Penile Intraepithelial Neoplasia (PeIN)

01PeIN is in-situ squamous cell carcinoma confined to the penile epithelium. Three clinically distinct variants account for most cases: Bowenoid papulosis (multiple red-brown verrucous papules on younger men, mean age in the 30s to late 50s, usually shaft), Bowen disease of the penis (solitary scaly pink to red plaque on the keratinized shaft, prepuce, or glans, typically older men), and erythroplasia of Queyrat (well-defined, bright red, moist or velvety plaque on the mucosal glans or visceral prepuce). Histopathologically these variants may be indistinguishable.

02The 2022 WHO Classification of Penile and Scrotal Cancers (Menon et al., Histopathology 2022; Moch et al., Eur Urol 2022) restructured the disease around HPV status. Squamous precursors are now classified as HPV-associated PeIN (subdivided into basaloid, warty, and mixed warty-basaloid) and HPV-independent PeIN (the differentiated subtype, classically arising in lichen sclerosus). The corresponding invasive carcinomas follow the same dichotomy. The 2023 EAU-ASCO collaborative guideline made p16(INK4a) immunohistochemistry reporting mandatory for any penile SCC pathology report.

03HPV-associated and HPV-independent pathways differ at the molecular level. High-risk HPV 16 dominates (46 to 62 percent of HPV-positive cases), with HPV 18 less common. E6 degrades p53 and E7 inactivates Rb, releasing p16(INK4a) from negative feedback so that the protein accumulates. p16 overexpression by IHC is therefore the standard surrogate for transcriptionally active HPV. Differentiated PeIN is HPV-negative, p16-negative, and frequently harbors TP53 mutations and 9p21/CDKN2A loss; it tends to behave more aggressively.

04Dermoscopic features of PeIN were systematically described by Chan et al. (Australas J Dermatol 2019) in 11 histopathologically confirmed cases. Across all variants the most consistent signs were structureless areas (100 percent of cases, pink in 72.7 percent), vascular structures (81.8 percent, predominantly clustered dotted vessels in 72.7 percent, with glomerular vessels in a further 27.3 percent), and absence of a true pigment network (100 percent). Other findings included scale (45.5 percent), scar-like areas (45.5 percent), erosions (27.3 percent), and brown-grey dots and globules in 27.3 percent (mostly Bowenoid papulosis and pigmented Bowen disease).

05Variant-specific dermoscopy is helpful. Bowenoid papulosis shows brown-grey dots and globules in a linear peripheral arrangement, may include crown vessels, and is often pigmented. Bowen disease of the penis (when non-pigmented) shows pink or skin-coloured structureless areas with clustered dotted or glomerular vessels, scale, and scar-like areas; pigmented Bowen disease adds brown to grey dots and granules in linear distribution. Erythroplasia of Queyrat is the purest mucosal pattern: pink structureless areas plus clustered dotted or glomerular vessels, often with erosion (60 percent of cases) and without pigmentation. Polymorphic vessel patterns (dotted plus glomerular plus linear or comma) and a sharp demarcation favor PeIN over inflammatory mimics.

06The clinical differential includes Zoon balanitis (orange-yellow background but with curved (focal) vessels and parallel orange-red structureless zones), lichen sclerosus (white-pink atrophic plaques with linear or branched vessels and absent dotted vessel clusters), lichen planus (Wickham striae, violaceous color, linear vessels), psoriasis (regular dotted vessels uniformly distributed, white scale), genital warts (papillary projections with central looped vessels), candidiasis, and fixed drug eruption. Up to 90 percent of PeIN patients have a coexisting genital dermatosis, making baseline pattern recognition essential.

07Management follows the WHO/NCCN/EAU-ASCO framework with organ-preservation as the goal in early disease. Topical 5-fluorouracil and topical imiquimod are accepted first-line non-invasive options; ablative CO2 or Er:YAG laser, cryotherapy, photodynamic therapy, and circumcision (for foreskin disease) are alternatives. Surgical excision, glans resurfacing, or glansectomy are reserved for extensive, recurrent, or treatment-refractory disease. p16-positive lesions in a 137-patient European cohort (Ashley et al., 2021) showed longer disease-free survival on imiquimod, 5-fluorouracil, or surgery regardless of modality.

08Risk of progression to invasive penile SCC is up to 30 percent if untreated, underscoring the value of dermoscopy-guided biopsy and ongoing surveillance. The largest meta-analysis to date (Mustasam et al., JNCCN 2025; 34 studies, 3,994 patients) confirmed that p16-positivity in invasive penile SCC predicts substantially better disease-specific survival (HR 0.34), overall survival (HR 0.54), and disease-free survival (HR 0.52); HPV DNA positivity correlated with improved DFS (HR 0.63) and DSS (HR 0.46). HPV-independent (differentiated) disease behaves more aggressively. Adjunctive imaging at the bedside (reflectance confocal microscopy and optical coherence tomography) can map mucosal lesions, define margins, and reduce unnecessary biopsies, although these tools remain research-stage in most centres.