Pulmonary MALT lymphoma is a rare mature B-cell lymphoma that presents with an indolent clinical course and lacks of specific manifestations in clinical ,imaging and laboratory examination, and about one-third of patients are asymptomatic at initial diagnosis[3]. Because of its low incidence rate and nonspecific clinical features, It‘s often confounded with other lung diseases with higher morbidity in China, including lung cancer, pneumonia and tuberculosis, without pathologically confirmation[4]. In addition, the specificity of this anatomical site makes it difficult to obtain tumor tissues from pulmonary lesion, and it is frequent that the tissues acquired by transbronchial lung biopsy or computed tomography-guided percutaneous lung puncture are too small to make a definite diagnosis. Therefore, diagnostic biopsy is essential at some cases. Meanwhile, surgical intervention possesses a therapeutic effect for those patients with localized lesions.
So far, only a few prospective small-scale studies on the treatment of pulmonary MALT lymphoma have been reported because of the extremely-low prevalence and fine clinical outcome. In a single-institution, retrospective study of 21 patients with bronchial-associated lymphoid tissue (BALT) MALT lymphomas who were initially managed with combination chemotherapy (n = 7), surgery (n = 5), observation (n = 4), single-agent rituximab (n = 3) and radioimmunotherapy (n = 2).There were 10 complete remission(CR),3 partial remission(PR),7 stable disease and 1 disease progression in the observation period, and PFS and OS were 90% and 95% at 80 months in the study. Besides, additional 326 BALT lymphoma patients recorded in the SEER database were generalized. Treatment modalities such as surgery (alone or with RT and/or chemotherapy), chemotherapy (single agents or combination chemotherapy, alone or with RT and/or surgery), radiotherapy (alone or with chemotherapy and/or surgery), immunotherapy or observation have been assessed and favorable treatment responses and clinical outcomes were observed. Moreover, there were no significant differences in outcomes between patients at different stages[5–10].In another retrospective study of patients with pulmonary MALT lymphoma(n = 51, Ann Arbor stage IE 76.5%),compared with advanced-stage disease group, longer PFS (40.7 months vs 24.9 months in median; P < .001) and lower probability of progression (hazard ratio, 9.24) were observed in early-stage pulmonary MALT lymphomas, in which the most common treatment modality was surgical resection(33/43,76.7% vs 0/8,0%;P < .001), during the follow-up period in a median of 40.7months. Among the 43 cases of patients with low-stage pulmonary MALT lymphoma,33 of them received complete surgical excision while the rest 10 cases underwent systemic chemotherapy(n = 6) or watch and wait(n = 4) instead. More patients have achieved complete remission (CR) through surgery resection (32/33, 97%) than those who didn’t take surgery resection (3/10,30%), and the difference of continuous CR rate between the two groups was statistically significant(P < .001). Nevertheless, no statistical differences were found not only in the proportion of patients with disease progression (1/33,3.0% vs 2/10, 20.0%;P = 0.256) but also in PFS(P = 0.319) between the two groups[11]. Watch-and-wait policy has also been evaluated in 11 patients who didn’t accept immediate treatment after initial diagnosis. Among them, the lesions of 5 patients were restricted to the lungs while the remaining 6 patients with pulmonary MALT lymphoma were found additional extrapulmonary sites when detected for staging. Extensive staging and restaging every three months were taken in all patients. During the long-term follow-up(28.1 months in median),there were 6 patients experienced spontaneous regressions without any manifestations outside the lung, one patients was received treatment for MALT lymphoma due to disease progression in the lung and 2 cases of extrapulmonary progression were found out. All of these patients were alive and kept in a stable state of disease, and 8 of whom were still only being closely watched. The findings of this retrospective study suggested that watch-and-wait policy was adoptable especially in those who were asymptomatic at diagnosis[12].
Based on the aforesaid small-sample size, single-center studies on pulmonary MALT lymphoma, in combination with several previous retrospective studies on non-gastric MALT Lymphomas with small sample size of pulmonary MALT lymphoma, different clinical efficacies achieved by ISRT (24-30Gy), surgery, targeted therapy (rituximab), systemic chemotherapy, antibiotics(clarithromycin) and observation, either alone or in combination, were observed [1,2,13−18].Some patients even presented a potential of spontaneous regression within long-term follow up [12, 14, 19, 20]. Generally, local therapies such as surgical resection and radiotherapy are widely used for focal lesions, and diffuse lesions are more likely to be treated with systemic immunochemotherapy[9]. However, till now, optimal treatment as well as the role of surgery in pulmonary MALT lymphoma still remains controversial[21].
