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 of uncertain differentiation’. This 2013 edition1 also now

The fourth edition of the World Health Organization (WHO) includes chapters devoted to gastrointestinal stromal tumours
Classification of Tumours of Soft Tissue and Bone was and nerve sheath tumours, which were formerly in other WHO
published in February 2013, and serves to provide an updated texts, and a newly introduced section for undifferentiated/
classification scheme and reproducible diagnostic criteria for unclassified sarcomas.
pathologists. Given the relative rarity of soft tissue tumours Herein we discuss updates in the new 2013 WHO classifi-
and the rapid rate of immunohistochemical and genetic/mol- cation,1 outlining changes from the 2002 WHO classification
ecular developments (not infrequently facilitating recognition scheme, with emphasis on newly described entities, novel
of new tumour entities), this updated text edited by a con- immunohistochemical markers, and new genetic/molecular data.
sensus group is important for both practising pathologists and
oncologists. The 2013 WHO classification includes several ADIPOCYTIC TUMOURS
changes in soft tissue tumour classification, including several There were no major changes for adipocytic tumours in the
new entities (e.g., pseudomyogenic haemangioendothe- fourth edition, with the exception of the removal of the terms
lioma, haemosiderotic fibrolipomatous tumour, and acral ‘round cell liposarcoma’ and ‘mixed-type liposarcoma’. ‘Rou-
fibromyxoma), three newly included sections for gastro- nd cell liposarcoma’ is no longer used, as the hypercellular and
intestinal stromal tumours, nerve sheath tumours, and high grade areas in myxoid liposarcoma are not exclusively
undifferentiated/unclassified soft tissue tumours, respect- round cell in morphological appearance and, in fact, are more
ively, various ‘reclassified’ tumours, and a plethora of new often spindle-celled. Tumours previously classified as ‘mixed-
genetic and molecular data for established tumour types that type liposarcoma’ are now thought mostly to be unusual
facilitate better definition and are useful as diagnostic tools. examples of dedifferentiated liposarcoma, based on currently
This article briefly outlines these updates based on the 2013 available immunohistochemical and molecular studies.
WHO classification of soft tissue tumours. Chondroid lipomas are now known to be associated with the
recurrent translocation t(11;16)(q13;p13), resulting in
Key words: Sarcoma, soft tissue, tumour, WHO classification. C11orf95-MKL2 fusion product,2 which has been validated
in a further study of eight cases since publication of the 2013
Received 28 October, accepted 13 November 2013
WHO classification.3
Since 2002, the immunohistochemical markers MDM2 and
INTRODUCTION CDK4 have come into widespread use for the diagnosis of
The publication of the fourth edition of the World Health atypical lipomatous tumour/well-differentiated liposarcoma
Organization (WHO) Classification of Tumours of Soft Tissue and dedifferentiated liposarcoma. These nuclear markers are
and Bone followed the meeting of an expert consensus group antibodies against the gene products coded on 12q13-15 that are
that convened in Zurich, Switzerland, 18–20 April 2012. The amplified (in either supernumerary ring or giant marker
WHO texts, which are updated every 5–10 years for nearly all chromosomes) in atypical lipomatous tumour/well-differen-
organ systems, ideally provide pathologists with updated tumour tiated liposarcoma and dedifferentiated liposarcoma.4,5 For
classification schemes based on currently available data (phe- negative or equivocal immunohistochemical results found in
notypic, cytogenetic, and molecular) and propagate reproducible clinically suspicious lesions, it is increasingly accepted that
diagnostic criteria. In the field of soft tissue pathology, this molecular studies (usually FISH) are necessary. This is now
consensus work is especially critical given the relative rarity critical given the current understanding that lipomas can
of soft tissue neoplasms and current rapid rate of immunohisto- (rarely) occur in the retroperitoneum, with a benign clinical
chemical and genetic/molecular developments and advances. course.6,7 The diagnosis of retroperitoneal lipoma generally
The WHO classification organises soft tissue neoplasms by requires confirmation of absent 12q13-15 amplification in
tumour type, as determined by morphological, immunohisto- order to exclude the statistically more likely possibility of
chemical and genetic features. The working group discussed well-differentiated liposarcoma.
and edited each tumour type in detail, each authored by selected The terminology ‘atypical lipomatous tumour’ and ‘well-
contributors, to provide a consensus text on all diagnostic differentiated liposarcoma’ continues to need clarification.
entities. The 2002 classification organised tumours as While the section heading now lists only ‘atypical lipomatous
adipocytic, fibroblastic/myofibroblastic, so-called fibrohistio- tumour’, the authors point out that retention of ‘well-differen-
cytic, smooth muscle, pericytic/perivascular, skeletal muscle, tiated liposarcoma’ is still appropriate for tumours in sites
vascular, chondro-osseous, and the group labelled as ‘tumours at which margin-negative resection is often impossible

Print ISSN 0031-3025/Online ISSN 1465-3931 # 2014 Royal College of Pathologists of Australasia
DOI: 10.1097/PAT.0000000000000050

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 96 JO and FLETCHER Pathology (2014), 46(2), February

(e.g., retroperitoneum, mediastinum), since such tumours are reactive process, though sometimes misinterpreted as a sarcoma
associated with substantial mortality. when biopsied during the active growth phase owing to the
Dedifferentiated liposarcoma is now known in some cases to troubling clinical presentation and frequently high mitotic
exhibit ‘homologous lipoblastic differentiation’, in which the activity. However, nodular fasciitis is now understood to be a
dedifferentiated component may exhibit lipoblasts and have ‘self-limiting’ clonal neoplasm with the discovery of
morphological features indistinguishable from pleomorphic the recurrent translocation involving 17p13 and 22q13.1, result-
liposarcoma8 (see Fig. 1). Since publication of the 2013 ing in MYH9-USP6 gene fusion.10 Notably, the USP6 gene is also
WHO classification, a further series of 18 such cases has been involved in the recurrent and consistent translocation in primary
published, which included two cases that showed a homologous aneurysmal bone cyst (but absent in secondary aneurysmal bone
lipoblastic component with low nuclear grade.9 cyst),11–13 most commonly being fused with CDH11.
Mammary-type myofibroblastoma, cellular angiofibroma,
FIBROBLASTIC/MYOFIBROBLASTIC TUMOURS and spindle cell lipoma/pleomorphic lipoma are closely related,
This category was updated to include major immunohistochem- as first appreciated by shared morphological features and now
ical and genetic/molecular developments for several tumours, confirmed by cytogenetic studies. Spindle cell lipoma/pleo-
including nodular fasciitis, myxoinflammatory fibroblastic sar- morphic lipoma has long been known to harbour consistent
coma, low grade fibromyxoid sarcoma, and sclerosing epithe- rearrangements of 13q and 16q.14,15 While morphological
lioid fibrosarcoma. Two tumour types formerly in the skin overlap has been recognised between spindle lipoma/pleo-
volume are now included in the soft tissue volume: giant cell morphic lipoma, mammary-type myofibroblastoma and cellu-
fibroblastoma and dermatofibrosarcoma protuberans [both lar angiofibroma, studies have demonstrated cytogenetic
defined by t(17;22)(q21;q13) resulting in PDGFB-COL1A1 similarities as well. Mammary-type myofibroblastoma, includ-
fusion] and which occasionally occur together as hybrid tumours. ing tumours occurring in extra-mammary sites, has been shown
Two entities are no longer included in this category: (1) myofi- to harbour both 13q and 16q abnormalities;16,17 more recently
broma/myofibromatosis, now classified as a ‘Pericytic (perivas- cellular angiofibroma has been shown to have aberrations
cular) tumour’; and (2) giant cell angiofibroma which is now involving the 13q14 locus.18,19 In spindle cell lipoma, re-
listed as a synonym for extrapleural solitary fibrous tumour. arrangement or deletion of 13q appears to affect the locus at
Nodular fasciitis, having the classical history of rapid growth 13q14, which includes the region encoding the tumour sup-
and spontaneous regression, was long considered by many to be a 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
A
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
B Low grade fibromyxoid sarcoma (LGFMS) harbours reci-
procal translocations of the FUS gene (on chromosome 16p11),
Fig. 1 Dedifferentiated liposarcoma showing homologous lipoblastic dedif- most frequently with CREB3L2 (7q33) or CREB3L1 (11p11). A
ferentiation. This retroperitoneal tumour has morphological features closely
resembling pleomorphic liposarcoma with abundant lipoblasts (A) but was newly described immunohistochemical marker, MUC4, has
strongly positive for MDM2 (B) and CDK4 (not shown). had major diagnostic impact; gene expression studies identified

