Definition/General
Introduction:
Enteropathy-associated T-cell lymphoma (EATL) is a rare intestinal T-cell lymphoma that typically arises in the setting of celiac disease
It represents <1% of all non-Hodgkin lymphomas but is the most common primary intestinal lymphoma in certain populations
The WHO recognizes two types: Type I (associated with celiac disease) and Type II (monomorphic epitheliotropic)
Poor prognosis with aggressive clinical course.
Origin:
Originates from intraepithelial T-lymphocytes in the small intestine
Type I EATL arises from CD4+ T-cells in celiac disease background
Type II EATL arises from CD8+ intraepithelial lymphocytes
Shows clonal T-cell receptor gene rearrangements
Chronic inflammatory stimulation in celiac disease predisposes to malignant transformation
Gluten sensitivity and HLA associations are important.
Classification:
WHO classification recognizes two distinct types: Type I EATL (classical, celiac-associated)
Type II EATL (monomorphic epitheliotropic intestinal T-cell lymphoma)
Type I more common in Northern Europeans
Type II more common in Asians and other populations
Different morphology and immunophenotype
Grade not applicable as both are high-grade.
Epidemiology:
Rare disease with geographic variation
Type I common in Northern Europe (celiac endemic areas)
Type II more common in Asia including India
Adult disease (median age 50-70 years)
Male predominance (M:F = 2-3:1)
Strong association with HLA-DQ2/DQ8 in Type I
Celiac disease background in 60-90% of Type I cases
Poor prognosis with median survival <2 years.
Clinical Features
Presentation:
Abdominal pain (most common symptom)
Diarrhea and malabsorption
Weight loss and constitutional symptoms
Intestinal obstruction or perforation
GI bleeding (overt or occult)
Palpable abdominal mass occasionally
B-symptoms (fever, night sweats)
Dermatitis herpetiformis in celiac-associated cases.
Symptoms:
Chronic diarrhea with steatorrhea
Severe abdominal pain (cramping, colicky)
Significant weight loss (>10% body weight)
Fatigue and weakness
Nausea and vomiting
Bloating and distension
Iron deficiency anemia
Protein-energy malnutrition
Vitamin deficiencies (B12, folate, fat-soluble vitamins).
Risk Factors:
Celiac disease (major risk factor for Type I)
HLA-DQ2/DQ8 haplotypes
Long-standing gluten sensitivity
Refractory celiac disease Type II
Family history of celiac disease
Northern European ancestry (Type I)
Male gender
Age >50 years
Immunosuppression (may contribute).
Screening:
Celiac serology (anti-tTG, anti-endomysial antibodies)
HLA typing (DQ2/DQ8)
Upper endoscopy with small bowel biopsies
Imaging studies (CT, MRI, PET-CT)
Complete blood count (anemia, lymphopenia)
Nutritional assessment (albumin, vitamins)
Stool studies (fat, inflammatory markers)
Flow cytometry of lymphocytes if indicated.
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Gross Description
Appearance:
Small bowel involvement most common (jejunum > ileum)
Multifocal ulcerative lesions
Strictures and stenosis
Thickened bowel wall
Mucosal atrophy and flattening
Perforation sites may be present
Adjacent lymphadenopathy variable.
Characteristics:
Geographic ulcers with irregular borders
Transmural involvement of bowel wall
Gray-white tumor nodules
Friable and necrotic tissue
Loss of normal mucosal architecture
Strictures causing luminal narrowing
Serosal involvement with adhesions.
Size Location:
Jejunum most commonly involved (60-70%)
Ileum second most common site
Multiple segments may be involved
Lesion size varies from few cm to extensive involvement
Regional lymph nodes involved in 30-50%
Liver involvement in advanced cases
Rarely involves colon.
Multifocality:
Multifocal intestinal involvement common
Skip lesions pattern frequent
Perforation at multiple sites possible
Mesenteric lymph node involvement
Liver infiltration in advanced disease
Spleen involvement less common
Bone marrow involvement rare at presentation.
Microscopic Description
Histological Features:
Type I: pleomorphic large cells with prominent nucleoli
Type II: monomorphic medium-sized cells
Epitheliotropism (lymphocytes infiltrating intestinal epithelium)
Transmural infiltration
Ulceration with granulation tissue
Adjacent villous atrophy (celiac changes)
Increased intraepithelial lymphocytes.
Cellular Characteristics:
Type I: large pleomorphic cells (>20 μm) with irregular nuclei and prominent nucleoli
Type II: medium-sized monomorphic cells (12-15 μm) with round nuclei
High mitotic activity in both types
Apoptotic figures frequent
Necrosis often present
Inflammatory background (histiocytes, eosinophils)
Reed-Sternberg-like cells may be seen in Type I.
Architectural Patterns:
Epitheliotropism characteristic feature
Transmural infiltration pattern
Diffuse growth predominates
Mucosal ulceration with lymphoid infiltrate
Villous atrophy in background mucosa
Crypt hyperplasia and distortion
Increased intraepithelial lymphocytes (>20 per 100 epithelial cells).
Grading Criteria:
Both types are high-grade by definition
High proliferation index (Ki-67 >70%)
Extensive necrosis indicates aggressive behavior
Degree of pleomorphism noted (more in Type I)
Mitotic rate invariably high
Depth of invasion assessed
Perforation indicates advanced local disease.
