Pre-cancerous Penile Lesions
allow the detection of viral genomic sequences within the DNA of tumour cells. Despite these molecular techniques and probably because of the high cost of and technical difficulties with diagnostic tools such as PCR and laser microdissection, it is difficult to compare the studies on the incidence of HPV infection in penile cancers, and highly variable frequencies of HPV detection have been reported.19
Recently, several cell-cycle-related proteins have been evaluated as surrogates for detection of high-risk HPV,20,21
The authors distinguish and a distinctive
association of p16INK4a overexpression with PeIN depicting warty and/or basaloid features has been reported.21
differentiated (‘usual’) low-grade keratinising PeIN from in situ basaloid or warty variants of PeIN by immunohistochemical pattern of expression of p16INK4a.21
significant relationship between HPV DNA and PeIN.22,23
Nowadays, there is consensus about the HPV 16 and 18
are commonly considered to be the most causative agents (high-risk types). Currently, there is enough evidence for carcinogenity of HPV 16 in penile cancer, while there is only limited evidence for HPV 18.24
Physical removal of diseased tissue includes surgery, photodynamic therapy and laser excision.3
A
recent meta-analysis of 31 studies that included 1,466 patients with penile cancer showed that the prevalence of HPV infection was 46.9%. HPV 16 was the predominant type, present in 60.2%, followed by HPV 18 (13.4%) and HPV 8 (8.1%). The vast majority of basaloid and warty cancers showed an HPV infection, although about 50% of keratinising and non-keratinising cancers also showed HPV infection.25
A strong
association between Bowenoid PeIN and warty and basaloid cancers on the one hand and between LS or SH and verrucous or usual squamous cell carcinoma on the other hand have been reported.11 Following a first event, where HPV infection plays a major role, different pre-invasive lesions may appear, each with specific histopathological features. Through a second step, these lesions may evolve to invasive cancers, which maintain the same histological aspects of corresponding pre-invasive counterparts and have a particular association with HPV infection.26
It is not completely clear how other factors, such as hygiene, smoking or other infections, interact to promote progression of disease. Risk factors associated with penile cancer include penile rashes lasting for more than one month (risk ratio [RR] 9.4), genital warts (RR 5.9), penile tear (RR 3.9), difficult foreskin retraction (RR 3.5), number of sexual partners during lifetime (> or
Therapy
The ideal treatment of pre-invasive lesions should be able to eradicate the disease, avoid recurrences and progression and preserve anatomy and functions. Both medical and surgical treatments have been used in this field. Many topical agents have been used in the last few decades, with heterogeneous results. In recent years imiquimod, a biological response modifier that is usually used for the management of genital warts, has been employed in different ano-genital pre-invasive lesions. A very recent review addressed this issue:28
27 patients with different penile intraepithelial
lesions were identified and 21 patients (78%) achieved a complete response, with an additional five (19%) having a partial response. The majority of patients were case reports, and the lesions were extremely heterogeneous, including BD, EQ and BP: moreover, follow-up is largely immature and the therapy schedules are extremely varied, thus there is a need for great caution when considering this drug for pre-invasive penile lesions.
EUROPEAN UROLOGICAL REVIEW
Different methods are used for laser therapy and the characteristics of the laser source are essential to define possible applications. There are lasers with high penetration in water and a very high destructive power, such as Nd:YAG or potassium–titanyl–phosphate (KTP) lasers. Alternatively, there are lasers with high water absorbance and low
penetration, such as CO2 lasers, which can be used for precise dissection as a scalpel with coagulation capacity. The Nd:YAG laser is the most popular treatment. Two recent reports addressed its use in small series of 1731
and six32 patients with penile intraepithelial
neoplasia. Immediate efficacy was very good, although there were recurrences in two of 17 and four of six patients, respectively. Moreover, one patient in each series progressed to invasive cancer and one in each series developed nodal metastases.
In 2008, our group published the largest experience with laser therapy in intraepithelial neoplasia.8
One hundred and six patients were 25 Surgery may consist of micrographic
surgery or the dissection of the glans followed by resurfacing. Mohs micrographic surgery (MMS) consists of immediate frozen sectioning of the specimen and identification and mapping of positive margins followed by repeated excision until tumour clearance. This technique permits total removal of disease and spares the unaffected portions of the penis. Sharp dissection of the glans with a cold knife followed by resurfacing with a skin graft from the thigh is a more recent alternative, and is associated with very good cosmetic results. Recent publications of small cohorts show that both techniques seem to be effective and safe. MMS necessitated repeated treatments, but no progression was documented. Of importance, both techniques allow a specimen to be taken for pathological testing.
In another study of 10 patients, application of a photo-sensitiser was followed by illumination: multiple treatments were necessary (two to eight), with three patients not rendered definitively disease-free.30
It is of importance that none of these treatments allows a definitive specimen to be taken for pathological reading.
Photodynamic therapies use photo-sensitisers that are applied to the surface of the penis; these sensitisers are metabolised differently by normal and affected cells. This approach can facilitate identification of disease, permitting more precise removal of diseased tissue, or can be used to destroy the affected tissue. A recent publication of photodynamic diagnosis included 11 patients in whom specified areas were treated with a neodymium:yttrium–aluminium–garnet (Nd:YAG) laser: all patients were rendered disease-free and no recurrence was recorded.29
Figure 3: CO2 Laser Biopsy at Low Magnification
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