Gynaecological perivascular epithelioid cell tumour (PEComa): comparative analysis of proposed algorithms for prediction of clinical outcome.

AIMS: Perivascular epithelioid cell tumours (PEComas) are rare mesenchymal tumours that coexpress smooth muscle and melanocytic markers. They have a predilection for gynaecological organs, where they present a unique diagnostic challenge, because of morphological and immunohistochemical overlap with more common smooth muscle and stromal tumours. Limited information regarding the natural history, owing to the rarity of this tumour, makes accurate risk stratification difficult. We aimed to review clinicopathological features of gynaecological PEComa and compare accuracy of five different classification systems for prediction of prognosis. METHODS AND RESULTS: We have described the clinicopathological features of 13 new cases and tested five prognostic algorithms in a total of 67 cases of gynaecological PEComa. Receiver operating characteristic curves were constructed and areas under the curve (AUCs) were calculated to evaluate predictive accuracy. The modified gynaecological-specific algorithm showed high sensitivity and specificity and yielded the highest AUC (0.864). It's earlier version, the gynaecological-specific algorithm, suffered from lower specificity (AUC = 0.843). The post-hoc McNemar test confirmed significant differences between the performances of the modified gynaecological-specific algorithm and the gynaecological-specific algorithm (P = 0.008). The original Folpe algorithm for PEComas of all sites showed low specificity, had a lower AUC (0.591), and was inapplicable in 18% of cases. Its two later versions (the revised Folpe algorithm and the modified Folpe algorithm) also yielded lower AUCs (0.690 and 0.591, respectively). CONCLUSION: We have shown that the modified gynaecological-specific algorithm predicts the clinical outcome of gynaecological PEComa with high accuracy, and have validated its use for prognostic stratification of gynaecological PEComa.

Genomic Profiling Aids Classification of Diagnostically Challenging Uterine Mesenchymal Tumors With Myomelanocytic Differentiation.

Although diagnosis of high-grade uterine mesenchymal tumors (UMTs) exhibiting classic morphologic features is straightforward, diagnosis is more challenging in tumors in which prototypical features are poorly developed, focal, and/or coexist with features seen in other neoplasms. Here, we sought to define the repertoire of somatic genetic alterations in diagnostically challenging UMTs with myomelanocytic differentiation, including some reported as perivascular epithelioid cell tumors (PEComas). In 17 samples from 15 women, the tumors were histologically heterogenous. Immunohistochemical expression of at least 1 melanocytic marker (HMB45, Melan-A, or MiTF) was identified in all tumors, and of myogenic markers (desmin or smooth muscle actin) in most tumors. Targeted massively parallel sequencing revealed several genetic alterations, most commonly in TP53 (41% mutation, 12% deletion), TSC2 (29% mutation, 6% deletion), RB1 (18% deletion), ATRX (24% mutation), MED12 (12% mutation), BRCA2 (12% deletion), CDKN2A (6% deletion) as well as FGFR3, NTRK1, and ERBB3 amplification (each 6%). Gene rearrangements (JAZF1-SUZ12; DNAJB6-PLAG1; and SFPQ-TFE3) were identified in 3 tumors. Integrating histopathologic, immunohistochemical, and genetic findings, tumors from 4 patients were consistent with malignant PEComa (1 TFE3-rearranged); 6 were classified as leiomyosarcomas; 3 showed overlapping features of PEComa and other sarcoma types (leiomyosarcoma or low-grade endometrial stromal sarcoma); and 2 were classified as sarcoma, not otherwise specified. Our findings suggest that diagnostically challenging UMTs with myomelanocytic differentiation represent a heterogenous group of neoplasms which harbor a diverse repertoire of somatic genetic alterations; these genetic alterations can aid classification.

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.

[Hepatic epithelioid angiomyolipoma/PEComa and focal nodular hyperplasia in a patient with a previous history of cutaneous melanoma]. / Angiomiolipoma epitelioide/PEComa hepático e hiperplasia nodular focal en una paciente con antecedentes de melanoma cutáneo.

Hepatic perivascular epithelioid cell tumors (PEComas) are uncommon mesenchymal neoplasms. PEComas concurrent with other hepatic lesions is a very rare occurrence, with only two previously reported cases. We report a primary hepatic PEComa associated with focal nodular hyperplasia in a patient with a previous history of cutaneous melanoma. Diagnostic imaging studies suggested a hepatic adenoma and the patient underwent a segmentectomy. The tumor was mainly composed of epithelioid cells, adipose tissue and smooth muscle fibers intermixed with blood vessels. The neoplastic cells were diffusely immunoreactive for HMB-45, Melan-A and smooth muscle actin, but not for Hepatocyte, S100, MITF or BRAF. Molecular studies were negative for BRAFV600 mutation. The final diagnosis was hepatic epithelioid angiomyolipoma/PEComa. The differential diagnosis of hepatic PEComa is discussed.

