicular nuclei with prominent nucleoli and often more
cytoplasm than Ewing sarcoma.
CONCLUSION
This article briefly outlines updates in the 2013 WHO classi-
fication of soft tissue tumours, with emphases on newly
described or included entities. This new volume is based upon
a multitude of studies that have helped better define tumour
types, with much unique new information regarding immuno-
histochemical markers and genetic/molecular data that provide
more uniform diagnostic criteria for pathologists to reference.
The prognostic and therapeutic significance of most of the
continually growing body of genetic/molecular data has yet to
be determined.
Conflicts of interest and sources of funding: The authors state
that there are no conflicts of interest to disclose.
Address for correspondence: Dr C. D. M. Fletcher, Department of Pathology,
Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA.
E-mail: cfletcher@partners.org
References
1. Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, editors. WHO
Classification of Tumours of Soft Tissue and Bone. Pathology and Genetics
of Tumours of Soft Tissue and Bone. 4th ed. Lyon: IARC Press, 2013.
2. Huang D, Sumegi J, Dal Cin P, et al. C11orf95-MKL2 is the resulting
fusion oncogene of t(11;16)(q13;p13) in chondroid lipoma. Genes Chro-
mosomes Cancer 2010; 49: 810–8.
3. Flucke U, Tops BB, de Saint Aubain Somerhausen N, et al. Presence of
C11orf95-MKL2 fusion is a consistent finding in chondroid lipomas: a
study of eight cases. Histopathology 2013; 62: 925–30.
4. Binh MB, Sastre-Garau X, Guillou L, et al. MDM2 and CDK4 immu-
nostainings are useful adjuncts in diagnosing well-differentiated and
dedifferentiated liposarcoma subtypes: a comparative analysis of 559
soft tissue neoplasms with genetic data. Am J Surg Pathol 2005; 29:
1340–7.
5. Sirvent N, Coindre JM, Maire G, et al. Detection of MDM2-CDK4
amplification by fluorescence in situ hybridization in 200 paraffin-
embedded tumor samples: utility in diagnosing adipocytic lesions and
comparison with immunohistochemistry and real-time PCR. Am J Surg
Pathol 2007; 31: 1476–89.
6. Ida CM, Wang X, Erickson-Johnson MR, et al. Primary retroperitoneal
lipoma: a soft tissue pathology heresy?: report of a case with classic
histologic, cytogenetics, and molecular genetic features. Am J Surg Pathol
2008; 32: 951–4.
7. Macarenco RS, Erickson-Johnson M, Wang X, et al. Retroperitoneal
lipomatous tumors without cytologic atypia: are they lipomas? A clin-
icopathologic and molecular study of 19 cases. Am J Surg Pathol 2009; 33:
1470–6.
8. Marino-Enriquez A, Fletcher CD, Dal Cin P, Hornick JL. Dedifferentiated
liposarcoma with ‘homologous’ lipoblastic (pleomorphic liposarcoma-
like) differentiation: clinicopathologic and molecular analysis of a
series suggesting revised diagnostic criteria. Am J Surg Pathol 2010;
34: 1122–31.

9. Liau JY, Lee JC, Wu CT, Kuo KT, Huang HY, Liang CW. Dedifferentiated
liposarcoma with homologous lipoblastic differentiation: expanding the
spectrum to include low-grade tumours. Histopathology 2013; 62: 702–
10.
10. Erickson-Johnson MR, Chou MM, Evers BR, et al. Nodular fasciitis: a
novel model of transient neoplasia induced by MYH9-USP6 gene fusion.
Lab Invest 2011; 91: 1427–33.
11. Oliveira AM, Hsi BL, Weremowicz S, et al. USP6 (Tre2) fusion onco-
genes in aneurysmal bone cyst. Cancer Res 2004; 64: 1920–3.
