**Meet the editor**

Rajamanickam Rajkumar, Professor of Community Medicine at Meenakshi Medical College, Kanchipuram, Tamil Nadu, India, was inspired at school age to become a doctor, by his mother Navamani, supported by Christine Matthews, an Irish missionary. He won a gold medal for his research on Leprosy Eradication in India, during his MD which he passed with distinction in 1993. Due to his

love to serve for the rural people, he worked at the Christian Fellowship Community Health Centre, Ambillikai, Tamil Nadu, greatly influenced by Padmabhushan Dr. Jacob Cherian. Burdened by the large number of cervical cancer cases attending this small rural hospital, Raj wrote to the IARC/ WHO for guidance to prevent and control cervical cancer. With IARC, he initiated a rural population-based cancer registry in 1996. He was honored with PhD, from Open University of Colombo, for this pioneer work. He received training in Colposcopy and Precancer management in UK and Ireland. In 2001, he implemented a large-scale screening program, using the village level workers. This project of IARC was a great success. In 2011, in collaboration with the Society for Colposcopy and Cervical Pathology, Singapore, and The Ohio State University Medical Center, USA, he formed a society for training doctors, nurses, in cervical cancer prevention. In 2012, he received the "Best Teacher and Researcher Award" from Meenakshi Academy of Higher Education and Research—MAHER, Chennai, India. In 2016, he is involved in forming a network of medical and nursing colleges, to undertake, cervical cancer and HPV screening programs, among the most underserved and unreached poor women of rural India.

## Contents

### **Preface XI**


Chapter 1 **Introductory chapter: Human Papillomavirus (HPV) Infections, Associated Diseases and Cervical Cancer Prevention and Control Initiate Countdown Using "The Raj's Cancer Control Clock" 3** Rajamanickam Rajkumar

### **Section 2 HPV Infections and Related Diseases - Screening 13**


## Preface

**Section 3 HPV Infections, Related Diseases and Cancers - Diagnosis,**

J. Rajčáni, K. Kajo, O. el Hassoun, M. Adamkov and M. Benčat

Ala-Eddin Al Moustafa, Noor Al-Antary and Amber Yasmeen

Adriana Plesa, Iulia V. Iancu, Anca Botezatu, Irina Huica, Mihai

**Control - Human Papillomavirus and Cancer - Immunological Consequences of MHC Class 1 Down - Regulation 241**

Naveed Shahzad, Muhammad Umer, Memoona Ramzan and Bilal

Chapter 7 **Diagnosis and Prevalence of High-Risk Human Papillomavirus**

Elena López-Díez, Sonia Pérez and Amparo Iñarrea

Chapter 9 **The Involvement of Epigenetic Mechanisms in HPV‐Induced**

**Section 5 HPV Infections, Related Diseases and Cancers - Prevention and**

Chapter 10 **Pathogenesis of Human Papillomavirus – Immunological**

Chapter 11 **Human Papillomavirus in Head and Neck Cancer 255** Makbule Tambas, Musa Altun and Deniz Tural

Chapter 12 **Preventive Strategies against Human Papillomaviruses 289**

**Responses to HPV Infection 243** G. Hossein Ashrafi and Nadia Aziz Salman

Chapter 6 **The Diagnostic of Cervical Carcinoma: From Theory to**

**Infection in Heterosexual Men 149**

Chapter 8 **High-Risk Human Papillomavirus and Colorectal**

**Management 107**

**Carcinogenesis 169**

**Cervical Cancer 191**

Stoian and Gabriela Anton

**Section 4 HPV - Vaccines 189**

Aslam

**Practice 109**

**VI** Contents

Human papillomavirus infection and related diseases are global problems. This book com‐ prises of worldwide research about HPV prevalence, causal factors for the HPV infections, latest methods in diagnosis, correlation of HPV test results with cervical cytology results, screening strategies for HPV, and cervical precancers. The natural history of HPV infections, genetic and epigenetic changes, means of detecting the lesions that will progress from pre‐ cancer stages to invasive stages, and therapeutic interventions to modify the epigenetic changes, thus preventing cervical cancers, and HPV in men—MSM, are discussed.

Important research findings on HPV vaccines of varied combination of strains, the feasibility of HPV vaccination programs in different countries, and the efficacy of the vaccines and its limitations are vividly described.

Researchers, health planners, and health care providers, in all the countries, would be great‐ ly benefitted from this book, and more so, for those who are in developing and underserved countries.

Individuals, especially women, have much to learn from self-collection techniques for HPV testing, which will be of great importance in prevention of cervical cancers.

The other HPV-related diseases and cancers, especially in high risk men, and the need for screening and treatment are well discussed.

The editor opines that, for the common man, the public health message for **HPV** would be: **H**ygiene— **P**rotected sex— **V**accination.

Adherence to these will lead to primordial, primary, and secondary prevention of **HPV** in‐ fections and the related diseases.

It is my privilege and pleasure to have served as an editor.

I highly appreciate all the authors, applaud the Intech Publishers, and congratulate their team, especially Andrea Koric, the Publishing Process Manager, for bringing out this valua‐ ble book, which achieves great significance for the contributions by esteemed authors, made toward achieving scientific excellence and social empowerment.

Wishing the readers a pleasurable and purposeful reading!

**Dr. Rajamanickam Rajkumar, MD, PhD** Professor, Community Medicine, Meenakshi Medical College Hospital & Research Institute, constituent of MAHER, Kanchipuram, Tamil Nadu, India

**Section 1**

## **Introduction**

**Introductory chapter: Human Papillomavirus (HPV) Infections, Associated Diseases and Cervical Cancer Prevention and Control Initiate Countdown Using "The Raj's Cancer Control Clock"**

## Rajamanickam Rajkumar

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/63488

## **1. Introduction**

### **1.1. For timely actions and targeted achievements—The clock ticks now**

I had the privilege of reading and revising all the chapters in this book. The authors have opened up a sea of information. It is time for the Healthcare planners and providers to act now. My introductory review chapter helps in this. To sail the uncharted sea of human papillomavirus (HPV)-related diseases and prevention, we need a compass. I am pleased to provide a guid‐ ing model, in the form of a clock, which will help us to move from time to time, with specific agenda, keeping the community needs and available resources in mind. This model is univer‐ sal and can be followed in any country for targeted health care services. All the research work written in this book by the eminent authors can be placed in a relevant position in this clock and the readers can pursue their research, revolving around the cycle, which will benefit the science and the society, as the two arms of the clock.

### **1.2. The 12' O clock: AREA**

It is imperative to have a defined geographical area and a resident population. The area could be of a relevant size with its own characteristics, such as rural, urban, hills, mountains, seashore, deserts, valleys, disaster prone, and others. Each of these will have typical populations which also differ in socioeconomic, cultural, and health standards, and all these are essential for our health programs as the types of interventions planned for need to be tailored accordingly.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **1.3. The 1' O clock: ENUMERATE**

This population should be enumerated meticulously and methodologically. All the socio, demographic, and health data should be inferred, and this will provide us the denominator for all types of epidemiological studies, both observational and experimental.

The enumeration needs to be undertaken in a sustainable method using volunteers residing in the same region which will facilitate all the follow-up measures.

### **1.4. The 2' O clock: INFERENCE**

From the health data collected, we can analyze the health problems, their magnitude, and other related factors. HPV infections and diseases will have the data regarding risk factors, causal associations and early signs, and symptoms. Especially the factors regarding menstrual and sexual hygiene, knowledge, attitude, and practice regarding HPV infections can also be studied. This will form the basis for further interventions.

### **1.5. The 3' O clock: EDUCATION**

Education is one such important intervention, and this should be highly focused, organized, and the process has to be measured by input and outcome analysis. Based on the impact of our health education, the next step is planned for.

### **1.6. The 4' O clock: INVITATION**

The invitation is targeted and individualized, based on the outcome of previous data regard‐ ing, knowledge, attitude, practice studies, and effect of the tailored health education process

### **1.7. The 5' O clock: COUNSELLING**

This very important intervention should be carefully undertaken by well trained personnel who would brief to the individuals, all the interventions and outcomes and obtain informed consent. The community/study subjects would then be sincere to the interventions, which will reduce the dropout rates, attrition, and noncompliance. The unwarranted litigations would be prevented and human rights would be ensured. Usually, in public health programs, the aspect of effective counseling is neglected or overlooked.

### **1.8. The 6' O clock: SCREENING**

Most of the studies begin directly from this 6'O clock position thus bypassing the previous five steps and hence, might lack community compliance and success. Validity and reliability are the important characteristics of the screening tools which should also fulfill the **A 6** model mentioned below. All screening programs are to be equipped to treat the disease outcome status, as otherwise people will lose faith in the screening measures. This bounds to happen in HPV screening and hence treatment of HPV positive/precancer lesions of uterine cervix is an example of offering screening outcome facilities.

## **1.9. The 7' O clock: PATTERNS**

**1.3. The 1' O clock: ENUMERATE**

4 Human Papillomavirus - Research in a Global Perspective

**1.4. The 2' O clock: INFERENCE**

**1.5. The 3' O clock: EDUCATION**

**1.6. The 4' O clock: INVITATION**

**1.7. The 5' O clock: COUNSELLING**

**1.8. The 6' O clock: SCREENING**

This population should be enumerated meticulously and methodologically. All the socio, demographic, and health data should be inferred, and this will provide us the denominator

The enumeration needs to be undertaken in a sustainable method using volunteers residing

From the health data collected, we can analyze the health problems, their magnitude, and other related factors. HPV infections and diseases will have the data regarding risk factors, causal associations and early signs, and symptoms. Especially the factors regarding menstrual and sexual hygiene, knowledge, attitude, and practice regarding HPV infections can also be

Education is one such important intervention, and this should be highly focused, organized, and the process has to be measured by input and outcome analysis. Based on the impact of

The invitation is targeted and individualized, based on the outcome of previous data regard‐ ing, knowledge, attitude, practice studies, and effect of the tailored health education process

This very important intervention should be carefully undertaken by well trained personnel who would brief to the individuals, all the interventions and outcomes and obtain informed consent. The community/study subjects would then be sincere to the interventions, which will reduce the dropout rates, attrition, and noncompliance. The unwarranted litigations would be prevented and human rights would be ensured. Usually, in public health programs, the aspect

Most of the studies begin directly from this 6'O clock position thus bypassing the previous five steps and hence, might lack community compliance and success. Validity and reliability are the important characteristics of the screening tools which should also fulfill the **A 6** model mentioned below. All screening programs are to be equipped to treat the disease outcome status, as otherwise people will lose faith in the screening measures. This bounds to happen in HPV screening and hence treatment of HPV positive/precancer lesions of uterine cervix is

for all types of epidemiological studies, both observational and experimental.

in the same region which will facilitate all the follow-up measures.

studied. This will form the basis for further interventions.

our health education, the next step is planned for.

of effective counseling is neglected or overlooked.

an example of offering screening outcome facilities.

