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Circumcision and Penile Cancer
CHAPTER 4
Circumcision and Penile Cancer ANTHONY EMMANUEL, BSc (Hons), DipRD, MD (Res), MRCS (Eng) • NICK WATKIN, MA, MChir, FRCS (Urol)
ABSTRACT Penile cancer is a rare malignancy, with wide variation in its global incidence rates and health burden. Multiple risk factors are linked to this debilitating disease and possible preventative strategies are well documented. Circumcision is one such strategy and has been shown to prevent this rare and potentially debilitating disease from occurring due to the improved penile hygiene, lower HPV and HIV transmission rates and reduction of chronic inflammatory conditions such as phimosis and balanitis. Although, whether circumcision should be advocated in all males to harness its multi-faceted benefits is controversial and currently, with no official recommendation, the decision will ultimately lie with parents and/or the patient.
KEYWORDS Balanitis; Circumcision; Human papilloma virus; Neonatal circumcision; Penile cancer.
occurs predominantly in elderly men, with an increasing incidence with age and the highest rate being between 50 and 70 years.3 Penile tumours, of which 95% are squamous cell carcinoma, originate most commonly from the epithelium of the penile glans, inner prepuce (foreskin) and coronal sulcus and less commonly on the penile shaft3e5 (Fig. 4.1). Several risk factors have been identified, which are thought to contribute to the development of penile cancer. One of the most important and extensively studied factor is infection with the human papilloma virus (HPV). Around 33% of all penile cancer cases are associated with HPV infection, similar to vulvar and head and neck cancers.4e7 Other risk factors include phimosis, chronic inflammation, poor penile hygiene, penile trauma, ultraviolet A photochemotherapy, multiple sexual partners and smoking. There is no evidence that smegma is carcinogenic.8 However, with poor penile hygiene, its prolonged presence within the prepuce may cause penile irritation and inflammation, which may increase the risk of penile cancer.7,9,10
INTRODUCTION Penile cancer is a rare malignancy with wide variations in its global incidence rates and health burden. Multiple risk factors are linked to this debilitating disease and possible preventative strategies are well documented, of which with incipient controversy and ongoing debate, circumcision has been advocated. This chapter aims to explore the relationship between circumcision and penile cancer.
PENILE CANCER: EPIDEMIOLOGY AND RISK FACTORS Briefly, penile cancer is a rare disease in the western world, with an overall incidence of <1 per 100,000 men.1 However, this figure is significantly higher in developing countries such as Brazil and Uganda, with rates up to 3e6.8 per 100,000 men.2 This malignancy
THE RELATIONSHIP BETWEEN CIRCUMCISION AND PENILE CANCER Circumcision, a long-standing practice that predates human history, is one if not the most common suprocedures performed worldwide. It is usually carried out to treat an underlying physiologic phimosis or a pathologic phimosis caused by traumatic injury or balanitis xerotica obliterans, refractory balanoposthitis, chronic, recurrent urinary tract infections, etc.10,11 In addition, it may be performed for religious (Jewish and Islamic faith), cultural (for example, Korean, Turkish and African groups) or social reasons.12 Circumcision has been widely debated as a preventative measure for urinary tract infections, sexually transmitted infections, human immunodeficiency virus/ acquired immunodeficiency syndrome (HIV/AIDS) and penile inflammation. The link between circumcision
Complications in Male Circumcision. https://doi.org/10.1016/B978-0-323-68127-8.00004-1 Copyright © 2019 Elsevier Inc. All rights reserved.
21
22
Complications in Male Circumcision
FIG. 4.1 Examples of penile cancer involving the prepuce.
