RARE DISEASE
Perivascular epithelioid cell neoplasm
Perivascular epithelioid cell neoplasm
Perivascular epithelioid cell neoplasm
Synonyms: PEComa, Perivascular epithelioid tumour
Synonyms: PEComa, Perivascular epithelioid tumour
Synonyms: PEComa, Perivascular epithelioid tumour
Drug discovery
2
drugs
With orphan designations
Overview
Perivascular epithelioid cell neoplasms (PEComas) are rare mesenchymal tumors showing myomelanocytic differentiation, characterized by coexpression of melanocytic markers (HMB-45, Melan-A) and smooth muscle markers (actin, desmin) [1][6][12]. These tumors exhibit uncertain malignant potential, with behavior ranging from benign to aggressive/metastatic [3][7][13]. PEComas occur across various anatomic sites and are associated with TSC1/2 mutations or TFE3 gene rearrangements in most cases [6][11][12].
Population
Predominantly affects females (70-80% of cases), with median age at diagnosis of 40-50 years [1][7][12]
Occurs in children/adolescents (median age 15 in pediatric cohorts), often alongside tuberous sclerosis complex (TSC) or Li-Fraumeni syndrome [2][12][15]
Renal angiomyolipoma (AML) and uterine PEComas are common subtypes [4][12][17]
Burden
Incidence estimated at 0.3-1 case per million, with ≤15% exhibiting malignant behavior [7][11][19]
Metastases occur in 6-15% of cases, predominantly to lungs/liver, with median survival <24 months in aggressive subtypes [7][12][13]
Diagnostic challenges due to histologic overlap with carcinomas, sarcomas, and melanomas [6][12][16]
Therapies
Surgical resection with negative margins remains primary treatment for localized disease [3][13][17]
mTOR inhibitors (sirolimus, temsirolimus) show durable responses in advanced/metastatic cases (41-73% response rates) [3][8][11]
Limited efficacy of conventional chemotherapy; emerging options include VEGFR inhibitors (pazopanib) and nab-sirolimus [3][12][16]
Categories: rare neoplastic diseases
Research Papers
404 drug discovery papers about Perivascular epithelioid cell neoplasm, with 1 first-in-class and 16 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
404 drug discovery papers about Perivascular epithelioid cell neoplasm, with 1 first-in-class and 16 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-27 | Epithelioid angiomyolipoma in a horseshoe kidney: a pediatric tuberous sclerosis case report
Abstract Background Epithelioid angiomyolipoma (EAML) is a rare, potentially malignant PEComa-family tumor strongly associated with tuberous sclerosis complex (TSC). Its fat-poor composition and diffusion restriction on MRI render it indistinguishable from renal cell carcinoma (RCC) without tissue sampling. Case presentation A 7-year-old boy with TSC (TSC2 mutation c.2220 + 1 G > T) was found on routine surveillance MRI to have a new left moiety horseshoe kidney mass with interval growth and restricted diffusion on follow-up imaging four months later. Atypical features for classic AML prompted percutaneous image-guided biopsy. Histopathology confirmed EAML; immunohistochemistry showed HMB-45+, SMA+, S-100−, CD10−, and EMA−, with no histologic features of malignancy. The patient was managed with active surveillance; mTOR inhibitor therapy (everolimus) is planned if further growth occurs. Conclusions In a child with TSC, a fat-poor renal mass with interval growth and diffusion restriction should prompt biopsy rather than assumption of classic AML. The ADC map is a critical imaging discriminator, and the characteristic IHC profile is diagnostic. To our knowledge, this is the youngest published case of biopsy-proven EAML in a horseshoe kidney.
2026-07-20 | Clinicopathological characteristics of primary malignant cutaneous perivascular epithelioid cell tumor: case report and literature review.
Primary cutaneous malignant perivascular epithelioid cell tumors (PEComas) are extremely rare. Accurate diagnosis is critical for prognostic evaluation and guiding clinical management. Here, we report a case of a 19-year-old woman with a 1.1 cm exophytic red mass on her left upper limb. Histological examination revealed a dermal tumor composed of clear cells with prominent nucleoli. The tumor cells displayed cytologic atypia, nuclear pleomorphism, multinucleated giant cells, mitoses and invasive growth, with a multinodular distribution within the dermis and vascular invasion. Immunohistochemically, the tumor cells expressed cathepsin K, HMB45, and CD10. Based on morphological and immunohistochemical findings, we classified it as a primary malignant cutaneous PEComa. To date, only eight reported cases have been described as primary malignant cutaneous PEComas. The present case appears to be the youngest patient reported among all malignant PEComas.
2026-07-16 | The many faces of perivascular epithelioid cell tumors: case series illustrating the spectrum of a rare mesenchymal tumor.
Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal neoplasms composed of distinctive perivascular epithelioid cells that exhibit both melanocytic and smooth muscle differentiation on immunohistochemistry. These tumors can develop in various anatomic locations and display variable biological behavior ranging from benign to aggressive malignant disease. We present a case series of four patients diagnosed with PEComa at different anatomic sites. Histopathological analysis in all cases demonstrated characteristic epithelioid or spindle-shaped morphology, with some cases showing positive staining for melanocytic markers such as HMB-45 and Melan-A, as well as smooth muscle markers. Due to their rarity, definitive management protocols are not yet well established. Surgical resection remains the primary treatment for localized disease, while systemic therapies targeting the mammalian target of rapamycin pathway may be considered for unresectable tumors or metastatic disease. This case series underscores the heterogeneity of PEComas and highlights the importance of multidisciplinary management and long-term follow-up.
2026-07-14 | Sustained Disease Control of High-Risk Metastatic Renal Epithelioid Angiomyolipoma through Multimodal Treatment Including Repeated Thoracic Resection and Systemic Therapy: A Case Report.
Renal epithelioid angiomyolipoma (EAML) is a rare perivascular epithelioid cell tumor with malignant potential. Radiologic distinction from renal cell carcinoma (RCC) may be difficult in fat-poor cases, and standardized treatment strategies for metastatic disease have not been established. A woman in her 30 s presented with a palpable right abdominal mass and anorexia. Contrast-enhanced computed tomography showed an 18-cm heterogeneous right renal mass and a 25-mm liver lesion suspicious for metastasis, without pulmonary metastasis at diagnosis. The pretreatment clinical stage was cT2bN0M1, stage IV. Imaging findings strongly suggested clear cell RCC, and the lesion was managed as presumed metastatic clear cell RCC. The International Metastatic RCC Database Consortium risk category was poor risk. Nivolumab plus cabozantinib was initiated without pretreatment biopsy. At Month 3, the primary tumor showed partial response and the liver lesion remained stable; however, cabozantinib became difficult to continue because of adverse effects, and right nephrectomy was performed in a setting analogous to deferred cytoreductive nephrectomy. Histopathology established renal EAML with pT2b disease, necrosis, mitotic count ≥2, atypical mitoses, severe nuclear atypia, smooth muscle actin negativity, and Ki-67 ≥ 10%, fulfilling six of seven adverse prognostic factors and indicating high-risk disease. Everolimus induced partial response of a new lung metastasis. Subsequent liver and bilateral lung metastases were managed with systemic therapy and staged thoracoscopic resections. Later, isolated subcarinal mediastinal lymph node progression was treated by thoracoscopic resection. The patient remains recurrence-free for 8 months on everolimus. Metastatic renal EAML lacks a standardized treatment strategy. This case suggests that durable disease control may be achievable in selected high-risk patients through individualized multimodal treatment integrating systemic therapy with repeated local treatment for thoracic oligoprogressive lesions.
2026-07-02 | An Evaluation of Radiotherapy and Response in the Management of Perivascular Epithelioid Cell Tumors.
Perivascular epithelioid cell tumours (PEComas) are ultra-rare soft tissue tumours with heterogeneous treatment approaches. While surgery is the standard for localized disease, the role of radiotherapy (RT) remains unclear. This retrospective study aims to evaluate tumour volume response, as well as local outcomes and Overall Survival, in patients with PEComa treated with RT. The cohort included patients diagnosed with PEComa between 2005 and 2023 at a single sarcoma centre. Demographic, clinical, RT, and volumetric tumour data were collected. Response was assessed using RECIST v1.1. In total, 24 lesions in 12 patients were evaluable for analysis, with a median radiological follow-up of 10 months. Of these, 7 lesions were treated with perioperative RT and 17 with palliative RT. Systemic treatments during imaging follow-up were administered in 19/24 lesions. Among 17 lesions treated with palliative intent without surgery, four local failures occurred- all at EQD2 (α/β = 5) <40 Gy- and the estimated 1-year local control rate was 61.9%.Among these 17 lesions, mean tumour volume decreased from 301.5 cm³ (range: 0.9-2251) to 108.3 cm³ (range: 0.1-754) as best response after RT. Seven patients (58.3%) died from their disease, with a median overall survival of 46 months after diagnosis. PEComas appear to be radiosensitive, with substantial tumour volume reduction after RT and a dose-response signal favouring higher EQD2 dose. Nonetheless, overall survival was poor, reflecting the aggressive nature of this disease. This is the largest RT series in PEComa to date and suggests radiosensitivity in this disease.
antibodies
2026-06-23 | MiT fusions, TSC1-TSC2 divergence, and stem-like programs reveal distinct origins and vulnerabilities in PEComa.
