To the Editor.—Our group previously described in this journal an underrecognized conjunctival nevus termed granular cell nevus (GCN) or a nevus with granular cell change (combined nevocellular and GCN)1  that can simulate melanoma clinically and histopathologically. Granular cell nevus features epithelioid and spindle cells with nuclear enlargement and pleomorphism and abundant, finely granular, lightly pigmented, periodic acid-Schiff (PAS)–positive cytoplasm in a background of melanophages.1,2  Similar to melanoma, GCN can demonstrate a pushing margin with loss of maturation and HMB45 expression. Young age at diagnosis, lack of associated conjunctival melanosis, bulbar location, cysts, and the absence of mitotic figures with a low Ki-67 proliferative index are helpful clinical and pathologic diagnostic clues that serve to distinguish GCN from melanoma.

Granular cell nevus and combined GCN are morphologically similar to deep penetrating nevus (DPN) and combined DPN (superficial DPN, melanocytic nevus with focal atypical epithelioid components, or clonal/inverted nevus). Similar to GCN, DPN expresses HMB45 intensely and demonstrates a low Ki-67 proliferative index. Deep penetrating nevus can rarely metastasize and is regarded as an intermediate melanocytic lesion in the most recent World Health Organization (WHO) Classification of Skin Tumours.3  Deep penetrating nevus is underrecognized in the conjunctiva and is not formally included in the current WHO Classification of Tumours of the Eye.4  Recent studies4,5  identified activation of the mitogen-activated protein (MAP) kinase and dysregulation of β-catenin pathways in cutaneous and conjunctival DPN. Šekoranja et al4  and de la Fouchardière et al5  showed that DPN strongly expresses nuclear β-catenin and its downstream effector cyclin D1 (CCND1), thus distinguishing DPN from other nevus variants.

In light of these recent data, we reevaluated 6 of the previously reported nevi with granular cell change with the PAS stain and immunohistochemical stains for β-catenin, CCND1, and PRAME. We found that PRAME was negative in all 6 lesions, further confirming their benign nature (Figure). Four lesions strongly and diffusely coexpressed nuclear β-catenin and CCND1 in the GCN component and were PAS negative, leading to reclassification of these lesions as combined DPN. In contrast, the GCN component in 2 lesions was β-catenin negative and PAS positive, whereas CCND1 was diffusely expressed in 1 of 2 lesions. Thus, it is possible that 2 PAS-positive and β-catenin–negative lesions are bona fide combined GCN. Alternatively, these lesions may represent a variant of combined DPN. Molecular studies are required to more conclusively distinguish between these possibilities. Finally, although DPN is considered to have potential for aggressive behavior, none of our reclassified 4 conjunctival DPNs recurred, supporting the previously reported benign nature of these lesions in conjunctival location.1,4 

Combined deep penetrating (DPN)/clonal nevus and nevus with granular cell change (GCN), a side-by-side comparison. A, Combined DPN/clonal nevus features nests of melanocytes with a voluminous lightly pigmented cytoplasm and mildly enlarged nuclei in a background of melanophages and nevocellular nevus nests. B, DPN component (asterisk), melanophages (arrowhead), and nevocellular nevus component (arrow). C, Periodic acid–Schiff (PAS) stain is positive in melanophages (arrowhead) and is negative in the nevus cells. D, Strong nuclear β-catenin staining in more than 50% of DPN nuclei. Nevocellular nevus component is negative for β-catenin. E, GCN features cells with abundant lightly pigmented cytoplasm (asterisk) morphologically similar to DPN. F, Higher magnification of granular cell nevus component. G, Strong cytoplasmic PAS positivity in GCN. H, Nuclear β-catenin is negative in GCN (hematoxylin-eosin, original magnifications ×200 [A and E] and ×400 [B and F]; original magnification ×400 [C and G]; original magnification ×400 [D and H]).

Combined deep penetrating (DPN)/clonal nevus and nevus with granular cell change (GCN), a side-by-side comparison. A, Combined DPN/clonal nevus features nests of melanocytes with a voluminous lightly pigmented cytoplasm and mildly enlarged nuclei in a background of melanophages and nevocellular nevus nests. B, DPN component (asterisk), melanophages (arrowhead), and nevocellular nevus component (arrow). C, Periodic acid–Schiff (PAS) stain is positive in melanophages (arrowhead) and is negative in the nevus cells. D, Strong nuclear β-catenin staining in more than 50% of DPN nuclei. Nevocellular nevus component is negative for β-catenin. E, GCN features cells with abundant lightly pigmented cytoplasm (asterisk) morphologically similar to DPN. F, Higher magnification of granular cell nevus component. G, Strong cytoplasmic PAS positivity in GCN. H, Nuclear β-catenin is negative in GCN (hematoxylin-eosin, original magnifications ×200 [A and E] and ×400 [B and F]; original magnification ×400 [C and G]; original magnification ×400 [D and H]).

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The authors have no relevant financial interest in the products or companies described in this article.