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Invasive squamous cell carcinoma (SCC) of the penis is rare in the United States. Although human papillomavirus (HPV) infection is an established etiologic agent in at least 40% of penile SCCs, relatively little is known about the epidemiology of this malignancy.
Population-based data from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) program, the Centers for Disease Control and Prevention's National Program for Cancer Registries, and the National Center for Health Statistics were used to examine invasive penile SCC incidence and mortality in the United States. SEER data were used to examine treatment of penile SCC.
From 1998 to 2003, 4967 men were diagnosed with histologically confirmed invasive penile SCC in the United States, representing less than 1% of new cancers in men. The annual, average age-adjusted incidence rate was 0.81 cases per 100,000 men, and rates increased steadily with age. Overall, penile SCC incidence was comparable in whites and blacks, but approximately 2-fold lower in Asians/Pacific Islanders. Rates among Hispanics were 72% higher compared with non-Hispanics. Blacks compared with whites and Asians/Pacific Islanders and Hispanics compared with non-Hispanics were diagnosed at significantly younger ages. Higher rates of mortality were also observed among blacks compared with whites and Hispanics compared with non-Hispanics. Penile SCC incidence and mortality were elevated in Southern states and in regions of low socioeconomic status (SES). Some histologic and anatomic site differences were observed by race and ethnicity. Treatment of penile SCC varied with age, stage, and other tumor characteristics.
There are considerable disparities in invasive penile cancer incidence and mortality in the United States. Key risk factors for excess incidence include Hispanic ethnicity and residence in the South and in low SES regions. Risks for excess mortality include these factors in addition to black race. Decreases in penile cancer incidence and mortality in the United States may be realized in the future as the indirect result of prophylactic HPV vaccination of females. Further research is needed to better understand the epidemiology of penile cancer including the role of HPV.
Invasive squamous cell carcinoma (SCC) of the penis is relatively rare in developed countries, accounting for less than 1% of malignancies among men.1 Some differences in penile cancer incidence, age and stage at diagnosis, and survival in the United States have been reported, but population-based studies have been few.2-5
It is estimated that at least 40% of penile cancers are attributable to human papillomavirus (HPV).1 The prevalence of HPV in penile tumors ranges from 29% to 82% in studies published in 2000 and later, which used polymerase chain reaction-based assays to detect viral DNA in formalin-fixed paraffin-embedded tissue.6-13 Oncogenic HPV 16 and/or 18, which are responsible for approximately 70% of cervical cancers,14 are the most common genotypes detected in penile SCC.6-10,13,15 The etiologic role of HPV 16 in penile cancers has also been supported by serologic studies.6,13,16
Squamous cell carcinomas comprise over 90% of all invasive penile cancers in the United States.4,5 Other less common penile cancers include basal and transitional cell carcinomas, adenocarcinomas, melanoma, and Kaposi sarcoma. A higher prevalence of HPV has been observed in basaloid and warty SCC compared with verrucous and keratinizing SCC,7,12 indicating possible differences in the etiologic role of HPV by histology.
In addition to HPV infection, studies of US populations have identified smoking, lack of circumcision, phimosis, and other penile conditions as risk factors for penile cancer. Current cigarette smokers have an elevated risk of penile malignancies,6,15,17 and the effect may be dose-responsive.17 Lack of neonatal circumcision is associated with an increased risk of penile cancer.6,15,17 The timing of circumcision may be critical, as an increased risk is observed not only among uncircumcised men but also among those circumcised in later childhood.15,17 A history of phimosis, or the inability of uncircumcised men to fully retract the foreskin, is also associated with an increased risk of penile cancer.6,15,17 It is not clear whether lack of circumcision is independently associated with penile cancer risk or whether this relationship is mediated by phimosis.6,15,17 Rash, tearing, and inflammation of the penis have also been identified as possible risk factors for malignancy.6,15,17
This chapter provides a comprehensive, population-based evaluation of the incidence, mortality, and treatment patterns of SCC of the penis. Comparisons by demographic and clinical characteristics may provide clues to the etiology of this malignancy and improve our understanding of its disease burden.
Data on primary, invasive SCC of the penis diagnosed in the United States between 1998 and 2003 were obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program and the Centers for Disease Control and Prevention's National Program for Cancer Registries (NPCR). Data used in the present analysis specifically came from 39 population-based cancer registries meeting the criteria for high-quality data. These data collectively cover approximately 83% of the US population. Data on treatment were limited to 17 SEER registries representing 26% of the US population. Mortality data were based on underlying cause of death derived from the National Vital Statistics System, National Center for Health Statistics.
Classification of penile tumor by stage, grade, and subsite were based on international and national standards.18-20 Classification of histologic types used the Berg classification system.21 The present analysis focused on SCC of the penis (International Classification of Diseases for Oncology [ICD-O]-3 codes 8050-8084 and 8120-8131). Histologic subgroup analysis was included for the largest groups: keratinizing SCC (ICD-O-3 code 8071) and verrucous SCC (ICD-O-3 code 8051). Race and ethnicity were analyzed separately and were not mutually exclusive. Race was limited to white, black, and Asians/Pacific Islanders. Ethnicity was delineated as Hispanic and non-Hispanic. US geographic region was based on the location of the state of residence as defined by the US Census. Measures of poverty and education level were indirect and based on the distribution of the population within the county of residence by Census-defined income and education levels. Analysis involving these county-level socioeconomic status (SES) indicators excluded 3 states: Hawaii, Illinois, and Minnesota.
Details of the general study methodology, including calculation of incidence and mortality rates, and data sources are outlined in an accompanying article.22 SEER*Stat (version 6.2.4; National Cancer Institute, Bethesda, Md) was used for all analyses. Incidence and mortality were calculated as annual average, age-adjusted rates. Rates based on cancer case and death counts <6 were suppressed. Rates based on counts between 6 and 15 were included in the analysis, but should be interpreted with caution because of their inherent instability. Rate ratios and 95% confidence intervals compared incidence in a given group to a reference group. Comparison of median age of diagnosis used the Mann-Whitney U test. Penile SCC treatment was compared by age and clinical characteristics using the chi-square test.
A total of 4967 cases of histologically confirmed, invasive SCC of the penis were diagnosed in the United States between 1998 and 2003, with an annual average, age-adjusted incidence rate of 0.81 per 100,000 men. Penile SCC accounted for 0.1% (4967 of 3462,606) of all invasive cancers diagnosed among US men during the same time period. Table 1 details the incidence of penile SCC by demographic and clinical characteristics.
The average, age-adjusted annual incidence of penile SCC steadily increased with age (Table 1). The incidence of penile SCC was comparable among blacks and whites and lower among Asians-Pacific Islanders in every age group (Fig. 1).
The incidence of penile SCC was 72% higher in Hispanics relative to non-Hispanics (Table 1). This disparity was observed in every age group (Fig. 2). Hispanic men aged 80 years and older had the highest incidence observed for any age-race/ethnic group.
Overall, the median age at diagnosis of penile SCC was 68 years, but there was considerable variation by race and ethnicity (Fig. 3). Blacks were diagnosed at younger ages (median 62 years) compared with whites (median 68 years) (P < .00001) and Asians/Pacific Islanders (median 68 years) (P = .01). Hispanics were diagnosed at substantially younger ages (median 58 years) compared with non-Hispanics (median 69 years) (P < .00001).
Compared with Western states, penis SCC was significantly higher in the South, Northeast, and Midwest (Table 1). Penile SCC incidence was highest in the South and lowest in the West. Racial and ethnic differences by geographic region were observed. In the West, the age-adjusted incidence of penile SCC was more than 2 times lower among Asians/Pacific Islanders (0.33 per 100,000; 95% confidence interval [CI], 0.23-0.45) compared with both whites (0.69 per 100,000; 95% CI, 0.65-0.75) and blacks (0.76 per 100,000; 95% CI, 0.52-1.05).