In the current study, survival analyses were conducted relied on the data of pulmonary MALT lymphoma patients from SEER database to investigate the value of surgery in treatment. Various treatment combinations of surgery and/or radiation were compared in all patients as well as patients stratified with different age of onset, clinical stages, laterality and primary site of lung. There was not any statistical difference in pulmonary MALT lymphoma patients with unilateral or bilateral sites(P = 0.7279),so was in those patients whose primary lesions were in the upper/middle/lower lobe or with overlapping lesion of lung(P = 0.4223). The other two indicators, different age of onset(P < 0.0001) and clinical stages(P = 0.0638),were further analyzed.
The group of patients that received both surgery and radiation demonstrated its survival superiority, and pairwise comparisons conducted between SR group and the other three groups revealed that, except for S group, differences between R and SR, NSR and SR groups had obvious statistical significance. The remaining three groups were compared pairwise as well, and the S group had a significant advantage of survival over the NSR group while the OS difference between the S and R group was insignificant. Statistically, the survival of the S group was neither inferior to the survival of the SR, nor better than the R group, while the OS of R group was not different from NSR group significantly. Possible explanation for the contradiction exhibited by the survival analysis results between S and SR, S and R groups was that, radiotherapy is a kind of treatment method with relatively excellent short-term efficacy but more pulmonary complications. It may be as effective as surgical resection in a certain period of time. After a long-term follow-up, the efficacy from radiotherapy would lapse and treatment-related side effects gradually emerged while positive results of surgical treatment were continuous. It could be due to the condition that the time span of follow-up was not long enough so that no statistical difference in OS between the S and R group was observed. As for the comparison between R and NSR group, patients undergoing radiotherapy gained therapeutic benefits over a period of time and then it appeared a cliff-like survival reduction on the survival curve, which narrowed the survival difference between the R and NSR group in some degree (Fig. 5A/B). Further investigation into the causes of death among patients who have received radiotherapy(R and SR) or not(S and NSR) revealed that the leading cause of death in patients treated with radiotherapy was pulmonary-related diseases (6/15,40.0%), including chronic obstructive pulmonary disease(n = 2), pneumonia and influenza (n = 1) or other lung and bronchus diseases(n = 3), and the proportion of patients in R and SR group dying from pulmonary-related diseases was approximately twice that of S(16/101, 15.8%) and NSR(23/131,17.6%) group. Therefore, it was reasonable to conjecture that lung injury and consequent pulmonary complications induced by radiotherapy were one of the possible reasons for the decline in survival of patients who received radiation therapy.
The above-mentioned results confirmed the effectiveness and sustainability of surgery in the treatment of pulmonary MALT lymphoma. Further subgroup analyses were performed on different ages of onset and clinical stages. Differences among the four treatment groups were statistically significant in the group in which patients were over 60 years old (P < 0.0001), especially in SR group(P = 0.0403) and S group(P < 0.0001) which demonstrated superior to NSR group statistically. For early-stage patients, the survival comparison of the four treatment groups were significant (P < 0.0001), especially the SR VS NSR groups(P = 0.0065) and S VS NSR groups(p < 0.0001), and the SR group indicated a prominent advantage than R group as well(P = 0.0283). Besides, In the young group, the four treatment methods didn’t show any advantages and disadvantages between each other. The phenomenon, on the one hand, may be attributed to the better physical status and treatment tolerance of the patients in this group, on the other hand, due to the insufficient follow-up time of the current study. The OS of advanced-stage patients (stage III-IV) also weren’t different between S group and NSR group.
The 5-year and 10 year cumulative survival rate of the patient population involved in the study were 82.57% and 73.88% respectively, which were similar to former reports[5, 21].During the period of follow-up, a total of 249 (29.0%) patients died, and the causes of death were classified in this study. Despite of the high survival rate in the patients with pulmonary MALT lymphoma, non-hodgkin lymphoma remained to be the major cause of death(n = 64,25.7%). Cardiovascular and cerebrovascular diseases were the second leading cause of death, and 47(18.9%) patients died because of them. Old age of onset may contribute to this phenomenon, as this kind of disease is one of the most common causes of death in the elderly patients originally. Besides, there were 45(18.1%) pulmonary MALT lymphoma patients died of pulmonary-related diseases.