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Journal of Clinical Oncology, Vol 22, No 11 (June 1), 2004: pp. 2244-2245 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.08.070
Paraneoplastic Syndromes in CancerCASE 3. Parathyroid Hormone-Related Hypercalcemia in CholangiocarcinomaDepartments of Medical Oncology and Therapeutics Research, Pathology, and Endocrinology, City of Hope National Medical Center, Duarte, CA A 50-year-old Asian female presented with jaundice and encephalopathy. Her chief complaints included mental status changes, nausea, abdominal discomfort, polydipsia, polyuria, and weakness. The blood tests were remarkable for serum calcium level of 13.4 mg/dL (normal range, 8.6 to 10.0 mg/dL) with albumin level of 3.7 G/dL. The serum alkaline phosphate was more than 600 u/L, ALT was three-fold of the normal level, and the ammonia level fluctuated up to 90 umol/L. Other blood tests were unremarkable. The parathyroid hormone-related peptide was significantly elevated at 38.7 pmol/L (normal range, 0.0 to 1.5) and intact parathyroid hormone (iPTH) was inappropriately suppressed at 21 pg/mL. Bone scan was normal without evidence of skeletal metastases. The computed tomography scan of the abdomen revealed enlarged liver with diffuse homogenous infiltrations consistent with neoplastic disease. Liver surgical biopsy was performed, and histology demonstrated a moderately differentiated adenocarcinoma (Fig 1A). Tumor cells formed solid nests diffusely replacing the liver parenchyma and were positive for cytokeratin 7 (Fig 1B) but negative for neuroendocrine markers (chromogranin and synaptophysin) and hepatocyte antigen, consistent with cholangiocarcinoma. The patient was treated with intravenous hydration and pamidronate along with cisplatin and gemcitabine. Her disease responded poorly to treatmen, and she died as a result of hepatorenal failure due to progressive disease within a month of diagnosis.
Hypercalcemia is a serious and frequent complication of malignant disease, occurring in 10% to 20% of patients with malignancies.1,2 Up to 80% of hypercalcemias are due to humoral hyperalcemia of malignancy (HHM)2,3. Recent investigations have identified parathyroid hormone-related peptide (PTH-rP) as a probable mediator of HHM. PTH-rP may act in conjunction with other factors (eg, transforming growth factor alpha, tumor necrosis factor, interleukin-1) to cause the effects seen in humoral hypercalcemia4. PTH-rP is a paracrine and/or autocrine factor produced in almost every cell type in the body at some point, whether in childhood or adult life, with involvement of cellular growth regulation and differentiation.5 It has structural similarities to PTH and shares the common PTH receptor. HHM is recognized as the result of the dysregulation of PTH-rP production by malignant cells in such a manner that PTH-rP gains access to the circulation (from which is normally excluded) and interacts with a PTH/PTH-rP receptor pool normally reserved exclusively for PTH.6 HHM is characterized biochemically by an elevated serum calcium, low serum phosphorous, low PTH, and low 1,25 (OH)2 vitamin D levels and elevated nephrogenous cyclic AMP excretion rate.3 Like PTH, PTH-rP stimulates osteoclastic bone resorption and enhances renal tubular calcium reabsorption by a systemic effect. Depending on the presence and the level of PTH-rp gene expression in different tissue, which in turn may be determined by differential transcription of PTH-rP gene promoter,7 HHM is usually only manifested in certain type of malignancies. It is most commonly seen in the squamous-cell carcinomas, such as lung, esophagus, skin, and head and neck cancer. Breast carcinoma may cause typical HHM or may lead to hypercalcemia through bone metastases. Other tumor types commonly associated with HHM are renal, bladder, ovarian cancer, human t-cell lymphotropic virus-1 lymphoma, and some endocrine tumors. It is rarely seen in association with colon adenocarcinoma, gastric carcinoma, small-cell carcinoma, and prostate cancer. There are only a few case reports about hypercalcemia in association with cholangiocarcinoma.8 Review of the literature revealed an autopsy case of cholangiocarcinoma with hypercalcemia in 1978.9 The largest trial to investigate hypercalcemia and the parathyroid-related protein was documented in 1980.10 In that report, 307 patients with hypercalcemia were examined. Of the 307 patients, 170 had concomitant examination of the parathyroid gland. A total of 34 cases revealed parathyroid hyperplasia or atypia. This frequency was higher than previously reported, but the majority of the cases still remain ill-defined. Only 61 cases can be confirmed of ectopic parathyroid hormone-related protein release examined by radioimmuno assay. It remains unclear whether the biology of the disease shows any impact in hypercalcemia or parathyroid hormone-related protein secretions. Hypercalcemia induced by the parathyroid hormone-related peptide associated with cholangiocarcinoma was reported in 1982.11 Of 190 patients examined, 17.5% had disease due to cholangiocarcinoma without bone involvements. Five patients had serum immunoreactive parathyroid hormone value consistent with ectopic hyperparathyroidism. However, this retrospective study could not point out whether hypercalcemia can be an early sign of cholangiocarcinoma. Here we described a patient in whom hypercalcemia associated with elevated parathyroid hormone-related peptide level was the earliest sign of the disease. The elevated PTH-rP level, sub-baseline PTH level, and absence of metastasis in the bone scan confirmed that the hypercalcemia in our patient was humoral, mediated by the cholangiocarcinoma. The presentation of high serum calcium and PTH-rP level early in the course of disease correlated to a poor response to treatment and rapid progression. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES 1. Birkeland KI, Gallefoss F, Olsson S, et al: Primary hyperparathyroidism or hypercalcemia of malignancy? Scand J Clin Lab Invest52:347–349, 1992[CrossRef][Medline] 2. Stewart AF: Humoral hypercalcemia of malignancy, in: Favus MJ, Christakos S, Goldring SR, et al (eds): Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism (ed 3). Philadelphia, PA, Lippincott-Raven, 1996, pp 198-203 3. Stewart AF, Horst R, Deftos LJ, et al: Biochemical evaluation of patients with cancer-associated hypercalcemia: evidence of humoral and non-humoral groups. N Engl J Med303:1377–1383, 1980[Abstract] 4. Cryer PE, Kissane JM: Clinicopathologic conference: Malignant hypercalcemia. Am J Med65:486–494, 1979[CrossRef]
5. Philbrick WM, Wysolmerski JJ, Galbraith S, et al: Defining the roles of parathyroid hormone- related protein in normal physiology. Physiol Rev76:127–173, 1996 6. Dunbar ME, Wysolmerski JJ, Broadus AE: Parathyroid hormone-related protein: From hypercalcemia of malignancy to developmental regulatory molecule. Am J Med Sci312:287–294, 1996[CrossRef][Medline]
7. Wysolmerski JJ, Vasavada R, Foley J, et al: Transactivation of the PTH-rP gene in squamous carcinomas predicts the occurrence of hypercalcemia in athymic mice. Cancer Res56:1043–1049, 1996 8. Davis JM, Sadasivan R, Dwyer T, et al: Case report: Cholangiocarcinoma and hypercalcemia. Am J Med Sci307:350–352, 1994[Medline] 9. Hirano T, Tsuchiyama H, Yanagawa M: An autopsy case of cholangiocarcinoma with hypercalcemia. Acta Pathologica Japonica28:465–469, 1978[Medline] 10. Skrabanek P, McPartlin J, Powell D: Tumor hypercalcemia and "ectopic hyperparathyroidism". Medicine59:262–282, 1980[Medline]
11. Oldenburg WA, van Heerden JA, Sizemore GW, et al: Hypercalcemia and primary hepatic tumors. Arch Surg117:1363–1366, 1982
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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