Human papillomavirus and Epstein-Barr virus infection in benign thyroid lesions.

INTRODUCTION: The objective was to investigate the correlation between Epstein-Barr virus (EBV) and human papillomavirus (HPV) infection in the development of benign thyroid lesions. MATERIAL AND METHODS: 29 cases of Hashimoto's thyroiditis (HT), 133 cases of thyroid adenoma, and 34 cases of HT with thyroid adenoma paraffin embedded tissue samples were used for EBV and HPV quantitative detection. RESULTS: None of the tissue samples carried HPV DNA. In HT tissue samples, the positive rate of EBV was 55.2% (16/29). In thyroid adenoma tissue samples, the positive rate was 37.6% (50/133). In HT combined with thyroid adenoma tissue samples, the positive rate of EBV was 67.6% (23/34). There was no correlation between EBV infection and clinical features such as age and gender. CONCLUSION: The occurrence and development of benign thyroid lesions are closely related to EBV infection. HT combined with thyroid adenoma may be more susceptible to EBV infection than simple HT and thyroid adenoma, which provides a new idea for the diagnosis and treatment of benign thyroid lesions.

Updated clinical management guidance during the COVID-19 pandemic: thyroid nodules and cancer.

Healthcare settings, including nuclear medicine (NM) departments, promptly adjusted their standard operating procedures to cope with the unprecedented crisis caused by coronavirus disease 19 (COVID-19) pandemic. Nuclear thyroidology has adopted changes and predicated on a careful risk-benefit analysis, in order to prevent a potential spread of the virus while being at the same time effective, safe and preserving their quality of essential services. Since most thyroid nodules (TNs) are benign, and malignant neoplasms are characterized by an indolent natural history, it is generally safe to delay diagnostic and therapeutic procedures. In this respect, the main adjustments that nuclear thyroidology has adopted are summarized into the following: general workplace adjustments including remote work for NM staff; postponing appointments for consultation, diagnostic and therapeutic purposes and rescheduling based on individualized risk stratification; telemedicine; preparation for possible issues on radiopharmaceuticals synthesis and delivery; preventing measures and protocols to minimize or avoid potential COVID-19 infection of patients and medical staff. This document should be considered as updated guidance on how clinical management of TNs and thyroid cancer has been altered, remodeled and adapted to the new circumstances in the COVID-19 era, based on the rapidly growing volume of scientific information regarding the new coronavirus.

Evidencing the presence of merkel cell polyomavirus in papillary thyroid cancer.

Merkel cell polyomavirus (MCPyV) infects most people asymptomatically, but recent reports indicate that the virus may be related to carcinogenesis. This study aimed to evaluate the impact of MCPyV on the development of papillary thyroid cancer (PTC). Totally, 1057 samples, including 412 fresh biopsy samples (FBS) and 645 paraffin-embedded PTC biopsy samples (PEBS), and 1057 adjacent non-cancerous samples were assessed for the presence of MCPyV DNA and RNA. MCPyV DNA was positive in 215 (20.3%) of samples, including 126 (30.6%) in FBS and 89 (13.8%) in PEBS. In MCPyV-positive samples, the mean MCPyV copy number was higher in the patients with FBS (2.3 × 10-1 ± 0.5 × 10-1 copies/cell) compared to PEBS (0.7 × 10-4 ± 0.1 × 10-4 copies/cell) and adjacent non-PTC normal samples (0.3 × 10-5 ± 0.02 × 10-5 copies/cell), indicating a statistically significant difference (P < 0.001). The LT-Ag RNA expression was higher in FBS compared to PEBS, while VP1 gene transcript was not detected in any samples. Although our findings showed the presence of MCPyV in a subset of PTC Iranian patients, further research is required to confirm these findings.

Mixed HPV-related Neuroendocrine Carcinoma and HPV-related Squamous Cell Carcinoma of the Base of Tongue in a Patient With Incidental Identification of Synchronous Metastatic Papillary Thyroid Carcinoma.

