Abstract
Primary esophageal lymphoma is a rare malignancy that is difficult to diagnose and treat. While there have been significant advances in understanding the pathogenesis, clinical features, and treatment options, there is a lack of consensus on the most effective treatment approach. This literature review provides a comprehensive overview of the use of available treatment options for primary esophageal lymphoma, including surgery, radiotherapy, and chemotherapy. The review also highlights the current knowledge gaps that need to be addressed through further research. While no single treatment modality has emerged as a clear front-runner, a combination of these treatments may be the most effective approach in managing primary esophageal lymphoma, tailored to the histological subtypes.
1 Introduction
Primary esophageal lymphoma is a rare malignancy that accounts for less than 1% of all esophageal neoplasms and only 0.3% of all primary non-Hodgkin’s lymphomas (1). This disease is challenging to diagnose and treat due to its nonspecific clinical presentation and variable histological features. As a result, the optimal management of primary esophageal lymphoma remains unclear, and there is no standard treatment approach. In recent years, there have been significant advances in the understanding of the pathogenesis, clinical features, and treatment options for primary esophageal lymphomas. However, the literature on this topic is limited, and there is a lack of consensus on the most effective treatment approach.
To date, various treatment modalities have been used, including surgery, radiotherapy, and chemotherapy. Each approach has its benefits and limitations, and the choice of treatment depends on the stage, histological type, and the patient’s overall health status. Given the rarity of this malignancy, there is a lack of large randomized controlled trials to establish the most effective treatment approach. As a result, the literature on the management of primary esophageal lymphoma consists primarily of case reports and small case series. In this literature review, we aimed to provide an overview of the use of available treatment options for primary esophageal lymphoma. We reviewed the existing evidence on the use of surgery, radiotherapy, chemotherapy, and immunotherapy and discuss their respective outcomes and limitations.
2 Search strategy
This literature review aimed to identify relevant studies related to primary esophageal lymphoma using the PubMed/Medline database. A comprehensive search was conducted using a combination of keywords and MeSH terms, including “primary esophageal lymphoma” OR “esophagus lymphoma” and various histology subtypes. No date or regional restrictions were applied, and all relevant analyses were included. The search yielded studies in several languages, and those in English, French, and Chinese were included in the analysis.
However, due to some studies being unavailable online, we only had limited access to their abstracts, resulting in some missing data. Despite this limitation, we included all available studies in our analysis to provide a comprehensive overview of the treatment options for primary esophageal lymphoma. The histological subtypes included in this study were MALT or mucosa-associated lymphoid tissue, DLBCL or diffuse large B-cell lymphoma, follicular lymphoma, Burkitt lymphoma, mantle cell lymphoma, T-cell lymphoma, ALCL or anaplastic large cell lymphoma, plasmablastic lymphoma, and Hodgkin lymphoma.
Overall, this review provides a comprehensive summary of the available literature on the management of primary esophageal lymphoma and highlights the current knowledge gaps that need to be addressed through further research.
3 Results
A total of 62 studies were included in this review. We found that most gastrointestinal tract lymphomas arise submucosally. They may be beyond the reach of endoscopic biopsy forceps, which can pose a problem for identifying histopathology and determining the best course of treatment (2). Reported reasons for choosing surgery, in indolent and less aggressive lymphomas like MALT lymphoma, included preliminary imaging, diagnosis, and a missing biopsy.
3.1 Mucosa-associated lymphoid tissue lymphoma
MALT lymphoma of the esophagus is a rare entity. In 2017, there were less than 20 reported cases of esophageal MALT lymphomas, most of which have been diagnosed in Japan (3). They are usually localized, but we found one case report of metastasis to the lungs and stomach (4) and one report of recurrence in the stomach and lung after initial radiotherapy (5). All treatment modalities have been used with generally good results, chemotherapy (CHOP-based) and resection being the most frequent (3, 4, 6–11). The main results of the available studies are summarized in Table 1.
Table 1
| Initial treatment | Modality details or adjuvant treatment | Outcome | Follow-up range | 2nd line treatment | Number of patients | Reference |
|---|---|---|---|---|---|---|
| Surgery | Thoracoscopic-assisted resection with gastroesophageal anastomosis and jejunostomy | Complete remission | 8 months | NA | 1 | (3) |
| Left postero-lateral thoracotomy | Complete remission | 1 year | NA | 1 | (43) | |
| + Radiation (34Gy/17 Fractions) + eradication | Recurrence as metastasis after 21 months | 21 months | CHOP | 1 | (5) | |
| Endoscopic mucosal resection | Complete remission | 7-57 months | NA | 4 | (6, 44–46) | |
| Endoscopic mucosal resection + Radiation 30-36Gy | Complete remission | 3-4 years | NA | 2 | (47, 48) | |
| Chemotherapy | CVP | Complete remission | 6 months | NA | 1 | (8) |
| R-mini-CHOP | Partial remission | NA | NA | 1 | (9) | |
| Rituximab | Partial remission | 1 year | NA | 1 | (10) | |
| R-CHOP + eradication | Complete remission, then sarcoidal granulomas | 2 years | NA | 1 | (11) | |
| Radiation therapy | 36Gy/18 Fractions | Complete remission | 9 months | NA | 1 | (49) |
| 36Gy 4 cycles + Rituximab | Complete remission | 3 years | NA | 1 | (50) | |
| Eradication therapy | Complete remission | 3 years | NA | 1 | (51) |
Treatment modalities and outcomes in primary esophageal MALT Lymphomas.
