Systematic analysis of perivascular epithelioid cell neoplasms in the female reproductive tract: a comprehensive review.

Perivascular epithelioid cell neoplasms (PEComas) are rare mesenchymal lesions, with gynecological PEComas accounting for just over a quarter of cases. Limited reports exist on gynecological PEComa, primarily treated with surgery; adjuvant therapy is considered in high-risk cases. This systematic review aims to summarize the origin and clinical, pathological and molecular characteristics of uterine PEComa, focusing on treatment options for gynecological PEComa. A comprehensive PubMed review of gynecological PEComa reports was conducted. A detailed examination of the literature ensured a thorough understanding. Gynecological PEComa diagnosis relies on histology and immunology. Despite therapy controversies, surgery remains the mainstay. Adjuvant therapy efficacy in high-risk cases is uncertain. mTOR inhibitors are the first line; alternative treatments, including angiogenesis and aromatase inhibitors, should be considered.

PEComa pancreático ¿una neoplasia no tan infrecuente? Revisión sistemática y actualización clínico-terapéutica / Pancreatic PEComa, a not so uncommon neoplasm? Systematic review and therapeutic update

Los PEComas pancreáticos son neoplasias con potencial maligno extremadamente raras, que afectan mayoritariamente a mujeres de mediana edad y que se caracterizan por presentar marcadores melanocíticos y miogénicos en el análisis inmunohistoquímico. No existen síntomas ni pruebas de imagen patognomónicas. El diagnóstico se establece con el análisis de la pieza quirúrgica o de la PAAF obtenida con ecoendoscopia preoperatoria. El tratamiento más habitual consiste en la exéresis radical, adecuando la intervención a la localización del tumor. Hasta la fecha se han descrito 34 casos, no obstante, más del 80% de los mismos han sido reportados en la última década, lo que sugiere que es una patología más frecuente de lo esperado. Se reporta un nuevo caso de PEComa pancreático y se realiza una revisión sistemática de la literatura de acuerdo con las guías PRISMA con el objetivo de difundir su existencia, profundizar en su conocimiento y actualizar su manejo (AU)

Pancreatic PEComas are extremely rare neoplasms with malignant potential, which mostly affect middle-aged women and are characterized by presenting melanocytic and myogenic markers in immunohistochemical analysis. There are no symptoms or pathognomonic imaging tests, so the diagnosis is established with the analysis of the surgical specimen or the FNA obtained with preoperative endoscopic ultrasound. The mean treatment consists on radical excision, adapting the intervention to the location of the tumor. To date, 34 cases have been described; however, more than 80% of them have been reported in the last decade, which suggests that it is a more frequent pathology than expected. A new case of pancreatic PEComa is reported and a systematic review of the literature is carried out according to the PRISMA guidelines with the aim of divulge this pathology, deepening its knowledge and updating its management (AU)

TFE3 activation in a TSC1-altered malignant PEComa: challenging the dichotomy of the underlying pathogenic mechanisms.

Perivascular epithelioid cell tumors (PEComas) form a family of rare mesenchymal neoplasms that typically display myomelanocytic differentiation. Upregulation of mTOR signaling due the inactivation of TSC1/2 (Tuberous Sclerosis 1 and 2) is believed to be a key oncogenic driver in this disease. Recently, a subgroup of PEComas harboring TFE3 (Transcription Factor E3) rearrangements and presenting with a distinctive morphology has been identified. TSC1/2 and TFE3 aberrations are deemed to be mutually exclusive in PEComa, with two different pathogenic mechanisms assumed to lead to tumorigenesis. Here, we challenge this dichotomy by presenting a case of a clinically aggressive TCS1-mutated PEComa displaying a TFE3-altered phenotype. FISH analysis was suggestive of a TFE3 inversion; however, RNA and whole genome sequencing was ultimately unable to identify a fusion involving the gene. However, a copy number increase of the chromosomal region encompassing TFE3 was detected and transcriptome analysis confirmed upregulation of TFE3, which was also seen at the protein level. Therefore, we believe that the TSC1/2-mTOR pathway and TFE3 overexpression can simultaneously contribute to tumorigenesis in PEComa. Our comprehensive genetic analyses add to the understanding of the complex pathogenic mechanisms underlying PEComa and harbor insights for clinical treatment options.

