Summary

Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal neoplasms that can arise in various anatomical locations, including the female genital tract, with the uterus being the most affected site. Malignant uterine PEComas are extremely uncommon and pose significant diagnostic challenges, particularly when they lack conventional immunohistochemical (IHC) marker expression. This report presents a rare case of a high-grade, TFE3-rearranged malignant PEComa of the uterus that defied routine diagnostic approaches.

This case underscores the diagnostic complexity of TFE3-rearranged PEComas, which can lack smooth muscle marker expression and mimic other high-grade uterine malignancies. Recognition of the nested vascular arrangement and utilization of melanocytic and TFE3 markers are key for diagnosis.

Introduction

The abbreviation PEComa stands for perivascular epithelioid cell tumours. PEComas are rare mesenchymal tumors that can occur in various anatomical sites, with the kidney, lung, and gynecologic tract being the most common locations. Within the gynecologic tract, PEComas primarily affect the uterus, although they have also been reported in the cervix, vagina, broad ligament, ovary, and, rarely, the vulva. The typical age range for patients with gynecologic PEComas is the fifth to sixth decade, although those affecting the vagina, broad ligament, and vulva tend to occur at an earlier age (1). Histomorphologically, these tumors display an epithelioid clear cell morphology arranged around blood vessels and on IHC express both melanocytic and smooth muscle markers. Most PEComas are benign and are managed by surgery. Malignant PEComas of the uterus are a rare occurrence and it is important to distinguish them from other types of uterine malignancies as the treatment approach for each type of cancer can vary significantly. We report a rare case of a malignant PEComa that posed a significant diagnostic challenge on biopsy and was found to be negative for a broad range of standard IHC including smooth muscle markers.

Case Presentation

A 47-year-old female presented with bleeding per vaginum in the gynecology outpatient department. Clinical examination revealed a bulky uterus with the presence of a polypoidal mass. Clinical findings on per vaginum and per speculum revealed a fungating growth arising from the endocervix but the cervical lip was free. Ultrasonography revealed a hypoechoic polypoidal mass measuring 72 mm × 48 mm × 35 mm arising from the corpus and protruding into the endometrial cavity. Based on clinic-radiological evaluation, a clinical diagnosis of malignant/sarcomatous polyp was made and biopsy was done. The biopsy revealed a high-grade tumour present in solid sheets. The tumour cells were epithelioid to spindle and at places had abundant eosinophilic to clear cytoplasm with the presence of high-grade nuclear atypia, prominent nucleoli, bizarre tumour giant cells along with the presence of rich vascularity. Morphological differential diagnosis included choriocarcinoma, undifferentiated sarcoma, epithelioid leiomyosarcoma, undifferentiated carcinomas and malignant PEComa. We conducted a comprehensive basic IHC panel with relevant controls, including markers for cytokeratins, vimentin, smooth muscle actin, S100 protein, and desmin.

To our surprise, the tumor was negative for all the markers. However, upon closer examination of the histopathology, we observed a nested arrangement of tumor cells around delicate vessels, suggesting a diagnosis of malignant PEComa. Our literature review revealed that TFE3-rearranged PEComas could show negative results for smooth muscle markers. Therefore, we performed immunohistochemistry with HMB-45, which showed strong and diffuse positivity. Based on these results, we proposed the possibility of a malignant PEComa on biopsy. Subsequently, a simple hysterectomy along with bilateral salpingo-oophorectomy was performed. The patient was lost to follow-up after the surgery.

Gross Findings
Uterus with cervix measured 10×8×5 cm. There was presence of a polypoidal mass measuring 7×5×4 cm arising from the near to the fundus and protruding into the cervical canal. On cut section the tumour was friable with large areas of necrosis with the presence of myometrial invasion (Figure 1A,B).

