ESSENTIAL THROMBOCYTHEMIA WITH TRANSITION INTO ACUTE LEUKEMIA

ESSENTIAL THROMBOCYTHEMIA WITH TRANSITION INTO ACUTE LEUKEMIA Sundara B. K. Raman, Ahmad Mahmood, Ellis J. Van Slyck, and Sheikh M. Saeed

Department of Pathology Division of Hematopathology; and the Section of Hematology Division of HematologylOncology Henry Ford Hospital Detroit, Michigan 48202

Since the syndrome of hemorrhagic thrombocythemia was described by Epstein and Goedel,' several subsequent reports have described this disease entity in association with other myeloproliferative disorders, particularly poly,~ cythemia Vera. Later reviews of the literature by Fanger et U Z . , ~ G u ~ z Ozer et al.,* and Silverstein have established this disease as a distinct clinical entity in the spectrum of myeloproliferative syndromes. Because of the qualitative and numerical platelet abnormalities found,6-10 the association of essential thrombocythemia with both hemorrhagic and thrombotic episodes is well recognized. To control these often serious complications, various - modalities of treatment have been tried, including ionizing I6 radiation," cytostatic agents,13. l4 and, recently, thrombocytophere~is.~~~ The few cases of primary thrombocythemia that terminated in acute leukemia 4 + 14,1 7 , l8 were all either treated with ionizing radiation and/or cytostatic agents. The case reported by us is of interest since acute leukemia developed within 16 months after the initial diagnosis of essential thrombocythewia in a patient who did not receive any significant treatment.

CASEREPORT A 57-year-old black man was first admitted to our hospital in August 1978 with complaints of exertional dyspnea of recent onset and episodes of weakness and abdominal pain of a few weeks' duration. He denied any episodes of gross bleeding. He admitted to heavy ethanol abuse, but not taken no medications. The physical examination was essentially negative. In particular, there were no palpable lymph nodes or demonstrable enlargement of spleen or liver. Upon admission laboratory tests showed a hemoglobin of 13.9 gin percent, with slight erythrocytosis (red blood cell count was 6 million/mm*), hypochromia (mean corpuscular hemoglobin concentration 3 1.1 percent, mean corpuscular hemoglobin 21.4 pg) and microcytosis (mean corpuscular volume 65 $). The white blood cell count was 8,800/mma with 70 percent polymorphonuclear cells, 1 percent bands, 21 percent lymphocytes, 6 percent monocytes, and 1 percent eosinophils. The platelet count was 1,160,000/mm*and the reticulocyte count was 3.7 percent. Examination of Wright-stained peripheral blood smear showed microcytic hypochromic red blood cells and increased platelets. Several platelets were bizarre and hypogranular. A few megakaryocytic fragments were seen. The serum iron was 22 pg/dL and the iron-binding capacity 504 pg/dL, which with the red blood cell indices and red cell morphology supported the diagnosis of iron deficiency. Tests of the stools for

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FIGURE1. Solitary expansile lesion (arrow) with sclerotic margins involving the sixth left rib.

FIGURE2. Photomicrograph of biopsy specimen of rib lesion showing features of a benign fibrous defect. Note that the bony trabeculae are lined by osteoclasts and osteoblasts, thus differentiating this lesion from the osteomyelosclerotic stage of a myeloproliferative disorder. Hematoxylin and eosin stain; original magnification x 100; reduced by 25 percent.

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occult blood gave strongly positive results. Of particular interest were the elevated serum values of potassium (7.3 mEq/L), calcium (11.2 mg/dL), and phosphate (5.3 mg/dL). The plasma values for these substances were normal, indicating that the serum abnormalities were spurious relative to thrombocythemia. Hyperparathyroidism was excluded by reason of normal parathyroid hormone and cyclic AMP values. Leukocyte alkaline phosphatase score was elevated at 188 (normal range 13 to 130). X-ray studies with barium enema and upper gastrointestinal series were normal. However, the chest X-ray film showed an expansile lesion with sclerotic margins in the left sixth rib (FIG. 1). Biopsy of this lesion indicated a benign fibrous defect (FIG. 2), but the adjacent marrow in the same specimen revealed findings of a myeloproliferative disease, that is, trilineage hyperplasia with mega-

