In children and adolescents, acute lymphoblastic leukemia (ALL) is one of the most prevalent cancer. Fever, arthralgia, lymphadenopathy, and bleeding manifestations are typical signs and symptoms of ALL. There are times when typical leukemic cells (blast cells) might not appear in the peripheral blood smear (PBS) (aleukemic leukemia) and are diagnosed only through bone marrow examination. ALL can occasionally manifest as osteolytic bone lesions with life-threatening hypercalcemia similar to other cancers of adulthood like multiple myeloma, T-cell lymphoblastic leukemia/lymphoma, and langerhans cell histiocytosis (LCH) [1].

Here, we are reporting two cases of pediatric ALL who presented with such atypical presentation, requiring a high index of suspicion to diagnose this life-threatening condition promptly for timely treatment and optimal outcomes.

1) Case-1

A 10-year-old male child presented with complaint of lower backache for 1 month, which had an insidious onset without any history of trauma/fever/radiation of pain/weakness/numbness in any limb/weight loss. The pain worsened to the point where he had difficulty in walking and climbing stairs. Physical examination was remarkable for tenderness on palpation along the lower thoracic, lumbar, and sacral spine, along with tenderness along both iliac crests, with no focal neurological deficit. There was no spine deformity. Flexion and extension of the back were restricted due to pain. Rest systemic examination was unremarkable. The initial possibilities of LCH, lymphoma, leukemia, secondary bony metastasis were considered.

(1) Investigations

Initial complete blood count (CBC) showed white blood cells of 10×10⁹/L, hemoglobin (Hb) level of 9.2 gm/dL, and platelet count of 285×10⁹/L. The PBS was not suggestive of any atypical cells. Chest X-ray (CXR) done was not suggestive of any mediastinal mass. Computed tomography (CT) whole spine was suggestive of multiple ill-defined lytic lesions involving all visualized vertebrae and pelvic bones (Fig. 1). Magnetic resonance imaging (MRI) whole spine revealed hypointense signals of all cervical, thoracic, lumbosacral bodies favouring malignant infiltrative disorder and pathological partial collapse of multiple thoracic vertebrae between D4 and L2 level, with up to 50% height loss. Positron emission tomography-computed tomography (PETCT) was also suggestive of diffuse hypermetabolism along bone marrow and skeletal lesions involving the axial and appendicular skeleton with partial collapse of a few dorso-lumbar vertebrae suggestive of the possibility of LCH and other haematological malignancies. In view of high suspicion of malignancy and outside bone marrow biopsy being negative, vertebral biopsy from L5 vertebra along with repeat bone marrow aspiration (BMA) and biopsy from both posterior superior iliac spine (PSIS) was done in the same setting. Both these biopsy samples were positive for ALL (80% lymphoblast in BMA) (Fig. 2) and flow cytometry results indicated positivity for the cluster of differentiation (CD) markers CD19, CD20, CD22, CD79a, CD38, CD45, HLA-DR which are suggestive of B-ALL.

Figure 1. (A) CT whole spine was suggestive of multiple ill-defined lytic lesions involving all visualised vertebra and pelvic bones: sagittal section. (B) CT whole spine was suggestive of multiple ill-defined lytic lesions involving all visualised vertebra and pelvic bones: coronal section.

Figure 2. (A) Giemsa-Stained vertebral aspirate smear (×100) shows sheet of blasts. Blasts are intermediate to large in size and exhibit high N/C ratio, with irregular nuclear membranes, immature opened-up chromatin, 1-2 prominent nucleoli and scant agranular cytoplasm. (B) Haematoxylin and eosin-stained trephine biopsy from vertebra (×40) shows sheet of immature cells exhibiting high N/C ratio, hyperchromatic nuclei, inconspicuous nucleoli and scant cytoplasm.

(2) Treatment and follow up

He was started on chemotherapy as per Indian Collabo-rative Childhood Leukemia Group (ICiCLe) 2014 protocol. After completing the induction phase of chemotherapy, minimal residual disease (MRD) analysis done through the flow cytometry showed residual blasts to be less than 0.01% of all leukocytes, suggesting complete remission.

2) Case 2

A 2-year-old boy presented with chronic intermittent low-grade fever and non-productive cough. He also had pain localized initially to the left hip region, later progressing to involve both legs. He was unable to bear his weight independently. The child had sub-acute onset breathing difficulty and was taken to a local hospital. Initial investigations revealed Hb 8.5 gm/dL, total leukocyte count (TLC) 6,500 cells/cubic mm with lymphocyte predominance, and normal platelet count. The PBS did not have any blast or atypical cells. CXR showed mediastinal widening with normal lung parenchyma, which on computed tomography thorax turned out to be a mass in the anterior mediastinum. Parents deferred CT-guided histopathological diagnosis of the mediastinal mass. The child was managed conservatively with intravenous antibiotics and respiratory support. Antibiotics were stopped after a sterile blood culture report and oxygen support was gradually made to room air. Parents were advised to take the child to a higher center for further evaluation and management, but parents took the child home. He remained well for a few days but again developed breathing difficulty, hence brought to our center. On examination, he had tachypnea with reduced air entry in the right infra-scapular and infra-axillary area, along with stony dullness on percussion. Possibilities of chronic infection i.e., tuberculosis with pleural effusion along with underlying malignancy with malignant pleural effusion were considered. Skeletal X-rays showed lytic lesions involving the neck of the left femur and the left humerus bone. CBC revealed anemia, elevated TLC with lympho-mononuclear cell predominance, and thrombocytopenia. PBS showed 80% circulating blasts. Molecular studies revealed T-cell ALL. He also had hypercalcemia with electrocardio-graphy (ECG) changes in form of short QTc interval (320 ms) with maximum serum calcium levels 17 mg/dL at arrival. Hypercalcemia was initially managed with intravenous fluids and furosemide. However, in view of non-improvement, one dose of zoledronate and 4 doses of calcitonin were also given following which serum calcium levels were normalized. Gradually the child developed symptomatic hypocalcemia in form of numbness of extremities, perioral region and tetany (therapy-related attributed to bisphosphonate therapy), with low serum calcium levels (iCa-0.88 mmol/L) on day 5 of hospital stay, which was managed with intravenous calcium gluconate correction with the addition of oral calcium supplementation (Fig. 3). After initial stabilization, the child was started on chemotherapy as per ICiCLe 2014 protocol.

