The 2026 World Health Organization Classification of Tumors of Soft Tissue and Bone

Abstract

The 6th edition of the World Health Organization Classification of Soft Tissue and Bone Tumors (STB6) integrates the latest scientific and molecular discoveries with decades of pathological expertise to establish a globally accepted common language for diagnosis and clinical behavior. In this volume, the “essential” and “desirable” diagnostic criteria have been refined, considering different resource settings, ensuring accuracy while maintaining flexibility. A tumor type (entity) is a tumor in which multiple parameters (eg, clinical, histopathological, and/or genetic features) differ from those of other tumor types. In total, 19 new entities met these criteria and were added. A subtype is different in at least one dimension from the main tumor type (clinical, histopathological, or genetic), preferably resulting in a different treatment or outcome. A morphological pattern (no longer “variant”) is important for pathologists to be aware of to facilitate recognition but is not associated with different clinical behavior. The classification was drafted by 203 editors and authors from 27 countries, representing genetics, medical oncology, surgical oncology, orthopedic surgery, and radiology, in addition to pathology. STB6 includes soft tissue tumors (n=116), bone tumors (n=46), vascular tumors of soft tissue and bone (n=18), undifferentiated spindle and round cell sarcomas (n=4), hematopoietic and dendritic cell neoplasms (n=6), and genetic syndromes (n=6). In total, 62 sarcomas are included. A consensus was reached among the expert editorial board. In this review, we highlight changes in tumor classification in STB6, including recently described tumor types, novel diagnostic markers, recent discoveries in molecular genetics, and improvements in prognostication.

The World Health Organization (WHO) classification of Tumors (WCT) provides a uniform nomenclature and standardized framework for categorizing tumors of soft tissue and bone, facilitating accurate diagnosis, guiding treatment, informing research, epidemiological reporting, and the development of international reporting and treatment guidelines. The 6th edition of the WHO Classification of soft tissue and bone tumors (STB6) is an update of the 5th edition classification, encompassing some major and minor changes. The 6th edition integrates the latest scientific and molecular discoveries with decades of pathological expertise to establish a globally accepted common language for soft tissue and bone tumor diagnosis and management. The criteria used for considering inclusion of new entities into this volume included publication of at least 5 cases of the neoplastic entity by 2 independent groups in peer-reviewed journals; any borderline entities included are referred to as “provisional” rather than “emerging.”

In this volume, the “essential and desirable diagnostic criteria” for tumors have been developed considering different resource settings, ensuring diagnostic accuracy while maintaining flexibility. The “essential criteria” are mostly morphology-based, including certain essential, invariably “basic” immunohistochemical (IHC) stains, except for molecularly defined tumors such as sarcomas with BCOR alterations, for which molecular confirmation is considered essential. The “desirable criteria” include an additional diagnostic layer of molecular tests and/or “newer” resources, including surrogate IHC markers. The morphology codes of the updated International Classification of Diseases Oncology, 4th iteration (ICDO-4) have been included for each tumor type and subtype in STB6, ensuring and facilitating more accurate and granular epidemiological data collection.¹ Inclusion of tumor types and subtypes is based on better definitions. A tumor type (entity) is a tumor in which multiple parameters (eg, clinical, anatomic, histopathological, and/or molecular features) differ from those of other tumor types. A subtype is recognized as being different in at least one dimension from the main tumor type (clinical, histopathological, or genetic), preferably resulting in a different treatment or outcome. A morphological pattern (no longer called “variant”) is defined as a specific morphology of a given tumor type, important for pathologists to be aware of to facilitate recognition, but not associated with different clinical behavior.

The classification was drafted by 203 editors and authors from 27 countries, representing radiology, medical oncology, genetics, surgical oncology, and orthopedic surgery, in addition to pathology. When appropriate, responsible authors from the previous 5th edition were acknowledged for their contributions, providing the basis for the 6th edition. A consensus was subsequently reached among the expert editorial board. Entities with specific organ-restricted presentation, such as biphenotypic sinonasal sarcoma or uterine sarcomas, are excluded from STB6 and instead discussed in other WCT volumes, with the exception of gastrointestinal stromal tumors, as in many centers, these are treated by sarcoma surgeons and medical oncologists and are discussed in sarcoma multidisciplinary teams.

CHANGES IN HISTONE GENE ANNOTATIONS

With regard to the annotation of histone H3 protein nomenclature, a hybrid format is used as a practical compromise that preserves the widely recognized legacy terminology (which uses protein numbering excluding the initiating methionine that is cleaved from the mature protein) while remaining aligned with genetic reporting standards;² specifically, the 3-letter amino acid description is omitted and the legacy terminology is given in parentheses, for example, H3.3 p.G35W (G34W) in giant cell tumor of bone. For IHC markers targeting histone proteins, we retain the established epitope-based terminology (eg, H3K36M and H3K27me3) without the “p.” prefix and with the conventionally used formatting (eg, H3K27me3 without spaces). These terms refer to protein expression or posttranslational modifications rather than genomic alterations and are therefore most consistent with current diagnostic practice and the published literature.