All the disease patterns which are observed as outcome of the screening process, need to be well documented and adequately addressed. For example, HPV negative women should be entered in a population based "registry" and followed up for periodical checkups, HPV positive are to be advised for visual inspection acetic acid (VIA)/colposcopy/biopsy, and development of precancers, if precancer lesions develop they are to be promptly treated, and also if invasive stages are found they have to be referred to higher centers for treatment.

### **1.10. The 8' O clock: CONFIRMATION**

In case of HPV screening in cervical cancer screening programs, the confirmation of the precancer/cancer disease status in HPV positive cases should be done by colposcopy directed biopsy and this is called as evidence-based practice. Also it is very important to prove the disease status during follow-up, and later to declare reduction in incidence as the success of interventions.

### **1.11. The 9' O clock: TREATMENT**

Most of the cervical cancer screening programs, especially in the resource limited settings, are not able to offer treatment for precancer lesions. The " see and treat" policy programs are able to overcome this constraint by offering cryotherapy/loop electro excision procedure (LEEP) services, under one roof, in the same sitting. The services are usually provided by specially trained nurses and doctors. This ensures prevention of the development of precancers in to invasive cancers and is an important outcome measure of screening programs.

### **1.12. The 10'O clock: FOLLOW-UP**

Meticulous follow-up, both socially and medically, earns good reputation for the intervention programs and will provide histopathological evidence of the disease status in the study population. Only with a stable and resident population, long-term follow-up is possible, and we can arrive at intermediate and terminal epidemiological indicators such as the incidence rate and prevalence rate.

### **1.13. The 11' O clock: MONITORING, EVALUATION, AND REPLAN**

Periodical and continuous monitoring is essential for the appropriate management of the resources. Initial, concurrent, and terminal evaluations done be internal and external quality assurance teams are vital for the programs to achieve their objectives. The lessons thus learned by the program managers, lead to modifications, restructuring, and redefining the targets and replan the next intervention for better cost–benefit and cost effectiveness, and focus further for achievement of our mission and vision.

### **1.14. Community-based 12 O' clock model**

**1. AREA—**define a geographic area for your study/services


**Figure 1.** Community-based 12 O' clock model.

## **2. The community-based HPV and related diseases prevention model**

## **2.1. The Raj's CANCER CONTROL CLOCK©**

### *2.1.1. Dedication*

**2. ENUMERATE—**the resident population, document the sociodemographic data

**4. EDUCATION—**about prevention at individual, family, and community levels

**7. SCREENING—A**cceptable, **A**vailable, **A**ccessible, **A**ffordable, **A**nswerable, **A**chievable

**8. PATTERNS—**of diseases detected in screening—Disclosure of results—individualized,

**10. TREATMENT—**of the HPV infections and related diseases, pre cancer lesions and ensure

**11. FOLLOW-UP—**by confirmation of disease free status, counseling, and referrals to the

**12. MONITORING, EVALUATION, REPLAN—**Effectiveness of interventions, Health

**3. INFERENCE—**prevalence of HPV-related diseases-Establish REGISTRIES

**5. INVITATION—**to attend awareness programs, screening, and vaccination

**6. COUNSELLING—**the participants about possible outcomes and solutions

—the **A-6** model for screening and vaccination programs

the availability of post-treatment services

Economics and advocating prevention policies.

Government/Private health systems

6 Human Papillomavirus - Research in a Global Perspective

**Figure 1.** Community-based 12 O' clock model.

ensure confidentiality and offer solution for health problems

**9. CONFIRMATION—**diagnosis – at screening and follow up stages

This chapter is dedicated to the healthcare planners and providers, serving in various part of the world in different levels of resources, diverse communities, and varied cultures. The editor presents his grass-root level practical experiences in a remote corner of rural India. If this could inspire others to take up challenges and serve for the underserved and reach the unreached and offer dedicated services for the prevention and control of HPV infections and related diseases, the mission of the Intech publishers, their team along with the inputs from the editor and valuable contributions from various authors, would be achieved.

### *2.1.2. Implementation of a large-scale cervical cancer screening and HPV study program in India: The challenges and solutions*

The editor narrates the experiences which are riddled with various constraints and challenges. Poverty, illiteracy, ignorance, conservative women community, inaccessible terrains, no gynecologists, no pathologists, and no electricity were some of the challenges, when the editor initiated the Cervical Cancer Screening Programs and HPV surveys, during 1996–2007.

To overcome the challenges, women self-help groups (SHGs) were started, cottage industries, farming, dairying, provided small income, and evening classes were conducted to educate women and several role-plays, skits, street plays, drama, and puppet shows were organized for health education, and we walked our way through where there were no roads, in the hills, valleys, and mountains. As there was no electricity, we took portable generators run with kerosene oil. The nurses were trained, and they provided diagnostic and therapeutic services under the supervision of junior doctors.

The village communities were met and local health volunteers were selected and trained. These volunteers were very influential in the community and were able to motivate large number of women for the screening camps.

The local women were much resistant to enter the mobile health clinics, usually set up in big vans or bus. The women feared stigma attached to gynecological examinations and were not comfortable with unfamiliar environment. Hence we set up health clinics in the community friendly areas, such as schools, ration shops, and local government buildings, to which the people were accustomed to.

The healthcare providers, at first-level contact, were the public health nurses, who are usually the local girls who have completed high school level and trained for couple of years in primary health care and midwifery. Hence the women were comfortable in seeking medical help from these nurses who also did the screening, for HPV and cervical cancer. The screening tool was VIA, which was not very expensive. The positive cases underwent colposcopy and directed biopsy, but were treated in the same sitting by cryotherapy.

The earlier step was the HPV prevalence survey in which the cervical cell samples were collected by cyto-brush and sent to designated laboratories for HPV study.

The editor, thus advocates the **6 "A" s strategy for the success of cervical cancer screening** camps in limited resource settings. The strategy is explained as follows:

**A**cceptable: Screening was done by the public health nurses, from the local community. The screening camps were held in local buildings, not strange to the community. The screening procedure was not complicated and not painful. The treatment of precancers was cryotherapy, done in the same sitting and the procedure was painless.

**A**vailable: The manpower—nurses were always available for the community health needs.

**A**ccessible: The screening and treatment centers were in the same locality and no need of travel, especially in the scorching sun, heavy rains, and on bad roads.

**A**ffordable: The screening tool was VIA, and treatment was cryotherapy, which were not of high cost and affordable by the healthcare systems, providers, and beneficiaries.

**A**nswerable: This is a symbiotic responsibility. The healthcare providers and beneficiaries are holding equal stake in the health programs. They are to understand each other and are answerable to all the inputs and outputs of the screening and treatment programs.

**A**chievable: It is essential to show that the objectives of the health programs are achievable, and the community should know that their expectations in attending the screening and treatment programs would be fulfilled. Thus the **A-6** model ensures the success for screening, and it can be followed for HPV vaccination programs.

### *2.1.3. The experiences are the sources of inspiration*

The editor was the principal investigator for initiating the First Population-Based Cancer Registry, in Tamil Nadu, south India, during 1996, in collaboration with the International Agency for Research on Cancer—IARC/WHO. The registry inferred that cervical cancer was very high among the rural women. A community-based screening program for cervical cancer was started in 2001 in collaboration with IARC/WHO. The program used VIA as the screening tool. The village health nurses offered the screening and precancer treatment services. In a period of about 3 years more than 30,000 women were screened, about 10% of the women were screen positive, and the disease was confirmed by colposcopy directed biopsy. Precancer lesions were treated by Cryotherapy/LEEP.

A 5-year follow-up of the treated women proved that the women treated for precancer lesions did not develop invasive cancers. The incidence rate for cervical cancer was brought down by 25% and mortality due to cervical cancer was reduced by 35%. Thus, it was proved that screening, early diagnosis, and prompt treatment of precancers will bring down the HPV associated cervical cancer. The editor emphasizes this strategy for developing and underde‐ veloped countries.

HPV prevalence studies were also undertaken, by the editor, in collaboration with IARC/ WHO, for the first time in south India, during 2005, which revealed that about 14% of the women were HPV positive. They were infected with multiple strains, and the infection rate was persistent among all age groups, suggesting low clearance of the viral infection and repeated infections.

## **3. Conclusion**

The earlier step was the HPV prevalence survey in which the cervical cell samples were

The editor, thus advocates the **6 "A" s strategy for the success of cervical cancer screening**

**A**cceptable: Screening was done by the public health nurses, from the local community. The screening camps were held in local buildings, not strange to the community. The screening procedure was not complicated and not painful. The treatment of precancers was cryotherapy,

**A**vailable: The manpower—nurses were always available for the community health needs. **A**ccessible: The screening and treatment centers were in the same locality and no need of travel,

**A**ffordable: The screening tool was VIA, and treatment was cryotherapy, which were not of

**A**nswerable: This is a symbiotic responsibility. The healthcare providers and beneficiaries are holding equal stake in the health programs. They are to understand each other and are

**A**chievable: It is essential to show that the objectives of the health programs are achievable, and the community should know that their expectations in attending the screening and treatment programs would be fulfilled. Thus the **A-6** model ensures the success for screening,

The editor was the principal investigator for initiating the First Population-Based Cancer Registry, in Tamil Nadu, south India, during 1996, in collaboration with the International Agency for Research on Cancer—IARC/WHO. The registry inferred that cervical cancer was very high among the rural women. A community-based screening program for cervical cancer was started in 2001 in collaboration with IARC/WHO. The program used VIA as the screening tool. The village health nurses offered the screening and precancer treatment services. In a period of about 3 years more than 30,000 women were screened, about 10% of the women were screen positive, and the disease was confirmed by colposcopy directed biopsy. Precancer

A 5-year follow-up of the treated women proved that the women treated for precancer lesions did not develop invasive cancers. The incidence rate for cervical cancer was brought down by 25% and mortality due to cervical cancer was reduced by 35%. Thus, it was proved that screening, early diagnosis, and prompt treatment of precancers will bring down the HPV associated cervical cancer. The editor emphasizes this strategy for developing and underde‐

HPV prevalence studies were also undertaken, by the editor, in collaboration with IARC/ WHO, for the first time in south India, during 2005, which revealed that about 14% of the

high cost and affordable by the healthcare systems, providers, and beneficiaries.

answerable to all the inputs and outputs of the screening and treatment programs.

collected by cyto-brush and sent to designated laboratories for HPV study.

camps in limited resource settings. The strategy is explained as follows:

done in the same sitting and the procedure was painless.

8 Human Papillomavirus - Research in a Global Perspective

and it can be followed for HPV vaccination programs.

*2.1.3. The experiences are the sources of inspiration*

lesions were treated by Cryotherapy/LEEP.

veloped countries.

especially in the scorching sun, heavy rains, and on bad roads.

