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

Abstract

Gastrointestinal (GI) lymphomas are a diverse group of extranodal non-Hodgkin lymphomas primarily affecting the stomach, small intestine, and colon. They present with non-specific symptoms such as abdominal pain, weight loss, or GI bleeding, making early diagnosis challenging. Histologic subtypes vary, with mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B-cell lymphoma (DLBCL) being the most common. Diagnosis involves endoscopic evaluation with biopsy, cross-sectional imaging, and often PET-CT. Management is subtype-dependent, including antibiotics for H. pylori-associated MALT lymphoma, chemotherapy, immunotherapy, and occasionally surgery. A multidisciplinary approach is essential for optimal outcomes. Core Tip: Gastrointestinal lymphomas are rare but clinically significant malignancies with variable presentations. Accurate diagnosis and tailored treatment based on the histologic subtype and site are critical, requiring close collaboration among gastroenterologists, pathologists, oncologists, and radiologists.

1. Introduction

Gastrointestinal (GI) lymphoma refers to a cancer of the lymphatic system that develops in the gastrointestinal tract, including the stomach, small intestine, and colon. The gastrointestinal tract (GIT) is a common site for extranodal lymphomas, accounting for 30–40% of extranodal lymphomas and 10–15% of all non-Hodgkin lymphoma cases [1]. Lymphomas involving the GIT might be primary or secondary as a result of dissemination. Lymphomas can develop in any part of the gastrointestinal tract, but the most commonly affected area is the stomach, followed by the small intestine and ileocecal region.

Lymphoid neoplasms can originate from mature B cells, T cells, and, less commonly, extranodal natural killer (NK)/T cells. Among these, the most prevalent histologic subtypes in the gastrointestinal tract are extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)—frequently linked to Helicobacter pylori infection—and diffuse large B-cell lymphoma (DLBCL) [2]. A subset of B-cell lymphomas is characterized by recurrent chromosomal abnormalities, underscoring the role of genetic alterations in lymphomagenesis. Enteropathy-associated T-cell lymphoma (EATL), particularly type I, commonly emerges in the context of longstanding celiac disease, with T-cell receptor (TCR) gene rearrangement studies used to confirm clonal proliferation. Extranodal NK/T-cell lymphomas, typically associated with Epstein–Barr virus (EBV) infection, exhibit an aggressive clinical course, necessitating careful distinction from benign NK-cell enteropathies due to their markedly different prognostic and therapeutic implications [3].

Individuals over the age of 50 exhibit a higher predisposition to primary gastrointestinal lymphoma (PGL), although cases have also been documented in individuals during the second decade of life [4]. Epidemiological data indicate a male predominance, with incidence rates two to three times higher in males compared to females. Histopathological studies reveal that the majority of GI lymphomas are non-Hodgkin lymphomas of B-cell lineage, with diffuse large B-cell lymphoma (DLBCL) and marginal-zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) comprising the majority of cases [5]. The diagnostic process for gastrointestinal lymphomas has historically been impeded by the non-specific clinical presentation and the overlap of symptoms with other gastrointestinal pathologies. However, recent advancements in diagnostic modalities—including high-resolution imaging, endoscopic techniques, and molecular biomarkers—have markedly enhanced early detection and enabled accurate disease staging and the formulation of evidence-based therapeutic strategies [6]. These developments have facilitated a paradigm shift toward precision medicine, enabling the implementation of individualized treatment regimens that account for the distinct molecular and clinical features of each patient’s malignancy. For example, the detection of t(11;18)(q21;q21) in gastric MALT lymphoma predicts resistance to Helicobacter pylori eradication, guiding clinicians toward radiotherapy or systemic therapy instead.

Significant progress has also been made in the therapeutic landscape of gastrointestinal lymphomas. This review endeavors to provide a comprehensive synthesis of recent advances in the diagnosis and treatment of gastrointestinal lymphomas, contextualized within the broader evolution of precision oncology. By critically examining the latest developments, ongoing challenges, and emerging opportunities, this article aims to enhance the understanding of the current state of the art and to illuminate potential future directions for the optimization of the management of these heterogeneous and clinically challenging malignancies.

2. Pathogenesis and Classification

2.1. GI Lymphoma Pathophysiology and Classification

Gastrointestinal (GI) lymphomas are a diverse group of neoplasms with distinct pathophysiological and molecular characteristics. The majority of GI lymphomas are non-Hodgkin lymphomas. They can be broadly classified into B-cell lymphomas, T-cell and NK-cell lymphomas, and other rare types.

2.2. B-Cell Lymphomas

2.2.1. Diffuse Large B-Cell Lymphoma (DLBCL)

Pathophysiology: DLBCL is the most common subtype of GI lymphoma. Up to 40% of patients diagnosed with DLBCL initially present with extranodal involvement, most commonly in the GI tract. It can arise de novo or from the transformation of low-grade lymphomas such as MALT lymphoma. It typically presents with extensive wall thickening or a bulky mass.

