Malignant melanotic Xp11 neoplasms exhibit a clinicopathologic spectrum and gene expression profiling akin to alveolar soft part sarcoma: a proposal for reclassification

The classification of the distinct group of mesenchymal neoplasms, first described as ‘Xp11 translocation perivascular epithelioid cell tumor (PEComa)’ and for which the term ‘melanotic Xp11 neoplasm’ or ‘Xp11 neoplasm with melanocytic differentiation’ has recently been proposed, remains challenging and controversial. We collected 27 melanotic Xp11 neoplasms, the largest series to date, for a comprehensive evaluation. Fourteen of the cases, together with eight alveolar soft part sarcomas (ASPS), nine conventional PEComas and a control group of seven normal tissues were submitted to RNA sequencing. Follow-up available in 22 patients showed 5-year overall survival and 5-year disease-free survival of 47.6 and 35.7%, respectively, which were similar to ASPS and significantly worse than conventional PEComa. Univariate analysis of location (occurring in the kidney versus not kidney), infiltrative growth pattern, nuclear pleomorphism, mitotic activity ≥2/50 high-power fields (HPF), necrosis and lymphovascular invasion were found to be associated with overall survival and/or disease-free survival. Multivariate analysis identified that location was the only factor found to independently correlate with disease-free survival. More importantly, RNA sequencing-based clustering analysis segregated melanotic Xp11 neoplasm and ASPS from other tumors, including conventional PEComa and Xp11 translocation renal cell carcinoma, and formed a compact cluster representative of the largely similar expression signature. Here we clearly define the true biologic nature of melanotic Xp11 neoplasms which are distinctive malignant mesenchymal tumors, rather than simply PEComa variants with occasionally unpredictable behavior. Meanwhile, melanotic Xp11 neoplasm and ASPS more likely represent phenotypic variants of the same entity, which is distinct from conventional PEComa and Xp11 translocation renal cell carcinoma. Based on these important findings, melanotic Xp11 neoplasm might be reclassified into a distinctive entity together with ASPS, independent from PEComa, in future revisions of the current WHO categories of tumors of soft tissue and bone for the improved reclassification. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Xp11.2 translocation renal neoplasm with features of TFE3 rearrangement associated renal cell carcinoma and Xp11 translocation renal mesenchymal tumor with melanocytic differentiation harboring NONO-TFE3 fusion gene

Xp11.2 translocation/TFE3 rearrangement-associated renal cell carcinoma (RCC) and Xp11 translocation renal mesenchymal tumor are distinct tumor entity. To broaden the spectrum of Xp11 neoplasms, we investigated a novel tumor exhibiting morphologies overlapping Xp11.2 translocation/TFE3 rearrangement-associated RCC and the mesenchymal counterpart with melanocytic differentiation by immunohistochemistry, fluorescence in situ hybridization (FISH) and RNA sequencing, as well as literature review. Histologically, the tumor was composed of three different types of tumor cells, including a large proportion of clear cells, small round cells, and a few spindle cells, presenting a relatively clear border in the majority area. The nuclei of all tumor cells showed extensively and strong positive expressions of TFE3. Whereas, the clear cells positively expressed the RCC-related markers including PAX8, RCC marker and CD10, and negatively expressed HMB45; On the contrary, the small round cells and spindle cells positively expressed melanocytic marker HMB45, and negatively expressed PAX8, RCC marker and CD10. The ki67 index was higher in the small round cells and spindle cells than that in the clear cells. FISH revealed the rearrangement of TFE3 gene in all the three types of cells. The NONO-TFE3 fusion gene was detected in all tumor cells by RNA sequencing. This unique Xp11 translocation-associated neoplasm might represent a distinct entity overlapping Xp11 translocation RCC and the mesenchymal counterpart with melanocytic differentiation, broadening the spectrum of Xp11 neoplasms. The patient died of tumor recurrence and lung metastasis after seven months after the surgery suggesting those tumors have an unfavorable prognosis.     

An adult case of melanotic Xp11 translocation renal cancers: distinct entity or sub-entity?

Melanotic Xp11 translocation renal cancer is a recently recognized aggressive epithelioid neoplasm with features overlapping between PEComa, carcinoma, and melanoma, in which TFE3 gene fusions coexist with melanin synthesis. These findings support the idea that melanotic Xp11 translocation renal cancer is a distinct variant of the MiT/TFE3 family neoplasms. The authors describe a pigmented renal tumor occurring in a 30-year-old woman with distinct morphology and immunohistochemical characteristics as Xp11 translocation renal cancer.     