Clinical features of 18 perivascular epithelioid cell tumor cases.

To investigate the biological behavior and clinical characteristics of perivascular epithelioid cell tumor (PEComa).Eighteen PEComa patients admitted to Zhongshan Hospital and the Central Hospital of Xuhui District in China from January 2006 to October 2018 were included. All patients were diagnosed based on pathological findings and treated with surgical resection or medication.Among the 18 patients, 1 underwent lymph node biopsy for multiple enlarged lymph nodes and 17 underwent mass resection. The median disease-free survival was 22 months after the first resection and over 12 months following a second resection. Treatment with mechanistic target of rapamycin (mTOR) inhibitors was effective for patients with unresectable or metastatic lesions. The median progression-free survival was approximately 13 months.Surgery is the predominant treatment approach for PEComa and patients can benefit from multiple operations. mTOR inhibitors are considered for patients with multiple lesions or intolerance to surgery. Anti-angiogenetic drugs can be selected when mTOR inhibitors fail to control the illness.

Medical treatment of advanced malignant perivascular epithelioid cell tumors.

PURPOSE OF REVIEW: Malignant PEComa are rare mesenchymal tumors characterized by genetic alterations actionable by target therapy. Indeed, they harbour loss of function of TSC1/TSC2, which lead to the activation of the mammalian target of rapamycin (mTOR) pathway, which is targetable therapeutically with mTOR inhibitors like sirolimus. A small subset of malignant PEComas instead harbor TFE3 gene fusions known to be mutually exclusive with TSC1/TSC2 loss-of-function mutations; therefore, leading to different therapeutic implication. RECENT FINDINGS: mTOR inhibitors showed a response rate around 40% with a median PFS of 9 months both in retrospective case series than in phase 2 prospective clinical trials, therefore, representing the most active therapeutic drug. Up to now, the issue is the lack of further therapeutic lines in the advanced setting. Chemotherapy has a marginal role, while some responses were reported using Vascular endothelial growth factor-Tyrosine kynase inhibitors (VEGF-TKI) inhibitors. SUMMARY: Malignant PEComas display some sensitivity to mTOR inhibitors. If progression thereto, no other drugs are available. Preclinical studies are ongoing to explore the potential combination of hormonal blockade in women and the potential use of PD1 checkpoint inhibitors.

Complexity of PEComas : Diagnostic approach, molecular background, clinical management.

Perivascular epithelioid cell neoplasms (PEComas) are a family of mesenchymal neoplasms with features of both melanotic and smooth muscle differentiation. PEComa morphology is highly variable and encompasses epithelioid to spindle cells often with clear cytoplasm and prominent nucleoli. Molecularly, most PEComas are defined by a loss of function of the TSC1/TSC2 complex. Additionally, a distinct small subset of PEComas harboring rearrangements of the TFE3 (Xp11) gene locus has been identified. By presenting a series of three case reports with distinct features, we demonstrate diagnostic pitfalls as well as the importance of molecular work-up of PEComas because of important therapeutic consequences.

