|Year : 2012 | Volume
| Issue : 1 | Page : 151-153
Obesity as the initial manifestation of central nervous system relapse of acute lymphoblastic leukemia: Case report and literature review
Li-Dan Zhang, Yan-Hong Li, Zhi-Yong Ke, Li-Bin Huang, Xue-Qun Luo
Department of Paediatric, The First Affiliated Hospital of Sun Yat-Sen University, Zhongshan Er Lu, Guangzhou, China
|Date of Web Publication||19-Apr-2012|
Department of Paediatric, The First Affiliated Hospital of Sun Yat-Sen University, Zhongshan Er Lu, Guangzhou 510080
Source of Support: None, Conflict of Interest: None
A 6-year-old boy with acute lymphoblastic leukemia in remission experienced hyperphagia, obesity, and emotional disorders. Cytomorphologic examination of cerebral spinal fluid (CSF) and cranial MRI did not help in differentiating between central nervous system leukemia (CNSL) and other CNS diseases including tuberculosis in this boy. Flow cytometric CSF analysis on repeated lumber puncture detected lymphoblasts, while microscopic CSF examination did not definitively show relapse disease. The diagnosis of CNSL was thus made and confirmed by the response to leukemia treatment. Obesity can be the first manifestation of CNSL and the diagnosis can be challenging. A combination of CSF cytomorphology, CSF flow cytometry, and cranial MRI can be useful in the diagnosis of the disease. Two mechanisms of CNSL-related obesity are discussed based on the literature review.
Keywords: Central nervous system leukemia, childhood, obesity
|How to cite this article:|
Zhang LD, Li YH, Ke ZY, Huang LB, Luo XQ. Obesity as the initial manifestation of central nervous system relapse of acute lymphoblastic leukemia: Case report and literature review. J Can Res Ther 2012;8:151-3
|How to cite this URL:|
Zhang LD, Li YH, Ke ZY, Huang LB, Luo XQ. Obesity as the initial manifestation of central nervous system relapse of acute lymphoblastic leukemia: Case report and literature review. J Can Res Ther [serial online] 2012 [cited 2020 Jun 4];8:151-3. Available from: http://www.cancerjournal.net/text.asp?2012/8/1/151/95200
| > Introduction|| |
In most cases, central nervous system leukemia (CNSL) can be diagnosed without difficulty. However, CNSL manifestations can vary. Some patients are asymptomatic and have only positive findings of leukemia cells in cerebrospinal fluid (CSF) following lumbar puncture (CNS2 status) and/or found to have CNS involvement following postmortem autopsy. , In rare cases, obesity can be the first manifestation of CNSL, and should be distinguished from other causes of obesity. Here we report a boy with this disorder and discuss two identified mechanisms of CNSL-induced obesity based on the literature review.
| > Case Report|| |
A 6-year-old boy with acute lymphoblastic leukemia (ALL) without evidence of CNSL at diagnosis  had been in continuous complete remission (CR) for 2 years on the modified ALLIC BFM2002 protocol  with total 14 intrathecal injections (methotrexate and dexamethasone). The patient's clinical data at diagnosis and treatment response are shown in [Table 1]. During the last 3 months of 1.5 years of maintenance chemotherapy, he experienced hyperphagia and excessive weight gain of 11 kg, and became introvert, taciturn, and sensitive without headache. Neither thirst nor polyuria was complained. He had previously been vaccinated with BCG and had no known history of tuberculosis (TB) contact.
Axillary temperature and blood pressure were normal on admission. His weight was 41 kg as compared to 30 kg, 3 months earlier, and his height 116.0 cm (−1 standard deviation for Chinese of his age). The body mass index was 30.84, over the 97 th percentile for age and sex. Physical examination including the neurological system was unremarkable except for generalized obesity accompanied by slightly increased back hair without hyperpigmentation, acne and acanthosis nigricans, and hepatomegaly of 6 cm below the costal margin without other organs enlargement. Testicular volume was 3 mL and pubic hair at Tanner stage 1 (prepubertal).
Endocrine studies suggest that the boy had normal levels of morning ACTH, morning cortisol, adrenal hormones, and had normal diurnal rhythm of cortisol and thyroid function. Fasting insulin level was normal; however, elevated HOMA index indicated mild insulin resistance [Table 2].