FIGURE3. Marrow adjacent to the bone defect showing panhyperplasia with megakaryocytic preponderance. Note clusters of megakaryocytes (arrows) and atypical forms. Hematoxylin and eosin stain; original magnification x 100; reduced by 25 percent. karyocytic preponderance and increased reticulin deposition (FIGS.3 and 4). A bone marrow aspirate and biopsy from the iliac crest confirmed the initial impression of a myeloproliferative disease. Coagulation studies included bleeding time (Duke), clotting time (Lee-White), activated partial thromboplasth time, prothrombin time, fibrinogen and whole blood clot lysis. All these studies gave results within normal limits. Platelet aggregation studies showed impaired platelet aggregation (FIG. 5) with adenosine diphosphate (ADP) (1 pg/ml, 2 pg/ml and 3 pg/ml) and epinephrine ( 1 &ml, 2 pg/ml and 3 pg/ml). Collagen-induced (0.1 rng/ml) and ristocetin-induced (1.5 mg/ml) aggregation were normal. Other platelet function studies (that is, retention, clot retraction, and prothrombin consumption) revealed no abnormalities.

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FIGURE 4. Marrow from same site as in FIGURE 3 showing coarse reticulin fibers with condensation. Reticulin stain; original magnification x 100; reduced by 25 percent. From these clinical laboratory and morphologic data, a diagnosis of essential thrombocythemia was made. The patient was placed on a regimen of iron therapy and his platelet count increased further to 2,015,000/mma. He was started on busulfan, 4 mg daily, on October 26, 1978. A week later his platelet count was 4,000,000/mm3 and busulfan was increased to 6 mg daily for the next 2 weeks. On November 28, the hemoglobin was 15.9 mg percent, white blood cell count 5,200/mms with a normal differential count, and platelet count 2,340,000/mm3. At this point, he did not return for further visits or medication and was lost to follow-up study for more than a year. In January 1980 the patient returned to the clinic with epistaxis and was admitted to the hospital. The laboratory values at this time were as follows: hemoglobin 8.6 gm percent with normal red blood cell indices; white blood cell count 3,400/mma, with 7 percent myeloblasts (FIG.6 ) , 3 percent myelocytes, and 1 percent metamyelocyte; platelet count 9,000/mmJ. Bone marrow biopsy (FIG.7 ) and aspirate (FIG.8) showed a cellularity of 95 percent with 40 percent leukemic stem cells (blast cells 16 percent. promyelocytes 23.5 percent). Megakaryocytes were almost absent. A diagnosis of acute leukemia was made. Recurrent nose bleeds and upper gastrointestinal hemorrhages necessitated the use of many transfusions with platelets and packed red blood cells over the succeeding 4 months. Chemotherapy for the patient's leukemia is currently under consideration.

DISCUSSION

On the basis of the unitarian concept of the myeloproliferative disorders advocated by Dameshek,lg essential thrornbocythemia is currently accepted

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within the spectrum of myeloproliferative diseases as a disease entity that contains its own distinct clinical morphologic features. The criteria outlined for diagnosis of this disease by Ozer et aL4 Silverstein,5 and Gunz3 include clinical expression of thrombosis, bleeding, or both (more conimonly bleeding), frequent splenomegaly, sustained platelet count of more than 1 million/ mm3, microcytic hypochromic red cell morphology, usually some neutrophilic leukocytosis, and bone marrow findings of trilineage hyperplasia with megakaryocytic preponderance. Sustained high platelet counts and the bone marrow characteristics were thought to be the most important criteria that we found in our 1). The slight erythrocytosis seen during his hospitalization could patient (FIG. be related to the intermittent bleeding and early iron deficiency anemia. Abnormal platelet functions have been reported in myeloproliferative d i s e a ~ e . ~ O -Studies ~~ of platelet aggregation have shown more consistently abnormal findings than have other functional teds in essential thrombocythemia.6-1012 5 This observation can be used as an aid in differentiating idiopathic thrombocythemia from secondary thrombocyt~sis.~-~ Attempts have been made to predict, monitor and even to prevent the hemorrhagic and/or thrombotic complications with the help of platelet aggregation and related tests.se9

FIGURE5. Defective platelet aggregation was seen after treatment with ADP and epinephrine, but normal aggregation was induced by collagen.

