Gastrointestinal Lymphoma

MONDO:0004699 Pathograph 13 Show in embeddings browser Lymphoma Digestive system cancer

Gastrointestinal lymphoma is a non-Hodgkin (rarely Hodgkin) lymphoma arising in the digestive tract with the bulk of disease localized to that site. The gastrointestinal tract is the commonest extranodal site of lymphoma; within it the stomach is most often involved, followed by the small intestine and the ileocecal region, and diffuse large B-cell lymphoma is the commonest histologic type at essentially every site. What distinguishes gastrointestinal lymphoma from nodal lymphoma is not a distinct histology but the route by which it arises: sustained, site-restricted antigenic stimulation of gut mucosal lymphoid tissue. Chronic Helicobacter pylori gastritis raises the risk of gastric — but specifically not non-gastric — non-Hodgkin lymphoma; coeliac disease drives the intraepithelial T lymphocytes of the small bowel toward enteropathy-associated T-cell lymphoma; and immunoproliferative small intestinal disease (alpha heavy chain disease) arises in chronically infected small bowel. Because the disease is driven from outside the tumour cell in its early, antigen-dependent phase, removing the antigen can be curative — the basis for treating early gastric lymphoma with antibiotics rather than cytotoxic therapy. Later acquisition of transforming genetic lesions renders growth antigen-independent and antigen-directed therapy ineffective.

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6
Pathophys.
11
Phenotypes
2
Gaps
13
Pathograph
4
Genes
4
Medical Actions
5
Subtypes
🏷

Classifications

ICD-O Morphology
Lymphoma
Harrison's Part
ONCOLOGY HEMATOLOGY
◆

Subtypes

5
Gastric Lymphoma MONDO:0001059
Lymphoma of the stomach, the commonest site of gastrointestinal lymphoma. Histologically dominated by diffuse large B-cell lymphoma and by extranodal marginal zone (MALT) lymphoma; the latter is the arm most tightly linked to chronic Helicobacter pylori infection and the one in which antibiotic eradication alone can induce remission. Gastric mantle cell lymphoma (MONDO:0006225) is a rarer site+histology combination not modelled as a separate subtype here.
Show evidence (1 reference)
PMID:33618613 SUPPORT Human Clinical
"The stomach was the most common site of gastrointestinal (GI) organ involvement by lymphoma (38.9%), followed by the small intestine (23.4%)"
Cohort of 175 primary gastrointestinal lymphomas quantifies the stomach as the most frequently involved site.
Small Intestine Lymphoma MONDO:0001852
Lymphoma of the small bowel, the second commonest gastrointestinal site. It carries the two distinctive non-gastric antigen-driven entities: enteropathy-associated T-cell lymphoma arising on a background of coeliac disease, and immunoproliferative small intestinal disease (alpha heavy chain disease). Small-bowel disease is disproportionately responsible for obstruction and perforation because the lumen is narrow and the wall thin.
Show evidence (1 reference)
PMID:21390139 SUPPORT Human Clinical
"the most frequent sites in order of its occurrence are the stomach followed by small intestine and ileocecal region"
Places the small intestine second in the site distribution of gastrointestinal lymphoma.
Colon Lymphoma MONDO:0002035
Lymphoma of the colon, most often diffuse large B-cell lymphoma, with colonic MALT lymphoma (MONDO:0006154) and colonic Burkitt lymphoma (MONDO:0006150) as recognized but uncommon site+histology combinations. Rare in absolute terms but of rising recorded incidence, with survival improving as management has shifted from resection toward systemic therapy.
Show evidence (1 reference)
PMID:33178655 SUPPORT Human Clinical
"The PCL incidence increased from 1.4 per 1 000 000 people in 1973 to 3.5 in 2014"
SEER analysis documents the low absolute incidence of primary colorectal lymphoma and its rise over four decades.
Esophagus Lymphoma MONDO:0001188
Lymphoma of the oesophagus, the rarest tubular gastrointestinal site. Presents with dysphagia and weight loss; diffuse large B-cell lymphoma predominates, with occasional low-grade MALT lymphoma.
Show evidence (1 reference)
PMID:36756091 SUPPORT Human Clinical
"PEL is an extremely rare disease with male predominance. DLBCL is the most common pathological type in our community."
Two-centre series over twenty years yielded only eight cases, establishing both the rarity of primary oesophageal lymphoma and DLBCL predominance.
Rectum Lymphoma MONDO:0002166
Lymphoma of the rectum, rare in adults and very rare in children. Grouped with colonic disease as colorectal lymphoma (MONDO:0024656) in most epidemiological series, including the SEER analysis cited for the colon subtype.
Show evidence (1 reference)
PMID:35125760 SUPPORT Human Clinical
"Rectum as primary site for lymphoma is rare in adults and extremely rare in children."
States the rarity of the rectum as a primary lymphoma site.
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Discussions and Knowledge Gaps

2
Should gastrointestinal lymphoma be modelled as a Disease entry with anatomic-site has_subtypes, or as a Grouping over the already-curated histology entries (MALT_Lymphoma, Diffuse_Large_B_Cell_Lymphoma, Mantle_Cell_Lymphoma, Peripheral_T_Cell_Lymphoma)?
INTERPRETATION RESOLVED gi_lymphoma_disease_vs_grouping
A dismech Grouping is an explicit union that points DOWN at its members and asserts that each listed member IS a member of the grouping. That assertion fails for the histology entries: MALT lymphoma also arises in lung, ocular adnexa, salivary gland and thyroid, and DLBCL, mantle cell and peripheral T-cell lymphoma are overwhelmingly nodal diseases. Listing them as members would assert that MALT_Lymphoma is-a gastrointestinal lymphoma, which is false; only their gastrointestinal-site restrictions are members, and those are not curated as separate entries. The site children that ARE genuine members (gastric, small intestine, colon, oesophagus, rectum lymphoma) do not exist as Disease entries either, so a Grouping over them would have no members to point at. The entry also carries a real, shared, non-trivial mechanism of its own — site-restricted antigen-driven chronic stimulation, evidenced by the gastric-versus-non-gastric contrast in the H. pylori risk data — which is a Disease-entry pathograph, not a membership union. A Grouping has no pathophysiology slot and could not hold it.
Posed by claude-code Posed 2026-08-18T00:00:00Z Resolved 2026-08-18T00:00:00Z
Resolution: Resolved as a Disease entry with anatomic-site has_subtypes, matching the priority dashboard's CURATE_ROOT_WITH_SUBTYPES recommendation and the Primary_Tonsillar_Lymphoma precedent for a site-defined lymphoma Disease entry. Revisit if the individual site lymphomas are ever curated as standalone Disease entries, at which point a Grouping over those five would become well-formed and this entry could be reduced to their shared mechanism.
Is Campylobacter jejuni a causal driver of immunoproliferative small intestinal disease, or an associated coloniser of an already-abnormal small bowel?
CONTROVERSY OPEN gi_lymphoma_ipsid_campylobacter_causality
Attached to
pathophysiology#Chronic Mucosal Antigenic Stimulation
The association is established and IPSID can regress on antibiotics, which parallels the H. pylori/gastric MALT paradigm and would make it a second antigen-driven, antibiotic-reversible gastrointestinal lymphoma. But the cited review states explicitly that the organism's pathogenetic role is contested, and IPSID occurs in settings of heavy polymicrobial exposure where response to broad-spectrum antibiotics does not identify a single organism. The distinction matters for this entry because it determines whether the exposure link is TRIGGERS or PREDISPOSES; it is currently curated as PREDISPOSES with PARTIAL evidence.
Proposed experiments
Organism-directed versus broad-spectrum antibiotic therapy in IPSID
gi_lymphoma_ipsid_targeted_antibiotic_cohort
A prospective cohort in an IPSID-endemic region testing whether Campylobacter jejuni-directed therapy outperforms broad-spectrum antibiotics for histological remission, with molecular detection of the organism in small-bowel biopsies before and after treatment.
Posed by claude-code Posed 2026-08-18T00:00:00Z
Show evidence (1 reference)
PMID:29372346 SUPPORT Other
"A link between Campylobacter jejuni infection and IPSID has been established, but there is controversy as to the role played by this organism in disease pathogenesis."
The review states the controversy that this discussion records. Evidence source is OTHER because this is a review article.
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Pathophysiology

6
Chronic Mucosal Antigenic Stimulation
A persistent, site-restricted antigenic stimulus drives chronic inflammation in gastrointestinal mucosa. The stimuli are organ-specific rather than systemic: Helicobacter pylori gastritis in the stomach, dietary gluten in coeliac disease in the small bowel, and chronic small-bowel infection in immunoproliferative small intestinal disease. The site-specificity is the defining feature and is directly evidenced: prior H. pylori infection raises the risk of gastric non-Hodgkin lymphoma roughly six-fold while conferring no measurable risk of non-gastric non-Hodgkin lymphoma. This is the disorder-specific substitution for the module's generic chronic inflammatory trigger.
inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED
stomach UBERON:0000945 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in stomach (UBERON:0000945). UBERON:0000945 is an anatomical location from the Uberon multi-species anatomy ontology. intestine UBERON:0000160 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in intestine (UBERON:0000160). UBERON:0000160 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Pro-Tumorigenic Mucosal Lymphoid Microenvironment Sustained antigenic stimulation recruits and organizes a chronic mucosal immune infiltrate at the future tumour site.
Show evidence (4 references)
PMID:8145781 SUPPORT Human Clinical
"Patients with gastric lymphoma were significantly more likely than matched controls to have evidence of previous H. pylori infection (matched odds ratio, 6.3; 95 percent confidence interval, 2.0 to 19.9)."
Nested case-control study within 230,593 prospectively followed participants quantifies chronic H. pylori infection as an antecedent risk factor for gastric lymphoma.
PMID:8145781 SUPPORT Human Clinical
"Non-Hodgkin's lymphoma affecting the stomach, but not other sites, is associated with previous H. pylori infection."
Establishes that the antigen drive is site-restricted, the feature that separates gastrointestinal from nodal lymphomagenesis in this model.
PMID:37627888 SUPPORT Other
"EATL is an aggressive T-cell non-Hodgkin lymphoma with poor prognosis and is largely localized to the small intestine. EATL is closely associated with coeliac disease (CD)"
Supplies the small-bowel, T-cell counterpart of the same chronic-antigen trigger. Evidence source is OTHER because this is a review article.
+ 1 more reference
Pro-Tumorigenic Mucosal Lymphoid Microenvironment
Chronic stimulation organizes lymphoid tissue in mucosa that normally contains little or none — acquired mucosa-associated lymphoid tissue in the H. pylori-infected stomach — together with macrophages and other innate cells and a cytokine-rich milieu. This infiltrate is not a bystander: the mucosal immune microenvironment actively enhances neoplastic transformation of the resident lymphocytes. It is the disorder-specific substitution for the module's central pro-tumorigenic inflammatory microenvironment node.
macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology. B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
positive regulation of cytokine production GO:0001819 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased positive regulation of cytokine production (GO:0001819). GO:0001819 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Antigen-Driven Clonal Lymphoid Expansion The organized mucosal infiltrate supplies the antigen and accessory-cell signals that select and expand a lymphoid clone.
IL-15-Driven JAK-STAT Activation in Intraepithelial Lymphocytes In the coeliac small bowel the same microenvironment supplies the IL-15 that deregulates intraepithelial lymphocyte signalling.
Show evidence (2 references)
PMID:37627888 SUPPORT Other
"The immune microenvironment of mucosal cells within the small intestine enhances the process of neoplastic transformation of IELs into EATL."
States directly that the mucosal immune microenvironment promotes neoplastic transformation, the claim this node makes. Evidence source is OTHER because this is a review article.
PMID:20303878 SUPPORT Other
"Immune cells that infiltrate tumors engage in an extensive and dynamic crosstalk with cancer cells"
The general infiltrating-immune-cell/tumour-cell crosstalk that this node specializes to gut mucosa, and the evidence the parent module node rests on. Evidence source is OTHER because this is a review article.
Antigen-Driven Clonal Lymphoid Expansion
Chronic antigen-receptor engagement plus accessory-cell help selects and expands a clonal lymphoid population within the mucosa. Growth at this stage is still driven from outside the tumour cell and therefore still dependent on the antigen — the property that makes early, antigen-dependent gastric lymphoma curable by eradicating the organism rather than by cytotoxic therapy. The B-cell (MALT) arm of this step is curated in depth in the MALT_Lymphoma entry.
marginal zone B cell CL:0009060 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves marginal zone B cell, annotated with marginal zone B cell of lymph node (CL:0009060). CL:0009060 is a cell type from the Cell Ontology.
B cell receptor signaling pathway GO:0050853 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased B cell receptor signaling pathway (GO:0050853). GO:0050853 is a biological process from the Gene Ontology. ↑ INCREASED B cell proliferation GO:0042100 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased B cell proliferation (GO:0042100). GO:0042100 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Transformation to Antigen-Independent Lymphoma Prolonged proliferation permits acquisition of transforming genetic lesions that uncouple growth from the antigen.
Mucosal and Transmural Lymphomatous Infiltration The expanding clone occupies the mucosa and submucosa of the involved gut segment. Progression to full-thickness, wall-destroying infiltration is carried on the edge from the transformation node rather than on this one.
Show evidence (1 reference)
PMID:21568677 SUPPORT Human Clinical
"Most gastric MALT lymphomas require ongoing antigenic stimulation for continued tumor growth, and Stage I disease is usually cured by eradicating the causative microorganism, Helicobacter pylori, with antibiotics."
Establishes that expansion at this stage remains dependent on continuing antigenic stimulation, which is what makes antigen removal curative.
IL-15-Driven JAK-STAT Activation in Intraepithelial Lymphocytes
The small-bowel T-cell arm. In coeliac disease the inflamed mucosa over-produces IL-15, which acts on receptors on intraepithelial lymphocytes and deregulates JAK-STAT signalling; these intraepithelial lymphocytes are the postulated cell of origin of enteropathy-associated T-cell lymphoma, and JAK/STAT pathway mutations have been associated with the type II refractory coeliac disease-derived form. This is the mechanistic reason a T-cell lymphoma arises specifically in the gut rather than in nodes.
intestinal intraepithelial lymphocyte CL:0020035 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves intestinal intraepithelial lymphocyte (CL:0020035). CL:0020035 is a cell type from the Cell Ontology.
JAK-STAT signalling GO:0007259 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased JAK-STAT signalling, annotated with cell surface receptor signaling pathway via JAK-STAT (GO:0007259). GO:0007259 is a biological process from the Gene Ontology. ↑ INCREASED T cell proliferation GO:0042098 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased T cell proliferation (GO:0042098). GO:0042098 is a biological process from the Gene Ontology. ↑ INCREASED
small intestine UBERON:0002108 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in small intestine (UBERON:0002108). UBERON:0002108 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Transformation to Antigen-Independent Lymphoma Deregulated JAK-STAT signalling contributes to overt transformation of the intraepithelial lymphocyte compartment.
Show evidence (3 references)
PMID:37627888 SUPPORT Other
"Cytokines such as IL-15 can activate and crucially deregulate the JAK-STAT signaling pathway by binding to receptors on the surface of IELs."
States the IL-15 to JAK-STAT deregulation step in intraepithelial lymphocytes modelled by this node. Evidence source is OTHER because this is a review article.
PMID:37627888 SUPPORT Other
"The cells of origin of EATL has been postulated to be normal small intestinal intraepithelial T-lymphocytes (IELs)"
Identifies the intraepithelial lymphocyte as the cell of origin annotated on this node. Evidence source is OTHER because this is a review article.
PMID:37627888 SUPPORT Other
"Furthermore, mutations in the JAK/STAT pathway have been associated with RCDII-derived EATL."
Supports the JAK/STAT-mutation clause of this node's description. Note the source claims association only — it does not report the mutations as recurrent or establish them as activating — so the description was softened to match rather than the stronger claim being left uncited. Evidence source is OTHER because this is a review article.
Transformation to Antigen-Independent Lymphoma
Acquisition of transforming genetic lesions during prolonged antigen-driven proliferation uncouples growth from the initiating stimulus. In the gastric MALT arm the paradigmatic lesions are translocations that constitutively activate NF-kB, above all t(11;18)(q21;q21) generating BIRC3::MALT1; in the coeliac arm they are JAK/STAT pathway mutations. The clinical corollary is direct and is why this node matters for management: once the tumour is antigen-independent, removing the antigen no longer treats it. The translocation biology itself is curated in MALT_Lymphoma and is referenced rather than duplicated here.
canonical NF-kappaB signal transduction GO:0007249 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased canonical NF-kappaB signal transduction (GO:0007249). GO:0007249 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Mucosal and Transmural Lymphomatous Infiltration Antigen-independent growth drives progressive, often bulky, infiltration of the gut wall.
Show evidence (2 references)
PMID:21568677 SUPPORT Human Clinical
"in a subset of MALT lymphomas, chromosomal translocations are acquired that render the lymphoma antigen-independent. The recurrent translocation t(11;18)(q21;q21) is associated with failure to respond to antibiotic therapy and increased rate of dissemination."
Establishes both the acquired lesion and its clinical consequence, loss of response to antigen-directed therapy.
PMID:29372346 SUPPORT Other
"IPSID is typically regarded as a pre-lymphomatous condition with eventual progression to frank lymphoma"
Supports the progression from an antigen-driven pre-lymphomatous lesion to overt lymphoma in the small-bowel arm. Evidence source is OTHER because this is a review article.
Mucosal and Transmural Lymphomatous Infiltration
The shared anatomic final common path. Lymphoma infiltrates the mucosa and then the full thickness of the gut wall, ulcerating the epithelium, narrowing or (because lymphoma tends to infiltrate without the desmoplastic stiffening of carcinoma) aneurysmally dilating the lumen, and thinning the wall. This single node accounts for the presenting syndrome shared across every site and histology — abdominal pain, bleeding from ulcerated mucosa, obstruction, and perforation — and for the fact that the presentation is clinically indistinguishable from other gastrointestinal disease. The diagnostic consequence of that non-specificity is modelled in the diagnosis: section rather than asserted here.
stomach UBERON:0000945 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in stomach (UBERON:0000945). UBERON:0000945 is an anatomical location from the Uberon multi-species anatomy ontology. intestine UBERON:0000160 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in intestine (UBERON:0000160). UBERON:0000160 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (2 references)
PMID:21390139 SUPPORT Human Clinical
"Gastrointestinal lymphomas are usually not clinically specific and indistinguishable from other benign and malignant conditions."
Supports the claim that infiltration of the gut wall produces a presentation indistinguishable from other gastrointestinal disease.
PMID:26988370 SUPPORT Human Clinical
"Some patients presented with systemic symptoms or complications, such as weight loss (35.6%) and digestive tract obstruction (13.8%)."
Documents obstruction as a direct structural consequence of lymphomatous infiltration of the gut wall.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Gastrointestinal Lymphoma Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

