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1.  Modulation of Sodium/Iodide Symporter Expression in the Salivary Gland 
Thyroid  2013;23(8):1029-1036.
Background
Physiologic iodide-uptake, mediated by the sodium/iodide symporter (NIS), in the salivary gland confers its susceptibility to radioactive iodine–induced damage following 131I treatment of thyroid cancer. Subsequent quality of life for thyroid cancer survivors can be decreased due to recurrent sialoadenitis and persistent xerostomia. NIS expression at the three principal salivary duct components in various pathological conditions was examined to better our understanding of NIS modulation in the salivary gland.
Methods
NIS expression was evaluated by immunohistochemistry in human salivary gland tissue microarrays constructed of normal, inflamed, and neoplastic salivary tissue cores. Cumulative 123I radioactivity reflecting the combination of NIS activity with clearance of saliva secretion in submandibular and parotid salivary glands was evaluated by single-photon emission computed tomography/computed tomography imaging 24 hours after 123I administration in 50 thyroid cancer patients.
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. The ratio of 123I accumulation between parotid and submandibular glands is 2.38±0.19. However, the corresponding ratio of 123I accumulation normalized by volume of interest is 1.19±0.06. The percentage of NIS-positive striated duct cells in submandibular salivary glands was statistically greater than in parotid salivary glands, suggesting a higher clearance rate of saliva secretion in submandibular salivary glands. NIS expression in striated ducts was heterogeneously decreased or absent in sialoadenitis. Most ductal salivary gland tumors did not express NIS. However, Warthin's tumors of striated duct origin exhibited consistent and intense NIS staining, corresponding with radioactive iodine uptake.
Conclusions
NIS expression is tightly modulated during the transition of intercalated to striated ducts and striated to excretory ducts in salivary ductal cells. NIS expression in salivary glands is decreased during inflammation and tumor formation. Further investigation may identify molecular targets and/or pharmacologic agents that allow selective inhibition of NIS expression/activity in salivary glands during radioactive iodine treatment.
doi:10.1089/thy.2012.0571
PMCID: PMC3752512  PMID: 23441638
2.  Mucoepidermoid carcinoma in a thyroglossal duct remnant 
Highlights
•Thyroglossal duct remnants should be surgically excised, if possible due to the risk of malignant transformation.•Mucoepidermoid carcinomas can present in diverse locations outside of salivary glands.•A high index of suspicion for malignancy is required with neck masses in adults, especially following a period of rapid growth.•If aggressively treated, patients with mucoepidermoid carcinoma outside of salivary glands may still have a favourable prognosis.
Introduction
Thyroglossal duct cysts (TDC) are common midline neck swellings resulting from embryological remnants of the thyroglossal duct. They often contain ectopic thyroid tissue and malignant transformation has been reported, most commonly to papillary thyroid carcinoma. Mucoepidermoid carcinoma (MEC) usually occurs in the salivary glands and only rarely in the thyroid. This is the first case of a MEC occurring within a thyroglossal duct remnant.
Presentation of a case
A 73 year old lady presented with a thyroglossal duct cyst. She declined surgical excision, as she was adamant she wanted to avoid surgery. The neck mass rapidly enlarged at two years following initial diagnosis. Fine needle aspiration cytology was suspicious for carcinoma. She underwent total thyroidectomy and selective central compartment neck dissection with adjuvant radiotherapy. She remains alive and well two years post treatment.
Discussion
Mucoepidermoid carcinoma is the most common malignant neoplasm of salivary glands, although it has rarely been reported in diverse locations including the thyroid, lung and pancreas. To the best of our knowledge, this is the first reported case of mucoepidermoid carcinoma arising from a thyroglossal duct remnant.
Conclusion
This case adds weight to the literature favouring surgical excision of thyroglossal duct remnants due to the risk of malignant transformation.
doi:10.1016/j.ijscr.2015.04.028
PMCID: PMC4529606  PMID: 26101054
Mucoepidermoid carcinoma; Thyroglossal duct; Head and neck neoplasm; Salivary gland
3.  Thyroid Abnormalities in Survivors of Childhood Cancer 
Ob­jec­ti­ve: To investigate the late side effects of childhood cancer therapy on the thyroid gland and to determine the risk factors for development of thyroid disorder among childhood cancer survivors.
Methods: One hundred and twenty relapse-free survivors of childhood cancer (aged 6-30 years) were included in this study. The diagnoses of patients were lymphoma, leukemia, brain tumor, rhabdomyosarcoma and nasopharyngeal carcinoma (NPC). The patients were divided into two groups depending on the treatment: group 1-chemotherapy (ChT) only (n=52) and group 2-combination therapy of ChT + radiotherapy (RT) (head/neck/thorax) (n=68). Thyroid function tests, urinary iodine levels, and thyroid gland ultrasound examinations were evaluated in both groups.
Results: Incidence of thyroid disease was 66% (n=79) in the survivors. The thyroid abnormalities were: hypothyroidism (HT) (n=32, 27%), thyroid nodules (n=27, 22%), thyroid parenchymal heterogeneity (n=40, 33%), autoimmune thyroiditis (n=36, 30%), and thyroid malignancy (n=3, 2%). While the incidence of HT and thyroid nodules in group 2 was significantly higher than in group 1, the incidence of thyroid parenchymal heterogeneity and autoimmune thyroiditis was similar in the two patient groups. HT and thyroid malignancy were seen only in group 2. In multivariate logistic regression analysis, a history of Hodgkin lymphoma (HL), brain tumor and NPC, as well as cervical irradiation and 5000-5999 cGy doses of radiation were found to constitute risk factors for HT. History of HL and 4000-5999 cGy doses of radiation were risk factors for thyroid nodules. Head/neck irradiation and treatment with platinum derivatives were risk factors for autoimmune thyroiditis. In univariate analysis, a history of NPC, cervical + nasopharyngeal irradiation, and treatment with platinum derivatives were risk factors for thyroid parenchymal heterogeneity.
