Enteropathy-associated T-cell lymphoma overview

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Overview
Historical Perspective
Classification
Pathophysiology
Causes
Differentiating Enteropathy-associated T-cell lymphoma from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
Diagnostic Study of Choice
History and Symptoms
Physical Examination
Laboratory Findings
Electrocardiogram
X-ray
Echocardiography and Ultrasound
CT
MRI
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
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Future or Investigational Therapies
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Nima Nasiri, M.D.[2] Sowminya Arikapudi, M.B,B.S. [3]

Synonyms and keywords: Enteropathy-type T-cell lymphoma; Intestinal T-cell lymphoma; EATL; ETTL

Overview

Enteropathy-associated T-cell Lymphoma (EATL), also enteropathy-type T-cell lymphoma (ETTL), is a type of T-cell non-hodgkin lymphoma that affects the small intestine, it is composed of large lymphoid cells. Enteropathy-associated T-cell lymphoma has two subtypes, type I enteropathy-associated T-cell lymphoma which has a strong association with celiac disease and it is more common in western countries and type II enteropathy-associated T-cell lymphoma which is mostly found among the Asian population. Genes involved in the pathogenesis of this disease include 8q24, T-cell receptor (TCR) beta and gamma, and 16q genes. On gross pathology, multiple intestinal ulcers are characteristic findings of EATL. On microscopic histopathological analysis, monotonous cells, round or angulated vesicular nuclei, and prominent nucleoli are characteristic findings of enteropathy-associated T-cell lymphoma. There are no established causes for enteropathy-associated T-cell lymphoma. EATL must be differentiated from other diseases such as peptic ulcer, poorly-differentiated adenocarcinoma, MALT lymphoma, diffuse large B cell lymphoma, and mantle cell lymphoma. The incidence of enteropathy-associated T-cell lymphoma is very low worldwide. There are no established risk factors for enteropathy-associated T-cell lymphoma. Common complications of enteropathy-associated T-cell lymphoma include ulcer, obstruction, and perforation of small intestine. Prognosis is generally poor. According to the Lugano classification, there are four stages of enteropathy-associated T-cell lymphoma based on the number of nodes and extranodal involvement. The most common symptoms of enteropathy-associated T-cell lymphoma include fever, weight loss, skin rash, night sweats, chest pain, abdominal pain, bone pain, and painless swelling in the neck, axilla, groin, thorax, and abdomen. Common physical examination findings of enteropathy-associated T-cell lymphoma include fever, rash, ulcer, chest tenderness, abdomen tenderness, bone tenderness, peripheral lymphadenopathy. Lymph node or endoscopic tissue biopsy is diagnostic of enteropathy-associated T-cell lymphoma. CT scan may be helpful in the diagnosis of enteropathy-associated T-cell lymphoma. Findings on CT scan suggestive of enteropathy-associated T-cell lymphoma include bowel wall thickening, mesenteric fat infiltration, mesentric lymph node cavitation, intussusception, and small-sized spleen. Other diagnostic studies for enteropathy-associated T-cell lymphoma include bone marrow aspiration and bone marrow biopsy. There is no treatment, the mainstay of therapy is supportive care. The optimal therapy depends on the extent and the location of the lymphoma in the small intestine. Surgery is not the first ­line treatment option for patients with enteropathy-associated T-cell lymphoma. Local debulking is usually reserved for patients with tumor masses with a high risk of obstruction, hemorrhage, and perforation.

Historical Perspective

The association between celiac disease and enteropathy-associated T cell lymphoma was made during 2008 by World Health Organization.

Classification

Enteropathy-associated T-cell lymphoma may be classified according to World Health Organization (WHO) into 2 subtypes:

• Type I enteropathy-associated T-cell lymphoma
• Type II enteropathy-associated T-cell lymphoma

Enteropathy-associated T-cell lymphoma classification

Name	Description
Classical enteropathy-associated T-cell lymphoma (Type I Enteropathy-associated T-cell lymphoma)	Covers 80-90% of all enteropathy-associated T-cell lymphoma cases. Is usually associated with refractory celiac disease that is sometimes accompanied by intestinal ulceration (ulcerative jejunitis) Most show adult onset disease or are diagnosed as having celiac disease in the same clinical episode in which the lymphoma is diagnosed. Frequently has large-cell or pleomorphic cytology. Seldom expresses CD8 and CD56.
Monomorphic enteropathy-associated T-cell lymphoma (Type II enteropathy-associated T-cell lymphoma)	Encountered in Asia and other regions where celiac disease is rare. Is sporadic, seldom associated with celiac disease. Covers 10-20% of all enteropathy-associated T-cell lymphoma cases. Is characterized by monomorphic cytology. Frequent expression of CD8 and CD56. The tumor forms an ulcerating mucosal mass that invades the wall of the intestine. Poor prognosis, death occurs from abdominal complications such as small bowel obstruction, perforation.

Pathophysiology

• Enteropathy-associated T-cell Lymphoma (EATL), also enteropathy-type T-cell lymphoma (ETTL), is a type of T-cell lymphoma that affects the small intestine.
• Frequent activating mutations in the JAK-STAT pathway in EATL suggests that deregulation of cytokine signaling is the early event in lymphomagenesis.
• Intraepithelial T cells are presumed to be the cell of origin of EATL (and RCD II).
• Variable degrees of transformations can be seen on histopathology of this tumor, but usually presents as large lymphoid cells.
• These cancerous T-cells are a possible consequence of either refractory cases of celiac disease or chronic untreated celiac disease patients.
• Most commonly occurs in the jejunum or ileum.
• SETD2 was found to be the most often silenced gene in EATL according to studies.
• The JAK-STAT pathway is the most frequently mutated pathway.
• Mutations in KRAS, TP53, and TERT Type I EATL and type II EATL (monomorphic intestinal T cell lymphoma) identified as well which have overlapping genetic alterations.

