Pure Apocrine Intraductal Carcinoma of Salivary Glands: Reassessment of Molecular Underpinnings and Behavior

Abstract

Background: Intraductal carcinoma (IDC) of the salivary glands is a confounding entity, our understanding of which continues to evolve. At least four forms have been elucidated based on histomorphology, immunophenotype, and molecular profile: (1) intercalated duct-like, S100/SOX10+ with frequent NCOA4::RET fusions; (2) oncocytic, S100/SOX10+ with TRIM33::RET, NCOA4::RET, and BRAF V600E; (3) apocrine, AR+ with PI3 kinase pathway mutations; and (4) mixed/hybrid intercalated duct-like/apocrine, with S100/SOX10+ and AR+ areas and frequent TRIM27::RET. The revelation that myoepithelial cells harbor the same fusion as luminal cells suggested that fusion-positive cases are not in situ carcinomas as previously believed. To this point, purely apocrine IDC with entirely intraductal growth has not been found to harbor fusions, but very few cases have been tested.

Methods: IDCs with pure apocrine morphology, entirely intraductal growth, and no precursor lesion (pleomorphic adenoma or sclerosing polycystic adenoma) were retrieved from the authors' archives. Several immunostains (S100, SOX10, GCDFP-15, AR, p40/SMA) and targeted next generation sequencing (NGS) panel including 1425 cancer-related genes were performed.

Results: Seven entirely IDC with pure apocrine type were collected. The cases arose in the parotid glands (mean, 1.9 cm) of 5 men and 2 women ranging from 51 to 84 years (mean, 69.7 years). Histologically, tumors consisted of rounded to angulated ductal cysts lined by epithelial cells with abundant finely granular eosinophilic cytoplasm and large nuclei with prominent nucleoli. Pleomorphism was mild to moderate, the mitotic rate was low, and necrosis was absent. Conventionally invasive foci or areas of intercalated duct-like morphology were not identified. In all cases, luminal cells were diffusely positive for AR and GCDFP-15 while negative for S100/SOX10, and the ducts were completely surrounded by myoepithelial cells highlighted by p40 and SMA. Molecular analysis was successful in 6 cases. Three harbored fusions: one with NCOA4::RET, another with STRN::ALK and one with both CDKN2A::CNTRL and TANC1::YY1AP1. The three fusion-negative cases all harbored HRAS mutations; additional mutations (PIK3CA, SPEN, ATM) were found in 2 of 3 cases. All patients were treated by surgery alone. Six of them are currently free of disease (follow up 12-190 months), but the case harboring NCOA4::RET developed lymph nodes metastasis in the form of a fusion-positive invasive salivary duct carcinoma.

Conclusions: Purely apocrine IDC is a heterogeneous disease. A subset seems to be genetically similar to salivary duct carcinoma and may indeed represent carcinoma in situ. The other group harbors fusions, similar to other forms of IDC. Moreover, the occurrence of lymph node metastasis discredits the idea that any fusion-positive IDC with a complete myoepithelial cell layer has no metastatic potential. With the wide use of RET-and ALK-based targeted therapies, our findings further underscore the importance of fusion analysis for IDC.

Keywords: NCOA4::RET; STRN::ALK; Intraductal carcinoma; Salivary duct carcinoma; Salivary gland neoplasms.

Fig. 1

At low power, all pure apocrine IDCs manifested as well defined unencapsulated and vaguely lobulated neoplasms composed of rounded cysts and nests of varying sizes with intraluminal proliferations set in a sclerotic background with pushing borders (a-b)

Fig. 2

The tumors consisted of mostly rounded smooth-edged cysts filled with delicate amphophilic to amorphous proteinaceous material, lined by proliferative epithelial cells surrounded by myoepithelial cells (a). Luminal cells are variably arranged in micropapillae, papillae, or in a Roman bridge-like architecture with occasional apical snouting and decapitation secretions (b). Epithelial cells display apocrine phenotype with abundant, finely granular to foamy eosinophilic cytoplasm and enlarged round nuclei with prominent nucleoli, while myoepithelial cells appear organized in a continuous monolayer of small ovoid cells with hyperchromatic nuclei and scant cytoplasm (c). One case demonstrated conspicuous brightly eosinophilic cytoplasmic granules (d)

Fig. 3

Luminal cells were diffusely and strongly positive for androgen receptor (a) and GCDFP-15 (b) while negative for p40 (c) and S100 (d) in all cases. The neoplastic cysts and nests were surrounded by an intact layer of myoepithelial cells positive for p40 (c) and S100 (d)

Fig. 4

Case #7. Low-grade pure apocrine IDC morphology in the parotid gland tumor (a). There was a complete layer of myoepithelial cells throughout, highlighted by p40 (b). Lymph node extensively replaced by invasive salivary duct carcinoma composed of ducts and nests with cribriform growth and intraluminal micropapillae (c) composed of cells with apocrine features, with high mitotic rate and focal necrosis (d). There was a complete absence of p40-positive myoepithelial cells in the metastasis (inset)