Gastrointestinal Lymphomas: A Comprehensive Review of Epidemiology, Clinical Features, Diagnosis, Histopathology, and Management

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is a review article discussing GI lymphomas. Overall, I recognize that this is an extensive topic to review but I believe the manuscript would benefit from substantial revisions to improve its flow, eliminate repetitive information, and provide more practical and clinically meaningful discussion. 

Comments:

Line 25: The original publication(s) reporting these % should be cited, rather than the current citation which only references these %.

Lines 44-46: “histopathological analyses demonstrate that only a minor subset of PGL cases, as well as certain Hodgkin and T-cell lymphomas, are of B-cell origin”. This sentence needs clarification/rephrasing.

Lines 52-54: “Can the authors expand on what they mean by this? How are molecular features or precision medicine driving treatment decisions in GI lymphomas?  To me, this is a generalized statement and does not reflect SOC treatment decisions in lymphomas (including GI lymphomas).

Lines 61-63: This also needs clarification and simplification. I'm not sure precision oncology needs to be mentioned again here.

Lines 88-89: “The presence of EZH2 mutations in GCB-DLBCL has led to the exploration of the use of EZH2 inhibitors like tazemetostat”. I don’t think the mention of tazemetostat fits here in this section and is of limited value.  

Line 101: MALT lymphoma is a valid current term for ENMZL (not formerly).

Lines 115-116: There are 4 morphological/pathological subtypes of MCL: blastoid, pleomorphic, classic, and small cell. Indolent MCL refers to clinical behavior and usually describes leukemic non-nodal MCL.

Lines 116-117: Needs rephrasing.

Lines 136-138: Also here, the mention of tazemetostat does not fit this section

Lines 226-229: this information is repeated

Lines 320-322: “A study by Dey et al. highlighted the interaction between tumor stage and age as independent prognostic factors in MCL, showing significantly poorer outcomes in older patients with advanced-stage disease”. This does not fit here. 

Lines 322-323: This information was mentioned earlier; no need to repeat it here.

Lines 411-413: Appropriate references for ORR with rituximab and R2 need to be included.

Lines 430-432: zanubrutinib + rituximab is not a SOC in MCL and if needed to be included in this text, a more detailed discussion is needed. In addition, the references cited do not represent the data on zanubrutinib and rituximab in MZL (one is a case report and another is in MZL).

Line 435; I couldn’t find information in reference #84 that mentions GI DLBCL.

Lines 437-439: This needs revision. This implies that bispecific antibodies are preferred as treatment before CART and/or axi-cel was studies in a patient population with prior exposure to BsAbs; neither statement is correct.

Rather than attempting to discuss generalized treatment approaches for different lymphoma subtypes (chemo, bispecific, tazemetostat, CAR T, etc), it would be more beneficial to review unique treatment approaches or challenges faced with GI lymphomas (such as the potential benefit from prephase steroids, data on low dose RT, risk of perforation with chemotherapy/CART, etc). 

The following studies are important to the discussion and should be included:

- Bowel perforation in intestinal lymphoma: incidence and clinical features; Vaidya et al, Annals of Oncology 24: 2439–2443, 2013

- Frequency of bowel perforation and impact of bowel rest in aggressive non-Hodgkin lymphoma with gastrointestinal involvement, BJH 2018 doi: 10.1111/bjh.15173

- Outcomes ofCD19 Chimeric Antigen Receptor T Cell Therapy in Patients with Gastrointestinal Tract Involvement of Large B Cell Lymphoma, Cortes-Bullich et al, TCT 2021

- Marginal zone lymphoma of the colon: case series from a single center and SEER data review. Trabolsi et al. Leukemia and Lymphoma 2021.

- The data on the use of response adapted ultra low dose RT (4 Gy) in gastric MALT lymphoma (Gunther et el, Lancet Haematol 2024; 11: e521–29)

Author Response

Reviewer 1

 

Line 25: The original publication(s) reporting these % should be cited, rather than the current citation which only references these %.

Re: Thank you for this keen observation, we have changed the citation and the original publication has been cited. All changes are highlighted in red

 

Lines 44-46: “histopathological analyses demonstrate that only a minor subset of PGL cases, as well as certain Hodgkin and T-cell lymphomas, are of B-cell origin”. This sentence needs clarification/rephrasing.

