Review Article

Sarcoma Classification: An Update Based on the 2013 World

Health Organization Classification of Tumors of Soft Tissue
and Bone
Leona A. Doyle, MD

The 2013 World Health Organization Classification of Tumors of Soft Tissue and Bone incorporates changes in tumor classification, as
well as new genetic insights into the pathogenesis of many different tumor types that have emerged over the 11 years since the publi-
cation of the prior volume. This article reviews changes in the classification of soft tissue and bone sarcomas as well as tumors of in-
termediate biologic potential in the 2013 World Health Organization volume, new molecular insights into these tumors, and
associated surgical and clinical implications. Cancer 2014;120:1763–74. VC 2014 American Cancer Society.

KEYWORDS: soft tissue, bone, tumor, sarcoma, World Health Organization, tumor classification.

INTRODUCTION
The current 2013 World Health Organization (WHO) Classification of Tumors of Soft Tissue and Bone1 was published
11 years after the prior volume.2 During that period, many changes have taken place in soft tissue and bone tumor classifi-
cation, predominantly based on the identification of new genetic findings in different tumor types. In addition, several
new morphologically distinct tumor types have been described, often along with their novel genetic changes. The advances
in classifying and understanding the pathogenesis of soft tissue and bone tumors based on the correlation of histologic and
genetic findings have been particularly significant in the field of soft tissue and bone oncopathology, perhaps more so than
in many other areas of pathology, with the exception of hematolymphoid neoplasia. Although many interesting molecular
genetic findings have been described in benign soft tissue and bone tumors, this article will focus on changes in the classifi-
cation of soft tissue and bone sarcomas as well as soft tissue and bone tumors of intermediate biologic potential (ie, locally
aggressive or rarely metastasizing tumors), new molecular insights into these tumors, and associated surgical and clinical
implications. The changes are reviewed according to the categorization of tumors in the WHO volume. These changes,
along with those in benign soft tissue and bone tumors, are summarized in Tables 1 and 2.

TUMORS OF SOFT TISSUES

Adipocytic Tumors
The most notable change in this category of tumors was the deletion of the term “round cell liposarcoma,” which describes a
morphologic appearance present in a subset of high-grade myxoid liposarcoma. Myxoid liposarcoma is graded using a 3-tier
system as low, intermediate, or high grade, based on the degree of cellularity. Transition between different grades may be
observed in a given tumor, and the highest grade should be reported. High-grade myxoid liposarcoma most often demon-
strates spindle cell morphology, but occasionally a round cell appearance predominates, which accounted for the previous
designation of “round cell liposarcoma”; the same genetic findings ie, FUS-DDIT3 [fused in sarcoma-DNA damage–induci-
ble transcript 3] or, less commonly, EWSR1-DDIT3 fusion genes are present in both histologic types. Regardless of round
cell or spindle cell tumor cell morphology, high-grade myxoid liposarcoma carries the same prognostic information, with a
greater frequency of metastasis and worse survival compared with low-grade tumors.3-5
The category of “mixed-type liposarcoma” was removed for the 2013 classification. This category had previously
been reserved for those tumors demonstrating apparently combined histologic features of myxoid and/or well-

Corresponding author: Leona A. Doyle, MD, Department of Pathology, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115; Fax: (617) 264-5118;
ladoyle@partners.org

Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.

DOI: 10.1002/cncr.28657, Received: January 21, 2014; Accepted: February 10, 2014, Published online March 19, 2014 in Wiley Online Library (wileyonlinelibrary.
com)

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Review Article

TABLE 1. Key Changes and Updates in the 2013 WHO Classification of Tumors of Soft Tissue

