Reappraisal of Oncocytic Adenocarcinoma: Unveiling Its Connection to Oncocytic Variants of Salivary Duct Carcinoma and Mucoepidermoid Carcinoma Through ImmunoHisto-Molecular Perspectives

Abstract

Oncocytic adenocarcinoma (OC) of the salivary glands is a rare and controversial entity. It was recently reclassified as "salivary carcinoma NOS and emerging entities" in the 2022 WHO classification of head and neck tumors. The lack of specific molecular alterations and its potential affiliation with other salivary gland carcinomas, such as the oncocytic mucoepidermoid carcinomas (OMEC) or the oncocytic subtype of salivary duct carcinomas (OSDC) justified this reclassification. It is becoming essential to clarify the complex spectrum of potential diagnoses surrounding oncocytic tumors. The objective of this study was to explore the histologic features, as well as the immunohistochemical and molecular profiles, of cases previously diagnosed as OC or OMEC of the salivary glands. This study involved 28 cases of carcinomas with a predominantly oncocytic component. The sex distribution was equal. The median age was 59 years (range 10 to 89). Most of these cases originated from the parotid gland (25/28). The mean tumor size was 2.4 cm (range 0.5 to 6.5). Primary immuno-morphological and mutation/gene fusion profiles reclassified mainly (64.3%, 18/28). Most of them were reclassified in descending order as OSDC (8/18), OMEC (5/18), and OC (2/18). But 3 cases remained unclassified (3/18). The transcriptomic analysis found a proximity of their transcriptomic profile with the OMEC group and a distance from the OSDCs. These findings imply that OC is not distinct but represents oncocytic variants of other salivary carcinomas. It underscores the importance of thorough morphologic, immunohistochemical, and molecular examinations to accurately diagnose carcinomas with predominant oncocytic components in the salivary glands.

FIGURE 1

Example of histopathologic features of an oncocytic variant of mucoepidermoid carcinoma (OMEC), an oncocytic subtype of salivary duct carcinoma (OSDC), and an oncocytic adenocarcinoma subtype of salivary carcinoma NOS (OC). OMEC (A and B) mostly lacked well-defined features, displaying extensive oncocytic proliferations without clear evidence of triphasic proliferation (A). Mucous cells were rare (B), and nuclear atypia was generally mild. OSDC (C and D) exhibited poorly defined features, characterized by extensive oncocytic proliferations without mucous cells (C). Severe nuclear atypia was present (D), with ∼≥4 mitoses per 10 high-power fields (HPF). Half of the cases showed tumor necrosis (A), lymphovascular invasion, and/or perineural invasion. OC (E and F) exhibited poorly defined features with extensive oncocytic proliferations devoid of mucous cells (E). A pronounced atypia with necrosis or invasion in small nests was observed (F), with ∼1 to 2 mitosis per 10 high-power fields (HPF).

FIGURE 2

Example of immunoprofile of an oncocytic variant of mucoepidermoid carcinoma (OMEC), an oncocytic subtype of salivary duct carcinoma (OSDC), and an oncocytic adenocarcinoma subtype of salivary carcinoma NOS (OC). OMEC (A–C) had a diffuse positivity for p63 in most cases (A), a variable expression for SOX10 (B), and a negativity for AR (C). OSDC (D–F) had a negativity for p63 (D), and SOX10 (E), while a positivity for AR (F). OC (G–I) had a positivity for p63 at the tumor periphery (G), while a negativity for SOX10 (H), and AR (I).

FIGURE 3

Example of histopathologic and immunohistochemical features of oncocytic adenocarcinoma subtype of salivary carcinoma NOS (OC) cases no. 1 (A–C) and no. 3 (D–F). Similar to case no. 2, the other cases displayed extensive oncocytic proliferations without mucous cells (A and D). One case displayed an overlapping morphologic appearance with an architecture arranged into a cord-like or compact structure (D). Immunohistochemical analysis showed the same profile of immunostaining: positivity for p63 at the tumor periphery (B and E), whereas SOX10 (C and F) and androgen receptor were negative.

FIGURE 4

Analysis of UMAP projection. The clustering analysis, using gene expression profiling, categorized cases into several groups: OMEC with (N=6) or without MAML2 fusion (N=3), OSDC (N=6), CSDC (N=6), and OC (N=3). Notably, distinct subgroups emerged, with OSDC further dividing into 2 distinct subgroups displaying transcriptomic similarities akin to CSDC. OMEC cases clustered together and were notably separated from both OSDC and CSDC. The OC group showed a close association with the OMEC clusters. Intriguingly, within the OC group, 2 cases appeared slightly separated from the typical OMEC clustering pattern, suggesting a minor transcriptomic difference. CSDC indicates conventional subtype of salivary duct carcinoma; OMEC, oncocytic variant of mucoepidermoid carcinoma; OSDC, oncocytic subtype of salivary duct carcinoma; OC, oncocytic adenocarcinoma subtype of salivary carcinoma NOS.