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Year : 2021  |  Volume : 64  |  Issue : 3  |  Page : 448-459
Recent updates in the diagnosis of soft tissue tumors: Newly described tumor entities, newer immunohistochemical and genetic markers, concepts, including “inter-tumor relationships”

Department of Surgical Pathology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India

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Date of Submission23-Nov-2020
Date of Decision13-Feb-2021
Date of Acceptance17-Feb-2021
Date of Web Publication28-Jul-2021


During the last two decades, there have been significant strides in the diagnosis of soft tissue tumors, including identification of various tumor entities, newer immunohistochemical markers, and an increasing number of molecular signatures, defining certain tumors. Lately, there are certain emerging tumor entities, defined by their molecular features with an impact on treatment. At the same time, there is a certain degree of overlap in the expression of certain immunohistochemical antibody markers, as well as genetic markers, with certain gene rearrangements and chimeric fusions observed among completely different tumors. Moreover, a certain amount of clinicopathological, immunohistochemical, and molecular proximity has been unraveled among certain tumor types. Over the years, the World Health Organization (WHO) fascicles on tumors of soft tissue have succinctly brought out these aspects. The present review describes recent updates in the diagnosis of soft tissue tumors, including certain newly described tumor entities; emphasizing upon newer, specific immunohistochemical and molecular markers, along with concepts, regarding “intertumor relationships”.

Keywords: New immunohistochemical markers in soft tissue tumors, newly described genetic fusions in sarcomas, sarcomas, soft tissue tumors, updates in soft tissue tumors

How to cite this article:
Rekhi B. Recent updates in the diagnosis of soft tissue tumors: Newly described tumor entities, newer immunohistochemical and genetic markers, concepts, including “inter-tumor relationships”. Indian J Pathol Microbiol 2021;64:448-59

How to cite this URL:
Rekhi B. Recent updates in the diagnosis of soft tissue tumors: Newly described tumor entities, newer immunohistochemical and genetic markers, concepts, including “inter-tumor relationships”. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 Oct 28];64:448-59. Available from: https://www.ijpmonline.org/text.asp?2021/64/3/448/322379

   Introduction Top

Soft tissue tumors are relatively common, but sarcomas are rare. These are complex and diagnostically challenging tumors, especially with limited biopsies, in view of clinical, radiological, histopathological, including immunohistochemical and even molecular overlap within certain tumors described. More than 100 soft tissue tumors and more than 80 different types of sarcomas have been described. More than one-thirds of soft tissue sarcomas are characterized by underlying specific genetic signatures.[1],[2],[3],[4]

While surgical resection with optional radiation therapy is the treatment of choice for most localized soft tissue sarcomas in adult patients, there are specific chemotherapies for certain sarcomas, for example, pediatric round cell sarcomas, which are expensive and might be toxic (as compared to the cost of a molecular test). Therefore, these need to be exactly tailored.[5] Certain histopathological subtypes of sarcomas, occurring in adult patients are associated with variable chemosensitivity. This assumes importance, especially in cases of recurrences and metastasis.[6] Gastrointestinal stromal tumors (GISTs) are candidates for targeted therapy, imatinib (Gleevac). The same therapy is being considered for treating other tumors, such as large, recurrent dermatofibrosarcoma protuberans (DFSP), and in certain cases of chordomas, to name but a few.[7] Therein lays the value of exact histopathological typing, preferably by a sarcoma expert, who is actively engaged in multidisciplinary sarcoma care.[8]

During the last two decades, there has been a flurry of information in the “realm” of soft tissue tumors, as the newer volumes of the World Health Organization (WHO) on tumors of soft tissues and bones have emerged, revealing newer tumor entities, immunohistochemical and genetic markers and exploring certain intertumor relationships. Soft tissue tumors, including sarcomas, were classified on the basis of lineage, which is currently followed. In the third edition of the WHO fascicle, the term “borderline” was replaced with “intermediate malignancy”. It was reported that benign lesions, such as cutaneous fibrous histiocytomas might rarely metastasize. The frequency of malignant fibrous histiocytomas, redesignated as undifferentiated pleomorphic sarcoma, was found to be restricted to 5%. Hemangiopericytomas were found to be synonymous with solitary fibrous tumors, further related to giant cell angiofibroma. A new entity that emerged was a sarcoma with uncertain differentiation, which did not show any specific lineage.[1],[2]

GISTs and nerve sheath tumors were incorporated in the fourth edition of the WHO fascicle on soft tissue tumors. The new entities that emerged were hemosiderotic fibrolipomatous tumor (HFLL), phosphaturic mesenchymal tumor (PMT), sclerosing/spindle cell rhabdomyosarcoma, pseudomyogenic hemangioendothelioma (PMHE), and undifferentiated sarcoma. Certain intertumor relationships were observed, for example between a low-grade fibromyxoid sarcoma (LGFMS) and a sclerosing epithelioid fibrosarcoma (SEF).[3] There was the evolution in the genetic profile of tumors, such as myoepithelial neoplasms, with identification of EWSR1 gene rearrangement and specific fusion transcripts, such as EWSR1-PBX and EWSR1-POU5F1, etc.[3],[9],[10],[11]

In the recent, fifth edition of the WHO fascicle, certain newer entities have been described, for example, atypical spindle cell/pleomorphic lipomatous tumor (lacking MDM2 gene amplification, otherwise noted in atypical lipomatous tumor/well-differentiated liposarcoma) [Figure 1]; myxoid pleomorphic liposarcoma (lacking FUS/EWSR1-DDIT3 fusion, which is seen in a myxoid liposarcoma), superficial CD34-positive fibroblastic tumor, angiofibroma, EWSR1-SMAD3 rearranged fibroblastic tumor (emerging), synovial hemangioma, intramuscular angioma, anastomosing hemangioma, Epstein–Barr virus (EBV)-associated smooth muscle tumor, inflammatory leiomyosarcoma, and NTRK3-rearranged spindle cell neoplasm (emerging). Various tumor entities have been described with their corresponding “essential” and “desirable” diagnostic criteria. Ectomesenchymoma is included within skeletal muscle tumors. Melanotic schwannoma has been redesignated as a malignant melanotic nerve sheath tumor, in view of its aggressive clinical course, in a significant number of cases. Undifferentiated round-cell sarcoma has been subtyped as Ewing sarcoma, round cell sarcoma with EWSR1-non ETS fusions, CIC-rearranged, sarcoma with BCOR genetic alterations.[4] Certain newer immunohistochemical markers, defining underlying associated molecular signatures have been identified, such as STAT6 for solitary fibrous tumor (SOFT) and FOSB for pseudomyogenic hemangioendothelioma, epithelioid hemangioma, and osteoblastoma.[12],[13]
Figure 1: Atypical spindle cell lipomatous tumor (negative for MDM2 gene amplification, by FISH). An 8 cm-sized mass in the thigh of a 26-year-old female. (a) Variation in the size of adipocytes with collagenous and myxoid stroma (H and E, x200). (b) Areas of myxoid change with interspersed spindly cells (H and E, x200). (c) Tumor cells displaying nuclear atypia (H and E, x400). (d) Atypical nuclei with areas of myxoid stroma (H and E, x400)

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The time-honored histomorphological approach for evaluating soft tissue tumors has progressed from a pattern-based approach, towards the integration of certain immunohistochemical markers for exact recognition of certain tumor entities. For example, hemangiopericytoma is replaced by a solitary fibrous tumor, and it has been realized that much earlier, several tumors considered as hemangiopericytomas, were actually various other tumors showing a hemangiopericytomatous growth pattern.[14] Some of these are monophasic synovial sarcoma, malignant peripheral nerve sheath tumor (MPNST), spindle cell rhabdomyosarcoma, and SFT [Figure 2] and [Figure 3]. Lately, STAT6 has been identified as a highly sensitive and specific immunohistochemical marker for the diagnosis of an SFT, which has NAB2-STAT6 as its underlying genetic signature [Figure 4].[12],[15],[16],[17] Previously, SFT was diagnosed with CD34, which is seen in a range of tumors, from benign to malignant, therefore, lacking its overall specificity.[18] Apart from its exact diagnosis, including at various unconventional sites, there is a risk stratification model for an SFT, in view of its uncertain malignant potential.[17],[19],[20],[21] Another example is an inaccurate association of “herringbone pattern” with the only fibrosarcoma. It has been realized that adult fibrosarcoma is much rarer or rather “extinct,” when compared to other tumors that exhibit “herringbone” patterns and can be underdiagnosed.[22] These are monophasic spindle cell types of synovial sarcoma, MPNST, SFT, and fibrosarcomatous transformation in a DFSP. Over the years, gene expression studies have revealed transducin-like enhancer of split-1 (TLE1) as an immunohistochemical marker for the diagnosis of synovial sarcoma.[23] Although this is a highly sensitive and reasonably specific marker in differentiating a synovial sarcoma from an adult fibrosarcoma, its overall specificity is limited, as it is expressed in other tumors, such as nerve sheath tumors [Figure 5].[24],[25] Recently, SS18-SSX fusion-specific antibody has been identified for the diagnosis of synovial sarcoma. In view of sensitivity up to 95% and specificity up to 100%, it seems to mirror the presence of underlying SS18-SSX gene fusion, a demonstration of which is presently the diagnostic gold standard of synovial sarcoma.[26]
Figure 2: (a) Spindle cell tumor, displaying hemangiopericytomatous (stag horn-like) vasculature (H and E, x200). (b) Diffuse myogenin positivity, besides desmin positivity (not shown), reinforcing a diagnosis of spindle cell rhabdomyosarcoma (Diaminobenzidine, x400). (c) Case of synovial sarcoma, comprising uniform, short spindly cells with intervening slit-like blood vessels (H and E, x 400). (d) Calponin positivity (Diaminobenzidine, x400). (e) Diffuse BCL2 positivity (Diaminobenzidine, x400) (f) Cytoplasmic MIC2 positivity (Diaminobenzidine, x400)

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Figure 3: (a) Spindle cell tumor with hemangiopericytomatous vasculature, including herniation of spindly cells (H and E, x400). (b) S100P positivity, reinforcing diagnosis of MPNST (Diaminobenzidine, x400). (c) Another spindle cell tumor with hemangiopericytomatous vasculature (H and E, x 400). (d) Diffuse CD34 positivity, reinforcing a diagnosis of the solitary fibrous tumor (SFT) (Diaminobenzidine, x400)

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Figure 4: Solitary fibrous tumor (a) Spindle cell tumor, including cells with minimal nuclear variation and intervening thin-walled branching blood vessels (H and E, x400). (b) Intervening stromal collagen (H and E, x400). (c) Diffuse D34 positivity (Diaminobenzidine, x400). (d) Diffuse intranuclear STAT6 positivity, reinforcing a diagnosis of SFT (Diaminobenzidine, x400)

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Figure 5: Monophasic spindle cell synovial sarcoma. (a) Spindle cell sarcoma with prominent hemangiopericytomatous vasculature (H and E, x200). (b) Diffuse, intense TLE1 positivity, reinforcing a diagnosis of synovial sarcoma (Diaminobenzidine, x400). (c) Spindle cell sarcoma, including cells exhibiting herring bone-like patterns (H and E, x300). (d) Diffuse TLE1 positivity, reinforcing a diagnosis of synovial sarcoma (Diaminobenzidine, x400)

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Some newly described soft tissue tumors in the last two WHO fascicles include

Phosphaturic mesenchymal tumor (PMT): It is defined as a tumor that leads to tumor-induced osteomalacia in most patients because of the production of fibroblast growth factor 23 (FGF23). These tumors occur in any soft tissue location and are histopathologically composed of bland spindle cells in a hyalinized to “smudgy” matrix; hemangiopericytomatous vascular pattern in some cases; variable number of osteoclasts, matrix, and a typical “grungy” type of calcification [Figure 6].[27] Lately, FNI-FGFR1 fusions have been identified as a frequent event underlying a PMT.[28]
Figure 6: Phosphaturic mesenchymal tumor. (a) Spindle cell tumor with intervening blood vessels and osteoclastic giant cells (arrowhead) (H and E, x200). (b) Grungy calcification (arrowhead) (H and E, x400). (c) Distinct chondroid formation (H and E, x200)

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Superficial CD34-positive fibroblastic tumor: This was previously misdiagnosed as malignant fibrous histiocytoma (MFH), including low-grade MFH, as described in the premier study by Carter et al.[29] According to the recent WHO fascicle, this is defined as a distinctive low-grade neoplasm of the skin and subcutis, characterized by a fascicular to a sheet-like proliferation of spindled cells with abundant, eosinophilic, granular to “glassy” cytoplasm, marked nuclear pleomorphism, low mitotic rate, diffuse CD34 immunoexpression, and frequent aberrant keratin immunoreactivity [Figure 7].[30] Furthermore, this entity seems to share the morphological spectrum with PRDM10-rearranged soft tissue tumor, especially with regards to the underlying molecular translocation.[31]
Figure 7: Superficial CD34-positive fibroblastic tumor. (a) Cellular tumor, composed of spindle and pleomorphic fibroblastic cells with interspersed inflammatory cells (H and E, x200). (b) Pleomorphic tumor cells with prominent nucleoli, intranuclear pseudoinclusions, and characteristic “glassy” cytoplasm, with infrequent mitoses (H and E, x400). (c) Diffuse CD34 positivity (Diaminobenzidine, x400). (d) Aberrant AE1/AE3 positivity (Diaminobenzidine, x400)

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EWSR1-SMAD3 rearranged fibroblastic tumors: This is an emerging tumor entity, which is very rare, invariably identified in superficial, mostly acral sites. Histopathologically, these are plexiform fibroblastic tumors, showing entrapment of adipose tissue, adnexal structures and characterized by early growth response protein 1 (ERG1) immunostaining. Demonstration of EWSR1-SMAD3 fusion constitutes the defining feature.[32]

This reflects how molecular diagnosis seems to be an integral part of diagnosing soft tissue tumors. A relatively newly described variant of rhabdomyosarcoma, namely spindle cell/sclerosing rhabdomyosarcoma has been found to be associated with a specific mutation, MYOD1 (L122R) in 41%–60% of cases, including association with relatively aggressive clinical outcomes [Figure 8].[33],[34],[35]
Figure 8: Sclerosing rhabdomyosarcoma. (a) Atypical tumor cells, arranged in a pseudoangiosarcomatous pattern in a densely sclerotic stroma (H and E, x400). (b) Tumor cells displaying focal desmin positivity (Diaminobenzidine, x400). (c) Diffuse MYOD1 positivity (Diaminobenzidine, x400)

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One of the categories of soft tissue tumors that have really evolved is the undifferentiated round cell sarcomas. These are now clearly subdivided as Ewing Sarcoma, characterized by underlying genetic fusions between FET/TET genes with ETS fusion partners, such as EWSR1-FLI1, EWSR1-ERG, followed by round cell sarcomas, characterized by fusion between EWSR1 gene and non-ETS partner genes, such as NFATC2 (more commonly in bones) and PATZ1.[36],[37],[38] Furthermore, two distinct tumors have been described, such as CIC-rearranged sarcoma, characterized by fusion genes, such as CIC-DUX4 and CIC-NUTM1, and sarcoma with BCOR-genetic alterations, such as BCOR-CCNB3, BCOR-MAML3-positive sarcomas.[39],[40]

While BCOR-CCNB3 positive sarcomas mostly occur in the bones (commonly tibia) of young patients and histopathologically show the presence of short spindly cells with twisted nuclei, interspersed blood vessels, and myxoid change; CIC-rearranged tumors, including CIC-DUX4 positive sarcomas more commonly occur in the soft tissues of older patients and histopathologically display tumor cells with epithelioid morphology, prominent nucleoli, myxoid change, and a variable amount of myxoid change. Immunohistochemically, BCOR and CCNB3 are useful in triaging cases for BCOR-CCNB3 fusion, whereas WT1 and ETV4 are useful for triaging sarcomas for CIC-rearranged tumors [Figure 9], [Figure 10], [Figure 11]. In terms of clinical outcomes, CIC-rearranged tumors are relatively more aggressive.[39],[40],[41],[42],[43] For a long time, there has not been a useful immunohistochemical antibody marker for Ewing sarcoma, apart from MIC2/CD99 and FLI-1, both, with their limited specificity, respectively. Lately, NKX2.2 has emerged as a sensitive marker for substantiating a diagnosis of Ewing sarcoma [Figure 12]a and [Figure 12]b. It is useful in differentiating Ewing sarcomas from undifferentiated sarcomas, including BCOR-CCNB3 and CIC-DUX4-positive, in view of its positive intranuclear expression in the former and negative expression in both the latter subtypes. At the same time, it is necessary to recognize its limited specificity, in view of its positive expression in cases of mesenchymal chondrosarcoma and olfactory neuroblastoma.[44] In cases of equivocal expression of immunohistochemical markers, including aberrant expression of cytokeratins, especially in rare cases of Ewing sarcoma with adamantinoma-like features, it is necessary to confirm the diagnosis with molecular tests including demonstration of EWSR1 rearrangement and or demonstration of EWS-FLI1 or EWS-ERG fusion transcript [Figure 12]c and [Figure 12]d.[45],[46]
Figure 9: BCOR-CCNB3 fusion-positive undifferentiated sarcoma. (a) A tumor composed of round to short spindly cells with hyperchromatic nuclei and indistinct nucleoli (H and E x400). (b) Tumor cells embedded in a myxoid stroma (H and E x400). (c). Polymerase chain reaction (PCR) result showing positive band for BCOR-CCNB3 fusion (140 bp) (arrow). (d) Sequencing result showing BCOR-CCNB3 fusion, an electropherogram

