Prognostic significance of tumor iNOS and COX-2 in stage III malignant cutaneous melanoma.
OBJECTIVE
New prognostic markers are needed for malignant melanoma. Inducible nitric oxide synthase (iNOS) and cyclooxygenase type 2 (COX-2) have been described to correlate with progression of melanoma. Moreover, activating mutations in BRAF/NRAS oncogenes are often detected in melanoma. The BRAF/NRAS mutation status and expression of COX-2 and iNOS were examined to compare their prognostic value for overall survival (OS) in stage III malignant cutaneous melanoma.


METHODS
The expression of iNOS and COX-2 in metastatic lymph nodes from 21 rapidly progressing (OS from date of diagnosis of stage III disease < or =14 months) and 17 slowly progressing (OS > or =60 months) stage III cutaneous melanoma patients was examined by immunohistochemistry. The presence of BRAF/NRAS mutations was analyzed using direct DNA sequencing. Chi2 exact trend test and logistic regression analysis were used for statistical analysis.


RESULTS
Both iNOS (P = 0.002) and COX-2 (P = 0.048) alone significantly predicted OS. The BRAF/NRAS mutation status did not significantly differ between patient groups, although iNOS significantly (P = 0.013) correlated with BRAF mutation frequency. Furthermore, the odds ratio (OR) with respect to OS of iNOS (OR = 10.4) was higher than that of COX-2 (OR = 5.6) and was stable in the multivariate analysis of OS together with disease stage IIIB/C, ulceration, number of metastatic lymph nodes, and Breslow tumor thickness.


CONCLUSIONS
Our data show that iNOS is an independent and stronger prognostic factor for OS in stage III malignant cutaneous melanoma than COX-2.
Johansson
C Christian
CC
Department of Oncology and Pathology, Cancer Center Karolinska, R8:01, Karolinska University Hospital, Karolinska Institutet, 171 76 Stockholm, Sweden.
Egyházi
Suzanne
S
Masucci
Giuseppe
G
Harlin
Helena
H
Mougiakakos
Dimitrios
D
Poschke
Isabel
I
Nilsson
Bo
B
Garberg
Liss
L
Tuominen
Rainer
R
Linden
Diana
D
Stolt
Marianne Frostvik
MF
Hansson
Johan
J
Kiessling
Rolf
R
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D016015:Logistic Models; D008207:Lymphatic Metastasis; D008297:Male; D008545:Melanoma / Q000201:enzymology / Q000401:mortality* / Q000473:pathology*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis*; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D012878:Skin Neoplasms / Q000201:enzymology / Q000401:mortality / Q000473:pathology
C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf