Malignant Myeloproliferative Disorder
Stenographic reports, edited by Philip E. Cryer, M.D. and John M. Kissane, M.D., of weekly clinicopathologlc conferences held in Barnes and Wohl Hospitals, are published in each issue of the Journal. These conferences are participated in jointly by members of the Departments of Internal Medicine, Radiology and Pathology of Washington University School of Medicine. A 35 year old woman with a diagnosis of myelofibrosis was admitted to Barnes Hospital on August 24, 1977. She died on the second hospital day. The patient was in apparent good health until January 1977 when fatigue was first noted. In February she was found to be anemic, with a hematocrit value of 13 per cent. A bone marrow biopsy specimen revealed myelofibrosis. She received more than 40 U of blood over the next six months. In July 1977 she was hospitalized elsewhere and underwent an emergency cholecystectomy. The postoperative period was complicated by gastrointestinal bleeding and by ventilatory failure for which she required tracheostomy and mechanical ventilatory support. The hematocrit value was 25 per cent at the time of discharge and 23 per cent one week later. One week prior to her Barnes Hospital admission she was given 4 U of blood. Additional history included a 60 pound weight loss. On examination, the patient was pale and appeared to be acutely ill. The blood pressure was 1 lo/60 mm Hg, the pulse rate 126/min, the respiratory rate 32/min, the temperature 36.2’C and the weight 147$ pounds. There were multiple small purpuric lesions over the forearms and legs, and crusted blood was noted on the gums. There was massive hepatosplenomegaly. The liver was palpable 19 cm below the right costal margin, and the spleen was palpable 22 cm below the left costal margin. There was 2f pitting edema of the lower extremities. Initial laboratory studies included a hemoglobin level of 7.3 g/dl, a hematocrit value of 20 per cent, a platelet count of 55,000/mm3 and a white blood cell count of 185,000/mm3 with 30 per cent segmented neutrophils, 16 per cent band forms, 12 per cent metamyelocytes, 14 per cent myelocytes, 3 per cent promyelocytes, 12 per cent lymphocytes, 8 per cent monocytes and 5 per cent blast forms. The peripheral blood smear also revealed 2 nucleated red blood cells/l00 white blood cells and cells with monocytoid nuclear chromatin as well as some cells with active erythrophagocytosis. The serum sodium was 134 meq/liter, the potassium 5.4 meq/liter, the chloride 95 meq/liter and the bicarbonate 7.5 meq/liter. The serum creatinine was 3.8 mg/dl and the glucose 2 mg/dl. The arterial pH was 7.0, the oxygen tension (PO,) 62 mm Hg and the carbon dioxide tension (PCO2) 20 mm Hg. The
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Figure 1. Chest film obtained on admission with patient supine demonstrates a large right pleural effusion and a smaller left pleural effusion. Air bronchograms indicating air space disease are present in both lungs. A central venous pressure line follows the course of the right subclavian vein, and the catheter tip is curved.
serum uric acid was 28 mg/dl, the albumin 3.1 g/dl, the alkaline phosphatase 175 mlU/ml and the lactic dehydrogenase (LDli) 1,575 mlU/ml. The blood lactate was 22.9 mmol/liter. Serum ketones were trace positive. Sinus tachycardia was noted on the electrocardiogram, and chest films showed opacification of the upper portion of the right lung field. The prothrombin time was 17.3 seconds (control of 13.7 seconds), the partial thromboplastin time 80.4 seconds and the fibrinogen level 230 mg/dl. The patient became hypotensive and obtunded shortly after admission. She was treated with gentamicin, a cephalosporin antibiotic and 5 per cent glucose in water. Intravenous fluids and dopamine were infused, a tracheostomy was performed, and mechanical ventilation was applied. Acidosis persisted despite the in-, travenous administration of sodium bicarbonate. Urine became available only after the intravenous adminstration of furosemide. Crystals were seen in the urine sediment. The urinary sodium was 154 meq/liter, the potassium 1.9 meq/liter and the osmolality 309 mosmol/kg. The urine to serum creatinine ratio was 2.0. Hemodialysis was performed; 2 liters of fluid was removed. The prothrombin time lengthened, the platelet count decreased to 14,000/mm3 and the fibrinogen to 145 mg/dl. Packed red blood cells, fresh plasma, corticosteroids and heparin were administered. Despite these efforts, the patient died during the second hospital day. Blood cultures were subsequently found to contain Staphylococcus aureus which was also recovered from cultures of the sputum.
