Characteristics of HPVRelated Precursor Lesions

Characteristics of HPV-related precursor lesions are presented in Fig. 1.1. Genital Bowen's disease, erythroplasia of Queyrat (EQ), and Bowenoid papulosis (BP) are clinical presentations of high-grade PIN. Bowen's disease and EQ are usually found in elderly men, being present on the follicle bearing skin and the mucosa of the penis (i.e., glans or prepuce), respectively. Bowen's disease presents as a single, scaly plaque, located on keratinized genital skin. EQ usually presents as one or more red, moist plaque on the mucosal surface of the glans, which may spread to the inner aspect of the prepuce. Multiple studies have consistently shown that there is a high prevalence of HPV in PIN (60-100%) corresponding with reported prevalences of 43-100% in Bowen's disease and EQ.26,40-43 HPV-16 is the most common type found in Bowen's disease, being present in 43-88% of the cases.26,42,43 Bowen's disease and EQ, corresponding with histologically identified high-grade PIN

Intraepithelial Lesion Penis
HPV related high grade intraepithelial neoplasia of the penis, showing strong nuclear and cytoplasmic staining with p16 and strong MIB-1 positivity over the full thickness of the epithelium.The lesion tested HPV-16 positive.
Healthy Penile Frenulum
HPV related low-grade intraepithelial neoplasia of the penis, showing multiple acetowhite spots, partly with a punctuated pattern on the frenulum at penoscopy. Histologically the lesions show mild dysplasia and convincing viral alterations. The lesion tested HPV-16 positive.

Fig. 1.1 Characteristic HPV-related lesions of the penis lesions, may progress to penile cancer.26,44,45 Progression into penile cancer is more common in EQ, occurring in approximately 30% of the cases.26 It is unclear whether there is a differential outcome for either HPV-positive or negative cases of Bowen's disease or EQ.

BP has been considered as a predominantly transient and self-limiting hrHPV-related disease in young men (usually under 40 years of age).41,46,47 This disease clinically presents as multiple, small, well-demarcated papules or small patches on the penile shaft, glans, or foreskin. BP is usually positive for hrHPV, mainly HPV-16. BP is highly contagious, presenting a high risk for cervical intraepithelial neoplasia (CIN) in female patients with BP on the vulva and in female sex partners of male patients with BP on the penis.48 The mean duration of the disease is less than 3 months and progression into penile cancer occurs in less than 1%, though persistent lesions may progress to Bowen's disease or EQ.46,48,49

Other hrHPV-associated penile lesions include flat penile lesions (FPL), which are also known as acetowhite lesions.40,50-52 Similar to the high-grade penile lesions described above, FPL are predominantly found at the mucosal site of the penis. Histological evaluation of FPL generally shows mild changes such as squamous hyperplasia or low-grade PIN. High-grade PIN is uncommon, being present in about 5% of the cases. FPL are found in about 50-70% of the male sexual partners of women with CIN versus about 10-20% in men who do not have a partner with CIN.40,50-53 In young male populations, not selected on the basis of a prevalent CIN lesion in the partner, prevalences of up to 36% have been reported.54,55 These data indicate that FPL have a much higher prevalence compared to Bowen's disease, EQ, or BP. Besides the association with HPV, it is important to realize that, in cases of HPV positivity, FPL display relatively high viral load levels. The presence of high viral loads in these lesions is clinically relevant as it indicates a potential increased risk for HPV transmission, similar to that which has been shown for other HPV-related lesions such as genital warts or BP.48,53,56 The clinical course of FPL is generally benign, showing healing of the majority of the cases within 2 years.53 However, a small proportion remains persistently HPV-positive and does not heal.53 Although not proven in clinical studies, it is plausible to assume that some of these persistent HPV positive FPL might progress to high-grade PIN and subsequent penile cancer.

Low-risk HPV (lrHPV)-associated condylomata acuminata do not have a malignant potential although in some cases, long-lasting giant condylomata acuminata (Buschke-Lowenstein tumor) might become malignant, showing invasion in 30% to 56% of cases.57 Although in the literature these tumors are sometimes classified as verrucous carcinomas, it seems best to consider this type of carcinoma as a separate entity which is supported by distinct clinicopathological characteristics like the presence of lrHPV (i.e., HPV-6 and 11), its relative young age at presentation, and their condylomatous appearance (both clinically and histopathologically).57-59 Yet, the role of lrHPV types in penile carcinogenesis needs further investigation especially considering the clinical behavior of lrHPV-positive penile carcinomas (i.e., its potential to metastasize).

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