Penile Cancer
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INTRODUCTION
Penile carcinoma in the United States is relatively uncommon compared to Asia and Africa and accounts for less than 1% of all cancers in males1. Squamous cell epithelium continues to be the most common histological pathology when it comes to penile carcinoma. Although associated with several risk factors, the lack circumcision remains a predominant predisposing factor that cause penile cancer. Squamous cell carcinoma of the penis usually has the tendency to infiltrate the underlying connective tissue and often metastasis by way of lymphatic spread. There are several modalities that can be employed in the treatment of penile cancer which may consist of surgical, laser ablation or medical treatment.
EPIDEMIOLOGY
The incidence of penile cancer increases abruptly in men aged 60 years or older and peaks in men aged 80 years1. Carcinoma of the penis is an uncommon malignancy in the United States, accounting for 0.4% of cancers in males2. By contrast, in some parts of Asia, Africa, and South America the incidence of carcinoma of the penis ranges from 10% to 20% of male malignancies3.
ETIOLOGY
Men who have been circumcised rarely develop penile cancer. Circumcision has been well established as an effective prophylactic measure for penile cancer4. Data from most large series have demonstrated that penile cancer is almost never observed in individuals who are circumcised in the neonatal period5. The disease is found more frequently when circumcision is delayed until puberty. Adult circumcision offers little or no protection. No firm evidence indicates that smegma acts as a carcinogen, although this belief continues to be widely held6. Phimosis, mostly secondary to lack of circumcision, confers a 7 to 10 -fold increased risk of penile cancer4. HPV-16 and HPV-18 have been found in up to 50 percent of men with penile cancer7. Other risk factors associated with penile cancer include smoking, urinary tract infections, genital warts, urethral stricture, poor genital hygiene and chronic penile rash lasting longer than one month8.
PATHOLOGY
Primary lesions are localized to the glans, prepuce and penile shaft in 60%, 23% and 9% respectively, with the remaining lesions overlapping between these sites1. Precancerous lesions which previously consisted of carcinoma in situ, erythroplasia of Queyrat and Bowen’s disease are now grouped together and classified as penile intraepithelial neoplasm (PeIN), which is further divided into differentiated and undifferentiated subtypes. Differentiated PeIN is associated with chronic inflammatory conditions such as phimosis, whereas undifferentiated PeIN is associated with HPV infection9. Squamous cell carcinoma (SCC), together with its variants account for up to 95 percent of invasive penile cancer10. This type of cancer usually begins on the glans or inner surface of the prepuce near the coronal sulcus. Two macroscopic patterns are seen—papillary and flat. The papillary lesions simulate condyloma acuminatum and may produce a cauliflower-like fungating mass. Flat lesions appear as areas of epithelial thickening accompanied by graying and fissuring of the mucosal surface. With progression, an ulcerated papule develops. The rates of growth of the papillary and ulcerative lesions are similar, but the flat, ulcerative tumor has a tendency toward earlier nodal metastasis and is associated with poorer 5-year survival rates. The earliest route of dissemination from penile carcinoma is metastasis to the superficial inguinal nodes which drain to the deep inguinal nodes. From there, drainage is to the pelvic nodes (external iliac, internal iliac, and obturator). Clinically patients with metastasis typically have palpable inguinal lymph nodes. Distant metastatic lesions to the lung, liver, bone, or brain are uncommon and are reported to occur in 1% to 10% of cases in most large series1. Microscopically, penile squamous cell carcinoma is typically well-differentiated and focally keratinizing.
Penile SCC can be characterized and subclassified by microscopic histologic features into several of the most common subtypes11:
●Usual type SCC (45 to 65 percent) – The biologic behavior of these tumors is related to size, histologic grade, depth and structure invaded, and the presence of lymphovascular or perineural invasion (which is present in approximately one-third of cases). The typical case is grade II with respect to differentiation and invades into the corpus spongiosum. Inguinal lymph node metastases are present in 25 to 40 percent of cases.
●Papillary carcinoma (2 to 15 percent) – These tumors are usually low grade (although grade II is found in some cases) but are superficially invasive into erectile tissue. Microscopically, they have evidence of both hyperkeratosis and papillomatosis. The lack of uniform papillae, absence of koilocytosis, and jagged stromal border distinguish it from either verrucous or warty carcinoma. Papillary tumors are not associated with human papillomavirus (HPV) infection. Vascular and perineural invasion, or nodal metastases are uncommon (up to 12 percent of cases).
●Warty (condylomatous) tumors (7 to 10 percent) – These are cauliflower-like cancers associated with HPV infection. The tumor is composed of a prominent fibrovascular core that exhibits papillomatous formations that penetrate the corpus cavernosum or spongiosum. The border with underlying stroma is jagged and irregular. The typical presentation is a grade II bulky slow-growing malignancy. Vascular and perineural invasion are uncommon. Inguinal node metastases are present in 17 to 25 percent of cases.
●Basaloid carcinoma (4 to 10 percent) – These are HPV related cancers that present as an ulcerated irregular mass. They are comprised of uniform and small basaloid cells with central necrosis and are deeply invasive into the corpus cavernosum or spongiosum. Mitotic figures predominate, and evidence of apoptosis is also seen microscopically. These are high-grade tumors, with more than one-half of patients exhibiting inguinal metastases.
●Verrucous carcinoma (3 to 7 percent) – These tumors are low grade and are associated with a broad pushing border instead of infiltrative growth. They are characterized by straight papillae lined by extremely well-differentiated neoplastic cells. There is hyperkeratosis on the surface, with interpapillary keratin also present. Tumors that meet the criteria of "true verrucous carcinoma" are distinct in that there is no metastatic potential. However, recurrence is common among tumors that are inadequately excised.