and penile cancer has been well documented, with the lack of circumcision and neonatal circumcision found to be a risk and protective factor, respectively.13 Owing to these factors, although controversial, some authors have advocated for universal male neonatal circumcision as a means to prevent penile cancer, while no current major medical organization has recommended or reprimanded this practice. Lack of circumcision is found to be a risk factor of penile cancer because of its association with an increased risk of phimosis and balanitis, which themselves, as shown by meta-analysis, increase the risk of penile cancer by 12- and 4-fold, respectively.14,15 The prevalence of HPV infection has been shown by several studies to be significantly less in circumcised individuals in comparison to their uncircumcised counterparts. This site-specific effect likely reflects the suitable environment for HPV infection created by the foreskin, as it surrounds the glans penis. Thereby, male circumcision reduces the risk of HPV infection among men and consequently reduces the exposure of women to high-risk HPV infection.16,17 In addition, multiple studies have shown that circumcised men clear penile oncogenic HPV infection faster than uncircumcised individuals, and this can further explain the lower risk of penile cancer and cervical cancer in female partners.17 Despite the obvious benefits of circumcision in reducing the risk of penile inflammatory conditions and HPV and HIV transmission, which can lead to penile cancer, interestingly, the incidence of penile cancer has been found to be similar in the United States and Denmark (w0.8 per 100,000) that have high and low rates of circumcision, respectively.18,19 In Denmark, one possible reason attributed to the low incidence of penile cancer despite a low rate of circumcision (<2%
of males) is improved penile hygiene, as the proportion of Danish people dwelling with a bath increased from 35% in 1940 to 90% in 1990.18 It has been shown that countries and cultures practising routine neonatal circumcision have a lower incidence of penile cancer. The incidence of penile cancer in the Jewish population, where neonatal circumcision is universally practiced is 0.3/100,000 per year in comparison to India, 3.32/100,000 per year, where neonatal circumcision is not routine.19 Neonatal circumcision removes approximately half the tissue that can develop into penile cancer. The protective effect of neonatal circumcision against penile cancer is in its prevention of penile inflammation caused by phimosis, among others. This was exemplified in a study of 100 matched case-control pairs, which compared those who underwent neonatal circumcision with those who were never circumcised and does not have a history of phimosis (odds ratio [OR] 0.41; 95% confidence interval [CI], 0.13e1.1 vs. OR 0.79; 95% CI, 0.29e2.6). This protective effect of circumcision against penile cancer is higher if performed in the neonatal period, and this effect diminishes if performed in later life, but to what extent remains unclear.20 There is a clear multi-faceted benefit to circumcision; however, the risks of possible complications, such as bleeding, infection and poor cosmesis, from undergoing this operation need to be considered.19,21 Other less invasive methods for the prevention of penile cancer do exist and these include following preventative strategies for sexually transmitted infection, such as condom use; promoting good penile hygiene; and HPV vaccination, either directly or from herd immunity from current vaccination programs in developed countries to prevent cervical cancer in women.21
CHAPTER 4 Circumcision and Penile Cancer
SUMMARY The presence of a foreskin does not increase the risk of penile cancer; however, the presence of phimosis in men with penile carcinoma is high. Circumcision has been shown to prevent this rare and potentially debilitating disease from occurring because of the improved penile hygiene, lower HPV and HIV transmission rates and reduction of chronic inflammatory conditions such as phimosis and balanitis. Whether circumcision should be advocated in all men to harness its multifaceted benefits is controversial, and currently, with no official recommendation, the decision will ultimately lie with parents and/or patients.
REFERENCES 1. Barski D, Georgas E, Gerullis H, et al. Metastatic penile carcinoma e an update on the current diagnosis and treatment options. Cent European J Urol. 2014;67(2): 126e132. 2. Christodoulidou M, Sahdev V, Houssein S, et al. Epidemiology of penile cancer. Curr Probl Cancer. 2015;39(3): 126e136. 3. Hakenberg OW, Comperat EM, Minhas S, et al. EAU guidelines on penile cancer: 2014 update. Eur Urol. 2014;67(1): 142e150. 4. Barnholtz-Sloan JS, Maldonado JL, Pow-sang J, et al. Incidence trends in primary malignant penile cancer. Urol Oncol. 2007;25(5):361e367. 5. Alemany L, Cubilla A, Halec G, et al. Role of human papillomavirus in penile carcinomas worldwide. Eur Urol. 2016, May;69(5):953e961. 6. Longpre MJ, Lange PH, Kwon JS, et al. Penile carcinoma: lessons learned from vulvar carcinoma. J Urol. 2013; 189(1):17e24. 7. Douglawi A, Masterson TA. Updates on the epidemiology and risk factors for penile cancer. Transl Androl Urol. 2017; 6(5):785e790. 8. Van Howe RS, Hodges FM. The carcinogenicity of smegma: debunking a myth. J Eur Acad Dermatol Venereol. 2006; 20(9):1046e1054.
