Value of p16(INK)⁴(a) in the pathology of invasive penile squamous cell carcinomas: A report of 202 cases.
BACKGROUND
One third to one half of penile squamous cell carcinomas (SCCs) are related to human papillomavirus (HPV) infection. Viral detection is usually carried out by polymerase chain reaction (PCR) or other molecular methods. In this study, we evaluated p16(INK)⁴(a) immunohistochemical expression, which is simpler and less costly, as a potential marker of high-risk HPV (HR-HPV) infection in penile SCC.


METHODS
We pathologically classified 202 invasive penile carcinomas and performed HPV genotyping by short PCR fragment (SPF)₁₀ PCR and p16(INK)⁴(a) immunohistochemistry. We also evaluated HPV and p16(INK)⁴(a) according to the histologic subtypes of penile SCC. Tumors depicting continuous p16(INK)⁴(a) immunostain in all neoplastic cells were considered positive. HPV and p16(INK)⁴(a) status were compared using classifier performances and concordance indexes.


RESULTS
Evidence of HPV (low-risk and high-risk genotypes) was found in 63 cases (31%) by PCR. Fifty-three p16(INK)⁴(a)-positive cases were identified (26%). Overexpression of p16(INK)⁴(a) had a sensitivity of 67% and a specificity of 91% for defining the HPV status. Concordance indexes between p16(INK)⁴(a) and HPV status were high (≥78%) in general cases and in all histologic subtypes of penile SCC. The stain was useful in the differential diagnosis of basaloid and low-grade warty carcinomas. Low-risk HPV genotypes were found in 5 tumors, 4 of which were p16(INK)⁴(a) negative. Basaloid and nonbasaloid high-grade (grade 3) SCCs were more likely to be HR-HPV positive when compared with grades 1 to 2 tumors (P<0.000001 and 0.0417, respectively).


CONCLUSIONS
p16(INK)⁴(a) overexpression was found to be a reliable marker for HR-HPV and a helpful tool in the differential diagnosis of low-grade verruciform and high-grade solid penile tumors. SCC variants depicting basaloid features were more likely to be HPV and p16(INK)⁴(a) positive than low-grade, keratinizing lesions. We also observed a tendency toward HPV positivity in high-grade nonbasaloid tumors. Our results indicated a concordance between HPV and p16(INK)⁴(a) status and this observation may have diagnostic and prognostic implications.
Instituto de Patología e Investigación, Asunción, Paraguay. acubilla@institutodepatologia.com.py
Antonio L
AL
Cubilla
Belén
B
Lloveras
Maria
M
Alejo
Omar
O
Clavero
Alcides
A
Chaux
Elena
E
Kasamatsu
Núria
N
Monfulleda
Sara
S
Tous
Laia
L
Alemany
Joellen
J
Klaustermeier
Nubia
N
Muñoz
Wim
W
Quint
Silvia
S
de Sanjose
Francisco Xavier
FX
Bosch
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D052685:Alphapapillomavirus / Q000235:genetics / Q000302:isolation & purification; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D030361:Papillomavirus Infections / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D010412:Penile Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000821:virology
D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16