Dr. Stuart Kornfeld: This patient apparently enjoyed good health until January 1977 when she noticed increased fatigability, weakness and some weight loss. In February, she was admitted to another hospital for evaluation of anemia, and an open bone marrow biopsy disclosed myelofibrosis. She was given androgen therapy but over the next seven months required about 40 U of red blood cells. In late June she was hospitalized elsewhere with abdominal pain and fever, and was noted to have massive hepatosplenomegaly. At that time the hemoglobin level was 8 g/dl, the platelet count 350,000/mm3 and the white blood cell count. 13,000/mm3 with a shift to the left. Giant platelets and nucleated red blood cells were noted on the peripheral smear. The leukocyte alkaline phosphatase level was elevated at 125 U. During that hospital stay pleuritic chest pain and increasing pulmonary infiltrates developed as well as massive pleural effusions. She was noted to have gallstones and underwent a cholecystectomy. A liver biopsy, performed at that time, disclosed evidence of extramedullary hematopoiesis. The postoperative course was very stormy. The pulmonary symptoms worsened, and a tracheostomy was required along with mechanical ventilatory support. In addition, renal failure developed as well as gastrointestinal bleeding. Despite these problems, the patient’s condition gradually improved, and she was discharged in early August. At the time of discharge, the serum creatinine was 2.2 mg/dl and the hematocrit value 22 per cent; the white blood cell count had increased to 30,000/mm3 and the platelet count had decreased to 48,000/mm3. Over the next few weeks progressive weakness and lethargy developed, and the patient was referred to Barnes Hospital for evaluation. On presentation she was acutely ill with profound lactic acidosis, severe hypoglycemia, hyperuricemia and renal failure. Shortly after admission she became semiobtunded and hypotensive; despite vigorous supportive therapy, she died on the second hospital day. Dr. Levitt will review the chest film. Dr. Robert Levitt: A chest film (Figure 1) obtained on admission showed opacification of the upper portion of the right hemithorax. This opacification is pleural fluid which collected near the apex of the lung because the chest film was obtained with the patient in the supine position. Parenchymal disease in the upper lobe of the right lung cannot be excluded because of the pleural effusion. A small left pleural effusion was also present. Air bronchograms were seen in the middle and lower lobes of the right lung, and in the lower lobe of the left lung. These indicate air space disease in both lungs. A central venous pressure catheter followed the course
of the right subclavian vein, and the catheter tip was curled. The curled tip of the catheter raises the possibility that a subclavian vessel has been punctured and that the pleural effusion is a hemothorax. Dr. Kornfeld: Thank you. I would like to begin the discussion by considering the patient’s underlying hematologic disorder. There is much evidence to support the diagnosis of primary myelofibrosis with myeloid metaplasia, a disorder which is also termed agnogenic myeloid metaplasia. An open bone marrow biopsy disclosed marrow fibrosis with increased megakaryocytes, a finding typical of myelofibrosis, and a liver biopsy specimen showed extramedullary hematopoiesis. Massive splenomegaly was present. The patient had severe anemia for which she required many transfusions over a short period of time as may occur in patients with severe myelofibrosis. The peripheral blood smear showed a leukoerythroblastic picture with a shift to the left of the white blood cell series and the presence of circulating nucleated red blood cells. Although this is not diagnostic of this condition, it is very typical. In addition, there were giant platelets and megakaryocytic fragments in the peripheral blood, additional findings which are typical of myelofibrosis with myeloid metaplasia. Finally, the marked weight loss, the susceptibility to infections and the very high uric acid level are findings often seen in patients with this disease. One has to keep in mind that myelofibrosis can be a secondary complication of several other conditions. It may be present in other myeloproliferative disorders, such as polycythemia vera and chronic myelocytic leukemia, and it may occur in patients who have bone marrow involvement with carcinoma or tuberculosis and, occasionally, in patients who have been exposed to certain toxins. In some patients the distinction between chronic myelocytic leukemia (CML) and agnogenic myeloid metaplasia may be very difficult. In these patients it is useful to perform a chromosome analysis looking for the Philadelphia chromosome which is diagnostic of CML. The leukocyte alkaline phosphatase level is also helpful since it is typically low in CML and normal to high in agnogenic myeloid metaplasia. In one large series [I] of patients with CML, about 3 per cent of the patients had severe fibrosis in the marrow at the time of initial presentation. However, six of the seven patients with marrow fibrosis had a low leukocyte alkaline phosphatase level and all of them had white blood cell counts greater than 10,000/mm3 which is contrary to what was found in this patient. Therefore, I think that the evidence is very strong that the patient’s illness started out as primary myelofibrosis with myeloid metaplasia. One unusual aspect of this patient’s illness was its very aggressive nature. Dr. Rogers, would you comment on the typical course of patients with myelofibrosis and
