This is usually a squamous cell carcinoma (SCC). There is a well differentiated verrucous type called a Buschke-Löwenstein tumour.¹ There is a tendency for early signs to be ignored so that they often present late and conservative surgery is impossible. The psychological impact of the disease is highly significant. The cause of penile SCC is unclear but human papillomavirus (HPV) appears to be an important causative factor.

Epidemiology

Penile carcinoma is rare and affects mainly elderly patients with the highest incidence in patients aged 75-84 years.² Epidermoid carcinoma is the most common histological type. The less common well differentiated type presents in a younger age group and about two-thirds present before the age of 50. The risk of penile carcinoma shows marked geographical variation with high rates being reported in Central and South America, parts of Asia and Africa. In western societies it represents about 2% of cancers of the male genital system and less than 1% of all male cancers. The rate is about 1 in 100,000. 95% of penile cancer is squamous cell carcinoma (SCC).

Risk factors and premalignant conditions

• Carcinoma in situ may progress to invasive carcinoma in 10-30% of cases. The problem is knowing which will progress.
• Bowen's disease is rare and most often occurs in elderly men. It is usually on the shaft of the penis and appears as a solitary, dull-red plaque with areas of crusting and oozing. Ulceration or papillomatous growth suggests that it has turned invasive as it does in approximately 5% of patients. Bowen's disease is treated with local excision.
• Queyrat's erythroplasia also tends to affect elderly, uncircumcised men. It appears as a solitary, sharply defined, bright red, glistening, velvety, nontender, plaque on the glans, the inner surface of the prepuce, or the coronal sulcus. Invasive transformation is more common than in Bowen's disease, with an incidence of 10-33%. Ulceration or papillary outgrowths are signs of the disease. Treatment is with circumcision and 5-fluorouracil (5-FU) cream.
• Bowenoid papulosis occurs mostly on the shaft of the penis in circumcised young men. It appears as multiple, small, slightly elevated, red or violet, slightly scaly or warty papules, which sometimes coalesce into large plaques. Histology is typical of Bowen's disease and it is associated with human papillomavirus (HPV) infection. Lesions may remain static, spontaneously regress, or progress to Bowen's disease.
• HPV infection: polymerase chain reaction (PCR) studies have shown a high incidence of HPV, especially type 16. It has been found in 50% of invasive cancer and 90% of carcinoma in situ. Subclinical infection is common, especially in the sexual partners of women with cervical carcinoma, invasive or in situ.³
• Other dermatological conditions: The role of such conditions as lichen planus and leukoplakia is disputed. There is an association between phimosis and risk of malignancy especially with balanitis xerotica obliterans.
• Other risk factors include exposure to chemicals such as insecticides, fertilisers, styrene and acrylonitrile as well as cigarette smoking.⁴ Ultraviolet radiation as in psoralen combined with ultraviolet A (PUVA) increases risk as does immune suppression.

Circumcision in early life appears to offer protection against penile malignancy, especially in those with poor personal hygiene. Retention of smegma causes phimosis and may lead on to malignant change. Those who are uncircumcised but attentive to personal hygiene are probably at no greater risk.

Presentation

Around half of presenting patients have had the lesion for 6 months or more.

• It can occur anywhere on the penis but about 50% start on the glans, 20% on the prepuce and 10% on both
• Itching or a burning sensation especially under the prepuce are common features. There may be ulceration of the glans or prepuce and this may progress to a mass.
• Tumours may be papillary and single or multiple and likely to coalesce, raised and possibly necrose or ulcerate. Flat lesions appear as small superficial ulcers.
• If ignored the tumour will destroy the glans and prepuce and invade the shaft of the penis. It may obstruct the urethra and cause fistulae
• Lymphatic spread is first to the deep and superficial inguinal nodes and then the pelvic nodes. Distant metastasis is usually to the liver or lung.
• Enlarged lymph nodes may also be due to secondary infection and a foul, purulent discharge may be noted.
• Verrucous carcinoma tends to grow and infiltrate rather than to produce distant spread.

Differential diagnosis

Metastatic skin cancer and genital warts.

Investigations

Biopsy is required to confirm the diagnosis. Imaging is required for staging and planning treatment.

Staging

Staging is important in planning treatment.
The histology is classified as grade I to IV based on cellular atypia and this dictates behaviour of the tumour and hence adds to prognosis.⁵ Staging may be by the Jackson classification or TNM classification of malignant tumours.

