A Myeloproliferative Disorder Associated with Isochromosome 14q

A Myeloproliferative Disorder Associated with Isochromosome 14q

A Myeloproliferative Disorder Associated with Isochromosome 14q FAISAL SAGHIR, MD; ELHAM ABBOUD, MD; CHRISTINE VERES, MD; LAWRENCE FELDMAN, MD ABSTRA...

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A Myeloproliferative Disorder Associated with Isochromosome 14q FAISAL SAGHIR, MD; ELHAM ABBOUD, MD; CHRISTINE VERES, MD; LAWRENCE FELDMAN, MD

ABSTRACT: We present a case of isochromosome 14qrelated myeloid cell disorder. To our knowledge, this report describes the first case of an unclassifiable chronic myeloproliferative disorder associated with this

karyotypic abnormality. KEY INDEXING TERMS: Isochrosome 14q; Myeloproliferative disorder; Anemia of chronic disease; Leukemoid reaction. [Am J Med Sci 2002;324(3):166–169.]


sions of packed red blood cells. The patient’s hemoglobin on admission was 8.2 g/dL, which had dropped; her previous posttransfusion level was 12.4 g/dL. This anemia was attributed to her past medical history of chronic mastoiditis, for which she had been receiving long-term antibiotic therapy. Her anemia workup included serum iron, total iron binding capacity, ferritin, serum folate, and vitamin B12 levels, all of which were normal; thyroid function tests were normal, lactate dehydrogenase was normal, reticulocyte count was 1% (uncorrected), and haptoglobin was not detectable. Coombs test was negative, and hemoglobin electrophoresis revealed sickle-cell trait. Erythropoietin level was 24 (reference range, ⬍ 20). The peripheral blood smear showed normocytic, normochromic red cells. She underwent a bone marrow biopsy that revealed a hypocellular bone marrow with 4⫹ iron stores and erythroid hyperplasia. No blasts, dysplastic changes, or marrow fibrosis was seen. No sideroblasts were seen. The patient also underwent karyotyping that revealed an apparently normal female karyotype and a single cell revealed an isochromosome 14q in 1 cell of the 6 examined; this was deemed not significant at that time. The patient was started on erythropoietin 3 times a week for a presumptive diagnosis of anemia of chronic inflammatory disease. The patient responded to erythropoietin well and maintained her hemoglobin in the 9 to 10 g/dL range. For the next 6 years, the patient required no additional transfusions. A few months before admission to the hospital, the patient complained of weight loss and underwent a work-up including a chest radiograph, panendoscopy, and computed tomography of the abdomen. This workup was negative for any malignancy. The patient had lost a total of about 20 pounds over a few months. She also had a few episodes of syncope that were attributed to a predisposition to ventricular tachycardia noticed on cardiac electrophysiological studies. The patient was started on amiodarone 3 months before her admission. She presented to the hospital in August of 1999 as a 73-year-old woman with a left hip fracture sustained during a motor vehicle accident. The patient was admitted for an open reduction and internal fixation procedure. Her past history was significant for hypertension, dilated cardiomyopathy, congestive heart failure, chronic mastoiditis, and anemia of chronic inflammatory disease. Medications on admission included amiodarone, recombinant erythropoietin, digoxin, carvedilol, lisinopril, enteric-coated aspirin, ibuprofen, omeprazole, docusate, and bisacodyl. Her social history included a 30 pack-year smoking history; she quit in 1990. She denied usage of alcohol or illicit drugs. There was no history of exposure to radiation or chemotherapeutic

nemia of chronic disease (ACD) is common in clinical practice and may be caused by any underlying condition (eg, infection) that results in systemic inflammation.2 It is usually considered to be a normocytic anemia associated with low levels of serum iron and transferrin (iron-binding capacity). Moreover, there are no cytogenetic abnormalities in the bone marrow and there may be abundant stainable iron.1 Lastly, therapeutic use of recombinant erythropoietin may be effective in some patients and lower the requirement for supportive blood transfusion therapy.2 Another not uncommon hematological manifestation of inflammation is a leukemoid reaction. It is characterized by profound leukocytosis [white blood cell (WBC) count between 25,000 and 45,000/␮L] often associated with low-grade fevers.3 Herein we describe a patient diagnosed with anemia of chronic disease due to chronic mastoiditis lasting for 6 years. She subsequently developed a leukemoid reaction and her bone marrow revealed the presence of an atypical myeloid disorder and isochromosome 14q. To our knowledge, this is the only reported case of a myeloproliferative disorder that could not be classified further [based on the French-American-British (FAB) classification4] with this cytogenetic abnormality. Case Report The patient was a 66-year-old African American woman who presented in 1993 with shortness of breath secondary to dilated cardiomyopathy and symptomatic, normocytic, normochromic anemia. She had recently started to require therapeutic transfu-

From the Departments of Medicine (FS, CV, LF) and Pathology (EA), Finch University of Health Sciences/The Chicago Medical School at Sinai Hospital Medical Center, Chicago, Illinois. Submitted January 7, 2002; accepted March 26, 2002. Correspondence: Lawrence Feldman, M.D., Dept. of Medicine, Mount Sinai Hospital Medical Center, Chicago, IL 60608 (E-mail: [email protected]).