Tumor Category Major Changes and Updates

Adipocytic Classification changes “Round cell liposarcoma” removed as a synonym for high-grade myxoid
liposarcoma.
Mixed-type liposarcoma removed.
New genetics Recurrent translocation t(11;16)(q13;p13) in chondroid lipoma.
Fibroblastic/ Classification changes DFSP and giant cell fibroblastoma included for first time.
myofibroblastic “Hemangiopericytoma” removed as a synonym for SFT.
New genetics MYH9-USP6 fusion gene in nodular fasciitis.
NAB2-STAT6 fusion gene in SFT.
Recognition of molecular and morphologic overlap of LGFMS and SEF; MUC4
overexpression in LGFMS and SEF.
So-called fibrohistiocytic Classification changes “Malignant fibrous histiocytoma” removed from WHO classification.
Smooth muscle Classification changes Angioleiomyoma moved to pericytic category.
Pericytic Classification changes Angioleiomyoma now classified as a pericytic tumor.
Myofibroma now classified as a pericytic tumor, on a spectrum with
myopericytoma.
New genetics NOTCH2/3 mutations in a subset of glomus tumors.
Skeletal muscle Classification changes Spindle cell/sclerosing rhabdomyosarcoma now classified together and
separate from other subtypes.
New genetics Rearrangement of NCOA2 gene in pediatric cases of spindle cell
rhabdomyosarcoma.
MYOD1 mutations in a subset of adult spindle cell rhabdomyosarcoma.
Vascular Classification changes New entity: pseudomyogenic/epithelioid sarcoma-like hemangioendothelioma,
with recurrent translocation t(7;19) resulting in SERPINE1-FOSB fusion gene.
New genetics Recurrent fusion genes in epithelioid hemangioendothelioma: WWTR1-CAMTA1
and YAP1-TFE3.
Amplification of MYC in postradiation angiosarcoma.
Chondroosseous Classification changes/ None.
new genetics
Gastrointestinal stromal Classification changes GIST included in soft tissue volume for first time.
New genetics Recognition of the clinicopathologically and genetically distinct group of
“succinate dehydrogenase-deficient GIST.”
Nerve sheath Classification changes Peripheral nerve sheath tumors included in soft tissue volume for first time.
Newly described hybrid benign nerve sheath tumors included (eg, hybrid
schwannoma/perineurioma).
Tumors of uncertain Classification changes Newly described entities: acral/digital fibromyxoma, hemosiderotic fibrolipoma-
differentiation tous tumor, phosphaturic mesenchymal tumor.
Atypical fibroxanthoma now included in soft tissue volume.
PNET removed as a synonym for Ewing sarcoma.
New genetics EWSR1 gene rearrangement in myoepithelial carcinoma.
PHF1 gene rearrangement in ossifying fibromyxoid tumor.
Undifferentiated/ Classification changes This new category recognizes tumors that cannot be classified into any of the
unclassified sarcoma other categories.
New genetics A subset of undifferentiated round cell (non-Ewing) sarcomas harbor CIC-DUX4
or BCOR-CCNB3 fusion genes.

Abbreviations: BCOR, BCL6 corepressor; CAMTA1, calmodulin-binding transcription activator 1; CCNB3, cyclin B1; CIC, capicua transcriptional repressor;
DFSP, dermatofibrosarcoma protuberans; DUX4, double homeobox, 4; EWSR1, EWS RNA-binding protein 1; FOSB, FBJ murine osteosarcoma viral oncogene
homolog B; GIST, gastrointestinal stromal tumor; LGFMS, low-grade fibromyxoid sarcoma; MUC4, mucin-4; MYH9, myosin, heavy chain 9, non-muscle;
MYOD1, myogenic differentiation 1; NAB2, NGFI-A binding protein 2; NCOA2, nuclear receptor coactivator 2; NOTCH, neurogenic locus notch homolog pro-
tein; PHF1, PHD finger protein 1; PNET, primitive neuroectodermal tumor; SEF, sclerosing epithelioid fibrosarcoma; SERPINE1, serpin peptidase inhibitor, clade
E (nexin, plasminogen activator inhibitor type 1); SFT, solitary fibrous tumor; STAT6; signal transducer and activator of transcription 6; TFE3, transcription factor
binding to IGHM enhancer 3; USP6, ubiquitin carboxyl-terminal hydrolase 6; WHO, World Health Organization; WWTR1, WW domain containing transcription
regulator 1; YAP1, yes-associated protein 1.

differentiated/dedifferentiated and/or pleomorphic lipo- The definition of dedifferentiated liposarcoma has

sarcoma. However, consensus opinion acknowledges that
tumors showing such a mixed pattern most likely repre-
sent dedifferentiated liposarcoma. For those rare cases of
liposarcoma that cannot be subclassified, the term
“liposarcoma not otherwise specified” is retained as an
International Classification of Diseases code.
been modified slightly from its prior definition as a
“nonlipogenic sarcoma” arising in association with well-
differentiated liposarcoma/atypical lipomatous tumor, to
recognize that a small subset of cases may in fact demon-
strate lipoblastic differentiation within the dedifferenti-
ated component (ie, rare cases may be “lipogenic”). This

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 WHO Update of Sarcoma Classification/Doyle

TABLE 2. Key Changes and Updates in the 2013 WHO Classification of Tumors of Bone