Neoplasia de células epiteloides perivasculares (PEComa) tibial. Reporte de un caso y revisión de la literatura / Tibial perivascular epithelioid cell tumour (PEComa). A case report and literature review

Introducción: La célula perivascular epiteloide (PEC) es un tipo celular constante presente en un grupo de tumores que incluyen el angiomiolipoma, tumores «de azúcar» de células claras pulmonares y de sitios extrapulmonares, linfangioleiomiomatosis, entre otros. Las características de la PEC incluyen: apariencia epiteloide con citoplasma claro agranular, un núcleo central redondo a oval y un nucléolo discreto además de expresar marcadores inmunohistoquímicos únicos. Únicamente han sido descritos 11 casos de presentación ósea primaria desde su primer reporte en 2002. Objetivo: Presentar el caso de un tumor de células perivasculares epiteloides óseo primario. Reporte de caso: Varón de 24 años de edad con dolor de un año de evolución y lesión lítica de tibia proximal derecha y extensión a partes blandas. Diagnóstico histológico de tumor de células perivasculares epiteloides óseo e inmunohistoquímica negativa. Resultados: Seguimiento de 2 años después del tratamiento con quimioterapia adyuvante (epirrubicina/cisplatino) y de la resección en bloque; el paciente se encuentra libre de enfermedad. Conclusiones: Este es el primer caso de tumor de células perivasculares epiteloides óseo primario reportado en Latinoamérica. No encontramos los marcadores inmunohistoquímicos y creemos que esto puede deberse a variaciones étnicas no descritas

Introduction: Perivascular epithelioid cell (PEC) is a cell type constantly present in a group of tumours including angiomyolipoma (AML), clear-cell «sugar» tumour (CCST) of the lung and extrapulmonary sites, lymphangioleiomyomatosis (LAM), and clear-cell tumours of other anatomical sites. It has morphologic distinctive features: epithelioid appearance with a clear to granular cytoplasm, a round to oval, centrally located nucleus and an inconspicuous nucleolus. Immunohistochemically, PEC expresses myogenic and melanocytic markers. Eleven cases of primary bone PEComa presentation have been described since 2002. Objective: To report a case of primary bone perivascular epithelioid cell tumour. Case report: 24 year-old male presented with pain. X-ray revealed an osteolytic lesion at right proximal tibia with soft tissue extension. Evaluation of slides identified a bony perivascular epithelioid cell tumour without immunohistochemical study confirmation. Results: Patient was treated by surgical excision and adjuvant chemotherapy (epirubicin/cysplatin). After two years of follow-up the patient remains disease free. Conclusions: This is the first-case report in Latin America. Immunohistochemical stains were negative and we believe it may be due to non-described ethnic variations

Tibial perivascular epithelioid cell tumour (PEComa). A case report and literature review. / Neoplasia de células epiteloides perivasculares (PEComa) tibial. Reporte de un caso y revisión de la literatura.

INTRODUCTION: Perivascular epithelioid cell (PEC) is a cell type constantly present in a group of tumours including angiomyolipoma (AML), clear-cell «sugar¼ tumour (CCST) of the lung and extrapulmonary sites, lymphangioleiomyomatosis (LAM), and clear-cell tumours of other anatomical sites. It has morphologic distinctive features: epithelioid appearance with a clear to granular cytoplasm, a round to oval, centrally located nucleus and an inconspicuous nucleolus. Immunohistochemically, PEC expresses myogenic and melanocytic markers. Eleven cases of primary bone PEComa presentation have been described since 2002. OBJECTIVE: To report a case of primary bone perivascular epithelioid cell tumour. CASE REPORT: 24 year-old male presented with pain. X-ray revealed an osteolytic lesion at right proximal tibia with soft tissue extension. Evaluation of slides identified a bony perivascular epithelioid cell tumour without immunohistochemical study confirmation. RESULTS: Patient was treated by surgical excision and adjuvant chemotherapy (epirubicin/cysplatin). After two years of follow-up the patient remains disease free. CONCLUSIONS: This is the first-case report in Latin America. Immunohistochemical stains were negative and we believe it may be due to non-described ethnic variations.

Malignant perivascular epithelioid cell tumor in the female genital tract: Preferred reporting items for systematic reviews and meta-analyses.