BACKGROUND: While it is not uncommon in patients with head and neck cancer to present with multiple metachronous primary neoplasms, rarely do these present as a singular mass composed of intertwined, histologically distinct malignant tumors. Sometimes referred to as collision tumors, these entities are poorly understood and only appear in a handful of case studies in the literature. CASE REPORT: Here we present a 58-year-old male diagnosed with a human papillomavirus-related collision tumor consisting of oropharyngeal squamous cell carcinoma and small-cell neuroendocrine carcinoma, as well as an incidentally discovered metastatic thyroid papillary carcinoma, despite an unremarkable thyroid gland. The patient underwent transoral robotic base-of-tongue resection and partial pharyngectomy with selective neck dissection followed by chemoradiotherapy. At the 18-month follow-up the patient was doing well. His thyroid was normal and no recurrent or metastatic carcinoma was identified on the computed tomography and positron-emission tomography/computed tomography imaging findings. CONCLUSION: To the best of our knowledge, this is the first such case in English literature. This case demonstrates the importance of tumor morphology and immunohistochemical testing in HPV-related oropharyngeal carcinomas, despite the overall good prognosis of such tumors, due to the possibility of synchronous or colliding primary neoplasms.

ENDOCRINOLOGY IN THE TIME OF COVID-19: Management of thyroid nodules and cancer.

Most patients with thyroid nodules and thyroid cancer (TC) referred for diagnostic work-up and treatment are not considered at higher risk of infection from SARS-CoV-2 compared to the general population. On the other hand, healthcare resources should be spared to the maximum extent possible during a pandemic. Indeed, while thyroid nodules are very common, only a small percentage are cancerous and, in turn, most thyroid cancers are indolent in nature. Accordingly, diagnostic work-up of thyroid nodules, thyroid surgery for either benign or malignant thyroid nodules and radioiodine treatment for differentiated thyroid cancers may be safely postponed during SARS-CoV-2 pandemic. Appropriate patient counselling, however, is mandatory and red flags should be carefully identified prompting immediate evaluation and treatment as appropriate. For these selected cases diagnostic work-up (e.g. ultrasound, scintigraphy, fine-needle aspiration), surgery and radioiodine therapy may proceed despite the threat of SARS-CoV-2 infection and COVID-19, after an individual risk-benefit analysis.

Viral infections and risk of thyroid cancer: A systematic review and empirical bayesian meta-analysis.

OBJECTIVE: The associations between viruses and the cancer have been conducted in several studies while there has been no systematic review and meta-analysis about the association between viral infections and thyroid cancer (TC). Therefore, we investigated the association between viral infection and TC risk. METHODS: Systematic search was done from 1994 to 2019 in Web of sciences (ISI), PubMed, and Scopus databases. Pooled logarithm of odds ratio (OR) and their corresponding 95 % confidence interval (CI) and pooled prevalence of viral infections were calculated to find the association between the viral infections and TC risk and overall prevalence of the viral infections in TC. RESULTS: Twenty-three of 852 original articles were selected and included in the study. According to the results of the random effect meta-analysis, the pooled prevalence of viral infections in the TC patients was 37 % (95 % C. I = 22 %-55 %). In addition, there was a significant association between viral infections (log (OR) = 1.51, 95 % credible interval = 0.68-2.39) and TC risk. The highest associations were observed between TC risk and Simian Vacuolating Virus 40 (SV40) and B19 infections, respectively. The lowest non-significant association was found between TC risk and Poliovirus type 1 infection. The significantly heterogeneity was observed between included studies (Q test: p-value<0.001; I2 = 73.82 %; τ2 = 1.08, 95 % Cr. I = 0.47-1.94). CONCLUSIONS: Results clearly demonstrated the potential pathogenetic association between viral infections and increased risk of TC.

Hepatitis C virus and risk of extrahepatic malignancies: a case-control study.

