Department of Urology, Royal Surrey County Hospital, Guildford, UK
Correspondence to Abdullah Zreik, MD, MRCS, MSc, Department of Urology, Royal Surrey County Hospital, Egerton Road, Guildford, Surrey, GU2 7XX, UK Tel: +44 1483464045; fax: +44 1483402718; e-mail: email@example.com
Received December 6, 2012
Accepted December 26, 2012
Background: Penile cancer is a rare malignancy that affects 1 in 100 000 men. Penile intraepithelial neoplasia (PeIN) is a premalignant lesion that can affect any part of the penile surface. PeIN shows different degrees of dysplasia and is therefore classified into PeIN 1, 2, and 3. PeIN 3 is also known as carcinoma in situ. PeIN is believed to have a close association with human papilloma virus infection. Treatment of PeIN can potentially prevent progression to penile cancer. This study aimed to report on the management and follow-up outcomes for patients diagnosed with PeIN.
Materials and methods: A total of 38 consecutive patients diagnosed with PeIN 3 were included in this review. Our institutional Penile Cancer database was used for data collection. We report on the demographics, risk factors, surgical management, recurrence rates, and follow-up outcomes.
Results: The median age of the patients was 63 years (range 24–86). Risk factors were present in 81.5% of patients. 81.6% of the patients had received surgical treatment with radical circumcision, wide local excision, and glans resurfacing. Topical treatment with 5-fluorouracil or imiquimod was used in 18.4% of patients. Five patients had recurrence of PeIN 3 and required further treatment. After a mean follow-up of 69 months (range 8–298), the cancer-free rate was 100%.
Conclusion: Surgical treatment of PeIN 3 leads to excellent outcomes and frequent follow-up is required.
Penile cancer is a rare malignancy, accounting for 0.4–0.6% of all malignancies in Western Europe and the USA 1. It has a peak incidence at the age of 67 years 2. Penile intraepithelial neoplasia (PeIN) is a premalignant lesion that can affect the glans, prepuce, or the shaft of the penis. On the basis of the degree of dysplasia, PeIN is divided into PeIN 1 (mild), PeIN 2 (moderate), and PeIN 3 (severe). PeIN 3 is otherwise known as carcinoma in situ, which in turn is eponymously known as Erythroplasia of Queyrat and Bowen’s disease. Both have the same histological appearances, differing in the site of the pathology. Lesions that arise from the mucosal surfaces of the penis (glans and prepuce) are known as Erythroplasia of Queyrat, whereas Bowen’s disease is a term reserved for lesions affecting the skin of the penile shaft 3. PeIN 2 is more synonymous with Bowenoid papulosis, which is characterized by mild to moderate dysplasia.
There are two theories explaining the development of PeIN. The first one pertains to the strong link to human papilloma virus (HPV) infection, with a reported rate of HPV in 80% of Bowen’s disease cases, 88% of Erythroplasia of Queyrat cases, and 70% in Bowenoid papulosis 4–6. The second route of development of PeIN is attributed to chronic inflammatory conditions, mainly Lichen Sclerosus et Atrophicus (LS), which was previously known as Balanitis Xerotica Obliterans (BXO). Diagnosis and differentiation between these lesions is important as the rate of development of penile cancer is 30% in Erythroplasia of Queyrat, 5% in Bowen’s disease, and 1% in Bowenoid papulosis 7,8.
The diagnosis of PeIN can be challenging as it is often difficult to distinguish benign dermatological lesions such as Zoon’s balanitis without the need for biopsy. The morphological features of PeIN can be classified as flat lesions, leukoplakic lesions, pigmented papules, or a mixture of the three 9.
The noninvasive nature of PeIN allows for curative penile-preserving therapy. The treatment options include topical chemotherapy, immunotherapy, laser treatment, photodynamic therapy, and surgical excision 10. Penile-sparing techniques are recommended by the European Association of Urology (EAU) guidelines for PeIN 11. Circumcision is an essential part of the treatment of PeIN 10. The recurrence of the disease after nonsurgical treatments can be as high as 30% 12–14; therefore, surgical excision is often advocated as treatment. Careful long-term follow-up with frequent evaluation of the penile surface is essential as patients may require a repeat or more aggressive treatment.
