Malignant PEComa Research Articles

PEComa-A Rare Uterine Neoplasm: A Case Report

Perivascular Epithelioid Cell Tumors (PEComas) are rare mesenchymal tumors originating from perivascular epithelioid cells. The second common affected organ is uterine. Most of PEComas are benign and patients have good prognosis. At the present time, surgery is the main treatment and adjuvant chemotherapy is used in malignant cases, although the best diagnostic and management method is yet to be discovered considering the rarity of this neoplasm. The patient was a 53 year old lady with a history of two vaginal deliveries and no previous surgery. She had severe pelvic pain and underwent MRI with the primary impression of sarcoma. In MRI, she had a 7 cm mass in lower segment of uterus. The patient underwent laparoscopic hysterectomy, bilateral oophorectomy, lymphadenectomy, and omental biopsy in Jam Hospital. Pathologic report of the patient revealed malignant PEComa without lymph node and omentum involvement. Diagnosis of PEComa before surgery is difficult and its differential diagnoses form uterine leiomyoma or leiomyosarcoma. Final diagnosis can be made after surgical biopsy and immunohistochemistry evaluation. Surgery is still the main treatment and adjuvant therapy is used in high risk patients.

Nab-Sirolimus for patients with advanced malignant PEComa with or without prior mTOR inhibitors: Biomarker results from AMPECT and an expanded access program.

11574 Background: Malignant perivascular epithelioid cell tumor (PEComa) is a rare and aggressive sarcoma. nab-Sirolimus is an albumin-bound intravenous (IV) mTOR inhibitor (mTORi) approved for the treatment of adult patients with locally advanced unresectable or metastatic malignant PEComa. The AMPECT trial (NCT02494570) was the first prospective study in advanced malignant PEComa. In exploratory biomarker analyses, TSC1 or TSC2 alterations were associated with response. We report data from the final analysis of AMPECT patients, who were naïve to mTORi, and in patients with malignant PEComa with prior mTORi exposure treated with nab-sirolimus in an expanded access program (EAP) (NCT03817515). Methods: In AMPECT, patients with malignant PEComa naïve to mTORi received nab-sirolimus (100 mg/m2 IV days 1 and 8 of every 21-day cycle) until progression or unacceptable toxicity. The primary endpoint was ORR by independent radiology review. Other endpoints included duration of response (DOR) and disease control rate (DCR), defined as complete response (CR), partial response (PR), or stable disease (SD) at ≥12 weeks. In the EAP, patients with malignant PEComa and prior mTORi exposure received the same dose of nab-sirolimus as in AMPECT. Responses and DCR were evaluated post hoc via electronic medical record review. Genetic profiling, including TSC1 or TSC2 status, was assessed in both protocols, but no specific mutation criteria were required for enrollment. Results: Data include 47 total efficacy-evaluable patients, 31 in AMPECT and 16 with malignant PEComa and prior mTORi exposure treated in the EAP from July 2019–July 2021. Prior mTORi on the EAP included sirolimus, everolimus, temsirolimus, or sapanisertib; 12 patients had exposure to 1 prior mTORi and 4 to ≥2 prior mTORi, and 50% had had progressive disease as best response on mTORi. In AMPECT, ORR was 39% (12/31 patients), and DCR was 71%. Median DOR was not reached after 3 years of follow-up. On the EAP, 4/16 patients (25%) achieved PR (DOR range: 1.3+–25.2+ months, 3 ongoing), and 8/16 (50%) had SD as best response; the DCR was 63% (10/16). Of patients with known TSC1 or TSC2 inactivating alterations in the combined datasets (n = 23), 57% had a response (AMPECT, 64%; EAP, 44%). There were no Grade 4 or 5 treatment-related adverse events on either protocol Conclusions: nab-Sirolimus provided durable responses in mTORi-naïve patients with malignant PEComa and clinical benefit in an expanded access protocol for patients with malignant PEComa with prior mTORi therapy. Although AMPECT and the EAP cannot be directly compared, response rates showed similar trends regardless of prior mTORi exposure and in patients with TSC1 or TSC2 alterations. Based on the emerging biomarker results, a tissue-agnostic study in patients with TSC1 and TSC2 alterations has been initiated (NCT05103358). Clinical trial information: NCT02494570, NCT03817515.

Distinct oncogenic signatures in malignant PEComa and leiomyosarcoma identified by integrative RNA-seq and H3K27ac ChIP-seq analysis.

