ΔNp63-restricted viral mimicry response impedes cancer cell viability and remodels tumor microenvironment in esophageal squamous cell carcinoma.

Tumor protein p63 isoform ΔNp63 plays roles in the squamous epithelium and squamous cell carcinomas (SCCs), including esophageal SCC (ESCC). By integrating data from cell lines and our latest patient-derived organoid cultures, derived xenograft models, and clinical sample transcriptomic analyses, we identified a novel and robust oncogenic role of ΔNp63 in ESCC. We showed that ΔNp63 maintains the repression of cancer cell endogenous retrotransposon expression and cellular double-stranded RNA sensing. These subsequently lead to a restricted cancer cell viral mimicry response and suppressed induction of tumor-suppressive type I interferon (IFN-I) signaling through the regulations of Signal transducer and activator of transcription 1, Interferon regulatory factor 1, and cGAS-STING pathway. The cancer cell ΔNp63/IFN-I signaling axis affects both the cancer cell and tumor-infiltrating immune cell (TIIC) compartments. In cancer cells, depletion of ΔNp63 resulted in reduced cell viability. ΔNp63 expression is negatively associated with the anticancer responses to viral mimicry booster treatments targeting cancer cells. In the tumor microenvironment, cancer cell TP63 expression negatively correlates with multiple TIIC signatures in ESCC clinical samples. ΔNp63 depletion leads to increased cancer cell antigen presentation molecule expression and enhanced recruitment and reprogramming of tumor-infiltrating myeloid cells. Similar IFN-I signaling and TIIC signature association with ΔNp63 were also observed in lung SCC. These results support the potential application of ΔNp63 as a therapeutic target and a biomarker to guide candidate anticancer treatments exploring viral mimicry responses.

Transcriptionally Active Human Papillomavirus Infection in a Minority of Esophageal Squamous Cell Carcinomas in North America.

The role of Human papillomavirus (HPV) infection in esophageal squamous cell carcinoma (ESCC) is a topic of ongoing debate. This study used two screening approaches to look for evidence of HPV infection in esophageal squamous cell carcinoma. We initially checked for HPV infection in a randomly selected group of 53 ESCC cases. We did not detect any tumors positive for high-risk HPV. However, during clinical practice, we identified an HPV-positive ESCC in the distal esophagus, which tested positive for HPV16. This index case was TP53 wild-type, as determined by next-generation DNA sequencing (NGS). Since TP53 mutations are rare in other HPV-driven cancers, we improved our screening method by limiting our screen to a subset of ESCC cases without TP53 mutations. A second screen of 95 ESCCs (from 93 patients) sequenced by NGS revealed an additional 7 ESCCs with TP53 wild-type status (7.3% of the total). Of the 7 cases, 2 cases were found to be high-risk HPV positive. Both patients also tested positive for circulating cell-free HPV DNA and had a complete response to neoadjuvant chemoradiation. The index patient had microscopic residual tumor following neoadjuvant therapy. The patient underwent adjuvant immunotherapy and remained disease free after 22 months of surveillance. This study affirms the transcriptionally active status of high-risk HPV in a minority of ESCC patients in North America.

Human papillomavirus is an important risk factor for esophageal carcinoma in a Chinese population.

PURPOSE: Different types of HPV have been associated with cancer in humans, but the role of HPV in esophageal cancer (EC) is controversial. The purpose of this study was to evaluate the correlation between HPV infection and EC in the Chinese population and to provide the scientific basis for the future prevention, control, early diagnosis, and treatment strategies of EC in China. METHODS: PCR detected HPV infection in 1112 esophageal cancer tissue samples, and 89 HPV-positive samples were detected by genotyping. Proximity ligation assays (PLAs) and immunohistochemistry were used to detect the expression of HPV E6 and E7 proteins. Real-time fluorescent quantitative PCR was used to detect the integration of HPV16 E6. The level of HPV-specific antibody IgG in serum was detected by ELISA and PLA. RESULTS: The positive rates of HPV L1, HPV16, HPV18, hpv16 + 18 E6 and hpv16/18 E6 in 1,112 EC tissue samples were 77.6%, 41.4%, 27.2%, 14.2% and 55.4% respectively. Multiple HPV subtypes were detected in HPV-positive EC samples. PLA showed that E6 and E7 were expressed in EC109 and formed complexes with p53 and pRb, respectively. Immunohistochemistry showed that the positive rates of hpv16 + 18 E6 and E7 in HPV-positive EC samples were 56.4% and 37.0%, respectively. HPV-DNA integration rate in HPV-positive EC tissues (88.79%) was higher than that in adjacent tissues (54.17%). HPV antibody was found in the serum of EC patients by a serological test. CONCLUSION: The study suggests that HPV, especially HPV16 and HPV18, the infection may be a risk factor for EC in the Chinese population and that the E6 protein may play a key role in HPV-associated malignancies. These results may be important for the prevention and treatment of HPV-positive EC in China.

