Malignant lymphomas are tumors with an increasing incidence. Despite wide geographic variations, the overall incidence is currently estimated at 2/100 000[ ¹]. As opposed to solid tumors, however, malignant lymphomas constitute a heterogeneous group of different disease entities. In view of this, an explanation for the rising incidence is difficult, as various types of lymphomas have distinct characteristics and contributing pathogenetic factors. In general, the presence of an autoimmune disease has been judged to be risk factor for the development of malignant lymphomas and Sjögren’s syndrome (SS), rheumatoid arthritis, autoimmune thyroiditis and Lupus erythematosus have especially been associated with the development of diffuse large B-cell lymphomas, extranodal marginal B-cell lymphomas of the mucosa associated lymphoid tissue (MALT lymphoma), but also Hodgkin’s disease[ ^{2 - 4}]. Controversially, immunosuppression has also been linked to lymphoma development, as evidenced by patients with post-transplant lymphoproliferative diseases and patients being given immunosuppression for rheumatoid diseases. In the latter, however, there is still some controversy as to whether lymphoma development is de facto linked to the underlying disease necessitating immunosuppression rather than the immunosuppressive agents[ ^{5 , 6}].

A familial background of non-Hodgkin’s lymphoma (NHL) has repeatedly been reported to constitute a significant risk factor for lymphoma development. In an evaluation of first-degree relatives of lymphoma patients, Paltiel et al[ ⁷] observed an increased rate of both NHL as well as Hodgkin’s lymphoma development among the population when compared to control groups. The Swedish Family Cancer database analyzed familial risk for NHL in terms of histopathological subtypes and showed a significantly increased risk for diffuse large B-cell lymphomas and follicular lymphomas[ ⁸].

MALT lymphoma is among the more common lymphoma subtypes and constitutes about 7%-8% of all newly diagnosed B-cell lymphomas[ ⁹]. In terms of pathogenesis, gastric MALT lymphoma is the paradigm for an immunomediated malignancy, as evidenced by the strong association with SS, autoimmune thyroiditis and, in case of gastric MALT lymphoma, infection with Helicobacter pylori ( H. pylori)[ ¹⁰]. The validity of the latter model/association has been demonstrated by the impressive response of gastric MALT lymphomas to eradication of the bacteria, resulting in complete remissions in up to 80% of selected patients[ ^{11 , 12}]. Apart from autoimmunity and chronic antigenic stimulation driven by infections, however, no risk factors for MALT lymphoma have been reported, and no evidence for familial clustering of MALT lymphomas can be found in the current literature.

A 65-year-old woman was admitted at our institution for further treatment of a recently diagnosed gastric MALT lymphoma in September 1998. Due to epigastric complaints for a period of about five mo, a gastroscopy was performed, which disclosed the presence of a gastric ulcer in the corpus. Multiple biopsies from the ulcer as well as from the surrounding hyperemic mucosa were taken, and disclosed the presence of extranodal marginal zone MALT lymphoma along with active infection with H. pylori. Antibiotic therapy with clarithromycin, metronidazole for 10 d and intake of pantoprazole were initiated. At our institution, a re-gastroscopy was performed 6 wk after eradication therapy, showing no evidence of H. pylori and healing of the ulcer, but unchanged histological presence of MALT lymphoma. RT-PCR performed on paraffin embedded specimens showed the presence of the MALT lymphoma specific t(11;18)(q21;q21)-translocation.

The patient’s initial physical condition was good and blood counts were normal except an elevated β2-microglobulin level (2.73 mg/L) and anemia grade I related to slight chronic blood loss from the gastritis. The medical history revealed appendectomy, cholecystectomy and hysterectomy and the familial history was positive for malignancies (mother died age 38 years from what the patient related as “acute leukemia” and a brother had died from pancreatic carcinoma). At the time of admission, the medical history of both the patient’s daughters was uneventful, except SS in the older daughter which had been histologically verified in 1993. Extensive staging including endosonography of the stomach and duodenum, colonoscopy with multiple biopsies, 18F-FDG-PET, CT-scan of thorax and abdomen, ultrasound of lymph nodes, thyroid and salivary glands as well as a bone marrow biopsy showed restriction of the lymphoma to the stomach, corresponding to stage I disease. Thyroid ultrasound, however, was suggestive of chronic autoimmune thyroiditis, which was also verified by the presence of elevated thyroid autoantibodies with subclinical hypothyreosis (TSH 8.9 mU/L and thyreoglobulin-autoantibodies 424 ng/mL).

Consecutive serial gastroscopies performed every three mo showed no chance of the MALT lymphoma infiltrate 1.5 years after initial diagnosis and chemotherapy with the nucleoside analogue cladribine was initiated. Treatment consisted of 0.12 mg/kg cladribine given i.v. days 1-5 every 28 d for four courses, resulting in complete remission (CR) of the gastric MALT lymphoma.

Thirteen months after initial CR, a control gastroscopy disclosed histological evidence for H. pylori-negative, t(11;18)(q21;q21)-positive relapse of gastric MALT lymphoma and endosonography showed enlarged lymph nodes along the lesser curvature. Consequently, the patient received radiotherapy at a dose of 46 Gy and again achieved a histologically verified CR. Upon the third follow-up gastroscopy, however, the presence of probable minimal residual disease (pMRD) was suspected and the CR was rated as a probable sampling error. All gastroscopies until the patient’s death repeatedly disclosed pMRD without progression in spite of the fact that no therapy was given.

