Long-term clinical outcomes of mediastinal lymphoma after surgical resection: reassessing the role of surgery

Introduction

Primary mediastinal lymphoma is a lymphoproliferative disorder involving the mediastinal lymph nodes, thymus, and extranodal mediastinal organs. It typically presents without evidence of systemic disease and includes various pathological subtypes (1). Standard treatment protocols generally involve chemotherapy or chemoimmunotherapy, with or without radiotherapy, tailored to the subtype and stage of the lymphoma (2).

The surgical approach to mediastinal lymphoma, particularly for diagnostic purposes, is well-documented; however, its therapeutic role remains to be further clarified (3). A previous study reviewed the role of surgery in managing isolated mediastinal lymphoma through a retrospective analysis (4). The authors concluded that surgery was primarily indicated for diagnostic purposes and that curative resection should be reserved for highly selected patients. Presently, there are few reports on the surgical resection of mediastinal lymphoma, partly due to skepticism about surgical outcomes and the rarity of the disease.

Most current guidelines recommend a preoperative biopsy to avoid unnecessary surgical treatment when mediastinal lymphoma is suspected, and generally, surgery is not recommended. However, based on our experience, we observed a favorable prognosis after surgical resection, particularly for incidentally detected lymphomas. Consequently, we expanded the surgical indications to include salvage operations for residual lymphoma after chemotherapy, as part of a multimodal treatment approach. Therefore, this study aimed to evaluate the long-term clinical outcomes of patients who underwent surgical resection for primary mediastinal lymphoma and to assess the role of surgery in its treatment. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-902/rc).

Methods

Study population

From March 2008 to April 2023, 31 patients underwent surgical resection for primary mediastinal lymphoma at Seoul National University Hospital, performed by four surgeons (Y.T.K., C.H.K., S.P., and K.J.N.). After excluding five surgical resections conducted for diagnostic biopsies, 26 patients were included in the study.

Surgical resection was indicated for incidentally detected anterior mediastinal tumors initially suspected to be thymic epithelial tumors (primary operation group). In this group, postoperative pathology confirmed mediastinal lymphoma as the diagnosis for the anterior mediastinal tumor. Surgery was also indicated for primary mediastinal lymphoma that was resistant to medical treatment, aimed at removing residual disease post-chemotherapy (salvage operation group). Salvage operation was defined as surgical resection performed in patients who did not have surgery included in their initial treatment plan and who had received high-dose chemotherapy with curative intent (5). Not all patients who failed standard-of-care chemotherapy underwent salvage operation; the decision for surgical resection was made through a multidisciplinary discussion when chemotherapy did not yield a favorable response despite adequate treatment. In accordance with the recent guidelines, mediastinal masses suspected to be thymic tumors and considered surgically resectable were treated with surgical resection without preoperative pathological diagnosis (6). Thus, in the primary operation group, the pathological diagnosis of mediastinal lymphoma was established postoperatively, whereas in the salvage operation group, the diagnosis was confirmed pathologically prior to surgery.

The pathological diagnosis and classification were based on the World Health Organization Classification of Thoracic Tumors (7). The stage of lymphoma was evaluated using the Ann Arbor staging system, and the response to medical therapy was assessed using the Response Evaluation Criteria in Solid Tumors (8,9).

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was reviewed by the Institutional Review Board of Seoul National University Hospital and approved as a minimal risk retrospective study (No. H-2308-061-1457, date: 2023.08.18), and individual consent was waived.

Evaluation of clinical outcomes

Total hospital stay was defined as the period from admission to discharge for each patient. Postoperative hospital stay refers to the duration spent in the hospital after the surgery. Postoperative complications were categorized using the Clavien-Dindo classification (10). Operative mortality was defined as any death occurring within 30 days following surgery. For long-term clinical outcomes, overall survival and recurrence were assessed.

Statistical analysis

Statistical analyses were performed using IBM SPSS Statistics (version 25.0; IBM Inc., Armonk, NY, USA), SAS (version 9.4; SAS Institute, Cary, NC, USA), and R (version 4.2.1; R Foundation for Statistical Computing, Vienna, Austria). Continuous variables were compared using the Mann-Whitney U test and are presented as medians with interquartile ranges (IQRs). Categorical variables were compared using the chi-square test and Fisher’s exact test and are presented as numbers and percentages. The log-rank test was used to compare the overall survival between subgroups. Univariable and multivariable analyses were conducted using the Cox proportional hazards model with Firth’s penalized maximum likelihood method to identify the prognostic factors associated with overall survival and recurrence. In the multivariable analysis, variables with a P<0.10 in the univariable analysis were included in a backward selection process with a threshold P<0.05. All tests were two-tailed, and a P<0.05 was considered statistically significant. All statistical analyses were conducted with support from the Medical Research Collaborating Center at our institute.