Xp11 Translocation Renal Cell Carcinoma and the Mesenchymal Counterparts: An Evolving Concept with Novel Insights on Clinicopathologic Features, Prognosis, Treatment, and Classification.

The TFE3 gene is one of four members of the micropathalima-associated transcription factor family, along with TFEB, TFEC, and MiTF, located on chromosome Xp11.2. The site is notable for its involvement in translocation in Xp11 translocation renal cell carcinoma (RCC) and the mesenchymal counterparts, including Xp11 neoplasm with melanocytic differentiation/TFE3 rearrangement-associated perivascular epithelioid cell tumor (PEComa)/ melanotic Xp11 translocation renal cancer/melanotic Xp11 neoplasm, and alveolar soft-part sarcoma. By morphologic, immunohistochemical, genetic, and prognostic similarities, alveolar soft-part sarcoma with the ASPSCR1-TFE3 gene fusion has a closer relationship with Xp11 neoplasm with melanocytic differentiation/TFE3 rearrangement-associated PEComa/melanotic Xp11 translocation renal cancer/melanotic Xp11 neoplasm. These Xp11 translocation mesenchymal neoplasms may represent a distinct entity, which overlaps with Xp11 translocation RCC and broadens the spectrum of Xp11 translocation-associated neoplasms. The impact of individual fusion variants on specific clinicopathologic features of Xp11 translocation RCC has only recently been described. This review provides insight into the clinicopathologic features, prognosis, treatment, and classification of Xp11 translocation RCC and its mesenchymal counterparts, emphasizing the impact of individual fusion variants on specific clinicopathologic features of Xp11 translocation RCC and the relationships among these Xp11 translocation-associated neoplasms.

Cutaneous PEComas Express CD10: Implications for the Classification of PEComas and the Differential Diagnosis With Metastatic Renal Cell Carcinoma.

Cutaneous perivascular epithelioid cell tumors (PEComas) are peculiar, rare mesenchymal tumors of uncertain lineage. They show a characteristic epithelioid morphology, and they are usually composed of monomorphous clear-to-granular appearing perivascular cells. One of the main differential diagnoses with PEComas is a cutaneous metastasis from renal cell carcinoma (RCC). CD10 has been emphasized to be a crucial marker in the diagnosis of metastasis from RCC. Although visceral PEComas have been studied for CD10 expression, primary cutaneous PEComas have not. Although it could be assumed a priori that cutaneous PEComas would stain as their visceral counterpart, there is increasing evidence that cutaneous PEComas could actually be unrelated to PEComas from other organs. In this report, the author's studied three primary cutaneous PEComas, and included CD10 in our immunohistochemical studies. All three PEComas expressed the marker. They conclude that a CD10 clear-cell dermal tumor is not necessarily equivalent to a metastasis from RCC and that additional stains should be added to rule out PEComa, even if the biopsy or the panel of antibodies is limited.

PSF/SFPQ is a very common gene fusion partner in TFE3 rearrangement-associated perivascular epithelioid cell tumors (PEComas) and melanotic Xp11 translocation renal cancers: clinicopathologic, immunohistochemical, and molecular characteristics suggesting classification as a distinct entity.

