Penile Intraepithelial Neoplasia and Other Premalignant Lesions of the Penis




Invasive penile cancer is an aggressive malignancy that often requires partial or complete penile amputation. Premalignant penile lesions, such as penile intraepithelial neoplasia, will have been present prior to the development of invasive disease in a substantial percentage of patients. Early detection and treatment of premalignant penile lesions may prevent malignant progression while avoiding penile amputation. This review focuses on premalignant penile lesions and the associations of these lesions with the development of invasive penile cancer.


Penile cancer is a rare disease whose incidence varies geographically throughout the world. In the United States it is estimated that approximately 1300 new cases will be diagnosed and 300 men will die of penile cancer in 2009. Although penile cancer only accounts for 1% of malignancies diagnosed in United State males, the rate is much greater in parts of Asia, South America, and Africa, where it approaches 10%. There are several known risk factors for the development of invasive cancer, including human papilloma virus (HPV) infection and premalignant penile lesions. The presence of prior or concomitant penile lesions and/or symptoms with cases of invasive penile cancer is reported in up to 42% of cases, which suggests an opportunity for intervention prior to the development of invasive and/or metastatic disease. In addition, it has been noted that approximately 25% of dysplastic or neoplastic penile lesions will have been incorrectly diagnosed as being benign by another practitioner, leading to delayed treatment. With prompt diagnosis and treatment of premalignant penile lesions, malignant progression may be evaded while avoiding the need for partial or complete penile amputation, which is often required for the treatment of invasive disease. This review discusses the role of HPV in the development of penile intraepithelial neoplasia (PIN), the malignant potential and recommended treatment of PIN, and potential strategies to prevent PIN. Additional premalignant penile lesions including lichen sclerosus (LS), pseudo-epitheliomatous keratotic and micaceous balanitis (PKMB), and penile cutaneous horn are discussed briefly.


Human papilloma virus


HPV is the most common sexually transmitted viral infection in the developed world, with a prevalence of approximately 5% in healthy males and a peak incidence occurring between the ages 16 and 35 years. While a large proportion of HPV infections will spontaneously regress, a number of patients will have persistent infection with a risk of developing PIN and, rarely, invasive penile cancer. Risk factors for contracting the virus include multiple sexual partners and the lack of barrier protection use. Infection with HPV is clinically variable and can be classified as latent, subclinical, and clinical. Latent HPV infection is defined by the presence of detectable HPV DNA, but without evidence of microscopic or macroscopic disease. Subclinical HPV infection is defined by the presence of detectable HPV DNA and microscopic disease, but without evidence of macroscopic infection. Clinical HPV infection is defined by the presence of macroscopic lesions. HPV types can be classified as low- and high-risk based on their association with premalignant and malignant lesions. High-risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 54, 56, 58, 59, 66, 68, 69) have been associated with several premalignant and malignant conditions including PIN, vulvar intraepithelial neoplasia, carcinoma in situ of cervix, and invasive carcinoma of the cervix. The most common and recognizable clinical manifestation of infection with HPV is the development of condyloma acuminatum, or genital warts. The most common sites of genital infection in males include the prepuce and glans in uncircumcised males and the penile shaft and glans in circumcised males. Lesions are typically multifocal, ranging from 1 to 10 mm in size. Genital warts resulting from HPV infection are frequently benign, with 90% being associated with HPV types 6 or 11. However, coinfection with high-risk HPV types may be present in 19% to 44% of patients.


Although the growth of most genital warts is limited, some may continue to grow to a much larger size and are then classified as giant condyloma. Giant condylomas have also been referred to as Buschke-Lowenstein tumors. Giant condylomas are thought to grow slowly and be related to poor hygiene. Although associated with the low-risk HPV types 6 and 11, giant condylomas can grow to involve underlying and surrounding structures such as the dermis, subcutaneous fat, urethra, corpora, and rectum. Even though giant condylomas can be locally destructive, they are not associated with the development of metastatic disease. During pathologic evaluation, care must be taken to differentiate giant condyloma from verrucous carcinoma. While histologic examination can often characterize giant condyloma, HPV typing is sometimes useful to differentiate it from verrucous carcinoma, the latter not being associated with HPV infection.


The prevalence of HPV infection associated with penile cancer ranges from 15% to 100%. The wide range in association reported is likely attributed to the method of HPV detection in cancer specimens. The most common type of HPV associated with penile cancer is HPV 16, being noted in 65% of HPV-associated penile cancers. The association with HPV and penile cancer also varies by subtype of penile cancer. Whereas HPV is commonly noted in basaloid and warty penile cancer (80%–100%), the association is much lower in keratinizing and verrucous penile carcinomas (0%–35%). The noted association between HPV and invasive penile carcinoma is more similar to that in vulvar intraepithelial neoplasia (VIN) (50%) and cervical intraepithelial neoplasia (CIN) (100%). Although a suggested association between age of onset of penile cancer and HPV infection has been made, this finding has not been noted in all series.


