Treatment and Outcomes of Stage I-II Pulmonary MALT Lymphoma: A Multi-Institutional Observational Study in Japan

Background: Pulmonary extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is a rare, indolent lymphoma that accounts for 7% of all MALT lymphomas. In contrast to other MALT lymphomas such as gastric or ocular adnexal, the site-specific etiology of pulmonary MALT lymphoma is largely unknown. There is no standard treatment for stage I-II pulmonary MALT lymphoma because of the lack of clinical trials. To clarify the patient characteristics, treatment, and prognosis of the patient with stage I-II pulmonary MALT lymphoma in the rituximab era, we conducted a multi-institutional observational study.

Methods: We retrospectively analyzed data from patients diagnosed with pulmonary MALT lymphoma at 31 institutes in Japan between 2013 and 2022. Data were collected from patients with MALT lymphoma with pulmonary involvement regardless of biopsy site and stage; subsequently, patients with stage I-II pulmonary MALT lymphoma were included. The staging was performed according to the Ann Arbor system modified by Ferraro et al (Ann Thorac Surg 2000). Patients with insufficient clinical data were excluded. The following data were collected: initial symptoms, comorbidities, smoking status, baseline laboratory data and chest CT findings (including site, number, and size of pulmonary involvement), treatment choice and response, and survival. Watchful waiting (WW) was defined as follow-up for at least three months after diagnosis. The primary endpoint was the overall survival (OS) of patients with stage I-II pulmonary MALT lymphoma. We analyzed risk factors for OS, progression-free survival (PFS), time to next treatment (TTNT), and time to chemotherapy (TTC) using Cox proportional hazards method. TTNT was assessed in patients who received WW or surgery as first-line treatment. TTNT was defined as the time from the initiation of each treatment until the start of the next treatment. If the initial treatment was WW, TTNT was defined as the time from diagnosis to the start of the next treatment. TTC was defined as the time from diagnosis to the time of initial chemotherapy and was assessed for patients who received WW, surgery, or rituximab monotherapy as first-line treatment.

Results: Of the 200 patients with pulmonary MALT lymphoma, 133 (67%) patients had stage I-II disease. The characteristics of the patients with stage I-II disease were as follows: median age, 68 years (range, 25-88); female, 54%; stage I, 84%; Eastern Cooperative Oncology Group performance score 0, 95%; smoking rate, 44%; history of autoimmune disease, 17%; respiratory symptoms, 12%; elevated serum lactate dehydrogenase level, 9%; Intermediate-risk MALT-International Prognostic Index (MALT-IPI) , 41%; and High-risk MALT-IPI, 5%. The radiologic patterns on chest CT were as follows: a nodule or mass, 55%; consolidation, 38%; multiple involvement, 53%; bilateral involvement, 38%; and median tumor size, 2.5 cm (range, 0.5-7.8). Patients received one of the following four first-line treatments: WW in 71 patients (53%), surgery in 45 (34%), rituximab monotherapy in 11 (8%), and chemoimmunotherapy in 6 (5%), including bendamustine and rituximab (n = 5). During the follow-up period, 2 (2%) patients experienced histological transformation. At a median follow-up of 55 months, the 4-year OS, PFS, TTNT, and TTC were 95%, 85%, 83%, and 89%, respectively. There were no significant differences in OS (P = 0.89) or PFS (P = 0.88) among the four treatment groups. The surgery group tended to be superior to the WW group in TTNT (P = 0.053). There were no significant differences in the TTC among the three treatment groups (P = 0.64). Multivariate analysis identified a single lesion (P = 0.04) as an independent risk factor for OS. Notably, a maximum tumor size ≥ 3 cm was identified as the only independent risk factor for PFS (P = 0.046). Involvement in the right middle lobe was identified as an independent risk factor for TTNT (P = 0.016).

Conclusions: There were no significant differences in survival, irrespective of the first-line treatment modality. A maximum tumor size ≥ 3 cm on CT scan at diagnosis was significantly associated with worse PFS, thus suggesting a potential target for treatment development.