Non-Hodgkin’s Lymphoma Case Study

INTRODUCTION

Hematological malignancy, including malignant lymphoma, acute leukemia, multiple myeloma, chronic lymphocytic leukemia, and other myeloproliferative disorders, occurred 3.6 times more frequently in families with hematological malignancy compared with the control study groups of non-neoplastic hematological disorders (1). Thus it seems that hereditary factors may play an important role in the etiology of hematological malignancy.

There have been few reports of familial occurrences of malignant lymphoma including Hodgkin’s disease (HD) and non-Hodgkin’s lymphoma (NHL) (1–7). Genetic, infectious, and environmental factors had been implicated in causing familial malignant lymphoma (1–7). The defective proto-oncogene and inactivation of the tumor suppressor gene, hereditary or acquired immune deficiency, vertical transmission of infectious agents, inability to detoxify carcinogens, and exposure to harmful environmental factors may also be involved in the pathogenesis of familial NHL (1–7).

We present two cases of NHL of B-cell origin in first-degree relatives, a father and a son, generated within a short period of each other, and discuss the possible common pathogenetic mechanism of the occurrence in these patients.

CASE REPORT

The pedigree chart is shown in Fig. 1.

Case 1

A 73-year-old male, a retired cloth maker, who had been suffering from chronic thyroiditis since September 1998, was admitted to our hospital. He complained of the neck lymph node swelling since March 1999. A thyroid tumor was not observed. Biopsy specimens of the lymph nodes revealed diffuse large cell NHL, and flow cytometric analysis of the lymphoma cells showed CD5 3.0%, CD10 1.1%, CD19 98.1%, CD20 98.3%. A gastroscopic examination of the stomach revealed multiple ulcers and biopsy showed the infiltration of lymphoma cells. HBs antigen and antibodies for HBs, HCV and human T-lymphotropic virus 1 (HTLV1) were negative. Antibodies for Epstein–Barr (EB) virus were not examined. Serum immunoglobulin levels at admission were IgG 400 mg/dl, IgA 98 mg/dl and IgM 17 mg/dl. These levels had not been measured before the onset of NHL. Soluble interleukin (IL)-2 receptor was 1380 u/ml (normal value 220–530 u/ml). Chromosome analysis of lymphoma cells did not reveal any abnormalities. The I (JH) gene had been rearranged. The rearrangement of the bcl-2 gene was studied by Southern blotting using a probe of 2.8 kb EcoRI–HindIII fragment in exon 3. The bcl-2 gene had not been rearranged. There had been no rearrangement of the chimeric IgH (JH)/bcl-2 genes. A mutation of the nucleotide of the p53 gene in codon 175 of exon 5 from CAG (Arg) to CAC (His) was observed by Southern blotting and direct sequencing. The EB virus DNA was not observed. The NHL was refractory to repeated courses of chemotherapy consisting of five courses of THP–CVP (pirarubicin, cyclophosphamide, vincristine, prednisolone), three courses of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) and one course of modified DHAP (dexamethasone, cytosine arabinoside, carboplatin). The patient died in January 2000.

Case 2

A 43-year-old male, the son of patient 1, was admitted to our hospital complaining of abdominal fullness in September 1999. The patients had been living together and the son had been working as a tire maker. Physical examination revealed huge hepatomegaly reaching into the pelvic cavity and generalized lymph node swelling. Biopsy of the lymph nodes revealed small cleaved cell follicular NHL and flow cytometric analysis showed CD5 19.1%, CD10 38.1%, CD19 84.6%, CD20 80.5%. Peripheral blood revealed a WBC of 12 600/µl with 34% atypical lymphocytes. HBs antigen and antibodies for HBs, HCV, and HTLV1 were negative. Anti-EB virus early antigen (EA)–DR IgG and viral capsid antigen (VCA) IgM were negative, whereas VCA IgG and Epstein–Barr nuclear antigen (EBNA) were positive. Serum immunoglobulin levels were IgG 674 mg/dl, IgA 85 mg/dl and IgM 9 mg/dl. The soluble IL-2 receptor was 12 800 u/ml. Chromosome analysis of lymphoma cells revealed (A) 46XY,t(14;18)(q32;q21) in 1/10 metaphases and (B) 46, idem add (1) (q32) in 9/10 metaphases. Rearrangement of the IgH (JH) gene was observed, but there was no change in the bcl-2 gene and the chimeric IgH(JH)/bcl-2. Mutation of the p53 gene was not observed. EB virus DNA was not observed. To date, the son’s NHL is responding to chemotherapy consisting of two courses of CHOP and four courses of modified DHAP followed by peripheral blood stem cell transplantation preconditioned with mitoxantrone, cyclophosphamide, and etoposide.

