Pre-cancerous Penile Lesions

European Urological Review, 2010;5(1):23-6

Pathological Studies
A heterogeneous group of abnormalities and pre-cancerous lesions affect the penis. The pre-cancerous lesions consist of cellular alterations of the squamous epithelium: proliferation, loss of polarity and nuclear atypia of varying degrees.1,2 Various terms, such as high-grade squamous intraepithelial lesion (HSIL), severe dysplasia or intraepithelial penile neoplasia (PeIN III), can be used synonymously with carcinoma in situ. Recently, European Association of Urology (EAU) guidelines on penile cancer reported three categories of pre-malignant lesion, each with a different probability of developing into squamous cell carcinoma (SCC) of the penis:

  • lesions sporadically associated with SCC of the penis (cutaneous horn of the penis and Bowenoid papulosis [BP]);
  • lesions at an intermediate risk of progression to SCC (balanitis xerotica obliterans/lichen sclerosus [LS]); and
  • lesions at a high risk of developing into SCC of the penis (penile intraepithelial neoplasia occurring as Bowen’s disease [BD] or erythroplasia of Queyrat [EQ]).3

These last two designations concern well-circumscribed scaly lesions of the skin of the shaft (BD) and irregular velvety red lesions of the glans (EQ). Both are human papillomavirus (HPV)-related lesions and microscopically have the features of carcinoma in situ.

The few pathological studies of pre-cancerous penile lesions are mostly related to carcinoma in situ and HPV, and information about low-grade atypical lesions is limited.4 Recently, morphological studies have reported precursor neoplastic lesions: squamous hyperplasia (SH), low-grade squamous intraepithelial lesion (LSIL) and HSIL. SH is observed in penile specimens with squamous, papillary or verrucous carcinoma, while SH is rarely observed associated with warty or basaloid carcinoma;5 macroscopically, it presents as a flat or slightly elevated white plaque.6 The lesion may be a linear pearly-white thickening on the cut surface. SH is characterised by acanthotic thickening (>15 layers) of the epithelium of the glans, coronal sulcus or foreskin, and lacks cytological atypia. LSIL and HSIL may present as single or multiple clinically localised lesions and may be detected by peniscopy.4,7 Microscopically, in LSIL atypical cells involve the basal, parabasal or lower third of the epithelium, while HSIL has atypical cells in the middle to upper third of the squamous epithelium.2,5 LSIL in its typical form, the differentiated squamous or simplex type, presents as keratinised, mature, flat lesions with atypical cells in the lower third of the epithelium. Other less frequently occurring patterns are warty (condylomatous), basaloid and differentiated papillary.5 HSILs are more heterogeneous, with most cases being keratinised squamous, designated as squamous or simplex type, with enlarged pleomorphic and hyperchromatic nuclei, thick nuclear membranes, prominent nucleoli and coarse chromatin. The epithelium presents normally, with abnormal mitosis and a high proliferative index (see Figure 1). In one-third of cases HSILs are basaloid, warty (condylomatous) or mixed (warty–basaloid). Correlation of special types of invasive carcinoma with subtypes of SIL revealed morphological correspondence between the invasive tumour and the associated intraepithelial lesion.

In a study of 288 carcinomas the entire surface of the penile specimen was microscopically observed to describe the morphological features of all epithelial alterations and to investigate their relationship with early carcinoma and subtypes of invasive carcinoma.5 SH, the most common lesion, was found in 83% of cases. In many cases the authors reported a morphological transition from SH to LSIL, while the association between SH and HSIL was infrequent and discontinuous. LSIL was associated with invasive SCC in 57% of cases, and HSIL in 44%. In 62% of cases more than one associated lesion was present. The high frequency of squamous hyperplasia and LSIL and the preferential association with usual, verrucous and papillary carcinomas suggest that, despite its benign appearance, SH may be a precursor of the aforementioned carcinomas. The association between the basaloid, warty or mixed forms of HSIL with their invasive counterparts indicates that these are their likely precursors.4,5