BACKGROUND: Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal tumor, located at various anatomic sites, including the female genital tract. This study aimed to evaluate the clinicopathological characteristics of patients with PEComa arising from the female genital tract. METHODS: A retrospective study was conducted in Taipei Veterans General Hospital (Taipei VGH) between 2008 and 2018. All published English cases based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement were also included in the current review. RESULTS: A total of 114 women from PRISMA and 3 women from Taipei VGH were identified. The uterus was the most commonly involved site (82/114, 71.9%), followed by the cervix (12/114, 10.5%). Immunohistochemical staining showed that nearly all gynecological PEComas were positive for human melanoma black 45 (113/114, 99.1%). More than half of the gynecological PEComas were immunoreactive for desmin (50/85, 58.8%). Multi-modality treatment, including surgery and mammalian target of rapamycin (mTOR) inhibitors as targeted therapy, provided long-term disease-free survival (cure rate ranging from 50% to 100%, based on the different anatomic sites of the female genital tract). CONCLUSION: Multi-modality treatment, including cytoreductive surgery and mTOR inhibitors with/without chemotherapy and/or radiation, should be considered for the management of women with PEComas in the genital tract.

Malignant perivascular epithelioid cell tumor of the oropharynx with strong TFE3 expression mimicking alveolar soft part sarcoma: a case report and review of the literature.

Perivascular epithelioid cell tumors (PEComas) in the head and neck region are rare, with 26 cases described in literature. These distinct mesenchymal tumors normally express both myoid and melanocytic markers. We here report an interesting and challenging case of malignant PEComa that showed transcription factor E3 (TFE3) protein expression and rearrangement, paucity of muscle and melanocytic marker expression, and morphologically mimicked alveolar soft part sarcoma. Awareness of this morphologic pitfall and recognition of TFE3 gene-rearranged PEComa, as a distinct subtype of PEComa, is essential to avoid misdiagnosis.

Malignant perivascular epithelioid cell tumor of the orbit: Report of a case and review of literature.

Perivascular epithelioid cell tumor (PEComa) is a rare neoplasm considered to arise from myomelanocytic cell lineage. The uterus is reportedly the most common site to be involved. Orbital PEComa is extremely rare with only two cases reported till date. A 5-year-old male presented with a right medial orbital mass for the last 6 months. The patient was diagnosed with alveolar soft part sarcoma elsewhere. Magnetic resonance imaging features were suggestive of lymphangioma with bleeding. The excision biopsy revealed multiple tumor cells comprising epithelioid cells with clear cytoplasm, along with nuclear atypia and mitosis. Immunohistochemistry was positive for HMB-45, smooth muscle actin, vimentin, and CD-34. It was negative for cytokeratin, S-100, and synaptophysin, which clinched the diagnosis of malignant orbital PEComa. Neoadjuvant chemotherapy was administered. There was no recurrence at 24 months of follow-up. At present, there is no consensus on management protocol for malignant PEComa. Complete surgical excision with chemotherapy appears to offer the best prognosis.

Hepatic perivascular epithelioid cell tumor treated by transarterial embolization plus radiofrequency ablation: A case report and literature review.

BACKGROUND: Perivascular epithelioid cell tumors (PEComas) are extremely rare mesenchymal entities with potentially malignant properties; the liver cases are not encountered frequently. Owing to themalignant potential, these tumors are treated by surgical methods to ensure total resection. In the present report, a case of liver PEComa treated by embolization combined with radiofrequency ablation (RFA) has been described. CASE SUMMARY: A 40-year-old female was admitted for the detection of a liver mass during an annual physical examination. The patient did not have any liver disease background, enhanced computed tomography (CT), and magnetic resonance revealed a huge mass in the right lobe. Pathology gave the diagnosis of PEComa, for disagreement of open surgery, a combination of transarterial embolization (TAE) and RFA were applied for treatment and the outcomes were acceptable, the patient was under follow-up to observe the long-term effect. CONCLUSION: Interventional procedures such as TAE and RFA are feasible and effective for such lesions and may serve as an alternate when resection is not indicated. Prospective studies are warranted to verify the long-term outcomes.