Results

Preoperative characteristics

The median age of the patients was 37.5 years (IQR, 25.8–61.0 years), with 15 patients being male. An anterior mediastinal mass was incidentally detected during a medical check-up in 11 patients (42.3%) out of a total of 26. Three patients had an autoimmune disease. The mean tumor size on preoperative computed tomography (CT) scans was 5.6 cm. Mucosa-associated lymphoid tissue lymphoma (MALToma) was the most common type of lymphoma (n=11), followed by primary mediastinal large B-cell lymphoma (PMBCL) (n=9), T-cell lymphoblastic lymphoma (T-LBL) (n=3), Hodgkin’s lymphoma (HL) (n=2), and follicular lymphoma (FL) (n=1). The stages of the disease were distributed as follows: 16 patients were in stage 1, three in stage 2, five in stage 3, and two in stage 4, with stage 1 being the most prevalent at 61.5%. When comparing the favorable group (MALToma, FL, and HL) with the unfavorable group (PMBCL and T-LBL), the favorable group was significantly older, more often diagnosed incidentally through health screenings, and had smaller tumor sizes on CT scan (Table 1).

Operative data and treatment after operation

Of the 26 patients, 18 underwent primary surgery, and eight underwent salvage surgery. Notably, all patients in the unfavorable group received salvage surgery. Sternotomy was the most common surgical approach, performed in 14 patients (53.8%), followed by video-assisted thoracoscopic surgery in four patients, and robot-assisted thoracoscopic surgery in eight patients. Total thymectomy was performed in 23 patients, partial thymectomy in one patient, and tumorectomy in two patients. Concurrent pericardial resection was performed in eight cases, and concomitant lung resection was undertaken in eight patients. Innominate vein and superior vena cava resections were performed in five and one patients, respectively. A complete (R0) resection was achieved in 23 patients, with no significant difference observed between the favorable and unfavorable groups. Additionally, concomitant procedures were performed in four patients; one underwent a wedge resection for bullae unrelated to the mediastinal lymphoma, another had liver cyst excision and cholecystectomy, the third underwent a right lower lobectomy for lung cancer, and the fourth had a robot-assisted laparoscopic prostatectomy for prostate cancer (Table 2). The concomitant procedures were performed after thorough multidisciplinary discussions, considering the patients’ clinical conditions and preferences, and were judged to be low-risk. No postoperative complications were observed in patients who underwent concomitant procedures.

After surgery, 12 patients received no additional treatment, 12 received chemotherapy, and two received both chemotherapy and radiotherapy (Figure 1). Of the 18 patients who underwent primary surgery, eight received postoperative chemotherapy. One patient underwent adjuvant radiotherapy (Table 3). Among patients who underwent primary surgery, the median age of those who did not receive adjuvant treatment was 62.0 years (IQR, 32.0–63.0 years), whereas it was 31.5 years (IQR, 25.5–44.0 years) in those who did receive adjuvant treatment, a difference that was statistically significant (P=0.007).

Figure 1 Sankey diagram on the postoperative treatment pathways. CTx, chemotherapy; FL, follicular lymphoma; HL, Hodgkin’s lymphoma; MALToma, mucosa-associated lymphoid tissue lymphoma; PMBCL, primary mediastinal large B-cell lymphoma; RT, radiotherapy; T-LBL, T-cell lymphoblastic lymphoma.

Early and long-term clinical outcomes

The median length of total hospital stay was 6 days, with a median postoperative hospital stay of 4 days. No surgical mortality was observed. Complications occurred in two cases: one involving recurrent laryngeal nerve injury and the other presenting with acute kidney injury (Table S1).

The median follow-up period was 4.7 years (IQR, 0.2–13.7 years). Of the 26 patients, three died, all of whom had undergone salvage operations. The causes of death were brain metastasis in two patients and septic shock in one patient (Table S2). Recurrence was observed in three patients, including the two who died from brain metastasis. One patient, who underwent curative resection for MALToma, experienced a recurrence in the left eye on postoperative day 178, requiring eyeball mass resection; however, no subsequent death or recurrence occurred following the second operation (Table S3).

