Viruses Cause Salivary Gland Cancers

Cytomegalovirus Causes Mucoepidermoid Carcinoma

Mucoepidermoid carcinoma (MEC) is the most common malignant tumor originating in major and minor salivary glands

Human cytomegalovirus and mucoepidermoid carcinoma of salivary glands: cell-specific localization of active viral and oncogenic signaling proteins is confirmatory of a causal relationship. M Melnick, PP Sedghizadeh, CM Allen, T Jaskoll. Exp Mol Pathol 2012 Feb;92(1):118-125. 39 human SG MECs selected randomly from a repository of cases spanning 2004-2011. "Given that hCMV is frequently resident in salivary gland (SG) ductal epithelium, we hypothesized that hCMV would be important to the pathogenesis of SG mucoepidermoid carcinoma (MEC). This was initially supported by our finding that purified CMV induces malignant transformation in SG cells in an in vitro mouse model, and utilizes a pathogenic pathway previously reported for human MEC... All four prospective causal criteria for viruses and cancer are fully satisfied: (1) protein markers for active hCMV are present in 97% of MECs; (2) markers of active hCMV are absent in non-neoplastic SG tissues; (3) hCMV-specific proteins (IE1, pp65) are in specific cell types and expression is positively correlated with severity; (4) hCMV correlates and colocalizes with an upregulation and activation of an established oncogenic signaling pathway (COX/AREG/EGFR/ERK). Thus, the evidential support reported here and previously in a mouse model is strongly confirmatory of a causal relationship between hCMV and SG mucoepidermoid carcinoma." And: CMV Infection May Cause Salivary Gland Cancer. By Kurt Ullman. MedPage Today, Nov. 16, 2011; Common Virus Identified as Cancer-causing Oncovirus. By Beth Newcomb. USC News, Nov. 15, 2011.

Melnick - Exp Mol Pathol 2012 abstract
CMV Infection May Cause Salivary Gland Cancer / MedPage Today 2011
Common Virus Identified as Cancer-causing Oncovirus / USC News 2011

Cytomegalovirus-induced salivary gland pathology: AREG, FGF8, TNF-α, and IL-6 signal dysregulation and neoplasia. M Melnick, KA Deluca, PP Sedghizadeh, T Jaskoll. Exp Mol Pathol 2013 Apr;94(2):386-397. "Here we present evidence of a highly significant upregulation of ligands for the EGFR, FGFR, IL-6R, and TNFR signaling pathways, all of which converge upon the Raf/MEK/ERK amplifier module. This explains our finding that even in the presence of the highest nontoxic dose of an ERK phosphorylation inhibitor, pERK is undiminished. Given the considerable pathway crosstalk, a deep understanding of subversion and dysregulation of the SG interactome by CMV is a priori quite daunting. Circumventing this dilemma, we present evidence that concurrent inhibition of ERK phosphorylation (U0126) and CMV replication (acyclovir) obviates progressive pathogenesis and results in complete SG rescue (tumor regression). These findings provide a mechanistic foundation for potential clinical trials that utilize similar concurrent treatment with extant FDA-approved drugs."

Melnick - Exp Mol Pathol 2013 abstract / PubMed

Cytomegalovirus and Mucoepidermoid carcinoma: A possible causal relationship? A pilot study. G Jayaraj, HJ Sherlin, P Ramani, P Premkumar, N Anuja. J Oral Maxillofac Pathol 2015 Sep-Dec;19(3):319-324. 4 cases. "The pp65 antigen expression was found to be negative in all the studied cases..."

Jayaraj - J Oral Maxillofac Pathol 2015 abstract / PubMed

Epstein-Barr Virus Causes Lymphoepithelial Carcinoma

LECs are rare except among the Inuits, where they are the majority of all salivary gland carcinomas, and Southeast Asians.