Tumor Category Major Changes and Updates

Chondrogenic Classification changes
New genetics
Osteogenic Classification changes
New genetics
Fibrogenic Classification changes
Fibrohistiocytic Classification changes
Ewing sarcoma Classification changes
New genetics
Osteoclastic giant cell-rich Classification changes
Notochordal Classification changes
New genetics
Vascular Classification changes
New genetics
Myogenic, lipogenic, Classification changes
and epithelial
Tumors of undefined Classification changes
neoplastic nature
New genetics
Undifferentiated high-grade Classification changes
pleomorphic sarcoma
New entity: osteochondromyxoma (associated with Carney complex) included.
Atypical cartilaginous tumor introduced as synonym for grade 1
chondrosarcoma.
IDH1/2 mutations in enchondroma, periosteal chondroma and
chondrosarcoma.
HEY1-NCOA2 fusion gene in mesenchymal chondrosarcoma.
Osteoma separated from osteoid osteoma.
Amplification of MDM2 and CDK4 in low-grade central and paraosteal osteo-
sarcomas, and less often in conventional osteosarcoma.
Fibrosarcoma strictly defined to exclude cases demonstrating any recognizable
line of differentiation other than fibroblastic.
“Malignant fibrous histiocytoma” removed.
PNET removed as a synonym for Ewing sarcoma.
A subset of undifferentiated round cell (non-Ewing) sarcomas harbor CIC-DUX4
or BCOR-CCNB3 fusion genes.
Giant cell tumor of bone is separated from giant cell lesion of the small bones.
Benign notochordal cell tumor added.
Copy number gain of brachyury in chordoma.
Epithelioid hemangioma added as a new entity and distinguished from
hemangioma.
Epithelioid hemangioendothelioma now included.
Recurrent fusion genes in epithelioid hemangioendothelioma: WWTR1-CAMTA1
and YAP1-TFE3.
Leiomyoma and schwannoma removed.
Chondromesenchymal hamartoma is new designation for tumors previously
classified as chest wall hamartoma.
USP6 gene rearrangement in 70% of primary aneurysmal bone cyst, usually
due to t(16;17)(q22;p13), and not present in secondary aneurysmal bone
cyst.
This new category recognizes pleomorphic sarcomas that cannot be classified
into any of the other categories.

Abbreviations: BCOR, BCL6 corepressor; CAMTA1, calmodulin-binding transcription activator 1; CCNB3, cyclin B1; CDK4; cyclin-dependent kinase 4; CIC,
capicua transcriptional repressor; DUX4, double homeobox, 4; HEY1, hairy/enhancer-of-split related with YRPW motif 1; IDH, isocitrate dehydrogenase;
MDM2, mouse double minute 2 homolog; NCOA2, nuclear receptor coactivator 2; PNET, primitive neuroectodermal tumor; TFE3, transcription factor binding
to IGHM enhancer 3; USP6, ubiquitin carboxyl-terminal hydrolase 6; WHO, World Health Organization; WWTR1, WW domain containing transcription regulator
1; YAP1, yes-associated protein 1.

finding is referred to as dedifferentiated liposarcoma with
“homologous lipoblastic differentiation” or “pleomorphic
liposarcoma-like features”.6,7
Fibroblastic/Myofibroblastic Tumors
Dermatofibrosarcoma protuberans and the closely related
giant cell fibroblastoma were included in the 2013 classifi-
cation; they were previously described in the WHO vol-
ume on skin tumors. Both these tumors harbor
rearrangements of chromosomes 17 and 22, which result
in the formation of the chimeric gene PDGFB-COL1A1
(platelet-derived growth factor beta polypeptide-collagen,
type I, alpha 1). Hybrid tumors demonstrating histologic
features of each exist, confirming their shared biologic ori-
gin. Dermatofibrosarcoma protuberans is categorized as a
rarely metastasizing (intermediate) tumor, although it
should be noted that metastatic potential is gained only
when a component of fibrosarcomatous change is present.
Giant cell fibroblastoma is classified in the locally aggres-
sive (intermediate) category because it recurs in approxi-
mately 50% of cases, but does not metastasize.
The subcategory of “hemangiopericytoma” has been
removed from the classification of “extrapleural solitary fi-
brous tumor” (SFT) because it is now well established that
this outdated term included tumors that represented cellu-
lar examples of SFT, as well as other distinct tumor types
that may histologically resemble SFT. A recurrent intra-
chromosomal rearrangement on chromosome 12q that
leads to the formation of a NAB2-STAT6 (NGFI-A bind-
ing protein 2-signal transducer and activator of transcrip-
tion 6) fusion oncogene was identified in SFT (including
malignant and dedifferentiated tumors, and tumors at vari-
ous anatomic locations) in 2013, just after the publication
of the current WHO volume.8-10 This finding has led to
the recognition that so-called meningeal hemangiopericy-
toma is in fact SFT arising in the meninges.11 Nuclear
expression of STAT6, a transcription factor and one of the

