Enteropathy associated T-cell lymphoma

What every physician needs to know:

Enteropathy associated T-cell lymphoma (EATL) is an aggressive peripheral T-cell lymphoma with a historically poor prognosis. EATL has been described as either arising from a background of celiac disease (type 1) or a monomorphic histology not necessarily related to celiac disease (type 2).

Type 1 represents about 80 to 90% of cases and most commonly, but not exclusively, arise from the jejunum. Suspected EATL type 1 follows the geographical distribution of celiac disease (Northern European) and is more common in those who evolve to refractory celiac disease (refractory to a strict gluten diet), whereas type 2 is more globally distributed. The cell of origin of type 2 EATL remains under investigation.

Commonly, patients with EATL will present with intestinal obstruction (regardless of type) and the diagnosis will be made at the time of surgical resection. There is a strong likelihood that the patients will have advanced stage disease either by Manchester, Lugano, or Ann Arbor staging systems. Significant proportion of the patients will have an underlying enteropathy that may lead to malnutrition which may complicate further management after the disease is diagnosed. An integrated approach to the nutritional needs of the patient prior to commencing chemotherapy is often required.

The treatment of EATL has been complicated by the initial diagnosis occurring at the time of resection of the tumor mass. Delays in initiation chemotherapy may be a result of the poor wound healing from surgery. Therapy with standard with anthracycline based regimens has led to short progression free survival and poor long term overall survival. The role of high dose chemotherapy followed by autologous stem cell transplantation in those patients who achieve a first chemosensitive response was recently demonstrated in a phase II Nordic study looking at this modality in multiple T-cell subtypes where EATL represented a surprising 20% of the cases.

Are you sure your patient has enteropathy associated T-cell lymphoma? What should you expect to find?

Abdominal pain
Nausea/vomiting
Unintentional weight loss
Acute abdomen secondary to visceral perforation (time of presentation)

Beware of other conditions that can mimic enteropathy associated T-cell lymphoma:

Appendicitis
Mechanical obstruction (volvulus, intussusception)
Small or large bowel adenocarcinoma
Celiac disease
Intestinal bacterial infection
Acute intermittent porphyria

Which individuals are most at risk for developing enteropathy associated T-cell lymphoma:

EATL appears to have a male gender predilection with the median age of 60 years of age. Celiac disease is the most common known diagnosis to precede the diagnosis of EATL. For those who have Celiac disease, there is a higher risk for evolution to EATL if refractory celiac disease has evolved; symptoms and histologic confirmation demonstrates clonal expansion of intraepithelial lymphocytes with aberrant phenotype.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Complete blood count

Anemia is considered a common finding at the time of diagnosis, possibly representing a underlying nutritional absorption component (iron, folate, B12).

Comprehensive metabolic panel

An initial albumin level may predict the degree of underlying enteropathy accompanying the EATL. Furthermore, evaluating for and treating aggressively an anion gap (lactic acid) metabolic acidosis, given the risk for perforation at presentation.

Lactate dehydrogenase

Often elevated, given the aggressive nature of the underlying disease.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of enteropathy associated T-cell lymphoma?

Helpful studies

Magnetic resonance imaging (MRI) scan of brain (mental state changes)

– Central nervous system (CNS) involvement uncommon but may be seen at relapse.

Computed tomography (CT) scan of chest, abdomen, pelvis

– In order to demonstrate perforation and lymphadenopathy.

Bone marrow biopsy

In selected cases

Lumbar puncture
Positron emission tomography (PET) scan

– But this should not hold up initial management in emergent situations.

If you decide the patient has enteropathy associated T-cell lymphoma, what therapies should you initiate immediately?

Aggressive intravenous hydration
Consider nutritional consultation for management of alimentary support

More definitive therapies?

The majority of patients present at the time of exploratory laparotomy and therefore further treatment strategies are limited by the speed of recovery from that. For those whom the diagnosis is made without impending obstruction, initiation of CHOEP (cyclophosphamide, doxorubicin, vincristine, oral prednisone and etoposide) may be a more active regimen than CHOP (CHOEP without the etoposide) alone.

The European regimen IVE/MTX (ifosfamide, etoposide, epirubicin alternation with intermediate dose methotrexate) demonstrated improved response rates and improved death rate when compared to historical controls treated with anthracycline based regimens. As in many T-cell lymphoma subtypes, primary refractory disease remains a major problem. If the disease is chemosensitive, consideration for an autologous stem cell transplantation should be given. In either presentation, consultation with gastroenterology and nutritional services is recommended.

What other therapies are helpful for reducing complications?

Consider early implementation of nutritional support (parenteral or oral supplementation)
CNS relapses are reported, although there is no data showing prophylaxis to reduce this complication
Consider antimicrobial prophylactic measures during induction therapy including:

– Antiviral: acyclovir

– Antifungal: fluconazole

– Anti-PCP (Pneumocytis pneumonia): Bactrim

What should you tell the patient and the family about prognosis?

Many times, patients present with abdominal pain and the finding of perforation, requiring emergent surgical intervention to prevent death. Regardless of the EATL type, the overall prognosis is poor, though, there are long term survivors, including those cured of the disease. The most favourable outcomes are seen in patients who undergo autologous stem cell transplantation. Significantly limiting the treatment of EATL is the underlying enteropathy from prior surgery and potentially residual celiac disease. Aggressive alimentary support is necessary to assure the best outcomes can be achieved.

"What if" scenarios.

Impending obstruction from mass

Discussion with the surgeon regarding the risk versus benefits of proceeding to a debulking laparotomy. Consideration of extent of disease (nodal and other visceral disease) may factor into the discussion.

Localized presentation without signs of lymphadenopathy

Given the rarity of the diagnosis, there are no prospective surgical studies for resection of localized disease. EATL is felt to represent a systemic disease and chemotherapy, with consideration of autologous stem cell transplant should be considered as the initial management.

Pathophysiology

Type 1

Arises in a background of celiac disease.
Represents about 80 to 90% of cases and follows the geographical distribution of celiac disease (Northern European)

Type 2

Typified by a monomorphic histology and is not necessarily related to related to celiac disease
More globally distributed

What other clinical manifestations may help me to diagnose enteropathy associated T-cell lymphoma?

Do they have a history of celiac disease?
How long have they abdominal pain and is it progressive?
Have they experienced unexpected weight loss, nausea, vomiting, and worsening fatigue?
Do they have a palpable abdominal mass?

What other additional laboratory studies may be ordered?

Antigliadin antibodies.

What’s the evidence?

Sabatino, AD, Biagi, F, Gobbi, PG. “How I treat enteropathy-associated T-cell lymphoma”. Blood.. vol. 119. 2012. pp. 2458-2468. [Excellent review of the characteristics of EATL and the management thereof.]

Delabie, J, Holte, H, Vose, JM. “Enteropathy-associated T-cell lymphoma: clinical and histological findings from The International Peripheral Lymphoma project”. Blood.. vol. 118. 2011. pp. 148-155. [Nice paper on the histologic characteristics, as well as the prognostic systems utilized in the management of EATL.]

Wohrer, S, Chott, A, Drach, J. “Chemotherapy with cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisone (CHOEP) is effective in patients with enteropathy-type intestinal T-cell lymphoma”. Ann Oncol. vol. 15. 2004. pp. 1680-1683. [Small study demonstrating the potential limitations of intense cytotoxic therapy in this patient cohort.]

Sieniawski, M, Agnamuthu, N, Boyd, K. “Evaluation of enteropathy associated T-cell lymphoma comparing standard therapies with a novel regimen including autologous stem cell transplantation.”. Blood.. vol. 115. 2010. pp. 3664-3670. [Historical comparison of CHOP like versus non-CHOP like therapy in EATL and outcome with autologous stem cell transplantation.]

Bishton, MJ, Haynes, AP. “Combination chemotherapy followed by autologous stem cell transplantation for enteropathy-associated T cell lymphoma”. Br J Haematol.. vol. 136. 2007. pp. 111-113. [Small series of patients treated with a non-CHOP based regimen proceeding to up front autologous stem cell transplantation with mediocre outcomes.]

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