Conclusion: Our results indicate that there is especially an increased risk of HT and thyroid nodules in patients treated with combination therapy of ChT with head/neck/thorax RT. Although chemotherapeutic agents per se do not seem to cause HT, longer follow-up is needed to assess whether or not there is an increased risk for autoimmune thyroiditis and thyroid parenchymal heterogeneity after antineoplastic therapy.
doi:10.4274/jcrpe.1326
PMCID: PMC4293642  PMID: 25241607
Childhood cancer survivors; Chemotherapy; Radiotherapy; Late effects; Thyroid
4.  A review: Immunological markers for malignant salivary gland tumors 
Salivary gland cancers are rare. Around 8 out of 10 salivary gland tumors (80%) are in the parotid. Just fewer than 2 out of 10 salivary gland cancers develop in the other two salivary glands – the submandibular or sublingual glands. Fewer than 1 in 10 cancers start in the minor salivary glands. There are many different types of salivary gland cancers. The most common is mucoepidermoid carcinoma (MEC). Just over 3 out of 10 (25–35%) salivary gland cancers (SGT, SGC) are of this type. The others include adenoid cystic carcinoma (ACC), acinic cell carcinoma, carcinoma ex-pleomorphic adenoma (Ca-PA), polymorphous low grade adenocarcinoma (PLGA) and some newly discovered salivary gland tumors. Because of the infrequency of salivary gland tumors and their complex histopathological diagnosis, it is difficult to exactly predict their clinical course by means of its recurrence, malignant progression or metastasis. Salivary gland tumors always pose problems in diagnosis.
This review provides an insight into the recent concepts and immunohistochemical markers to diagnose the malignant salivary gland tumors (SGT), thus guiding the Ear, Nose and Throat specialists, Oral and Maxillofacial Surgeons, General Pathologists and other medical and dental specialists thereby enabling them to make correct diagnosis and provide the appropriate treatment.
doi:10.1016/j.jobcr.2014.05.003
PMCID: PMC4252643  PMID: 25737930
Salivary gland diseases; Malignancy of salivary gland; Mucoepidermoid carcinoma; Adenoid cystic carcinoma; Markers for salivary gland malignancies
5.  Assessment of Salivary Gland Function Using Salivary Scintigraphy in Pre and Post Radioactive Iodine Therapy in Diagnosed Thyroid Carcinoma Patients 
Introduction
Thyroid carcinoma represents less than 1% of all cancers. The first line of treatment for thyroid cancer is partial/total thyroidectomy. High-dose Iodine131 therapy using Iodine radioisotopes is commonly used in patients with well differentiated thyroid carcinoma after total thyroidectomy. In this process, the non-thyroidal tissues, such as, salivary gland, stomach and breast tissues also take up radioactive iodine. Salivary gland scintigraphy is widely accepted as a sensitive and valid method for evaluation of salivary gland dysfunction after Radioactive Iodine131 Therapy (RIT).
Aim
To assess and compare the salivary flow rates, relative uptake and ejection fractions in parotid and submandibular glands just before and one month after Iodine131 therapy.
Materials and Methods
The study was conducted on 24 patients diagnosed with well differentiated thyroid carcinoma who underwent partial/total thyroidectomy and were due for radioactive iodine therapy. These patients were divided into two groups based on the lesion based dosimetry (Group A: 60-100Gy; Group B: 100-150Gy). Salivary gland assessment was done by salivary gland scintigraphy before and after RIT.
Statistical Analysis
The data collected was tabulated and statistically analysed using SPSS software version16 using paired t-test and individual sample t-test.
Results
A statistically significant difference in the uptake percent and ejection fraction percent in the parotid and submandibular glands before RIT and one month after RIT was observed in the study.
Conclusion
We inferred from the study that there was an overall decrease in uptake percent and ejection fraction percent one month post RIT in both parotid and submandibular glands. Also, a statistically significant difference was noted in the uptake and ejection fraction percent between Group A and Group B concluding the fact that the damage is dose related.
doi:10.7860/JCDR/2016/16091.7121
PMCID: PMC4740706  PMID: 26894178
Radionuclide imaging; Radioisotopes; Xerostomia
6.  Analysis of the tumour suppressor genes, FHIT and WT-1, and the tumour rejection genes, BAGE, GAGE-1/2, HAGE, MAGE-1, and MAGE-3, in benign and malignant neoplasms of the salivary glands 
Molecular Pathology  2003;56(4):226-231.
Aims: Molecular genetic changes involved in tumorigenesis and malignant transformation of human tumours are novel targets of cancer diagnosis and treatment. This study aimed to analyse the expression of putative tumour suppressor genes, FHIT and WT-1, and tumour rejection genes, BAGE, GAGE-1/2, MAGE-1, MAGE-3, and HAGE (which are reported to be important in human cancers), in salivary gland neoplasms.
Methods: Gene expression was analysed by reverse transcription polymerase chain reaction (RT-PCR) in normal salivary gland tissue and 44 benign and malignant salivary gland tumours.
Results: Aberrant FHIT transcripts were found in one of 38 normal salivary glands, three of 28 adenomas, and two of 16 carcinomas. WT-1 mRNA was detectable in two adenomas and five carcinomas. Immunoblotting showed that WT-1 mRNA expression was associated with raised WT-1 protein concentrations. RT-PCR for detection of BAGE, GAGE, and MAGE gene expression was positive in two adenomas and nine carcinomas, but negative in normal salivary gland tissue. HAGE mRNA was found in two normal salivary glands, 11 benign, and eight malignant tumours.
Conclusions: FHIT mRNA splicing does not appear to be involved in the genesis of salivary gland neoplasms. The upregulation of WT-1 mRNA in tumours of epithelial/myoepithelial phenotype may imply a potential role of WT-1 in the genesis and/or cellular differentiation of these salivary gland tumours. The tumour rejection genes were more frequently, but not exclusively, expressed in malignant salivary gland tumours than in benign neoplasms, although none was suitable as a diagnostic marker of malignancy in salivary gland neoplasms.
PMCID: PMC1187325  PMID: 12890744
salivary gland neoplasms; FHIT; WT-1; BAGE; GAGE; MAGE; HAGE
7.  A review on thyroid cancer during pregnancy: Multitasking is required 
Journal of Advanced Research  2016;7(4):565-570.
Graphical abstract
Thyroid cancer is the second most common cancer diagnosed during pregnancy after breast cancer. The goal of management is to control malignancy and prevent maternal and fetal complications as a result of maternal hypothyroidism. The role of female sex hormones as an etiologic factor was investigated, with no clear association. Pregnancy can cause an increase in size of a previously existed thyroid nodule through the structural similarity between TSH and BHCG, and the normally expressed estrogen receptors on thyroid gland cells. Effect of pregnancy on development and prognosis of differentiated thyroid malignancies (papillary and follicular) has also been studied. The prognosis of thyroid cancer is not worse in patients diagnosed during pregnancy or those who got pregnant after curative treatment. Termination of pregnancy is not indicated at all, surgery can be delayed till after delivery except in rapidly growing aggressive tumors. While radioactive iodine ablation is absolutely contra-indicated, the new systemic therapies are not well studied during pregnancy. However, almost all these new agents are classified as FDA category C or D and are better to be avoided. The effect of pregnancy on other types of thyroid cancer (medullary and anaplastic thyroid tumors) is not well studied because of very low incidence with pregnancy. The endocrinological management of thyroid cancer during pregnancy is of utmost importance. The hypothyroidism after total thyroidectomy can cause fetal hypothyroidism. Therefore, the management of thyroid cancer related to pregnancy needs a multidisciplinary team.
doi:10.1016/j.jare.2016.02.007
PMCID: PMC4921779  PMID: 27408758
Thyroid cancer; Pregnancy; Pregnancy related disorders; Tyrosine kinase inhibitors; Radioactive iodine
8.  RETRACTED ARTICLE: Radiation Sialadenitis Induced by High-dose Radioactive Iodine Therapy 
Radioactive iodine (131I) is accumulated in the thyroid tissue and plays an important role in the treatment of differentiated papillary and follicular cancers after thyroidectomy. Simultaneously, 131I is concentrated in the salivary glands and secreted into the saliva. Dose-related damage to the salivary parenchyma results from the 131I irradiation. Salivary gland swelling and pain, usually involving the parotid, can be seen. The symptoms may develop immediately after a therapeutic dose of 131I and/or months later and progress in intensity with time. In conjunction with the radiation sialadenitis, secondary complications reported include xerostomia, taste alterations, infection, increases in caries, facial nerve involvement, candidiasis, and neoplasia. Prevention of 131I sialadenitis may involve the use of sialogogic agents to hasten the transit time of the radioactive iodine through the salivary glands. However, studies are not available to delineate the efficacy of this approach. Treatment of the varied complications that may develop encompass numerous approaches and include gland massage, sialogogic agents, duct probing, antibiotics, mouthwashes, good oral hygiene, and adequate hydration. Recently interventional sialoendoscopy has been introduced an effective tool for the management of patients with 131I-induced sialadenitis that is unresponsive to medical treatment.
doi:10.1007/s13139-010-0027-y
PMCID: PMC4035796  PMID: 24895501
Salivary gland; Radioiodine
9.  Oncocytic tumours of the salivary gland, kidney, and thyroid: nuclear DNA patterns studied by flow cytometry. 
British Journal of Cancer  1986;53(6):799-804.
Nuclear DNA ploidy studies were performed by flow cytometry on extracted nuclei from 12 oncocytic tumours of the salivary gland, 65 oncocytic tumours of the kidney, and 37 oncocytic tumours of the thyroid gland from the pathology archives of the Mayo Clinic. In order to provide an interesting clinical spectrum, three different classes of well-differentiated oncocytic tumours were selected for examination. Salivary gland oncocytic tumours were chosen for their generally benign behaviour. Oncocytic thyroid cancers exhibiting malignant potential because of local invasion, were thought to represent the opposite extreme of aggressiveness. Renal oncocytic tumours were known to demonstrate an intermediate degree of malignancy. All of the oncocytic salivary gland tumours showed a 'normal' DNA histogram and had a benign clinical course. For the oncocytic tumours of the kidney, 45% of DNA histograms were normal, 40% exhibited a significant increase in the DNA tetraploid/polyploid (4C) peak, and 15% showed a DNA aneuploid peak. Three patients with a DNA tetraploid pattern developed tumour metastasis and two have died from metastatic renal cancer. Among the oncocytic thyroid cancers, 27% were normal, 22% exhibited an increased DNA tetraploid peak, and 51% had a distinct DNA aneuploid peak. None of the thyroid tumour patients with a normal DNA pattern or with an increased DNA tetraploid peak died as a result of thyroid malignancy. In contrast, 58% of patients whose thyroid tumours showed a DNA aneuploid peak subsequently died from thyroid cancer.
PMCID: PMC2001404  PMID: 3718832
10.  Suppression of Radiation-Induced Salivary Gland Dysfunction by IGF-1 
PLoS ONE  2009;4(3):e4663.
Background
Radiation is a primary or secondary therapeutic modality for treatment of head and neck cancer. A common side effect of irradiation to the neck and neck region is xerostomia caused by salivary gland dysfunction. Approximately 40,000 new cases of xerostomia result from radiation treatment in the United States each year. The ensuing salivary gland hypofunction results in significant morbidity and diminishes the effectiveness of anti-cancer therapies as well as the quality of life for these patients. Previous studies in a rat model have shown no correlation between induction of apoptosis in the salivary gland and either the immediate or chronic decrease in salivary function following γ-radiation treatment.
Methodology/Principal Finding
A significant level of apoptosis can be detected in the salivary glands of FVB mice following γ-radiation treatment of the head and neck and this apoptosis is suppressed in transgenic mice expressing an activated mutant of Akt (myr-Akt1). Importantly, this suppression of apoptosis in myr-Akt1 mice preserves salivary function, as measured by saliva output, three and thirty days after γ-radiation treatment. In order to translate these studies into a preclinal model we found that intravenous injection of IGF1 stimulated activation of endogenous Akt in the salivary glands in vivo. A single injection of IGF1 prior to exposure to γ-radiation diminishes salivary acinar cell apoptosis and completely preserves salivary gland function three and thirty days following irradiation.
Conclusions/Significance
These studies suggest that apoptosis of salivary acinar cells underlies salivary gland hypofunction occurring secondary to radiation of the head and neck region. Targeted delivery of IGF1 to the salivary gland of patients receiving head and neck irradiation may be useful in reducing or eliminating xerostomia and restoring quality of life to these patients.
doi:10.1371/journal.pone.0004663
PMCID: PMC2646143  PMID: 19252741
11.  Aberrant Activation of the RANK Signaling Receptor Induces Murine Salivary Gland Tumors 
PLoS ONE  2015;10(6):e0128467.
Unlike cancers of related exocrine tissues such as the mammary and prostate gland, diagnosis and treatment of aggressive salivary gland malignancies have not markedly advanced in decades. Effective clinical management of malignant salivary gland cancers is undercut by our limited knowledge concerning the key molecular signals that underpin the etiopathogenesis of this rare and heterogeneous head and neck cancer. Without knowledge of the critical signals that drive salivary gland tumorigenesis, tumor vulnerabilities cannot be exploited that allow for targeted molecular therapies. This knowledge insufficiency is further exacerbated by a paucity of preclinical mouse models (as compared to other cancer fields) with which to both study salivary gland pathobiology and test novel intervention strategies. Using a mouse transgenic approach, we demonstrate that deregulation of the Receptor Activator of NFkB Ligand (RANKL)/RANK signaling axis results in rapid tumor development in all three major salivary glands. In line with its established role in other exocrine gland cancers (i.e., breast cancer), the RANKL/RANK signaling axis elicits an aggressive salivary gland tumor phenotype both at the histologic and molecular level. Despite the ability of this cytokine signaling axis to drive advanced stage disease within a short latency period, early blockade of RANKL/RANK signaling markedly attenuates the development of malignant salivary gland neoplasms. Together, our findings have uncovered a tumorigenic role for RANKL/RANK in the salivary gland and suggest that targeting this pathway may represent a novel therapeutic intervention approach in the prevention and/or treatment of this understudied head and neck cancer.
doi:10.1371/journal.pone.0128467
PMCID: PMC4464738  PMID: 26061636
12.  Diagnosis and Treatment of Patients with Thyroid Cancer 
Background
Thyroid cancer is the most common malignancy of the endocrine system, representing 3.8% of all new cancer cases in the United States and is the ninth most common cancer overall. The American Cancer Society estimates that 62,450 people in the United States will be diagnosed with thyroid cancer in 2015, and 1950 deaths will result from the disease.
Objective
To review the current approach to the diagnosis and treatment of patients with thyroid cancer.
Discussion
Over the past 3 decades, there has been a dramatic increase in the number of people diagnosed with thyroid cancer, which may be attributable to the wide use of imaging studies, including ultrasounds, computed tomography, magnetic resonance imaging, and positron emission tomography scans that incidentally detect thyroid nodules. Thyroid cancer is divided into several main types, with papillary thyroid cancer being the most common. The treatment options for patients with thyroid cancer include the surgical removal of the entire thyroid gland (total thyroidectomy), radioactive iodine therapy, and molecular-targeted therapies with tyrosine kinase inhibitors. This article summarizes the diagnosis and treatment of thyroid cancer, with recommendations from the American Thyroid Association regarding thyroid nodules and differentiated thyroid cancer. Recently approved drugs and treatment trends are also explored.
Conclusion
The prognosis and treatment of thyroid cancer depend on the tumor type and its stage at the time of diagnosis. Many thyroid cancers remain stable, microscopic, and indolent. The increasing treatment options for patients with thyroid cancer, including therapies that were recently approved by the US Food and Drug Administration, have kept the mortality rate from this malignancy low, despite the increase in its incidence. Early diagnosis and appropriate treatment can improve prognosis and reduce mortality.
PMCID: PMC4415174  PMID: 25964831
endocrine system; thyroid cancer; thyroidectomy; tyrosine kinase inhibitors; radioactive iodine; fine-needle aspiration biopsy
13.  Salivary Function after Radioiodine Therapy: Poor Correlation between Symptoms and Salivary Scintigraphy 
Objective
Symptoms of salivary gland dysfunction frequently develop after radioactive iodine (RAI) therapy, but have generally not been correlated with assessment of salivary gland functioning. The aim of this study was to determine whether there was a correlation between salivary symptoms and salivary functioning as assessed by salivary scan parameters.
Methods
This was a non-randomized observational study. Fifteen patients receiving RAI therapy for differentiated thyroid cancer completed a questionnaire assessing their salivary and nasal symptoms prior to their therapy and 3 and 12 months after their therapy. Salivary gland scanning using technetium-99m pertechnetate was performed at the same time points. In addition, protective measures used at the time of radioiodine administration, such as use of fluids and sour candy, were also documented. Measures of salivary gland accumulation and secretion were correlated with scores of salivary and nasal symptomatology and any effects of protective measures were assessed.
Results
The mean number of salivary, nasal, and total symptoms at 3 months increased significantly over the number of symptoms at baseline by 3.7, 2.7, and 6.3 symptoms, respectively (p values 0.001, 0.0046, and <0.001, respectively). The mean increases in the number of salivary, nasal, and total symptoms at 12 months were non-significant at 1.3, 1.3, and 2.5 symptoms, respectively. The mean right parotid gland accumulation and secretion of radioisotope declined significantly at 3 months, compared with baseline. The changes in left parotid and right and left submandibular function were non-significant. There was no association between the increase in salivary, nasal, or total symptoms and the change in scintigraphy measures. However, the increases in nasal and total symptoms were significantly greater in those with co-existent Hashimoto’s disease, compared with those without this condition (p values 0.01 and 0.04, respectively). Nasal symptoms decreased (p value 0.04) and total symptoms trended to decrease (p value 0.08) in those who used sour candies, compared with those who did not. Increasing body mass index was significantly associated with increasing nasal symptoms (p value 0.05). Greater decline in salivary parameters at 3 months compared with baseline was generally associated with heavier body weight, decreased thyroid cancer stage, absence of Hashimoto’s thyroiditis, and pre-menopausal status.
Conclusion
Salivary and nasal symptoms increased and salivary scintigraphy parameters decreased after radioiodine therapy. However, the increased symptoms did not correlate with decrements in salivary gland accumulation or secretion. Moreover, the variables associated with symptoms and changes in salivary scan parameters differed. Therefore, a better understanding of the relationship between salivary gland symptoms and functioning is needed. Factors affecting susceptibility to salivary and nasal damage after radioiodine therapy need to be better elucidated, so that modifiable factors can be identified.
doi:10.3389/fendo.2015.00100
PMCID: PMC4470264  PMID: 26136724
salivary symptoms; salivary dysfunction; salivary scintigraphy; nasal symptoms; radioiodine therapy
14.  Anatomy, biogenesis, and regeneration of salivary glands 
An overview of the anatomy and biogenesis of salivary glands is important in order to understand the physiology, functions and disorders associated with saliva. A major disorder of salivary glands is salivary hypofunction and resulting xerostomia, or dry mouth, which affects hundreds of thousands of patients per year who suffer from salivary gland diseases or undergo head and neck cancer treatment. There is currently no curative therapy for these patients. To improve these patients’ quality of life, new therapies are being developed based on findings in salivary gland cell and developmental biology. Here we discuss the anatomy and biogenesis of the major human salivary glands and the rodent submandibular gland (SMG), which has been used extensively as a research model. We also include a review of recent research on the identification and function of stem cells in salivary glands, and the emerging field of research suggesting nerves play an instructive role during development and may be essential for adult gland repair and regeneration. Understanding the molecular mechanisms involved in gland biogenesis provides a template for regenerating, repairing or reengineering diseased or damaged adult human salivary glands. We provide an overview of three general approaches currently being developed to regenerate damaged salivary tissue, including gene therapy, stem cell-based therapy, and tissue engineering. In the future, it may be that a combination of all three will be used to repair, regenerate and reengineer functional salivary glands in patients to increase the secretion of their saliva, the focus of this monograph.
doi:10.1159/000358776
PMCID: PMC4048853  PMID: 24862590
15.  Salivary Gland Function 5 Years After Radioactive Iodine Ablation in Patients with Differentiated Thyroid Cancer: Direct Comparison of Pre- and Postablation Scintigraphies and Their Relation to Xerostomia Symptoms 
Thyroid  2013;23(5):609-616.
Background
Chronic sialadenitis is one of the most frequent chronic complications after radioactive iodine (RAI) therapy for thyroid cancer. To evaluate the long-term effects of RAI ablation on salivary gland function, we investigated scintigraphic changes in salivary glands by direct comparison of two salivary gland scintigraphies (SGSs) taken before and at 5 years after an RAI ablation.
Methods
SGS was performed just before RAI ablation (pre-SGS) and ∼5 years after RAI ablation (F/U SGS) in 213 subjects who underwent thyroidectomy for thyroid cancer. The uptake score (U score) was graded, and the ejection fraction (EF) was quantified for the parotid and submandibular glands at pre-SGS and F/U SGS. Changes in salivary gland function were graded as mild, moderate, or severe according to the differences in U score and EF between the two SGSs. Xerostomia was assessed and compared with the SGS findings.
Results
Worsening of the U score was observed in 182 of 852 salivary glands (total: 21.3%; mild: 4.2%, moderate: 7.4%, severe: 9.7%), and 47.4% of the patients had a worsening U score for at least one of four salivary glands. A decrease in EF was observed in 173 of 852 salivary glands (total: 20.3%; mild: 5.4%, moderate: 6.8%, severe: 8.1%), and 43.7% of the patients experienced a decrease in the EF of at least one of the four salivary glands. Bilateral parotid gland dysfunction was the most commonly observed condition. Thirty-five (16.4%) patients complained of xerostomia at 5 years after RAI ablation. Scintigraphic changes in salivary gland function and xerostomia were more common in patients receiving 5.55 GBq, compared with 3.7 GBq. Xerostomia was more common in patients with submandibular gland dysfunction than those with parotid gland dysfunction (68.8% vs. 33.3%, p<0.05). The number of dysfunctional salivary glands was correlated with xerostomia (p<0.01).
Conclusion
About 20% of the salivary glands were dysfunctional on SGS 5 years after a single RAI ablation, especially in patients who received higher doses of RAI. While parotid glands are more susceptible to 131I-related damage, xerostomia was more associated with submandibular gland dysfunction and the prevalence of dysfunctional salivary glands.
doi:10.1089/thy.2012.0106
PMCID: PMC3643252  PMID: 23153322
16.  The efficacy of iodine-125 permanent brachytherapy versus intensity-modulated radiation for inoperable salivary gland malignancies: study protocol of a randomised controlled trial 
BMC Cancer  2016;16:193.
Background
Radiation therapy is the method of choice for subjects with inoperable salivary gland malignancies. I-125 brachytherapy, delivering a high radiation dose to a tumor but sparing surrounding normal tissues, is supposed to be ideal modality for the treatment of salivary gland malignancies. We designed a randomised controlled clinical trial to compare the efficacy of I-125 permanent brachytherapy (PBT) versus intensity-modulated radiation therapy (IMRT) for inoperable salivary gland malignancies.
Methods/Design
In this study, inclusion criteria are subjects with inoperable salivary gland malignancies, aged 18–80 years, have provided informed consent, with at least one measurable tumor focus, be able to survive ≥3 months, Karnofsky performance status ≥60, have adequate hematopoietic function of bone marrow, have normal liver and kidney function, and are willing to prevent pregnancy.
Exclusion criteria include a history of radiation or chemotherapy, a history of other malignant tumors in the past 5 years, receiving other effective treatments, participating in other clinical trials, with circulatory metastasis, cognitive impairment, severe cardiovascular and cerebrovascular diseases, acute infection, uncontrolled systemic disease, history of interstitial lungdisease, and being pregnant or breast feeding.
The study will be conducted as a clinical, prospective, randomised controlled trial with balanced randomisation (1:1). The planned sample size is 90 subjects. Subjects with inoperable salivary gland malignancies are randomised to receive either I-125 PBT or IMRT, with stratification by tumor size and neck lymph node metastasis. Participants in both groups will be followed up at 2, 4, 6, 9, 12, 15, 18, 21 and 24 months after randomization. The primary outcome is local control rate of the primary site (based on imaging findings and clinical examination, RECIST criteria) in 1 year. Secondary outcomes are progression-free survival, overall survival, quality of life (QOL) measured with the European Organization for Research and Treatment of Cancer QOL Questionnaire (EORTC QLQ-C30 and QLQ-H&N35) of Chinese version, and safety of treatment. Chi-squared test is used to compare the local control rates in both groups. The survival curves are estimated by the Kaplan-Meier method, and log-rank test is used to test the significant difference.
Discussion
Only few observational studies have investigated the effect of I-125 PBT on inoperable salivary gland malignancies. To our knowledge, this is the first randomised controlled trial to investigate the efficacy of I-125 PBT for subjects with inoperable salivary gland malignancies, and will add to the knowledge base for the treatment of these subjects.
Trial registration
The study is registered to Clinical Trials.gov (NCT02048254) on Jan 29, 2014.
doi:10.1186/s12885-016-2248-7
PMCID: PMC4782516  PMID: 26951097
I-125 permanent brachytherapy; Intensity-modulated radiation therapy; Inoperable salivary gland malignancy; Local control rate; Quality of life
17.  Monte Carlo-based 3-dimensional dosimetry of salivary glands in radioiodine treatment of differentiated thyroid cancer estimated using 124I PET 
Aim
Salivary gland toxicity is of concern in radioiodine treatment of thyroid cancer. Toxicity is often observed while the estimated radiation absorbed dose (AD) values are below expected toxicity thresholds. Monte Carlo-based voxelized 3-dimensional radiobiological dosimetry (3D-RD) calculations of the salivary glands from eight metastatic thyroid cancer patients treated with 131I are presented with the objective of resolving this discrepancy.
Methods
GEANT4 Monte Carlo simulations were performed for 131I, based on pretherapeutic 124I PET/CT imaging corrected for partial volume effect, and the results scaled to the therapeutic administered activities. For patients with external regions of high uptake proximal to the salivary glands, such as thyroid remnants or lymph node metastases, separate simulations were run to quantify the AD contributions from both (A) the salivary glands themselves, and (B) the external proximal region of high uptake (present for five patients). The contribution from the whole body outside the field of view was also estimated using modeling. Voxelized and average ADs and biological effective doses (BEDs) were calculated.
Results
The estimated average therapeutic ADs were 2.26 Gy considering all contributions and 1.94 Gy from the self-dose component only. The average contribution from the external region of high uptake was 0.54 Gy. This difference was more pronounced for the submandibular glands (2.64 versus 2.10 Gy) compared to the parotid glands (1.88 Gy versus 1.78 Gy). The BED values were on average only 6.6 % higher than (2.41 Gy) the ADs.
Conclusion
The external sources of activity contribute significantly to the salivary gland AD, however neither this contribution, nor the radiobiological effect quantified by the BED are in themselves sufficient to explain the clinically observed toxicity.
PMCID: PMC4037814  PMID: 23474639
Salivary glands; Radiometry; Thyroid neoplasms
18.  The Sodium Iodide Symporter (NIS): Regulation and Approaches to Targeting for Cancer Therapeutics 
Pharmacology & therapeutics  2012;135(3):355-370.
Expression of the sodium iodide symporter (NIS) is required for efficient iodide uptake in thyroid and lactating breast. Since most differentiated thyroid cancer expresses NIS, β-emitting radioactive iodide is routinely utilized to target remnant thyroid cancer and metastasis after total thyroidectomy. Stimulation of NIS expression by high levels of thyroid-stimulating hormone is necessary to achieve radioiodide uptake into thyroid cancer that is sufficient for therapy. The majority of breast cancer also expresses NIS, but at a low level insufficient for radioiodine therapy. Retinoic acid is a potent NIS inducer in some breast cancer cells. NIS is also modestly expressed in some non-thyroidal tissues, including salivary glands, lacrimal glands and stomach. Selective induction of iodide uptake is required to target tumors with radioiodide. Iodide uptake in mammalian cells is dependent on the level of NIS gene expression, but also successful translocation of NIS to the cell membrane and correct insertion. The regulatory mechanisms of NIS expression and membrane insertion are regulated by signal transduction pathways that differ by tissue. Differential regulation of NIS confers selective induction of functional NIS in thyroid cancer cells, as well as some breast cancer cells, leading to more efficient radioiodide therapy for thyroid cancer and a new strategy for breast cancer therapy. The potential for systemic radioiodide treatment of a range of other cancers, that do not express endogenous NIS, has been demonstrated in models with tumor-selective introduction of exogenous NIS.
doi:10.1016/j.pharmthera.2012.06.007
PMCID: PMC3408573  PMID: 22750642
Sodium iodide symporter; thyroid cancer; breast cancer; Transcriptional regulation; Posttranslational regulation
19.  Late Simultaneous Metastasis of Renal Cell Carcinoma to the Submandibular and Thyroid Glands Seven Years after Radical Nephrectomy 
Background. Renal cell carcinoma (RCC) metastasis to the salivary glands is extremely rare. Most cases reported previously have involved the parotid gland and only six cases involving the submandibular gland exist in the current literature. Metastasis of RCC to thyroid gland is also rare but appears to be more common than to salivary glands. Methods and Results. We present the first case of simultaneous metastasis to the submandibular and thyroid glands from clear cell RCC in a 61-year-old woman who presented seven years after the primary treatment. The submandibular and thyroid glands were excised completely with preservation of the marginal mandibular and recurrent laryngeal nerves, respectively. Conclusion. Metastatic disease should always be considered in the differential diagnosis for patients who present with painless salivary or thyroid gland swelling with a previous history of RCC. If metastatic disease is confined only to these glands, prompt surgical excision can be curative.
doi:10.1155/2010/698014
PMCID: PMC2913808  PMID: 20706636
20.  Targeted next generation sequencing of parotid gland cancer uncovers genetic heterogeneity 
Oncotarget  2015;6(20):18224-18237.
Salivary gland cancer represents a heterogeneous group of malignant tumors. Due to their low incidence and the existence of multiple morphologically defined subtypes, these tumors are still poorly understood with regard to their molecular pathogenesis and therapeutically relevant genetic alterations.
Performing a systematic and comprehensive study covering 13 subtypes of salivary gland cancer, next generation sequencing was done on 84 tissue samples of parotid gland cancer using multiplex PCR for enrichment of cancer related gene loci covering hotspots of 46 cancer genes.
Mutations were identified in 22 different genes. The most frequent alterations affected TP53, followed by RAS genes, PIK3CA, SMAD4 and members of the ERB family. HRAS mutations accounted for more than 90% of RAS mutations, occurring especially in epithelial-myoepithelial carcinomas and salivary duct carcinomas. Additional mutations in PIK3CA also affected particularly epithelial-myoepithelial carcinomas and salivary duct carcinomas, occurring simultaneously with HRAS mutations in almost all cases, pointing to an unknown and therapeutically relevant molecular constellation. Interestingly, 14% of tumors revealed mutations in surface growth factor receptor genes including ALK, HER2, ERBB4, FGFR, cMET and RET, which might prove to be targetable by new therapeutic agents. 6% of tumors revealed mutations in SMAD4.
In summary, our data provide novel insight into the fundamental molecular heterogeneity of salivary gland cancer, relevant in terms of tumor classification and the establishment of targeted therapeutic concepts.
PMCID: PMC4627247  PMID: 26053092
salivary gland cancer; individualized therapy; PIK3CA; HRAS; carcinogenesis
21.  Current concepts in diagnosis of unusual salivary gland tumors 
Dental Research Journal  2012;9(Suppl 1):S9-S19.
Salivary gland tumors are relatively uncommon and account for approximately 3-6% of all neoplasms of the head and neck. Tumors mostly involve the major salivary glands, 42.9-90% of which occur in the parotid glands and 8-19.5% in the sub-mandibular glands; tumors in the sub-lingual glands being uncommon. Despite the plethora of different malignant salivary gland tumor presented to pathologists for diagnosis, there is consensus on a limited number of pathologic observations that determine treatment and outcome. There are few absolutes in salivary gland tumor diagnosis given the marked spectrum and overlap of differentiated cell types that participate in the numerous benign and malignant tumors. Thus, there are enumerating antibodies that may be helpful in resolving difficult differential diagnoses when applied with astute morphologic correlation. In general, immunohistochemistry as an ancillary diagnostic tool should be used sparingly and wisely as a morphologic adjunct because of the lack of specificity of many markers for specific histologic tumor types. The aim of this review is to discuss the molecular profiling of salivary gland neoplasms and correlate this with histogenesis of salivary gland neoplasms. We have elected to discuss and illustrate some of the unusual salivary gland tumors that the practicing pathologist find difficult to diagnose. These have been selected because they readily simulate each other but have very different clinical therapies and, therefore, should be included routinely in differential diagnosis.
PMCID: PMC3692207  PMID: 23814569
Histogenesis; IHC; unusual salivary gland
22.  Effect of Leflunomide, Cidofovir and Ciprofloxacin on Replication of BKPyV in a Salivary Gland In Vitro Culture System 
Antiviral research  2015;118:46-55.
BK polyomavirus (BKPyV) is a known kidney tropic virus that has been detected at high levels in HIV-associated salivary gland disease (HIV-SGD), one of the most important AIDS associated oral lesions. BKPyV has been detected in HIV-SGD patient saliva and replicates in salivary gland cells in vitro. BKPyV antivirals are currently in wide use to guard against BKPyV mediated organ rejection in kidney transplant recipients. The goal of this study was to investigate the inhibitory effects of three such antiviral agents, ciprofloxacin, cidofovir, and leflunomide in BKPyV infected salivary gland cells. Human salivary gland cells, and Vero cells, were infected with BKPyV, treated with antiviral drugs and assessed for BKPyV gene expression and viral replication for up to 5 days post infection. The kinetics of BKPyV replication were different in salivary gland cells compared to kidney cells. Ciprofloxacin and cidofovir had minimal effect on metabolic activity and host cell DNA replication, however, cell toxicity was detected at the protein level with leflunomide treatment. Ciprofloxacin decreased BKV T Ag and VP1 mRNA expression by at least 50% in both cell types, and decreased T Ag protein expression at days 3 and 4 post infection. A 2.5 – 4 log decrease in intracellular DNA replication and a 2 – 3 log decrease in progeny release were detected with ciprofloxacin treatment. Cidofovir and leflunomide also inhibited BKPyV gene expression and DNA replication. The three drugs diminished progeny release by 30–90% and 2 – 6 fold decreases in infectious virus were detected post drug treatment by fluorescence focus assay. Additionally, three clinical BKPyV isolates were assessed for their responses to these agents in vitro. Cidofovir and leflunomide, but not ciprofloxacin treatment resulted in statistically significant inhibition of BKPyV progeny release from salivary gland cells infected with HIV-SGD BKPyV isolates. All three drugs decreased progeny release from cells infected with a transplant derived viral isolate. In conclusion, treatment of human salivary gland cells with each of the three drugs produced modest decreases in BKPyV genome replication. These data highlight the need for continued studies to discover more effective and less toxic drugs that inhibit BKPyV replication in salivary gland cells.
doi:10.1016/j.antiviral.2015.02.002
PMCID: PMC4424161  PMID: 25790744
Polyomavirus; HIV-associated salivary gland disease; BKPyV; Leflunomide; Cidofovir; Ciprofloxacin; Salivary gland cells
23.  Evaluation of PAX2 and PAX8 Expression in Salivary Gland Neoplasms 
Head and Neck Pathology  2014;9(1):47-50.
PAX2 and PAX8 are transcription factors involved in embryogenesis that have been utilized as immunohistochemical indicators of tumor origin. Specifically, PAX2 is a marker of neoplasms of renal and müllerian origin, while PAX8 is expressed by renal, müllerian, and thyroid tumors. While studies examining these transcription factors in a variety of tumors have been published, data regarding their expression in salivary gland neoplasms are limited. The goal of this study was to assess expression of PAX2 and PAX8 in a large cohort of salivary gland tumors. Utilizing tissue microarrays, samples of normal salivary glands (n = 68) and benign and malignant salivary gland neoplasms (n = 442) were evaluated for nuclear immunoreactivity with PAX2 and PAX8. No expression was observed with either marker in the normal salivary glands, and PAX8 was negative in all neoplasms. Focal expression of PAX2 was observed in one example each of oncocytoma and acinic cell carcinoma. These results indicate that evaluation of PAX2 and/or PAX8 expression would be valuable in differentiating primary salivary gland tumors from metastases known to express PAX2 and/or PAX8.
doi:10.1007/s12105-014-0546-4
PMCID: PMC4382472  PMID: 24771139
Salivary gland neoplasms; PAX2; PAX8
24.  Decrease in thyroid adenoma associated (THADA) expression is a marker of dedifferentiation of thyroid tissue 
Background
Thyroid adenoma associated (THADA) has been identified as the target gene affected by chromosome 2p21 translocations in thyroid adenomas, but the role of THADA in the thyroid is still elusive. The aim of this study was to quantify THADA gene expression in normal tissues and in thyroid hyper- and neoplasias, using real-time PCR.
Methods
For the analysis THADA and 18S rRNA gene expression assays were performed on 34 normal tissue samples, including thyroid, salivary gland, heart, endometrium, myometrium, lung, blood, and adipose tissue as well as on 85 thyroid hyper- and neoplasias, including three adenomas with a 2p21 translocation. In addition, NIS (sodium-iodide symporter) gene expression was measured on 34 of the pathological thyroid samples.
Results
Results illustrated that THADA expression in normal thyroid tissue was significantly higher (p < 0.0001, exact Wilcoxon test) than in the other tissues. Significant differences were also found between non-malignant pathological thyroid samples (goiters and adenomas) and malignant tumors (p < 0.001, Wilcoxon test, t approximation), anaplastic carcinomas (ATCs) and all other samples and also between ATCs and all other malignant tumors (p < 0.05, Wilcoxon test, t approximation). Furthermore, in thyroid tumors THADA mRNA expression was found to be inversely correlated with HMGA2 mRNA. HMGA2 expression was recently identified as a marker revealing malignant transformation of thyroid follicular tumors. A correlation between THADA and NIS has also been found in thyroid normal tissue and malignant tumors.
Conclusions
The results suggest THADA being a marker of dedifferentiation of thyroid tissue.
doi:10.1186/1472-6890-11-13
PMCID: PMC3229435  PMID: 22050638
25.  The Risk of Second Cancers After Diagnosis of Primary Thyroid Cancer Is Elevated in Thyroid Microcarcinomas 
Thyroid  2013;23(5):575-582.
Background
Thyroid cancers have increased dramatically over the past few decades. Comorbidities may be important, and previous studies have indicated elevated second cancer risk after initial primary thyroid cancers. This study examined the risk of second cancers after development of a thyroid cancer, primary utilizing the Surveillance, Epidemiology, and End Results (SEER) program database.
Methods
The cohort consisted of men and women diagnosed with first primary thyroid cancer who were reported to a SEER database in 1973–2008 (n=52,103). Standardized incidence ratios (SIR) were calculated for all secondary cancers. Confidence intervals and p-values are at 0.05 significance alpha level and are two-sided based on Poisson exact methods.
Results
In this cohort, 4457 individuals developed second cancers. The risk of developing second cancers after a primary thyroid cancer varied from 10% to 150% depending on different cancer types. Cancers in all sites, breast, skin, prostate, kidney, brain, salivary gland, second thyroid, lymphoma, myeloma, and leukemia were elevated. The magnitude of the risk varied by histology, tumor size, calendar year of first primary thyroid cancer diagnosis, and the treatment of the primary thyroid cancer. The risk of a second cancer was elevated in patients whose first primary thyroid carcinomas were small, or were diagnosed after 1994, or in whom some form of radiation treatment was administered.
Conclusions
This large population-based analysis of second cancers among thyroid cancer patients suggests that there was an increase of second cancers in all sites, and the most commonly elevated second cancers were the salivary gland and kidney. Additionally, the increase in second cancers in patients with recently diagnosed thyroid microcarcinomas (<10 mm) suggests that aggressive radiation treatment of the first primary thyroid cancer, the environment, and genetic susceptibility, may increase the risk of a second cancer.
doi:10.1089/thy.2011.0406
PMCID: PMC3643257  PMID: 23237308

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