Molecular Genetics: Common genetic alterations include BCL6, MYC, and BCL2 translocations. Mutations in genes such as CD79B and MYD88 are also frequently observed [7]. DLBCL is generally classified through gene expression profiling by the B cell of origin (COO). DLBCL resembling germinal center B cells is termed germinal center B-cell-like DLBCL. On the other hand, those resembling activated B cells are designated activated B-cell-like DLBCL (ABC-DLBCL); 10–15% of cases are unclassifiable by COO [8]. ABC-DLBCL is characterized by chronic B-cell receptor signaling and the activation of the nuclear factor KB (NF KB) pathway [9,10,11]. Immunohistochemical algorithms are usually used as surrogates for COO to differentiate between GCB and non-GCB DLBCL. GCB DLBCL cases are usually CD10-positive, BCL6-positive, and MUM-negative with BCL2 translocations on FISH. On the other hand, non-GCB DLBCL cases are CD10-positive and MUM-positive. BCL6 staining can be positive or negative. Gastric DLBCL is more frequently non-GC as opposed to intestinal DLBCL, reflecting a potential relationship with low-grade marginal-zone-type B-cell lymphoma [12]. This is particularly important as patients with non-GC DLBCL have inferior survival outcomes compared to GC DLBCL patient who are treated with CHOP or RCHOP.

2.2.2. MALT Lymphoma

Pathophysiology: The basic idea of lymphoma as an antigen-driven disease is best described in MALT lymphoma. H. pylori chronically irritates gastric mucosal B as well as T cells, causing their proliferation. This chronic process causes B cells to become autoreactive and subsequently develop into an H. pylori-dependent lymphoma. It presents as mucosal nodularity or ulceration [13].

Molecular Genetics: Marginal cells generally exhibit positivity to CD19 and CD20, while being CD10-negative. The t(11;18)(q21;q21) translocation is performed by FISH or PCR to exclude MALT1 translocation. T(11,18) is often predictive of a lack of response to H. pylori eradication therapy [13]. Other genetic alterations include trisomy 3 and mutations in TNFAIP3 [7].

2.2.3. Mantle Cell Lymphoma (MCL)

Pathophysiology: MCL typically presents as lymphomatous polyposis, involving multiple polyps or nodules throughout the GI tract. MCL is generally an uncommon B- cell NHL subtype. Malignant cells share features with chronic lymphocytic leukemia (CLL) malignant cells. There are four main pathological variants of MCL: classic MCL, blastoid MCL, pleomorphic MCL, and small-cell MCL. Classic MCL is the most common pathological variant and is the subtype most frequently associated with extranodal involvement in the GI tract [14].

Molecular Genetics: Malignant cells, as mentioned previously, share characteristics with CLL malignant cells, as they are CD5+ and CD20+. However, unlike CLL and follicular lymphoma, MCL malignant cells do not express CD23 or CD10, respectively [15]. The t(11;14)(q13;q32) translocation, resulting in the overexpression of cyclin D1, is characteristic of MCL. Additional mutations in genes such as ATM and TP53 are common. Although TP53 mutation is present in a minority of cases with newly diagnosed MCL, it is associated with a poorer prognosis and chemoresistance with intensive therapy when present [16].

2.2.4. Follicular Lymphoma (FL)

Pathophysiology: FL is less common in the GI tract and can present with multiple nodules. Lymph node biopsy shows a mixture of centrocytes and centroblasts forming a follicle growth-like pattern. Based on the 2022 WHO classification, two other FL variants have emerged. Follicular large B-cell lymphoma is characterized by predominant centroblasts, whereas FL with uncommon features is characterized by a diffuse growth pattern [17].

Molecular Genetics: Characteristic immunophenotyping shows a germinal center origin and is positive for CD20 and CD10. CD5 is negative. The t(14;18)(q32;q21) translocation, leading to BCL2 overexpression, is a defining feature in more than 85% of patients having FL [18,19]. Mutations in genes such as EZH2 and CREBBP are also observed. Activating EZH2 mutation has become a targetable mutation for patients with relapsed/refractory FL (after two or more lines of therapy) [20,21].

2.2.5. Burkitt Lymphoma

Pathophysiology: Burkitt lymphoma is a rare, highly aggressive tumor that constitutes 2% of all NHL cases [22]. It has three types; the first is the endemic type, which presents as jaw tumors in children from the sub-Saharan area and is almost always associated with EBV. The second type is HIV-associated and develops in patients with long-standing HIV viremia. The third type is the sporadic type, which typically presents as an ileocecal mass in children, is often associated with widespread disease, and is less associated with EBV [23].

Molecular Genetics: Burkitt lymphoma is characterized by a very high proliferation index, with a Ki67 score often at 100%. It carries a mature B-cell phenotype (CD10, CD19, CD20, CD22, CD38, and CD43; BCL6; and monoclonal surface IgM). The t(8;14)(q24;q32) translocation involving the MYC gene is characteristic. t(2,8) and t(8,22) are less common but can also occur [23,24]. Additional mutations in genes such as ID3 and TCF3 are also common [25].