Perivascular epithelioid cell neoplasms (PEComas) are ultra-rare mesenchymal tumors lacking a molecular classification to guide therapy. Here we perform comprehensive multi-omic profiling of an unselected PEComa cohort. We identify frequent MITF rearrangements involving actin gene partners (ACTA2, ACTG1 and ACTB). Anatomical stratification reveals cyclin-dependent kinase module mutations in gynecologic tumors, whereas soft tissue, gastrointestinal, and pelvic tumors lacked mTOR pathway alterations but are enriched for TFE3/MITF rearrangements. Transcriptomic analysis defines four subtypes with distinct lineage programs-melanocytic, mesenchymal, or adipogenic-as well as unique mutational patterns and clinical behaviors. Notably, an aggressive stem-like subtype enriched for TP53/RB1 mutations exhibits high proliferation, activation of embryonic and Hedgehog signaling, immune infiltration, and resistance to mTOR inhibitors, but potential responsiveness to immunotherapy. Single-nucleus RNA sequencing reveals intra-tumoral heterogeneity within this subtype, including divergent inflammatory states. Together, these findings establish a molecular classification framework and identify actionable vulnerabilities in PEComa.
2026-04-23 | Durable Disease Control With Nivolumab in Malignant Epithelioid Angiomyolipoma: A Case Report.
Epithelioid angiomyolipoma is a subtype of perivascular epithelioid cell tumors that may exhibit malignant behavior. While mammalian target of rapamycin inhibitors are commonly used for systemic treatment, the efficacy of immune checkpoint inhibitors remains unclear. A 58-year-old man was diagnosed with epithelioid angiomyolipoma after partial nephrectomy of a right renal mass. The tumor recurred locally, and multiple lung metastases developed despite surgical resection. Nivolumab was initiated after disease progression on everolimus, resulting in durable disease control for over 3 years. Immunohistochemistry revealed high PD-L1 expression and CD8+ T-cell infiltration within the primary tumor. Immune checkpoint inhibitors may be effective treatment options for malignant epithelioid angiomyolipoma with PD-L1 expression and CD8+ T-cell infiltration.
2026-02-18 | Metastatic PEComa successfully treated with pembrolizumab: A case report and review of the literature
Perivascular epithelioid cell tumours (PEComas) are rare mesenchymal neoplasms with the potential for malignant biological behavior. Patients with metastatic PEComas may benefit from effective biomarker-driven treatments. Genetic alterations associated with mismatch repair deficiency (MMRd) and microsatellite instability-high (MSI-high) are rarely identified in PEComas but have emerged as successful predictors of response to pembrolizumab in a variety of solid tumours. Here, we report a case of a 29-year-old female who presented with an enlarging lesion in her left femoral neck, which was resected and diagnosed as malignant PEComa. Two metastatic pulmonary nodules then appeared and were resected. After another large metastatic lesion appeared in her left lung, the patient elected to start systemic therapy. Next-generation sequencing performed on one of the metastatic tumours did not identify actionable genetic variants, however several microsatellite sites were noted to be unstable, manifesting as small duplications and deletions within mononucleotide repeats. Subsequent immunohistochemical evaluation for MMR expression was performed, showing subtotal expression loss of MLH1 and PMS2, and MSI testing revealed the tumour to be MSI-high. These findings suggested the use of the anti-PD-1 agent pembrolizumab in a patient who would otherwise not have been able to access this medication in Canada at the time of her diagnosis. The patient was referred to medical genetics where she was found to not have Lynch syndrome. Sixteen months after initiating pembrolizumab, the patient continues to show reduction in the size of her metastatic lung lesion. This case is the first to our knowledge to describe the successful use of immunotherapy for metastatic MSI-high PEComa arising in a patient without Lynch syndrome.
2025-10-31 | GPNMB immunohistochemistry is a useful ancillary tool for the diagnosis of pulmonary lymphangioleiomyomatosis.
Lymphangioleiomyomatosis (LAM) is a PEComa that primarily affects premenopausal women and is associated with the cystic destruction of the lung. Although smooth muscle and melanocytic markers can be helpful, histologic diagnosis of LAM remains challenging, especially in small biopsies. Glycoprotein non-metastatic melanoma protein B (GPNMB) expression has recently been identified as a highly specific and sensitive immunohistochemical marker for PEComas. Nevertheless, only a few LAM cases have been studied so far. The aim of this study was to assess the utility of GPNMB immunohistochemistry as an ancillary marker in a larger cohort of LAM samples. Immunohistochemistry for GPNMB was performed on cases of LAM (N = 15), potential differential diagnostic mimics (N = 30) and normal lung tissue (N = 2). Immunohistochemistry was assessed using the H-score method; an H-score above 100 was considered 'high'. All LAM cases showed strong cytoplasmic expression, with cell membrane accentuation in some areas. In contrast, differential diagnostic mimics were either negative or only weakly positive. Normal lung parenchyma was negative for GPNMB; however, weak-to-moderate expression was seen in alveolar macrophages in both the normal and diseased lung tissues in most cases. Considering only 'high' positivity, GPNMB immunohistochemistry showed 100% sensitivity and specificity for the diagnosis of LAM in our cohort. Based on its 100% sensitivity and specificity, GPNMB appears to be a highly valuable immunohistochemical marker for the diagnosis of pulmonary LAM. Besides its diagnostic value, the membrane positivity of GPNMB on LAM cells may predict a response to glembatumumab vedotin, an antibody-drug conjugate targeting GPNMB.
