hypercalcemia complicating childhood malignancies

256

Hypercalcemia Complicating Childhood Malignancies Charles McKay, M.D.,*,§ and Wayne L. Furman, M.D. t$

Background. Hypercalcemia complicating malignancy is a frequent complication in adults, but little has been published about the pathogenesis or the true incidence of hypercalcemia in children with cancer.

Methods. Hypercalcemia developing in childhood malignancies was studied retrospectively at St. Jude Children’s Research Hospital to determine its incidence, the timing of its presentation, and its response to therapy.

Results. Over a 29-year period, 25 children (median age, 9.5 years) had been diagnosed and treated for hypercalcemia that occurred during the course of their malignancy. These 25 represented 0.4% of the total number of children treated for cancer at the institution during that period. Their malignancies comprised acute leukemias (11; O.6%), rhabdomyosarcoma (4; 1.2%), malignant rhabdoid tumor (Z), Hodgkin disease (I), non-Hodgkin lymphoma (I), hepatoblastoma (2), neuroblastoma (I), brain tumor (11, angiosarcoma (I), and a solid malignant tumor of undetermined type.

Conclusions. Patients with acute lymphoblastic leukemia were more likely to present with hypercalcemia at the time of their initial diagnosis and to achieve resolution of this complication, whereas patients with solid tumors presented with hypercalcemia later in the course of their disease and had hypercalcemia that was more resistant to therapy. In contrast to adults with cancer, hypercalcemia of malignancy is extremely rare in children. Cuncer 1993: 72:256-60.

From the Divisions of *Nephrology and tHematology/Oncol- ogy of the Department of Pediatrics, College of Medicine, The Univer- sity of Tennessee, Memphis; and the $Department of Hematology- Oncology, St. Jude Children’s Research Hospital, Memphis, Tennes- see.

Supported in part by grants CA-23099, CA-20180, and CA- 21765 and by the American Lebanese Syrian Associated Charities (ALSAC).

Current address: Division of Pediatric Nephrology, Duke Uni- versity Medical Center, Durham, North Carolina.

The authors thank Ann Shinall and Vicki Gray for manuscript preparation and Kate Thomas for editorial review.

Address for reprints: Wayne L. Furman, M.D., Department of Hematology-Oncology, St. Jude Childrens’ Research Hospital, P.O. Box 318, Memphis, TN 38101-0318.

Accepted for publication February 22, 1993.

Key words: hypercalcemia of malignancy, pediatric cancer. calcium metabolism.

Hypercalcemia reportedly occurs in 5% to 20% of adults with malignant disease,’ but little has been published about the pathogenesis or the true incidence of this metabolic complication in children with cancer. The literature on hypercalcemia of malignancy in children consists of case reports, pathology series, and the inclusion of children in adult series.’-15 Which children with cancer are likely to have hypercalcemia and how this complication might affect their outcome have been unclear. We undertook this retrospective review to char- acterize better the incidence, symptoms, evaluation, treatment, and outcome of children with hypercalcemia of malignancy. Defining the nature of this complication in children will allow the recent advances in under- standing16-19 and treatment this disorder in adults to be applied to pediatric patients.

Methods

Twenty-five children with hypercalcemia were identified from the charts of 3239 patients with malignant solid tumors and 2816 patients with acute leukemia or lymphoma treated at St. Jude Children’s Research Hos- pital (SJCRH) from March, 1962 through June 30,1991 (Table 1). Hypercalcemia was defined as total serum calcium of 11.5 mg/dl or greater. We further character- ized the identified patients according to diagnosis; age at diagnosis; timing, severity, and symptoms of the hypercalcemia; treatment administered; and response to treatment (Table 1). The immunophenotype and cytogenetics of the children with hematologic malignancies are listed in Table 2.

The etiology of hypercalcemia was examined by re- viewing the records for radiologic evidence of bone metastases (technetium 99 bone scan or skeletal radiographs) and for data on calciotropic hormones and renal function.

