Perianal Linear Syringocystadenoma Papilliferum, Apocrine Sweat Glands, Postzygotic BRAF Mutation and Genetic Mosaicism

To the Editor: Syringocystadenoma papilliferum (SCAP) is a benign adnexal neoplasm of the skin showing apocrine features.1 This relatively unusual lesion mostly occurs alone or in association with nevus sebaceus.1 It can present at birth or develop later, mainly on the head and neck, where it may be associated with nevus sebaceus, less frequently on the trunk and extremities, and exceptionally in the anogenital region.1–3 SCAP usually presents as a solitary tumor, but grouped lesions have been reported, too.1–3 In fact, such agminated forms of SCAP are particularly rare and, therefore, little studied in the literature. We report here a case of linear SCAP, located in the perianal area of a child. Our findings, which are consistent with a cutaneous mosaicism related to a postzygotic BRAF mutation, allow some interesting comments to be made. A 9-year-old boy with no personal or family history presented with a perianal skin lesion evolving since birth (Fig. 1). This lesion, which displayed multiple wart-like papules in a linear array, extended along the right side of the anus toward the scrotal raphe, without crossing the midline (Fig. 1). At the age of 11 months, a biopsy was performed, which led to a diagnosis of cutaneous hamartoma, not otherwise specified. Thereafter, the lesion gradually increased in size. Owing to troublesome perianal location and chronic irritation, it was completely excised.FIGURE 1.: Clinical illustration of the lesion. Although slightly out of focus, this picture shows a perianal lesion featuring a linear arrangement and extending toward the scrotal raphe. Note the budding or vaguely warty appearance.The elongated surgical specimen, which closely followed the lesion, measured 4 × 1 × 0.5 cm. Microscopic examination revealed multiple tubular or cystic structures, regularly arranged next to each other in the upper part of the dermis, thus giving the surface of the skin a multinodular appearance, without being truly papillomatous or warty (Fig. 2A). Connected to the epidermis and apparently developed at the expense of sweat glands, these glandular structures contained small papillary formations (Fig. 2A), made up of a fibrous and vascular axis lined with a multilayered epithelium, whose luminal layer displayed apocrine characteristics (Figs. 2B, C). A discrete lymphoplasmacytic infiltrate was sometimes observed within papillae. There was some epithelial hyperplasia and squamous metaplasia, but no significant atypia, mitotic activity, or features suggestive of human papillomavirus infection. Using BRAF V600E-specific VE1 antibody (Ventana Medical Systems, Tucson, AZ), a BRAF c.1799T>A p.V600E mutation was initially detected by immunohistochemistry (Fig. 3), then documented further by next-generation sequencing (NGS) analysis, with a variant allele frequency of 18.2%. No HRAS, KRAS, NRAS, AKT1, or PIK3CA mutations could be demonstrated. Interestingly, the epithelium of neighboring apocrine glands, which seemed normal at first glance, also expressed BRAF V600E, suggesting that this mutation was also present in normal-appearing apocrine glands (Figs. 3A, B). It should be noted that the epidermis and other components of the skin, including eccrine, sebaceous, and follicular structures, were distinctively negative (Figs. 3A, B). Re-examination of the skin biopsy taken at 11 months of age revealed a small and superficial skin sample, in which a small neoplastic structure like those seen in the current surgical resection was found, but at a less developed stage (Figs. 4A, B). The epithelial cells of this nascent neoplastic structure also expressed BRAF V600E, confirming that BRAF mutation was already present at that time (Fig. 4C). Based on these results, a diagnosis of linear SCAP was made. No further events came to our attention, approximately 2 years after surgery.FIGURE 2.: Microscopic aspects of the lesion. A, At low magnification, several tumor foci are arranged side by side. These tumor foci seem to have developed at the expense of sweat glands, the superficial part of which, connected to the epidermis, shows cystic dilation filled with papillary structures, thus giving the skin surface a particular multinodular appearance (H&E, original magnification ×20). B and C, At higher magnification, these papillary structures have a fibrous and vascular axis containing a few lymphoplasmacytic cells and are covered by a multilayered apocrine-like epithelium (H&E, B: original magnification ×100 and C: original magnification ×400). There is no suspicious atypia. H&E, hematoxylin and eosin.FIGURE 3.: Immunostaining against BRAF V600E. A and B, Tumor foci are strongly positive. Note that lining epithelium of normal-appearing sweat glands also expresses BRAF V600E, suggesting that mutation is also present within epithelial cells of normal sweat glands. By contrast, the epidermis, eccrine glands, and pilosebaceous units are clearly negative.FIGURE 4.: Illustration of the skin biopsy performed at the age of 11 months. A and B, Despite the relatively superficial nature of this skin fragment, this picture shows a glandular structure connected to the epidermis and featuring neoplastic alterations like those observed in the surgical resection performed later, but at a less developed stage (H&E, A: original magnification ×100 and B: original magnification ×400). C, Immunostaining against BRAF V600E is also positive.According to our literature