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9. Krustrup D, Jensen HL, van den Brule AJ, et al. Histological characteristics of human papilloma-virus-positive and negative invasive and in situ squamous cell tumours of the penis. Int J Exp Pathol. 2009;90(2):182e189. 10. Morris BJ, Waskett JH, Banerjee J, et al. A ‘snip’ in time: what is the best age to circumcise? BMC Pediatr. 2012;28: 12e20. 11. Malone P, Steinbrecher H. Medical aspects of male circumcision. BMJ. 2007;335(7631):1206e1290. 12. Hayashi Y, Kohri L. Circumcision related to urinary tract infection, sexually transmitted infections, human immunodeficiency virus infections, and penile and cervical cancer. Int J Urol. 2013;20(8):769e775. 13. Perera CL, Bridgewater FH, Thavaneswaran P, et al. Safety and efficacy of nontherapeutic male circumcision: a systematic review. Ann Fam Med. 2010;8(1):64e72. 14. Larke NL, Thomas SL, dos Santos Silva I, et al. Male circumcision and penile cancer: a systematic review and metaanalysis. Cancer Causes Control. 2011;22(8):1097e1110. 15. Morris BJ, Gray RH, Castellsague, et al. The strong protective effect of circumcision against cancer of the penis. Adv Urol. 2011;2011:812368. 16. Auvert, Sobngwi-Tambekou J, Cutler E, et al. Effect of male circumcision on the prevalence of high-risk human papillomavirus in young men: results of a randomized controlled trial conducted in Orange Farm, South Africa. J Infect Dis. 2009;199(1):14e19. 17. Lu B, Wu Y, Nielson CM, et al. Factors associated with acquisition and clearance of human papillomavirus infection in a cohort of US men: a prospective study. J Infect Dis. 2009;199(3):362e371. 18. Frisch M, Friis S, Kjaer SK, et al. Falling incidence of penis cancer in an uncircumcised population (Denmark 1943e90). BMJ. 1995;311(7018):1471. 19. Ornellas AA, Ornellas P. Should routine neonatal circumcision be a policy to prevent penile cancer? j Opinion: Yes. Int Braz J Urol. 2017;43(1):7e9. 20. Tsen HF, Morgenstern H, Mack T, Peters RK. Risk factors for penile cancer: results of a population-based casecontrol study in Los Angeles County (United States). Cancer Causes Control. 2001;12(3):267e277. 21. Tang DH, Spiess PE. Should routine neonatal circumcision be a policy to prevent penile cancer? j Opinion: No. Int Braz J Urol. 2017;43(1):10e12.
Circumcision and Penile Cancer ANTHONY EMMANUEL, BSc (Hons), DipRD, MD (Res), MRCS (Eng) • NICK WATKIN, MA, MChir, FRCS (Urol)
ABSTRACT Penile cancer is a rare malignancy, with wide variation in its global incidence rates and health burden. Multiple risk factors are linked to this debilitating disease and possible preventative strategies are well documented. Circumcision is one such strategy and has been shown to prevent this rare and potentially debilitating disease from occurring due to the improved penile hygiene, lower HPV and HIV transmission rates and reduction of chronic inflammatory conditions such as phimosis and balanitis. Although, whether circumcision should be advocated in all males to harness its multi-faceted benefits is controversial and currently, with no official recommendation, the decision will ultimately lie with parents and/or the patient.
KEYWORDS Balanitis; Circumcision; Human papilloma virus; Neonatal circumcision; Penile cancer.
occurs predominantly in elderly men, with an increasing incidence with age and the highest rate being between 50 and 70 years.3 Penile tumours, of which 95% are squamous cell carcinoma, originate most commonly from the epithelium of the penile glans, inner prepuce (foreskin) and coronal sulcus and less commonly on the penile shaft3e5 (Fig. 4.1). Several risk factors have been identified, which are thought to contribute to the development of penile cancer. One of the most important and extensively studied factor is infection with the human papilloma virus (HPV). Around 33% of all penile cancer cases are associated with HPV infection, similar to vulvar and head and neck cancers.4e7 Other risk factors include phimosis, chronic inflammation, poor penile hygiene, penile trauma, ultraviolet A photochemotherapy, multiple sexual partners and smoking. There is no evidence that smegma is carcinogenic.8 However, with poor penile hygiene, its prolonged presence within the prepuce may cause penile irritation and inflammation, which may increase the risk of penile cancer.7,9,10
INTRODUCTION Penile cancer is a rare malignancy with wide variations in its global incidence rates and health burden. Multiple risk factors are linked to this debilitating disease and possible preventative strategies are well documented, of which with incipient controversy and ongoing debate, circumcision has been advocated. This chapter aims to explore the relationship between circumcision and penile cancer.