  1. Young RH, Srigley JR, Amin MB, et al., Tumors of the Prostate Gland, Seminal Vesicles, Male Urethra, and Penis, AFIP Fascicle, 3rd series, Washington DC, 2000.
  2. Cubilla AL, Meijer CJLM, Young RH, Morphological features of epithelial abnormalities and precancerous lesions of the penis, Scand J Urol Nephrol Suppl., 2000;205:215–19.
  3. Pizzocaro G, Algaba F, Horenblas S, et al., EAU Penile Cancer Guidelines 2009, Eur Urol, 2010;57:1002–12.
  4. Velazquez EF, Cubilla AL, Penile squamous cell carcinoma: anatomic, pathologic and viral studies in Paraguay (1993–2007). Penile squamous cell carcinoma: anatomic, pathologic and viral studies in Paraguay (1993–2007), Anal Quant Cytol Hystol, 2007;29:185–98.
  5. Cubilla AL, Velazquez EF, Young RH, Epithelial lesions associated with invasive penile squamous cell carcinoma: a pathologic study of 288 cases, Int J Surg Pathol, 2004;12: 351–64.
  6. Cubilla AL, Barreto JE, Ayala G, The penis. In: Sternberg SS (ed.), Diagnostic Surgical Pathology, Philadelphia, PA: William & Wilkins, 1999;2035–64.
  7. Barraso R, De Brux J, Croissant O, et al., High prevalence of papillomavirus-associated penile intraepithelial neoplasia in sexual partners of women with cervical intraepithelial neoplasia, N Engl J Med, 1987;317:916–23.
  8. Bandieramonte G, Colecchia M, Mariani L, et al., Peniscopically controlled CO2 laser excision for conservative treatment of in situ and T1 penile carcinoma: report on 224 patients, Eur Urol, 2008;54:875–84.
  9. Stumer A, Balanitis xerotica obliterans (post-operationem) und ihre Beziehungen zur Kraurosis glandis et praeputii penis, Rch Dermato l Syph, 1928;156:613–23.
  10. Velazquez EF, Cubilla AL, Lichen sclerosus in 68 patients with squamous cell carcinoma of the penis: frequent atypias and correlation with special carcinoma variants suggests a precancerous role, Am J Surg Pathol, 2003;27: 1448–53.
  11. Vilmer C, Cavelier-Balloy B, Verola O, et al., J Am Acad Dermatol, 2009;62:284–90.
  12. von Krogh G, Horenblas S, Diagnosis and clinical presentation of premalignant lesions of the penis, Scand J Urol Nephrol, 2000;(Suppl. 205):201–14.
  13. Powell J, Robson A, Cranston D, et al., High incidence of lichen sclerosus in patients with squamous cell carcinoma of the penis, Br J Derm, 2001;145:85–9.
  14. Pietrzak P, Hadway P, Corbishley CM, et al., Is the association between balanitis xerotica obliterans and penile carcinoma underestimated? BJU Int, 2006;98:74–6.
  15. Nasca MR, Innocenzi D, Micali G, Penile cancer among patients with genital lichen sclerosus, J Am Acad Dermatol, 1999;41:911–14.
  16. Lesourd A, Anatomo-pathologic report and classifications of penile carcinomas, Prog Urol, 2005;15:801–4.
  17. Powell JJ, Wojnarowska F, Lichen sclerosus, Lancet, 1999;353:1777–83.
  18. Cubilla AL, Reuter V, Velazquez EF, et al., Histologic classification of penile carcinoma and its relation to outcome in 61 patients with primary resection, Int J Surg Pathol, 2001;9:11–20.
  19. Griffiths TRL, Mellon JK, Human papillomavirus and urological tumours: I. Basic science and role in penile cancer, BJU Int, 1999;84:579–86.
  20. Agoff SN, Lin P, Morihara J, et al., p16(INK4a) expression correlates with degree of cervical neoplasia: a comparison with Ki-67 expression and detection of high-risk HPV types, Mod Pathol, 2003;16:665–73.
  21. Chaux A, Pfannl R, Lloveras B, et al., Distinctive association of p16INK4a overexpression with penile intraepithelial neoplasia depicting warty and/or basaloid features: a study of 141 cases evaluating a new nomenclature, Am J Surg Pathol, 2010;34:385–92.
  22. Rubin MA, Kleter B, Zhou M, Detection and typing of human papillomavirus DNA in penile carcinoma: evidence for multiple independent pathways of penile carcinogenesis, Am J Pathol, 2001;159:1211–18.
  23. Gregoire L, Cubilla A, Reuter V, et al., Preferential association of human papillomavirus with high-grade histologic variants of penile-invasive squamous cell carcinoma, J Natl Cancer Inst, 1995; 87:1705–9.
  24. IARC Monograph on the Evaluation of Carcinogenic Risks to Humans, Lyon 2007 vol. 90.
  25. Miralles-Guri C, Bruni L, Cubilla AL, et al., Human papillomavirus prevalence and type distribution in penile carcinoma, J Clin Pathol, 2009;62:870–78.
  26. Bleeker MC, Heideman DA, Pawita M, et al., Penile cancer: epidemiology, pathogenesis and prevention, World J Urol, 2009;27:141–50.
  27. Maden C, Sherman KJ, Beckmann AM, et al., History of circumcision, medical conditions, and sexual activity and risk of penile cance, J Natl Cancer Inst, 1993;85:19–24.
  28. Mahto M, Nathan M, O'Mahony C, et al., More than a decade on: review of the use of imiquimod in lower anogenital intraepithelial neoplasia, Int J STD & AIDS, 2010;21:8–16.
  29. Hadway P, Corbishley CM, Watkin NA, et al., Total glans resurfacing for premalignant lesions of the penis: initial outcome data, Br J Urol Int, 2006;98:532–6.
  30. Shindel AW, Mann MW, Lev RY, et al., Mohs micrographic surgery for penile cancer: management and long-term follow up, J Urol, 2007;178:1980–85.
  31. Frimberger D, Hungerhuber E, Zaak D, et al., Penile carcinoma. Is Nd:YAG laser therapy radical enough, J Urol, 2002;168:2412–21.
  32. Meijer RP, Boon TA, van Venrooij GE, et al. Long-term follow-up after laser therapy for penile carcinoma, Urology, 2007;69:759–62.
  33. Colecchia M, Nicolai N, Secchi P, et al., pT1 penile squamous cell carcinoma: a clinicopathologic study of 56 cases treated by CO2 laser therapy, Anal Quant Cytol Histol, 2009;31:153–60.
  34. Reisinger KS, Block SL, Lazcano-Ponce E, et al., Safety and persistent immunogenicity of a quadrivalent human papillomavirus types 6, 11, 16, 18 L1 virus-like particle vaccine in preadolescents and adolescents: a randomized controlled trial, Pediatr Infect Dis J, 2007;(3):201–9.
  35. Palefsky JM, Human papillomavirus-related disease in men: not just a women’s issue, J Adolesc Health, 2010;46 (Suppl. 4):S12–19.