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 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.

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 98 JO and FLETCHER 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
A cell/sclerosing rhabdomyosarcoma as a separate category. Pre-
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
B within an extensively hyalinised stroma (thus sometimes appear-
Fig. 5 Epithelioid ‘inflammatory myofibroblastic sarcoma’ (A) shows epithe-
ing ‘pseudovascular’)47,48 (Fig. 6). Some spindle cell rhabdo-
lioid morphology and a characteristic nuclear membrane staining pattern for myosarcomas show sclerosing morphology in proportions
ALK (B). 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.
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 VASCULAR TUMOURS
gene on chromosome 2q37.38–40 This section includes numerous updates from the 2002 edition,
including the addition of the entity of pseudomyogenic hae-
SMOOTH MUSCLE TUMOURS mangioendothelioma and genetic characterisation of epithe-
lioid haemangioendothelioma and secondary angiosarcomas.
The only notable change in this tumour group is that angio-
The entity pseudomyogenic (epithelioid sarcoma-like) hae-
leiomyoma is now classified under ‘Pericytic (perivascular)
mangioendothelioma49,50 was introduced in the 2013 WHO
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, Fig. 6 Sclerosing rhabdomyosarcoma. Tumour cells are embedded in a densely
or having atypical mitotic figures. In 2002, tumour size greater hyaline stroma.

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 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).

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 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

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 WHO CLASSIFICATION OF SOFT TISSUE TUMOURS: AN UPDATE 101

Fig. 10 Hybrid schwannoma/perineurioma with storiform architecture. Fig. 12 Haemosiderotic fibrolipomatous tumour showing an admixture of
bland fibroblastic cells and adiopocytes with associated haemosiderin depo-
essentially no risk for recurrence or metastasis. These lesions sition.
are rapidly growing, nodular/polypoid and usually associated
with solar elastosis. Atypical fibroxanthoma is completely of malignancy and follow a benign clinical course; osteoma-
confined to the dermis, usually shows smooth demarcation lacia typically resolves after resection. Malignant examples
from normal dermis, and often ‘pushes down’ normal skin are infrequent.
adnexal structures. The tumour cells are typically pleomorphic Since the last WHO edition, myoepithelial neoplasms have
with frequent mitotic activity. Spindle cell squamous cell been further characterised by morphological, immunohisto-
carcinoma and malignant melanoma must always be excluded, chemical, and genetic means. These tumours are now known
usually by immunohistochemistry. to occur over a wide age range in a broad anatomical distri-
Haemosiderotic fibrolipomatous tumour is a locally aggres- bution (including visceral locations). Mixed tumours show
sive tumour that most frequently occurs on the distal lower ductal differentiation, while myoepithelioma is comprised
extremity in adult females,77,78 and as mentioned above, shares of purely myoepithelial cells. Myoepithelial carcinoma of
the same t(1;10) translocation as myxoinflammatory fibroblas- skin and soft tissue is defined strictly by cytological atypia
tic sarcoma (with which it occasionally occurs in hybrid (although often associated with high mitotic rate and necro-
tumours).28,29 Microscopically, tumours are comprised of sis) and often shows an aggressive clinical course in both
fibroblastic spindle cells lacking significant atypia or mitotic children and adults80,81 (Fig. 14), in contrast to salivary gland
activity, arranged in fascicles with associated haemosiderin counterparts in which malignancy is largely based on architec-
deposition, haemosiderin-laden macrophages, osteoclastic-like tural features (i.e., invasive growth). Mixed tumours and myoe-
giant cells, and interdigitating in a complex fashion with a pitheliomas typically show a benign clinical course, with a low
mature adipocytic component (Fig. 12). CD34 is frequently risk of recurrence (20%) usually following incomplete excision.
positive. Tumours have a recurrence rate of 30–50% when Notably, mixed tumours show PLAG1 gene rearrangement (also
incompletely excised. observed by immunohistochemistry),82,83 supporting a relation-
Phosphaturic mesenchymal tumour, which had inadvertently ship with the salivary counterpart. In contrast, a subset of
been omitted from prior editions, typically affects adults in a myoepitheliomas and myoepithelial carcinomas of soft tissue
wide anatomical distribution, and is notable for its association are associated with EWSR1 translocations.84–88 Likely owing to
with osteomalacia, related to over-expression of FGF23 (which functional loss of material on chromosome 22q, SMARCB1/
is also elevated in serum).79 These tumours are comprised of INI1 expression is lost in a subset of myoepitheliomas and
bland spindle to stellate cells growing in sheets with haeman- myoepithelial carcinomas.89
giopericytoma-like vessels and stromal calcifications often Ossifying fibromyxoid tumours are now known to be associ-
described as ‘grungy’ (Fig. 13). Most tumours lack features ated with recurrent rearrangement of PHF1, located on 6p21.90,91