Epidemiological studies have demonstrated an increased risk of non-Hodgkin lymphoma (NHL) in patients with chronic hepatitis C virus (HCV) infection. Therefore, we investigated the risk of extrahepatic malignancies associated with HCV infection. Inpatients diagnosed with lymphoma, breast, thyroid, kidney, or pancreatic cancer (research group, n = 17,925) as well as inpatients with no malignancies (control group, n = 16,580) matched by gender and age were enrolled from The First Affiliated Hospital of Nanjing Medical University between January 2008 and December 2016. A case-control study was conducted by retrospective analysis. The difference in HCV prevalence was analyzed between the research group and the control group. Also, the research group was compared to the 2006 National Hepatitis C sero-survey in China. A total of 86 cases were positive for anti-HCV in the research group. Compared with the control group (103 cases were anti-HCV positive), no significant associations between extrahepatic malignancies and HCV infection were observed. Meanwhile, compared to the 2006 National Hepatitis C sero-survey, we observed a significant association between the chronic lymphoma leukemia/small lymphocytic lymphoma (CLL/SLL) and HCV seropositivity in females in the research group aged 1-59 years old (OR = 14.69; 95% CI, 1.94-111.01). HCV infection had a potential association with CLL/SLL in females aged 1-59 years old. Our study did not confirm an association between HCV infection and the risk of extrahepatic malignancies. In regions with a low HCV prevalence, the association between HCV infection and extrahepatic malignancies needs further investigation.

Thyroid autoimmune diseases and thyroid tumors: Would EBV infection be the link?

The role of EBV in thyroid cancer development and the patient's outcome is still unclear. Using nested-PCR, Moghoofei et al. reported a high incidence of a virus in thyroid tumor samples, different from our results, obtained by quantitative real-time PCR and confirmed by in situ hybridization. Because lymphocytes are the main reservoir of the virus and tumor-infiltrating lymphocytes are commonly observed in thyroid cancer, it is important to distinguish follicular cells infection from lymphoid tissue infection. The association between autoimmune diseases and thyroid cancer raises the importance of continuing to investigate the role of ubiquitous pathogens in thyroid tumorigenesis.

Head and neck carcinoma of unknown primary.

In adult cervicofacial pathology, carcinoma of unknown primary is defined as lymph-node metastasis the anatomic origin of which is not known at the time of initial management. It constitutes up to 5% of head and neck cancers. Presentation may suggest benign pathology, delaying and confusing oncologic treatment. Diagnostic strategy in cervical lymph node with suspicion of neoplasia requires exhaustive work-up to diagnose malignancy and, in 45% to 80% of cases, depending on the series, to identify the primary site. Histologic types comprise squamous cell carcinoma, thyroid carcinoma, adenocarcinoma, neuroendocrine carcinoma and undifferentiated carcinoma. Association is sometimes found with human papilloma virus or Epstein Barr virus, guiding treatment. The objective of the present study was to provide clinicians with the necessary diagnostic tools, based on the current state of clinical, imaging and pathologic knowledge, and to detail treatment options.

Epstein-Barr Virus and Thyroid Cancer.

Epstein-Barr virus (EBV) seroprevalence is extremely high worldwide. This member of the herpesvirus family is considered to be a human carcinogen, implicated in lymphoid and epithelial malignancies. Because of its characteristics, EBV has been investigated in thyroid specimens, especially in autoimmune and neoplastic lesions. However, the role of EBV in thyroid diseases is still unclear. Reports on its presence in thyroid cancer (TC) vary drastically according to population and applied methodology. This review presents the history of EBV and TC, aiming to better understand the role of this oncogenic virus in thyroid tumorigenesis. We hope to assist researchers, and we discuss possible approaches to better understand the role of EBV in TC.

Epstein-Barr virus and thyroid cancer: The role of viral expressed proteins.

