Yonago Acta medica 2000;43:81–86

Successful Management of Humoral Hypercalcemia of Malignancy in
A Patient with Ovarian Cancer
Fuminori Taniguchi, Junzo Kigawa, Riko Kitazawa* and Naoki Terakawa
Department of Obstetrics and Gynecology, Faculty of Medicine, Tottori University, Yonago 6830826 and *Second Department of Pathology, Kobe University School of Medicine, Kobe 6500017, Japan
We present here successful treatment with bisphosphonate pamidronate of a 54-yearold patient with advanced ovarian cancer and humoral hypercalcemia of malignancy,
followed by cytoreductive surgery and postoperative chemotherapy. Concentration ofserum calcium increased to 16.8 mg/dL and parathyroid hormone-related protein(PTHrP)-intact was remarkably elevated. Interestingly, the 1,25-dihydroxyvitamin D(1,25-DHD) was high in this case. Treatment with bisphosphonate pamidronate was
effective for the improvement of hypercalcemia so that she could undergo optimal
surgery followed by postoperative chemotherapy. The histochemical examination of
PTHrP using anti-human monoclonal antibody showed positive staining in the cancer
cells of the ovary.
Key words: bisphosphonate pamidronate; humoral hypercalcemia of malignancy; parathyroid
hormone-related proteinof HHM with ovarian cancer. Serum dihydroxyvitamin D (1,25-DHD) concentrations arecommonly low in patients with HHM. However, the concentration of 1,25-DHD was highin this case.
We present an ovarian adenocarcinoma
patient with HHM who underwent successful
management with bisphosphonate pamidronate.
Additionally, PTHrP metabolism including
1,25-DHD was investigated.

Hypercalcemia is frequently associated withmalignancy, and is often a major contributor tomorbidity and complicates clinical management (Allan et al., 1984; Fujino et al., 1992).
Humoral hypercalcemia of malignancy (HHM)
is defined as hypercalcemia in malignant tumor
patients without bone metastasis (Martin et al.,1991). Parathyroid hormone-related protein(PTHrP) is one main causative substance for
HHM. HHM is commonly found in squamouscell carcinoma, renal cell carcinoma, andhematopoietic malignancies (Honda et al.,
1988; Kitazawa et al., 1991; Gotoh et al., 1993).
There are a few reports of HHM in patients withovarian cancer (Kitazawa et al., 1997).
Bisphosphonate pamidronate strongly
inhibits bone resorption, probably by exerting acytotoxic effect on mature osteoclasts and impairing recruitment and maturation of osteoclast-precursor cells (Thiebaud et al., 1990).
This agent has been considered effective for
HHM, but there are few reports on the efficacy

Patient Report
A 54-year-old postmenopausal woman, gravida
0, presented herself to Tottori University Hospital on August 30, 1995. She had a 4-week history of lower abdominal pain, constipation,
nausea, general malaise and a loss of weight of
5 kg. Upon presentation, her weight was 43 kg,
height, 148 cm, pulse rate, 72 beats/min andregular, and blood pressure, 106/70 mmHg. A

Abbreviations: DHD, dihydroxyvitamin D; HHM, humoral hypercalcemia of malignancy; PTH, parathyroid
hormone; PTHrP, parathyroid hormone-related protein; TGF, transforming growth factor

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F. Taniguchi et al.

Table 1. Biochemical data of bone and mineral metabolism before therapy
Laboratory findings

Measured values

Serum

Calcium(mg/dL)
16.8
Phosphate(mg/dL)
1.1
Creatinine(mg/dL)
0.7
Alkaline phosphatase(IU/L)
259
Alkaline phosphatase isozyme 3(%)
28
Osteocalcin(ng/mL)
4.9
PTH-intact(pg/mL)< 2.0
PTHrP-intact(pmol/L)10
1,25-DHD(pg/mL)104
25-Hydroxyvitamin D(ng/mL)10
24,25-DHD(ng/mL)
1.2
Urine
Calcium(mg/dL)
21.3
Phosphate(g/day)0.72
Nephrogeneous cyclic AMP(µmol/day)
4.8
Pyridinoline(µmol/molCr)
120
Deoxypyridinoline(µmol/molCr)
16
DHD, dihydroxyvitamin D; PTH, parathyroid hormone; PTHrP, PTH-related protein.