12. Oliveira AM, Perez-Atayde AR, Inwards CY, et al. USP6 and CDH11
oncogenes identify the neoplastic cell in primary aneurysmal bone cysts
and are absent in so-called secondary aneurysmal bone cysts. Am J Pathol
2004; 165: 1773–80.
13. Oliveira AM, Perez-Atayde AR, Dal Cin P, et al. Aneurysmal bone cyst
variant translocations upregulate USP6 transcription by promoter swap-
ping with the ZNF9, COL1A1, TRAP150, and OMD genes. Oncogene
2005; 24: 3419–26.
14. Dal Cin P, Sciot R, Polito P, et al. Lesions of 13q may occur independently
of deletion of 16q in spindle cell/pleomorphic lipomas. Histopathology
1997; 31: 222–5.
15. Dahlen A, Debiec-Rychter M, Pedeutour F, et al. Clustering of deletions
on chromosome 13 in benign and low-malignant lipomatous tumors. Int J
Cancer 2003; 103: 616–23.
16. Pauwels P, Sciot R, Croiset F, Rutten H, Van den Berghe H, Dal Cin P.
Myofibroblastoma of the breast: genetic link with spindle cell lipoma.
J Pathol 2000; 191: 282–5.
17. Magro G, Righi A, Casorzo L, et al. Mammary and vaginal myofibro-
blastomas are genetically related lesions: fluorescence in situ hybridiza-
tion analysis shows deletion of 13q14 region. Hum Pathol 2012; 43:
1887–93.
18. Maggiani F, Debiec-Rychter M, Vanbockrijck M, Sciot R. Cellular
angiofibroma: another mesenchymal tumour with 13q14 involvement,
suggesting a link with spindle cell lipoma and (extra)-mammary myofi-
broblastoma. Histopathology 2007; 51: 410–2.
19. Flucke U, van Krieken JH, Mentzel T. Cellular angiofibroma: analysis of
25 cases emphasizing its relationship to spindle cell lipoma and mam-
mary-type myofibroblastoma. Mod Pathol 2011; 24: 82–9.
20. Bartuma H, Nord KH, Macchia G, et al. Gene expression and single
nucleotide polymorphism array analyses of spindle cell lipomas and
conventional lipomas with 13q14 deletion. Genes Chromosomes Cancer
2011; 50: 619–32.
21. Chen BJ, Marino-Enriquez A, Fletcher CD, Hornick JL. Loss of retino-
blastoma protein expression in spindle cell/pleomorphic lipomas and
cytogenetically related tumors: an immunohistochemical study with
diagnostic implications. Am J Surg Pathol 2012; 36: 1119–28.
22. Chen E, Fletcher CD. Cellular angiofibroma with atypia or sarcomatous
transformation: clinicopathologic analysis of 13 cases. Am J Surg Pathol
2010; 34: 707–14.
23. Robinson DR, Wu YM, Kalyana-Sundaram S, et al. Identification of
recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by inte-
grative sequencing. Nat Genet 2013; 45: 180–5.
24. Mohajeri A, Tayebwa J, Collin A, et al. Comprehensive genetic analysis
identifies a pathognomonic NAB2/STAT6 fusion gene, nonrandom sec-
ondary genomic imbalances, and a characteristic gene expression profile
in solitary fibrous tumor. Genes Chromosomes Cancer 2013; 52: 873–86.
25. Schweizer L, Koelsche C, Sahm F, et al. Meningeal hemangiopericytoma
and solitary fibrous tumors carry the NAB2-STAT6 fusion and can be
diagnosed by nuclear expression of STAT6 protein. Acta Neuropathol
2013; 125: 651–8.
26. Doyle LA, Vivero M, Fletcher CD, Mertens F, Hornick JL. Nuclear
expression of STAT6 distinguishes solitary fibrous tumor from histologic
mimics. Mod Pathol 2013; Sep 13: (Epub ahead of print).
