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CORRESPONDENCE
Year : 2018  |  Volume : 14  |  Issue : 12  |  Page : 1244-1246

Severe hypercalcemia: A rare and unusual presentation of acute lymphoblastic leukemia


1 Department of Pediatrics, Sri Ramachandra University, Porur, Chennai, Tamil Nadu, India
2 Division of Pediatric Hemato Oncology, Sri Ramachandra University, Porur, Chennai, Tamil Nadu, India

Date of Web Publication11-Dec-2018

Correspondence Address:
Julius Xavier Scott
Division of Pediatric Hemato Oncology, Sri Ramachandra Medical Centre, No. 1, Ramachandra Nagar, Porur, Chennai - 600 116, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.187240

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 > Abstract 


Hypercalcemia is a rare and unusual complication of childhood malignancies. Acute lymphoblastic leukemia (ALL) presenting with hypercalcemia and lytic bone lesions is very rare in children. Here, we report a case of a 4-year-old girl with ALL who presented with severe hypercalcemia and radiological evidence of osteolytic lesions. Malignancies are the most common parathyroid hormone-independent cause of hypercalcemia. Severe hypercalcemia is a life-threatening emergency that should be addressed immediately. Effective treatment includes intense hydration, frusemide, calcitonin, and bisphosphonate in addition to the treatment of underlying cause.

Keywords: Acute lymphoblastic leukemia, children, hypercalcemia, osteolytic lesion


How to cite this article:
Dhivyasree S, Dhivyalakshmi J, Sankaranarayanan S, Scott JX. Severe hypercalcemia: A rare and unusual presentation of acute lymphoblastic leukemia. J Can Res Ther 2018;14, Suppl S5:1244-6

How to cite this URL:
Dhivyasree S, Dhivyalakshmi J, Sankaranarayanan S, Scott JX. Severe hypercalcemia: A rare and unusual presentation of acute lymphoblastic leukemia. J Can Res Ther [serial online] 2018 [cited 2019 Sep 20];14:1244-6. Available from: http://www.cancerjournal.net/text.asp?2018/14/12/1244/187240




 > Introduction Top


Leukemia is the most common malignant neoplasm in childhood worldwide accounting for approximately one-third of all malignancies that occur in children younger than 15 years of age.[1] Acute lymphoblastic leukemia (ALL) accounts for approximately 75% of the cases of childhood leukemia. The initial presentation of ALL is usually with low-grade fever, anorexia, weight loss, exquisite bone pain, pallor, lymphadenopathy, hepatosplenomegaly, and bleeding manifestations. Hypercalcemia is an uncommon but serious metabolic disorder in children. The differential diagnosis of hypercalcemia includes metabolic, nutritional, drug-induced, genetic, inflammatory, and neoplastic factors. Compared to adults, hypercalcemia of malignancy is rare in children, and its overall incidence at different stages of the disease is 0.4–1.3%.[2] Presence of frank osteolytic lesions with hypercalcemia is infrequent.[3] Here, we report a child with ALL who presented with severe hypercalcemia and radiological evidence of osteolytic lesions.


 > Case Report Top


A 4-year-old girl child presented to us with fever for 2 months, excruciating pain of both lower limbs and refusal to stand for 15 days. Two weeks prior to admission, she was treated elsewhere with antibiotics, analgesics, and a short course of dexamethasone for 5 days. The investigations done at that time were reportedly inconclusive. On admission, she was febrile, pale, distressed in pain, and not allowing to touch her limbs. Systemic examination showed no organomegaly or lymphadenopathy.

Initial laboratory investigation revealed hemoglobin of 6.8 g/dl, white blood cell count of 6.9 × 109/L with polymorphs of 65%, and lymphocytes of 35% with platelets of 277 × 109/L. Biochemical investigation revealed serum calcium of 13.3 mg/dl, phosphorus of 5.7 mg/dl, sodium of 140 mmol/L, potassium of 2.9 mmol/L, chloride of 101 mmol/L, bicarbonate of 29 mmol/L, lactate dehydrogenase of 195 U/L, and uric acid of 6.4 mg/dl. Her renal and liver functions were normal.

