Advanced enteropathy-associated T cell lymphoma (EATL) presenting with severe malabsorption and concomitantly diagnosed coeliac disease (CD)

Abstract

Enteropathy-associated T cell lymphoma (EATL) is an aggressive subtype of non-Hodgkin’s lymphoma often associated with coeliac disease (CD). We describe a previously healthy man in his 50 s who presented with a history of abdominal pain, failure to thrive and significant weight loss over a 3-month period. Investigations revealed a positive coeliac serology, diffuse duodenal atrophy with multiple duodenal and jejunal ulcers on endoscopy and mesenteric lymphadenopathy on CT imaging. Duodenal tissue biopsy confirmed a diagnosis of EATL Stage IVB. Chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone regimen was initiated. This case highlights the need for greater awareness and consideration of EATL in individuals with worsening malabsorption and abdominal pain, irrespective of coeliac history.

Background

Enteropathy-associated T cell lymphoma (EATL) is a rare T cell lymphoma that originates from the intraepithelial lymphocytes (IEL) of the gastrointestinal (GI) tract.¹ The 2016 revision of the WHO classification of lymphoid neoplasms² documents two morphological and immunophenotypic variants of this entity. The previously recognised type I EATL is now known as EATL, whereas type II EATL is referred to as monomorphic epitheliotropic intestinal T cell lymphoma (MEITL). EATL is strongly associated with coeliac disease (CD) and is more commonly observed in Western countries.^{1 3} On the other hand, MEITL has no clear association with CD and occurs worldwide, with a higher prevalence in Asian populations.⁴ The incidence of EATL varies geographically with the prevalence of CD.⁴ Epidemiological studies based on older classifications describe an incidence of EATL in CD patients ranging from 0.22 to 1.9 per 100 000.^{5 6}

Case presentation

A previously healthy man in his 50 s presented to our emergency department with a 3-month history of abdominal pain, nausea, inability to tolerate food and 120 lb weight loss. He had recently been hospitalised for anaemia, melena and weakness, requiring packed red blood cell transfusions. CT imaging of the abdomen and pelvis during that hospitalisation showed enlarged lymph nodes in the mesentery and inguinal region, as well as increased mesenteric density. A core inguinal lymph node biopsy was non-diagnostic.

Vitals were notable for tachycardia (120 beats per minute). Mild, diffuse lower abdominal tenderness was present on physical examination. Laboratory results revealed a haemoglobin level of 114 g/L, platelet count of 626×10⁹ /L, white blood cell count of 11×10⁹ /L, sodium of 134 mmol/L, alkaline phosphatase level of 494 U/L and albumin level of 3.1 g/dL. Patient was subsequently admitted.

Small bowel enteroscopy was notable for gastric mucosal atrophy, diffuse duodenal atrophy and non-bleeding duodenal and jejunal ulcers with diffuse inflammation. Malignant-appearing stenosis of the proximal jejunum was observed (figure 1). ^18F-Fluorodeoxyglucose positron emission tomography/CT (¹⁸FDG PET/CT) showed the presence of multifocal nodular and segmental intense FDG activity involving the proximal jejunum, duodenum and ileum with associated wall thickening and areas of dilatation favouring lymphoma over inflammatory bowel disease (figure 2). Moderately FDG-avid small bowel mesentery and right inguinal lymphadenopathy were present, also suspicious for lymphoma.

Figure 1.

Small bowel enteroscopy (A–D) illustrating findings of gastric mucosal atrophy (A), non-bleeding duodenal ulcers and jejunal ulcers and jejunal stenosis (D).

Figure 2.

Positron emission tomography/CT images depicting intense, multifocal FDG avidity of the small intestine, associated with moderate FDG avidity in the mesenteric and inguinal lymph nodes (blue arrows). FDG, fluorodeoxyglucose.

Esophagogastroduodenoscopy revealed the presence of gastric mucosal atrophy, duodenal and jejunal ulcers and jejunal stenosis. Jejunal biopsy showed T cell lymphoma, best classified as EATL. Serology and genetic studies revealed suggested CD.

During this hospitalisation course, the patient required initiation of total parenteral nutrition (TPN) in view of malnutrition and inability to tolerate oral intake. The patient was advised to remain on a strict gluten-free diet with a continued plan for TPN at home for 3 to 6 months postdischarge. The patient was then referred to the haematology clinic for further evaluation and treatment.

Investigations

Surgical pathology (small bowel)

• Multiple adhesions were identified causing loops of bowel to be adhesed on itself. The serosa was diffusely involved with tan-white to yellow exudate.

• Multiple transmural perforations were identified, ranging from 0.9 cm to 1.5 cm in greatest dimension. 2.5×2×0.7 cm serosal mass was identified. The mass grossly involved the bowel wall muscle.

• The mucosa was diffusely atrophied and oedematous with polyps observed, ranging from 0.6 cm to 1.4 cm in greatest dimension.

Immunophenotyping with flow cytometry (small bowel)

• Immunoperoxidase studies were performed on paraffin sections of the small bowel with tumour using antibodies directed against the following antigens: CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD30, CD103, granzyme B, kappa, lambda, TCR beta F1, TCR delta and TIA1.

• Sections showed a diffuse infiltrate of intermediate-sized CD3-positive T cells with irregular nuclei, partially condensed chromatin and occasional small nucleoli.

• The neoplastic T cells coexpressed CD2, CD5, CD4 and TCR beta F1 (partial) and demonstrated aberrant loss of CD7.

• Background plasma cells showed polytypic expression of kappa and lambda.

Treatment

The patient was diagnosed with EATL Stage IVB in the setting of CD. Performance score (PS) was 3. Treatment with cyclophosphamide, etoposide, doxorubicin, vincristine and prednisone chemotherapy at six cycles was recommended. Brentuximab vedotin was not included due to a lack of CD30 expression, and etoposide was held during cycle 1 due to PS. If chemosensitivity was demonstrated, subsequent autologous peripheral blood stem cell transplant was planned.

Outcome and follow-up

The patient received three cycles of chemotherapy but unfortunately developed several complications during his course. He experienced multiple episodes of significant GI haemorrhage further complicated by deep vein thrombosis and multiple pulmonary emboli requiring inferior vena cava filter placement. He subsequently developed pneumoperitoneum secondary to tumour necrosis which required surgical resection and duodenojejunostomy. He also developed acute cholecystitis with gallbladder perforation mandating percutaneous cholecystostomy tube drainage and intensive care unit admission due to septic shock.

In light of these complications and worsening lymphoma on PET/CT, palliative care was recommended over further chemotherapy. The patient elected to pursue an illness directed plan of care which included rehospitalisation for complications, TPN continuation, transfusions and follow-up in the outpatient setting.

Discussion

A rare case of EATL in the background of CD is described in this case study. EATL most commonly affects the small intestine (>90%) though extraintestinal manifestations may occur.⁴ A brief review of similar cases has been summarised in table 1. The prognosis for EATL is poor with a median overall survival (OS) of 10 months and failure-free survival of 6 months.³ An estimated 64% of patients present with Stage IV disease.³

Table 1.

Brief review of case reports on EATL*

Year	Patient demographics, country	Clinical presentation, diagnosis	Relevant comorbidities	Treatment	Follow-up/outcome	Additional comments
202016	58/Male, Austria	Cerebellar symptoms (ataxia, double vision, dizziness) EATL with CNS involvement	Coeliac disease (RCD II with ulcerative jejunitis)	Single-dose intravenous methotrexate	Transient clinical improvement. Patient passed away 3 weeks postdiagnosis	Patient had multifocal supratentorial and infratentorial cerebral involvement. Neurological symptoms in a patient with RCD II should prompt EATL evaluation
202017	67/Male, China	5-month history of diarrhoea. EATL with colon adenocarcinoma	None	Five cycles of CHOP+two cycles of GeMoxED+five additional cycles of unspecific regimen	Patient passed away 1 year postchemotherapy initiation due to severe bone marrow suppression and a perianal abscess	EATL involving the whole colon, duodenum and small intestine was identified. Delay in diagnosis occurred due to overlapping systems with early colon adenocarcinoma
201818	69/Male; United States	Acute abdomen secondary to small bowel perforation. Jejunal EATL	Asymptomatic childhood-onset coeliac disease	Six cycles of CHOEP+autologous stem cell transplant	Disease free for 6 months; eventually relapsed with involvement of colon and terminal ileum. Patient did not wish to pursue treatment and expired shortly	Presented with diarrhoea, abdominal pain and weight loss 4 months prior. Despite being asymptomatic on a gluten diet for years, latest tests confirmed CD, and a GFD was started
201919	45/Male; Japan	Acute abdomen due to ileal perforation. EATL	Ulcerative colitis	Eight cycles of CHOP+PSL (maintenance); achieved full remission	Disease free for 5 years; eventually died due to recurrence	Though CD is rare in Japan, recognising risk of EATL is important in individuals carrying the HLA-DQ2 gene
201420	62/Female; India	Features of intestinal obstruction EATL	None	Right hemicolectomy	Patient was lost to follow-up	No preceding history of sprue-like symptoms was observed

*Case reports which explicitly mentioned a diagnosis of ‘EATL’ or ‘EATL type I’ were included.

CD, coeliac disease; CHOEP, cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; EATL, enteropathy-associated T cell lymphoma; GeMoxED, gemcitabin, oxaliplatin, etoposide, dexamethasone; GFD, gluten-free diet; PSL, prednisolone; RCD, refractory coeliac disease.