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.

Update on the imaging of malignant perivascular epithelioid cell tumors (PEComas).

Malignant perivascular epithelioid cell tumors (PEComas) are a histologic group of mesenchymal neoplasms that share a distinctive histological phenotype, the perivascular epithelioid cell. These tumors are known for their perivascular distribution. Malignant PEComas have a female predominance and are associated with aggressive disease and poor prognosis, making timely diagnosis critical to management. Imaging features of malignant PEComas are nonspecific and mimic other benign and malignant neoplasms. Surgery is the mainstay in the management of malignant PEComas. Promising novel molecular targeted therapies like m-TOR inhibitors have been shown to be effective in the metastatic setting. The aim of this review is to familiarize radiologists with the imaging appearances of and potential therapies for primary and metastatic malignant PEComa.

Perivascular epithelioid cell neoplasm (PEComa) of the uterus: A systematic review.

BACKGROUND: Perivascular epithelioid cell neoplasm (PEComa) is a rare mesenchymal tumor. Gynecological PEComas account for just over one-fourth of the overall PEComa cases reported in the literature. Surgery is the most recommended primary treatment while adjuvant therapy is generally reserved for high-risk cases. However, the best management of this neoplasia has not been well established, primarily because of the paucity of cases described to date. OBJECTIVES: The aim of this systematic review is to summarize what is known thus far regarding the etiopathogenesis, clinical and pathologic features of PEComas, focusing also on the most valid treatment options for uterine cases. DATA SOURCES: Pubmed articles on PEComas published in various journals over the past 70 years were analyzed. CONCLUSIONS AND KEY FINDINGS: Although the optimal treatment of gynecological PEComas is controversial, surgical resection remains the cornerstone. The use of adjuvant treatment is warranted in high risk patients to increase disease control. A multidisciplinary approach should be key in treatment decision-making regarding gynecological PEComas.

PEComa of the mesentery coexisting with colon cancer: a case report.

Perivascular epithelioid cell tumor (PEComa) is a rare entity originating from mesenchymal tissue, which stains for both melanocytic and smooth muscle markers. We would like to present an unusual case of the PEComa of the mesentery which was unexpected discovery in a female patient with colonic adenocarcinoma. The tumour was revealed on the computer tomography and then resected during surgery, with subsequent chemotherapy for the colon adenocarcinoma. Furthermore we would like to discuss PEComa biology, emphasizing histological criteria of malignancy, possible treatment options and differential diagnosis which is mostly based on immunohistochemistry. Virtual slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1809062291157051 .

TFE3 translocation-associated perivascular epithelioid cell neoplasm (PEComa) of the gynecologic tract: morphology, immunophenotype, differential diagnosis.

TFE3 translocation-associated PEComa is a distinct form of perivascular epithelioid cell neoplasm, the features of which are poorly defined owing to their general infrequency and limited prior reports with confirmed rearrangement or fusion. Recent investigation has found a lack of TSC gene mutation in these tumors compared with their nonrearranged counterparts, which underscores the importance of recognizing the translocated variant because of hypothetical ineffectiveness of targeted mTOR inhibitor therapy. Six cases were identified, and TFE3 rearrangement was confirmed by fluorescence in situ hybridization. Patient age ranged from 46 to 66 years (median 50 y), and none had a history of a tuberous sclerosis complex. Three cases arose in the uterine corpus, 1 in the vagina, 1 pelvic tumor, and 1 pulmonary tumor that was likely a recurrence/metastasis from a probable uterine primary. Five cases had clear cell epithelioid morphology that showed a spectrum of atypia, while 1 case had a mixture of clear cell epithelioid and spindle cells. A mostly consistent immunophenotype was observed in the clear cell epithelioid cases: each demonstrated diffuse TFE3, HMB45, cathepsinK labeling, either focal or no melanA staining, and variably weak reactivity to smooth muscle markers. The mixed clear cell epithelioid and spindle cell case had a similar expression pattern in its epithelioid component but strong muscle marker positivity in its spindle cell component. Follow-up ranged from 1 to 57 months. Three cases demonstrated aggressive behavior, and 3 cases had no evidence of recurrence. Both GYN-specific and traditional sets of criteria for malignancy were evaluated. The GYN model showed improved inclusion and specificity in comparison to the traditional model.