The readers are welcome to read the publications of the editor enumerated in the references, and also to contact the editor, for more details and possible collaborations, to address the important problem of HPV and related diseases. The editor had the privilege of serving all the above programs as principal investigator and as his personal opinion, he recommends simple models, as illustrated above, for the prevention and control of HPV infections and cervical cancer. Hope that these suggestions would specially inspire grassroot-level health workers, in resource-limited settings, to initiate community-based programs for the prevention and control of HPV infections in general and cervical cancer in particular.

### **RECOMMENDATION**

The editor / author endorses the following recommendation to all researchers in the medical domain. It is the " QUEEN concept of Raj, in Research ". ( copyright Dr.R Rajkumar )

Q = Question - the research question and its validity, thus avoiding bias

U = Use - of research findings to the universal benefit for community.

E = Effectiveness - whether the findings are scientifically,and, socially acceptable and effective

E = Extrapolate - we should be able to extrapolate the findings of research,

N = New- what are the unique, novel, innovative findings, and their applications, implications

## **Author details**

Rajamanickam Rajkumar

Address all correspondence to: rajcfchc@gmail.com

Meenakshi Medical College Hospital & Research Institute of MAHER, Kanchipuram, Tamil Nadu, India.

## **References**

[1] Suba EJ, Sankaranarayanan R, Nene BM, Sastry S, Esmy PO, Rajkumar R, et al. (2014) US-funded measurements of cervical cancer death rates in India: scientific and ethical concerns. Indian Journal of Medical Ethics. Online ISSN: 0975-5691. Print ISSN: 0974-6456.


[10] Franceschi S, Rajkumar R, Snijders PJF, Arslan A, Mahé C, Plummer M, Sankaranar‐ ayanan R, Cherian J, Meijer CJLM, Weiderpass E. (2005) Papillomavirus infection in rural women in southern India. British Journal of Cancer. 92(3):601–6.

concerns. Indian Journal of Medical Ethics. Online ISSN: 0975-5691. Print ISSN:

[2] Sankaranarayanan R, Esmy PO, Rajkumar R, Muwonge R, Swaminathan R. (2014)

[3] Chen AA, Heideman DA, Boon D, Gheit T, Snijders PJ, Tommasino M, Franceschi S, Clifford GM, Rajkumar R; IARC HPV Variant Study Group, et al. (2014) Human papillomavirus 45 genetic variation and cervical cancer risk worldwide. Journal of

[4] Wright TC, Blumenthal P, Bradley J, Denny L, Esmy PO, Jayant K, Nene BM, Pollack AE, Rajkumar R, Sankaranarayanan R, Sellors JW, Shastri SS, Sherris J, Tsu V. (2007) Cervical cancer prevention for all the world's women: new approaches offer opportu‐

[5] Sankaranarayanan R, Esmy PO, Rajkumar R, Muwonge R, Swaminathan R, Shantha‐ kumari S, Fayette J-M, Cherian J. (2007) Effect of visual screening on cervical cancer incidence and mortality in Tamil Nadu, India: a cluster-randomised trial. Lancet.

[6] Sankaranarayanan R, Rajkumar R, Esmy PO, Fayette JM, Shanthakumary S, Frappart L, Thara S, Cherian J. (2007) Effectiveness, safety and acceptability of "see and treat" with cryotherapy by nurses in a cervical screening study in India. British Journal of

[7] Franceschi S, Herrero R, Clifford GM, Snijders PJF, Arslan A, Anh PTH, Bosch FX, Ferreccio C, Hieu NT, Lazcano-Ponce E, Matos E, Molano M, Qiao Y-L, Rajkumar R, Ronco G, de Sanjosé S, Shin H-R, Sukvirach S, Thomas JO, Meijer CJLM, Muñoz N. (2006) Variations in the age-specific curves of human papillomavirus prevalence in

[8] Vaccarella S, Herrero R, Dai M, Snijders PJF, Meijer CJLM, Thomas JO, Hoang APT, Ferreccio C, Matos E, Posso H, de Sanjosé S, Shin H-R, Sukvirach S, Lazcano-Ponce E, Ronco G, Rajkumar R, Qiao Y-L, Muñoz N, Franceschi S. (2006) Reproductive factors, oral contraceptive use, and human papillomavirus infection: pooled analysis of the IARC HPV prevalence surveys. Cancer Epidemiology, Biomarkers & Prevention: A Publication of the American Association for Cancer Research, cosponsored by the

[9] Clifford GM, Gallus S, Herrero R, Muñoz N, Snijders PJF, Vaccarella S, Anh PTH, Ferreccio C, Hieu NT, Matos E, Molano M, Rajkumar R, Ronco G, de Sanjosé S, Shin HR, Sukvirach S, Thomas JO, Tunsakul S, Meijer CJLM, Franceschi S. (2005) Worldwide distribution of human papillomavirus types in cytologically normal women in the International Agency for Research on Cancer HPV prevalence surveys: a pooled

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**HPV Infections and Related Diseases - Screening**

## **Genital Human Papillomavirus (HPV) Infections in Men as a Factor for the Development of Cervical Cancer**

Slawomir A. Dutkiewicz, Anna Rezner, Witold Rezner and Jack Chalasinski

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/62954

#### **Abstract**

The prevalence of human papillomavirus (HPV) infection in males is comparable to females, although in men it is largely unknown. HPV infections may be connected with the development of carcinomas and other dermoepithelial changes such as intraepithe‐ lial neoplasia. Multidirectional studies have shown that chronic HPV infection is a necessary, though insufficient factor for the development of cervical cancer. Although men are regarded as the dominant vector of HPV transmission to their female sexual partners, they do not develop clinically significant HPV-related lesions and are usually asymptomatic during relatively short infections.

Analysis of data from a multicenter, clinical preventive trial was to estimate the incidence of type-specific genital infection among men and HPV transmission dynamics. The routine clinical examination included a peniscopy and detection of HPV DNA in smears using hybrid capture and in biopsy material using PCR.

It is necessary to establish prevention strategies for HPV infection in men whose female sexual partners have cervical cancer. Cervical cancer prevention strategies are likewise needed and should include the use of prophylactic HPV vaccines.

**Keywords:** human papillomavirus, genital infection, sexually transmitted disease, cer‐ vical cancer, HPV free

### **1. Introduction**

Numerous infectious, inflammatory, and neoplastic diseases arise in male sexual organs. Infection of the genitalia with human papillomavirus (HPV) is worldwide and is currently

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

the most frequent sexually transmitted infection [1]. For unknown reasons, clinical changes are absent in most infected individuals as the virus remains in a latent phase until spontaneous elimination occurs by unknown mechanisms. On the other hand, immuno‐ suppressed individuals frequently present with the clinical changes caused by HPV. Their clinical course is more severe, and their therapy is impeded since the immune system is compromised. Furthermore, genital HPV infections in women and subclinical changes of various degrees of cervical intraepithelial neoplasia (CIN 1–3) that can pave the way for the development of cervical cancer are relatively well understood. However, little is known about the subclinical infections in men that cause penile intraepithelial neoplasia (PIN). The significance of PIN is clear, since men who are carriers of HPV can be frequently undiscovered sources of infection for their female sexual partners [2, 3].

### **2. The risk of HPV infections**

HPV is known for its characteristic heterogeneity, and the viral infection can run its course asymptomatically, subclinically, or symptomatically. Thanks to the polymerase chain reaction (PCR), over 200 types of HPV have been identified and subsequently classified according to changes induced, that is high risk (e.g., types 16, 18, 31, and 33) and low risk (e.g., 6 and 11) [2, 4]. Infection with HPV types 16 and 18 carries a large risk of precancerous and cancerous changes, while the appearance of genital warts caused by HPV types 6 and 11 is accompanied by a small risk of cancer development. Evaluation of risk and detection of HPV infection when clinical symptoms are absent is possible with a number of investigations, which include peniscopy, hybrid capture II (HC2), and PCR. The results of tested specimens, however, are variable and largely de‐ pend on anatomic sampling site and method of investigation [5, 6]. For instance, HPV DNA was found around the glans penis and external prepuce in 24% of individuals studied, while in 44% it was found on the inner (mucosal) prepuce where low-risk HPV types predominated. When material was collected using a brush, 70–92% of obtained samples were positive and 33% of which were high-risk types [6]. Furthermore, the re‐ sults of a peniscopy only suggest the probability of HPV infection, since the presence of HPV DNA was not confirmed in 57% of positive peniscopy results [5, 7]. Nonetheless, peniscopy is necessary for gross identification of lesions, and the biopsy allows for his‐ topathologic assessment of character to differentiate inflammatory changes (e.g., lichen sclerosus) from neoplastic changes of low- and high-grade PIN. PCR and HC2 examina‐ tions together with peniscopy allow for evaluation of the infection and defining its risk group. Also, positive findings upon acetowhitening, PCR, and HC2 are sufficient to es‐ tablish diagnosis [7].

## **3. The risk of HPV infection transmission to partners depending on type of changes**

### **3.1. Genital warts**

the most frequent sexually transmitted infection [1]. For unknown reasons, clinical changes are absent in most infected individuals as the virus remains in a latent phase until spontaneous elimination occurs by unknown mechanisms. On the other hand, immuno‐ suppressed individuals frequently present with the clinical changes caused by HPV. Their clinical course is more severe, and their therapy is impeded since the immune system is compromised. Furthermore, genital HPV infections in women and subclinical changes of various degrees of cervical intraepithelial neoplasia (CIN 1–3) that can pave the way for the development of cervical cancer are relatively well understood. However, little is known about the subclinical infections in men that cause penile intraepithelial neoplasia (PIN). The significance of PIN is clear, since men who are carriers of HPV can be frequently

HPV is known for its characteristic heterogeneity, and the viral infection can run its course asymptomatically, subclinically, or symptomatically. Thanks to the polymerase chain reaction (PCR), over 200 types of HPV have been identified and subsequently classified according to changes induced, that is high risk (e.g., types 16, 18, 31, and 33) and low risk (e.g., 6 and 11) [2, 4]. Infection with HPV types 16 and 18 carries a large risk of precancerous and cancerous changes, while the appearance of genital warts caused by HPV types 6 and 11 is accompanied by a small risk of cancer development. Evaluation of risk and detection of HPV infection when clinical symptoms are absent is possible with a number of investigations, which include peniscopy, hybrid capture II (HC2), and PCR. The results of tested specimens, however, are variable and largely de‐ pend on anatomic sampling site and method of investigation [5, 6]. For instance, HPV DNA was found around the glans penis and external prepuce in 24% of individuals studied, while in 44% it was found on the inner (mucosal) prepuce where low-risk HPV types predominated. When material was collected using a brush, 70–92% of obtained samples were positive and 33% of which were high-risk types [6]. Furthermore, the re‐ sults of a peniscopy only suggest the probability of HPV infection, since the presence of HPV DNA was not confirmed in 57% of positive peniscopy results [5, 7]. Nonetheless, peniscopy is necessary for gross identification of lesions, and the biopsy allows for his‐ topathologic assessment of character to differentiate inflammatory changes (e.g., lichen sclerosus) from neoplastic changes of low- and high-grade PIN. PCR and HC2 examina‐ tions together with peniscopy allow for evaluation of the infection and defining its risk group. Also, positive findings upon acetowhitening, PCR, and HC2 are sufficient to es‐

undiscovered sources of infection for their female sexual partners [2, 3].

**2. The risk of HPV infections**

16 Human Papillomavirus - Research in a Global Perspective

tablish diagnosis [7].

HPV DNA is detected in approximately 5–11% of sexually active and healthy men aged 16–35 years [8]. The HPV types responsible for the development of genital warts (main‐ ly types 6 and 11) are the predominant cause of infection. Other viral types are strong‐ ly associated with cancer of the cervix and are therefore termed "high-risk" types, and they include 16, 18, 31, 33, 39, 42, and 51–54 [9]. HPV viruses 16 and 18 are diagnosed most often in infections running subclinical courses in genital cancer patients. The risk of infecting sexual partners is estimated at 60%. However, although the peak of infection detection is in the age of 18–25 years, peak incidence of cervical cancer occurs around the fifth decade of life. Thus, the process of tumor progression is slow, and additional factors, so-called cocarcinogens, are necessary for the development of the cancer [10, 11].

Warts are most often multifocal. The following are three main types affecting the geni‐ tal region:


Warts may also occur at the urethral meatus or navicular fossa, where they are diag‐ nosed in approximately 28% of patients [8]. In men who use condoms, warts are often localized in the suprapubic area. Interestingly, apart from prevention, condoms may ac‐ celerate the regression of flat warts on the penis [14]. In addition, they prevent reinfec‐ tion and formation of new growths on the penis, but only when the same type of HPV occurs in partners. When different HPV types are present in the female partner, con‐ doms do not protect against infection [15]. Condoms minimize the risk of so-called neo‐ plasm transmission because they block the transmission of oncogenic HPV [16]. By minimizing the risk of penile cancer formation, the risk of cervical cancer is significant‐ ly limited. Moreover, with circumcision, the risk of penile cancer is decreased from 19.6 to 5.5% and subsequently the risk of cervical cancer formation in female sexual partners is also decreased [17, 18].

In a study of a large number of patients and a group of healthy controls, HPV DNA was found in 25% of men whose female partners had been diagnosed with CIN. HPV DNA was found in 6% of healthy women, but there was often discord with the results in their partners. Consequently, it has been proposed that no investigations are required in the absence of clinical changes in the partner of a woman with diagnosed CIN. It is also emphasized that HPV DNA results be assessed diligently because HPV DNA was not found in 25% of positive acetowhitening and 57% of those diagnosed with penis‐ copy [19]. In addition, up to 30% of warts have been found to regress spontaneously over the course of 3 months owing to immune system functions dominated by a cellmediated response [10].

The treatment of warts includes the use of podofilox in 0.5% gel or solution, dichloroacetic acid or trichloroacetic acid, 5% imiquimod cream, cryotherapy with liquid nitrogen, destruction of tissue with electrofulguration, and laser ablation [20].

### **3.2. Buschke-Lowenstein tumor**

Large warts resembling tumors were first described in 1925 by Buschke and Lowenstein—the Buschke and Lowenstein tumor [21]. This rare wart variant is associated with HPV infection types 6 and 11 and is characterized by deep rooting into the stroma that results in damage to deep-lying tissues. Its aggressive growth produces tumors of large dimensions. Histopatho‐ logically, typically mild warts are found alternating in coexistence with foci of atypical epithelial cells or cells of highly differentiated squamous cell carcinoma. Patient history is positive for inflammation or ulceration and phimosis of the glans penis. The warts may ulcerate or cause fistulation. Diagnosis of this tumor may require multiple biopsies or imaging studies that include computed tomography (CT) and magnetic resonance imaging (MRI) [22].

### **3.3. Changes in female partners of men having intraepithelial neoplasia**

Intraepithelial neoplasia may involve both male and female genitalia—penile intraepithelial neoplasia (PIN), cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN), and vaginal intraepithelial neoplasia (VaIN), respectively. Additionally, the anus may be involved in either gender—anal intraepithelial neoplasia (AIN). The changes can have a character of bowenoid papulosis or Bowen's disease. Moreover, female sexual partners of men with diagnosed PIN can have changes corresponding to CIN, VIN, or VaIN in various degrees of advancement. They require long-term observation over several months because these changes often resolve spontaneously. Fortunately, neoplastic transformation of PIN is very rare [23]. Although the infection status of female partners of men with subclinical infection of the penis is not determined, it has been accepted that subclinical changes and latent infections do not require treatment, which would be ineffective in such cases.

### **3.4. Risk of bowenoid papulosis (BP) development in sexual partners**

Bowenoid papulosis (BP), also described as Bowen's atypia, is an advanced phase of intrae‐ pithelial changes with features of PIN. These warts are generally numerous and tend to form clusters on the penile shaft and scrotum [22]. In young men, BP resolves spontaneously, but in the elderly it can maintain itself for years with a tendency to progression. Progression to squamous cell carcinoma is marked. BP characterizes itself with the occurrence of flat warts (papulae) of skin color, but they may also be pink or sometimes brown. In men, it mainly occurs on the glans, while in women on the labia, groin, and around the anus. It is evoked by HPV 16, but other types (e.g., 18 and 31) may be culprits. The threat to infected women is the development of cervical cancer; for men, it is that they can infect their female partners and in doing so predispose them to cervical cancer [24]. Since the presence of BP is entwined with great risk of cancer development, treatment is considered crucial; excision of the change is most effective. Cryoablation with liquid nitrogen or laser ablation is also used. Recurrence should be taken into consideration since it has been estimated as high as 33% [20].

### **3.5. Erythroplasia of Queyrat**

in their partners. Consequently, it has been proposed that no investigations are required in the absence of clinical changes in the partner of a woman with diagnosed CIN. It is also emphasized that HPV DNA results be assessed diligently because HPV DNA was not found in 25% of positive acetowhitening and 57% of those diagnosed with penis‐ copy [19]. In addition, up to 30% of warts have been found to regress spontaneously over the course of 3 months owing to immune system functions dominated by a cell-

The treatment of warts includes the use of podofilox in 0.5% gel or solution, dichloroacetic acid or trichloroacetic acid, 5% imiquimod cream, cryotherapy with liquid nitrogen, destruction of

Large warts resembling tumors were first described in 1925 by Buschke and Lowenstein—the Buschke and Lowenstein tumor [21]. This rare wart variant is associated with HPV infection types 6 and 11 and is characterized by deep rooting into the stroma that results in damage to deep-lying tissues. Its aggressive growth produces tumors of large dimensions. Histopatho‐ logically, typically mild warts are found alternating in coexistence with foci of atypical epithelial cells or cells of highly differentiated squamous cell carcinoma. Patient history is positive for inflammation or ulceration and phimosis of the glans penis. The warts may ulcerate or cause fistulation. Diagnosis of this tumor may require multiple biopsies or imaging studies that include computed tomography (CT) and magnetic resonance imaging (MRI) [22].

Intraepithelial neoplasia may involve both male and female genitalia—penile intraepithelial neoplasia (PIN), cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN), and vaginal intraepithelial neoplasia (VaIN), respectively. Additionally, the anus may be involved in either gender—anal intraepithelial neoplasia (AIN). The changes can have a character of bowenoid papulosis or Bowen's disease. Moreover, female sexual partners of men with diagnosed PIN can have changes corresponding to CIN, VIN, or VaIN in various degrees of advancement. They require long-term observation over several months because these changes often resolve spontaneously. Fortunately, neoplastic transformation of PIN is very rare [23]. Although the infection status of female partners of men with subclinical infection of the penis is not determined, it has been accepted that subclinical changes and latent infections

Bowenoid papulosis (BP), also described as Bowen's atypia, is an advanced phase of intrae‐ pithelial changes with features of PIN. These warts are generally numerous and tend to form clusters on the penile shaft and scrotum [22]. In young men, BP resolves spontaneously, but in the elderly it can maintain itself for years with a tendency to progression. Progression to squamous cell carcinoma is marked. BP characterizes itself with the occurrence of flat warts

**3.3. Changes in female partners of men having intraepithelial neoplasia**

do not require treatment, which would be ineffective in such cases.

**3.4. Risk of bowenoid papulosis (BP) development in sexual partners**

mediated response [10].

**3.2. Buschke-Lowenstein tumor**

18 Human Papillomavirus - Research in a Global Perspective

tissue with electrofulguration, and laser ablation [20].

Erythroplasia of the glans penis is a form of carcinoma *in situ* occurring in uncircumcised men. Macroscopically, the change is erythematous, well demarcated, and slightly raised above the level of the skin on the glans penis or on the internal (mucosal) prepuce.

Histologically, it resembles Bowen's disease; it occurs on mucosal surfaces. The changes are singular or multiple and painless. Their surface tends to be smooth, scaly, or verrucous. The most frequent patient complaints are itching and bleeding with difficulties in retracting the prepuce. Diagnosis is made on the basis of biopsy specimen evaluation. Transformation of erythroplasia into penile squamous cell carcinoma occurs in 10–33% of patients [25]. Treatment of choice is surgical excision of the lesions.

### **3.6. Bowen's disease**

Bowen's disease is most often observed as a solitary focus that is demarcated, flat, and reddish in color. Histopathological assessment reveals a squamous cell carcinoma in situ (correspond‐ ing to changes of PIN 3 and VIN 3). The disease is mainly caused by HPV 16 and 18, but sometimes also by HPV 31, 33, 45, and other oncogenic types. It occurs less often in women, growing slowly over years though it does not resolve spontaneously. The possibility of progression to invasive cancer should be considered when induration of the base, ulceration, or bleeding occurs, or the lesions increase in size. Changes on the vulva classified as intraepi‐ thelial neoplasia VIN 1–3 occur particularly in young women. The possible risk of progression of VIN3 to invasive cancer should be considered during therapy [22, 26]. In men who are partners of women with CIN 1–3 or VIN 1–3, changes consistent with PIN 1–3 are relatively frequent (up to 40%) in comparison with partners of women with genital warts (approximately 5%) [22]. Advanced changes corresponding to PIN 3 are diagnosed more often in older men in comparison with PIN 1–2. Clinical observations show that BP occurs more often than Bowen's disease in younger men [22].

### **3.7. Penile cancer**

Penile cancer is not analogous to cervical cancer. While the detection of HPV DNA approaches 100% in cervical cancer cases, it is found in approximately 40% of penile cancer cases. Differ‐ ences in frequency of finding HPV DNA (50–70%) exist and it depends on the type of cancer. HPV DNA is diagnosed most often in early premalignant changes corresponding to PIN 3, and in warts undergoing malignant transformation. For female sexual partners, infectivity is greater in cases with PIN 2 and 3 than in those with invasive cancers. The risk of infecting male partners of women with invasive cancer is not greater than when compared to women with CIN 2 [27].