It is imperative to report on case series of PeIN as it is probably underdiagnosed 15. The aim of this study is to report the findings of case series from a tertiary penile cancer center.
Materials and methods
Thirty-eight consecutive patients who were diagnosed with PeIN 3 were included in this review. Patients who had PeIN 3 with a simultaneous diagnosis of penile cancer were not included. The Royal Surrey Penile Cancer database was used for data collection. Patients were seen in the clinic 3 monthly for the first year, 6 monthly for the second year, and yearly thereafter. Visual inspection was carried out on each visit with selective 5% acetic acid staining 16. We report on the demographics, risk factors, histopathological findings, surgical management, and outcomes.
A total of 38 patients were available for analysis. The median age of patients at the time of diagnosis was 63 years (range 24–86). Three patients had been circumcised before presentation. PeIN 3 was located in the glans in 20 patients, the prepuce in 11, both the glans and the prepuce in four, and on the penile shaft skin in three (Figs 1–3).
Risk factors were found in 31 patients (81.5%). Twenty-one patients had evidence of viral infection on histology, seven had a background of LS, and four had phimosis. One patient had both LS and viral warts.
Fourteen patients were treated with radical circumcision and 17 with wide local excision and glans resurfacing. Topical treatment with 5-fluorouracil or imiquimod was used in seven patients. The topical treatment was applied on alternate days for 4 weeks. Four patients who were treated topically had recurrence of the lesion and required further surgical treatment (Table 1). Seven patients had positive surgical margins. However, none of these patients had recurrence of the disease at follow-up. A total of five (13.2%) patients had recurrent disease, four had topical treatment, and one had wide local excision. The latter had recurrence at a different site on the penile shaft skin. The recurrent disease required further surgical treatment with wide local excision in all of the seven patients.
The median follow-up was 69 months (range 8–298), with a mean follow-up of 75 months. Two patients died because of unrelated conditions whereas the remaining 36 continue to be followed up, with a cancer-free rate of 100%. All glans-resurfacing procedures were successful, with no reported complications. In particular, none of the patients developed meatal stenosis or graft loss.
Most of the evidence related to the management of PeIN is based on retrospective case series with small numbers of cases. This paucity of data is because of few cases being diagnosed. Our sample size is comparable with other studies reporting different aspects of the management of PeIN 15,17.
The median age of our patients (63 years) is higher compared with the median age in other studies 15,17. Wikström and colleagues reported on patients with genital HPV infection attending venereological clinics; therefore, this cohort was younger. The median age in our study is more likely to be representative because it reports on all patients diagnosed with PeIN 3 in the region referred to our center.
PeIN is strongly associated with HPV infection. Wikström et al. 15 reported that 16% of patients who have HPV were found to have PeIN. Moreover, HPV is present in 80% of patients with Bowen’s disease and 88% of patients with Erythroplasia of Queyrat 4,5. Although eight of our patients were already known to have evidence of viral infection, subtype testing for HPV was not a routine part of our investigation policy. These data are now being prospectively collected. The histopathologists reported the presence of viral induced changes in 21 patients (55.3%).
Most of our patients (35/38) had PeIN on the glans or the prepuce, whereas three patients (7.9%) had PeIN on the shaft. This could suggest that PeIN of the glans or prepuce (Erythroplasia of Queyrat) is more prevalent. However, because of the sample size of our cohort, it is difficult to extrapolate this accurately to the wider population. Nevertheless, if the aetiology is either HPV infection or LS, the predominant location would be consistent with those theories.
It is reported that the rate of transformation of PeIN 3 into penile cancer is 30% 5. Therefore, treatment options that have the lowest recurrence rates are advantageous. Recurrence rates can be as high as 30% when using photodynamic therapy, laser therapy, or topical chemotherapy 12,13. In contrast, Shabbir et al. 17 reported a recurrence rate of only 4% following surgical excision and resurfacing. The total recurrence rate in our cohort was 13.8%, but if the treatment was divided into surgical and topical treatment, the recurrence rates would be 57% for topical treatment and 3.4% for surgical excision. This shows a clear advantage for the surgical management of PeIN 3.