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Figure 1. Sclerosing rhabdomyosarcoma composed of round
tumor cells with minimal cytoplasm embedded within a
densely sclerotic stroma; dyshesion between tumor cells may
result in a pseudovascular growth pattern.
fusion gene partners, has proven to be an extremely useful
immunohistochemical marker for SFT.12
The synonym “atypical myxoinflammatory fibro-
blastic tumor” was introduced for “myxoinflammatory
fibroblastic sarcoma.” This is to reflect the extremely low
risk of metastasis for this tumor type.
The 2013 WHO classification recognizes the close
relationship between “low-grade fibromyxoid sarcoma”
(LGFMS) and a subset of “sclerosing epithelioid
fibrosarcoma” (SEF). Both are malignant neoplasms that
demonstrate fibroblastic differentiation and that show
overlapping immunohistochemical and molecular genetic
features. Hybrid tumors that demonstrate histologic fea-
tures of both tumor types exist. The t(7;16)(q33;p11) that
results in a FUS-CREB3L2 (cAMP responsive element
binding protein 3-like 2) fusion gene in approximately
90% of LGFMS cases is also found in a subset of
SEF.13,14 In some cases, EWSR1 acts as an alternate fusion
partner to FUS; this is more common in SEF or hybrid
tumors than in pure LGFMS, and CREB3L1 is usually
the fusion partner with EWSR1 in these cases.15-18
MUC4 (mucin-4) is a newly described immunohisto-
chemical marker identified through gene expression
profiling that has proven to be highly sensitive and specific
for LGFMS and SEF.15,19,20 Despite histologic and
genetic similarities, the clinical course of LGFMS and
SEF differ somewhat. Early recurrence of LGFMS is
uncommon, and metastasis of LGFMS often occurs many
years after the initial diagnosis, with long-term follow-up
1766
metastatic rates of approximately 50%. Multiple recur-
rences of SEF are common and occur in approximately
50% of patients. Metastasis of SEF is frequent, developing
in up to 80% of patients, typically to the lung, bone, and
brain, and usually occurs earlier than in patients with
LGFMS.
Finally, although a benign tumor, the recent identi-
fication of a recurrent MYH9-USP6 (myosin, heavy
chain 9, non-muscle–ubiquitin carboxyl-terminal hy-
drolase 6) fusion gene in nodular fasciitis due to a trans-
location between chromosomes 17p13 and 22q13.1 is of
particular interest.21 Nodular fasciitis was previously
believed to be a reactive process, but the finding of this
recurrent translocation supports the theory that it is in
fact an example of a “self-limiting” neoplasm, given that
the natural history of nodular fasciitis is spontaneous
regression.
So-Called Fibrohistiocytic Tumors
The category of “malignant fibrous histiocytoma” was
deleted from the 2013 WHO classification, reflecting the
outdated terminology that formerly included many
tumors that can now be accurately classified as specific sar-
coma types. Unclassified/undifferentiated sarcomas are
now classified separately (see below).
Smooth Muscle Tumors
The only change in this group was the removal of
“angioleiomyoma,” which is now included in the category
of pericytic tumors.
Skeletal Muscle Tumors
The category of “spindle cell/sclerosing rhabdomyosarcoma”
was separated from embryonal rhabdomyosarcoma, with the
recognition that the spindle cell and sclerosing subtypes share
a spectrum of morphologic appearances22-24 and lack genetic
changes typically observed in either embryonal or alveolar
rhabdomyosarcoma (Fig. 1). Even since the publication of
the 2013 WHO classification, new insights into the biology
of these tumors has emerged. Rearrangement of the NCOA2
(nuclear receptor coactivator 2) gene has been identified in
pediatric cases of spindle cell rhabdomyosarcoma, but not in
adult cases.25 Mutations in MYOD1 (myogenic differentia-
tion 1), a transcription factor involved in skeletal muscle dif-
ferentiation, have been identified in 40% of adult spindle cell
rhabdomyosarcomas.26 The prognosis of spindle cell rhabdo-
myosarcoma in adults is worse than in children, and recent
insights into the genetics of this tumor suggest that there may
be underlying genetic differences between pediatric and adult
cases.
Cancer June 15, 2014
 WHO Update of Sarcoma Classification/Doyle

Figure 2. Pseudomyogenic hemangioendothelioma often presents with multiple discontiguous nodules and may involve bone.
(A) This coronal T2 fat-suppressed magnetic resonance image of the left arm shows a T2 hyperintense enhancing lesion in the
distal radius with cortical disruption and a soft tissue component (white arrow); additional lesions are observed in the radial
head and proximal ulna (black arrows). (B) The tumor is composed of spindled-shaped tumor cells with abundant eosinophilic
cytoplasm reminiscent of smooth muscle differentiation. (C) ERG, a marker of endothelial differentiation, is positive in tumor cells.
Magnetic resonance image courtesy of Dr. Jyothi Jagannathan of the Dana-Farber Cancer Institute, Boston, Massachusetts.