2025-10-22 | Multicenter phase II trial of ipilimumab and nivolumab in metastatic or unresectable perivascular epithelioid cell tumor (PEComa): a substudy of Dual Anti-CTLA-4 and Anti-PD-1 blockade in Rare Tumors (DART) SWOG S1609 (Cohort 38).
Malignant perivascular epithelioid cell tumors (PEComas) are ultra-rare, aggressive mesenchymal neoplasms associated with poor outcomes. Standard-of-care systemic therapy includes mammalian target of rapamycin (mTOR) inhibition and chemotherapy. Immune checkpoint inhibition has not been previously studied in patients with advanced PEComas in a prospective clinical trial. This is an open-label phase 2 trial of ipilimumab (1 mg/kg intravenously every 6 weeks) plus nivolumab (240 mg intravenously every 2 weeks) in rare tumors; here we report the cohort of patients with advanced malignant PEComa recruited from >1,000 sites across the USA. Primary end point was objective response rate, with progression-free survival, overall survival, and toxicity as secondary end points. 17 patients were enrolled (N=16 evaluable). Median age was 59.5 years (range, 22-77 years) and the majority were female (81%). Best responses included partial response (18.8%), stable disease for <6 months (25.0%), and progressive disease (56.3%). Median OS was 7.5 months (95% CI 3.4 to 34.6) and median PFS was 1.9 months (95% CI 1.8 to 11.8). PFS in responding patients was 11.8, 18.9, and 34.6 months. Available genomic sequencing showed TSC, ATRX, and TP53 mutations; no TFE3 fusions were identified (N=7). Nearly all patients experienced a treatment-related adverse event (AE) of any grade, while 37.5% experienced a grade 3-4 AE. Most common AEs were fatigue (43.8%), pruritus (37.5%), rash (25.0%), and aspartate aminotransferase increase (25.0%). There were no grade 5 AEs. The combination of ipilimumab and nivolumab demonstrated responses in 18.8% of patients with advanced malignant PEComas. Dual immunotherapy may be an alternative treatment option for certain patients, including those who are unable to tolerate or do not desire prolonged treatment with chemotherapy or mTOR inhibition or have failed to respond to other therapies. Ipilimumab and nivolumab warrants further investigation in this and other rare soft tissue sarcomas.
proteins
2025-07-11 | Modulation of infiltrating CD206+ macrophages restricts progression of pulmonary lymphangioleiomyomatosis.
Lymphangioleiomyomatosis (LAM) is a low-grade neoplasm caused by the proliferation of tuberous sclerosis complex (TSC) 1- or TSC2-deficient LAM cells, resulting in progressive cystic lung disease. The currently approved treatment for LAM delays disease progression but the disease recurs if treatment is discontinued. Therefore, new therapeutic targets and/or strategies are necessary for a cure. Immunosuppressive M2-like macrophages are involved in the progression of various cancers, but their role in the pathophysiology of LAM and as a putative therapeutic target is unknown. To identify the different immune cell populations involved in LAM, we generated a single-cell transcriptomic map of pulmonary LAM. Interactions between macrophages and LAM cells were studied using the Visium spatial transcriptomic platform and immunofluorescence staining on human pulmonary LAM specimens. Direct co-culture models were used to characterise the influence of TSC2-deficient cells on macrophage differentiation. The efficacy of targeting M2-like macrophages was assessed in preclinical mouse models of TSC2-deficient subcutaneous tumours treated with RP-182, a synthetic peptide which reprogrammes macrophages towards an antitumour M1-like phenotype. Single-cell RNA-sequencing analysis revealed that the majority of macrophages in pulmonary LAM display immunosuppressive markers, including CD206/MRC1 and CD163. Spatial transcriptomic and immunofluorescence analyses showed that M2 macrophages are in close proximity to LAM cells and that LAM cells that are in close proximity to macrophages highly express macrophage-homing factor chemokine ligand CXCL12. In vitro, co-culture of human and mouse macrophages with TSC2-deficient cells resulted in the upregulation of M2-marker-expressing macrophages. Targeting M2 macrophages via treatment with the CD206 modulator RP-182 impaired the growth of TSC2-deficient tumours in vivo. LAM cells recruit and polarise macrophages towards an M2 phenotype. M2-like CD206high macrophages may represent a potential therapeutic target in LAM.
oligonucleotides
2026-03-06 | Clinicopathological and molecular features of gynecologic perivascular epithelioid cell tumors: a single-center study.
