Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Idiopathic cytopenias of undetermined significance (ICUS), clonal hematopoiesis of indeterminate potential (CHIP), and clonal cytopenias of undetermined significance (CCUS)

David P Steensma, MD
Section Editor
Stanley L Schrier, MD
Deputy Editor
Alan G Rosmarin, MD


Peripheral blood cytopenias are common in adults, especially the elderly, and can either be inconsequential or a sign of serious disease. A specific cause for anemia, neutropenia, or thrombocytopenia can be identified in most cases after a careful medical history, targeted physical examination, and appropriate laboratory and imaging tests, supplemented in some circumstances by a bone marrow aspirate and biopsy. (See "Approach to the adult patient with anemia" and "Approach to the adult with unexplained neutropenia" and "Approach to the adult with unexplained thrombocytopenia".)  

However, diagnostic uncertainty persists in some patients and cytopenias may remain unexplained even after careful, thorough evaluation [1]. Several terms are used to describe individuals who have cytopenias, clonal mutations in genes known to be associated with hematologic neoplasia, or both, yet who do not meet World Health Organization (WHO) diagnostic criteria for a specific disease entity. These terms are described further below (table 1).

The entities described below are not included in the current WHO classification of tumors of the hematopoietic system (4th edition, 2008), and will not be formal categories in the 5th edition (scheduled for publication in 2016 to 2017), since they are not clearly neoplastic [2,3].


Definitions — The following terms have been proposed to describe individuals who have cytopenias, clonal mutations in genes known to be associated with hematologic neoplasia, or both, yet who do not meet World Health Organization (WHO) diagnostic criteria for a specific disease entity (table 1) [4]:

Idiopathic cytopenia of undetermined significance (ICUS) – Single or multiple blood cytopenias that remain unexplained despite an appropriate evaluation including marrow examination. Excludes patients with a known clonal mutation. (See 'ICUS definition' below.)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Dec 2016. | This topic last updated: Wed Aug 10 00:00:00 GMT 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Valent P. Low blood counts: immune mediated, idiopathic, or myelodysplasia. Hematology Am Soc Hematol Educ Program 2012; 2012:485.
  2. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, Fourth Edition, IARC Press, Lyon 2008.
  3. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127:2391.
  4. Steensma DP. Cytopenias + mutations - dysplasia = what? Blood 2015; 126:2349.
  5. Beloosesky Y, Cohen AM, Grosman B, Grinblat J. Prevalence and survival of myelodysplastic syndrome of the refractory anemia type in hospitalized cognitively different geriatric patients. Gerontology 2000; 46:323.
  6. Bain BJ. The bone marrow aspirate of healthy subjects. Br J Haematol 1996; 94:206.
  7. Valent P, Horny HP. Minimal diagnostic criteria for myelodysplastic syndromes and separation from ICUS and IDUS: update and open questions. Eur J Clin Invest 2009; 39:548.
  8. Valent P, Horny HP, Bennett JM, et al. Definitions and standards in the diagnosis and treatment of the myelodysplastic syndromes: Consensus statements and report from a working conference. Leuk Res 2007; 31:727.
  9. Brunning RD, Orazi A, Germing U, et al. Myelodysplastic syndromes/neoplasms, overview. In: WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues, Fourth edition, Swerdlow SH, Campo E, Harris NL, et al (Eds), IARC Press, Lyon 2008. p.89.
  10. Guralnik JM, Eisenstaedt RS, Ferrucci L, et al. Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia. Blood 2004; 104:2263.
  11. Joosten E, Pelemans W, Hiele M, et al. Prevalence and causes of anaemia in a geriatric hospitalized population. Gerontology 1992; 38:111.
  12. Robinson B, Artz AS, Culleton B, et al. Prevalence of anemia in the nursing home: contribution of chronic kidney disease. J Am Geriatr Soc 2007; 55:1566.
  13. Artz AS, Fergusson D, Drinka PJ, et al. Prevalence of anemia in skilled-nursing home residents. Arch Gerontol Geriatr 2004; 39:201.
  14. Holstege H, Pfeiffer W, Sie D, et al. Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis. Genome Res 2014; 24:733.
  15. Wimazal F, Fonatsch C, Thalhammer R, et al. Idiopathic cytopenia of undetermined significance (ICUS) versus low risk MDS: the diagnostic interface. Leuk Res 2007; 31:1461.
  16. Valent P, Bain BJ, Bennett JM, et al. Idiopathic cytopenia of undetermined significance (ICUS) and idiopathic dysplasia of uncertain significance (IDUS), and their distinction from low risk MDS. Leuk Res 2012; 36:1.
  17. Hanson CA, Hoyer JD, Zakko L, et al. Is idiopathic cytopenia of undetermined significance (ICUS) a valid clinical concept? A longitudinal clinicopathological study. Leuk Res (Abstracts of the 10th International Symposium on Myelodysplastic Syndromes, Abstract P089) 2009; 33, Supplement 1:S109.
  18. Cargo CA, Rowbotham N, Evans PA, et al. Targeted sequencing identifies patients with preclinical MDS at high risk of disease progression. Blood 2015; 126:2362.
  19. Steensma DP, Bejar R, Jaiswal S, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 2015; 126:9.
  20. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 2014; 371:2488.
  21. Biernaux C, Loos M, Sels A, et al. Detection of major bcr-abl gene expression at a very low level in blood cells of some healthy individuals. Blood 1995; 86:3118.
  22. Limpens J, Stad R, Vos C, et al. Lymphoma-associated translocation t(14;18) in blood B cells of normal individuals. Blood 1995; 85:2528.
  23. Nielsen C, Birgens HS, Nordestgaard BG, Bojesen SE. Diagnostic value of JAK2 V617F somatic mutation for myeloproliferative cancer in 49 488 individuals from the general population. Br J Haematol 2013; 160:70.
  24. Laurie CC, Laurie CA, Rice K, et al. Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nat Genet 2012; 44:642.
  25. Busque L, Patel JP, Figueroa ME, et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet 2012; 44:1179.
  26. Xie M, Lu C, Wang J, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 2014; 20:1472.
  27. Genovese G, Kähler AK, Handsaker RE, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 2014; 371:2477.
  28. Goldin LR, McMaster ML, Caporaso NE. Precursors to lymphoproliferative malignancies. Cancer Epidemiol Biomarkers Prev 2013; 22:533.
  29. Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med 2006; 354:1362.
  30. Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89:2079.
  31. Malcovati L, Cazzola M. The shadowlands of MDS: idiopathic cytopenias of undetermined significance (ICUS) and clonal hematopoiesis of indeterminate potential (CHIP). Hematology Am Soc Hematol Educ Program 2015; 2015:299.
  32. Bejar R. Myelodysplastic Syndromes Diagnosis: What Is the Role of Molecular Testing? Curr Hematol Malig Rep 2015; 10:282.
  33. Kwok B, Hall JM, Witte JS, et al. MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance. Blood 2015; 126:2355.
  34. Malcovati L, Karimi M, Papaemmanuil E, et al. SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts. Blood 2015; 126:233.