Figure 3. Line diagram showing trends of biochemical parameters and ap-propriate management during hos-pital stay.

Typical signs and symptoms of acute leukemia include fever, pallor, petechiae, ecchymosis, hepatosplenomegaly, lymphadenopathy, and bone aches. These patients can also present with bone and joint pain alone. Only a few cases of ALL that manifested as generalized osteolytic lesions and hypercalcemia have been documented.

Multiple myeloma, lymphoma, LCH, breast or lung cancer metastases are major causes of osteolytic lesions and are more prevalent in the adult population. About 5-20% of malignancies in adults have hypercalcemia. However, in children, it only occurs in 0.4-1.3% of childhood malignancies, making it incredibly rare [2].

In a comprehensive retrospective analysis conducted over a 29-year period at St. Jude’s Children’s Cancer Hospital, only 0.4% had hypercalcemia during the course of malignancy [3]. Hibi et al. observed a greater incidence (4.8%) in 83 participants with pre-B ALL [4].

In a different study, there were less than 20 cases of hypercalcemia complicating acute leukemia and shared similar features i.e., age between 10 and 20 years, osteolytic lesions, normal white cell count without circulating blasts in the peripheral smear [5].

The most common cause of malignancy-related hypercalcemia is ectopic production of parathyroid hormone related protein (PTHrP). Other causes include direct tumor infiltration causing osteolysis and infrequently excessive synthesis of vitamin D metabolites [6,7].

Hypercalcemia at presentation in ALL has prognostic implications with refractoriness to conventional chemo-therapy. These patients might benefit from early treatment intensification because of poor response to traditional chemotherapy [8]. Table 1 enlist various reported cases of pediatric leukaemia presenting as osteolytic lesion and hypercalcemia [4,9-15].

Table 1 . Summary of reported cases of pediatric leukemia presenting with osteolytic lesion and hypercalcemia: literature review.

Authors	Case number	Age/sex	Leukemia phenotype	Osteolytic bone involvement
Hibi et al. [4]	Case 1	8 year/M	BCP-ALL	Hypercalcemia and multiple osteolytic lesion and fractures
	Case 2	3 year/F	BCP-ALL	Hypercalcemia and multiple osteolytic lesion
Chen et al. [9]	Case 3	13 year/M	BCP-ALL	Hypercalcemia and osteolytic lesion in skull and extremities
Shahnazi et al. [10]	Case 4	4 year/F	ALL	Dorso-lumbar vertebra
	Case 5	4 year/F	ALL	Metacarpal bones, radius & ulna metaphysis
	Case 6	8 year/M	ALL	Right humerus
	Case 7	6 year/F	AML	Distal femur, proximal tibia, left femur neck
	Case 8	5 year/M	AML	Right humeral metaphysis
	Case 9	8 year/M	ALL	Thoraco-lumbar vertebra
	Case 10	6 year/F	ALL	Bilateral distal femur, proximal tibia Right distal radius, ulna
	Case 11	9 year/M	ALL	Left femur epiphysis and proximal metaphysis
	Case 12	13 year/F	ALL	Skull bone, iliac bones, lumbar vertebra, bilateral scapular bone
	Case 13	2 year/F	ALL	Left humerus
Sirelkhatim et al. [11]	Case 14	17 year/M	ALL	Lumbosacral area, pelvic bones
	Case 15	12 year/F	ALL	Thoracic vertebra and femur
	Case 16	7 year/M	ALL	Lumbosacral vertebra
Buonuomo et al. [12]	Case 17	9 year/F	BCP-ALL	Right proximal femur, bilateral tibia and ulna, right distal humerus
Shanks et al. [13]	Case 18	14 year/F	BCP-ALL	Hypercalcemia and rib osteolytic lesion
Ganesan et al. [14]	Case 19	16 year/M	ALL	Hypercalcemia and osteolytic lesion of skull, ribs, vertebral bodies, pelvis and long bones of extremities
Trehan et al. [15]	Case 20	9 year/M	B-ALL	Hypercalcemia
	Case 21	8 year/M	Philadelphia positive ALL	Hypercalcemia and osteolytic lesion of thoraco-lumbar vertebra

In conclusion, hypercalcemia alone or combined with osteolytic lesions may be the main clinical presentation of leukemia in children. Clinicians should be extremely vigilant, especially in the early stage of disease onset when the initial hemogram and PBS are completely normal, and no typical clinical sign and symptoms of leukemia are present therefore it is very likely to be misdi-agnosed or mistreated. Hence keeping high suspicion in such cases bone marrow examination should be done at earliest. In addition, hypercalcemia caused by ALL usually responded poorly to hydration and diuretics [9]. Calcium-lowering drugs such as bisphosphonates and calcitonin should be initiated on time. At the same time, blood calcium changes should be closely monitored to avoid therapeutic hypocalcaemia, which is commonly associated with bisphosphonates.

The authors have no conflict of interest to declare.