Vascular Tumors t(7;19)(q22;q13) is present in this tumor type and results

A newly recognized entity designated “pseudomyogenic
hemangioendothelioma” (and also known as “epithelioid
sarcoma-like hemangioendothelioma”) was included in
this category.27,28 This tumor is classified as a rarely meta-
stasizing endothelial neoplasm. The name reflects the his-
tologic appearance of spindle-shaped cells with bright
eosinophilic cytoplasm that appear myoid, but the tumor
cells express endothelial markers and are consistently neg-
ative for desmin (Fig. 2). This tumor most commonly
arises in young adult males, and often presents as multiple
discontiguous nodules in different tissue planes of a limb,
and may involve the skin as well as deep soft tissues and
bone. Pseudomyogenic hemangioendothelioma tends to
be highly [18F]fluorodeoxyglucose (FDG)-avid, and
therefore positron emission tomography scan is useful for
the detection of deep lesions. A recurrent translocation
in the formation of the very recently recognized fusion
gene SERPINE1-FOSB (serpin peptidase inhibitor, clade
E [nexin, plasminogen activator inhibitor type 1]-FBJ
murine osteosarcoma viral oncogene homolog B).29 The
clinical course of patients with pseudomyogenic heman-
gioendothelioma is characterized by repeated local recur-
rences or the development of new tumor nodules within
the same anatomical region, but metastasis is very rare.
The relationship between margin status and risk of disease
recurrence has not been established, and at this point con-
servative management is the treatment of choice.
The classification of angiosarcoma and epithelioid
hemangioendothelioma (EHE) has remained the same.
However, new insights into the molecular genetics of
these tumors warrant mention. Recurrent fusion
genes have been identified in EHE, specifically WWTR1-

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Figure 3. (A) Succinate dehydrogenase (SDH)-deficient gas-
trointestinal stromal tumor demonstrating a characteristic
multinodular growth pattern on low power. (B) Tumor cells
are usually epithelioid, and lack expression of SDHB, in con-
trast to surrounding normal endothelial cells and lympho-
cytes, which show retained cytoplasmic expression of SDHB
(C).
1768
CAMTA1 (WW domain containing transcription regula-
tor 1–calmodulin-binding transcription activator 1),
which results from a t(1;3)(p36.3;q25) translocation and
is the most common fusion gene in EHE,30,31 and less
commonly YAP1-TFE3 (yes-associated protein 1-
transcription factor binding to IGHM enhancer 3),32
which occurs in tumors from young adults and is associ-
ated with distinctive morphologic findings such as the for-
mation of well-formed vascular channels and voluminous
eosinophilic cytoplasm. Furthermore, by analyzing break-
points in these genes, it has been shown that multifocal
EHE most likely arises as a result of metastatic disease
rather than representing synchronous primary tumors as
previously thought.33
The presence of MYC amplification in post-radiation
angiosarcomas was described within the last few years, and
the detection of MYC overexpression at the protein level
has proved to be a useful immunohistochemical tool for
distinguishing angiosarcoma from atypical postradiation
vascular proliferations, which are negative for MYC.34,35
Gastrointestinal Stromal Tumor
For the first time, gastrointestinal stromal tumor (GIST)
is now included in the WHO soft tissue classification; it
previously was part of the volume of WHO Tumors of
the Digestive System. The most notable change in the
classification of GIST is the recognition of the category of
“succinate dehydrogenase (SDH)-deficient GIST”.
Tumors in this group are wild-type for KIT and PDGFRA
mutations, and demonstrate loss of expression of the
SDH complex, subunit B (SDHB) protein immunohisto-
chemically, which reflects dysfunction of the SDH
enzyme complex of the Krebs cycle.36-38 This dysfunction
may arise due to the presence of mutations in any of the 4
SDH subunit genes (namely SDHA, SDHB, SDHC, and
SDHD) which can be detected by sequencing methods,
but can also occur in the absence of demonstrable muta-
tions due to as yet unknown mechanisms. Mutations in
SDHA appear to be the most common mutation in SDH-
deficient GIST in adults (present in 35% of cases), and
can be confirmed by the additional loss of expression of
SDHA protein by immunohistochemistry.39-42
Clinically, these tumors always arise in the stomach,
especially the antrum, where they may be multifocal, and
often spread to lymph nodes, which is an extremely
uncommon pattern of spread in KIT- or PDGFRA-mu-
tant GIST. Histologically, SDH-deficient GISTs demon-
strate a distinctive multinodular growth pattern and are
usually purely epithelioid or mixed epithelioid and spin-
dle cell type (Fig. 3). The clinical course tends to be
Cancer June 15, 2014