tell us if you think that this patient had the entity termed acute myelofibrosis? Dr. John Rogers: Our patient is difficult to classify. Let me review some of the features of her illness so that we can contrast the features of so-called “acute” myelofibrosis with the classic features of agnogenic myeloid metaplasia with myelofibrosis. First, the majority of patients with idiopathic myelofibrosis live longer than just a few months. The range of survival varies among the published series, but average about four to five years. It is thought that patients who have very prominent organomegaly at the time of diagnosis live a shorter period of time . This probably reflects the duration of disease prior to diagnosis. Ward and Block  plotted the increase in spleen size over the course of years in 16 untreated patients and found that, as a rough average, spleen size increased 1 cm below the costal margin each year. However, this figure varied widely and there were patients whose spleens enlarged rapidly. Another point worth mentioning is that myelofibrosis is usually a disease of older people, the average age being about 60 years, but there are occasional patients in their third or fourth decade with otherwise typical features of the disease. Our patient was atypical, then, in that she was young and that she lived less than a year after the diagnosis was made. We do not know whether her spleen was enlarged when she first presented, so we can only guess that it grew at a remarkable rate within eight months. The entity called acute myelofibrosis  has been described in a unique set of patients. These are patients who present with bone marrow fibrosis and with a peripheral blood picture that resembles leukemia in that they have many circulating myeloblasts and immature cells. They usually do not have hepatosplenomegaly. The disease progresses very rapidly and such patients usually die within a few months. At autopsy, they do not have leukemic infiltration of other organs and on this point rests the distinction between acute myelofibrosis and fibrosis that might be secondary to a malignancy such as leukemia. Our patient had hepatosplenomegaly, but otherwise her course was consistent with this syndrome. Dr. Kornfeld: Now I would like to consider some questions about the etiology of primary myelofibrosis. A prominent finding in most of these patients is proliferation of fibroblasts in the bone marrow. Yet, it has been very difficult to determine whether this process represents a primary proliferation of primitive mesenchymal reticulum cells or a secondary response of these cells to marrow injury or to the release of a growth-stimulating factor. Dr. Herzig, would you review the current status of this controversy. Dr. Geoffrey Herzig: Although the final answer is still not available, I believe the data favor the conclusion that
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idiopathic myelofibrosis is due to a primary abnormality in the hematopoietic stem cell with secondary effects on the wow fibroblasts. To review briefly, the normal bone marrow fibroblast arises from a nonhematopoietic (mesenchymal) stem cell; this is demonstrated most strikingly by observations in human recipients of bone marrow transplants in whom hematopoietic tissue can be shown by karyotyping to be of donor origin whereas fibroblasts are of host origin. The fibroblast is an important part of the bone marrow hematopoietic inductive microenvironment, that is the stromal milieu which is needed for proliferation and differentiation of the hematopoietic stem cells. Recent studies of two patients with primary myelofibrosis documented the clonal proliferation of hematopoietic stem cells by karyotypic and enzyme (glucose-6-phosphate dehydrogenase) markers, whereas cultured marrow fibroblasts from these patients showed no evidence of clonal proliferation [4,5]. This may be interpreted as indicating that the fibrosis is secondary to the expansion of an abnormal hematopoietic stem cell clone. Dr. Kornfeld: An interesting and striking finding in myelofibrosis is the very high levels of circulating granulocytic stem cells, the so-called CFU-C . Dr. Herzig, would you explain what CFU-Cs are and speculate for us what this finding may mean in terms of the pathbphysiology of myelofibrosis? Dr. Herzlg: The CFU-C, or colony-forming unit in culture, is believed to be a stem cell which is committed to the production of neutrophils and monocytes, and their precursors in the bone marrow. It arises from the pluripotent hematopoietic stem cell under the influence of stromal and humoral factors which are still poorly understood, but include colony-stimulating factor, a humoral substance which is roughly analogous to erythropoietin. Colony-stimulating factor can be produced by a variety of cells including the bone marrow fibroblast. CFU-Cs can be enumerated by their ability to form colonies (of neutrophils and monocytes) when cultured in semisolid media in the presence of colonystimulating factor. Under normal conditions CFU-Cs are readily demonstrated in marrow cell suspensions and occur with low frequency in the circulating blood. Marked increases in the number of circulating CFU-Cs occur in several pathologic states including acute lymphocytic leukemia, chronic myelocytic leukemia and, perhaps most strikingly, in myelofibrosis. The significance of this finding with respect to the pathophysiology of myelofibrosis is uncertain-it may be due to either an abnormal stem cell clone (with abnormal homing patterns or marked clonal expansion) or to abnormal fibroblast proliferation (with increased production of colony-stimulating factor or abnormalities in the marrow microenvironment). Extramedullary he-
