Chronic myelogenous leukemia simulating chronic granulomatous disease
Table Il-Leukocyte metabolic functions* Age (yr) Function Glucose utilization (i..mol/h.105 cells) Resting Phagocytosing
Glycogen transfer (p.mol/h.105 cells) Resting 0.16 0.10 Phagocytosing 0.11 0.09 Pentose cycle activity (%) Resting 0.9 0.7 Phagocytosing 13.5 8.6 *lnterpretation: In both studies glucose utilization was normal, while glycogen turnover was decreased. Pentose cycle activity during phagocytosis was below the normal range of 30 to 35%. The fact that the patient's cells responded to bacterial challenge by greatly increasing pentose cycle activity when bacteria were present made diagnosis of chronic granulomatosis untenable.
admissions were required for acute bacterial infections. During this period the total leukocyte count steadily increased (Table I) and there was a relative increase in the proportions of neutrophils and primitive granulocytic forms. Coincident with this change, bone marrow examination showed an apparent maturational arrest of all cell lines, with an accumulation of promyelocytic and myelocytic forms. The final admission, at the age of 6 years, was prompted by the appearance of petechial lesions and cutaneous nodules. Hepatosplenomegaly was now detected. Hematologic data (Table I) indicated anemia, leukocytosis and thrombocytopenia. Myeloblastic forms were seen in the peripheral blood film for the first time. Further laboratory studies: Results of the NBT test remained abnormal but differed from those of the first test. At this time a stimulated NBT slide test revealed dye reduction in approximately 50% of the granulocytic cells; extensive phagocytosis of latex particles was also noted. A differential leukocyte count at this time revealed 2% blasts, 23% myelocytes, 54% metamyelocytes, 8% polymorphonuclear cells, 4% lymphocytes and 9% monocytes and there were 13 nucleated erythrocytes per 100 leukocytes. However, as Table II shows, results of leukocyte metabolic function studies at this juncture were similar to the initial determinations. A biopsy of one of the multiple cutaneous lesions was interpreted as showing "leukemia cutis, a manifestation of leukemia of unknown type". For the first time in the patient's course, material from a bone marrow aspirate was obtained for karyotype analysis and a Philadelphia chromosome was identified in 2 of 52 metaphases examined. A leukocyte alkaline phosphatase assay was not done. The morphologic appearance of the bone marrow aspirate was reported as follows: "Active marrow with approximately 2:1 M:E ratio. Most striking is developmental lag of both erythrocyte and leukocyte series. Most of the developing granulocytes are myelocytes and metamyelocytes. The few adult granulocytes seen demonstrate vacuolization. The erythrocytes show marked dysmaturity and some megaloblastosis with nuclear development lagging behind cytoplasmic maturation. Occasional large myelocytes are seen. No megakaryocytes are visualized." Final clinical course During the last 2 months of the patient's life, the clinical course was characterized
by progressive anemia, which necessitated repeated blood transfusions, and recurrent bleeding episodes related to thrombocytopenia. Splenomegaly became massive; a trial of irradiation of the spleen was not followed by any decrease in the spleen's size. Death ensued after sudden cardiorespiratory arrest, approximately 4 years after his first admission. Permission for autopsy was refused.
Discussion This patient's clinical course was marked by an initial phase consisting of recurrent bacterial infections in the absence of gross hematologic abnormalities; a transitional phase during which
the peripheral leukocyte count increased progressively, the leukocyte metabolic functions were abnormal and the electron microscopy studies demonstrated morphologic abnormalities; and a terminal malignant phase during which morphologic and chromosomal
features of chronic myeloid leukemia of adult type became obvious. Though
the percentage of Philadelphia-chromosome-positive cells was low, a similar low frequency has been reported for another patient with chronic myeloid leukemia, and in that patient the leukocyte alkaline phosphatase value was normal.6 Though low concentrations of leukocyte alkaline phosphatase are reported in cases of chronic myeloid leukemia, decreases in enzyme activity occur in other hematologic disorders.7 During the patient's disease, recurrent bacterial infections and the failure
of the neutrophils to reduce NBT suggested chronic granulomatous disease. The normal leukocyte pentose cycle activity, however, and the presence of several infections by catalase-negative6 bacteria made that diagnosis untenable. Although this patient's course was unusual, a similar progression of illness initially characterized by recurrent bacterial infections suggestive of a pre-
leukemic state has been reported..11 Johnson, Griep and Baehner10 studied a disorder in a girl with a history of recurrent infections in whom "abnormal histiocytes" were identified in bone marrow aspirates for 4 years prior to the "onset" of histiocytic leukemia;
FIG. 1-Electron photomicrograph of granulocytes from peripheral blood. Note phagocytosis of two erythrocytes (E). (Magnification, x 100 000.)
