A Contemporary Review of HPV and Penile Cancer | Cancer Network https://www.cancernetwork.com/oncology-journal/contemporary-review...

A Contemporary Review of HPV and Penile

Cancer
By Kelly L. Stratton, MD and Daniel J. Culkin, MD, FACS, MBA
March 16, 2016

Volume: 30 Issue: 3

Oncology Journal, Genitourinary Cancers

Oncology (Williston Park). 30(3):245–249, 252.

Table 1. HPV Genotype Distribution in Penile Carcinomas

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Table 2. High-Risk HPV Detection by Penile Squamous Cell Carcinoma Subtype

Abstract / Synopsis:
Human papillomavirus (HPV) is a widespread sexually transmitted infection. In both men and
women, HPV infection can result in a spectrum of genitourinary manifestations ranging from
genital warts to cancer. Cervical cancer is nearly always associated with high-risk HPV infection.
For men, penile cancer can develop following or independently of HPV infection. Basaloid and
warty subtypes of penile squamous cell carcinoma are most frequently associated with HPV
infection. Further research into the molecular alterations caused by HPV infection may provide
prognostic markers and future treatment targets. Until an effective treatment for HPV infection is
developed, prevention will remain the focus of disease control. For women, vaccination is
increasingly utilized to prevent HPV infection and subsequent cervical cancer development. New
recommendations for routine male vaccination may further reduce cancers for both men and
women.

Introduction
Penile cancer is a relatively rare malignancy in the United States. Delay in presentation and misdiagnosis
can result in both poor functional outcomes following treatment and reduced survival. Several risk factors
have been identified for the development of penile cancer, demonstrating two pathways to malignant
transformation, with the presence or absence of human papillomavirus (HPV) infection a central
distinction between them. In addition to penile cancer, HPV infection is associated with several other
malignancies, including cervical cancer, anal cancer, and oropharyngeal cancer. The nearly ubiquitous
association between HPV infection and cervical cancer has resulted in widespread efforts to better
understand and prevent HPV infection. In men, HPV infection results in a wide range of genitourinary
pathology, ranging from genital warts to penile and anal carcinoma. HPV has been detected in one-third
to one-half of penile cancers. This article provides a comprehensive and up-to-date review of the role of
HPV infections in men and in the development of penile cancer.

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Genital HPV Infection in Men

HPV infection is the most common sexually transmitted infection in the United States.[1] Infection with
oncogenic HPV appears to be required for the development of cervical cancer. From this observation,
association studies of cervical cancer development have identified high-risk and low-risk HPV genotypes,
classified by their oncogenicity.[2] High-risk genotypes include 16, 18, 33, and 35, while low-risk
genotypes include 6 and 11. Although HPV infection appears to cause all cervical cancer, it causes only a
fraction of penile cancers. This may be due to increased resistance to malignant transformation in penile
tissue compared with cervical tissue.

To improve our understanding of the relationship between HPV infection and genital disease in men,
studies have been conducted evaluating the prevalence of HPV infection and carriage in men. In studies
attempting to detect HPV DNA from male anogenital sampling, the prevalence is often 20% or higher.[3,4]
The prevalence of HPV infection in adult men appears to be constant across age groups, without showing
a decline in older men, as is seen in older women.[4]

HPV infection can result in a spectrum of genitourinary manifestations. In men, infection can cause
genital warts, penile intraepithelial neoplasia (PeIN), and penile carcinomas. Most HPV infections remain
asymptomatic, and up to 70% are cleared within 1 year.[3] In a multinational, prospective, longitudinal
study (HPV Infection in Men [HIM]), the median time to clearance of infection was 7.5 months.[5] For HPV
16—a high-risk oncogenic HPV—median clearance was longer, at 12.2 months. When the infections are
not cleared, they most commonly manifest as genital warts. Although warts are benign and typically
asymptomatic, the lesions can become problematic, with pain, itching, and bleeding. The presence of
warts is cosmetically disfiguring and can cause patient distress. Warts can also become larger and
spread to new locations. Genital warts are highly infectious, and up to 64% of sexual partners will
eventually develop warts as well.[6] However, it is unlikely that treating genital warts would prevent
transmission, as partners typically have already become infected before lesions appear.

