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.