CHANGES IN THE CLASSIFICATION FRAMEWORK OF STB6

In the 5th edition, separate sections on vascular tumors were included in both the soft tissue and bone tumor chapters, which was mainly driven by their different clinical behavior. Vascular tumors in bone often present as multifocal disease, and epithelioid hemangioma is locally aggressive in bone, while benign in soft tissue. In this edition, these sections were combined to limit redundancy; differences between bone and soft tissue presentation are clearly marked within the respective sections.

STB6 has also taken a different approach to hematolymphoid tumors of the soft tissues and bone, combining them into one chapter. Tumors included in this chapter are hematopoietic neoplasms typically derived from lymphoid, plasma cell, or histiocytic/dendritic cell lineages that arise in nonmucosal extranodal soft tissues or involve bone primarily, often presenting as mass-forming and/or destructive osseous lesions.

In other WHO 6th edition books (released and upcoming), various soft tissue tumor entities are presented in a harmonized way, mostly within a combined chapter of “mesenchymal tumors.”

SOFT TISSUE TUMORS

Significant Changes in Soft Tissue Tumor Classification

Adipocytic Tumors

One new tumor type is introduced as lipoblastoma-like tumor, a benign spindle cell neoplasm of mature and immature adipocytic differentiation sharing morphologic features of spindle cell lipoma, myxoid liposarcoma, and lipoblastoma (Tables 1 and 2).^3–6 It has a lobulated growth pattern, delineated by variably sized septa; an admixture of mature adipocytes, univacuolated and/or bivacuolated lipoblasts, and bland spindle cells; with variably myxoid to collagenous matrix and thin-walled plexiform vasculature (Fig. 1A).

TABLE 1.

Summary of New and Dissolved Entities in Soft Tissue and Bone Tumor Classification in STB6

Chapter	Newly added tumors	Deleted tumors
Soft tissue tumors
Adipocytic tumors	Lipoblastoma-like tumor
Fibroblastic and myofibroblastic tumors	PRRX1-rearranged fibroblastic tumor Nodular necrotizing fibroblastic tumor Calcifying fibrous tumor*	Adult fibrosarcoma
Fibrohistiocytic and synovial tumors	Chondroid synoviocytic neoplasm Keratin-positive giant cell-rich tumor	Deep fibrous histiocytoma
Pericytic (perivascular) tumors	SRF-rearranged myoid neoplasm
Smooth muscle tumors		Inflammatory leiomyosarcoma
Skeletal muscle tumors	Inflammatory rhabdomyoblastic tumor Fusion-associated spindle cell rhabdomyosarcoma† MYOD1-mutant spindle cell/sclerosing rhabdomyosarcoma†	Ectomesenchymoma
Gastrointestinal stromal tumor	Succinate dehydrogenase-deficient gastrointestinal stromal tumor
Tumors of uncertain differentiation	OGT-rearranged mesenchymal neoplasm (formerly known as OGT-rearranged acral mesenchymal neoplasm) Acral fibrochondromyxoid tumor GLI1-altered mesenchymal tumors Superficial FET-ETS family neurocristic tumor Pseudoendocrine sarcoma NUT-rearranged sarcoma FET-CREB family epithelioid mesenchymal tumor PATZ1-rearranged sarcoma‡
Vascular tumors of soft tissue and bone	YAP1::TFE3 hemangioendothelioma Spindle cell hemangioma*
Undifferentiated spindle and small round cell sarcomas	NFATC2-rearranged sarcoma‡
Bone tumors
Osteoclastic giant cell-rich tumors	Brown tumor of hyperparathyroidism
Fibrogenic tumors§		Fibrosarcoma of bone
Other tumors of bone	TFCP2-rearranged rhabdomyosarcoma†

^*Inadvertently omitted in the 2020 WCT.

^†Spindle cell/sclerosing rhabdomyosarcoma has been split into these 3 separate entries.

^‡The category round cell sarcomas with EWSR1-non-ETS fusions has been split into NFATC2-rearranged sarcoma and PATZ1-rearranged sarcoma.

^§The family of fibrogenic tumors that was listed under bone tumors in STB5 has been removed in STB6.

TABLE 2.

Key Features of New Entities Included in Soft Tissue and Bone Tumor Classification in STB6