X. 4 FIG. 2-Electron photomicrograph of a monocyte is peripheral blood Note unusual clover-leaf confIguratIon of nucleus. (Magnification, x 16000)
1030 CMA JOURNAL/MAY 7, 1977/VOL. 116
leukocyte metabolic functions and phagocytic activity were abnormal during the terminal phase. In the case we describe the metabolic studies were useful in indicating to us that the patient did not have chronic granulomatous disease as suggested by the NBT test.3 The similarity between the clinical presentation of chronic myeloid leukemia (juvenile type) and chronic granulomatous disease has been remarked by Mauer, Lampkin and McWilliams.12 Both our patient and the child whose case was described by Johnson and colleagues10 manifested a number of abnormalities that suggested the ultimate declaration of malignancy early in the illness. The identification by electron microscopy of structural defects and the abnormal patterns of leukocyte metabolic function suggest the ominous nature of the process. It can equally be argued that "preleukemia" is a term applied in retrospect,2 and reflects a failure to recognize the variations of leukemia that cannot be defined by the more traditional, morphologic criteria for diagnosis. It may be more reasonable and, in terms of understanding pathophysiology, more enlightening to develop further and use the results of such studies of leukocyte function and structure as already considered. Whether patients such as ours should be managed with specific antileukemic therapy when "suspicious" abnormalities in leukocyte metabolic functions and structure are identified, and whether institution of therapy would lengthen survival or improve clinical response are speculative questions. The documentation of the course of patients with similar findings may help to clarify these dilemmas. References 1. RHEINGOLD JJ: Acute leukemia. Its smoldering phase, or leukemia never starts on Thursday. JAMA 230: 985, 1974 2. UNMAN .w, SAARNI MI: The preleukemic syndrome. Semin Hematol 11: 93, 1974 3. BAEHNER RL, NATHAN DG: Leukocyte oxidase: defective activity in chronic granulomatous disease. Science 155: 835, 1967 4. WooD HG, KATZ J, LANDAU BR: Estimation of pathways of carbohydrate metabolism. Biochem Z 338: 809, 1963 5. JOHNSON RB JR. BAEHNER RL: Improvement of leukocyte bactericidal activity in chronic granulomatous disease. Blood 35: 350, 1970 6. CANELLOS GP, WHANG-PENG 3: Philadelphiachromosome-positive preleukaemic state. Lancei 2: 1227, 1972 7. CLINE MJ: Metabolism of the circulating leukocyte. Physiol Rev 45: 674, 1965 8. BAEHNER RL: Disorders of leukocyte function and development, in Hematology in Injancy and Childhood, NAIMAN D, Osics FA (eds), Philadelphia, Saunders, 1974, p 493 9. BLOCK M, JACOBSEN LO, BEThARD WF: Preleukemic acute human leukemia. JAMA 152: 1018, 1953 10. JoHNsON DE, GasEs' JA, BAEHNER RL: Histiocytic leukemia following lifelong infection and thrombocytopenia: histologic, metabolic, and bactericidal studies. J Pediate 82: 664, 1973 11. GILMAN PA, JACKSON DP, GUILD HG: Congenital agranulocytosis: prolonged survival and terminal acute leukemia. Blood 36: 576, 1970 12. MAILER AM, LAMPKIN BC, MCVo.stLs.S NB: The leukemias and reticuloendothelioses, in. Hematology in Infancy and Childhood, op cit. p 665