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Journal of Clinical Oncology, Vol 17, Issue 12 (December), 1999: 3804-3809
© 1999 American Society for Clinical Oncology

Classical Hodgkin's Disease and Follicular Lymphoma Originating From the Same Germinal Center B Cell

Theresa Marafioti, Michael Hummel, Ioannis Anagnostopoulos, Hans-Dieter Foss, Dieter Huhn, Harald Stein

From the Institute of Pathology and Consultation and Reference Center for Lymph Node Pathology and Haematopathology, University Hospital Benjamin Franklin, Free University Berlin; and Hematological Clinic at Virchow Klinikum of Charité, Humboldt University Berlin, Germany.

Address reprint requests to Harald Stein, MD, Institute of Pathology, Benjamin Franklin University Hospital, Free University Berlin, Hindenburgdamm 30, 12200 Berlin, Germany; email stein{at}ukbf.fu-berlin.de


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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- ({kappa}) 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.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
MALIGNANT LYMPHOMAS are traditionally classified into Hodgkin's disease and non-Hodgkin's lymphomas because they are regarded as distinct disease entities. However, recent studies suggest a closer relationship. Hodgkin's disease and non-Hodgkin's lymphomas have been observed to occur more frequently in the same patient than expected by chance.1,2 The vast majority of non-Hodgkin's lymphomas associated with Hodgkin's disease are of B-cell origin and most commonly represent follicular lymphomas.3,4 It was shown recently that Reed-Sternberg cells are also B-cell derivatives in most instances.4-7 This raised the question as to whether Hodgkin's disease and B-cell non-Hodgkin's lymphomas occurring in the same patient originate from the same B cell, or from unrelated B cells. In the latter case, the associated occurrence would be merely coincidental. To answer this question, we investigated the immunoglobulin gene rearrangements amplified from single isolated Reed-Sternberg cells of a case of classical Hodgkin's disease and compared these with the immunoglobulin gene rearrangements of the follicular lymphoma that developed 2 years later in the same patient.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Case Report
A 38-year-old male patient presented in 1993 with a cervical, axillary, and para-aortal lymphadenopathy. Biopsy of a cervical lymph node revealed a classical Hodgkin's disease of nodular sclerosing type, determined as Ann Arbor stage IIIB. Four cycles of chemotherapy (cyclophosphamide, vincristine, procarbazine, prednisone/doxorubicin, bleomycin, vinblastine, dacarbazine plus granulocyte-macrophage colony-stimulating factor) and para-aortal irradiation (30.6 Gy) resulted in a complete response. Two years later, the patient presented with enlarged cervical, para-aortal, and inguinal lymph nodes. The biopsies of a cervical lymph node and of the bone marrow showed the histologic and immunophenotypical features of a follicular lymphoma. The patient was treated with six cycles of cyclophosphamide, vincristine, and prednisone and six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone without response. Autologous bone marrow transplantation and mantle-field irradiation of the Waldeyer's ring and the abdomen were without significant effect. The patient died in 1997 of generalized manifestation of lymphoma. An autopsy was not performed.

Immunohistochemistry
Both lymph node biopsies were immunohistochemically analyzed by a panel of monoclonal and polyclonal antibodies against CD30 (Ber-H2), CD15 (C3D-1), LMP-1 (CS1-4), CD20 (L26), BCL-2 (clone 124), BCL-6 (clone 594), immunoglobulin M (IgM), IgD, IgG, CD3 (all from DAKO, Glostrup, Denmark), and CD10 (clone 5GC6; Novocastra, Newcastle-upon-Tyne, UK). All primary antibodies were applied after a high-pressure cooking pretreatment for antigen retrieval in a 10 mmol/L citrate buffer, pH 6.0. Specific binding of the antibodies was visualized either by alkaline phosphatase-antialkaline phosphatase (APAAP) technique or the biotin-avidin method.8,9

Isolation of Single Cells
A total of 32 CD30-positive single Reed-Sternberg cells were isolated from immunostained frozen sections of classical Hodgkin's disease using a hydraulic micromanipulation system.10 The isolated Reed-Sternberg cells were digested with proteinase K followed by polymerase chain reaction (PCR). Aliquots of the buffer covering the tissue sections during the cell isolation procedure served as negative controls.