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matopoiesis (in the spleen) also has been found to be a source of circulating CFU-Cs presumably due to the lack of normal mechanisms controlling the release of immature cells which operate in the bone marrow. Dr. Kornfeld: Thank you. A very difficult problem in managing this patient was the severe anemia. The patient required approximately 40 transfusions over a seven month period, suggesting the presence of enhanced red cell destruction as well as decreased production. Dr. Rogers, would you comment on the etiology of the anemia in these patients and the role of androgens and splenectomy in the management of the anemia? Dr. Rogers: Anemia in myelofibrosis is a complicated problem since a number of different factors are involved. First, patients with myelofibrosis reproducibly have an increased plasma volume, so there is some hemodilution. Secondly, most patients have accelerated destruction of their red blood cells and, although variable, this seems to correlate with the size of the spleen. In a patient with a large spleen and a large transfusion requirement, we usually suspect that the spleen is sequestering and destroying red cells. I will come back to that shortly. Thirdly, patients with myelofibrosis do not produce red cells normally for two reasons. The fibrotic marrow certainly is not a healthy environment for red cell precursors. There may be an absolute decrease in the quantity of red cell precursors but, also, there may be a considerable amount of ineffective erythropoiesis. Ineffective erythropoiesis is defined by showing that there are red cell precursors maturing within hematopoietic tissue but the mature products do not reach the peripheral blood. Androgens have been used to treat anemia in patients with myelofibrosis and may be effective in patients with decreased red cell production. It is said that young women are more likely to respond . However, some patients treated with androgens show deterioration; it is thought that this accompanies increasing ineffective erythropoiesis. These patients have been reported to experience rapid hepatic and splenic enlargement, and their uric acid levels may increase dramatically over the period of a few months . It is interesting that our patient had those two problems and had been given androgens. To return to the problem of shortened red cell survival, if this can be demonstrated, for instance by 51Cr labeling of the patient’s erythrocytes, splenectomy may be beneficial. This procedure is reasonably safe, but it may be complicated by postsplenectomy thrombocytosis. Occasional patients with platelet counts over 1,000,000/mm3 may experience bleeding difficulties and may require therapy to lower the platelet count to more normal levels. Dr. Kornfeld: Thank you. Now I would like to discuss
several aspects of the terminal course. On admission to Barnes Hospital, there was evidence of severe lactic acidosis, hypoglycemia, renal failure, probable pneumonia and staphylococcal septicemia. In addition, this patient’s myeloproliferative disease had worsened with the white cell count increasing to 180,000/mm3. Dr. Permutt, what do you think was the etiology of the severe lactic acidosis in this patient? Dr. Alan Permutt: The first question I asked was, “Is lactic acidosis solely responsible for her arterial pH of 7.0?” The anion gap was about 36 meq/liter, normal being less than 15 meq/liter. The blood lactate was 23 mmol/liter, sufficiently high to account for the excess anion gap. I first considered that starvation and hypoglycemia with very low insulin levels would promote marked lipolysis with accelerated ketosis. Ketoacidosis does occur in children with glycogen storage diseases, hypoglycemia and low plasma insulin levels. Decreased renal function can increase the ketonemia. However, the serum ketones were only trace positive and probably contributed little to this patient’s acidosis. Lactate, derived from pyruvate, is the end-product of anaerobic metabolism. Increased lactate production occurs in states of diminished oxygenation [8,9]. In experimental studies it has been observed that the liver can utilize all the lactate that the body can produce under the most extreme conditions. It, therefore, seems quite clear that hepatic underutilization must be playing a role in the accumulation of lactate in the blood in virtually every patient with lactic acidosis. The clinical conditions which are associated with lactic acidosis are cardiovasculature insufficiency, septic shock, acute hypoxemia, severe anemia, leukemia and diabetes. In some patients the cause of lactic acidosis is unknown. Death usually occurs when patients have blood lactate levels greater than 7 mmol/ liter. Acute hypoxemia produces increased blood lactate levels with oxygen saturations in the range 60 to 74 per cent. This occurs, for instance, in status asthmaticus. Anemia can be associated with elevated blood lactate levels, but hemoglobin levels are usually less than 6 g/dl, and the blood lactate levels are usually less than 2 mmol/liter. I investigated lactic acidosis occurring in association with leukemia. In one series there were 13 patients with myeloproliferative disorders and lactic acidosis [lo]. Most had acute leukemia, one had multiple myeloma and one had a lymphoma. Six of the 13 patients had shock which could account for the lactic acidosis, but seven of the patients with leukemia had no sign of tissue hypoxia. Four of these patients had rapidly progressive leukemia and it was said that the lactic acidosis was ameliorated with institution of chemotherapy. Therefore, there is reason to believe that the leukocytes were responsible for the excess lactate production.
