Hodgkin lymphoma with in-situ follicular lymphoma
The lymph node shows histological findings typical for the nodular sclerosis variant of classical Hodgkin lymphoma (Images 1, 2, 3, 4 and 5). The nodal architecture is effaced by large nodules and thick fibrous bands. The nodules are composed of numerous large atypical cells with multilobated nuclei and prominent nucleoli admixed with small lymphocytes, plasma cells, and granulocytes. "Mummified" cells and "lacunar" cells with prominent cytoplasmic retraction artifact are also seen.
Immunohistochemical studies reveal that the large cells have a profile compatible with classic Hodgkin lymphoma including positivity for CD30, CD15, MUM-1, PAX5, OCT-2 and negativity for BOB.1, CD45, and EBER (Images 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 and 22). Some of the larger cells appear to express T-cell antigens including CD2, CD3, CD4, CD5, and CD8. Although the expression of T-cell antigens on Hodgkin and Reed-Sternberg cells (HRS) cells is not common, it has been reported (1).
Additionally, the lymph node shows involvement by an in-situ follicular lymphoma (Images 6, 7 and 8). Immunohistochemical stains highlight some residual small follicles that are positive for CD20, CD10, and bcl-2 (Images 23, 24, 25 and 26). Furthermore, this diagnosis is supported by the flow cytometric studies which reveal a small population of kappa restricted cells that are positive for CD20, CD19, CD10, and bcl-2, and negative for CD5 (Images 27, 28, 29, 30, 31, 32 and 33).
Polymerase chain reaction (PCR) analyses of the immunoglobulin heavy chain and kappa light chain reveal patterns suspicious for monoclonal rearrangement using BIOMED-2 primers directed at the framework region 1 (FR1), framework region 2 (FR2), and kappa light chain (Images 34, 35, 36, 37 and 38). The monoclonal bands seen using probes directed at the FR1 and FR2 regions are just outside of the size range that is typically assessed for rearrangement. The kappa light chain analysis demonstrates a signal at a position that is typically viewed as nonspecific, but the intensity of the amplification is marked. PCR analyses using probes directed at the framework region 3 and kappa deleting element are negative. No clonal rearrangements are detected in the T-cell receptor beta chain and T-cell receptor gamma chain genes.
Previous reports have described Hodgkin lymphoma and follicular lymphoma in the same patient. In one report, individual cells from both tumors were isolated through microdissection and the two tumors were shown to have identical rearrangements in the VH, VK, and Vλ genes. Additionally, the two tumors were found to have V gene somatic mutations that were common and also mutations that were found in only the Hodgkin lymphoma or follicular lymphoma (2). In a second reported case, an individual underwent treatment for a Hodgkin lymphoma and developed a follicular lymphoma two years later. After microdissection of the tumors, analysis of the immunoglobulin gene revealed the same sequences in the CDR3, the heavy chain joining segment (JH5) and the variable segment DP42 (VH3). Seven VH gene somatic mutations were found in the Hodgkin lymphoma while 21 were found in the follicular lymphoma; however, six of the mutations were identical (3). Similar findings were described in a third case in an individual with a composite Hodgkin lymphoma and follicular lymphoma. In this case, immunoglobulin gene analysis showed identical VH and Vλ clones in the Hodgkin and follicular lymphomas, but the two lymphomas had both common and distinct somatic mutations (4).
These cases of Hodgkin lymphoma and follicular lymphoma occurring in the same individual provide insight into the pathogenesis of these diseases. The finding of shared immunoglobulin genes in the Hodgkin and follicular lymphomas in each case shows that they were derived from the same precursor B-cell. Additionally, the finding that the two tumors contained common and exclusive VH gene somatic mutations demonstrates that the precursor cell was of germinal center phenotype as these mutations are only introduced in germinal center reactions (5). These cases also showed continuing somatic mutations within the immunoglobulin genes of the follicular lymphomas, which is typical. It is likely that the precursor B-cells in each case underwent a transforming event that was shared by both tumors and then additional transforming events specific to each tumor subsequently occurred.
Contributed by Stephen Hastings, MD, Marie DeFrances, MD, PhD, Miroslav Djokic, MD