Persistent Gastrointestinal GVHD: The Application and Utility of Histologic Grading Schemes

  • Howard M. ShulmanEmail author
  • David W. Woolston
  • David Myerson


Prolonged GVHD is a major cause of morbidity and mortality. The damages are not uniform for different regions of the gut. Previous grading methods using the Lerner-Sale scheme have not been useful at predicting outcome at early stages. However, more recent studies indicate involvement of the lower gut, with Lerner-Sale grade I portending a worse outcome. The Myerson apoptotic activitiy index, a second grading scheme which quantitiates the range of apoptotic bodies within Lerner-Sale grade I, provides useful information for guiding therapeutic intervention. The spectrum of gut GVHD, from a single apoptosis to diffuse intestinal ulceration, is presented along with the therapeutic implications.


Prolonged gut GVHD Grading of gut GVHD Lerner-Sale gut GVHD grading Myerson gut GVHD activity score Gut GVHD histology and prognosis 


  1. 1.
    Socie G, Mary JY, Lemann M, et al. Prognostic value of apoptotic cells and infiltrating neutrophils in graft-versus-host disease of the gastrointestinal tract in humans: TNF and Fas expression. Blood. 2004;103(1):50–7.CrossRefGoogle Scholar
  2. 2.
    Daneshpouy M, Socie G, Lemann M, Rivet J, Gluckman E, Janin A. Activated eosinophils in upper gastrointestinal tract of patients with graft-versus-host disease. Blood. 2002;99(8):3033–40.CrossRefGoogle Scholar
  3. 3.
    McHugh JB, Gopal P, Greenson JK. The clinical significance of focally enhanced gastritis in children. Am J Surg Pathol. 2013;37(2):295–9.CrossRefGoogle Scholar
  4. 4.
    Levine JE, Huber E, Hammer ST, et al. Low Paneth cell numbers at onset of gastrointestinal graft-versus-host disease identify patients at high risk for nonrelapse mortality. Blood. 2013;122(8):1505–9.CrossRefGoogle Scholar
  5. 5.
    McDonald GB. How I treat acute graft-versus-host disease of the gastrointestinal tract and the liver. Blood. 2016;127(12):1544–50.CrossRefGoogle Scholar
  6. 6.
    Kreft A, Neumann H, Schindeldecker M, Wagner-Drouet EM. Diagnosis and grading of acute graft-versus-host disease in endoscopic biopsy series throughout the upper and lower intestine in patients after allogenic hematopoietic stem cell transplantation: a systematic approach. Leuk Lymphoma. 2018. In press.Google Scholar
  7. 7.
    Shulman HM, Cardona DM, Greenson JK, et al. NIH Consensus development project on criteria for clinical trials in chronic graft-versus-host disease: II. The 2014 Pathology Working Group Report. Biol Blood Marrow Transpl. 2015;21(4):589–603.CrossRefGoogle Scholar
  8. 8.
    Cox GJ, Matsui SM, Lo RS, et al. Etiology and outcome of diarrhea after marrow transplantation: a prospective study. Gastroenterology. 1994;107(5):1398–407.CrossRefGoogle Scholar
  9. 9.
    Lerner KG, Kao GF, Storb R, Buckner CD, Clift RA, Thomas ED. Histopathology of graft-vs.-host reaction (GvHR) in human recipients of marrow from HL-A-matched sibling donors. Transplant Proc. 1974;6(4):367–71.Google Scholar
  10. 10.
    Sale GE, Shulman HM, McDonald GB, Thomas ED. Gastrointestinal graft-versus-host disease in man. A clinicopathologic study of the rectal biopsy. Am J Surg Pathol. 1979;3(4):291–9.CrossRefGoogle Scholar
  11. 11.
    Abraham J, Janin A, Gornet JM, et al. Clinical severity scores in gastrointestinal graft-versus-host disease. Transplantation. 2014;97(9):965–71.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Castilla-Llorente C, Martin PJ, McDonald GB, et al. Prognostic factors and outcomes of severe gastrointestinal GVHD after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2014;49(7):966–71.CrossRefGoogle Scholar
  13. 13.
