A Comprehensive Biomarker Study in Spindle Cell- and Desmoplastic Melanoma Reveals a Marker-Panel for Diagnostic Distinction and Identification of Patient Subsets That May Benefit from Molecularly Targeted Therapy
Stephanie E Weissinger, Philipp Keil, Peter Moller, Basil Horst, Jochen K Lennerz. Ulm University, Ulm, Germany; Columbia University, New York, NY
Background: The histopathological distinction of spindle cell- (SCM) and desmoplastic melanoma (DM) is not always straightforward; however, different prognostic and therapeutic implications make this distinction clinically important. While numerous studies have assessed individual markers in each subtype, a comparison of diagnostically and therapeutically relevant biomarkers has not been performed. Here, we present an array-based analysis in two independent cohorts.
Design: Archival searches for SCM and DM were performed at both institutions (Ulm/NYC) and samples were mounted in tissue-microarrays for the assessment of the following biomarkers: HER,EGFR,cMET,MDM2,p53,ALK,MYC,CCND1,MYB,RREB1 and corresponding chromosome-enumeration probes by fluorescent in-situ hybridization (FISH). In addition, we screened for LAM,S100c,S100n,NSE,VIM,GFAP,CD34,CD56,CD57,FLI-1,NF,Melan-A/MART-1,MIB-1/Ki-67,COL-IVt,COL-IVn,HMB45,KIT,CD99,CD68t,CD68n,Desmin,SMA,AE1.3,CAM5.2,HER2,MUM1,EGFR,MET,MDM2,P53,ALK,MYC,P75, and DOG1 by immunohistochemistry (IHC). Statistical testing included class-correlation as well as Fisher's/Chi-square tests; significant markers were defined as P<0.01 and distinct markers as P<0.05.
Results: We assessed a total of 42 cases composed of 16 SCM, 20 DM and 6 SCM/DM in two subsets (Ulm: 9DM/9SM and NYC). Analysis generated 1514 IHC- and 831 FISH readouts. Intraclass correlation derived a 12 component biomarker signature (CBS:7 significant/5 distinct) composed of 5 biomarkers that were positive in DM (COL-IV;CD68;p75;Trichrome;CNL2p) and 7 biomarkers that were present in SM (LAM; Melan-A/MART1;HMB45;KIT;MDM2,p53;CNG8q24). In cross-validation between Ulm and NYC cases, Melan-A/MART-1, KIT and HMB45 (DM–; SM+) were diagnostically most reliable. Based on the 12-CBS assessment, all but 1 of the 6 combined SCM/DM cases were more similar to DM rather than SCM. Marker analysis of 9 potentially targetable molecular aberrations revealed -with the exception of one combined MET and KIT-positive case- a total of 16 cases (38%) with mutually exclusive labeling for CKIT/HER2/EGFR/MET, or ALK.
Conclusions: Our comprehensive analysis shows that identification of DM/SCM-patient subsets that may benefit from molecularly targeted therapy will require more than one biomarker. In addition, we provide a diagnostic panel that allows distinction of these melanoma subtypes when histological analysis is not straightforward.
Tuesday, March 5, 2013 9:30 AM
Poster Session III # 41, Tuesday Morning