The incidence of penile SCC was higher among Hispanics than non-Hispanics in all geographic regions, and these differences were statistically significant. This disparity was most pronounced in the Northeast, where the age-adjusted incidence of penile SCC among Hispanics (1.77 per 100,000; 95% CI, 1.47-2.11) was more than 2 times that of non-Hispanics (0.78 per 100,000; 95% CI, 0.74-0.83).
Penile SCC risk was 43% higher among men from counties with 20% or more of the population at the poverty level compared with men living in regions of less than 10% poverty (Table 1). Penile SCC incidence was elevated among men in counties where fewer than 75% of the population completed high school relative to those living in better educated communities.
Sixty-two percent of penile SCCs were diagnosed at a localized stage, and 65% were well or moderately differentiated (Table 1). Racial and ethnic differences were observed by stage (Table 2). Thirty-six percent of blacks were diagnosed at a regional or distant stage compared with 31% of whites. Relative to whites, blacks were at significantly increased risk of regional disease; whereas Asians/Pacific Islanders were at significantly decreased risk of local and regional disease. Thirty-six percent of Hispanics were diagnosed at regional or distant stages, compared with 30% of non-Hispanics. Hispanics were at significantly increased risk for all stages of disease, including unstaged tumors, compared with non-Hispanics, but the magnitude of increased risk was greatest for the most advanced stages.
The 2 largest SCC histologic subgroups were keratinizing SCC (14.1%) and verrucous SCC (6.3%) (Table 1). Tumors also included 12 other SCC types, including nonkeratinizing large cell and basaloid squamous cell carcinoma. The distribution of penile SCC by histologic subtypes was similar among whites and blacks. Some histologic differences were observed by race and ethnicity. Compared with whites, Asians/Pacific Islanders were at decreased risk of keratinizing SCC (rate ratio [RR] = 0.46, 95% CI, 0.22-0.83). Conversely, compared with non-Hispanics, Hispanic men were at significantly increased risk of keratinizing SCC (RR = 2.39, 95% CI, 1.90-2.97).
An anatomic subsite of origin was not specified in 43% of SCC cancers (Table 1). Among cases with subsite information, the glans was the most common subsite, comprising 60% of penile SCCs. Compared with the body of the penis, the risk of malignancy was elevated for both the prepuce and glans. Racial and ethnic differences were observed. Relative to whites, Asians/Pacific Islanders had a reduced risk of SCC of the glans penis, whereas blacks had an increased risk of tumors at unspecified sites. Compared with non-Hispanics, Hispanic men had an increased risk of tumors of both the prepuce (RR = 1.86, 95% CI 1.42-2.39) and the glans penis (RR = 1.86, 95% CI 1.58-2.17).
There were 1257 deaths among men with invasive penile SCC in the United States between 1998 and 2003. This represented 0.1% (1257 of 1,717,790) of all invasive cancers deaths in US men.
Penile SCC mortality increased with age (Table 3). Blacks had the lowest incidence-to-mortality ratio among any group. Mortality was significantly higher among blacks and lower among Asians/Pacific Islanders relative to whites. Mortality was also significantly elevated in Hispanics compared with non-Hispanics.
Penile SCC mortality was significantly lower among men in the West than in the South, paralleling regional differences in incidence (Table 3). Southern states accounted for 31% of penile SCC cases, but 41% of deaths. Mortality was elevated among men residing in the most impoverished regions and lower among those living in more educated areas.
Data on treatment were limited to first course of treatment for 1148 penile SCC cases reported to SEER registries from 1998 to 2003. Analysis of treatment by stage and grade excluded 40 unstaged tumors and 195 tumors with unknown grade, respectively. Nearly all men with invasive penile SCC received some form of surgical treatment. Sixty-two percent (713 of 1148) underwent resection surgery, also referred to as penis amputation, which included partial and total penectomy. Twenty-nine percent of penile SCC patients (332 of 1148) were treated with excisional biopsy or other local tumor removal techniques.
