Hypercalcemia Induced by Parathyroid Hormone-Related Peptide after Treatment of Carcinoma.
Hypercalcemia was recognized as the most common paraneoplastic syndrome as early as 1924. (1) Initial studies implicated parathyroid hormone in the development of hypercalcemia. The exact role of parathyroid hormone in the development of hypercalcemia of malignancy was questioned in the early 1970s. (2) The discovery of PTH-rP in 1987 by Mosley et al (3) evoked interest in the mechanisms by which certain cancers cause hypercalcemia without necessarily metastasizing to the bone. Hypercalcemia of malignancy is thought to be due to the PTH-rP elaborated by the tumor cells in the advanced stage of the disease. We report a case of squamous cell carcinoma of the oral cavity that elaborated PTH-rP and caused hypercalcemia only after radiotherapy and chemotherapy.
A 65-year-old woman presented a 2-week history of right-sided gum pain. She had been a heavy smoker and drinker in the past. Physical examination revealed a fun-gating mass measuring 5 x 3 x 2 cm on the right side of the floor of the mouth. There were multiple enlarged submental and submandibular lymph nodes on the right side. The rest of the examination was unremarkable.
Laboratory values were hemoglobin 4.8 g/dL, hematocrit 16%, mean corpuscular volume 68 fL, calcium 8.3 mg/dL (reference range, 8.5 to 10.2 mg/dL), phosphorus 2.9 mg/dL (reference range, 2.5 to 4.5 mg/dL), alkaline phosphatase 65 U/L (reference range, 30 to 120 U/L), and albumin 3.2 g/dL (reference range, 3.5 to 5.0 g/dL). Computed tomography (CT) of the neck showed a mass on the floor of the mouth with erosion of the right horizontal ramus of the mandible and right jugular, right submandibular, and submental lymphadenopathy. Bone scan revealed abnormal uptake in the mandible and no distant bony metastases. Findings on chest x-ray films were normal. Histopathology of the lesion showed poorly to moderately differentiated invasive squamous cell carcinoma (Fig 1).
The patient received radiotherapy with a total dose of 7,560 cGy given over a period of 2 months and chemotherapy with 150 mg of intravenous carboplatin weekly for 2 months and paclitaxel initially 50 mg IV weekly for 1 month and later 100 mg IV weekly for another month. Despite treatment, the tumor continued to grow. Eight months later, partial tumor excision was done to prevent asphyxia. Histopathology showed an anaplastic tumor invading the mandible and marked stimulation of osteoclasts in the vicinity of the tumor cells (Figs 2 and 3). The patient became lethargic a few days after operation. There were no focal neurologic deficits. Calcium level was 15.6 mg/dL, phosphorus 3 mg/dL, albumin 3.2 g/dL, total protein 6.7 g/dL, creatinine 0.8 mg/dL, PTH 37 pg/mL (reference range, 11 to 54 pg/mL), and PTH-rP 16 pmol/L (reference range, 0 to 1.5 pmol/L). She was treated with intravenous saline infusion and pamidronate. Four days later, she died of asphyxia from upper airway obstruction.
It is now known that PTH-rP is produced by most solid tumors, particularly squamous and renal carcinomas. (4) Approximately 4.2% of patients with squamous cell carcinoma of the head and neck have hypercalcemia mediated by PTH-rP, which is thought to be an ominous prognostic sign. (5)
Although PTH and PTH-rP are products of different genes, they share many functional and structural similarities and may have evolved from the same ancestral gene as a result of a duplication event. (6) The amino-terminal portions of PTH-rP and PTH have essentially identical actions through a common receptor. They increase plasma calcium by promoting bone resorption and decreasing calcium excretion. Although PTH-rP is widely distributed in normal tissues such as brain, kidney, skin, uterus, and breast, PTH-rP has little physiologic role in adults. It is involved in local signaling only, and is not released into the general circulation? On the contrary, in disease states, benign or malignant tumor may overproduce PTH-rP causing hppercalcemia. (8) The presence of hypercalcemia in malignancy is correlated with the expression of the PTH-rP gene. (9)
Our patient initially did not have hypercalcemia and presumably did not elaborate PTH-rP despite a large tumor volume. Later, after irradiation and chemotherapy, histopathologic appearance of the tumor cells changed from moderately differentiated to poorly differentiated. The tumor tissue then produced PTH-rP, resulting in hypercalcemia. This may be deduced from the florid presence of osteoclasts in the vicinity of the tumor (Fig 3), presumably stimulated by a high local concentration of PTH-rP. Thus, we postulate that radiotherapy or chemotherapy might have caused further cancer cell gene amplification or clonal rearrangement, resulting in overproduction of PTH-rP, though it is possible that this event occurred de novo.
From the Department of Medicine, Huron Hospital, Cleveland clinic Health System, Cleveland, Ohio.
Supported by the Department of Medicine, Huron Hospital, Cleveland Clinic Health System.
Reprint requests to Keyvan Ravakhah, MD, Cleveland Clinic Health System, Huron Hospital, Department of Medicine, 13951 Terrace Rd, Cleveland, OH 44112.
(1.) Rankin W, Grill v, Martin J: Parathyroid hormone-related protein and hypercalcemia. Cancer 1997; 80:1564-1571
(2.) Budayr AA, Nissenson RA, Klein RF, et al: Increased serum levels of a parathyroid hormone-like protein in malignancy-associated hypercalcemia. Ann Intern Med 1989; 111:807-812
(3.) Mosley IM, Kubota M, Dief Renbach-Jagger H, et al: Parathyroid hormone-related protein purified from a human lung cancer cell line. Proc Natl Acad Sci USA 1987; 84:5048-5052
(4.) Nielsen PK, Rasmussen AK, Feldt-Rasmussen U, et al: Ectopic production of intact parathyroid hormone by squamous cell lung carcinoma in vivo and in vitro. J Clin Endocrinol Metab 1996; 81:3793-3796
(5.) Dorman EB, Yang H, Vaughan CW, et al: The incidence of hypercalcemia in squamous cell carcinoma of the head and neck. Head Neck Surg 1984; 7:95-98
(6.) Mangin M, Ikeda K, Dreyer BE, et al: Isolation and characterization of the human parathyroid hormone-like peptide gene. Proc Natl Acad Sci USA 1989; 86:2408-2412
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(8.) Ravakhah K, Gover A, Mukunda B: Humoral hypercalcemia associated with a uterine fibroid. Ann Intern Med 1999; 130:703
(9.) Kao PC, Klee GG, Taylor RL: Parathyroid hormone-related peptide in plasma of patients with hypercalcemia and malignant lesion. Mayo Clin Proc 1990; 655:1399-1407
RELATED ARTICLE: KEY POINTS
* The most common paraneoplastic syndrome is parathyroid hormone-related peptide induced hypercalcemia.
* Squamous cell carcinoma of the head and neck is a rare cause of hypercalcemia of malignancy.
* Despite wide distribution in normal tissues such as brain, kidney, skin, uterus, and breast, parathyroid hormone-related peptide has little physiologic role in adults.
* In squamous cell carcinoma of the head and neck, radiotherapy or chemotherapy might cause overproduction of parathyroid hormone-related peptide and subsequently hypercalcemia.