11
Blood 1
Gastrointestinal Hemorrhage OCCASIONAL HP:0002239 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastrointestinal hemorrhage (HP:0002239). HP:0002239 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26988370 SUPPORT Human Clinical
"Clinical symptoms of PGIL were indistinguishable from other digestive system diseases, which included abdominal pain or discomfort (72.4%), lack of appetite (16.3%), gastrointestinal hemorrhage (14.9%), and diarrhea (12.8%)."
Reports gastrointestinal haemorrhage in 14.9% of 87 patients, within the OCCASIONAL (5-29%) band.
Digestive 5
Gastrointestinal Obstruction OCCASIONAL HP:0004796 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastrointestinal obstruction (HP:0004796). HP:0004796 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26988370 SUPPORT Human Clinical
"Some patients presented with systemic symptoms or complications, such as weight loss (35.6%) and digestive tract obstruction (13.8%)."
Reports digestive tract obstruction in 13.8% of 87 patients, within the OCCASIONAL (5-29%) band.
Diarrhea OCCASIONAL HP:0002014 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Diarrhea (HP:0002014). HP:0002014 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26988370 SUPPORT Human Clinical
"Clinical symptoms of PGIL were indistinguishable from other digestive system diseases, which included abdominal pain or discomfort (72.4%), lack of appetite (16.3%), gastrointestinal hemorrhage (14.9%), and diarrhea (12.8%)."
Reports diarrhoea in 12.8% of 87 patients, within the OCCASIONAL (5-29%) band.
Anorexia OCCASIONAL HP:0002039 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anorexia (HP:0002039). HP:0002039 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26988370 SUPPORT Human Clinical
"Clinical symptoms of PGIL were indistinguishable from other digestive system diseases, which included abdominal pain or discomfort (72.4%), lack of appetite (16.3%), gastrointestinal hemorrhage (14.9%), and diarrhea (12.8%)."
Reports lack of appetite in 16.3% of 87 patients, within the OCCASIONAL (5-29%) band.
Malabsorption HP:0002024 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Malabsorption (HP:0002024). HP:0002024 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38142052 SUPPORT Human Clinical
"This case highlights the need for greater awareness and consideration of EATL in individuals with worsening malabsorption and abdominal pain, irrespective of coeliac history."
Reports malabsorption as the presenting syndrome of small-bowel enteropathy-associated T-cell lymphoma.
Dysphagia HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36756091 SUPPORT Human Clinical
"The clinical manifestation included dysphagia and loss of weight."
Reports dysphagia as a presenting manifestation in a series of primary oesophageal lymphoma.
Constitutional 1
Abdominal Pain FREQUENT HP:0002027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abdominal pain (HP:0002027). HP:0002027 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26988370 SUPPORT Human Clinical
"Clinical symptoms of PGIL were indistinguishable from other digestive system diseases, which included abdominal pain or discomfort (72.4%), lack of appetite (16.3%), gastrointestinal hemorrhage (14.9%), and diarrhea (12.8%)."
Reports abdominal pain or discomfort in 72.4% of 87 patients, within the FREQUENT (30-79%) band.
Growth 1
Weight Loss FREQUENT HP:0001824 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Weight loss (HP:0001824). HP:0001824 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26988370 SUPPORT Human Clinical
"Some patients presented with systemic symptoms or complications, such as weight loss (35.6%) and digestive tract obstruction (13.8%)."
Reports weight loss in 35.6% of 87 patients, within the FREQUENT (30-79%) band.
Other 3
B-Cell Lymphoma VERY_FREQUENT HP:0012191 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is B-cell lymphoma (HP:0012191). HP:0012191 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:21390139 SUPPORT Human Clinical
"Diffuse large B-cell lymphoma is the most common pathological type of gastrointestinal lymphoma in essentially all sites of the gastrointestinal tract"
Establishes B-cell (DLBCL) predominance across gastrointestinal sites.
PMID:26988370 SUPPORT Human Clinical
"Most of PGIL were derived from B cell (93.1%)."
Quantifies B-cell lineage in 93.1% of 87 primary gastrointestinal lymphomas, supporting the VERY_FREQUENT (80-100%) frequency band.
T-Cell Lymphoma HP:0012190 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is T-cell lymphoma (HP:0012190). HP:0012190 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37627888 SUPPORT Other
"EATL is an aggressive T-cell non-Hodgkin lymphoma with poor prognosis and is largely localized to the small intestine."
Establishes a T-cell non-Hodgkin lymphoma localized to the gastrointestinal tract. Evidence source is OTHER because this is a review article.
Intestinal Perforation HP:0031368 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intestinal perforation (HP:0031368). HP:0031368 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38235779 SUPPORT Human Clinical
"Most of the cases were at an advanced stage at diagnosis and were treated with a combination of surgery and chemotherapy."
Marked PARTIAL: the SEER analysis documents the routine need for surgery alongside chemotherapy in small-bowel lymphoma, consistent with obstructive and perforating complications, but does not itself enumerate perforation events.
🧬

Genetic Associations

4
JAK1 (Somatic driver of the JAK/STAT axis in EATL and refractory coeliac disease type II)
Gene: JAK1 hgnc:6190 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is JAK1 (hgnc:6190). hgnc:6190 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (2 references)
PMID:37627888 SUPPORT Other
"The acquisition of these mutations by IELs allows them to progressively expand at the expense of other IELs, as JAK1 or STAT3 gain-of-function mutations garner the cells with hyper-responsiveness to IL-15"
Names JAK1 gain-of-function mutation and gives its functional consequence, IL-15 hyper-responsiveness driving clonal outgrowth. The statement sits in the body of this full-text-cached review, not in its abstract. Evidence source is OTHER because this is a review article.
PMID:37627888 SUPPORT Other
"The JAK/STAT pathway is considered to be among the most commonly mutated signaling pathways in EATL pathogenesis"
Places the pathway among the most commonly mutated in this disease, supporting its curation as a driver rather than an incidental finding. Full-text statement, not abstract. Evidence source is OTHER because this is a review article.
STAT3 (Somatic driver of the JAK/STAT axis in EATL and refractory coeliac disease type II)
Gene: STAT3 hgnc:11364 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is STAT3 (hgnc:11364). hgnc:11364 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (2 references)
PMID:37627888 SUPPORT Other
"The acquisition of these mutations by IELs allows them to progressively expand at the expense of other IELs, as JAK1 or STAT3 gain-of-function mutations garner the cells with hyper-responsiveness to IL-15"
Names STAT3 gain-of-function mutation alongside JAK1 with the same functional consequence. Full-text statement, not abstract. Evidence source is OTHER because this is a review article.
PMID:37627888 SUPPORT Other
"mutations activating JAK1-STAT3 may synergize with mutations activating NF-kB"
Supports the JAK1-STAT3 axis being activating and cooperating with the NF-kB lesions modelled on the transformation node. Full-text statement, not abstract. Evidence source is OTHER because this is a review article.
SETD2 (Somatic driver and diagnostic marker in MEITL)
Gene: SETD2 hgnc:18420 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SETD2 (hgnc:18420). hgnc:18420 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (2 references)
PMID:37627888 SUPPORT Other
"the most frequently mutated gene in MEITL is the SETD2 tumor suppressor gene (TSG)"
Identifies SETD2 as the most frequently mutated gene in MEITL. Full-text statement, not abstract. Evidence source is OTHER because this is a review article.
PMID:37627888 SUPPORT Other
"The majority of SETD2 mutations are a loss of function, exhibiting frameshift or nonsense mutations"
Establishes the loss-of-function direction curated here, consistent with SETD2's tumour-suppressor role. Full-text statement, not abstract. Evidence source is OTHER because this is a review article.
HLA-DQ2.5 haplotype (Germline HLA susceptibility haplotype for coeliac disease and its progression to EATL)
Gene: HLA-DQB1 (HLA-DQ2.5 haplotype, with HLA-DQA1) hgnc:4944 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is HLA-DQB1 (HLA-DQ2.5 haplotype, with HLA-DQA1), annotated with HLA-DQB1 (hgnc:4944). hgnc:4944 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (2 references)
PMID:37627888 SUPPORT Other
"In one systematic review, HLA-DQ2.5 homozygosity was found in 53.3% of patients with EATL and 44.1% of patients with RCDII"
Quantifies HLA-DQ2.5 homozygosity among EATL and RCDII patients. Full-text statement, not abstract. Evidence source is OTHER because this is a review article.
PMID:37627888 SUPPORT Other
"Furthermore, there is a strong correlation between HLA-DQ2.5 homozygosity and the development of EATL"
States the correlation between the haplotype and EATL development, supporting the SUSCEPTIBILITY relationship type — the source claims a correlation, which is why this is curated as risk rather than causation. Full-text statement, not abstract. Evidence source is OTHER because this is a review article.
💊

