Sarcomas are malignant tumors that arise in the bone and soft tissue.  With numerous subtypes of sarcoma that can have overlapping histological, immunophenotypic, and clinical features, diagnosis can be extremely challenging. This challenge increases when rare subtypes are encountered for which most pathologists will have little experience.

Case #1

Background

A 49-year-old male presented with an ankle mass.  A biopsy was performed to further characterize the mass.

Histopathological Findings

• The biopsy showed a monotonous spindle cells arranged in a herringbone/fascicular growth pattern. Mitotic figures were easily identified. The differential diagnoses based on morphologic assessment  included synovial sarcoma, fibrosarcomatous dermatofibrosarcoma protuberans (DFSP) and malignant peripheral nerve sheath tumor (MPNST).
• Immunohistochemical analysis showed the neoplastic cells to be negative for cytokeratin AE1/3, S100 protein, CD34, TLE1 and desmin. H3K27me3 expression was retained.
• A negative TLE1 makes synovial sarcoma less likely but does not exclude it. Similarly, a negative CD34 argues against fibrosarcomatous DFSP.

Genetic Testing

The sarcoma NGS panel was performed and showed a COL1A1-PDGFB fusion, supporting the diagnosis of fibrosarcomatous dermatofibrosarcoma protuberans.

Teaching Points

• The differential diagnosis of a sarcoma with herringbone/fascicular morphology primarily includes synovial sarcoma, fibrosarcomatous DFSP and malignant peripheral nerve sheath tumor.
• While the negative CD34 stain initially made a Fibrosarcomatous DFSP diagnosis less likely, it is known that DFSP with a fibrosarcomatous features may lose CD34 expression, making its identification more difficult, especially in small samples.
• Identification of fibrosarcomatous change in DFSP is important as these tumors are more aggressive than conventional DFSP and may metastasize in 10-15% of cases.

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Case #2

Background

A 22-year-old male with a large abdominal mass. A core biopsy was performed.

Histopathological Findings

Histologic exam shows an undifferentiated small round cell tumor expressing several cytokeratins and CD99. Desmin and several other markers were negative. This immunohistochemical profile suggested the diagnosis of Ewing sarcoma since these can be cytokeratin positive. However, the anatomic location and morphologic features were more consistent with desmoplastic small round cell tumor.

Genetic Testing

The sarcoma panel was performed and showed a EWSR1-WT1 fusion, supporting the diagnosis of desmoplastic small round cell tumor and excluding the possibility of Ewing sarcoma. FISH for EWSR1 cannot be used since both tumors show rearrangements of this gene.

Teaching Points

• Small round cell tumors comprise a large variety of tumors that may include carcinomas, sarcomas and hematologic tumors.
• The EWSR1-WT1 fusion is diagnostic of desmoplastic small round cell tumor.
• The unusual finding of this tumor was the lack of desmin expression, which could be due to sampling - an area of the tumor showing no desmin expression. This illustrates two important points: (1) SARCP can be easily performed in limited samples and (2) the immunophenotype of a tumor in small samples may not be typical due to variations of antigen expression in different areas/subclones of the tumor.

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Case #3

Background

 A 67-year-old woman presented with a destructive sacral mass. A needle biopsy was performed.

Histopathological Findings

Sections showed a highly cellular malignant neoplasm composed of essentially undifferentiated-appearing round to slightly spindled cells. A panel of immunohistochemical markers was performed, showing the tumor to be variably positive for desmin and cytokeratins, diffusely MyoD1-positive (shown), and focally myogenin-positive. Expression of ALK protein was not present.

Genetic Testing

The sarcoma panel was performed and showed the MEIS1-NCOA2 fusion transcript.

Teaching Points

• Rhabdomyosarcomas are unusual in bone, except when metastatic.
• This is a clinically, morphologically and immunohistochemically typical example of a recently described type of osseous rhabdomyosarcoma, of the type that most often shows FUS/EWSR1-TFCP2 fusions, and less often MEIS1-NCOA2 fusions.
• These lesions usually occur in older adults and may show strong expression of cykeratins, a potential pitfall.
• ALK protein expression is characteristic of tumors with TFCP2 rearrangement and is less common in tumors having the MEIS1-NCOA2 fusion. ALK gene rearrangement is not present and these lesions do not appear to respond to ALK inhibition.
• Based on the small number of reported cases, these appear to represent an aggressive subtype of adult rhabdomyosarcoma.  

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Case #4

Background

A 32-year-old male with a penile nodule. A biopsy was performed.