The 5-year overall survival rate was 85.9% [95% confidence interval (CI): 62.2–95.2%] for the entire group and 71.6% for the unfavorable group (95% CI: 35.0–89.9%). In the favorable group, there were no deaths; however, the difference between the two groups was not statistically significant (P=0.07) (Figure 2A,2B). There was one death in the PMBCL group and two deaths in the T-LBL group, with 5-year overall survival rates of 87.5% (95% CI: 38.7–98.1%) and 33.3% (95% CI: 0.9–77.4%), respectively (Figures S1,S2).

Figure 2 Overall survival curves. The shading represents the 95% CI. (A) Entire cohort. (B) Favorable group vs. unfavorable group. (C) MALToma vs. others. (D) Stage 1 vs. others. (E) R0 resection vs. others. (F) Primary surgery vs. salvage surgery. CI, confidence interval; MALToma, mucosa-associated lymphoid tissue lymphoma.

When categorizing lymphoma types into MALToma and others, there were no deaths in the MALToma group. In contrast, the 5-year overall survival rate for other types was 76.2% (95% CI: 42.7–91.7%), with no statistically significant difference (P=0.13) (Figure 2C). When categorized by lymphoma stage into stage 1 and other stages, the 5-year overall survival was 91.7% (95% CI: 53.9–98.8%) for stage 1 and 78.8% (95% CI: 38.1–94.3%) for stages 2, 3, and 4, showing no statistically significant difference (P=0.43) (Figure 2D). However, when categorized by resection margin into R0 resection and incomplete resection, the 5-year overall survival was 94.7% (95% CI: 68.1–99.2%) for R0 resection and 33.3% (95% CI: 0.9–77.4%) for incomplete resection, indicating a statistically significant difference (P=0.003) (Figure 2E). When categorized by operation type, there were no deaths occurred in the primary operation group, and the 5-year overall survival was 60.0% (95% CI: 19.5–85.2%) in the salvage operation group, also showing a statistically significant difference (P=0.01) (Figure 2F).

Prognostic factors for overall survival and recurrence

Univariable analysis identified salvage surgery [P=0.02, hazard ratio (HR) =14.84], pericardial resection (P=0.03, HR =13.42), and incomplete resections (P=0.03, HR =15.75) as significant risk factors for long-term mortality. However, these factors were not significant in the multivariable analysis (Table 4).

In univariable analysis, pericardial resection was associated with recurrence, showing a significant HR (P=0.02, HR =15.07). Furthermore, multivariable analysis revealed that both pericardial resection (P=0.04, HR =13.53) and adjuvant radiotherapy (P=0.04, HR =25.58) were significantly associated with an increased risk of recurrence (Table 5).

Discussion

This study yielded two key findings. First, primary surgical resection of incidentally detected mediastinal lymphomas demonstrated satisfactory long-term clinical outcomes. Second, complete resection significantly benefits long-term survival when surgical resection of a mediastinal lymphoma is planned.

Chemotherapy, either alone or combined with radiotherapy, is the standard treatment for both HL and non-HL (11). There are various subtypes of lymphoma, each associated with specific standard chemotherapy regimens that lead to different clinical outcomes, including overall and disease-free survival. For instance, the R-CHOP regimen (cyclophosphamide, doxorubicin, vincristine, prednisolone, and rituximab) has shown an approximately 80% 5-year progression-free survival rate in patients with PMBCL, whereas patients with T-LBL have exhibited event-free survival rates ranging from 75% to 90% with standard chemotherapy regimens (12,13).

In contrast, surgical treatment for mediastinal lymphoma is not widely recommended in clinical practice. A previous study reported that resection was performed in only 14 out of 104 patients who underwent surgery for mediastinal lymphoma (4). The authors of this study suggest that surgical resection should be reserved for highly selected patients. Historically, the reluctance to perform resection for mediastinal lymphoma stems from the poor outcomes of surgery compared with the favorable results of chemotherapy. The primary indication for surgery is often diagnostic, aimed at distinguishing mediastinal lymphoma from other surgically manageable mediastinal tumors. Thus, the role of surgery in managing mediastinal lymphoma has primarily been confined to diagnostic purposes rather than therapeutic interventions (14,15).

The therapeutic role of surgery in lymphomas originating from organs other than the mediastinum remains debatable. For gastric MALToma, a retrospective study showed that radical gastrectomy with systematic lymphadenectomy alone achieved a 5-year survival rate exceeding 95%, suggesting that surgery could be considered an initial management approach in lymphoma treatment (16). Similarly, for primary gastric B-cell lymphoma, radical gastrectomy with systematic lymphadenectomy has demonstrated long-term outcomes comparable to those of chemotherapy. Additionally, surgery aids in accurate staging, facilitating appropriate adjuvant treatment planning (17). However, some reports argue that chemotherapy should be the primary treatment, based on evidence of frequent intraabdominal and disseminated relapse even after complete resection in early-stage primary gastric diffuse large cell lymphoma (18,19).