solid ovarian tumor with a diameter of 8 cm inits greatest dimension revealed by computed
tomography was observed in the lower abdomen. Serum levels of CA125 and small cell
cancer were slightly elevated to 120 U/mL
(normal range < 35 U/mL) and 1.7 ng/mL (normal
range < 1.5 ng/mL), respectively. The serum
calcium concentration increased to 16.8 mg/dL.
Biochemical examination revealed that her
urinary calcium excretion, cyclic AMP, alcohol
dehydrogenase and free T3 were within normal
ranges, but that the serum phosphate extremely
decreased and the 1,25-DHD increased to 104
pg/mL. PTHrP-intact was elevated to 10.0
pmol/L (PTHrP C-terminal 442 pg/mL). On theother hand, parathyroid hormone (PTH)-intact
fell to < 2.0 pg/mL, (PTH C-terminal < 0.6 ng/mL). Biochemical data are shown in Table 1.
The bone mineral density of the spine measured
by dual energy X-ray absorptiometry was in thenormal range. Whole body computed tomography, X-ray, and bone scintigram revealed noevidence of bone metastasis.
The serum calcium concentration raised to
16.8 mg/dL and an abnormal electrocardiogram
reading due to hypercalcemia (shortened QT)
was observed. For the treatment of hypercalcemia, 45 mg of bisphosphonate pamidro-

Normal values
8.6 – 11
3–5
0.6 – 1.6
111– 295
29 – 62
2.5 – 13
6.5 – 59.7
< 1.1
20 – 60
10 – 55
1.8 – 3.8
5.3 – 30
0.3 – 2.2
1.8 – 6.3
13 – 36<7nate was injected intravenously over a 240-min
period on October 25. After the treatment,
serum calcium decreased to 8.5 mg/dL. As aresult, her complaints, such as nausea, vertigo,
drowsiness, arrhythmia and muscle pain, disappeared.
On October 31, laparotomy was carried out,
but it was judged impossible to achieve optimal
operation criteria, because of the presence of aresidual tumor mass smaller than 2 cm, so anomentectomy was performed without bowel
resection. A biopsy specimen from the left
ovarian tumor revealed a grade-1 adenocarcinoma (Fig. 1). Under diagnosis of stage IIIbovarian cancer, she underwent chemotherapy
consisting of a combination of 50-mg/m 2
cisplatin, 40-mg/m2 adriamycin and 400-mg/m2
cyclophosphamide. Serum calcium was wellcontrolled by bisphosphonate pamidronate, andhydration with 3000 mL/day of saline and furosemide. In spite of 2 courses of chemotherapy,
the tumor increased to 166% in the size of themeasurable lesion. We conducted 2nd surgery
consisting of total hysterectomy, bilateralsalpingo-oophorectomy, retroperitoneal lymphadenectomy including the para-aortic nodes.
On December 26, she underwent 2nd surgery
and a segment of the sigmoid colon and the82Successful management of HHM

rectum were removed to achieve optimal tumor
resection. After this surgery, serum calcium,
PTHrP and 1,25-DHD fell to normal limits
without other therapy. PTH was recovered 2
months later (Fig. 2). Tissue diagnosis showedadenocarcinoma. The histochemical examination of PTHrP using the anti-human monoclonal antibody, 4B3, showed positive staining
in tumor cells (Fig. 3) (Kitazawa et al., 1991).

A

B

Fig. 1. Photomicrograph of cancer tissues. A: Low magnification. There is papillary
proliferation of cancer cells (hematoxylin and eosin stain). Original magnification, × 40. B:
High magnification (hematoxylin and eosin stain). Original magnification, × 200.