indolent, even in the presence of metastatic disease. Stand-
ard risk stratification criteria for assessing the malignant
potential of GISTs (ie, evaluation of mitotic activity and
tumor size) do not predict the clinical behavior of this
subtype.37,43,44 It is important to note that SDH-
deficient GISTs are imatinib-resistant, but may respond
better to second-generation and third-generation tyrosine
kinase inhibitors such as sunitinib, sorafenib, nilotinib,
and dasatinib.37,45,46
The diagnosis of SDH-deficient GIST is important
not only because of the prognostic and predictive infor-
mation mentioned above, but also because of its syn-
dromic associations. While SDH-deficient GISTs may
arise sporadically in adults and represent the vast majority
of pediatric GIST cases, they also occur in the setting of
the Carney triad (GIST, paraganglioma/pheochromocy-
toma, and pulmonary chondroma) and Carney-Stratakis
syndrome (GIST and paraganglioma/pheochromocy-
toma). For this reason, it is recommended that all patients
with SDH-deficient GIST be referred for genetic counsel-
ing. In addition, in many cases, GIST is the sentinel tu-
mor in these syndromes, and the time interval before the
development of a second tumor may be delayed by many
years; long-term clinical follow-up for the development of
additional gastric GISTs or other tumor types is therefore
warranted for all patients with SDH-deficient GIST. The
frequency of SDH-deficient tumors among all gastric
GISTs is estimated to be 7.5%.43
Nerve Sheath Tumors
For the first time, nerve sheath tumors (including both be-
nign and malignant peripheral nerve sheath tumors) are
now included in the WHO soft tissue classification.
Although several newly described histological variants of
benign peripheral nerve sheath tumors have been
included, there have been no changes to the classification
of malignant peripheral nerve sheath tumors.
Tumors Of Uncertain Differentiation
There were 2 new additions to this category. The first is
“hemosiderotic fibrolipomatous tumor” (HFLT), a
locally aggressive neoplasm that typically arises in middle-
aged women, most commonly around the ankle or wrist.
HFLT is an unencapsulated lesion composed of adipo-
cytes, hemosiderin-laden spindle cells, and chronic
inflammatory cells, which impart a yellow-brown color
grossly. These lesions may reach large sizes, and the rate of
local recurrence approaches 50% if they are incompletely
excised.47,48 With complete excision, the recurrence rate
is low. It is interesting to note that HFLT demonstrates
Cancer June 15, 2014
WHO Update of Sarcoma Classification/Doyle
the same translocation t(1;10)(p22;q24) noted in myx-
oinflammatory fibroblastic sarcoma (MIFS), a rarely
metastasizing lesion that is included in the category of
fibroblastic tumors.49-51 Tumors demonstrating hybrid
features of both these entities exist, suggesting a close bio-
logical relationship between HFLT and MIFS.
The second addition to this category is phosphaturic
mesenchymal tumor (PMT), which is classified as a rarely
metastasizing lesion. PMT is an extremely rare but clini-
cally and histologically distinctive tumor. The tumor pro-
duces fibroblast growth factor 23, a hormone that inhibits
renal proximal tubule phosphate reuptake, resulting in
phosphaturia and tumor-induced osteomalacia.52 Clini-
cally, elevated serum levels of fibroblast growth factor 23
can be demonstrated in the majority of patients with
PMT. Although most of these lesions are benign, disease
recurrence is common with incomplete excision, and rare
malignant cases with metastasis occur.53 Complete exci-
sion leads to the resolution of osteomalacia.
The term “primitive neuroectodermal tumor”
(PNET) has been removed as a synonym for Ewing sar-
coma. This is to minimize confusion with the histologically
and genetically different, but similarly named, PNET of
the central nervous system and female genital tract.
Undifferentiated/Unclassified Sarcoma
This category of tumors is new to the 2013 WHO classi-
fication, and recognizes those tumors that cannot be clas-
sified into any of the other categories due to lack of a
demonstrable line of differentiation or lack of distin-
guishing histologic, immunohistochemical, or genetic
features. Tumors in this category may have spindled, epi-
thelioid, pleomorphic, or round cell morphology.54
Interestingly, it has been very recently recognized that a
subset of otherwise undifferentiated round cell (non-
