International Journal of Celiac Disease
ISSN (Print): 2334-3427 ISSN (Online): 2334-3486 Website: Editor-in-chief: Samasca Gabriel
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International Journal of Celiac Disease. 2015, 3(2), 59-68
DOI: 10.12691/ijcd-3-2-1
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Primary Intestinal Malignant Lymphomas Associated With Celiakia – A Pathologist´s Review

Lukáš Plank1,

1Department of Pathology, Comenius University in Bratislava Jessenius Medical Faculty and University Hospital in Martin and Martin´s Biopsy Center, Ltd., Slovakia

Pub. Date: March 16, 2015

Cite this paper:
Lukáš Plank. Primary Intestinal Malignant Lymphomas Associated With Celiakia – A Pathologist´s Review. International Journal of Celiac Disease. 2015; 3(2):59-68. doi: 10.12691/ijcd-3-2-1


Celiakia represents a prototype of chronic antigenic stimulation and autoimmune dysregulation leading to the accumulation of reactive cytotoxic intraepithelial lymphocytes (IEL) and small intestinal mucosal injury. These lymphocytes possess a potential of transformation, gaining an aberrant phenotype and genotype during their clonal expansion. The development of type I enteropathy –associated T-cell lymphoma (EATL) in patients with celiac disease might represent a gradual multistep transformation process starting from the increasing accumulation of IEL, and developing through the refractory celiac disease I and refractory celiac disease II, the last representing probably a lymphoma in situ. These transformational stages of the progressing celiac disease are showing increasing risk of type I EATL development, and decreasing survival of the patients. The whole process of progressing EATL lymphomagenesis resembles the hyperplasia-adenoma-dysplasia-adenocarcinoma sequence of colorectal carcinomas. Similar to the already more understood multistep developmental process from CD to type I EATL, an overt type II EATL lymphoma might represent a final step in a process of progression from IEL, representing the lymphoma precursors. However, the patients with the type II lymphoma show signs of celiakia neither clinically nor morphologically and the pathogenetical link to CD is missing. The lymphomagenesis of EATL type II seems to utilize activation of other pathways than that of type I. The recent data support the attempts to set apart the type II from the EATL category and to rename it.

Celiakia refractory celiac disease primary intestinal lymphoma enteropathy-associated T-cell lymphoma type I enteropathy-associated T-cell lymphoma type II monomorphic CD56+ intestinal lymphoma lymphoma in situ

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[1]  Isaacson, P.G., Norton, A.J, Malignant lymphomas of the gastrointestinal tract, Churchill Livingstone, Edinburg, 1994, 15-66.
[2]  Jain, D, Lymphoproliferative disorders of gastrointestinal tract. Walters Klewer, Philadelphia, 2014, 123-189.
[3]  Foukas, P.G., de Leval L, Recent advances in intestinal lymphomas, Histopathology, 66. 112-136. 2015.
[4]  Du, M.-Q., Wotherspoon, A.C, Gastrointestinal lymphomas and lymphoid hyperplasias, Lippincott William&Wilkins, a Wolters Kluwer business. Philadelphia, 2014, 785-813.
[5]  Fairley, N.H., Mackie, F.P.: Clinical and biochemical syndrome in lymphadenoma. Br Med J, 1. 375-404. 1937.
[6]  O´Farelly, C., Feighery, C., O ´Brian, D.S., et al, Humoral response to wheat protein in patients with coeliac disease and enteropathy associated T-cell lymphoma, Br Med J, 293, 908-910. 1986.
[7]  Shroff, S., Ganapathi, K.A, “Enteropathy associated T-cell lymphoma: a review of diagnostic findings and therapeutic strategies”, Diagn Histopathol, 20 (4). 151-155. 2014.
[8]  Green, P.H.R., Fleischauer, A.T., Bhagat, G., Goyal, R., Jabri, B., Neugut, A.I, “Risk of malignancy in patients with celiac disease”, Am J Med, 115. 191-195. 2003
[9]  Robert, M.E., Gibson, J.A, Inflammatory disorders of the small intestine. Elsevier, Saunders, Philadelphia, 2015, 402-435.
[10]  Isaacson, P.G., Chott, A., Ott, G., Stein, H, Enteropathy-associated T-cell lymphoma, IARC, Lyon, 2008, 289-291.
[11]  Swerdlow, S.H., Jaffe, E.S., Brousset, P., Chan, J.K., de Leval, L., Gaulard, Ph., Harris, NL, Pileri, S., Weiss, L.M., on behalf of the International Lymphoma Study Group, Cytotoxic T-cell and NK-cell lymphomas: current questions and controversies, Am J Surg Pathol, 38. 60-71. 2014.
[12]  Müller-Hermelink, H.K., Delabie, J., Ko, Y.H., Jaffe, E.S., Nakamura, S, T-cell lymphoma of the small intestine, IARC, Lyon, 2010, 112-114.
[13]  Tan, S.Y., Chuang, S.S., Tang, T., Tan, L., Ko, Y.H., Chuah, K.L., Ng, Chng, W.J., Gatter, K., Loong, F., Liu, Y.H., Hosking, P., Cheah, P.L., Teh, B.T., Tay, K., Koh, M., Lim, S.T, Type II EATL (epitheliotropic intestinal T-cell lymphoma): a neoplasm of intra-epithelial T-cells with predominant CD8αα phenotyp, Leukemia, 27 (8). 1688-1696. 2013.
[14]  Ferry, J.A, Hematolymphoid tumors of the gastrointestinal tract, hepatobiliary tract and Pancreas, Elsevier, Saunders, Philadelphia, 2015, 846-885.
[15]  Cellier, C., Delabesse, E., Helmer, C., Patey, N., Matuchansky, C., Jabri, B., Macintyre, E., Cerf-Bensussan, N., Brousse, N, “Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma”. French Coeliac Disease Study Group, Lancet, 356 (9225). 203-208. Jul 2000.
[16]  Makovický, P., Makovický, P., Greguš, M., Klimik, M., Zimmermann, M, Histopathological Diagnosis of Celiac Disease in Adults with Functional Dyspeptic Syndrome (In Slovak). Čes.-slov. Patol., 44 (1). 16-19. 2008.
[17]  Dickson B.C., Streutker, C.J., Chetty, R.: “Coeliac disease: an update for pathologists”, J Clin Pathol 59. 1008–1016. 2006.
[18]  Greenson, J.K., Jain, D, Small bowel mucosal disease. Walters Klewer, Philadelphia, 2014, 929-982.
[19]  Mühr-Wilkenshoff, F., Friedrich, M., Foss, H.D., Hummel, M., Zeitz, M., Daum, S, “Immune modulation by non-hodgkin lymphoma in a patient with two primary intestinal T-cell lymphomas and long-standing celiac disease”, Digestion, 81(4). 231-234. 2010.
[20]  Catassi, C., Bearzi, I., Holmes, G. K, “Association of celiac disease and intestinal lymphomas and other cancers”, Gastroenterology, 128 (4 Suppl. 1). S79-86. Apr 2005.
[21]  Zettl, A., deLeeuw, R., Haralambieva, E., Mueller-Hermelink, H.-K, “Enteropathy-type T-cell lymphoma”, Am J Clin Pathol 127. 701-706. 2007.
[22]  Chan, J. K.C., Chan, A. C.L., Cheuk, W., Wan, S.-K., Lee, W.-K., Lui, Y.-H., Chan, W.-K, “Type II Enteropathy-Associated T-Cell Lymphoma: A Distinct Aggressive Lymphoma With Frequent γδ T-cell Receptor Expression”, Am J Surg Pathol, 35 (10). 1557-1569. Oct 2011.
[23]  Kikuma, K., Yamada, K., Nakamura, S., Ogami, A., Nimura, S., Hirahashi, M., Yonemasu, H., Urabe, S., Naito, S., Matsuki, Y., Sadahira, Y., Takeshita, M, “Detailed clinicopathological characteristics and possible lymphomagenesis of type II intestinal enteropathy–associated T-cell lymphoma in Japan”, Human Pathology.
[24]  Wieke, H.M., Verbeek, W.H.M. , Van De Water, J.M.W., Al-Toma, A., Oudejans, J.J., Chris J. J. Mulder, C.J.J., Veerle M. H, Coupé Incidence of enteropathy - associated T-cell lymphoma: A nation-wide study of a population-based registry in The Netherlands“, Scandinavian J Gastroenterol 43 (11). 1322-1328. 2008.
[25]  Macon, W.R, Peripheral T-cell lymphomas, Elsevier Saunders, Philadelphia, 2012, 293-326.
[26]  Akiyama, T., Okino, T., Konishi, H., Wani, Y., Notohara, K., Tsukayama, C., Tsunoda, T., Tasaka, T., Masaki, Y., Sugihara, T., Sadahira, Y, “CD8+, CD56+ (natural killer-like) T-cell lymphoma involving the small intestine with no evidence of enteropathy: clinicopathology and molecular study of five Japanese patients”, Pathol Int, 58 (10). 626-634. Oct 2008.
[27]  Chuang, S.S., Chang, S.T., Chuang, W.Y., Huang, W.T., Hsieh, P.P., Tsou, M.H., Liao, Y.L., Lin, S.H., Hsieh, Y.C., Lu, C.L., Sheu, M.J., Liu, H, “NK-cell lineage predicts poor survival in primary intestinal NK-cell and T-cell lymphomas”, Am J Surg Pathol, 33 (8). 1230-1240. Aug 2009.
[28]  Sun, J., Lu, Z., Yang, D., Chen, J, “Primary intestinal T-cell and NK-cell lymphomas: a clinicopathological and molecular study from China focused on type II enteropathy-associated T-cell lymphoma and primary intestinal NK-cell lymphoma”, Mod Pathol, 24 (7). 983-992. Jul 2011.
[29]  Lebwohl, B., Granath, F., Ekbom, A., Smedby, K.E., Murray, J.A., Neugut, A.I. Green, P.H.R., Ludvigsson, J.F, “Mucosal Healing and Risk for Lymphoproliferative Malignancy in Celiac Disease: A Population-Based Cohort Study”, Ann Intern Med. 159 (3). 169-175. 2013.
[30]  Khalaf, W.F., Meghan E. Caldwell, M.E., Reddy,N, “Brentuximab in the Treatment of CD30-Positive Enteropathy-Associated T-Cell Lymphoma”, JNCCN 11(2). 137-140. 2013.
[31]  Tan, S.Y., Ooi, A.S., Ang, M.K., Koh, M., Wong, J.C., Dykema, K., Dykema, K., Ngeow, J., Loong, S Gatter, K., Tan, L., Lim, L.C., Furge, K., Tao, M., Lim, S.T., Loong, F., Cheah, P.L., Teh, B.T, Nuclear expression of MATK is a novel marker of type II enteropathy-associated T-cell lymphoma, Leukemia, 25. 555-557. 2011.
[32]  Wilson, A.L., Swerdlow, S.H., Przybylski, G.K., Surti, U., Choi, J.K., Campo, E., Trucco, M.M., Van Oss, S.B., Felgar, R.E, Intestinal gd T-cell lymphomas are most frequently of type II enteropathy-associated T-cell type, Hum Pathol, 44 (6). 1131-1145. 2013.
[33]  Varghese, D., Koya, H.H., Cherian, S.V., Mead K., Sharma, A., Sharma, N., Knohl, S.J., Benjamin, S, “Hemophagocytic Lymphohistiocytosis: An Uncommon Presentation of Enteropathy-Associated T-Cell Lymphoma”, J Clin Oncol 31 (13). 226-230. May 2013.
[34]  Liu, H., Brais, R., Lavergne-Slove, A., Jeng, Q., Payne, K., Ye, H., Liu, Z., Carreras, J., Huang, Y., Bacon, C.M., Hamoudi, R.A., Save, V., Venkatraman, L., Isaacson, P.G., Woodward, J., Du, M.-Q, Continual monitoring of intraepithelial lymphocyte immunophenotype and clonality is more important than snapshot analysis in the surveillance of refractory coeliac disease. Gut, 59. 452-460. 2010.