HPV16 infection promotes an M2 macrophage phenotype to promote the invasion and metastasis of esophageal squamous cell carcinoma

Objectives High-risk human papillomavirus (HR-HPV) is an important risk factor for esophageal cancer. Macrophages constitute a crucial immune medium for regulating HPV-related tumors; however, the specific regulatory mechanisms remain unknown. Therefore, the purpose of our current study was to investigate the mechanism by which HPV16E6 regulates macrophages to promote the invasion and metastasis of esophageal cancer. Methods HPV16E6 infection was detected by polymerase chain reaction. Immunohistochemistry was used to verify the distribution of tumor-associated macrophages (TAMs) and MMP-9 expression in esophageal squamous cell carcinoma tissues (ESCCs), and cancer adjacent normal tissues (CANs) from Kazakh patients. ESCC cells were transfected with a plasmid over-expressing HPV16E6 and non-contact cocultured with macrophages. Results The infection rate of HPV16E6 in Kazakh ESCCs was clearly higher than that in CANs (P < 0.05). The density of CD163-positive TAMs was significantly positively correlated with HPV16E6 infection in ESCCs (P < 0.05). After coculturing macrophages and EC9706 cells transfected with the HPV16E6 plasmid, the phenotype of macrophages transformed into M2 macrophages. The migration and invasion ability of ESCC cells were higher in the HPV16E6-transfected and coculture group than in the HPV16E6 empty vector-transfected and non-cocultured HPV16E6-transfected groups (all P < 0.05). The density of M2-like TAMs in ESCCs was positively correlated with the level of MMP-9 expression. MMP-9 expression in the HPV16E6-ESCC coculture macrophages group was substantially higher than that in controls (all P < 0.05). Conclusions HPV16 infection mediates tumor-associated macrophages to promote ESCC invasion and migration (AU)

Cytomegalovirus reactivation in esophageal cancer patients receiving chemoradiotherapy: A retrospective analysis.

BACKGROUND: Although rare, cytomegalovirus (CMV) reactivation can be lethal in patients with cancer. However, the criteria for the prevention of cytomegalovirus reactivation during cancer treatment are unclear. This study aimed to identify factors associated with CMV reactivation in patients with esophageal cancer who were receiving chemoradiotherapy. METHODS: This retrospective study included esophageal cancer patients receiving definitive or palliative chemoradiotherapy during April 2013-March 2020. Patients with fever during chemoradiotherapy underwent a systemic work-up to detect the primary focus of infection, and CMV antigenemia was assessed in cases of unidentifiable infection. RESULTS: Among 132 patients (80.3% male, median age 69 years [range, 39-86 years]), 124 received 5-fluorouracil plus cisplatin and 8 received oxaliplatin-5-fluorouracil-levofolinate chemotherapy. Overall, 19 patients had CMV reactivation, 37 had other infections, and 76 had no identified infection (groups 1, 2, and 3, respectively). Median minimum lymphocyte counts were 81.0/µl (interquartile range: 52.0-144.0/µl), 120.0/µl (81.0-162.5/µl), and 185.5/µl (120.5-328.0/µl) in groups 1, 2, and 3, respectively, with counts being significantly lower in groups 1 and 2 than in group 3 (p < 0.001). In multiple logistic regression analysis, the minimum lymphocyte count was associated with CMV reactivation (odds ratio 0.983, 95% confidence interval: 0.973-0.994, p = 0.002). CONCLUSION: CMV reactivation is not rare in patients with esophageal cancer who were receiving chemoradiotherapy and is associated with the minimum lymphocyte counts. CMV reactivation should be considered during differential diagnosis for patients with a severe decline in lymphocyte counts when receiving chemoradiotherapy.

