Paroxysmal nocturnal hemoglobinuria

Leukemic transformation of chronic idiopathic myelofibrosis (CIMF) to acute lymphoblastic leukemia (ALL) is rare. We report a case of a patient with CIMF who developed paroxysmal nocturnal hemoglobinuria (PNH) 2 years after initial presentation. His disease eventually transformed to ALL of precursor B-cell type. In that CIMF and PNH are clonal stem cell disorders with different pathogeneses, there may be an association between them. However, leukemic transformation is a rare sequel of both disorders. Coexistence of CIMF and PNH and subsequent transformation to ALL have, to our knowledge, never been previously reported in the world literature. The simultaneous presentation of CIMF and PNH, complicated by the rare sequela of leukemic transformation, raises important issues with regard to diagnosis and treatment.

(Arch Pathol Lab Med. 2005;129:96-99)

Chronic idiopathic myelofibrosis (CIMF), previously termed agnogenic myelofibrosis with myeloid metaplasia, is a chronic myeloid disorder that results from an abnormal clonal proliferation of stem cells with multilineage potential and is characterized by myelofibrosis and extramedullary hematopoiesis.1 Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal stem cell disorder of hematopoiesis, leading to formation of defective platelets, granulocytes, erythrocytes, and possibly lymphocytes. To our knowledge, no cases of CIMF and PNH with transformation to acute lymphoblastic leukemia (ALL) have been previously reported. We describe herein a patient with CIMF and PNH whose condition eventually transformed into ALL. The diagnosis and management of such patients, as well as questions regarding pathogenesis, are discussed.

REPORT OF A CASE

A 53-year-old white man was seen in May 2001 for marked splenomegaly, leukocytosis (white blood cell count, 16900/µL reference range, 5200-12 400/µL), leukocyte alkaline phosphatase score of 102 (reference range, 13-130), and elevated lactic acid dehydrogenase level of 1170 U/L (reference range, 300-650 U/ L). Peripheral blood smear showed anisocytosis, mild basophilic stippling and polychromasia, dacryocytes, and increased nucleated red cells and immature granulocytes (Figure 1). Bone marrow aspirate performed at that time snowed severe granulocytic hyperplasia consistent with a chronic myeloproliferative disorder. Karyotype analysis for the Philadelphia chromosome and fluorescence in situ hybridization analysis for the BCR-ABL translocation were nonrevealing. No treatment was required at that time.

In February 2003, the patient experienced his third myocardial infarction and shortly thereafter developed congestive heart failure. He was found to have severe mitral valve regurgitation and massive splenomegaly. A complete blood cell count revealed a white blood cell count of 10 400/µL and iron deficiency anemia (hemoglobin, 10.9 g/dL; reference range, 14-18 g/dL) in the absence of overt blood loss and negative repeated hemoccult study results. The hematology department was consulted to investigate the cause of the anemia and to provide a prognostic estimate for mitral valve repair.

A subsequent bone marrow aspiration was performed with difficulty. The aspirate was profoundly hypocellular. The bone marrow biopsy specimen showed the following: increased reticulin fibrosis, 95% cellularity, a myeloid-erythroid ratio of 4:1, increased maturing trilineage hematopoiesis with clusters of megakaryocytes, and dilated sinusoids that contained hematopoietic precursors (Figures 2 through 4). These findings were consistent with the fibrotic phase of CIMF. Immunohistochemical studies performed on the marrow biopsy specimen showed scattered (not clustered) cells that were reactive for CD117 (Dako Corporation, Carpinteria, Calif) without coexpression of CD25 (Dako). This excluded the possibility of systemic mast cell disease from the differential diagnosis, leading to a diagnosis of CIMF. Peripheral blood submitted for flow cytometric assays revealed decreased expression of CD59 (membrane inhibitor of reactive lysis) in neutrophils, consistent with PNH. The patient was deemed a poor surgical candidate and heart failure was managed medically.

Treatment of CIMF with interferon and hydroxyurea was initiated. The patient soon developed pancytopenia, and use of hydroxyurea was discontinued. The patient completed an 8-week course of interferon, resulting in a mild reduction in spleen size. Transfusions of packed red blood cells and platelets were used to treat pancytopenia. By August 2003, the requirement for transfusions increased, and the patient was admitted on several occasions for overt bleeding. Leukocytosis (white blood cell count, 50 800/µ) with 60% blasts per 100 nucleated cells were found in his peripheral smear (Figure 5). Flow cytometric immunophenotyping was performed on a bone marrow aspirate and revealed positivity for CD10 (bright), CD20 (bright), CD19, CD34, and HLA-DR. Although CD20 positivity suggests a stage slightly more mature than pre-B cell, the immunophenotype was compatible with ALL, precursor-B cell type. Repeat karyotype analysis showed a normal male karyotype. An 8-day course of palliative splenic irradiation gave no clinical improvement. The patient deteriorated, first experiencing intracranial bleeding followed by sepsis and death.