In view of hypercalcemia, the child was started on hyperhydration and furosemide. X-ray long bones revealed multiple osteolytic lesions [Figure 1]. Serial calcium value showed raising trend, for which evaluation done showed normal parathyroid hormone (PTH), urine calcium creatinine ratio, Vitamin D levels, and thyroid function test.
Figure 1: X-ray long bones showing multiple osteolytic lesions

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The child had persistent hypercalcemia despite hydration and diuretics, hence received pamidronate and calcitonin subsequently. Meantime, in view of pain and osteolytic lesion, the child underwent bone marrow aspiration and bone biopsy, which was consistent with common ALL antigen positive pre-B ALL.

Cerebrospinal fluid analysis was negative for malignant cells. Chromosomal analysis of bone aspirate cells revealed a normal female karyotype (46, XX).

With informed consent, the child was started on induction phase chemotherapy with anti-tumor lysis measure. There is a progressive decline in serum calcium and normalization of electrolyte within 10 days of initiating therapy [Figure 2]. The serum calcium returned to normal only after starting chemotherapy in addition to pamidronate and calcitonin. Currently, the child is on regular chemotherapy with normocalcemia.
Figure 2: Progressive decline of calcium levels

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 > Discussion Top


Hypercalcemia is defined as a serum calcium level of more than 12 mg/dl.[4] The causes of hypercalcemia are associated with elevated PTH or a PTH-independent mechanism. The types of PTH-mediated hypercalcemia are primary hyperparathyroidism, familial hypocalciuric hypercalcemia, familial hyperparathyroidism, and secondary hyperparathyroidism. Malignancies are the most common PTH-independent cause of hypercalcemia.[5] Primary hyperparathyroidism and malignancy account for more than 90% of cases of hypercalcemia.[6]

Hypercalcemia in malignancy is mainly because of ectopic production of PTH-related protein (PTHrP), which increases bone resorption by osteoclasts, increases renal reabsorption of calcium, and increases renal excretion of phosphate. Unlike PTHrP or other cytokines such as tumor necrosis factor (TNF), interleukin-1 (IL-1), prostaglandin E2, and TGF-α have also been implicated.[7] In one series of 21 patients, 11 had PTHrP-mediated hypercalcemia, while two patients had raised IL-6 and TNF-α.[7]

Hypercalcemia of malignancy in children has been reported in rhabdomyosarcoma, hepatoblastoma, Hodgkin and non-Hodgkin's lymphoma, brain tumors, neuroblastoma, angiosarcoma, ALL, and myeloid leukemia.[2] The incidence has been reported to be 0.4–1.3% in childhood malignancy with hypercalcemia.[2] ALL presenting with hypercalcemia and lytic bone lesions is a rare event in children, unlike adults, only few cases are reported so far.[4] In ALL, an association with hypercalcemia in patients with t(17;19) has been reported.[7] Hibi et al. reported a higher incidence (4.8%) in a studied group of 83 patients with pre-B ALL.[8] In a large retrospective study of more than 6000 pediatric cancer patients from St. Jude's children's cancer hospital over a 29-year period, only 10 from 2816 children with lymphohematopoietic malignancy had ALL-induced hypercalcemia, of them only seven had hypercalcemia at diagnosis.[2]

ALL presenting with hypercalcemia has a distinctive clinical profile, and most of the reported cases show certain common characteristics.[7] The children tend to be older (second decade of life) and have normal or low white blood cell counts with rare or absent circulating blasts.[5] Characteristically they show a pre-B ALL phenotype with aberrant expression of CD13 and other myeloid antigens and often are positive for t(17;19) on cytogenetic studies. Hypercalcemia is seen more in ALL than myeloid leukemia.