11552 Background: Malignant perivascular epithelioid cell tumor (PEComa) and leiomyosarcoma (LMS) are two sarcomas with overlapping morphologic and immunophenotypic features which can make their diagnostic distinction challenging. We aimed to characterize the transcriptional and epigenetic landscape of PEComa and LMS to identify distinguishing features. Methods: We performed whole transcriptome RNA-sequencing on 19 PEComas and compared their gene expression profile to 259 sarcomas from The Cancer Genome Atlas (TCGA) including 104 LMS. ChIP-sequencing for H3K27ac, a histone modification associated with activation of nearby genes/open chromatin, was conducted on 9 malignant PEComas and 12 LMS and were compared with publicly available data from 4 other sarcoma subtypes (chordoma; osteosarcoma; undifferentiated pleomorphic sarcoma; rhabdomyosarcoma; n = 29 tumors). Results: Genome-wide epigenetic and transcriptional analyses revealed overlapping patterns between PEComa and LMS, which were distinct from other sarcomas. However, we also identified a set of highly expressed and epigenetically distinct transcripts which may represent diagnostic?biomarkers: e.g., DAPL1, MLANA, SULT1C2, GPR143, and CHI3L1 for PEComa; and MYOCD, WDFC2, DES, MYH11, and CNN1 for LMS; each of which showed >17x fold higher expression for each tumor entity by DESeq2 (FDR<0.0001). Gene Set Enrichment Analyses (GSEA) demonstrated enrichment in the KEGG Lysosome pathway for PEComa (FDR=0.11), whereas myogenesis and smooth muscle contraction pathways were enriched in LMS (FDR=0.09). Integrative transcriptomic and epigenetic analyses revealed a unique set of master core transcription factors for each tumor type including among others MYOCD for LMS; MITF for PEComa, which require further functional investigation. Twelve selected genes including new as well as known and standard diagnostic markers (e.g., DAPL1, MLANA, GPR143, PNL2, CHI3L1, DES, MYH11, ER, CD68, PU.1, pS6 and CNN1) were validated by immunohistochemistry (IHC) in multiple sections from PEComa and LMS (n = 26). The combination of three melanocytic markers (HMB45, MLANA, PNL2) and pS6 can distinguish LMS from PEComas (**** p<0.0001). IHC for CD68 and PU.1 macrophage markers did not show any difference regarding the degree of immune infiltration in PEComa vs. LMS. Conclusions: Our studies revealed novel epigenetic signatures translating into lysosomal and melanocytic proteins for PEComa and myogenic proteins for LMS, which may serve as useful diagnostic biomarkers in the distinction of these two sarcoma subtypes.

Uterine PEComas: correlation between melanocytic marker expression and TSC alterations/TFE3 fusions

Uterine PEComas often present a diagnostic challenge as they share morphological and immunohistochemical features with smooth muscle tumors. Herein we evaluated a series of 19 uterine PEComas to compare the degree of melanocytic marker expression with their molecular profile. Patients ranged from 32–77 (median 48) years, with six tumors classified as malignant based on the modified gynecologic-specific prognostic algorithm. All patients with malignant PEComas were alive with disease or dead of disease at last follow-up, while all those of uncertain malignant potential were alive and well (median follow-up, 47 months).Seventeen of 19 (89%) PEComas harbored either a TSC1 or TSC2 alteration. One of the two remaining tumors showed a TFE3 rearrangement, but the other lacked alterations in all genes evaluated. All showed at least focal (usually strong) positivity for HMB-45, with 15/19 (79%) having >50% expression, while the tumor lacking TSC or TFE3 alterations was strongly positive in 10% of cells. Melan-A and MiTF were each positive in 15/19 (79%) tumors, but staining extent and intensity were much more variable than HMB-45. Five of six (83%) malignant PEComas also harbored alterations in TP53, ATRX, or RB1, findings not identified in any tumors of uncertain malignant potential. One malignant PEComa was microsatellite-unstable/mismatch repair protein-deficient.In summary, TSC alterations/TFE3 fusions and diffuse (>50%) HMB-45 expression are characteristic of uterine PEComas. In morphologically ambiguous mesenchymal neoplasms with myomelanocytic differentiation, especially those with metastatic or recurrent disease, next-generation sequencing is recommended to evaluate for TSC alterations; as such, patients can be eligible for targeted therapy.

