Uterine PEComas: A Morphologic, Immunohistochemical, and Molecular Analysis of 32 Tumors

Abstract

Uterine perivascular epithelioid cell tumors (PEComas) are rare neoplasms that may show overlapping morphology and immunohistochemistry with uterine smooth muscle tumors. In this study, we evaluated the morphologic, immunohistochemical, and molecular features of 32 PEComas, including 11 with aggressive behavior. Two distinct morphologies were observed: classic (n=30) and those with a lymphangioleiomyomatosis appearance (n=2). In the former, patients ranged from 32 to 77 (mean: 51) years and 13% had tuberous sclerosis. Tumors ranged from 0.2 to 17 (mean: 5.5) cm with 77% arising in the corpus. Epithelioid cells were present in 100% and a spindled component was seen in 37%. Nuclear atypia was low (53%), intermediate (17%), or high (30%). Mitoses ranged from 0 to 36 (mean: 6) and 0 to 133 (mean: 19) per 10 and 50 high-power fields, with atypical mitoses present in 30%. Thin and delicate vessels were noted in 100%, clear/eosinophilic and granular cytoplasm in 93%, stromal hyalinization in 73%, necrosis in 30%, and lymphovascular invasion in 10%. All tumors were positive for HMB-45, cathepsin K, and at least one muscle marker, with most expressing melan-A (77%) and/or MiTF (79%). A PSF-TFE3 fusion was identified in one while another showed a RAD51B-OPHN1 fusion. Follow-up ranged from 2 to 175 (mean: 41) months, with 63% of patients alive and well, 20% dead of disease, 13% alive with disease, and 3% dead from other causes. In the latter group (n=2), patients were 39 and 49 years old, one had tuberous sclerosis, while the other had pulmonary lymphangioleiomyomatosis. Both tumors expressed HMB-45, cathepsin K, and muscle markers, but lacked TFE3 and RAD51B rearrangements. The 2 patients are currently alive and well. Application of gynecologic-specific criteria (≥4 features required for malignancy: size ≥5 cm, high-grade atypia, mitoses >1/50 high-power fields, necrosis, and lymphovascular invasion) for predicting outcome misclassified 36% (4/11) of aggressive tumors; thus, a modified algorithm with a threshold of 3 of these features is recommended to classify a PEComa as malignant.

Keywords: perivascular epithelioid cell tumor; PEComa; uterus; tuberous sclerosis; diagnostic criteria; TFE3; RAD51B.

Figure 1

Uterine PEComas ranged from tan-pink and well-demarcated in the cervix (A) and corpus (B) to diffusely necrotic and infiltrative (C).

Figure 2

A well-circumscribed and pushing border was infrequent (A). Most PEComas were infiltrative (B) and a subset showed permeative growth (C).

Figure 3

Cytologic atypia was low (A), intermediate (B), or high (C). Clear/eosinophilic and granular cytoplasm (D) was noted in most PEComas with a subset having a focal rhabdoid (E) or foamy (F) appearance.

Figure 4

Other histologic features in uterine PEComas included ‘melanoma-like’ macronucleoli (A), multinucleated cells (B), melanin pigment (C), and focal stromal hyalinization (D). Thin and delicate, capillary-like vasculature was a constant feature (E), but perivascular/radial distribution of cells (F) was only noted in a subset of tumors.

Figure 5

In case 11, spindled cells with striking smooth muscle-like differentiation (left) co-existed with epithelioid cells (right) (A). The epithelioid component (right) was strongly positive for cathepsin K (B), HMB-45 (C), and melan-A (D), but negative for desmin (E) and h-caldesmon (F). The inverse staining pattern was noted in the spindled component.

Figure 6

In case 14, epithelioid clear cells with alveolar and nested patterns (A) were strongly positive for TFE3 by immunohistochemistry (B) with PSF and TFE3 rearrangements by FISH (C), as is typically seen in TFE3-rearranged PEComas. In case 12, diffuse sheets of highly atypical and mitotically active epithelioid cells (D) showed unbalanced complex RAD51B (E) and OPHN1 (F) gene rearrangements by FISH.

Figure 7

In case 27, a well-circumscribed mass was noted in the uterine wall (A) that had morphologic features characteristic of lymphangioleiomyomatosis (B).