An increasing number of TFE3 rearrangement-associated tumors, such as TFE3 rearrangement-associated perivascular epithelioid cell tumors (PEComas), melanotic Xp11 translocation renal cancers, and melanotic Xp11 neoplasms, have recently been reported. We examined 12 such cases, including 5 TFE3 rearrangement-associated PEComas located in the pancreas, cervix, or pelvis and 7 melanotic Xp11 translocation renal cancers, using clinicopathologic, immunohistochemical, and molecular analyses. All the tumors shared a similar morphology, including a purely nested or sheet-like architecture separated by a delicate vascular network, purely epithelioid cells displaying a clear or granular eosinophilic cytoplasm, a lack of papillary structures and spindle cell or fat components, uniform round or oval nuclei containing small visible nucleoli, and, in most cases (11/12), melanin pigmentation. The levels of mitotic activity and necrosis varied. All 12 cases displayed moderately (2+) or strongly (3+) positive immunoreactivity for TFE3 and cathepsin K. One case labeled focally for HMB45 and Melan-A, whereas the others typically labeled moderately (2+) or strongly (3+) for 1 of these markers. None of the cases were immunoreactive for smooth muscle actin, desmin, CKpan, S100, or PAX8. PSF-TFE3 fusion genes were confirmed by reverse transcription polymerase chain reaction in cases (7/7) in which a novel PSF-TFE3 fusion point was identified. All of the cases displayed TFE3 rearrangement associated with Xp11 translocation. Furthermore, we developed a PSF-TFE3 fusion fluorescence in situ hybridization assay for the detection of the PSF-TFE3 fusion gene and detected it in all 12 cases. Clinical follow-up data were available for 7 patients. Three patients died, and 2 patients (cases 1 and 3) remained alive with no evidence of disease after initial resection. Case 2 experienced recurrence and remained alive with disease. Case 5, a recent case, remained alive with extensive abdominal cavity metastases. Our data suggest that these tumors belong to a single clinicopathologic spectrum and expand the known characteristics of TFE3 rearrangement-associated tumors.

Recently characterized soft tissue tumors that bring biologic insight.

Previously unrecognized but clinicopathologically (and often molecularly) distinct types of soft tissue tumor continue to be characterized, allowing wider recognition, more consistent application of diagnostic criteria, more reliable prediction of tumor behavior and enhancement of existing classification schemes. Examples of such 'entities' that have become much better understood over the past decade or so include deep 'benign' fibrous histiocytoma, hemosiderotic fibrolipomatous tumor, PEComa, spindle cell liposarcoma, myoepithelial tumors of soft tissue and spindle cell/sclerosing rhabdomyosarcoma. These tumor types, as well as the insights which they have engendered, are briefly reviewed here.

Primary perivascular epitheloid cell tumour (PEComa) of the liver: case report and review of the literature.

PURPOSE: Perivascular epitheloid cell tumour [PEComa] is a rare neoplasm entity, characterized by perivascular epitheloid cells with a coexpression of smooth muscle and melanocytic markers. PEComas are found in a variety of localizations, though lesions within the liver are still scarcely found. Although the majority of these tumours are recognized as benign, there are some reports about advanced and aggressive tumours even with fatal outcome. By means of this case report and literary review including other 21 published cases, potential treatment modalities concerning clinical diagnostics, therapy and the follow-up care should be discussed. METHODS: The following report presents the case of a 53-year old woman with a known liver lesion, since four years under regularly sonographic controls. Finally, after a haemorrhage episode, the lesion was resected and the diagnosis found. For the literary review a systematic search for case reports published between January 1, 1999 and May 1, 2012 was performed on Pubmed. RESULTS: The only way, till now, of confirming the diagnosis is through immunohistochemical examinations. The already published Malignancy criteria by Folpe et al. must be taken carefully in question, as there are cases of malignant behaviour, that do not exactly coincide with these. CONCLUSION: Primary PEComa of the liver must be treated as potential malignant and therefore a close follow-up is demanded.

Sinonasal perivascular epithelioid cell tumor: benign or malignant neoplasm?

BACKGROUND: Neoplasms showing perivascular epithelioid cell differentiation (PEComas) are uncommon tumors of the sinonasal tract. They are often misdiagnosed as angiomyolipoma or a simple benign tumor or polyp. We present a further case of a sinonasal PEComa and review the literature in an attempt to ascertain their malignant potential. METHODS: Published evidence on invasiveness and characteristics were defined on systematic review. MEDLINE and EMBASE were searched from 1966 and 1980, respectively, to week 3 of December 2010. Publications reporting PEComa or angiomyolipoma were sought. Only those describing a sinonasal origin were included. Demographics, anatomic site, local invasion, recurrence rates, and mortality were recorded. A case report of a locally invasive intranasal PEComa is described. RESULTS: In addition to the case we present, 12 case reports were located (n = 13). The mean age of patients was 59.6 (SD, 14.98 years) years. The location was within the right sinonasal tract in 54% of cases, the left sinonasal tract in 38% of cases, and not reported in 8% of cases. Treatment focused on local surgical excision and this was achieved endoscopically in 100% of cases. Recurrence rate was 8%. Mean follow-up was 17.4 (SD, 20.68 months) months. Invasion was noted in 23% of cases. There was a single death recorded. CONCLUSION: PEComas of the paranasal sinuses and skull base appear to have a biological behavior different from simple benign angiomyolipomas reported elsewhere in the body. PEComa may be more intermediate or malignant in clinical behavior.