Men younger than 50 years were more likely to undergo lymphadenectomy (30%, 50 of 169) compared with those 50 years and older (13%, 105 of 800) (P < .05). Younger men were also more likely to be treated with radiation (13%, 22 of 169) than men 60 to 79 years old (7%, 41 of 574) (P < .05).
There were statistically significant differences in treatment by stage of diagnosis. Forty-three percent (286 of 664) of men with localized disease compared with only 10% (46 of 444) with advanced disease were treated with localized surgery (P < .05). Conversely, 82% (364 of 444) of men diagnosed at regional or distant stages underwent penis amputation, compared with 53% (349 of 664) of men with localized disease (P < .05). Men with advanced disease were also more likely to undergo lymphadenectomy (37%, 163 of 444) and radiation (16%, 69 of 444). This compares to lymphadenectomy in 6% (38 of 664) and radiation in 5% (32 of 664) of men with localized tumors (P < .05).
There were also statistically significant differences in treatment by tumor site, histologic subtype, and tumor grade. Penile SCCs occurring on the glans were more likely to be treated with penis amputation (75%, 296 of 397) compared with other sites combined (57%, 429 of 751) (P < .05). Keratinizing SCCs were more likely to be treated by amputation (77%, 150 of 196) than other SSC subtypes combined (60%, 575 of 952) (P < .05). Compared with well-differentiated tumors, moderately differentiated tumors were more likely to be treated by amputation (62%, 194 of 313 vs 72%, 313 of 432) (P < .05). Lymphadenectomy and radiation were also more common treatments for moderately differentiated penile SCCs (22%, 93 of 432 and 9%, 41 of 432, respectively) and poorly differentiated tumors (27%, 57 of 207 and 15%, 32 of 208), compared with well-differentiated SCCs (11%, 33 of 313 and 5%, 17 of 313, respectively) (P < .05).
Invasive SCC of the penis is rare in the US, comprising 0.1% of all cancer diagnoses and deaths in men during 1998 to 2003. The average annual age-adjusted incidence of 0.81 per 100,000 is consistent with other Western countries, where incidence is below 1 per 100,000.1 There is considerable variation in the incidence of penile cancers. Reported incidence ranges from 0.04 per 100,000 in Jewish populations in Israel to 3 to 4 per 100,000 in Brazil and Uganda. High rates of penile cancer are also observed in India, Southeast Asia, Latin America, and Eastern and Southern Africa. The international variation in rates likely reflects differences in risk factors, which may also account for the disparities observed within the United States.
Although the overall burden of invasive penile cancer is limited in this country, there is considerable variation in its incidence and mortality. Hispanic men and those living in the South and in low socioeconomic areas were at substantially increased risk for penile SCC. The increased risk of penile SCC among Hispanics and the reduced risk among Asians-Pacific Islanders is consistent with 2 recent analyses and may reflect racial/ethnic differences in risk factors for penile carcinoma, including HPV exposure, circumcision status, and cigarette smoking.4,5
Genital HPV is a common, usually asymptomatic infection in men, with prevalence estimates from 1% to 73%.23 The excess risk of penile SCC among Hispanics may be at least partly attributed to circumcision status. Fewer Mexican Americans are circumcised than non-Hispanic whites,24 and uncircumcised men may be at increased risk of HPV infection25-29 and penile cancer.6,15,17,30
It is also possible that regional, socioeconomic, and racial/ethnic differences in penile cancer incidence reflect differences in sexual and other practices that influence exposure to HPV. Poverty, race, and ethnicity have been identified as risk factors for genital HPV infection in women.31 The younger age at diagnosis among blacks and Hispanics may be attributed to earlier exposure to HPV via early sexual contact.