review, rare cases of perianal SCAP have been reported, most of them solitary lesions occurring in adults.2,3 A single case of perianal linear SCAP with clinical and pathologic features like our patient has been previously reported, but no immunohistochemical or molecular studies were performed.3 The pathogenesis of SCAP, including that of linear variant, remains yet to be fully elucidated. Several studies have demonstrated the presence of postzygotic mutations affecting either BRAF (mostly BRAF c.1799T>A p.V600E) or other genes that are also implicated in the RAS/mitogen-activated protein kinase (RAS-MAPK) signaling pathway, such as HRAS or KRAS.2,4–7 Schematically, these mutations, which are mutually exclusive, lead to activation of this pathway, resulting in uncontrolled cell proliferation and growth.2,4–7 In our patient, the clinical aspect of the lesion, which characteristically followed a linear distribution without crossing midline, suggests a blaschkolinear type of cutaneous mosaicism, because 2 genetically different cell populations, 1 of which carrying a BRAF mutation, were apparently clustered along a Blaschko line.8 In this regard, immunohistochemistry enabled us to better characterize the cellular component carrying such BRAF mutation. In fact, cells strongly expressing BRAF V600E were strictly confined to neoplastic areas and normal apocrine sweat glands. In contrast, the epidermis, eccrine glands, pilosebaceous units, including those closely associated with BRAF-mutated apocrine glands, were negative, reducing apparently the cell line carrying such mutation to apocrine cells only. Interestingly, such expression pattern of BRAF V600E, restricted to apocrine cells only, is somewhat different from that reported by Friedman et al,9 who also investigated BRAF V600E expression in a series of sporadic SCAP with contiguous verrucous proliferations. In their study, BRAF V600E was present in both glandular and contiguous hyperplastic squamous epithelia, suggesting not only a common origin for both epithelial components of the lesion, but also metaplastic changes. Unfortunately, this study did not clarify whether BRAF V600E expression was strictly limited to neoplastic areas or whether it was also observed in normal apocrine glands, as in our patient. Beyond a possible technical bias, such difference in the expression of BRAF V600E between a congenital form of SCAP and a sporadic one could be explained by the level of differentiation of the cell where mutation occurred. Similarly, it remains to be demonstrated whether this difference in BRAF V600E expression can serve as a clue to distinguish between congenital and sporadic forms of SCAP. According to our current knowledge on cutaneous mosaicism,8 we can assume that BRAF mutation in our patient likely arose in utero, in a precursor cell of cutaneous apocrine glands just before their appearance or at least at an early stage of their development (i.e. in a cell that has fully committed to apocrine lineage), during the embryonic period and in a limited region of the body, as demarcated by Blaschko line. This could explain both the limited extent of the patient's lesion and its presence at birth.8 Clinically, perianal SCAP should be distinguished from other lesions of the skin featuring a papillomatous or verrucous aspect, such as warts, condylomata, angiokeratoma, or lymphangioma circumscriptum, all of which can arise in children or infants. Microscopically, SCAP should not be confused with other apocrine neoplasms that can also develop within the anogenital area, particularly hidradenoma papilliferum.1,10 This tumor, which occurs primarily in the vulvar area of adult women, is extremely rare in children.10 Like SCAP, it is also composed of multiple papillary structures covered with a multilayered epithelium that exhibits apocrine features.10 However, HP is usually not connected to pre-existing follicular infundibula and classically does not contain plasma cells in the stroma.10 In contrast to SCAP, it is frequently associated with somatic mutations in AKT1 or PIK3CA.10 Finally, SCAP should not be confused with its malignant counterpart, namely syringocystadenocarcinoma papilliferum (SCACP), a rare and aggressive neoplasm that may occasionally develop within SCAP.11,12 To our knowledge, only 1 pediatric case of SCACP originating from a congenital SCAP has been reported to date.11 Unlike our patient, this tumor was characterized by a very large size, florid epithelial cell proliferation with cellular crowding, disorganized architecture, infiltrative features, marked cellular atypia, and significant mitotic activity.11 Like other cases of SCAP or SCACP that are associated with RAS-activating mutations, this tumor harbored an in-frame alteration within MAP2K1, which is also implicated in the RAS-MAPK pathway.11,12 In summary, this study describes a very unusual variant of linear SCAP, located in the perianal area. This congenital lesion, which showed a blaschkolinear distribution, was associated with a postzygotic BRAF c.1799T>A p.V600E mutation. As demonstrated by immunohistochemistry, this BRAF mutation was also present in epithelial cells of normal-appearing apocrine sweat glands, an underrecognized finding to our knowledge that may serve as an immunohistochemical clue in favor of genetic mosaicism. Finally, in addition to aesthetic or functional consequences that can be associated with such lesion, the possible progression toward SCACP, although very rare, also argues in favor of complete resection, whenever possible.