PENILE CANCER: EPIDEMIOLOGY AND RISK FACTORS Briefly, penile cancer is a rare disease in the western world, with an overall incidence of <1 per 100,000 men.1 However, this figure is significantly higher in developing countries such as Brazil and Uganda, with rates up to 3e6.8 per 100,000 men.2 This malignancy
THE RELATIONSHIP BETWEEN CIRCUMCISION AND PENILE CANCER Circumcision, a long-standing practice that predates human history, is one if not the most common suprocedures performed worldwide. It is usually carried out to treat an underlying physiologic phimosis or a pathologic phimosis caused by traumatic injury or balanitis xerotica obliterans, refractory balanoposthitis, chronic, recurrent urinary tract infections, etc.10,11 In addition, it may be performed for religious (Jewish and Islamic faith), cultural (for example, Korean, Turkish and African groups) or social reasons.12 Circumcision has been widely debated as a preventative measure for urinary tract infections, sexually transmitted infections, human immunodeficiency virus/ acquired immunodeficiency syndrome (HIV/AIDS) and penile inflammation. The link between circumcision
Complications in Male Circumcision. https://doi.org/10.1016/B978-0-323-68127-8.00004-1 Copyright © 2019 Elsevier Inc. All rights reserved.
21
22
Complications in Male Circumcision
FIG. 4.1 Examples of penile cancer involving the prepuce.
and penile cancer has been well documented, with the lack of circumcision and neonatal circumcision found to be a risk and protective factor, respectively.13 Owing to these factors, although controversial, some authors have advocated for universal male neonatal circumcision as a means to prevent penile cancer, while no current major medical organization has recommended or reprimanded this practice. Lack of circumcision is found to be a risk factor of penile cancer because of its association with an increased risk of phimosis and balanitis, which themselves, as shown by meta-analysis, increase the risk of penile cancer by 12- and 4-fold, respectively.14,15 The prevalence of HPV infection has been shown by several studies to be significantly less in circumcised individuals in comparison to their uncircumcised counterparts. This site-specific effect likely reflects the suitable environment for HPV infection created by the foreskin, as it surrounds the glans penis. Thereby, male circumcision reduces the risk of HPV infection among men and consequently reduces the exposure of women to high-risk HPV infection.16,17 In addition, multiple studies have shown that circumcised men clear penile oncogenic HPV infection faster than uncircumcised individuals, and this can further explain the lower risk of penile cancer and cervical cancer in female partners.17 Despite the obvious benefits of circumcision in reducing the risk of penile inflammatory conditions and HPV and HIV transmission, which can lead to penile cancer, interestingly, the incidence of penile cancer has been found to be similar in the United States and Denmark (w0.8 per 100,000) that have high and low rates of circumcision, respectively.18,19 In Denmark, one possible reason attributed to the low incidence of penile cancer despite a low rate of circumcision (<2%
of males) is improved penile hygiene, as the proportion of Danish people dwelling with a bath increased from 35% in 1940 to 90% in 1990.18 It has been shown that countries and cultures practising routine neonatal circumcision have a lower incidence of penile cancer. The incidence of penile cancer in the Jewish population, where neonatal circumcision is universally practiced is 0.3/100,000 per year in comparison to India, 3.32/100,000 per year, where neonatal circumcision is not routine.19 Neonatal circumcision removes approximately half the tissue that can develop into penile cancer. The protective effect of neonatal circumcision against penile cancer is in its prevention of penile inflammation caused by phimosis, among others. This was exemplified in a study of 100 matched case-control pairs, which compared those who underwent neonatal circumcision with those who were never circumcised and does not have a history of phimosis (odds ratio [OR] 0.41; 95% confidence interval [CI], 0.13e1.1 vs. OR 0.79; 95% CI, 0.29e2.6). This protective effect of circumcision against penile cancer is higher if performed in the neonatal period, and this effect diminishes if performed in later life, but to what extent remains unclear.20 There is a clear multi-faceted benefit to circumcision; however, the risks of possible complications, such as bleeding, infection and poor cosmesis, from undergoing this operation need to be considered.19,21 Other less invasive methods for the prevention of penile cancer do exist and these include following preventative strategies for sexually transmitted infection, such as condom use; promoting good penile hygiene; and HPV vaccination, either directly or from herd immunity from current vaccination programs in developed countries to prevent cervical cancer in women.21
CHAPTER 4 Circumcision and Penile Cancer
SUMMARY The presence of a foreskin does not increase the risk of penile cancer; however, the presence of phimosis in men with penile carcinoma is high. Circumcision has been shown to prevent this rare and potentially debilitating disease from occurring because of the improved penile hygiene, lower HPV and HIV transmission rates and reduction of chronic inflammatory conditions such as phimosis and balanitis. Whether circumcision should be advocated in all men to harness its multifaceted benefits is controversial, and currently, with no official recommendation, the decision will ultimately lie with parents and/or patients.