Penile cancer is a rarely diagnosed neoplasm (<1% of neoplasms in men) occurring mainly in older individuals. In recent years, however, this cancer is being diagnosed in younger men. It predominantly arises on preexisting PIN 3, but, in addition to infection with high-risk oncogenic HPV types, other factors play a significant role: tobacco smoking, poor hygiene, phimosis, and changes consistent with lichen sclerosus [28, 29]. When PIN lesions are sus‐ tained, circumcision should be performed for its protective effect.

Chronic infection with oncogenic HPV types, specifically 16 and 18, is the most significant factor favoring penile cancer. Depending on the method used, HPV DNA is found in up to 90% of penile cancer in such cases. The risk of developing cervical cancer is increased in female partners of men having penile cancer [30]. As in women, an association between lichen sclerosus and cancer of genital organs has also been described in men [29, 31]. In one study, it was shown that neoplastic changes of the penis occur in approximately 8% of men with lichen sclerosus localized there for 10–23 years [32]. In subsequent studies, it was concluded that lesions consistent with lichen sclerosus coexisted or preceded penile squamous cell carcinoma in eight of 20 cases [33]. The etiopathogenesis of lichen sclerosus is unknown, but genetic, immunologic, infectious (bacteria such as Borrelia), or environmental factors may be possible. The disease is chronic in character. An association between lichen sclerosus and squamous cell carcinoma, which is diagnosed in 6% of patients with lesions on the labia, exists in women. Lichen sclerosus is an inflammatory disease in which involved tissues are affected by atrophic changes and indurations. Secondary phimosis or induration of the urethral meatus may be observed in men [31, 33]. In a study of 86 uncircumcised men affected by lichen sclerosus (the disease most often concerns the uncircumcision of middle age), malignant changes occurred in five (6%) [32]. The presence of HPV 16 was found in PCR studies while another study found histologic features of lichen sclerosus in 10 of 20 patients with diagnosed penile squamous cell carcinoma [33]. A significant role is attributed to genital HPV types. Men affected by lichen sclerosus report to physicians due to itching and burning sensations, they have painful erections and difficulties retracting the prepuce, and also they complain of voiding symptoms. If lichenification involves the glans penis, there is often bleeding, ulceration, and fistulas, and hemorrhagic bullae may also occur. Progression of changes often expands to involve the glans penis and prepuce, as well as the frenulum. An indurated white ring around the rim of the prepuce is a significant finding. It can present with strangulation of the prepuce (paraphimosis) or phimosis [34, 35]. Genital HPV types are regarded as dominating in the development of cancer on preexisting lichen sclerosus [36]. It is possible that the long-term inflammation favors proliferation of epidermal cells and causes activation of the HPV life cycle. Another favoring factor is local immunosuppression caused by use of preparations containing potent cortico‐ steroids [36]. Due to the risk of phimosis, especially in young men, circumcision is most often performed following diagnosis of lichen sclerosis.

Since HPV is a proliferating virus, it should be remembered that it multiplies only in prolif‐ erating cells. Therefore, an underlying inflammatory state or irritation in the genital region increases the proliferation of epidermis, which in this way supports infection and multiplica‐ tion of the virus. Significantly more often, infections with genital HPV types occur in immu‐ nosuppressed patients, such as those undergoing treatment with cytostatic agents, those after organ transplant, and also women during pregnancy [37–39]. The clinical course of HPV infection in patients infected with HIV is very aggressive [40]. The changes caused by HPV are more extensive in such cases. The risk of progression of preneoplastic lesions into invasive cancer increases, and the changes occur rapidly. The risk of neoplasm development increases fivefold in patients after organ transplant [41, 42]. This is linked to HPV infection and impair‐ ment of T lymphocyte and natural killer (NK) cell function by the immunosuppressive preparations. T lymphocytes and NK cells are responsible for elimination of neoplastic cells in early oncogenesis [43].

## **4. Discussion**

and in warts undergoing malignant transformation. For female sexual partners, infectivity is greater in cases with PIN 2 and 3 than in those with invasive cancers. The risk of infecting male partners of women with invasive cancer is not greater than when compared to women with

Penile cancer is a rarely diagnosed neoplasm (<1% of neoplasms in men) occurring mainly in older individuals. In recent years, however, this cancer is being diagnosed in younger men. It predominantly arises on preexisting PIN 3, but, in addition to infection with high-risk oncogenic HPV types, other factors play a significant role: tobacco smoking, poor hygiene, phimosis, and changes consistent with lichen sclerosus [28, 29]. When PIN lesions are sus‐

Chronic infection with oncogenic HPV types, specifically 16 and 18, is the most significant factor favoring penile cancer. Depending on the method used, HPV DNA is found in up to 90% of penile cancer in such cases. The risk of developing cervical cancer is increased in female partners of men having penile cancer [30]. As in women, an association between lichen sclerosus and cancer of genital organs has also been described in men [29, 31]. In one study, it was shown that neoplastic changes of the penis occur in approximately 8% of men with lichen sclerosus localized there for 10–23 years [32]. In subsequent studies, it was concluded that lesions consistent with lichen sclerosus coexisted or preceded penile squamous cell carcinoma in eight of 20 cases [33]. The etiopathogenesis of lichen sclerosus is unknown, but genetic, immunologic, infectious (bacteria such as Borrelia), or environmental factors may be possible. The disease is chronic in character. An association between lichen sclerosus and squamous cell carcinoma, which is diagnosed in 6% of patients with lesions on the labia, exists in women. Lichen sclerosus is an inflammatory disease in which involved tissues are affected by atrophic changes and indurations. Secondary phimosis or induration of the urethral meatus may be observed in men [31, 33]. In a study of 86 uncircumcised men affected by lichen sclerosus (the disease most often concerns the uncircumcision of middle age), malignant changes occurred in five (6%) [32]. The presence of HPV 16 was found in PCR studies while another study found histologic features of lichen sclerosus in 10 of 20 patients with diagnosed penile squamous cell carcinoma [33]. A significant role is attributed to genital HPV types. Men affected by lichen sclerosus report to physicians due to itching and burning sensations, they have painful erections and difficulties retracting the prepuce, and also they complain of voiding symptoms. If lichenification involves the glans penis, there is often bleeding, ulceration, and fistulas, and hemorrhagic bullae may also occur. Progression of changes often expands to involve the glans penis and prepuce, as well as the frenulum. An indurated white ring around the rim of the prepuce is a significant finding. It can present with strangulation of the prepuce (paraphimosis) or phimosis [34, 35]. Genital HPV types are regarded as dominating in the development of cancer on preexisting lichen sclerosus [36]. It is possible that the long-term inflammation favors proliferation of epidermal cells and causes activation of the HPV life cycle. Another favoring factor is local immunosuppression caused by use of preparations containing potent cortico‐ steroids [36]. Due to the risk of phimosis, especially in young men, circumcision is most often

tained, circumcision should be performed for its protective effect.

performed following diagnosis of lichen sclerosis.

CIN 2 [27].

20 Human Papillomavirus - Research in a Global Perspective

Most men infected with HPV are naive, either because they have no signs and symptoms or because the signs and symptoms are so mild that they persist unrecognized or ignored. Men with HPV infection are a frequent source of infection for their female sexual partners who are at great risk of death resulting from the development of cervical cancer. Identification of infected men may reduce transmission and subsequent preneoplastic and neoplastic changes; however, numerous factors reduce the plausibility of testing men. Unlike the consistent sampling site in women (the cervix), the sampling site in men varies from anus and perianal area to the scrotum up to the urethral meatus and into the navicular fossa. Incomplete anogenital sampling is a major factor contributing to the variability in HPV prevalence estimates [44]. This variability together with spontaneous elimination of the virus will pose difficulties for recommendations regarding duration of abstinence and frequency of followup. It has been suggested that for optimal detection, scrotal, perianal, or anal samples should be included together with the minimum protocol of penile shaft, glans penis, and coronal sulcus [44].

Surely, we may infer that the knowledge of the presence of HPV infection in the man may reduce the incidence of cervical cancer in woman by reducing transmission resulting from proper condom use or sexual abstinence until the virus is eradicated. However, how can the man be inspired to do comply with such recommendations and what findings can be used to determine when the man is HPV free and allowed to resume unrestricted coitus? For what duration and frequency should the man be tested to determine the continued presence of HPV after the initial positive result? When and for how long should he be tested after changing partners? This can be considered a serious issue since HPV can be deadly for the woman who contracts HPV from the unsuspecting man and develops cervical cancer as a result. Yearly PAP testing for women is already a standard of care in many countries, but what can be done in developing and underdeveloped countries? How can illiterate populations be educated about the risks of HPV infection and consequences, and also how they can avoid it? What solutions can we implement in poor communities, whose women may not visit their gynecol‐ ogists yearly, or ever? HPV is currently the leading sexually transmitted infection. In countries where resources are limited or women must travel hours or days by foot to visit their physician, the implications of late diagnosis may be deadly.

### **5. Conclusion**

In summary, it must be stated that chronic immunosuppression favors HPV infection, allows for its self-preservation, and also favors activation of the viral life cycle, which is a primary factor triggering proliferative changes on genital organs. The therapeutic options for HPVrelated changes are numerous (superficial preparations, cryotherapy, laser therapy, surgical excision) but are unfortunately burdened with recurrence and complications to a large degree. The changes caused by genital HPV types in the region of the sexual organs demand elimina‐ tion of coexisting inflammatory states and treatment of sexual partners when indicated. It also appears that using a polyvalent HPV vaccine may prove effective in preventing benign and malignant changes, especially in groups of patients at increased risk [45]. Vaccination strat‐ egies, however, may be met with difficulties given geographic (e.g., access to facilities), cultural (e.g., core beliefs), and socio-demographic limitations (e.g., access to information) [46].

### **Author details**

Slawomir A. Dutkiewicz1 , Anna Rezner1 , Witold Rezner2 and Jack Chalasinski3\*

\*Address all correspondence to: drjackmd@live.com

1 Department of Prevention and Epidemiology of Neoplasms, Medical School and Faculty of Health Sciences, Institute of Public Health, Jan Kochanowski University, Kielce, Poland

2 Neoplasm Pathology Department, The Holycross Cancer Centre in Kielce, Kielce, Poland

3 Atlantic University School of Medicine, Gros Islet Highway, Rodney Bay, Saint Lucia, West Indies

### **References**


solutions can we implement in poor communities, whose women may not visit their gynecol‐ ogists yearly, or ever? HPV is currently the leading sexually transmitted infection. In countries where resources are limited or women must travel hours or days by foot to visit their physician,

In summary, it must be stated that chronic immunosuppression favors HPV infection, allows for its self-preservation, and also favors activation of the viral life cycle, which is a primary factor triggering proliferative changes on genital organs. The therapeutic options for HPVrelated changes are numerous (superficial preparations, cryotherapy, laser therapy, surgical excision) but are unfortunately burdened with recurrence and complications to a large degree. The changes caused by genital HPV types in the region of the sexual organs demand elimina‐ tion of coexisting inflammatory states and treatment of sexual partners when indicated. It also appears that using a polyvalent HPV vaccine may prove effective in preventing benign and malignant changes, especially in groups of patients at increased risk [45]. Vaccination strat‐ egies, however, may be met with difficulties given geographic (e.g., access to facilities), cultural (e.g., core beliefs), and socio-demographic limitations (e.g., access to information) [46].