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Figure 1. Patient’s WBC and temperature during hospital stay.

agents. She was a retired schoolteacher. The family history was negative for cancer or blood dyscrasias. The review of systems was significant for hearing loss and pruritic skin lesions over her extremities. She denied fever, chills, sweats, cough, dysuria, headache, photophobia, and swollen glands. Her physical exam was significant for a yellowish discharge from her right ear, papular skin lesions over her back and extensor surface of the arms with marks of excoriations. Her left leg was externally rotated and there was tenderness over the left hip. Her laboratory values on admission were significant for a WBC count of 14,200 with a left shift (segmented neutrophils, 63%; banded neutrophils, 23%; lymphocytes, 12%; monocytes, 1%; metamyelocytes, 1%), hemoglobin was 9.3 g/dL, and platelet count was 365,000. The patient was empirically started on antibiotics a day later when she developed a low-grade fever and the WBC count increased further to 15,000 with 32% banded neutrophils (segmented neutrophils, 59%; lymphocytes, 7%; monoocytes, 2%). The urine culture was positive for Enterococcus coli and E fecalis. The patient continued to run a high WBC count with low-to-moderate grade fever despite antibiotics and negative blood cultures. The patient’s subsequent hospital course was one of low-grade fever and high WBC count (Figure 1). On the tenth day of hospitaliza-

tion, the patient developed intractable, unexplained abdominal pain for which she underwent an exploratory laparotomy that yielding no information. The later part of her hospital admission was complicated by Clostridium difficile colitis a few days after undergoing open reduction and internal fixation. Five weeks into her admission, the WBC count started increasing rapidly (see Figure 1) from 17,000 (neutrophils, 94.6%; lymphocytes, 4.6%; monocytes, 0.2%; eosinophils, 0.6%) to a peak of about 168,000 (segmented neutrophils, 21%; banded neutrophils, 33%; lymphocytes, 6%; monocytes, 3%; metamyelocytes, 23%; myelocytes, 10%; promyelocytes, 4%) over the course of 1 week. A hematological consultation was obtained. The peripheral blood smear showed a marked leukocytosis due to an absolute granulocytosis in which there was left shifted maturation. There was no peripheral basophilia or dysplastic change and the platelet count was normal. Leukocyte alkaline phosphatase score was 85 (reference range, 20 –137). At this time, the patient underwent a repeat bone marrow aspirate and biopsy that revealed a hypercellular marrow with proliferation of immature myeloid cells; on paraffin immunoperoxidase stains, these cells were myeloperoxidase-positive but negative for CD3, CD 20, CD 34, hemoglobin, and CD 61. These findings supported a diagnosis of a myeloproliferative disorder without evidence of acute transformation. Subsequently, the cy-

Table 1. Comparison between Anemia of Chronic Disease (ACD) and Refractory Anemia (RA)5

Hemoglobin (g/dL) Mean cell volume7 Serum iron concentration Total iron-binding capacity Bone marrow cellularitya Macrophage irona Erythroid hyperplasiaa Cytogeneticsa Underlying Inflammatory Disease May respond to recombinant erythropoietin a



7–11 range Normocytic Low Low to normal Normocellular Increased Absent Normal Present Yes

Variable Macrocytic Normal or increased Normal Usually hypercellular Often increased Frequent Normal, 5q-, Monosomy 7, Trisomy 8 Absent Yes

Bone marrow



Myeloproliferative Disorder and Isochromosome 14q

Table 2. Comparison between Leukemoid Reaction (LR) and myeloproliferative disorder (MPD)4 LR Underlying infection Leukocyte alkaline phosphatase (LAP) score5

Yes Increased

Usually responds to antimicrobial therapy Often associated with fever Degree of leukocytosis

Yes Yes Usually between 25 to 45,000/␮L

togenetic study reported an isochromosome 14q in 18 of the 20 cells studied. The patient’s condition rapidly deteriorated, her family declined further medical intervention, and she died.

Discussion This patient’s initial diagnosis pointed toward anemia of chronic disease based on normocytic red blood cell indices, lack of bone marrow hypercellularity, normal cytogenetic report, and the presence of an underlying chronic inflammatory disease. The only inconsistency was a normal level of serum iron.5,6 At her initial presentation, the diagnosis of refractory anemia could not be confirmed (see Table 1) based on a hypocellular bone marrow, a normal mean corpuscular volume, and lack of cytogenetic abnormalities (cytogenetic study revealed only 1 of 6 studied cells bearing the isochromosome 14, which was considered not significant). The patient did well and remained transfusion-independent on longterm recombinant erythropoietin therapy for about 6 years. Her presentation 6 years later with a persistently elevated leukocyte count favored a leukemoid reaction secondary to infection based on the criteria listed in Table 2. However, after about 6 weeks in the hospital, her white blood cell (WBC) count rose above 45,000/␮L and the diagnosis of a myeloproliferative disorder was suspected (Figure 1). A bone marrow aspirate and biopsy confirmed the presence of a chronic myeloproliferative disorder associated with isochromosome 14q. The presentation is reminiscent of a myelodysplastic syndrome (MDS) transforming into an acute myeloid leukemia. The clinical course of progression of a chronic anemia to myeloproliferative disorder (MPD) is consistent with the concept that MDS and MPD may simply represent different phenotypes along a continuum of a clonal myeloid stem cell disorder.7 Isochromosome 14q has been associated both with refractory anemia8 and chronic myelomonocytic leukemia.9 In our patient, however, the lack of dysplastic features, ringed sideroblasts, or blasts in the peripheral blood or bone marrow ruled against the presence of refractory anemia or other forms of MDS. MPD has been classified into several different subtypes as listed in Table 3. Chronic myelocytic leukemia is characterized by peripheral basophilia, 168

