Coexistence of malignant melanoma, Hodgkin's disease and follicular lymphoma with expression of the B-cell leukaemia/lymphoma (bcl-2) oncogene

PURPOSE: Classical Hodgkin's disease and non-Hodgkin's B-cell lymphoma occasionally occur in the same patient. To clarify whether these different diseases share a common precursor cell, we analyzed the immunoglobulin rearrangements in tumor cells of the classical Hodgkin's disease and the follicular lymphoma that developed in the same patient 2 years apart. PATIENTS AND METHODS: Polymerase chain reaction (PCR) for the detection of rearranged immunoglobulin genes was carried out on single Reed-Sternberg cells and on whole tissue DNA extracted from the follicular lymphoma. PCR products were sequenced and compared with each other and with germ line immunoglobulin variable segments. Immunoglobulin heavy- and light-chain transcripts were analyzed by radioactive in-situ hybridization. RESULTS: The same monoclonal immunoglobulin gene rearrangement was found in both neoplasms. The variable region of the immunoglobulin heavy-chain genes of the Reed-Sternberg and of the follicular lymphoma cells were differently mutated, but six somatic mutations were shared by both lymphoma cells. Although the coding capacity of the immunoglobulin genes was preserved in both neoplastic cell populations, immunoglobulin heavy- (μ) and light- (κ) chain expression was restricted to the follicular lymphoma cells, except for small amounts of kappa light-chain mRNA in some Reed-Sternberg cells. CONCLUSIONS: The neoplastic cells of the Hodgkin's disease and the follicular lymphoma that occurred in this patient derived from a common precursor B cell. Its differentiation stage could be identified as that of a germinal center B cell. Thus, transforming events can be more important than the cell of origin in determining a disease entity.

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Common Germinal-Center B-Cell Origin of the Malignant Cells in Two Composite Lymphomas, Involving Classical Hodgkin’s Disease and Either Follicular Lymphoma or B-CLL

Molecular Medicine ◽

10.1007/bf03402211 ◽

2001 ◽

Vol 7 (5) ◽

pp. 285-292 ◽

Cited By ~ 63

Author(s):

Ralf Küppers ◽

Ana B. Sousa ◽

Audrey S. Baur ◽

John G. Strickler ◽

Klaus Rajewsky ◽

...

Keyword(s):

Follicular Lymphoma ◽

B Cell ◽

Germinal Center ◽

Hodgkin's Disease ◽

Hodgkin’S Disease ◽

Malignant Cells ◽

Germinal Center B Cell

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Distinctive expression pattern of the BCL-6 protein in nodular lymphocyte predominance Hodgkin's disease

Blood ◽

10.1182/blood.v87.2.465.bloodjournal872465 ◽

1996 ◽

Vol 87 (2) ◽

pp. 465-471 ◽

Cited By ~ 79

Author(s):

B Falini ◽

B Bigerna ◽

L Pasqualucci ◽

M Fizzotti ◽

MF Martelli ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

B Cell ◽

Germinal Center ◽

Hodgkin's Disease ◽

Cd4 T Cells ◽

Zinc Finger Protein ◽

Hodgkin’S Disease ◽

Malignant Cell ◽

Germinal Center B Cells

The BCL-6 gene encoding a nuclear-located Kruppel-type zinc finger protein is rearranged in about 30% diffuse large B-cell lymphomas and is expressed predominantly in normal germinal center B cells and related lymphomas. These findings suggest that BCL-6 may play a role in regulating differentiation of normal germinal center B cells and that its deregulated expression caused by rearrangements may contribute to lymphomagenesis. This prompted us to investigate the expression of the BCL-6 protein in Hodgkin's disease (HD), focusing on the nodular lymphocyte predominance subtype (NLPHD), which differs from classical HD by virtue of the B-cell nature of the malignant cell population (so- called L&H cells) and its relationship with germinal centers. Forty-one HD samples (19 NLPHD, 12 nodular sclerosis, and 10 mixed cellularity) were immunostained with the monoclonal antibodies PG-B6 and PG-B6p that react with a fixative-sensitive and a formalin-resistant epitope on the aminoterminal region of the BCL-6 gene product, respectively. Strong nuclear positivity for the BCL-6 protein was detected in tumor (L&H) cells in all cases of NLPHD. In contrast, BCL-6 was expressed only in a small percentage of Hodgkin and Reed-Sternberg cells in about 30% of classical HD cases. Notably, the nuclei of reactive CD3+/CD4+ T cells nearby to and rosetting around L&H cells in NLPHD were also strongly BCL-6+, but lacked CD40 ligand (CD40L) expression. This staining pattern clearly differed from that of classical HD, whose cellular background was made up of CD3+/CD4+ T cells showing the BCL-6-/CD40L+ phenotype. These results further support the concept that NLPHD is an histogenetically distinct, B-cell-derived subtype of HD and suggest a role for BCL-6 in its development.

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T-cell-rich B-cell lymphoma and lymphocyte-predominant Hodgkin's disease: two closely related entities?

British Journal of Haematology ◽

10.1111/j.1365-2141.1995.tb05165.x ◽

1995 ◽

Vol 90 (2) ◽

pp. 398-403 ◽

Cited By ~ 28

Author(s):

U. SCHMIDT ◽

K. A. METZ ◽

L.-D. LBDER

Keyword(s):

T Cell ◽

B Cell ◽

Hodgkin's Disease ◽

Cell Lymphoma ◽

Hodgkin’S Disease ◽

B Cell Lymphoma

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MALIGNANT LYMPHOMA IN CHILDREN

PEDIATRICS ◽

10.1542/peds.28.6.985 ◽

1961 ◽

Vol 28 (6) ◽

pp. 985-992

Author(s):

Richard J. Bailey ◽

E. Omer Burgert ◽

David C. Dahlin

Keyword(s):

Follicular Lymphoma ◽

Malignant Lymphoma ◽

Hodgkin's Disease ◽

Radiation Treatment ◽

Hodgkin’S Disease ◽

Effective Means ◽

Surgical Removal ◽

Term Survival ◽

Localized Disease

On the basis of observations made on 76 children with malignant lymphoma, of whom 28 had Hodgkin's disease (25 with Hodgkin's granuloma and 3 with Hodgkin's sarcoma) and 48 had lymphosarcoma, the following conclusions are drawn: Hodgkin's granuloma has a fairly prolonged course in childhood with a relatively good outlook for 5-year survival, but late recurrences are more common than in the lymphosarcoma group. Lymphosarcoma, excluding giant follicular lymphoma, has a more rapidly malignant course than does Hodgkin's granuloma, but long-term survival does occur in instances of localized disease involving the peripheral nodes on the small intestine. Chemotherapy and radiation therapy provide effective means for controlling Hodgkin's disease and giant follicular lymphoma, even when disease is widespread. Localized disease, when it occurs in malignant lymphoma, requires vigorous radiation treatment. In selected cases, radical surgical removal prior to radiation is indicated. The outlook for these patients is good.

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Nodular lymphocyte-predominant Hodgkin's disease associated with large- cell lymphoma: analysis of Ig gene rearrangements by V-J polymerase chain reaction

Blood ◽

10.1182/blood.v88.2.657.bloodjournal882657 ◽

1996 ◽

Vol 88 (2) ◽

pp. 657-666 ◽

Cited By ~ 57

Author(s):

TC Greiner ◽

RD Gascoyne ◽

ME Anderson ◽

DW Kingma ◽

SA Adomat ◽

...

Keyword(s):

Polymerase Chain Reaction ◽

B Cell ◽

Hodgkin's Disease ◽

Hodgkin’S Disease ◽

Large Cell ◽

Single Step ◽

Chain Gene ◽

Gene Rearrangements ◽

Chain Reaction ◽

Polymerase Chain

The clonality of nodular lymphocyte-predominant Hodgkin's disease (NLPHD) and the relationship to composite or sequential large-cell lymphomas (LCLs) is poorly understood. Clonal Ig heavy-chain gene rearrangements (lgHGR) have infrequently been observed in NLPHD by Southern hybridization. The goals of this study were (1) to determine if IgHGR could be identified by polymerase chain reaction (PCR) techniques in the LCL associated with NLPHD; (2) to determine if the lgHGR identified in the LCL could also be found in the associated NLPHD; and (3) to determine if Epstein-Barr virus (EBV) played a role a role in histologic progression to LCL. Using consensus primers to conserved regions in the lgH variable (V) and joining (J) region genes, we analyzed formalin-fixed paraffin-embedded sections from the biopsies of 25 patients referred to the National Cancer Institute (NCI) registry for NLPHD and LCL using both single-step and seminested V-J PCR. The histologically aggressive component was further subclassified as frank LCL or as L&H-cell-rich, but not fulfilling criteria for LCL. Matched samples representing both NLPHD and aggressive components were available in 13 cases. In 12 cases, only one component was available (aggressive, n = 8; NLPHD, n = 4). In addition, we also amplified, with 32P labeling, 12 cases of NLPHD without associated LCL. Two clonal IgHGR were identified in 29 cases (7%) of typical NLPHD, both of which were associated with LCL containing a similar sized band by PCR. The clonal identity of the bands in the NLPHD and associated LCL was confirmed by sequencing the products in these two cases. Eight of 10 cases (80%) of LCL associated with NLPHD contained a clonal band by this technique. By contrast, none of the cases classified as L&H-cell- rich contained an IgHGR. The single-step and seminested PCR methods produced identical results. All clonal LCLs were studied for EBV sequences by in situ hybridization using the EBER1 probe, and were negative. We conclude that the LCLs associated with NLPHD are clonal B- cell malignancies. However, by these methods, the same clone can be identified in only a minority of cases of NLPHD and LCL. EBV does not appear to play a role in histologic progression. Moreover, our results suggest that many cases suspected of being LCL may actually represent NLPHD with increased numbers of L&H cells. In histologically equivocal cases, the diagnosis of LCL should be reserved for those cases in which a clonal B-cell neoplasm can be demonstrated.

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Serum-Protein Changes in Malignant Disease. II. The Chronic Leukemias, Hodgkin's Disease, and Malignant Melanoma

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/25.6.1381 ◽

1960 ◽

Keyword(s):

Malignant Melanoma ◽

Serum Protein ◽

Hodgkin's Disease ◽

Malignant Disease ◽

Hodgkin’S Disease

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CD30 (Ki-1)-positive malignant lymphomas: clinical, immunophenotypic, histologic, and genetic characteristics and differences with Hodgkin's disease

Blood ◽

10.1182/blood.v87.7.2905.bloodjournal8772905 ◽

1996 ◽

Vol 87 (7) ◽

pp. 2905-2917 ◽

Cited By ~ 44

Author(s):

DA Filippa ◽

M Ladanyi ◽

N Wollner ◽

DJ Straus ◽

JP O'Brien ◽

...

Keyword(s):

Bone Marrow ◽

B Cell ◽

Hodgkin's Disease ◽

Hodgkin’S Disease ◽

Bone Marrow Involvement ◽

Skin Lesions ◽

Cell Phenotype ◽

Cell Type ◽

Null Cell

This study compares the histologic and immunophenotypic features of 71 cases of primary CD30+ diffuse large-cell lymphomas (DLCL) and 128 cases of Hodgkin's disease (HD) and discusses the clinical features of 52 patients with CD30+ DLCL. It includes analysis of sites of involvement, staging, response to treatment, sites and treatment of recurrences, and disease-free and overall survival. Diagnostic immunophenotypic differences were found between CD30+ DLCL and HD. All cases of CD30+ DLCL were positive for one or more common or lineage- specific lymphocyte antigens or for EMA. In contrast, 96.9% of HD cases were negative for CD45, CD45-RO, CD43, and CD20. The four exceptions are discussed. All cases of HD were negative for EMA. In patients with CD30+ DLCL, a T-cell phenotype was found in 60%, a null-cell type in 22%, and a B-cell type in 18% of the cases. The median age of patients with T- and null-cell phenotype was 22 years (range, 4 to 72). Fifty- two percent of them had high-stage (III and IV) disease and 61% had extranodal involvement at presentation, including 25% with skin lesions. Lymph nodes draining the skin lesions became involved in seven of 11 patients. No patient had initial bone marrow involvement. Most patients were treated with chemotherapy, and 83% had a complete remission. Fifty-four percent remain free of disease with a median follow-up of 47 months. Thirteen patients (29%) had one or more recurrences and five of them remain free of disease after salvage therapy, with a median follow-up period of 79 months. The clinical stage did not affect survival, probably as a result of different therapy. The t(2;5) translocation was found in five of 15 patients who had cytogenetic abnormalities. Of the other 10 cases, the translocation was detected by reverse transcriptase-polymerase chain reaction (RT- PCR) in four of five cases studied. All nine cases were of T- or null- cell phenotype. The cases of B-cell CD30+ DLCL had a characteristic immunophenotype. All were negative for EMA. These patients were older and had frequent bone marrow involvement but no skin infiltration by lymphoma. All three patients who were human immunodeficiency virus- positive (HIV+) had lymphomas of B-cell lineage. Detection of the t(2;5) translocation by molecular genetics is a useful and highly specific marker in the differential diagnosis between HD and CD30+ DLCL.

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Hodgkin's disease with a B-cell phenotype often shows a VDJ rearrangement and somatic mutations in the VH genes

Blood ◽

10.1182/blood.v84.3.708.708 ◽

1994 ◽

Vol 84 (3) ◽

pp. 708-715 ◽

Cited By ~ 83

Author(s):

J Tamaru ◽

M Hummel ◽

M Zemlin ◽

B Kalvelage ◽

H Stein

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Hodgkin's Disease ◽

Somatic Mutations ◽

Hodgkin’S Disease ◽

Receptor Gene ◽

High Sensitivity ◽

Cell Phenotype ◽

Igh Genes

Abstract The nature of Hodgkin and Reed-Sternberg (HRS) cells remains in question. Immunophenotypic studies favor a relation to the lymphoid lineage with the existence of B- and T-cell types. However, studies on the detection of antigen (Ag) receptor gene rearrangements provided inconsistent results. They concur in that rearranged Ig and T-cell receptor (TCR) genes are not demonstrable in most Hodgkin's disease (HD) cases. To clarify whether this is because of the insensitivity of the method of detection or a real absence of clonal Ig heavy chain (IgH) rearrangements, a polymerase chain reaction (PCR) method with high sensitivity was applied, allowing the detection of less than 50 cells with clonally rearranged IgH genes in a mixture of 100,000 germline or individually rearranged cells. In 67 cases of HD, most of those (67%) with B-Ag+ HRS cells express clonal VDJ rearrangements of the IgH gene. No cases with T-cell Ag+ HRS cells harbored detectable clonal VDJ rearrangements. Of 10 sequenced rearranged IgH genes, the VH segment of six contained considerable somatic mutations. These results suggest that the demonstrated VDJ rearrangements stem from the HRS cells themselves and that the HRS cells of cases with rearranged IgH genes are B-cell related and correspond in their differentiation stage either to naive pregerminal center B cells or (more commonly) to germinal center/postgerminal center-derived memory B cells.

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