DNA Extraction
DNA was extracted from 20-µm thick, formalin-fixed, paraffin-embedded sections of the follicular lymphoma, as described elsewhere.11 The DNA was dissolved in 100 µL distilled water, quantified photometrically, and used as a template for PCR.

Polymerase Chain Reaction, Cloning, and DNA Sequencing
PCR for the detection of rearranged Ig heavy- and {kappa} light-chain genes was performed, as previously described.7,10 In brief, for the detection of Ig heavy-chain gene rearrangement, a full-nested PCR, using family-specific frame-work (FW) 1 primers for the first amplification and family-specific FW2 primers for reamplification, was used in conjunction with two-nested primers for the Ig heavy-chain gene (JH) joining region. For amplification of rearranged {kappa} light-chain genes, a full-nested PCR was applied with nested family-specific FW1 primers in combination with two different sets of primers specific for Ig kappa-chain gene (JK). For single cell analysis, the first and second amplifications were carried out with 40 cycles each; whereas, the investigation for the presence of clonal variable domain of heavy-chain gene Ig (VH) rearrangements in whole-tissue DNA extracts was performed with 40 and 25 cycles. PCR products were cut out from the gel and subjected to direct DNA sequencing or, alternatively, cloned into plasmid for the determination of ongoing mutations. The resulting sequences were compared with corresponding germ-line segments (VBASE) for analysis of somatic mutations or with each other to detect intraclonal diversities.11 To determine the coding capacity of the rearranged genes, the sequences were translated into amino acids.11,12

The major break point region of the (14;18) translocation was analyzed by semi-nested PCR using the BCL-2 primers, described by Stetlet-Stevenson et al,13 in conjunction with the JH primers described above. Several follicular lymphomas with known (14;18) translocation served as positive controls.

In-Situ Hybridization
In-situ hybridization for the detection of mRNA transcripts was carried out as previously reported.14 The Ig light-chain probes were kindly provided by Dr. Philip Leder, Harvard Medical School (Boston, MA). The probes for the constant region of the Ig heavy-chains (µ, {delta}, and {gamma}) were prepared from cDNA obtained from peripheral blood lymphocytes or B-cell lines. The nucleotide sequence of all probes was confirmed by DNA sequencing.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Phenotypical Features
The results of the immunohistochemical analysis of the Hodgkin's disease and the follicular lymphoma that developed in the same patient 2 years apart are summarized in Table 1 and illustrated in Fig 1. In brief, the Reed-Sternberg cells were positive for CD30 and CD15 and negative for CD20, CD3, CD10, BCL-6, and for the Epstein-Barr virus encoded latent membrane protein-1. BCL-2 expression was found in the majority of the Reed-Sternberg cells. Radioactive in-situ hybridization revealed a weak expression of Ig {kappa} light-chain mRNA in some Reed-Sternberg cells, whereas Ig heavy-chain (µ, {delta}, and {gamma}) and Ig {lambda} light-chain mRNA proved to be completely absent. The neoplastic cells of the follicular lymphoma showed a typical immunophenotype characterized by the expression of CD20, CD10, BCL-6, and BCL-2. Ig heavy (µ) and light ({kappa}) chain were detectable at both the protein and the RNA level.


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  		Table 1. Comparison of Phenotypical Features of a Case of Hodgkin's Disease With a Follicular Lymphoma That Developed 2 Years Later in the Same Patient
 


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  		Fig 1. Morphologic and phenotypical features of the two different lymphomas occurring in the same patient. Hodgkin's disease: (A) Hematoxylin and eosin stain. (C) Immunolabeled for CD30; all Reed-Sternberg cells are CD30-positive. (APAAP) (E) In-situ hybridization for IgL{kappa} transcripts; Reed-Sternberg cells are negative (arrows), with the exception of low amounts of the IgL{kappa} mRNA (insert) in some cells. Follicular lymphoma: (B) Follicular lymphoma with neoplastic follicles (hematoxylin and eosin staining) consisting of centroblasts and centrocytes (insert; Giemsa staining). (D) Immunolabeling for BCL-2 protein (APAAP). The neoplastic cells are positive. (F) In-situ hybridization for IgL{kappa} transcripts. The neoplastic cells are strongly positive. Note: In (E) and (F), normal plasma cells show strong positive signal, the scattered reactive B lymphocytes are moderately labeled.

 

Genotypical Features
The tumor cells of both lymphomas showed the same VH gene rearrangement involving the same variable segment DP42 (VH3) and the same joining segment (JH5). The rearranged VH genes of the Reed-Sternberg cells and those of the follicular lymphoma cells carried seven and 21, somatic mutations, respectively, when compared with the corresponding germ-line segment (DP42) (Fig 2). Six of the 21 mutations present in the follicular lymphoma cells were identical to those found in the Reed-Sternberg cells (Table 2). The complementarity determining region 3 (CDR3) was 15 base pairs long in the Reed-Sternberg cells and 30 base pairs in the follicular lymphoma cells. The 15 base pairs present in both CDR3s proved to be identical in sequence (Fig 2). Identically rearranged Ig {kappa} light-chains were detectable in all PCR-positive Reed-Sternberg cells. The comparison with the corresponding databank germ-line sequence (VK2) demonstrated eight somatic mutations.



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  		Fig 2. Rearranged Ig gene sequences in the tumor cells of Hodgkin's disease and follicular lymphoma occurring in the same patient. VH3(DP42): Corresponding germ-line segment; dashes indicate sequence identity. Letters in bold show identical mutations in the Reed-Sternberg cells and follicular lymphoma cells; the 15 base deletion in the CDR3 of the Reed-Sternberg cells is indicated by dots.

 

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  		Table 2. Comparison of Molecular Features of the Rearranged Ig Heavy-Chain Gene of the Reed-Sternberg Cells and Follicular Lymphoma Cells in the Same Patient
 

All Ig heavy- and light-chain gene rearrangements obtained from the isolated Reed-Sternberg cells were identical, whereas cloning of the VH rearrangement derived from the follicular lymphoma disclosed intraclonal diversities (data not shown). The translation of the Ig gene heavy- and light-chain rearrangements into amino acids showed a preserved coding capacity for all rearranged Ig genes. Furthermore, no (14;18) translocation was detectable by PCR for the major break point region in either lesions.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Hodgkin's disease and follicular lymphoma represent two morphologically, immunophenotypically, and clinically different lymphoid neoplasms. Here we report a patient who developed follicular lymphoma 2 years after Hodgkin's disease. There are three possible explanations for this associated occurrence (Fig 3): (1) Both neoplasms arose coincidentally from two unrelated B cells; (2) the Hodgkin's disease progressed linearly to a follicular lymphoma; or (3) both lymphomas derived from a common precursor cell. To determine which of these possibilities is valid, we compared the Ig gene rearrangements amplified from single Reed-Sternberg cells of the Hodgkin's disease with those in DNA extracted from the follicular lymphoma. Both neoplastic populations shared the same sequence in the CDR3, the same Ig heavy-chain joining segment (JH5), and the same VH3 segment (DP42), demonstrating their derivation from the same B cell.



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  		Fig 3. Possible models for the development of Hodgkin's disease and associated follicular lymphoma. (A) Hodgkin's disease and follicular lymphoma arise from unrelated B cells. (B) Linear progression of Hodgkin's disease to follicular lymphoma. (C) Hodgkin's disease and follicular lymphoma evolve from a common precursor B cell.

 

The VH genes of both tumor cell populations displayed different somatic mutations. Seven mutations were present in the Reed-Sternberg cells and 21 in the follicular lymphoma, six of which proved to be identical in both tumor cell populations. This revealed a common precursor B cell with six VH gene mutations (Fig 4). Because VH gene mutations are introduced only in a germinal center reaction, the differentiation stage of the common precursor could be determined as that of a germinal center B cell.



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  		Fig 4. Development of Hodgkin's disease and follicular lymphoma from the same germinal center B-cell precursor identified by six common somatic VH gene mutations. The descendants giving rise to Reed-Sternberg cells acquired one further mutation and a 15 base-pair deletion, whereas those transforming into follicular lymphoma cells gained 16 additional mutations (15 in the VH region and one in the CDR3). Symbols: •, VH mutation; {bigtriangleup}, Fifteen base-pair deletion in the CDR3;    , Transforming event.

 
The differences in the VH mutations show that the descendants of the common precursor cell developed independently of each other into Reed-Sternberg cells and follicular lymphoma cells. The descendants giving rise to Reed-Sternberg cells acquired one further mutation and lost 15 bases in the CDR3, whereas the descendants developing into the follicular lymphoma gained 16 more mutations (Fig 4). In addition, the follicular lymphoma cells showed signs of ongoing mutations. These findings exclude a direct progression of Hodgkin's disease into the follicular lymphoma but indicate that the development into the two independent lymphomas took place from a common precursor cell within a germinal center under the influence of its mutational machinery. Previous reports on the simultaneous or subsequent occurrence of classical Hodgkin's disease or lymphocyte predominance Hodgkin's disease with other B-type non-Hodgkin's lymphomas (eg, B-cell chronic lymphocytic leukemia, marginal zone lymphomas, and large B-cell lymphomas) favor a direct progression.15-17 This also holds true for the association of follicular lymphoma and Hodgkin's disease, where a derivation from follicular lymphoma tumor cells into Reed-Sternberg cells was proposed based on the rare finding of an identical translocation (14;18).4 Our findings, however, challenge the general validity of this view and show that associated B-cell neoplasms may also derive from a common precursor (Fig 4).

It is widely believed that in lymphomas transforming events usually more or less preserve the phenotype of the cell that is the precursor of the tumor cell clone.1 This is seen in the follicular lymphoma of our patient, which shares the phenotypical features with the precursor cell. The development of the same precursor cell into Reed-Sternberg cells reveals, however, that the malignant transformation can also be associated with a complete change of the phenotype, which is characterized by a huge cell size, frequent multinuclearity, very prominent eosinophilic nucleoli, loss of expression of Ig, CD10, BCL-6, and gain of CD30 and CD15. Of particular interest is the loss of Ig expression at the protein and transcriptional level because this phenomenon has been generally attributed to crippling mutations in the V genes of the Reed-Sternberg cells.7,18 However, in the present Hodgkin's disease case, the coding region of the Ig gene was (despite the deletion in the CDR3) functional in the Reed-Sternberg cells as in the follicular lymphoma cells, implying that mechanisms other than crippling mutations, eg, alterations in the regulatory Ig gene segments or inactivation of the transcription machinery, were responsible for the loss of Ig expression.

In conclusion, the Hodgkin's disease and the follicular lymphoma that occurred in the same patient are derived from a common germinal center B cell. A linear progression of the Reed-Sternberg cells into the tumor cells of the follicular lymphoma and the derivation of both tumor cell populations from two unrelated B cells can be ruled out on the basis of our data. This indicates that the transforming events are more important than the cell of origin in determining the morphologic, immunophenotypical, and clinical features of a lymphoma entity and that Hodgkin's disease is more closely related (in difference to previously held views) to B-cell non-Hodgkin's lymphomas than to CD30-positive anaplastic large-cell lymphomas.


   ACKNOWLEDGMENTS
 
We thank H. Lammert, H.-H. Müller, D. Jahnke, H. Protz, and E. Berg for their excellent technical assistance and L. Udvarhelyi for his editorial assistance.

Supported by grants from the Deutsche Krebshilfe and by the Berliner Krebsgesellschaft


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Harris NL: The relationship between Hodgkin's disease and non-Hodgkin's lymphoma. Sem Diagn Pathol9:304-310, 1992

2. Jaffe ES, Zarate-Osorno A, Medeiros LJ: The interrelationship of Hodgkin's disease and non-Hodgkin's lymphoma: Lessons learned from composite and sequential malignancies. Semin Diagn Pathol9:297-303, 1992[Medline]

3. Gonzalez CL, Medeiros J, Jaffe ES: Composite lymphoma: A clinicopathologic analysis of nine patients with Hodgkin's disease and B-cell non-Hodgkin's lymphoma. Am J Clin Pathol96:81-89, 1991[Medline]

4. LeBrun DP, Ngan BY, Weiss LM, et al: The bcl-2 oncogene in Hodgkin's disease arising in the setting of follicular non-Hodgkin's lymphoma. Blood83:223-230, 1994[Abstract/Free Full Text]

5. Hummel M, Marafioti T, Zieman K, et al: Ig rearrangement in isolated Reed-Sternberg cells: Conclusions from four different studies. Ann Oncol7:31-35, 1996[Abstract/Free Full Text]

6. Hummel M, Ziemann K, Lammert H, et al: Hodgkin's disease with monoclonal and polyclonal populations of Reed-Sternberg cells. N Engl J Med333:901-906, 1995[Abstract/Free Full Text]

7. Kanzler H, Kueppers R, Hansmann ML, et al: Hodgkin and Reed-Sternberg cells in Hodgkin's disease represent the outgrowth of a dominant tumor clone derived from (crippled) germinal center B cells. J Exp Med184:1495-1505, 1996[Abstract/Free Full Text]

8. Hsu SM, Raine L, Fanger H: Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: A comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem29:577-580, 1981[Abstract]

9. Cordell JL, Falini B, Erber WN, et al: Immunoenzymatic labelling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP complexes). J Histochem Cytochem32:219-229, 1984[Abstract]

10. Marafioti T, Hummel M, Anagnostopoulos I, et al: Origin of nodular lymphocyte-predominant Hodgkin's disease from a clonal expansion of highly mutated germinal-center B cells. N Engl J Med337:453-458, 1997[Abstract/Free Full Text]

11. Cook GP, Tomlinson IM: The human immunoglobulin VH repertoire. Immunol Today16:237-242, 1995[Medline]

12. Hummel M, Tamaru J, Kalvelage B, et al: Mantle cell (previously centrocytic) lymphomas express VH genes with no or very little somatic mutations like the physiologic cells of the follicle mantle. Blood84:403-407, 1994[Abstract/Free Full Text]

13. Stetlet-Stevenson M, Raffeld M, Cohen P, et al: Detection of occult follicular lymphoma by specific DNA amplification. Blood72:1822-1825, 1988[Abstract/Free Full Text]

14. Foss HD, Herbst H, Oelmann E, et al: Lymphotoxin, tumour necrosis factor and interleukin-6 gene transcripts are present in Hodgkin and Reed-Sternberg cells of most Hodgkin's disease cases. Br J Haematol84:627-635, 1993[Medline]

15. Wickert RS, Weisenburger DD, Tierens A, et al: Clonal relationship between lymphocytic predominance Hodgkin's disease and concurrent or subsequent large-cell lymphomas of B-cell lineage. Blood86:2312-2320, 1995[Abstract/Free Full Text]

16. Ohno T, Trenn G, Wu G et al: The clonal relationship between nodular sclerosis Hodgkin's disease with a clonal Reed-Sternberg cell population and a subsequent B-cell small noncleaved lymphoma. Mod Pathol11:485-490, 1998[Medline]

17. Ohno T, Smir BN, Weisenburger DD, et al: Origin of the Hodgkin/Reed-Sternberg cells in chronic lymphocytic leukemia with Hodgkin's transformation. Blood91:1757-1761, 1998[Abstract/Free Full Text]

18. Kueppers R, Rajewsky K: The origin of Hodgkin and Reed-Sternberg cells in Hodgkin's disease. Annu Rev Immunol16:471-493, 1998[Medline]

Submitted April 2, 1999; accepted July 22, 1999.




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