There are case reports of severe hypercalcemia with osteolytic lesion developing alveolar calcification.[9] Severe hypercalcemia is a life-threatening emergency that should be addressed immediately. The main aim of treatment include both lowering the serum calcium and to treat the underlying cause. Effective treatments reduce serum calcium by inhibiting bone resorption, increasing urinary calcium excretion, or decreasing intestinal calcium absorption. Saline hydration and frusemide help in increasing the excretion of calcium. Calcitonin helps in increasing renal calcium excretion and decreasing bone resorption via interference with osteoclast function. Its efficacy is limited to initial 48 h. Bisphosphonate such as pamidronate and zoledronic acid provides sustained maximum effect in 2–4 days. In the series by Inukai et al., in their first cohort study confirmed that hypercalcemia resolved quickly with intravenous bisphosphonate therapy in the 10 of 12 patients.[7] Pamidronate use in conjunction with saline and calcitonin reduces calcium concentration more rapidly. Zoledronic acid, an intravenous biphosphonate, is rarely used in pediatrics for the management of hypercalcemia. Lokadasan et al. had used zoledronic acid in a child and found to be effective in decreasing the calcium level.[4] If the hypercalcemia is refractory to conventional measures, then the use of continuous venovenous hemodiafiltration has been identified as an effective treatment.[10]


 > Conclusion Top


This case is reported to make physicians aware of this rare association if they see any child with bone pain osteolytic lesions and hypercalcemia, malignancy especially ALL should be suspected. Even if the complete blood counts and peripheral smear study are normal, bone marrow aspirate is mandatory to rule out leukemia.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Hossain MJ, Xie L, McCahan SM. Characterization of pediatric acute lymphoblastic leukemia survival patterns by age at diagnosis. J Cancer Epidemiol 2014;2014:865979.  Back to cited text no. 1
    
2.
McKay C, Furman WL. Hypercalcemia complicating childhood malignancies. Cancer 1993;72:256-60.  Back to cited text no. 2
    
3.
Shimonodan H, Nagayama J, Nagatoshi Y, Hatanaka M, Takada A, Iguchi H, et al. Acute lymphocytic leukemia in adolescence with multiple osteolytic lesions and hypercalcemia mediated by lymphoblast-producing parathyroid hormone-related peptide: A case report and review of the literature. Pediatr Blood Cancer 2005;45:333-9.  Back to cited text no. 3
    
4.
Lokadasan R, Prem S, Koshy SM, Jayasudha AV. Hypercalcaemia with disseminated osteolytic lesions: A rare presentation of childhood acute lymphoblastic leukaemia. Ecancermedicalscience 2015;9:542.  Back to cited text no. 4
    
5.
Trehan A, Cheetham T, Bailey S. Hypercalcemia in acute lymphoblastic leukemia: An overview. J Pediatr Hematol Oncol 2009;31:424-7.  Back to cited text no. 5
    
6.
Lafferty FW. Differential diagnosis of hypercalcemia. J Bone Miner Res 1991;6 Suppl 2:S51-9.  Back to cited text no. 6
    
7.
Inukai T, Hirose K, Inaba T, Kurosawa H, Hama A, Inada H, et al. Hypercalcemia in childhood acute lymphoblastic leukemia: Frequent implication of parathyroid hormone-related peptide and E2A-HLF from translocation 17;19. Leukemia 2007;21:288-96.  Back to cited text no. 7
    
8.
Hibi S, Funaki H, Ochiai-Kanai R, Ikushima S, Todo S, Sawada T, et al. Hypercalcemia in children presenting with acute lymphoblastic leukemia. Int J Hematol 1997;66:353-7.  Back to cited text no. 8
    
9.
Colleti Junior J, Carla Armelin Benites E, Spadaccia Dos Santos Fernandes G, Antonio Freddi N, Koga W, Brunow de Carvalho W. Case report: Pulmonary alveolar calcification as a result of severe hypercalcemia due to acute lymphoblastic leukemia. F1000Res 2015;4:111.  Back to cited text no. 9
    
10.
Wang CC, Chen YC, Shiang JC, Lin SH, Chu P, Wu CC. Hypercalcemic crisis successfully treated with prompt calcium-free hemodialysis. Am J Emerg Med 2009;27:1174.e1-3.  Back to cited text no. 10
    


    Figures

  [Figure 1], [Figure 2]



 

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