COMMENT

The diagnosis of CIMF is established by clinical and morphologic criteria. Clinical criteria include splenomegaly and anemia. Morphologic criteria include the following: (1) myelophthisis of peripheral blood (leukoerythroblastosis and teardrop-shaped erythrocytes or dacryocytes, manifestations of extramedullary hematopoiesis); (2) marrow hypercellularity with megakaryocytic hyperplasia and dysplasia (clustered and pleomorphic megakaryocytes), granulocytic hyperplasia, and increased ratio of immature granulocytic cells to total granulocytes (left shift); and (3) varying degrees of medullary fibrosis (myelofibrosis). Myelofibrosis can be seen in other clonal or nonclonal diseases, such as systemic mast cell disease, acute myelofibrosis, myelodysplastic syndrome with myelofibrosis, acute megakaryocytic leukemia, overwhelming infection, malignancy, and other chronic myeloproliferative disorders. The absence of the BCR-ABL abnormality excludes chronic myelogenous leukemia.2-4

Paroxysmal nocturnal hemoglobinuria is caused by a somatic mutation in an X-linked gene, PIGA (phosphatidyl inositol glycan complementation group A).5 The mutation occurs in a hematopoietic stem cell, leading to partial or total deficiency of the PIG-A protein. The PIG-A protein is involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) molecule on the cell surface of hematopoietic cells and erythrocytes.5 The GPI molecule serves as an anchor for multiple cell surface GPI-linked proteins. Some of these proteins include CD55 (decay accelerating factor) and CD59 (membrane inhibitor of reactive lysis), both of which protect hematopoietic cells from complement lysis.5 This deficiency of anchored proteins gives rise to defective platelets, granulocytes, erythrocytes, and possibly lymphocytes, resulting in chronic hemolytic anemia, thrombotic episodes, and pancytopenia.5

Chronic idiopathic myelofibrosis can progress to acute leukemia (leukemic transformation) in 14% to 20% of cases, with virtually all cases progressing to AML.M There are only 2 reported cases of CIMF that transformed to ALL.7 Leukemic transformation has been attributed to gene loss and/or inactivation.46 Between 1% and 5% of PNH has been known to evolve to acute leukemia, mainly nonlymphocytic (AML).58 Meletis et al9 compared expression of CD55 (decay accelerating factor) and CD59 in the red blood cells of 88 acute leukemic patients (both AML and ALL), with 8 PNH patients serving as controls. Their proposed mechanisms of PNH phenotype in acute leukemic patients include either a mutation in the leukemic clone affecting the PIGA gene (or genes coding for CD55 or CD59) or alteration in the leukemic bone marrow microenvironment that offers a survival advantage to the growth of the PNH clone. Paroxysmal nocturnal hemoglobinuria that evolves to ALL has been previously described in only 2 known cases.10,11

Kuo et al12 reported PNH-like defects or PNH developing in the course of CIMF. Twenty years later, Graham et al" proposed that aberrations in hematopoietic stem cells in CIMF may predispose to erythroid cell membrane abnormalities that produce a PNH-like defect. They also stated that such impairments in granulocytic precursors increase the risk for subsequent leukemic transformation.13 Paroxysmal nocturnal hemoglobinuria has been seen in various bone marrow failure syndromes, such as aplastic anemia, myelodysplastic syndromes, and autoimmune disorders.5 8 In a background of suppressed hematopoiesis that characterizes bone marrow failure, GPI-deficient cells are resistant to cytotoxic cells, suggesting that GPI-deficient cells escape immunologie tolerance and may be positively selected in bone marrow failure environments.5,8,14,15 Harris et al's attempted to integrate the roles of marrow microenvironment, oncogenic and other tumor suppressor gene alterations, DNA repair enzymes, and PICA mutability in the transformation of PNH to AML. Applying these concepts to our case, it is possible that selective damage to normal hematopoiesis (ie, myelofibrosis associated with CIMF) could be one mechanism that allows PNH clones to proliferate in CIMF.

Treatment in our patient was challenging. Mitral valve replacement for valvular regurgitation usually requires platelet transfusion. Such surgery may mitigate heart failure. Since PNH is associated with a thrombotic tendency, intraoperative platelet transfusions may accelerate thrombosis. The median survival of CIMF is 3.5 to 5.5 years; accordingly, treatment is generally palliative, and allogeneic stem cell transplantation may offer remission.1 Other options include splenectomy or splenic irradiation, drug therapy, autologous stem cell transplantation, and antifibrotic and antiangiogenic therapies.1 None of these provide long-lasting benefit.146 We believe that PNH that arises secondary to CIMF complicates treatment even further. In PNH, the following treatments are palliative: iron and folate replacement, transfusions, prednisone, stimulants of red blood cell production (erythropoietin), anticoagulation treatment, immunosuppression, and stem cell transplantation.816 Our patient had many negative factors for CIMF and PNH, indicating a poor prognosis that was made worse by leukemic transformation. Supportive treatment became the only option.