    Kreft A, Mottok A, Mesteri I, et al. Consensus diagnostic histopathological criteria for acute gastrointestinal graft versus host disease improve interobserver reproducibility. Virchows Arch. 2015;467(3):255–63.CrossRefGoogle Scholar
  14. 14.
    Myerson D, Steinbach G, Gooley TA, Shulman HM. Graft-versus-host disease of the gut: a histologic activity grading system and validation. Biol Blood Marrow Transpl. 2017;23:1573.CrossRefGoogle Scholar
  15. 15.
    Jagasia M, Arora M, Flowers ME, et al. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood. 2012;119(1):296–307.CrossRefGoogle Scholar
  16. 16.
    Lee SJ. Classification systems for chronic graft-versus-host disease. Blood. 2017;129(1):30–7.CrossRefGoogle Scholar
  17. 17.
    Pidala J, Kim J, Jim H, et al. A randomized phase II study to evaluate tacrolimus in combination with sirolimus or methotrexate after allogeneic hematopoietic cell transplantation. Haematologica. 2012;97(12):1882–9.CrossRefGoogle Scholar
  18. 18.
    Sauvestre F, Belleannee G, Breal C, et al. Histologic analysis has a prognostical value in colorectal biopsies assessed for suspicion of graft-versus-host disease. Virchows Arch. 2018;472(2):213–20.CrossRefGoogle Scholar
  19. 19.
    Im JS, Abraham SC, Saliba RM, et al. Histologic grade 1 is associated with increased nonrelapsed mortality in lower gastrointestinal graft versus host disease. Am J Surg Pathol. 2017;41(11):1483–90.CrossRefGoogle Scholar
  20. 20.
    Akpek G, Chinratanalab W, Lee LA, et al. Gastrointestinal involvement in chronic graft-versus-host disease: a clinicopathologic study. Biol Blood Marrow Transpl. 2003;9(1):46–51.CrossRefGoogle Scholar
  21. 21.
    Patey-Mariaud de Serre N, Reijasse D, Verkarre V, et al. Chronic intestinal graft-versus-host disease: clinical, histological and immunohistochemical analysis of 17 children. Bone Marrow Transplant. 2002;29(3):223–30.CrossRefGoogle Scholar
  22. 22.
    Martin PJ. Pathogenic neutrophils in acute GVHD. Blood. 2018;131(16):1774–5.CrossRefGoogle Scholar
  23. 23.
    Hulsdunker J, Ottmuller KJ, Neeff HP, et al. Neutrophils provide cellular communication between ileum and mesenteric lymph nodes at graft-versus-host disease onset. Blood. 2018;131(16):1858–69.CrossRefGoogle Scholar
  24. 24.
    Abu Zaid M, Wu J, Wu C, et al. Plasma biomarkers of risk for death in a multicenter phase 3 trial with uniform transplant characteristics post-allogeneic HCT. Blood. 2017;129(2):162–70.CrossRefGoogle Scholar
  25. 25.
    Harris AC, Ferrara JL, Braun TM, et al. Plasma biomarkers of lower gastrointestinal and liver acute GVHD. Blood. 2012;119(12):2960–3.CrossRefGoogle Scholar
  26. 26.
    Ferrara JL, Harris AC, Greenson JK, et al. Regenerating islet-derived 3-alpha is a biomarker of gastrointestinal graft-versus-host disease. Blood. 2011;118(25):6702–8.CrossRefGoogle Scholar
  27. 27.
    Levine JE, Harris AC, Taylor A, Braun TM, Magenau J, Ferrara JLM. A biomarker-based grading system at onset of GvHD predicts NRM better than the modified Glucksberg grading system. Blood. 2013;122(21):145.Google Scholar
  28. 28.
    Zeiser R, Blazar BR. Acute graft-versus-host disease – biologic process, prevention, and therapy. N Engl J Med. 2017;377(22):2167–79.CrossRefGoogle Scholar
  29. 29.
    Star KV, Ho VT, Wang HH, Odze RD. Histologic features in colon biopsies can discriminate mycophenolate from GVHD-induced colitis. Am J Surg Pathol. 37(9):1319–28.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Howard M. Shulman
    • 1
    • 2
    • 3
    Email author
  • David W. Woolston
    • 1
  • David Myerson
    • 1
    • 2
    • 3
  1. 1.Clinical Research DivisionFred Hutchinson Cancer Research CenterSeattleUSA
  2. 2.Department of PathologyUniversity of Washington School of MedicineSeattleUSA
  3. 3.Pathology SectionSeattle Cancer Care AllianceSeattleUSA

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