Bin Yang - Molecular Cytopathology

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Molecular genetic analyses have been increasingly performed on cytologic specimens to facilitate management of cancer patients. Before developing and validating a molecular assay for clinical utility, it is important to evaluate if the assay will significantly change the patient management, e.g., its impacts in diagnosis, risk assessment, prognosis and prediction of therapeutic response. Gene fusions or rearrangements associated with chromosome translocations in neoplasm, mostly in lymphomas and soft tissue tumors, are useful biomarkers for purpose of diagnosis owing to their higher frequency and specificity. For example, detections of gene fusions of BCR-ABL1 and EWS-FLI1 have been used for diagnosis and minimal disease monitoring of CML and diagnosis for Ewings tumor, respectively. Genetic alterations in epithelial or neuroepithelial neoplasms, mostly point mutation, insertion/deletion and amplification, are usually not applied for purpose of diagnosis due to their lower frequency (<50%) and lack of organ/tissue specificity, but they are successfully applied for prediction to therapeutic response and prognosis. For example, N-myc gene amplification and 1p/19q deletions have been used for prognosis/risk assessment of neuroblastoma and oligodendroglioma respectively, and EGFR , KRAS , and BRAF mutations for prediction of response to biomarker-driven (targeted) therapies for lung adenocarcinoma, colon adenocarcinoma and melanoma respectively. Selection and decision of a molecular assay may be affected by many factors, such as official clinical guidelines for patient management including CAP and NCCA guidelines, availability of FDA-approved companion molecular assays for targeted therapy, requests by clinicians for a specific gene or disease, and reimbursable molecular-based assays by insurance company.

Cytologic specimen may contains less amount of target cells compared with formalin-fixed paraffin-embeded (FFPE) surgical specimen. However, cytologic specimens, especially those obtained through fine needle aspiration, are often more suitable for molecular assays due to the high quality nucleic acids by non-formalin fixation and less fragmented genome.