Enteropathy associated T-cell lymphoma: a review of diagnostic findings and therapeutic strategies

MINI-SYMPOSIUM: PATHOLOGY OF GASTROINTESTINAL LYMPHOMAS

Enteropathy associated T-celllymphoma: a review ofdiagnostic findings andtherapeutic strategiesStuti Shroff

Karthik A Ganapathi

Abstract
Enteropathy associated T-cell lymphoma (EATL) is an uncommon type of
non-Hodgkin T-cell lymphoma of the intestinal intraepithelial T lympho-

cytes. Frequently presenting as intestinal perforation, ulceration, or a

mass in the jejunum and proximal ileum in the gastrointestinal tract,

EATL carries a poor prognosis with absence of well-defined therapeutic

protocols for management. The WHO recognizes two distinct variants of

EATL, the type I/classical variant and type II/monomorphic variant,

based on different clinical features and histopathologic findings. EATL

type I has a higher incidence in geographic regions with a high prevalence

of celiac disease such as Northern Europe and is rare in the Asian popu-

lation, in whom celiac disease is also rare. EATL type II can occur sporad-

ically, has a higher incidence in Asian populations, with no definite

association with celiac disease. This review aims to summarize the clini-

copathologic findings of EATL and current approaches to management.

Keywords enteropathy associated T-cell lymphoma; intraepithelial lym-

phocytes; refractory celiac disease

Introduction

The first association between malabsorption and intestinal lym-

phoma was made in 1937 by Fairley and Mackie.1 It was believed

for several years that malabsorption was the sequelae of intes-

tinal lymphoma. This perception changed in 1962 when Gough

et al. described a series of three patients who developed intestinal

lymphoma as a complication of malabsorption.2 In 1978 Isaacson

et al. first suggested,3 and later in 1985, demonstrated that the

intraepithelial T cells were the cells of origin for this celiac dis-

ease associated lymphoma.4 The term enteropathy associated T-

cell lymphoma (EATL) was introduced by O’Farrelly et al. in

1986 to distinguish it from an uncomplicated form of celiac

disease.5

Formerly known as enteropathy-type-T-cell lymphoma, en-

teropathy associated T-cell lymphoma is a rare form of non-

Hodgkin lymphoma. With an annual incidence of 0.5e1 per

million in the Western countries,6 and comprising 10e25% of

Stuti Shroff MD PhD Assistant Professor Department of Pathology and

Laboratory Medicine, Hospital of the University of Pennsylvania,

Philadelphia, PA, USA. Conflicts of interest: none.

Karthik A Ganapathi MD PhD Clinical Fellow Department of Pathology,

National Cancer Institute, National Institutes of Health, Bethesda, MD,

USA. Conflicts of interest: none.

DIAGNOSTIC HISTOPATHOLOGY 20:4 151

all primary lymphomas of the intestine, EATL is the most

common primary gastrointestinal T-cell lymphoma. The inci-

dence of EATL varies geographically. It is often, but not al-

ways, associated with celiac disease and follows the frequency

of celiac disease worldwide. Though uncomplicated celiac

disease has a higher incidence in the female population, a

population based study in the Netherlands revealed that EATL

affects men more frequently than women. Patients affected by

EATL typically present in the age range of 50e70 years with a

mean age of 64 years. The peak incidence is in the seventh

decade of life.7

Though EATL can involve any part of the gastrointestinal

tract, such as the stomach, duodenum and colon, the jejunum

and proximal ileum are the most common sites of involvement.

Extra-intestinal involvement, though reported, is rare. Patients

can present with celiac-disease related symptoms such as

malabsorption, abdominal pain, and weight loss. The first pre-

sentation in several cases, however, is perforation or obstruction

of the small intestine, with the diagnosis being made at the time

of laparotomy.

The WHO recognizes two variants of EATL, each with

different genetic alterations and histomorphologic findings.

