TFE3 translocation-associated perivascular epithelioid cell neoplasm (PEComa) of the gynecologic tract: morphology, immunophenotype, differential diagnosis

Abstract

TFE3 translocation-associated PEComa is a distinct form of perivascular epithelioid cell neoplasm, the features of which are poorly defined owing to their general infrequency and limited prior reports with confirmed rearrangement or fusion. Recent investigation has found a lack of TSC gene mutation in these tumors compared with their nonrearranged counterparts, which underscores the importance of recognizing the translocated variant because of hypothetical ineffectiveness of targeted mTOR inhibitor therapy. Six cases were identified, and TFE3 rearrangement was confirmed by fluorescence in situ hybridization. Patient age ranged from 46 to 66 years (median 50 y), and none had a history of a tuberous sclerosis complex. Three cases arose in the uterine corpus, 1 in the vagina, 1 pelvic tumor, and 1 pulmonary tumor that was likely a recurrence/metastasis from a probable uterine primary. Five cases had clear cell epithelioid morphology that showed a spectrum of atypia, while 1 case had a mixture of clear cell epithelioid and spindle cells. A mostly consistent immunophenotype was observed in the clear cell epithelioid cases: each demonstrated diffuse TFE3, HMB45, cathepsinK labeling, either focal or no melanA staining, and variably weak reactivity to smooth muscle markers. The mixed clear cell epithelioid and spindle cell case had a similar expression pattern in its epithelioid component but strong muscle marker positivity in its spindle cell component. Follow-up ranged from 1 to 57 months. Three cases demonstrated aggressive behavior, and 3 cases had no evidence of recurrence. Both GYN-specific and traditional sets of criteria for malignancy were evaluated. The GYN model showed improved inclusion and specificity in comparison to the traditional model.

Figure 1

TFE3 translocation associated PEComa typically shows a nested or alveolar architecture supported by thin-walled vascular spaces, but has a spectrum of cytologic appearance. TFE3 rearranged tumors may show the typical PEC morphology of a cell with clear to granular eosinophilic cytoplasm, round to ovoid nucleus, prominent nucleolus (A, 200×). These neoplasms tend to have a uniform appearance and scattered melanin-containing cells are sometimes seen (B, 400×). Infiltration is routinely identified, in this case into myometrium (C, 200×) although the cells have low grade features and are associated with equally low grade appearing multinucleated tumor cells. Some tumors demonstrate extensively clear cytology (D, 200×). High grade features are seen in this case: nuclear enlargement, coarse chromatin and conspicuous nucleoli, but the cells maintain their nested pattern and have correspondingly high grade multinucleated tumor cells (E, 400×). Sheet-like growth and considerable pleomorphism may be found in some cases. A helpful feature for assessing grade is the degree of atypia present in the multinucleated tumor cells (F, 200×). The mixed clear cell epithelioid and spindle cell rearranged case showed features of purely epithelioid tumors (G, 400×), but also had distinct areas of spindling and fascicular architecture (H, 400×). The expected immunophenotype of TFE3 translocation associated PEComa is strong and diffuse TFE3 (I, 200×), HMB45 (J, 200×) and CathepsinK (K, 200×). TFE3 FISH consisted of red 5′centromeric and green 3′telomeric probes as well as an aqua X centromere probe. A pattern of 2 yellow and 2 aqua signals indicative of normal or intact TFE3 present on both X chromosomes. Balanced break apart of TFE3 showed spatially split red and green signals resulting in a 1 red, 1 green, 1 fusion and 2 aqua ratio per nucleus (L).

Figure 1

TFE3 translocation associated PEComa typically shows a nested or alveolar architecture supported by thin-walled vascular spaces, but has a spectrum of cytologic appearance. TFE3 rearranged tumors may show the typical PEC morphology of a cell with clear to granular eosinophilic cytoplasm, round to ovoid nucleus, prominent nucleolus (A, 200×). These neoplasms tend to have a uniform appearance and scattered melanin-containing cells are sometimes seen (B, 400×). Infiltration is routinely identified, in this case into myometrium (C, 200×) although the cells have low grade features and are associated with equally low grade appearing multinucleated tumor cells. Some tumors demonstrate extensively clear cytology (D, 200×). High grade features are seen in this case: nuclear enlargement, coarse chromatin and conspicuous nucleoli, but the cells maintain their nested pattern and have correspondingly high grade multinucleated tumor cells (E, 400×). Sheet-like growth and considerable pleomorphism may be found in some cases. A helpful feature for assessing grade is the degree of atypia present in the multinucleated tumor cells (F, 200×). The mixed clear cell epithelioid and spindle cell rearranged case showed features of purely epithelioid tumors (G, 400×), but also had distinct areas of spindling and fascicular architecture (H, 400×). The expected immunophenotype of TFE3 translocation associated PEComa is strong and diffuse TFE3 (I, 200×), HMB45 (J, 200×) and CathepsinK (K, 200×). TFE3 FISH consisted of red 5′centromeric and green 3′telomeric probes as well as an aqua X centromere probe. A pattern of 2 yellow and 2 aqua signals indicative of normal or intact TFE3 present on both X chromosomes. Balanced break apart of TFE3 showed spatially split red and green signals resulting in a 1 red, 1 green, 1 fusion and 2 aqua ratio per nucleus (L).

Figure 2

Recommended classification of gynecologic PEComa. * Rearranged mixed clear cell epithelioid and spindle cell type shows marked expression of HMB45, melanA and TFE3 in its epithelioid cells.