Hypercalcemia in Childhood Malignancies/McKay and Furman

Table 1. Clinical Characteristics, Treatment, and Outcome of Children With Hypercalcemia of Malignancy

257

Timing of Specific Outcome of Sex hypercalcemia treatment hypercalcemia Status*

Patient Age no. Diagnosis (yr)

1 2 3 4 5 6 7 8 9

10 11 12 13 14 15 16 17 18 19 20 21 22 23

24

25

HD ALL AMoL Unk ALL RMS HB ALL RMS ALL ALL RMS ALL ALL RMS ALL NHL Rhabdoid tumor Rhabdoid tumor BT ALL HB NF TYpe I

ALL

NB

angiosarcoma

17 18 18 14 4

15

14 3

13 2 4

10 16 6 7

13 6 mo 3

10 16

16

15

22 mo

7 mo

7 mo

M M F F F M M F F M M F F M F F M M F F F M F

M

M

15+ mo post-Dx 46 mo post-Dx At Dx At Dx At Dx 8+ mo post-Dx 1+ mo post-Dx At Dx 22+ mo post-Dx At Dx 23+ mo post-Dx 1+ yr post-Dx At Dx At Dx At Dx At Dx 9+ mo post-Dx At Dx 8+ mo post-Dx 40 mo post-Dx 21 mo post-Dx 1 mo post-Dx 2 mo post-Dx

At Dx

29 mo post-Dx

IVF, L, Cs, P IVF, L, Cs None IVF, L, Cs, M IVF IVF, L, Cs, C, M IVF, L IVF, L, C, Cs IVF, L, Cs IVF, L, C IVF, L IVF, L, Cs, C, P c s IVF, L, Cs IVF, L, Cs, M Dialysis (tumor lysis) IVF, L, Cs, C, EHDP IVF, L, Cs IVF, L IVF, L, C IVF, L, C IVF, L IVF, L

IVF, L, C, Cs

Resolved Resolved Early death Early death Resolved Persisted Resolved Resolved Persisted Resolved Resolved Persisted Resolved Resolved Resolved Resolved Resolved Resolved Resolved Resolved Resolved Resolved Resolved

Resolved

DOD 20 mo DOD 92 mo 3 days-Met death DOD 6 days DOD 7 mo DOD 10 mo DOD 7 mo Death 1 yr CMVP DOD 23 mo Alive CCR 1 yr Septic death 23 mo DOD 14 mo CCR 6+ yr DOD 20 mo Alive Alive CCR-3 yr DOD 1 yr DOD 5 mo DOD 10 mo DOD 42 mo DOD 23 mo DOD 13 mo DOD 4 mo

Alive on treatment 13+ mo

DOD 30 mo IVF Persisted

Dx: Diagnosis; HD: Hodgkin disease; ALL acute lymphoblastic leukemia; AMoL acute monocytic leukemia; Unk: unknown type of solid tumor; RMS: rhabdomyosarcoma; HB hepatoblastoma; NHL non-Hodgkin lymphoma; BT, brain tumor; NB: neuroblastoma; I V F intravenous fluids; L: furosemide; Cs: corticosteroids; P: oral phosphate; M: mithramycin (plicamycin); C: calcitonin; EHDP etidronate disodium diphosphonate; DOD dead of disease; Met: metabolic; C M V P cytomegalo- virus pneumonia; CCR continuous complete remission. * Time from diagnosis of malignancy.

Results

The 25 children identified with hypercalcemia of malignancy ranged in age from 6 months to 18 years (median age, 9.5 years; Table 1). Most patients had either acute lymphoblastic leukemia (ALL; n = lo), or rhabdomyosarcoma (n = 4); there were two cases of malignant rhabdoid tumor, two of hepatoblastoma, one case each of Hodgkin disease, non-Hodgkin lymphoma, acute monocytic leukemia, brain tumor, neuroblastoma, angiosarcoma, and malignant abdominal tumor of unknown origin. Patient 19 presented with a primitive neuroectodermal tumor of the brain and was found to have a malignant rhabdoid tumor of the left kidney about 1 month later.