MPD No Low (in chronic myeloid leukemia; variable in others) No No May be ⬎45,000/␮L

low leukocyte alkaline phosphatase score, and presence of the 8:22 translocation (ie, Philadelphia chromosome). These features were not seen in our patient. Similarly, diagnostic criteria for the other known MPDs (Table 3) were not met in our patient’s case.1,10 Therefore, this patient’s MPD could not be classified according to the FAB classification. To date isochromosome 14 or trisomy 14 as the sole karyotypic abnormality has been reported in a total of 58 cases11 ranging from myeloproliferative disorders to MDS. A search of the databank (European Bioinformatics Institute) did not reveal any relevant gene associated with anemia or myeloproliferative disorders on chromosome 14q. The overwhelming majority of patients with i14q have myeloid cell disorder, based on review of literature (31 cases).12

Table 3. Types of Chronic Myeloproliferative Disorders (CMPD) as Classified by the FAB Cooperative Leukemia Group1,10 and Number of Reported Cases Associated with Isochromosome 14 or Trisomy 14 as the Sole Karyotypic Abnormality12 Number of Cases with Chromosome 14 Abnormality

CMPD Chronic myelocytic leukemia (CML) Polycythemia vera (PV) Essential thrombocythemia (ET) Agnogenic myeloid metaplasia (AMM) Atypical chronic myelocytic leukemia (aCML) Chronic myelomonocytic leukemia (CMML) Other Chronic neutrophilic leukemia (CNL) Mast cell disease (MCD) Chronic eosinophilic leukemia (CEL) Myelodysplastic Syndrome (MDS) Refractory anemia (RA) RA with ringed sideroblasts RA with excess blasts (RAEB) RAEB in transformation (RAEB-t) Acute myeloid leukemia (AML) Unclassifiable

0b 0 0 0 6 3 0 0 0 2 5 1 2 2 7 1c


Based on 31 cases. Primary karyotypic abnormality is t (9,22). c Our case. b

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Conclusion Isochrosome 14q has now been reported in 59 cases associated with predominantly myeloid cell disorders and thus should be considered a nonrandom marker for myeloid cell disorders. References 1. Schilling RF. Anemia of chronic disease: a misnomer. Ann Intern Med 1991;115:572–3. 2. Erslev A. Erythropoietin. N Engl J Med 1991;324:1339 – 44. 3. Reding MT, Hibbs JR, Morrison VA, et al. Diagnosis and outcome of 100 consecutive patients with extreme granulocytic leukocytosis. Am J Med 1998;104:12– 6. 4. Bennet JM, Catovsky D, Daniel MT, et al. The chronic myeloid leukemias: guidelines for distinguishing granulocytic, atypical chronic myeloid, and chronic myelomonocytic leukemia. Br J Haematol 1994;87:746 –54. 5. Wallach J. Interpretation of diagnostic tests, 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2000. p. 349.


6. Beutler E, Lichtman MA, Coller BS, et al. William’s hematology, 6th ed. New York: McGraw-Hill; 2001. p. 1031–2. 7. Michaux JL, Martiat P. Chronic myelomonocytic leukemia (CMML)—a myelodysplastic or myeloproliferative syndrome? Leuk Lymphoma 1993;9:35– 41. 8. Boavida MG, Ambrosio P, Dhermy D, et al. Isochromosome 14q in refractory anemia. Cancer Genet Cytogenet 1997;97:155– 6. 9. Flaherty L, Jarvis A, Harris M, et al. A case of chronic myelomonocytic leukemia with isochromosome 14q. Cancer Genet Cytogenet 1998;101:134 –7. 10. Tefferi A. The Philadelphia chromosome negative chronic myeloproliferative disorders: a practical overview. Mayo Clin Proc 1998;73:1177– 84. 11. Horton YM, Johnson PR. Trisomy 14 in myeloid malignancies: report of two cases and review of the literature. Cancer Genet Cytogenet 2001;124:172– 4. 12. Poirel H, Jonveaux P, Daniel MT, et al. Trisomy 14: a recurring cytogenetic abnormality associated with myeloid disorders. Leuk Lymphoma 1995;17:455–7.