Medical Actions

4
Helicobacter pylori Eradication
Action: antibiotic therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is antibiotic therapy (NCIT:C15620). NCIT:C15620 is a clinical intervention from the NCI Thesaurus. Ontology label: Antibiotic Therapy NCIT:C15620
Antibiotic eradication of H. pylori is first-line therapy for early-stage H. pylori-positive gastric MALT lymphoma and induces complete remission in about three quarters of such patients. It is the clearest demonstration in oncology that removing a driving antigen can cure a lymphoma, and it works only while the tumour remains antigen-dependent — the t(11;18)-positive, antigen-independent tumours modelled by the transformation node do not respond.
Mechanism Target:
INHIBITS Chronic Mucosal Antigenic Stimulation — Eradicating the organism removes the antigenic stimulus that sustains the antigen-dependent phase of the disease.
Show evidence (1 reference)
PMID:21568677 SUPPORT Human Clinical
"Most gastric MALT lymphomas require ongoing antigenic stimulation for continued tumor growth, and Stage I disease is usually cured by eradicating the causative microorganism, Helicobacter pylori, with antibiotics."
Directly links removal of the antigenic stimulus to cure of early-stage disease, the mechanism this treatment edge asserts.
Show evidence (2 references)
PMID:37122607 SUPPORT Human Clinical
"The pooled CR of H. pylori-positive early-stage GML after bacterial eradication was 75.18% (95%CI: 70.45%-79.91%)."
Meta-analysis quantifies complete remission after eradication in early-stage H. pylori-positive gastric MALT lymphoma.
PMID:37122607 SUPPORT Human Clinical
"Meta-regression analysis identified statistically significant effect modifiers, including the proportion of patients with t(11;18)(q21;q21)-positive GML and the risk of bias in each study."
Shows that t(11;18) positivity modifies response, consistent with loss of antigen dependence after transformation.
Rituximab-Containing Immunochemotherapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986 Regimen: R-CHOP regimenNCI Thesaurus (NCIT) Relation: this regimen component is this clinical intervention This regimen component is R-CHOP regimen (NCIT:C9760). NCIT:C9760 is a clinical intervention from the NCI Thesaurus. Ontology label: R-CHOP Regimen NCIT:C9760
Agent: rituximab NCIT:C1702 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses rituximab (NCIT:C1702). NCIT:C1702 is a therapeutic agent from the NCI Thesaurus.
Anti-CD20 immunochemotherapy, typically R-CHOP, is standard systemic therapy for aggressive B-cell gastrointestinal lymphoma, which is predominantly diffuse large B-cell lymphoma. Its adoption is associated with improved overall survival in primary gastrointestinal lymphoma cohorts.
Mechanism Target:
INHIBITS Transformation to Antigen-Independent Lymphoma — Cytotoxic immunochemotherapy targets the transformed, antigen-independent lymphoma clone, which no longer responds to removal of the initiating antigen.
Show evidence (1 reference)
PMID:33618613 SUPPORT Human Clinical
"The probability of having a better OS was demonstrated in patients with a good performance status who received a rituximab-containing regimen."
Associates rituximab-containing therapy with improved survival in primary gastrointestinal lymphoma, the population dominated by transformed aggressive disease.
Show evidence (1 reference)
PMID:33618613 SUPPORT Human Clinical
"Diffuse large B-cell lymphoma (DLBCL) had the highest proportion of PGIL, accounting for 61.1%."
Establishes that the majority of primary gastrointestinal lymphoma is DLBCL, the histology for which rituximab-containing immunochemotherapy is standard.
Surgical Resection
Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Surgery is no longer primary therapy for most gastrointestinal lymphoma but remains necessary for obstruction, perforation and uncontrolled bleeding, and is still commonly used in small-bowel disease. Its role has declined steadily as systemic therapy has improved.
Mechanism Target:
INHIBITS Mucosal and Transmural Lymphomatous Infiltration — Resection removes the infiltrated gut segment responsible for obstruction, perforation and bleeding.
Show evidence (1 reference)
PMID:33178655 SUPPORT Human Clinical
"the proportion of patients who received surgical therapy decreased gradually from 83.3-100 to 47.7-52.6% throughout the studied time period."
Marked PARTIAL: documents that resection of the involved bowel segment remains in substantial use while its share has fallen, but does not itself measure the effect of resection on the infiltration node.
Show evidence (1 reference)
PMID:33178655 SUPPORT Human Clinical
"The 5-year CSS of PCL increased continuously, while the rate of surgical resection decreased steadily."
Documents the declining role of surgery alongside improving survival with systemic therapy.
Gluten-Free Diet
Action: dietary interventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is dietary intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. Ontology label: Dietary Intervention NCIT:C15447
Strict lifelong gluten exclusion is the treatment of coeliac disease and removes the antigenic drive underlying enteropathy-associated T-cell lymphoma. It is included here as the small-bowel counterpart of H. pylori eradication — antigen removal acting on the same trigger node — and not as a treatment for established lymphoma, for which it is not sufficient.
Mechanism Target:
INHIBITS Chronic Mucosal Antigenic Stimulation — Removing dietary gluten withdraws the antigenic stimulus sustaining the coeliac enteropathy on which EATL arises.
Show evidence (1 reference)
PMID:37627888 SUPPORT Other
"EATL is closely associated with coeliac disease (CD) and is seen mostly in patients originating from Northern Europe."
Marked PARTIAL: the review establishes the coeliac-disease dependence that makes gluten withdrawal the corresponding antigen-removal intervention, but does not report a trial of gluten exclusion as lymphoma prophylaxis or therapy. Evidence source is OTHER because this is a review article.
Show evidence (2 references)
PMID:37627888 SUPPORT Other
"CD is an autoimmune disease of the small intestine caused by exposure to gluten in a genetically susceptible individual"
Establishes gluten exposure as the cause of the coeliac enteropathy that this intervention removes, which is the rationale for curating gluten exclusion as the small-bowel antigen-removal counterpart of H. pylori eradication. Full-text statement, not abstract. Evidence source is OTHER because this is a review article.
PMID:37627888 SUPPORT Other
"many cases of EATL arise despite a strict GFD"
Recorded as PARTIAL, and deliberately paired with the item above so the treatment is not left looking curative: unlike H. pylori eradication, gluten withdrawal does not abolish the lymphoma risk. This is the honest bound on the antigen-removal analogy and is why the treatment description states it is not sufficient for established lymphoma. Full-text statement, not abstract. Evidence source is OTHER because this is a review article.
🌍

Environmental Factors

3
Chronic Helicobacter pylori infection
exposure to Helicobacter pylori ECTO:3000003 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to Helicobacter pylori (ECTO:3000003). ECTO:3000003 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Persistent gastric colonization by Helicobacter pylori, which induces the acquired mucosa-associated lymphoid tissue on which gastric lymphoma develops. The exposure is the archetype of a site-restricted antigenic drive: it raises gastric lymphoma risk about six-fold while conferring no detectable risk of lymphoma at other sites.
Show evidence (1 reference)
PMID:37122607 SUPPORT Human Clinical
"The pooled CR of H. pylori-positive early-stage GML after bacterial eradication was 75.18% (95%CI: 70.45%-79.91%)."
Regression of lymphoma on removing the organism is the strongest evidence that the exposure is causal rather than merely associated.
Mechanism Target:
TRIGGERS Chronic Mucosal Antigenic Stimulation — Chronic H. pylori gastritis is the route by which sustained mucosal antigenic stimulation is established in the stomach.
Show evidence (2 references)
PMID:8145781 SUPPORT Human Clinical
"Patients with gastric lymphoma were significantly more likely than matched controls to have evidence of previous H. pylori infection (matched odds ratio, 6.3; 95 percent confidence interval, 2.0 to 19.9)."
Prospective nested case-control evidence that antecedent H. pylori infection raises gastric lymphoma risk, supporting this exposure as the trigger of the mucosal antigenic-stimulation node.
PMID:8145781 SUPPORT Human Clinical
"No association was found between nongastric non-Hodgkin's lymphoma and previous H. pylori infection"
The internal negative control showing the effect is confined to the site of infection, which is what makes this a gastrointestinal rather than a systemic lymphomagenic exposure.
Dietary gluten exposure in coeliac disease
Deliberately left without an exposure_term. ECTO was searched (sqlite:obo:ecto) and contains no term for gluten or gluten-containing-food exposure. Per the dismech terms rule, no term is preferred to a bad one.
Continued exposure to dietary gluten in a genetically susceptible (HLA-DQ2/DQ8) individual sustains the coeliac enteropathy on which enteropathy-associated T-cell lymphoma arises, particularly via type II refractory coeliac disease.
Show evidence (2 references)
PMID:37627888 SUPPORT Other
"Furthermore, poor adherence to a GFD, HLA-DQ2 homozygosity, and late diagnosis of CD are recognized as risk factors for the malignant evolution of CD"
Poor adherence to a gluten-free diet is continued gluten exposure, so naming it a risk factor for malignant evolution is the most direct available support for treating the exposure itself — rather than coeliac disease alone — as the modifiable driver. Evidence source is OTHER because this is a review article.
PMID:37627888 SUPPORT Other
"Although the duration of gluten diet exposure plays an important role in EATL pathogenesis via the enhancement of inflammatory signaling pathways mediated by CD4+ T-cells, many cases of EATL arise despite a strict GFD"
Recorded as PARTIAL because the source supports and bounds the claim in one sentence: exposure duration matters mechanistically, but a strict gluten-free diet does not abolish EATL risk. Removing this exposure is therefore not curative, which is the honest limit on the eradication analogy drawn from the H. pylori arm.
Mechanism Target:
TRIGGERS Chronic Mucosal Antigenic Stimulation — Gluten-driven coeliac enteropathy is the route by which sustained mucosal antigenic stimulation is established in the small bowel.
Show evidence (2 references)
PMID:37627888 SUPPORT Other
"EATL is closely associated with coeliac disease (CD) and is seen mostly in patients originating from Northern Europe."
Links the coeliac enteropathy to the small-bowel lymphoma modelled downstream of this node. Evidence source is OTHER because this is a review article.
PMID:37627888 SUPPORT Other
"Although EATL can occur de novo, individuals with RCDII are at a higher risk of developing EATL."
Identifies refractory coeliac disease type II as the high-risk intermediate on this exposure route. Evidence source is OTHER because this is a review article.
Chronic small-bowel bacterial infection in immunoproliferative small intestinal disease
Deliberately left without an exposure_term. ECTO was searched (sqlite:obo:ecto) and contains no exposure term for Campylobacter jejuni. The organism's causal role is explicitly contested in the cited review, so the mechanism link is recorded as PREDISPOSES rather than TRIGGERS, with causal_link_type UNKNOWN, and the controversy is carried as a discussion.
Chronic small-intestinal infection, with Campylobacter jejuni the organism most often implicated, associated with immunoproliferative small intestinal disease (alpha heavy chain disease) in areas of poor sanitation. IPSID behaves as a pre-lymphomatous lesion that can regress on antibiotics and can progress to overt small-bowel lymphoma.
Show evidence (1 reference)
PMID:29372346 SUPPORT Other
"IPSID is typically regarded as a pre-lymphomatous condition with eventual progression to frank lymphoma; however, recent reports of longstanding non-progressive cases have expanded its clinical spectrum."
Supports the exposure-associated lesion being pre-lymphomatous, which is what connects this exposure to small-bowel lymphoma rather than to IPSID alone. PARTIAL because the same sentence records non-progressive cases, so progression is characteristic but not obligate — consistent with this entry's PREDISPOSES / UNKNOWN framing. Evidence source is OTHER because this is a review article.
Mechanism Target:
PREDISPOSES Chronic Mucosal Antigenic Stimulation — Chronic small-bowel infection is associated with the sustained mucosal antigenic stimulation underlying IPSID, but the causal contribution of the implicated organism is not settled.
Show evidence (1 reference)
PMID:29372346 SUPPORT Other
"A link between Campylobacter jejuni infection and IPSID has been established, but there is controversy as to the role played by this organism in disease pathogenesis."
Supports an established association while explicitly withholding a causal claim, which is why this link is PREDISPOSES and the evidence is PARTIAL. Evidence source is OTHER because this is a review article.
🔬

Diagnosis

3
Endoscopic biopsy with histopathological analysis
The confirmatory test. Because lymphomatous infiltration of the gut wall produces a presentation and a radiological appearance indistinguishable from other benign and malignant gastrointestinal disease, definitive diagnosis requires tissue: endoscopic biopsy of the lesion with histopathological analysis and immunophenotyping. A first biopsy is not invariably diagnostic — repeat biopsy, or in a minority of cases surgical resection, may be needed — which matters clinically because the differential it must resolve includes carcinoma.
endoscopic biopsy of the gastrointestinal lesion NCIT:C15389 NCI Thesaurus (NCIT)
Results: Histopathology and immunophenotype establishing lymphoma and its lineage and subtype (most often diffuse large B-cell or extranodal marginal zone MALT lymphoma).
Show evidence (4 references)
PMID:21390139 SUPPORT Human Clinical
"they are not specific, thus mandating histopathological analysis for its definitive diagnosis"
States that imaging features are non-specific and that histopathological analysis is required for definitive diagnosis, which is the claim this diagnostic entry makes.
PMID:36756091 SUPPORT Human Clinical
"Six cases were diagnosed based on endoscopic biopsies and two after resection."
Documents endoscopic biopsy as the route to diagnosis in the majority of a consecutive series, with resection needed in the remainder.
PMID:36756091 SUPPORT Human Clinical
"The first biopsies were diagnostic in five of them, and repeated biopsies were required to make the diagnosis in one case."
Supports the caveat curated here that a first endoscopic biopsy is not invariably diagnostic and may need repeating.
+ 1 more reference
Helicobacter pylori testing
Determination of H. pylori status in gastric lymphoma. This is not a diagnostic test for the lymphoma itself but the test that GATES first-line therapy: eradication is recommended as the initial treatment of early-stage gastric MALT lymphoma, and the entire evidence base for that recommendation is drawn from H. pylori-positive patients, so a patient cannot be assigned to antigen-removal therapy without it.
Helicobacter pylori testing NCIT:C189536 NCI Thesaurus (NCIT)
Results: H. pylori positive or negative status in a patient with gastric lymphoma.
Curated as the gate on treatment 1 (Helicobacter pylori Eradication) rather than as a confirmatory test for lymphoma. The cached sources establish that the eradication evidence base is restricted to H. pylori-positive early-stage disease; they do not compare the individual assays (urea breath test, stool antigen, histology, serology), so no specific method is asserted and the NCIT term is left at the general measurement level.
Show evidence (2 references)
PMID:37122607 SUPPORT Human Clinical
"Prospective and retrospective observational studies evaluating the CR of early-stage GML following bacterial eradication in H. pylori-positive patients."
The meta-analysis eligibility criterion shows the eradication evidence base is defined by H. pylori-positive status, which is what makes testing the gate on that therapy.
PMID:37122607 SUPPORT Human Clinical
"Clinical practice guidelines currently recommend H. pylori eradication as the preferred initial treatment for early-stage GML."
Establishes the treatment that this test gates.
Staging and extent-of-disease workup
Assessment of disease extent once lymphoma is confirmed. Stage is load-bearing for management in this disease — antigen-removal therapy is offered for early-stage gastric disease and systemic therapy for advanced disease — and cross-sectional and functional imaging with histologic identification of lesions is what establishes it. The workup described for the small-bowel T-cell arm comprises magnetic resonance enteroclysis, positron emission tomography, and histologic identification of lesions.
positron emission tomography as part of the staging workup NCIT:C17007 NCI Thesaurus (NCIT)
Results: Anatomic extent of disease, used to assign stage and select between antigen-directed and systemic therapy.
The NCIT term binds the positron emission tomography component only; the cached source names magnetic resonance enteroclysis in the same workup, and NCIT has no enteroclysis term (searched via sqlite:obo:ncit). No formal staging system is asserted here: a stages: section using the Lugano classification would be the right home for that and is deliberately left to separate work rather than invented from these sources.
Show evidence (2 references)
PMID:37627888 SUPPORT Other
"An extensive clinical diagnostic workup involves magnetic resonance enteroclysis, a positron emission tomography scan, and a histologic identification of lesions present"
Enumerates the diagnostic and staging workup curated here. Stated for the enteropathy-associated T-cell arm, and the statement sits in the body of this full-text-cached review rather than in its abstract. Evidence source is OTHER because this is a review article.
PMID:26988370 SUPPORT Human Clinical
"Multivariate analysis showed that clinical stage and sources of cells were the significant independent prognostic factors."
Establishes that clinical stage is an independent prognostic factor in primary gastrointestinal lymphoma, which is why extent-of-disease assessment is curated as a distinct diagnostic step.
📊