, Witold Rezner2

1 Department of Prevention and Epidemiology of Neoplasms, Medical School and Faculty of Health Sciences, Institute of Public Health, Jan Kochanowski University, Kielce, Poland

2 Neoplasm Pathology Department, The Holycross Cancer Centre in Kielce, Kielce, Poland

3 Atlantic University School of Medicine, Gros Islet Highway, Rodney Bay, Saint Lucia,

[1] Centers for Disease Control (CDC) Fact Sheet: HPV and Men; February 4, 2015, accessed

[2] Schiffman M, Kjaer SK. Natural history of anogenital human papillomavirus infection

and neoplasia. Chapter 2. J Nat Cancer Inst Monogr 2003; 31: 14–19.

and Jack Chalasinski3\*

the implications of late diagnosis may be deadly.

22 Human Papillomavirus - Research in a Global Perspective

**5. Conclusion**

**Author details**

West Indies

**References**

Slawomir A. Dutkiewicz1

, Anna Rezner1

\*Address all correspondence to: drjackmd@live.com

at www.cdc.gov, on February 21, 2016.


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## **HPV Infection and Prevention of HPV Infection in Men Who Have Sex with Men (MSM)**

Corinna Sadlier, Orla Sheils and Colm Bergin

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/62780

### **Abstract**

The research landscape in relation to human papillomavirus (HPV) infection has evolved rapidly since the causal association between the virus and cervical cancer was made in the 1970s. Cervical screening programmes have resulted in a dramatic decrease in the incidence of cervical cancer. The first vaccine for HPV was licensed in 2006 with real‐ world data demonstrating high levels of vaccine efficacy.

In the setting of decreased rates of cervical cancer, the burden of HPV‐associated disease in men (including genital warts, anal cancer, penile cancer and oropharyngeal cancer) has become more apparent. The incidence of anal cancer is increasing steadily. Men who have sex with men (MSM) in particular HIV‐infected MSM are disproportionately affected. In contrast to the successes observed with cervical screening programmes, anal cancer screening tools have not demonstrated improvements in morbidity or mortality, and while many experts recommend screening high‐risk groups for anal cancer, no consen‐ sus recommendations exist.

HPV vaccine has potential to decrease HPV‐related malignancies including anal cancer. The majority of countries including Ireland offer HPV vaccine to females through national immunization programmes. However, only a minority of countries have extended the HPV vaccine recommendation to include males. The HPV vaccine is most effective prior to sexual debut; thus, immunisation programmes, including boys and girls, offer the greatest preventative opportunity. However, such programmes will not impact the high burden of HPV‐associated disease currently observed in groups at high risk of HPV infection and HPV‐associated disease such as men who have sex with men (MSM).

This chapter focuses on HPV infection and associated disease in MSM with particular focus on HIV‐infected MSM. Host and viral factors influencing HPV infection and progression to disease are reviewed.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The potential for primary preventative strategies such as vaccination as well as secondary preventative strategies such as screening to impact on the burden of anal cancer in this cohort are reviewed.

**Keywords:** HPV, MSM, HIV, anal cancer, vaccine, screening

## **1. Introduction**

Human papillomavirus (HPV) is the most common sexually transmitted infection (STI) worldwide. It is highly prevalent in the sexually active population and rapidly acquired after sexual debut [1]. The majority of HPV infections are subclinical and clear spontaneously; however, HPV can result in a wide variety of presentations ranging from benign genital dermatoses to disseminated invasive malignancy.

HPV is causally associated with genital warts, cervical cancer, vulvar cancer, anal cancer, penile cancer, and head and neck cancers [2]. HPV now accounts for approximately 5% of all cancers worldwide [3]. Over 150 types of HPV have been identified with over a dozen HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82) classified as highly oncogenic [4].

The incidence of cervical cancer has decreased dramatically since the introduction of cervical screening programmes [5]. In the same time period, the incidence of extra‐cervical HPV‐ associated cancers, particularly oropharyngeal and anal cancers, have increased steadily [6].

Anal cancer is a relatively rare occurrence in the general population (1–2 cases per 100,000) [7]; however, certain risk groups including MSM (up to 40 cases per 100,000) and in particular HIV‐infected MSM are disproportionately affected (up to 135 cases per 100,000) [8, 9]. The incidence of anal cancer in MSM is now greater than the incidence of cervical cancer pre‐ introduction of cervical screening programs [5, 10]. To date, screening programs for anal cancer have failed to demonstrate improvements in morbidity or mortality relating to anal cancer. Some experts advocate screening of at risk populations such as MSM for anal cancer [11, 12]. However, the utility of screening for prevention of anal cancer remains very much debated and no consensus recommendations for anal cancer screening exist.

Three HPV vaccines have been licensed. The bivalent HPV vaccine (HPV‐2v) (Cervarix™, GlaxoSmithKline) protects against oncogenic HPV types 16 and 18. The quadrivalent HPV vaccine (HPV‐4v) (Gardasil™, Merck and Co., Inc.) offers additional protection against HPV types 6 and 11, commonly associated with genital warts. The recently licensed nonavalent HPV vaccine (HPV‐9v) (Gardasil 9™, Merck and Co., Inc.) provides protection against five addi‐ tional oncogenic HPV types (31, 33, 45, 52, and 58).

National immunization programs delivering HPV vaccine to females have been established in the majority of developed countries. In recent years, there has been a move by countries including the United States, Canada, and Australia to recommend HPV‐4v for boys also, given the broader benefits of the vaccine. The majority of European countries do not recommend HPV vaccine for boys due to lack of cost‐effectiveness data in the setting of high vaccine coverage in girls. Where high levels of HPV vaccine coverage have been achieved in females, heterosexual men have been observed to benefit from herd immunity; however, no protective effect has been observed in MSM, the highest group for HPV infection and associated disease [13].

HPV vaccine has been shown to be most effective prior to exposure to HPV [14]. Gender neutral immunization programmes providing vaccine for boys and girls will offer the greatest preventative potential; however, such programmes will not address the increased risk of HPV‐ associated disease in high‐risk groups such as MSM. In addition, universal immunisation programmes are unlikely to be implemented in the short term given cost implication.

HPV vaccine has been demonstrated to be cost effective in MSM up to the age of 26 years over a range of assumptions [15]. Emerging evidence suggests that the vaccine may offer additional protective benefits in older MSM and that the vaccine may be cost effective in this group [16, 17].

The overarching aim of this chapter is to examine the burden of HPV infection and HPV‐ associated disease in MSM and HIV‐infected MSM and to review potential preventative strategies.

Specifically this chapter examine the following:


The potential for primary preventative strategies such as vaccination as well as secondary preventative strategies such as screening to impact on the burden of anal

Human papillomavirus (HPV) is the most common sexually transmitted infection (STI) worldwide. It is highly prevalent in the sexually active population and rapidly acquired after sexual debut [1]. The majority of HPV infections are subclinical and clear spontaneously; however, HPV can result in a wide variety of presentations ranging from benign genital

HPV is causally associated with genital warts, cervical cancer, vulvar cancer, anal cancer, penile cancer, and head and neck cancers [2]. HPV now accounts for approximately 5% of all cancers worldwide [3]. Over 150 types of HPV have been identified with over a dozen HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82) classified as highly oncogenic [4]. The incidence of cervical cancer has decreased dramatically since the introduction of cervical screening programmes [5]. In the same time period, the incidence of extra‐cervical HPV‐ associated cancers, particularly oropharyngeal and anal cancers, have increased steadily [6]. Anal cancer is a relatively rare occurrence in the general population (1–2 cases per 100,000) [7]; however, certain risk groups including MSM (up to 40 cases per 100,000) and in particular HIV‐infected MSM are disproportionately affected (up to 135 cases per 100,000) [8, 9]. The incidence of anal cancer in MSM is now greater than the incidence of cervical cancer pre‐ introduction of cervical screening programs [5, 10]. To date, screening programs for anal cancer have failed to demonstrate improvements in morbidity or mortality relating to anal cancer. Some experts advocate screening of at risk populations such as MSM for anal cancer [11, 12]. However, the utility of screening for prevention of anal cancer remains very much debated

Three HPV vaccines have been licensed. The bivalent HPV vaccine (HPV‐2v) (Cervarix™, GlaxoSmithKline) protects against oncogenic HPV types 16 and 18. The quadrivalent HPV vaccine (HPV‐4v) (Gardasil™, Merck and Co., Inc.) offers additional protection against HPV types 6 and 11, commonly associated with genital warts. The recently licensed nonavalent HPV vaccine (HPV‐9v) (Gardasil 9™, Merck and Co., Inc.) provides protection against five addi‐

National immunization programs delivering HPV vaccine to females have been established in the majority of developed countries. In recent years, there has been a move by countries including the United States, Canada, and Australia to recommend HPV‐4v for boys also, given the broader benefits of the vaccine. The majority of European countries do not recommend

cancer in this cohort are reviewed.

28 Human Papillomavirus - Research in a Global Perspective

dermatoses to disseminated invasive malignancy.

**1. Introduction**

**Keywords:** HPV, MSM, HIV, anal cancer, vaccine, screening

and no consensus recommendations for anal cancer screening exist.

tional oncogenic HPV types (31, 33, 45, 52, and 58).


## **2. HPV infection in MSM and HIV‐positive MSM**

HPV is the most common sexually transmitted infection worldwide. Lifetime risk of infection is estimated at 80% [18]. The vast majority of HPV infections are sub‐clinical resolving spontaneously; however, a broad spectrum of presentations exist ranging from benign genital dermatoses to invasive malignancy. A complex interplay between host factors and viral factors impact on transmission and clearance as well as the clinical manifestation of HPV.

HPV infection in females has been the primary focus of research until recently given the causal link between HPV and cervical cancer. As the burden of extra‐cervical HPV‐associated malignancies has increased, and with the emergence of particular high‐risk groups such as MSM, the research focus shifted.

While the natural history of HPV in females is well described, less is known about HPV infection in men. Numerous large longitudinal cohort studies have been undertaken in recent years to address this issue; however, eliciting the natural history of HPV infection is difficult. Distinguishing between reinfection, reactivation of latent infection, incident infection, and clearance of infection is challenging in the setting of a multitude of host, viral, behavioral as well as sampling and analysis factors.

