Perivascular Epitheloid Cell Tumor Research Articles

Abstract ED01-01: Successes and failures of targeted drug development in adult and pediatric sarcomas

Abstract Development of molecularly targeted anticancer agents has seen major successes in the last 2 decades, also in Soft Tissue Sarcomas. But at the same time, many of those agents never made it beyond the stage of initial excitement. Moreover, the rare incidence of soft tissue sarcomas, and the even more rare incidence of its enormously high number of subtypes, frequently with subtype specific molecular aberrations in the malignancy, has led to different levels of evidence for success, if any. The development of Imatinib in c-KIT expressing GIST, does not only exemplify hallmarks of success, but also identifies some features of development failure. In Pediatric GIST for instance, Imatinib is basically ineffective. This was found to be due to the absence of KIT mutations in pediatric GIST, and the likely presence of different tumor growth drivers that are not sensitive to Imatinib. Taken together these features indicate that similar histologies do not necessarily express similar genetic changes in adult vs pediatric sarcomas, and indicate that it is essential to identify changes that represent true driving factors of tumor growth. And likely crucial to genetically analyse the tumor specimens of individual patients prior to treatment- and/or clinical trial selection. Apart from GIST, most of the other interesting suggestions of clinically successful specific targeting are yet based on fairly limited data. And thus, the level of evidence is much less than for Imatinib in adult GIST. These other subtypes and treatments include for instance Imatinib in PDGFR-beta mutant Dermatofibrosarcoma protruberans (DFSP), PLX3397 in colony-stimulating factor 1 (CSF1) expressing (1;2) translocated Tenosynovial Giant Cell Tumors (TGCT), Larotrectinib in TRK mutated Infantile Fibrosarcoma, Sirolimus in TSC1 or TSC2 mutated Perivascular Epitheloid Cell tumors (PEComa) and Crizotinb for ALK mutated Inflammatory Myofibroblastic Tumor (IMT). While the anti-VEGF monoclonal antibody Bevazicumab as a single agent hardly yielded effect in soft tissue sarcoma subsets such as angiosarcomas and hemangioendothelial sarcomas, the effect of multitargeted agents that a.o included VEGF as a target, has been proven effective in diseases such as non-subtype specific soft tissue Sarcomas (Pazopanib), GIST (Sunitinib, Regorafinib) Desmoid tumors (Sorafenib), and Alveolar Soft Part Sarcoma (Cediranib). Yet, given the inability to differentiate one target from the other, it is difficult to ascribe the successful trials to any of them. While for some drugs and targets (such as MDM2 and CDK4/6) the jury is still out, there is a large number of targets and targeted agents that failed the threshold. Among these are the mTOR inhibitors for other soft tissue sarcoma subtypes than PEComa, pPARgamma inhibitors for liposarcomas, EGFR inhibitors in synovial sarcomas, MET inhibitors in soft tissue sarcomas with specific amplifications and translocations, and again most recently the PDGFR-alpha monoclonal antibody Olaratumab. The failure to achieve clinical effect by inhibition of PDGFR will be discussed in somewhat more detail. In conclusion, to increase success rates and reduce failures, it seems important to closely analyze which preclinical biological factors can better predict clinical success and/or failure. Citation Format: Jaap Verweij. Successes and failures of targeted drug development in adult and pediatric sarcomas [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr ED01-01. doi:10.1158/1535-7163.TARG-19-ED01-01

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.

Perivascular Epithelioid Cell Tumor: A Rare Liver Primary of Mesenchymal Origin

Perivascular Epithelioid Cell Tumors (PEComas) are a family of rare neoplasms defined as mesenchymal tumors composed of histologically and immunohistochemically distinctive perivascular epithelioid cells. There are only few reports in the literature of PEComas of liver origin. We presented a female patient with a perivascular epitheloid cell tumor of the liver treated with laparoscopic liver resection that remains disease free after 1 year. Surgical treatment should be considered in all patients with resectable PEComas. Follow-up is indicated based on the potential for malignancy and metastasis of these lesions.

