title: Expression of activated TrkA protein in melanocytic tumors: relationship to cell proliferation and clinical outcome.
abstract: We evaluated expression of activated nerve growth factor receptor tyrosine kinase (p-TrkA) by immunohistochemical analysis in 152 primary and 64 metastatic human melanoma biopsy specimens and 8 nevi. Membranous, cytoplasmic, and/or nuclear expression of p-TrkA was seen in 54.6% of primary melanomas and 30% of metastases. Membranous p-TrkA was detected in 21.7% of primary and 14% of metastatic melanomas and cytoplasmic immunoreactivity in 28.9% of primary tumors and in 22% of metastases. Significantly fewer metastases than primary tumors expressed nuclear p-TrkA (16% vs 39.5%; P = .006). A significantly higher percentage of nodular than superficial spreading melanomas expressed membranous (40% vs 11%; P < .0001) p-TrkA. Nevi expressed no membranous or cytoplasmic p-TrkA; 63% showed nuclear reactivity. p-TrkA expression varied significantly with thickness of primary tumors (lower expression in thinner lesions: membranous, P = .004; cytoplasmic, P = .001; nuclear, P = .031). An association between ulceration and membranous (P = .054), cytoplasmic (P < .0001), and nuclear (P = .022) p-TrkA expression was found. Membranous p-TrkA significantly predicted decreased overall survival (P = .002). A significant association between membranous p-TrkA and cyclin A (P = .004) and Ki-67 (P < .0001) and between cytoplasmic p-TrkA and cyclin A (P < .0001), Ki-67 (P = .004), and cyclin D3 (P = .027) was found. p-TrkA had no effect on MAPK(ERK1/2) activation. A significant inverse association between cytoplasmic beta-catenin and cytoplasmic p-TrkA levels (P = .006) and between nuclear p-TrkA and cytoplasmic E-cadherin (P = .022) was seen. We present the first evidence of a role for TrkA activation in a subset of melanomas as a predictor of an aggressive phenotype and poor outcome.
authors.affiliation: Department of Pathology, Norwegian Radium Hospital, HF, Montebello, Oslo.
authors.forename: Vivi Ann
authors.initials: VA
authors.lastname: Flørenes
authors.forename: Gunhild M
authors.initials: GM
authors.lastname: Maelandsmo
authors.forename: Ruth
authors.initials: R
authors.lastname: Holm
authors.forename: Reuven
authors.initials: R
authors.lastname: Reich
authors.forename: Philip
authors.initials: P
authors.lastname: Lazarovici
authors.forename: Ben
authors.initials: B
authors.lastname: Davidson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002455:Cell Division; D003598:Cytoskeletal Proteins / Q000096:biosynthesis; D004789:Enzyme Activation; D006801:Humans; D007150:Immunohistochemistry; D008545:Melanoma / Q000201:enzymology* / Q000401:mortality / Q000473:pathology*; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000473:pathology; D009506:Nevus / Q000201:enzymology / Q000473:pathology; D011379:Prognosis; D020917:Receptor, trkA / Q000096:biosynthesis*; D015534:Trans-Activators / Q000096:biosynthesis; D016896:Treatment Outcome; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; D020917:Receptor, trkA