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Figure 10: BCOR-CCNB3 fusion-positive sarcoma. (a) Round to oval to short spindly cells with hyperchromatic nuclei, in a sheeted pattern with intervening thin-walled blood vessels and focal myxoid stroma (H and E, x400). (b) Cytoplasmic membranous MIC2/CD99 positivity (Diaminobenzidine, x400). (c) Diffuse SATB2 positivity (Diaminobenzidine, x400). (d) Diffuse, intense BCOR positivity (Diaminobenzidine, x400) (e) PCR result showing positive band for BCOR-CCNB3 fusion (140 bp) (arrow). PC: Positive control

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Figure 11: CIC-DUX4 fusion-positive undifferentiated sarcoma. (a) Round to polygonal and short spindle cells with prominent apoptosis and mitotic figures (H and E, x200). (b) WT1 positivity (Diaminobenzidine, x400). (c) RT-PCR showing the positive band at the level of control 165 bp, for CIC-DUX4 fusion (Type 1). PC: Positive control

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Figure 12: (a) Malignant small round cell tumor (H and E, x400). (b) Diffuse, intense NKX2.2 positivity, reinforcing a Ewing sarcoma (Diaminobenzidine, x400). Tumor cells showed membranous positivity for CD99/MIC2 and EWSR1 gene rearrangement (not shown). (c) Malignant round cell tumor in the scalp of an infant (H and E, x400). (d) EWSR1 gene rearrangement, in the form of red-green split signals, confirming Ewing sarcoma (Diaminobenzidine, x1000). Tumor cells were positive for MIC2/CD99, FLI-1, and NKX2.2 (not shown)

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Among vascular tumors, two distinct tumor entities have been reasonably discussed. These include pseudomyogenic hemangioendothelioma (PMHE) and anastomosing hemangioma. PMHE, which was previously termed as epithelioid sarcoma-like hemangioendothelioma, is presently an intermediate malignant, rarely metastasizing neoplasm, displaying vascular/endothelial differentiation that mostly occurs in the soft tissues of lower extremities of young adult males, and frequently characterized by multifocal lesions. Histopathologically, PMHE is composed of plump spindle cells with interested polymorphonuclear leukocytes and simulates high-grade sarcomas, such as spindle cell rhabdomyosarcoma and epithelioid sarcoma. However, it lacks frequent mitotic figures and tumor necrosis, unlike these mimics. Immunohistochemically, it is characterized by positive expression of CD31, keratins, and ETS-related gene (ERG) in most cases [Figure 13]a, [Figure 13]b, [Figure 13]c.[47] This tumor is also reported in the skin and rarely in the bones.[48],[49] Subsequent to the description of PMHE as a distinct vascular tumor, SERPINE1-FOSB fusion has been identified, which constitutes a consistent genetic alteration underlying this tumor.[50] Thereafter, FOSB has been reported as a useful immunohistochemical marker for reinforcing a diagnosis of PMHE. At the same time, it is positively expressed in an epithelioid hemangioma and an osteoblastoma.[13] Anastomosing hemangioma is a benign vascular neoplasm, consisting of thin-walled anastomosing blood vessels, lined by a monolayer of plump, protruding endothelial cells. Although it was initially described in the male genital tract, its most common location is the kidney and the retroperitoneal adipose tissues. Immunohistochemically, the tumor cells show positive expression of endothelial markers, namely CD34, CD31, Fli1, and ERG [Figure 13]c and [Figure 13]d.[51],[52] Subsequently, inactivating hot spot mutation in GNAQ or GNA14 has been reported in most cases of anastomosing hemangiomas.[53],[54]
Figure 13: Pseudomyogenic hemangioendothelioma (a-c). (a) Plump spindly cells, containing moderate to abundant, eosinophilic cytoplasm with interspersed occasional osteoclastic giant cell and few polymorphonuclear leukocytes (H and E, x400). (b) AE1/AE3 positivity (Diaminobenzidine, x400). (c) CD31 positivity (Diaminobenzidine, x400).Anastomosing hemangioma (d and e). (d) Thin-walled anastomosing blood vessels, lined by protruding endothelial cells (H and E, x400). (e) CD34 highlighting anastomosing blood vessels (Diaminobenzidine, x400)

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A small subset of epithelioid hemangioendothelioma (EHE), which is defined as a malignant vascular neoplasm, comprising plump, epithelioid endothelial cells, has been found to harbor YAP1-TFE3 gene fusion, instead of the relatively more common WWTR1-CAMTA1 fusion. YAP1-TFE3-positive EHE mostly occurs in young patients and histopathologically displays large epithelioid cells, arranged in a nested to focally, vasoformative patterns, containing abundant eosinophilic cytoplasm. Immunohistochemically, tumor cells show TFE3 positivity [Figure 14].[55] Recent studies have shown its relatively favorable clinical course.[56]
Figure 14: TFE3-positive epithelioid hemangioendothelioma. (a) Nests and cords of cells, with abundant eosinophilic cytoplasm, focally forming vascular channels, in a myxohyaline stroma (H and E, x400). (b) CD31 positivity (Diaminobenzidine, x400). (c) FLI1-1 positivity (Diaminobenzidine, x400). (d) Diffuse TFE3 positivity (Diaminobenzidine, x400)

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In the category of tumors of uncertain differentiation, an emerging tumor entity has appeared, neurotrophic tropomyosin receptor kinase (NTRK)-rearranged spindle cell neoplasms. These tumors occur more frequently in pediatric patients and are characterized by NTRK gene alterations, including translocations, amplification, deletions, and point mutations.[57],[58],[59] These tumors display a variety of histological patterns, ranging from “fibrosarcoma-like “ to neural and “SFT-like,” all these tumors constituting as differential diagnoses of NTRK-rearranged spindle cell neoplasms [Figure 15]. While the demonstration of NTRK gene rearrangement and/or its fusion with various partner genes, excluding ETV6, remains the diagnostic gold standard, a reasonable way of triaging cases for molecular testing includes testing these with NTRK antibody. The utility of identifying NTRK-positive neoplasms is in view of the availability of first-generation TRK inhibitor, such as LOXO-101 (larotrectinib) or entrectinib, which can be offered in cases of recurrent, unresectable tumors.[60]
Figure 15: NTRK-positive spindle ell tumor in a child. (a) Hypercellular tumor composed of monotonous, spindle-shaped fibroblastic cells with interspersed collagen deposition and adipose tissue (H and E, x200). (b) Spindle cells with minimal atypia and intervening strands of collagen (H and E, x400)

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Among nerve sheath tumors, a category of hybrid nerve sheath tumors appeared in the fourth edition of the WHO classification of tumors of soft tissue. This entity includes two different types of nerve sheath tumors within the same tumor, for example, hybrid neurofibroma/schwannomas, which may occ'ur in cases of neurofibromatosis, and the relatively newer, hybrid schwannoma/perineuriomas, which occur sporadically.[61],[62] Rare examples of malignant transformation in hybrid nerve sheath tumors have also been documented.[63] Genomic studies have taken a further leap within MPNSTs, with the identification of inactivating somatic mutations in the genes encoding polycomb repressive complex 2 (PRC2), SUZ12, or EED, leading to loss of trimethylation of lysine 12 of histone 3 (H3K27me3), which can be detected by immunohistochemistry [Figure 16].[64],[65] A distinct variant of MPNST, namely epithelioid MPNST, is characterized by diffuse immunoexpression of S100 protein and SOX10 invariably, along with loss of INI1/SMARCB1 in up to 67% cases.[66],[67]
Figure 16: Malignant peripheral nerve sheath tumor(MPNST) showing loss of H3K27me3. (a) Cellular tumor composed of atypical spindleshaped and pleomorphic nuclei arranged in fascicles and whorls with interspersed mitotic figures and scattered lymphocytes (H and E, x 400). (b) Tumor cells displaying peritheliomatous growth pattern and focus of necrosis (H and E, x 400). (c) Tumor cells displaying loss of H3K27me3 (Diaminobenzidine, x 400)

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Another significant conceptual update within nerve sheath tumors is the designation of melanotic schwannoma as malignant melanotic nerve sheath tumor (MMNST), in view of an aggressive clinical course in a significant number of such cases. The essential features include tumor origin from the paraspinal or autonomic nerves; microscopically, presence of plump spindle cells, arranged in a diffuse and fascicular growth pattern with densely pigmented tumor cells and immunohistochemical expression of S100 protein and/or SOX10, along with HMB45 and/or Melan A.[68] This tumor shows loss of protein kinase A regulatory subunit 1 alpha (PRKAR1) immunoexpression.[69]

GIST, including succinate dehydrogenase (SDH)-deficient subtype has been included in the fourth and fifth editions of the WHO classification of soft tissue tumors. SDH-deficient GISTs have been described in more detail in the recent edition.[70] These constitute about 7.5% of cases of GISTs, mostly in the pediatric population; in gastric location and characterized by slow progression. These have a multinodular architecture, lymphovascular invasion, rarely nodal metastasis, epithelioid cytomorphology, and display loss of immunohistochemical expression of succinate dehydrogenase B (SDHB).[71] The importance of identifying this subset of tumors is in view of their resistance to tyrosine kinase inhibitors, including imatinib.[70] [Table 1].
Table 1: Newly introduced soft tissue tumor entities in the last two WHO fascicles with an impact and their differential diagnosis

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Apart from newer diagnostic entities and markers, certain intertumor relationships have been observed. Low-grade fibromyxoid sarcoma (LGFMS), including hyalinizing spindle cell tumor with giant rosettes and sclerosing epithelioid fibrosarcoma (SEF) constitute as distinct fibroblastic tumors, with their respective genetic signatures, namely FUS-CREB3L2/L1 of the former and EWSR1-CREB3L1 of the latter tumor.[72],[73],[74] SEF is a relatively more aggressive tumor. However, certain studies have shown a morphological link between the two tumors.[75],[76] This was followed by the demonstration of mucin 4 (MUC4), which is a consistent immunohistochemical antibody marker of LGFMS, in 70% of cases of SEF [Figure 17] and [Figure 18].[77] Various authors have demonstrated FUS gene rearrangement in cases of SEF, showing areas of LGFMS.[78] Conversely, the authors have shown EWSR1-CREB3L1 fusions in few cases of LGFMS.[79] This clearly proves a clinicopathological, immunohistochemical and genetic “link” between the two tumors, in a subset of tumors, including recognition of few hybrid forms of LGFMS and SEF.[74],[75],[76],[78],[79]
Figure 17: Low-grade fibromyxoid sarcoma. (a) An arcuate pattern of blood vessels in a spindle cell sarcoma with myxoid and collagenous stroma (H and E, x400). (b) Focal areas (same tumor) showing epithelioid cells in a hyalinised stroma, reminiscent of sclerosing epithelioid fibrosarcoma (H and E, x400). (c) Focal collagenous rosettes, indicative of hyalinizing spindle cell tumor with giant collagenous rosettes (H and E, x400). (d) Tumor cells displaying diffuse MUC4 positivity (Diaminobenzidine, x400)

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Figure 18: Sclerosing epithelioid fibrosarcoma (a) Polygonal-shaped cells embedded in a dense hyalinised/sclerotic stroma, resembling osteoid (H and E, x400). (b) Tumor cells displaying diffuse MUC4 positivity (Diaminobenzidine, x400). Tumor cells were negative for SATB2 (not shown)

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Despite some morphological, immunohistochemical, and molecular overlapping features between a clear cell sarcoma and malignant gastrointestinal neuroectodermal tumor (GNET), the latter is the preferred terminology for such a tumor occurring in the gastrointestinal tract, considering these tumors lack melanocytic differentiation, unlike clear cell sarcoma of the soft tissues.[80]

Another entity, recognized as a distinct entity in the fourth edition of the WHO classification of soft tissue tumors was hemosiderotic fibrolipomatous tumor (HFLT), characterized by the presence of adipocytes and hemosiderin-laden spindle cells, focally prominent hemosiderin-laden macrophages, and scattered chronic inflammatory cells.[81] Subsequently, areas reminiscent of HFLT have been reported in two tumors, namely myxoinflammatory fibroblastic sarcoma (MIFS) and pleomorphic telangiectatic tumors (PHAT).[82],[83],[84],[85] Moreover, certain cases of MIFS are known to harbor tumor areas reminiscent of PHAT (”early PHAT”), indicating some level of proximity between these tumors [Figure 19]. Genetically, all these three tumors have been reported to harbor a common fusion transcript, namely t(1;10)(p22;q24) TGFBR3 and/or MGEA5, with varying frequency, including in hybrid cases of HFLT/MIFS.[86],[87] Some authors have postulated that cases showing hybrid HFLL-MIFS” actually represent a form of malignant progression within HFLL, rather than a lesion strictly related to classic MIFS.[88] In yet another study, Carter et al.[89] concluded that with the presence of TGFBR3 and/or MGEA5 rearrangements among these three tumors, HFLT is related to both, PHAT and MIFS and that the latter two tumors might represent morphologic variants of a single, genetically-defined entity, in which only MIFS has acquired the capacity to metastasize.
Figure 19: Myxoinflammatory fibroblastic sarcoma (MIFS), with areas resembling pleomorphic hyalinising angiectatic tumor (PHAT). (a) MIFS, showing myxoid areas with inflammatory cells including pigmented macrophages and “Reed Sternberg's-like” giant cells (inset) (H and E, x200). (b) Many pleomorphic giant cells and intervening blood vessels, with perivascular hyalinization (H and E, x200). Inset: Intranuclear pseudoinclusion (c) Perivascular hyalinization, reminiscent of PHAT (H and E, ×200). (d) Dilated thrombosed vascular channels with pleomorphic cells, reminiscent of PHAT (H and E, ×200)

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Spindle cell rhabdomyosarcomas seem to form a morphological continuum with sclerosing rhabdomyosarcomas, including MYOD1 mutations seen in both the tumors. Therefore, these continue to be included as a distinct tumor entity, spindle cell/sclerosing rhabdomyosarcoma.[33],[34],[35],[36]

The newly described superficial CD34-positive fibroblastic tumor seems to be related to the PRDM10-rearranged soft tissue tumors.[31]

Apart from nodular fasciitis and aneurysmal bone cyst, USP6 gene rearrangement has also been documented in myositis ossificans, indicating proximity among these tumors.[90] While there are specific genetic signatures for several tumors, a common genetic rearrangement and/or a fusion can be seen in completely different tumors, for example, EWSR1 gene rearrangement, seen in a variety of tumors.[91] Loss of retinoblastoma tumor suppressor gene (RB1), seen in spindle cell/pleomorphic lipoma, is also documented in cellular angiofibroma, atypical spindle cell/lipomatous tumor, and myofibroblastoma.[92]

In conclusion,there is an expansion in knowledge regarding newer soft tissue tumor entities, immunohistochemical makers (STAT6, FOSB, BCOR, CCNB3, and H3K27), and newer genetic signatures (BCOR-CCNB3, CIC-DUX, MYOD1 (L122R), YAP1-TFE3, etc.) related to diagnostics, prognosis, and theranostics (NTRK-rearranged soft tissue tumors) of sarcomas. Morphology, in the form of “pattern-based” approach remains the initial point in the diagnosis of soft tissue tumors, which is a guide for further testing with an optimal panel of immunohistochemical markers and triaging for an appropriate molecular test. Newer diagnostic markers, such as NKX2.2, SS18-SSX are on the horizon. An optimal panel of immunohistochemical antibody markers, preferably highly sensitive and specific markers should be included in the diagnostic armamentarium, which would also be cost-effective. Fluorescence in situ hybridization (FISH), reverse transcriptase-polymerase chain reaction (RT-PCR), and next-generation sequencing (NGS) constitute useful ancillary techniques. NGS, although relatively expensive, is a high throughput technique, for simultaneous testing of several genes, for example in undifferentiated round cell sarcomas, rhabdomyosarcomas, liposarcomas, etc. It is prime time to include molecular techniques as a part of the diagnostic armamentarium of sarcomas, in view of its value in achieving a more precise diagnosis, including of entities defined by molecular signatures. Immunohistochemical and molecular results must be interpreted in a clinicopathological context. Newer tumor entities, genetic markers are being unraveled. An overlap within certain soft tissue tumors exists. Newer “inter-tumor relationships” are being explored.


I am very grateful to the immunohistochemistry laboratory and division of molecular diagnostics and translational medicine, Department of Surgical Pathology of our institute.

Guarantor: Bharat Rekhi.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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Correspondence Address:
Bharat Rekhi
Room 818, 8th Floor, Department of Pathology, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_1361_20

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