An invasive adenocarcinoma of the accessory parotid gland: a rare example developing from a low-grade cribriform cystadenocarcinoma?

Delgado et al originally described low-grade cribriform cystadenocarcinoma (LGCCA) as a rare low-grade variant of salivary duct carcinoma (SDC) in 1996 [1]. This tumor predominantly consists of intraductal components of the tumor and frequently exhibits papillary-cystic or cribriform proliferation similar to a low-grade ductal carcinoma in situ or atypical ductal hyperplasia of the breast in its histology and biologically indolent features [1‐9]. This low-grade variant of SDC makes a contrast with conventional SDC, which is a clinically aggressive tumor that exhibits high-grade histology similar to an invasive ductal carcinoma of the breast [10, 11]. Evidence for distinct relationships between these 2 entities has not been demonstrated; therefore, this low-grade variant of SDC is categorized as a variant of cystadenocarcinoma, termed LGCCA, in the World Health Organization classification (2005) due to its cystic morphology [2]. Past literatures have described rare cases with LGCCA that subsequently exhibited overt invasive growth in their clinical courses [6]. Herein, we present a case of invasive adenocarcinoma of the accessory parotid gland in a young male that had left vestiges of LGCCA in its histology. The invasive component of the tumor was histologically defined as adenocarcinoma, not otherwise specified (ANOS). This is an interesting case suggests that ANOS could secondarily arise from LGCCA of the salivary gland.

The tumor of the present case was grossly separated from the parotid gland. As the tumor was located on the masseter muscle and a histologically normal salivary gland was observed in the periphery of the tumor, the tumor might have developed from the accessory parotid gland. An accessory salivary gland is occasionally observed on the masseter muscle along with Stensen's duct. Neoplasms arising from an accessory parotid gland are relatively rare, and variable types of malignant tumor have been reported in the literature: carcinoma ex pleomorphic adenoma [12], squamous cell carcinoma [13], mucoepidermoid carcinoma [14], acinic cell carcinoma [15], oncocytic carcinoma [16], basal cell carcinoma [14], and small cell carcinoma [14].

The tumor of the present case included a component exhibiting papillary-cystic proliferation and another component with obvious invasion to the parenchyma with a tubular or scirrhous pattern. Since the invasive component of the tumor did not exhibit specific histological features of any other defined carcinoma, we made the diagnosis of ANOS. There was myoepithelial rimming of the tumor cell nest with positivity for SMA, p63, and CK14 in some areas within the tumor, indicating intraductal proliferation of the duct epithelium. Additionally, the PAS reaction clearly revealed thickened basement membranes around the tumor cell nests. These findings allowed the presumption that the present tumor might have developed in the precedent intraductal tumor. In addition, the tumor cells presented an apocrine-like appearance and included PAS-positive/diastase-resistant granules and hemosiderin in the cytoplasm, in line with findings frequently observed in LGCCA [1‐9]. Strong positivity of S-100 in immunohistochemistry in almost all tumor cells was also characteristic of LGCCA. The aforementioned histological findings indicated the presence of histological vestiges of LGCCA in this tumor, suggesting the possibility that ANOS in this case might have arise secondarily from the tumor initially developing as LGCCA in the salivary gland. In principle, LGCCA has good clinical behavior and exhibits neither recurrence nor metastasis [1‐9], although Weinreb et al reported a rare case of a low-grade intraductal carcinoma of the parotid gland that subsequently progressed to adenosquamous carcinoma [6]. Ihrler et al revealed that an intraductal component was identified in 15 of 22 patients (68%) with ANOS and speculated that the intraductal tumor is identified as the preinvasive precursor of ANOS [17]. Although there has never been a description of the association between ANOS and LGCCA, the present case suggested the possibility that a certain group of ANOS could develop secondarily from LGCCA. To verify this speculation, accumulation of the evidence about ANOS and LGCCA using molecular biology techniques will be required hereafter.

One of the most important differential diagnoses of the present case is a papillary cystic variant of acinic cell carcinoma (PCV-ACC). PCV-ACC preferentially affects young people [18]. Tumor cells of PCV-ACC have intracytoplasmic PAS-positive/diastase-resistant granules (zymogen) and hemosiderin, as observed in LGCCA [18]. However, PCV-ACC is typically negative for S-100 and typically does not exhibit predominance of the intraductal component of the tumor in histology. Sebaceous cell-like foamy cells with microvacuoles are sometimes seen in cystadenocarcinoma of the salivary gland. Intracytoplasmic vacuoles are found also in PCV-ACC, but uniformly-sized, fine microvacuoles might be considered characteristic of cystadenocarcinomas, including LGCCA, rather than PCV-ACC [19]. Another differential diagnosis is SDC. SDC is a high-grade adenocarcinoma that is common in elderly people over 50 years of age [10, 11]. Histologically, SDC resembles a high-grade invasive ductal carcinoma of the breast, frequently accompanied by comedonecrosis and cribriform proliferation [10, 11]. SDC exhibits an apocrine-like appearance with positivity for GCDFP-15 and androgen receptor, which is occasionally observed in LGCCA, but SDC is negative for S-100. SDC usually exhibits a high Ki-67 labeling index, whereas the index in our case was low (approximately 5%). Pleomorphic adenoma and carcinoma ex pleomorphic adenoma should be listed as a differential diagnosis [20], although the tumor of our case did not include a component showing typical histology of pleomorphic adenoma, such as transition from myoepithelium to stromal spindle cell and myxoid or cartilaginous stroma. Neuroendocrine tumors were excluded because rosette-like or trabecular configuration was not observed and almost all tumor cells did not express neuroendocrine markers except for scattered CD56-positive cells.

We presented a case of ANOS developing in the accessory salivary gland that suggests an association with LGCCA. This is an interesting case when considering the relationship between ANOS and LGCCA in oncogenesis. This case is meaningful in reconsidering the disease entity and the process of development of ANOS of the salivary gland.

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