Contrasting BRAF Mutational Status and Solar UV Radiation Associations in Primary Versus Metastatic Melanoma
Cleo YoussefMassad, Asif Loya, Suad Taraif, Christian Oberkanins, Ibrahim Khalifeh. American University of Beirut Medical Center, Beirut, Lebanon; Shaukat Khanum Memorial Cancer Center, Lahore, Pakistan; Vienna Lab Diagnostics GmbH, Vienna, Austria; SAAD Specialist Center, Al Khobar, Saudi Arabia
Background: Melanoma has been viewed as a heterogeneous molecular entity for which solar UV radiation (UVR) and BRAF mutation status (BMS) are important determinants. We studied primary (PM) and metastatic (MM) melanomas from 2 UVR-distinct regions to elucidate the effect of prognostic predictors and UVR on BMS.
Design: Extended BRAF testing for 9 mutations was obtained for 95 PM [Lebanon (LB, n=55), Pakistan (PK, n=40)] and 65 MM [(LB, n=36), Pakistan (PK, n=29)] from 92 and 57 patients, respectively. Collected clinical data included age, size, gender and anatomic location. Histologically, prognostic parameters and solar elastosis grade for PM were recorded. In MM multiple parameters including the site of metastasis, necrosis magnitude and degree of pigmentation were observed. Cumulative 21-year averages of UVR for LB (110 kJ/m2/yr) and PK (128 kJ/m2/yr) were derived from the National Center for Atmospheric Research databases.
Results: The overall BRAF mutation rate was 27.3% in PM and 56.9% in MM. V600E was the predominant mutation in 88% of PM and 92% of MM. A 3/9 (33.3%) discordant mutation rate was identified, 2 patients lost the mutation in the metastasis and 1 gained it. The relative incidence of BRAF mutation with UVR exposure was reversed for primary [PM (Low vs. High UVR): 5.4% vs. 43%] compared to metastatic [MM: 57% vs. 22%] melanomas (p<0.05). Predictors of BRAF mutation were trunk location and epithelioid cytology for PM versus subcutaneous metastasis and decreased pigmentation for MM (p<0.05). In PK, BRAF positivity was significantly more encountered in the absence of ulceration in PM and with decreased necrosis in MM. The other examined parameters did not affect the BMS in both PM and MM, irrespective of region. BRAF positive status in PM was reasonably predicted by multivariate binary logistic regression [C-statistic (95% confidence interval (C.I.) =0.67 (0.53-0.81) with two independent predictors 1) High UVR [odds ratio (OR) (95% C.I.) =14.947 (3.086-72.400); P=0.001] and 2) Trunk location OR (95% C.I.)= 3.646 (1.057-12.579); P= 0.041]. In MM, only high UVR [OR (95% C.I.)= 0.208 (0.063-0.0689); P=0.010] predicted BRAF mutation.
Conclusions: BMS in regions with different UVR exposures is reversed for PM as compared to MM. In view of newly invested targeted therapy, discordance in the BMS between PM and MM highlights the need for routine BRAF testing on both sites prior to treatment.
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 72, Monday Morning