Flat penile lesions associated with HPV are commonly located on the glans and prepuce. Histologically, flat penile lesions demonstrate squamous hyperplasia and features of low-grade PIN. The occurrence of flat penile lesions in men is strongly associated with CIN in female sexual partners, with 50% to 70% of affected men having CIN-positive female partners compared with 10% to 20% of men whose sexual partners are CIN negative. The majority of flat penile lesion will regress in 1 to 2 years; however, a small percentage may persist. The natural history of persistent flat penile lesions associated with HPV is currently unknown, but these lesions may potentially progress to high-grade PIN and/or invasive penile cancer.




Penile intraepithelial neoplasia


PIN is characterized by epithelial dysplasia equal to that of squamous cell carcinoma in situ, and includes erythroplasia of Queyrat (EQ), Bowen disease (BD), and bowenoid papulosis (BP). The differential diagnosis when considering PIN is presented in Box 1 . PIN can be characterized in several ways based on clinicopathologic features, including the degree of dysplasia, location, age of onset, and morphologic features. When categorizing PIN according to the degree of dysplasia, mild dysplasia is equivalent PIN I, moderate dysplasia is equivalent to PIN II, and severe dysplasia is categorized as PIN III. When comparing the PIN I, II, and III classification system with categories of PIN based on other clinicopathologic features, PIN II is synonymous with BP, and PIN III is synonymous with EQ and BD. EQ, BD, and BP can be further distinguished based on clinical features ( Table 1 ).



Box 1





  • Benign Conditions



  • Benign pigmented warts



  • Lichen sclerosus



  • Seborrheic keratosis



  • Melanocytic nevi



  • Angiokeratoma



  • Lichen planus



  • Psoriasis



  • Balanitis



  • Eczema



  • Contact dermatitis




  • Malignant Conditions



  • Malignant melanoma



  • Paget disease



  • Basal cell carcinoma



  • Kaposi sarcoma



Differential diagnosis of PIN


Table 1

Clinical characteristics of PIN


































Bowenoid Papulosis Erythroplasia of Queyrat Bowen Disease
Age at diagnosis <40 years >40 years >40 years
Location Penile shaft, glans, or prepuce Glans and prepuce Follicle-bearing skin of the genitals
Size 2–10 mm 10–15 mm 10–15 mm
Gross appearance Multiple small well-demarcated smooth brown, red, or pink papillomatous papules or patches One or more moist velvety shiny red patches Single scaly red or slightly pigmented plaque
Malignant progression <1% 10%–20%% 10%–20%


When comparing types of PIN, BP is more common in young men and is known to spontaneously regress. The mean duration of disease is approximately 2 years, with the majority (73%) of lesions regressing or not recurring after excision. However, the lesions can also recur, progress to EQ or BD, and become malignant. BP has also been noted to have a strong relationship with the occurrence of CIN in female sexual partners. Suspected risk factors for malignant progression of BP include smoking, immune suppression, high-risk HPV types, and genetics. In contrast to BP, EQ and BD are more commonly detected in older men. In addition, the malignant progression rate of EQ and BD is considerably higher, being noted in up to 10% to 20% of cases. A series by Malek and colleagues evaluating the natural history of PIN, with follow-up ranging from 3 to 19 years, noted an 89% rate of progression to invasive penile cancer. The estimated time for malignant progression for cases of low-grade PIN may be up to 20 years. This estimate is based on series that show a mean onset age of PIN I to II lesions as 35.8 years, PIN III lesions as 56.1 years, and invasive penile cancer of 65.3 years. The association between PIN and invasive penile cancer was also noted in a series by Cubilla and colleagues. In this series the occurrence of associated epithelial lesions with invasive penile cancer was examined in 288 cases of invasive penile cancer. The presence of squamous hyperplasia, low-grade PIN, and high-grade PIN were present in 89%, 59%, and 44% of cases, respectively. The observed association with squamous hyperplasia was more common with keratinizing and verrucous carcinomas than with basaloid and warty penile carcinoma. However, the association with high-grade PIN was stronger with basaloid and warty penile cancer than with keratinizing and verrucous penile carcinoma.