In summary, then, this patient had multiple reasons for lactic acidosis. First, she had a myeloproliferative disorder with a white blood cell count of 185,000/mm3. She was anemic, although her hemoglobin level was 7 g/dl, which probably did not contribute significantly. She had an arterial PO2 of 62 mm Hg, and this could have contributed somewhat to the lactic acidosis. Lastly, and probably most important, was the presence of septic shock. Dr. Kornfeld: The patient’s plasma glucose concentiation was extremely low, ranging from 2 to 5 mg/dl on several determinations. Do you think that this was true hypoglycemia or possibly spurious values due to ongoing glucose utilization by the large number of leukocytes after the blood samples were drawn? Dr. Permutt: It is well known that in the absence of a glycolytic inhibitor, such as fluoride, leukemic patients can have a so-called pseudohypoglycemia. If you do not separate the plasma from the cells you will get spuriously low values even with normal white blood cell counts. There was no fluoride in the SMA-6 tubes, but how often do we see leukemic patients with serum glucose values of 2 mg/dl? I think that she had true hypoglycemia. There was one report of a plasma glucose of 170 mg/dl with the blood processed as for the other determinations. Most of these glucose determinations were carried out “stat” and I imagine that these cells were spun away from the serum within 15 to 20 minutes of being drawn from the patient. Dr. Kornfeld: Most of the blood samples for glucose determinations were drawn in tubes without fluoride. I calculated that with a white cell count of 180,000/mm3 glucose could be consumed at a rate of 150 mg/ 100 ml/hour. If 15 minutes passed before the blood was centrifuged, about 40 mg of glucose would be metabolized/ 100 ml of blood. Clearly, it is essential to draw the blood into a fluoride-containing tube in order to obtain accurate glucose values in patients such as this one. Dr. Permutt: With that in mind, we assume that the patient did indeed have hypoglycemia. What could have been the etiology? Clearly, the utilization of glucose must exceed glucose production for hypoglycemia to occur. The normal turnover is about 4 to 12 g of glucose/hour, or about 100 to 150 g of glucose/day. Therefore, if the liver makes absolutely no glucose, a patient receiving 100 to 150 g of glucose/day will not become hypoglycemic. In less than 24 hours, this patient received at least 180 g of glucose plus the glucose in the dialysis fluid. The glucose concentration in the dialysis bath is 150 mg/dl. Let us discuss the case for decreased glucose production first, and then increased utilization. First of all, this patient had a 60 pound weight loss with very poor food intake. Thus, she had poor glycogen stores and
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decreased substrate availability for glucose production. In addition to that, lactic acidosis has been shown to be associated with increased levels of glucogenic amino acids in the blood; this is undoubtedly due to impaired utilization by the liver of the gluconeogenic amino acids [ 111. There has been a report of three cases in which the patients had lactic acidosis and hypoglycemia [ 121. All three of these patients had heart disease with severe passive congestion of the liver and, perhaps, that alone could have caused the hypoglycemia. The other condition suggesting that today’s patient had impaired glucose production by the liver is the association of impaired glycogenolysis with sepsis [ 131. Now let us turn to the case for increased glucose utilization. The patient was given more than 150 g of glucose over 24 hours, and still severe hypoglycemia developed. I do not think it is likely that an insulinoma or tumor production of an insulin-like growth factor could account for this increased utilization. Insulin or insulin-like activity inhibits ketosis and she would not have had trace ketonemia. What about glucose utilization in shock? There have been a lot of experimental studies [ 14-161. Wolfe et al. [ 141 reported that, in dogs, endotoxic shock first increases the plasma glucose, but then there is a progressive fall to severe hypoglycemic levels. The reason offered was that there is increased glucose utilization and decreased hepatic glucose production. Incidentally, in the endotoxic shock dogs, the blood lactate level rose from 1 to 8 mmol/liter. Similar results with increased glucose utilization have been observed in burned animals or in those with hemorrhagic shock [15-i 71. What about glucose utilization and white cells? Remember that the body uses about 150 g of glucose/day. If you assume that the white cells are using less than 10 per cent of total daily requirements, they probably would not utilize more than 5 g of glucose/day. But, knowing that this woman had a white blood cell count of 185,000/ mm3, with massive infiltration of the liver and spleen, you could estimate that her total white blood cell mass would be 10 times, and maybe even 100 times, increased over normal. And you could surmise that perhaps her glucose utilization by the white blood cells alone could be as high as 500 g/day. Why does not every patient with leukemia become hypoglycemic? Well, the answer is perhaps that the liver can increase glucose output, maybe fivefold over normal. So, it is only with the combination of increased utilization and decreased production of glucose that these patients would become hypoglycemic: in fact, there have been terminal leukemic patients who have been noted to be hypoglycemic [ 181. So, in summary, this patient had increased utilization of glucose by white cells, she had increased utilization secondary to septic shock, and she had decreased glucose production due to shock, malnutrition and lactic acidosis.