Prevalence

3
Worldwide
Unknown Rare
Reported as a proportion of gastrointestinal cancers rather than as a population rate; the cited figure is a share of GI malignancies (1-4%), not an incidence or prevalence, so no rate_per_100000 is asserted.
Show evidence (1 reference)
PMID:33618613 SUPPORT Human Clinical
"Primary gastrointestinal lymphoma (PGIL), an uncommon subtype of lymphoma, accounts for 1%-4% of gastrointestinal cancers."
Establishes that primary gastrointestinal lymphoma is an uncommon tumour, quantified as a share of gastrointestinal cancers.
United States (SEER, 2014)
Annual Incidence 0.35 per 100,000 1–9 per 1,000,000
Colorectal subtype only. SEER-reported primary colorectal lymphoma incidence of 3.5 per 1,000,000 in 2014, normalized to 0.35 per 100,000.
Show evidence (1 reference)
PMID:33178655 SUPPORT Human Clinical
"The PCL incidence increased from 1.4 per 1 000 000 people in 1973 to 3.5 in 2014"
Provides the population-based annual incidence of primary colorectal lymphoma normalized in this record.
United States (SEER, 2000-2020)
Annual Incidence 0.014 per 100,000 <1 in 1,000,000
Enteropathy-associated T-cell lymphoma only, the coeliac-associated small-bowel subtype; age-adjusted incidence per 100,000.
Show evidence (1 reference)
PMID:38235779 SUPPORT Human Clinical
"The 2000-2020 age-adjusted incidence rate per 100,000 people was 0.014, and the incidence increased between 2000 and 2020, with an annual percent change of 2.58 ( P < 0.05)."
Provides the age-adjusted population incidence of EATL used in this record.
{ }

Source YAML

click to show 
name: Gastrointestinal Lymphoma
creation_date: "2026-08-18T13:20:00Z"
description: >-
  Gastrointestinal lymphoma is a non-Hodgkin (rarely Hodgkin) lymphoma arising in
  the digestive tract with the bulk of disease localized to that site. The
  gastrointestinal tract is the commonest extranodal site of lymphoma; within it
  the stomach is most often involved, followed by the small intestine and the
  ileocecal region, and diffuse large B-cell lymphoma is the commonest histologic
  type at essentially every site. What distinguishes gastrointestinal lymphoma
  from nodal lymphoma is not a distinct histology but the route by which it
  arises: sustained, site-restricted antigenic stimulation of gut mucosal
  lymphoid tissue. Chronic Helicobacter pylori gastritis raises the risk of
  gastric — but specifically not non-gastric — non-Hodgkin lymphoma; coeliac
  disease drives the intraepithelial T lymphocytes of the small bowel toward
  enteropathy-associated T-cell lymphoma; and immunoproliferative small
  intestinal disease (alpha heavy chain disease) arises in chronically infected
  small bowel. Because the disease is driven from outside the tumour cell in its
  early, antigen-dependent phase, removing the antigen can be curative — the
  basis for treating early gastric lymphoma with antibiotics rather than
  cytotoxic therapy. Later acquisition of transforming genetic lesions renders
  growth antigen-independent and antigen-directed therapy ineffective.
categories:
- Neoplastic
- Hematologic Malignancy
- Non-Hodgkin Lymphoma
parents:
- Lymphoma
- Digestive system cancer
disease_term:
  preferred_term: gastrointestinal lymphoma
  term:
    id: MONDO:0004699
    label: gastrointestinal lymphoma
notes: >-
  SUBTYPE AXIS (curation decision). MONDO offers three cuts through this
  concept: anatomic site (gastric, small intestine, colon, esophagus, rectum
  lymphoma), histology (MALT, DLBCL, mantle cell, Burkitt, EATL), and
  site+histology leaves (e.g. MONDO:0006226 gastric MALT lymphoma,
  MONDO:0006158 colorectal DLBCL). This entry models the ANATOMIC SITE axis
  only, and deliberately does not mix the three. Reasons: (i) site is the axis
  that constitutes the concept — MONDO defines gastrointestinal lymphoma as the
  intersection of lymphoma with location in the digestive system, so the site
  children are the immediate specializations of the defining property;
  (ii) site subtypes partition the disease cleanly, since a primary tumour has
  one primary site, whereas histology does not partition it and the
  site+histology leaves overlap the site subtypes (gastric MALT lymphoma is a
  proper part of gastric lymphoma), which is exactly the query-breaking mixture
  to avoid; (iii) the histology axis is already curated as standalone Disease
  entries — MALT_Lymphoma, Diffuse_Large_B_Cell_Lymphoma, Mantle_Cell_Lymphoma,
  Peripheral_T_Cell_Lymphoma — collected by the B-Cell_Non-Hodgkin_Lymphoma
  grouping, so re-listing them here as subtypes would duplicate rather than add.
  Histology is instead carried as prose and evidence on this entry and on the
  site subtypes.

  SCOPE. Restricted to the tubular gastrointestinal tract, matching clinical
  usage of "primary gastrointestinal lymphoma". The five site subtypes curated
  here (oesophagus, stomach, small intestine, colon, rectum) were selected by
  prevalence and are NOT an exhaustive enumeration of the tubular-GI
  descendants of MONDO:0004699: MONDO:0002034 cecum lymphoma, MONDO:0001237
  appendix lymphoma and MONDO:0001888 anus lymphoma are also tubular-GI
  descendants and are not modelled as separate subtypes. The cecum omission is
  the one worth flagging, since this entry cites the ileocecal region as the
  third commonest site; ileocecal disease is carried under the Small Intestine
  and Colon subtypes rather than as its own node. MONDO:0004699 has further
  descendants covering the accessory digestive organs (liver, pancreas,
  gallbladder lymphoma) and Waldeyer's ring (MONDO:0044884 tonsillar lymphoma)
  because its logical definition uses the whole digestive system
  (UBERON:0001007); those are outside the tubular-tract scope, and tonsillar
  lymphoma already has its own entry (Primary_Tonsillar_Lymphoma).
  MONDO:0002966 and MONDO:0004104 are splenic manifestations of prolymphocytic
  and hairy cell leukaemia and are out of scope entirely — they are not
  gastrointestinal lymphomas.

  CELL TYPE IMPRECISION (on the record, deliberately not "fixed"). The
  Antigen-Driven Clonal Lymphoid Expansion node is annotated with CL:0009060,
  whose canonical label is "marginal zone B cell of lymph node" — anatomically
  wrong for gut MALT, where the cell is not in a lymph node. CL currently
  offers nothing better: the only sibling is CL:0000845 marginal zone B cell of
  spleen, and there is no mucosa-associated marginal zone B cell term. The term
  is retained for consistency with the existing MALT_Lymphoma precedent, and
  the preferred_term is written as the unqualified "marginal zone B cell" so
  the display does not assert the nodal location. This is recorded here rather
  than left looking settled; a CL new-term request for a mucosa-associated
  marginal zone B cell would resolve it.

  RELATION TO EXISTING ENTRIES. This entry is the anatomic/mechanistic umbrella
  and cross-references rather than duplicates the histology entries. The
  H. pylori-driven MALT arm is curated in depth in MALT_Lymphoma (including the
  t(11;18)/BIRC3::MALT1 translocation biology); what is added here is the
  site-specificity of the antigen drive and the shared final common path by
  which any gut lymphoma produces bleeding, obstruction and perforation.

  GENETIC SCOPE. The genetic: section here is deliberately restricted to the
  gastrointestinal T-cell arm (EATL and MEITL) and to the coeliac HLA
  susceptibility haplotype that gates it. The B-cell/MALT genetics —
  t(11;18)(q21;q21) and the BIRC3::MALT1 fusion above all — are curated in
  MALT_Lymphoma and are referenced from the transformation node rather than
  duplicated. The T-cell genetics have no such home: there is no EATL or MEITL
  entry anywhere in kb/disorders/, so leaving them out would leave them
  uncurated in the KB entirely, which is why they are carried here.