2.3. T-Cell and NK-Cell Lymphomas

2.3.1. Enteropathy-Associated T-Cell Lymphoma (EATL)

Pathophysiology: EATL accounts for approximately 5% of TCL cases and is more commonly present in geographic areas with a higher incidence of celiac disease. This includes Europe and North America. EATL associated with celiac disease usually displays a polymorphic histology and expresses CD3 and CD7. However, it lacks CD56. Meanwhile, EATL patients who do not have celiac disease typically exhibit a monomorphic histology with CD56 expression, and this is now classified as a separate intestinal TCL and termed monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL). EATL usually presents with jejunal wall thickening, ulceration, and potential perforation [26].

Molecular Genetics: Common genetic alterations include mutations in the JAK-STAT pathway, particularly STAT3 and JAK2 fusions. Other mutations in genes such as SETD2 and TP53 are also observed [27]. Gains at chromosomes 9q33–q34 are observed in 70% of patients with EATL [28].

2.3.2. Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma (MEITL)

Pathophysiology: Previously known as EATL type 2, MEITL involves the small intestine and presents with similar features to EATL. It is now recognized as a distinct subtype of intestinal TCL.

Molecular Genetics: It exhibits CD56 expression. Genetic alterations are almost the same in EATL and include mutations in the JAK-STAT pathway. However, MEITL is characterized by more frequent gains of the MYC oncogene locus and less frequent gains of chromosomes 1q and 5q as compared with EATL [29].

2.4. Other Lymphomas

Primary GI Hodgkin Lymphoma

Pathophysiology: This is rare and can present with a variety of findings, including stenosis. Molecular Genetics: Genetic alterations are less well characterized but may include EBV association in some cases [30].

This detailed classification and molecular genetic analysis enables a comprehensive understanding of the pathophysiology of GI lymphomas, aiding in accurate diagnosis and targeted treatment strategies.

3. Sites of Involvement

Gastrointestinal (GI) lymphomas represent a significant subset of extranodal lymphomas, with varied anatomical involvement across the GI tract. The distribution and characteristics of these lymphomas have been extensively studied in recent years. The distribution of GI lymphomas are shown in Figure 1.

3.1. Stomach

The stomach is the most common site of primary GI lymphoma, accounting for 60–75% of cases. The most frequent histologic subtypes are DLBCL and MALT lymphoma. Helicobacter pylori infection is strongly associated with gastric MALT lymphoma, and eradication therapy may lead to remission in early-stage disease [1]. Gastric lymphomas typically present with non-specific symptoms like epigastric pain, anorexia, or bleeding [31].

3.2. Small Intestine

The small intestine, particularly the ileum, is the second most commonly affected site, comprising about 20–30% of cases. DLBCL is again the predominant subtype, but unique variants such as enteropathy-associated T-cell lymphoma (EATL) occur, especially in patients with celiac disease [32]. Jejunal and ileal lesions often present with obstruction, perforation, or bleeding [33].

3.3. Colon and Rectum

Colonic involvement is less common, found in 10–20% of GI lymphomas. The cecum is the most frequent site in the colon, likely due to its high lymphoid tissue content [34]. MALT lymphoma is also occasionally found in the rectum, particularly in East Asian populations [35]. Colorectal lymphomas typically present with hematochezia, masses, or altered bowel habits.

3.4. Esophagus

Primary esophageal lymphoma is extremely rare, representing < 1% of GI lymphomas. Most reported cases are DLBCL and are usually seen in immunocompromised individuals or those with chronic inflammatory conditions [36].

3.5. Pancreas

Primary pancreatic lymphoma (PPL) is rare, constituting less than 0.7% of extranodal lymphomas. It is more prevalent in middle-aged and elderly individuals, often presenting with abdominal pain or a pancreatic mass mimicking adenocarcinoma [37].

3.6. Ileocecal Region

The ileocecal area is a common site for intestinal lymphomas, likely due to the abundance of lymphoid tissue in the terminal ileum and cecum. DLBCL is the dominant histological type, often presenting as an abdominal mass or intussusception [38].

3.7. Multifocal Involvement

Although rare, multifocal involvement of the GI tract can occur and is often seen in aggressive lymphomas or advanced-stage disease. These cases require comprehensive staging and are associated with a worse prognosis [39].

4. Clinical Presentation

Gastrointestinal (GI) lymphomas, while relatively rare compared to other malignancies of the digestive tract, remain the most common extranodal types of non-Hodgkin lymphoma (NHL), accounting for approximately 30–40% of extranodal cases and 10–15% of all NHLs [31]. The clinical manifestations of GI lymphomas are highly variable and frequently non-specific, complicating early diagnosis. Presenting symptoms depend on the anatomical site, histologic subtype, disease burden, and depth of mucosal or transmural infiltration [40].

4.1. General Symptoms

The most frequently reported symptoms include the following:

• Abdominal pain, occurring in 50–75% of patients, is often localized to the epigastric or periumbilical region. This pain may be persistent or colicky, frequently mimicking peptic ulcer disease or inflammatory bowel disease [38].
• Weight loss is reported in 30–50% of patients and may be attributed to anorexia, malabsorption, or the increased catabolic activity of tumor cells [41].
• Gastrointestinal bleeding, both occult and overt, is seen in up to 30% of patients. Melena or hematemesis is common when the stomach or duodenum is involved, while hematochezia may indicate colonic or rectal disease [42].
• Nausea, vomiting, or early satiety, especially in gastric lymphomas, may suggest luminal obstruction or gastric motility dysfunction due to tumor infiltration [43].
• Intestinal obstruction is a hallmark of advanced disease, particularly in small bowel lymphomas such as DLBCL or EATL, often requiring surgical intervention [44].
• Perforation, although less common, represents a life-threatening emergency and may occur spontaneously or during chemotherapy, especially in high-grade lymphomas [45].