Hypercalcemia of malignancy had developed in 11 of the 25 children at the time of their original diagnosis. In the other 14 patients, hypercalcemia was noted from 1 month to 3 years after the original diagnosis during periods of disease recurrence or progression. HypercaI-

cemia at diagnosis was seen most often in patients with ALL (7/10), whereas the patients with lymphomas or solid tumors had hypercalcemia later in the course of their disease (10/14).

The symptoms associated with the onset of hypercalcemia were nonspecific and included abdominal or back pain, hypertension, fatigue, poor appetite, nausea, vomiting, polyuria, constipation, and irritability. There were no identifiable differences in the pattern of symptoms among the different types of malignancies. The degree of hypercalcemia ranged from mild to severe, with 10 of the 25 patients manifesting total serum calcium concentrations greater than 15 mg/dl.

Acute renal failure was evident in six patients. In one of these, tumor lysis (and not hypercalcemia) seemed to have caused the acute renal failure; the patient’s creatinine level had been normal at diagnosis of hypercalcemia and malignancy, and had risen only with the institution of chemotherapy. During the period of tumor lysis, this patient had become hypocalce-

258 CANCER July 1, 1993, Volume 72, No. 1

Table 2. Immunophenotype and Cytogenetics of the Children With Hematologic Malignancies

Patient FAB no. subtype Immunophenotype C ytogenetics

2 N A N A N A 3 M 5 Acute monocytic leukemia Probable t(15:17) 5 L3 Matu re B ALL 4 6 XX/46,XX, 14q+/46,XX,lq+,14q+ 8 L1 Pre-B ALL 46,XX

1 0 L3 Matu re B ALL 46,XY, -9,+f, t(8: 14),dir ins( 13; 14) 11 L1 Common ALL (B lineage) N A 13 L1 Early pre-B ALL 53,XX,+5,+12,+18,+21,+de1(6)(q2lq23),

1 4 L1 Early pre-B ALL 46,XY,t(l7;19)(qZZ;p13.3)

21 L2 Early pre-B ALL 46,XX,t( 17: 19)(q22:pl3) 24 L1 Pre-B ALL 46,XY 17 NHL T-cell lymphoblastic 46,XY,del(7)(q32),del(lO)(p14),t( 1: 10)

FAB, French-American-British; N A not available; ALL: acute lymphoblastic leukemia; N H L non-Hodgkin lymphoma; Early pre-B ALL: cytoplasmic j~ negative and cell surface immunoglobulin negative; Pre-B ALL: cytoplasmic p positive and surface immunoglobulin negative; Mature B ALL: surface immunoglobulin positive; Common ALL: B-cell antigen and CALLA positive; immunoglobulin studies not performed.

del( 12)(pl2)(variation)

1 6 L3 Matu re B ALL 45,X,-X,t(8:14)(924:q32)

l ymphoma (p36:q26)

mic and hyperphosphatemic, as expected.26 After the resolution of tumor lysis, the child’s total calcium re- mained in the low normal range. In patient 15 (see Ta- ble l), a renal biopsy, which was obtained because of persistent mild renal insufficiency, revealed nephrocal- cinosis.

The evaluation of these patients generally did not establish the pathogenesis of the hypercalcemic epi- sodes. Seven patients (1, 4, 6 , 9, 15, 17, and 23) had evidence of metastatic disease involving the skeleton. In 11 patients, parathyroid hormone (PTH) had been measured by a variety of assays over the 29 years of the survey. In 10 of these children, the level was normal to low, whereas in the 11th patient, who had mild renal insufficiency, a PTH assay to the C-terminal end of the molecule was marginally elevated. In patient 17, the level of 25-(OH) vitamin D was 10 ng/ml (normal: 10- 55 ng/ml), and the level of 1,25-(OH), vitamin D was 7.7 pg/ml (normal: 21-48 pg/ml). In no patient was the PTH-related peptide measured.

