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The World Health Organization (WHO) classification system for cancer represents the common nomenclature for cancer

world wide. In the United States, it has been adopted by the American Joint Cancer Commission (AJCC) for sarcoma
staging and by the College of American Pathologists (CAP) Cancer Protocols for bone and soft tissue sarcomas. This
common lexicon is critical for the performance of clinical trials, which are increasingly international in scale, and for
translational research to be comparable. The WHO system helps to assure doctors and researchers that we are on the
same diagnostic page in such undertakings.

The fourth edition of the WHO Classification of Tumours of Soft Tissue and Bone blue book was published in February
2013. The new book surpasses the previous edition of the book published in 2002 in regards to its number of pages,
illustrations, and authors. In all, 159 authors from 24 different countries contributed to this book. Eleven of them are the
members of IARC/WHO committee for the International Classification of Diseases for Oncology (ICD-O). The editors of this
volume are Christopher D.M. Fletcher (soft tissue), Pancras C.W. Hogendoorn (bone), Fredrik Mertens and Julia Bridge
(genetics).

"In keeping with the rapidly increasing knowledge and the extensive studies of the genetics of tumours that took place
over the past decade, the new book has incorporated more detailed cytogenetic and molecular data."

Of the major modifications made to the previous edition is the addition of three new chapters (gastrointestinal stromal
tumours, nerve sheath tumours and undifferentiated high-grade pleomorphic sarcoma of bone).

In keeping with the rapidly increasing knowledge and the extensive studies of the genetics of tumours that took place over
the past decade, the new book has incorporated more detailed cytogenetic and molecular data.

The grading of soft tissue tumours has always been a controversial issue. While the WHO does not strictly state a
preference in grading systems, one of the major modifications that have been made to the current WHO classification is
the designation of two distinct types of intermediate malignancy in terms of biological potential: the "locally aggressive"
and the "rarely metastasizing."

The authors acknowledged the poorly defined nature of malignant fibrous histiocytoma, MFH, (also known as UPS,
undifferentiated pleomorphic sarcoma) and haemangiopericytoma (now considered within the spectrum of solitary fibrous
tumor).

With the current advances in molecular and genetic studies, a subset of tumours has been moved into new sections
including angiomatoid MFH and extraskeletal myxoid chondrosarcoma which were reclassified under "Tumours of Uncertain
Differentiation." Multiple entities were newly recognized, and a few entities belonging to tumours of skin were also added
to this book. A few entities that were found to probably represent morphologic variants of other tumours were deleted
from the current classification and subsumed into other sections.

What follows is a series of brief highlights of this new WHO edition from each section of the soft tissue and bone sections.

Soft Tissue Tumours


Adipocytic tumours
Benign
Lipoma
Lipomatosis
Lipomatosis of nerve
Lipoblastoma / lipoblastomatosis
Angiolipoma
Myolipoma of soft tissue
Chondroid lipoma
Extra-renal angiomyolipoma
Extra-adrenal myelolipoma
Spindle cell / pleomorphic lipoma
Hibernoma

Intermediate (locally aggressive)


Atypical lipomatous tumour / well differentiated liposarcoma

Malignant
Dedifferentiated liposarcoma
Myxoid liposarcoma
Pleomorphic liposarcoma
Liposarcoma, not otherwise specified

General Changes
The current classification no longer includes mixed-type liposarcoma. Cases previously diagnosed as mixed-type
liposarcoma were almost always discovered to fall within a specific type of liposarcoma when subjected to molecular and
genetic testing. Myxolipoma was also deleted from the current classification. Most of the so-called myxolipomas are now
considered variants of spindle cell lipoma. Diffuse lipoblastoma is now the preferred term for lipoblastomatosis.

Atypical lipomatous tumour (ALT)


ALT in this book is divided into 3 main subgroups (rather than 4 as done previously):

1. adipocytic (lipoma-like)
2. sclerosing

3. inflammatory types

A description of spindle cell liposarcoma still appears in the text. The lack of MDM2 immunopositivity or 12q15
amplification in this tumor type suggests spindle cell liposarcoma represents a separate group.