27. Hallor KH, Sciot R, Staaf J, et al. Two genetic pathways, t(1;10) and
amplification of 3p11-12, in myxoinflammatory fibroblastic sarcoma,
haemosiderotic fibrolipomatous tumour, and morphologically similar
lesions. J Pathol 2009; 217: 716–27.
28. Antonescu CR, Zhang L, Nielsen GP, Rosenberg AE, Dal Cin P, Fletcher
CD. Consistent t(1;10) with rearrangements of TGFBR3 and MGEA5 in
both myxoinflammatory fibroblastic sarcoma and hemosiderotic fibroli-
pomatous tumor. Genes Chromosomes Cancer 2011; 50: 757–64.
29. Elco CP, Marino-Enriquez A, Abraham JA, Dal Cin P, Hornick JL. Hybrid
myxoinflammatory fibroblastic sarcoma/hemosiderotic fibrolipomatous
tumor: report of a case providing further evidence for a pathogenetic
link. Am J Surg Pathol 2010; 34: 1723–7.
30. Moller E, Hornick JL, Magnusson L, Veerla S, Domanski HA, Mertens F.
FUS-CREB3L2/L1-positive sarcomas show a specific gene expression
profile with upregulation of CD24 and FOXL1. Clin Cancer Res 2011; 17:
2646–56.
31. Doyle LA, Moller E, Dal Cin P, Fletcher CD, Mertens F, Hornick JL.
MUC4 is a highly sensitive and specific marker for low-grade fibromyxoid
sarcoma. Am J Surg Pathol 2011; 35: 733–41.
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
WHO CLASSIFICATION OF SOFT TISSUE TUMOURS: AN UPDATE 103
32. Doyle LA, Wang WL, Dal Cin P, et al. MUC4 is a sensitive and extremely
useful marker for sclerosing epithelioid fibrosarcoma: association with
FUS gene rearrangement. Am J Surg Pathol 2012; 36: 1444–51.
33. Guillou L, Benhattar J, Gengler C, et al. Translocation-positive low-grade
fibromyxoid sarcoma: clinicopathologic and molecular analysis of a series
expanding the morphologic spectrum and suggesting potential relation-
ship to sclerosing epithelioid fibrosarcoma: a study from the French
Sarcoma Group. Am J Surg Pathol 2007; 31: 1387–402.
34. Marino-Enriquez A, Wang WL, Roy A, et al. Epithelioid inflammatory
myofibroblastic sarcoma: An aggressive intra-abdominal variant of in-
flammatory myofibroblastic tumor with nuclear membrane or perinuclear
ALK. Am J Surg Pathol 2011; 35: 135–44.
35. Nascimento AF, Bertoni F, Fletcher CD. Epithelioid variant of
myxofibrosarcoma: expanding the clinicomorphologic spectrum of
myxofibrosarcoma in a series of 17 cases. Am J Surg Pathol 2007;
31: 99–105.
36. Hollowood K, Fletcher CD. Malignant fibrous histiocytoma: morphologic
pattern or pathologic entity? Semin Diagn Pathol 1995; 12: 210–20.
37. Fletcher CD, Gustafson P, Rydholm A, Willen H, Akerman M.
Clinicopathologic re-evaluation of 100 malignant fibrous histiocytomas:
prognostic relevance of subclassification. J Clin Oncol 2001; 19: 3045–
50.
38. West RB, Rubin BP, Miller MA, et al. A landscape effect in tenosynovial
giant-cell tumor from activation of CSF1 expression by a translocation in a
minority of tumor cells. Proc Natl Acad Sci USA 2006; 103: 690–5.
39. Cupp JS, Miller MA, Montgomery KD, et al. Translocation and expres-
sion of CSF1 in pigmented villonodular synovitis, tenosynovial giant cell
tumor, rheumatoid arthritis and other reactive synovitides. Am J Surg
Pathol 2007; 31: 970–6.
40. Moller E, Mandahl N, Mertens F, Panagopoulos I. Molecular identification
of COL6A3-CSF1 fusion transcripts in tenosynovial giant cell tumors.