Entity	Behavior	Section	Key molecular	Morphology	Note
Lipoblastoma-like tumor	Benign	Adipocytic	No fusions	Reminiscent of lipoblastoma and myxoid liposarcoma
PRRX1-rearranged fibroblastic tumor	Benign	Fibroblastic/myofibroblastic	PRRX1 rearrangement	Paucicellular circumscribed bland spindle cell neoplasm; hyalinized stroma with variably wire-like and ropey collagen; prominent ectatic and irregular vascular spaces
Nodular necrotizing fibroblastic tumor	Intermediate	Fibroblastic/myofibroblastic	YAP1::MAML2 fusion	Well-defined nodules of neoplastic cells with surrounding and/or admixed inflammation; tumor cells with copious, eosinophilic-to-amphophilic cytoplasm and enlarged, vesicular nuclei with prominent nucleoli; often central necrosis.
Chondroid synoviocytic neoplasm	Intermediate	Fibrohistiocytic/synovial	FN1 fusions (various partners)	Nodules of large, eosinophilic, moderately pleomorphic synoviocytes, surrounded by calcified matrix and cartilage, with sparse histiocytes, osteoclasts, and foamy macrophages.	Temporomandibular joint region
Keratin-positive giant cell-rich tumor	Intermediate	Fibrohistiocytic/synovial	HMGA2::NCOR2	Polymorphous population of giant cells (osteoclast-type or Touton), histiocytes, inflammatory cells, and keratin-positive mononuclear cells
SRF-rearranged myoid neoplasm	Benign	Pericytic (perivascular)	SRF gene fusions (various partners)	Monomorphic ovoid to spindle cells with fibrillary cytoplasm; arranged in short fascicles; myoid or immature smooth muscle differentiation
Inflammatory rhabdomyoblastic tumor	Intermediate	Skeletal muscle	Near haploidy	Spindled or epithelioid cells with eosinophilic cytoplasm, variable degrees of nuclear atypia, and low mitotic activity; massive intratumoral lymphohistiocytic infiltration; skeletal muscle differentiation	Previously “inflammatory leiomyosarcoma”
Fusion-associated spindle cell rhabdomyosarcomas	Malignant	Skeletal muscle	Fusions due to rearrangement of genes in various combinations (ZFP64, NCOA2, NCOA3, VGLL3, CITED2, and others)	Monomorphic spindle cell morphology; expression of at least 2 skeletal muscle markers	Split from spindle cell/sclerosing RMS; variable prognosis depending on fusions
MYOD1-mutant spindle cell/sclerosing rhabdomyosarcoma	Malignant	Skeletal muscle	MYOD1 mutation p.L122R	Spindle cells arranged in fascicles and/or oval to spindle cells with variable amount of sclerotic stroma; MYOD1 typically diffuse and intense	Split from spindle cell/sclerosing RMS; aggressive; poor prognosis
OGT-rearranged mesenchymal neoplasm	Benign	Uncertain differentiation	OGT rearrangement	Cords or nests of epithelioid cells within a hyalinized or fibromyxoid stroma	Acral location
Acral fibrochondromyxoid tumor	Benign	Uncertain differentiation	THBS1 rearrangement (frequently with ADGRF5 or rarely other)	Multinodular tumor with fibrous, myxoid or chondroid stroma; fibrovascular septa; bland spindle or round cells; CD34 and ERG positive	Acral location
GLI1-altered mesenchymal tumors	Variable	Uncertain differentiation	GLI1 amplification or rearrangement	Lobular architecture; nested growth; epithelioid or ovoid cytology; prominent admixed branching capillary vessels
Superficial FET-ETS family neurocristic tumor	Benign	Uncertain differentiation	FET-ETS family fusions (EWSR1 or FUS and FLI1, ERG, ETV1, ETV5, and others)	Nests, cords, and trabeculae of small, bland, round to ovoid cells; lack of significant cytologic atypia or tumor necrosis; strong and diffuse expression of SOX10, S100 protein, and CD99
Pseudoendocrine sarcoma	Malignant	Uncertain differentiation	CTNNB1 alteration	Mimics neuroendocrine tumor morphologically; lacks expression of keratins and neuroendocrine markers; β-catenin nuclear positivity	Paravertebral soft tissues
NUT-rearranged sarcoma	Malignant	Uncertain differentiation	NUT family (mainly NUTM1) rearrangement (various partners)	Heterogeneous: pure or mixed population of round-epithelioid-spindle cells with monomorphic nuclei; arranged in sheets, nests or fascicles; variable collagenous-myxoid stroma, NUT positive	Highly aggressive
FET-CREB family epithelioid mesenchymal tumor	Malignant	Uncertain differentiation	FET-CREB family fusions (EWSR1 or FUS and CREM, ATF1, or CREB1)	Monomorphic epithelioid to round cells; keratin positive	Mesothelial-lined cavities
YAP1::TFE3 hemangioendothelioma	Malignant	Vascular tumors	YAP1::TFE3 fusion	Solid growth and/or well-formed vascular channels lined by epithelioid endothelial cells with abundant eosinophilic cytoplasm; TFE3 positive	Now separated from epithelioid hemangioendothelioma
Brown tumor of hyperparathyroidism	Benign	Osteoclastic giant cell-rich	KRAS mutation	Monomorphic spindle cells in a storiform pattern; osteoclastic giant cells; hemorrhage	Elevated PTH; regresses with PTH normalization
TFCP2-rearranged rhabdomyosarcoma	Malignant	Other bone tumors	TFCP2 rearrangement (EWSR1::TFCP2 or FUS::TFCP2)	Epithelioid, spindle cell, or mixed appearance; skeletal muscle differentiation; co-expression of keratins and ALK	Predilection for maxillofacial bones; highly aggressive

FIGURE 1.

(A) Lipoblastoma-like tumor. Bland spindle cells and lipoblasts set in a myxoid stroma with abundant capillaries. (B) PRRX1-rearranged fibroblastic tumor. Bland uniform spindle cells with ovoid nuclei and scant cytoplasm are embedded within a hyalinized stroma. Bright eosinophilic ropey collagen is present, as well as staghorn-shaped vessels.