4.2. Systemic and Constitutional Symptoms

In addition to GI symptoms, some patients may present with B symptoms—fever, night sweats, and weight loss—particularly in high-grade lymphomas such as DLBCL and NK/T-cell lymphomas [46].

4.3. Anatomic and Histologic Correlations

4.3.1. Stomach

The stomach is the most common site of GI lymphoma, particularly for extranodal marginal-zone B-cell lymphoma of MALT lymphoma, which is frequently associated with Helicobacter pylori infection [47]. Patients typically present with epigastric pain, dyspepsia, or GI bleeding and, in rare cases, gastric outlet obstruction [48]. In contrast, gastric DLBCL presents more aggressively, with systemic symptoms, mass effects, and bleeding [48].

4.3.2. Small Intestine

The small bowel, particularly the ileum and jejunum, is the second most frequently involved site. Symptoms include vague abdominal pain, diarrhea, obstruction, and weight loss. EATL, closely associated with celiac disease, presents with severe abdominal pain, diarrhea, and, frequently, intestinal perforation [49]. MCL may also involve the small intestine, often presenting as multiple lymphomatous polyposis [50].

4.3.3. Ileocecal Region

The ileocecal region is frequently involved in aggressive B-cell lymphomas, with presentations mimicking appendicitis or Crohn’s disease. A right lower-quadrant mass, pain, and obstructive symptoms are characteristic [51].

4.3.4. Colon and Rectum

Colorectal lymphomas are uncommon (<10% of GI lymphomas) and may mimic adenocarcinoma or inflammatory bowel disease. Common presentations include hematochezia, altered bowel habits, and tenesmus [52].

4.4. Histologic Subtype-Specific Presentations

• MALT Lymphoma: Indolent, often asymptomatic or presents with dyspepsia; strongly associated with H. pylori infection [53].
• DLBCL: Aggressive, often presents with rapidly progressing mass, bleeding, or obstruction [54].
• EATL: Aggressive T-cell neoplasm linked to refractory celiac disease; frequently presents with perforation or obstruction [55].
• Extranodal NK/T-Cell Lymphoma: Rare, aggressive tumor typically associated with Epstein–Barr virus; non-specific abdominal symptoms and systemic features are typical [53].

4.5. Selected Subtypes in Detail

4.5.1. Extranodal Marginal-Zone B-Cell Lymphoma of MALT Lymphoma

MALT lymphoma is the most common indolent lymphoma of the stomach and is frequently associated with chronic Helicobacter pylori infection. Patients typically present with vague dyspeptic symptoms, including epigastric pain, nausea, and early satiety, although some may be asymptomatic and diagnosed incidentally during endoscopic procedures [56]. Hematemesis or melena can occur with mucosal ulceration. The eradication of H. pylori often results in remission, especially in early-stage disease confined to the mucosa and submucosa [1].

4.5.2. Diffuse Large B-Cell Lymphoma (DLBCL)

DLBCL is the most prevalent aggressive subtype of GI lymphoma, comprising 30–50% of primary GI lymphomas. It typically involves the stomach or small intestine and presents with acute symptoms such as abdominal pain, obstruction, and GI hemorrhage due to deep transmural infiltration [57]. DLBCL is frequently associated with elevated LDH levels and a high proliferation index, necessitating prompt diagnosis and the initiation of immunochemotherapy [51].

4.5.3. Mantle Cell Lymphoma (MCL)

MCL is a mature B-cell neoplasm that often presents with widespread disease, including nodal and extranodal involvement. GI involvement is frequent and may be identified in up to 90% of cases, often manifesting as multiple lymphomatous polyposis (MLP) distributed throughout the colon and small bowel [58]. Clinical features include abdominal discomfort, diarrhea, weight loss, and, occasionally, intussusception or obstruction [50,51].

4.5.4. Enteropathy-Associated T-Cell Lymphoma (EATL)

EATL is a rare and aggressive peripheral T-cell lymphoma predominantly involving the jejunum and ileum. It is closely linked to long-standing celiac disease and often presents with severe abdominal pain, diarrhea, weight loss, and signs of intestinal perforation [59]. Malabsorption and villous atrophy are common. Histologic examination reveals pleomorphic lymphoid infiltrates with extensive necrosis, and T-cell receptor (TCR) gene rearrangement studies are typically necessary to confirm clonality [52].

