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Like cervical cancer, anal cancer is often caused by a human papillomavirus and has a premalignant stage called high-grade squamous intraepithelial lesion or anal intraepithelial neoplasia. A randomized trial showed that treating HSIL led to a 57% reduction in progression to anal cancer as compared with active surveillance.

Infection with human papillomavirus (HPV) is recognized as one of the major causes of infection-related cancer worldwide, as well as the causal factor in other diseases. Strong evidence for a causal etiology with HPV has been stated by the International Agency for Research on Cancer for cancers of the cervix uteri, penis, vulva, vagina, anus and oropharynx (including base of the tongue and tonsils). Of the estimated 12.7 million new cancers occurring in 2008 worldwide, 4.8% were attributable to HPV infection, with substantially higher incidence and mortality rates seen in developing versus developed countries. In recent years, we have gained tremendous knowledge about HPVs and their interactions with host cells, tissues and the immune system; have validated and implemented strategies for safe and efficacious prophylactic vaccination against HPV infections; have developed increasingly sensitive and specific molecular diagnostic tools for HPV detection for use in cervical cancer screening; and have substantially increased global awareness of HPV and its many associated diseases in women, men, and children. While these achievements exemplify the success of biomedical research in generating important public health interventions, they also generate new and daunting challenges: costs of HPV prevention and medical care, the implementation of what is technically possible, socio-political resistance to prevention opportunities, and the very wide ranges of national economic capabilities and health care systems. Gains and challenges faced in the quest for comprehensive control of HPV infection and HPV-related cancers and other disease are summarized in this review. The information presented may be viewed in terms of a reframed paradigm of prevention of cervical cancer and other HPV-related diseases that will include strategic combinations of at least four major components: 1) routine introduction of HPV vaccines to women in all countries, 2) extension and simplification of existing screening programs using HPV-based technology, 3) extension of adapted screening programs to developing populations, and 4) consideration of the broader spectrum of cancers and other diseases preventable by HPV vaccination in women, as well as in men. Despite the huge advances already achieved, there must be ongoing efforts including international advocacy to achieve widespread—optimally universal—implementation of HPV prevention strategies in both developed and developing countries. This article summarizes information from the chapters presented in a special ICO Monograph ‘Comprehensive Control of HPV Infections and Related Diseases’ Vaccine Volume 30, Supplement 5, 2012. Additional details on each subtopic and full information regarding the supporting literature references may be found in the original chapters.

Human papillomavirus (HPV), a common sexually transmitted virus infecting mucosal or cutaneous stratified epithelia, is implicated in the rising of associated cancers worldwide. While HPV infection can be cleared by an adequate immune response, immunocompromised individuals can develop persistent, treatment-refractory, and progressive disease. Primary immunodeficiencies (PIDs) associated with HPV-related disease include inborn errors of GATA, EVER1/2, and CXCR4 mutations, resulting in defective cellular function. People living with secondary immunodeficiency (e.g. solid-organ transplants recipients of immunosuppression) and acquired immunodeficiency (e.g. concurrent human immunodeficiency virus (HIV) infection) are also at significant risk of HPV-related disease. Immunocompromised people are highly susceptible to the development of cutaneous and mucosal warts, and cervical, anogenital and oropharyngeal carcinomas. The specific mechanisms underlying high-risk HPV-driven cancer development in immunocompromised hosts are not well understood. Current treatments for HPV-related cancers include surgery with adjuvant chemotherapy and/or radiotherapy, with clinical trials underway to investigate the use of anti-PD-1 therapy. In the setting of HIV co-infection, persistent high-grade anal intraepithelial neoplasia can occur despite suppressive antiretroviral therapy, resulting in an ongoing risk for transformation to overt malignancy. Although therapeutic vaccines against HPV are under development, the efficacy of these in the setting of PID, secondary- or acquired- immunodeficiencies remains unclear. RNA-based therapeutic targeting of the HPV genome or mRNA transcript has become a promising next-generation therapeutic avenue. In this review, we summarise the current understanding of HPV pathogenesis, immune evasion, and malignant transformation, with a focus on key PIDs, secondary immunodeficiencies, and HIV infection. Current management and vaccine regimes are outlined in relation to HPV-driven cancer, and specifically, the need for more effective therapeutic strategies for immunocompromised hosts. The recent advances in RNA-based gene targeting including CRISPR and short interfering RNA (siRNA), and the potential application to HPV infection are of great interest. An increased understanding of both the dysregulated immune responses in immunocompromised hosts and of viral persistence is essential for the design of next-generation therapies to eliminate HPV persistence and cancer development in the most at-risk populations.

