Causal Link of Human Papillomavirus in Barrett Esophagus and Adenocarcinoma: Are We There Yet?

Esophageal cancer is a relatively common malignancy worldwide with a high mortality (5-year survival of <15%). Despite screening, surveillance, improved imaging and treatment, the exponential rise in OAC continues. The strongest risk factors for OAC are chronic heartburn and metaplastic transformation of the lower third of the esophagus (Barrett's esophagus). The risk profile includes Caucasian race, male gender older age, obesity and smoking. Although the tumor risk in BO has been progressively revised downwards, the exponential rise in OAC remains unchecked. This paradox points to an unidentified missing link. Relatively recently, we provided the world's initial data for a strong association of biologically relevant hr-HPV with BD and OAC. Since then, systematic reviews and meta-analysis have documented HPV DNA prevalence rates in OAC of between 13 to 35%. In this review, we provide some evidence for a probable causal relationship between hr-HPV and OAC. This is challenging given the multifactorial etiology and long latency. Increasingly, high-risk HPV (hr-HPV) is regarded as a risk factor for OAC. This discovery will aid identification of a sub-group of high-risk progressors to esophageal cancer by surveillance and the development of effective preventive strategies including vaccination.

A Review of the Impact of the COVID-19 Pandemic on Colorectal Cancer Screening: Implications and Solutions.

The COVID-19 pandemic has impacted all aspects of medical care, including cancer screening and preventative measures. Colorectal cancer screening declined significantly at the onset of the pandemic as the result of an intentional effort to conserve resources, prioritize emergencies and reduce risk of transmission. There has already been an increase in diagnosis at more advanced stages and symptomatic emergencies due to suspended screenings. As endoscopy units find their way back to pre-pandemic practices, a backlog of cases remains. The missed CRC diagnoses amongst the missed screenings carry a risk of increased morbidity and mortality which will only increase as time-to-diagnosis grows. This review discusses the impact of COVID-19 on colonoscopy screening rates, trends in stages/symptoms/circumstances at diagnosis, and economic and social impact of delayed diagnosis. Triaging and use of FITs are proposed solutions to the challenge of catching up with the large number of pandemic-driven missed CRC screenings.

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.

Antibodies against human papillomavirus proteins in Barrett's dysplasia and intramucosal esophageal adenocarcinoma.

High-risk human papillomavirus (HPV) types 16/18 have been associated with Barrett's dysplasia (BD)/esophageal adenocarcinoma (EAC). Nevertheless, no data exist in relation to serological analysis for HPV antibodies in BD/EAC with site-specific viral DNA status. We prospectively examined antibodies to multiple HPV types in 438 patients representing hospital/reflux controls and Barrett's metaplasia (BM)/BD/intramucosal EAC. Antibody responses to HPV6/11/16/18/31/33/45/52/58 were analyzed using multiplex serology, including antibodies to E6/E7/E1/E2 and L1 antigens. Seropositivity for individual HPV proteins was infrequent in both cases and controls and was ≤10.2%. There was no difference in the seroprevalence of antibodies to any HPV antigen/antibody combination between reclassified cases (BD/EAC) and controls (hospital/reflux/BM) or between HPV16 or HPV18 DNA cases and controls, respectively. Among HPV16 DNA-positive BD/EAC cases, antibodies to HPV16 E7 were significantly more prevalent (3/26, 11.5%) than in hospital and reflux controls plus BM (5/328, 1.5%) (adjusted OR = 10.12, 95% CI: 1.61-63.73, P = 0.014). Among HPV18 DNA-positive cases, antibodies to HPV18 E1 were present in 3/6 (50%) cases versus 5/328 (1.5%) controls (adjusted OR = 44.28, 95% CI: 6.10-321.47, P = 0.0002). Although antibodies against HPV were generally uncommon in cases and controls, immune responses against two early proteins of HPV16/18 were significantly more frequent in viral DNA-positive BD/intramucosal EAC.

Association of Biomarkers for Human Papillomavirus With Survival Among Adults With Barrett High-grade Dysplasia and Esophageal Adenocarcinoma.