Long-term follow-up is essential in studies reporting premalignant conditions. Our study reports a median follow-up of 69 months (range 8–298). This is longer than most of the other published studies of PeIN. Regular reviews of patients following treatment allow early detection of recurrence and prompt further management. This is likely to improve survival rates and ensure good control of PeIN 3.
PeIN 3 is a noninvasive penile premalignant condition that can recur and progress into invasive malignancy. We report good local control with surgical techniques, resulting in very low recurrence rates and a cancer-free rate of 100%. Surgical resection appears to be superior to topical treatments. Patients should receive regular long-term follow-up to diagnose any recurrence and improve survival. Topical treatments should be reserved for low grades of dysplasia such as PeIN 1 or PeIN 2.
Conflicts of interest
There are no conflicts of interest.
1. Parkin D, Muir CS. Cancer incidence in five countries. Comparability and quality of data. IARC Sci Publ. 1992;120:45–173
2. Frisch M, Friis S, Kruger Kjaer S, Melbye M. Falling incidence of penis cancer in an uncircumcised population (Denmark 1943–90). BMJ. 1995;311:1471
3. Porter WM, Francis N, Hawkins D, Dinneen M, Bunker CB. Penile intraepithelial neoplasia: clinical spectrum and treatment of 35 cases. Br J Dermatol. 2002;147:1159–1165
4. Ikenberg H, Gissmann L, Gross G, Grussendorf-Conen EI, zur Hausen H. Human papillomavirus type-16-related DNA in genital Bowen’s disease and in bowenoid papulosis. Int J Cancer. 1983;32:563–565
5. Wieland U, Jurk S, Weissenborn T, Krieg T, Pfister H, Ritzkowsky A. Erythroplasia of queyrat: coinfection with cutaneous carcinogenic human papillomavirus type 8 and genital papillomaviruses in a carcinoma in situ.
J Invest Dermatol. 2000;115:396–401
6. Von Krogh G, Horenblas S. Diagnosis and clinical presentation of premalignant lesions of the penis. Scand J Urol Nephrol Suppl. 2000;34:201–214
7. Mikhail GR. Cancers, precancers, and pseudocancers on the male genitalia. A review of clinical appearances, histopathology, and management. J Dermatol Surg Oncol. 1980;6:1027–1035
8. Lucia MS, Miller GJ. Histopathology of malignant lesions of the penis. Urol Clin North Am. 1992;19:227–246
9. Markos AR. The management of penile intraepithelial neoplasia in genitourinary medicine. Int J STD AIDS. 2003;14:314–319
10. Shabbir M, Watkin N, Muneer AMuneer A. Premalignant lesions of the penis. Textbook of penile cancer. 20121st ed. London, UK Springer-Verlag:103–124
12. Morales A, Chin JL, Ramsey EW, Newling DWW. Laser therapy for carcinoma in situ
of the penis. J Urol. 2001;166:1670–1671
13. Salim A, Leman JA, McColl JH, Chapman R, Morton CA. Randomized comparison of photodynamic therapy with topical 5-fluorouracil in Bowen’s disease. Br J Dermatol. 2003;148:539–543
14. Paoli J, Ternesten Bratel A, Löwhagen G-B, Stenquist B, Forslund O, Wennberg A-M. Penile intraepithelial neoplasia: results of photodynamic therapy. Acta Derm Venereol. 2006;86:418–421
15. Wikström A, Hedblad M-A, Syrjänen S. Penile intraepithelial neoplasia: histopathological evaluation, HPV typing, clinical presentation and treatment. J Eur Acad Dermatol Venereol. 2012;26:325–330
16. Frega A, French D, Pace S, Maranghi L, Palazzo A, Iacovelli R, et al. Prevalence of acetowhite areas in male partners of women affected by HPV and squamous intra-epithelial lesions (SIL) and their prognostic significance. A multicenter study. Anticancer Res. 2006;26(4B):3171–3174
17. Shabbir M, Muneer A, Kalsi J, Shukla CJ, Zacharakis E, Garaffa G, et al. Glans resurfacing for the treatment of carcinoma in situ
of the penis: surgical technique and outcomes. Eur Urol. 2011;59:142–147