## **3. Prevalence of HPV infection in MSM**

Prevalence of ano‐genital HPV infection in men in the general population has been reported 1–84% [19, 20]. The wide range in prevalence observed is likely multifactorial relating to differences in study populations, sampling methods (including the anatomical sites of sampling), and analysis methods used.

The prevalence of anal HPV infection in MSM is higher than that observed in heterosexual men (47.2% versus 12.2%) [21]. The prevalence of high‐risk (hr) or oncogenic anal HPV infection is documented at 26–73% in HIV negative MSM [10, 22, 23]. Prevalence of hr HPV has been shown to be significantly higher in HIV‐infected MSM compared to HIV negative MSM with prevalence reported at up to 93% [24‐26]. Receptive anal intercourse, number of sexual partners in the preceding six months and HIV infection have been identified as independent predictors of anal HPV infection [27, 28].

Prevalence of oropharyngeal and genital HPV infection has also been reported at significant rates (up to 45%) in MSM and HIV‐infected MSM [29, 30].

Studies examining point prevalence of HPV infection provide important epidemiological insights. However, it is persistence of hr HPV infection that is the critical factor associated with development of malignancy.

## **4. Clearance of HPV infection**

Clearance rates of hr HPV 16 anal infection have been reported at 12.2–18.7 per 1000 person months [31, 32]. Decreased clearance rates of hr HPV have been observed in HIV‐infected compared with HIV‐negative MSM, after adjusting for sexual behavior [28].

HIV infection has been identified as an independent predictor of HPV infection. Neither CD4 count nor nadir CD4 count has not been shown to influence clearance of HPV infection [10, 28, 33, 34]. This may partly explain high incidence of anal cancer observed in HIV‐infected individuals despite immune reconstitution in the setting of highly active antiretroviral therapy (HAART).

## **5. Persistence of anal HPV infection**

Persistence of hr HPV infection is the most important factor associated with anal cancer. MSM are frequently found to have multiple concurrent HPV infections in the anal canal. The most oncogenic hr HPV type 16 has been identified as the most likely HPV type to persist over time [35].

Given that prevalence of hr HPV is more common in HIV‐infected MSM and rates of clearance are decreased, it is unsurprising that persistence of anal HPV in HIV‐infected individuals is higher compared to HIV negative individuals [29, 36].

## **6. Incidence of HPV infection**

Incidence of hr HPV type 16 in HIV‐negative MSM ranged from 4.5 to 12.4 per 100 person‐ years. Incidence of hr HPV‐16 in HIV‐infected MSM is reported at 7.1 to 13.0 per 100 person years [28, 31, 32]. It remains unclear whether CD4 T cell count influences the incidence rate of anal hr HPV infection. One study reported increased hazards ratio in people with CD4 counts 200–499 cells/mm<sup>3</sup> , compared to those with CD4 >500 cells/mm<sup>3</sup> [37]; however, this has not been a consistent finding [38].

## **7. Anal cancer**

Distinguishing between reinfection, reactivation of latent infection, incident infection, and clearance of infection is challenging in the setting of a multitude of host, viral, behavioral as

Prevalence of ano‐genital HPV infection in men in the general population has been reported 1–84% [19, 20]. The wide range in prevalence observed is likely multifactorial relating to differences in study populations, sampling methods (including the anatomical sites of

The prevalence of anal HPV infection in MSM is higher than that observed in heterosexual men (47.2% versus 12.2%) [21]. The prevalence of high‐risk (hr) or oncogenic anal HPV infection is documented at 26–73% in HIV negative MSM [10, 22, 23]. Prevalence of hr HPV has been shown to be significantly higher in HIV‐infected MSM compared to HIV negative MSM with prevalence reported at up to 93% [24‐26]. Receptive anal intercourse, number of sexual partners in the preceding six months and HIV infection have been identified as

Prevalence of oropharyngeal and genital HPV infection has also been reported at significant

Studies examining point prevalence of HPV infection provide important epidemiological insights. However, it is persistence of hr HPV infection that is the critical factor associated with

Clearance rates of hr HPV 16 anal infection have been reported at 12.2–18.7 per 1000 person months [31, 32]. Decreased clearance rates of hr HPV have been observed in HIV‐infected

HIV infection has been identified as an independent predictor of HPV infection. Neither CD4 count nor nadir CD4 count has not been shown to influence clearance of HPV infection [10, 28, 33, 34]. This may partly explain high incidence of anal cancer observed in HIV‐infected individuals despite immune reconstitution in the setting of highly active antiretroviral therapy

Persistence of hr HPV infection is the most important factor associated with anal cancer. MSM are frequently found to have multiple concurrent HPV infections in the anal canal. The most

compared with HIV‐negative MSM, after adjusting for sexual behavior [28].

well as sampling and analysis factors.

30 Human Papillomavirus - Research in a Global Perspective

sampling), and analysis methods used.

development of malignancy.

(HAART).

**4. Clearance of HPV infection**

**5. Persistence of anal HPV infection**

**3. Prevalence of HPV infection in MSM**

independent predictors of anal HPV infection [27, 28].

rates (up to 45%) in MSM and HIV‐infected MSM [29, 30].

Anal squamous cell cancer (ASCC) accounts for 80% of all anal cancers. ASCC is a relatively rare occurrence in the general population with a reported incidence of 1–2 cases per 100,000 [8]; however, certain risk groups such as MSM and HIV‐infected MSM are disproportionately affected. The incidence of anal cancer in MSM is reported at up to 40 cases per 100,000 [39] with up to 135 cases per 100,000 reported in HIV‐infected MSM [8, 35].

The majority of AIDS defining malignancies have decreased since the advent of HAART; however, the incidence of anal cancer has increased dramatically [40]. The survival benefits associated with HAART have unmasked a cumulative risk of anal cancer which was not evident previously due to premature mortality relating to HIV infection.

HPV infection is causally associated with over 80% of anal cancers. HPV type 16 causes 66% of anal cancers while HPV type 18 is responsible for an additional 6% of cases [41]. Prevalence and persistence of the oncogenic HPV 16 are high in MSM and particularly HIV‐positive MSM. So too is anal intraepithelial neoplasia (AIN), the precursor lesion for anal cancer. The natural history of progression from AIN to anal cancer differs from that of cervical intraepithelial neoplasia and remains poorly understood.

## **8. Similarities between anal cancer and cervical cancer**

A number of similarities exist between ASCC and cervical cancer. Both cancers occur at the squamo‐columnar junction epithelium. These transformation zones are characterised by high turnover epithelium that is thought to be particularly vulnerable to malignancy‐inducing genetic alterations [42]. Both cancers are HPV associated. HPV is thought to promulgate changes to cells' DNA [43]. Immunosuppression is an important risk factor for both cancers with increased incidence observed in immunosuppressed patients such as transplant recipi‐ ents and HIV‐infected individuals [28, 44]. Both types of cancer also have widely divergent outcomes for early *vs* late presenting disease [45].

Similar to cervical cytology, cytological examination of anal cells can detect dysplastic cells. In contrast to the successes observed with cervical screening programmes, no effective screening modality has been demonstrated to impact on the morbidity and mortality associated with anal cancer.

## **9. Anal cancer and screening for anal cancer**

Anal cancer frequently presents late (39% stage 3A or higher at diagnosis) with a lump, bleeding, incontinence from sphincter infiltration, fissure or fistula, and pain but also with nonspecific symptoms such as pruritus, discomfort, pelvic mass sensation, or change in bowel habit [46, 47].

Progression from normal epithelial mucosa to anal cancer transits through several precancer‐ ous stages, named anal intra‐epithelial neoplasia (AIN) 1 to 3. AIN1 is considered low grade AIN (LGAIN); AIN 2 and 3 are considered high‐grade AIN (HGAIN). AIN of any grade is common in MSM with rates of up to 50% reported in the literature [35].

Nearly a quarter of HGAIN lesions regress spontaneously within one year, while a minority of HGAIN (∼1% per year) progresses to anal cancer [48].

Screening for anal cancer is a topic of much international debate. Some experts advocate for screening of high‐risk populations such as MSM [49, 50]. However, no screening tool has been shown to impact morbidity or mortality of anal cancer.

Anal cytology is a poor predictor of HGAIN [51]. High resolution anoscopy (HRA) and biopsy of suspect lesions is considered the gold standard for detection of AIN in high‐risk groups, although there are several important challenges including high cost, intra and inter‐observer variability, and varying acceptability rates for HRA in patients [52]. In addition, the optimal treatment for HGAIN is yet to be established. Rate of recurrence of HGAIN after treatment is relatively high [50].

## **10. Head and neck cancer**

Persistent infection with human papillomavirus (HPV) type 16 is also a major risk factor for the development of head and neck squamous cell carcinoma (HNSCC) and particularly development of oropharyngeal squamous cell carcinoma (OPSCC) [53]. HNSCCs include cancers of the oropharynx, oral cavity, and larynx. The incidence of HNSCC is increasing [54] and HNSCCs are now one of the 10 most common cancer seen worldwide [55].

HPV positive OPSCC has a unique clinical, histological, and molecular profile compared to HPV‐negative OPSCC. Prognosis for HPV positive versus HPV negative OPSCC is signifi‐ cantly better independent of stage at diagnosis [56, 57]. HPV‐negative OPSCC is associated with exposure to traditional carcinogens, such as tobacco and alcohol.

HIV‐infected individuals are at increased risk of HPV infection and persistence of HPV infection. Similar to findings with other HPV‐associated malignancies, prevalence of HNSCC is higher in HIV‐infected individuals compared to the general population [58, 59]. The incidence of HNSCC is reported at 2–3 folds higher in HIV‐infected individuals [60].

## **11. Penile cancer**

genetic alterations [42]. Both cancers are HPV associated. HPV is thought to promulgate changes to cells' DNA [43]. Immunosuppression is an important risk factor for both cancers with increased incidence observed in immunosuppressed patients such as transplant recipi‐ ents and HIV‐infected individuals [28, 44]. Both types of cancer also have widely divergent

Similar to cervical cytology, cytological examination of anal cells can detect dysplastic cells. In contrast to the successes observed with cervical screening programmes, no effective screening modality has been demonstrated to impact on the morbidity and mortality associated with

Anal cancer frequently presents late (39% stage 3A or higher at diagnosis) with a lump, bleeding, incontinence from sphincter infiltration, fissure or fistula, and pain but also with nonspecific symptoms such as pruritus, discomfort, pelvic mass sensation, or change in bowel

Progression from normal epithelial mucosa to anal cancer transits through several precancer‐ ous stages, named anal intra‐epithelial neoplasia (AIN) 1 to 3. AIN1 is considered low grade AIN (LGAIN); AIN 2 and 3 are considered high‐grade AIN (HGAIN). AIN of any grade is

Nearly a quarter of HGAIN lesions regress spontaneously within one year, while a minority

Screening for anal cancer is a topic of much international debate. Some experts advocate for screening of high‐risk populations such as MSM [49, 50]. However, no screening tool has been

Anal cytology is a poor predictor of HGAIN [51]. High resolution anoscopy (HRA) and biopsy of suspect lesions is considered the gold standard for detection of AIN in high‐risk groups, although there are several important challenges including high cost, intra and inter‐observer variability, and varying acceptability rates for HRA in patients [52]. In addition, the optimal treatment for HGAIN is yet to be established. Rate of recurrence of HGAIN after treatment is

Persistent infection with human papillomavirus (HPV) type 16 is also a major risk factor for the development of head and neck squamous cell carcinoma (HNSCC) and particularly development of oropharyngeal squamous cell carcinoma (OPSCC) [53]. HNSCCs include cancers of the oropharynx, oral cavity, and larynx. The incidence of HNSCC is increasing [54]

and HNSCCs are now one of the 10 most common cancer seen worldwide [55].

common in MSM with rates of up to 50% reported in the literature [35].

outcomes for early *vs* late presenting disease [45].

32 Human Papillomavirus - Research in a Global Perspective

**9. Anal cancer and screening for anal cancer**

of HGAIN (∼1% per year) progresses to anal cancer [48].

shown to impact morbidity or mortality of anal cancer.

anal cancer.

habit [46, 47].

relatively high [50].

**10. Head and neck cancer**

Invasive penile cancer is rare. Over a third of penile cancer is associated with HPV, most commonly HPV type 16 and 18 [61]. The risk of penile cancer is up to four fold greater in HIV infected individuals compared to the general population [59].

## **12. HPV vaccine**

Three vaccines have been licensed for the prevention of persistent HPV infection. All are subunit vaccines which use a recombinant form of the L1 major capsid protein of HPV as an antigen. L1 proteins self‐assemble into noninfectious, nononcogenic units called virus‐like particles (VLP).

The bivalent HPV vaccine HPV‐2v (Cervarix™, GlaxoSmithKline) was approved by the FDA in 2009. The vaccine is approved for females 9 through 25 years of age. HPV2 is not approved for males. It protects against oncogenic HPV types 16 and 18 [62].

The quadrivalent HPV vaccine (HPV‐4v) (Gardasil™, Merck and Co., Inc.) was approved by the FDA in June 2006. The vaccine is approved for females and males, 9 through 26 years of age. It offers additional protection against HPV types 6 and 11 commonly associated with genital warts as well as oncogenic HPV types 16 and 18 [63].

The nonavalent HPV vaccine (HPV‐9v) (Gardasil 9™, Merck and Co., Inc.) was approved by the FDA in December 2014 and provides protection against 5 additional oncogenic HPV types (31, 33, 45, 52, and 58) [64].

HPV vaccines are highly immunogenic. More than 99% of recipients develop an antibody response to HPV types included in the respective vaccines one month after completing the three‐dose series with comparable levels of antibody response following two doses [65]. However, there is no known serologic correlate of immunity and no known minimal titer has been determined to be protective.

HPV‐4v has been demonstrated to be highly efficacious in preventing infection with HPV vaccine types related to external genital lesions, and anal intraepithelial neoplasia (AIN) in men [66]. The HPV‐9v has been demonstrated to be highly efficacious in preventing infection with HPV vaccine types and disease related to the additional 5 types HPV‐31, 33, 45, 52, and 58 in a susceptible population. Antibody response generated to HPV‐6, 11, 16, and 18 were non‐inferior to that generated by the HPV‐4v vaccine, and thus the same indication as HPV‐ 4v was applied [67]. No HPV vaccine has demonstrated protection beyond type covered in the vaccine.

The majority of developed countries have introduced national HPV immunization pro‐ grammes for girls. A minority of countries including the US, Canada, and Australia now recommend provision of HPV vaccine for boys and girls.

While gender neutral vaccination programmes offer the best preventive opportunities, such programmes are unlikely to be implemented where levels of female vaccination coverage is high due to lack of cost‐effectiveness evidence [68]. HPV vaccination of boys and male adolescents is not yet recommended in Ireland or in the majority of European countries that provide HPV vaccination for girls through national immunisation programs due to lack of cost effectiveness data.

High levels of female vaccination coverage have been shown to decrease genital warts in both females and unvaccinated heterosexual males through herd immunity; however, no protection has been observed in MSM. [13] Targeted vaccination of MSM has been shown to be cost‐ effective up to and beyond the age of 26 years [15, 16].

Despite the substantial clinical benefit of HPV vaccine in males, mathematical models suggest that HPV vaccination of males would exceed a cost‐effectiveness threshold when vaccination coverage in females is high [68].

As yet no therapeutic benefit of the HPV vaccine has been demonstrated for the treatment of active disease present at the time of vaccination although early data suggests possible benefit of HPV vaccine in the setting of previous disease. This finding may represent an important opportunity for intervention in older high‐risk patient groups such as HIV‐infected MSM [69].

A single study has indicated that if the HPV vaccine proved efficacious in the HIV‐positive population against vaccine sub‐types, the potential reduction in anal cancer rates could be up to 61% [25].

In addition, data from female studies suggests that HPV vaccine of seropositive individuals who have cleared infection will provide increased protection against future infection [26].

In November 2014, the Joint Committee on Immunisation and Vaccination in the United Kingdom HPV sub‐committee recommended implementation of a targeted programme of HPV vaccination for MSM >18 years to 40 years of age in GUM and HIV clinics if it could be delivered cost effectively [27].

## **13. Targeted HPV vaccine programmes**

For HPV immunization programmes to have the desired effect, high levels of vaccine uptake are required. When considering feasibility of targeted HPV immunization programmes for MSM, HPV vaccine acceptability and factors influencing vaccine acceptability must be examined.

HPV vaccine acceptability in MSM is in Ireland is reported at 31–78%. Acceptability varied with stated vaccine cost and efficacy [70]. A meta‐analysis of HPV vaccine acceptability in MSM including data from North America and Australia (where HPV vaccine is offered to boys and MSM up to the age of 26 years through national programmes) reported similar accepta‐ bility (47–74%) [71].

Factors identified as positively associated with HPV vaccine acceptability include knowledge of HPV infection and associated disease in MSM and no cost vaccine. Recommendation from a medical practitioner was also identified as being associated with HPV vaccine acceptability [72].

Evidence suggest that uptake of HPV vaccination in MSM would likely be high and would be expected to increase following implementation of health education programs outlining the risks of HPV‐associated disease and efficacies of the HPV vaccine. Much of this education could be delivered synergistically using existing infrastructure alongside HIV prevention programmes.

## **14. Conclusion**

HPV‐4v has been demonstrated to be highly efficacious in preventing infection with HPV vaccine types related to external genital lesions, and anal intraepithelial neoplasia (AIN) in men [66]. The HPV‐9v has been demonstrated to be highly efficacious in preventing infection with HPV vaccine types and disease related to the additional 5 types HPV‐31, 33, 45, 52, and 58 in a susceptible population. Antibody response generated to HPV‐6, 11, 16, and 18 were non‐inferior to that generated by the HPV‐4v vaccine, and thus the same indication as HPV‐ 4v was applied [67]. No HPV vaccine has demonstrated protection beyond type covered in the

The majority of developed countries have introduced national HPV immunization pro‐ grammes for girls. A minority of countries including the US, Canada, and Australia now

While gender neutral vaccination programmes offer the best preventive opportunities, such programmes are unlikely to be implemented where levels of female vaccination coverage is high due to lack of cost‐effectiveness evidence [68]. HPV vaccination of boys and male adolescents is not yet recommended in Ireland or in the majority of European countries that provide HPV vaccination for girls through national immunisation programs due to lack of cost

High levels of female vaccination coverage have been shown to decrease genital warts in both females and unvaccinated heterosexual males through herd immunity; however, no protection has been observed in MSM. [13] Targeted vaccination of MSM has been shown to be cost‐

Despite the substantial clinical benefit of HPV vaccine in males, mathematical models suggest that HPV vaccination of males would exceed a cost‐effectiveness threshold when vaccination

As yet no therapeutic benefit of the HPV vaccine has been demonstrated for the treatment of active disease present at the time of vaccination although early data suggests possible benefit of HPV vaccine in the setting of previous disease. This finding may represent an important opportunity for intervention in older high‐risk patient groups such as HIV‐infected MSM [69].

A single study has indicated that if the HPV vaccine proved efficacious in the HIV‐positive population against vaccine sub‐types, the potential reduction in anal cancer rates could be up

In addition, data from female studies suggests that HPV vaccine of seropositive individuals who have cleared infection will provide increased protection against future infection [26].

In November 2014, the Joint Committee on Immunisation and Vaccination in the United Kingdom HPV sub‐committee recommended implementation of a targeted programme of HPV vaccination for MSM >18 years to 40 years of age in GUM and HIV clinics if it could be

recommend provision of HPV vaccine for boys and girls.

34 Human Papillomavirus - Research in a Global Perspective

effective up to and beyond the age of 26 years [15, 16].

vaccine.

effectiveness data.

to 61% [25].

coverage in females is high [68].

delivered cost effectively [27].

The incidence of anal cancer is high in MSM, particularly HIV‐infected MSM. Almost 80% of anal cancer is caused by persistent infection with hr HPV type 16 which is preventable through vaccination. While many experts advocate routine screening for anal cancer in high‐risk groups such as MSM, it has not been demonstrated to impact on anal cancer related morbidity or mortality to date.

A growing body of evidence supports the potential of HPV vaccine to prevent development of HPV‐associated disease in older MSM [69, 73]. Although no definite therapeutic benefit of HPV vaccine has been demonstrated for the treatment of active disease present at the time of vaccination, emerging data suggests a possible benefit of HPV vaccination in the setting of previous disease [16, 17].

Sexual health and HIV clinics would be well placed to facilitate targeted/catch‐up HPV vaccination for the high‐risk groups including HIV‐infected and HIV negative MSM, partic‐ ularly in the setting of similar effective models for hepatitis B vaccination[74, 75].

Further research is needed to assess potential for alternative screening modalities to impact the burden of anal cancer currently observed in MSM. Targeted HPV vaccine has potential to greatly reduce the burden of HPV‐associated anal cancer in MSM and HIV‐infected MSM in the future. Given the potential individual and population health benefits conferred, the HPV vaccine should not be withheld.

## **Author details**

Corinna Sadlier1,2\*, Orla Sheils3 and Colm Bergin1,2

\*Address all correspondence to: sadliecm@tcd.ie

1 Department of Genitourinary Medicine and Infectious Diseases (GUIDE), St James's Hospital, Dublin, Ireland

2 Trinity College Dublin, Dublin, Ireland

3 Department of Histopathology, Trinity College Dublin, St James's Hospital, James's Street, Dublin, Ireland

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3 Department of Histopathology, Trinity College Dublin, St James's Hospital, James's Street,

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