Importance: The presence of high-risk human papillomavirus (HPV) has been associated with a favorable outcome in Barrett high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). Nevertheless, the prognostic significance of other HPV-related biomarkers (ie, retinoblastoma protein [pRb], cyclin D1 [CD1], minichromosome maintenance protein [MCM2] and Ki-67) is unknown. Objective: To examine the association between HPV-related biomarkers and survival in adult patients with Barrett HGD and EAC. Design, Setting, and Participants: This retrospective case-control study examined the hypothesis that the HPV-related cell cycle markers (pRb, CD1, and Ki-67) and the viral surrogate marker (MCM2) may be associated with a favorable prognosis in Barrett HGD and EAC. Pretreatment biopsies were used for HPV DNA determination via polymerase chain reaction and immunohistochemistry for the HPV-related biomarkers. Recruitment of patients occurred in secondary and tertiary referral centers, with 151 patients assessed for eligibility. The study period was from December 1, 2002, to November 28, 2017, and the dates of analysis were from September 9, 2011, to November 28, 2017. Main Outcomes and Measures: Disease-free survival and overall survival. Results: Of 151 patients assessed for eligibility, 9 were excluded. Among the 142 patients with Barrett HGD or EAC (126 [88.7%] men; mean [SD] age, 66.0 [12.1] years; 142 [100%] white), 37 were HPV positive and 105 were HPV negative. No association with disease-free survival was noted for pRb, CD1, Ki-67, and MCM2. In regard to overall survival, only low expression of CD1 had a favorable prognosis (hazard ratio [HR], 0.53; 95% CI, 0.30-0.95; adjusted P = .03). All the biomarkers stratified by HPV status showed significant associations with survival. Patients with HPV-positive, low-expression pRb esophageal tumors were associated with a significantly improved disease-free survival compared with the HPV-negative, high-expression Rb tumors (HR, 0.33; 95% CI, 0.12-0.93; adjusted P = .04). Similarly, HPV-positive, low-expression CD1 was associated with a significantly favorable disease-free survival (HR, 0.26; 95% CI, 0.09-0.76; adjusted P = .01), as was HPV-positive, high-expression MCM2 (HR, 0.27; 95% CI, 0.09-0.78; adjusted P = .02). In regard to overall survival, HPV was significantly associated only with low CD1 (HR, 0.38; 95% CI, 0.15-0.94; adjusted P = .04). Conclusions and Relevance: This study's findings suggest that low expression of CD1 appears to be an independent prognostic marker in Barrett HGD and EAC. Human papillomavirus positivity in combination with pRb, CD1, MCM2, and Ki-67 was associated with a survival benefit in esophageal tumors. These findings suggest the possibility of personalization of therapy for Barrett HGD and EAC based on viral status.

Risk factors for esophageal cancer: emphasis on infectious agents.

Risk factors for esophageal cancer include genetic factors (such as tylosis) and infectious agents. A variety of organisms have been implicated in esophageal carcinogenesis, either directly or indirectly. In this review, we explore the normal esophageal flora and how it may be controlled, and also the variety of organisms that may affect esophageal carcinogenesis, either directly or indirectly. The organisms with potential direct effects in squamous cell carcinoma include human papillomavirus (HPV), Epstein-Barr virus, and polyoma viruses. Interestingly, HPV is now implicated in esophageal adenocarcinoma (EAC), not in its initiation but in the development of dysplasia, in which HPV33 in particular has been associated. Indirectly, Helicobacter pylori has been associated with EAC by, initially, causing increased acid secretion that increases acid reflux, and by reducing lower esophageal sphincter pressure, which increases gastroesophageal reflux; the latter increases the risk of Barrett's esophagus, and hence EAC. Conversely, subsequent atrophic gastritis may normalize that risk.

Survival Rates for Patients With Barrett High-grade Dysplasia and Esophageal Adenocarcinoma With or Without Human Papillomavirus Infection.