Perivascular epithelioid cell tumors (PEComas) are rare neoplasms characterized by the expression of both melanocytic and myoid markers. Gynecologic PEComa may show overlapping with smooth muscle tumors and other uterine tumors. The rarity and ill-defined risk stratification make the diagnosis challenging. The current study was aimed to more fully characterize gynecologic PEComas. We investigated the clinicopathological and immunohistochemical features of nine gynecological PEComas from a single center. The molecular landscape was assessed using a combined DNA-RNA hybrid capture-based comprehensive genomic profiling assay. Patients, aged from 27 to 79 years old, presented with the disease predominantly located in the uteri (5/9) and cervix (3/9). Histologically, six cases were classified as malignant and three as having uncertain malignant potential. All tumors were composed of epithelioid or spindled cells arranged around the vessels, with variable nuclear atypia and necrosis. Immunohistochemical analysis revealed universal HMB45 and TFE3 positivity, and variable myoid marker expression. HMB45 was confirmed as the most sensitive diagnostic marker. Mutually exclusive genetic alterations were identified in all six tested cases with TSC2 mutations/deletions in three tumors and TFE3 fusions in another three. And here we reported a novel YAP1-TFE3 gene fusion in gynecological site. It was found TSC2-altered tumors harbored more additional mutations, whereas TFE3-rearranged tumors occurred in younger patients. Most cases showed malignant potential or malignancy, necessitating risk stratification according to the current WHO algorithms. This study highlights the key histological and molecular features, and advocates for integrated DNA/RNA sequencing to guide prognosis and targeted therapies.
small molecules
2026-07-27 | Epithelioid angiomyolipoma in a horseshoe kidney: a pediatric tuberous sclerosis case report
Abstract Background Epithelioid angiomyolipoma (EAML) is a rare, potentially malignant PEComa-family tumor strongly associated with tuberous sclerosis complex (TSC). Its fat-poor composition and diffusion restriction on MRI render it indistinguishable from renal cell carcinoma (RCC) without tissue sampling. Case presentation A 7-year-old boy with TSC (TSC2 mutation c.2220 + 1 G > T) was found on routine surveillance MRI to have a new left moiety horseshoe kidney mass with interval growth and restricted diffusion on follow-up imaging four months later. Atypical features for classic AML prompted percutaneous image-guided biopsy. Histopathology confirmed EAML; immunohistochemistry showed HMB-45+, SMA+, S-100−, CD10−, and EMA−, with no histologic features of malignancy. The patient was managed with active surveillance; mTOR inhibitor therapy (everolimus) is planned if further growth occurs. Conclusions In a child with TSC, a fat-poor renal mass with interval growth and diffusion restriction should prompt biopsy rather than assumption of classic AML. The ADC map is a critical imaging discriminator, and the characteristic IHC profile is diagnostic. To our knowledge, this is the youngest published case of biopsy-proven EAML in a horseshoe kidney.
2026-07-20 | Clinicopathological characteristics of primary malignant cutaneous perivascular epithelioid cell tumor: case report and literature review.
Primary cutaneous malignant perivascular epithelioid cell tumors (PEComas) are extremely rare. Accurate diagnosis is critical for prognostic evaluation and guiding clinical management. Here, we report a case of a 19-year-old woman with a 1.1 cm exophytic red mass on her left upper limb. Histological examination revealed a dermal tumor composed of clear cells with prominent nucleoli. The tumor cells displayed cytologic atypia, nuclear pleomorphism, multinucleated giant cells, mitoses and invasive growth, with a multinodular distribution within the dermis and vascular invasion. Immunohistochemically, the tumor cells expressed cathepsin K, HMB45, and CD10. Based on morphological and immunohistochemical findings, we classified it as a primary malignant cutaneous PEComa. To date, only eight reported cases have been described as primary malignant cutaneous PEComas. The present case appears to be the youngest patient reported among all malignant PEComas.
2026-07-16 | The many faces of perivascular epithelioid cell tumors: case series illustrating the spectrum of a rare mesenchymal tumor.
Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal neoplasms composed of distinctive perivascular epithelioid cells that exhibit both melanocytic and smooth muscle differentiation on immunohistochemistry. These tumors can develop in various anatomic locations and display variable biological behavior ranging from benign to aggressive malignant disease. We present a case series of four patients diagnosed with PEComa at different anatomic sites. Histopathological analysis in all cases demonstrated characteristic epithelioid or spindle-shaped morphology, with some cases showing positive staining for melanocytic markers such as HMB-45 and Melan-A, as well as smooth muscle markers. Due to their rarity, definitive management protocols are not yet well established. Surgical resection remains the primary treatment for localized disease, while systemic therapies targeting the mammalian target of rapamycin pathway may be considered for unresectable tumors or metastatic disease. This case series underscores the heterogeneity of PEComas and highlights the importance of multidisciplinary management and long-term follow-up.
2026-07-14 | Sustained Disease Control of High-Risk Metastatic Renal Epithelioid Angiomyolipoma through Multimodal Treatment Including Repeated Thoracic Resection and Systemic Therapy: A Case Report.