BACKGROUND: Thyroid cancer is a common endocrine malignancy whose incidence has increased in recent years. Several internal and external risk factors are involved in the development of this cancer, such as infectious agents. Evidence supporting the role of viral infection as an etiology for the invasiveness of thyroid cancer is increasing. The aim of this study was to determine the presence of the Epstein-Barr virus (EBV) and the association between viral gene products and thyroid tumor development. METHODS: Fifty-seven thyroid cancer specimens were collected from the same number of patients as well as 18 samples from healthy controls. The presence of the EBV genome and the genotyping was examined by polymerase chain reaction (PCR). Also, an enzyme-linked immunosorbent assay and real-time PCR were used to measure the expression levels of viral and cellular genes. RESULTS: The EBV DNA was detected in 71.9% of the samples, and it was also found that the presence of the EBV was associated with increasing development of thyroid tumor. CONCLUSION: Our results demonstrated that EBV infection may play a role in the development of thyroid tumor.

EBV-associated lymphoepithelioma-like thyroid carcinoma with favorable outcome: case report with cytopathologic and histopathologic study.

BACKGROUND: Lymphoepithelioma-like carcinoma (LELC) is a rare entity among thyroid tumors. Based on the limited number of case reports that exist, the association of Epstein-Barr virus (EBV) with primary thyroid LELCs seems inconsistent. CASE PRESENTATION: We present a confusing cytological case of lymphoepithelioma-like thyroid carcinoma with expression of EBV. The patient presented with a central neck mass and bilateral lymphadenopathy. Fine-needle aspiration cytology revealed three-dimensional and syncytial fragments of epithelioid cells accompanied by small lymphocytes. The surgical specimen of resected thyroid tumor disclosed typical histopathological features of LELC. Metastatic papillary carcinoma was also discovered in the metastatic lymph nodes. In situ hybridization for EBV-encoded RNA (EBER-ISH) was positive in the tumor cells. Negative immunoreactivity for TTF-1, Pax-8, and CD5 was observed. The patient is currently undergoing regular follow-up and is 1 year and 10 months postresection with no evidence of recurrence. CONCLUSIONS: Long-term survival is discussed in relation to this variant of thyroid carcinoma, which might differ in behavior from anaplastic carcinoma. Further investigation is required to elucidate the clinical significance of EBV expression and progression of this unique variant of thyroid carcinoma.

Hepatitis C and Risk of Nonhepatic Malignancies.

Epidemiologic studies show an increased risk of mortality among hepatitis C virus (HCV)-infected individuals compared with uninfected individuals from hepatic and nonhepatic causes. This article reviews the biologic plausibility of and epidemiologic evidence for the association between HCV and five extrahepatic malignancies: cholangiocarcinoma (CCA), pancreatic adenocarcinoma, papillary thyroid cancer, oral squamous cell cancer, and renal/kidney cancer. There is sufficient evidence to suggest that HCV is associated with intrahepatic CCA. The evidence for the link between HCV and pancreatic adenocarcinoma, oral squamous cell cancer, and renal/kidney cancer is compelling but requires further study. Based on available studies, there is no significant association between HCV, extrahepatic CCA, and papillary thyroid cancer.

Detection and a possible link between parvovirus B19 and thyroid cancer.

Human parvovirus B19 (B19) is a small, non-enveloped virus and belongs to Parvoviridae family. B19 persists in many tissues such as thyroid tissue and even thyroid cancer. The main aim of this study was to determine the presence of B19, its association with increased inflammation in thyroid tissue, and thus its possible role in thyroid cancer progression. Studies have shown that virus replication in non-permissive tissue leads to overexpression of non-structural protein and results in upregulation of proinflammatory cytokines such as interleukin 6 and tumor necrosis factor alpha. A total of 36 paraffin-embedded thyroid specimens and serum were collected from patients and 12 samples were used as control. Various methods were employed, including polymerase chain reaction, real-time polymerase chain reaction, and enzyme-linked immunosorbent assay. The results have shown the presence of B19 DNA in 31 of 36 samples (86.11%). Almost in all samples, the levels of non-structural protein 1, nuclear factor kappa B, tumor necrosis factor alpha, and interleukin 6 were simultaneously high. The presence of parvovirus B19 has a significant positive correlation with nuclear factor kappa B, tumor necrosis factor alpha, and interleukin 6 levels. This study suggests that B19 infection may play an important role in tumorigenesis and thyroid cancer development via the inflammatory mechanisms.