4.5.5. Extranodal NK/T-Cell Lymphoma, Nasal Type

This rare Epstein–Barr virus (EBV)-associated lymphoma usually involves the nasal cavity but may also present with primary or secondary GI involvement, most frequently in the small bowel or colon. It often follows an aggressive course, with GI bleeding, perforation, and severe abdominal pain [59]. Endoscopy may reveal ulcerative or necrotic lesions. Accurate diagnosis depends on the immunohistochemical identification of NK/T-cell markers and EBV-encoded RNA (EBER) via in situ hybridization [59]. Distinguishing it from benign NK-cell enteropathy is critical due to significant differences in prognosis and therapeutic approach.

4.6. Summary

Differences in clinical presentation by site and histologic subtype are summarized in the following

Table 1. Clinical presentation by anatomic location.

Site	Common Subtypes	Characteristic Symptoms	Common Subtypes (%)
Stomach	MALT lymphoma, DLBCL	Epigastric pain, dyspepsia, nausea, GI bleeding, early satiety; DLBCL may cause systemic symptoms	DLBCL (40–70%), MALT (40%), MCL/Burkitt rare
Small Intestine	DLBCL, EATL, MCL	Vague pain, diarrhea, obstruction, weight loss; EATL is linked to celiac disease, often presents with perforation	DLBCL, MCL, Burkitt (~ 9%)
Ileocecal Region	Aggressive B-cell lymphomas	Mimics appendicitis/Crohn’s; RLQ mass, obstructive symptoms	Similar to small intestine types
Colon/Rectum	MCL, DLBCL, others (rare)	Hematochezia, altered bowel habits, tenesmus, may mimic adenocarcinoma	DLBCL, MALT, MCL

and

Table 2. Clinical presentation by histological subtype.

Subtype	Presentation
MALT Lymphoma	Indolent; dyspepsia, epigastric pain, nausea; associated with H. pylori; responds to eradication therapy
Diffuse Large B-Cell Lymphoma (DLBCL)	Aggressive; mass effect, bleeding, perforation, B symptoms; rapid progression
Mantle Cell Lymphoma (MCL)	Multiple lymphomatous polyposis; diarrhea, abdominal discomfort, obstruction
EATL	Associated with celiac disease; severe pain, diarrhea, weight loss, perforation; aggressive course
Extranodal NK/T-Cell Lymphoma	Rare, EBV-associated; GI bleeding, perforation, abdominal pain; systemic symptoms often present

respectively

5. Diagnosis

5.1. Endoscopy/Colonoscopy

Endoscopic evaluation of the gastrointestinal tract is a vital tool for early detection and the characterization of regions displaying qualities suggestive of malignancy, e.g., premalignant lesions such as Barrett’s esophagus and gastric intestinal metaplasia [60]. Endoscopy and colonoscopy are first-line approaches when evaluating for gastrointestinal malignancies and are crucial to the multimodal diagnostic evaluation that a patient would undergo. Endoscopic findings of gastrointestinal malignancies can be described in terms of a superficial form, giant fold form, multiple-nodule form, protruding without ulcer form, protruding with ulcer form, and fungating form [60]. While each of these unique findings can be suggestive of particular pathologies, biopsy and histology are the only means to definitively characterize these lesions as malignancies.

5.2. Capsule Endoscopy and Balloon-Assisted Enteroscopy

Capsule endoscopy plays an important role in the evaluation of gastrointestinal malignancies that require surveillance to allow for the guidance of treatment decisions. For example, in patients diagnosed with follicular lymphoma involving the small intestine, it becomes crucial to undergo regular surveillance for the evaluation of the disease burden. While endoscopy is a valid option in evaluating the disease burden, its repetition would introduce opportunities for injury given the more invasive nature of this procedure [61,62]. While this becomes an option for surveillance, any findings that are concerning enough to warrant a biopsy would ultimately require more invasive action, as one of the major drawbacks of video capsule endoscopy is the inability to take biopsy samples [63].

5.3. CT, PET/CT, and MRI

Imaging plays a large role in the diagnosis and management of intestinal lymphomas. Contrast-enhanced CT and PET-CT are the preferred modalities for the diagnosis of gastrointestinal lymphomas [64]. While these modalities have played a large role in the detection and management of gastrointestinal lymphomas, most PET/CT tracers used in clinical practice have variable degrees of uptake in different regions of the bowel, making diagnosis in regions of higher uptake less specific to malignant pathologies. It is also important to note that there are various disease states, and non-pathological variation can lead to false positive uptake on PET/CT [65]. While PET/CT remains the preferred imaging modality for staging, MRI has the potential to replace PET/CT and CT imaging.

Recent studies have demonstrated this efficacy by comparing whole-body MRI to 18F-FDG- PET/CT in terms of diagnostic performance for the staging of patients with lymphomas. WB-MRI was found to have similar performance and offers a promising technique for the accurate assessment of the extent of disease [66]. With the advantage of not relying on radiation, MR imaging offers a harmless means of lymphoma surveillance in patients who are at increased risk [67]. Major drawbacks to MR imaging are limited availability and prolonged examination times.

5.4. Histopathology and Immunohistochemistry

Few reliable prognostic factors for GI lymphomas have been identified, and, at present, aspects such as histopathological classification and immunophenotyping offer the greatest information for prognosis. This becomes greatly important when using these prognostic factors to guide treatment decisions [68]. Molecular techniques such as genomic sequencing offer a promising avenue towards identifying mutations/alterations that can serve as prognostic markers and guide treatment decisions [68]. Currently, our practice relies on the use of traditional histology and immunohistochemistry, but recent advances have allowed the use of circulating tumor DNA or liquid biopsy (LiqBio) as potential prognostic markers [69].

