Salivary Sialadenoma Papilliferum Consists of Two Morphologically, Immunophenotypically, and Genetically Distinct Subtypes

Abstract

Papillary salivary gland neoplasms are rare tumors usually arising in the minor salivary glands of the oral cavity. Their classification has been historically confusing due to overlapping histologic features, but molecular analysis may clarify these entities. Sialadenoma papilliferum (SP) is a peculiar member of this group that demonstrates both an endophytic ductal and an exophytic squamous component. SP closely resembles syringocystadenoma papilliferum of the skin, a tumor which has recently been shown to harbor BRAF V600E or HRAS mutations. We sought to perform histologic and immunophenotypic analysis of a group of SP, along with BRAF and HRAS mutational analysis. We collected 13 SP cases from 7 females and 6 males ranging from 2 to 91 years (mean 62.8). Five exophytic ductal papillomas were also analyzed as controls. Histological analysis was performed along with immunohistochemistry for CK7, p63, and SOX10. BRAF VE1 immunohistochemistry was done in all tumors, and BRAF V600E and HRAS Sanger sequencing was successfully performed in all but two cases. Histologic analysis revealed that SP consisted not only of classic SP (9 of 13 cases) but also an oncocytic variant (4 of 13 cases) characterized by a glandular component that uniformly exhibited abundant granular cytoplasm and prominent nucleoli. By immunohistochemistry, all SP demonstrated luminal CK7 and basal p63 expression, but SOX10 was expressed only in conventional SP (9 of 9 cases). BRAF VE1 immunohistochemistry was positive in 9 of 9 conventional SP but 0 of 4 oncocytic SP; staining was present in both the exophytic and endophytic components. BRAF V600E mutational status was confirmed by Sanger sequencing in 11 cases (7 conventional and 4 oncocytic). The exophytic ductal papillomas were negative for BRAF mutations, and all tumors tested were negative for HRAS mutations. In summary, we demonstrated that SP consists of two variants: (1) conventional SP which is SOX10-positive and harbors BRAF V600E mutations similar to syringocystadenoma papilliferum of the skin; and (2) an oncocytic variant which is SOX10-negative and negative for BRAF mutations. We also demonstrated that both the endophytic glandular component and exophytic squamous components of conventional SP harbor BRAF V600E mutations and are therefore neoplastic.

Keywords: BRAF; Exophytic ductal papilloma; Salivary gland; Sialadenoma papilliferum.

Fig. 1

Examples of classic sialadenoma papilliferum (a–c), oncocytic sialadenoma papilliferum (d–f) and exophytic ductal papilloma (g–i). a Classic sialadenoma papilliferum showing a papillary squamous surface and a contiguously endophytic ductal proliferation. b The endophytic ductal proliferation sometimes extends deeply into underlying minor salivary glands. c The ductal cells are composed of columnar to cuboidal cells and arranged in bilayered to multilayered structures. d Oncocytic variant of sialadenoma papilliferum has a similar arrangement with both exophytic papillary surface and an endophytic ductal component. e The oncocytic ductal cells merge with overlying stratified squamous epithelium and form papillary structures. f Oncocytic variant of sialadenoma papilliferum comprised of oncocytic cells with round nuclei, abundant eosinophilic cytoplasm, and bland-looking nuclei. g Exophytic ductal papilloma has only exophytic papillary projections and lacks the endophytic ductal hyperplasia. h and i Exophytic ductal papilloma with mixed stratified squamous epithelium and columnar epithelium with variable numbers of mucous/goblet cells admixed (h & e staining; original magnification, a, b, d, g × 40; c,i, × 400; e: × 100; f, h: × 200)

Fig. 2

Examples of SOX10 and BRAF V600E Immunohistochemistry staining of classic sialadenoma papilliferum. a–c Classic sialadenoma papilliferum showing b, c positive staining for SOX10 in the endophytic ductal component and d–f BRAF V600E (VE1) in both the glandular (left) and squamous (right) tumor components and the ductal cells of classic sialadenoma papilliferum showing e moderate or f weak staining. (A: h & e staining; b, c: SOX10; d–f: BRAF V600E; original magnifications, a, b, × 40; c, d, × 200; e, f × 400)

Fig. 3

Examples of SOX10 and BRAF V600E Immunohistochemistry staining of (a–c) oncocytic sialadenoma papilliferum and (d–f) exophytic ductal papilloma. a–c) Oncocytic sialadenoma papilliferum and d–f exophytic ductal papilloma was b, e) consistently negative for SOX10 and (c, f) BRAF V600E (VE1). (a, d: h & e staining; b, e: SOX10; c, f: BRAF V600E; original magnifications, a–c and e, f, × 40; d, × 20)