In this study, most patients in the primary surgery group underwent a complete total thymectomy, similar to the approach for thymic epithelial tumors, which involves the removal of all thymic tissues and adjacent peri-thymic lymph nodes. Systematic lymph node dissection was performed when lymph node involvement was suspected. Given the absence of a definitive preoperative pathological diagnosis in the primary operation group, oncologically competent procedures were undertaken, anticipating other potential thymic malignancies, such as thymic carcinoma or neuroendocrine tumors. The 5-year overall survival rate among patients in the primary operation group reached 100%, with no locoregional recurrence. Although only one patient experienced recurrence in the left eyeball, subsequent surgery effectively managed this recurrence. These findings suggest that effective oncological management during surgery may enable control of locoregional lymphoma progression.

The efficacy of surgery in achieving locoregional control was also evident in the salvage operation group, where no instances of locoregional recurrence were observed among the eight patients who underwent salvage surgery. However, two patients developed brain metastases and succumbed to lymphoma progression within the brain, while one patient died from causes not related to tumor progression. However, caution is warranted when considering surgery in advanced lymphoma cases following unsuccessful chemotherapy, given the challenges associated with achieving complete surgical resection in advanced mediastinal lymphoma. The propensity for invasion into critical structures such as the superior vena cava, trachea, and major vessels is common in large, advanced lymphomas (20), often rendering complete R0 resection unfeasible. Previous studies on head and neck lymphomas have underscored the significance of tumor location over histological type in salvage surgical approaches, particularly when critical organ invasion precludes complete resection (21). In our study, three patients succumbed during long-term follow-up, resulting in an overall 5-year survival rate of 60%. Despite these outcomes being better than anticipated, cautious interpretation is warranted, given our patient selection criteria favoring those with a high likelihood of complete resection. Therefore, salvage operations for mediastinal lymphoma should be performed with utmost caution, requiring meticulous patient selection and thorough multidisciplinary evaluation to ensure that only carefully chosen cases proceed to surgery.

The effect of adjuvant chemotherapy after surgical resection remains uncertain. Decisions regarding adjuvant therapy were made through multidisciplinary discussions, considering factors such as histology, completeness of resection, tumor invasiveness, and other clinical factors. Although all patients with PMBCL received adjuvant chemotherapy, only 18% of those with MALToma underwent such treatment. This difference is attributed to the potential for achieving long-term complete remission with local therapies alone, such as surgery or radiotherapy, in limited-stage MALToma cases, thus often eliminating the need for chemotherapy (22). Second, both completeness of resection and tumor invasiveness were important considerations. Among patients who received adjuvant therapy, excluding those with PMBCL and T-LBL, there were two patients with MALToma (ID 5 and 6) and two with HL (ID 9 and 26). Although all these patients underwent R0 resection, intraoperative findings suggested pericardial invasion, leading to concurrent resection. Third, other clinical factors were also taken into account, with age being a representative example. Younger patients tend to have better performance status and are therefore more likely to tolerate additional treatments following surgery, leading to a more aggressive therapeutic approach. In fact, among patients who underwent primary surgery, the median age of those who did not receive adjuvant treatment was 62.0 years (IQR, 32.0–63.0 years), whereas it was 31.5 years (IQR, 25.5–44.0 years) in those who did receive adjuvant treatment, a difference that was statistically significant (P=0.007).