Figure 1: A) A polypoidal mass measuring 7×5×4 cm arising from the near to the fundus of the uterus and protruding into the cervical canal. B) Cut section of the tumor is friable with large areas of necrosis with the presence of myometrial invasion. C) High-grade tumor arranged in nests and sheets around blood vessels (H&E, 200x). D, E) Tumor cells are polygonal with the presence of clear to eosinophilic cytoplasm (H&E, 400x). F) Melan A - Positive (IHC, 100x). G) TFE 3 - shows diffuse nuclear positivity (IHC, 100x).

Histological Findings
Sections from the polyp showed a high-grade tumor arranged in nests and sheets around blood vessels (Figure 1C). The tumor cells were polygonal with the presence of clear to eosinophilic cytoplasm (Figure 1D,E). There were large areas of necrosis with the presence of a mitotic rate of 53/50 HPF (Figure 2A-D). Numerous tumor giant cells were present; the nuclei were hyperchromatic to vesicular with the presence of large macro nucleoli (Figure 2E). CK, Vimentin, SMA, S100 and Desmin were negative on IHC. HMB 45 was positive (Figure 2F). Melan A (Figure 1F) also showed positivity but SOX 10 was negative. TFE3 showed diffuse nuclear positivity in line with TFE3 rearranged PEComas (Figure 1G).

Figure 2: A-C) Tumor with large areas of necrosis with mitosis (H&E, 100x), D) Tumor arranged in nests with polygonal cells with clear to eosinophilic cytoplasm (H&E, 400x), F) HMB 45 - positive (IHC, 100x).

Discussion

The clinical presentation of gynecologic PEComas is often nonspecific and may include abnormal uterine bleeding, abdominopelvic pain, the misdiagnosis of `fibroids,` or the identification of a mass on imaging. In the present case the patient had heavy menstrual bleeding (2,3). In rare cases, patients may present with uterine rupture and/or hemoperitoneum, particularly during pregnancy (4). A history of tuberous sclerosis is present in about 10% of patients (2). An accurate preoperative diagnosis is difficult as the findings on clinicoradiological grounds are non-specific. Hence a preoperative biopsy becomes important. Compared to the benign PEComas it is highly challenging to identify the malignant subtype in a biopsy. IHC too can be confusing if one is not aware of the TFE3 rearranged subtype. PEComas may present as a myometrial-based tumor, although in some cases, they may appear grossly as a polypoid or pedunculated mass that protrudes into the endometrial cavity. In our case, a friable polypoidal mass was observed protruding into the cavity (5).

PEComa is classified as benign, of uncertain malignancy potential, or malignant based on six key factors. These are tumor size (greater than 5 cm), infiltration, high-grade nuclei, high cellularity, high mitotic activity (more than 2 mitotic figures per 50 high-power fields), tumor necrosis, and vascular invasion. According to these criteria in general, a PEComa is classified as `benign` if it does not have any of these features, `of uncertain malignant potential` if it only shows nuclear pleomorphism or multinucleated giant cells, or if it is larger than 5 cm, and `malignant` if it exhibits two or more concerning features. However, for the female genital tract a PEComa is considered malignant if any 3 of the above atypical features are present. If less than 3 atypical features are present it is considered of uncertain malignant potential (6).

Schoolmeester et al. studied 6 cases of TFE3 rearranged PEComas and found that 5 out of 6 cases had a pure clear cell morphology and all cases expressed diffuse HMB 45 and TFE3 and had weak immunoreactivity for smooth muscle markers (3). In our case, the tumour showed a predominant clear cell epithelioid morphology and was negative for pan cytokeratin, vimentin, SMA, S100 and desmin. HMB45 and TFE3 were diffusely positive. Melan A showed focal positivity. Qin et al. reported eight cases of malignant PEComa, three of which exhibited features of malignancy, including bizarre nuclei, necrosis, and increased mitotic activity. All cases showed positive immunoreactivity for TFE3 (7). Table I summarizes the clinical, morphological and immunohistochemical characteristics of various malignant TFE3-rearranged PEComas reported in the literature. The majority of cases lacked expression of smooth muscle markers but showed positivity for melanocytic markers, similar to our case.