The vast majority of the patients were treated with intravenous hydration plus furosemide. Patient 3 died before any specific therapy could be performed, and tumor lysis syndrome quickly developed in patient 6. In patient 13, who had received only prednisone as part of her chemotherapy protocol, the hypercalcemia resolved. Eight patients had received calcitonin (five in conjunction with steroids); two had been given oral phosphate, three had received plicamycin, and one child had received etidronate. With the exclusion of Pa- tient 3, who died during the induction phase of therapy, all 13 of the children with leukemia or lymphoma achieved resolution of their hypercalcemia. In contrast,

the hypercalcemic children with solid tumors had a more difficult course. One child with an abdominal primary tumor of undetermined type died during induction therapy. An infant with hepatoblastoma achieved resolution of his hypercalcemia but died 6 months later. Only one of the four patients with rhabdomyosarcoma had complete resolution of hypercalcemia, despite in- tensive therapy (e.g., calcitonin, prednisone, plicamycin, and oral phosphate). Overall patient survival was poor; however, four patients with ALL and hypercalcemia are alive, three of whom are off all therapy.

Discussion

Hypercalcemia is the most common life-threatening metabolic complication of malignancy in adults”; it is especially common in patients with squamous cell carci- noma of the lung, breast cancer, and T-cell leukemia- lymphoma, particularly those associated with human T-cell lymphotrophic virus-type 1 (HTLV-1).27

In contrast, the 25 cases of hypercalcemia of malignancy presenting to SJCRH represented 0.4% of the total number of patients diagnosed and treated at the institution during the 29-year period from 1962 to 1991. In contrast to hypercalcemia of malignancy in adults, most of our patients had acute leukemia, a find- ing consistent with other small pediatric serie~.’ ,~,~-’~ Rhabdomyosarcomas, associated with hypercalcemia in children in other s t ~ d i e s , ’ ’ ~ ~ ~ ~ ~ ’ were present in 4 of these 25 children; however, we saw no cases of hypercalcemia of malignancy in infants associated with unusual childhood renal tumors, as described else- Where.5,6.13-15

Hypercalcemia in Childhood Malignancies/McKay and Furman 259

In adults, the symptoms of hypercalcemia are nei- ther specific nor easily differentiated from those result- ing from cancer or other causes of hypercalcemia such as hyperparathyroidism, hyperthyroidism, or vitamin D intoxication." Our study indicates this is true in children as well.

Acute renal failure was demonstrated in two of our patients. Whereas mild increases in serum creatinine due to volume depletion from hypercalcemia-induced polyuria and poor intake are not uncommon in hypercalcemia of malignancy, acute renal failure is uncommon in adults except in those with myeloma.'6,'8 One child in this series had acute renal failure from tumor lysis syndrome that was unrelated to, and which in fact resulted in the resolution of, the hypercalcemia. On renal biopsy, a second patient demonstrated nephrocal- cinosis, which reportedIy is uncommon in adults with hypercalcemia of malignan~y.'~,'~

The mechanisms responsible for this condition are heterogenous. The patterns of disturbances in calcium homeostasis differ among the types of malignancy. 'J~-" Both impaired renal excretion and increased bone resorption (caused by skeletal metastases or factors produced by the tumor) play roles, with one or the other being relatively more important in any given patient.'r'6-'9 Eight of our patients (all with solid tumors) had radiologic evidence of bone metastases. Whether this bony involvement was directly responsible for the hypercalcemia or only a marker of the extent of their tumor burden is not clear.