Re. Thank you. We have rephrased the sentence to clarify the statement. The changed sentence has been highlighted.

 

Lines 52-54: “Can the authors expand on what they mean by this? How are molecular features or precision medicine driving treatment decisions in GI lymphomas?  To me, this is a generalized statement and does not reflect SOC treatment decisions in lymphomas (including GI lymphomas).

Re: We have explained with examples how molecular features or precision medicine can drive treatment decisions in GI lymphoma. It has been highlighted in red.

 

Lines 61-63: This also needs clarification and simplification. I'm not sure precision oncology needs to be mentioned again here.

Re: Agree with the reviewer’s comment that precision oncology doesn’t need to be mentioned again, hence the sentences have been deleted.

 

Lines 88-89: “The presence of EZH2 mutations in GCB-DLBCL has led to the exploration of the use of EZH2 inhibitors like tazemetostat”. I don’t think the mention of tazemetostat fits here in this section and is of limited value.  

Re: We appreciate the reviewer’s comment. The sentence referring to tazemetostat has been deleted from the revised manuscript.

 

Line 101: MALT lymphoma is a valid current term for ENMZL (not formerly).

Re: The term ENMZL has been deleted and replaced with the valid term MALT lymphoma.

 

Lines 115-116: There are 4 morphological/pathological subtypes of MCL: blastoid, pleomorphic, classic, and small cell. Indolent MCL refers to clinical behavior and usually describes leukemic non-nodal MCL.

Re:We appreciate the correction. Indolent MCL has been removed from the list, and the four correct subtypes noted above have been incorporated into the revised manuscript.

 

Lines 116-117: Needs rephrasing.

Re: The sentence has been rephrased for clarity and has been highlighted in red.

 

Lines 136-138: Also here, the mention of tazemetostat does not fit this section

Re: The sentence mentioning tazemetostat has been deleted.

 

Lines 226-229: this information is repeated.

Re: The redundant wording has been deleted to improve clarity in the revised manuscript.

 

Lines 320-322: “A study by Dey et al. highlighted the interaction between tumor stage and age as independent prognostic factors in MCL, showing significantly poorer outcomes in older patients with advanced-stage disease”. This does not fit here. 

Re: Thank you for the suggestion, the mentioned sentence has been deleted. 

 

Lines 322-323: This information was mentioned earlier; no need to repeat it here.

Re: The sentence has been deleted from the revised manuscript.

Lines 411-413: Appropriate references for ORR with rituximab and R2 need to be included.

Re: The original article reporting the overall response rate (ORR) for rituximab and R2 has been included as reference #74 and is highlighted in red in the reference list.

 

Lines 430-432: zanubrutinib + rituximab is not a SOC in MCL and if needed to be included in this text, a more detailed discussion is needed. In addition, the references cited do not represent the data on zanubrutinib and rituximab in MZL (one is a case report and another is in MZL).

Re: The statement has been revised to update the standard of care (SOC) for MCL alongside emerging treatment options. The relevant reference has been updated and is highlighted as reference #82 in the reference list below.

 

Line 435; I couldn’t find information in reference #84 that mentions GI DLBCL.

Re:Reference #84 has been updated to the correct source containing information on GI DLBCL.

 

Lines 437-439: This needs revision. This implies that bispecific antibodies are preferred as treatment before CART and/or axi-cel was studies in a patient population with prior exposure to BsAbs; neither statement is correct.

Re: The statement has been removed from the revised manuscript.

 

Rather than attempting to discuss generalized treatment approaches for different lymphoma subtypes (chemo, bispecific, tazemetostat, CAR T, etc), it would be more beneficial to review unique treatment approaches or challenges faced with GI lymphomas (such as the potential benefit from prephase steroids, data on low dose RT, risk of perforation with chemotherapy/CART, etc). 

