Primary pulmonary lymphoma (PPL) refers to lymphomas occurring primarily from the lungs representing 0.4% of all lymphomas, 3–4% of extranodal lymphoma, and only 0.5%-1% of primary pulmonary neoplasms (1, 2). PPL is defined as a malignant clonal proliferation of lymphatic tissue in the lung, which must be differentiated from the metastasis to lung of lymphoma from other sites, such as stomach. In 1993, Cordier developed the following diagnostic criteria for PPL (3) (1) definite pathological evidence showing pulmonary lymphoma (2) chest X-ray showing the lesions in the unilateral or bilateral lungs without evidence of mediastinal adenopathy or mass, or computed tomography (CT) scan showing predominant pulmonary involvement with mediastinal adenopathy (3) no extrathoracic lymphoma previously diagnosed (4) no extrathoracic lymphoma or lymphatic leukemia detected at diagnosis (5) no detectable extrathoracic involvement at diagnosis or in the next 3 months.

The most common type of PPL is the mucosa-associated lymphoid tissue (MALT) derived lymphoma followed by diffuse large B-cell lymphoma (DLBCL), and these two types of lymphomas account for 90% of PPL (4, 5). A survey showed an 18% increase in the incidence of MALT-type PPL between 2006 and 2009 compared with 2001 and 2005, indicating that the number of the patients is gradually increasing (6). MALT-type lymphoma was first described by Isaacson and Wright in 1983, and can be seen in a variety of organs containing epithelial tissues, such as the stomach, salivary gland, lung, and small intestine (7). The gastrointestinal tract is the most common site of involvement, with lung involvement accounting for 15% (8). Due to the low incidence of MALT-type PPL, lack of specificity in clinical and radiological manifestations, and insufficient understanding of the disease, it was difficult to give a definite diagnosis, leading to a high misdiagnosis rate (9). Fortunately, it was widely admitted that MALT-type PPL has a favorable prognosis because of its indolent nature (10–12). To date, there is no consensus concerning the treatment of MALT-type PPL. The regimens included “watch and wait”, surgery, chemotherapy, radiotherapy, immunotherapy and so on, which could be used alone or in combination (13–16).

Given the lack of analysis of population-based data and consensus on treatment, this study attempted to compare the efficacy of different treatment modalities on early-stage MALT-type PPL using the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program database.

To our knowledge, this analysis has been the largest population-based series to investigate the treatment strategies for early-stage MALT-type PPL. From our work, it was easily observed that MALT-type PPL considerably increased in the past two decades, which indicated that it was imperative to conduct deeper research on MALT-type PPL. Similar to favorable outcomes previously mentioned in the literatures (5, 14, 15, 19), our results reinforced the favorable outcome of early-stage MALT-type PPL with high OS and CSS rates. After Cox regression analyses, we found that increasing age, tumor located in the lower lobe, and stage II were independent predictors of poorer OS while increasing age and tumors located in the bilateral lungs were associated with lower CSS. To minimize the chance for error and bias, PSM analyses were used to balance the variables among the groups and we found that patients treated with surgery, chemotherapy or a combination of surgery and chemotherapy did not show improved OS and CSS.

In 1963, Saltzstein and his colleague first described the concept of “pseudolymphoma” in the lung (20). However, since the perception of MALT and advances in diagnostic techniques such as immunohistochemistry and gene detection, most of those “pseudolymphomas” were considered to be MALT-type lymphoma (21). Bienenstock first described the existence of pulmonary MALT in 1973 (22). It is generally accepted that human bronchial mucosa is similar to gastric mucosa under normal circumstances, and MALT usually does not exist. However, acquired MALT mucosa could be induced by various antigenic stimulations such as smoking, infection and autoimmune diseases, which may lead to MALT-type PPL (23, 24).

In our analysis, we adopted Ann Arbor staging system because it has been widely used in the clinical staging of PPL (25). It was reported that MALT-type PPL tended to be in early stages (I-II), which was why we focused on early-stage MALT-type PPL (25, 26). The treatments for MALT-type PPL comprised of “watch and wait”, surgery, chemotherapy, radiotherapy and immunotherapy (13–16). However, the optimal treatment is still controversial.

In recent years, an increasing number of studies have stated that “watch and wait” could be an option for early-stage MALT-type PPL. One retrospective analysis identified 11 patients with MALT-type PPL who did not receive any treatment from initial diagnosis. Ultimately, all patients were alive with 3 patients experiencing progression and 8 patients still being watched. It is worth mentioning that the tumors spontaneously regressed or waxed and waned in six of the eleven patients (13). Likewise, a recent study enrolled 14 patients in the “watch and wait” cohort, and 14 were immediately treated with rituximab single agent or combined chemotherapy (R/R-Chemo). The estimated median time of OS was not statistically significant between the “watch and wait” cohort and the immediate R/R-Chemo cohort, with values of 78 months and 76 months, respectively (27). Although we could not recognize whether “watch and wait” or immunotherapy was given to those not treated with chemotherapy or surgery in our work, we deduced that a majority of these patients underwent “watch and wait” remedy on account of infrequent utilization of immunotherapy for MALT-type PPL (17). Thus, our results that patients in the None group did not show inferior OS and CSS indicated that “watch and wait” was a rational choice to a great extent. Furthermore, we built this perspective on the basis of the indolent nature and phenomenon of spontaneous regression of MALT-type PPL (28, 29).