Table I: Clinicopathological and Immunohistochemical Features of Reported Malignant TFE3-Rearranged PEComas

One of the challenging aspects of our case was the pre-surgical biopsy, which revealed cells with a high-grade morphology and tested negative for standard IHC markers. This emphasizes the significance of considering PEComa in the list of differential diagnoses and being knowledgeable about TFE3 rearranged PEComas, which can exhibit negative results for smooth muscle markers. In conventional PEComas, both sporadic and syndromic types, TSC2 mutation and loss of heterozygosity (LOH) are common, whereas TSC1 mutation and LOH are rare. LOH at TSC1/2 leads to upregulation of mTOR signaling, which is the basis of mTORC1 targeted therapy often used in PEComa treatment. However, TFE3 rearranged tumors were found to lack TSC2 inactivating mutations (8). Perivascular epithelioid cell tumors (PEComas) harboring TFE3 gene rearrangements lack the TSC2 alterations characteristic of conventional PEComas. These findings have critical implications for treatment, particularly for the effectiveness of targeted mTOR inhibitors, which may be minimized in TFE3 rearranged PEComas. Therefore, identifying the rearranged variant of PEComa may help make important decisions for clinical management.

PEComas of the uterus are relatively rare, and accurate diagnosis can be challenging. The primary treatment for these tumors typically involves surgery, which may involve complete or partial removal of the uterus. In some cases, radiation therapy or chemotherapy may also be used alongside surgery to improve outcomes. If the PEComa is malignant, adjuvant therapy may be recommended to reduce the risk of recurrence and improve the patient`s overall prognosis. The specific type of adjuvant therapy will depend on various factors such as the tumor`s features and the patient`s overall health. Given the uncommon nature of these tumors and their challenging diagnosis, close collaboration between the patient, healthcare provider, and pathologist is vital to ensure an accurate diagnosis and development of the best possible treatment plan.

mTOR inhibitors such as sirolimus, everolimus, and temsirolimus, have shown inconsistent responses in treating patients with malignant PEComas. Specifically, for malignant PEComas with TFE rearrangement, mTOR inhibitor therapy has demonstrated limited effectiveness, which highlights the need for alternative treatments. One approach is to target an alternative VEGF/VEGFR signaling pathway. One study investigated the use of aptanib in combination with mTOR inhibitor therapy, which may offer improved efficacy in treating malignant PEComas by targeting both the mTOR and VEGF pathways (9).

Conflict of Interest
Authors declare no conflict of interest

Authorship Contributions
Concept: ACP, Design: ACP, SS (Sonal Sharma), Data collection or processing: ACP, GG, S (Swati), Analysis or Interpretation: ACP, S, SS, Literature search: ACP, GG, Writing: ACP, GG, Approval: All authors.

Reference

1) Bennett JA, Oliva E. Perivascular epithelioid cell tumors (PEComa) of the gynecologic tract. Genes Chromosomes Cancer. 2021;60:168-79. PMID: 33099813 doi: 10.1002/gcc.22908

2) Bennett JA, Braga AC, Pinto A, Van de Vijver K, Cornejo K, Pesci A, Zhang L, Morales-Oyarvide V, Kiyokawa T, Zannoni GF, Carlson J, Slavik T, Tornos C, Antonescu CR, Oliva E. Uterine PEComas: A Morphologic, Immunohistochemical, and Molecular Analysis of 32 Tumors. Am J Surg Pathol. 2018;42:1370-83. PMID: 30001237 DOI: 10.1097/PAS.0000000000001119