Despite the limited number of patients treated with radiotherapy in our review, extrapolation from other tumor sites would encourage the use of this modality, as MALT lymphomas are usually sensitive to radiation. In gastric lymphomas, radiotherapy can lead to 85-100% remission rates (4-5 years of disease-free survival), according to multiple small studies, especially in low-grade stages I and IIE (12–14). For this reason, since surgery—often indicated due to inconclusive biopsy results—and radiation therapy are effective treatment options with high remission rates, the safety profiles and tolerability of both modalities should be considered when treating patients with low-grade esophageal MALT lymphomas. Low doses of radiation therapy, compared to surgical resection, can be curative and associated with minimal side effects.
3.2 Follicular lymphoma
We found a single case of follicular lymphoma, described by Taal et al. in 1976. Based on the Working Formulation classification, it was diagnosed as a “small cleaved cell non-Hodgkin’s lymphoma” associated with extensive fistula formation, mainly to the left main bronchus. No manifestations of lymphoma were found outside of the esophagus. As dyspnea developed, the patient received a single dose of emergency chemotherapy but died three weeks later from sepsis (15).
3.3 Diffuse large B-cell lymphoma
DLBCL predominantly involves immunocompromised patients with HIV infection as a potential risk factor (16). All treatment modalities combined, outcomes were generally poor, and robust data is still lacking. While the results summarized in Table 2 show a 50% complete response rate, in most case reports, follow-up duration was either lacking or was very short, thus masking early disease progression, which would have been attributed to treatment failure. However, combined modalities, including radiation therapy, seem to yield better results, as all 5 patients who received either chemotherapy plus radiation therapy or surgery followed by chemotherapy and radiation therapy had a complete response, with the reports covering a follow-up period of up to 3 years.
Table 2
| Initial treatment | Modality details or adjuvant treatment | Outcome | Follow-up range | 2nd line treatment | Number of patients | Reference |
|---|---|---|---|---|---|---|
| Radiation therapy | NA | NA | NA | NA | 1 | (52) |
| (“large cell lymphoma”) 30Gy | Complete remission | 1 month | NA | 1 | (52) | |
| NA, Palliative treatment | Death | 1 month | NA | 1 | (20) | |
| Chemotherapy | CHOP | Death during chemo | NA | NA | 2 | (53, 54) |
| Nd-YAG laser, m-BACOD | Death from pneumonia | 3 months | 1 | (20) | ||
| R-CHOP (one patient stage 4) | Improvement | 0-4 months | NA | 3 | (20, 55, 56) | |
| R-CHOP + Radiation | Complete remission | 3 years | NA | 2 | (57, 58) | |
| Combination therapy | Complete remission | NA | NA | 1 | (59) | |
| R-CVP | Complete remission | NA | NA | 1 | (60) | |
| CEOP + radiation | Complete remission | 3 years | NA | 1 | (61) | |
| Surgery | Subtotal esophagectomy + R-CHOP + radiation | Complete remission | 1 year | NA | 1 | (62) |
| No treatment | Patient refusal | Death, NA | 6 weeks, NA | NA | 2 | (54, 62) |
Treatment modalities and outcomes in primary esophageal Diffuse Large B-Cell Lymphomas (DLBCL).
3.4 T-Cell lymphoma
Similarly to other types of esophageal lymphomas, T-cell lymphoma reports are scarce, and detailed treatment outcomes are missing in the literature. While two cases of primary NK/T-cell lymphoma were treated with chemotherapy only and achieved complete remission with a follow-up of up to 24 months (17, 18), a 40-year-old man in stage IE was also treated with CHOP but died due to complications (19).
Chemotherapy should be the mainstay of treatment, with a possible benefit when combined with radiation therapy. A review including Chinese case reports noted that systemic chemotherapy combined with concurrent radiotherapy might be an effective treatment for esophageal NK/T-cell lymphoma (17). Our literature search tends to validate this conclusion, as we noted a few cases of diffuse large T-cell Lymphomas treated with radiation therapy followed by either the HADAP regimen (patient survival of 14 months) or the CHOP regimen (2 patients, one with a survival of 7 months who died of sepsis despite evidence of early anti-tumor response, and one who survived ten months of follow-up) (20, 21). A fourth patient received two cycles of systemic chemotherapy with concurrent radiotherapy, but his general condition gradually worsened, and he passed away four months after admission (22).