6. Management

Primary gastrointestinal (GI) lymphomas encompass a heterogeneous group of B- and T-cell neoplasms whose optimal care relies on coupling histology with the anatomic site. Their management now follows a staircase model that begins with Helicobacter pylori (H. pylori) eradication, escalates through organ-preserving radiotherapy (RT) and chemo-immunotherapy, and reserves surgery or highly targeted agents for exceptional circumstances.

Early-stage gastric mucosa-associated lymphoid tissue (MALT) lymphoma typifies this paradigm. Dual clarithromycin resistance has rendered classical triple therapy sub-optimal, so modern guidelines recommend 14-day bismuth-based quadruple or vonoprazan triple regimens, which induce lasting histological remission in 60–90% of stage I/II tumors [70]. Deep infiltration, t(11;18)(q21;q21), and H. pylori negativity predict antibiotic failure; yet, even in these settings, upfront eradication remains appropriate because late complete responses still occur and toxic therapy can be deferred [71,72]. When lymphoma persists or recurs, involved-site RT at 24–30 Gy yields ≥ 95% local control with negligible gastric toxicity, and prospective data now support further de-escalation to 24 Gy without compromising efficacy [73,74]. Systemic therapy is rarely required, but single-agent rituximab and rituximab–lenalidomide show an overall response rate of >80% in disseminated or multiply relapsed disease [71,75].

Diffuse large B-cell lymphoma (DLBCL) accounts for most high-grade primary gastric lymphomas. Six cycles of R-CHOP remain curative, delivering 5-year overall survival rates above 85% in a recent multicenter series [76]. Where resources allow, PET-adapted shortening to four cycles in stage I–II disease limits hematological toxicity without eroding disease control. The pola-R-CHOP regimen has marginally improved event-free survival over R-CHOP in the international POLARIX trial and is increasingly adopted for gastric and intestinal presentations [77].

Primary intestinal DLBCL behaves more aggressively and carries an intrinsic risk of chemotherapy-related perforation. Contemporary population data show that full-dose R-CHOP, with vigilant surgical standby, remains appropriate; prophylactic resection is limited to bulky proximal jejunal lesions threatening imminent rupture [78]. Elective RT is generally avoided because of radiation enteritis.

Extranodal indolent B-cell entities also occur below the pylorus. Duodenal-type follicular lymphoma is typically incidental, remains mucosal, and is safely observed; in a 2023 series, overall survival exceeded 95% with a watch-and-wait strategy and the selective use of rituximab [79].

Targeted immunotherapy is rapidly redefining salvage options. Fixed-duration glofitamab, a CD3 × CD20 bispecific antibody, produced 57% complete responses and durable 2-year disease control in real-world GI-involved DLBCL [80], while longer-term follow-up of the pivotal phase II cohort confirmed that these remissions persisted for 36 months [80].

Enteropathy-associated T-cell lymphoma (EATL) remains the most lethal GI lymphoma, but registry data from the Netherlands show that anthracycline–etoposide induction followed by a consolidative autologous stem-cell transplant doubled the 3-year overall survival versus chemotherapy alone [81]. Nevertheless, emergent perforation mandates instant surgery, underscoring that operative management, although rare, still has an irreplaceable role across histologies when catastrophic complications arise.

7. Other Unique Treatment Approaches for Lymphomas and Challenges Faced with GI Lymphomas

DLBCL and Burkitt lymphoma are aggressive lymphomas treated with multiagent chemotherapy. High-risk patients, such as the elderly or those with a heavy disease burden, may experience serious treatment toxicities. Pre-phase therapy using corticosteroids, with or without low-dose chemotherapy, is given beforehand to reduce these risks [82].

Autologous CD19-directed CAR T-cell therapy has shown durable remission in relapsed or refractory large B-cell lymphoma (LBCL). Currently, three commercial CAR T products are available for LBCL treatment: axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel. CD19 CAR T-cell therapies (axi-cel, tisa-cel, liao-cel) are standard treatments for relapsed/refractory large B-cell lymphoma [83]. Patients with GI tract involvement face a risk of perforation before or after CAR T infusion. Despite this, their rates of severe side effects and treatment outcomes are similar to those in patients without GI involvement. Durable remissions can be achieved, but close monitoring is needed due to the perforation risk. Cortes et al. performed a retrospective study that evaluated 130 large B-cell lymphoma patients treated with CAR T therapy, including 24 with GI tract involvement. Three patients with GI involvement experienced perforations, leading to death, but the overall rates of severe toxicity and treatment outcomes were similar between patients with and without GI involvement [83].

Perforation is a life-threatening complication of gastrointestinal (GI) lymphomas, occurring either at initial presentation or after chemotherapy initiation. A single-center study performed by Vaidya et al. found that perforations were more common in aggressive GI lymphomas compared to indolent types, highlighting the ongoing risk associated with these tumors [84].

NHL is associated with bowel perforation, occurring in roughly 10% of aggressive cases and 3% post-chemotherapy. Perforation can cause serious complications, and routine bowel rest or hospitalization does not improve outcomes. Patients should promptly report symptoms of perforation [85].

8. Prognosis

Gastrointestinal (GI) lymphomas display highly variable prognoses, influenced by the histologic subtype, anatomic site, clinical stage, and molecular features. Indolent forms such as extranodal marginal-zone lymphoma of mucosa-associated lymphoid tissue (MALT) and primary gastrointestinal follicular lymphoma (PGI-FL) generally have favorable outcomes, with median overall survival exceeding 10 years and 5-year survival rates above 75% [86]. In contrast, aggressive subtypes including gastrointestinal diffuse large B-cell lymphoma (GI-DLBCL) and T-cell lymphomas are linked with poorer outcomes, particularly in advanced stages or when high-risk molecular abnormalities are present.

For PGI-FL, recent population-based data report a 5-year transformation rate to DLBCL of approximately 2%, with survival outcomes superior to those of nodal follicular lymphoma. Prognostic determinants include age, sex, histological grade, Ann Arbor stage, tumor location, and receipt of radiotherapy. Nomogram-based tools enable personalized survival prediction in clinical settings [87].

GI-DLBCL carries a worse prognosis when associated with an advanced Lugano or TNM stage, elevated LDH, anemia, hypoalbuminemia, older age, or a large tumor burden. The HLAMA model—comprising hemoglobin, LDH, age, albumin, and the maximum intra-abdominal lesion diameter—along with its simplified version, outperforms the International Prognostic Index (IPI) in localized disease. MYC rearrangements and certain high-risk genetic subtypes (A53, MCD, N1) are linked to significantly inferior outcomes [88].

In extranodal marginal-zone lymphoma, the MALT International Prognostic Index is the preferred tool for risk stratification. Among patients experiencing disease progression within two years of initial therapy, median survival drops markedly to 3–5 years. In early-stage disease of the lower intestinal tract, 10-year overall survival exceeds 80% for colon and rectal primaries but falls to approximately 65% for small intestinal disease, irrespective of the treatment modality [86].

Across all subtypes, common adverse prognostic factors include an advanced stage, the T-cell phenotype, elevated LDH, a poor performance status, and the involvement of multiple extranodal sites [89]. By contrast, B-cell lineage and localized disease are consistently associated with more favorable outcomes. Surgical intervention is generally reserved for managing complications, as chemotherapy-based regimens remain the cornerstone of treatment. Surgery alone is linked with inferior outcomes across most subtypes [90].

GI Burkitt lymphoma is highly aggressive but potentially curable with intensive chemotherapy. In adult cohorts, 3-year overall survival approximates 70%, although outcomes worsen with older age, high LDH, a poor performance status, CNS involvement, or multiple high-risk features. Gastric localization is associated with particularly poor survival (5-year OS: 37.8%) compared to intestinal disease (5-year OS: 70.2%). In pediatric patients, the prognosis is more favorable, with 5-year survival rates exceeding 85% [91].

Primary GI follicular lymphoma is typically indolent, often presenting with localized disease. The prognosis is excellent, with 5-year OS above 90% and 10-year OS near 87% in intestinal presentations managed conservatively. Transformation to aggressive histology remains rare, with a 5-year transformation rate near 2.1%. Outcomes are superior to nodal follicular lymphoma, and prognostic variation is influenced by the patient age, disease stage, tumor grade, and site of involvement.

Among rarer GI lymphomas, mantle cell lymphoma is associated with significantly poorer survival than other B-cell subtypes [92]. T-cell lymphomas, including enteropathy-associated T-cell lymphoma, are infrequent but carry an adverse prognosis, commonly presenting with advanced disease and systemic B symptoms. Marginal zone/MALT lymphomas, while rare, are generally indolent and associated with favorable outcomes, particularly when detected early and confined to a single site [93].

In summary, indolent lymphomas such as MALT and primary GI follicular lymphoma are linked to excellent long-term survival. Conversely, aggressive forms such as GI-DLBCL and T-cell lymphomas carry a poorer prognosis, especially in the presence of high-risk molecular features or advanced disease. Burkitt lymphoma, although aggressive, remains potentially curable with intensive chemotherapy, although the prognosis is less favorable in older adults and in cases with gastric involvement [94].

Key prognostic factors across all subtypes include the disease stage, LDH level, performance status, cell lineage, and extent of extranodal involvement [3]. Risk stratification tools—including the HLAMA model, MALT IPI, and disease-specific nomograms—support clinical decision making and guide treatment selection [95].

9. Special Considerations

9.1. Primary vs. Secondary GI Lymphomas

Primary GI lymphomas are rarer than secondary GI lymphomas. Patients with primary mantle cell lymphoma tend to be treated less aggressively than those with secondary mantle cell lymphoma; however, it was noted that there seemed to be similar outcomes between the two types of lymphomas [35]. Secondary gastrointestinal sites of MCL are fairly common, with a study showing that GI involvement was present in 90% of cases of untreated MCL. Primary GI MCL, however, is rare and only presents 4–9% of the time [31]. A diagnosis of primary gastrointestinal lymphoma is given when there is no additional nodal or extranodal lymphoma presence [31]. Overall, 90% of primary GI lymphomas are of B-cell lineage, with the remaining 10% coming from T-cell lineage and Hodgkin lymphomas [96]. Primary and secondary GI lymphomas are distinguished by histopathological diagnosis [96].