Differential Diagnosis of Focal Non-Cystic Pancreatic Lesions With and Without Proximal Dilation of Pancreatic Duct Noted on CT Scan

OBJECTIVES:Pancreatic duct (PD) dilation proximal to a solid focal pancreatic lesion on computed tomography (CT) scan is considered highly suggestive of pancreatic adenocarcinoma. There is, however, no published data on the differential diagnosis of focal non-cystic pancreatic lesions with and without PD dilation. We assessed the diagnostic utility of this radiologic finding.METHODS:This is a retrospective analysis of a prospectively maintained database of university-based clinical practice. A total of 445 non-jaundiced patients who underwent endoscopic ultrasound (EUS) (2002–2010) for evaluation of solid pancreatic lesions noted on CT scan were included. Final diagnosis was based on surgical pathology or definitive cytology with supporting clinical follow-up of ≥12 months. Main outcome measurements included (1) differential diagnoses and (2) performance characteristics of EUS-fine needle aspiration (FNA) for diagnosing neoplasm in patients with non-cystic pancreatic lesions with and without PD dilation.RESULTS:A neoplasm was finally diagnosed in 152 of 187 patients with and 87 of 258 patients without PD dilation on CT scan. Chronic pancreatitis (diffuse and focal) was the predominant non-malignant diagnosis in patients with PD dilation. In patients without PD dilation, malignant lesions included neuroendocrine tumor, adenocarcinoma, metastasis, PEComa (perivascular epitheloid cell tumor), and lymphoma; and the non-neoplastic diagnosis included chronic pancreatitis, intrapancreatic lymph nodes, and infected pancreatic fluid collection. EUS-FNA had 97.6% accuracy for diagnosing a neoplasm in these patients.CONCLUSIONS:Dilation PD proximal to a focal solid pancreatic lesion increases the likelihood of malignancy but the performance characteristics of this radiologic finding are probably inadequate to guide clinical management. Neoplasms without dilated PD often require immunostaining for a definitive diagnosis.

Primary Perivascular Epitheloid Cell Tumour (PEComa) of the Liver: Case Report and Review of the Literature

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

Malignant Perivascular epithelioid cell tumour (Pecoma) of the gastrointestinal tract

Perivascular epithelioid cell tumours are a family of mesenchymal neoplasm that include angiomyolipoma, lymphangiomyomatosis, clear cell sugar tumour of the lung and a group of morphologically and immunophenotypically similar lesions that show immunoreac-tivity for both melanocytic (HMB-45 and melan-A) and smooth muscle (actin and desmin) markers. PEComa has been identified at multiple anatomical sites such as the liver, uterus, rectum, heart, breast, bladder, abdominal wall and pancreas. Perivascular epithelioid cell tumour of the gastrointestinal tract is very rare and there have been only a few reported cases. Most PEComas follow a benign course and relatively few malignant PEComas have been reported. We report the case of a 53-year-old woman who presented with in-tra-abdominal mass and bowel obstruction. The tumour displayed the typical morphological and immunohistochemical features of a malignant perivascular epitheloid cell tumour. Presentation is not specific and clinical diagnosis is not generally possible. Correct diagnosis depends on histology and immunohis-tochemistry. We conclude that malignant PEComa should be considered in the differential diagnosis of all pleomorphic sarcomas.

KBA62 and PNL2

Identification of metastatic melanoma can be difficult because of its considerable morphologic variation and mimicry of a wide variety of other tumors. The more melanoma-specific melanoma markers, MelanA/MART-1, HMB45, and tyrosinase, used in addition to S100 protein, all have limitations in sensitivity and specificity. In this study, we evaluated 2 new melanoma markers, monoclonal antibodies KBA62 and PNL2 to yet unidentified antigens, using a large panel of metastatic melanomas (n=214), desmoplastic melanomas (n=34), gastrointestinal mucosal melanomas (n=54), benign nevi (n=27), clear cell sarcomas (n=16), and nonmelanocytic tumors (n=1218). Immunoreactivity for KBA62 and PNL2 was found in all pigmented nevi and in 86% and 90% of metastatic melanomas, respectively. Mucosal melanomas showed a similar rate of PNL2 immunoreactivity but somewhat less frequent KBA62 positivity (72%). In addition, KBA62 was found to be a sensitive diagnostic marker for desmoplastic melanoma (28 of 34; 82%), whereas PNL2 was only rarely positive (2 of 34; 6%). KBA62-positive normal tissues included pericytes, vascular and parenchymal smooth muscles, and basal cells of complex epithelia, including myoepithelia, whereas PNL2 labeled only melanocytes and neutrophils. Among nonmelanocytic tumors, those that were KBA62 positive were nodular fasciitis, leiomyoma and leiomyosarcoma, gastrointestinal stromal tumors, benign and malignant nerve sheath tumors, synovial sarcoma, and subsets of various carcinomas, especially those with squamous cell/stratified epithelial differentiation. PNL2 positivity in nonmelanocytic tumors was more restricted but occurred consistently in angiomyolipoma and other perivascular epitheloid cell tumor and in chronic myeloid leukemia tissue infiltrates. KBA62 may assist in the identification of desmoplastic melanomas, but its widespread occurrence in nonmelanomas limits utility. PNL2 is highly specific for melanomas but lacks reactivity with desmoplastic melanomas. It is also an excellent supplementary marker for perivascular epitheloid cell tumor at various sites.