Human papillomavirus (HPV) types 16 and 18 infection and esophageal squamous cell carcinoma: a systematic review and meta-analysis.

OBJECTIVE: The human papillomavirus (HPV) is implicated in the pathogenesis of several cancers among humans. The role of HPV as one of the etiological agents in esophageal carcinogenesis is partially unknown. We assessed whether the available evidence supports the association of HPV with risk and prognosis in patients with esophageal squamous cell carcinomas (ESCCs). DESIGN: For this systematic review and meta-analysis, PubMed, Embase, Cochrane Library, and SCOPUS were searched up to February 2021. The included studies were prospective or retrospective studies that evaluated the incidence, risk, and prognosis of HPV-16/18-related ESCCs in adult subjects. The primary outcome was the incidence rate of ESCC in HPV-16/18 carriers. Secondary outcomes included the risk of ESCCs compared with healthy HPV-16/18 carriers (expressed as odds ratios [ORs] with 95% confidence intervals [CIs]) and the survival of HPV + versus HPV- ESCCs. RESULTS: The search identified 1649 unique citations, of which 145 met the inclusion criteria and were included in the pooled analysis (16,484 patients). The pooled HPV prevalence in ESCCs was 18.2% (95% CI 15.2-21.6%; P < 0.001). A significantly increased ESCC risk was associated with HPV infection (OR = 3.81; 95% CI 2.84-5.11; P < 0.001). Main limitation were methods of HPV detection (DNA only), race of populations included (mainly Asiatic countries) and lack of adjustment for other prognostic factors. CONCLUSIONS: The findings suggest that HPV-16/18 is detectable in about 1 on 5 cases of ESCC with different prevalences across the world. It is moderately but significantly associated with a diagnosis of ESCC. Further epidemiological studies are needed to confirm and increase the current knowledge of the subject.

Infection with Human Papillomavirus 18 Promotes Alkylating Agent-Induced Malignant Transformation in a Human Esophageal Cell Line.

The relationship between human papillomavirus (HPV) and esophageal cancer (EC) has been controversial, which may be caused by the difference in geographic regions of sample origin. Thus, we conducted a case-control study to find that HPV increased the risk of esophageal cancer, and the HPV18 detection rate is the highest (24.2%) among patients with EC, suggesting that HPV18 could be the most risk subtype of HPV infected. We then identified high-risk HPV18 and N-methyl-N'-nitro-N-nitroso-guanidine (MNNG) to establish a model on the viral etiology cooperating with environmental carcinogens. Het-1A cells containing HPV18 were continuously exposed to MNNG or not; then the morphological phenotype and function assays were performed in 25th passage cells. MNNG promoted the proliferation and invasion abilities and inhibited apoptosis both in Het-1A-HPV18 and control group. However, the Het-1A-HPV18 had a stronger change in phenotypic features and formed more transformed foci in soft agar. Further, Western blot found p53 and p21 were down-regulated, and expression of c-Myc, MMP-2, and MMP-9 and Bcl-2/Bax ratio were up-regulated. Our results revealed that MNNG was easier to induce malignant transformation of Het-1A cells transfected with HPV18. It is good evidence for the close relationship between HPV and the etiology of EC, providing foundation for further study in molecular mechanism and specific intervention targets.

HPV16 infection promotes an M2 macrophage phenotype to promote the invasion and metastasis of esophageal squamous cell carcinoma.

OBJECTIVES: High-risk human papillomavirus (HR-HPV) is an important risk factor for esophageal cancer. Macrophages constitute a crucial immune medium for regulating HPV-related tumors; however, the specific regulatory mechanisms remain unknown. Therefore, the purpose of our current study was to investigate the mechanism by which HPV16E6 regulates macrophages to promote the invasion and metastasis of esophageal cancer. METHODS: HPV16E6 infection was detected by polymerase chain reaction. Immunohistochemistry was used to verify the distribution of tumor-associated macrophages (TAMs) and MMP-9 expression in esophageal squamous cell carcinoma tissues (ESCCs), and cancer adjacent normal tissues (CANs) from Kazakh patients. ESCC cells were transfected with a plasmid over-expressing HPV16E6 and non-contact cocultured with macrophages. RESULTS: The infection rate of HPV16E6 in Kazakh ESCCs was clearly higher than that in CANs (P < 0.05). The density of CD163-positive TAMs was significantly positively correlated with HPV16E6 infection in ESCCs (P < 0.05). After coculturing macrophages and EC9706 cells transfected with the HPV16E6 plasmid, the phenotype of macrophages transformed into M2 macrophages. The migration and invasion ability of ESCC cells were higher in the HPV16E6-transfected and coculture group than in the HPV16E6 empty vector-transfected and non-cocultured HPV16E6-transfected groups (all P < 0.05). The density of M2-like TAMs in ESCCs was positively correlated with the level of MMP-9 expression. MMP-9 expression in the HPV16E6-ESCC coculture macrophages group was substantially higher than that in controls (all P < 0.05). CONCLUSIONS: HPV16 infection mediates tumor-associated macrophages to promote ESCC invasion and migration.

p16 in highly malignant esophageal carcinomas: the correlation with clinicopathological factors and human papillomavirus infection.

p16 is generally considered to be a surrogate maker of human papillomavirus (HPV) infection and also a predictive marker of favorable clinical outcome of patients with squamous cell carcinoma of the oropharynx. p16 overexpression is also known to be induced by deregulation of RB1 in neuroendocrine carcinomas. In highly malignant esophageal neoplasms, however, the status of p16 has remained largely unknown. We immunolocalized p16 and Rb1 in 82 surgically resected esophageal high-grade squamous cell carcinomas (46 poorly differentiated and 36 basaloid squamous cell carcinomas) and 15 esophageal small-cell carcinomas in order to clarify the clinical and biological significance of p16. p16 immunoreactivity was detected in 7/82 (9%) high-grade squamous cell carcinomas and 15 (100%) small-cell carcinomas. p16 immunoreactivity was significantly associated with Rb1 protein loss in both groups (P < 0.001). HPV was detected in none of the p16-positive cases examined. Clinical outcome of the p16-positive high-grade squamous cell carcinomas was not different from that of the p16-negative counterparts (P = 0.687) but significantly better than those with the small-cell carcinomas (P = 0.023). p16 was therefore considered to be induced through an inactivation of the RB1 signaling pathway and not through HPV infection in highly malignant esophageal neoplasms. Nevertheless, patients' clinical outcome of these neoplasms significantly differs; therefore, small-cell carcinomas have to be carefully differentiated from other neoplasms. In addition, p16 overexpression is not predictive of favorable clinical outcome in high-grade squamous cell carcinomas of the esophagus.

Synchronous primary neoplasia in patients with oropharyngeal cancer: Impact of tumor HPV status. A GETTEC multicentric study.

INTRODUCTION: Patients with oropharyngeal squamous cell carcinoma (OPSCC) display a significant risk of synchronous primary neoplasia (SPN) which could impact their management. The aims of this study were to evaluate the risk and distribution of SPN in OPSCC patients according to their HPV (p16) status, the predictive factors of SPN and the impact of SPN on therapeutic strategy and oncologic outcomes. MATERIAL AND METHODS: All OPSCC patients treated from 2009 to 2014 were included in this multicentric retrospective study. Univariate analyses were conducted using Chi-2 and Fisher exact tests. For multivariate analyses, all variables associated with a p ≤ 0.10 in univariate analysis were included in logistic regression models. RESULTS: Among the 1291 patients included in this study, 75 (5.8%) displayed a SPN which was preferentially located in the upper aerodigestive tract, lung and esophagus. Comorbidity level (p = 0.03), alcohol (p = 0.005) and tobacco (p = 0.01) consumptions, and p16 tumor status (p < 0.0001) were significant predictors of SPN. In multivariate analysis, p16+ status was significantly associated with a lower risk of SPN (OR = 0.251, IC95% [0.133;0.474]). Patients with a SPN were more frequently referred for non-curative treatment (p = 0.02). In patients treated with curative intent, there was no impact of SPN on the therapeutic strategy (surgical vs. non-surgical treatment). We observed no overall survival differences between patients with or without SPN. CONCLUSION: P16 tumor status is the main predictive factor of SPN in OPSCC patients. This study provides crucial results which should help adapt the initial work-up and the global management of OPSCC patients.

Human papillomavirus infection and p53 mutation in esophageal squamous cell carcinoma and its impact on treatment outcome.

INTRODUCTION: Human papillomavirus (HPV) is emerging as a risk factor for esophageal squamous carcinoma. The prognostic value of the HPV status has been investigated. However, the results are much controversial. AIM: This study aims to document the association of HPV infection and mutation of p53 gene in esophageal squamous cell carcinoma (ESCC) and its impact on treatment outcome. SUBJECTS AND METHODS: The study was conducted over a period of 12 months. A total of 30 cases of ESCC who were primarily to be treated with radiotherapy/chemoradiotherapy were included in the study. All the tissue samples for biopsy were subjected to immunohistochemistry to study p53 and p16 expression, which is a surrogate marker for HPV. The patients were treated by radiotherapy alone or concurrent chemoradiotherapy depending on performance status and stage of disease. The impact of p16 and p53 on overall survival (OS) and disease-free survival (DFS) was determined. RESULTS: The median OS of HPV-positive patients was 22 months (95% confidence interval [CI] 12-31) as compared to 13 months (95% CI 7-18) for HPV-negative patients (P = 0.298). The median DFS for HPV-positive patients was 16 months (95% CI 7-24) as compared to 5 months (95% CI 4-6) for HPV-negative patients (P = 0.048). The median OS of p53-positive patients was 13 months (95% CI 6.7-19) as compared to 22 months (95% CI 12.7-31.2) for p53-negative patients (P = 0.080). The median DFS for p53-positive patients was 5 months (95% CI 3.7-6.2) as compared to 22 months (95% CI 15.7-29.4) for p53-negative patients (P = 0.014). CONCLUSION: Clinical findings of our result can be used to sum up that both HPV infection and p53 mutation status are reliable biomarkers and can help clinicians to predict treatment outcome and prognosticate patients better.

Different Genotype Distribution of Human Papillomavirus between Cervical and Esophageal Cancers: A Study in Both High-Incidence Areas, Xinjiang, China.

The aim of this study is to reveal the certain human papillomavirus (HPV) genotype distribution between cervical cancer and esophageal cancer in the both high-incidence geographic regions. For this study, we collected and detected the infection of HPV in 120 paraffin-embedded esophageal tissues and 152 paraffin-embedded cervical tissues, respectively. The esophageal tissues include 40 normal epithelium (ENOR), 26 dysplasia (DYS), and 54 invasive squamous cell carcinoma (ESCC). The cervical tissues consisted of 40 normal epithelium (CNOR), 53 intraepithelial neoplasia (CIN), and 59 invasive squamous cell carcinoma (CSCC). Both esophageal and cervical tissues collected in this study came from the same area, in which both the ESCC and CSCC were in high incidence, Xinjiang province, China. HPV GenoArray test kits were served to analyze the HPV infection. The result shows that among the 59 CSCC tissues, the total infection rate of HPV was 98.3% (58/59). The positive rate of HPV-16 infection was 63.8% (37/58). It indicated that HPV-16 is the most common infection among all of the high-risk HPV. The multiple infection rate was 19.0% (11/58). Among the 54 ESCC, a total of 7 genotypes were detected. The total infection rate of HPV was 61.1% (33/54). The positive rate of HPV-16 infection was 63.6% (21/33). The multiple infection rate was 6.1% (2/33). Our result shows that high-risk-type HPV-16 was associated with both cervical cancer and esophageal cancer, which play a role in the high-incidence area in Xinjiang. We hope that our results could point out the direction for the treatment strategy of HPV-associated cancer, cervical cancer, and esophageal cancer and for the application of HPV vaccines in the future.

Frequency and genotype distribution of high risk human papillomavirus in esophageal squamous cell carcinoma.