Ewing) sarcomas harbor CIC-DUX4 or BCOR-CCNB3
fusion genes, suggesting that some of these undifferenti-
ated/unclassified sarcomas will in time be recognized as
genetically distinct tumor types. Although the number of
reported cases is small, round cell sarcomas with the
CIC-DUX4 fusion gene are more common in males,
demonstrate variable expression of CD99, and arise in
soft tissues more often than in bone (Fig. 4).55-60 Round
cell sarcomas with the BCOR-CCNB3 fusion gene typi-
cally arise in bone, but may also arise in soft tissues and
also demonstrate variable expression of CD99.61 Data
regarding these tumor types are still emerging, but at this
time it appears that they are best managed with systemic
chemotherapy in addition to locoregional treatment,
similar to Ewing sarcoma.
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Figure 4. Round cell sarcoma with the CIC-DUX4 fusion gene
is composed of round to ovoid tumor cells with amphophilic
cytoplasm and variably prominent nucleoli. (B) CD99 may
demonstrate patchy expression, in contrast to the diffuse
membranous pattern characteristic of Ewing sarcoma. Case
courtesy of Dr. Christopher Fletcher of Brigham and Women’s
Hospital, Boston, Massachusetts.
BONE TUMORS
Chondrogenic Tumors
A new addition to this category is osteochondromyxoma,
a benign but locally aggressive tumor that demonstrates
both osteoid and chondroid production.62 This rare tu-
mor arises in approximately 1% of patients with Carney
complex. Sites of involvement include the tibia and sino-
nasal bones, and destructive growth with extension into
soft tissue can occur. Disease recurrence is more likely at
sites where complete resection is difficult; metastases have
not been reported.
Chondrosarcoma is now separated into two Interna-
tional Classification of Diseases codes, which reflects the
different prognosis of chondrosarcoma based on grade,
1770
with grade 1 distinguished from cases of grade 2 and grade
3 chondrosarcoma. In addition, the synonym “atypical
cartilaginous tumor” was introduced for “grade 1
chondrosarcoma.” These tumors are locally aggressive but
metastasize only extremely rarely; the 5-year survival rate
is 83%, with death from disease occurring due to uncon-
trollable tumor growth, especially in patients with pelvic
tumors.63,64 Curettage/simple excision alone is consid-
ered adequate treatment. For those tumors that recur,
approximately 10% demonstrate an increase in cellularity
warranting a change in grade. In contrast, grade 2 and 3
chondrosarcomas frequently metastasize and have a 5-year
survival rate of 53%; en bloc resection is recommended
for this group of patients. Tumors should be graded based
on the area of highest histologic grade in cases in which
variable histologic grades exist within the same tumor.
Minor clarifications and expansions to the defini-
tions of chondrosarcoma were as follows: primary central
chondrosarcoma (chondrosarcoma arising centrally in
bone without a benign precursor); secondary central
chondrosarcoma (chondrosarcoma arising centrally in
bone in a preexisting enchondroma); and secondary pe-
ripheral chondrosarcoma (chondrosarcoma arising in
association with the cartilaginous cap of osteochon-
droma). The classification of periosteal, dedifferentiated,
clear cell, and mesenchymal chondrosarcoma remains
unchanged.
The most significant new genetic finding in chondro-
sarcoma is the recognition of mutations in the isocitrate de-
hydrogenase 1 (IDH1) and isocitrate dehydrogenase 2
(IDH2) genes, which code for the metabolic enzymes
IDH1 and IDH2 that are now recognized to play a role in
tumorigenesis. IDH1 and IDH2 mutations are present in
up to 70% of primary central chondrosarcomas, 80% of
secondary central chondrosarcomas, virtually all periosteal
chondrosarcomas, and 50% of dedifferentiated chondro-
sarcomas.65,66 These mutations also occur in enchon-
droma, both the sporadic type and those associated with
Ollier disease and Maffucci syndrome.67
A recurrent fusion gene, HEY1-NCOA2 (hairy/
enhancer-of-split related with YRPW motif 1-NCOA2),
has been identified in mesenchymal chondrosarcoma.68
Given the close proximity of these 2 genes on chromo-
some 8, this fusion most likely results from a small inter-
stitial deletion between these loci.
Osteogenic Tumors
The only change in the classification of osteogenic tumors
is the incorporation of secondary osteosarcoma into the
category of conventional osteosarcoma for descriptive
Cancer June 15, 2014

