Recent molecular studies have shown that this chromosomal translocation results in the juxtaposition of the candidate proto-oncogene bcl-2 (B-cell leukemia-lymphoma) on chromosome 18 with the immunoglobulin heavy-chain locus on chromosome 14.
To define the role of the protein product of the bcl-2 gene in lymphoid cancers, we used anti-bcl-2 antibodies to perform immunohistochemical studies of frozen sections of 136 tissue specimens affected by lymphoma or non-neoplastic lymphoid disorders.
These data indicate that primary cutaneous lymphomas of B-cell origin share morphological and phenotypic similarities with the nodal B-cell lymphomas of follicular histotype, are proliferating, and express in 45% of cases clear monoclonal immunoglobulin light chain; the molecular analysis confirms the B-cell derivation and the monoclonal nature of this neoplasia; it also shows that neither bcl-2 nor c-myc oncogenes are involved and that no inappropriate rearrangements of the T-cell receptor genes are found in this lymphoma.
Furthermore, this case is unique in the direct demonstration of the histologic and clinical progression of a human lymphoma associated with the sequential rearrangement of the bcl-2 gene and the c-myc oncogene.
To determine the utility of Southern blot analysis for fine-needle aspiration samples, the authors prospectively analyzed immunoglobulin, T-cell receptor, c-myc, and bcl-2 gene rearrangements in 27 cases of known or suspected lymphoma.
That bcl-2 is involved in a major class of lymphoma in addition to follicular lymphoma implies a role for additional factors responsible for generating the two distinctive clinical and pathologic disease states.
It has been reported previously that the bcl-2 protooncogene protein is detectable in neoplastic cells from cases of human lymphoma in which the 14;18 chromosomal translocation is present, but not in lymphomas that lack this chromosomal rearrangement or in normal lymphoid tissue.
These included 12 of 20 cases of nodular follicular center cell lymphoma (nine small cleaved cell, one mixed small and large cell, and two large cell types). bcl-2 translocation was detected in only three of 45 cases of diffuse B-cell lymphoma, and cases of AIDS-related malignant lymphoma, monocytoid B-cell lymphoma, and mantle zone lymphoma were all negative.
Very high levels of BCL2 protein were found in three of nine neuroblastoma (NB) cell lines examined; these levels of p26-BCL2 were comparable to lymphoma cell lines that contain a t(14;18).
A bcl-2/JH gene fusion was detected only in three lymphoma subgroups: 13 of 33 centroblastic-centrocytic (39%), 2 of 37 centroblastic (6%), and 2 of 27 immunocytic (8%) were positive.
Breakpoints of a lymphoma case with bcl-2 gene rearrangement that did not show comigration of immunoglobulin (Ig) heavy chain joining (JH) fragment were cloned.
From these studies it is inferred that secondary dysregulation of a c-MYC in a lymphoma tumor carrying dysregulated BCL2 gene leads to rapid progression to high grade disease.
The t(14;18) chromosomal translocation that results in the juxtaposition of the bcl-2 proto-oncogene with the heavy chain JH locus is a common cytogenetic abnormality in human lymphoma.
In the immunophenotype study of 33 patients with FL, the expression of CD10 antigen correlated with bcl-2 involvement, whereas none of the other B markers emerged as parameters to distinguish between the two lymphoma groups; those with, and without, the rearrangements.
All 18 pretransformation follicular lymphoma specimens displayed at least one immunoglobulin gene and BCL-2 rearrangement in common with the corresponding histologically progressed lymphoma, indicating a clonal relationship between the original follicular lymphoma and the histologically transformed lymphoma.
PCR is a rapid and easy technique that can detect the abnormal rearrangement of the bcl-2 gene and clonal IgH rearrangement, indicating the presence of lymphoma.
BCL-2/IgH transcripts were demonstrated in 16 follicular center cell lymphoma cases (five high, 11 low) and were not present in any of the five non-neoplastic lymph nodes.
However, immunoblot analysis using antibodies specific for the Bcl-2 protein showed that 14 of 20 cases (70%) contained levels of p26-Bcl-2 that were equal to or greater than those found in a t(14;18)-bearing lymphoma cell line.
This tumor, only the fourth example of primary hepatic lymphoma in a child, has the rare finding of an HSR before treatment and is the first human lymphoma with t(8;14) that expresses bcl-2 protein.
The bcl-2-MBR gene rearrangement may possibly be associated with a shorter disease-free period, particularly in the specific setting of a lymphoma with extranodal presentation.