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

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