Genes Chromosomes Cancer 2008; 47: 21–5.
41. Brems H, Park C, Maertens O, et al. Glomus tumors in neurofibromatosis
type 1: genetic, functional, and clinical evidence of a novel association.
Cancer Res 2009; 69: 7393–401.
42. Stewart DR, Pemov A, Van Loo P, et al. Mitotic recombination of
chromosome arm 17q as a cause of loss of heterozygosity of NF1 in
neurofibromatosis type 1-associated glomus tumors. Genes Chromosomes
Cancer 2012; 51: 429–37.
43. Chakrapani A, Warrick A, Nelson D, Beadling C, Corless CL. BRAF and
KRAS mutations in sporadic glomus tumors. Am J Dermatopathol 2012;
34: 533–5.
44. Mosquera JM, Sboner A, Zhang L, et al. Novel MIR143-NOTCH fusions
in benign and malignant glomus tumors. Genes Chromosomes Cancer
2013; 52: 1075–87.
45. Nascimento AF, Fletcher CD. Spindle cell rhabdomyosarcoma in adults.
Am J Surg Pathol 2005; 29: 1106–13.
46. Mosquera JM, Sboner A, Zhang L, et al. Recurrent NCOA2 gene
rearrangements in congenital/infantile spindle cell rhabdomyosarcoma.
Genes Chromosomes Cancer 2013; 52: 538–50.
47. Mentzel T, Katenkamp D. Sclerosing, pseudovascular rhabdomyosarcoma
in adults. Clinicopathological and immunohistochemical analysis of three
cases. Virchows Arch 2000; 436: 305–11.
48. Folpe AL, McKenney JK, Bridge JA, Weiss SW. Sclerosing rhabdomyo-
sarcoma in adults: report of four cases of a hyalinizing, matrix-rich variant
of rhabdomyosarcoma that may be confused with osteosarcoma, chon-
drosarcoma, or angiosarcoma. Am J Surg Pathol 2002; 26: 1175–83.
49. Billings SD, Folpe AL, Weiss SW. Epithelioid sarcoma-like hemangioen-
dothelioma. Am J Surg Pathol 2003; 27: 48–57.
50. Hornick JL, Fletcher CD. Pseudomyogenic hemangioendothelioma: a
distinctive, often multicentric tumor with indolent behavior. Am J Surg
Pathol 2011; 35: 190–201.
51. Trombetta D, Magnusson L, von Steyern FV, Hornick JL, Fletcher CD,
Mertens F. Translocation t(7;19)(q22;q13)-a recurrent chromosome aber-
ration in pseudomyogenic hemangioendothelioma? Cancer Genet 2011;
204: 211–5.
52. Errani C, Zhang L, Sung YS, et al. A novel WWTR1-CAMTA1 gene
fusion is a consistent abnormality in epithelioid hemangioendothelioma of
different anatomic sites. Genes Chromosomes Cancer 2011; 50: 644–53.
53. Tanas MR, Sboner A, Oliveira AM, et al. Identification of a disease-
defining gene fusion in epithelioid hemangioendothelioma. Sci Transl
Med 2011; 3: 98ra82.
54. Errani C, Sung YS, Zhang L, Healey JH, Antonescu CR. Monoclonality of
multifocal epithelioid hemangioendothelioma of the liver by analysis of
WWTR1-CAMTA1 breakpoints. Cancer Genet 2012; 205: 12–7.
55. Antonescu CR, Le Loarer F, Mosquera JM, et al. Novel YAP1-TFE3
fusion defines a distinct subset of epithelioid hemangioendothelioma.
Genes Chromosomes Cancer 2013; 52: 775–84.
56. Deyrup AT, Tighiouart M, Montag AG, Weiss SW. Epithelioid heman-
gioendothelioma of soft tissue: a proposal for risk stratification based on
49 cases. Am J Surg Pathol 2008; 32: 924–7.
