p53 as a new prognostic factor for lymph node metastasis in penile carcinoma: analysis of 82 patients treated with amputation and bilateral lymphadenectomy.
OBJECTIVE
Gold standard treatment for invasive penile carcinoma remains amputation and lymphadenectomy. This procedure has high morbidity and new prognostic factors on the incidence of metastasis would help select candidates to lymphadenectomy. Mutations in the p53 gene common in several neoplasms can be related to the prognosis. We studied 82 patients with penile carcinoma staged according to the 1978 TNM system who underwent amputation and bilateral lymphadenectomy to evaluate the prognostic value of immunohistochemical p53 staining in the primary tumor.


METHODS
Immunoreactivity of p53 was studied with other clinicopathological variables, including patient age, stage, histological grade, tumor thickness, lymphatic and venous embolization, corpora cavernosa, corpus spongiosum and urethral infiltration, and human papillomavirus (HPV) status. We also determined its association with lymph node metastasis, the survival rate and the risk of death. In addition, we studied the association of p53 and HPV DNA with prognosis. All slides were reviewed by 1 pathologist. HPV DNA was detected by polymerase chain reaction using GP5/6+ generic primers. p53 expression was measured by immunohistochemical testing with monoclonal Clone DO-7 mouse anti-human p53 protein antibody (Dako A/S, Glostrup, Denmark). The Cox regression hazards method was used for multifactorial analysis.


RESULTS
Nuclear accumulation of p53 was detected in 34 of 82 samples (41.5%). Clinical lymph node N stage (p = 0.045), lymphatic (p <0.001) and venous (p = 0.04) embolization by neoplastic cells, p53 positivity (p = 0.012) and p53 grade (p = 0.004) were significantly associated with lymph node metastasis. Followup was 0.1 to 453 months (mean 88.7). Multivariate analysis revealed that only lymphatic embolization (relative risk 9.4, 95% confidence interval [CI] 2.8 to 31.6) and p53 positivity (relative risk 4.8, 95% CI 1.6 to 14.9) were independent factors for lymph node metastasis. Patients with negative p53 had significantly better 5 and 10-year overall survival than those in whom tumors stained positive for p53 (64.5% and 54.6% versus 30.2% and 26.4%, respectively, p = 0.009). When tumors were p53 positive and HPV DNA positive, overall survival was worse. Multivariate analysis revealed that only age (relative risk 2.9, 95% CI 1.6 to 5.1) and lymph node metastasis (relative risk 3.2, 95% CI 1.8 to 5.8) were independent risk factors for death.


CONCLUSIONS
Immunoreactivity of p53 is an independent factor for lymph node metastasis. The association of positive p53 with positive HPV DNA was related to a worse prognosis.
Lopes
Ademar
A
Division of Urology and Department of Pelvic Surgery, Ludwig Institute for Cancer Research, São Paulo Branch and Cancer Hospital A. C. Camargo, Fundação Antonio Prudente, São Paulo, Brasil.
Bezerra
Artur Licio R
AL
Pinto
Clovis Antonio Lopes
CA
Serrano
Sergio Vicente
SV
de MellO
Celso Abdon
CA
Villa
Luisa Lina
LL
D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor / Q000032:analysis*; D002467:Cell Nucleus / Q000473:pathology; D006801:Humans; D008197:Lymph Node Excision; D008198:Lymph Nodes / Q000473:pathology*; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008875:Middle Aged; D009367:Neoplasm Staging; D009360:Neoplastic Cells, Circulating; D030361:Papillomavirus Infections / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D010412:Penile Neoplasms / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D011379:Prognosis; D012189:Retrospective Studies; D016159:Tumor Suppressor Protein p53 / Q000032:analysis*
D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D016159:Tumor Suppressor Protein p53