  MODULE CONFORMANCE. Two nodes conform to tumor_promoting_inflammation
  (Chronic Inflammatory Stimulus, Pro-Tumorigenic Inflammatory
  Microenvironment). Conformance to the module's third node,
  "Hallmark-Promoting Inflammatory Output", is deliberately NOT declared: that
  node models bioactive molecules supplied by the inflammatory microenvironment
  to the tumour, whereas the corresponding node here ("Transformation to
  Antigen-Independent Lymphoma") models an acquired tumour-cell-intrinsic
  genetic lesion that uncouples growth from that microenvironment. Declaring
  conformance would misstate the mechanism.
has_subtypes:
- name: Gastric
  display_name: Gastric Lymphoma
  description: >-
    Lymphoma of the stomach, the commonest site of gastrointestinal lymphoma.
    Histologically dominated by diffuse large B-cell lymphoma and by
    extranodal marginal zone (MALT) lymphoma; the latter is the arm most
    tightly linked to chronic Helicobacter pylori infection and the one in
    which antibiotic eradication alone can induce remission. Gastric mantle
    cell lymphoma (MONDO:0006225) is a rarer site+histology combination not
    modelled as a separate subtype here.
  subtype_term:
    preferred_term: gastric lymphoma
    term:
      id: MONDO:0001059
      label: gastric lymphoma
  evidence:
  - reference: PMID:33618613
    reference_title: "A 10-year cohort study of 175 primary gastrointestinal lymphoma cases in Thailand: clinical features and outcomes in the immunochemotherapy era."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The stomach was the most common site of gastrointestinal (GI) organ involvement by lymphoma (38.9%), followed by the small intestine (23.4%)"
    explanation: Cohort of 175 primary gastrointestinal lymphomas quantifies the stomach as the most frequently involved site.
- name: Small Intestine
  display_name: Small Intestine Lymphoma
  description: >-
    Lymphoma of the small bowel, the second commonest gastrointestinal site.
    It carries the two distinctive non-gastric antigen-driven entities:
    enteropathy-associated T-cell lymphoma arising on a background of coeliac
    disease, and immunoproliferative small intestinal disease (alpha heavy
    chain disease). Small-bowel disease is disproportionately responsible for
    obstruction and perforation because the lumen is narrow and the wall thin.
  subtype_term:
    preferred_term: small intestine lymphoma
    term:
      id: MONDO:0001852
      label: small intestine lymphoma
  evidence:
  - reference: PMID:21390139
    reference_title: "Primary gastrointestinal lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the most frequent sites in order of its occurrence are the stomach followed by small intestine and ileocecal region"
    explanation: Places the small intestine second in the site distribution of gastrointestinal lymphoma.
- name: Colon
  display_name: Colon Lymphoma
  description: >-
    Lymphoma of the colon, most often diffuse large B-cell lymphoma, with
    colonic MALT lymphoma (MONDO:0006154) and colonic Burkitt lymphoma
    (MONDO:0006150) as recognized but uncommon site+histology combinations.
    Rare in absolute terms but of rising recorded incidence, with survival
    improving as management has shifted from resection toward systemic therapy.
  subtype_term:
    preferred_term: colon lymphoma
    term:
      id: MONDO:0002035
      label: colon lymphoma
  evidence:
  - reference: PMID:33178655
    reference_title: "Changes in Incidence and Survival by Decade of Patients With Primary Colorectal Lymphoma: A SEER Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The PCL incidence increased from 1.4 per 1 000 000 people in 1973 to 3.5 in 2014"
    explanation: SEER analysis documents the low absolute incidence of primary colorectal lymphoma and its rise over four decades.
- name: Esophagus
  display_name: Esophagus Lymphoma
  description: >-
    Lymphoma of the oesophagus, the rarest tubular gastrointestinal site.
    Presents with dysphagia and weight loss; diffuse large B-cell lymphoma
    predominates, with occasional low-grade MALT lymphoma.
  subtype_term:
    preferred_term: esophagus lymphoma
    term:
      id: MONDO:0001188
      label: esophagus lymphoma
  evidence:
  - reference: PMID:36756091
    reference_title: "Primary Esophageal Lymphoma: A Histopathological Experience from Two Tertiary Hospitals, Western Saudi Arabia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PEL is an extremely rare disease with male predominance. DLBCL is the most common pathological type in our community."
    explanation: Two-centre series over twenty years yielded only eight cases, establishing both the rarity of primary oesophageal lymphoma and DLBCL predominance.
- name: Rectum
  display_name: Rectum Lymphoma
  description: >-
    Lymphoma of the rectum, rare in adults and very rare in children. Grouped
    with colonic disease as colorectal lymphoma (MONDO:0024656) in most
    epidemiological series, including the SEER analysis cited for the colon
    subtype.
  subtype_term:
    preferred_term: rectum lymphoma
    term:
      id: MONDO:0002166
      label: rectum lymphoma
  evidence:
  - reference: PMID:35125760
    reference_title: "Primary Rectal Lymphoma: A Case Report and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rectum as primary site for lymphoma is rare in adults and extremely rare in children."
    explanation: States the rarity of the rectum as a primary lymphoma site.
pathophysiology:
- name: Chronic Mucosal Antigenic Stimulation
  conforms_to: "tumor_promoting_inflammation#Chronic Inflammatory Stimulus"
  biological_scale: TISSUE
  description: >-
    A persistent, site-restricted antigenic stimulus drives chronic inflammation
    in gastrointestinal mucosa. The stimuli are organ-specific rather than
    systemic: Helicobacter pylori gastritis in the stomach, dietary gluten in
    coeliac disease in the small bowel, and chronic small-bowel infection in
    immunoproliferative small intestinal disease. The site-specificity is the
    defining feature and is directly evidenced: prior H. pylori infection raises
    the risk of gastric non-Hodgkin lymphoma roughly six-fold while conferring
    no measurable risk of non-gastric non-Hodgkin lymphoma. This is the
    disorder-specific substitution for the module's generic chronic
    inflammatory trigger.
  locations:
  - preferred_term: stomach
    term:
      id: UBERON:0000945
      label: stomach
  - preferred_term: intestine
    term:
      id: UBERON:0000160
      label: intestine
  biological_processes:
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: PMID:8145781
    reference_title: "Helicobacter pylori infection and gastric lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with gastric lymphoma were significantly more likely than matched controls to have evidence of previous H. pylori infection (matched odds ratio, 6.3; 95 percent confidence interval, 2.0 to 19.9)."
    explanation: Nested case-control study within 230,593 prospectively followed participants quantifies chronic H. pylori infection as an antecedent risk factor for gastric lymphoma.
  - reference: PMID:8145781
    reference_title: "Helicobacter pylori infection and gastric lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Non-Hodgkin's lymphoma affecting the stomach, but not other sites, is associated with previous H. pylori infection."
    explanation: Establishes that the antigen drive is site-restricted, the feature that separates gastrointestinal from nodal lymphomagenesis in this model.
  - reference: PMID:37627888
    reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "EATL is an aggressive T-cell non-Hodgkin lymphoma with poor prognosis and is largely localized to the small intestine. EATL is closely associated with coeliac disease (CD)"
    explanation: Supplies the small-bowel, T-cell counterpart of the same chronic-antigen trigger. Evidence source is OTHER because this is a review article.
  - reference: PMID:29372346
    reference_title: "Heavy Chain Disease of the Small Bowel."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A link between Campylobacter jejuni infection and IPSID has been established, but there is controversy as to the role played by this organism in disease pathogenesis."
    explanation: >-
      Supports a third chronic-infection trigger in the small bowel, but is
      marked PARTIAL because the review states explicitly that the organism's
      causal role remains contested. Evidence source is OTHER because this is a
      review article.
  downstream:
  - target: Pro-Tumorigenic Mucosal Lymphoid Microenvironment
    description: >-
      Sustained antigenic stimulation recruits and organizes a chronic mucosal
      immune infiltrate at the future tumour site.
    evidence:
    - reference: PMID:20303878
      reference_title: "Immunity, inflammation, and cancer."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "tumorigenic pathogens subvert host immunity and establish persistent infections associated with low grade but chronic inflammation"
      explanation: >-
        States the general step this edge asserts — a persistent infectious
        antigenic stimulus establishing a chronic inflammatory infiltrate that
        precedes tumour development. Evidence source is OTHER because this is a
        review article.
    - reference: PMID:37627888
      reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "RCDII is characterized by unresponsiveness to a GFD, providing a chronic inflammatory environment, which promotes genotoxic stress, ultimately leading to malignant transformation"
      explanation: >-
        The small-bowel instance of the same edge: continued gluten exposure in
        a patient not responding to a gluten-free diet is what supplies the
        chronic inflammatory environment modelled by the downstream node.
        Evidence source is OTHER because this is a review article.
- name: Pro-Tumorigenic Mucosal Lymphoid Microenvironment
  conforms_to: "tumor_promoting_inflammation#Pro-Tumorigenic Inflammatory Microenvironment"
  biological_scale: TISSUE
  description: >-
    Chronic stimulation organizes lymphoid tissue in mucosa that normally
    contains little or none — acquired mucosa-associated lymphoid tissue in the
    H. pylori-infected stomach — together with macrophages and other innate
    cells and a cytokine-rich milieu. This infiltrate is not a bystander: the
    mucosal immune microenvironment actively enhances neoplastic transformation
    of the resident lymphocytes. It is the disorder-specific substitution for
    the module's central pro-tumorigenic inflammatory microenvironment node.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: positive regulation of cytokine production
    modifier: INCREASED
    term:
      id: GO:0001819
      label: positive regulation of cytokine production
  evidence:
  - reference: PMID:37627888
    reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The immune microenvironment of mucosal cells within the small intestine enhances the process of neoplastic transformation of IELs into EATL."
    explanation: States directly that the mucosal immune microenvironment promotes neoplastic transformation, the claim this node makes. Evidence source is OTHER because this is a review article.
  - reference: PMID:20303878
    reference_title: "Immunity, inflammation, and cancer."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Immune cells that infiltrate tumors engage in an extensive and dynamic crosstalk with cancer cells"
    explanation: The general infiltrating-immune-cell/tumour-cell crosstalk that this node specializes to gut mucosa, and the evidence the parent module node rests on. Evidence source is OTHER because this is a review article.
  downstream:
  - target: Antigen-Driven Clonal Lymphoid Expansion
    description: >-
      The organized mucosal infiltrate supplies the antigen and accessory-cell
      signals that select and expand a lymphoid clone.
    evidence:
    - reference: PMID:21568677
      reference_title: "Protease activity of the API2-MALT1 fusion oncoprotein in MALT lymphoma development and treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a prototypical cancer that occurs in the setting of chronic inflammation"
      explanation: >-
        Marked PARTIAL: establishes that the clonal MALT lymphoma of this
        downstream node arises specifically in the chronic-inflammatory setting
        modelled by the upstream node, but does not itself demonstrate that the
        infiltrate supplies the accessory-cell signals that select the clone.
  - target: IL-15-Driven JAK-STAT Activation in Intraepithelial Lymphocytes
    description: >-
      In the coeliac small bowel the same microenvironment supplies the IL-15
      that deregulates intraepithelial lymphocyte signalling.
    evidence:
    - reference: PMID:37627888
      reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The mechanism of this uncontrolled chronic antigenic stimulation is facilitated by the IL-15Rα, which can bind IL-15 and form enduring complexes at the cell membrane, subsequently activating RCDII IELs"
      explanation: >-
        States the edge directly: IL-15 held in the inflamed mucosal
        microenvironment acts through IL-15Rα on intraepithelial lymphocytes to
        activate them. The statement sits in the body of this full-text-cached
        review rather than in its abstract. Evidence source is OTHER because
        this is a review article.
    - reference: PMID:37627888
      reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Epithelial-derived IL-15 plays an important role in the expansion of aberrant cell population and its subsequent conversion to EATL."
      explanation: >-
        Identifies the mucosal epithelium as the source of the IL-15 acting on
        the intraepithelial lymphocyte compartment, which is what makes this a
        microenvironment-to-lymphocyte edge rather than a cell-autonomous step.
        Full-text statement, not abstract. Evidence source is OTHER because this
        is a review article.
- name: Antigen-Driven Clonal Lymphoid Expansion
  biological_scale: CELLULAR
  description: >-
    Chronic antigen-receptor engagement plus accessory-cell help selects and
    expands a clonal lymphoid population within the mucosa. Growth at this stage
    is still driven from outside the tumour cell and therefore still dependent
    on the antigen — the property that makes early, antigen-dependent gastric
    lymphoma curable by eradicating the organism rather than by cytotoxic
    therapy. The B-cell (MALT) arm of this step is curated in depth in the
    MALT_Lymphoma entry.
  cell_types:
  - preferred_term: marginal zone B cell
    term:
      id: CL:0009060
      label: marginal zone B cell of lymph node
  biological_processes:
  - preferred_term: B cell receptor signaling pathway
    modifier: INCREASED
    term:
      id: GO:0050853
      label: B cell receptor signaling pathway
  - preferred_term: B cell proliferation
    modifier: INCREASED
    term:
      id: GO:0042100
      label: B cell proliferation
  evidence:
  - reference: PMID:21568677
    reference_title: "Protease activity of the API2-MALT1 fusion oncoprotein in MALT lymphoma development and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most gastric MALT lymphomas require ongoing antigenic stimulation for continued tumor growth, and Stage I disease is usually cured by eradicating the causative microorganism, Helicobacter pylori, with antibiotics."
    explanation: Establishes that expansion at this stage remains dependent on continuing antigenic stimulation, which is what makes antigen removal curative.
  downstream:
  - target: Transformation to Antigen-Independent Lymphoma
    description: >-
      Prolonged proliferation permits acquisition of transforming genetic
      lesions that uncouple growth from the antigen.
    evidence:
    - reference: PMID:21568677
      reference_title: "Protease activity of the API2-MALT1 fusion oncoprotein in MALT lymphoma development and treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "in a subset of MALT lymphomas, chromosomal translocations are acquired that render the lymphoma antigen-independent"
      explanation: >-
        States this edge exactly — the antigen-dependent clone acquires
        chromosomal translocations that make it antigen-independent. Same quote
        already verified on the downstream node itself; carried here because the
        causal edge is its own claim.
  - target: Mucosal and Transmural Lymphomatous Infiltration
    description: >-
      The expanding clone occupies the mucosa and submucosa of the involved gut
      segment. Progression to full-thickness, wall-destroying infiltration is
      carried on the edge from the transformation node rather than on this one.
    evidence:
    - reference: PMID:36756091
      reference_title: "Primary Esophageal Lymphoma: A Histopathological Experience from Two Tertiary Hospitals, Western Saudi Arabia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "MALT lymphoma is composed of submucosal proliferation of small centrocyte-like cells."
      explanation: >-
        Marked PARTIAL, and the weakest of this entry's edge citations: the
        histopathology series shows that the low-grade antigen-driven clone
        modelled by the upstream node presents as a proliferation occupying the
        submucosa, which is why the edge description was narrowed to mucosal and
        submucosal occupation. It does not evidence transmural progression, and
        no cached source states that step for the antigen-dependent stage.
- name: IL-15-Driven JAK-STAT Activation in Intraepithelial Lymphocytes
  biological_scale: CELLULAR
  description: >-
    The small-bowel T-cell arm. In coeliac disease the inflamed mucosa
    over-produces IL-15, which acts on receptors on intraepithelial
    lymphocytes and deregulates JAK-STAT signalling; these intraepithelial
    lymphocytes are the postulated cell of origin of enteropathy-associated
    T-cell lymphoma, and JAK/STAT pathway mutations have been associated with
    the type II refractory coeliac disease-derived form. This is the mechanistic
    reason a T-cell lymphoma arises specifically in the gut rather than in nodes.
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  cell_types:
  - preferred_term: intestinal intraepithelial lymphocyte
    term:
      id: CL:0020035
      label: intestinal intraepithelial lymphocyte
  biological_processes:
  - preferred_term: JAK-STAT signalling
    modifier: INCREASED
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
  - preferred_term: T cell proliferation
    modifier: INCREASED
    term:
      id: GO:0042098
      label: T cell proliferation
  evidence:
  - reference: PMID:37627888
    reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cytokines such as IL-15 can activate and crucially deregulate the JAK-STAT signaling pathway by binding to receptors on the surface of IELs."
    explanation: States the IL-15 to JAK-STAT deregulation step in intraepithelial lymphocytes modelled by this node. Evidence source is OTHER because this is a review article.
  - reference: PMID:37627888
    reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The cells of origin of EATL has been postulated to be normal small intestinal intraepithelial T-lymphocytes (IELs)"
    explanation: Identifies the intraepithelial lymphocyte as the cell of origin annotated on this node. Evidence source is OTHER because this is a review article.
  - reference: PMID:37627888
    reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Furthermore, mutations in the JAK/STAT pathway have been associated with RCDII-derived EATL."
    explanation: >-
      Supports the JAK/STAT-mutation clause of this node's description. Note the
      source claims association only — it does not report the mutations as
      recurrent or establish them as activating — so the description was softened
      to match rather than the stronger claim being left uncited. Evidence source
      is OTHER because this is a review article.
  downstream:
  - target: Transformation to Antigen-Independent Lymphoma
    description: >-
      Deregulated JAK-STAT signalling contributes to overt transformation of
      the intraepithelial lymphocyte compartment.
    evidence:
    - reference: PMID:37627888
      reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Ultimately, this results in the inhibition of elimination and enables the acquisition of mutations and malignant transformation into EATL"
      explanation: >-
        Supports the causal step from deregulated IL-15/JAK-STAT signalling to
        malignant transformation of the intraepithelial lymphocyte compartment.
        Marked PARTIAL because the source establishes malignant transformation
        but does not itself assert that the resulting tumour is
        antigen-independent, which is the further claim carried by the target
        node's name. Full-text statement, not abstract. Evidence source is OTHER
        because this is a review article.
- name: Transformation to Antigen-Independent Lymphoma
  biological_scale: MOLECULAR
  description: >-
    Acquisition of transforming genetic lesions during prolonged
    antigen-driven proliferation uncouples growth from the initiating stimulus.
    In the gastric MALT arm the paradigmatic lesions are translocations that
    constitutively activate NF-kB, above all t(11;18)(q21;q21) generating
    BIRC3::MALT1; in the coeliac arm they are JAK/STAT pathway mutations. The
    clinical corollary is direct and is why this node matters for management:
    once the tumour is antigen-independent, removing the antigen no longer
    treats it. The translocation biology itself is curated in MALT_Lymphoma and
    is referenced rather than duplicated here.
  biological_processes:
  - preferred_term: canonical NF-kappaB signal transduction
    modifier: INCREASED
    term:
      id: GO:0007249
      label: canonical NF-kappaB signal transduction
  evidence:
  - reference: PMID:21568677
    reference_title: "Protease activity of the API2-MALT1 fusion oncoprotein in MALT lymphoma development and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in a subset of MALT lymphomas, chromosomal translocations are acquired that render the lymphoma antigen-independent. The recurrent translocation t(11;18)(q21;q21) is associated with failure to respond to antibiotic therapy and increased rate of dissemination."
    explanation: Establishes both the acquired lesion and its clinical consequence, loss of response to antigen-directed therapy.
  - reference: PMID:29372346
    reference_title: "Heavy Chain Disease of the Small Bowel."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "IPSID is typically regarded as a pre-lymphomatous condition with eventual progression to frank lymphoma"
    explanation: Supports the progression from an antigen-driven pre-lymphomatous lesion to overt lymphoma in the small-bowel arm. Evidence source is OTHER because this is a review article.
  downstream:
  - target: Mucosal and Transmural Lymphomatous Infiltration
    description: >-
      Antigen-independent growth drives progressive, often bulky, infiltration
      of the gut wall.
    evidence:
    - reference: PMID:37627888
      reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "the angiocentricity and angioinvasion displayed by these cells may lead to extensive necrosis, often resulting in obstruction, intestinal perforation, and peritonitis"
      explanation: >-
        Supports the edge from overt lymphoma to destructive full-thickness
        involvement of the gut wall, and names the obstruction and perforation
        that the downstream node accounts for. Stated for the small-bowel T-cell
        arm specifically. Full-text statement, not abstract. Evidence source is
        OTHER because this is a review article.
    - reference: PMID:37627888
      reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The expression of the enterocyte marker NKp46 on aberrant IELs in the presence of IL-15 confers the tumor with the ability to carry out enterocyte killing, resulting in severe ulceration"
      explanation: >-
        Gives the mechanism by which the lymphoma cells ulcerate the epithelium,
        one of the two structural consequences the downstream node models.
        Full-text statement, not abstract. Evidence source is OTHER because this
        is a review article.
- name: Mucosal and Transmural Lymphomatous Infiltration
  biological_scale: TISSUE
  description: >-
    The shared anatomic final common path. Lymphoma infiltrates the mucosa and
    then the full thickness of the gut wall, ulcerating the epithelium,
    narrowing or (because lymphoma tends to infiltrate without the desmoplastic
    stiffening of carcinoma) aneurysmally dilating the lumen, and thinning the
    wall. This single node accounts for the presenting syndrome shared across
    every site and histology — abdominal pain, bleeding from ulcerated mucosa,
    obstruction, and perforation — and for the fact that the presentation is
    clinically indistinguishable from other gastrointestinal disease. The
    diagnostic consequence of that non-specificity is modelled in the
    diagnosis: section rather than asserted here.
  locations:
  - preferred_term: stomach
    term:
      id: UBERON:0000945
      label: stomach
  - preferred_term: intestine
    term:
      id: UBERON:0000160
      label: intestine
  evidence:
  - reference: PMID:21390139
    reference_title: "Primary gastrointestinal lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gastrointestinal lymphomas are usually not clinically specific and indistinguishable from other benign and malignant conditions."
    explanation: Supports the claim that infiltration of the gut wall produces a presentation indistinguishable from other gastrointestinal disease.
  - reference: PMID:26988370
    reference_title: "Anatomic distribution, clinical features, and survival data of 87 cases primary gastrointestinal lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some patients presented with systemic symptoms or complications, such as weight loss (35.6%) and digestive tract obstruction (13.8%)."
    explanation: Documents obstruction as a direct structural consequence of lymphomatous infiltration of the gut wall.
phenotypes:
- category: Neoplastic
  name: B-Cell Lymphoma
  description: >-
    Most gastrointestinal lymphomas are of mature B-cell lineage, with diffuse
    large B-cell lymphoma the single commonest histologic type at essentially
    every gastrointestinal site.
  phenotype_term:
    preferred_term: B-cell lymphoma
    term:
      id: HP:0012191
      label: B-cell lymphoma
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:21390139
    reference_title: "Primary gastrointestinal lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diffuse large B-cell lymphoma is the most common pathological type of gastrointestinal lymphoma in essentially all sites of the gastrointestinal tract"
    explanation: Establishes B-cell (DLBCL) predominance across gastrointestinal sites.
  - reference: PMID:26988370
    reference_title: "Anatomic distribution, clinical features, and survival data of 87 cases primary gastrointestinal lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most of PGIL were derived from B cell (93.1%)."
    explanation: >-
      Quantifies B-cell lineage in 93.1% of 87 primary gastrointestinal
      lymphomas, supporting the VERY_FREQUENT (80-100%) frequency band.
- category: Neoplastic
  name: T-Cell Lymphoma
  description: >-
    A minority of gastrointestinal lymphomas are of T-cell lineage, most
    distinctively enteropathy-associated T-cell lymphoma of the small bowel
    arising on a background of coeliac disease. Frequency is deliberately
    omitted: T-cell proportions vary widely by geography and are not quantified
    by the sources cited here.
  phenotype_term:
    preferred_term: T-cell lymphoma
    term:
      id: HP:0012190
      label: T-cell lymphoma
  evidence:
  - reference: PMID:37627888
    reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "EATL is an aggressive T-cell non-Hodgkin lymphoma with poor prognosis and is largely localized to the small intestine."
    explanation: Establishes a T-cell non-Hodgkin lymphoma localized to the gastrointestinal tract. Evidence source is OTHER because this is a review article.
- category: Clinical
  name: Abdominal Pain
  description: >-
    Abdominal pain or discomfort is the commonest presenting symptom, and is
    nonspecific.
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
  frequency: FREQUENT
  evidence:
  - reference: PMID:26988370
    reference_title: "Anatomic distribution, clinical features, and survival data of 87 cases primary gastrointestinal lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical symptoms of PGIL were indistinguishable from other digestive system diseases, which included abdominal pain or discomfort (72.4%), lack of appetite (16.3%), gastrointestinal hemorrhage (14.9%), and diarrhea (12.8%)."
    explanation: >-
      Reports abdominal pain or discomfort in 72.4% of 87 patients, within the
      FREQUENT (30-79%) band.
- category: Clinical
  name: Weight Loss
  description: Constitutional weight loss at presentation.
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
  frequency: FREQUENT
  evidence:
  - reference: PMID:26988370
    reference_title: "Anatomic distribution, clinical features, and survival data of 87 cases primary gastrointestinal lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some patients presented with systemic symptoms or complications, such as weight loss (35.6%) and digestive tract obstruction (13.8%)."
    explanation: >-
      Reports weight loss in 35.6% of 87 patients, within the FREQUENT (30-79%)
      band.
- category: Clinical
  name: Gastrointestinal Hemorrhage
  description: >-
    Bleeding from lymphomatous ulceration of the mucosa, ranging from occult
    blood loss to overt haemorrhage.
  phenotype_term:
    preferred_term: Gastrointestinal hemorrhage
    term:
      id: HP:0002239
      label: Gastrointestinal hemorrhage
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:26988370
    reference_title: "Anatomic distribution, clinical features, and survival data of 87 cases primary gastrointestinal lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical symptoms of PGIL were indistinguishable from other digestive system diseases, which included abdominal pain or discomfort (72.4%), lack of appetite (16.3%), gastrointestinal hemorrhage (14.9%), and diarrhea (12.8%)."
    explanation: >-
      Reports gastrointestinal haemorrhage in 14.9% of 87 patients, within the
      OCCASIONAL (5-29%) band.
- category: Clinical
  name: Gastrointestinal Obstruction
  description: >-
    Luminal obstruction by an infiltrating or bulky mass, most often in the
    small bowel.
  phenotype_term:
    preferred_term: Gastrointestinal obstruction
    term:
      id: HP:0004796
      label: Gastrointestinal obstruction
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:26988370
    reference_title: "Anatomic distribution, clinical features, and survival data of 87 cases primary gastrointestinal lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some patients presented with systemic symptoms or complications, such as weight loss (35.6%) and digestive tract obstruction (13.8%)."
    explanation: >-
      Reports digestive tract obstruction in 13.8% of 87 patients, within the
      OCCASIONAL (5-29%) band.
- category: Clinical
  name: Diarrhea
  description: Diarrhoea, prominent in small-bowel and enteropathy-associated disease.
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:26988370
    reference_title: "Anatomic distribution, clinical features, and survival data of 87 cases primary gastrointestinal lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical symptoms of PGIL were indistinguishable from other digestive system diseases, which included abdominal pain or discomfort (72.4%), lack of appetite (16.3%), gastrointestinal hemorrhage (14.9%), and diarrhea (12.8%)."
    explanation: >-
      Reports diarrhoea in 12.8% of 87 patients, within the OCCASIONAL (5-29%)
      band.
- category: Clinical
  name: Anorexia
  description: Loss of appetite at presentation.
  phenotype_term:
    preferred_term: Anorexia
    term:
      id: HP:0002039
      label: Anorexia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:26988370
    reference_title: "Anatomic distribution, clinical features, and survival data of 87 cases primary gastrointestinal lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical symptoms of PGIL were indistinguishable from other digestive system diseases, which included abdominal pain or discomfort (72.4%), lack of appetite (16.3%), gastrointestinal hemorrhage (14.9%), and diarrhea (12.8%)."
    explanation: >-
      Reports lack of appetite in 16.3% of 87 patients, within the OCCASIONAL
      (5-29%) band.
- category: Clinical
  name: Malabsorption
  description: >-
    Malabsorption, characteristic of small-bowel disease and in particular of
    enteropathy-associated T-cell lymphoma arising on coeliac villous atrophy,
    where worsening malabsorption is the signal that should prompt suspicion of
    lymphomatous transformation.
  phenotype_term:
    preferred_term: Malabsorption
    term:
      id: HP:0002024
      label: Malabsorption
  subtype: Small Intestine
  evidence:
  - reference: PMID:38142052
    reference_title: "Advanced enteropathy-associated T cell lymphoma (EATL) presenting with severe malabsorption and concomitantly diagnosed coeliac disease (CD)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case highlights the need for greater awareness and consideration of EATL in individuals with worsening malabsorption and abdominal pain, irrespective of coeliac history."
    explanation: Reports malabsorption as the presenting syndrome of small-bowel enteropathy-associated T-cell lymphoma.
- category: Clinical
  name: Dysphagia
  description: >-
    Difficulty swallowing, the presenting complaint of the rare oesophageal
    subtype.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  subtype: Esophagus
  evidence:
  - reference: PMID:36756091
    reference_title: "Primary Esophageal Lymphoma: A Histopathological Experience from Two Tertiary Hospitals, Western Saudi Arabia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical manifestation included dysphagia and loss of weight."
    explanation: Reports dysphagia as a presenting manifestation in a series of primary oesophageal lymphoma.
- category: Clinical
  name: Intestinal Perforation
  description: >-
    Perforation of the thinned, infiltrated bowel wall, a surgical emergency
    that may occur at presentation or during chemotherapy-induced tumour
    regression.
  phenotype_term:
    preferred_term: Intestinal perforation
    term:
      id: HP:0031368
      label: Intestinal perforation
  evidence:
  - reference: PMID:38235779
    reference_title: "The Rising Incidence and Poor Outcomes of Enteropathy-Associated T-Cell Lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most of the cases were at an advanced stage at diagnosis and were treated with a combination of surgery and chemotherapy."
    explanation: >-
      Marked PARTIAL: the SEER analysis documents the routine need for surgery
      alongside chemotherapy in small-bowel lymphoma, consistent with
      obstructive and perforating complications, but does not itself enumerate
      perforation events.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: >-
    Reported as a proportion of gastrointestinal cancers rather than as a
    population rate; the cited figure is a share of GI malignancies (1-4%), not
    an incidence or prevalence, so no rate_per_100000 is asserted.
  evidence:
  - reference: PMID:33618613
    reference_title: "A 10-year cohort study of 175 primary gastrointestinal lymphoma cases in Thailand: clinical features and outcomes in the immunochemotherapy era."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Primary gastrointestinal lymphoma (PGIL), an uncommon subtype of lymphoma, accounts for 1%-4% of gastrointestinal cancers."
    explanation: Establishes that primary gastrointestinal lymphoma is an uncommon tumour, quantified as a share of gastrointestinal cancers.
- population: United States (SEER, 2014)
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.35
  notes: >-
    Colorectal subtype only. SEER-reported primary colorectal lymphoma
    incidence of 3.5 per 1,000,000 in 2014, normalized to 0.35 per 100,000.
  evidence:
  - reference: PMID:33178655
    reference_title: "Changes in Incidence and Survival by Decade of Patients With Primary Colorectal Lymphoma: A SEER Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The PCL incidence increased from 1.4 per 1 000 000 people in 1973 to 3.5 in 2014"
    explanation: Provides the population-based annual incidence of primary colorectal lymphoma normalized in this record.
- population: United States (SEER, 2000-2020)
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.014
  notes: >-
    Enteropathy-associated T-cell lymphoma only, the coeliac-associated
    small-bowel subtype; age-adjusted incidence per 100,000.
  evidence:
  - reference: PMID:38235779
    reference_title: "The Rising Incidence and Poor Outcomes of Enteropathy-Associated T-Cell Lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 2000-2020 age-adjusted incidence rate per 100,000 people was 0.014, and the incidence increased between 2000 and 2020, with an annual percent change of 2.58 ( P < 0.05)."
    explanation: Provides the age-adjusted population incidence of EATL used in this record.
genetic:
- name: JAK1
  gene_term:
    preferred_term: JAK1
    term:
      id: hgnc:6190
      label: JAK1
  association: Somatic driver of the JAK/STAT axis in EATL and refractory coeliac disease type II
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  notes: >-
    Gain-of-function mutation of JAK1, one of the two commonest lesions of the
    JAK/STAT axis in the gastrointestinal T-cell arm. The functional consequence
    reported is hyper-responsiveness of the aberrant intraepithelial lymphocyte
    to IL-15, which is the mechanism by which the mutant clone outgrows its
    normal polyclonal neighbours. Curated from the full-text body of
    PMID:37627888 rather than its abstract, which mentions JAK/STAT mutation
    only in general terms. The cited source is a narrative review, not a primary
    sequencing cohort, so no mutation frequency is asserted here.
  evidence:
  - reference: PMID:37627888
    reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The acquisition of these mutations by IELs allows them to progressively expand at the expense of other IELs, as JAK1 or STAT3 gain-of-function mutations garner the cells with hyper-responsiveness to IL-15"
    explanation: >-
      Names JAK1 gain-of-function mutation and gives its functional consequence,
      IL-15 hyper-responsiveness driving clonal outgrowth. The statement sits in
      the body of this full-text-cached review, not in its abstract. Evidence
      source is OTHER because this is a review article.
  - reference: PMID:37627888
    reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The JAK/STAT pathway is considered to be among the most commonly mutated signaling pathways in EATL pathogenesis"
    explanation: >-
      Places the pathway among the most commonly mutated in this disease,
      supporting its curation as a driver rather than an incidental finding.
      Full-text statement, not abstract. Evidence source is OTHER because this
      is a review article.
- name: STAT3
  gene_term:
    preferred_term: STAT3
    term:
      id: hgnc:11364
      label: STAT3
  association: Somatic driver of the JAK/STAT axis in EATL and refractory coeliac disease type II
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  notes: >-
    Gain-of-function mutation of STAT3, the partner lesion to JAK1 on the same
    axis and reported in the same setting. Mutations activating JAK1-STAT3 are
    described as capable of synergizing with NF-kB-activating lesions, which is
    the link to the transformation node's NF-kB biology.
  evidence:
  - reference: PMID:37627888
    reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The acquisition of these mutations by IELs allows them to progressively expand at the expense of other IELs, as JAK1 or STAT3 gain-of-function mutations garner the cells with hyper-responsiveness to IL-15"
    explanation: >-
      Names STAT3 gain-of-function mutation alongside JAK1 with the same
      functional consequence. Full-text statement, not abstract. Evidence source
      is OTHER because this is a review article.
  - reference: PMID:37627888
    reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "mutations activating JAK1-STAT3 may synergize with mutations activating NF-kB"
    explanation: >-
      Supports the JAK1-STAT3 axis being activating and cooperating with the
      NF-kB lesions modelled on the transformation node. Full-text statement,
      not abstract. Evidence source is OTHER because this is a review article.
- name: SETD2
  gene_term:
    preferred_term: SETD2
    term:
      id: hgnc:18420
      label: SETD2
  association: Somatic driver and diagnostic marker in MEITL
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  subtype: Small Intestine
  notes: >-
    Loss-of-function mutation of the SETD2 tumour suppressor, the commonest
    mutation of monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL),
    the de novo small-bowel T-cell lymphoma separated from EATL in the 2016
    reclassification. Scoped to MEITL, not to EATL: the cited review is explicit
    that SETD2 mutation characterizes MEITL, whereas EATL cases in the same
    comparison showed DNA-repair (TP53), NOTCH, VEGF and PI3K/AKT lesions
    instead.
  evidence:
  - reference: PMID:37627888
    reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the most frequently mutated gene in MEITL is the SETD2 tumor suppressor gene (TSG)"
    explanation: >-
      Identifies SETD2 as the most frequently mutated gene in MEITL. Full-text
      statement, not abstract. Evidence source is OTHER because this is a review
      article.
  - reference: PMID:37627888
    reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The majority of SETD2 mutations are a loss of function, exhibiting frameshift or nonsense mutations"
    explanation: >-
      Establishes the loss-of-function direction curated here, consistent with
      SETD2's tumour-suppressor role. Full-text statement, not abstract.
      Evidence source is OTHER because this is a review article.
- name: HLA-DQ2.5 haplotype
  gene_term:
    preferred_term: HLA-DQB1 (HLA-DQ2.5 haplotype, with HLA-DQA1)
    term:
      id: hgnc:4944
      label: HLA-DQB1
  association: Germline HLA susceptibility haplotype for coeliac disease and its progression to EATL
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  subtype: Small Intestine
  notes: >-
    The coeliac-disease HLA class II risk haplotype. This is a germline
    susceptibility/risk association, NOT a somatic driver: the haplotype is a
    common population variant that sets the risk of coeliac disease and of its
    malignant evolution, and is neither necessary nor sufficient for lymphoma.
    The gene_term slot is single-valued, so it is bound to HLA-DQB1; the
    HLA-DQ2.5 heterodimer is encoded jointly by HLA-DQA1 (hgnc:4942) and
    HLA-DQB1, and neither locus alone names the haplotype. The reported 53.3% is
    the proportion of EATL patients who are HLA-DQ2.5 homozygous — a frequency
    among cases, not a relative risk, an attributable fraction, or a per-gene
    case fraction — so it is not recorded in frequency or case_fractions.
  evidence:
  - reference: PMID:37627888
    reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In one systematic review, HLA-DQ2.5 homozygosity was found in 53.3% of patients with EATL and 44.1% of patients with RCDII"
    explanation: >-
      Quantifies HLA-DQ2.5 homozygosity among EATL and RCDII patients. Full-text
      statement, not abstract. Evidence source is OTHER because this is a review
      article.
  - reference: PMID:37627888
    reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Furthermore, there is a strong correlation between HLA-DQ2.5 homozygosity and the development of EATL"
    explanation: >-
      States the correlation between the haplotype and EATL development,
      supporting the SUSCEPTIBILITY relationship type — the source claims a
      correlation, which is why this is curated as risk rather than causation.
      Full-text statement, not abstract. Evidence source is OTHER because this
      is a review article.
environmental:
- name: Chronic Helicobacter pylori infection
  description: >-
    Persistent gastric colonization by Helicobacter pylori, which induces the
    acquired mucosa-associated lymphoid tissue on which gastric lymphoma
    develops. The exposure is the archetype of a site-restricted antigenic
    drive: it raises gastric lymphoma risk about six-fold while conferring no
    detectable risk of lymphoma at other sites.
  effect: Increases risk of gastric lymphoma
  exposure_term:
    preferred_term: exposure to Helicobacter pylori
    term:
      id: ECTO:3000003
      label: exposure to Helicobacter pylori
  influences_mechanisms:
  - target: Chronic Mucosal Antigenic Stimulation
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Chronic H. pylori gastritis is the route by which sustained mucosal
      antigenic stimulation is established in the stomach.
    evidence:
    - reference: PMID:8145781
      reference_title: "Helicobacter pylori infection and gastric lymphoma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients with gastric lymphoma were significantly more likely than matched controls to have evidence of previous H. pylori infection (matched odds ratio, 6.3; 95 percent confidence interval, 2.0 to 19.9)."
      explanation: Prospective nested case-control evidence that antecedent H. pylori infection raises gastric lymphoma risk, supporting this exposure as the trigger of the mucosal antigenic-stimulation node.
    - reference: PMID:8145781
      reference_title: "Helicobacter pylori infection and gastric lymphoma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "No association was found between nongastric non-Hodgkin's lymphoma and previous H. pylori infection"
      explanation: The internal negative control showing the effect is confined to the site of infection, which is what makes this a gastrointestinal rather than a systemic lymphomagenic exposure.
  evidence:
  - reference: PMID:37122607