Genetics of rare mesenchymal tumors: implications for targeted treatment in DFSP, ASPS, CCS, GCTB and PEComa.

Soft tissue and bone sarcomas comprise a heterogeneous group of mesenchymal tumors that include roughly 130 distinct diagnostic entities. Many of them are exceptionally rare, with only few cases diagnosed worldwide each year. Development of novel targeted treatment in this group of tumors is of special importance since many sarcoma subtypes are resistant to conventional chemotherapy and the effective therapeutic options are limited. In this review we aim to discuss the molecular implications for targeted therapy in selected rare soft tissue and bone sarcoma subtypes, including dermatofibrosarcoma protuberans (DFSP), alveolar soft part sarcoma (ASPS), clear cell sarcoma (CCS), giant cell tumor of bone (GCTB) and perivascular epithelioid cell neoplasms (PEComas). This article is part of a Directed Issue entitled: Rare cancers.

Perivascular epithelioid cell neoplasm (PEComa) of the gynecologic tract: clinicopathologic and immunohistochemical characterization of 16 cases.

Perivascular epithelioid cell tumor (PEComa) belongs to a family of tumors characterized by coexpression of melanocytic and muscle markers. Recent studies have shown that sporadic and tuberous sclerosis complex-associated PEComa may respond to mTOR inhibitors underscoring the importance of recognizing this tumor. However, its occurrence in the gynecologic tract continues to be disputed owing to its common misclassification as other types of uterine sarcoma and its controversial relationship with epithelioid smooth muscle tumors. To more fully characterize PEComa of the female genital tract, 16 cases of gynecologic PEComa were identified (1990 to 2012) and formed the basis of this study. Each case was analyzed for conventional morphologic and immunohistochemical characteristics established for PEComa of extrauterine sites; clinical outcome data were obtained for all cases. The 16 patients were aged 28 to 60 (mean 49; median 50) years, and 1 had a history of tuberous sclerosis complex. Thirteen cases were primary of the uterus, 2 of the adnexa, and 1 of the vagina. Tumor size ranged from 0.3 to 25.0 (mean 8.7) cm. Three patients died of disease, 6 were alive with disease, and 7 were alive without evidence of disease at last follow-up (1 mo to 13 y follow-up; mean 26 mo). All patients with an adverse outcome met established criteria for malignancy as proposed for extrauterine sites (ie, 2 or more features present: size ≥5 cm, high-grade nuclear features, infiltration, necrosis, lymphovascular invasion, or a mitotic rate ≥1/50 high-power fields). Of the melanocytic markers, HMB45 was most commonly expressed (16/16 positive, 100%), followed by microphthalmia transcription factor (11/12 positive, 92%), MelanA (14/16 positive, 88%), and S100 protein (2/10 positive, 20%). Of the smooth muscle markers, desmin was most commonly expressed (15/15 cases, 100%), followed by SMA (14/15 cases, 93%) and h-caldesmon (11/12 cases, 92%). TFE3 immunopositivity was identified in 5 of 13 cases; however, 3 tested cases were negative for a TFE3 rearrangement by fluorescence in situ hybridization. Current criteria for malignancy appear to be valid in the female genital tract, although modified criteria, as described herein, may be more specific. Awareness of the characteristic features of PEComa is important to help distinguish it from epithelioid smooth muscle tumors and other mimics as PEComa may respond to unique chemotherapeutic regimens.