The diagnostic criteria for atypical spindle cell/pleomorphic lipomatous tumors are clarified in this edition, and they are now separated into atypical spindle cell and atypical pleomorphic subtypes.⁷ Nonlipogenic tumors within the spectrum of well-differentiated liposarcoma and dedifferentiated liposarcoma are now distinguished based on mitotic rate: owing to survival differences, tumors with up to 4 mitoses per 10 HPF are classified as cellular well-differentiated liposarcoma (atypical lipomatous tumor), while tumors with 5 mitoses or more are classified as dedifferentiated liposarcoma (of note, HPF diameter was not indicated for most of these studies, so the number of mitoses/mm² cannot be accurately determined).⁸ The designation “low-grade dedifferentiated liposarcoma” is therefore no longer recommended. More precise grading parameters for myxoid liposarcoma are specified, with explicit distinction between low-grade and higher-grade disease. Higher-grade myxoid liposarcoma is defined by the presence of more cellular areas with round cells exceeding 5% of the tumor, usually accompanied by diminished myxoid matrix.

Fibroblastic and Myofibroblastic Tumors

Two new tumor types are included under this category as PRRX1-rearranged fibroblastic tumor^9,10 and nodular necrotizing fibroblastic tumor (see Tables 1 and 2). PRRX1-rearranged fibroblastic tumor is a benign spindle cell neoplasm characterized by PRRX1 rearrangements, most often with NCOA1 (Fig. 1B). While initially suggested to be a subtype of myxoinflammatory fibroblastic sarcoma, nodular necrotizing fibroblastic tumor is now recognized as a separate entity specified as a superficial mesenchymal neoplasm composed of epithelioid cells with a brisk inflammatory infiltrate and, in many cases, central necrosis, showing indolent behavior (Fig. 2).¹¹ Most of these lesions harbor YAP1::MAML2 fusions.

FIGURE 2.

Nodular necrotizing fibroblastic tumor. (A) The tumor shows a nodular architecture with a lymphoid rim. (B) The lesion shows a mixture of epithelioid and histiocytoid cells.

There were small changes in nomenclature: EWSR1::SMAD3-positive fibroblastic tumor was modified to SMAD3-rearranged fibroblastic tumor (anticipating the future identification of fusion partners involving other members of the FET family of genes), and the word “pleomorphic” was added to superficial CD34-positive pleomorphic fibroblastic tumor (given the importance of cytologic pleomorphism in both recognition of this tumor type and possible confusion with pleomorphic sarcomas). Calcifying fibrous tumor, inadvertently omitted from the 2020 classification, has been included in STB6. Tumors that resemble sclerosing epithelioid fibrosarcoma with MUC4 negativity and the presence of gene fusions involving YAP1 and KMT2A were co-classified with sclerosing epithelioid fibrosarcoma, recognizing that this may change as more outcome data are collected.^12–14 Notably, adult fibrosarcoma has been removed from the classification, as essentially all tumors diagnosed as adult fibrosarcoma in the past can now be reclassified as other sarcoma types using contemporary methods (eg, monophasic synovial sarcoma, malignant peripheral nerve sheath tumor, and the fibrosarcomatous variant of dermatofibrosarcoma protuberans). However, infantile fibrosarcoma (IFSC) remains in the classification, as it is a distinctive tumor type occurring in children with specific morphological and genetic abnormalities; when IFSC presents in the kidney, the most common and acceptable terminology is “cellular congenital mesoblastic nephroma.” Finally, undifferentiated pleomorphic sarcoma (UPS) has been moved from tumors of uncertain differentiation (where it was considered a subtype under the umbrella term of “undifferentiated soft tissue sarcoma”) to the section on fibroblastic and myofibroblastic tumors, since in many cases the tumor cells appear to show fibroblastic and sometimes myofibroblastic differentiation, despite the “undifferentiated” designation. UPS is still considered a diagnosis of exclusion. Low-grade, uniform and monomorphic spindle cell sarcomas should not be classified as UPS, as they increasingly seem to be resolving into other entities.

Fibrohistiocytic and Synovial Tumors

This chapter’s heading, “fibrohistiocytic tumors” in the 5th edition, is changed to “Fibrohistiocytic and synovial tumors” in STB6.

Two new tumor types are included here as chondroid synoviocytic neoplasm and keratin-positive giant cell-rich tumor (KPGCT) (see Tables 1 and 2). Chondroid synoviocytic neoplasm (a.k.a. “chondroid tenosynovial giant cell tumor” or “calcified chondroid mesenchymal neoplasm”) has a predilection for the temporomandibular joint region, is composed of varying amounts of large, eosinophilic synoviocytes, osteoclastic giant cells, hyaline cartilage, and calcified matrix (Fig. 3), and frequently harbors FN1 rearrangements.^15–19 KPGCT is a mesenchymal neoplasm of uncertain lineage, composed of multinucleated giant cells, mixed inflammatory cells, histiocytes, and a small number of keratin-positive mononuclear cells (Fig. 4A, B), harboring HMGA2::NCOR2 fusions.^20–23 Deep fibrous histiocytoma has been removed from this classification, since it is a subtype of cutaneous benign fibrous histiocytoma (dermatofibroma), which is included in the WHO classification of skin tumors.

FIGURE 3.

Chondroid synoviocytic neoplasm. Chondroid matrix production within the neoplasm.

FIGURE 4.

