Oncocytic intraductal carcinoma of salivary glands: a distinct variant with TRIM33-RET fusions and BRAF V600E mutations

Abstract

Aims: Salivary gland intraductal carcinoma (IDC) is a complex ductal neoplasm surrounded by a layer of myoepithelial cells. Recent insights have shown that there are three different types: intercalated duct-like, with frequent NCOA4-RET fusions; apocrine, with salivary duct carcinoma-like mutations; and mixed intercalated duct-like/apocrine, with RET fusions, including TRIM27-RET. In addition, an oncocytic IDC has been described, but it remains unclear whether it represents a fourth variant or simply oncocytic metaplasia of another IDC type. Our aim was to more completely characterize oncocytic IDC.

Methods and results: Six IDCs with oncocytic changes were retrieved from the authors' archives, from three men and three women ranging in age from 45 to 75 years (mean, 63 years). Five arose in the parotid gland, with one in an accessory parotid gland. Four patients with follow-up were free of disease after 1-23 months. Several immunostains (S100, mammaglobin, androgen receptor, and p63/p40) and molecular tools (RNA sequencing, RET fluorescence in-situ hybridisation, BRAF V600E VE1 immunohistochemistry, and Sanger sequencing) were applied. Histologically, the tumours were variably cystic with solid intracystic nodules often difficult to recognise as intraductal. In all, tumour ducts were positive for S100 and mammaglobin, negative for androgen receptor, and completely surrounded by myoepithelial cells positive for p63/p40. Molecular analysis revealed TRIM33-RET in two of six cases, NCOA4-RET in one of six cases, and BRAF V600E in two of six cases. One case had no identifiable alterations.

Conclusions: Oncocytic IDC shares similarities with intercalated duct-like IDC. Although additional verification is needed, the oncocytic variant appears to be sufficiently unique to be now regarded as the fourth distinct subtype of IDC. Because of its indolent nature, oncocytic IDC should be distinguished from histological mimics.

Keywords: NCOA4-RET; TRIM33-RET; BRAF V600E; intraductal carcinoma; salivary gland neoplasms.

Figure 1.

Most oncocytic intraductal carcinomas (case 2 is shown) were partly macrocystic with intracystic secretions and haemorrhage (left), and intracystic solid tumour nodules (right) (A). Case 4, however, had no significant cystic growth and instead appeared as a solid, nodular tumour (B).

Figure 2.

The solid areas of oncocytic intraductal carcinoma (IDC) consisted of back-to-back solid nodules, punctuated by scattered ducts (cases 4 and 1 are shown) (A, B). Most cases also showed areas that were more typical of IDC, with cribriform nodules (case 4 is shown) (C) and papillary cystic growth (case 1 is shown) (D).

Figure 3.

Oncocytes in the oncocytic intraductal carcinomas had abundant, eosinophilic, granular cytoplasm, with round nuclei that have prominent nucleoli (case 4 is shown) (A). Two cases had mixed oncocytic (left) and intercalated duct-like (right) cellular features. The intercalated duct-like cells had a more basophilic appearance, with less cytoplasm and more oval, pale nuclei (case 2 is shown) (B).

Figure 4.

Oncocytic intraductal carcinoma was diffusely positive for S100 (A) and mammaglobin (B). The myoepithelial marker p63 was positive around cysts and cribriform nests (C) and also within the solid tumour components (D). Case 4 is shown.

Figure 5.

Two cases of oncocytic intraductal carcinoma (A) were positive for anti-BRAF V600E VE1 immunohistochemistry (B), with mutations confirmed by Sanger sequencing (inset). Case 6 is shown.