Low-grade Apocrine Intraductal Carcinoma: Expanding the Morphologic and Molecular Spectrum of an Enigmatic Salivary Gland Tumor

Abstract

Intraductal carcinoma (IDC) is the current designation for a salivary gland neoplasm previously referred to as "low-grade salivary duct carcinoma" and "low-grade cribriform cystadenocarcinoma," among others. IDC is conceptually believed to be similar to ductal carcinoma in-situ of the breast. Although IDC is one entity in the current WHO Classification of Head and Neck Tumors, recent studies have suggested that at least three subtypes exist: a low-grade, intercalated duct-like variant with frequent RET rearrangements; a high-grade apocrine variant with complex, salivary duct carcinoma-like genetics; and a mixed variant. We sought to characterize an unusual form of low-grade, purely apocrine IDC. Three cases of apocrine-type IDC with low-grade histology were retrieved from the authors' consultation files. Immunohistochemistry for androgen receptor, GCDFP-15, S100, smooth muscle actin, and p40 was performed. A custom, targeted next generation sequencing (NGS) panel including 1425 cancer-related genes was also done on all cases. All three cases developed in the parotid glands of men, aged 51, 63, and 73 years (mean, 62 years). All cases consisted of large, rounded macrocysts surrounded by smaller nests which were lined by cells with abundant granular eosinophilic cytoplasm and large round nuclei with prominent nucleoli. Pleomorphism was mild, the mitotic rate was low, and necrosis was absent. No cases had any invasive foci or areas of intercalated duct-like morphology. By immunohistochemistry, all cases were diffusely positive for androgen receptor and GCDFP-15, surrounded entirely by an intact layer of small myoepithelial cells positive for S100, smooth muscle actin, and p40. Targeted NGS results were obtained from two cases: both harbored HRAS mutations and copy number losses in TP53, while one case each harbored mutations in PIK3CA, SPEN, and ATM. Fusions were absent in both cases. All three patients were treated by surgery alone, and are currently free of disease (follow up 12-190 months). This study confirms the existence of a low-grade, purely apocrine form of IDC. In its pure form, i.e., without an intercalated duct-type component, low-grade apocrine IDC is genetically similar to high-grade salivary duct carcinoma, with frequent HRAS and PI3K pathway mutations. Despite its molecular similarities to the aggressive salivary duct carcinoma, low-grade apocrine IDC appears to behave in a very indolent manner, supporting is classification as a non-invasive neoplasm, and underscoring the need to distinguish these tumors from each other.

Keywords: HRAS; Intraductal carcinoma; Oncogenes; Parotid gland; Phosphatidylinositol 3-Kinases (PI3K); Salivary duct carcinoma; Salivary gland neoplasms.

Fig. 1

On cut section, this low-grade apocrine intraductal carcinoma appeared as a cyst with an adjacent solid nodule within the parotid gland

Fig. 2

At low power, this low-grade apocrine intraductal carcinoma consists of variably sized cysts and nests with intraluminal proliferations (a). The large cysts and small nests are rounded a have smooth edges, suggestive of a non-invasive process (b). The cases exhibited apocrine features in the form of abundant granular eosinophilic cytoplasm with apical snouts and decapitation secretions (c). In keeping with their apocrine differentiation, the tumor cells had large round nuclei with prominent nucleoli. However, pleomorphism and mitotic activity was minimal. This case also had unusual hypereosinophilic cytoplasmic granules similar to those seen in sclerosing polycystic adenoma (d)

Fig. 3

All three cases were strongly positive for androgen receptor (a) and GCDFP-15 (b). The cysts and nests were surrounded by an intact layer of benign myoepithelial cells that were positive for p40 (c) and S100 (d); the luminal tumor cells themselves were negative for these markers