INTRODUCTION: Esophageal squamous cell carcinoma (ESCC) is a dismal disease exhibiting striking geographical differences in its incidence. It is multifactorial in origin. Among infectious agents, human papillomavirus (HPV) was introduced as a possible causative agent in the development of ESCC in 1982. Subsequent studies using various methods have confirmed the presence of HPV in ESCC. We aimed to determine the frequency of HPV in ESCC in northwest Pakistan which is part of high risk belt for this disease. METHODOLOGY: This study was conducted on two hundred and forty-three (243) diagnosed cases of ESSC at two tertiary care hospitals of Peshawar, Pakistan, from 2011 to 2016. DNA was extracted from all specimens. Polymerase chain reaction (PCR) was used to check the quality of DNA using ß-globin primers and frequency and genotypes of HPV using HPV general primers and type-specific primers respectively. HPV and its genotypes were confirmed through the sequencing of a few selected cases. RESULTS: Two hundred and three (203) tissue specimens had adequate DNA and were further analyzed. HPV positivity with general primers alone was 15.7% (32/203). Using HPV general primers and type-specific primers (HPV 16 or HPV 18), the overall positivity of HPV was 31% (63/203). For type-specific primers, frequency of HPV types 16 and 18 was 20.19% (41) and 7.8% (16) respectively where 6 cases were positive for both HPV 16 and 18. CONCLUSIONS: The overall high prevalence of HPV indicates it as a possible risk factor for ESSC.

Significance of druggable targets (PD-L1, KRAS, BRAF, PIK3CA, MSI, and HPV) on curatively resected esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) still remains intractable disease with few therapeutic options. Programmed death-ligand 1 (PD-L1), which is essential for immune evasion, is involved in the pathogenesis of ESCC and thus is a potential therapeutic target. PIK3CA, KRAS, and BRAF mutations, microsatellite instability (MSI) caused by deficient mismatch repair (dMMR), and human papillomavirus (HPV) can potentially upregulate PD-L1 expression, which might contribute to the clinical outcome of patients with ESCC. METHODS: We investigated the significance of the present druggable markers [PD-L1, PIK3CA, KRAS, and BRAF mutations, MSI caused by deficient dMMR, and HPV] in 64 curatively resected ESCCs, using immunohistochemistry (PD-L1 and MMR protein expression), direct sequencing (KRAS, BRAF, and PIK3CA mutations), real-time PCR (HPV infection), and MSI using quasi-monomorphic markers. RESULTS: PD-L1 expression, PIK3CA mutation, and MSI/dMMR were detected in 35.9, 12.5, and 17.2% of ESCCs, respectively. HPV was rarely detected (1.6%) (high-risk HPV68), whereas KRAS and BRAF mutations were not detected in ESCCs. PD-L1-positive tumors were not correlated with PIK3CA mutation or MSI/dMMR (all P > 0.05). PD-L1, PIK3CA mutation, and MSI/dMMR characterized the patients associated with light smoking, female and younger age, and younger age and well-differentiated tumors, respectively (all P < 0.05). In multivariate analysis, only PD-L1-positivity was an independent favorable prognostic factor for overall survival (OS) and disease-free survival (DFS) (P = 0.023, P = 0.014). In the PD-L1-negative ESCCs, PIK3CA mutation had a poor prognostic impact on both OS and DFS (P = 0.006, P = 0.002). CONCLUSIONS: PIK3CA mutation may be an alternative prognostic biomarker in PD-L1-negative curatively resected ESCCs that can be optional to identify high-risk patients with worse clinical outcome who require more intensive therapy and follow-up.

Human papillomavirus infection in esophageal squamous cell carcinoma and esophageal adenocarcinoma: a concise review.

The causal link between high-risk human papillomavirus (hr-HPV) infection and cervical, anogenital, and some oropharyngeal malignancies has been established by both molecular and epidemiological data. The association between HPV and esophageal squamous cell carcinoma (ESCC) remains controversial, as is the true prevalence of HPV infection in ESCC. The wide range in reported rates reflects variability in the primary literature, with some larger scale case-control studies suggesting the infection rates range from 0% to 78%. Interactions between HPV and the Barrett's metaplasia-dysplasia-carcinoma sequence have been explored, and these studies have shown some conflicting data. Overall, systematic reviews have reported the prevalence of HPV-positive DNA in esophageal adenocarcinoma patients of between 13% and 35%. Postulated reasons for discrepancies in HPV prevalence rates in esophageal cancer include variations in testing methodology and assay sensitivities; technical issues, including the lack of a gold-standard primer; types of specimens utilized (fresh-frozen versus formalin-fixed tissue); geographical variation; cross-contamination; and small sample sizes. Thus, efforts must be undertaken to (1) standardize HPV testing, ideally in a central laboratory and utilizing tests that detect viral transcriptional activity; (2) avoid cross-contamination; and (3) recruit large numbers of patients to accurately ascertain HPV rates in esophageal malignancy.