Renal epithelioid angiomyolipoma (EAML) is a rare perivascular epithelioid cell tumor with malignant potential. Radiologic distinction from renal cell carcinoma (RCC) may be difficult in fat-poor cases, and standardized treatment strategies for metastatic disease have not been established. A woman in her 30 s presented with a palpable right abdominal mass and anorexia. Contrast-enhanced computed tomography showed an 18-cm heterogeneous right renal mass and a 25-mm liver lesion suspicious for metastasis, without pulmonary metastasis at diagnosis. The pretreatment clinical stage was cT2bN0M1, stage IV. Imaging findings strongly suggested clear cell RCC, and the lesion was managed as presumed metastatic clear cell RCC. The International Metastatic RCC Database Consortium risk category was poor risk. Nivolumab plus cabozantinib was initiated without pretreatment biopsy. At Month 3, the primary tumor showed partial response and the liver lesion remained stable; however, cabozantinib became difficult to continue because of adverse effects, and right nephrectomy was performed in a setting analogous to deferred cytoreductive nephrectomy. Histopathology established renal EAML with pT2b disease, necrosis, mitotic count ≥2, atypical mitoses, severe nuclear atypia, smooth muscle actin negativity, and Ki-67 ≥ 10%, fulfilling six of seven adverse prognostic factors and indicating high-risk disease. Everolimus induced partial response of a new lung metastasis. Subsequent liver and bilateral lung metastases were managed with systemic therapy and staged thoracoscopic resections. Later, isolated subcarinal mediastinal lymph node progression was treated by thoracoscopic resection. The patient remains recurrence-free for 8 months on everolimus. Metastatic renal EAML lacks a standardized treatment strategy. This case suggests that durable disease control may be achievable in selected high-risk patients through individualized multimodal treatment integrating systemic therapy with repeated local treatment for thoracic oligoprogressive lesions.
2026-07-02 | An Evaluation of Radiotherapy and Response in the Management of Perivascular Epithelioid Cell Tumors.
Perivascular epithelioid cell tumours (PEComas) are ultra-rare soft tissue tumours with heterogeneous treatment approaches. While surgery is the standard for localized disease, the role of radiotherapy (RT) remains unclear. This retrospective study aims to evaluate tumour volume response, as well as local outcomes and Overall Survival, in patients with PEComa treated with RT. The cohort included patients diagnosed with PEComa between 2005 and 2023 at a single sarcoma centre. Demographic, clinical, RT, and volumetric tumour data were collected. Response was assessed using RECIST v1.1. In total, 24 lesions in 12 patients were evaluable for analysis, with a median radiological follow-up of 10 months. Of these, 7 lesions were treated with perioperative RT and 17 with palliative RT. Systemic treatments during imaging follow-up were administered in 19/24 lesions. Among 17 lesions treated with palliative intent without surgery, four local failures occurred- all at EQD2 (α/β = 5) <40 Gy- and the estimated 1-year local control rate was 61.9%.Among these 17 lesions, mean tumour volume decreased from 301.5 cm³ (range: 0.9-2251) to 108.3 cm³ (range: 0.1-754) as best response after RT. Seven patients (58.3%) died from their disease, with a median overall survival of 46 months after diagnosis. PEComas appear to be radiosensitive, with substantial tumour volume reduction after RT and a dose-response signal favouring higher EQD2 dose. Nonetheless, overall survival was poor, reflecting the aggressive nature of this disease. This is the largest RT series in PEComa to date and suggests radiosensitivity in this disease.
antibodies
2026-06-23 | MiT fusions, TSC1-TSC2 divergence, and stem-like programs reveal distinct origins and vulnerabilities in PEComa.
Perivascular epithelioid cell neoplasms (PEComas) are ultra-rare mesenchymal tumors lacking a molecular classification to guide therapy. Here we perform comprehensive multi-omic profiling of an unselected PEComa cohort. We identify frequent MITF rearrangements involving actin gene partners (ACTA2, ACTG1 and ACTB). Anatomical stratification reveals cyclin-dependent kinase module mutations in gynecologic tumors, whereas soft tissue, gastrointestinal, and pelvic tumors lacked mTOR pathway alterations but are enriched for TFE3/MITF rearrangements. Transcriptomic analysis defines four subtypes with distinct lineage programs-melanocytic, mesenchymal, or adipogenic-as well as unique mutational patterns and clinical behaviors. Notably, an aggressive stem-like subtype enriched for TP53/RB1 mutations exhibits high proliferation, activation of embryonic and Hedgehog signaling, immune infiltration, and resistance to mTOR inhibitors, but potential responsiveness to immunotherapy. Single-nucleus RNA sequencing reveals intra-tumoral heterogeneity within this subtype, including divergent inflammatory states. Together, these findings establish a molecular classification framework and identify actionable vulnerabilities in PEComa.
2026-04-23 | Durable Disease Control With Nivolumab in Malignant Epithelioid Angiomyolipoma: A Case Report.
Epithelioid angiomyolipoma is a subtype of perivascular epithelioid cell tumors that may exhibit malignant behavior. While mammalian target of rapamycin inhibitors are commonly used for systemic treatment, the efficacy of immune checkpoint inhibitors remains unclear. A 58-year-old man was diagnosed with epithelioid angiomyolipoma after partial nephrectomy of a right renal mass. The tumor recurred locally, and multiple lung metastases developed despite surgical resection. Nivolumab was initiated after disease progression on everolimus, resulting in durable disease control for over 3 years. Immunohistochemistry revealed high PD-L1 expression and CD8+ T-cell infiltration within the primary tumor. Immune checkpoint inhibitors may be effective treatment options for malignant epithelioid angiomyolipoma with PD-L1 expression and CD8+ T-cell infiltration.
