Lymphoid malignancies: Molecular diagnostics

The vast increase of knowledge regarding genetic abnormalities in lymphomas has contributed significantly not only in the better understanding of the pathobiology of the disease but also in the classification, diagnosis, prognosis, and therapeutic management of malignant lymphomas. The need for incorporation of morphology, immunophenotype, and genotype is reflected in the integration of tumor genetics in the current World Health Organization (WHO) classification of hematopoietic and lymphoid tumors. This indicates that today molecular diagnostics is important for appropriate clinical management of patients with malignant lymphomas. Molecular diagnostics comprises molecular techniques such as polymerase chain reaction (PCR), quantitative real-time PCR, mutational analysis, as well as cytogenetic methods such as fluorescence in situ hybridization (FISH). Currently, molecular analysis in malignant lymphomas is usually applied to search for single or few genetic abnormalities that will help in the diagnosis or prognosis. For example, PCR studies for detect clonality can support the diagnosis of malignant lymphoma in cases where morphology and/or immunophenotype is inconclusive. The detection of specific chromosomal translocations by molecular or FISH methods can help to further classify a malignant lymphoma. The detection of MYC gene rearrangements in patients with diffuse large B cell lymphoma has therapeutic implications, and the detection of both MYC and BCL2 and/or BCL6 gene rearrangements defines a new novel category of malignant lymphomas with a very poor prognosis. Molecular methods are characterized by high sensitivity and can provide a molecular fingerprint for a particular lymphoma; these features make some of the molecular diagnostic techniques the gold standard for monitoring minimal residual disease. However, novel genome-wide scale techniques (array comparative genomic hybridization, genomic mutation analysis, and gene expression profile) are starting to provide a broader spectrum of mutations and genetic abnormalities that are not only relevant in the pathogenesis but also may help to differentiate lymphomas that look similar under the microscope and will help to identify more targeted and effective therapies. Without a doubt, the molecular analysis of malignant lymphomas will refine our understanding of malignant lymphomas in a not-so-distant future. In this chapter, we have reviewed the main molecular features of malignant lymphomas. We also briefly reviewed the molecular biology of B and T lymphocytes and the main molecular techniques currently used in most of the laboratories for the diagnosis and clinical management of patients with malignant lymphomas.