Abstract P138: nab-Sirolimus improves mTOR pathway suppression and antitumor activity versus oral mTOR inhibitors in PTEN null bladder cancer (UMUC3) and TSC2 null liver cancer (SNU398) xenografts

Abstract Background: TSC1, TSC2, and PTEN genes are tumor suppressors in the mTOR pathway and can be inactivated or deleted across many cancers (Kwiatkowski, Clin Cancer Res 2016). The mTORC1 pathway is frequently activated in cancer and causes phosphorylation of downstream targets S6K (activation) and 4EBP1 (inactivation). Nanomolar concentrations of mTOR inhibitors (mTORi) sirolimus and everolimus can effectively inhibit S6K but not 4EBP1 and may lead to therapeutic resistance (Kang, Science 2013). In a registrational phase 2 trial (AMPECT) with malignant PEComa, nab-sirolimus (ABI-009) had a response rate of 64% (9/14) in patients with TSC1 or TSC2 mutations. In an expanded access program (NCT03817515), of 8 patients with TSC1 or TSC2 mutations (2 had prior mTORi) treated with nab-sirolimus, 5 had partial responses (all mTORi naïve). This study investigated mTOR pathway inhibition, tumor drug levels, and antitumor activity of nab-sirolimus vs equal doses of oral mTORi in PTEN-null and TSC2-null xenograft models. Methods: Athymic mice bearing subcutaneous PTEN-null UMUC3 bladder cancer xenografts were treated with either saline or equal weekly doses (15 mg/kg) of nab-sirolimus (IV, 7.5 mg/kg, 2x/wk), and sirolimus or everolimus (PO, 3 mg/kg/day, 5 days/wk). Tumors were harvested and analyzed for tumor drug levels (LC-MS/MS) and pS6 inhibition by immunohistochemistry (IHC). The same treatment conditions were repeated in a subsequent experiment with TSC2-null SNU-398 hepatocellular carcinoma xenografts, which further analyzed pS6K, pS6, and p4EBP1 via western blot (WB). Results: In UMUC3 xenografts, compared with oral mTORi, IV nab-sirolimus resulted in significantly higher drug exposure (AUC 7d) in the tumor (P<0.0001) and greater pS6 inhibition as measured by IHC (P=0.0001 vs sirolimus, P=0.0034 vs everolimus). Correspondingly, nab-sirolimus resulted in significantly greater tumor growth inhibition (TGI) than sirolimus (69.6% vs 24.3%, P<0.0001) and everolimus (36.2%, P=0.0023), and prolonged animal survival vs both oral mTORi (P<0.05 log-rank). Based on WB in SNU-398 xenografts, IV nab-sirolimus consistently inhibited mTOR targets pS6K, pS6, and p4EBP1, whereas oral sirolimus only partially decreased pS6K and pS6 and did not appear to reduce p4EBP1 levels. Correspondingly, nab-sirolimus resulted in significantly greater TGI than sirolimus (67.8% vs 36.2%, P<0.05) and prolonged animal survival (P<0.05 log-rank). Conclusions: The relatively low tumor concentrations achieved with oral mTORi may limit their effectiveness as anticancer therapies. IV nab-sirolimus at equal dose showed significantly higher tumor accumulation and inhibition of pS6 in a PTEN-null bladder cancer xenograft and increased inhibition of mTOR targets pS6K, pS6, and p4EBP1 in a TSC2-null hepatocellular carcinoma xenograft. This was accompanied with significantly greater antitumor activity, suggesting that nab-sirolimus may have a more optimal pharmacologic profile than the oral mTORi. Clinical studies in cancers harboring these alterations are planned. Citation Format: Shihe Hou, Heng Du, Anita N. Schmid, David J. Kwiatkowski, Neil P. Desai. nab-Sirolimus improves mTOR pathway suppression and antitumor activity versus oral mTOR inhibitors in PTEN null bladder cancer (UMUC3) and TSC2 null liver cancer (SNU398) xenografts [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P138.

Malignant perivascular epithelioid cell neoplasm in the liver: report of a pediatric case

BackgroundPerivascular epithelioid cell neoplasm (PEComa) in a child is very rare. We herein report the first malignant case of PEComa developing in the liver of a pediatric patient.Case presentationA 10-year-old boy visited a private clinic with prolonged fever of unknown etiology. Abdominal ultrasonography was performed to evaluate the fever’s origin, revealing a large tumor in the liver. He was thus referred to a nearby hospital to investigate the tumor further. Enhanced computed tomography (CT) showed a 6.8 × 5.9 × 10.5-cm solid lesion on S4 and S5. On magnetic resonance imaging (MRI), the tumor had a low signal intensity on T1 imaging and high signal intensity on T2 imaging, with partial diffusion restriction. 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) showed a marked uptake in the mass lesion with no evidence of metastasis. The patient was negative for all tumor markers, including AFP, CEA and PIVKA-II. The results of a needle biopsy suggested hepatocellular carcinoma. The tumor’s rapid growth suggested malignancy. Hepatic segmentectomy (S4 + S5 + S8) was performed. The tumor was resected en bloc with a margin. Microscopically, the tumor showed atypical spindle, polygonal or oval-shaped cells with a high nuclear grade, and vascular invasion. Immunohistochemistry was positive for alpha-smooth muscle antigen (α-SMA), human melanin black-45 (HMB-45) and melan A. The pathological diagnosis was malignant PEComa. In the 6 months after surgery, the patient complained of shoulder pain. MRI showed a dumbbell-shaped tumor at the 2nd thoracic vertebrae, which was confirmed to be bone metastasis of PEComa. After chemotherapy, including ifosfamide and doxorubicin, vertebrectomy was performed. Two years later, thoracoabdominal CT showed a 10-cm solid mass occupying the pelvis and a 15-mm nodule in the middle lobe of the right lung. Under a diagnosis of peritoneal and lung metastases, they were surgically removed and metastasis of PEComa was pathologically confirmed. Four months after the 2nd relapse, pelvic metastasis appeared again and mTOR (mammalian target of rapamycin) inhibitor was initiated. To our knowledge, this is the first report of malignant hepatic PEComa in a pediatric patient.ConclusionAlthough extremely rare, malignant hepatic PEComa can develop in a child.

Clinicopathological features and treatment of perivascular epithelioid cell tumor.

e23538 Background: Perivascular epithelioid cell tumor (PEComa) is a rare form of mesenchymal neoplasms. No clinical trial of large sample size regarding medical treatment of PEComa has been reported so far. Previous retrospective studies with small sample size have showed efficacy of mTOR inhibitors as treatment of PEComa. This study aimed to analyze the clinicopathological features of PEComa, and the efficacy of mTOR inhibitor in advanced PEComa. Methods: Medical information of patients diagnosed with PEComa and treated in Fudan University Shanghai Cancer Center were collected. Survival analysis was performed by Kaplan-Meier method. Radiological response was assessed according to RECIST version1.1. Results: A total of 17 patients were treated in our center during June 2007 to June 2020. PEComa mostly occurs in middle-aged women. The most common primary sites are pelvis, lung and abdomen. Relapse usually occurs within 2 years after radical surgery. Radical surgery is the main treatment for PEComa of limited stage, and remains the main option for those with limited recurrent lesions. Of the 13 patients with advanced malignant PEComa in our cohorts, the objective response rate of mTOR inhibitors in advanced malignant PEComa was 45.5%, and median progression-free survival was 27.7 months (95% CI 4.7-50.5 months). 2 patients discontinued mTOR inhibitor treatment due to pneumonitis combined with dyspnea and fever respectively. Conclusions: For advanced malignant PEComa, mTOR inhibitors are effective. Lung toxicity of mTOR inhibitor should be monitored.

Metastatic malignant PEComa of the brain: An unusual entity with rare presentation

Perivascular epithelioid cell tumor (PEComa) is an unusual mesenchymal tumor comprised histological and immunohistochemically distinctive perivascular epithelioid cells exhibiting myomelanocytic phenotype. We hereby report the case of a 59-year-old female who presented with sudden headache, vomiting, and transient decreased vision with contrast MRI suggestive of the right occipital mass. Biopsy from the right occipital craniotomy mass was reported as metastatic malignant melanoma. The case was referred to our hospital for review. We considered a differential diagnosis of metastasis from malignant melanoma, poorly differentiated carcinoma, high-grade glioma, PEComa, hemangioblastoma, and high-grade sarcoma. A post-operative whole-body PET/CT scan revealed a metabolically active lesion in the endometrium that seems to be primary. It is suggested to consider PEComa as a differential diagnosis in poorly differentiated malignancy and to evaluate accordingly with appropriate immunohistochemistry markers. This is the third reported case of metastatic malignant PEComa to the brain as per the English literature.

Addition of Antiestrogen Treatment in Patients with Malignant PEComa Progressing to mTOR Inhibitors.

