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Male With Nonproductive Cough.

A 68-year-old Hispanic man who complained of a nonproductive cough, fever (temperature, 37-38 [degrees] C [99-100 [degrees] F]), abdominal distention, and left upper quadrant pain of 1 week's duration was admitted to the hospital. He denied chills, night sweats, sore throat, headache, stiff neck, nausea, vomiting, diarrhea, dysuria, or change in weight or appetite. His medical history revealed the presence of polycythemia vera (PV) diagnosed 13 years ago and treated with phlebotomy and hydroxyurea. On admission, he was not in acute distress. Physical examination showed low-grade fever and a slightly tender, markedly enlarged spleen. Complete blood cell count revealed the following values: hemoglobin, 109 g/L; hematocrit, 0.33; red blood cell count, 4.13 x [10.sup.12]/L; white blood cell count, 5.5 x [10.sup.9]/L; and platelet count, 21 x [10.sup.9]/L. The white cell differential showed 0.15 neutrophils, 0.07 bands, 0.42 lymphocytes, and 0.36 blasts. The blasts in the peripheral blood varied in appearance from small cells showing lymphoid features with a high nucleus-cytoplasmic ratio, sparse cytoplasm, dense nuclear chromatin, and inconspicuous nucleoli to larger forms with a lower nucleus-cytoplasmic ratio, a moderate amount of basophilic cytoplasm, few fine perinuclear azurophilic granules, occasional cytoplasmic blebs or buds, dispersed nuclear chromatin, and distinct nucleoli. Occasional micromegakaryocytes and large hypogranular platelets were also seen. Bone marrow aspiration and a trephine biopsy were performed. The aspirate smear yielded 2 populations of cells. It contained blasts exhibiting the same morphologic features as those in the peripheral blood and small megakaryocytes (7-10 [micro]m) with small, round, nonlobulated nuclei (Figure 1). Erythrocytic and granulocytic elements were extremely rare. Auer rods were not seen. The trephine biopsy specimen was 100% cellular (Figure 2) and recapitulated the findings in the aspirate smear of a striking proliferation of immature cells with high nuclear-cytoplasmic ratios, open chromatin, and nucleoli consistent with blasts and micromegakaryocytes with hypolobated round nuclei (Figure 3). Reticulin stain showed markedly increased reticular fiber deposition. The blasts showed coarse granular staining for periodic acid-Schiff, but failed to stain with Sudan black B and chloroacetate esterase. Some blasts showed myeloperoxidase staining. Megakaryocytes showed diffuse pale cytoplasmic periodic acid-Schiff staining. Focal granular staining for chloroacetate esterase was noted in some of the more mature forms. Stains for CD61 (platelet glycoprotein IIIa) (Figure 4, B) and factor VIII-related antigen (Figure 4, A) were strongly positive in the mature dysplastic megakaryocytes, intermediate forms, and a small number of blasts. The blasts and megakaryocytes were CD43(+), CD45(-), CD34(-), CD20(-), CD3(-), terminal deoxynucleotidyltransferase (-), and CD68/PG-M1 (-) by immunohistochemistry.


The patient was initially treated with idarubicin and cytarabine, which he tolerated well; however, he remained neutropenic and displayed temperatures up to 38 [degrees] C (101 [degrees] F) despite wide-spectrum antibiotic coverage. A second bone marrow biopsy specimen showed unchanged findings. The patient did not respond to 2 additional chemotherapeutic regimens and died approximately 3 months after admission.

What is your diagnosis?

Pathologic Diagnosis: Polycythemia Vera With Transformation to Acute Megakaryocytic Leukemia

The occurrence of acute leukemic transformation in PV is well documented.[1,2] Based on the results of the first study conducted by the Polycythemia Vera Study Group, Landaw concluded that acute leukemia is part of the natural history of PV, occurring in 2 of 134 patients treated with phlebotomy alone (1%-2%). It was also concluded that the incidence of leukemic transformation increases markedly to 10% to 15% in patients who receive radio-phosphorus and alkylating agents such as chlorambucil.[2]

Since 1985, when the French-American-British Cooperative Group published the official criteria for acute megakaryocytic leukemia (AML-M7),[3] there have been at least 4 reported cases of acute megakaryoblastic transformation of PV. In a review of 15 cases of acute megakaryoblastic leukemia, Cuneo et al[4] found one case. In 1990, Terpstra and his associates[5] reported a case that was also associated with multiple myeloma. In 1992, Hino et al[6] identified a single case in which disseminated intravascular coagulation occurred. Wong et al[7] reported a case associated with hypercalcemia. In addition, Wong and associates noted that patients with PV experience a disproportionate rate of transformation to acute erythroleukemia (AML-M6), whereas transformation to AML-M7 is distinctly uncommon.

The diagnostic criteria for acute megakaryoblastic leukemia associated with myeloproliferative disorders is the same as de novo disease. This requires identification of 30% or more blasts in the bone marrow or blood, with 50% or more of the bone marrow cells showing evidence of megakaryocytic lineage (megakaryoblasts, promegakaryocytes, and megakaryocytes) based on immunohistochemical positivity for platelet glycoproteins, factor VIII-related antigen, or ultrastructural cytochemical identification of platelet peroxidase localized to the nuclear envelope and endoplasmic reticulum. If these studies cannot be performed, clear morphologic evidence of a predominant megakaryocytic component in either smear or section specimens must be present.[3,8] The features of this case, in particular, the morphologic predominance of dysplastic megakaryocytes mixed with blasts and transitional forms in the bone marrow, some of which were positive for platelet glycoprotein IIIa (CD61) and factor VIII-related antigen, constitute evidence of a predominant megakaryocytic differentiation and fulfill the criteria for an AML-M7 type of transformation occurring in this patient with PV.