Epstein-Barr virus infected lymphoepithelial carcinomas of the salivary gland in the Russia-Asia area: a clinicopathologic study of 160 cases. T Saku, J Cheng, KY Jen, M Tokunaga, J Li, W Zhang, A Liu, L Wu, Y Lu, Z Zhou, Y Li, R Li, J Ouyang, L Yang, S Yu, T Lou, S Wang, D Lin, H Rao, H Lin, P Sderk, Z Chen, Z Chen, C Cai, H Kim, S Hong. Arkh Patol 2003 Mar-Apr;65(2):35-39. "All the cases examined by PCR for EBV DNA BamHI fragment and in-situ hybridization for EBER-1, EBV encoded small RNA, showed positivity for EBV infection in LEC cells, while no positive signals were found in any other salivary neoplasm examined... There were ninety-five cases found with LEC in the parotid gland (75%), 20 in the submandibular gland (5%), and 28 in the minor salivary gland (20%)."

Saku - Arkh Patol 2003 abstract / PubMed

[Epstein-Barr virus infection in benign lymphoepithelial lesions with malignant transformation of salivary glands]. LY Wu, J Cheng, Y Lu, ZY Zhou, T Saku. Zhonghua Kou Qiang Yi Xue Za Zhi 2004 Jul;39(4):291-293. 2 cases benign lymphoepithelial lesions with focal malignant transformation (BLEL-FMT), 14 cases of malignant lymphoepithelial lesion (MLEL) and 4 cases of benign lymphoepithelial lesion (BLEL) of salivary glands, 4 cases of nonspecific chronic sialadenitis. "In ISH, strong signals for EBER-1 were obtained in most of epithelial cell nuclei in examined specimens of BLEL-FMT, no matter in benign or malignant areas and in all specimens of MLEL (14/14), PCR demonstrated a DNA fragment of 123 kbp in 2 cases of BLEL-FMT and 12 cases of MLEL (12/14). In contrast, there were no significant ISH/PCR signals in examined BLEL and nonspecific chronic sialadenitis."

Wu - Zhonghua Kou Qiang Yi Xue Za Zhi 2004 abstract / PubMed

Sporadic EBV-associated lymphoepithelial salivary gland carcinoma with EBV-positive low-grade myoepithelial component. H Herbst, G Niedobitek. Virchows Arch 2006 May;448(5):648-654. Two cases in Caucasians. "Tumour cells of case 1 showed expression of EBNA1 only, corresponding to an EBV latency type I... In case 2, the high-grade tumour showed an EBV lantency II pattern with expression of EBNA1, LMP1 and LMP2A (latency II). The spindle cell lesion of this case was also EBV-infected and showed low levels of EBNA1 and LMP1 expression, while LMP2A was not detectable. The detection of EBV in both components of case 2 together with immunophenotypic evidence of transition between both components supports the notion that at least some LECs arise through a low-grade myoepithelial intermediate."

Herbst - Virchows Arch 2006 abstract / PubMed

Epstein-Barr virus associated lymphoepithelial carcinoma of the parotid gland; a clinicopathological report of three cases. N Larbcharoensub, M Tubtong, V Praneetvatakul, A Pongtippan, J Leopairat, V Sirikulchayanonta. J Med Assoc Thai 2006 Sep;89(9):1536-1541. 3 cases were EBV positive.

Larbcharoensub - J Med Assoc Thai 2006 abstract / PubMed

CT features and pathologic characteristics of lymphoepithelial carcinoma of salivary glands. G Zhang, J Tang, Y Pan, Q Zhuang, C Wu. Int J Clin Exp Pathol 2014 Feb 15;7(3):1004-1011. 7 out of 8 were positive for EBV, while 1 "had LEC secondary to Benign Lymphoepithelial Lesion."

Zhang - Int J Clin Exp Pathol 2014 full article / PubMed Central

Lymphoepithelial Carcinoma of the Salivary Gland: Morphologic Patterns and Imaging Features on CT and MRI. X Ban, J Wu, Y Mo, Q Yang, X Liu, C Xie, R Zhang. AJNR Am J Neuroradiol 2014 Sep;35(9):1813-1819. 28 cases. "96.4% of patients were positive for Epstein-Barr virus both on histologic staining and Epstein-Barr virus serology."

Ban - AJNR Am J Neuroradiol 2014 abstract / PubMed

See Also:

Epstein-Barr Virus Causes Sjogren’s Syndrome

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cast 03-17-16