Uterine perivascular epitheloid cell tumor (PEComa) with CD117 and PNL2 positivity and entrapped endometriotic glands, mimicking sex-cordlike differentiation

Uterine perivascular epitheloid cell tumor (PEComa) with CD117 and PNL2 positivity and entrapped endometriotic glands, mimicking sex-cordlike differentiation

Perivascular epitheloid cell tumour (PEComa) of the retroperitoneum – a rare tumor with uncertain malignant behaviour: a case report

IntroductionPerivascular epitheloid cell tumours are rare mesenchymal neoplasms characterized by a proliferation of perivascular cells with an epitheloid phenotype and expression of myomelanocytic markers.Case presentationHere we present the case of a cystic perivascular epitheloid cell tumour of the retroperitoneum associated with multifocal lung lesions. A 27-year-old woman underwent laparotomy to remove a 10 × 6 × 4 cm sized retroperitoneal mass. The resected specimen was subjected to frozen and permanent histological sections with conventional and immunohistochemical stains, including antibodies against HMB45. The tumour displayed the typical morphological and immunohistochemical features of a perivascular epitheloid cell tumour. Focal necrosis and a proliferative index of 10% suggested a malignant potential. Moreover, postoperative computed tomography scans demonstrated multiple lung lesions, which were radiologically interpreted as being most likely compatible with lymphangioleiomyomatosis.ConclusionSince lymphangioleiomyomatosis, an otherwise benign condition, belongs to the family of perivascular epitheloid cell tumours, it cannot be excluded that the lung lesions in this case in fact represent metastases from the retroperitoneal perivascular epitheloid cell tumour rather than independent neoplasms. More experience with this new and unusual tumour entity is clearly needed in order to define reliable criteria for benign or malignant behaviour.

Renal capsular PEComa––a rare cause of surgically correctable renal hypertension

We report a 40-year-old lady who presented with severe headaches, persistent microscopic haematuria and hypertension requiring anti-hypertensive medication. Investigations for secondary hypertension were all normal except for a CT scan. This indicated a complex cystic lesion, measuring 2.4 x 5 x 10 cms , arising from the right kidney. She underwent an open right partial nephrectomy. The patient made an un-eventful postoperative recovery and her blood pressure returned to normal. The mass had a smooth outer surface and the cut surface showed firm whitish tissue with a few small cysts. Microscopy showed a bland spindle cell lesion staining positively for SMA, desmin, caldesmon, focally for HMB45 amd very focally for S100. The mass was reported as a Perivascular Epitheloid Cell (PEC) lesion (PEComa) arising from the renal capsule. Perivascular Epitheloid Cell tumor (PEComa), a recently defined tumor, is extremely rare. The lesion presents a distinct muscular immunophenotype (actin+, desmin+), with co-expression of the melanogenesis marker (HMB45). This combined immunophenotype is a characteristic feature of the Perivascular Epitheloid Cell (PEC) lesions. PEComa's are usually benign, but cases have been reported in the literature which has an unfavourable outcome with metastatic dissemination. We report this case because of its rarity and also Renal Capsular PEComa should be considered as a rare cause of renal hypertension, which can be surgically cured.