PRAME and LEF1 in Combined Deep Penetrating Nevus and Combined Blue Nevus: Utility and Pitfalls

Abstract

Deep penetrating nevi (DPN), particularly those showing combined features, or combined deep penetrating nevi (CDPN), may show histopathological resemblance to blue nevus (BN) and melanoma. Preferentially Expressed Antigen in MElanoma (PRAME) is a marker that helps distinguish melanoma from benign melanocytic lesions. Lymphoid enhancer-binding factor 1 (LEF1) has been proposed to be used in conjunction with β-catenin for diagnosis of DPN. The immunohistochemical expression of PRAME and LEF1 was evaluated in 10 DPN (including 6 CDPN and 2 DPN-like proliferations with atypical features), 16 BN (including combined and cellular BN), and 2 melanomas with features of DPN or BN. PRAME was negative in most DPN (n = 10/10, n = 9/10, one case with discrepancy between readers) and all BN (n = 16/16), while the 2 melanomas included were positive (n = 2/2). All DPN were positive for LEF1 (n = 9/9) while only a subset of BN were positive (n = 6/16, P = 0.0028; n = 5/16, P = 0.001, per both readers). LEF1 seemed to be easier to interpret than β-catenin because of its nuclear pattern of expression. The expression of LEF1 in the regular nevus component of combined BN presents a potential pitfall in practice because it may lead to misinterpretation of LEF1 as positive in the BN component of the lesion. However, a subset (approximately one-third) of combined BN seemed to show true LEF1 expression. Taking into account pitfalls in interpretation, the combinatorial panel of PRAME and LEF1, in addition to conventional histopathological features, may be useful to distinguish CDPN from combined BN and other benign and malignant mimics.

Figure 1:

Expression of PRAME in deep penetrating nevus (DPN) and DPN-like lesions. A: Deep penetrating nevus with combined intradermal nevus. A proliferation of spindle and epithelioid melanocytes arranged in a plexiform architecture is present, associated with heavily pigmented melanocytes (H&E, x 10), B: Combined blue nevus (BN). The blue nevus component of the lesion shows similar morphological features to those seen in the DPN (H&E, x 20), C: Melanoma with DPN-like features. This malignant proliferation of melanocytes also shows a plexiform pattern of growth and associated melanophages (H&E, x 10) D: Both components of this combined DPN are negative for PRAME (x10). E: Both components of this combined BN are negative for PRAME (x 20); F: In contrast to DPN and BN, the DPN-like melanoma shows diffuse positivity for PRAME (x 10).

Figure 2:

Combined deep penetrating nevus (CDPN). A: The lesion shows a wedge-shaped architecture and biphenotypic cytology (H&E, x 4). B: The melanocytes display spindle cell (DPN) and nevoid (intradermal nevus) morphology (H&E, x 10). C: HMB45 reveals strong labeling in the DPN component while the conventional nevus cells are negative (x 10). D: The DPN cells are strongly positive for cyclin D1, in contrast to the conventional nevus cells (x 10). E: β-catenin shows strong cytoplasmic labeling in both components of the lesion, which may make interpretation difficult. The DPN cells appear to also exhibit nuclear staining (x 10) Inset: Nuclear expression of β-catenin in the DPN cells (blue arrow). Notice the membranous pattern of expression of surrounding regular nevus cells. Even at high magnification, evaluation of nuclear staining of β-catenin can be difficult (x 40). F: LEF1 shows clean and diffuse nuclear labeling in the DPN cells (blue arrow). The inset shows higher magnification of cells displaying nuclear expression of LEF1 (blue arrow) and adjacent melanophages (x 40). The conventional nevus cells show nuclear positivity predominantly in the superficial cells (red arrow), while the deeper cells appear to be negative (“maturation pattern”) (x 10).

Figure 3:

Combined blue nevus (BN). A: The lesion shows a biphenotypic appearance, similar to the combined DPN seen in Figure 2 (H&E x4), B: The blue nevus is composed of spindle and epithelioid cells admixed with melanophages. A conventional intradermal nevus is present in the upper right quadrant of the figure (H&E x 10), C: HMB45 is strongly expressed by the blue nevus cells. Inset shows a higher magnification view of the blue nevus cells that are strongly positive for HMB45 and are associated with abundant melanophages (x 40). The adjacent conventional nevus cells reveal loss of HMB45 with descent (“maturation pattern”) (x10), D: cyclin D1 labels scattered cells, mostly in the upper portions of the conventional nevus component of the lesion (x 10), E: β-catenin shows diffuse cytoplasmic staining in both blue nevus and conventional nevus cells, which may make interpretation difficult (x 10). Higher magnification (inset) fails to show unequivocal nuclear expression of the marker, although evaluation is still challenging (x40), F: LEF1 reveals lack of nuclear staining in the blue nevus cells (blue arrows; Inset: a higher magnification view, (x40). The conventional nevus cells show labeling in the superficial portion (red arrow) (x 10).