●Sarcomatoid (spindle cell) carcinoma (1 to 6 percent) – These are rare tumors of the penis that can be confused with malignant melanoma or sarcoma. They appear as deeply invasive, ulcerated or rounded polypoid masses. Microscopically, both SCC and spindle cell carcinoma components are seen. It may mimic features of heterologous sarcomas (eg, leiomyosarcoma, fibrosarcoma, and angiosarcoma). These tumors are the most aggressive variant of penile cancer, commonly presenting with vascular and perineural invasion in addition to inguinal and distant metastases.
In terms of prognostic characteristics, verrucous, pseudohyperplastic, andcuniculatum carcinomas have an excellent prognosis with no risk of metastatic spread to regional lymph nodes or association with disease-specific death. Warty and papillary carcinomas are associated with a metastatic rate of approximately 20% and an overall low mortality rate11. Adenosquamous carcinomas have a much higher metastatic potential (~50%) but are associated with a negligible mortality rate. The subtypes with the worst prognosis remain the sarcomatoid and basaloid carcinomas, in which metastatic spread is seen in 50-100% of patients and in whom most affected patients ultimately succumb to their disease. While histologic subtypes serve as discriminatory features for prognostic comparison, the most important pathologic predictors for metastatic spread and survival outcomes remain tumor grade, depth of invasion, and the presence of perineural invasion12.
Penile SCC can be characterized and subclassified by microscopic histologic features into several of the most common subtypes11:
●Usual type SCC (45 to 65 percent) – The biologic behavior of these tumors is related to size, histologic grade, depth and structure invaded, and the presence of lymphovascular or perineural invasion (which is present in approximately one-third of cases). The typical case is grade II with respect to differentiation and invades into the corpus spongiosum. Inguinal lymph node metastases are present in 25 to 40 percent of cases.
●Papillary carcinoma (2 to 15 percent) – These tumors are usually low grade (although grade II is found in some cases) but are superficially invasive into erectile tissue. Microscopically, they have evidence of both hyperkeratosis and papillomatosis. The lack of uniform papillae, absence of koilocytosis, and jagged stromal border distinguish it from either verrucous or warty carcinoma. Papillary tumors are not associated with human papillomavirus (HPV) infection. Vascular and perineural invasion, or nodal metastases are uncommon (up to 12 percent of cases).
●Warty (condylomatous) tumors (7 to 10 percent) – These are cauliflower-like cancers associated with HPV infection. The tumor is composed of a prominent fibrovascular core that exhibits papillomatous formations that penetrate the corpus cavernosum or spongiosum. The border with underlying stroma is jagged and irregular. The typical presentation is a grade II bulky slow-growing malignancy. Vascular and perineural invasion are uncommon. Inguinal node metastases are present in 17 to 25 percent of cases.
●Basaloid carcinoma (4 to 10 percent) – These are HPV related cancers that present as an ulcerated irregular mass. They are comprised of uniform and small basaloid cells with central necrosis and are deeply invasive into the corpus cavernosum or spongiosum. Mitotic figures predominate, and evidence of apoptosis is also seen microscopically. These are high-grade tumors, with more than one-half of patients exhibiting inguinal metastases.
●Verrucous carcinoma (3 to 7 percent) – These tumors are low grade and are associated with a broad pushing border instead of infiltrative growth. They are characterized by straight papillae lined by extremely well-differentiated neoplastic cells. There is hyperkeratosis on the surface, with interpapillary keratin also present. Tumors that meet the criteria of "true verrucous carcinoma" are distinct in that there is no metastatic potential. However, recurrence is common among tumors that are inadequately excised.
●Sarcomatoid (spindle cell) carcinoma (1 to 6 percent) – These are rare tumors of the penis that can be confused with malignant melanoma or sarcoma. They appear as deeply invasive, ulcerated or rounded polypoid masses. Microscopically, both SCC and spindle cell carcinoma components are seen. It may mimic features of heterologous sarcomas (eg, leiomyosarcoma, fibrosarcoma, and angiosarcoma). These tumors are the most aggressive variant of penile cancer, commonly presenting with vascular and perineural invasion in addition to inguinal and distant metastases.
In terms of prognostic characteristics, verrucous, pseudohyperplastic, andcuniculatum carcinomas have an excellent prognosis with no risk of metastatic spread to regional lymph nodes or association with disease-specific death. Warty and papillary carcinomas are associated with a metastatic rate of approximately 20% and an overall low mortality rate11. Adenosquamous carcinomas have a much higher metastatic potential (~50%) but are associated with a negligible mortality rate. The subtypes with the worst prognosis remain the sarcomatoid and basaloid carcinomas, in which metastatic spread is seen in 50-100% of patients and in whom most affected patients ultimately succumb to their disease. While histologic subtypes serve as discriminatory features for prognostic comparison, the most important pathologic predictors for metastatic spread and survival outcomes remain tumor grade, depth of invasion, and the presence of perineural invasion12.
STAGING
The following is the staging for penile cancer based on The International Society of Urologic Pathology (ISUP) Grading System13,14.