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Another major problem was renal failure. Dr. Kornfeld: Dr. Martin, what do you think was going on in her kidneys? Dr. Kevin Martin: This patient had a mild episode of renal failure in the postoperative period at the other hospital about which we have little information. But this appeared to be resolving at the time of discharge, when her serum creatinine was approximately 2 mg/dl. So, on admission here, her serum creatinine of 3.8 mg/dl indicates another acute deterioration in her renal function. A clue to the possible cause for this is from her laboratory data on admission. Specifically, the extreme leukocytosis, raised serum phosphate level out of proportion to her serum creatinine and serum uric acid levels of 28 mg/dl strongly suggest the possibility of an acute uric acid nephropathy. The mechanism involved here is that of precipitation of uric acid in the distal tubule and collecting duct in which the tubule fluid is acidified, decreasing the solubility of uric acid, and the tubular fluid becomes concentrated. Also, this patient’s severe systemic acidosis would increase the likelihood of uric acid precipitation although hyperphosphatemia and hyperuricemia may also be seen in lactic acidosis. More uncommon is an extrarenal ureteral obstruction by uric acid stones. In addition, we are told that this patient was anuric which is an uncommon finding in most of the causes of acute renal failure and strongly supports the probability of obstruction. Also, there is the suggestion of some uric acid crystals in the small amount of urine that was obtained after a relatively large dose of furosemide was given. The urine electrolytes do not really help us here, since they were determined after the administration of a diuretic. Typically, one might expect a relatively low urine sodium and a urine:plasma creatinine ratio greater than 20 in acute uric acid nephropathy. Although uric acid nephropathy is usually thought of as a complication of chemotherapy for leukemia and lymphomas, this can occur spontaneously in conditions of increased cell turnover such as in this patient. The serum uric acid level of 28 mg/dl here is consistent with the levels found in the other cases. The mean level is usually around 20 mg/dl although levels up to 90 mg/dl have been reported. I would like to conclude with a word about treatment. Probably the best treatment of this entity is prevention, which can be achieved by beginning alkaline diuresis and allopurinol prior to chemotherapy for leukemias and lymphomas. For mild to moderate renal failure, these measures are usually sufficient. However, for severe renal failure or markedly elevated levels of uric acid, treatment should be with dialysis. Peritoneal dialysis is extremely inefficient for uric acid removal with uric acid clearances of approximately 10 ml/min. Hemodialysis with modern dialysers can achieve uric acid clearances
in excess of 150 ml/min. A rapid diuresis usually occurs once the serum uric acid has been normalized. So, in conclusion, I believe that the rapid decrease in renal function was most likely due to acute uric acid nephropathy, probably complicated terminally by her hypotension. Dr. Kornfeld: Finally the patient’s terminal course was complicated by bleeding from the gastrointestinal tract and venipuncture sites, most likely due to the development of disseminated intravascular coagulation. This could have been triggered by the sepsis, the hypotension or by the release of proteases from the circulating granulocytes. I would like to summarize the case in the following way. This was a patient who had very aggressive myelofibrosis leading to severe anemia and an increased susceptibility to infection which was manifested by staphylococcal septicemia as well as probable pneumonia. The combination of septicemia, hypotension and the rapidly increasing white blood cell count probably led to the development of lactic acidosis and disseminated intravascular coagulation. The patient probably did have true hypoglycemia although perhaps not as severe as the laboratory values indicate. This was probably due to several factors, including a poor dietary intake and decreased glucose production by the liver secondary to the sepsis and the presence of lactic acidosis. In addition, the accelerated myelofibrosis led to increased uric acid production and, in the presence of lactic acidosis, this probably led to acute renal failure. PATHOLOGIC
Figure 2. Bone marrow biopsy specimen obtained eight months prior to death. The marrow is fibrotic and hypocellular. Magnification X 120, reduced by 30 per cent.