Management

• Surgical procedures may be local excision (Mohs micrographic surgery for small and superficial invasive carcinomas located on the glans or near the preputial sulcus has been used with good results), circumcision, glansectomy, partial penectomy, total penectomy, and demasculinisation. The psychological implications of all but the first two are enormous. The last 3 procedures may be accompanied by lymph node dissection.
• Verrucous carcinoma may be treated with cryosurgery, with or without 5-fluorouracil (5-FU).
• Medical therapy and radiotherapy may be needed. Medical therapy can be local or systemic. Drugs used include bleomycin, methotrexate, cisplatin, vincristine, and 5-FU and interferons may be of value.
• Careful follow-up is required, especially over the first year when the risk of recurrence is greatest.

Prognosis

Survival is very much related to lymph node status. It is unrelated to human papillomavirus (HPV) status.⁶ The 5 years' survival is:⁷

• Stage I, T1-3, N0, M0: 93%
• Stage II, T1-3, N1-2, M0: 55%
• Stage III, T4 or N3 or M1: 30%

Prevention

Circumcision would appear to offer protection but personal hygiene is more important. Not only does circumcision protect against carcinoma of the penis but, in men who have had multiple partners, it reduces the risk of cervical carcinoma in the current partner.⁸ Preventative measures include prevention of phimosis, treatment of chronic inflammatory conditions, limiting psoralen combined with ultraviolet A (PUVA) treatment, smoking cessation and prophylactic prevention of human papillomavirus (HPV) infection.⁹ Use of condoms may be a preventative factor.^10,11 Lesions should be reported early and the possibility of malignancy given due consideration.

Document references

1. Schwartz RA; Verrucous carcinoma of the skin and mucosa. J Am Acad Dermatol. 1995 Jan;32(1):1-21; quiz 22-4. [abstract]
2. Rando Sous A, Perez-Utrilla Perez M, Aguilera Bazan A, et al; A review of penile cancer. Adv Urol. 2009:415062. Epub 2010 Feb 16. [abstract]
3. Bleeker MC, Hogewoning CJ, Van Den Brule AJ, et al; Penile lesions and human papillomavirus in male sexual partners of women with cervical intraepithelial neoplasia. J Am Acad Dermatol. 2002 Sep;47(3):351-7. [abstract]
4. Harish K, Ravi R; The role of tobacco in penile carcinoma. Br J Urol. 1995 Mar;75(3):375-7. [abstract]
5. Cubilla AL, Reuter V, Velazquez E, et al; Histologic classification of penile carcinoma and its relation to outcome in 61 patients with primary resection. Int J Surg Pathol. 2001 Apr;9(2):111-20. [abstract]
6. Bezerra AL, Lopes A, Santiago GH, et al; Human papillomavirus as a prognostic factor in carcinoma of the penis: analysis of 82 patients treated with amputation and bilateral lymphadenectomy. Cancer. 2001 Jun 15;91(12):2315-21. [abstract]
7. Horenblas S, van Tinteren H; Squamous cell carcinoma of the penis. IV. Prognostic factors of survival: analysis of tumor, nodes and metastasis classification system. J Urol. 1994 May;151(5):1239-43. [abstract]
8. Castellsague X, Bosch FX, Munoz N, et al; Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. N Engl J Med. 2002 Apr 11;346(15):1105-12. [abstract]
9. Dillner J, von Krogh G, Horenblas S, et al; Etiology of squamous cell carcinoma of the penis. Scand J Urol Nephrol Suppl. 2000;(205):189-93. [abstract]
10. Bleeker MC, Hogewoning CJ, Voorhorst FJ, et al; Condom use promotes regression of human papillomavirus-associated penile lesions in male sexual partners of women with cervical intraepithelial neoplasia. Int J Cancer. 2003 Dec 10;107(5):804-10. [abstract]
11. Hogewoning CJ, Bleeker MC, van den Brule AJ, et al; Condom use promotes regression of cervical intraepithelial neoplasia and clearance of human papillomavirus: a randomized clinical trial. Int J Cancer. 2003 Dec 10;107(5):811-6. [abstract]

Internet and further reading

• Micali G et al; Penile Squamous Cell Carcinoma, eMedicine, Mar 2009

Acknowledgements