3) Schoolmeester JK, Howitt BE, Hirsch MS, Dal Cin P, Quade BJ, Nucci MR. Perivascular epithelioid cell neoplasm (PEComa) of the gynecologic tract: clinicopathologic and immunohistochemical characterization of 16 cases. Am J Surg Pathol. 2014;38:176-88. PMID: 24418852 DOI: 10.1097/PAS.0000000000000133

4) Vang R, Kempson RL. Perivascular epithelioid cell tumor (`PEComa`) of the uterus: a subset of HMB-45-positive epithelioid mesenchymal neoplasms with an uncertain relationship to pure smooth muscle tumors. Am J Surg Pathol. 2002;26:1-13. PMID: 11756764 DOI: 10.1097/00000478-200201000-00001

5) Bosincu L, Rocca PC, Martignoni G, Nogales FF, Longa L, Maccioni A, Massarelli G. Perivascular epithelioid cell (PEC) tumors of the uterus: a clinicopathologic study of two cases with aggressive features. Mod Pathol. 2005;18:1336-42. PMID: 15920549 DOI: 10.1038/modpathol.3800433

6) Bennett JA, Schoolmeester JK. Tumors of uterine corpus. In: Kim KR, Lax SF, Lazar AJ, editors. Female genital tumours. Lyon (France): International Agency for Research on Cancer; 2020. pp. 296-7. (WHO classification of tumours series, 5th ed.; vol. 4). https://publications.iarc.fr/592.

7) Qin Y, Yang L, Zhang HJ, Wei J, Liu YX, Zhang WH, Wen Z, Wang Z, Fan LN. TFE3-rearranged perivascular epithelioid cell tumors: a clinicopathological analysis of eight cases. Zhonghua Bing Li Xue Za Zhi. 2024;53:822-9. PMID: 39103264.DOI:10.3760/cma.j.cn112151-20240524-00335.

8) Malinowska I, Kwiatkowski DJ, Weiss S, Martignoni G, Netto G, Argani P. Perivascular epithelioid cell tumors (PEComas) harboring TFE3 gene rearrangements lack the TSC2 alterations characteristic of conventional PEComas: further evidence for a biological distinction. Am J Surg Pathol. 2012;36:783-4. PMID: 22456611 DOI: 10.1097/PAS.0b013e31824a8a37

9) Xu J, Gong XL, Wu H, Zhao L. Case Report: Gastrointestinal PEComa With TFE3 Rearrangement Treated with Anti-VEGFR TKI Apatinib. Front Oncol. 2020;10:582087. PMID: 33330059 DOI: 10.3389/fonc.2020.582087

10) Zhong Y, Yang H. mTOR inhibitor in the treatment of TFEpositive advanced malignant PEComa of the uterus: a case report and literature review. Ginekologia Polska. 2025;96:206-13. PMID: 39469825 DOI:10.5603/gpl.99247.

11) Liu F, Zhang R, Wang ZY, Xia Q, Shen Q, Shi S, Tu P, Shi Q, Zhou X, Rao Q. Malignant perivascular epithelioid cell tumor (PEComa) of cervix with TFE3 gene rearrangement: a case report. Int J Clin Exp Pathol. 2014;7:6409-14. PMID: 25337301.

12) Argani P, Wobker SE, Gross JM, Matoso A, Fletcher CDM, Antonescu CR. PEComa-like Neoplasms Characterized by ASPSCR1- TFE3 Fusion: Another Face of TFE3-related Mesenchymal Neoplasia. Am J Surg Pathol. 2022;46:1153-9. PMID: 35848761 doi: 10.1097/PAS.0000000000001894. Epub 2022 Apr 5..

13) Bouzid N, Bugada M, Pissaloux D, Burillon C, Tirode F, Barbier J, de la Fouchardière A, Kielwasser G. An orbital perivascular epithelioid cell tumor (PEComa) in a 9-year-old boy: Case report and review of the literature. J Fr Ophtalmol. 2024;47:104215. PMID: 38843609 doi: 10.1016/j.jfo.2024.104215. Epub 2024 Jun 5.