REFERENCES 1. Barski D, Georgas E, Gerullis H, et al. Metastatic penile carcinoma e an update on the current diagnosis and treatment options. Cent European J Urol. 2014;67(2): 126e132. 2. Christodoulidou M, Sahdev V, Houssein S, et al. Epidemiology of penile cancer. Curr Probl Cancer. 2015;39(3): 126e136. 3. Hakenberg OW, Comperat EM, Minhas S, et al. EAU guidelines on penile cancer: 2014 update. Eur Urol. 2014;67(1): 142e150. 4. Barnholtz-Sloan JS, Maldonado JL, Pow-sang J, et al. Incidence trends in primary malignant penile cancer. Urol Oncol. 2007;25(5):361e367. 5. Alemany L, Cubilla A, Halec G, et al. Role of human papillomavirus in penile carcinomas worldwide. Eur Urol. 2016, May;69(5):953e961. 6. Longpre MJ, Lange PH, Kwon JS, et al. Penile carcinoma: lessons learned from vulvar carcinoma. J Urol. 2013; 189(1):17e24. 7. Douglawi A, Masterson TA. Updates on the epidemiology and risk factors for penile cancer. Transl Androl Urol. 2017; 6(5):785e790. 8. Van Howe RS, Hodges FM. The carcinogenicity of smegma: debunking a myth. J Eur Acad Dermatol Venereol. 2006; 20(9):1046e1054.
23
9. Krustrup D, Jensen HL, van den Brule AJ, et al. Histological characteristics of human papilloma-virus-positive and negative invasive and in situ squamous cell tumours of the penis. Int J Exp Pathol. 2009;90(2):182e189. 10. Morris BJ, Waskett JH, Banerjee J, et al. A ‘snip’ in time: what is the best age to circumcise? BMC Pediatr. 2012;28: 12e20. 11. Malone P, Steinbrecher H. Medical aspects of male circumcision. BMJ. 2007;335(7631):1206e1290. 12. Hayashi Y, Kohri L. Circumcision related to urinary tract infection, sexually transmitted infections, human immunodeficiency virus infections, and penile and cervical cancer. Int J Urol. 2013;20(8):769e775. 13. Perera CL, Bridgewater FH, Thavaneswaran P, et al. Safety and efficacy of nontherapeutic male circumcision: a systematic review. Ann Fam Med. 2010;8(1):64e72. 14. Larke NL, Thomas SL, dos Santos Silva I, et al. Male circumcision and penile cancer: a systematic review and metaanalysis. Cancer Causes Control. 2011;22(8):1097e1110. 15. Morris BJ, Gray RH, Castellsague, et al. The strong protective effect of circumcision against cancer of the penis. Adv Urol. 2011;2011:812368. 16. Auvert, Sobngwi-Tambekou J, Cutler E, et al. Effect of male circumcision on the prevalence of high-risk human papillomavirus in young men: results of a randomized controlled trial conducted in Orange Farm, South Africa. J Infect Dis. 2009;199(1):14e19. 17. Lu B, Wu Y, Nielson CM, et al. Factors associated with acquisition and clearance of human papillomavirus infection in a cohort of US men: a prospective study. J Infect Dis. 2009;199(3):362e371. 18. Frisch M, Friis S, Kjaer SK, et al. Falling incidence of penis cancer in an uncircumcised population (Denmark 1943e90). BMJ. 1995;311(7018):1471. 19. Ornellas AA, Ornellas P. Should routine neonatal circumcision be a policy to prevent penile cancer? j Opinion: Yes. Int Braz J Urol. 2017;43(1):7e9. 20. Tsen HF, Morgenstern H, Mack T, Peters RK. Risk factors for penile cancer: results of a population-based casecontrol study in Los Angeles County (United States). Cancer Causes Control. 2001;12(3):267e277. 21. Tang DH, Spiess PE. Should routine neonatal circumcision be a policy to prevent penile cancer? j Opinion: No. Int Braz J Urol. 2017;43(1):10e12.