Primary tumor (pT)
• pTX: Cannot be assessed
• pT0: No evidence of primary tumor
• pTa: Noninvasive localized carcinoma
• pTis: Carcinoma in situ
• pT1a: Subepithelial invasion without lymphovascular invasion, perineural invasion or grade 3
• pT1b: Subepithelial invasion with lymphovascular invasion, perineural invasion or grade 3
• pT2: Invasion of corpus spongiosum
• pT3: Invasion of corpus cavernosum
• pT4: Invasion of adjacent structures including scrotum, prostate and pubic bone
Primary tumor (pT)
• pTX: Cannot be assessed
• pT0: No evidence of primary tumor
• pTa: Noninvasive localized carcinoma
• pTis: Carcinoma in situ
• pT1a: Subepithelial invasion without lymphovascular invasion, perineural invasion or grade 3
• pT1b: Subepithelial invasion with lymphovascular invasion, perineural invasion or grade 3
• pT2: Invasion of corpus spongiosum
• pT3: Invasion of corpus cavernosum
• pT4: Invasion of adjacent structures including scrotum, prostate and pubic bone
DIAGNOSIS AND EVALUATION
Penile Cancer is assessed by obtaining a focused and detailed history consisting of prior circumcision, the age at which circumcision was done (i.e. pre or post-puberty) and a history of phimosis, balanitis, chronic penile inflammation, genital hygiene habits, tobacco use, trauma, sexual habits and history of HPV. It is vital to carefully inspect the entire penis, from the meatus and glans to the shaft, together with palpation of the bilateral inguinal regions. The penile lesion must be assessed noting its diameter, fixed or mobile, location with regards to the phallus and relation to relevant anatomical structures (corpus spongiosum, corpus cavernosum, urethra), and morphological features (keratinization, papillary, nodular, erythematous, neovascularity, ulcerated). Patients should be placed supine in a slight frog-leg position when examining the inguinal region. Any palpable inguinal lymph nodes should be characterized pertaining to shotty (i.e. small clinically insignificant palpable lymph nodes) versus grossly evident, mobile versus fixed, involvement of surrounding skin, and suspicion of an underlying infection (erythema, purulent drainage). Obtaining a tissue biopsy continues to remain the gold standard in assessing and confirming penile cancer. Various biopsy techniques can be employed including a punch, incisional, or excisional biopsy. Imaging techniques such as penile MRI or ultrasound can also be used to help assess primary tumor stage and suitability for penile sparing surgical approaches. Serum calcium levels should also be obtained as it may help in ascertaining whether there is a presence of bone metastasis since hypercalcemia is characteristic of all types of squamous cell cancer. If an infection appears to be more likely (eg, erythema, swelling, discharge), a four- to six-week course of antifungals or antibiotics may be indicated, depending on the clinical exam. The use of steroids is reserved for patients with a biopsy-confirmed diagnosis of an inflammatory lesion. Lesions that do not resolve after six weeks or that progress at any time during antibiotic or antifungal therapy should be biopsied.
MANAGEMENT OF PRIMARY TUMOR
Management of primary penile cancer is guided by 2016 National Comprehensive Cancer Network (NCCN) PC guidelines.
For Tis and Ta primary penile tumors, topical therapy using imiquimod (5 percent cream applied five days a week for four to six weeks) or 5-fluorouracil (5 percent cream applied every other day for four to six weeks), together with wide local excision encompassing circumcision for penile tumors situated on the penile foreskin are the preferred primary treatment approaches15. Laser ablation involves using a laser energy source such as carbon dioxide (CO2), argon, neodymium-doped yttrium aluminium garnet (Nd:YAG), and potassium titanyl phosphate, to infiltrate and ablate the penile lesion. It is most effective against Tis and has a high success rate of regaining sexual function16,17. Patients presenting with clinical stage T1 primary penile tumors should be subdivided into lower (grade 1-2) and higher (grade 3-4) grade tumors in defining the treatment approaches they are offered. Patients with T1 low grade tumors are preferably offered penile preserving surgery consisting of a wide local excision +/- thick split thickness (STSG) or full thickness (FTSG) skin graft, with alternative options being laser ablative therapy or radiotherapy. In contrast, patients with T1 high grade tumors can be offered a host of therapeutic options including wide local excision +/- STSG or FTSG, glansectomy, partial penectomy, and total penectomy with perineal urethrostomy18. Total penectomy should only be considered if a functional penile stump cannot be preserved (typically greater than 2 cm) while insuring complete tumor eradication with negative surgical margins18. Alternative options for patients with T1 high-grade tumors include primary radiotherapy and radiation with systemic chemotherapy. Patients presenting with more locally advanced primary penile tumors (T2 or greater) are preferably recommended partial or total penectomy with perineal urethrostomy, with an alternative option for T2 only tumors being radiotherapy +/- systemic chemotherapy.
For Tis and Ta primary penile tumors, topical therapy using imiquimod (5 percent cream applied five days a week for four to six weeks) or 5-fluorouracil (5 percent cream applied every other day for four to six weeks), together with wide local excision encompassing circumcision for penile tumors situated on the penile foreskin are the preferred primary treatment approaches15. Laser ablation involves using a laser energy source such as carbon dioxide (CO2), argon, neodymium-doped yttrium aluminium garnet (Nd:YAG), and potassium titanyl phosphate, to infiltrate and ablate the penile lesion. It is most effective against Tis and has a high success rate of regaining sexual function16,17. Patients presenting with clinical stage T1 primary penile tumors should be subdivided into lower (grade 1-2) and higher (grade 3-4) grade tumors in defining the treatment approaches they are offered. Patients with T1 low grade tumors are preferably offered penile preserving surgery consisting of a wide local excision +/- thick split thickness (STSG) or full thickness (FTSG) skin graft, with alternative options being laser ablative therapy or radiotherapy. In contrast, patients with T1 high grade tumors can be offered a host of therapeutic options including wide local excision +/- STSG or FTSG, glansectomy, partial penectomy, and total penectomy with perineal urethrostomy18. Total penectomy should only be considered if a functional penile stump cannot be preserved (typically greater than 2 cm) while insuring complete tumor eradication with negative surgical margins18. Alternative options for patients with T1 high-grade tumors include primary radiotherapy and radiation with systemic chemotherapy. Patients presenting with more locally advanced primary penile tumors (T2 or greater) are preferably recommended partial or total penectomy with perineal urethrostomy, with an alternative option for T2 only tumors being radiotherapy +/- systemic chemotherapy.