 104 JO and FLETCHER
57. Manner J, Radlwimmer B, Hohenberger P, et al. MYC high level gene
amplification is a distinctive feature of angiosarcomas after irradiation or
chronic lymphedema. Am J Pathol 2010; 176: 34–9.
58. Guo T, Zhang L, Chang NE, Singer S, Maki RG, Antonescu CR.
Consistent MYC and FLT4 gene amplification in radiation-induced
angiosarcoma but not in other radiation-associated atypical vascular
lesions. Genes Chromosomes Cancer 2011; 50: 25–33.
59. Mentzel T, Schildhaus HU, Palmedo G, Buttner R, Kutzner H. Postradia-
tion cutaneous angiosarcoma after treatment of breast carcinoma is
characterized by MYC amplification in contrast to atypical vascular
lesions after radiotherapy and control cases: clinicopathological, immu-
nohistochemical and molecular analysis of 66 cases. Mod Pathol 2012; 25:
75–85.
60. Italiano A, Thomas R, Breen M, et al. The miR-17-92 cluster and its target
THBS1 are differentially expressed in angiosarcomas dependent on MYC
amplification. Genes Chromosomes Cancer 2012; 51: 569–78.
61. Antonescu CR, Yoshida A, Guo T, et al. KDR activating mutations in
human angiosarcomas are sensitive to specific kinase inhibitors. Cancer
Res 2009; 69: 7175–9.
62. Nascimento AF, Raut CP, Fletcher CD. Primary angiosarcoma of the
breast: clinicopathologic analysis of 49 cases, suggesting that grade is not
prognostic. Am J Surg Pathol 2008; 32: 1896–904.
63. West RB, Corless CL, Chen X, et al. The novel marker, DOG1, is
expressed ubiquitously in gastrointestinal stromal tumors irrespective
of KIT or PDGFRA mutation status. Am J Pathol 2004; 165: 107–13.
64. Miettinen M, Wang ZF, Lasota J. DOG1 antibody in the differential
diagnosis of gastrointestinal stromal tumors: a study of 1840 cases. Am J
Surg Pathol 2009; 33: 1401–8.
65. Liegl B, Hornick JL, Corless CL, Fletcher CD. Monoclonal antibody
DOG1.1 shows higher sensitivity than KIT in the diagnosis of gastro-
intestinal stromal tumors, including unusual subtypes. Am J Surg Pathol
2009; 33: 437–46.
66. Demetri GD, von Mehren M, Antonescu CR, et al. NCCN Task Force
report: update on the management of patients with gastrointestinal stromal
tumors. J Natl Compr Canc Netw 2010; 8 (Suppl 2): S1–41.
67. Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the
stomach: a clinicopathologic, immunohistochemical, and molecular ge-
netic study of 1765 cases with long-term follow-up. Am J Surg Pathol
2005; 29: 52–68.
68. Miettinen M, Makhlouf H, Sobin LH, Lasota J. Gastrointestinal stromal
tumors of the jejunum and ileum: a clinicopathologic, immunohistochem-
ical, and molecular genetic study of 906 cases before imatinib with long-
term follow-up. Am J Surg Pathol 2006; 30: 477–89.
69. Rege TA, Wagner AJ, Corless CL, Heinrich MC, Hornick JL. Pediatric-
type’ gastrointestinal stromal tumors in adults: distinctive histology predicts
genotype and clinical behavior. Am J Surg Pathol 2011; 35: 495–504.
70. Dwight T, Benn DE, Clarkson A, et al. Loss of SDHA expression identifies
SDHA mutations in succinate dehydrogenase-deficient gastrointestinal
stromal tumors. Am J Surg Pathol 2013; 37: 226–33.
71. Gill AJ, Pachter NS, Chou A, et al. Renal tumors associated with germline
SDHB mutation show distinctive morphology. Am J Surg Pathol 2011; 35:
1578–85.
