The salivary gland tumor currently known as intraductal carcinoma (IDC) has had a tortuous history. Originally described as IDC by Chen et al in 1983,1 this tumor was subsequently called “low-grade salivary duct carcinoma” and “low-grade cribriform cystadenocarcinoma” until the 2017 World Health Organization classification, which went full circle and came back to the original IDC terminology.2, 3 Conceptually, IDC was believed for years to represent the salivary gland analogue of breast atypical ductal hyperplasia or ductal carcinoma in situ, and much attention was historically given to what relationship, if any, IDC had with salivary duct carcinoma.

Much has been learned recently about IDC. It has become clear that IDC is not a homogeneous entity but rather exists as at least 3 subtypes: 1) classic intercalated duct-like, 2) purely apocrine, and 3) mixed or hybrid. There is a fourth type, oncocytic IDC, which has yet to be characterized completely, and it is possible that even more subtypes may be discovered. It has been shown that each subtype of IDC has unique molecular underpinnings, with intercalated duct-type and mixed/hybrid IDC usually harboring unique RET fusions, with oncocytic IDC harboring RET fusions or BRAF V600E, and with pure apocrine IDC having complex genetics mirroring salivary duct carcinoma.4-10 We now know that IDC can show foci of traditional invasion with a loss of myoepithelial cells.5, 6, 11 Although this appears to be common in pure apocrine IDC where the invasive component is salivary duct carcinoma, it is rare in the other types, where the significance is unclear, and there is no accepted terminology. We also know that although RET rearrangements are common in IDC and are targetable by new systemic agents, the most common (NCOA4-RET) is easily missed on break-apart fluorescence in situ hybridization because this alteration is a tight inversion. Finally, perhaps most surprisingly, it has been shown that for fusion-positive IDC, the characteristic fusion is present not only in the ductal cells known to be neoplastic, but also in the surrounding myoepithelial cells previously presumed to be native.12 Accordingly, although pure apocrine IDC may indeed represent the in situ form of salivary duct carcinoma, the other IDC types are apparently biphasic neoplasms, either benign or possibly low-grade malignant.

In this issue of Cancer Cytopathology, Viswanathan et al13 further unravel the IDC concept by detailing the cytopathologic features of 13 cases, the largest series to date. This group found that IDC is usually classified as salivary gland neoplasm of uncertain malignant potential or malignant in the current Milan classification. Moreover, they found distinct differences between the cellular features of low-grade intercalated duct-like IDC and high-grade apocrine IDC. Particularly interesting was the fact that the myoepithelial cells of IDC are also present on fine-needle aspiration (FNA) smears, and as a result, IDC must now be included in the FNA differential diagnosis of biphasic salivary gland neoplasms. With increased recognition of the existence of IDC as well as its cytopathologic, immunohistochemical, and molecular features, it may soon be feasible to identify IDC prospectively on FNA with a combined cytopathology/immunohistochemical/molecular approach. Accurately identifying IDC on FNA will not only allow clinicians to appropriately plan their surgical approach but also allow oncologists to know the RET fusion status early on; this is particularly important in the case of an IDC with frank tissue invasion and/or metastasis. This article is an important next step in the recent explosion of knowledge surrounding IDC, and it is hoped that further studies will build on it to understand this enigmatic tumor more completely.

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The author made no disclosures.