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Chin Med J (Taipei) 1997;60:213-8.
Section of Medical Oncology, Department of Medicine, Veterans General Hospital-Taipei, and National Yang-Ming University School of Medicine, Taipei, Taiwan, R.O.C.
The patient, a 28 year-old female, received treatment for secondary amenorrhea two months before her first admission to our hospital. She was later found to have central type diabetes insipidus and acute myelomonocytic leukemia. A diagnosis of panhypopituitarism was established but there was no laboratory or radiological evidence of neuroleukemia. Complete remission was obtained after one course of induction chemotherapy. She received four more courses of chemotherapy including one course of high-dose cytosine arabinoside (Ara-C) and 14-day granulocytic colony-stimulating factor (G-CSF) for peripheral blood stem cell (PBSC) mobilization. Then she received autologous PBSC transplantation (Auto-PBSCT). Unfortunately leukemia relapsed 4 months after transplantation. The patient expired soon due to severe electrolyte imbalance and sepsis. Throughout the whole course, her pituitary function was only partially recovered after treatment and there was no laboratory or radiological evidence of CNS leukemia.
[Chin Med J (Taipei) 1997;60:213-8.]
Keywords: acute myeloid leukemia, amenorrhea, diabetes insipitus, panhypopituitarism
Received: October 13, 1996.
Accepted: July 14, 1997.
Address reprint requests to: Dr. Chueh-Chuan Yen, Section of Medical Oncology, Department of Medicine, Veterans General Hospital-Taipei, No. 201, Sec. 2, Shih-Pai Road, Taipei, Taiwan, R.O.C.
Diabetes insipidus (DI) or other pituitary dysfunction occurs only rarely in patients with acute myeloid leukemia (AML). Less than 60 cases have been reported in the literature [1-5]. Cytogenetic abnormalities are frequently found, with chromosome 7 being most commonly involved. Most of these patients have poor prognosis and are refractory to treatment [1-5]. Here we report a patient with AML that was complicated with panhypopituitarism.
Except for history of having glucose-6-phosphate dehydrogenase deficiency (G6PD), the patient, a 28 year-old married female, has apparently been in good health. She has undergone Caesarian section twice without any complication. Two months before admission, she developed secondary amenorrhea. She went to a local clinic and was told to have inadequate serum levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH). Some medication was given and she resumed normal menstruation. Unfortunately symptoms of polyuria and polydipsia appeared one month later. A hemogram check made at that time was normal. She was transferred to another hospital with an impression of DI. CT scan of brain was done but no definite abnormality was found. Generalized ecchymosis developed subsequently and a hemogram showed WBC of 40.5 x 109/L with 35% blast cells. Bone marrow aspiration disclosed a picture of AML. She was then referred to our hospital.
The bone marrow smear revealed an excess of both myeloblasts and monoblasts with relative eosinophilia. Cytochemistry showed positive for myeloperoxidase (92%), chloroacetate esterase (42%), non-specific esterase (27%) and negative for periodic-acid Schiff. Immuno-phenotyping revealed My4 (CD14) : 28%; My7 (CD13) : 71%; My9 (CD33) : 57%; MO1 (CD11b) : 21% and MO2 (CD14) : 16% (Coulter Immunology, U.S.A ). The results were in favor of a diagnosis of acute myelomonocytic leukemia with eosinophilia (M4EO) (Figure 1). Chromosomal study, however, was not rewarding due to a poor sampling. Induction chemotherapy with Ara-C 100 mg/m2 every 12 hours for seven days and daunorubicin 45 mg/m2 daily for three days were given shortly after establishment of the diagnosis. Polyuria with daily urine output up to 10 liters, low urine osmolality (159 mosm/kg) and hypernatremia (serum sodium = 168 mmol/l) were found upon admission. Desamino-8-D-arginine vasopression (DDAVP) 20 micron g was given by nasal spray twice a day with a good response. Central type DI was blamed for the complication. Magnetic resonance image (MRI) study of the brain was done but no abnormality was found over pituitary gland or hypothalamus. Cerebrospinal fluid (CSF) study had no evidence of leukemia, either.