megakaryocytes and nucleated red cells. Myelocytic elements were observed at all stages of maturation; however, there were relatively few blasts or fully mature forms. The liver was greatly enlarged, weighing 4,500 g. The microscopic appearance did not differ appreciably from that of the biopsy specimen except for extensive centrilobular necrosis, which I would attribute to heart failure, although other factors may also have been contributory. The extent of necrosis may well have been
The pathologic findings as well Dr. Joseph Williamson: as the clinical features of this woman’s disease were most interesting. The appearance of the bone marrow at autopsy was strikingly different from that of the biopsy specimen obtained eight months previously. In the biopsy specimen (Figure 2), the marrow was hypocellular and fibrotic with normal appearing bony trabeculas. At autopsy, the marrow was hypercellular (Figure 3), with a marked increase in the ratio of myelocytic elements to megakaryocytes and nucleated red cells, and the appearance of the bony trabeculas was truly remarkable. The outlines of what appeared to be preexisting relatively normal trabeculas were clearly evident; however, they were extensively decorated or ornamented with very irregular new bone growth with wide bands of osteoid. The few remaining fat cells in the marrow were located in the interstices of the new bone growth. Osteoblasts were numerous; however, no multinucleated osteoclasts were seen. This remarkable pattern was observed both in ribs and vertebral bodies. The femoral marrow was also hyperplastic and, like that in the ribs and vertebrae, contained relatively few
Figure 3. Rib marrow specimen at autopsy. The bony trabe&urn running through the center of the micrograph is comparable to that in the original biopsy specimen except that its surface is extensively ornamented with irregular new bone growth. Note fat ccl/s present in interstice of new bone. The marrow is hypercellular with relatively few megakaryocytes and nucleated red cells. Magnification X 120, reduced by 30 per cent.
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N&e 4. Spleen. The normal architecture of the spleen has been effaced by proliferating immature myelocylic elements. Megakaryocytes and nucleated red cells are much more numerous in the spleen than the bane marrow or in other sites of extramedullary hematopoiesis. Magnification X 480, reduced by 30 per cent.
Figure 5. Extramedullary myelopoiesis in the kidney. Occasional megakaryocytes are present (arrow); however, practically all of the infiltrating cells are immature myelocytic elements. Magnification X 480, reduced by 30 per cent.
Figure 6. Sectioned surface of a kidney demonstrating marked infiltration by myelopoietic cells, sharply restricted to outer medulla.
Figure 7. Perivascular infiltrate of immature myelocytic elements in the pericardium. Magnification X 300, reduced by 30 per cent.