Imaging findings were hepatomegaly with fatty changes on ultrasound, normal chest x-ray, slight low signal on T1WI, and high signal on T2WI and FLAIR MR images in the cerebral cortex, basal ganglia nuclei, hypothalamus, midbrain, pons, and symmetrical bilateral periventricular areas; on enhanced T1-weighted images, mild increase in thickness and enhancement of meninges, and mild nodular enhancement of trigeminal, oculomotor, optic chiasm, hypophyseal infundibulum and acoustic nerves, as well as mild enhancement of pituitary stalk with partial empty sella and loss of the normal hyperintense signal of the posterior pituitary [Figure 1]a and b.
|Figure 1: The MRI shows thickening and mild nodular enhancement of the optic chiasm (arrow a) and hypophyseal infundibulum (arrow b) on T1WI (a) and enhanced T1WI (b) in hypothalamic area, and mild|
enhancement of meninges (arrow c) on enhanced T1WI, as well as partial empty sella (arrow d) before treatment. The thickened optic chiasm and hypophyseal infundibulum returned to their normal sizes on T1WI (c) after treatment; however, the partial empty sella remained unchanged
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Data of CSF examination are shown in [Table 2] and [Figure 2]. Bone marrow aspiration showed hematological remission (1% immature lymphocytes). All the tests performed for TB were negative, including CSF examination [Table 3], PPD skin test and serum anti-PPD IgG.
|Figure 2: CSF fl ow cytometry analysis showed the blasts (arrow) were positive for CD22, CD10, CD34, HLA-DR, CD19, and CD79a|
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After an extensive workup, the boy was diagnosed with isolated CNS relapse of ALL according to the results of flow cytometric CSF analysis on repeated lumber puncture. He then received induction chemotherapy with vincristine, daunorubicin, L-asparaginase, dexamethasone, and intrathecal injection with methotrexate and dexamethasone every 3 days for 3 doses followed by every week for another three doses. Cranial MRI showed marked improvement [Figure 1]c and the CSF normalized after the third intrathecal injection. The body weight was reduced to 28 kg within 5 months on continued treatment.
| > Discussion|| |
Two different mechanisms of CNSL-induced obesity associated with hypothalamic dysfunctions have been described in the literature. One of those is related to dysfunction of ventromedial hypothalamus due to leukemia infiltration, which integrates peripheral neural and hormonal afferent signals of satiety and energy reserve and directs neuroendocrine efferent arms to effect energy storage versus expenditure. The dysfunction leads to hyperphagia and vagally mediated potentiation of insulin secretion, resulting in intractable weight gain, termed "hypothalamic obesity". , Except for leukemia, other tumors such as glioma with invation of hypothalamus found on cranial MRI at the level of the optic chiasm can also cause hypothalamic obesity.  Another leukemia-related obesity results from destructive infiltrate of the corticotropin-releasing hormone (CRH) system mainly distributed in paraventricular nucleus of hypothalamus. The infiltrate removes a restraining influence on pituitary function, resulting in adrenocorticotropic hormone (ACTH) hypersecretion, adrenocortical hypertrophy, and clinical consequences of Cushing's disease. , In patients with leukemic involvement of hypothalamic region, some other unusual clinical manifestations were also reported, such as diabetes insipidus  and emotional or behavior disorders. 
In this case, a differential diagnosis was mandatory. Although there were abnormal findings on cranial MRI and CSF examination, no morphologically definitive lymphoblasts were detected in CSF. Therefore, the diagnosis of CNSL could not be confirmed or excluded. Some diseases besides leukemia can cause hypothalamic damage resulting in obesity and emotional changes, such as brain tumors and TB. ,, In the present patient, cranial MRI did not suggest brain tumors. It was more important in this boy to differentiate between CNSL-induced and TB-induced obesity because (1) the boy's CSF changes in white blood cell count as well as levels of chlorine, glucose and protein were similar to those seen in CNS TB; (2) he was on maintenance chemotherapy and susceptible to TB infection; and (3) China is one of the TB-endemic countries. Misdiagnosis would lead to wrong treatment and devastating consequences. However, further investigations failed to support the diagnosis of TB [Table 2]. A repeated lumber puncture and flow cytometric CSF analysis detected many lymphoblasts, even though routine light microscopic examination only showed "a few suspected immature lymphocytes". The diagnosis of CNSL was thus made and confirmed by the response to leukemia treatment.
The boy had hypothalamic obesity rather than Cushing's disease because no Cushing's syndrome and excessive ACTH secretion were found; however, hyperinsulinemia was not found as there was no sign of acanthosis nigricans and the fasting insulin level was normal. Although MRI showed partial empty sella in this patient, diabetes insipidus was not observed. It is interesting that our patient and the other previously reported  with extensive cerebral leukemic involvement only exhibited hypothalamic obesity without additional neurological signs.
The conventional method of diagnosing CNSL is morphological examination of CSF sample by light microscopy. Interpretation of the findings, however, may be difficult partially because of the morphological similarities between benign and malignant cells in CSF sample. Flow cytometry is more sensitive than cytomorphology in the detection of leukemic cells in CSF.  For patients with atypical CNSL, it is particularly useful for making the diagnosis by a combination of cytomorphology, flow cytometry and cranial MRI, as shown in this case.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]