Dedifferentiated liposarcoma
The new addition to this liposarcoma type is the recognition of the rare situation in which the high grade (dedifferentiated)
component shows lipoblastic differentiation and resembles pleomorphic liposarcoma. This phenomenon has been referred
to as homologous lipoblastic differentiation or pleomorphic liposarcoma-like features.

Fibroblastic / myofibroblastic tumours


Benign
Nodular fasciitis
Proliferative fasciitis
Proliferative myositis
Myositis ossifficans
Fibro-osseous pseudotumour of digits
Ischemic fasciitis
Elastofibroma
Fibrous hamartoma of infancy
Fibromatosis colli
Juvenile hyaline fibromatosis
Inclusion body fibromatosis
Fibroma of tendon sheath
Desmoplastic fibroblastoma
Mammary-type myofibroblastoma
Calcifying aponeurotic fibroma
Angiomyofibroblastoma
Cellular angiofibroma
Nuchal-type fibroma
Gardner fibroma
Calcifying fibrous tumour

Intermediate (locally aggressive)


Palmar / plantar fibromatosis
Desmoids-type fibromatosis
Lipofibromatosis
Giant cell fibroblastoma

Intermediate (rarely metastasizing)


Dermatofibrosarcoma protuberans
Fibrosarcomatous dermatofibrosarcoma protuberans
Pigmented dermatofibrosarcoma protuberans
Solitary fibrous tumour
Solitary fibrous tumour, malignant
Inflammatory myofibroblastic tumour
Low grade myofibroblastic sarcoma
Myxoinflammatory fibroblastic sarcoma /
Atypical myxoinflammatory fibroblastic tumour
Infantile fibrosarcoma

Malignant
Adult fibrosarcoma
Myxofibrosarcoma
Low-grade fibromyxoid sarcoma
Sclerosing epithelioid fibrosarcoma

Nodular fasciitis
The identification of MYH9-USP6 gene fusion as a recurrent event in nodular fasciitis has confirmed its previously
controversial neoplastic nature.

Extrapleural solitary fibrous tumour


The term haemangiopericytoma was abandoned. It is used only to describe a morphological pattern that is shared by
different entities. Currently, solitary fibrous tumour, haemangiopericytoma, lipomatous haemangiopericytoma and giant
cell angiofibroma are all lumped under the extrapleural solitary fibrous tumour category. Giant cell angiofibroma is now
considered a synonym for extrapleural solitary fibrous tumour rather than being a separate entity. Tumours previously
called giant cell angiofibromas are characterized by the presence of multinucleated giant cells and pseudo-vascular
spaces. This tumor is now known to be associated with a recurrent NAB2-STAT6 gene fusion.

Low grade fibromyxoid sarcoma (LGFMS)


MUC4 is found to be highly sensitive and specific for LGFMS and linked to the presence of the FUS-CREB3L2 or FUS-
CREB3L1fusion genes.

Sclerosing epithelioid fibrosarcoma (SEF)


MUC4 immunoexpression is reported in up to 70% of cases suggesting that at least a subset are related to LGFMS, though
genetic exploration indicates that this class is a minority. SEF-like areas can be seen in a subset of genetically confirmed
LGFMS cases, but the characteristic translocation is seen in only a small subset of pure SEF cases (i.e., those that lack
identifiable LGFMS-like areas).

So-called fibrohistiocytic tumours


Benign
Tenosynovial giant cell tumour
Localized type
Diffuse type
Malignant
Deep benign fibrous histiocytoma

Intermediate (rarely metastasizing)


Plexiform fibrohistiocytic tumour
Giant cell tumour of soft tissue

The malignant counterpart of so-called fibrohistiocytic tumours, formerly known as malignant fibrous histiocytoma and its
subtypes was renamed undifferentiated sarcoma and reclassified under the undifferentiated / unclassified sarcomas
section described further below.

Tenosynovial giant cell tumour, localized type and diffuse type


The most common translocation in tenosynovial giant cell tumour is found to involve CSF1 gene on chromosome 1
and COL6A3on chromosome 2.

