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Risk of lymphoproliferative malignancy in celiac patients with a family history of lymphoproliferative malignancy

  • Original Article—Alimentary Tract
  • Published:
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Abstract

Background

Individuals with celiac disease (CD) are at increased risk of lymphoproliferative malignancy (LPM). We examined if a family history of LPM or any cancer influenced the risk of LPM in individuals with CD.

Methods

We identified 28,996 individuals with biopsy-verified CD (equal to villous atrophy, Marsh histopathology stage 3), of whom 616 had family history of LPM. Cox regression then estimated hazard ratios (HRs) for LPM in these 616 compared with two control groups. We also examined the risk of LPM in CD individuals with a family history of any cancer (n = 8,439).

Results

During follow-up, 2/616 CD individuals with a family history of LPM, and 235/28,380 CD individuals without a family history of LPM developed LPM themselves. CD individuals with a family history of LPM were not at increased risk of LPM compared to general population controls (HR = 1.18; 95 % CI = 0.27–5.10), or compared to CD individuals without a family history of LPM (adjusted HR = 0.31; 95 % CI = 0.08–1.23). We found no increased risk of LPM in CD individuals with a family history of any cancer.

Conclusion

This study found no evidence that a family history of LPM or any cancer increases the risk of future LPM in individuals with CD. Despite the large number of study participants, this study is nevertheless limited by few positive events due to a low absolute risk of LPM even in individuals with CD.

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Abbreviations

CD:

Celiac disease

CI:

Confidence interval

HR:

Hazard ratio

LPM:

Lymphoproliferative malignancy

NHL:

Non-Hodgkin lymphoma

OR:

Odds ratio

VA:

Villous atrophy

References

  1. Ludvigsson JF, Leffler DA, Bai JC, Biagi F, Fasano A, Green PH, et al. The Oslo definitions for coeliac disease and related terms. Gut. 2013;62:43–52.

    Article  PubMed  Google Scholar 

  2. Dube C, Rostom A, Sy R, Cranney A, Saloojee N, Garritty C, et al. The prevalence of celiac disease in average-risk and at-risk Western European populations: a systematic review. Gastroenterology. 2005;128:S57–67.

    Article  PubMed  Google Scholar 

  3. Tio M, Cox MR, Eslick GD. Meta-analysis: coeliac disease and the risk of all-cause mortality, any malignancy and lymphoid malignancy. Aliment Pharmacol Ther. 2012;35:540–51.

    Article  CAS  PubMed  Google Scholar 

  4. Askling J, Linet M, Gridley G, Halstensen TS, Ekstrom K, Ekbom A. Cancer incidence in a population-based cohort of individuals hospitalized with celiac disease or dermatitis herpetiformis. Gastroenterology. 2002;123:1428–35.

    Article  PubMed  Google Scholar 

  5. Anderson LA, McMillan SA, Watson RG, Monaghan P, Gavin AT, Fox C, et al. Malignancy and mortality in a population-based cohort of patients with coeliac disease or “gluten sensitivity”. World J Gastroenterol. 2007;13:146–51.

    CAS  PubMed  Google Scholar 

  6. Catassi C, Fabiani E, Corrao G, Barbato M, De Renzo A, Carella AM, et al. Risk of non-Hodgkin lymphoma in celiac disease. JAMA. 2002;287:1413–9.

    Article  PubMed  Google Scholar 

  7. Elfstrom P, Granath F, Ekstrom Smedby K, Montgomery SM, Askling J, Ekbom A, et al. Risk of lymphoproliferative malignancy in relation to small intestinal histopathology among patients with celiac disease. J Natl Cancer Inst. 2011;103:436–44.

    Article  PubMed  Google Scholar 

  8. Gao Y, Kristinsson SY, Goldin LR, Bjorkholm M, Caporaso NE, Landgren O. Increased risk for non-Hodgkin lymphoma in individuals with celiac disease and a potential familial association. Gastroenterology. 2009;136:91–8.

    Article  PubMed Central  PubMed  Google Scholar 

  9. Mearin ML, Catassi C, Brousse N, Brand R, Collin P, Fabiani E, et al. European multi-centre study on coeliac disease and non-Hodgkin lymphoma. Eur J Gastroenterol Hepatol. 2006;18:187–94.

    Article  PubMed  Google Scholar 

  10. Smedby KE, Hjalgrim H, Askling J, Chang ET, Gregersen H, Porwit-MacDonald A, et al. Autoimmune and chronic inflammatory disorders and risk of non-Hodgkin lymphoma by subtype. J Natl Cancer Inst. 2006;98:51–60.

    Article  PubMed  Google Scholar 

  11. West J, Logan RF, Smith CJ, Hubbard RB, Card TR. Malignancy and mortality in people with coeliac disease: population based cohort study. BMJ. 2004;329:716–9.

    Article  PubMed Central  PubMed  Google Scholar 

  12. Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS. Lymphoma incidence patterns by WHO subtype in the United States, 1992–2001. Blood. 2006;107:265–76.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Smedby KE, Askling J, Mariette X, Baecklund E. Autoimmune and inflammatory disorders and risk of malignant lymphomas—an update. J Intern Med. 2008;264:514–27.

    Article  CAS  PubMed  Google Scholar 

  14. Linet MS, Pottern LM. Familial aggregation of hematopoietic malignancies and risk of non-Hodgkin’s lymphoma. Cancer Res. 1992;52:5468s–73s.

    CAS  PubMed  Google Scholar 

  15. Goldgar DE, Easton DF, Cannon-Albright LA, Skolnick MH. Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands. J Natl Cancer Inst. 1994;86:1600–8.

    Article  CAS  PubMed  Google Scholar 

  16. Altieri A, Bermejo JL, Hemminki K. Familial risk for non-Hodgkin lymphoma and other lymphoproliferative malignancies by histopathologic subtype: the Swedish Family-Cancer Database. Blood. 2005;106:668–72.

    Article  CAS  PubMed  Google Scholar 

  17. Wang SS, Slager SL, Brennan P, Holly EA, De Sanjose S, Bernstein L, et al. Family history of hematopoietic malignancies and risk of non-Hodgkin lymphoma (NHL): a pooled analysis of 10 211 cases and 11 905 controls from the International Lymphoma Epidemiology Consortium (InterLymph). Blood. 2007;109:3479–88.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Goldin LR, Bjorkholm M, Kristinsson SY, Turesson I, Landgren O. Highly increased familial risks for specific lymphoma subtypes. Br J Haematol. 2009;146:91–4.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Au WY, Gascoyne RD, Klasa RD, Connors JM, Gallagher RP, Le ND, et al. Incidence and spectrum of non-Hodgkin lymphoma in Chinese migrants to British Columbia. Br J Haematol. 2005;128:792–6.

    Article  CAS  PubMed  Google Scholar 

  20. Straus SE, Jaffe ES, Puck JM, Dale JK, Elkon KB, Rosen-Wolff A, et al. The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis. Blood. 2001;98:194–200.

    Article  CAS  PubMed  Google Scholar 

  21. Ludvigsson JF, Brandt L, Montgomery SM, Granath F, Ekbom A. Validation study of villous atrophy and small intestinal inflammation in Swedish biopsy registers. BMC Gastroenterol. 2009;9:19.

    Article  PubMed Central  PubMed  Google Scholar 

  22. Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’). Gastroenterology. 1992;102:330–54.

    CAS  PubMed  Google Scholar 

  23. Ludvigsson JF, Otterblad-Olausson P, Pettersson BU, Ekbom A. The Swedish personal identity number: possibilities and pitfalls in healthcare and medical research. Eur J Epidemiol. 2009;24:659–67.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Ludvigsson JF, Montgomery SM, Ekbom A, Brandt L, Granath F. Small-intestinal histopathology and mortality risk in celiac disease. JAMA. 2009;302:1171–8.

    Article  CAS  PubMed  Google Scholar 

  25. Mattsson B, Wallgren A. Completeness of the Swedish Cancer Register. Non-notified cancer cases recorded on death certificates in 1978. Acta Radiol Oncol. 1984;23:305–13.

    Article  CAS  PubMed  Google Scholar 

  26. Swedish Cancer Registry, by the Swedish National Board of Health and Welfare. http://www.socialstyrelsen.se/register/halsodataregister/cancerregistret/inenglish.

  27. Barlow L, Westergren K, Holmberg L, Talback M. The completeness of the Swedish Cancer Register: a sample survey for year 1998. Acta Oncol. 2009;48:27–33.

    Article  PubMed  Google Scholar 

  28. Ekbom A. The Swedish Multi-generation Register. Methods Mol Biol. 2011;675:215–20.

    Article  PubMed  Google Scholar 

  29. Leslie LA, Lebwohl B, Neugut AI, Gregory Mears J, Bhagat G, Green PH. Incidence of lymphoproliferative disorders in patients with celiac disease. Am J Hematol. 2012;87:754–9.

    Article  PubMed  Google Scholar 

  30. Grainge MJ, West J, Solaymani-Dodaran M, Card TR, Logan RF. The long-term risk of malignancy following a diagnosis of coeliac disease or dermatitis herpetiformis: a cohort study. Aliment Pharmacol Ther. 2012;35:730–9.

    Article  CAS  PubMed  Google Scholar 

  31. Nogai H, Dorken B, Lenz G. Pathogenesis of non-Hodgkin’s lymphoma. J Clin Oncol. 2011;29:1803–11.

    Article  CAS  PubMed  Google Scholar 

  32. Olen O, Askling J, Ludvigsson JF, Hildebrand H, Ekbom A, Smedby KE. Coeliac disease characteristics, compliance to a gluten free diet and risk of lymphoma by subtype. Dig Liver Dis. 2011;43:862–8.

    Article  PubMed  Google Scholar 

  33. Godfrey JD, Brantner TL, Brinjikji W, Christensen KN, Brogan DL, Van Dyke CT, et al. Morbidity and mortality among older individuals with undiagnosed celiac disease. Gastroenterology. 2010;139:763–9.

    Article  PubMed Central  PubMed  Google Scholar 

  34. Elli L, Contiero P, Tagliabue G, Tomba C, Bardella MT. Risk of intestinal lymphoma in undiagnosed coeliac disease: results from a registered population with different coeliac disease prevalence. Dig Liver Dis. 2012;44:743–7.

    Article  PubMed  Google Scholar 

  35. Lohi S, Maki M, Rissanen H, Knekt P, Reunanen A, Kaukinen K. Prognosis of unrecognized coeliac disease as regards mortality: a population-based cohort study. Ann Med. 2009;41:508–15.

    Article  PubMed  Google Scholar 

  36. Lohi S, Maki M, Montonen J, Knekt P, Pukkala E, Reunanen A, et al. Malignancies in cases with screening-identified evidence of coeliac disease: a long-term population-based cohort study. Gut. 2009;58:643–7.

    Article  CAS  PubMed  Google Scholar 

  37. Canavan C, Logan RF, Khaw KT, West J. No difference in mortality in undetected coeliac disease compared with the general population: a UK cohort study. Aliment Pharmacol Ther. 2011;34:1012–9.

    Article  CAS  PubMed  Google Scholar 

  38. Castillo JJ, Dalia S. Cigarette smoking is associated with a small increase in the incidence of non-Hodgkin lymphoma: a meta-analysis of 24 observational studies. Leuk Lymphoma. 2012;53:1911–9.

    Article  PubMed  Google Scholar 

  39. Austin AS, Logan RF, Thomason K, Holmes GK. Cigarette smoking and adult coeliac disease. Scand J Gastroenterol. 2002;37:978–82.

    Article  CAS  PubMed  Google Scholar 

  40. Snook JA, Dwyer L, Lee-Elliott C, Knan S, Wheeler DW, Nicholas DS, et al. Smoking benefits celiac sprue and pouchitis: implications for nicotine therapy? Gastroenterology. 1997;112:1048–50.

    Article  CAS  PubMed  Google Scholar 

  41. Ludvigsson JF, Brandt L, Montgomery SM. Symptoms and signs in individuals with serology positive for celiac disease but normal mucosa. BMC Gastroenterol. 2009;9:57.

    Article  PubMed Central  PubMed  Google Scholar 

  42. Pais WP, Duerksen DR, Pettigrew NM, Bernstein CN. How many duodenal biopsy specimens are required to make a diagnosis of celiac disease? Gastrointest Endosc. 2008;67:1082–7.

    Article  PubMed  Google Scholar 

  43. Corazza GR, Villanacci V, Zambelli C, et al. Comparison of the interobserver reproducibility with different histologic criteria used in celiac disease. Clin Gastroenterol Hepatol. 2007;5(7):838–43.

    Article  PubMed  Google Scholar 

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Acknowledgments

JFL: Örebro University Hospital, Karolinska Institutet, the Swedish Society of Medicine, the Swedish Research Council—Medicine (522-2A09-195), the Swedish Celiac Society, the Fulbright commission. BL: The American Scandinavian Foundation, the Celiac Sprue Association, and the National Center for Research Resources, a component of the National Institutes of Health (KL2 RR024157). JAM: The National Institutes of Health—DK071003 and DK057892. AE was supported by Stockholm county council (ALF).

Conflict of interest

JAM: Grant support: Alba Therapeutics (>$50,000 USD); Advisory board: Alvine Pharmaceuticals, Inc. (<$10,000 USD), Nexpep (<$10,000 USD), Consultant (none above 10,000 USD): Ironwood, Inc., Flamentera, Actogenix, Ferring Research Institute inc., Bayer Healthcare Pharmaceuticals, Vysera Biomedical, 2G Pharma, Inc, ImmunosanT, Inc and Shire US Inc. With the exception of JAM, all authors declare that they have no conflicts of interest and nothing to declare.

Ethical approval

This project (2006/633-31/4) was approved by the Research Ethics Committee of the Karolinska Institute, Sweden on June 14, 2006.

Author information

Authors and Affiliations

  1. Department of Medicine, Clinical Epidemiology Unit, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden

    Jonas F. Ludvigsson & Anders Ekbom

  2. Department of Paediatrics, Örebro University Hospital, Örebro University, Örebro, Sweden

    Jonas F. Ludvigsson

  3. Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic College of Medicine, Rochester, USA

    Jonas F. Ludvigsson, Alberto Rubio-Tapia & Joseph A. Murray

  4. Department of Medicine, Celiac Disease Center, Columbia University College of Physicians and Surgeons, New York, NY, USA

    Benjamin Lebwohl & Peter H. R. Green

Authors
  1. Jonas F. Ludvigsson
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Corresponding author

Correspondence to Jonas F. Ludvigsson.

Appendix

Appendix

The Swedish histopathology SnoMed classification compared to other international histopathology classifications.

Comparison of small intestinal histopathology classifications [43]

Classification used in this project

Villous atrophy

Marsh classification

Type IIIa

Type IIIb

Type IIIc

Marsh description

Flat destructive

Corazza et al. [43]

Grade B1

Grade B2

SnoMed codes

M58, D6218, M58005

M58, D6218, M58006

M58, D6218, M58007

KVAST/Alexander classification

III partial VA

IV subtotal VA

IV total VA

Characteristics

   

 Villous atrophy

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++

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 IEL

+

+

+

 Crypt hyperplasia

+

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Ludvigsson, J.F., Lebwohl, B., Rubio-Tapia, A. et al. Risk of lymphoproliferative malignancy in celiac patients with a family history of lymphoproliferative malignancy. J Gastroenterol 48, 1324–1331 (2013). https://doi.org/10.1007/s00535-013-0757-6

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  • DOI: https://doi.org/10.1007/s00535-013-0757-6

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