A novel RBMX‐TFE3 gene fusion in a highly aggressive pediatric renal perivascular epithelioid cell tumor

We report an Xp11 translocation perivascular epithelioid cell tumor (PEComa) with a novel RBMX‐TFE3 gene fusion, resulting from a paracentric X chromosome inversion, inv(X)(p11;q26). The neoplasm occurred in an otherwise healthy 12‐year‐old boy who presented with a large left renal mass with extension into the inferior vena cava. The patient was found to have multiple pulmonary metastases at diagnosis and died of disease 3 months later. The morphology (epithelioid clear cells with alveolar and nested architecture) and immunophenotype (TFE3 and HMB45 strongly positive; actin, desmin, and PAX8 negative) was typical of an Xp11 translocation PEComa; however, TFE3 rearrangement was initially not detected by routine TFE3 break‐apart fluorescence in situ hybridization (FISH). Further RNA sequencing revealed a novel RBMX‐TFE3 gene fusion, which was subsequently confirmed by fusion assay FISH, using custom design RBMX and TFE3 come‐together probes. This report describes a novel TFE3 gene fusion partner, RBMX, in a pediatric renal PEComa patient associated with a fulminant clinical course. As documented in other intrachromosomal Xp11.2 inversions, such as fusions with NONO, RBM10, or GRIPAP1 genes, the TFE3 break‐apart might be below the FISH resolution, resulting in a false negative result.     

Recent advances in the diagnosis,classification and molecular pathogenesis of cutaneous mesenchymal neoplasms

The diagnosis of cutaneous mesenchymal neoplasms remains challenging, due to a combination of overlapping histological features, the rarity of some diagnoses and often inadequate sampling in superficial biopsies. Here, we describe recent advances in cutaneous mesenchymal neoplasms. We discuss improvements in our understanding of the molecular pathogenesis of non-neural granular cell tumour, epithelioid fibrous histiocytoma, composite and retiform haemangioendothelioma and dermatofibrosarcoma protuberans. We also discuss recently described tumour types, including some discovered via molecular testing: EWSR1::SMAD3-rearranged fibroblastic tumour, clear cell neoplasm with MITF::CREM rearrangement and melanocytoma with CRCT1::TRIM11 rearrangement, and some discovered via traditional histopathology: superficial CD34-positive fibroblastic tumour, plexiform myofibroblastoma and clear cell neoplasm with melanocytic differentiation and ACTIN::MITF translocation.     

Renal cancer associated with Xp11.2 translocation/TFE3 gene fusion: Clinicopathological analysis of 13 cases

ObjectiveTo explore the clinicopathological characteristics, immunohistochemical phenotype, diagnosis and differential diagnosis of renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion.MethodsThe clinical history, pathological morphology, immunohistochemical phenotype and related molecular test results of 13 cases of Xp11.2 translocation/TFE3 gene fusion-related renal cell carcinoma were retrospectively analyzed, and the relevant literature was reviewed.ResultsOf the 13 patients, 5 were males and 8 were females. The age of onset ranges from 8 to 73 years old, most of which were middle-aged and elderly patients. Among them, there were 3 cases of left kidney tumor and 10 cases of right kidney tumor. In the treatment method, 2 of the 13 patients underwent partial nephrectomy, and 11 underwent radical nephrectomy. Histopathological morphology showed papillary, nested, tubular and acinar structures. The cytoplasm was transparent or eosinophilic, and the interstitial fibrosis was accompanied by chronic inflammatory cell infiltration, hemosiderin deposition and foam cell aggregation. The immunohistochemical analysis of 13 patient specimens all expressed TFE3 antibody, and the expression intensity was strongly positive; gene FISH detection technology revealed the breakage and rearrangement of TFE3 gene in 12 assessable cases. One of thirteen patients had a metastasis at follow-up from 3 to 69 months.ConclusionsThis type of kidney cancer was a rare subtype. Because of its complex and changeable shape, it has a high degree of overlap with other kidney cancer subtypes, and the missed diagnosis rate and misdiagnosis rate are extremely high. The diagnosis is mainly based on pathomorphology and immunohistochemistry, TFE3 positive expression and TFE3 gene destruction and rearrangement.     

Das Translokationskarzinom

The MiT family of translocation-associated renal cell carcinomas comprise approximately 40?% of renal cell carcinomas in young patients but only up to 4?% of renal cell carcinomas in adult patients. The Xp11.2 translocation-associated tumors are the most frequent and were included in the 2004 World Health Organization (WHO) classification. They contain a fusion of the TFE3 gene with ASPSCR1, PRCC, NONO, SPFQ or CLTC resulting in an immunohistochemically detectable nuclear overexpression of TFE3. The Xp11.2 translocation-associated renal cell carcinomas are characterized by ample clear cytoplasm, papillary architecture and abundant psammoma bodies. The TFEB translocation-associated renal cell carcinomas are much rarer and show a biphasic architecture. Fluorescence in situ hybridization permits the detection of a translocation by means of a break apart probe for the TFE3 and TFEB genes and is recommended for the diagnosis of renal cell carcinomas in patients under 30 years of age. The TFE3 and TFEB translocation-associated tumors are classified as MiT family translocation carcinomas in the new WHO classification.The rare renal cell carcinomas harboring an ALK rearrangement with fusion to VCL in young patients with sickle cell trait show a characteristic morphology and are listed in the new WHO classification as a provisional entity.     