As expected, the measurement of PTH in our patients was consistent with a nonparathyroid mecha- nism of their hypercalcemia. The two-site immunora- diometric assay, which is more specific for measuring intact PTH, enhanced the ability to distinguish hyperparathyroidism from hypercalcemia of malignancy.'8 This assay avoids measurement of the PTH fragments that occur with renal insufficiency, discerns more accu- rately low from normal levels of PTH, and does not cross-react with the newly described PTH-related pep-

This peptide, a 144-amino acid protein, is a separate gene product that mimics the actions of parathyroid hormone. PTH-related peptide most likely ac- counts for most cases of "ectopic hyperparathyroidism" and "humoral" hypercalcemia of malignancy. l6,I7 Re- cently available assays have allowed measurement of this peptide in many patients with hypercalcemia of malignan~y.'~,'~ In the single patient in whom both vitamin D metabolites 25-(OH) vitamin D and 1,25- (OH), vitamin D were measured, the levels were normal. It has been reported that some patients with leukemia or lymphoma have elevated levels of 1,25-(OH), vitamin D.'6,27 In two other patients in whom 25-(OH)

tide. 16-19

vitamin D levels were measured, the levels also were normal.

To investigate the etiology of hypercalcemia in a child with malignancy, we recommend evaluation for bone metastases with technetium 99 bone scan or plain skeletal radiographs, and measuring the serum levels of PTHZ7 and PTH-related peptide,'8,'9 as well as the levels of 25-(OH) vitamin D and 1,25-(OH), vitamin D. This array of tests should point to the common etiolo- gies for hypercalcemia of malignancy and help to rule out nonmalignant causes of hypercalcemia." Recent research has focused on other factors that may play a role in the pathogenesis of hypercalcemia in particular cancers, including transforming growth factor-a, lym- photoxin, tumor necrosis factor, interleukin-1, and pros- taglandins.16 Clinical evaluation of the role of these factors in patients with hypercalcemia of malignancy is not yet available.

A better understanding of the pathogenesis of this condition has led to improved therapy and the recent availability of new, less toxic agent^.''-'^ Therapy generally is aimed at reducing or eliminating the tumor burden, increasing renal calcium clearance, and inhibiting osteoclastic bone resorption." Vigorous hydration with normal saline and augmentation of calciuresis with furosemide have been the initial forms of therapy.','' The 11 children presenting with hypercalcemia at the time of diagnosis of cancer (7/10 with acute leukemia) generally responded to therapy with resolution of the hypercalcemia (see Table 1). This pattern generally agrees with the experience of other pediatric investigations.3r8f9 An argument against the use of furosemide has arisen because of the dangers of hypovolemia and the possible worsening of the hypercalcemia.16

Hypercalcemia may persist despite enhancement of renal clearance. This was the more typical clinical set- ting for children with solid tumors, and is similar to that of hypercalcemia in adults with cancer. Other agents that may be effective include glycocorticoids, calcitonin, oral phosphorus, and plicamycin.'*'6t20*21 All of these compounds were used in one or more of our patients with rhabdomyosarcoma with varying degrees of success. Newer compounds such as gallium nitrate" and the bisphosphonates etidronateZ3 and aminohy- droxypropylidene biphosphonate (AHPrBP)'4 are now being evaluated. Because the use of AHPrBP has been reported in only one pediatric ~at ient , '~ experience has not been sufficient to determine which agent is most appropriate for use in children. The size and nature of this retrospective study did not allow a comparison of the efficacy of different forms of therapy in patients who were unresponsive to hydration, furosemide, and primary treatment of their malignancy.

260 CANCER July 1, 1993, Volume 72, No. 1

In summary, hypercalcemia of malignancy in children is a rare complication, occurring most frequently with ALL and rhabdomyosarcoma. Children with ALL are most likely to present with hypercalcemia at diagnosis, and usually respond to therapy for hypercalcemia combined with therapy for the primary disease. This differs greatly from the experience of adults with leukemia.16 Children with solid tumors are more likely to present with hypercalcemia later in the course of their treatment for malignancy, and their hypercalcemia is more likely to be resistant to all therapy. Further evaluation of hypercalcemia in children with cancer will allow the recent advances in the adult experience to be applied toward more effective and less toxic management of this disorder in children.

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hypercalcemia complicating childhood malignancies

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