72. Barletta JA, Hornick JL. Succinate dehydrogenase-deficient tumors:
diagnostic advances and clinical implications. Adv Anat Pathol 2012;
19: 193–203.
73. Hornick JL, Bundock EA, Fletcher CD. Hybrid schwannoma/perineur-
ioma: clinicopathologic analysis of 42 distinctive benign nerve sheath
tumors. Am J Surg Pathol 2009; 33: 1554–61.
74. Harder A, Wesemann M, Hagel C, et al. Hybrid neurofibroma/schwan-
noma is overrepresented among schwannomatosis and neurofibromatosis
patients. Am J Surg Pathol 2012; 36: 702–9.
75. Fetsch JF, Laskin WB, Miettinen M. Superficial acral fibromyxoma: a
clinicopathologic and immunohistochemical analysis of 37 cases of a
distinctive soft tissue tumor with a predilection for the fingers and toes.
Hum Pathol 2001; 32: 704–14.
76. Hollmann TJ, Bovee JV, Fletcher CD. Digital fibromyxoma (superficial
acral fibromyxoma): a detailed characterization of 124 cases. Am J Surg
Pathol 2012; 36: 789–98.
77. Marshall-Taylor C, Fanburg-Smith JC. Hemosiderotic fibrohistiocytic
lipomatous lesion: ten cases of a previously undescribed fatty lesion of
the foot/ankle. Mod Pathol 2000; 13: 1192–9.
78. Browne TJ, Fletcher CD. Haemosiderotic fibrolipomatous tumour
(so-called haemosiderotic fibrohistiocytic lipomatous tumour): analysis
of 13 new cases in support of a distinct entity. Histopathology 2006; 48:
453–61.
79. Bahrami A, Weiss SW, Montgomery E, et al. RT-PCR analysis for FGF23
using paraffin sections in the diagnosis of phosphaturic mesenchymal
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
Pathology (2014), 46(2), February
tumors with and without known tumor induced osteomalacia. Am J Surg
Pathol 2009; 33: 1348–54.
80. Hornick JL, Fletcher CD. Myoepithelial tumors of soft tissue: a clinico-
pathologic and immunohistochemical study of 101 cases with evaluation
of prognostic parameters. Am J Surg Pathol 2003; 27: 1183–96.
81. Gleason BC, Fletcher CD. Myoepithelial carcinoma of soft tissue in
children: an aggressive neoplasm analyzed in a series of 29 cases. Am
J Surg Pathol 2007; 31: 1813–24.
82. Bahrami A, Dalton JD, Krane JF, Fletcher CD. A subset of cutaneous and
soft tissue mixed tumors are genetically linked to their salivary gland
counterpart. Genes Chromosomes Cancer 2012; 51: 140–8.
83. Antonescu CR, Zhang L, Shao SY, et al. Frequent PLAG1 gene rearran-
gements in skin and soft tissue myoepithelioma with ductal differentiation.
Genes Chromosomes Cancer 2013; 52: 675–82.
84. Brandal P, Panagopoulos I, Bjerkehagen B, et al. Detection of a
t(1;22)(q23;q12) translocation leading to an EWSR1-PBX1 fusion gene
in a myoepithelioma. Genes Chromosomes Cancer 2008; 47: 558–64.
85. Brandal P, Panagopoulos I, Bjerkehagen B, Heim S. t(19;22)(q13;q12)
translocation leading to the novel fusion gene EWSR1-ZNF444 in soft
tissue myoepithelial carcinoma. Genes Chromosomes Cancer 2009; 48:
1051–6.
86. Antonescu CR, Zhang L, Chang NE, et al. EWSR1-POU5F1 fusion in soft
tissue myoepithelial tumors. A molecular analysis of sixty-six cases,
including soft tissue, bone, and visceral lesions, showing common in-
volvement of the EWSR1 gene. Genes Chromosomes Cancer 2010; 49:
1114–24.