2026-02-18 | Metastatic PEComa successfully treated with pembrolizumab: A case report and review of the literature
Perivascular epithelioid cell tumours (PEComas) are rare mesenchymal neoplasms with the potential for malignant biological behavior. Patients with metastatic PEComas may benefit from effective biomarker-driven treatments. Genetic alterations associated with mismatch repair deficiency (MMRd) and microsatellite instability-high (MSI-high) are rarely identified in PEComas but have emerged as successful predictors of response to pembrolizumab in a variety of solid tumours. Here, we report a case of a 29-year-old female who presented with an enlarging lesion in her left femoral neck, which was resected and diagnosed as malignant PEComa. Two metastatic pulmonary nodules then appeared and were resected. After another large metastatic lesion appeared in her left lung, the patient elected to start systemic therapy. Next-generation sequencing performed on one of the metastatic tumours did not identify actionable genetic variants, however several microsatellite sites were noted to be unstable, manifesting as small duplications and deletions within mononucleotide repeats. Subsequent immunohistochemical evaluation for MMR expression was performed, showing subtotal expression loss of MLH1 and PMS2, and MSI testing revealed the tumour to be MSI-high. These findings suggested the use of the anti-PD-1 agent pembrolizumab in a patient who would otherwise not have been able to access this medication in Canada at the time of her diagnosis. The patient was referred to medical genetics where she was found to not have Lynch syndrome. Sixteen months after initiating pembrolizumab, the patient continues to show reduction in the size of her metastatic lung lesion. This case is the first to our knowledge to describe the successful use of immunotherapy for metastatic MSI-high PEComa arising in a patient without Lynch syndrome.
2025-10-31 | GPNMB immunohistochemistry is a useful ancillary tool for the diagnosis of pulmonary lymphangioleiomyomatosis.
Lymphangioleiomyomatosis (LAM) is a PEComa that primarily affects premenopausal women and is associated with the cystic destruction of the lung. Although smooth muscle and melanocytic markers can be helpful, histologic diagnosis of LAM remains challenging, especially in small biopsies. Glycoprotein non-metastatic melanoma protein B (GPNMB) expression has recently been identified as a highly specific and sensitive immunohistochemical marker for PEComas. Nevertheless, only a few LAM cases have been studied so far. The aim of this study was to assess the utility of GPNMB immunohistochemistry as an ancillary marker in a larger cohort of LAM samples. Immunohistochemistry for GPNMB was performed on cases of LAM (N = 15), potential differential diagnostic mimics (N = 30) and normal lung tissue (N = 2). Immunohistochemistry was assessed using the H-score method; an H-score above 100 was considered 'high'. All LAM cases showed strong cytoplasmic expression, with cell membrane accentuation in some areas. In contrast, differential diagnostic mimics were either negative or only weakly positive. Normal lung parenchyma was negative for GPNMB; however, weak-to-moderate expression was seen in alveolar macrophages in both the normal and diseased lung tissues in most cases. Considering only 'high' positivity, GPNMB immunohistochemistry showed 100% sensitivity and specificity for the diagnosis of LAM in our cohort. Based on its 100% sensitivity and specificity, GPNMB appears to be a highly valuable immunohistochemical marker for the diagnosis of pulmonary LAM. Besides its diagnostic value, the membrane positivity of GPNMB on LAM cells may predict a response to glembatumumab vedotin, an antibody-drug conjugate targeting GPNMB.
2025-10-22 | Multicenter phase II trial of ipilimumab and nivolumab in metastatic or unresectable perivascular epithelioid cell tumor (PEComa): a substudy of Dual Anti-CTLA-4 and Anti-PD-1 blockade in Rare Tumors (DART) SWOG S1609 (Cohort 38).
Malignant perivascular epithelioid cell tumors (PEComas) are ultra-rare, aggressive mesenchymal neoplasms associated with poor outcomes. Standard-of-care systemic therapy includes mammalian target of rapamycin (mTOR) inhibition and chemotherapy. Immune checkpoint inhibition has not been previously studied in patients with advanced PEComas in a prospective clinical trial. This is an open-label phase 2 trial of ipilimumab (1 mg/kg intravenously every 6 weeks) plus nivolumab (240 mg intravenously every 2 weeks) in rare tumors; here we report the cohort of patients with advanced malignant PEComa recruited from >1,000 sites across the USA. Primary end point was objective response rate, with progression-free survival, overall survival, and toxicity as secondary end points. 17 patients were enrolled (N=16 evaluable). Median age was 59.5 years (range, 22-77 years) and the majority were female (81%). Best responses included partial response (18.8%), stable disease for <6 months (25.0%), and progressive disease (56.3%). Median OS was 7.5 months (95% CI 3.4 to 34.6) and median PFS was 1.9 months (95% CI 1.8 to 11.8). PFS in responding patients was 11.8, 18.9, and 34.6 months. Available genomic sequencing showed TSC, ATRX, and TP53 mutations; no TFE3 fusions were identified (N=7). Nearly all patients experienced a treatment-related adverse event (AE) of any grade, while 37.5% experienced a grade 3-4 AE. Most common AEs were fatigue (43.8%), pruritus (37.5%), rash (25.0%), and aspartate aminotransferase increase (25.0%). There were no grade 5 AEs. The combination of ipilimumab and nivolumab demonstrated responses in 18.8% of patients with advanced malignant PEComas. Dual immunotherapy may be an alternative treatment option for certain patients, including those who are unable to tolerate or do not desire prolonged treatment with chemotherapy or mTOR inhibition or have failed to respond to other therapies. Ipilimumab and nivolumab warrants further investigation in this and other rare soft tissue sarcomas.