(A) Keratin-positive giant cell-rich tumor. Scattered mononuclear cells with bright eosinophilic cytoplasm, giant cells, and numerous foamy histiocytes. (B) Keratin immunohistochemistry (AE1/AE3) highlights mononuclear cells with a paranuclear pattern. (C) SRF-rearranged myoid neoplasm. Tumor cells with elongated nuclei and dense eosinophilic cytoplasm. (D) Solid sheets of monomorphic ovoid cells with ill-defined cell borders. The cells show fibrillary eosinophilic cytoplasm and uniform nuclei with vesicular chromatin and small nucleoli. (E) Inflammatory rhabdomyoblastic tumor. Epithelioid tumor cells with eosinophilic cytoplasm and mild nuclear atypia. (F) The tumor is consistently positive for desmin.

Pericytic (Perivascular) Tumors

A new tumor type, SRF-rearranged myoid neoplasm, has been introduced (see Tables 1 and 2), encompassing a group of predominantly benign tumors exhibiting myoid or immature smooth muscle differentiation and characterized by SRF gene fusions with various partners (Fig. 4C, D).^24–26 In the previous 5th edition, a subset of these tumors was described as an “atypical cellular variant” of myofibroma.

Smooth Muscle Tumors

Inflammatory leiomyosarcoma has been omitted from this section, as tumors in this category are now designated as inflammatory rhabdomyoblastic tumor (see the Skeletal Muscle Tumors section).

Skeletal Muscle Tumors

Inflammatory rhabdomyoblastic tumor is introduced in this volume (see Tables 1 and 2), including tumors formerly designated inflammatory leiomyosarcoma. It is defined as an intermediate (rarely metastasizing) neoplasm, characterized by skeletal muscle differentiation, a marked lymphohistiocytic infiltrate (Fig. 4E, F), and near-haploidization.^27–30 Malignant progression to rhabdomyosarcoma can be seen and is characterized by high mitotic activity and often necrosis.³¹ Based on genetic features and differences in clinical behavior, spindle cell/sclerosing rhabdomyosarcoma has been split into 3 separate entities: fusion-associated spindle cell rhabdomyosarcomas and MYOD1-mutant spindle cell/sclerosing rhabdomyosarcoma are discussed in the soft tissue chapter, while TFCP2-rearranged rhabdomyosarcoma predominantly occurs in bone and is discussed in the bone chapter (see Tables 1 and 2). Fusion-associated spindle cell rhabdomyosarcomas are a heterogeneous group of sarcomas with skeletal muscle differentiation and fascicular spindle cell morphology, defined by recurrent pathognomonic fusions, including, among others, NCOA2 or CITED2, ZFP64, and VGLL3 as fusion partners.^32–34 MYOD1-mutant spindle cell/sclerosing rhabdomyosarcoma is an aggressive subtype of rhabdomyosarcoma, characterized by fascicular spindle cell and/or sclerosing morphology and MYOD1 p.L122R mutation.^31,35–37 Ectomesenchymoma, an extremely rare and predominantly pediatric tumor, was removed as a separate entity from the classification; this lesion is now recognized as a subtype of embryonal rhabdomyosarcoma and referred to as “embryonal rhabdomyosarcoma with divergent neuroectodermal differentiation” based on the presence of intermixed neuroblastic elements.

Gastrointestinal Stromal Tumor

Succinate dehydrogenase-deficient gastrointestinal stromal tumor has been recognized as a separate category, given the distinct molecular pathogenesis, implications for possible familial syndromic associations, and differences in clinical behavior.^38–42

Chondro-Osseous Tumors

No significant changes were made to this section.

Peripheral Nerve Sheath Tumors

Epithelioid malignant peripheral nerve sheath tumor (EMPNST), previously considered a subtype of MPNST, is now recognized as a separate entity, based on its distinctive epithelioid morphology and specific molecular pathogenesis (loss of SMARCB1 [INI1] expression).^43,44

Tumors of Uncertain Differentiation

A large number of recently recognized tumor types are included for the first time in this volume, including OGT-rearranged mesenchymal neoplasm (formerly known as OGT-rearranged acral mesenchymal neoplasm) (Fig. 5),⁴⁵ acral fibrochondromyxoid tumor (AFCMT),⁴⁶ GLI1-altered mesenchymal tumors,^47–49 superficial FET-ETS family neurocristic tumor,^50,51 pseudoendocrine sarcoma,^52,53 NUT-rearranged sarcoma,^54,55 and FET-CREB family epithelioid mesenchymal tumors (see Tables 1 and 2).^56–58 AFCMT is a benign mesenchymal neoplasm of uncertain differentiation arising in acral sites and composed of bland spindle or round cells arranged in a chondromyxoid stroma lobulated by fibrovascular septa (Fig. 6A, B). GLI1-altered mesenchymal tumors have variable clinical behavior, often nested epithelioid morphology and a rich capillary network (Fig. 6C-E), and are driven by fusions or amplification of GLI1. Superficial FET-ETS family neurocristic tumor is an indolent superficial neoplasm that shares similar fusion events with Ewing sarcoma (Fig. 7A, B). Pseudoendocrine sarcoma is a malignant neoplasm of uncertain lineage, predominantly arising in paravertebral soft tissues, morphologically resembling a well-differentiated neuroendocrine tumor (Fig. 7C, D), but lacking expression of keratins and neuroendocrine markers, while harboring CTNNB1 mutations. NUT-rearranged sarcoma is an aggressive malignant mesenchymal neoplasm characterized by heterogeneous morphology (Fig. 7E, F) and gene fusions involving NUTM1. FET-CREB family malignant epithelioid mesenchymal tumors typically involve mesothelial-lined cavities, show epithelioid morphology and epithelial marker expression (Fig. 8), and are characterized by fusions between EWSR1 or FUS genes with members of the CREB family of transcription factors (ATF1, CREB1, and CREM).