DISCUSSION

The familial risk of NHL is influenced primarily by hematological malignancies rather than other cancers (7). The risk is associated with a history of lymphoma, the odds ratio being 3.0 in the first degree relatives relative to normal controls, and other hematological malignancies, the odds ratio being 2.0 (7). In another study, the familial relative risk (FRR) of NHL had been reported as 1.68 in the first degree relatives (5). Horizontal transmission in HD/HD pairs (6) and even concordance for HD in identical twins (2), and vertical transmission in NHL/NHL pairs, have been observed (6). The median difference in the age of incidence was markedly greater in NHL/NHL pairs than in HD/HD pairs (6). For NHL/NHL pairs, it was 21 (range 5–32) years, but only 3.5 (range 1–8) years for HD/HD pairs (6). There was a greater tendency for gender concordancy in NHL/NHL pairs, 75%, than in HD/HD and HD/NHL pairs, 39% (6). A higher familial risk of NHL for male relatives of male probands had been observed, and FRR was 3.18 for males and 1.09 for females (5). Our cases were in accordance with these results with the NHL generated in both a father and a son; the difference in the age of disease onset was 30 years, but, they occurred within a short period of 6 months.

Hereditary immune deficiency syndromes such as agammaglobulinemia, Wiskott–Aldrich syndrome and ataxia-telangiectasia (3,8), and acquired immune deficiency such as systemic lupus erythematosus, autoimmune thrombocytopenia or rheumatoid arthritis have frequently been reported in NHL/NHL pairs (3,6). It is also known that B-cell lymphoma frequently develops during immune deficiency after allogeneic bone marrow transplantation (9). The father in our case suffered from chronic thyroiditis, and chronic antigeneic stimulation in the pathogenesis of autoimmune disorders may cause B-lymphocyte stimulation for proliferation. In addition, both patients had low serum immunoglobulin levels when they were examined at admission. However, those in the father before onset of NHL had not been examined.

A two-hit theory for the pathogenesis of familial NHL has been considered. In the first hit, somatic mutation in proto-oncogene or deletion or inactivation of the tumor suppressor gene occurs, while the second hit might consist of environmental factors (1).

The bcl-2 gene was originally discovered owing to its involvement in the t(14;18) (q32;q21) translocation. The cytogenetic abnormality causes irregularities in the bcl-2 gene and Bcl-2 protein, and is found in the majority of follicular lymphoma and a variable number of diffuse large cell lymphoma (10,11). In the son, the t(14;18) (q32;q21) was observed,but rearrangements of the bcl-2 gene or chimeric bcl-2/IgH (JH) genes were not observed. The rearrangements of these genes of B-cell lymphoma including folllicular lymphoma occur less frequently in Japan than in the USA (12,13). Also, the breakpoint of 18q21 in the present case may be differently located from the major breakpoint cluster region (13, 14).

A relatively higher mutation of the p53 gene has been observed in B-cell intermediate-grade NHL, as in the father in this study, and in T cell high-grade immunoblastic NHL, in contrast to the relatively low mutation rate in other histopathological subtypes of low-grade NHL such as in follicular mixed or follicular small cleaved NHL (14). The most frequent genetic alteration that had been observed was a mis-sense mutation that was mainly detected within the region of exons 5–8 (14). The father in our study exhibited a similar mutation.

The NHL of both patients were pathologically different but they were both of B-cell origin. However, it is considered that most follicular lymphoma will undergo transformation into an aggressive lymphoma, usually exhibiting diffuse large cell histology (10). Indeed, the majority of hematological malignancy among family members did not belong to the same histological category (1). The familial link of NHL increased the risk of developing the low-grade follicular type of NHL (3). The son in our study also had this risk.

The vertical transmission of viruses such as hepatitis B and C, HTLV1 and EB can act as infectious agents for the pathogenesis of NHL (3,4); however, in our cases, the infection by hepatitis B and C virus and HTLV1 was negative, and EB virus DNA in the lymphoma cells was not observed.

Occupational and environmental factors could affect the pathogenesis of NHL (3,4). Farmers have an increased risk of NHL since they may be exposed to oncogenic viruses carried by farm animals and to pesticides (3,4). An increased risk of NHL through work with exposure to solvents, related chemicals and hair dyes has also been reported (3,4). In our study, the environmental and occupational risk factors were unknown; however, since NHL in both patients developed at almost the same time while they were living together, it is possible that environmental factors might have played some part in the development of NHL.

In conclusion, our findings suggest that there may be a possible common pathogenetic mechanism in these two cases of NHL in first degree relatives, although the precise mechanism is unknown. The understanding of gene–environment interactions may provide the answer.

familial occurrence of non-Hodgkin’s lymphoma. The shaded squares indicated by arrows represent a father (I-3) and a son (II-2). The black squares and circles indicate dead persons. The other members are healthy and had not been engaged in special occupations. The age of each family member (years) and cause of death are also shown. Abbreviations: ut ca, uterine cancer; ac, accident.

References