Evaluation of the presence of Epstein-Barr virus (EBV) in Iranian patients with thyroid papillary carcinoma.

BACKGROUND AND PURPOSE: Papillary thyroid carcinoma (PTC) is the most common thyroid cancer. EBV is one of the most important viruses related to different types of malignancies. This study investigated the relationship between EBV and papillary thyroid carcinoma. MATERIAL AND METHODS: In this study the presence of Epstein-Barr Nuclear Antigen 1 (EBNA1) gene in papillary thyroid carcinoma tissues were examined by nested-PCR method. Paraffin-embedded tissues (N=41) blocks of thyroid cancer were used. DNA was extracted from all samples and then samples were evaluated for the presence of EBV gene. RESULTS: In 41 samples, EBNA1 was detected in 65.8% of patients with papillary thyroid carcinoma which was significantly higher in younger ages. CONCLUSION: The significant presence of EBV genome in papillary thyroid carcinoma suggests that this virus may play a role in this cancer especially in younger ages. As a result, monitoring of patients with EBV latent infection for PTC can be very important.

Investigation on the association between thyroid tumorigeneses and herpesviruses.

Herpesviruses have been associated with various human malignancies and with thyroid autoimmunity. Aiming to investigate the presence of these viruses in thyroid nodules, we analyzed serum and thyroid tissue from 183 patients (83 benign and 100 malignant thyroid nodules). We also obtained 104 normal thyroid tissues extracted from the contralateral lobe of these patients. We used ELISA to screen the serology of all patients and a real-time quantitative PCR to analyze thyroid tissue viral load in antibody-positive patients. In addition, the presence of herpesviruses was tested by histological analysis in 20 EBV-positive tissues using the expression of LMP-1 by immunohistochemistry (IHC) and EBER by in situ hybridization (ISH). There was no evidence of HSV-2 or CMV DNA, but we found EBV DNA sequences in 29 (16%) thyroid tissue samples. We also found 7 positive EBV cases out of 104 normal tissues. Viral load was higher in tumors than in their respective normal tissues (p = 0.0002). ISH analysis revealed EBER expression in 11 out of 20 (52%) EBV-positive tissues, mostly in malignant cases (8/11, 73%). The presence of high EBV copy numbers in thyroid tumors and the expression of EBER only in malignant cases suggest an association between EBV and thyroid malignancies. However, we did not find any association between the presence of EBV and/or its viral load and any clinical or pathological tumor feature. Further studies aiming to clarify the mechanisms of EBV infection in thyroid cells are necessary to support a possible role in the development of thyroid cancer.

The Epstein-Barr virus EBNA2 protein induces a subset of NOTCH target genes in thyroid cancer cell lines but fails to suppress proliferation.

BACKGROUND: Epstein-Barr virus is associated with lymphoid and epithelial malignancies and has been reported to infect thyroid cells. The Epstein-Barr virus protein, EBNA2, regulates viral and cellular promoters by binding to RBP-jκ. Similarly, NOTCH1, a tumor suppressor protein in thyroid epithelial cells, competes with EBNA2 for binding to overlapping sites on RBP-jκ. EBNA2 activates a subset of NOTCH-responsive genes in lymphocytes and myocytes; however, the effect of EBNA2 expression on NOTCH targets in epithelial cells is unknown. Here we have explored whether EBNA2 activates NOTCH1 targets in thyroid cancer lines and examined its effect on cellular proliferation. METHODS: Two human thyroid cancer lines, follicular FTC-236 and anaplastic HTh7, were transfected with EBNA2, NOTCH1, or control vectors. Notch targets were measured using quantitative reverse transcriptase polymerase chain reaction. Cellular proliferation was measured by MTT analysis. RESULTS: EBNA2 activated only a subset of NOTCH1 targets. Expression of HES1 and HEY1 were increased 10-fold in FTC-236 and HTh7 cells, respectively, but the majority of NOTCH1 targets examined were not affected. In contrast to NOTCH1, EBNA2 did not suppress proliferation. CONCLUSION: EBNA2 does not activate most Notch1-responsive genes or suppress proliferation in human thyroid cancer cells. Instead, EBNA2 may compete with NOTCH1 for limiting amounts of RBP-jκ in epithelial cells and inhibit certain aspects of NOTCH1 signaling.

