title: Clear-cell differentiation and lymphatic invasion, but not the revised TNM classification, predict lymph node metastases in pT1 penile cancer: a clinicopathologic study of 76 patients from a low incidence area.
abstract: OBJECTIVE
  Prediction of lymph node (LN) metastases in penile invasive cancer relies on clinical features and histologic characteristics of the primary tumor. Correct prediction, however, is difficult, as only 50% patients undergoing lymphadenectomies will have LN metastases. In 2009, the tumor, nodes, metastases (TNM) classification for staging of early penile cancers was revised. We tested the predictive accuracy of the revised TNM classification in a low incidence area for penile carcinoma.
  
  
  METHODS
  The presence of LN metastases in 76 men with pT1 penile cancers was correlated with the 2009 TNM subclassification, which is based on a combined evaluation of tumor grade and lymphatic invasion, but also with individual parameters, such as histologic grade, lymphatic invasion, perineural invasion, invasion depth, growth pattern and human papilloma virus (HPV) status.
  
  
  RESULTS
  76pT1 penile cancers were reclassified into 31pT1a squamous cell carcinomas (SCC) and 45pT1b (41 SCC; 4 clear-cell carcinomas); 12/22 men (55%; 8 SCC, 4 clear-cell carcinomas) undergoing lymphadenectomy for enlarged inguinal lymph nodes had metastases, 54 patients without enlarged LN and lymphadenectomies had no LN metastases during follow-up of median 47 months. Statistically, clear cell differentiation of the primary carcinoma was highly associated with metastases (100% clear-cell carcinomas vs. 11% SCC) and poor survival (50% vs. 5.5%). Among conventional SCC, only lymphatic invasion showed a highly significant association with metastases with 100% specificity. The 2009 TNM classification, tumor grade alone, perineural invasion, growth pattern, invasion depth or HPV status could not predict LN status. Lymphadenectomy for enlarged LN resulted in 100% sensitivity and 42% predictive probability for identifying metastases and a 16% false positive rate. Statistically, survival correlated significantly with clear-cell differentiation and with lymphatic invasion in both clear-cell carcinomas and conventional SCC.
  
  
  CONCLUSIONS
  Penile clear-cell carcinomas are more aggressive cancers than SCC. Our observation suggests a benefit of a prophylactic lymphadenectomy for patients with clear-cell carcinomas. Among conventional SCC, only lymphatic invasion predicted LN metastases. Neither tumor grade alone nor perineural invasion, growth pattern, depth of invasion, and subgrouping according to the revised TNM classification correlated with metastases. Clinical evaluation of the LN status was superior to histologic risk stratification.
authors.affiliation: Institute of Pathology, Medical University Graz, Graz, Austria.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mannweiler
authors.forename: Stephan
authors.initials: S
authors.lastname: Sygulla
authors.forename: Oleksiy
authors.initials: O
authors.lastname: Tsybrovskyy
authors.forename: Yas
authors.initials: Y
authors.lastname: Razmara
authors.forename: Karl
authors.initials: K
authors.lastname: Pummer
authors.forename: Sigrid
authors.initials: S
authors.lastname: Regauer
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000453:epidemiology / Q000473:pathology* / Q000601:surgery; D001317:Austria / Q000453:epidemiology; D002294:Carcinoma, Squamous Cell / Q000453:epidemiology / Q000473:pathology* / Q000601:surgery; D015897:Comorbidity; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D008197:Lymph Node Excision; D008198:Lymph Nodes / Q000473:pathology* / Q000601:surgery; D008207:Lymphatic Metastasis; D008297:Male; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D030361:Papillomavirus Infections / Q000453:epidemiology / Q000473:pathology / Q000601:surgery; D010412:Penile Neoplasms / Q000453:epidemiology / Q000473:pathology* / Q000601:surgery