9.2. Immunocompromised Hosts (e.g., HIV, Transplant Patients)

Immunocompromised states such as those associated with HIV and human T-cell lymphotropic virus (HTLV-1) have been implicated in the pathogenesis of gastrointestinal lymphomas [35]. In approximately 25% of patients with AIDS and systemic lymphomas, gastrointestinal lymphomas were present, which were associated with a poorer prognosis. Non-Hodgkin B-cell lymphoma (NHL), mostly affecting the gastrointestinal tract, is one of the most common malignancies noted in AIDS patients [81]. The most common types of GI NHL are diffuse B-cell lymphomas or Burkitt cell lymphomas. GI non-Hodgkin lymphomas in immunocompromised patients present similarly to those in immunocompetent patients, usually consisting of polyploid lesions with ulcerations. In immunocompromised patients, Burkitt cell lymphomas can spread, leading to the complete replacement of the mucosa, submucosa, and muscularis propria, often causing ulcerations on the surface [97]. Other types of NHL affecting the gastrointestinal tract in HIV patients include immunoblastic lymphoma and centroblastic lymphoma. Plasmablastic lymphoma is a specific type of lymphoma that has a predilection for the oral cavity and is commonly seen in HIV patients [96]. GI MALT lymphomas are commonly seen in HIV-positive patients. Post-transplant lymphoproliferative disorder is a type of lymphoma that is seen due to an immunocompromised state after bone marrow or solid organ transplantation [96]. PTLD occurs in approximately 30% of cases after transplantation, and the gastrointestinal tract is commonly affected [96].

10. Future Directions

Bispecific antibodies such as glofitamab have demonstrated effectiveness in both primary and relapsed/refractory diffuse large B-cell lymphoma (DLBCL) [80,98]. A phase III open-label randomized trial found that the combination of glofitamab with gemcitabine and oxaliplatin (Glof-GemOx) outperformed rituximab with gemcitabine and oxaliplatin (R-GemOx) in treating relapsed or refractory DLBCL [97]. Additionally, epcoritamab has been shown to produce deep and lasting responses in patients with relapsed/refractory DLBCL based on findings from a phase 1b/II trial [97].

Autologous CAR T-cell therapies have demonstrated durable remission in patients with relapsed or refractory DLBCL. In the ZUMA-1 trial evaluating axi-cel, 83% of patients exhibited an objective response, with 39% maintaining an ongoing response at a median follow-up duration of 27.1 months. Patients with gastrointestinal lymphoma face risks such as perforation, hemorrhage, or infection due to tumor progression or necrotic tissue damage [99]. A recent analysis suggests a higher incidence of bleeding and perforation in cases involving gastrointestinal involvement [100].

Advancements in understanding DLBCL heterogeneity have enabled the development of targeted therapies. Activated B-cell-like DLBCL, characterized by NF-kB activation and chronic B-cell receptor signaling, responds to treatments such as lenalidomide or ibrutinib in relapsed cases. Germinal center-like DLBCL frequently exhibits EZH2 mutations and is treated with tazemetostat, whereas double-hit lymphoma—marked by MYC and BCL2 and/or BCL6 translocations—carries a poor prognosis [101].

11. Conclusions

Gastrointestinal (GI) lymphomas, the predominant extranodal non-Hodgkin lymphomas, are a heterogeneous group with diverse epidemiology, pathogenesis, and clinical features, commonly occurring in the stomach and small intestine. Diagnosis, classification, and treatment guidance rely critically on advanced endoscopy, imaging, histopathology, and molecular profiling. Clinical presentations vary from non-specific symptoms to acute complications, depending on the anatomical site and specific subtypes like MALT lymphoma, DLBCL, MCL, and EATL [14]. Management has advanced significantly, with personalized treatment strategies based on the histologic subtype, stage, and molecular features, including Helicobacter pylori eradication for gastric MALT lymphoma, R-CHOP-based immunochemotherapy for DLBCL, and selective radiotherapy. Surgery is now mainly used for complications as the therapeutic arsenal expands. Prognosis varies with these factors and the treatment response, with immunocompromised patients presenting unique challenges.

The future of GI lymphoma treatment is evolving, with novel immunotherapies like bispecific antibodies (e.g., glofitamab, epcoritamab) and CAR T-cell therapies (e.g., axicabtagene ciloleucel) showing substantial activity, especially in aggressive or relapsed/refractory DLBCL [73]. Targeted agents exploiting the molecular vulnerabilities of specific lymphoma subtypes, such as those in DLBCL, based on the cell of origin or mutations, further advance precision oncology. Despite these strides, the diversity of GI lymphomas and their potential for severe complications necessitate continued research into their complex biology, biomarker identification, and the development of more effective, less toxic therapies to improve patient survival and quality of life.