The high rates of penile cancer among Hispanic men in the United States parallel the increased risk of cervical cancer among US Hispanics.32 High geographic correlation between the penis and cervical cancer incidence worldwide is evidence of a shared risk factor, namely, HPV infection.1 Nevertheless, although all cervical cancers are attributable to HPV, it is estimated that HPV is etiologically involved in approximately 40% of penile cancers. Multiple independent pathways for penis carcinogenesis, including those involving and not involving HPV, have been suggested.7
Previous studies have observed that HPV is detected less often in keratinizing and verrucous SCC than in other types such as basaloid and warty SCC.7,12 We were only able to examine 2 of the larger SCC subgroups: keratinizing and verrucous types. We observed some histologic differences by race and ethnicity. Asians/Pacific Islanders were at decreased of keratinizing SCC compared with whites, whereas Hispanic men were at increased risk of keratinizing SCC relative to non-Hispanics.
It is possible that penile cancers diagnosed at younger ages may have a poorer prognosis, which may account for the higher mortality observed in Hispanics and blacks. Alternatively, excess mortality of Hispanics and blacks and those living in the South and low SES regions may reflect disparities in health-care access.
Our results were consistent with other analyses demonstrating that the glans is the most common subsite of penis carcinoma.4,33 In situ tumors of the glans penis are clinically distinct from in situ cancers occurring on the shaft.34 Accordingly, invasive penile cancers occurring on the glans and shaft may have etiologic differences.
Penis amputation is standard therapy for invasive penile cancers.35 Local excision is generally used for more confined cancers. Advances in penile cancer treatment in the United States have emphasized more conservative surgical approaches, while also placing greater emphasis on lymphadenectomy to decrease the risk of metastasis and less emphasis on primary radiation treatment, given a high rate of recurrence.35
More aggressive treatment—including penile amputation and lymphadenectomy—was observed in advanced-stage disease, glans penis tumors, keratinizing SCCs, and moderately or poorly differentiated tumor grade. Younger men with penile SCCs were more likely to undergo lymphadenectomy and radiation. However, they were not more likely to undergo penile amputation, possibly reflecting concerns over preservation of sexual function. Glans penis tumors and keratinizing SCCs, which were more common among Hispanics, were more frequently treated through nonconservative means, possibly reflecting a more aggressive disease course.
There were several limitations to the present analysis. Population-based data from NPCR registries were not available before 1998; therefore, the present analysis was not able to examine national temporal trends in penile SCC incidence in the United States. Two recent studies of SEER data observed an overall decrease in penile cancer incidence over the past 3 decades.4,36 Subgroup analysis of histologic types was limited to the 2 largest groups: keratinizing and verrucous. We were not able to analyze other histologic types, such as basaloid and warty SCC. The ability to analyze differences by anatomic subsite was limited by missing data in a large proportion of cases. This may reflect gaps in reporting, which may be magnified for rarer cancers such as these. Measurements of SES were indirect and did not permit evaluation of the interaction of SES with geographic region, race, and ethnicity. The population coverage for treatment data, which was limited to SEER registries, was lower than that of incidence and mortality data, and this may have limited its representativeness. Treatment data were limited to first course rather than the complete treatment regimen.
The availability of prophylactic HPV vaccination for females may result in a decline in the incidence of HPV-associated penile malignancies in the United States in future years.37 Decreases in its incidence may also occur more directly should males become candidates for HPV immunization. Disparities in vaccine coverage within certain populations, including the medically underserved, however, may exacerbate the present disparities in penile SCC incidence and mortality. Further research is needed to better understand the epidemiology of penile cancer including the role of HPV and implications of prophylactic vaccination.
This supplement to Cancer was supported by Cooperative Agreement Number U50 DP424071-04 from the Centers for Disease Control and Prevention. Anna Giuliano received a research grant from and is on the advisory committee and speakers bureau of Merck.
The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.