What is Penile Intraepithelial Neoplasia (PeIN)?
Penile intraepithelial neoplasia (PeIN) is a precancerous lesion of the penis characterized by intraepithelial atypia that can progress to invasive squamous cell carcinoma, occurring in 2.6–13% of patients despite treatment. 1
Classification and Pathophysiology
PeIN represents the precursor lesion to penile squamous cell carcinoma (SCC), which comprises over 95% of penile cancers. The 2022 WHO classification divides PeIN into two distinct pathways based on HPV status 1, 2:
HPV-Associated PeIN (Undifferentiated)
- Affects younger men
- Includes basaloid, warty (condylomatous), and warty-basaloid subtypes 3
- Characterized by monotonous basaloid cells or pleomorphic koilocytosis
- Shows block-type p16 immunohistochemistry positivity (the most practical diagnostic method) 2
- HPV 16 is the most common genotype 1
HPV-Independent PeIN (Differentiated)
- Affects elderly men
- Associated with chronic inflammatory dermatoses, particularly lichen sclerosus 4, 5
- Shows acanthosis, parakeratosis, enlarged keratinocytes with abundant eosinophilic cytoplasm, and hyperchromatic basal cells 3
- Demonstrates p53 overexpression and harbors TP53/CDKN2A mutations 5
- Carries greater risk of progression to invasion compared to HPV-associated forms 4
Clinical Presentation and Location
Most PeIN lesions occur on the mucosal surfaces of the glans or prepuce 1. The lesions are macroscopically indistinguishable between subtypes and can present as raised or ulcerated lesions, sometimes hidden under the foreskin in phimosis 1.
Critical Clinical Consideration
Up to 20% of patients with apparent PeIN harbor occult invasive disease 1. This finding has profound implications for treatment selection, as it mandates histopathological confirmation and careful surveillance regardless of initial treatment approach.
Progression Risk
The progression rate to invasive penile SCC is 2.6–13% despite treatment 1, 6. This relatively low but clinically significant risk necessitates long-term follow-up, as insufficient treatment responses and recurrences may indicate underlying invasive disease 1.
Diagnostic Approach
Physical examination should document morphology, size, and location of lesions. Biopsy is mandatory when malignancy is not clinically obvious or when nonsurgical treatment is planned 1. The pathology report must include p16 immunohistochemistry to distinguish HPV-associated from HPV-independent disease 1, 2.
Common Pitfall
The distinction between HPV-associated and HPV-independent PeIN is not merely academic—it has direct implications for prognosis, treatment selection, and surveillance intensity. Differentiated (HPV-independent) PeIN carries higher invasion risk and typically requires more aggressive management 4, 5.