Importance: High-risk human papillomavirus (HPV) has been associated with Barrett dysplasia and esophageal adenocarcinoma. Nevertheless, the prognostic significance of esophageal tumor HPV status is unknown. Objective: To determine the association between HPV infection and related biomarkers in high-grade dysplasia or esophageal adenocarcinoma and survival. Design, Setting, and Participants: Retrospective case-control study. The hypothesis was that HPV-associated esophageal tumors would show a favorable prognosis (as in viral-positive head and neck cancers). Pretreatment biopsies were used for HPV DNA determination via polymerase chain reaction, in situ hybridization for E6 and E7 messenger RNA (mRNA), and immunohistochemistry for the proteins p16INK4A and p53. Sequencing of TP53 was also undertaken. The study took place at secondary and tertiary referral centers, with 151 patients assessed for eligibility and 9 excluded. The study period was from December 1, 2002, to November 28, 2017. Main Outcomes and Measures: Disease-free survival (DFS) and overall survival (OS). Results: Among 142 patients with high-grade dysplasia or esophageal adenocarcinoma (126 [88.7%] male; mean [SD] age, 66.0 [12.1] years; 142 [100%] white), 37 were HPV positive and 105 were HPV negative. Patients who were HPV positive mostly had high p16INK4A expression, low p53 expression, and wild-type TP53. There were more Tis, T1, and T2 tumors in HPV-positive patients compared with HPV-negative patients (75.7% vs 54.3%; difference, 21.4%; 95% CI, 4.6%-38.2%; P = .02). Mean DFS was superior in the HPV-positive group (40.3 vs 24.1 months; difference, 16.2 months; 95% CI, 5.7-26.8; P = .003) as was OS (43.7 vs 29.8 months; difference, 13.9 months; 95% CI, 3.6-24.3; P = .009). Recurrence or progression was reduced in the HPV-positive cohort (24.3% vs 58.1%; difference, -33.8%; 95% CI, -50.5% to -17.0%; P < .001) as was distant metastasis (8.1% vs 27.6%; difference, -19.5%; 95% CI, -31.8% to -7.2%; P = .02) and death from esophageal adenocarcinoma (13.5% vs 36.2%; difference, -22.7%; 95% CI, -37.0% to -8.3%; P = .01). Positive results for HPV and transcriptionally active virus were both associated with a superior DFS (hazard ratio [HR], 0.33; 95% CI, 0.16-0.67; P = .002 and HR, 0.44; 95% CI, 0.22-0.88; P = .02, respectively [log-rank test]). Positivity for E6 and E7 mRNA, high p16INK4A expression, and low p53 expression were not associated with improved DFS. On multivariate analysis, superior DFS was demonstrated for HPV (HR, 0.39; 95% CI, 0.18-0.85; P = .02), biologically active virus (HR, 0.36; 95% CI, 0.15-0.86; P = .02), E6 and E7 mRNA (HR, 0.36; 95% CI, 0.14-0.96; P = .04), and high p16 expression (HR, 0.49; 95% CI, 0.27-0.89; P = .02). Conclusions and Relevance: Barrett high-grade dysplasia and esophageal adenocarcinoma in patients who are positive for HPV are distinct biological entities with a favorable prognosis compared with viral-negative esophageal tumors. Confirmation of these findings in larger cohorts with more advanced disease could present an opportunity for treatment de-escalation in the hope of reducing toxic effects without deleteriously affecting survival.

Active human papillomavirus involvement in Barrett's dysplasia and oesophageal adenocarcinoma is characterized by wild-type p53 and aberrations of the retinoblastoma protein pathway.

