Follicular Lymphoma „In Situ“ and with Partial Lymph Node Involvement Represent Genetically Early Stages of Follicular Lymphoma Development.
Patrick Adam, Itziar Salaverria, Irina Bonzheim, Miguel A Piris, Santiago Montes-Moreno, Falko Fend, Reiner Siebert, Leticia Quintanilla-Martinez. Eberhard-Karls-University, Tubingen, Germany; Christian-Albrechts-University, Kiel, Germany; Spanish National Cancer Center, Madrid, Spain
Background: Follicular lymphoma (FL) is characterized, in most cases, by the t(14;18) translocation resulting in BCL2 gene rearrangement. Secondary genetic alterations have been found in 70-90% of manifest FL (mFL), and are thought to play a role in the progression and/or transformation of the disease. Although most patients with FL have widespread disease at diagnosis, one third of them present with stage I-II disease, and often show only partial lymph node (LN) involvement by FL at diagnosis. Furthermore, cases with normal LN architecture and strong BCL2-expression in follicular center cells without any other evidence of disease have been designated as FL “in situ” (FLIS). The biological significance of these findings is still unclear. The main aim of the study was to identify possible early secondary genetic events in the evolution of t(14;18) positive FL.
Design: Twelve cases of FL (5 pure FLIS, 3 “paired samples” of FLIS with their corresponding mFL, 3 FL with partial LN involvement and 1 FL with partial involvement and “in situ” component) were analyzed by oligonucleotide-based array CGH (244K arrays, Agilent Technologies) following microdissecting. The t(14;18) was evaluated with a BCL2 break-apart probe by FISH. Clonality analysis of the IGH gene was performed in the 3 “paired samples”.
Results: All FLIS cases showed a BCL2 break by FISH indicative of the presence of a t(14;18). IGH PCR analysis demonstrated that FLIS and their corresponding mFL were clonally related. CGH analysis did not detect secondary chromosomal imbalances in any FLIS or FL with partial LN involvement; however, known copy number variations (CNVs) were identified in all cases. The three mFL showed secondary genetic imbalances (e.g. -6q, -10q) frequently reported in FL. One of the mFL was negative for BCL2 expression whereas the FLIS component was strongly positive. Both of them had a BCL2 break by FISH, suggesting secondary alterations of the BCL2 gene during the progression of the disease.
Conclusions: 1) FLIS and FL with partial lymph node involvement probably represent early stages of FL lymphomagenesis, as evidenced by the absence of secondary genetic alterations. 2) The FLIS were clonally related to the syn-/metachronous mFL. 3) Array CGH identified secondary genetic aberrations in mFL, suggesting that additional genetic alterations are needed to progress from FLIS to manifest FL.
Wednesday, March 2, 2011 1:00 PM
Poster Session VI # 203, Wednesday Afternoon