PeIN is a clinical entity associated with HPV infection, with several differing classification systems. Similar
to squamous cell carcinoma (SCC) in situ, PeIN represents a dysplastic premalignant lesion. To classify
PeIN, doctors use a system similar to that used for cervical intraepithelial neoplasia, with the categories
PeIN I, II, and III.[4] Clinically, PeIN is often subdivided into erythroplasia of Queyrat (EQ), Bowen disease
(BD), and bowenoid papulosis. EQ arises from the mucosal surfaces of the glans and foreskin, while BD
is found on the keratinized skin of the penile shaft.[7] EQ lesions typically have the highest risk of
progressing to SCC.[8] Studies evaluating the prevalence of HPV DNA in PeIN lesions have found that
60% to 100% of lesions test positive.[4] In one of the larger studies, which also evaluated for HPV
subtypes, 90% of PeIN lesions tested positive for HPV, with HPV 16 being the most common type
(40.7%).[9] The lower frequency of HPV-associated invasive penile carcinoma relative to the more
widespread correlation of HPV with PeIN has led to the proposal of a new classification system consisting
of four categories based on immunohistochemical profiles: differentiated, basaloid, warty, and warty-
basaloid PeIN.[7] The classification system identifies differentiated PeIN based on a lack of HPV
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TO PUT THAT INTO CONTEXT

Anna R. Giuliano, PhD

Gregory J. Diorio, DO
Center for Infection Research in Cancer (CIRC), Moffitt Cancer Center, Tampa, Florida

What Do We—and Don’t We—Know About Penile Cancers?

Penile cancer is a rare cancer in the United States and other high-resource countries; however,
incidence rates are significantly higher among US Hispanics and in men residing in low-resource
countries. Due to its rarity, penile cancer is an understudied cancer; therefore, robust level 1 evidence
that can drive treatment guidelines is lacking. More research focused on improving treatment options
and maximizing survivorship is needed.

What Is the Role of HPV in Penile Cancer?

Infection with high-risk human papillomavirus (HPV) types 16 and 18 causes a subset of penile
cancers, specifically those with warty and basaloid histologies. In contrast to cervical cancer and other
HPV-associated malignancies, it remains unclear where HPV status stands as a prognostic factor in
patients with penile cancer, and whether positivity for high-risk HPV is associated with a difference in
the response to treatment.

How Can the Burden of HPV-Associated Penile Cancer Be Most Effectively Reduced?

While factors such as neonatal circumcision have been associated with a reduced incidence of penile
cancer, vaccination against HPV types 16 and 18 will likely be the most effective method for reducing
penile cancer and other HPV-related diseases in the future. Unfortunately, few countries currently have
national recommendations for male HPV vaccination (the United States, Australia, and Austria are the
only three to date), and uptake of the vaccine in both males and females in the United States has been
relatively low. Broad dissemination of the cancer-preventing HPV vaccine and further research
investigating HPV-specific targeted therapies are needed to reduce the burden of penile cancers and
other HPV-related disease worldwide.

Financial Disclosure: Dr. Giuliano has received grants from and consults for Merck.

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association, while the undifferentiated or basaloid/warty/warty-basaloid lesions are typically HPV-positive.
This system provides a basis for the bimodal pathogenesis of PeIN based on the presence or absence of
HPV.[7] Differentiated PeIN appears more commonly in countries with a higher incidence of penile cancer,
while undifferentiated PeIN is more common in areas with a lower incidence of penile cancer.[10] The
College of American Pathologists has adopted the differentiated/undifferentiated classification system for
PeIN.[11]

The progression of precursor lesions to invasive penile carcinoma is not completely understood. In a
study of 288 invasive penile cancers and associated lesions, squamous hyperplasia was present in 83%
of cases, low-grade PeIN in 59%, and high-grade PeIN in 44%.[12] This would suggest a progression
from hyperplasia to low-grade PeIN to high-grade PeIN. It was noted that hyperplasia was more frequent
in the usual and verrucous SCC, while high-grade PeIN was more common in warty/basaloid tumors.[12]