We have previously demonstrated that transcriptionally active high-risk HPV (hr-HPV) is strongly incriminated in Barrett's dysplasia (BD) and oesophageal adenocarcinoma (OAC) using mainly fresh frozen tissue. This study aimed to identify biomarkers of active HPV infection in Barrett's metaplasia, (BM)/BD/OAC by immunohistochemical staining (IHC) of formalin-fixed paraffin embedded (FFPE) tissue for aberrations of p53 and the retinoblastoma (pRb) pathway, which are targets for the viral oncoproteins, E6/E7, respectively. Prospectively, BM (n = 81)/BD (n = 72)/OAC (n = 65) FFPE specimens were subjected to IHC staining for pRb, p16INK4A , cyclin D1 , p53 and RNA in-situ hybridization for E6/E7 transcripts. HPV DNA was determined via PCR in fresh frozen specimens. Viral load measurement (real-time PCR) and Next Generation Sequencing of TP53 was performed. Of 218 patients, 56 were HPV DNA positive [HPV16 (n = 42), 18 (n = 13), 6 (n = 1)]. Viral load was low. Transcriptionally active HPV (DNA+ /RNA+ ) was only found in the dysplastic and adenocarcinoma group (n = 21). The majority of HPV DNA+ /RNA+ BD/OAC were characterized by p 16highINK4A (14/21, 66.7%), pRblow (15/21, 71.4%) and p53low (20/21, 95%) and was significantly different to controls [combination of HPV DNA- /RNA- (n = 94) and HPV DNA+ /RNA- cohorts (n = 22)]. p53low had the strongest association with DNA+ /RNA+ oesophageal lesions (OR = 23.5, 95% CI = 2.94-187.8, p = 0.0029). Seventeen HPV DNA+ /RNA+ BD/OAC identified as p53low, were sequenced and all but one exhibited wild-type status. pRblow /p53low provided the best balance of strength of association (OR = 8.0, 95% CI = 2.6-25.0, p = 0.0003) and sensitivity (71.4%)/specificity (71.6%) for DNA+ /RNA+ BD/OAC. Active HPV involvement in BD/OAC is characterized by wild-type p53 and aberrations of the retinoblastoma protein pathway.

Barrett Esophagus and Intramucosal Esophageal Adenocarcinoma.

Barrett esophagus (BE) is a precursor lesion for esophageal adenocarcinoma (EAC). Developments in imaging and molecular markers, and endoscopic eradication therapy, are available to curb the increase of EAC. Endoscopic surveillance is recommended, despite lack of data. The cancer risk gets progressively downgraded, raising questions about the understanding of risk factors and molecular biology involved. Recent data point to at least 2 carcinogenic pathways operating in EAC. The use of p53 overexpression and high-risk human papillomavirus may represent the best chance to detect progressors. Genome-wide technology may provide molecular signatures to aid diagnosis and risk stratification in BE.

Genomic analysis of HPV-positive versus HPV-negative oesophageal adenocarcinoma identifies a differential mutational landscape.

BACKGROUND: High-risk human papillomavirus (hr-HPV) has been implicated in a subset of patients with oesophageal adenocarcinoma (OAC). We therefore hypothesised that HPV associated OAC may have distinct genomic aberrations compared with viral negative oesophageal cancer. METHODS: Whole exome sequencing was performed to explore the mutational landscape and potential molecular signature of HPV-positive versus HPV-negative OAC. Four hr-HPV-positive and 8 HPV-negative treatment-naive fresh-frozen OAC tissue specimens and matched normal tissue were analysed to identify somatic genomic mutations. Data were subjected to cancer driver gene identification and pathway analysis. RESULTS: The HPV-positive cohort harboured approximately 50% less non-silent somatic mutations than the virus-negative patients with oesophageal cancer (1.31 mutations/Mb vs 2.56 mutations/Mb, p=0.048). TP53 aberrations were absent in the HPV-positive OAC group whereas 50% of the HPV-negative patients with OAC exhibited TP53 mutations. HPV-negative cancers were enriched with non-silent mutations in cancer driver genes, but not HPV-positive tumours. Enriched A>C transversions at adenine-adenine (AA) dinucleotide was observed in 5/7 Siewert class I OAC samples but none (0/5) in Siewert class II tumours (p=0.027). CONCLUSIONS: These findings demonstrate distinct genomic differences between HPV-positive and HPV-negative OACs indicating different biological mechanisms of tumour formation.

Barrett's oesophagus: can meaningful screening and surveillance guidelines be formulated based on new data and rejigging the old paradigm?