HPV infection has been associated with all types of PIN, and the rate HPV infection in PIN ranges from 70% to 100%. In addition, a history of having anogenital warts was noted to be a significant risk factor for the development of PIN and penile cancer, with an odds ratio of 7.01 (95% confidence interval: 2.48–19.8). HPV types 16 and 18 have been associated with PIN in several series, and it is not uncommon for PIN lesions to be associated with more than one type of HPV. Concurrent infection with HPV 8, 16, 39, and 51 have been noted in EQ. In a report by Wieland and colleagues, all patients with EQ demonstrated HPV 8 DNA, 88% demonstrated HPV 16 DNA, and 50% demonstrated HPV 39 or 51 DNA. Further evidence linking HPV and PIN is provided by series that evaluate the relationship between HPV-related genital lesions in sexual partners. The rate of PIN in males whose female partner has CIN is 33% compared with 1.4% in men whose female partner has condyloma. In addition, similar lesions (VIN and CIN) have been noted in the sexual partners of men with PIN.


Malignant potential of PIN is known to be dependent on the type of PIN with BP rarely progressing to invasive squamous cell carcinoma (SCC), while EQ and BD have been clearly documented as precursors of invasive penile carcinoma. Despite the association between high-risk HPV infection and PIN and PIN being an established precursor of invasive penile carcinoma, there is a disconnect with regard to the number HPV-positive cases of invasive penile cancer. The percentage of HPV-positive PIN cases, 70% to 100%, has been noted to be significantly higher than the percentage of HPV-positive invasive penile carcinoma cases, 54%. Several theories for this apparent disconnect between high-risk HPV infection and the development of invasive penile cancer have been made, the first of which is based on discrepancies in the methods used in detecting HPV infection, including the assays used and the methods of tissue preparation. The second theory is based on the potential clearance of HPV during progression from PIN to invasive penile carcinoma. The third and most likely explanation involves 2 separate pathways for the development of penile cancer: an HPV-dependent and an HPV-independent pathway. The observed disconnect between high-risk HPV infection and invasive penile cancer also raises the question of whether another unknown precursor of invasive penile cancer exists that has yet to be identified.


The current understanding of the tumorigenesis of penile cancer speculates that 2 different pathways may lead to invasive penile cancer, with one leading to basaloid and warty penile cancer and the other leading to keratinizing and verrucous penile cancer. Keratinizing is the most common type of penile cancer, accounting for approximately 50% of cases. Basaloid, warty, verrucous, and warty-basaloid account for 4%, 6%, 8%, and 17% of penile cancer, respectively. The remaining cases comprise papillary, SCC mixed, and sarcomatoid carcinomas of the penis. With its known associations with HPV infections it is believed that PIN is a precursor lesion of basaloid and warty penile cancer, while the precursor lesions of keratinizing and verrucous carcinoma remain unknown. The strongest association between HPV infection and development of penile cancer is seen in basaloid penile cancer, with 70% to 100% of basaloid carcinomas being HPV positive while 47% of basaloid and/or warty, 11% of keratinizing, and 0% of verrucous penile carcinoma are associated with HPV infection.




Penile intraepithelial neoplasia


PIN is characterized by epithelial dysplasia equal to that of squamous cell carcinoma in situ, and includes erythroplasia of Queyrat (EQ), Bowen disease (BD), and bowenoid papulosis (BP). The differential diagnosis when considering PIN is presented in Box 1 . PIN can be characterized in several ways based on clinicopathologic features, including the degree of dysplasia, location, age of onset, and morphologic features. When categorizing PIN according to the degree of dysplasia, mild dysplasia is equivalent PIN I, moderate dysplasia is equivalent to PIN II, and severe dysplasia is categorized as PIN III. When comparing the PIN I, II, and III classification system with categories of PIN based on other clinicopathologic features, PIN II is synonymous with BP, and PIN III is synonymous with EQ and BD. EQ, BD, and BP can be further distinguished based on clinical features ( Table 1 ).



Box 1





  • Benign Conditions



  • Benign pigmented warts



  • Lichen sclerosus



  • Seborrheic keratosis



  • Melanocytic nevi



  • Angiokeratoma



  • Lichen planus



  • Psoriasis



  • Balanitis



  • Eczema



  • Contact dermatitis




  • Malignant Conditions



  • Malignant melanoma



  • Paget disease



  • Basal cell carcinoma



  • Kaposi sarcoma



Differential diagnosis of PIN


Table 1

Clinical characteristics of PIN


































Bowenoid Papulosis Erythroplasia of Queyrat Bowen Disease
Age at diagnosis <40 years >40 years >40 years
Location Penile shaft, glans, or prepuce Glans and prepuce Follicle-bearing skin of the genitals
Size 2–10 mm 10–15 mm 10–15 mm
Gross appearance Multiple small well-demarcated smooth brown, red, or pink papillomatous papules or patches One or more moist velvety shiny red patches Single scaly red or slightly pigmented plaque
Malignant progression <1% 10%–20%% 10%–20%


When comparing types of PIN, BP is more common in young men and is known to spontaneously regress. The mean duration of disease is approximately 2 years, with the majority (73%) of lesions regressing or not recurring after excision. However, the lesions can also recur, progress to EQ or BD, and become malignant. BP has also been noted to have a strong relationship with the occurrence of CIN in female sexual partners. Suspected risk factors for malignant progression of BP include smoking, immune suppression, high-risk HPV types, and genetics. In contrast to BP, EQ and BD are more commonly detected in older men. In addition, the malignant progression rate of EQ and BD is considerably higher, being noted in up to 10% to 20% of cases. A series by Malek and colleagues evaluating the natural history of PIN, with follow-up ranging from 3 to 19 years, noted an 89% rate of progression to invasive penile cancer. The estimated time for malignant progression for cases of low-grade PIN may be up to 20 years. This estimate is based on series that show a mean onset age of PIN I to II lesions as 35.8 years, PIN III lesions as 56.1 years, and invasive penile cancer of 65.3 years. The association between PIN and invasive penile cancer was also noted in a series by Cubilla and colleagues. In this series the occurrence of associated epithelial lesions with invasive penile cancer was examined in 288 cases of invasive penile cancer. The presence of squamous hyperplasia, low-grade PIN, and high-grade PIN were present in 89%, 59%, and 44% of cases, respectively. The observed association with squamous hyperplasia was more common with keratinizing and verrucous carcinomas than with basaloid and warty penile carcinoma. However, the association with high-grade PIN was stronger with basaloid and warty penile cancer than with keratinizing and verrucous penile carcinoma.


HPV infection has been associated with all types of PIN, and the rate HPV infection in PIN ranges from 70% to 100%. In addition, a history of having anogenital warts was noted to be a significant risk factor for the development of PIN and penile cancer, with an odds ratio of 7.01 (95% confidence interval: 2.48–19.8). HPV types 16 and 18 have been associated with PIN in several series, and it is not uncommon for PIN lesions to be associated with more than one type of HPV. Concurrent infection with HPV 8, 16, 39, and 51 have been noted in EQ. In a report by Wieland and colleagues, all patients with EQ demonstrated HPV 8 DNA, 88% demonstrated HPV 16 DNA, and 50% demonstrated HPV 39 or 51 DNA. Further evidence linking HPV and PIN is provided by series that evaluate the relationship between HPV-related genital lesions in sexual partners. The rate of PIN in males whose female partner has CIN is 33% compared with 1.4% in men whose female partner has condyloma. In addition, similar lesions (VIN and CIN) have been noted in the sexual partners of men with PIN.


Malignant potential of PIN is known to be dependent on the type of PIN with BP rarely progressing to invasive squamous cell carcinoma (SCC), while EQ and BD have been clearly documented as precursors of invasive penile carcinoma. Despite the association between high-risk HPV infection and PIN and PIN being an established precursor of invasive penile carcinoma, there is a disconnect with regard to the number HPV-positive cases of invasive penile cancer. The percentage of HPV-positive PIN cases, 70% to 100%, has been noted to be significantly higher than the percentage of HPV-positive invasive penile carcinoma cases, 54%. Several theories for this apparent disconnect between high-risk HPV infection and the development of invasive penile cancer have been made, the first of which is based on discrepancies in the methods used in detecting HPV infection, including the assays used and the methods of tissue preparation. The second theory is based on the potential clearance of HPV during progression from PIN to invasive penile carcinoma. The third and most likely explanation involves 2 separate pathways for the development of penile cancer: an HPV-dependent and an HPV-independent pathway. The observed disconnect between high-risk HPV infection and invasive penile cancer also raises the question of whether another unknown precursor of invasive penile cancer exists that has yet to be identified.


The current understanding of the tumorigenesis of penile cancer speculates that 2 different pathways may lead to invasive penile cancer, with one leading to basaloid and warty penile cancer and the other leading to keratinizing and verrucous penile cancer. Keratinizing is the most common type of penile cancer, accounting for approximately 50% of cases. Basaloid, warty, verrucous, and warty-basaloid account for 4%, 6%, 8%, and 17% of penile cancer, respectively. The remaining cases comprise papillary, SCC mixed, and sarcomatoid carcinomas of the penis. With its known associations with HPV infections it is believed that PIN is a precursor lesion of basaloid and warty penile cancer, while the precursor lesions of keratinizing and verrucous carcinoma remain unknown. The strongest association between HPV infection and development of penile cancer is seen in basaloid penile cancer, with 70% to 100% of basaloid carcinomas being HPV positive while 47% of basaloid and/or warty, 11% of keratinizing, and 0% of verrucous penile carcinoma are associated with HPV infection.

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Mar 11, 2017 | Posted by in UROLOGY | Comments Off on Penile Intraepithelial Neoplasia and Other Premalignant Lesions of the Penis

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