Perivascular epithelioid cell tumors (PEComa) are rare mesenchymal neoplasms. mTOR inhibitors are the most active agents in PEComa and in patients progressing to mTOR inhibitors, other available therapies have limited benefit. Preclinical evidences showed a cross-talk between the mTOR pathway and estrogen receptor signaling. This provided a rationale for adding an antiestrogen treatment in female patients becoming resistant to mTOR inhibitors. Since April 2018, female patients with advanced/metastatic PEComa progressing to mTOR inhibitors were treated with a combination of sirolimus and exemestane with or without LHRH analogue (based on menopausal status). This case series was retrospectively reviewed. Survival analyses were performed using the Kaplan-Meier method. A total of seven consecutive patients treated with the combination of sirolimus and antiestrogen treatment were retrospectively reviewed. Six (86%) received a combination of sirolimus and exemestane, whereas one patient (14%) received a combination of sirolimus, exemestane, and triptorelin since in premenopausal status. After a median follow-up of 13.1 months, three patients (43%) experienced a partial response, three patients (43%) experienced a stabilization of disease, and one patient (14%) had disease progression with an overall response rate of 43% and a disease control rate of 86%. In this small retrospective case series, the addition of antiestrogen treatment in female patients with advanced PEComa progressing to mTOR inhibitors resulted in a remarkable clinical benefit in a setting where no other options are available.

A STRANGE CAUSE OF A PULMONARY NODULE

SESSION TITLE: Medical Student/Resident Lung Cancer Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Perivascular epithelioid cell tumors (PEComas) are part of an uncommon group of mesenchymal tumors with histological and immunohistochemical markers for myogenic and melanocytic tissue. Its prevalence is very low, accounting for approximately 100 reported cases in the literature with 20 % of them exhibiting lung metastasis. Nonspecific gynecologic symptoms appear to be the most common manifestation. The majority of these cases are classified as non-malignant, thus making our case very atypical. Given that these tumors are extremely rare, there are no specific therapeutic guidelines in the literature. Some experts recommend tumoral resection and adjuvant chemotherapy or radiotherapy in malignant cases. CASE PRESENTATION: We describe a 62-year-old nulligravid female with no known past medical history who came to the emergency room with suprapubic discomfort of one-day evolution. An abdominopelvic computed tomography (CT) revealed a large pelvic mass of 27 cm x 19 cm x 22 cm with heterogeneous density and calcifications, ascites, as well as bibasilar pulmonary nodules. A subsequent chest CT scan showed the presence of multiple bilateral nodular lesions, the largest one measuring 3.6cm x 2.6 cm. Histological sampling was obtained via CT guided biopsy from lung and uterus which came back positive for HMB45, CD10, and for desmin consistent with a metastatic malignant PEComa of gynecologic origin. The patient underwent pelvic mass surgical resection and at the moment is receiving mTOR inhibitors. DISCUSSION: This extremely rare type of tumor is immunoreactive for smooth muscle and melanocytic markers. Its behavior is marked by invasion of the vessel wall and smooth muscle. While some PEComas occur in patients with tuberous sclerosis, it’s lack of association often leads to an inverse relation of malignant potential. Proposed guidelines for classification of PEComas divide them into benign, uncertain malignant potential and malignant. In view of the low prevalence of PEComas, treatment options are limited and prognostic factors are uncertain. Several case studies have discussed the benefit of mTOR inhibitors, chemotherapy, and radiotherapy. Initial therapy with mTOR inhibitors seems to be the best approach while disease progression allows. CONCLUSIONS: PEComas are an extremely rare type of sarcoma very rarely showing metastasis. Typical symptoms can be nonspecific and diverse given organ involvement. PEComa must be kept in the differential diagnosis of gynecological tumors despite its low prevalence. All PEComas exhibit both melanocytic (HMB45, Melan-A, tyrosinase, microphthalmia transcription factor) and myoid (desmin, smooth muscle actin, muscle-specific actin, caldesmon, calponin) markers. Treatment strategies include tumor resection and a combination of mTOR inhibitors, chemotherapy or radiation. Lung nodularities may represent metastasis and in appropriate setting may lead to diagnosis. Reference #1: Henry B Armah; Anil V Parwani. Malignant perivascular epithelioid cell tumor (PEComa) of the uterus with late renal and pulmonary metastases: a case report with review of the literatura. Diagnostic Pathology 2, Article number: 45 (2007) Reference #2: Valentina Natella; et al. A huge malignant perivascular epithelioid cell tumor (PEComa) of the uterine cervix and vagina. Pathology - Research and Practice, Volume 210, Issue 3 (2014) Reference #3: Óscar Cuevas Herreros;Lilian Escobar Lezcano; Manuel Rodriguez Blaco; Vicente Artigas Raventós. PEComa, un raro tumor de células epiteliodes. Cirugia Española.Vol 93. Num. 7. 65-67 (2015) DISCLOSURES: no disclosure on file for Rosangela Fernandez-Medero; No relevant relationships by Juan Garcia-Puebla, source=Web Response No relevant relationships by Ricardo Hernandez, source=Web Response No relevant relationships by Kimberly Padilla Rodriguez, source=Web Response no disclosure on file for Ileana Rivera Burgos; No relevant relationships by Gabriela Torres, source=Web Response No relevant relationships by Marina Torres Torres, source=Web Response