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F. Taniguchi et al.

2nd CAP

1st CAPBP 45 mg
Ca (mg/dL)

2nd EP

1st EP

Hydration (3000 mL/day), furosemide
BP 45 mg BP 45 mg
2nd surgery

1st surgery

16
14
12
10
8
PTHrP-intact (pmol/L)

10.0

10.0

< 1.1

PTH-intact (pg/mL)

< 2.0

< 2.0

2.3

8.8

1,25-DHD (pg/mL)

104

86

39.5

38.1

CA125 (U/mL)

120

72

6

3

November

DecemberJanuary

1995

< 1.1

February

1996

Fig. 2. Treatment and changes of calcium, PTHrP-intact, PTH-intact and CA125. BP, bisphosphonate
pamidronate; CAP, cisplatin, adriamycin and cyclophosphamide; EP, etoposide and cisplatin.

She received 5 courses of post operative
chemotherapy consisting of 100-mg/bodyetoposide daily from days 1 to 5 and 50-mg/m2
cisplatin on day 5. She has had no evidence ofrecurrence for 24 months.

Discussion
Several agents, such as prostaglandin, interleukin 1, transforming growth factor (TGF)α, TGF-β and colony stimulating factor, have

Fig. 3. Immunohistochemical demonstration of PTHrP production by the tumor. Positive
staining is shown in the cytoplasm of the cancer cells. Original magnification, × 100.

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Successful management of HHM

been reported as inducing HHM factor(Bringhurst et al., 1986; Tashjian et al., 1986;
Sato et al., 1987; Linkhart et al., 1989). These
are considered to be local factors of osteolytic
hypercalcemia. In this case, since immunohistochemistry revealed the production of
PTHrP, PTHrP was causative for HHM.
PTHrP acted very similarly to the PTH, but
the clinical syndrome of HHM has distinct
differences from primary hyperparathyroidism.
For example, in HHM, an increase in bone resorption is not coupled with increased boneformation as in primary hyperthyroidism. In
our case, bone mineral density and serum osteocalcin were in the normal range and urine
pyridinoline and deoxypyridinoline were high.
Additionally, serum 1,25-DHD concentrations
are commonly low in patients with HHM(Schilling et al., 1993). However, 1,25-DHD
concentration was extremely high in this case.
The concentration of 1,25-DHD is considered
to relate to renal function. Most cases of HHM
have damage in renal function because of longstanding hypercalcemia and so 1,25-DHD concentrations are low (Hoekman et al., 1991). In
contrast, this case might have been in its earlystages and had normal renal function. Therewas some possibility that several cytokines
produced by cancer cells and the low serum
phosphate may stimulate the renal 1α-hydroxylase activity.
Since HHM has been commonly observedin the end stages of malignancy, the prognosisof this disease is poor. Additionally, appropriate management for HHM has been not established. Bisphosphonate pamidronate was effective in normalizing the serum calcium level ofhypercalcemic patients with malignancies(Harinck et al., 1987). However, the efficacy
for HHM was transient. In our case, bisphosphonate pamidronate reduced serum calcium
levels, but the serum level of PTHrP did not decrease. The management of HHM with bisphosphonate pamidronate is not easy, i.e.,
hydration is necessary to maintain urine flow
and a proper level of sodium chloride. Our patient needed hydration with 3000 mL/day ofsaline and furosemide.

In our case, the patient could undergo tumor
resection after the management of hypercalcemia with bisphosphonate pamidronate andthen have a good prognosis.
These results suggest that bisphosphonate
pamidronate may be useful for the managementof hypercalcemia, but this management should
be followed by radical treatment for HHM suchas tumor reduction for improving prognosis,
including the quality of life of patients with HHM.

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Received November 5, 1999; accepted November 24, 1999
Corresponding author: Dr. Fuminori Taniguchi

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