In the management of MALT-type PPL, surgery was considered to be an effective option. A study on B-cell PPL suggested that surgery should be preferred if complete resection can be achieved. Through complete resection, patients with confined PPL could reach excellent long-term survival rates of approximately 90% (30). In a cohort of 43 patients diagnosed with stage I/II MALT-type PPL, 33 patients underwent complete surgical resection and 10 patients did not undergo surgical resection. Consequently, the proportion of patients reaching complete remission was higher in patients undergoing complete surgical resection (97.0% [32/33] vs. 50.0% [5/10], P < 0.001). In addition, postoperative complications (chylothorax and prolonged air leakage) occurred in only two patients. As a result, the authors believed that surgical resection was the mainstay treatment for early-stage MALT-type lymphoma (31). In contrast, a previous study of 38 early-stage MALT lymphoma patients showed no significant difference in OS between patients who underwent surgery and those who did. However, patients treated with chemotherapy had better progression-free survival than those treated with surgery (32). Although the most common treatment was surgery in our analysis, it showed no benefit to OS and CSS. In our opinion, the role of surgery on MALT lymphoma may lie in obtaining adequate tissue for correct diagnosis if it is difficult to clarify the diagnosis (1).

A variety of chemotherapeutic agents, either single or combined, have been widely used in the treatment of MALT-type PPL, but no standard regimen has been established. Zinzani et al. reviewed 31 patients suffering from Stage IE MALT-type lymphoma who accepted either fludarabine/mitoxantrone (FM) or cyclophosphamide, vincristine and prednisone (CVP). In their series, the estimated OS and disease-free survival rates reached 100% and 85%, respectively, at 60 months. In addition, they also found that the fludarabine-containing FM regimen was superior to CVP in terms of efficacy for patients with non-gastrointestinal stage IE MALT lymphoma (33). In 2009, Borie et al. reported that patients with MALT lymphoma receiving chemotherapy with chlorambucil, cyclophosphamide and anthracycline/fludarabine were associated with 3-year progression-free survival rates of 75%, 40%, and 25%, respectively (10). Overall, it was generally admitted that chemotherapy including chlorambucil, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), CHOP-like or fludarabine-containing regimens should be the first-line remedy for MALT-type PPL (17). Nevertheless, our results demonstrated that chemotherapy failed to bring better OS or CSS for early-stage MALT-type PPL. In addition, adjuvant chemotherapy followed by radical resection may not provide additional survival benefits (1). Our results also demonstrated that surgery plus chemotherapy could not improve survival.

Radiotherapy with moderate-dose has been reported to provide excellent clinical outcomes for extranodal MALT-type lymphomas (34, 35). However, for cases with MALT-type PPL the outcomes were not as good as MALT-type lymphomas of other sites. Part of the answer may be the fact that the lungs are mobile organs (36). Radiotherapy should be reserved for MALT-type patients with localized lesions in poorly mobile sites and with contraindications to surgery (17). Owing to the limited number of patients treated with radiotherapy, we did not perform an analysis to clarify its role.

Immunotherapy has been widely applied in the therapy of MALT-type lymphomas in different extranodal organs (37, 38). However, there are few studies on its application to MALT-type PPL. A case series reported eight MALT-type PPL patients treated with systemic rituximab monotherapy (375 mg m−2 day−1, 4–8 cycles), of which 6 patients were in stage I/II and 2 were in stage IV. Among them, five patients achieved a complete response, one achieved a partial response, and two were in a stable condition (39). This study showed a bright future of immunotherapy in the therapy of MALT-type PPL. Regretfully, we had no access to immunotherapy information.

We admitted several limitations to our work. First, because of the lack of some clinical characteristics in the SEER database, including tumor size, number of tumors and laboratory measurements, a certain degree of bias may be introduced into the Cox regression analyses and propensity score-matching analysis. Furthermore, the specific chemotherapy plans were unclear, and thus we were unable to separately evaluate the efficacy of different chemotherapy regimens. In addition, it was unknown if those patients not treated with surgery or chemotherapy received “watch and wait” or immunotherapy. Despite these shortcomings in our analysis, we believe that this analysis will provide new perspectives of the treatments of early-stage MALT-type PPL.

In conclusion, early-stage MALT-type PPL has an indolent course with a favorable long-term survival. In addition, neither surgery, chemotherapy nor a combination of surgery and chemotherapy can improve OS and CSS. In these circumstances, “watch and wait” may be a reasonable alternative. Large and well-designed randomized controlled trials are needed to confirm our results.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ Supplementary Material .

Ethical approval was not provided for this study on human participants because the data of this study was extracted from the public SEER database and we have permission to the database. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

HHL and KZ: concept, design, data acquisition, statistical analysis, and drafting of the manuscript. ZYP, JC and LCL: interpretation of data and review. JDM: concept, design, funding acquisition, supervision and editing. All authors contributed to the article and approved the submission.

This work is supported by the 1.3.5 Project for Disciplines of Excellence (ZYJC18009), West China Hospital, Sichuan University to Dr. Mei.

The authors appreciate the SEER program for granting access to the database.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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