FIGURE 5.

OGT-rearranged mesenchymal neoplasm. A striking feature in some tumors is the cellular myxoid areas alternating with hypocellular zones showing stromal and sometimes perivascular hyalinization, imparting a 2-toned appearance.

FIGURE 6.

(A) Acral fibrochondromyxoid tumor. A low-magnification view shows a multinodular tumor with chondromyxoid stroma and fibrovascular septa. (B) The tumor is composed of cords and nests of ovoid cells with reniform or round nuclei. (C) GLI1-altered mesenchymal tumor. Neoplastic cells show uniform, ovoid nuclei. Bland examples with a relative paucity of mitotic activity, as seen here, generally follow an indolent clinical course. (D) Perivascular proliferation of neoplastic cells is commonly seen at the tumor periphery. Sometimes this proliferation manifests as small tumor lobules bulging into vascular lumina. (E) S100 protein is expressed in about 30% of tumors, generally those with a nested architecture.

FIGURE 7.

(A) Superficial neurocristic tumor with an EWSR1::ERG fusion. A trabecular growth pattern is a common feature. (B) Superficial neurocristic tumor with FUS::ETV5 fusion. Diffuse expression of SOX10. (C) Pseudoendocrine sarcoma. Neoplastic cells show pale eosinophilic cytoplasm and monomorphic round nuclei with speckled chromatin. (D) Immunohistochemistry for β-catenin shows strong, diffuse nuclear expression in essentially all cases, consistent with an underlying CTNNB1 mutation. (E) NUT-rearranged sarcoma with MXD4::NUTM1 fusion gene. Prominent rhabdoid phenotype in a colonic sarcoma. (F) Tumor cells typically display uniform nuclear staining for the NUT protein.

FIGURE 8.

FET-CREB family epithelioid mesenchymal tumor. (A) The neoplastic epithelioid cells have indistinct cell borders and are intermixed with a mixed chronic inflammatory infiltrate, similar to the architecture of angiomatoid fibrous histiocytoma. (B) The tumor cells form sheets and tubular structures. The morphology resembles epithelioid mesothelioma. (C) The neoplastic cells demonstrate strong diffuse labeling for keratins 5/6.

The former “emerging” category of NTRK-rearranged spindle cell neoplasms was expanded to kinase-altered spindle cell neoplasms, since it is now recognized that a wide range of kinase gene fusions (as well as point mutations) can be identified in this tumor class.^59–61 PATZ1-rearranged sarcoma was introduced into this section; this tumor was included within round cell sarcomas with EWSR1-non-ETS fusions in the 5th edition. These tumors show more morphologic heterogeneity than round cell sarcomas, with round and spindle cell morphology, co-express myoepithelial and skeletal muscle markers, and are characterized by fusions involving EWSR1 and PATZ1. Two entities (atypical fibroxanthoma and ectopic hamartomatous thymoma) were no longer included, and the umbrella term “undifferentiated soft tissue sarcoma” is no longer recommended as a miscellaneous category for the group of tumors including undifferentiated pleomorphic sarcoma (moved to (myo)fibroblastic tumors; see above), undifferentiated spindle cell sarcoma, and undifferentiated round cell sarcoma.

VASCULAR TUMORS OF SOFT TISSUE AND BONE

The most significant change in this section is the nomenclature for lesions formerly known as hemangiomas and lymphangiomas, introducing the term vascular anomalies (and lymphatic malformations) to align the classification with the International Society for the Study of Vascular Anomalies (ISSVA).⁶² Spindle cell hemangioma was inadvertently omitted from the 2020 classification; it has been included in STB6. YAP1::TFE3 hemangioendothelioma has been separated from epithelioid hemangioendothelioma given the differences in histopathology, molecular pathogenesis, and clinical behavior (see Tables 1 and 2).⁶³ YAP1::TFE3 hemangioendothelioma is a malignant vascular neoplasm composed of epithelioid endothelial cells that often display abundant eosinophilic cytoplasm and vasoformative features (Fig. 9A), characterized by YAP1::TFE3 fusion. Patients with this tumor type have a more favorable clinical outcome than those with conventional epithelioid hemangioendothelioma.

FIGURE 9.

(A) YAP1::TFE3 hemangioendothelioma. Tumor cells arranged in solid nests and sheets with abundant glassy cytoplasm. (B) Brown tumor of hyperparathyroidism. Monomorphic and fibroblast-like spindle cells lacking cytologic atypia admixed with multinucleated giant cells. (C) TFCP2-rearranged rhabdomyosarcoma. A proliferation of spindle cells with distinct nucleoli, a high mitotic index, and mild anisokaryosis. This tumor was associated with a FUS::TFCP2 fusion.