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FIGURE6. Peripheral blood smear showing a myeloblast. Leishman stain; original magnification x 100; reduced by 25 percent.

FIGURE7. Photomicrograph of bone marrow biopsy specimen showing marked hyperplasia with granulocytic bulge and absent megakaryocytes (compare this with FIG.3). Hematoxylin and eosin stain; original magnification x 100; reduced by 25 percent.

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In our patient, platelets showed abnormal aggregation with ADP and epinephrine, but collagen-induced aggregation was normal. Both ADP and epinephrine were used in thrice the threshold concentrations and fresh ADP from a new lot was tried. The abnormalities persisted after all these maneuvers. This aggregation defect pattern was similar to that described by Spaet et aLZ5 in 1969 in three cases of essential thrombocythemia. These authors suggested that the observed platelet aggregation defect might be specific for essential thrombocythemia. However, subsequently, other patterns of aggregation defects in response to single or multiple aggregating agents have been reported in patients with essential thrombocythemia. Recently, Ts’ao et d Z e described a case with reduced platelet aggregation to four inducers (ADP, collagen,

FIGURE8. Bone marrow aspirate smear showing clusters of myeloblasts (arrows) and promyelocytes. Leishman stain; original magnification x 800; reduced by 25 percent. epinephrine, and ristocetin) . They also demonstrated various structural abnormalities of platelets by electron microscope studies. Kaywin et aZ.27speculated that the diminished aggregative response to epinephrine that they demonstrated in two patients with essential thrombocythemia might have resulted from the deficiency in a-adrenergic receptors found in the platelets of these patients. Further chemical and ultrastructural studies may unveil the relationship between structural and functional abnormalities in this now well-recognized clinical entity. Only a few cases diagnosed initially as essential thrombocythemia have terminated in acute granulocytic leukemia.4~1 4 . 1 7 , l8 All these cases occurred in patients who had received ionizing radiation and/or cytostatic agents in significant quantities,lR suggesting a causal role for these agents in the develop-

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ment of leukemia. However, our case was unique in that the patient received a cytostatic agent for only a very short period of time, and, in fact, may actually have received little or no drug because of poor compliance. Onset of leukemia within 16 months after the primary disease was diagnosed reaffirms the fact that the course of the disease is not always indolent and benign. CONCLUSIONS

1. Essential thrombocythemia is now a well-described, distinct clinical entity with characteristic clinical morphologic features. 2. Platelet functional abnormalities, in particular aggregation defects, have been consistently seen in this disease and have been useful as diagnostic tools to differentiate idiopathic thrombocythemia from other causes of thrombocytosis. Attempts have been made to correlate different functional abnormalities and aggregation patterns with chemical and structural defects. Studies along these lines may help to monitor the complications seen in this disease. 3. Although many of the cases of essential thrornbocythemia follow an indolent course, this case emphasizes the fact that transition to acute leukemia with and without therapy with cytostatic agents does occur and may be quite rapid.

SUMMARY A 57-year-old black man with sustained platelet count of 2 million/mm3 and evidence of intermittent gastrointestinal bleeding was diagnosed as having essential thrornbocythemia. Studies of bonz marrow morphology, platelet aggregation, and other variables were confirmatory of the disease. The patient was treated briefly with low doses of Myleran" for less than three weeks. He was then lost to follow-up study. Approximately 16 months later he reappeared complaining of recurrent nose bleeds. He was found to be pancytopenic and diagnosis of acute leukemia was made on the basis of bone marrow aspiration. REFERENCES

EPSTEIN,E., & A. GOEDEL. 1934. Hamorrhagische thrombocythamie bei vascularer schrumpfmilz. Virch. Arch. 193: 233-238. 2. FANGER, H., L. J. CELLA6( H. LITCHMAN.1954. Thrombocythemia: Report of three cases and review of literature. N. Engl. 1. Med. 250(11): 456461. 3. GUNZ,F. W. 1960. Hemorrhagic thronibocythemia: A critical review. Blood 1.

