Moffitt Cancer Center classifies intraepithelial penile lesions by HPV status and cancer risk
Journal: Advances in Anatomic Pathology | Published: 2026-01-22 | Type: Review | PMID:41568455Authors: Xu Hongzhi (H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL); Dhillon Jasreman
Funding/COI: No funding or conflicts of interest disclosed
Summary
A narrative review from Moffitt Cancer Center cataloguing the spectrum of intraepithelial penile lesions — from benign condylomas to preneoplastic penile intraepithelial neoplasia (PeIN) to rare primary melanoma in situ. The paper maps these lesions by HPV status, geographic prevalence, molecular markers, and associated risk factors. It's a pathology reference, not a clinical trial — its value is taxonomic clarity, not new data.
Claims
Low-risk HPV types 6 and 11 are most prevalent in penile condylomas, though high-risk HPV types can be co-detected in a subset of patients
HPV-associated PeIN accounts for the majority of PeIN cases in North America and Europe, where penile cancer incidence is lower
HPV-associated PeIN is divided into basaloid, warty, and mixed subtypes (predominant), with rarer pagetoid, clear-cell, and spindle-cell subtypes
HPV-associated PeIN is immunohistochemically p16-positive and high-risk HPV ISH-positive; p53 typically shows wild-type staining
HPV-independent (differentiated) PeIN predominates in high-incidence countries with high rates of uncircumcision
Differentiated PeIN is associated with lichen sclerosus, lichen planus, lichen simplex chronicus, and phimosis
Differentiated PeIN frequently involves TP53 mutations with additional alterations in PIK3CA and HRAS
Extramammary Paget disease (EMPD) of the penis can be primary or secondary; secondary EMPD may indicate underlying prostate or urothelial carcinoma
Primary penile melanoma in situ is rare (documented via case reports only); the glans penis is the most commonly reported site
Study Quality
This is a narrative review — there is no primary data collection, no patient cohort, no statistical analysis. That's not a flaw; it's the format. A narrative review from a major cancer center synthesizing existing pathology literature has legitimate value as a clinical reference. The authors cover diagnostic criteria, immunohistochemical profiles, molecular alterations, and epidemiological context in one place.
The paper does not report PRISMA compliance or a systematic search strategy, so it cannot be evaluated as a systematic review. Which papers were included, and why, is opaque. The review reflects expert synthesis from pathologists at a high-volume cancer center, which carries practical credibility, but also selection bias toward the institutional experience at Moffitt.
Red Flags
No systematic methodology described — inclusion/exclusion criteria for cited literature are not stated
No quantitative synthesis — effect sizes, prevalence figures, and progression rates are referenced descriptively but not pooled
No sample sizes reported for the underlying literature in the abstract; the claims about geographic prevalence lack cited denominators here
"Recently, it has been proposed to further subclassify differentiated PeIN" — the proposal is mentioned without citing the source or its reception in the field
Case reports are cited as evidence for penile melanoma in situ; the rarity is acknowledged but the evidentiary weight is minimal
Strengths
Covers the full spectrum of intraepithelial penile pathology in a single document — useful reference for a fragmented literature
Clear HPV-associated vs. HPV-independent classification framework with corresponding immunohistochemical and molecular markers
Moffitt Cancer Center affiliation is relevant — the institution has an active genitourinary oncology program with direct exposure to these cases
No industry funding or COI, removing a common source of bias in oncology reviews
Includes rare entities (EMPD, penile melanoma in situ) that are easily overlooked in broader urology literature
Verdict
This is a pathology-focused taxonomy review, not a clinical study with new findings. Its utility is as a reference map for clinicians and researchers who need to distinguish condyloma from PeIN from EMPD from melanoma in situ — conditions that look different under a microscope and carry vastly different prognoses. The lack of a systematic search strategy and the absence of pooled data limit its evidentiary weight, but that's the wrong frame for this paper type. Evaluated as expert synthesis, it's competent and current. Evaluated as evidence for any specific clinical claim, it doesn't meet the bar — and it doesn't try to.