Hormonal studies showed panhypopituitarism (Table 1). Hypothalamic function was not examined due to her critical condition. Replacement therapy with cortisone acetate, thyroxine and DDAVP was given. She also had menorrhagia during hospitalization, which, most probably due to oxytocin deficiency, could only be controlled by ergonovine. She showed good response to both chemotherapy and hormonal replacement. Bone marrow examination two weeks after completion of chemotherapy showed complete remission. Two courses of intrathecal chemotherapy with Ara-C, methotrexate and dexamethasone were given. She was discharged with a normal hemogram whilst still on hormonal replacement therapy.
A human leukocyte antigen (HLA) typing of possible donors did not find a single matched sibling or relative . She was then given 3 courses of consolidation chemotherapy and one course of high dose Ara-C treatment. For the purpose of PBSC mobilization, granulocytic colony-stimulating factor (G-CSF) 10 micron g/kg/day was given subcutaneously for 14 days after high dose Ara-C therapy. Peripheral blood stem cells (PBSC) were collected by a Fenwell 3000-plus cell apparatus system for 4 days with a daily processed blood volume up to 10 liters. Also another six courses of intrathecal chemotherapy with Ara-C, methotrexate and dexamethasone were given during this period of time.
Pretransplant conditioning regimen consisted of busulfan 16 mg/kg in 4 days and cyclophosphamide 60 mg/kg/day for two consecutive days. Cryopreserved PBSC was thawed at bedside in a 37OC water bath and was transfused to patient immediately with an estimated mononuclear cell loading 8.2 x 108 / kg . The whole transplant course was uneventful. Her neutrophil was over 0.5 x 109 /L on day 15 after transplant and her platelet count over 20 x 109 /L on day 17. She was discharged on day 22.
Unfortunately, leukemia relapsed 4 months after transplantation. She was admitted again and received high dose Ara-C for salvage treatment. However, abdominal pain with diarrhea occurred three days after initiation of chemotherapy. Stool culture yielded Pseudomonas aeruginosa. So strong antibiotics were used. In the mean time, hyponatremia (Na=107 mmol/l) developed. Serum cortisol level was below normal (Table 1). DDAVP was hold and sodium chloride solution was given for correction. Also supplement of glucocorticoid was increased. Her serum sodium level was corrected up to 136 mmol/l in two days. But her consciousness was changed and was progressed into deep coma in the following two days. Neurological examination disclosed four limbs paralysis with nystagmus. Emergent brain CT yielded negative findings. Lumbar puncture was performed but found no evidence of CNS infection or leukemia. Central pontine myelinolysis due to rapid correction of hyponatremia was highly suspected. Spiking fever developed subsequently and patient's condition deteriorated rapidly despite our intensive treatment. Patient expired 15 days after admission.
Medication with thyroxine, cortisone acetate and DDAVP had continued throughout the whole course, but follow-up study showed only partial recovery of LH and FSH level (Table 1). Polyuria and hypernatremia recurred, however, once DD-AVP was abruptly withdrawn. Throughout the ill course, there was no laboratory or imaging evidence of CNS leukemia.
Many disorders can cause panhypopituitarism: neogrowth (adenoma, metastatic tumor, or leukemia); inflammatory disease (sarcoidosis, tuberculosis), vascular disorder (Sheehan's syndrome, carotid artery aneurysm), trauma, development anomalies, hemochromatosis, amyloidosis, or idiopathic. Although none of the radiological and laboratory examinations could find any evidence in this case, the most possible cause of panhypopituitarism, based on the clinical course, was leukemic cell infiltration over pituitary-hypothalamus system.
Involvement of the central nervous system by leukemia cells could occur in patients with acute leukemia of lymphoid or monocytic origin. Such involvement, however, is seldom presenting as central DI or panhypopituitarism. In review of English literature, about 60 patients with both leukemia and DI have been described [1-5]. In this group, about 40 patients had AML [1]. The possible pathogenesis of DI or pituitary dysfunction in patients with acute leukemia included diffuse leukemic cell infiltration of pituitary gland and/or hypothalamus and thrombosis of small vessel in pituitary gland or hypothalamus. Masses et al have reported perihypophyseal leukemic infiltrates in 46% of patients with acute leukemia at autopsy, but none of them had DI antemortemly [6]. In contrast, Miller et al have reported 9 cases of acute leukemia with DI and concomitant leukemic cell infiltration over neurohypophyseal system at autopsy [7]. Rosenzweig and Kendall, on the other hand, have reported thrombosis of small vessels and coagulative necrosis in the paraventricular nuclei and congestion of the supraoptic nuclei in a patient with AML [8]. Nonetheless, it is hard to prove any of these unless in an autopsy setting.