The role of human parvovirus B19 and hepatitis C virus in the development of thyroid disorders.

The presence of viruses in the thyroid has been shown, but whether they are implicated in thyroid diseases or are only spectators is under investigation. The most important candidate viruses for autoimmune thyroid disorders (AITD) are hepatitis C virus (HCV) and human parvovirus B19 (or Erythrovirus B19 or EVB19). Retrospective and prospective case-control studies conducted on pathology slides showed (by PCR, in situ hybridization or immunohistochemistry) EVB19 was present in thyroid tissues of patients with autoimmune thyroiditis (AT), Graves' disease and thyroid cancer. Though AITD can be associated with acute EVB19 infection, it is not clear whether EVB19 could have a pathogenetic role in autoimmune thyroid diseases pathophysiology. Many studies have shown that frequently, patients with HCV chronic infection (CHC) show elevated serum anti-thyroperoxidase (TPOAb) and/or anti-thyroglobulin autoantibodies levels, ultrasonographic signs of chronic AT, and subclinical hypothyroidism. In patients with HCV-associated mixed cryoglobulinemia (MC + HCV), AITD were more prevalent with respect to controls, and also vs HCV patients without cryoglobulinemia. Papillary thyroid cancer was more prevalent in MC + HCV or CHC patients than in controls, especially in patients with AT. Recently it has been shown an elevated incidence of new cases of AT and thyroid dysfunction in MC patients. These results suggest an attentive monitoring of thyroid function and nodules in HCV patients with risk factors (female gender, a borderline high initial thyrotropin, TPOAb positivity, a hypoechoic and small thyroid) for the development of thyroid disorders.

The oncolytic virus dl922-947 reduces IL-8/CXCL8 and MCP-1/CCL2 expression and impairs angiogenesis and macrophage infiltration in anaplastic thyroid carcinoma.

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human solid tumor and current treatments are ineffective in increasing patients' survival. Thus, the development of new therapeutic approaches for ATC is needed. We have previously shown that the oncolytic adenovirus dl922-947 induces ATC cell death in vitro and tumor regression in vivo. However, the impact of dl922-947 on the pro-tumorigenic ATC microenvironment is still unknown. Since viruses are able to regulate cytokine and chemokine production from infected cells, we sought to investigate whether dl922-947 virotherapy has such effect on ATC cells, thereby modulating ATC microenvironment. dl922-947 decreased IL-8/CXCL8 and MCP-1/CCL2 production by the ATC cell lines 8505-c and BHT101-5. These results correlated with dl922-947-mediated reduction of NF-κB p65 binding to IL8 promoter in 8505-c and BHT101-5 cells and CCL2 promoter in 8505-c cells. IL-8 stimulates cancer cell proliferation, survival and invasion, and also angiogenesis. dl922-947-mediated reduction of IL-8 impaired ATC cell motility in vitro and ATC-induced angiogenesis in vitro and in vivo. We also show that dl922-947-mediated reduction of the monocyte-attracting chemokine CCL2 decreased monocyte chemotaxis in vitro and tumor macrophage density in vivo. Interestingly, dl922-947 treatment induced the switch of tumor macrophages toward a pro-inflammatory M1 phenotype, likely by increasing the expression of the pro-inflammatory cytokine interferon-γ. Altogether, we demonstrate that dl922-947 treatment re-shape the pro-tumorigenic ATC microenvironment by modulating cancer-cell intrinsic factors and the immune response. An in-depth knowledge of dl922-947-mediated effects on ATC microenvironment may help to refine ATC virotherapy in the context of cancer immunotherapy.