Primary carcinoma of salivary gland with neuroendocrine differentiation is rare accounting for only 1% of all parotid gland tumors [1
]. Neuroendocrine tumors of the parotid gland that have been reported previously were most commonly metastatic or seen in association with co-existing carcinoid tumor elsewhere [1
]. The various primary salivary gland carcinomas that have been reported to show positivity for neuroendocrine markers include a large majority of small cell carcinoma, occasional cases of adenocarcinoma, Warthin’s tumor, adenoid cystic carcinoma, and ACC [5
ACCs occur usually in the 3rd and 4th decade with a mean age of 44 years and shows predilection to occur in females [9
]. Our patient was a 48 year old lady. Most commonly the parotid gland is affected (84%) [9
] as was in our case, however it is also known to occur in submandibular and minor salivary glands [9
]. Clinically, it presents as a slowly growing painless or painful mass with infrequent facial nerve involvement (5–10%) and pursues a protracted clinical course [9
]. Our patient had a gradually increasing painless swelling with rapid increase in size of recent onset without clinical and intraoperative evidence of facial nerve involvement.
ACCs are usually rounded and partially or completely encapsulated with predominant solid, brown cut surface with or without cystic areas [9
]. In our case the tumor was predominantly solid with a small superficial cyst filled with clear fluid. ACCs have been reported to mimic pleomorphic adenoma grossly especially if it is recurrent [10
Microscopically, the tumor is comprised of variably sized lobules of neoplastic cells with broad fronts of invasion [9
]. The cells have a small central to eccentrically placed nuclei with a finely granular to clear cytoplasm—features suggestive of differentiation towards the ductal and acinar cells of normal salivary gland. The granules are fine, numerous, basophilic, and PAS positive [9
]. The granularity of the cells is markedly variable in the same tumor field [9
]. Similar features were seen in the ACC component of the tumor in our case. Immunohistochemically, the tumor cells express Cytokeratin (especially low molecular weight), Carcinoembryonic antigen and amylase [9
]. In our case the cells of ACC component showed focal positivity for Cytokeratin.
ACCs expressing neuroendocrine markers have been reported. Although not yet accepted as a distinct clinicopathological entity, some studies have reported neuroendocrine differentiation in ACC based on immunohistochemistry and ultra structural studies [5
Hayashi et al. [5
] in 1987 performed a study of expression of neuropeptides in various parotid gland tumors which included 11 cases of ACCs along with other benign and malignant tumors. They reported the expression of Vasoactive Intestinal Polypeptide (VIP) in all the 11 cases of ACCs however was not seen in any other parotid gland tumor. The cells of the ACCs stained with Grimelius impregnation and six of these cases on ultra structural study demonstrated presence of large dense core granules along with smaller numerous secretory granules and well developed golgi apparatus and rough endoplasmic reticulum.
In another study by Hayashi et al. [6
] in 1990, they studied the expression of neuroendocrine markers—NSE and Leu-7 in various parotid gland tumors. Included in this study were 12 cases of ACC of which seven expressed only Leu-7 only. Other tumors of the salivary gland expressed either or both NSE and Leu-7.
Ito et al. [7
] in 1990 reported a case of ACC with neuroendocrine differentiation in the parotid gland. Light microscopy showed a classical clear cell ACC. Staining for Grimelius impregnation and ultra structural evidence of dense core granules were suggestive of neuroendocrine features in the cells of the tumor.
In all the above studies, the evidence of neuroendocrine differentiation was evident only on special staining, immunoexpression of neuropeptides and ultra structural morphology. However, none of the cases showed any histomorphological evidence of neuroendocrine differentiation. The studies conducted by Hayashi et al. [5
], screened for neuropeptide expression in various tumors of the parotid gland. None of the cases of ACC in their studies showed histomorphological features of neuroendocrine tumor. Similarly the reported case by Ito et al. [7
] had a histomorphology, compatible with classical clear cell ACC without any histological feature suggestive of neuroendocrine differentiation.
However, in our case the diagnosis of this tumor was very intriguing. Preoperatively there were varied diagnosis of pleomorphic adenoma radiologically and oncocytic tumor versus Warthin’s tumor on cytopathology. Intraoperatively, the suspicion of Warthin’s tumor was high. Even the initial histological sections were suggestive of a very rare diagnosis of primary neuroendocrine tumor. However, after further sectioning of the tumor mass in search of other commoner primary tumors, small areas of ACC was documented. Such extensive degree of neuroendocrine differentiation in an ACC, morphologically and immunohistochemically, to the extent as to mimic a primary neuroendocrine tumor of the parotid gland, has not been reported previously to the best of our knowledge.
A possibility of peripheral entrapped acinic cell with primary neuroendocrine tumor was also ruled out; since both the morphological areas of the tumor were in gradual continuity with each other and neither did the acinic cells appear to be compressed at the periphery.
Hayashi et al. used Leu-7, NSE, and VIP to demonstrate the neuroendocrine differentiation [5
]. In our case confirmation of neuroendocrine differentiation was done using Synaptophysin, NSE, Chromogranin A, and S-100.
A possibility of divergent differentiation or de-differentiation has been discussed previously. De-differentiated ACC is an aggressive form of the tumor requiring adjuvant treatment, carrying a poor prognosis. It is histologically characterized as a composite tumor with ACC along with a poorly or undifferentiated carcinoma [11
]. Ito et al. [7
] suggested that a tumor arising from a common stem cell can lead to divergent differentiation into both ACC and neuroendocrine tumor in the same mass. However, in our case, there were no areas showing poor differentiation or markedly anaplastic morphology. Also after 6 months of follow-up the patient had no evidence of tumor recurrence. The concept of divergent differentiation could be a possible explanation for the phenomenon, however requiring further studies on these tumors.
Grading of ACC has been attempted based on histo-morphological features, segregating them into well, moderately and poorly differentiated tumor [11
], showing good prognostic correlation. However, it does not account into presence of neuroendocrine features as affecting the grading of the tumor. Also the presented tumor is very rare, making it difficult to assess the impact on grading and prognosis.
Tumors with similar morphology have been reported in the pancreas also. The reported tumors demonstrated acinar cell tumors with variable component of neuroendocrine differentiation. The neuroendocrine nature of the cells was proven predominantly on the basis of immunohistochemistry and electron microscopy [13
]. Some authors have reported that the presence of neuroendocrine differentiation in pancreatic acinar cell carcinoma carries a better prognosis that the tumor without it [15