15: 706-723. 4. OZER,F. L., W. E. TRUM, D. C. MIESCH& W. C. LEVIN. 1960. Primary hemorrhagic thrombocythemia. Am. J. Med. 2 8 807-823. 5. SILVERSTEIN, M. N. 1968. Primary or hemorrhagic thrombocythemia. Arch. Intern. Med. 122: 18-22. 6. HARDISTY, R. M. & H. H. WOLFF. 1955. Hemorrhagic thrombocythaemia: A clinical and laboratory study. Br. J. Hematol. 1: 390-405. 7. MCCLIJRE, P. D., G. I. C. INGRAM, R. S. STACEY, V. H. GLASS& M. MATCHETT. 1966. Platelet function tests in thrombocythemia and thrombocytosis. Br.

J. Hematol. 12: 478-498.

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8. ZUCKER,S. & C. H. MIELKE. 1972. Classification of thrombocytosis based on platelet function tests: Correlation with hemorrhagic and thrombotic complications. J. Lab. Clin. Med. 8 0 385-394. 9. GINSBURG,A. D. 1975. Platelet function with high platelet counts. Ann. Intern. 82: 506-51 1. 10. WEINFELD,A., J. BRANEHOO & J. KUTTI. 1975. Platelets in myeloproliferative syndrome. Clin. Haematol. 4(2) : 373-392. 11. FOUNTAIN,J. R. & M. S. LOSOWSKY. 1962. Haemorrhagic thrombocythemia and its treatment with radioactive phosphorus. Quart. J. Med. 31: 207-220. 12. MODAN,B. & A. M. LILIENFIELD. 1965. Polycythemia and leukemia. The role of radiation treatment. A study of 1222 patients. Medicine 4 4 305-344. 13. BENSINGER,T. A., G. L. LOGUE& R. W. RUNDLES. 1970. Hemorrhagic thrombocythemia: Control of postsplenectomy thrombocytosis with melphalan. Blood 36( 1): 61-69. 14. LEWIS, S. M., L. SZUR & A. V. HOFFBRAND.1972. Thrombocythemia. Clin. Hematol. l ( 2 ) : 229-357 15. GREENBERG, B. R. & E. J. WATSON-WILLIAMS.1975. Successful control of life-threatening thrombocytosis with blood processor. Transfusion 15(6) : 620-622. W. B. SCHARFMAN & A. P. TARTAGLIA. 1977. 16. TAFT, E. G., R. B. BABCOCK, Plateletpheresis in the management of thrombocytosis. Blood 50(5) : 927-933. 17. MCCABE,W. R., R. M. BIRD& R. A. MCLAUGHLIN.1955. Is primary thrombocythaemia a clinical myth? Ann. Intern. Med. 43: 182-190. 18. FICKERS,M. & B. SPECK. 1974. Thrombocythaemia: Familial occurrence and transition into blast crisis. Acta Haematol. 51: 257-265. 19. DAMESHEK,W. 1951. Some speculations on myeloproliferative syndromes. Blood 6 372-375. 20. TANGUN, Y. 1971. Platelet aggregation and platelet factors in myeloproliferative disorders. Thromb. Diath. Hemorrh. 25: 241-251. 21. CARDAMONE, J. M., J. R. EDSON,J. R. MCARTHUR & H. S. JACOB. 1972. Abnormalities of platelet function in the myeloproliferative disorders. JAMA 221 (3): 270-273. 22. NEEMAH,J. A. 1972. Quantitation of platelet aggregation in myeloproliferative disorders. Am. J. Clin. Pathol. 57: 336-347. 23. CAEN, J. P., Y. SULTAN& J. DELOBEL. 1969. Les 'thrombopathies acquires. Nouv. Rev. F. Hematol. 9: 553-567. 24. BARBUI,T., R. BATTISTA& E. DINI. 1973. Spontaneous platelet aggregation in myeloproliferative disorders. Acta Haematol. 50: 25-29. & M. L. GOLDSTEIN. 1969. Defective 25. SPAET,T. H., I. LEJNIEKS,E. GAYNOR platelets in essential thrombocythemia. Arch. Intern. Med. 124: 135-141. 26. TS'AO, C., E. C. ROSSI & F. C. LESTINA. 1977. Abnormalities in platelet function and morphology in a case of thrombocythemia. Arch. Pathol. Lab. Med. 101: 526-533. 27. KAYWN,P., M. MCDONOUGH, P. A. INSEL & S. I. SHATTL. 1978. Platelet function in essential thrombocythemia: Decreased epinephrine responsiveness associated with deficiency of platelet a-adrenergic receptors. N. Engl. J. Med. 299( 10) : 505-509.