INTERESTING STUDIES
CRP and SCC-Ag levels were significantly associated with lymph node metastasis, pathological tumor stage and disease specific survival in a retrospective study of 124 patients. (1) One study of buried penis showed 7% had SCC and 35% had premalignant penile lesions. (22)
- Hernandez BY, Barnholtz-Sloan J, German RR, et al. Burden of invasive squamous cell carcinoma of the penis in the United States, 1998-2003. Cancer 2008; 113:2883.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018; 68:7.
- Ornellas AA. Management of penile cancer. J Surg Oncol 2008; 97:199.
- Daling JR, Madeleine MM, Johnson LG, et al. Penile cancer: importance of circumcision, human papillomavirus and smoking in in situ and invasive disease. Int J Cancer 2005; 116:606.
- Schoen EJ. Neonatal circumcision and penile cancer. Evidence that circumcision is protective is overwhelming. Bmj. 1996 Jul 6;313(7048):46; author reply 7.
- Cubilla AL, Dillner J, Schellhammer PF, et al. Tumours of the penis. In: Tumors of the Urinary System and Mail Genital Organs, Eble JN, Sauter G, Epstein JI, et al (Eds), World Health Organization, Lyon 2010. p.279.
- Centers for Disease Control and Prevention (CDC). Human papillomavirus-associated cancers - United States, 2004-2008. MMWR Morb Mortal Wkly Rep 2012; 61:258.
- Bleeker MC, Heideman DA, Snijders PJ, Horenblas S, Dillner J, Meijer CJ. Penile cancer: epidemiology, pathogenesis and prevention. World journal of urology. 2009 Apr;27(2):141-50.
- Chaux et al, Am J Surg Pathol 2010;34:385-92.
- Cubilla AL, Dillner J, Schellhammer PF, et al. Tumours of the penis. In: Tumors of the Urinary System and Mail Genital Organs, Eble JN, Sauter G, Epstein JI, et al (Eds), World Health Organization, Lyon 2010. p.279.
- Sanchez DF, Soares F, Alvarado-Cabrero I, et al. Pathological factors, behavior, and histological prognostic risk groups in subtypes of penile squamous cell carcinomas (SCC). Semin Diagn Pathol 2015; 32:222.
- Chaux A, Torres J, Pfannl R, Barreto J, Rodriguez I, Velazquez EF, et al. Histologic grade in penile squamous cell carcinoma: visual estimation versus digital measurement of proportions of grades, adverse prognosis with any proportion of grade 3 and correlation of a Gleason-like system with nodal metastasis. The American journal of surgical pathology. 2009 Jul;33(7):1042-8.
- Pettaway CA, Srigley JR, Brookland RK, et al. Penis. In: AJCC Cancer Staging Manual, Eighth, Amin MB (Ed), 2017. p.701
- Zynger, D. Staging of penile carcinoma. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/penscrotumpenisstaging.html. Accessed September 28th, 2018
- Leone A, Inman B, Spiess PE. Need for Evidence and Consensus on Laser Treatment for Management of Select Primary Penile Tumors. Eur Urol 2017.
- Feldman AS, McDougal WS. Long-term outcome of excisional organ sparing surgery for carcinoma of the penis. Journal of urology 2011;186:1303-1307.
- Pietrzak P, Corbishley C, Watkin N. Organ-sparing surgery for invasive penile cancer: early follow-up data. BJU international 2004;94:1253-1257.
- Hatzichristou DG, Apostolidis A, Tzortzis V, et al. Glansectomy: an alternative surgical treatment for Buschke-Lowenstein tumors of the penis. Urology 2001;57:966-969.
- Kumar, Vinay, and Stanley L. 1915- Robbins. Robbins Basic Pathology. 8th ed. Philadelphia, PA: Saunders/Elsevier, 2007.
- https://university.auanet.org/core_topic.cfm?coreid=79&AUAID=00896295&ct=f93b27aa751343d61b9042f692418381a732c82ac373a0147d6cd309624cfd65ea670bd4f4270f2fba66b9ae744cf1fe6977990144b92d350c497c3a37184436, Penile neoplasms. Accessed September 28th, 2018
- Li, Zai‐Shang, et al. "Clinical significance of preoperative C‐reactive protein and squamous cell carcinoma antigen levels in patients with penile squamous cell carcinoma." BJU international118.2 (2016): 272-278.
- Pekala, Kelly R., et al. “The Prevalence of Penile Cancer in Patients With Adult Acquired Buried Penis.” Urology, 2019.
FULL TEXT FOR SEARCHABLE MATERIAL
Penile Cancer
Introduction
Penile carcinoma in the United States is relatively uncommon compared to Asia and Africa and accounts for less than 1% of all cancers in males1. Squamous cell epithelium continues to be the most common histological pathology when it comes to penile carcinoma. Although associated with several risk factors, the lack circumcision remains a predominant predisposing factor that cause penile cancer. Squamous cell carcinoma of the penis usually has the tendency to infiltrate the underlying connective tissue and often metastasis by way of lymphatic spread. There are several modalities that can be employed in the treatment of penile cancer which may consist of surgical, laser ablation or medical treatment.