Smooth-muscle tumours
Benign
Leiomyoma of deep soft tissue

Malignant
Leiomyosarcoma (excluding skin)

Angioleiomyoma was reclassified under pericytic (perivascular) tumours.

Leiomyosarcoma
Cytogenetic analysis of several gene-expression profiling datasets identified multiple molecular subgroups of
leiomyosarcoma, including a muscle-enriched subtype and less differentiated group with varying prognoses. Some
tumours classified as UPS cluster closely with a subset of leiomyosarcoma suggesting the existence of dedifferentiated
leiomyosarcoma.

Pericytic (perivascular) tumours

Glomus tumour (and variants)


Glomangiomatosis
Malignant glomus tumour
Myopericytoma
Myofibroma
Myofibromatosis
Angioleiomyoma

Myofibroma and myofibromatosis were reclassified under myopericytoma instead of fibroblastic / myofibroblastic tumours.

Skeletal-muscle tumours
Rhabdomyoma
Embryonal rhabdomyosarcoma
Alveolar rhabdomyosarcoma
Pleomorphic rhabdomyosarcoma
Spindle cell / Sclerosing rhabdomyosarcoma

Spindle cell / Sclerosing rhabdomyosarcoma was felt to now be well enough recognized and defined to be added to this
group.

Alveolar rhabdomyosarcoma (ARMS)


Tumours with mixed embryonal and alveolar pattern were previously considered to be variants of ARMS, but most of these
lack PAX3-FOXO1 fusions, thus appearing to be clinically and biologically more akin to embryonal rhabdomyosarcoma.

Vascular tumours

Benign
Haemangioma
Synovial
Venous
Arteriovenous haemangioma / malformation
Epithelioid haemangioma
Angiomatosis
Lymphangioma

Intermediate (locally aggressive)


Kaposiform haemangioendothelioma

Intermediate (rarely metastasizing)


Retiform haemangioendothelioma
Papillary intralymphatic angioendothelioma
Composite haemangioendothelioma
Pseudomyogenic (epithelioid sarcoma-like) haemangioendothelioma
Kapsoi sarcoma

Malignant
Epithelioid haemangioendothelioma
Angiosarcoma of soft tissue

Pseudomyogenic (epithelioid sarcoma-like) haemangioendothelioma was added to the intermediate (rarely metastasizing)
subgroup.

Two intermediate vascular neoplasms that the Working Group had previously considered for inclusion in the 2002
classification, namely giant cell angioblastoma and polymorphous haemangioendothelioma, were not added to the current
classification due to the limited number of reported cases and lack of sufficient data. Recently, epithelioid
hemangioendothelioma has also been shown to be associated with a WWTR1-CAMTA1 translocation.

Gastrointestinal stromal tumours

Benign gastrointestinal stromal tumour


Gastrointestinal stromal tumour, uncertain malignant potential
Gastrointestinal stromal tumour, malignant

This chapter is a major and important addition to the new book. In the current classification, the benign category of GIST
corresponds to the AFIP prognostic groups 1, 2 and 3a. The uncertain malignant potential category corresponds to group
4, and the malignant category corresponds to groups 3b, 5, 6a and 6b.

Nerve sheath tumours


Benign
Schwannoma (including variants)
Melanotic schwannoma
Neurofibroma (including variants)
Plexiform neurofibroma
Perineurioma
Malignant perineurioma
Granular cell tumour
Dermal nerve sheath myxoma
Solitary circumscribed neuroma
Ectopic meningioma
Nasal glial heterotopia
Benign Triton tumour
Hybrid nerve sheath tumours

Malignant
Malignant peripheral nerve sheath tumour
Epithelioid malignant nerve sheath tumour
Malignant Triton tumour
Malignant granular cell tumour
Ectomesenchymoma

This chapter was added to the new book. It was previously included with the 2007 WHO classification of tumours of the
central nervous system. The current WHO classification included tumours previously classified under cranial and peripheral
nerves, head and neck and skin tumours. This represents an important initiative to present the diverse family of
mesenchymal tumors into a single reference source. The 2007 classification did not include the following:

Granular cell tumour

Dermal nerve sheath myxoma

Solitary circumscribed neuroma

Ectopic meningioma / meningothelial hamartoma

Nasal glial heterotopia

Benign Triton tumour

Hybrid nerve sheath tumours

Malignant Triton tumour


Malignant granular cell tumour

Ectomesenchymoma

Tumours of uncertain differentiation


Benign
Acral fibromyxoma
Intramuscular myxoma (including cellular variant)
Juxta-articular myxoma
Deep (aggressive) angiomyxoma
Pleomorphic hyalinizing angiectatic tumour
Ectopic hamartomatous thymoma

Intermediate (locally aggressive)


Haemosiderotic fibrolipomatous tumour

Intermediate (rarely metastasizing)


Atypical fibroxanthoma
Angiomatoid fibrous histiocytoma
Ossifying fibromyxoid tumour
Ossifying fibromyxoid tumour, malignant
Mixed tumour NOS
Mixed tumour NOS, malignant
Myoepithelioma
Myoepithelial carcinoma
Phosphaturic mesenchymal tumour, benign
Phosphaturic mesenchymal tumour, malignant

Malignant
Synovial sarcoma NOS
Synovial sarcoma, spindle cell
Synovial sarcoma, biphasic
Epithelioid sarcoma
Alveolar soft-part sarcoma
Clear cell sarcoma of soft tissue
Extraskeletal myxoid chondrosarcoma
Extraskeletal Ewing sarcoma
Desmoplastic small round cell tumour
Extra-renal rhabdoid tumour
Neoplasms with perivascular epithelioid cell differentiation (PEComa)
PEComa NOS, benign
PEComa NOS, malignant
Intimal sarcoma

Malignant mesenchymoma is not included in the current classification. Most cases of malignant mesenchymoma reported
previously probably represent heterologous line of differentiation in specific sarcomas such as myxoid liposarcomas with
cartilaginous metaplasia, ALT and dedifferentiated liposarcomas with osseous, cartilaginous, smooth muscle or skeletal
muscle elements, MPNST with heterologous components and others.

Undifferentiated / unclassified sarcomas


Undifferentiated spindle cell sarcoma
Undifferentiated pleomorphic sarcoma
Undifferentiated round cell sarcoma
Undifferentiated epithelioid sarcoma
Undifferentiated sarcoma NOS

This chapter was added to encompass a group of malignant tumours that were previously included in the fibrohistiocytic
tumours, namely malignant fibrous histiocytomas. These tumours lack a specifically identified line of differentiation
when analyzed by presently available technology. Dedifferentiated types of specific sarcomas are not included in this
category. Undifferentiated/unclassified sarcomas account for up to 20% of all sarcomas and about a quarter of these are
radiation-associated tumours. These tumours do not have distinct clinical or morphological characteristics that would
otherwise place them under specific types of sarcomas. Genetic subgroups, however, are emerging within this family and
this important work is ongoing.

Undifferentiated round cell and spindle cell sarcoma

In this group, EWSR1 is involved in non-ETS fusions with genes such as PATZ1, POU5F1, SMARCA5, NFATC2 or SP3.
Another recurrent rearrangement involves CIC-DUX4 fusion gene resulting in the chimeric CIC-DUX4 protein which
upregulates genes of the PEA3 subclass of ETS family.

It remains to be seen whether these cases represent one or more separate entities, or whether they are better classified
as variants of Ewing sarcoma.

Undifferentiated pleomorphic sarcoma (UPS)


UPS was most often called malignant fibrous histiocytoma in the past. Historically, many believe this entity is difficult to
evaluate because of the shifting diagnostic criteria throughout the years. Analysis of 70 cases diagnosed as MFH of no
specific type, storiform or pleomorphic malignant fibrous histiocytoma, pleomorphic sarcoma or undifferentiated
pleomorphic sarcoma showed highly complex karyotype with no specific recurrent aberrations. Undifferentiated sarcomas
with 12q13~15 amplification including MDM2 and CDK4 are best classified as dedifferentiated liposarcomas. The
relationship between this tumor and the family of undifferentiated/unclassified tumors with spindle cell morphology above
remains relatively undefined and is somewhat problematic in application at a practical level.