87. Flucke U, Palmedo G, Blankenhorn N, Slootweg PJ, Kutzner H, Mentzel
T. EWSR1 gene rearrangement occurs in a subset of cutaneous
myoepithelial tumors: a study of 18 cases. Mod Pathol 2011; 24:
1444–50.
88. Jo VY, Antonescu CR, Zhang L, Dal Cin P, Hornick JL, Fletcher CD.
Cutaneous syncytial myoepithelioma: clinicopathologic characterization
in a series of 38 cases. Am J Surg Pathol 2013; 37: 710–8.
89. Hornick JL, Dal Cin P, Fletcher CD. Loss of INI1 expression is char-
acteristic of both conventional and proximal-type epithelioid sarcoma. Am
J Surg Pathol 2009; 33: 542–50.
90. Gebre-Medhin S, Nord KH, Moller E, et al. Recurrent rearrangement of
the PHF1 gene in ossifying fibromyxoid tumors. Am J Pathol 2012; 181:
1069–77.
91. Endo M, Kohashi K, Yamamoto H, et al. Ossifying fibromyxoid tumor
presenting EP400-PHF1 fusion gene. Hum Pathol 2013; 44: 2603–8.
92. Graham RP, Weiss SW, Sukov WR, et al. PHF1 rearrangements in
ossifying fibromyxoid tumors of soft parts: a fluorescence in situ hybri-
dization study of 41 cases with emphasis on the malignant variant. Am J
Surg Pathol 2013; 37: 1751–5.
93. Folpe AL, Mentzel T, Lehr HA, Fisher C, Balzer BL, Weiss SW.
Perivascular epithelioid cell neoplasms of soft tissue and gynecologic
origin: a clinicopathologic study of 26 cases and review of the literature.
Am J Surg Pathol 2005; 29: 1558–75.
94. Hornick JL, Fletcher CD. Sclerosing PEComa: clinicopathologic analysis
of a distinctive variant with a predilection for the retroperitoneum. Am J
Surg Pathol 2008; 32: 493–501.
95. Argani P, Aulmann S, Illei PB, et al. A distinctive subset of PEComas
harbors TFE3 gene fusions. Am J Surg Pathol 2010; 34: 1395–406.
96. Laskin WB, Silverman TA, Enzinger FM. Postradiation soft tissue sarco-
mas. An analysis of 53 cases. Cancer 1988; 62: 2330–40.
97. Gladdy RA, Qin LX, Moraco N, et al. Do radiation-associated soft tissue
sarcomas have the same prognosis as sporadic soft tissue sarcomas? J Clin
Oncol 2010; 28: 2064–9.
98. Wang L, Bhargava R, Zheng T, et al. Undifferentiated small round cell
sarcomas with rare EWS gene fusions: identification of a novel EWS-SP3
fusion and of additional cases with the EWS-ETV1 and EWS-FEV
fusions. J Mol Diagn 2007; 9: 498–509.
99. Deng FM, Galvan K, de la Roza G, Zhang S, Souid AK, Stein CK.
Molecular characterization of an EWSR1-POU5F1 fusion associated with
a t(6;22) in an undifferentiated soft tissue sarcoma. Cancer Genet 2011;
204: 423–9.
100. Italiano A, Sung YS, Zhang L, et al. High prevalence of CIC fusion with
double-homeobox (DUX4) transcription factors in EWSR1-negative un-
differentiated small blue round cell sarcomas. Genes Chromosomes
Cancer 2012; 51: 207–18.
101. Choi EY, Thomas DG, McHugh JB, et al. Undifferentiated small round
cell sarcoma with t(4;19)(q35;q13.1) CIC-DUX4 fusion: a novel highly
aggressive soft tissue tumor with distinctive histopathology. Am J Surg
Pathol 2013; 37: 1379–86.
102. Pierron G, Tirode F, Lucchesi C, et al. A new subtype of bone sarcoma
defined by BCOR-CCNB3 gene fusion. Nat Genet 2012; 44: 461–6.