Additionally, in 1999, 65 Gy irradiation was used to treat a primary esophageal T-cell lymphoma in clinical stage I(E)B with complete remission (23). The role of radiation therapy in T-cell lymphomas warrants further study, as radiotherapy has been considered of paramount importance for patients with clinically localized nasal disease, with approximately 70% of patients achieving complete remission after treatment (24).
3.5 Mantle cell lymphoma
Multifocal gut involvement has been described in mantle cell lymphoma (MCL) (25). However, esophageal involvement is uncommon. A retrospective study collecting data from 35 MCL patients with GI involvement found that the esophagus was affected in only 2 (5.7%) cases (26). All published cases were treated with chemotherapy, as lesions were usually seen in multiple locations in the GI tract. Of the few available cases, one died before receiving treatment (27); one was lost to follow-up, two had a good response to chemotherapy (28, 29), while one had no response to treatment (30). A “mantle cell lymphoma-like tumor” was treated with rituximab postoperatively and has been disease-free for more than 28 months after surgery (31).
3.6 Anaplastic large cell lymphoma
ALCL was first described in 1985 as a large-cell neoplasm with an expression of CD30 in all neoplastic cells (32). It is an uncommon T-cell lymphoma, defined as a separate entity since the 2008 WHO lymphoma classification (33). ALCL can be ALK+ or ALK-. Radiotherapy in esophageal ALCL has not yet been reported. Only one case report in 1992 mentioned a treatment plan including chemotherapy followed by radiotherapy, but the patient was lost to follow-up (34).
The few other published cases were treated with chemotherapy (usually CHOP), sometimes followed by autologous peripheral blood hematopoietic stem cell transplantation, with partial (2 cases) or complete (2 cases) remission (2, 35–37). Also, one patient was diagnosed post-mortem (38). Usually, ALK+ lymphoma is very sensitive to chemotherapy; thus, if the diagnosis is made without the need for thoracotomy and resection, chemoradiotherapy may be sufficient.
In other types and locations of ALCL, such as limited-stage systemic ALCL or breast implant-associated ALCL, radiation therapy was used in association with chemotherapy (39): for example, following doxorubicin-based chemotherapy and radiotherapy, in early-stage primary systemic anaplastic large-cell lymphoma, the 5-year overall survival (OS), progression-free survival (PFS), and local control rates for all patients were 84.4%, 63.6%, and 90.8%, respectively (40).
3.7 Burkitt
No case of adult esophageal Burkitt lymphoma was found in our database search. However, although it does not match our initial inclusion criteria, we found a case report of a 17-year-old patient in India with stage II intermediate risk, Group-B disease by Murphy staging system managed with LMB-96 protocol for intermediate-risk BL. She had a complete response and no recurrence after nine months (41).
3.8 Plasmablastic lymphoma
We found a single case of plasmablastic lymphoma treated in 2016 with resection followed by chemotherapy, without further details (42).
4 Discussion and conclusion
In conclusion, primary esophageal lymphoma, though rare, is a potentially life-threatening condition, requiring careful evaluation and management. The literature review explored various treatment options, including surgery, chemotherapy, and radiotherapy, with varying degrees of success. While no single treatment has emerged as a clear front-runner, a combination of those treatment modalities may be the most effective approach in managing primary esophageal lymphoma, and the choice should be tailored to the histological subtypes. Radiation therapy should be considered in patients with low-grade esophageal lymphomas as a definitive therapy, and as a consolidation therapy to chemotherapy in patients with high-grade esophageal lymphomas. Additional research is crucial to determine the most effective treatment strategies that could improve patient outcomes for this disease.
Statements
Author contributions
JK: Writing – original draft, Writing – review & editing. RD: Writing – original draft, Writing – review & editing. NK: Writing – original draft, Writing – review & editing. JE: Writing – original draft, Writing – review & editing. BI: Writing – original draft, Writing – review & editing. JY: Writing – original draft, Writing – review & editing. CH: Writing – original draft, Writing – review & editing.
Funding
The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.
Conflict of interest
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.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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Summary
Keywords
esophageal lymphoma, DLBCL, follicular lymphoma, radiation treatment, MALT lymphoma
Citation
El Khoury J, Daou R, Kim N, Bou Eid J, Imber B, Yahalom J and Hajj C (2025) Treatment of primary esophageal lymphomas: A review. Front. Oncol. 15:1475153. doi: 10.3389/fonc.2025.1475153
Received
02 August 2024
Accepted
17 January 2025
Published
06 February 2025
Volume
15 - 2025
Edited by
Liang Qiao, The University of Sydney, Australia
Reviewed by
Lara Hilal, American University of Beirut Medical Center, Lebanon
Updates
Copyright
© 2025 El Khoury, Daou, Kim, Bou Eid, Imber, Yahalom and Hajj.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Neal Kim, KimN4@mskcc.org
†These authors have contributed equally to this work
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