Fig. 11 Acral fibromyxoma showing uniform spindle cell morphology with Fig. 13 Phosphaturic mesenchymal tumour with bland myoid-appearing spin-
vaguely fascicular or whorled growth patterns within a collagenous stroma. dle cells and ‘grungy’ calcification.

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 102 JO and FLETCHER Pathology (2014), 46(2), February

Fig. 15 Undifferentiated round cell sarcoma with CIC-DUX4 translocation

Fig. 14 Myoepithelial carcinoma in soft tissue showing cytological atypia and typically shows vesicular nuclei with prominent nucleoli and often more
mitoses. cytoplasm than Ewing sarcoma.

The designation of tumours as ‘atypical’ or ‘malignant’ remains CONCLUSION

in discussion, but features such as high nuclear grade, high This article briefly outlines updates in the 2013 WHO classi-
cellularity, mitotic activity >2 per 50 high power fields, and fication of soft tissue tumours, with emphases on newly
atypical ossification within tumour nodules have been suggested described or included entities. This new volume is based upon
as features of malignancy. Since publication of the WHO a multitude of studies that have helped better define tumour
classification, a large series of conventional, atypical, and malig- types, with much unique new information regarding immuno-
nant tumours have been shown to have PHF1 gene rearrange- histochemical markers and genetic/molecular data that provide
ment by FISH,92 confirming that genetically-defined ossifying more uniform diagnostic criteria for pathologists to reference.
fibromyxoid tumour shows a wide range of morphology and The prognostic and therapeutic significance of most of the
behaviour. continually growing body of genetic/molecular data has yet to
For PEComa, malignant criteria remain to be clearly defined be determined.
and validated, but certain histological features appear predic-
tive of malignant behaviour: mitotic activity, necrosis, marked Conflicts of interest and sources of funding: The authors state
nuclear atypia, pleomorphism, large size, and infiltrative that there are no conflicts of interest to disclose.
growth.93 A sclerosing variant is also now recognised, charac-
terised by densely collagenous stroma in which cords of tumour Address for correspondence: Dr C. D. M. Fletcher, Department of Pathology,
cells are embedded; this variant is reported to occur most Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA.
E-mail: [email protected]
frequently in the retroperitoneum (often perirenal).94 While
PEComas have long been known to express both myoid and
melanocytic immunohistochemical markers, a small percen- References
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