Our study observed a recurrence pattern where all recurrences appeared as distant metastases, notably in the central nervous system (CNS). This highlights a significant pattern of failure in our cohort that underwent both surgery and chemotherapy. Conventional chemotherapeutic agents have limited efficacy in controlling CNS metastases due to the restricted blood-brain barrier permeability to these agents (23). Although recurrence in the CNS is rare, it is highly devastating when it occurs. Unlike in HL, where CNS relapse is exceedingly uncommon, even in diffuse large B-cell lymphoma (DLBCL)—one of the most common and aggressive subtypes of non-HL—the incidence of CNS relapse has been reported to be around 3–5% (24,25). Previous studies on CNS relapse in mediastinal lymphoma are limited; however, there have been some reports regarding PMBCL and T-LBL, and insights can also be drawn from studies on DLBCL, which shares certain clinical and biological features with PMBCL (26). A recent study focusing on PMBCL reported CNS relapse rates of 1.43% at 1 year and 2.21% at both 2 and 5 years (27). Notably, all of these cases represented CNS relapse associated with systemic relapse rather than isolated CNS involvement, and only one of the three patients who experienced CNS relapse had received intrathecal prophylaxis. The situation is similar in T-LBL. Cranial radiotherapy for prophylaxis has been associated with an increased risk of brain tumors and neurocognitive deterioration, and instead, intrathecal prophylaxis or systemic high-dose methotrexate and cytarabine are used as alternatives for CNS prophylaxis (28-30). However, even in DLBCL, routine CNS prophylaxis with high-dose methotrexate is not generally recommended due to its toxicity and financial burden relative to its limited efficacy. Instead, it has been suggested that decisions regarding CNS prophylaxis should be made cautiously, incorporating risk stratification such as the CNS-International Prognostic Index (CNS-IPI) and the CNS relapse In T-cell lymphoma Index (CITI) (27,31,32). Therefore, exploring alternative treatment modalities is crucial for effectively managing brain metastases in patients with lymphoma.

Despite the relatively small size of our patient cohort, this study represents one of the first attempts to identify the risk factors associated with long-term survival and recurrence following surgical resection for mediastinal lymphoma. Complete resection, pericardial involvement, and adjuvant radiotherapy were identified as significant risk factors for poor long-term prognosis. While the impact of complete resection has been previously discussed, the significance of pericardial involvement and adjuvant radiotherapy highlights the advanced nature of some lymphomas necessitating extensive resection and local adjuvant therapy. However, larger-scale studies involving more extensive patient populations are necessary to fully delineate the risk factors affecting long-term prognosis following surgical interventions for mediastinal lymphoma.

This study has several limitations. First, it was a retrospective single-center study with a relatively small sample size. This limitation arises largely due to the rarity of mediastinal lymphoma, which makes it difficult to enroll a sufficiently large cohort for comparative analyses. The favorable outcomes observed in the primary surgery group are largely attributable to the predominance of MALToma cases, which inherently have a better prognosis. Additionally, the finding that adjuvant radiotherapy was associated with an increased risk of recurrence is likely due to the small sample size in our study. In fact, among the 26 patients included, only two received adjuvant radiotherapy, both of whom had stage IVB disease, and one developed brain metastasis. Further studies with larger patient cohorts and multi-center studies are warranted to validate these findings. Second, it was a single-arm study that did not compare clinical outcomes between cases of mediastinal lymphoma treated with and without surgery. Comparing outcomes only within the surgery group may have introduced selection bias. Nonetheless, our primary goal was to evaluate outcomes in patients who underwent surgery for suspected thymic tumors and were incidentally diagnosed with lymphoma, providing practical insights relevant to surgical decision-making. Third, there is a risk of confounding due to indication bias. The primary surgery group predominantly included patients with early-stage disease who were eligible for surgery, while the salvage surgery group consisted mainly of highly selected cases, which could potentially lead to an overestimation of the effect of surgical intervention. Therefore, instead of comparing primary surgery and salvage surgery directly, we compared patients with favorable vs. unfavorable pathological subtypes. Caution is warranted in interpreting the results.

Conclusions

Surgical resection has demonstrated favorable early and long-term clinical outcomes in patients with incidentally detected mediastinal lymphomas. Additionally, surgical intervention can serve as salvage therapy for selected patients with mediastinal lymphoma following chemotherapy. Nevertheless, incomplete resection is associated with poor long-term survival and systemic recurrence, particularly in the CNS, and is emerging as the predominant failure pattern. Therefore, a multidisciplinary approach, incorporating multimodal discussions and treatment strategies, is imperative to achieve successful surgical outcomes in the management of mediastinal lymphoma.

Acknowledgments

The authors extend their gratitude to Soohee Kang, MS, from the Medical Research Collaborating Center, Seoul National University Hospital, for her assistance with the statistical analysis of the data.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-902/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-902/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-902/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-902/coif). T.M.K. has consulting or advisory roles outside this work with the following companies: Amgen, AstraZeneca/MedImmune, Boryung, Daiichi-Sankyo, HK inno.N, IMBDx. Inc., Janssen, Novartis, Regeneron, Roche/Genentech, Samsung Bioepis, Takeda, and Yuhan. K.J.N. is a co-founder and chief medical officer of Portrai, Inc. (Republic of Korea). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was reviewed by the Institutional Review Board of Seoul National University Hospital and approved as a minimal risk retrospective study (No. H-2308-061-1457, date: 2023.08.18), and individual consent was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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