Squamous cell carcinomas of the anus and anal canal represent a model of a cancer and perhaps the first where level 1 evidence supported primary chemoradiotherapy (CRT) in treating locoregional disease with curative intent. The majority of tumours are associated with infection with oncogenic subtypes of human papilloma virus and this plays a significant role in their sensitivity to treatment. However, not all tumours are cured with CRT and there remain opportunities to improve outcomes in terms of oncological control and also reducing late toxicities. Understanding the biology of ASCC promises to allow a more personalised approach to treatment, with the development and validation of a range of biomarkers and associated techniques that are the focus of this review.

In the last 4 decades, survival among patients with human papillomavirus (HPV)-associated cancers has improved, while the incidence of these cancers has increased among younger cohorts. Among survivors of HPV-associated cancers, persistent HPV infection may remain a risk factor for preventable HPV-associated second primary cancers (HPV-SPCs). To investigate the risk of HPV-SPCs among survivors of HPV-associated index cancers and to test the hypothesis that the HPV-SPC risk among these persons has increased over the last 4 decades. A retrospective cohort study of 9 cancer registries of the Surveillance, Epidemiology, and End Results (SEER) database was conducted to identify patients with HPV-associated (cervical, vaginal, vulvar, oropharyngeal, anal, and penile) cancers diagnosed from January 1, 1973, through December 31, 2014. The dates of analysis were July 1, 2017, to January 31, 2018. The HPV-SPC risk was quantified by calculating standard incidence ratios (SIRs) and excess absolute risks (EARs) per 10 000 person-years at risk (PYR). The HPV-SPC risk by time was estimated using Poisson regression. From 113 272 (73 085 female and 40 187 male) survivors of HPV-associated cancers, 1397 women and 1098 men developed HPV-SPCs. The SIRs for HPV-SPCs were 6.2 (95% CI, 5.9-6.6) among women and 15.8 (95% CI, 14.9-16.8) among men. The EARs were 18.2 per 10 000 PYR for women and 53.5 per 10 000 PYR for men. Among both women and men, those who had index oropharyngeal cancers had the highest HPV-SPC risk (SIR, 19.8 [95% CI, 18.4-21.4] and EAR, 80.6 per 10 000 PYR among women; SIR, 18.0 [95% CI, 16.9-19.1] and EAR, 61.5 per 10 000 PYR among men). Women who had index cervical cancers and men who had index anal cancers had the lowest HPV-SPC risk (SIR, 2.4 [95% CI, 2.2-2.7] and EAR, 4.5 per 10 000 PYR among women; SIR, 6.5 [95% CI, 4.7-8.8] and EAR, 18.5 per 10 000 PYR among men). Both women and men who had index HPV-associated cancers of any kind had a significantly higher risk of oropharyngeal HPV-SPCs. Over the last 4 decades, the risk of developing most types of HPV-SPCs after index cervical, vaginal, and vulvar cancers increased. According to this study, the HPV-SPC risk among survivors of HPV-associated cancers is significant, implying that persistent HPV infection at multiple sites may be associated with HPV-SPCs. These findings have the potential to inform surveillance recommendations for survivors of HPV-associated cancers.

Patients with pathogenic variants in the GATA Binding Protein 2 ( ), a hematopoietic transcription factor, are at risk for human papillomavirus-related (HPV) anogenital cancer at younger than expected ages. A female cohort with haploinsufficiency was systematically assessed by two gynecologists to characterize the extent and severity of anogenital HPV disease, which was also compared with affected males. A 17-year retrospective review of medical records, including laboratory, histopathology and cytopathology records was performed for patients diagnosed with haploinsufficiency followed at the National Institutes of Health. Student's -test and Mann-Whitney U test or Fisher's exact test were used to compare differences in continuous or categorical variables, respectively. Spearman's rho coefficient was employed for correlations. Of 68 patients with haploinsufficiency, HPV disease was the initial manifestation in 27 (40%). HPV occurred at median 18.9 (15.2-26.2) years in females, and 25.6 (23.4-26.9) years in males. Fifty-two (76%), 27 females and 25 males, developed HPV-related squamous intraepithelial lesions (SIL) including two males with oral cancer. Twenty-one patients developed anogenital high-grade SIL (HSIL) or carcinoma (16 females versus 5 males, (59% versus 20%, respectively, p=0.005) at median 27 (18.6-59.3) years for females and 33 (16.5-40.1) years for males. Females were more likely than males to require >2 surgeries to treat recurrent HSIL (p=0.0009). Of 30 patients undergoing hematopoietic stem cell transplant (HSCT) to manage disease arising from haploinsufficiency, 12 (nine females, three males) had persistent HSIL/HPV disease. Of these nine females, eight underwent peri-transplant surgical treatment of HSIL. Five of seven who survived post-HSCT received HPV vaccination and had no or minimal evidence of HPV disease 2 years post-HSCT. HPV disease persisted in two receiving immunosuppression. HPV disease/low SIL (LSIL) resolved in all three males. Females with haploinsufficiency exhibit a heightened risk of recurrent, multifocal anogenital HSIL requiring frequent surveillance and multiple treatments. haploinsufficiency must be considered in a female with extensive, multifocal genital HSIL unresponsive to multiple surgeries. This population may benefit from early intervention like HSCT accompanied by continued, enhanced surveillance and treatment by gynecologic oncologists and gynecologists in those with anogenital HPV disease.

In recent decades, several Western countries have reported an increase in oropharyngeal and anal cancers caused by human papillomavirus (HPV). Trends in HPV-associated cancers in Asia have not been as well described. We describe the epidemiology of potentially HPV-related cancers reported to the Singapore Cancer Registry from 1968-2012. Analysis included 998 oropharyngeal squamous cell carcinoma (OPSCC), 183 anal squamous cell carcinoma (ASCC) and 8,019 invasive cervical cancer (ICC) cases. Additionally, 368 anal non-squamous cell carcinoma (ANSCC) and 2,018 non-oropharyngeal head and neck carcinoma (non-OP HNC) cases were included as comparators. Age-standardized incidence rates (ASR) were determined by gender and ethnicity (Chinese, Malay and Indian). Joinpoint regression was used to evaluate annual percentage change (APC) in incidence. OPSCC incidence increased in both genders (men 1993-2012, APC = 1.9%, p<0.001; women 1968-2012, APC = 2.0%, p = 0.01) and was 5 times higher in men than women. In contrast, non-OP HNC incidence declined between 1968-2012 among men (APC = -1.6%, p<0.001) and women (APC = -0.4%, p = 0.06). ASCC and ANSCC were rare (ASR = 0.2 and 0.7 per 100,000 person-years, respectively) and did not change significantly over time except for increasing ANSCCs in men (APC = 2.8%, p<0.001). ICC was the most common HPV-associated cancer (ASR = 19.9 per 100,000 person-years) but declined significantly between 1968-2012 (APC = -2.4%). Incidence of each cancer varied across ethnicities. Similar to trends in Western countries, OPSCC incidence increased in recent years, while non-OP HNC decreased. ICC remains the most common HPV-related cancer in Singapore, but Pap screening programs have led to consistently decreasing incidence.

Individuals with human immunodeficiency virus (HIV) infection are at increased risk for human papillomavirus—related squamous cell cancer of the anus. Screening HIV-infected patients for squamous cell cancer of the anus and human papillomavirus—related anal dysplasia may prevent excess morbidity and mortality. We have conducted a systematic review of the indirect evidence in the literature regarding the utility of anal Papanicolau (Pap) smear screening of HIV-infected individuals in the highly active antiretroviral therapy era. Although there are no published studies evaluating the efficacy of anal Pap smear screening for preventing squamous cell cancer of the anus or anal intraepithelial neoplasia, we reviewed data regarding the burden of disease, anal Pap smear sensitivity and specificity, the prevalence of anal dysplasia, and 1 cost effectiveness study. The available evidence demonstrates that HIV-infected individuals have an increased risk for squamous cell cancer of the anus and anal intraepithelial neoplasia. This review identifies important areas for further study before routine anal Pap smear screening can be recommended.

Objectives This case–control study was aimed to investigate associations between HBV infection and extrahepatic digestive system cancers. Methods The patients of gastric, small intestinal, colonic, rectal, anal, biliary tract, and pancreatic cancers were retrospectively collected between 2016.5 and 2017.12. Simultaneously, the healthy controls were collected from the health check‐up registry, and cancer‐free status was confirmed based on medical records. Propensity score matching was performed to reduce bias. Multinomial logit model and conditional logistic regression model were used to assess the risk of individual cancer according to HBV serological markers and classifications. Results Totally, 4748 patients involving seven cancers, and 57,499 controls were included. After matching, HBsAg was associated with increased risk of gastric cancer (aOR = 1.39, 95% CI: 1.05–1.85), and anti‐HBs served as a protective factor for gastric (aOR = 0.72, 95% CI: 0.61–0.85), colonic (aOR = 0.73, 95% CI: 0.60–0.89), rectal (aOR = 0.73, 95% CI: 0.63–0.85), and pancreatic (aOR = 0.58, 95% CI: 0.42–0.82) cancers. Compared to subgroups with non‐infection and vaccination status, inactive HBsAg carriers and active HBV infection subgroup were correlated with gastric carcinogenesis (aOR = 1.41, 95% CI: 1.03–1.93). However, no clear association was found between HBV infection and other cancers. Conclusions HBV infection was potentially associated with an increased risk of gastric cancer. The development mechanism of HBV‐associated gastric cancer needs to investigate further. This case–control study was aimed to investigate associations between HBV infection and extrahepatic digestive system cancers. Our study revealed that HBV infection was potentially associated with an increased risk of gastric cancer. However, because of the limited ability to establish a causal relationship for case–control study, large‐scale prospective cohort studies are urgencies, and the latent mechanism about HBV extrahepatic carcinogenesis needs to be investigated as well.