It is crucial to understand the distinction between refractory coeliac disease (RCD) types I and II and EATL, which often have overlapping clinical symptoms but vary in severity. RCD is defined as persistent malabsorption and villous atrophy despite adherence to a strict gluten-free diet for a minimum period of 12 months.⁷ RCD type I exhibits an increase in pathological IEL populations resembling regular CD; however, RCD II is associated with the development of aberrant IELs, which are often premalignant.^{1 7} EATL usually occurs as a consequence of RCD type I or II, though de novo occurrences in individuals with newly diagnosed or uncomplicated CD have also been reported (primary EATL).^{5 8} Diagnosis of EATL may unfortunately be delayed due to symptomatic overlap with more common conditions such as Gastroesophageal Reflux Disease (GERD) or CD.

The pathogenesis of EATL in the setting of CD occurs due to a complex interplay of environmental, inflammatory, immune and molecular mechanisms (see figure 3), often with a progression from RCD II.^{5 9} The presence of HLA DQ2/8 alleles indicates a strong genetic predisposition for CD and consequently EATL.^{1 5} A significant proportion of individuals with RCD II and EATL exhibit somatic gain-of-function mutations in the JAK1-STAT3 pathway. Additionally, mutations in negative regulators of the NF-κB pathway and oncogenic mutations in TET2 and KMT2D (epigenetic modifiers) have also been implicated.⁹ EATL tumour cells are typically CD4-, CD8-/+, CD3+, CD5-,CD56-, TIA-1+ and CD30+/-.² The clinical significance of unusual CD4+T-lymphocytes in this case is unclear.

Figure 3.

Schematic representation of key findings in the pathogenesis of coeliac disease (CD) to refractory CD (RCD) type II and EATL. Dietary gluten consists of gliadin peptides which are deamidated by tissue transglutaminase enabling their presentation to T cells by dendritic cells in conjunction with HLA-DQ2 or HLA-DQ8 molecule. This triggers cytotoxic responses and proinflammatory cytokine release, causing enterocyte death and inflammation. Progression to RCD II and consequently EATL is driven by somatic gain-of-function mutations in the JAK1-STAT3 pathway. Recurrent mutations in negative regulators of the NF-κB pathway (TNFAIP3 and TNIP3) and oncogenic mutations in TET2, KMT2D and DDX3X have also been implicated. Interleukin 15 (IL-15), along with other mediators, promotes activation of cytotoxic CD-8+T-lymphocytes and inhibits apoptosis. T cell receptor (TCR) rearrangement also plays important roles in the clonal proliferation of malignant intraepithelial lymphocytes in the landscape of chronic inflammation^{1 5 9} (figure created with BioRender.com).

The mainstay of treatment for this condition is a combination of chemotherapy followed by autologous stem cell transplantation, though no established guidelines exist for EATL.⁴ Palliative surgery may also be pursued. CHOP, with or without etoposide, is commonly employed as first-line induction therapy.¹⁰ Brentuximab vedotin (anti-CD30) therapy is indicated in CD30+ cases, although CD30 expression is often a poor prognostic factor.¹¹ Autologous stem cell transplantation (ASCT) may be considered for consolidation therapy.^{10 12} Studies have demonstrated improved survival outcomes when high-dose chemotherapy is combined with ASCT.¹² Surgical resection is primarily performed for debulking purposes and is performed prior to chemotherapy.¹³ It may also be indicated in treatment-resistant cases or when complications such as obstruction or perforation arise.¹

Newer molecular targets^{14 15} hold promise in cases unamenable to conventional therapy. Unfortunately, the variable presentation of EATL, advanced stage at diagnosis and poor nutrition affecting performance status collectively impede the implementation of clinical studies.¹⁰

Learning points.

• Enteropathy-associated T cell lymphoma (EATL) is a rare and aggressive non-Hodgkin’s lymphoma that most often presents with abdominal pain, fatigue and malabsorption. Type I and type II EATL are obsolete entities and newer classifications include EATL and MEITL.

• EATL may occur due to long-standing or refractory coeliac disease (CD). However, CD is often diagnosed concomitantly with EATL. Environmental (dietary gluten exposure) and genetic factors (HLA DQ2/DQ8 alleles) play a strong role in CD pathogenesis. Progression to RCD II and EATL is driven by gain-of-function mutations in the JAK1-STAT3 pathway, alterations in NF-κB signalling (TNFAIP3 and TNIP3) and oncogenic mutations in TET2, KMT2D and DDX3X among other factors.

• Treatment methods include chemotherapy (eg, CHOP regimen), autologous stem cell transplant and palliative surgical resection.

• Symptoms of persistent malabsorption and failure to thrive should prompt evaluation for CD and underlying malignancy. Timely diagnosis, intervention and exploring novel treatment options are important for improving patient outcomes.

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