Discussion
The BALT lymphoma is a rare hematologic entity with less than 1% occurrence of all pulmonary tumors, but it represents the most common histologic subtype in all primary pulmonary lymphomas. The pathology and genetics are not completely deciphered, however, prognosis and 5-year OS rate with 85% are favorable. The BALT lymphoma is not easy to diagnose because of its rarity, heterogeneity and nonspecific symptoms as well as often oligo- or asymptomatic patients. In our case, one patient developed dry cough and exertional dyspnea over few months without further symptoms. In line with previous reports CT-scan showed solitary pulmonary nodules in all lung lobes. Based on the CT scan, a biopsy of lung tissue, clonality and immunohistochemistry analysis were performed as recommended (NCI SEER database). The clonality analysis detected immunoglobulin gene rearrangements in IGHA, IGHB and IGHC, which have previously been described to be affected in BALT lymphomas. The immunostaining of the lung tissue identified CD20 positive B-cells in the infiltrate without any co-expression of CD5, CD10, CD23, BCL6 or BCL2, compatible with a BALT lymphoma. Most of the patients are diagnosed with stage I or II disease, but roughly 40% show involvement of multiple extranodal sites. Staging in patients with multiple extranodal lesions may be challenging, since at least some cases constitute multiple clonally unrelated proliferations rather than truly disseminated disease.
For the diagnosis of a BALT lymphoma various methods including radiologic imaging, histology and genetic analysis are needed. Additional investigations should also be taken into account such as gastroscopy to identify a possible involvement of other organ systems. In our cases, one patient showed paraaortic, iliac and inguinally enlarged lymph nodes and the other patient presented with splenomegaly as well as a gastric manifestation.
The treatment of BALT lymphoma is not well standardized due to the rarity and heterogeneity of involved sites. Indeed, many therapeutic options are available including surgery, radiotherapy, immunotherapy and chemotherapy. In many MALT lymphoma patients, there is a history of a chronic inflammatory disorder resulting in the accumulation of extranodal lymphoid tissue. The chronic inflammation may be the result of an infection, autoimmunity or other unknown stimuli. This link is most clearly established for Helicobacter pylori and gastric MALT lymhoma. The importance of this stimulation in vivo has been clearly demonstrated by the induction of remissions in gastric MALT lymphomas with antibiotic treatment to eradicate Helicobacter pylori. A role for antigenic stimulation by Chlamydia psittaci and Borrelia burgdorferi has been proposed for some cases of ocular adnexal and cutaneous MALT lymphomas, respectively. A similar role has been proposed for Campylobacter infection in patients with heavy chain disease. The eradication of Helicobacter pylori associated with gastric or Chlamydia psittaci causing ocular adnexia MALT lymphoma by antibiotic therapy led to protracted remissions. Thus, successful eradication or removal of suspected trigger factors e.g. smoking should be of utmost priority.
If BALT lymphoma is localized and accessible, surgery is also a possible treatment option compared to chemotherapy. Our patients showed bi-pulmonary and extrapulmonary manifestations. Therefore, local surgery was not an option and an immunochemotherapy with rituximab and bendamustine was performed. A large, prospective randomized multicenter phase III study including over 500 patients with indolent lymphomas including MALT lymphomas and mantle-cell lymphomas showed an increased progression-free survival and fewer toxic effects of rituximab/bendamustine as compared to rituximab, cyclophosphamide, vincristine, doxorubicin and prednisolone (R-CHOP). In addition, Salar et al. showed in a multicenter, single-arm, non-randomized, phase 2 trial on 60 patients with MALT lymphoma at any site and stage a progression-free survival after 7-years of 92.8%. Combinations of the regimen with other therapeutics including the bruton’s tyrosine kinase inhibitor PCI-32765, idelalisib, or the PI3Kδ inhibitor IBI376 are also investigated in different clinical trials (ClinicalTrials.gov: NCT01479842, NCT03424122). Further clinical studies are evaluating other biologicals, such as obinutuzumab (ClinicalTrials.gov: NCT03322865), venetoclax (ClinicalTrials.gov: NCT04447716) or lenalidomide (ClinicalTrials.gov: NCT03015896, NCT04604028). In previous case reports and studies, rituximab as single agent or combined therapy with chlorambucil, cladribine or CHOP led to good responses with long-term survival up to 70%. Finally, radiation and eradication therapies are also investigated (ClinicalTrials.gov: NCT01820910, NCT03680586, NCT02494700).
Due to previous publications, case reports and our observations, rituximab/bendamustine represents an efficient and well tolerated first-line therapy for MALT lymphoma. Given the safety, tolerability and efficacy we would recommend this immunochemotherapy as first-line therapy, if other trigger factors can be excluded.
Nevertheless, further data, ideally within prospective clinical trials, are required to evaluate the efficacy and safety of immunochemotherapies in BALT lymphoma for various patient collectives. Based on the data from clinical trials future directions for an approved standard treatment with more targeted agents seem to be on the horizon.