PNL2: A Useful Adjunct Biomarker to HMB45 in the Diagnosis of Uterine Perivascular Epithelioid Cell Tumor (PEComa)

Abstract

Perivascular epithelioid cell tumors (PEComa) are rare neoplasms characterized by co-expression of melanocytic and muscle markers. HMB45 and Melan-A are used to confirm a PEComa diagnosis; however, both are often focally expressed and sensitivity for Melan-A is low. PNL2 is a reliable biomarker for epithelioid melanoma and renal angiomyolipoma/PEComa. The objective of this study was to determine PNL2 utility in diagnosing uterine PEComas as well as distinguishing PEComas from uterine smooth muscle tumors (SMTs). Twenty-one uterine PEComas and 45 SMTs were analyzed for PNL2; a subset was also stained for HMB45, Melan-A, Cathepsin-K, Desmin, and h-Caldesmon. Cases were scored as negative (0), focal (<10% of tumor cells), or patchy to diffusely positive (>10% of tumor cells). PEComas were positive for PNL2, HMB45, and Melan-A in 86%, 100%, and 57% of cases, respectively. In PEComas, PNL2 was patchy to diffusely positive more frequently (10/18, 56%) than Melan-A (4/12, 33%). In contrast, 2 of 45 (4%) SMTs were focally PNL2 positive; HMB45 was focally positive in 4 SMTs (11%) and all were negative for Melan-A. Desmin and h-Caldesmon were positive in 90% and 57% of PEComas, and 91% and 82% of SMTs. Cathepsin-K was positive in 100% of PEComas and 93% of SMTs. PNL2 is a useful biomarker for the diagnosis of uterine PEComa, with comparable sensitivity and specificity to HMB45. In contrast, PNL2 stains more PEComas when compared with Melan-A. Cathepsin-K, Desmin, and h-Caldesmon are of little utility for distinguishing PEComas and SMTs; however, lack of Cathepsin-K argues against PEComa. These results suggest that PNL2 should be used in conjunction with HMB45 in the diagnosis of PEComa of the uterine corpus.

Perivascular epithelioid cell tumors (PEComa) of the gynecologic tract

“…However, cathepsin K expression has also been described in SMTs, 17,59,107 albeit usually not diffuse, but highlights that this marker also is not specific for PEComas. Likewise, PNL2 may also rarely be focally positive (< 10%) in uterine SMTs, but results are limited to a single series of 45 tumors 59 …”

“…PEComas are characterized by expression of myomelanocytic markers (Figure 3A,B; Table 1), but the extent and intensity of staining required for their diagnosis remains controversial. Among large studies HMB‐45 is expressed in 99% of all PEComas 17,23,40,41,59 ; however, the extent of staining is highly variable. In two studies, only 13% (1/8 and 2/16, respectively) of tumors showed >25% staining 23,40 while in a third series, 28/32 (88%) 17 reached this threshold.…”

“…Cathepsin K, a protease involved in osteoclast function and regulated by the MiTF family, 62 is often strongly and diffusely positive (Figure 3C) 17,23,59 whereas PNL2, a novel marker for non‐desmoplastic melanomas and melanocytic/MiTF‐related tumors, shows variable cytoplasmic expression among PEComas 59,63 . AE1/AE3, S100, and CD10 are only rarely positive, while PAX8 is negative 23,40 .…”

“…As two of their PEComas were Melan‐A negative, but strongly and diffusely cathepsin K positive, they proposed that if the appropriate morphology was present, cathepsin K may be used as a substitute for Melan‐A. However, cathepsin K expression has also been described in SMTs, 17,59,107 albeit usually not diffuse, but highlights that this marker also is not specific for PEComas. Likewise, PNL2 may also rarely be focally positive (< 10%) in uterine SMTs, but results are limited to a single series of 45 tumors 59 …”

“…Thus, staining for HMB‐45 may be limited to isolated cells. Other melanocytic markers including Melan‐A and MiTF are also variably expressed, with melan‐A staining often being focal and less extensive than HMB‐45, 17,23,59 and MiTF having a tendency to be weak 17,23 . However, MiTF, is not a very reliable marker as it lacks specificity 60 .…”