Epidemiology
The incidence of penile cancer increases abruptly in men aged 60 years or older and peaks in men aged 80 years1. Carcinoma of the penis is an uncommon malignancy in the United States, accounting for 0.4% of cancers in males2. By contrast, in some parts of Asia, Africa, and South America the incidence of carcinoma of the penis ranges from 10% to 20% of male malignancies3.
Etiology.
Men who have been circumcised rarely develop penile cancer. Circumcision has been well established as an effective prophylactic measure for penile cancer4. Data from most large series have demonstrated that penile cancer is almost never observed in individuals who are circumcised in the neonatal period5. The disease is found more frequently when circumcision is delayed until puberty. Adult circumcision offers little or no protection. No firm evidence indicates that smegma acts as a carcinogen, although this belief continues to be widely held6. Phimosis, mostly secondary to lack of circumcision, confers a 7 to 10 -fold increased risk of penile cancer4. HPV-16 and HPV-18 have been found in up to 50 percent of men with penile cancer7. Other risk factors associated with penile cancer include smoking, urinary tract infections, genital warts, urethral stricture, poor genital hygiene and chronic penile rash lasting longer than one month8.
Pathology
Primary lesions are localized to the glans, prepuce and penile shaft in 60%, 23% and 9% respectively, with the remaining lesions overlapping between these sites1. Precancerous lesions which previously consisted of carcinoma in situ, erythroplasia of Queyrat and Bowen’s disease are now grouped together and classified as penile intraepithelial neoplasm (PeIN), which is further divided into differentiated and undifferentiated subtypes. Differentiated PeIN is associated with chronic inflammatory conditions such as phimosis, whereas undifferentiated PeIN is associated with HPV infection9. Squamous cell carcinoma (SCC), together with its variants account for up to 95 percent of invasive penile cancer10. This type of cancer usually begins on the glans or inner surface of the prepuce near the coronal sulcus. Two macroscopic patterns are seen—papillary and flat. The papillary lesions simulate condyloma acuminatum and may produce a cauliflower-like fungating mass. Flat lesions appear as areas of epithelial thickening accompanied by graying and fissuring of the mucosal surface. With progression, an ulcerated papule develops. The rates of growth of the papillary and ulcerative lesions are similar, but the flat, ulcerative tumor has a tendency toward earlier nodal metastasis and is associated with poorer 5-year survival rates. The earliest route of dissemination from penile carcinoma is metastasis to the superficial inguinal nodes which drain to the deep inguinal nodes. From there, drainage is to the pelvic nodes (external iliac, internal iliac, and obturator). Clinically patients with metastasis typically have palpable inguinal lymph nodes. Distant metastatic lesions to the lung, liver, bone, or brain are uncommon and are reported to occur in 1% to 10% of cases in most large series1. Microscopically, penile squamous cell carcinoma is typically well-differentiated and focally keratinizing.
Penile SCC can be characterized and subclassified by microscopic histologic features into several of the most common subtypes11:
●Usual type SCC (45 to 65 percent) – The biologic behavior of these tumors is related to size, histologic grade, depth and structure invaded, and the presence of lymphovascular or perineural invasion (which is present in approximately one-third of cases). The typical case is grade II with respect to differentiation and invades into the corpus spongiosum. Inguinal lymph node metastases are present in 25 to 40 percent of cases.
●Papillary carcinoma (2 to 15 percent) – These tumors are usually low grade (although grade II is found in some cases) but are superficially invasive into erectile tissue. Microscopically, they have evidence of both hyperkeratosis and papillomatosis. The lack of uniform papillae, absence of koilocytosis, and jagged stromal border distinguish it from either verrucous or warty carcinoma. Papillary tumors are not associated with human papillomavirus (HPV) infection. Vascular and perineural invasion, or nodal metastases are uncommon (up to 12 percent of cases).
●Warty (condylomatous) tumors (7 to 10 percent) – These are cauliflower-like cancers associated with HPV infection. The tumor is composed of a prominent fibrovascular core that exhibits papillomatous formations that penetrate the corpus cavernosum or spongiosum. The border with underlying stroma is jagged and irregular. The typical presentation is a grade II bulky slow-growing malignancy. Vascular and perineural invasion are uncommon. Inguinal node metastases are present in 17 to 25 percent of cases.
●Basaloid carcinoma (4 to 10 percent) – These are HPV related cancers that present as an ulcerated irregular mass. They are comprised of uniform and small basaloid cells with central necrosis and are deeply invasive into the corpus cavernosum or spongiosum. Mitotic figures predominate, and evidence of apoptosis is also seen microscopically. These are high-grade tumors, with more than one-half of patients exhibiting inguinal metastases.
●Verrucous carcinoma (3 to 7 percent) – These tumors are low grade and are associated with a broad pushing border instead of infiltrative growth. They are characterized by straight papillae lined by extremely well-differentiated neoplastic cells. There is hyperkeratosis on the surface, with interpapillary keratin also present. Tumors that meet the criteria of "true verrucous carcinoma" are distinct in that there is no metastatic potential. However, recurrence is common among tumors that are inadequately excised.
●Sarcomatoid (spindle cell) carcinoma (1 to 6 percent) – These are rare tumors of the penis that can be confused with malignant melanoma or sarcoma. They appear as deeply invasive, ulcerated or rounded polypoid masses. Microscopically, both SCC and spindle cell carcinoma components are seen. It may mimic features of heterologous sarcomas (eg, leiomyosarcoma, fibrosarcoma, and angiosarcoma). These tumors are the most aggressive variant of penile cancer, commonly presenting with vascular and perineural invasion in addition to inguinal and distant metastases.