sufficient to compromise gluconeogenesis. Large amounts of iron were present in hepatic cells as well as in Kupffer cells and in sinus lining cells and macrophages in liver, spleen, lymph nodes and bone marrow. Extramedullary hematopoiesis was extensive throughout the liver. As in the marrow, immature myelocytic elements predominated; megakaryocytes were much more numerous than in the marrow, but erythrocyte precursors were still uncommon. The spleen weighed 2,500 g and contained several
recent infarcts. The normal architectural pattern was effaced by proliferating hematopoietic elements in which megakaryocytes and nucleated red cell precursors were much more numerous than in the bone marrow (Figure 4). Extramedullary hematopoietic elements consisting primarily of immature myelocytic cells were also observed in sections of myocardium, epicardium, breast, adrenals, lungs, esophagus, brain, kidney and lymph nodes. In sections of lymph nodes, nucleated red cells were also identifiable and in sections of kidney, occasional megakaryoctyes (Figure 5) were
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present. The infiltrates in the other tissues were virtually indistinguishable from those of classic granulocytic leukemia. The kidneys were of particular interest. They weighed 280 g each, and the hematopoietic infiltrates were restricted to a sharply demarcated zone in the outer medulla bordering the corticomedullary junction (Figure 6). A chronic ulcer was present on the epiglottis. Numerous plasma cells as well as polymorphonuclear leukocytes and macrophages in addition to immature myelocytic elements were present at the margins of the ulcer. Numerous gram-positive cocci and gram-negative rods were present in the base of the ulcer. There were acute and chronic tracheobronchitis with numerous gram-positive cocci and gram-negative rods present. The lungs were quite heavy, the right weighing 900 g and the left 800 g. A large, chronic abscess was present in the upper lobe of the right lung and there was extensive intraalveolar hemorrhage with consolidation of the remaining lobes. The heart weighed 410 g, which represents only a moderate enlargement. There were nonbacterial thrombotic vegetations on the aortic and the mitral valves which were otherwise normal in appearance. Perivascular infiltrates of immature myelocytic elements in the myocardium and in the epicardium (Figure 7) were indistinguishable from those associated with typical granulocytic leukemia. Many of the clinical features and pathologic findings in this patient are consistent with granulocytic leukemia as well as with myeloid metaplasia; in the absence of chromosome studies and leukocyte alkaline phosphatase data, the distinction between these two diseases may be very difficult if not impossible. The extraordinary high white cell count, the effacement of splenic architecture and the widespread infiltrates of immature myelocytic elements with only very occasional megakaryocytes and/or nucleated red cells in numerous tissues in addition to spleen and liver, although consistent with myeloid metaplasia, are highly suggestive of granulocytic leukemia. Unfortunately, chromosome studies were not available. However, the leukocyte alkaline phosphatase data clearly weigh strongly in favor of idiopathic myeloid metaplasia. In this regard, it is of interest that there has been
considerable controversy [2,19] regarding whether myeloid metaplasia can undergo transformation into leukemia and vice versa. Some investigators claim that it is exceedingly rare for acute granulocytic leukemia to develop in subjects with myeloid metaplasia; others estimate that it occurs with a frequency between 5 and 10 per cent. I am not aware of any reports of chronic granulocytic leukemia in subjects with myeloid metaplasia; however, myelofibrosis has been reported to develop in cases of chronic granulocytic leukemia. The nomenclature of this family of disorders is most confusing and reflects the considerable variability in manifestations of the disease in different tissues at any given moment in time as well as progressive changes in a given tissue over a period of time. In this patient, for example, the initial white blood cell count was low to normal, the bone marrow (on biopsy) was hypocellular and fibrotic, with normal appearing bony trabeculas, and the liver biopsy specimen showed extramedullary hematopoiesis. Terminally, the white blood cell count was extraordinarily high, the bone marrow was hypercellular without fibrosis or an increase in reticulin fibers, but with marked osteosclerosis, and there was extensive infiltration of immature hematopoietic elements in many tissues. Although the term myelofibrosis appropriately describes the appearance of the bone marrow at the onset of this particular patient’s disease and is considered to be a fundamental event in myeloid metaplasia, in general it would appear to be a much more variable feature of the basic disorder than the generalized myeloid metaplasia itself which is consistently present in spleen .and liver whether or not the marrow is involved. Thus, I prefer to diagnose this patient’s disorder as idiopathic myeloid metaplasia, which presented initially with myelofibrosis and terminally with osteosclerosis. For reasons which are not clear, the bone marrow was hypocellular early in the course of the disease but became hypercellular terminally. In conclusion, this patient had a rapidly progressive myeloproliferative disorder which in terms of its clinical behavior and pathologic features was clearly malignant. Of the conventional categories of myeloproliferative disorders, idiopathic myeloid metaplasia seems to best fit this patient’s disease. The immediate cause of death was infection with involvement of the upper and lower respiratory tract, culminating in sepsis.
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