The diversity of soft tissue tumours with EWSR1 gene rearrangements: a review

Many soft tissue sarcomas have chromosomal translocations with resultant formation of new fusion genes. Among the genes that can be rearranged, the EWSR1 gene has been identified as a partner in a wide variety of clinically and pathologically diverse sarcomas as well as some non‐mesenchymal tumours. The former include Ewing sarcoma and similar (Ewing‐like) small round cell sarcomas, desmoplastic small round cell tumour, myxoid liposarcoma, extraskeletal myxoid chondrosarcoma, angiomatoid fibrous histiocytoma, clear cell sarcoma of soft tissue and clear cell sarcoma‐like tumours of the gastrointestinal tract, primary pulmonary myxoid sarcoma, extrasalivary myoepithelial tumours and sporadic examples of low‐grade fibromyxoid sarcoma, sclerosing epithelioid fibrosarcoma and mesothelioma. EWSR1 is a ‘promiscuous’ gene that can fuse with many different partner genes, but sometimes this results in phenotypically identical tumours. EWSR1 can, conversely, partner with the same genes in morphologically and behaviourally different neoplasms. This paper reviews the diversity of the several soft tissue tumour types that are associated with rearrangement of the EWSR1 gene.     

Primary cardiac sarcomas may develop from resident or bone marrow‐derived mesenchymal stem cells: use of immunohistochemistry including CD44 and octamer binding protein 3/4

Hegyi L, Thway K, Fisher C & Sheppard M N
(2012) Histopathology  61, 966–973 Primary cardiac sarcomas may develop from resident or bone marrow‐derived mesenchymal stem cells: use of immunohistochemistry including CD44 and octamer binding protein 3/4 Aims: To provide evidence that cardiac sarcomas ‘not otherwise specified’ express markers that might indicate their cellular origin or identify any lines of differentiation. Methods and results: We reviewed all 11 cases of primary undifferentiated cardiac sarcomas found in the archives of the Royal Marsden and Royal Brompton Hospitals, London, UK during the period 2000–2009. Five cases with appropriate consent and archived material were investigated using immunohistochemistry. We found that the spindle, pleomorphic or occasionally epithelioid cell sarcomas showed no lineage‐specific differentiation other than partial myofibroblastic or ‘myoid’ differentiation (all cases). All tumours showed some degree of cytoplasmic positivity for the mesenchymal stem cell marker CD44. In contrast, no nuclear octamer binding protein 3/4 (Oct3/4) expression was seen in any of the tumours, although very patchy cytoplasmic positivity was seen in some tumours. Conclusions: The cytoplasmic positivity for CD44 and the absence of nuclear Oct3/4 suggest that the cells of these sarcomas may represent ‘daughter’ stem cells that no longer have the capacity for tumour initiation, but have subsequently developed new lines of partial differentiation. Primary cardiac sarcomas may arise from mesenchymal stem cells with the ability to generate tumours with multilineage differentiation.     

A renal cell carcinoma with EWSR1‐TFE3 fusion gene

Both EWSR1 and TFE3 are well‐known oncogenes. EWSR1 encodes an RNA‐binding protein involved in multiple soft tissue tumors, including Ewing's sarcoma/peripheral neuroectodermal tumor, desmoplastic small round cell tumor, soft tissue clear cell sarcoma (malignant melanoma of soft parts), extraskeletal myxoid chondrosarcoma, and myxoid liposarcomas. TFE3 regulates both Golgi and lysosomal homeostasis and is rearranged in renal cell carcinoma (RCC), alveolar soft part sarcoma, epithelioid hemangioendothelioma, and perivascular epitheloid cell tumors (PEComas). In this report, we found a rare case of RCC with a fusion between 5′ EWSR1 and 3′ TFE3. The fusion product retained most functional motifs of TFE3. The oncogenic mechanism likely involves TFE3 overexpression through its juxtaposition with the regulatory elements of EWSR1 and its translocation to the nucleus, resulting in the deregulation of Golgi and lysosomal homeostasis. This is a second case of RCC containing EWSR1‐TFE3 fusion.