UNDIFFERENTIATED SPINDLE AND SMALL ROUND CELL SARCOMAS

Given the fact that some of these high-grade sarcomas show not only round cell but also spindle cell morphology, the chapter name has been modified accordingly. The tumors included in this section are Ewing sarcoma, NFATC2-rearranged sarcoma, sarcomas with BCOR genetic alterations, and CIC-rearranged sarcoma. As mentioned above, the category round cell sarcomas with EWSR1-non-ETS fusions in the 5th edition has been split into NFATC2-rearranged sarcoma (included in this section)^64–66 and PATZ1-rearranged sarcoma (included under tumors of uncertain differentiation in the soft tissue tumors chapter). NFATC2-rearranged sarcoma is a round and spindle cell sarcoma with fibrohyaline stroma, associated with EWSR1::NFATC2 or FUS::NFATC2 fusions.

BONE TUMORS

Significant Changes in Bone Tumor Classification

Chondrogenic Tumors

A multidisciplinary approach for diagnosing these lesions with radiological correlation is emphasized in this edition . In the 5th edition, the terms “atypical cartilaginous tumor” and “chondrosarcoma, grade 1” were further defined: cartilaginous tumors in the appendicular skeleton (long and short tubular bones) are diagnosed as atypical cartilaginous tumors, and the term “chondrosarcoma, grade 1,” is reserved for tumors of the axial skeleton, including the pelvis, scapula, and skull base (flat bones), reflecting the poorer clinical outcome of these tumors at these sites.⁶⁷ Using different terminology for tumors with identical histomorphology could be considered counterintuitive and controversial. However, this terminology has the dual benefit of being simple in application and reflecting the worse outcome for tumors at these sites where there is a need for more extensive surgery.⁶⁷ Consequently, this terminology is further endorsed in the current classification. Chondromesenchymal hamartoma of the chest wall, based on the presence of cartilage, is discussed in STB6 under chondrogenic tumors instead of other tumors of bone as in STB5. In STB6, based on recent publications,⁶⁸ it is now recognized that a very small subset of chondroblastomas is malignant. These tumors show atypia and permeation, occur in the flat bones of older individuals, and are H3K36M positive by IHC.

Osteogenic Tumors

Benign osteogenic tumors include osteoma, osteoid osteoma, and osteoblastoma. Osteosarcoma is the most common malignant bone sarcoma, and multiple types as well as morphological patterns are distinguished based on location as well as morphology. No changes were made in their classification as compared to the 5th edition.

Fibrogenic Tumors

The category of “fibrogenic tumors” has been deleted from the bone tumor classification. Desmoplastic fibroma of bone was moved to “other tumors of bone.” Fibrosarcoma of bone, formerly considered a diagnosis of exclusion, was removed (similar to the soft tissue chapter), since most of these seem to represent dedifferentiated chondrosarcoma or leiomyosarcoma of bone, or rare bone presentations of soft tissue tumors such as solitary fibrous tumor, kinase-altered spindle cell neoplasms, or synovial sarcoma.

Osteoclastic Giant Cell-Rich Tumors

While many bone tumors can contain osteoclasts, they are a defining feature in giant cell tumor of bone, aneurysmal bone cyst, and nonossifying fibroma. Brown tumor of hyperparathyroidism, which was shown to be neoplastic when KRAS mutations were found to be necessary for their development, in addition to elevated parathyroid hormone (PTH) levels,⁶⁹ is included as a separate entity in STB6. It is defined as a benign spindle cell neoplasm with intermingled osteoclastic giant cells (Fig. 9B), occurring in the context of hyperparathyroidism.

In the previous edition, the occurrence of H3.3 p.G35W (G34W) in bone sarcomas (osteosarcoma, undifferentiated pleomorphic sarcoma) without associated giant cell tumor histology was acknowledged, suggesting a relationship to giant cell tumor of bone. More recent evidence showed that undifferentiated pleomorphic sarcoma or osteosarcoma with H3.3 p.G35 (G34) mutations show similar molecular and methylation profiles and thus may represent malignant giant cell tumors of bone.⁷⁰ However, studies with larger cohorts are needed to confirm this association and direct clinical management.

Notochordal Tumors

Notochordal tumors include benign notochordal cell tumor, conventional chordoma (including chondroid chordoma), dedifferentiated chordoma, and poorly differentiated chordoma. No changes were made in their classification as compared to the 5th edition.

Other Tumors of Bone

In this 6th edition, “osteofibrous dysplasia (OFD)-like adamantinoma” has been renamed as “atypical OFD” and is now considered a locally aggressive subtype of OFD. This better reflects the nonmalignant behavior of atypical OFD and should avoid overtreatment of these tumors in young patients.⁷¹ The diagnosis can nevertheless be difficult, and interobserver variability is high. TFCP2-rearranged rhabdomyosarcoma is a novel type of high-grade sarcoma with skeletal muscle differentiation (Fig. 9C), characterized by the fusion of TFCP2 to EWSR1 or FUS, with a predilection for the maxillofacial bones.⁷² This tumor is now included as a new bone tumor entity (see Tables 1 and 2).

HEMATOPOIETIC AND DENDRITIC CELL NEOPLASMS OF SOFT TISSUE AND BONE

Significant Changes in Hematopoietic and Dendritic Cell Neoplasms

Based on the approach taken by STB6 of describing only hematopoietic neoplasms that arise in nonmucosal extranodal soft tissues or involve bone primarily, this chapter includes plasmacytoma; diffuse large B-cell lymphoma, not otherwise specified (NOS) involving bone; Langerhans cell histiocytosis; Erdheim-Chester disease; follicular dendritic cell sarcoma; and Rosai-Dorfman disease.

Myeloid neoplasms and other medullary proliferations arising within the bone marrow compartment are excluded from this chapter. However, it should also be noted that virtually any hematolymphoid neoplasm may secondarily involve soft tissue and/or bone in the setting of locally extensive or systemic disease. Accordingly, diagnostic evaluation requires integration of morphological, immunophenotypic, and molecular findings with appropriate imaging and clinical assessment to determine the extent of involvement and to establish whether the lesion represents a primary neoplasm of soft tissue or bone.

GENETIC TUMOR SYNDROMES OF SOFT TISSUE AND BONE

Significant Changes in Genetic Tumor Syndromes

Germline (constitutional) pathogenic variants associated with an increased risk of developing soft tissue and/or bone tumors are being identified in a growing list of genes through the application of sequencing technology such as massively parallel DNA sequencing (Table 3). These tumor-predisposing genetic variants often have additional phenotypic consequences, resulting in clinically recognizable syndromes. As germline pathogenic variants are often inherited from one of the parents, it is important to recognize such tumor-predisposing syndromes to screen at-risk individuals in affected families for referral to genetic counseling and implementation of guideline-based surveillance for early cancer detection. While most of these syndromes demonstrate Mendelian inheritance, patients with disorders caused by postzygotic mutations have now been recognized and may need distinct forms of therapy and personalized follow-up. The study of germline tumor-predisposing variants may shed light on the pathogenesis of sporadic tumors.

TABLE 3.

Summary of the Syndromes Presented in Genetic Tumor Syndromes Chapter

Disease/phenotype	MIM number*	Inheritance	Locus	Gene	Gene/locus MIM number	Protein	Normal protein function
Enchondromatosis (Ollier disease and Maffucci syndrome)	166000	PZ	2q34	IDH1	147700	IDH1	Isocitrate dehydrogenase; conversion of isocitrate to α-ketoglutarate; NADPH production and control of mitochondrial redox balance
			15q26.1	IDH2	147650	IDH2
Li-Fraumeni syndrome	151623	AD	17p13.1	TP53	191170	TP53 (p53)	DNA damage response, “guardian of the genome”
McCune-Albright syndrome	174800	PZ	20q13.32	GNAS	139320	Gsα	The alpha subunit of a G protein; signal transduction from the 7 transmembrane to the cAMP second messenger
Multiple osteochondromas	133700	AD	8q24.11	EXT1	608177	EXT1	EXT1 and EXT2 form a hetero-oligomeric complex involved in heparan sulfate production; essential for bone and cartilage formation
	133701	AD	11p11.2	EXT2	608210	EXT2
Trichorhinophalangeal syndrome type 2	150230		8q24.q11-q24.13	A contiguous gene deletion syndrome encompassing EXT1
Potocki-Shaffer syndrome	601224		11p11.2	A contiguous gene deletion syndrome encompassing EXT2
Neurofibromatosis type 1	162200	AD	17q11.2	NF1	613113	Neurofibromin (NF1)	Regulation of RAS signaling
Paget disease of bone	—	AD	17p13.2	PFN1	176610	PFN1	Regulation of NFκB signaling
	167250	AD	5q35.3	SQSTM1	601530	SQSTM1 (p62)	Regulation of NFκB signaling
	602080	AD	18q21.33	TNFRSF11A	603499	RANK	Master regulator of osteoclasts
	239000	AR	8q24.12	TNFRSF11B	602643	Osteoprotegerin	Decoy receptor for TNFSF11/RANKL
	616833	AD	1q21.3	ZNF687	610568	ZNF687	Unknown

AD indicates autosomal dominant; AR, autosomal recessive; PZ, postzygotic.

^* OMIM indicates Online Mendelian Inheritance in Man (https://www.omim.org).

This chapter provides detailed descriptions of 6 syndromes associated with predisposition to the development of bone or soft tissue tumors (see Table 3). These well-characterized syndromes are included because the tumor manifests in the bone or soft tissues as part of the syndrome at high frequency and is a primary outcome of the genetic alteration underlying that syndrome, often with neoplasm features that are different from those of their sporadic counterparts.

Changes in STB6 related to genetic tumor syndromes include the removal of Rothmund-Thomson syndrome and Werner syndrome from having their own sections in the 5th edition to now only being mentioned in a table in the introduction. Paget disease of bone was selected to move from the introductory table in the 5th edition to currently having an extended section.

CONCLUSION

The 6th edition of the soft tissue and bone tumors volume provides an updated classification and comprehensive overview of tumors arising in soft tissue and bone based on the current best available evidence. It has attempted to meet global requirements while balancing scientific advances.