purposes. Conventional osteosarcoma is subclassified
based on histologic features (eg, osteoblastic, chondro-
blastic), but there remains no relationship between the
subtype of conventional osteosarcoma and treatment and
prognosis, in contrast to other types of osteosarcoma.
Amplification of mouse double minute 2 homolog
(MDM2) and cyclin-dependent kinase 4 (CDK4) have
now been well documented in low-grade central osteosar-
coma and paraosteal osteosarcoma, and immunohisto-
chemistry for these 2 markers can be a helpful tool,
especially in those cases that have undergone dedifferenti-
ation to a high-grade osteosarcoma and in which recogni-
tion of the precursor low-grade lesion is difficult clinically
or pathologically.69,70
Fibrogenic Tumors
The definition of “fibrosarcoma of bone” is clarified as
an intermediate- to high-grade spindle cell malignant
neoplasm that lacks significant pleomorphism and lacks
any line of differentiation other than fibroblastic. This
clarification addresses several issues. First, although his-
torically the classification of fibrosarcoma of bone was
used relatively commonly, it is now recognized that a
fascicular or “herringbone” pattern of growth may be
observed in many different tumor types that can be clas-
sified in other specific diagnostic categories.71 Second,
this pattern of growth may also be seen in otherwise
unclassified high-grade pleomorphic sarcomas, and if
significant pleomorphism is present the tumor is best
classified as the latter. Fibrosarcoma of bone is therefore
a diagnosis of exclusion, and the diagnosis cannot be
made on limited biopsy samples, because thorough
sampling is needed to exclude other lines of differentia-
tion. The incidence of fibrosarcoma is likely much less
than the 5% documented in the prior WHO
classification.
Fibrohistiocytic Tumors
Similar to soft tissue tumor classification, the category of
“malignant fibrous histiocytoma” of bone has been
removed from the 2013 classification of bone tumors.
Ewing Sarcoma
The term PNET has been removed as a synonym for
Ewing sarcoma, as previously discussed. Of round cell
sarcomas of bone that do not fulfill criteria for Ewing
sarcoma, 2 genetically distinct groups of tumors have
been recognized that harbor CIC-DUX4 (Fig. 4) or
BCOR-CCNB3 fusion genes; these tumors are discussed
in the section on undifferentiated sarcomas of soft tis-
sues above.
Cancer June 15, 2014
WHO Update of Sarcoma Classification/Doyle
Osteoclastic Giant Cell-Rich Tumors
In this category, “giant cell tumor of bone” is now sepa-
rated from “giant cell lesion of the small bones.” Giant
cell lesion of the small bones is a very rare tumor-like
lesion that arises in the small bones of the hands and feet
and commonly recurs after initial curettage, but is almost
always cured after the second excision. Giant cell tumor of
bone is a locally aggressive neoplasm that may very rarely
metastasize or undergo malignant transformation into a
high-grade sarcoma, either de novo or after radiotherapy.
Notochordal Tumors
Benign notochordal cell tumor was added to this category,
which previously only included chordoma. This benign
tumor may represent persistent notochord rather than a
true neoplastic proliferation; benign notochordal cell tu-
mor arises at the base of skull, vertebral bodies, and sacro-
coccygeal bones and is usually an incidental finding.
Vascular Tumors
Hemangioma (a benign tumor composed of capillary-like
blood vessels most commonly involving vertebral bones,
with a low rate of local recurrence) is separated from epi-
thelioid hemangioma, a recently characterized locally
aggressive neoplasm composed of small vessels lined by
epithelioid endothelial cells. Epithelioid hemangioma
most often arises in long tubular bones, followed by flat
bones and vertebrae.72 In contrast to conventional he-
mangioma, epithelioid hemangioma is locally aggressive:
recurrence occurs in approximately 10% of cases. Treat-
ment consists primarily of curettage, and less often local
resection. Epithelioid hemangioma should also be distin-
guished from EHE, which is classified separately in this
category. EHE is a malignant neoplasm that demonstrates
endothelial differentiation, and the mainstay of treatment
is wide resection. The mortality rate is approximately
20% and histologic features do not predict the develop-
ment of metastases. As discussed in the section on soft tis-
sue tumors, very recent work has identified recurrent
fusion genes in EHE, namely WWTR1-CAMTA1 and
YAP1-TFE3. These fusion genes are not present in angio-
sarcoma or benign vascular tumors. There are no signifi-
cant updates to the classification of angiosarcoma of bone.
Undifferentiated High-Grade Pleomorphic
Sarcoma
High-grade pleomorphic malignant tumors that lack a
specific line of differentiation are classified as
“undifferentiated high-grade pleomorphic sarcoma.” This
diagnosis is one of exclusion, and thorough sampling is
needed to exclude osteoid deposition, which would
1771
Review Article
necessitate a diagnosis of osteosarcoma, as well as other
histologic features that may suggest a specific diagnosis.71
Tumors in this category have a metastatic rate of at least
50%. Treatment generally involves neoadjuvant therapy
followed by wide excision for potentially resectable
lesions. Similar to osteosarcoma, the degree of tumor ne-
crosis after neoadjuvant chemotherapy is an important
prognostic factor.73
Conclusions
Since the publication of the prior WHO Classification of
Tumors of Soft Tissue and Bone 11 years ago, new clini-
copathologic and genetic features of many soft tissue and
bone tumors have been characterized, which has led to
more reproducible classifications of these tumors and
therefore more effective treatment stratification. This has
also allowed wastebasket diagnostic categories and obso-
lete tumor types such as hemangiopericytoma and so-
called malignant fibrous histiocytoma to be removed
from the 2013 WHO classification. In addition, several
new entities have been included for the first time in this
volume. Huge advances have been made, and continue to
be made at an ever-increasing pace, in defining the genetic
basis of both benign and malignant mesenchymal tumors;
these findings and the major classification changes in the
current 2013 WHO classification have been reviewed in
this article, along with new genetic data that have emerged
even since the publication of the current volume.
FUNDING SUPPORT
No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
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