    reference_title: "Effectiveness of Helicobacter pylori eradication in the treatment of early-stage gastric mucosa-associated lymphoid tissue lymphoma: An up-to-date meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pooled CR of H. pylori-positive early-stage GML after bacterial eradication was 75.18% (95%CI: 70.45%-79.91%)."
    explanation: Regression of lymphoma on removing the organism is the strongest evidence that the exposure is causal rather than merely associated.
- name: Dietary gluten exposure in coeliac disease
  description: >-
    Continued exposure to dietary gluten in a genetically susceptible
    (HLA-DQ2/DQ8) individual sustains the coeliac enteropathy on which
    enteropathy-associated T-cell lymphoma arises, particularly via type II
    refractory coeliac disease.
  effect: Increases risk of enteropathy-associated T-cell lymphoma
  notes: >-
    Deliberately left without an exposure_term. ECTO was searched
    (sqlite:obo:ecto) and contains no term for gluten or gluten-containing-food
    exposure. Per the dismech terms rule, no term is preferred to a bad one.
  influences_mechanisms:
  - target: Chronic Mucosal Antigenic Stimulation
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Gluten-driven coeliac enteropathy is the route by which sustained mucosal
      antigenic stimulation is established in the small bowel.
    evidence:
    - reference: PMID:37627888
      reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "EATL is closely associated with coeliac disease (CD) and is seen mostly in patients originating from Northern Europe."
      explanation: Links the coeliac enteropathy to the small-bowel lymphoma modelled downstream of this node. Evidence source is OTHER because this is a review article.
    - reference: PMID:37627888
      reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Although EATL can occur de novo, individuals with RCDII are at a higher risk of developing EATL."
      explanation: Identifies refractory coeliac disease type II as the high-risk intermediate on this exposure route. Evidence source is OTHER because this is a review article.
  evidence:
  - reference: PMID:37627888
    reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Furthermore, poor adherence to a GFD, HLA-DQ2 homozygosity, and late diagnosis of CD are recognized as risk factors for the malignant evolution of CD"
    explanation: >-
      Poor adherence to a gluten-free diet is continued gluten exposure, so
      naming it a risk factor for malignant evolution is the most direct
      available support for treating the exposure itself — rather than coeliac
      disease alone — as the modifiable driver. Evidence source is OTHER because
      this is a review article.
  - reference: PMID:37627888
    reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Although the duration of gluten diet exposure plays an important role in EATL pathogenesis via the enhancement of inflammatory signaling pathways mediated by CD4+ T-cells, many cases of EATL arise despite a strict GFD"
    explanation: >-
      Recorded as PARTIAL because the source supports and bounds the claim in
      one sentence: exposure duration matters mechanistically, but a strict
      gluten-free diet does not abolish EATL risk. Removing this exposure is
      therefore not curative, which is the honest limit on the eradication
      analogy drawn from the H. pylori arm.
- name: Chronic small-bowel bacterial infection in immunoproliferative small intestinal disease
  description: >-
    Chronic small-intestinal infection, with Campylobacter jejuni the organism
    most often implicated, associated with immunoproliferative small intestinal
    disease (alpha heavy chain disease) in areas of poor sanitation. IPSID
    behaves as a pre-lymphomatous lesion that can regress on antibiotics and can
    progress to overt small-bowel lymphoma.
  effect: Associated with immunoproliferative small intestinal disease and small-bowel lymphoma
  notes: >-
    Deliberately left without an exposure_term. ECTO was searched
    (sqlite:obo:ecto) and contains no exposure term for Campylobacter jejuni.
    The organism's causal role is explicitly contested in the cited review, so
    the mechanism link is recorded as PREDISPOSES rather than TRIGGERS, with
    causal_link_type UNKNOWN, and the controversy is carried as a discussion.
  influences_mechanisms:
  - target: Chronic Mucosal Antigenic Stimulation
    environmental_effect: PREDISPOSES
    causal_link_type: UNKNOWN
    description: >-
      Chronic small-bowel infection is associated with the sustained mucosal
      antigenic stimulation underlying IPSID, but the causal contribution of the
      implicated organism is not settled.
    evidence:
    - reference: PMID:29372346
      reference_title: "Heavy Chain Disease of the Small Bowel."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "A link between Campylobacter jejuni infection and IPSID has been established, but there is controversy as to the role played by this organism in disease pathogenesis."
      explanation: >-
        Supports an established association while explicitly withholding a
        causal claim, which is why this link is PREDISPOSES and the evidence is
        PARTIAL. Evidence source is OTHER because this is a review article.
  evidence:
  - reference: PMID:29372346
    reference_title: "Heavy Chain Disease of the Small Bowel."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "IPSID is typically regarded as a pre-lymphomatous condition with eventual progression to frank lymphoma; however, recent reports of longstanding non-progressive cases have expanded its clinical spectrum."
    explanation: >-
      Supports the exposure-associated lesion being pre-lymphomatous, which is
      what connects this exposure to small-bowel lymphoma rather than to IPSID
      alone. PARTIAL because the same sentence records non-progressive cases, so
      progression is characteristic but not obligate — consistent with this
      entry's PREDISPOSES / UNKNOWN framing. Evidence source is OTHER because
      this is a review article.
diagnosis:
- name: Endoscopic biopsy with histopathological analysis
  description: >-
    The confirmatory test. Because lymphomatous infiltration of the gut wall
    produces a presentation and a radiological appearance indistinguishable
    from other benign and malignant gastrointestinal disease, definitive
    diagnosis requires tissue: endoscopic biopsy of the lesion with
    histopathological analysis and immunophenotyping. A first biopsy is not
    invariably diagnostic — repeat biopsy, or in a minority of cases surgical
    resection, may be needed — which matters clinically because the differential
    it must resolve includes carcinoma.
  diagnosis_term:
    preferred_term: endoscopic biopsy of the gastrointestinal lesion
    term:
      id: NCIT:C15389
      label: Endoscopic Biopsy
  results: >-
    Histopathology and immunophenotype establishing lymphoma and its lineage
    and subtype (most often diffuse large B-cell or extranodal marginal zone
    MALT lymphoma).
  evidence:
  - reference: PMID:21390139
    reference_title: "Primary gastrointestinal lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "they are not specific, thus mandating histopathological analysis for its definitive diagnosis"
    explanation: States that imaging features are non-specific and that histopathological analysis is required for definitive diagnosis, which is the claim this diagnostic entry makes.
  - reference: PMID:36756091
    reference_title: "Primary Esophageal Lymphoma: A Histopathological Experience from Two Tertiary Hospitals, Western Saudi Arabia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six cases were diagnosed based on endoscopic biopsies and two after resection."
    explanation: Documents endoscopic biopsy as the route to diagnosis in the majority of a consecutive series, with resection needed in the remainder.
  - reference: PMID:36756091
    reference_title: "Primary Esophageal Lymphoma: A Histopathological Experience from Two Tertiary Hospitals, Western Saudi Arabia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The first biopsies were diagnostic in five of them, and repeated biopsies were required to make the diagnosis in one case."
    explanation: Supports the caveat curated here that a first endoscopic biopsy is not invariably diagnostic and may need repeating.
  - reference: PMID:35125760
    reference_title: "Primary Rectal Lymphoma: A Case Report and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "it may be difficult to distinguish the primary adenocarcinoma of the colon/rectum on radiology and biopsy is therefore crucial"
    explanation: Names the specific differential — colorectal adenocarcinoma — that radiology cannot resolve and biopsy must.
- name: Helicobacter pylori testing
  description: >-
    Determination of H. pylori status in gastric lymphoma. This is not a
    diagnostic test for the lymphoma itself but the test that GATES first-line
    therapy: eradication is recommended as the initial treatment of early-stage
    gastric MALT lymphoma, and the entire evidence base for that recommendation
    is drawn from H. pylori-positive patients, so a patient cannot be assigned
    to antigen-removal therapy without it.
  diagnosis_term:
    preferred_term: Helicobacter pylori testing
    term:
      id: NCIT:C189536
      label: Helicobacter pylori Measurement
  results: H. pylori positive or negative status in a patient with gastric lymphoma.
  notes: >-
    Curated as the gate on treatment 1 (Helicobacter pylori Eradication) rather
    than as a confirmatory test for lymphoma. The cached sources establish that
    the eradication evidence base is restricted to H. pylori-positive
    early-stage disease; they do not compare the individual assays (urea breath
    test, stool antigen, histology, serology), so no specific method is asserted
    and the NCIT term is left at the general measurement level.
  evidence:
  - reference: PMID:37122607
    reference_title: "Effectiveness of Helicobacter pylori eradication in the treatment of early-stage gastric mucosa-associated lymphoid tissue lymphoma: An up-to-date meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prospective and retrospective observational studies evaluating the CR of early-stage GML following bacterial eradication in H. pylori-positive patients."
    explanation: The meta-analysis eligibility criterion shows the eradication evidence base is defined by H. pylori-positive status, which is what makes testing the gate on that therapy.
  - reference: PMID:37122607
    reference_title: "Effectiveness of Helicobacter pylori eradication in the treatment of early-stage gastric mucosa-associated lymphoid tissue lymphoma: An up-to-date meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical practice guidelines currently recommend H. pylori eradication as the preferred initial treatment for early-stage GML."
    explanation: Establishes the treatment that this test gates.
- name: Staging and extent-of-disease workup
  description: >-
    Assessment of disease extent once lymphoma is confirmed. Stage is
    load-bearing for management in this disease — antigen-removal therapy is
    offered for early-stage gastric disease and systemic therapy for advanced
    disease — and cross-sectional and functional imaging with histologic
    identification of lesions is what establishes it. The workup described for
    the small-bowel T-cell arm comprises magnetic resonance enteroclysis,
    positron emission tomography, and histologic identification of lesions.
  diagnosis_term:
    preferred_term: positron emission tomography as part of the staging workup
    term:
      id: NCIT:C17007
      label: Positron Emission Tomography
  results: Anatomic extent of disease, used to assign stage and select between antigen-directed and systemic therapy.
  notes: >-
    The NCIT term binds the positron emission tomography component only; the
    cached source names magnetic resonance enteroclysis in the same workup, and
    NCIT has no enteroclysis term (searched via sqlite:obo:ncit). No formal
    staging system is asserted here: a stages: section using the Lugano
    classification would be the right home for that and is deliberately left to
    separate work rather than invented from these sources.
  evidence:
  - reference: PMID:37627888
    reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "An extensive clinical diagnostic workup involves magnetic resonance enteroclysis, a positron emission tomography scan, and a histologic identification of lesions present"
    explanation: >-
      Enumerates the diagnostic and staging workup curated here. Stated for the
      enteropathy-associated T-cell arm, and the statement sits in the body of
      this full-text-cached review rather than in its abstract. Evidence source
      is OTHER because this is a review article.
  - reference: PMID:26988370
    reference_title: "Anatomic distribution, clinical features, and survival data of 87 cases primary gastrointestinal lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Multivariate analysis showed that clinical stage and sources of cells were the significant independent prognostic factors."
    explanation: Establishes that clinical stage is an independent prognostic factor in primary gastrointestinal lymphoma, which is why extent-of-disease assessment is curated as a distinct diagnostic step.
treatments:
- name: Helicobacter pylori Eradication
  description: >-
    Antibiotic eradication of H. pylori is first-line therapy for early-stage
    H. pylori-positive gastric MALT lymphoma and induces complete remission in
    about three quarters of such patients. It is the clearest demonstration in
    oncology that removing a driving antigen can cure a lymphoma, and it works
    only while the tumour remains antigen-dependent — the t(11;18)-positive,
    antigen-independent tumours modelled by the transformation node do not
    respond.
  context: Gastric subtype; early-stage, H. pylori-positive disease.
  treatment_term:
    preferred_term: antibiotic therapy
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy
  target_mechanisms:
  - target: Chronic Mucosal Antigenic Stimulation
    treatment_effect: INHIBITS
    description: >-
      Eradicating the organism removes the antigenic stimulus that sustains the
      antigen-dependent phase of the disease.
    evidence:
    - reference: PMID:21568677
      reference_title: "Protease activity of the API2-MALT1 fusion oncoprotein in MALT lymphoma development and treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Most gastric MALT lymphomas require ongoing antigenic stimulation for continued tumor growth, and Stage I disease is usually cured by eradicating the causative microorganism, Helicobacter pylori, with antibiotics."
      explanation: Directly links removal of the antigenic stimulus to cure of early-stage disease, the mechanism this treatment edge asserts.
  evidence:
  - reference: PMID:37122607
    reference_title: "Effectiveness of Helicobacter pylori eradication in the treatment of early-stage gastric mucosa-associated lymphoid tissue lymphoma: An up-to-date meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pooled CR of H. pylori-positive early-stage GML after bacterial eradication was 75.18% (95%CI: 70.45%-79.91%)."
    explanation: Meta-analysis quantifies complete remission after eradication in early-stage H. pylori-positive gastric MALT lymphoma.
  - reference: PMID:37122607
    reference_title: "Effectiveness of Helicobacter pylori eradication in the treatment of early-stage gastric mucosa-associated lymphoid tissue lymphoma: An up-to-date meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Meta-regression analysis identified statistically significant effect modifiers, including the proportion of patients with t(11;18)(q21;q21)-positive GML and the risk of bias in each study."
    explanation: Shows that t(11;18) positivity modifies response, consistent with loss of antigen dependence after transformation.
- name: Rituximab-Containing Immunochemotherapy
  description: >-
    Anti-CD20 immunochemotherapy, typically R-CHOP, is standard systemic therapy
    for aggressive B-cell gastrointestinal lymphoma, which is predominantly
    diffuse large B-cell lymphoma. Its adoption is associated with improved
    overall survival in primary gastrointestinal lymphoma cohorts.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
  regimen_term:
    preferred_term: R-CHOP regimen
    term:
      id: NCIT:C9760
      label: R-CHOP Regimen
  target_mechanisms:
  - target: Transformation to Antigen-Independent Lymphoma
    treatment_effect: INHIBITS
    description: >-
      Cytotoxic immunochemotherapy targets the transformed, antigen-independent
      lymphoma clone, which no longer responds to removal of the initiating
      antigen.
    evidence:
    - reference: PMID:33618613
      reference_title: "A 10-year cohort study of 175 primary gastrointestinal lymphoma cases in Thailand: clinical features and outcomes in the immunochemotherapy era."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The probability of having a better OS was demonstrated in patients with a good performance status who received a rituximab-containing regimen."
      explanation: Associates rituximab-containing therapy with improved survival in primary gastrointestinal lymphoma, the population dominated by transformed aggressive disease.
  evidence:
  - reference: PMID:33618613
    reference_title: "A 10-year cohort study of 175 primary gastrointestinal lymphoma cases in Thailand: clinical features and outcomes in the immunochemotherapy era."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diffuse large B-cell lymphoma (DLBCL) had the highest proportion of PGIL, accounting for 61.1%."
    explanation: Establishes that the majority of primary gastrointestinal lymphoma is DLBCL, the histology for which rituximab-containing immunochemotherapy is standard.
- name: Surgical Resection
  description: >-
    Surgery is no longer primary therapy for most gastrointestinal lymphoma but
    remains necessary for obstruction, perforation and uncontrolled bleeding,
    and is still commonly used in small-bowel disease. Its role has declined
    steadily as systemic therapy has improved.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Mucosal and Transmural Lymphomatous Infiltration
    treatment_effect: INHIBITS
    description: >-
      Resection removes the infiltrated gut segment responsible for obstruction,
      perforation and bleeding.
    evidence:
    - reference: PMID:33178655
      reference_title: "Changes in Incidence and Survival by Decade of Patients With Primary Colorectal Lymphoma: A SEER Analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the proportion of patients who received surgical therapy decreased gradually from 83.3-100 to 47.7-52.6% throughout the studied time period."
      explanation: >-
        Marked PARTIAL: documents that resection of the involved bowel segment
        remains in substantial use while its share has fallen, but does not
        itself measure the effect of resection on the infiltration node.
  evidence:
  - reference: PMID:33178655
    reference_title: "Changes in Incidence and Survival by Decade of Patients With Primary Colorectal Lymphoma: A SEER Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 5-year CSS of PCL increased continuously, while the rate of surgical resection decreased steadily."
    explanation: Documents the declining role of surgery alongside improving survival with systemic therapy.
- name: Gluten-Free Diet
  description: >-
    Strict lifelong gluten exclusion is the treatment of coeliac disease and
    removes the antigenic drive underlying enteropathy-associated T-cell
    lymphoma. It is included here as the small-bowel counterpart of H. pylori
    eradication — antigen removal acting on the same trigger node — and not as
    a treatment for established lymphoma, for which it is not sufficient.
  context: Small Intestine subtype; coeliac-associated disease.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Chronic Mucosal Antigenic Stimulation
    treatment_effect: INHIBITS
    description: >-
      Removing dietary gluten withdraws the antigenic stimulus sustaining the
      coeliac enteropathy on which EATL arises.
    evidence:
    - reference: PMID:37627888
      reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "EATL is closely associated with coeliac disease (CD) and is seen mostly in patients originating from Northern Europe."
      explanation: >-
        Marked PARTIAL: the review establishes the coeliac-disease dependence
        that makes gluten withdrawal the corresponding antigen-removal
        intervention, but does not report a trial of gluten exclusion as
        lymphoma prophylaxis or therapy. Evidence source is OTHER because this
        is a review article.
  evidence:
  - reference: PMID:37627888
    reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CD is an autoimmune disease of the small intestine caused by exposure to gluten in a genetically susceptible individual"
    explanation: >-
      Establishes gluten exposure as the cause of the coeliac enteropathy that
      this intervention removes, which is the rationale for curating gluten
      exclusion as the small-bowel antigen-removal counterpart of H. pylori
      eradication. Full-text statement, not abstract. Evidence source is OTHER
      because this is a review article.
  - reference: PMID:37627888
    reference_title: "Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "many cases of EATL arise despite a strict GFD"
    explanation: >-
      Recorded as PARTIAL, and deliberately paired with the item above so the
      treatment is not left looking curative: unlike H. pylori eradication,
      gluten withdrawal does not abolish the lymphoma risk. This is the honest
      bound on the antigen-removal analogy and is why the treatment description
      states it is not sufficient for established lymphoma. Full-text statement,
      not abstract. Evidence source is OTHER because this is a review article.
discussions:
- discussion_id: gi_lymphoma_disease_vs_grouping
  kind: INTERPRETATION
  status: RESOLVED
  prompt: >-
    Should gastrointestinal lymphoma be modelled as a Disease entry with
    anatomic-site has_subtypes, or as a Grouping over the already-curated
    histology entries (MALT_Lymphoma, Diffuse_Large_B_Cell_Lymphoma,
    Mantle_Cell_Lymphoma, Peripheral_T_Cell_Lymphoma)?
  rationale: >-
    A dismech Grouping is an explicit union that points DOWN at its members and
    asserts that each listed member IS a member of the grouping. That assertion
    fails for the histology entries: MALT lymphoma also arises in lung, ocular
    adnexa, salivary gland and thyroid, and DLBCL, mantle cell and peripheral
    T-cell lymphoma are overwhelmingly nodal diseases. Listing them as members
    would assert that MALT_Lymphoma is-a gastrointestinal lymphoma, which is
    false; only their gastrointestinal-site restrictions are members, and those
    are not curated as separate entries. The site children that ARE genuine
    members (gastric, small intestine, colon, oesophagus, rectum lymphoma) do
    not exist as Disease entries either, so a Grouping over them would have no
    members to point at.