TFE3-expressing malignant perivascular epithelioid cell tumor of the mesentery: A case report and review of literature

BACKGROUNDPerivascular epithelioid cell tumor (PEComa) is a rare mesenchymal tumor that exhibits an epithelioid and spindle cell morphology. The tumor is characterized by immunoreactivity for melanocytic and myogenic markers but can be misdiagnosed as more common tumors with similar characteristics, including gastrointestinal stroma tumors or leiomyosarcomas. Recently, a subset of PEComas has been reported to harbor a transcription factor binding to TFE3 fusion. Herein, we report a rare case of TFE3-expressing malignant PEComa arising from the mesentery.CASE SUMMARYA 50-year-old woman presented with abdominal discomfort for 3 months. Results of laboratory tests were all within the normal ranges, and the patient had no notable medical history. Magnetic resonance imaging revealed a large tumor on the right side of the pelvic floor, which was originally suspected to be a primary ovarian tumor. However, during surgery, the tumor was revealed to have originated from the mesentery. Histologically, the tumor was composed of bundles of spindle cells and sheets of epithelioid cells. Extensive coagulative necrosis and numerous mitotic figures were observed. Immunohistochemistry revealed that the tumor cells were positive for smooth muscle actin, HMB-45, and TFE3 expression. Tumor involvement of the rectal serosa was identified, leading to a final diagnosis of malignant PEComa of the mesentery. Surgical resection was followed by adjuvant chemotherapy. No recurrence or metastasis was observed over a 6-month follow-up period.CONCLUSIONMalignant PEComa of the mesentery is extremely rare and should be distinguished from morphological mimics through differential diagnosis and immunohistochemistry.

Characterization of Clinical Cases of Malignant PEComa via Comprehensive Genomic Profiling of DNA and RNA

Purpose: Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal soft tissue neoplasm often linked to mTOR pathway activation via TSC2 mutation. We analyzed a series of 31 consecutive metastatic PEComa (mPEComa) cases using a combined DNA/RNA hybrid capture-based comprehensive genomic profiling (CGP) assay to assess the genomic landscape of mPEComa. Patients and Methods: Formalin-fixed, paraffin-embedded (FFPE) blocks or slides were obtained from tumors from 31 unique patients with mPEC­oma. DNA and RNA were extracted and CGP was performed on 405 genes using a targeted next-generation sequencing (NGS) assay in a CLIA-certified lab. Results: All cases had locally advanced or metastatic disease, and 58% of patients were female with a median age of 50 years (range 8–76), and 17 and 14 specimens were from primary and metastatic sites, respectively. One hundred genomic alterations were identified in the cohort, with an average of 3.2 genomic alterations/case including alterations in TSC2 32.3% of cases (10), TSC1 9.6% (3), TFE3 16.1% (5, all fusions), and folliculin (FLCN) 6.4% (2), with all occurring in mutually exclusive fashion. Of TSC2 mutant cases, 70% had biallelic inactivation of this locus, as were 100% of TSC1 mutant cases. Two TSC1/2 wildtype cases harbored truncating mutations in FLCN, both of which were under LOH. Five TFE3 fusion cases were identified including the novel 5′ fusion partner ZC3H4. Conclusions: We describe for the first time mPEComa cases with FLCN mutations under LOH, further characterizing dysregulation of the mTOR pathway as a unifying theme in mPEC­oma. Cumulatively, we demonstrate the feasibility and potential utility of segregating mPEComa by TSC, TFE3, and FLCN status via CGP in clinical care.

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.

Medical treatment of advanced malignant perivascular epithelioid cell tumors.

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. 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. 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.

Long-term follow-up for duration of response (DoR) after weekly nab-sirolimus in patients with advanced malignant perivascular epithelioid cell tumors (PEComa): Results from a registrational open-label phase II trial, AMPECT.