Immunohistochemistry
Positive Markers:
CD3 (pan-T-cell marker, positive)
Type I: CD4+ (helper phenotype), CD30+ (often)
Type II: CD8+ (cytotoxic phenotype), CD56+ (often)
Cytotoxic markers (TIA-1, granzyme B, perforin) in Type II
CD103 (αEβ7 integrin) positive
CD7 may be lost
TCR-αβ usually positive.
Negative Markers:
CD20 (B-cell marker, negative)
CD5 (often lost)
ALK (negative)
EBER (EBV marker, negative)
CD10 (negative)
BCL6 (negative in T-cells)
Type I: CD8 negative, cytotoxic markers negative
Type II: CD4 negative, CD30 negative.
Diagnostic Utility:
CD103 positivity supports intestinal T-cell origin
Cytotoxic phenotype distinguishes Type II from Type I
Loss of pan-T-cell antigens (CD5, CD7) supports neoplasia
Ki-67 shows high proliferation (>70%)
CD30 helps distinguish Type I from other lymphomas
Flow cytometry useful for intraepithelial lymphocyte analysis.
Molecular Subtypes:
Type I EATL: CD4+, CD8-, often CD30+
Type II EATL: CD8+, CD4-, CD56+
Cytotoxic phenotype (Type II): TIA-1+, granzyme B+, perforin+
Helper phenotype (Type I): cytotoxic markers negative
Intraepithelial phenotype: CD103+ in both types.
Molecular/Genetic
Genetic Mutations:
Clonal T-cell receptor rearrangements (both types)
Type I: complex chromosomal abnormalities, 9q gains
Type II: 8q24 gains/amplifications (MYC region)
TP53 mutations in both types
STAT5B mutations in Type II
JAK3 mutations in Type II
SETD2 mutations
CDKN2A deletions.
Molecular Markers:
Gene expression profiling shows intestinal T-cell signature
Cytotoxic program activation in Type II
NF-κB pathway activation
JAK/STAT pathway dysregulation
MYC overexpression especially in Type II
Tumor suppressor gene inactivation
DNA repair gene mutations.
Prognostic Significance:
Poor prognosis for both types (5-year OS <20%)
Type II may have slightly better outcome than Type I
Stage at presentation important
Performance status crucial
Age >60 years worse prognosis
Perforation at presentation indicates poor outcome
Multifocal disease worse than localized.
Therapeutic Targets:
Aggressive chemotherapy (CHOP, dose-intensive regimens)
Autologous stem cell transplant in selected patients
Gluten-free diet (preventive in celiac patients)
Surgical resection for localized disease
Palliative care for advanced disease
Novel agents under investigation
Immunotherapy approaches being studied.
Differential Diagnosis
Similar Entities:
Primary intestinal diffuse large B-cell lymphoma
Mantle cell lymphoma (intestinal polyposis)
Other T-cell lymphomas with GI involvement
Inflammatory bowel disease with dysplasia
Adenocarcinoma of small bowel
Gastrointestinal stromal tumor (GIST)
Refractory celiac disease Type II.
Distinguishing Features:
EATL: T-cell markers+, epitheliotropism, CD103+, celiac background
DLBCL: CD20+, B-cell markers
Mantle cell lymphoma: CD5+, cyclin D1+, different morphology
Adenocarcinoma: cytokeratin+, glandular morphology
GIST: c-KIT+, CD117+, spindle cell morphology
Refractory celiac: polyclonal, lacks mass lesions.
Diagnostic Challenges:
Distinguishing from refractory celiac disease Type II
Limited tissue due to ulceration and necrosis
Reactive vs neoplastic intraepithelial lymphocytes
Background inflammation may obscure tumor cells
Sampling issues in multifocal disease
Need for adequate tissue for immunophenotyping.
Rare Variants:
EATL with B-cell component (composite lymphoma)
EATL with histiocytic component
Colonic involvement (unusual)
Extraintestinal EATL (rare)
EATL in non-celiac patients
Transformation from refractory celiac disease
Perforation-associated EATL.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
[Small bowel resection/biopsy] from [jejunum/ileum], showing ulcerative lesions
Primary Diagnosis
Enteropathy-associated T-cell lymphoma, Type [I/II]
WHO Classification
Enteropathy-associated T-cell lymphoma (WHO 2016)
Histological Features
Shows [pleomorphic/monomorphic] T-cell infiltrate with epitheliotropism and transmural involvement
Cellular Morphology
Type [I/II]: [large pleomorphic/medium monomorphic] cells with [high/moderate] mitotic activity
Epitheliotropism
Epitheliotropism: present; Intraepithelial lymphocytes: increased (>[number] per 100 epithelial cells)
Background Mucosa
Adjacent mucosa shows [villous atrophy/normal architecture]; Celiac changes: [present/absent]
Immunohistochemistry
CD3+, [CD4+/CD8+], CD103+, [CD30+/-], CD20-, Ki-67: [percentage]%
Molecular Studies
T-cell receptor rearrangement: clonal; [Additional molecular findings if available]
Staging Assessment
Extent: [localized/multifocal]; Perforation: [present/absent]; Lymph node involvement: [present/absent]
Final Diagnosis
Enteropathy-associated T-cell lymphoma, Type [I/II], WHO 2016