In terms of prognostic characteristics, verrucous, pseudohyperplastic, andcuniculatum carcinomas have an excellent prognosis with no risk of metastatic spread to regional lymph nodes or association with disease-specific death. Warty and papillary carcinomas are associated with a metastatic rate of approximately 20% and an overall low mortality rate11. Adenosquamous carcinomas have a much higher metastatic potential (~50%) but are associated with a negligible mortality rate. The subtypes with the worst prognosis remain the sarcomatoid and basaloid carcinomas, in which metastatic spread is seen in 50-100% of patients and in whom most affected patients ultimately succumb to their disease. While histologic subtypes serve as discriminatory features for prognostic comparison, the most important pathologic predictors for metastatic spread and survival outcomes remain tumor grade, depth of invasion, and the presence of perineural invasion12.
Staging
The following is the staging for penile cancer based on The International Society of Urologic Pathology (ISUP) Grading System13,14.
Primary tumor (pT)
• pTX: Cannot be assessed
• pT0: No evidence of primary tumor
• pTa: Noninvasive localized carcinoma
• pTis: Carcinoma in situ
• pT1a: Subepithelial invasion without lymphovascular invasion, perineural invasion or grade 3
• pT1b: Subepithelial invasion with lymphovascular invasion, perineural invasion or grade 3
• pT2: Invasion of corpus spongiosum
• pT3: Invasion of corpus cavernosum
• pT4: Invasion of adjacent structures including scrotum, prostate and pubic bone
Diagnosis and Evaluation
Penile Cancer is assessed by obtaining a focused and detailed history consisting of prior circumcision, the age at which circumcision was done (i.e. pre or post-puberty) and a history of phimosis, balanitis, chronic penile inflammation, genital hygiene habits, tobacco use, trauma, sexual habits and history of HPV. It is vital to carefully inspect the entire penis, from the meatus and glans to the shaft, together with palpation of the bilateral inguinal regions. The penile lesion must be assessed noting its diameter, fixed or mobile, location with regards to the phallus and relation to relevant anatomical structures (corpus spongiosum, corpus cavernosum, urethra), and morphological features (keratinization, papillary, nodular, erythematous, neovascularity, ulcerated). Patients should be placed supine in a slight frog-leg position when examining the inguinal region. Any palpable inguinal lymph nodes should be characterized pertaining to shotty (i.e. small clinically insignificant palpable lymph nodes) versus grossly evident, mobile versus fixed, involvement of surrounding skin, and suspicion of an underlying infection (erythema, purulent drainage). Obtaining a tissue biopsy continues to remain the gold standard in assessing and confirming penile cancer. Various biopsy techniques can be employed including a punch, incisional, or excisional biopsy. Imaging techniques such as penile MRI or ultrasound can also be used to help assess primary tumor stage and suitability for penile sparing surgical approaches. Serum calcium levels should also be obtained as it may help in ascertaining whether there is a presence of bone metastasis since hypercalcemia is characteristic of all types of squamous cell cancer. If an infection appears to be more likely (eg, erythema, swelling, discharge), a four- to six-week course of antifungals or antibiotics may be indicated, depending on the clinical exam. The use of steroids is reserved for patients with a biopsy-confirmed diagnosis of an inflammatory lesion. Lesions that do not resolve after six weeks or that progress at any time during antibiotic or antifungal therapy should be biopsied.
Management of Primary Tumor
Management of primary penile cancer is guided by 2016 National Comprehensive Cancer Network (NCCN) PC guidelines.
For Tis and Ta primary penile tumors, topical therapy using imiquimod (5 percent cream applied five days a week for four to six weeks) or 5-fluorouracil (5 percent cream applied every other day for four to six weeks), together with wide local excision encompassing circumcision for penile tumors situated on the penile foreskin are the preferred primary treatment approaches15. Laser ablation involves using a laser energy source such as carbon dioxide (CO2), argon, neodymium-doped yttrium aluminium garnet (Nd:YAG), and potassium titanyl phosphate, to infiltrate and ablate the penile lesion. It is most effective against Tis and has a high success rate of regaining sexual function16,17. Patients presenting with clinical stage T1 primary penile tumors should be subdivided into lower (grade 1-2) and higher (grade 3-4) grade tumors in defining the treatment approaches they are offered. Patients with T1 low grade tumors are preferably offered penile preserving surgery consisting of a wide local excision +/- thick split thickness (STSG) or full thickness (FTSG) skin graft, with alternative options being laser ablative therapy or radiotherapy. In contrast, patients with T1 high grade tumors can be offered a host of therapeutic options including wide local excision +/- STSG or FTSG, glansectomy, partial penectomy, and total penectomy with perineal urethrostomy18. Total penectomy should only be considered if a functional penile stump cannot be preserved (typically greater than 2 cm) while insuring complete tumor eradication with negative surgical margins18. Alternative options for patients with T1 high-grade tumors include primary radiotherapy and radiation with systemic chemotherapy. Patients presenting with more locally advanced primary penile tumors (T2 or greater) are preferably recommended partial or total penectomy with perineal urethrostomy, with an alternative option for T2 only tumors being radiotherapy +/- systemic chemotherapy.
AUTHOR:
Frank Boayke, MS IV
Virginia College of Osteopathic Medicine
Penile Cancer
Introduction
Penile carcinoma in the United States is relatively uncommon compared to Asia and Africa and accounts for less than 1% of all cancers in males1. Squamous cell epithelium continues to be the most common histological pathology when it comes to penile carcinoma. Although associated with several risk factors, the lack circumcision remains a predominant predisposing factor that cause penile cancer. Squamous cell carcinoma of the penis usually has the tendency to infiltrate the underlying connective tissue and often metastasis by way of lymphatic spread. There are several modalities that can be employed in the treatment of penile cancer which may consist of surgical, laser ablation or medical treatment.
