ABSTRACT
Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare, low-grade soft tissue neoplasm preferentially arising in the extremities of young to middle-aged adults characterized histologically by a variegated appearance and absence of a distinctive immunophenotype. Herein we have evaluated a series of 73 cases of MIFS to define potential features and markers that may facilitate diagnosis. An immunohistochemical study with a large panel of antibodies showed strong positivity of the tumor cells for bcl-1 (94.5%), FXIIIa (89%), CD10 (80%), and D2-40 (56%). FISH and array comparative genomic hybridization (aCGH) were performed in a large subset of cases to investigate the utility for detecting the TGFBR3 and OGA t(1;10) rearrangement and BRAF abnormalities. Using a combination of FISH and/or aCGH, t(1;10) was detected in only 3 of 54 cases (5.5%). The aCGH study also demonstrated amplification of VGLL3 on chromosome 3 that was detected in 8 of 20 cases (40%). BRAF alterations were observed by FISH in 4 of 70 cases (5.7%) and correlated with gain of chromosome 3p12 (VGLL3). A novel fusion transcript involving exon 6 of ZNF335 and exon 10 of BRAF was identified in one case. Demonstration of amplification of VGLL3 on chromosome 3 in combination with expression of bcl-1 and FXIIIa may help support the diagnosis, however, due to their low specificity these markers are not sufficient for a definitive diagnosis in the absence of the appropriate clinical-pathological context. Until a more robust genetic or immunohistochemical signature is identified, the diagnosis of MIFS rests on its characteristic clinicopathological features.
Subject(s)
Biomarkers, Tumor , Fibroblasts/chemistry , Fibrosarcoma/chemistry , Fibrosarcoma/genetics , Immunohistochemistry , Molecular Diagnostic Techniques , Soft Tissue Neoplasms/chemistry , Soft Tissue Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , Comparative Genomic Hybridization , Europe , Female , Fibroblasts/pathology , Fibrosarcoma/pathology , Gene Amplification , Gene Fusion , Gene Rearrangement , Genetic Predisposition to Disease , High-Throughput Nucleotide Sequencing , Humans , In Situ Hybridization, Fluorescence , Male , Middle Aged , Phenotype , Soft Tissue Neoplasms/pathology , Translocation, Genetic , United States , Young AdultABSTRACT
The Idylla Mutation Test System is an automated, PCR-based mutation testing system. The advantages of this system can greatly impact the delivery of precision medicine. We describe our evaluation, validation, and implementation of this system for routine testing of BRAF, EGFR, KRAS, and NRAS using formalin-fixed, paraffin-embedded cancer samples. All four Idylla test systems showed excellent concordance with reference methods. The analytical sensitivity ranged from 94.66% to 100%, depending on the cartridge, and specificity was 100%. A few discordant results were noted and further investigated: KRAS Q61L was misclassified as Q61H; KRAS Q61R was not identified; there was a false-negative EGFR double mutation (L861Q and G719A); and there was a false-negative EGFR double mutation (T790M and exon 19 deletion). The limit of detection was determined to be 1% or 5% for the variants with available reference material. The turnaround time was shortened by 7 days on average. Idylla testing of a cohort of 25 non-small-cell lung cancer samples with insufficient material for next-generation sequencing testing delivered results for all cases and identified actionable results for eight cases. In addition, patient care would have been changed in four of these cases: targeted therapies were identified in two cases, and repeated biopsies would have been avoided in two cases. The Idylla molecular testing system is an accessible, rapid, robust, and reliable testing option for both routine and challenging formalin-fixed, paraffin-embedded specimens.