    The entry also carries a real, shared, non-trivial mechanism of its own —
    site-restricted antigen-driven chronic stimulation, evidenced by the
    gastric-versus-non-gastric contrast in the H. pylori risk data — which is a
    Disease-entry pathograph, not a membership union. A Grouping has no
    pathophysiology slot and could not hold it.
  resolution_note: >-
    Resolved as a Disease entry with anatomic-site has_subtypes, matching the
    priority dashboard's CURATE_ROOT_WITH_SUBTYPES recommendation and the
    Primary_Tonsillar_Lymphoma precedent for a site-defined lymphoma Disease
    entry. Revisit if the individual site lymphomas are ever curated as
    standalone Disease entries, at which point a Grouping over those five would
    become well-formed and this entry could be reduced to their shared
    mechanism.
  posed_by: claude-code
  posed_date: "2026-08-18T00:00:00Z"
  resolved_date: "2026-08-18T00:00:00Z"
- discussion_id: gi_lymphoma_ipsid_campylobacter_causality
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - "pathophysiology#Chronic Mucosal Antigenic Stimulation"
  prompt: >-
    Is Campylobacter jejuni a causal driver of immunoproliferative small
    intestinal disease, or an associated coloniser of an already-abnormal small
    bowel?
  rationale: >-
    The association is established and IPSID can regress on antibiotics, which
    parallels the H. pylori/gastric MALT paradigm and would make it a second
    antigen-driven, antibiotic-reversible gastrointestinal lymphoma. But the
    cited review states explicitly that the organism's pathogenetic role is
    contested, and IPSID occurs in settings of heavy polymicrobial exposure
    where response to broad-spectrum antibiotics does not identify a single
    organism. The distinction matters for this entry because it determines
    whether the exposure link is TRIGGERS or PREDISPOSES; it is currently
    curated as PREDISPOSES with PARTIAL evidence.
  proposed_experiments:
  - experiment_id: gi_lymphoma_ipsid_targeted_antibiotic_cohort
    name: Organism-directed versus broad-spectrum antibiotic therapy in IPSID
    description: >-
      A prospective cohort in an IPSID-endemic region testing whether
      Campylobacter jejuni-directed therapy outperforms broad-spectrum
      antibiotics for histological remission, with molecular detection of the
      organism in small-bowel biopsies before and after treatment.
  evidence:
  - reference: PMID:29372346
    reference_title: "Heavy Chain Disease of the Small Bowel."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A link between Campylobacter jejuni infection and IPSID has been established, but there is controversy as to the role played by this organism in disease pathogenesis."
    explanation: The review states the controversy that this discussion records. Evidence source is OTHER because this is a review article.
  posed_by: claude-code
  posed_date: "2026-08-18T00:00:00Z"
classifications:
  icdo_morphology:
    classification_value: Lymphoma
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY