A 38-year-old black man with known sickle cell anemia and multiple episodes of painful crises was admitted to our hospital with chief complaints of severe extensive joint pain, shortness of breath, and fatigue, accompanied with a various degree of leukocytosis for 3 months. Family history revealed both parents had sickle cell trait. His previous hemoglobulin electrophoresis demonstrated 87% hemoglobulin S and 13% hemoglobulin F. He had histories of deep venous thrombosis and avascular necrosis with subsequent bilateral hip replacement and had never been treated with hydroxyurea. On admission, physical examination was remarkable only for an enlarged liver, which was palpable 4 cm below the right costal margin. A complete blood cell count showed a red blood cell count (RBC) of 3.10 × 10^sup 6^/µL, hemoglobulin level of 8.7 g/dL, hematocrit of 26.0%, and platelet count of 447 × 10^sup 3^/µL. The white blood cell (WBC) count was 42.4 × 10^sup 3^/µL, with 70% segmented neutrophils, 9.0% band neutrophils, 9.0% lymphocytes, 6.0% monocytes, 4.0% metamyelocytes, 2.0% myelocytes, and rare blasts. The peripheral blood smear revealed 23 nucleated RBCs per 100 WBCs, anisopoikilocytosis with sickle cells, target cells, microspherocytes, hypochromasia, polychromasia, and occasional Pappenheimer bodies. The patient's condition improved following intravascular hydration, analgesic therapy, and transfusion of 2 U of packed RBCs. One week later, the WBC count was 55.4 × 10^sup 3^ /µL, with 41.0% segmented neutrophils, 13.0% band neutrophils, 4.0% lymphocytes, 13.0% monocytes, 1.0% basophils, 14.0% metamyelocytes, 14.0% myelocytes, and rare myeloblasts. Thirty nucleated RBCs per 100 WBCs were noted. The platelet count was 413 × 10^sup 3^ /µL. The patient refused bone marrow biopsy. The photomicrograph of the peripheral blood smear demonstrates immature granulocytes, nucleated RBCs, sickle cells, target cells, anisopoikilocytosis (Figures 1 and 2), and occasional Pappenheimer bodies. Cytogenetic evaluation of a peripheral blood sample revealed a karyotype of 46 XY, t(9;22)(q34;q11.2) (Figure 2, inset), characteristic of chronic myelogenous leukemia.
Chronic myelogenous leukemia in patients with sickle cell anemia is rare; to our knowledge, only 5 cases have been reported.1,2 A plausible explanation for the rarity of hematologic malignancies, such as chronic myelogenous leukemia, present in sickle cell anemia is likely due to the short life expectancy of these patients. With modern medical care, the average life expectancy of a sickle cell disease patient was improved from approximately 14 years in 1973 to 42 years for men and 48 years for women in 1994; therefore, more hematologie malignancies along with other medical complications are expected to be observed in elderly patients with sickle cell anemia. Special risk factors related to the malignancy formation in sickle cell disease have been proposed,2 which include infection (eg, human immunodeficiency virus or hepatitis C), transfusion-related immunomodulation, and persistent cellular and organ damage induced by inflammation and exposure to bone marrow transplantation or modern chemotherapy, such as hydroxyurea.3,4
Hydroxyurea therapy has been effective in preventing complications in sickle cell disease, reducing the need for transfusions, decreasing pain, and reducing the need for hospitalization,5 and is approved for use in patients 18 years and older who have had at least 3 painful crises in the previous year. Hydroxyurea, a ribonucleotide reductase inhibitor, causes an immediate inhibition of DNA synthesis and a subsequent increase in hemoglobin F level, thus markedly reducing hemoglobin S polymerization. Although exact incidence of secondary malignancies in patients with sickle cell anemia treated with hydroxyurea is not known, occurrence of secondary malignancies after long-term use of hydroxyurea has been reported and reviewed in the literature.2,4,5 Consideration of its carcinogenic potential should be given, because more and more patients with sickle cell anemia may be treated with hydroxyurea and pathologists should be also alerted to this potential.
The leukoerythroblastic blood picture in peripheral blood is generally considered as a secondary reaction to severe anemia, infection, or other stresses that commonly occur in patients with sickle cell anemia. As demonstrated in this case, chronic myelogenous leukemia should be included in differential diagnoses in patients with sickle cell anemia who present with a persistent leukoerythroblastic picture and hepatomegaly.
References
1. Philips G, Hartman J, Kinney TR, et al. Chronic granulocytic leukemia in a patient with sickle cell anemia. Am J Med. 1988:85:567-569.
2. Schultz WH, Ware RE. Malignancy in patients with sickle cell disease. Am J Hematol. 2003:74:249-253.
3. Aguiar RC. Therapy-related chronic myeloid leukemia: an epidemiological, clinical and pathogenetic appraisal. Leukemia Lymphoma. 1998:29:17-26.
4. Rauch A, Borromeo M, Ghafoor A, et al. Leukemogenesis of hydroxyurea in the treatment of sickle cell anemia [abstract]. Blood. 1999:94:415a.
5. Steinberg MH, Barton F, Castro O, et al. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. JAMA. 2003;289:1645-1651.
Lugen Chen, MD, PhD; Minsheng Zhuang, MD; Harshad Q. Shah, PhD; Jen H. Lin, MD
Accepted for publication September 15, 2004.
From the Department of Pathology and Laboratory Medicine, Nassau University Medical Center (Drs Chen, Zhuang, Shah, and Lin), East Meadow, NY, and School of Medicine, State University of New York at Stony Brook (Dr Lin).
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Jen H. Lin, MD, Department of Pathology and Laboratory Medicine, Nassau University Medical Center, 2201 Hempstead Turnpike, East Meadow, NY 11554 (e-mail: jlin@numc.edu).
Copyright College of American Pathologists Mar 2005
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