11516 Background: Malignant PEComa is a rare, aggressive sarcoma, with no approved medical treatment. Cytotoxic chemotherapies have limited benefit for patients with advanced disease. The AMPECT trial measured the effects of nab-sirolimus (ABI-009) and is the first prospective study in advanced malignant PEComa. nab-Sirolimus is a nanoparticle albumin-bound mTOR inhibitor with significantly higher intratumoral drug levels, mTOR target suppression, and anti-tumor activity in animal models versus other mTOR inhibitors. This report presents long-term follow-up of DoR after the primary analysis. Methods: Patients (N=34) received nab-sirolimus (100mg/m2 IV, weekly, 2/3 weeks) until progression or unacceptable toxicity. Primary endpoint: ORR by IRR. Key secondary endpoints included DoR, PFS6, OS, and safety. Exploratory endpoints included correlation of tumor genotype and outcome. The sample size of 30 efficacy-evaluable patients was based on an estimated ORR of 30% and the lower bound of the 95%CI of ORR to exclude values less than 14.7%. The primary analysis was conducted when all patients were treated ≥6 months (May 22, 2019). This report updates the primary response analysis and DoR with an additional 8.5-month of follow-up. Results: As of Feb 06, 2020, of the 31 efficacy-evaluable patients, the confirmed ORR by IRR was 39% (12/31, 95%CI: 21.8, 57.8), with 1 complete response (CR) and 11 partial responses (PR), 52% stable disease (SD, 16/31, with 10/16 SD ≥12 weeks), and 10% progressive disease (3/31); the disease control rate (CR+PR+SD ≥12 weeks) was 71%. PFS6 was 71% (95%CI: 47.7, 85.1). The majority of responses (67%) were reached at the first post-baseline scan at week 6, with a median time to response of 1.4 months (95%CI: 1.3 to 2.8). The median DoR by IRR was not yet reached (range 5.6-38.7+ months; calculated median 22.2+ months) with 8/12 (67%) responders still on treatment for >1 year and 5/12 (42%) >2 years. Mutational analysis available for 25 patients identified that TSC2 loss-of-function mutations significantly correlated with response; 8/9 (89%) patients with TSC2 had a confirmed response. Conclusions: Responses of advanced malignant PEComa to nab-sirolimus were highly durable and occurred in 39% of patients based on independent review. The high disease control rate with manageable toxicities suggest that nab-sirolimus is effective and represents an important new treatment option for these patients. NCT02494570. Clinical trial information: NCT02494570 .

Diagnosis and treatment of malignant PEComa tumours

PEComa (PEC tumours; perivascular epithelioid cell tumours) is a family of rare tumours of mesenchymal origin, consisting of epithelial perivascular cells expressing melanocytic and myioid markers. This group includes benign tumours — such as angiomyolipoma (AML) of the kidney, and poorly differentiated malignant PEComa tumours with potential for an aggressive clinical course, which is the main focus of this review. PEComas are most often diagnosed in middle-aged women as extensive tumours located in the abdominal cavity or pelvis, manifesting as pain and complaints related to pressure on nearby organs. PEComa tumours should be differentiated from gastrointestinal stromal tumours (GIST), leiomyosarcoma, melanoma metastasis, chromophobic renal cell carcinoma, clear cel sarcoma, and other clear cell component tumours. Somatic inactivating mutations within the TSC1/TSC2 genes, resulting in excessive activation of the mTORC1 complex, are characteristic for this group of tumour. Recently, a separate PEComa subgroup has been distinguished, characterised by the presence of the TFE3 gene fusion, which also causes increased activity of the mTOR signalling pathway. Negative prognostic factors that indicate an increased risk of PEComa malignant biology are most often: tumour size > 5 cm, increased cytological and nuclear atypia, infiltration of surrounding tissues and blood vessels, presence of necrosis, and high mitotic activity. Radical resection remains the primary treatment method for PEComas because these tumours are characterised by high resistance to radiation and chemotherapy. In the case of locally advanced or metastatic disease, only single reports of short-term responses to palliative chemotherapy containing doxorubicin, gemcitabine, or ifosfamide are available in the literature. There are an increasing number of reports, in the form of several case reports and a few retrospective analyses, about the potential effectiveness of using mTOR inhibitors in unresectable cases. These drugs result in a reduction in primary tumour size and metastasis, as well as symptom relief, with controllable side effects. Unfortunately, case reports of complete resistance to mTOR inhibitor therapy are also available.

1464 Malignant Perivascular Epithelioid Cell Neoplasm of Colon in Young Male

INTRODUCTION: Perivascular epithelioid cell neoplasms (PEComas) are a rare type of mesenchymal tumor that can be found in various visceral and soft tissues in the body. Approximately fifty cases have been reported in the gastrointestinal (GI) tract. Typically, management of these lesions is laparoscopic or open surgical resection followed by chemotherapy if there is metastatic disease. The majority of GI PEComas are benign, colonic masses in middle-aged females. This case describes a malignant, colonic PEComa in a 16-year-old male. To the best of our knowledge, this is the largest malignant, colonic PEComa in an adolescent, and this is the first case to demonstrate successful endoscopic mucosal resection (EMR) of a PEComa. CASE DESCRIPTION/METHODS: A 16-year-old male with history of IgA vasculitis during childhood presented with acute onset of bilious emesis in the setting of severe, intermittent, left lower quadrant abdominal pain and constipation for one month. Lab testing was unremarkable. Computed tomography revealed a non-obstructing, nodular mass in the transverse colon. The patient underwent colonoscopy, during which the 6-cm large, semi-sessile, broad-based polyp was removed by piecemeal EMR. EMR was technically challenging due to the size, broad base, and location of the mass. Histology of the tissue showed a predominance of fascicular spindled cells, scattered areas with epithelioid morphology, and prominent vasculature, consistent with a PEComa. The tissue stained positive for HMB-45, MART-1, and cathepsin. Based on the size (>5 cm), nuclear atypia, and high mitotic activity, the lesion was defined as malignant. Though the lesion was removed to the submucosa, there was concern for deeper extension, so he underwent laparoscopic transverse colectomy with primary anastomosis. Pathology confirmed there was not any residual tumor in the resected colon or metastasis to lymph nodes. Positron emission tomography did not show metastasis. Fifteen months have elapsed and the patient has not had recurrence on imaging. DISCUSSION: There are few cases of GI PEComas. This case demonstrates a rare presentation of a large, malignant GI PEComa in a young male and is the first case of successful endoscopic removal of a malignant PEComa. The surgical specimen revealed no evidence of residual PEComa, and the patient has not had evidence of recurrence on imaging, verifying successful removal of his PEComa. This supports the notion that EMR should be considered for definitive management in patients with these lesions.

1698P - Reversion of resistance to mTOR inhibitors with the addition of exemestane in patients with malignant PEComa

1698P - Reversion of resistance to mTOR inhibitors with the addition of exemestane in patients with malignant PEComa

Malignant Perivascular Epitheloid Cell Tumor with an Unusual Immunophenotype in a Ten-Year-Old Child

Introduction: Perivascular epitheloid cell tumors (PEComa) represent a group of usually benign mesenchymal neoplasms. Malignant variants are usually found only in adults.Case: We present a 10-year-old girl with infraclavicular malignant PEComa, negative for HMB-45 and Melan A but focally positive for MITF.Conclusion: To the best of our knowledge, no malignant variant of PEComa has been described in soft tissue in a child. Generally, PEComas are immunoreactive for HMB-45 and/or Melan A while our case was negative for both. Further studies are necessary to elucidate the significance of this immunohistochemical finding.

Characteristics of mismatch repair deficiency in sarcomas

Due to the efficacy of immune checkpoint inhibitor therapy in tumors with deficient mismatch repair, there has been a surge in demand for mismatch repair deficiency testing in various tumor types. Mismatch repair deficiency is not known to play a significant role in the pathogenesis of sarcomas, and the utility of testing these tumor types is not established. This study aimed to determine the frequency, pattern, and clinicopathologic correlates of mismatch repair deficiency in sarcomas. Three hundred and four sarcomas were profiled using a genomic platform that employs massively parallel sequencing to interrogate 447 cancer-associated genes. Mismatch repair status was evaluated by determining the number of small insertion/deletion events occurring in homopolymer regions per megabase of exonic sequence data across all genes. Molecular characteristics of mismatch repair-deficient sarcomas were compared to mismatch repair-deficient carcinomas (n = 70) also identified using the sequencing panel. Seven sarcomas (2.3%) were classified as mismatch repair-deficient: four unclassified sarcomas, and one each of pleomorphic rhabdomyosarcoma, epithelioid leiomyosarcoma and malignant PEComa. One patient had an established diagnosis of Lynch syndrome. In the remaining patients, the mismatch repair gene mutation was confirmed or suspected to be somatic. Mismatch repair immunohistochemistry confirmed the mismatch repair-deficiency status of all cases with alterations in the tested proteins. As expected, mismatch repair-deficient sarcomas showed a significantly elevated tumor mutation burden relative to mismatch repair-proficient sarcomas (median 16 versus 4.6, p < 0.001). However, in comparison to mismatch repair-deficient carcinomas, mismatch repair-deficient sarcomas showed a lower tumor mutation burden (median 28 versus 16, p = 0.006) and a significantly greater degree of chromosomal instability. Among mismatch repair-deficient sarcomas, PD-L1 was variably expressed on tumor-associated macrophages but not on tumor cells. Three patients received pembrolizumab: two progressed and one has stable disease with five months follow-up. Mismatch repair deficiency in histologically classifiable sarcomas is rare (1%) and is more common in unclassified sarcomas (10%). Additional study is required to determine the predictive role of mismatch repair-deficiency in sarcomas for immunotherapy.