Epidemiology
The incidence of penile cancer increases abruptly in men aged 60 years or older and peaks in men aged 80 years1. Carcinoma of the penis is an uncommon malignancy in the United States, accounting for 0.4% of cancers in males2. By contrast, in some parts of Asia, Africa, and South America the incidence of carcinoma of the penis ranges from 10% to 20% of male malignancies3.
Etiology.
Men who have been circumcised rarely develop penile cancer. Circumcision has been well established as an effective prophylactic measure for penile cancer4. Data from most large series have demonstrated that penile cancer is almost never observed in individuals who are circumcised in the neonatal period5. The disease is found more frequently when circumcision is delayed until puberty. Adult circumcision offers little or no protection. No firm evidence indicates that smegma acts as a carcinogen, although this belief continues to be widely held6. Phimosis, mostly secondary to lack of circumcision, confers a 7 to 10 -fold increased risk of penile cancer4. HPV-16 and HPV-18 have been found in up to 50 percent of men with penile cancer7. Other risk factors associated with penile cancer include smoking, urinary tract infections, genital warts, urethral stricture, poor genital hygiene and chronic penile rash lasting longer than one month8.
Pathology
Primary lesions are localized to the glans, prepuce and penile shaft in 60%, 23% and 9% respectively, with the remaining lesions overlapping between these sites1. Precancerous lesions which previously consisted of carcinoma in situ, erythroplasia of Queyrat and Bowen’s disease are now grouped together and classified as penile intraepithelial neoplasm (PeIN), which is further divided into differentiated and undifferentiated subtypes. Differentiated PeIN is associated with chronic inflammatory conditions such as phimosis, whereas undifferentiated PeIN is associated with HPV infection9. Squamous cell carcinoma (SCC), together with its variants account for up to 95 percent of invasive penile cancer10. This type of cancer usually begins on the glans or inner surface of the prepuce near the coronal sulcus. Two macroscopic patterns are seen—papillary and flat. The papillary lesions simulate condyloma acuminatum and may produce a cauliflower-like fungating mass. Flat lesions appear as areas of epithelial thickening accompanied by graying and fissuring of the mucosal surface. With progression, an ulcerated papule develops. The rates of growth of the papillary and ulcerative lesions are similar, but the flat, ulcerative tumor has a tendency toward earlier nodal metastasis and is associated with poorer 5-year survival rates. The earliest route of dissemination from penile carcinoma is metastasis to the superficial inguinal nodes which drain to the deep inguinal nodes. From there, drainage is to the pelvic nodes (external iliac, internal iliac, and obturator). Clinically patients with metastasis typically have palpable inguinal lymph nodes. Distant metastatic lesions to the lung, liver, bone, or brain are uncommon and are reported to occur in 1% to 10% of cases in most large series1. Microscopically, penile squamous cell carcinoma is typically well-differentiated and focally keratinizing.
Penile SCC can be characterized and subclassified by microscopic histologic features into several of the most common subtypes11:
●Usual type SCC (45 to 65 percent) – The biologic behavior of these tumors is related to size, histologic grade, depth and structure invaded, and the presence of lymphovascular or perineural invasion (which is present in approximately one-third of cases). The typical case is grade II with respect to differentiation and invades into the corpus spongiosum. Inguinal lymph node metastases are present in 25 to 40 percent of cases.
●Papillary carcinoma (2 to 15 percent) – These tumors are usually low grade (although grade II is found in some cases) but are superficially invasive into erectile tissue. Microscopically, they have evidence of both hyperkeratosis and papillomatosis. The lack of uniform papillae, absence of koilocytosis, and jagged stromal border distinguish it from either verrucous or warty carcinoma. Papillary tumors are not associated with human papillomavirus (HPV) infection. Vascular and perineural invasion, or nodal metastases are uncommon (up to 12 percent of cases).
●Warty (condylomatous) tumors (7 to 10 percent) – These are cauliflower-like cancers associated with HPV infection. The tumor is composed of a prominent fibrovascular core that exhibits papillomatous formations that penetrate the corpus cavernosum or spongiosum. The border with underlying stroma is jagged and irregular. The typical presentation is a grade II bulky slow-growing malignancy. Vascular and perineural invasion are uncommon. Inguinal node metastases are present in 17 to 25 percent of cases.
●Basaloid carcinoma (4 to 10 percent) – These are HPV related cancers that present as an ulcerated irregular mass. They are comprised of uniform and small basaloid cells with central necrosis and are deeply invasive into the corpus cavernosum or spongiosum. Mitotic figures predominate, and evidence of apoptosis is also seen microscopically. These are high-grade tumors, with more than one-half of patients exhibiting inguinal metastases.
●Verrucous carcinoma (3 to 7 percent) – These tumors are low grade and are associated with a broad pushing border instead of infiltrative growth. They are characterized by straight papillae lined by extremely well-differentiated neoplastic cells. There is hyperkeratosis on the surface, with interpapillary keratin also present. Tumors that meet the criteria of "true verrucous carcinoma" are distinct in that there is no metastatic potential. However, recurrence is common among tumors that are inadequately excised.
●Sarcomatoid (spindle cell) carcinoma (1 to 6 percent) – These are rare tumors of the penis that can be confused with malignant melanoma or sarcoma. They appear as deeply invasive, ulcerated or rounded polypoid masses. Microscopically, both SCC and spindle cell carcinoma components are seen. It may mimic features of heterologous sarcomas (eg, leiomyosarcoma, fibrosarcoma, and angiosarcoma). These tumors are the most aggressive variant of penile cancer, commonly presenting with vascular and perineural invasion in addition to inguinal and distant metastases.