Gastro-oesophageal reflux disease (GORD) and Barrett's oesophagus (BO) have been considered to be the most important known risk factors for oesophageal adenocarcinoma (OAC). It has been the fastest growing cancer in the Western World and has occurred against a backdrop of progressive reduction in the risk estimate of malignancy associated with BO and no reduction in mortality from OAC using the prevailing screening and surveillance guidelines. The recently published link between high risk HPV and Barrett's dysplasia/cancer may be the 'missing' strong risk factor responsible for the significant rise of OAC since the 1970's, as has been the case with head and neck tumours, another viral associated cancer. P53 immunohistochemistry has been proposed as a good molecular marker for predicting disease progression in BD. Nevertheless, significant negative staining for this mutation in BD remains a major hurdle to widespread routine clinical use as a sole molecular marker. Recent data raises the distinct possibility of at least 2 (probably more) carcinogenic pathways operating in OAC. One is HPV mediated devoid largely of p53 mutations and the other p53 dependent. The joint use of both these markers as part of a molecular panel may represent the best bet yet of detecting the high risk group of progressors to OAC. Patients who are positive for either or both biomarkers i.e p53 or/and transcriptional markers of HPV may warrant more intensive screening. In future, genome wide technology may provide molecular signatures to aid diagnosis and risk stratification in BO.

Persistence of Human Papillomavirus, Overexpression of p53, and Outcomes of Patients After Endoscopic Ablation of Barrett's Esophagus.

We investigated the role of high-risk human papillomavirus (hr-HPV) in patients with Barrett's dysplasia and adenocarcinoma (EAC). Clearance vs persistence of HPV (DNA, E6 or E7 mRNA, and p16INK4A protein) and overexpression or mutation of p53 were determined for 40 patients who underwent endotherapy for Barrett's dysplasia or EAC. After ablation, dysplasia or neoplasia was eradicated in 34 subjects (24 squamous, 10 intestinal metaplasia). Six patients had detectable lesions after treatment; 2 were positive for transcriptionally active hr-HPV, and 4 had overexpression of p53. Before endotherapy, 15 patients had biologically active hr-HPV, 13 cleared the infection with treatment, and dysplasia or EAC was eliminated from 12 patients. One patient who cleared HPV after ablation acquired a p53 mutation, and their cancer progressed. Of 13 patients with overexpression of p53 before treatment, 10 cleared the p53 abnormality after ablation with eradication of dysplasia or neoplasia, whereas 3 of 13 had persistent p53 mutation-associated dysplasia after endotherapy (P = .004). Immunohistochemical and sequence analyses of p53 produced concordant results for 36 of 40 samples (90%). Detection of dysplasia or neoplasia after treatment was associated with HPV persistence or continued p53 overexpression.

Infection and esophageal cancer.

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on infection and cancer, and includes commentaries on the influence of bacterial infections on mucin expression and cancer risk; the role of esophageal bacterial biota in the incidence of esophageal disease; the association between human papilloma virus (HPV) and esophageal squamous cell carcinoma; the role of HPV in esophageal adenocarcinoma; the role of Helicobacter pylori in cardiac carcinoma; and the role of Epstein-Barr virus infection in esophageal cancer.

Barrett's Esophagus.

OPINION STATEMENT: Barrett's esophagus (BE) is the most important and recognizable precursor lesion for esophageal adenocarcinoma (EAC), which is the one of the fastest-growing cancers in the Western world (600 % in the U.S. in the last 40 years), and therefore it is critical to manage the risk of cancer present in BE. New developments in imaging and molecular markers, as well as an armamentarium of novel and effective endoscopic eradication therapy - especially radio-frequency ablation (RFA) and endoscopic mucosal resection (EMR) - are now available to the interventional endoscopist to help curb the significant rise of esophageal adenocarcinoma (EAC). Endoscopic surveillance is currently recommended by most gastroenterology societies worldwide, although there is no data to support this practice in relation to reducing mortality from EAC. Paradoxically, the cancer risk in Barrett's esophagus is being progressively downgraded, which raises fundamental questions about our understanding of the risk factors and molecular biology of the Barrett's metaplasia-dysplasia-adenocarcinoma sequence. The recent discovery of a strong association of transcriptionally active high-risk human papillomavirus (hr-HPV) with Barrett's dysplasia (BD) and EAC may shed some light on this anomaly. It is imperative that we identify the high-risk group of progressors to EAC. While p53 immunohistochemistry is currently probably the best clinical molecular marker for predicting disease progression in BD, we must think outside the box and cast the net wide in search of additional biomarkers (e.g., high-risk human papilloma virus (hr-HPV)].