proteins
2025-07-11 | Modulation of infiltrating CD206+ macrophages restricts progression of pulmonary lymphangioleiomyomatosis.
Lymphangioleiomyomatosis (LAM) is a low-grade neoplasm caused by the proliferation of tuberous sclerosis complex (TSC) 1- or TSC2-deficient LAM cells, resulting in progressive cystic lung disease. The currently approved treatment for LAM delays disease progression but the disease recurs if treatment is discontinued. Therefore, new therapeutic targets and/or strategies are necessary for a cure. Immunosuppressive M2-like macrophages are involved in the progression of various cancers, but their role in the pathophysiology of LAM and as a putative therapeutic target is unknown. To identify the different immune cell populations involved in LAM, we generated a single-cell transcriptomic map of pulmonary LAM. Interactions between macrophages and LAM cells were studied using the Visium spatial transcriptomic platform and immunofluorescence staining on human pulmonary LAM specimens. Direct co-culture models were used to characterise the influence of TSC2-deficient cells on macrophage differentiation. The efficacy of targeting M2-like macrophages was assessed in preclinical mouse models of TSC2-deficient subcutaneous tumours treated with RP-182, a synthetic peptide which reprogrammes macrophages towards an antitumour M1-like phenotype. Single-cell RNA-sequencing analysis revealed that the majority of macrophages in pulmonary LAM display immunosuppressive markers, including CD206/MRC1 and CD163. Spatial transcriptomic and immunofluorescence analyses showed that M2 macrophages are in close proximity to LAM cells and that LAM cells that are in close proximity to macrophages highly express macrophage-homing factor chemokine ligand CXCL12. In vitro, co-culture of human and mouse macrophages with TSC2-deficient cells resulted in the upregulation of M2-marker-expressing macrophages. Targeting M2 macrophages via treatment with the CD206 modulator RP-182 impaired the growth of TSC2-deficient tumours in vivo. LAM cells recruit and polarise macrophages towards an M2 phenotype. M2-like CD206high macrophages may represent a potential therapeutic target in LAM.
oligonucleotides
2026-03-06 | Clinicopathological and molecular features of gynecologic perivascular epithelioid cell tumors: a single-center study.
Perivascular epithelioid cell tumors (PEComas) are rare neoplasms characterized by the expression of both melanocytic and myoid markers. Gynecologic PEComa may show overlapping with smooth muscle tumors and other uterine tumors. The rarity and ill-defined risk stratification make the diagnosis challenging. The current study was aimed to more fully characterize gynecologic PEComas. We investigated the clinicopathological and immunohistochemical features of nine gynecological PEComas from a single center. The molecular landscape was assessed using a combined DNA-RNA hybrid capture-based comprehensive genomic profiling assay. Patients, aged from 27 to 79 years old, presented with the disease predominantly located in the uteri (5/9) and cervix (3/9). Histologically, six cases were classified as malignant and three as having uncertain malignant potential. All tumors were composed of epithelioid or spindled cells arranged around the vessels, with variable nuclear atypia and necrosis. Immunohistochemical analysis revealed universal HMB45 and TFE3 positivity, and variable myoid marker expression. HMB45 was confirmed as the most sensitive diagnostic marker. Mutually exclusive genetic alterations were identified in all six tested cases with TSC2 mutations/deletions in three tumors and TFE3 fusions in another three. And here we reported a novel YAP1-TFE3 gene fusion in gynecological site. It was found TSC2-altered tumors harbored more additional mutations, whereas TFE3-rearranged tumors occurred in younger patients. Most cases showed malignant potential or malignancy, necessitating risk stratification according to the current WHO algorithms. This study highlights the key histological and molecular features, and advocates for integrated DNA/RNA sequencing to guide prognosis and targeted therapies.
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Drug Discovery Landscape
2 orphan drug designations for Perivascular epithelioid cell neoplasm, including 1 approved therapy.
2 orphan drug designations for Perivascular epithelioid cell neoplasm, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Sirolimus | small molecules | EMA | 2021-07-19 | — | PharmaLex GmbH |
sirolimus protein-bound particles for injectable suspension (albumin-bound) [Fyarro] | small molecules | FDA | 2017-12-21 | 2021-11-22 | Aadi Bioscience, Inc. |
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