Causes

• There are no established causes for enteropathy-associated T-cell lymphoma.

Differentiating Enteropathy-associated T cell lymphoma from Other Diseases

Enteropathy-associated T-cell lymphoma must be differentiated from other diseases such as:

• Peptic ulcer
• Poorly-differentiated adenocarcinoma
• MALT lymphoma
• Diffuse large B cell lymphoma (DLBCL)
• Mantle cell lymphoma

Epidemiology and Demographics

• Enteropathy-associated T cell lymphoma is a very rare form of extranodal non-Hodgkin lymphoma, with an average incidence of 0.10 to 1.5 per 100,000 inhabitants per year, mostly occurs in the older adult, peak incidence average of 59 years old and involves proximal small intestine (duodenum and jejunum). Type II EATL is more common in the Asian population and not related to celiac disease, whereas type I EATL is more frequently happens in western Europe.

Risk Factors

• There are no established risk factors for enteropathy-associated T cell lymphoma.

Screening

• There is insufficient evidence to recommend routine screening for enteropathy-associated T-cell lymphoma.

Natural History, Complications, and Prognosis

• Enteropathy-associated T-cell lymphoma is usually a fast-growing (aggressive) lymphoma.
• It is associated with celiac disease (sprue).
• Most adults are diagnosed with celiac disease at the same time as their lymphoma or shortly before their lymphoma is diagnosed.
• Enteropathy-associated T-cell lymphoma may spread to the liver, spleen, lymph nodes, gallbladder, stomach, colon or skin.

Diagnosis

Diagnostic Study of Choice

• Endoscopic biopsy is the diagnostic study of choice for enteropathy-associated T cell lymphoma, though CT scan and other imaging studies can be helpful.

History and Symptoms

• Symptoms of the enteropathy-associated T-cell lymphoma include:
  • Fever
  • Weight loss
  • Night sweats
  • Diarrhea
  • Skin rash
  • Chest pain
  • Abdominal pain
  • Bone pain
  • Painless swelling in the neck, axilla, groin, thorax, and abdomen

Vitals

• Fever is often present

Skin

• Rash
• Ulcer

HEENT

• Cervical lymphadenopathy

Thorax

• Thoracic masses suggestive of central lymphadenopathy
• Chest tenderness

Abdomen

• Abdominal masses suggestive of central lymphadenopathy
• Abdomen tenderness

Extremities

• Peripheral lymphadenopathy
• Bone tenderness

Laboratory Findings

• Laboratory tests for enteropathy-associated T-cell lymphoma include:
  • Complete blood count (CBC)
  • Blood chemistry studies
  • Cytogenetic analysis
  • Flow cytometry
  • Immunohistochemistry
  • Immunophenotyping: CD3+, CD4-, CD5-, CD7+, CD30+, CD56+, CD103+, CD8+/-, and TCR beta+/-

Electrocardiogram

• There are no ECG findings associated with enteropathy-associated T cell lymphoma.

X-ray

• There are no x-ray findings associated with enteropathy-associated T cell lymphoma.

Echocardiography or Ultrasound

• There are no echocardiography/ultrasound findings associated with enteropathy-associated T cell lymphoma.

CT scan

• CT scan may be helpful in the diagnosis of enteropathy-associated T-cell lymphoma.
• Findings on CT scan suggestive of enteropathy-associated T-cell lymphoma include:

• Bowel wall thickening
• Mesenteric fat infiltration
• Mesenteric lymph node cavitation
• Intussusception
• Small-sized spleen

MRI

• MRI may be helpful in the diagnosis of enteropathy-associated T-cell lymphoma, especially in those EATL involved epithelial layers of the small intestine and also for response to treatment

Other Imaging Findings

• Other diagnostic studies for enteropathy-associated T-cell lymphoma include:

• PET scan
• Barium study
• Colonoscopy

• Findings on barium study suggestive of enteropathy-associated T-cell lymphoma include:

• Multiple aphthous ulcers
• Segmental luminal narrowing

• Finding on colonoscopy suggestive of enteropathy-associated T-cell lymphoma includes:

• Aphthous ulcers

Other Diagnostic Studies

• Other diagnostic studies for enteropathy-associated T-cell lymphoma include:
  • Bone marrow aspiration
  • Bone marrow biopsy

Treatment

Medical Therapy

• There is no treatment for enteropathy-associated T-cell lymphoma; the mainstay of therapy is supportive care. The optimal therapy for enteropathy-associated T-cell lymphoma depends on the extent and the location of the lymphoma in the small intestine. Stem cell transplant can be helpful in those patients that are in remission phase of disease.

Treatment of enteropathy-associated T-cell lymphoma

Therapy	Description
Supportive therapy	People often need nutritional support A gluten-free diet is also recommended
Surgery	May be an option Done to remove the damaged small intestine
Chemotherapy	May be offered to people who can tolerate it: Following surgery When the cancer cannot be removed by surgery or is extensive Combination chemotherapy is often used for this aggressive lymphoma Drug regimen: (CHOP) Cyclophosphamide AND Doxorubicin AND Vincristine AND Prednisone

Surgery

• Surgery is not the first ­line treatment option for patients with enteropathy-associated T-cell lymphoma.
• Local debulking is usually reserved for patients with tumor masses with a high risk of obstruction, hemorrhage, and perforation.

Primary Prevention

• There are no established measures for the primary prevention of enteropathy-associated T cell lymphoma.

Secondary Prevention

There are no established measures for the secondary prevention of enteropathy-associated T cell lymphoma.