In July 2004, the patient developed acute dyspnea and a CT scan showed a subglottic mass leading to massive tracheal compression. Histological assessment showed the presence of anaplastic large B-cell lymphoma associated with Epstein-Bar virus. Molecular assessment disclosed the absence of t(11,18)(q21;q21) and no clonal relationship to the initial MALT lymphoma and was thus rated as a second malignancy. Two cycles of chemotherapy were administered containing rituximab, mitoxantrone, cyclophosphamide and vincristine, resulting in complete remission of the lymphoma. The patient, however, refused any further therapy and remained in CR until February 2006, when the patient had to be re-admitted due to rapidly progressing dyspnea and deteriorating general condition, resulting in the patient’s death in May 2006.

In February 2008, the patient’s daughter was admitted at our institution at the age of 55 years. After having been diagnosed with SS in 1993, she had developed a painless swelling in the right parotid gland. Ultrasound and a consecutive MRI were suggestive of a Warthin tumor and the patient underwent superficial parotidectomy. Upon histological assessment, infiltration of the parotid with MALT lymphoma was found. Apart from the diagnosis of SS with consecutive dryness of eyes and mouth, the patient’s general condition was excellent and her medical history uneventful.

A familial background of non-Hodgkin lymphoma or other lymphoproliferative malignancies has repeatedly been reported as a significant risk factor for NHL. A computerized literature research identified nine recent analyses, including a total of 21 378 patients with NHL for assessment of familial risk[ ^{7 , 8 , 13 - 19}]. An analysis of the Swedish Family Cancer Database, including 4.445 patients diagnosed with NHL having at least one first-degree relative diagnosed with NHL, has assessed the familial risk in terms of standardized incidence ratios (SIRs). A first-degree relative suffering from NHL significantly increased the general risk for NHL (SIR = 1.8), with the SIR for diffuse large B-cell lymphoma being 1.8, follicular lymphoma 2.0 and “B-cell lymphoma, not otherwise specified” being 3.4[ ⁸].

Wang et al[ ¹⁸] evaluated 10 211 cases and 11 905 controls from the International Lymphoma Epidemiology Consortium comprising 17 case control studies and reported similar results. The overall NHL risk for a person with a first-degree relative compared to a stratified control collective was reported at an odds ratio (OR) of 1.5. Controversial findings, however, were reported whether a parent or sibling with NHL provides a higher risk for consecutive NHL-development. Furthermore, the level of risk seemed to be higher for histopathological specific concordant neoplasm than for other subtypes in various reports, but due to the limited number of cases, statistical significance was not reached[ ^{8 , 18}].

While infectious agents and autoimmune diseases have repeatedly been linked with MALT lymphoma pathogenesis, no data on a familial background in patients with MALT lymphoma have been published so far.

As it is, the case of the patient with gastric MALT lymphoma also highlights various clinically relevant points. First of all, it underscores the potential influence of chronic autoimmune disease on the development of gastric MALT lymphoma, as recently highlighted by Troch et al[ ²⁰]. As has been shown, these lymphomas might be independent of H. pylori even at early stages and the presence of an underlying autoimmune disease has been reported as a negative prognostic risk factor for lymphoma regression after H. pylori eradication[ ⁴]. In addition, the lymphoma cells in our patient harbored the t(11;18)(q21;q21) translocation, which is also thought to confer resistance to antibiotic therapy. Consequently, no response was seen with H. pylori eradication and chemotherapy subsequently resulted in complete remission (CR). This CR was nevertheless relatively short and consecutive radiation resulted in pMRD, which was initially erroneously assessed as CR probably due to a sampling error. In spite of the fact that no further therapy was applied, the MALT lymphoma was stable for a prolonged time, i.e., until the patient’s death. This is in keeping with recent data published by Fischbach et al[ ²¹] who have shown that patients with pMRD after H. pylori-eradication should not undergo further therapy, as has also been underscored by the recently published EGILS-consensus for management of gastric MALT-lymphoma[ ²²]. To our knowledge, the cases presented in this article constitute the first report of MALT lymphoma developing in first degree relatives. A computerized search of the published literature disclosed no information on MALT lymphoma and a familial background, and “MALT lymphoma” as a distinct lymphoma entity was not listed in the Swedish Family Cancer Database or in any other article related to familial NHL development.

The MALT lymphomas diagnoses in our patients, however, showed different characteristics, as the mother’s lymphoma developed in the stomach, while the daughter was diagnosed with parotid MALT lymphoma. As expected in a t(11;18)(q21;q21) positive gastric MALT lymphoma, no response to H. pylori eradication was seen and necessitated chemotherapy. In the parotid MALT lymphoma, no genetic abnormalities could be detected and no evidence of gastric MALT lymphoma or H. pylori infection was seen at a staging gastroscopy. Interestingly, both mother and daughter suffered not only from MALT lymphoma but were also diagnosed with an autoimmune disorder (chronic autoimmune thyroiditis in the mother, SS in the daughter).