Transcriptionally active human papillomavirus is strongly associated with Barrett's dysplasia and esophageal adenocarcinoma.

OBJECTIVES: The role of human papillomavirus (HPV) in Barrett's esophagus (BE) remains unclear. The few studies that have previously investigated HPV and esophageal adenocarcinoma (EAC) or BE have produced either negative data or positive results of doubtful clinical/etiological significance or have detected only low-risk HPV types. We therefore prospectively determined the prevalence of biologically active HPV in esophageal epithelium of patients representing the Barrett's metaplasia-dysplasia-adenocarcinoma sequence. METHODS: HPV DNA was estimated by nested PCR and viral transcriptional activity detected by E6/7 oncogene mRNA expression and p16INK4A immunohistochemistry in fresh frozen and paraffin-embedded esophageal biopsies of patients with BE, Barrett's dysplasia (BD), and EAC, as well as controls. Biopsies were obtained from the transformation zone (squamocolumnar junction (SCJ)) and the lesion, or corresponding site in controls, i.e., 2 cm above the gastroesophageal junction (GEJ). RESULTS: Of the 261 patients, 81 were positive for HPV DNA. In controls and BE, the virus was mostly detected at the transformation zone. Compared with controls (18.0%), HPV positivity was significantly more common in BD (68.6%, incidence rate ratio (IRR) 2.94, 95% confidence interval (CI) 1.78-4.85, P<0.001) and EAC (66.7%, IRR 2.87, 95% CI 1.69-4.86, P<0.001), but not in BE (22.1%, IRR 1.06, 95% CI 0.60-1.85, P=0.85). Of the patients, 92.6% were high-risk (HR) HPV, i.e., types 16 and 18. Again, p16INK4A positivity was greatest in BD and EAC and much less in BE patients (44.1%, IRR 17.0 (95% CI 4.86-59.6, P<0.001), 44.4%, 17.0 (95% CI 4.87-59.4, P<0.001), and 10.6%, 3.93 (95% CI 1.01-15.3, P=0.048) respectively). In 66 HPV DNA-positive patients tested for E6/E7 mRNA, none of the control (n=16) or BE (n=13) individuals were positive, whereas 9/22 BD and 9/15 EAC patients demonstrated oncogene expression (P<0.001). When HPV DNA, p16INK4A, and E6/E7 mRNA were all positive, there was a very strong association with disease severity (SCJ: odds ratio (OR) 104, 95% CI 20.3-529, P<0.001; lesion: OR 62.2, 95% CI 12.4-311, P<0.001) than when all were negative. CONCLUSIONS: Transcriptionally active HR-HPV was strongly associated with BD and EAC, but was largely biologically irrelevant in BE and controls, suggesting a potential role in esophageal carcinogenesis. These data provide robust justification for further detailed longitudinal, interventional, and molecular studies.

Management of Barrett's oesophagus and intramucosal oesophageal cancer: a review of recent development.

Barrett's oesophagus is the most important and recognizable precursor lesion for oesophageal adenocarcinoma, which is the one of the fastest growing cancers in the Western World. The incidence of oesophageal adenocarcinoma has increased 600% in the United States between 1975 and 2001 and is thought to represent a real increase in burden rather than a result of histologic or anatomical misclassification or overdiagnosis. Thus, the cancer risk in Barrett's oesophagus has to be managed and involves prevention (surveillance endoscopy), treating underlying gastroesophageal reflux disease (medically and or surgically) and endoscopic therapy to remove diseased epithelium in appropriate patient subgroups. In the last decade, new developments in imaging and molecular markers as well as an armamentarium of novel and effective endoscopic eradication therapy has become available to the endoscopist to combat this exponential rise in oesophageal adenocarcinoma. Paradoxically, the cancer risk in Barrett's oesophagus gets progressively downgraded which raises fundamental questions about our understanding of the known and unknown risk factors and molecular aberrations that are involved in the Barrett's metaplasia-dysplasia-carcinoma sequence. Future research has to be directed at these areas to fine tune our screening and surveillance programs to identify more accurately the high-risk group of progressors to oesophageal adenocarcinoma who would benefit most from endoscopic therapy.