A. Type I or classical variant

The classical or type I variant is the more common variant of

EATL, comprising 66e90% of the cases.8,9 It is characterized by

strong association to celiac disease and is most frequent in in-

dividuals with the celiac-disease associated human leukocyte

antigen (HLA) DQA1*0501, DBQ1*0201 genotypes. Additional

HLA-DR/DQ alleles may increase the risk of lymphoma in these

patients. Type I or classic EATL is also characterized by chro-

mosomal aberrations with a gain in the 9q region or a deletion in

the 16q region.10

Celiac disease is an immune-mediated gluten sensitive enter-

opathy induced as a result of consumption of Triticeae glutens in

genetically susceptible individuals. Ingestion of gluten found in

wheat, barley and rye leads to intraepithelial lymphocytosis with

epithelial damage, expansion of lamina propria, villous atrophy

and crypt hyperplasia. The histologic findings are supported by

detection of circulating serum IgA autoantibodies against trans-

glutaminase and endomysium.

Refractory celiac disease (RCD) with or without mucosal ul-

ceration may precede EATL. RCD is defined as persistence or

recurrence following a former good response, of clinical and

histologic findings of celiac disease after a rigorous gluten free

diet for a period of greater than 12 months. Two subtypes of RCD

have been identified, RCD I and RCD II. Individuals with RCD I

demonstrate less than 20% intraepithelial lymphocytes. These

intraepithelial lymphocytes have a normal phenotype and are

polyclonal. Patients with RCD II have greater than 20% intra-

epithelial lymphocytes with aberrant expression of CD3, CD4 and

down-regulation of CD8, and monoclonal gT cell receptor rear-

rangements. This aberrant T cell phenotype has also been

demonstrated in the enteropathic mucosa adjacent to the tumor

in EATL, type I, suggesting that RCD II is likely a precursor, and

may represent an intraepithelial cryptic T cell lymphoma or an

in-situ lesion of EATL, type I. Additional support for RCD II as the

precursor lesion for EATL, type I, is that the intraepithelial

lymphocytes both in RCD II and EATL, type I, harbor gains of

chromosome 1q and 5q.11

� 2014 Elsevier Ltd. All rights reserved.

http://dx.doi.org/10.1016/j.mpdhp.2014.02.006


Studies have shown that the interval of time between the

diagnosis of celiac disease and the onset of type I EATL is vari-

able. Most patients with type I EATL have adult-onset celiac

disease. The diagnosis of celiac disease in some patients is in the

same clinical episode as the diagnosis of type I EATL. In other

individuals this interval can be more than 5 years.12

The tumor cells in type I EATL are medium-to-large pleo-

morphic cells with irregular nuclei, with vesicular chromatin,

prominent nucleoli and a pale rim of cytoplasm. Mitotic figures

are frequent. A wide range of cytologic appearances have been

noted, with morphologic features mimicking anaplastic large cell

lymphoma in some cases. A characteristic morphologic feature of

EATL type I, is a prominent inflammatory background composed

of histiocytes and eosinophils, which in some cases can obscure

the population of neoplastic cells (Figure 1AeC).

Immunohistochemical studies reveal that the neoplastic T-

cells in EATL, type I are positive for CD3 (Figure 1D), CD7 and

CD103, and contain cytotoxic granule-associated proteins such as

TIA-1 (Figure 1F), granzyme and perforin. Variable positivity for

CD8 (Figure 1E) and T-cell receptor b is also noted. The tumor

cells are typically negative for CD4, CD5 and CD56 (Figure 1G).

Some cases demonstrate a proportion of neoplastic cells

Figure 1 EATL, type I (a) Small bowel mucosa involved by EATL type I (highlight

mucosa and wall diffusely infiltrated by an atypical lymphoid proliferation wit

large and pleomorphic with indented nuclear contours, prominent nucleoli, sca

and (f ) TIA and are negative for (e) CD8 and (g) CD56.


expressing CD30, especially prominent in the anaplastic variant

of EATL, type I. Molecular analyses reveal clonal rearrangements

of the T-cell Receptor-b (TCRb) and T-cell Receptor-g (TCRg)

genes, in the neoplastic cells. The intraepithelial lymphocytes in

the adjacent enteropathic mucosa are positive for CD3 and

negative for CD4, CD5 and CD8.

The differential diagnosis of EATL, type I includes peripheral

T-cell lymphoma, not otherwise specified (PTCL, NOS). PTCL,

NOS can have similar morphologic features, including a

background mixed inflammatory infiltrate. However, the

neoplastic T-cells in PTCL, NOS most commonly express CD4.

EATL, type I with increased CD-30 expressing large cells can

mimic Anaplastic large cell lymphoma (ALCL), especially

ALK-negative ALCL (ALCL, ALK-). ALCL, ALK- usually

expresses CD4 and EMA, usually negative in EATL, type I. The

most helpful features are the lack of association with

celiac disease and absence of enteropathic changes in the

non-tumoral small intestinal mucosa.

B. Type II or monomorphic variant

The type II or monomorphic variant of EATL comprises

approximately 10e34% of the cases.8,9 Though type II EATL can

occur in the setting of celiac disease, most cases are sporadic.

ed) with intraepithelial lymphocytosis and villous blunting. (b) Small bowel

h associated histiocytic and eosinophilic infiltrate. (c) The tumor cells are

nt cytoplasm and numerous mitotic figures. They are positive for (d) CD3




The frequency of HLA-DQ2/HLA-DQ8 in Caucasian patients with

this variant EATL is 30e40%, which is comparable to the normal

frequency HLA-DQ2/HLA-DQ8 in the Caucasian population.8

EATL type II is more common in the Asian population from

Japan and Taiwan, in whom celiac disease is rare.10,13 The eti-

ology of EATL type II in this population remains unknown.

Chromosomal aberrations with a gain in the 9q region or a

deletion in the 16q region have also been reported, however, this

lymphoma more frequently demonstrates gains in the 8q24

(MYC) region.10 Unlike RCD II and EATL type I, EATL type II

rarely demonstrates gains of chromosome 1q and 5q.10

No precursor lesion has been identified for EATL type II, but

the invasive tumor is frequently associated with prominent

intraepithelial population of T cells with an identical

morphology and immunophenotype. The tumor cells are seen

in sheets infiltrating the bowel wall leading to villous atrophy

and gland dropout. They are monomorphic and small to in-

termediate in size with small nuclei, inconspicuous nucleoli

and minimal pale cytoplasm. Mitotic figures are frequent, and

necrosis is identified in the areas adjacent to the mucosal ul-

ceration (Figure 2AeB). The tumor cells may be sparsely

associated with a mixed inflammatory infiltrate of histiocytes

and eosinophils.

Figure 2 EATL type II (a) Small bowel mucosa and wall diffusely infiltrated by

medium-sized with clumped chromatin, smooth nuclear contours, inconspicuo

CD56, (f ) TIA-1 and (g) BetaF1.


Immunohistochemical stains reveal that the neoplastic cells are

positive for CD3 (Figure 2C), CD8 (Figure 2D), CD56 (Figure 2E)

and contain cytotoxic granule-associated proteins such as TIA-1

(Figure 2F), granzyme and perforin. Cells are either the ab sub-

type expressing Beta-F1 (bF1) (Figure 2G) or gd subtype. They are

negative for CD4, CD5, B-cell markers such as CD20 and Epstein

Barr Virus (EBV) by in situ hybridization for Epstein Barr Virus

(EBV) encoded RNA (EBER). The intraepithelial T cell population

demonstrates positivity for CD56 with about 15% cases demon-

strating positivity for TCR-ab.13

The differential diagnosis of Type II EATL includes small to

intermediate sized B cell lymphomas, the extranodal nasal-type

NK/T-cell lymphoma involving the small intestine and Periph-

eral T-cell lymphoma, not otherwise specified, gd subtype

(PTCL, NOS gd). Extranodal NK-T-cell lymphoma, nasal type,

can have similar morphologic and immunophenotypic features,

but the expression of EBER is positive and mandatory for diag-

nosis. Additionally TCR are in germline configuration. PTCL,

NOS gd-subtype, is a rare variant of PTCL, NOS and is seen in

sites of innate immunity including gastrointestinal tract and skin.

Since a significant subset of EATL, type II are of gd-subtype, this

distinction is challenging.13 Differentiation from B cell lym-

phomas such as Burkitt lymphoma and mantle cell lymphoma is

an atypical, monomorphic lymphoid proliferation. (b) The tumor cells are

us nucleoli and scant cytoplasm. They are positive for (c) CD3, (d) CD8, (e)




made on clinical presentation and immunohistochemistry. Bur-

kitt lymphoma is more common in the younger age group, and

mantle cell lymphoma involving the bowel presents more

frequently as polyps rather than ulcerative or tumoral lesions.

Immunohistochemistry for B-cell markers such as CD20, CD10

and cyclin-D1 also aids in the differentiation of these cases.

Clinical presentation and diagnosis

EATL often presents with multifocal masses that ulcerate and

invade the wall of the small intestine. Jejunum and proximal

terminal ileum are the most commonly involved sites in the

gastrointestinal tract. Abdominal pain, weight loss, diarrhea, and

symptoms of bowel obstruction are noted in some cases.

Involvement of the distal small intestine, ileocecal region and

colon are more frequent in type II EATL compared to EATL

type I. Extraintestinal involvement by EATL can be seen in the

mesenteric, paraaortic or iliac lymph nodes.9

In patients who present in an emergency scenario with a

perforation, the diagnosis is usually made at the time of laparot-

omy. In other patients, the diagnosis of the ulcerative or tumoral

lesions of EATL is made with the help of imaging techniques such

as CT scan combined with 18F-fluorodeoxyglucose positron

emission tomography (18F-FDG-PET) scan. Video capsule

enteroscopy (VCE) and magnetic resonance enteroclysis (MRE)

are additional diagnostic modalies for examination of the small

intestine and can be used to monitor tumor size following

chemotherapy.8 Double-balloon enteroscopy (DBE), first

described by Yamamoto et al., allows for a detailed examination of

the small bowel and identification of diminutive small intestine

lesions.14,15 On histologic examination, features of celiac disease

such as intraepithelial lymphocytosis, crypt hyperplasia and

villous hypertrophy are noted in the non-tumoral mucosa of the

adjacent small intestine in EATL type I.

Therapeutic options

There are no established standardized therapeutic protocols for

the treatment of EATL. For disease localized to a small segment

of bowel, surgical resection is the first modality of management,

followed by chemotherapy. Numerous different chemothera-

peutic regimens containing anthracycline have been adminis-

tered. Relapses after administration of CHOP

(cyclophosphamide, doxorubicin, vincristine, prednisone),

ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin,

prednisone) and CHOP-like chemotherapeutic regimens are

frequent.9 IVE (ifosfamide, etoposide, epirubicin), followed by

high-dose methotrexate with folinic acid rescue and BEAM

(carmustine, etoposide, cytarabine, melphalan) followed by

consolidative autologous stem cell transplantation regimens have

also been administered with better survival, albeit limited suc-

cess.16,17 Radiation is indicated in patients with bulky disease or

with incomplete resection.

Prognosis

Despite numerous therapeutic regimens, the prognosis both

subtypes of EATL remains poor, since patients present with

multifocal and advanced stage disease with complications of

intestinal perforation at the time of presentation. Additionally, a


significant proportion of patients do not complete their chemo-

therapeutic regimen or do not receive radiotherapy secondary to

poor nutritional status, performance status impairment, other

complications or rapid disease progression despite therapy.18,19

In a study of 62 patients by Delabie et al. the median overall

survival was 10 months and the median failure-free survival was

only 6 months.9 Recurrences are frequent and most common in

the small intestine. The 5-year overall survival is reportedly 20%,

however, the failure-free survival at 5 years is low at 4%.9

Conclusion

In summary, EATL is a rare type of aggressive non-Hodgkin T-

cell lymphoma with two distinct histologic subtypes. The classic

and monomorphic variants of EATL have different histo-

morphologic features and precursor lesions. Despite numerous

therapeutic regimens, the prognosis of EATL is poor with un-

satisfactory survival outcomes. A

REFERENCES

1 Fairley NH, Mackie FP. Clinical and biochemical syndrome in lym-

phadenoma. Br Med J 1937; 1. 375e404.4.

2 Gough KR, Read AE, Naish JM. Intestinal reticulosis as a complication

of idiopathic steatorrhoea. Gut 1962; 3: 232e9.

3 Isaacson P, Wright DH. Malignant histiocytosis of the intestine. Its

relationship to malabsorption and ulcerative jejunitis. Hum Pathol

1978; 9: 661e77.

4 Isaacson PG, O’Connor NT, Spencer J, et al. Malignant histiocytosis of

the intestine: a t-cell lymphoma. Lancet 1985; 2: 688e91.

5 O’Farrelly C, Feighery C, O’Briain DS, et al. Humoral response to wheat

protein in patients with coeliac disease and enteropathy associated t

cell lymphoma. Br Med J (Clin Res Ed) 1986; 293: 908e10.

6 Catassi C, Bearzi I, Holmes GK. Association of celiac disease and

intestinal lymphomas and other cancers. Gastroenterology 2005;

128: S79e86.

7 Verbeek WH, Van De Water JM, Al-Toma A, Oudejans JJ, Mulder CJ,

Coupe VM. Incidence of enteropathy-associated t-cell lymphoma: a

nation-wide study of a population-based registry in the Netherlands.

Scand J Gastroenterol 2008; 43: 1322e8.

8 van de Water JM, Cillessen SA, Visser OJ, Verbeek WH, Meijer CJ,

Mulder CJ. Enteropathy associated t-cell lymphoma and its precursor

lesions. Best Pract Res Clin Gastroenterol 2010; 24: 43e56.

9 Delabie J, Holte H, Vose JM, et al. Enteropathy-associated t-cell

lymphoma: clinical and histological findings from the international

peripheral t-cell lymphoma project. Blood 2011; 118: 148e55.

10 Deleeuw RJ, Zettl A, Klinker E, et al. Whole-genome analysis and HLA

genotyping of enteropathy-type t-cell lymphoma reveals 2 distinct

lymphoma subtypes. Gastroenterology 2007; 132: 1902e11.

11 Verkarre V, Romana SP, Cellier C, et al. Recurrent partial trisomy 1q22-

q44 in clonal intraepithelial lymphocytes in refractory celiac sprue.

Gastroenterology 2003; 125: 40e6.

12 Ilyas M, Niedobitek G, Agathanggelou A, et al. Non-hodgkin’s lym-

phoma, coeliac disease, and epstein-barr virus: a study of 13 cases

of enteropathy-associated t- and b-cell lymphoma. J Pathol 1995;

177: 115e22.

13 Chan JK, Chan AC, Cheuk W, et al. Type ii enteropathy-associated t-cell

lymphoma: a distinct aggressive lymphomawith frequent gammadelta

t-cell receptor expression. Am J Surg Pathol 2011; 35: 1557e69.


http://refhub.elsevier.com/S1756-2317(14)00048-6/sref1





















































14 Yamamoto H, Sekine Y, Sato Y, et al. Total enteroscopy with a

nonsurgical steerable double-balloon method. Gastrointest Endosc

2001; 53: 216e20.

15 Matsumoto T, Nakamura S, Esaki M, et al. Double-balloon endoscopy

depicts diminutive small bowel lesions in gastrointestinal lymphoma.

Dig Dis Sci 2010; 55: 158e65.

16 Bishton MJ, Haynes AP. Combination chemotherapy followed by

autologous stem cell transplant for enteropathy-associated t cell

lymphoma. Br J Haematol 2007; 136: 111e3.


17 Jantunen E, Boumendil A, Finel H, et al. Autologous stem cell trans-

plantation for enteropathy-associated t-cell lymphoma: a retrospec-

tive study by the EBMT. Blood 2013; 121: 2529e32.

18 Daum S, Ullrich R, Heise W, et al. Intestinal non-hodgkin’s lym-

phoma: a multicenter prospective clinical study from the German

study group on intestinal non-hodgkin’s lymphoma. J Clin Oncol

2003; 21: 2740e6.

19 Ferreri AJ, Zinzani PL, Govi S, Pileri SA. Enteropathy-associated t-cell

lymphoma. Crit Rev Oncol Hematol 2011; 79: 84e90.



























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Enteropathy associated T-cell lymphoma: a review of diagnostic findings and therapeutic strategies