 

The following studies are important to the discussion and should be included:

- Bowel perforation in intestinal lymphoma: incidence and clinical features; Vaidya et al, Annals of Oncology 24: 2439–2443, 2013

- Frequency of bowel perforation and impact of bowel rest in aggressive non-Hodgkin lymphoma with gastrointestinal involvement, BJH 2018 doi: 10.1111/bjh.15173

- Outcomes ofCD19 Chimeric Antigen Receptor T Cell Therapy in Patients with Gastrointestinal Tract Involvement of Large B Cell Lymphoma, Cortes-Bullich et al, TCT 2021

- Marginal zone lymphoma of the colon: case series from a single center and SEER data review. Trabolsi et al. Leukemia and Lymphoma 2021.

- The data on the use of response adapted ultra low dose RT (4 Gy) in gastric MALT lymphoma (Gunther et el, Lancet Haematol 2024; 11: e521–29)

 

Re: Thank you for the suggestion. A separate section titled “Other Unique Treatment Approaches for Lymphomas and Challenges Faced with GI Lymphomas” has been added, with the mentioned studies appropriately referenced and cited.

 

Reviewer 2 Report

Comments and Suggestions for Authors

This review contains very clear and useful information, including the following: A comprehensive review of the epidemiology, clinical characteristics, diagnosis, histopathology, and management of gastrointestinal (GI) lymphoma is provided. GI lymphoma is a rare but clinically important malignant tumor with diverse symptoms. Clinically, accurate diagnosis and personalized treatment based on histological subtype and site are essential, and close collaboration between gastroenterologists, pathologists, oncologists, and radiologists is required, which is an important perspective. Therapeutically, traditional chemotherapy still serves as the foundational treatment, but in recent years, new treatment strategies have been developed, including targeted drugs, immunomodulatory compounds, and combination therapy. Innovative approaches have shown promising efficacy profiles with relatively low toxicity, opening new avenues for the management of refractory or recurrent disease. In summary, this review aims to comprehensively integrate recent advances in the diagnosis and treatment of GI lymphoma within the context of the broader evolution of precision oncology. The diversity of gastrointestinal lymphomas and the potential for serious complications necessitate continued research into their complex biology, identification of biomarkers, and development of more effective and less toxic treatments to improve patient survival and quality of life.

However, the following five points regarding incidence would be improved if they were added to Table 2: (1) Incidence of DLBCL and MALT in the stomach (2) Incidence of DLBCL, EATL, and MCL in the small intestine (3) Incidence of Bukitt lymphoma and DLBCL in the ileocecal region (4) Incidence of DLBCL, MALT, and MCL in the colon and rectum (5) Incidence of DLBCL in the esophagus

Author Response

This review contains very clear and useful information, including the following: A comprehensive review of the epidemiology, clinical characteristics, diagnosis, histopathology, and management of gastrointestinal (GI) lymphoma is provided. GI lymphoma is a rare but clinically important malignant tumor with diverse symptoms. Clinically, accurate diagnosis and personalized treatment based on histological subtype and site are essential, and close collaboration between gastroenterologists, pathologists, oncologists, and radiologists is required, which is an important perspective. Therapeutically, traditional chemotherapy still serves as the foundational treatment, but in recent years, new treatment strategies have been developed, including targeted drugs, immunomodulatory compounds, and combination therapy. Innovative approaches have shown promising efficacy profiles with relatively low toxicity, opening new avenues for the management of refractory or recurrent disease. In summary, this review aims to comprehensively integrate recent advances in the diagnosis and treatment of GI lymphoma within the context of the broader evolution of precision oncology. The diversity of gastrointestinal lymphomas and the potential for serious complications necessitate continued research into their complex biology, identification of biomarkers, and development of more effective and less toxic treatments to improve patient survival and quality of life.

 

However, the following five points regarding incidence would be improved if they were added to Table 2: (1) Incidence of DLBCL and MALT in the stomach (2) Incidence of DLBCL, EATL, and MCL in the small intestine (3) Incidence of Bukittlymphoma and DLBCL in the ileocecal region (4) Incidence of DLBCL, MALT, and MCL in the colon and rectum (5) Incidence of DLBCL in the esophagus

 

Re: Thank you for your kind feedback. Following the reviewer’s suggestion, we have added a new table (Table 3) titled “Common Histological Subtypes of GI Lymphomas by Site” to the revised manuscript.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Despite these revisions, the article would still benefit from additional major revisions to enhance its flow and readability. It is currently fragmented, with numerous repetitions. A few examples are below, but the authors are advised to review the entire article. Citations should also be confirmed. There are statements without appropriate supporting references (for example, response rate with R2). 