Penile Cancer Incidence

Penile SCC is uncommon in the developed world. In 2015, an estimated 1,820 men were diagnosed in
the United States, and it was estimated that 310 would die from the disease.[13] The incidence in the
United States is around 0.8 per 100,000 men.[14] However, in the developing world, an incidence of up to
4.4 per 100,000 men is reported but is declining.[15,16] Penile cancer most often occurs in older men,
with a peak incidence in the seventh decade.[17] Two pathways have been proposed for penile cancer
development—one related to HPV infection and the other related to phimosis and/or chronic
inflammation. Several risk factors have been identified for the development of penile cancer, including
poor hygiene, phimosis, smoking, and lack of circumcision. Other risk factors include increased number of
sexual partners, lack of condom use, and presence of balanitis or lichen sclerosus.[4] Penile cancer is
rare in men who are circumcised at birth. Even in the developing countries with high rates of penile
cancer, subgroups within the population who conduct neonatal circumcision have lower rates of penile
cancer.[17]

HPV Presence in Penile Carcinomas

In women, nearly all invasive cervical cancers are associated with detectable oncogenic HPV when using
sensitive polymerase chain reaction.[18] However, HPV detection in men is more variable, and it has thus
been proposed that some penile cancers are associated with HPV while others are not.[9] A systematic
review of studies evaluating HPV prevalence in penile cancers found that 48% of evaluated tumors tested
positive for HPV.[19] Another study confirmed these findings, identifying HPV in 46.9% of tumors, with
HPV 16 and 18 representing the most common types (Table 1).[20]

Similar to the variation in HPV infection between differentiated and undifferentiated PeIN, variation in HPV
rates among the differing SCC histologic subtypes has been observed. The more keratinized subtypes,
such as usual and verrucous SCC, have lower HPV detection compared with warty and basaloid SCC. In
a systematic review of HPV infection in penile cancer, HPV prevalence varied significantly among SCC

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histologic subtypes.[19] In this study, HPV was detected in only 22.4% of verrucous SCC but in 66.3% in
the basaloid/warty subtypes. The most common HPV type identified was HPV 16, seen in 30.8%, while
HPV 6 and HPV 18 represented 6.7% and 6.6%, respectively. Other studies have confirmed the highest
rate of HPV detection in basaloid SCC, an intermediate rate in warty SCC, and low rates in usual and
papillary carcinomas (Table 2).[21]

The heterogeneity of HPV-associated tumors has increased consideration of HPV presence as a

prognostic marker for survival. In other HPV-related malignancies, studies have found that HPV
association may result in improved survival. Among patients undergoing chemoradiation therapy for
oropharyngeal SCC, those with HPV-positive tumors had improved 3-year overall survival.[22] Similarly,
in anal cancer, HPV positivity was associated with improved overall and disease-specific survival.[23] In a
multivariate model using p16 status as a surrogate for HPV, an independent and significant relationship
between p16 and improved survival for anal cancer was reported. In penile carcinoma, an early study
evaluated HPV prevalence with respect to survival in 176 patients treated between 1963 and 2001.[24]
High-risk HPV was detected in 29% of tumors and was associated with better 5-year disease-specific
survival—92%, compared with 78% for HPV-negative tumors. In a multivariate analysis, tumor HPV
status was an independent predictor of survival. The same group recently conducted an updated study in
contemporary penile cancer patients treated between 2001 and 2009.[25] High-risk HPV was detected in
25% of patients and was associated with improved 5-year disease-specific survival—96% compared with
82% (P = .016). This survival benefit remained significant on multivariate analysis (hazard ratio [HR], 0.2;
P = .03). However, other studies have failed to show a survival benefit for HPV positivity. In a study of 82
men treated with penectomy and bilateral lymphadenectomy, HPV-positive tumors were associated with
less lymphatic embolization by neoplastic cells, but this did not result in differences in lymph node
metastases or 10-year overall survival.[26] Moreover, a study evaluating p53 status as a prognostic factor
found that patients positive for p53 and HPV DNA had worse overall survival.[27] These conflicting results
may be related to geographic variations in the frequency and pathogenesis of HPV-related penile cancer.
A better understanding of the genetic pathways involved in malignant transformation may improve our
understanding of HPV infection as a prognostic marker.

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