In terms of prognostic characteristics, verrucous, pseudohyperplastic, andcuniculatum carcinomas have an excellent prognosis with no risk of metastatic spread to regional lymph nodes or association with disease-specific death. Warty and papillary carcinomas are associated with a metastatic rate of approximately 20% and an overall low mortality rate11. Adenosquamous carcinomas have a much higher metastatic potential (~50%) but are associated with a negligible mortality rate. The subtypes with the worst prognosis remain the sarcomatoid and basaloid carcinomas, in which metastatic spread is seen in 50-100% of patients and in whom most affected patients ultimately succumb to their disease. While histologic subtypes serve as discriminatory features for prognostic comparison, the most important pathologic predictors for metastatic spread and survival outcomes remain tumor grade, depth of invasion, and the presence of perineural invasion12.
Staging
The following is the staging for penile cancer based on The International Society of Urologic Pathology (ISUP) Grading System13,14.
Primary tumor (pT)
• pTX: Cannot be assessed
• pT0: No evidence of primary tumor
• pTa: Noninvasive localized carcinoma
• pTis: Carcinoma in situ
• pT1a: Subepithelial invasion without lymphovascular invasion, perineural invasion or grade 3
• pT1b: Subepithelial invasion with lymphovascular invasion, perineural invasion or grade 3
• pT2: Invasion of corpus spongiosum
• pT3: Invasion of corpus cavernosum
• pT4: Invasion of adjacent structures including scrotum, prostate and pubic bone
Diagnosis and Evaluation
Penile Cancer is assessed by obtaining a focused and detailed history consisting of prior circumcision, the age at which circumcision was done (i.e. pre or post-puberty) and a history of phimosis, balanitis, chronic penile inflammation, genital hygiene habits, tobacco use, trauma, sexual habits and history of HPV. It is vital to carefully inspect the entire penis, from the meatus and glans to the shaft, together with palpation of the bilateral inguinal regions. The penile lesion must be assessed noting its diameter, fixed or mobile, location with regards to the phallus and relation to relevant anatomical structures (corpus spongiosum, corpus cavernosum, urethra), and morphological features (keratinization, papillary, nodular, erythematous, neovascularity, ulcerated). Patients should be placed supine in a slight frog-leg position when examining the inguinal region. Any palpable inguinal lymph nodes should be characterized pertaining to shotty (i.e. small clinically insignificant palpable lymph nodes) versus grossly evident, mobile versus fixed, involvement of surrounding skin, and suspicion of an underlying infection (erythema, purulent drainage). Obtaining a tissue biopsy continues to remain the gold standard in assessing and confirming penile cancer. Various biopsy techniques can be employed including a punch, incisional, or excisional biopsy. Imaging techniques such as penile MRI or ultrasound can also be used to help assess primary tumor stage and suitability for penile sparing surgical approaches. Serum calcium levels should also be obtained as it may help in ascertaining whether there is a presence of bone metastasis since hypercalcemia is characteristic of all types of squamous cell cancer. If an infection appears to be more likely (eg, erythema, swelling, discharge), a four- to six-week course of antifungals or antibiotics may be indicated, depending on the clinical exam. The use of steroids is reserved for patients with a biopsy-confirmed diagnosis of an inflammatory lesion. Lesions that do not resolve after six weeks or that progress at any time during antibiotic or antifungal therapy should be biopsied.
Management of Primary Tumor
Management of primary penile cancer is guided by 2016 National Comprehensive Cancer Network (NCCN) PC guidelines.
For Tis and Ta primary penile tumors, topical therapy using imiquimod (5 percent cream applied five days a week for four to six weeks) or 5-fluorouracil (5 percent cream applied every other day for four to six weeks), together with wide local excision encompassing circumcision for penile tumors situated on the penile foreskin are the preferred primary treatment approaches15. Laser ablation involves using a laser energy source such as carbon dioxide (CO2), argon, neodymium-doped yttrium aluminium garnet (Nd:YAG), and potassium titanyl phosphate, to infiltrate and ablate the penile lesion. It is most effective against Tis and has a high success rate of regaining sexual function16,17. Patients presenting with clinical stage T1 primary penile tumors should be subdivided into lower (grade 1-2) and higher (grade 3-4) grade tumors in defining the treatment approaches they are offered. Patients with T1 low grade tumors are preferably offered penile preserving surgery consisting of a wide local excision +/- thick split thickness (STSG) or full thickness (FTSG) skin graft, with alternative options being laser ablative therapy or radiotherapy. In contrast, patients with T1 high grade tumors can be offered a host of therapeutic options including wide local excision +/- STSG or FTSG, glansectomy, partial penectomy, and total penectomy with perineal urethrostomy18. Total penectomy should only be considered if a functional penile stump cannot be preserved (typically greater than 2 cm) while insuring complete tumor eradication with negative surgical margins18. Alternative options for patients with T1 high-grade tumors include primary radiotherapy and radiation with systemic chemotherapy. Patients presenting with more locally advanced primary penile tumors (T2 or greater) are preferably recommended partial or total penectomy with perineal urethrostomy, with an alternative option for T2 only tumors being radiotherapy +/- systemic chemotherapy.
AUTHOR:
Frank Boayke, MS IV
Virginia College of Osteopathic Medicine
CRP and SCC-Ag levels were significantly associated with lymph node metastasis, pathological tumor stage and disease specific survival in a retrospective study of 124 patients. (1) One study of buried penis showed 7% had SCC and 35% had premalignant penile lesions. (22)