Our case appears to be the only case in which CIMF, PNH, and ALL were coexistent, making treatment difficult. It may not be clinically expedient to establish whether CIMF or PNH gave rise to ALL with certainty, because ALL was the terminal event. Because current flow cytometric diagnosis of PNH is established on collection of peripheral blood (and not bone marrow), we propose that analysis for mutation of the PICA gene in the leukemic blasts would establish with certainty whether CIMF or PNH led to leukemia.

This work was supported by Pathology and Laboratory Medicine Service, Department of Veterans Affairs Medical Center, Louisville, Ky. Special thanks to Carmen V. Sciortino, Jr, PhD, for providing us with photographic and computer software support and to Alvin W. Martin, MD, for flow cytometric support.

References

1. Ward HP, Block MH. The natural history of agnogenic myeloid metaplasia (AMM) and a critical evaluation of its relationship with the myeloproliferative syndrome. Medicine (Baltimore). 1971;50:357-420.

2. Thiele J, Pierre R, Imbert M, Vardiman JVV, Brunning RD, Flandrin C. Chronic idiopathic myelofibrosis. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001:35-38. World Health Organization Classification of Tumours; vol 3.

3. Tefferi A. Myelofibrosis with myeloid metaplasia. N Engl J Med. 2000:342: 1255-1265.

4. Reilly JT, Messinezy M, Pearson TC. The diagnosis and treatment of essential thrombocythemia and chronic idiopathic myelofibrosis-chronic idiopathic myelofibrosis. In: Wiernik PH, Goldman JM, Dutcher JP, Kyle RA, eds. Neoplastic Diseases of the Blood. 4th ed. New York, NY: Cambridge University Press; 2003: 128-132.

5. Rosse WF. Paroxysmal nocturnal hemoglobinuria as a medical disease. Medicine (Baltimore). 1997;76:63-93.

6. Barosi G. Myelofibrosis with myeloid metaplasia. Hematol Oncol Clin North Am. 2003;17:1211-1226.

7. Polliack A, Prokocimer M, Matzner Y. Lymphoblastic leukemic transformation (lymphoblastic crisis) in myelofibrosis and myeloid metaplasia. Am J Hematol. 1980;9:211-220.

8. Rosse WF. New insights into paroxysmal nocturnal hemoglobinuria. Curr Opin Hematol. 2001:8:61-67.

9. Meletis J, Terpos E, Samarkos M, et al. Red cells with paroxysmal nocturnal hemoglobinuria-phenotype in patients with acute leukemia. Hematology. 2002; 7:69-74.

10. Ariel I, Weiler-Ravell D, Stalnikowicz R. Preleukemia in acute lymphoblastic leukemia. Acta Haematol. 1981:66:50-52.

11. Katahira J, Aoyama M, Oshimi K, Mizoguchi H, Okada M. Paroxysmal nocturnal hemoglobinuria terminating in TdT-positive acute leukemia. Am 1 Hematol. 1983:14:79-87.

12. Kuo C, Van Voolen A, Morrison A. Primary and secondary myelofibrosis: its relationship to "PNH-like defect." Blood. 1972:40:875-880.

13. Graham DL, Castineau DA. Paroxysmal nocturnal hemoglobinuria as a marker for clonal myelopathy. Am J Med. 1992:93:671-674.

14. Inoue N, Murakami Y, KinoshitaT. Molecular genetics of paroxysmal nocturnal hemoglobinuria. Intl J Hematol. 2003:77:107-112.

15. Harris JW, Koscick R, Lazarus HM, Eshleman JR, Medof ME. Leukemia arising out of paroxysmal nocturnal hemoglobinuria. Leuk Lymphoma. 1999;32: 401-426.

16. Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl I Med. 1995;333:1253-1258.

Saad Paul Shaheen II, MD; Sameer S. Talwalkar, MD; Ruth Simons, MD; Lung Yam, MD

Accepted for publication August 20, 2004.

From the Departments of Pathology and Laboratory Medicine (Drs Shaheen and Talwalkar), Medicine (Dr Simons), and Medicine/Hematology (Dr Yam), University of Louisville, Louisville, Ky.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Saad Paul Shaheen II, MD, Department of Pathology and Laboratory Medicine (113), Veterans Affairs Medical Center, 800 Zorn Ave, Louisville, KY 40206 (e-mail: spshaheen@pol.net).

Copyright College of American Pathologists Jan 2005
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