title: The impact of immunohistochemical expression of nitric oxide synthases on clinical and pathological features of renal cell carcinoma.
abstract: OBJECTIVE
  To evaluate the immunohistochemical expression of nitric oxide synthase (NOS) types 1, 2, and 3 in intratumoral and non-neoplastic samples of renal cell carcinoma (RCC) and correlate it with the clinical and pathological features of this malignancy.
  
  
  METHODS
  We analyzed 110 patients with RCC underwent radical nephrectomy (RN) or partial nephrectomy (PN) by streptavidin-biotin peroxidase method, tissue microarray, and digital microscopy. As endpoints, NOS expression was correlated with pathological features, overall survival (OS), and cancer-specific survival (CSS).
  
  
  RESULTS
  Non-neoplastic samples had higher NOS3 and lower NOS 2 levels than RCC tissues. Greater expression of all NOS isoforms was associated with larger tumors. High NOS1 expression correlated with microscopic venous invasion (MVI) (p = 0.046) and lymph node metastases (p = 0.007). High NOS2 expression was linked to MVI, more RN performed, and male gender (p = 0.035, p = 0.003, and p = 0.027, respectively). High NOS3 expression correlated with lymph node metastases (p = 0.039), microlymphatic invasion (p = 0.029), invasion of the renal pelvis and ureter (p = 0.004), RN (p = 0.003), and shorter OS (58.1 vs. 79.4 % respectively, p = 0.033) by univariate analysis. DFS was not influenced by any NOS isoform. By multivariate analysis, the risk factors for death were TNM stages III and IV (hazard ratio [HR] = 4.5), high Fuhrman's grade (HR = 2.9), Karnofsky performance status ≤80 (HR = 2.5), progression (HR = 5.5), and recurrence (HR = 6.3). Stage III disease was an independent risk factor for recurrence (HR = 9.5).
  
  
  CONCLUSIONS
  High NOS expression in RCC is associated with a poor prognosis and larger tumors. NOS3 influences OS by univariate analysis.
authors.affiliation: Urology Division, Department of Pelvic Surgery, Hospital AC Camargo, Rua Professor Antonio Prudente, 211, Sao Paulo, SP, 01509-010, Brazil, steniozequi@uol.com.br.
authors.forename: Stênio de
authors.initials: Sd
authors.lastname: Cássio Zequi
authors.forename: José Humberto G T
authors.initials: JH
authors.lastname: Fregnani
authors.forename: Ricardo L
authors.initials: RL
authors.lastname: Favaretto
authors.forename: Walter H
authors.initials: WH
authors.lastname: Costa
authors.forename: Rodrigo S
authors.initials: RS
authors.lastname: Madeira Campos
authors.forename: Francisco P
authors.initials: FP
authors.lastname: Fonseca
authors.forename: Gustavo C
authors.initials: GC
authors.lastname: Guimaraes
authors.forename: Fernando A
authors.initials: FA
authors.lastname: Soares
authors.forename: Isabela W
authors.initials: IW
authors.lastname: da Cunha
authors.forename: Ademar
authors.initials: A
authors.lastname: Lopes
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009392:Nephrectomy; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: C496320:NOS1 protein, human; C496319:NOS2 protein, human; C496314:NOS3 protein, human; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III