Lines 44-46: The revised statement is still unclear/confusing. If “B-cell origin occurs in only a limited subset of cases, specifically a minority of PGL cases”. So if B-cell is a minority, what’s the majority? And “certain Hodgkin and T-cell lymphoma” is out of context here. Also, reference #5 is for a study of gastric DLBCL and does not support this statement and needs to be revised.

Lines 57-59: Next-generation sequencing and molecular profiling allow identification of actionable targets, enabling enrollment in clinical trials of novel agents (e.g., BTK inhibitors, PI3K inhibitors, checkpoint inhibitors). This statement does not reflect the current standard of care practices or clinical trial landscape. In diseases where the BTKi are commonly used (examples: MCL, MZL, WM), this is not based on “actionable” targets. PI3Ki are rarely used these days in B cell after their withdrawals and even before, their use was not guided by “actionable mutations”. Same applies to CPI

Reference #74 does not include data on responses to lenalidomide.

Lines 429-436. This doesn’t fit here. Why is the treatment of r/r MCL being discussed here? This was not the point of my previous comment.

Table 3 is redundant and any additional information can be incorporated into Table 1

Reference 69 is a review article. The study that compared whole body MRI with PET should be cited instead.

Acronyms (MALT, MCL, Gi, DLBCL, etc) are defined repeatedly throughout the text

Line 461: remove “recently” since liso-cel has been approved in DLBCL for several years.

Line 462: liso-cel is also a standard treatment

Section 7. There is repetition again here with poor flow. “10–15% of NHL cases involve the GI tract” – statements like this fragment the article and make it seem like it was written by several people who did not read the entire article.  

Author Response

Lines 44-46: The revised statement is still unclear/confusing. If “B-cell origin occurs in only a limited subset of cases, specifically a minority of PGL cases”. So if B-cell is a minority, what’s the majority? And “certain Hodgkin and T-cell lymphoma” is out of context here. Also, reference #5 is for a study of gastric DLBCL and does not support this statement and needs to be revised.

Thank you for this keen observation , changes have been made and new reference has been added

Lines 57-59: Next-generation sequencing and molecular profiling allow identification of actionable targets, enabling enrollment in clinical trials of novel agents (e.g., BTK inhibitors, PI3K inhibitors, checkpoint inhibitors). This statement does not reflect the current standard of care practices or clinical trial landscape. In diseases where the BTKi are commonly used (examples: MCL, MZL, WM), this is not based on “actionable” targets. PI3Ki are rarely used these days in B cell after their withdrawals and even before, their use was not guided by “actionable mutations”. Same applies to CPI

Thank you for the keen observation the statement has been deleted

Reference #74 does not include data on responses to lenalidomide.

Thank you for this keen observation , Reference 78 with data on lenalidomide has been added

Lines 429-436. This doesn’t fit here. Why is the treatment of r/r MCL being discussed here? This was not the point of my previous comment.

Thank you for the keen observation the statement has been deleted

Table 3 is redundant and any additional information can be incorporated into Table 1

Thank you for this observation, changes have been made

Reference 69 is a review article. The study that compared whole body MRI with PET should be cited instead.

Thank you for this point, the reference is a prospective study with link

Acronyms (MALT, MCL, Gi, DLBCL, etc) are defined repeatedly throughout the text

Thank you for this keen observation , corrections have been made

Line 461: remove “recently” since liso-cel has been approved in DLBCL for several years.

Thank you for this keen observation , corrections have been made

Line 462: liso-cel is also a standard treatment

Thank you for this keen observation , corrections have been made

Section 7. There is repetition again here with poor flow. “10–15% of NHL cases involve the GI tract” – statements like this fragment the article and make it seem like it was written by several people who did not read the entire article.  

Thank you for this keen observation , corrections have been made

Round 3

Reviewer 1 Report

Comments and Suggestions for Authors

None