Several clinical and pathological features are characteristics of these patients with AML and DI. First is the association of monosomy 7 or other abnormality of chromosome 7 and myelodysplastic syndrome (MDS) with these patients (Table 2). Eight out of ten patients with AML and DI, in whom banded chromosomal analysis was done, had monosomy 7 [1]. Of the other two patients, one had del(7)(q22), that preceded the development of monosomy ; the other had inversion of chromosome 16 and deletion of short arm of chromosome 17. Monosomy 7 is a common cytogenetic abnormality seen in AML patients, with a reported incidence of 7.4-9.5% in de novo AML and 28.6% in secondary AML [9]. Monosomy 7 has been found to associate with defective chemotaxis of neutrophil. This defect is associated with a marked reduction of GP130, a major surface glycoprotein of the granulocyte, which leads some to propose that change in the surface properties of neutrophil might predispose them to aberrant function leading to DI [10]. The actual mechanism, however, remains unsettled.
Secondly, a clinical evidence of neuroleukemia of the affected patients is often lacking. A brain image study of 23 patients reported to have acute leukemia and concomitant DI showed only four of them (17.4%) with abnormal findings. Empty sella syndrome was found in two and enhancing lesions over pituitary stalk or suprasellar region were found in another two [1-4,11]. Cerebrospinal fluid was analyzed in 12 patients and leukemia cells were found in only two cases (11.8%). For the present case, results of both MRI of brain and CSF studies were negative.
The third is the inconsistent temporal relationship between endocrine dysfunction and leukemia (Table 2). Ra'anani [2] has reviewed 21 cases of AML in association with DI and found that DI occurred before clinical leukemia in 6 cases, concurrently with it in 10 cases, and after leukemia presentation in 5 cases. In our case, leukemia was clinically noted shortly after the occurrence of DI.
The fourth is the resistance of the symptoms of DI to chemotherapy. None of the reported cases had their DI reversed after chemotherapy, suggesting a destructive nature of the lesions over pituitary or hypothalamus system [12,13]. In our patient, partial recovery of her hypothalamus-pituitary function has been obtained , but she still needed DDAVP to maintain her fluid and electrolyte balance.
Finally, response of leukemia to chemotherapy has been poor. No prolonged complete responder has ever been reported and most of the reported cases died soon after diagnosis, possibly because they were derived from MDS or had unfavorable cytogenetic abnormality (monosomy 7). The present case, initially responded well to chemotherapy and remained in continuous remission until four months after auto-PBSCT when relapse was found. However, her relapse-free survival was longer than that reported by others (1 year vs 1-8 months) [1]. It may be due to the more favorable subtype of AML of this case (M4EO). Castagnola et al [1] had reported a case with inversion of chromosome 16 who survived for 20 months, much longer than ever reported. Cytogenetic study was not available for our patient, however.
In her final clinical course, severe hyponatremia developed soon after chemotherapy. The causes of hyponatremia may be multifactorial: overdose of DDAVP, adrenal insufficiency, diarrhea, or combination of these. Her subsequent change of consciousness was most probably due to central pontine myelinolysis resulting from rapid correction of hyponatremia [14]. Although MRI of brain was not done due to her poor condition, her clinical course was in favor of this diagnosis.
Some of the case reported in the literature are summarized in table 2. Patients with AML associated with central DI or panhypopituitarism often have monosomy or other abnormality of chromosome 7. Laboratory or imaging evidence of neuroleukemia is often lacking. They often respond poorly to chemotherapy and their pituitary gland function could not be reversed completely by chemotherapy. The few cases that had responded well to treatment may belong to a favorable prognostic type, like M4EO.
Copyright: 1997, Chinese Medical Association (Taipei)