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Note that two tumor cores were examined from each case, except one case of pleomorphic adenoma, carcinoma ex pleomorphic adenoma, mucoepidermoid carcinoma, and polymorphous low-grade adenocarcinoma, in which only one tumor core was generated and examined. Among the three major salivary glands, the parotid gland has the highest proportion of ductal components, yet the submandibular gland has the highest proportion of striated duct cells Fig. Tumors derived from striated ducts, such as Warthin's tumor, retained NIS expression albeit at reduced levels.

NIS expression was also retained in one in three mucoepidermoid carcinomas derived from excretory ducts, and one in five adenoid cystic carcinomas derived from intercalated ducts. NIS expression in Warthin's tumors corroborates their reported scintigraphic characteristics, that is, accumulation of RAI and 99m Tc-pertechnetate 13 , Co-existence of Warthin's tumor in thyroid cancer patients may present as a potential source of diagnostic error for metastasis.

A year-old female with a history of follicular thyroid cancer presented post-thyroidectomy with postsurgical hypothyroidism. Focal areas of increased I uptake were identified in the bilateral superior neck regions Fig. The cytologic diagnosis of fine-needle aspirates from these bilateral discrete foci was oncocytic neoplasm, suspicious for Warthin's tumor. Accordingly, the patient was not subjected to additional I treatment. In this study, we found that NIS expression in salivary ductal cells is tightly modulated among the three components of salivary ducts; that is, NIS expression is primarily restricted to striated ducts.

NIS expression in striated ducts is heterogeneously decreased in inflamed salivary glands and remains, albeit at reduced levels, in tumors derived from striated ducts. The discordance between the greater percentage of NIS-positive striated duct cells and the lower cumulative I radioactivity in submandibular versus parotid glands supports a higher clearance rate of saliva secretion in submandibular glands. Finally, the finding that cumulative I radioactivity in submandibular gland increases with age suggests that the incidence of I-induced submandibular dysfunction may be increased in older patients.

Although salivary secretion decreases with age 15 , 16 , the submandibular gland is known to have a higher spontaneous saliva secretion rate than the parotid gland. Based on studies of external radiation-induced salivary gland damage, it is widely accepted that the parotid gland is more radiosensitive than the submandibular gland. This is attributed in part to its acinar phenotype, composed entirely of serous cells, which are susceptible to membrane lipid peroxidation, resulting in inhibited water excretion While the submandibular gland is a mixture of serous- and mucous-secreting acini, serous-secreting acini predominate 5.

In addition, the relative acinar component in the submandibular gland is greater than in the parotid gland 5.

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Accordingly, radiosensitivity in serous acinar cells may not fully explain the prevalence of parotid dysfunction in I-treated patients. In contrast to patients with head and neck cancer who receive external radiation, we believe that ductal cells rather than acinar cells are the primary targets of I damage in patients with thyroid cancer. This is supported by patients treated with I who often suffer from obstructive symptoms reflecting ductal damage and xerostomia, which is contingent on the extent of acinar damage developed over time 7.

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However, acinar cells may atrophy after prolonged and severe obstruction of salivary ducts The decreased and heterogenous NIS expression noted in numerous cases of sialoadenitis offers insight into the functional alterations observed in salivary glands following I treatment. Patients who suffer from recurrent and chronic I-induced sialoadenitis are characterized by minimal uptake and no secretory clearance when evaluated with 99m Tc-pertechnetate TPT time activity graph 7. The failure of secretory clearance of TPT reflects underlying ductal cell damage. If we could identify the factors that contribute to loss of NIS expression in a subset of striated ducts in inflamed salivary tissues, we may be able to devise novel strategies to shut down NIS expression selectively in striated ducts during RAI treatment to prevent I-induced salivary gland damage.

Taken together, we have further investigated NIS expression in various ductal components of the salivary gland, documented decreased NIS expression in sialoadenitis, and linked NIS expression in salivary gland neoplasms to a subset of ductal cells. Future studies elucidating the mechanisms of NIS modulation in the transitions between intercalated to striated ducts and striated to excretory ducts, as well as in aging and inflamed salivary glands, will facilitate the development of novel strategies to preserve salivary gland function in I-treated thyroid cancer patients.

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Viy McGaughy and Ms. Susie Jones in the Pathology Core Facility for immunohistochemistry services. The authors declare that they have no commercial associations that might create a conflict of interest in connection with this article.

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Find articles by David Jarjoura. Find articles by Sissy M. Copyright , Mary Ann Liebert, Inc. This article has been cited by other articles in PMC. Methods NIS expression was evaluated by immunohistochemistry in human salivary gland tissue microarrays constructed of normal, inflamed, and neoplastic salivary tissue cores.

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Results NIS is highly expressed in the basolateral membranes of the majority of striated ducts, yet weakly expressed in few intercalated and excretory duct cells. Conclusions NIS expression is tightly modulated during the transition of intercalated to striated ducts and striated to excretory ducts in salivary ductal cells. Open in a separate window. Results NIS expression is primarily restricted to the striated ducts of the salivary gland As depicted in Figure 1A , NIS is highly expressed along the basolateral membrane of striated duct cells with decreased expression of much fewer excretory duct cells.

The percentage of NIS-positive striated ducts in parotid glands is statistically lower than in submandibular glands To investigate whether there is a difference in NIS-mediated radionuclide uptake between parotid and submandibular glands, we compared the percentage of NIS-positive duct cells among different salivary glands utilizing a grid superimposed over each NIS-stained normal salivary gland tissue core Fig. NIS expression is reduced in sialoadenitis and absent in most salivary gland neoplasms As summarized in Figure 4A , NIS expression in striated ducts is reduced in inflamed salivary glands and is absent in the majority of salivary gland neoplasms.

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Modulation of Sodium/Iodide Symporter Expression in the Salivary Gland

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