Jerry L. Spivak, M.D.
Dr. Spivak is currently a Professor of Medicine and Oncology at Johns Hopkins University.

Case Presentation:
A 48-year-old woman was referred for advice concerning the management of her chronic myeloproliferative disorder. She had been known to have thrombocytosis with platelet counts as high as 1,400,000/µl for eight years; splenomegaly and an increase in marrow reticulin had also developed over the same period of time. She was asymptomatic and had received no treatment. Physical examination was notable for massive splenomegaly with the spleen extending below the iliac crest and the presence of an ill-defined, irregular, nontender pelvic mass. The hematocrit was 0.41, hemoglobin 13.9 gm percent, red cell count 5,600,000/µl, MCV 75 fl, leukocyte count 25,500/µl, and platelet count 958,000/µl. The differential count revealed 5 percent promyelocytes, 7 percent myelocytes, 33 percent bands, 41 percent neutrophils, 6 percent lymphocytes, 4 percent eosinophils and 4 percent monocytes. There was one nucleated red cell per 100 leukocytes and the blood smear showed microcytic and teardrop-shaped erythrocytes and giant platelets. A bone marrow aspirate was hypocellular, but the bone marrow biopsy was hypercellular with increased and dysplastic megakaryocytes and increased marrow reticulin.

What is the Diagnosis?
Although the question was how best to treat this patient, as with any illness, appropriate treatment is predicated on an accurate diagnosis, and, in patients with a chronic myeloproliferative disorder, phenotype can be misleading. Because thrombocytosis was the initial manifestation of the patient's myeloproliferative disorder, it had been labeled as essential thrombocytosis with myeloid metaplasia and myelofibrosis. However, the disorder could equally well have been labeled idiopathic myelofibrosis since hypercellularity of the bone marrow, megakaryocyte dysplasia, increased reticulin and massive splenomegaly are features more typical of the latter than the former. They are also features of polycythemia vera, which is the only one of the three chronic myeloproliferative disorders in which there is microcytic erythrocytosis such as was present in this patient. Since splenomegaly is usually accompanied by plasma volume expansion, in the setting of a chronic myeloproliferative disorder a normal hemoglobin level in the presence of splenomegaly should always arouse suspicion that the red cell mass is actually increased.

This possibility can only be evaluated by direct measurement of the red cell mass and plasma volume. In this patient, the red cell mass was 52 ml/kg (expected 26 ml/kg), the plasma volume 72 ml/kg (expected 41 ml/kg), and the total blood volume 124 ml/kg (expected 67 ml/kg). Thus, an expanded plasma volume was masking a marked increase in the red cell mass, and the correct diagnosis in this patient was polycythemia vera, not essential thrombocytosis or idiopathic myelofibrosis. Given the massive splenomegaly, portal hypertension from increased blood flow was a possibility, and completion of the diagnostic evaluation included an assessment for esophageal varices by endoscopy, which was negative, and abdominal sonography to define the pelvic mass. This proved to be an enlarged myomatous uterus with cystic ovaries rather than extramedullary hematopoiesis.

It is worth emphasizing that a hypocellular marrow aspirate with increased reticulin is not synonymous with the disease, idiopathic myelofibrosis. In this patient with polycythemia vera, erythrocytosis, leukocytosis, and thrombocytosis were present despite increased marrow reticulin. Although it is generally assumed that marrow fibrosis in polycythemia vera is associated with a spent phase and marrow failure, it is also compatible with trilineage hematopoietic cell hyperplasia and in this context does not have an adverse prognostic significance.

How should this patient be managed?
Given the doubling of the red cell mass, phlebotomy therapy was initiated to lower it to normal and thereby reduce the twin risks of hemorrhage and thrombosis. Since the starting hemoglobin was normal, the necessary number of phlebotomies was guided initially by the extent to which the red cell mass was elevated above normal, with a future goal of keeping the hemoglobin level below 12 gm percent. The next management issue in this patient was how to address the extensive extramedullary hematopoiesis manifested by the massive splenomegaly. Interferon-alpha is the agent of choice in this situation, but, in this particular patient, discomfort from the enlarged uterus together with weight loss associated with increasing spleen size as well as patient reluctance to receive interferon-alpha led to a decision to surgically remove both the spleen and uterus after the red cell mass had been restored to normal.

It is always difficult to decide when to intervene surgically with respect to splenomegaly in patients with a chronic myeloproliferative disorder because of the risks of the surgery plus the exuberant extramedullary hematopoiesis and extreme thrombocytosis or leukocytosis that can follow splenectomy in this situation. Flow-induced portal hypertension with esophageal varices, mechanical discomfort, progressive weight loss, and failure of medical therapy are four indications for splenectomy in patients with a chronic myeloproliferative disorder. Splenic irradiation is a temporizing solution best reserved for patients unfit for surgery.

Further Reading:

• Bessman DJ. Microcytic Polycythemia: frequency of nonthalassemic causes. JAMA 1977; 238:2391-92.
• Lamy T, Devillers A, Bernard M, Moisan A, Grulois I, Drenou B, Amiot L, Fauchet R, Le Prise PY. Inapparent polycythemia vera: an unrecognized diagnosis. Am J Med 1997; 102:14-20.

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