The phenotypic profile of the megakaryoblasts (Table) aid in ruling out the following differential diagnostic concerns. French-American-British Cooperative group AML-M0 through M6 are excluded because of the apparent megakaryocytic differentiation of the blasts morphologically and phenotypically (CD61 and factor VIII-related antigen positivity). Furthermore, these are not AML-M1 blasts because they do not stain for myeloperoxidase or Sudan black B. This case is not AML-M5 because the blasts are CD68/PG-MI(-). This case is not acute lymphoblastic leukemia because of the absence of lymphoid antigens (CD3, CD20) and terminal deoxynucleotidyl-transferase. Acute myelofibrosis, a panmyeloid hyperplasia, can be ruled out because the blasts and other immature forms are predominantly of megakaryocytic lineage. Metastatic tumor is an important diagnostic consideration, especially in very young children, in whom clustering of megakaryoblasts may resemble neuroblastoma or other small blue cell tumors.[9] Rare myelodysplastic processes or transformed leukemias following myelodysplastic disorders may present with abnormal megakaryocytopoiesis reflected in abnormal megakaryocytes and normal or increased platelets. Such entities, often associated with chromosome 3 abnormalities and unfavorable prognoses, have been difficult to classify according to the French-American-British Cooperative Group criteria.[9]

Staining Characteristics of Acute Megakaryotic Leukemia Blasts and Micromegakaryocytes
Cytochemistry Immunophenotype

(-) Sudan black B (+) Platelet glycoprotein Ib

(-) Myeloperoxidase (+) Platelet glycoprotein IIb/
 IIIa (CD41)

(-) Terminal (+) Platelet glycoprotein IIIa
deoxynucleotidyltransferase (CD61)

(+) Periodic acid-Schiff, (+) Factor VIII-related antigen
acid phosphatase

(+/-) Nonspecific esterase (+/-) HLA-DR, CD33, CD34
(focal, paranuclear)

Acute leukemias occurring in PV are usually of the myeloid type. Compared with de novo disease, these are generally less responsive to therapy.[2] Of de novo myeloid leukemias, AML-M7 is considered to have an even less favorable prognosis and to be particularly resistant to therapy. Three different chemotherapeutic regimens failed in our patient, who died 3 months after diagnosis. Fortunately, transformation of PV to acute leukemia is uncommon, and although very rare, transformation to AML-M7 is also a consideration in patients who experience rapid clinical deterioration. The events that may lead to such a transformation are poorly understood.


[1.] Vardiman JW. Chronic myelogenous leukemia and the myeloproliferative disorders. In: Knowles DM, ed. Neoplastic Hematopathology. Baltimore, Md: Williams & Wilkins; 1992:1405-1438.

[2.] Landaw SA. Acute leukemia in polycythemia vera. Semin Hematol. 1986; 23:156-165.

[3.] Bennett JM, Catovsky D, Daniel MT, et al. Criteria for the diagnosis of acute leukemia of megakaryocyte lineage (M7): a report of the French-American-British Cooperative Group. Ann Intern Med. 1985;103:460-462.

[4.] Cuneo A, Mecucci C, Kerim S, et al. Multipotent stem cell involvement in megakaryoblastic leukemia: cytologic and cytogenetic evidence in 15 patients. Blood. 1989;74:1781-1790.

[5.] Terpstra WE, Meuwissen OJ, Hagemeijer A, Michiels JJ. Multiple myeloma and acute megakaryoblastic leukemia in spent phase polycythemia vera. Am J Clin Pathol. 1990;94:786-789.

[6.] Hino K, Sato S, Sakashita A, Tomoyasu S, Tsuruoka N, Koike T. Megakaryoblastic transformation associated with disseminated intravascular coagulation in the course of polycythemia vera: a case report. Rinsho Ketsueki. 1992;33:500-506.

[7.] Wong KF, Chan JKC, Ma SK, Chu YC. Megakaryoblastic transformation of polycythemia vera associated with hypercalcemia. Am J Hematol. 1993;43:240-242.

[8.] Litz CE, Brunning RD. Acute myeloid leukemias. In: Knowles DM, ed. Neoplastic Hematopathology. Baltimore, Md: Williams & Wilkins; 1992:1315-1347.

[9.] Brunning RD, McKenna RW. Acute leukemias. In: Rosai J, ed. Tumors of the Bone Marrow. Washington, DC: Armed Forces Institute of Pathology; 1994: 19-142. Atlas of Tumor Pathology;, 3rd series, fascicle 9.

Accepted for publication October 7, 1999.

From the University of Illinois Metropolitan Group Hospitals Residency in Pathology and the Departments of Pathology, Illinois Masonic Medical Center (Drs de Luna, Eldibany, Weisenberg, and Rhone), Rush Medical College (Drs Eldibany and Weisenberg), and University of Illinois at Chicago College of Medicine (Dr Rhone), Chicago, Ill.

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Author:de Luna, Regina; Eldibany, Mohamed M.; Weisenberg, Elliot; Rhone, Douglas P.
Publication:Archives of Pathology & Laboratory Medicine
Geographic Code:1USA
Date:Sep 1, 2000
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