Histopathological Findings

The histologic section revealed a small tumor composed of poorly formed fascicles of moderately atypical spindle to epithelioid cells with prominent nucleoli and abundant eosinophilic cytoplasm, focally resembling strap cells. The superficial aspect showed ulceration and granulation tissue with extravasation of red blood cells. The tumor cells were positive for CD31, ERG, FLI1, FOSB and keratin and showed retained nuclear expression of INI1.

Genetic Testing

Teaching Points

• Vascular tumors are a large group of entities and the differential diagnosis can be extensive.
• Angiosarcomas, hemangiomas and hemangioendotheliomas, can all show epithelioid cytology, which can sometimes makes their distinction difficult, particularly in small samples.
• The differential diagnosis in this case was between a penile type epithelioid hemangioma (a benign lesion) and a pseudomyogenic hemangioendothelioma (a tumor of intermediate malignancy). Epithelioid hemangiomas are vasoformative while pseudomyogenic hemangioendothelioma do not form vessels. However, the presence of overlying ulceration and granulation tissue complicated the interpretation.
• An immunostain for FOSB was positive in the tumor cells, but this antibody can be positive in both epithelioid hemangiomas and pseudomyogenic hemangioendotheliomas.
• The sarcoma panel revealed a SERPINE1-FOSB fusion, which is characteristic of pseudomyogenic hemangioendothelioma.

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Case #5

Background

A 17-year-old-male presented with a submental soft tissue mass. A biopsy was performed.

Histopathological Findings

The histologic section (H&E stain) showed a proliferation of mildly atypical and relatively monomorphic epithelioid cells, arranged in cords and nests, with focal reactivity for cytokeratins and S100 protein. The differential diagnosis was broad with this relatively non-specific immunoprofile.

Genetic Testing

The sarcoma panel was performed and showed an ACTB1-GLI1 gene fusion, supporting the diagnosis of a recently described soft tissue neoplasm known as “Malignant epithelioid neoplasm with GLI1 rearrangement”

Teaching Points

• “Malignant epithelioid neoplasm with GLI1 rearrangement” is a recently characterized group of neoplasm that morphologically resemble glomus/pericytic tumors or myoepitheliomas but that harbor fusions involving the GLI1 gene with a variety of other genes, including ACTB, MALAT1, and PTCH1.
• The ACTB1-GLI1 gene fusion has been previously documented in a group of perivascular myoid tumors known as pericytomas with t(7;12). However, these pericytomas seem to behave in a benign fashion and occur predominantly in the tongue, while the “Malignant epithelioid neoplasm with GLI1 rearrangements” do not show a pericytic immunoprofile and can behave in a malignant fashion.
• Since some tumors with GLI1 oncogenic activation might be sensitive to sonic hedgehog pathway inhibitors, this group of tumors could potentially be candidates for targeted therapy.

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References

Case 1

Thway K, Noujaim J, Jones RL, Fisher C. Dermatofibrosarcoma protuberans: pathology, genetics, and potential therapeutic strategies. Ann Diagn Pathol. 2016 Dec;25:64-71.

Case 2

Mora J, Modak S, Cheung NK, Meyers P, de Alava E, Kushner B, Magnan H, Tirado OM, Laquaglia M, Ladanyi M, Rosai J. Desmoplastic small round cell tumor 20 years after its discovery. Future Oncol. 2015;11(7):1071-81.

Case 3

Agaram NP, Zhang L, Sung YS, Cavalcanti MS, Torrence D, Wexler L, Francis G, Sommerville S, Swanson D, Dickson BC, Suurmeijer AJH, Williamson R, Antonescu CR. Expanding the Spectrum of Intraosseous Rhabdomyosarcoma: Correlation Between 2 Distinct Gene Fusions and Phenotype. Am J Surg Pathol. 2019 May;43(5):695-702.

Case 4

Walther C, Tayebwa J, Lilljebjörn H, Magnusson L, Nilsson J, von Steyern FV, Øra I, Domanski HA, Fioretos T, Nord KH, Fletcher CD, Mertens F. A novel SERPINE1-FOSB fusion gene results in transcriptional up-regulation of FOSB in pseudomyogenic haemangioendothelioma. J Pathol. 2014 Apr;232(5):534-40.

Case 5

Antonescu CR, Agaram NP, Sung YS, Zhang L, Swanson D, Dickson BC. A Distinct Malignant Epithelioid Neoplasm With GLI1 Gene Rearrangements, Frequent S100 Protein Expression, and Metastatic Potential: Expanding the Spectrum of Pathologic Entities With ACTB/MALAT1/PTCH1-GLI1 Fusions. Am J Surg Pathol. 2018 Apr;42(4):553-560.