Importance of investigating high-risk human papillomavirus in lymph node metastasis of esophageal adenocarcinoma.

High-risk human papillomavirus has been suggested as a risk factor for esophageal adenocarcinoma. Tumor human papillomavirus status has been reported to confer a favorable prognosis in esophageal adenocarcinoma. The size of the primary tumor and degree of lymphatic spread determines the prognosis of esophageal carcinomas. Lymph node status has been found to be a predictor of recurrent disease as well as 5-year survival in esophageal malignancies. In human papillomavirus driven cancers, e.g. cervical, anogenital, head and neck cancers, associated lymph nodes with a high viral load suggest metastatic lymph node involvement. Thus, human papillomavirus could potentially be useful as a marker of micro-metastases. To date, there have been no reported studies regarding human papillomavirus involvement in lymph nodes of metastatic esophageal adenocarcinoma. This review highlights the importance of investigating human papillomavirus in lymph node metastasis of esophageal adenocarcinoma based on data derived from other human papillomavirus driven cancers.

Early esophageal squamous cell carcinoma in a western series is not associated with active HPV infection.

Few data are available concerning human papillomavirus (HPV) in early esophageal squamous cell carcinoma (ESCC) in Western population. Our study intended to determine the prevalence of HPV infection and the histological characteristics in such early tumors. A monocentric and retrospective study was conducted including 86 patients with early ESCC treated by endoscopic resection or esophagectomy, from 2012 to 2018. Histopathological prognostic criteria were evaluated. Immunohistochemistry for p16 and p53 and an HPV mRNA in situ hybridization were performed. The tumors were composed of 25 (29%) in situ carcinomas, 21 (24%) intramucosal carcinomas, and 40 (47%) submucosal carcinomas, of which 34 had a deep infiltration (> 200 µm). Emboli, present in 12 cases, were associated with deep infiltration. P16-positive ESCC accounted for 21% of the patients. It was not correlated with active HPV infection as no cases were found to be positive in RISH analysis for RNA detection of this virus. However, there was a correlation between p16 expression and alcohol or tobacco consumption. The only histopathological criterion correlated with p16 positivity was marked inflammatory infiltrate. Local or distant neoplastic recurrence occurred in 25% of patients. Overall survival was 95.8% and local or metastatic recurrence-free survival was 75%. There was a correlation between positive resection margins and tumor recurrence. In contrast to oropharynx carcinoma, our study showed that ESCC were not associated with an active HPV infection, highlighting the negligible role of this virus in early ESCC carcinogenesis in the Western world.

Detection of HPV DNA in Esophageal Lesions: a Cross-Sectional Study.

BACKGROUND: Several studies have documented human papillomavirus (HPV) in extra-cervical tumors. We aimed to detect HPV type 16 and HPV other than type 16 (OT-16) DNA in esophageal papilloma and esophagus squamous cell carcinoma (ESCC) samples and to compare clinicopathological features of HPV positive and negative patients. METHODS: Materials were obtained from a tertiary care public hospital and studied in an university hospital for this cross-sectional study. Seventy-six tissue samples (50 papilloma and 26 ESCC) were included. After deparaffinization by xylene and DNA extraction by phenol chloroform-isoamyl-alcohol, 76 samples were studied with a G6PDH control kit. Forty-four papilloma and 21 ESCC samples with enough tissues were studied for HPV DNA. HPV OT-16 DNA and HPV type 16 were detected by real time-polymerase chain reaction. RESULTS: Twelve (27.3%) and one (2.3%) of the papilloma samples were HPV type 16 and other than type 16 positive, respectively. Eleven (52.4%) and one (4.8%) of ESCC samples were HPV type 16 and mixed type positive, respectively. CONCLUSIONS: We suggest that HPV infection is common in esophageal papilloma and ESCC. Due to the wellknown association of HPV with premalignant and malignant conditions, follow-up of these patients accompanied by HPV should be implemented.