Immunophenotypic and Genotypic Characterization of Progression in Follicular Lymphomas

Abstract

Progression of follicular lymphomas (FLs) is often accompanied by a spectrum of histologic changes and an aggressive clinical course. Although molecular alterations have been implicated in this event, the underlying factors are largely unknown. We studied the expression of selected tumor suppressor genes (P53 and retinoblastoma [RB]), oncogenes (MYC and BCL2), and a transferrin-receptor related protein (Trump) in sequential biopsies in 16 patients. Eleven patients progressed from grade I or II FL to aggressive B-cell lymphomas with diffuse morphology, whereas 5 patients presented with diffuse aggressive lymphomas and recurred with indolent lymphomas. Immunoreactivity for P53 correlated with higher histologic grade in lymphomas progressing from indolent to aggressive; however, only 1 patient who presented with aggressive lymphoma demonstrated a P53 gene mutation. Neither P53 immunoreactivity nor genotypic alterations correlated with presentation with an aggressive histology and relapse with FL. Growth fraction, as assessed by Ki-67 staining, and Trump expression correlated with histologic grade. Immunoreactivity for RB, BCL2, and MYC was seldom associated with progression. Eight of 9 cases tested exhibited identical immunoglobulin heavy and light chain rearrangements or identical BCL2 gene rearrangements in the sequential lymphomas. We conclude that P53 and Trump protein expression and proliferation activity correlate with histologic grade, but not with recurrence or progression of FL. Our results further indicate that progression of FL to diffuse aggressive lymphomas and presentation of an aggressive B-cell lymphoma followed by FL are clonally related.

Differential expression of cell-cycle regulatory proteins defines distinct classes of follicular lymphoma

“…In the image at the right side, note that p16 INK4a is expressed in B (CD20-positive) cells in most instances (B). mutations with FL progression and transformation [10][11][12], and IHC-detectable p53 protein expression with higher grade FL tumors, transformation, or accelerated progression [13][14][15][16]. We are aware of only 2 previous reports that directly evaluate the relationship between IHC-detectable p53 expression and survival in FL.…”

Low Stage Follicular Lymphoma: Biologic and Clinical Characterization According to Nodal or Extranodal Primary Origin

“…Immunohistochemical studies were performed on formalin-fixed, paraffin-embedded whole tissue sections as previously reported 21–23 using the following antibodies: BCL6 (mouse monoclonal, prediluted, Cell Marque), BCL2 (mouse, 1:20, Cell Marque), CD3 (rabbit polyclonal, 1:200, Cell Marque), CD10 (mouse, 1:20, Novacastra), CD21 (mouse, 1:20, Dako), Ki-67 (mouse, 1:200, Dako), CD20 (mouse, 1:1000, Dako). Human germinal center-associated lymphoma (HGAL) and LMO2 staining was performed as previously described.…”

Transformed follicular lymphoma

“…FL is composed of cells that resemble normal germinal centers, while aggressive lymphomas are characterized by the diffuse proliferation of large cells that efface the follicular architecture [14,56]. Biopsy with immunohistochemical examination remains the standard that is used to confirm t-FL.…”

“…At the time of transformation, 30% of DLBCL cases are BCL-6-positive, and more than 10% demonstrate translocation of MYC and BCL-2 in the germinal center [60]. Furthermore, while FL has a low proliferative index, t-FL usually has high Ki-67 expression (staining and transferrin receptor-related protein), which indicates a high proliferative index [56].…”