Hypercalcaemia induced by excessive parathyroid hormone secretion in a patient with a neuroendocrine tumour

Henri Vacher-Coponat1, Adriana Opris1, Anne Denizot2, Bertrand Dussol1 and Yvon Berland1

1 Department of Nephrology, Hopital Conception, Marseille, France and 2 Department of Surgery, Hopital Nord, Marseille, France

Correspondence and offprint requests to: H. Vacher-Coponat, Service de néphrologie, Hôpital Conception, 147 Bd Baille, 13005 Marseille, France. Email: hvacher{at}mail.ap-hm.fr

Keywords: hypercalcaemia; neoplasia; neuroendocrine tumour; PTH; PTHrP



   Introduction
 Top
 Introduction
 Case report
 Discussion
 References
 
Hyperparathyroidism and neoplasia account for 80–90% of the patients with hypercalcaemia. Serum levels of 1-84 parathyroid hormone (PTH) is the key parameter for the diagnosis and treatment of hypercalcaemia. PTH is elevated in hyperparathyroidism and low in neoplasia [1]. Hypercalcaemia associated with malignancy is most often secondary to a plasma factor, the PTH-related protein (PTHrP), which is responsible for bone resorption. This factor has a PTH-like effect related to its similarity with the PTH N-terminal sequence. However, the biological effects of PTHrP are different from those of PTH as the C-terminal sequences of the two hormones are not the same [2].

PTHrP is not detected by the new technique used for PTH, the immunoradiometric assay (IRMA) [3]. Using this method, both N- and C-terminal sequences of PTH are recognized. PTH level is consistently low in paraneoplastic hypercalcaemia related to PTHrP [4], but exceptionally hypercalcaemia can be due to a nonparathyroid tumour secreting PTH.

We report on a patient with hypercalcaemia related to a PTH-secreting neuroendocrine tumour of the pancreas. In our opinion, this is the first observation of a PTH-secreting neuroendocrine tumour of the pancreas.



   Case report
 Top
 Introduction
 Case report
 Discussion
 References
 
A 58-year-old woman was admitted for severe hypercalcaemia discovered during a confusional syndrome. She had no clinical signs other than those due to hypercalcaemia. Serum biochemical and haematological tests were as follows: calcium 22.4 mg/dl, phosphorus 4.7 mg/dl, proteins 93 g/l, albumin 51 g/l, creatinine 1.38 mg/dl, BUN 56 mg/dl, bicarbonate 33 mmol/l, red blood cells 5.71 tera/l, haemoglobin 178 g/l, platelet count 225 000/l, white blood cells 19 giga/l with 90% polynuclear cells, erythrocyte sedimentation rate 46 mm at 1 h and 55 mm at 2 h, fibrinogen 4.9 g/l, LDH 600 UI/l (N, 120–350 UI/l), and {gamma}GT 150 UI/l (N, 9–55 UI/l); other liver tests were normal.

Emergency treatment was begun with pamidronate, hydratation and haemodialysis. Plasma calcium quickly normalized and neurological symptoms disappeared within 48 h. A diagnostic procedure was performed. 1-84 PTH level was 394 pg/ml (IMRA, ELSA-PTH method from CIS bio international; N, 8–50 pg/ml), 25-hydroxyvitamin D <5 ng/ml (N, 16–38 ng/ml), and osteocalcin 3 ng/ml (N, 8–50 ng/ml). 1-25dihydroxyvitamin D was not evaluated. Serum and urinary immunoelectrophoreses were normal. Abdominal tomodensitometry showed multiple small hyperdense nodules in the liver, suggestive of a metastatic dissemination. Parathyroid ultrasonography and CT scanning were compatible with an adenoma of the parathyroid. PTHrP dosage was not realized in our laboratory and was never done in this patient.

The initial diagnosis was primary hyperparathyroidism associated with an unspecified neoplasia.

Three days later, a cervical parathyroid exploration failed to unveil an adenoma. PTH level rose to 1587 pg/ml and plasma calcium to 13.7 mg/dl. A search for an ectopic parathyroid was performed. A Sestamibi radionuclide scan found nodular liver fixation. PTH levels in serum samples collected on the 5th day of hospitalization from veins in the neck and in the mediastin revealed no gradient of secretion; the highest levels were 5200 pg/ml in the suprahepatic veins and 3500 pg/ml in the peripheral vein. A second abdominal tomodensitometry evidenced a large increase in the size of the liver nodules and a large nodular lesion in the pancreas. Biopsies of one liver nodule showed highly undifferentiated neoplastic cells. Tumoural markers related to the diagnosis of neuroendocrine tumour were elevated in the serum: neuron-specific enolase, 180 ng/ml (N, <20 ng/ml), carcino-embryonic antigen, 494 ng/ml (N, <10 ng/ml), CA125, 102 ng/ml (N, <35 ng/ml). Pancreas echoendoscopy showed diffuse neoplasia.

Chemotherapy with cyclophosphamide, adriamycin and VP16 was started. During the first week of treatment, PTH rose to 8000 pg/ml and hypercalcaemia recurred despite repeated injections of pamidronate, calcitonin, mithramycin, hydratation with furosemide, steroids, and daily haemodialysis with a low calcium dialysate. Ten days after the chemotherapy, plasma calcium began to fall. After several rounds of chemotherapy, PTH levels decreased in parallel with the tumour regression (Figure 1).



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Fig. 1. Calcaemia and PTH evolution after treatment.

 
Six months later, a dramatic decrease in the neoplasm was observed. PTH was 100 pg/ml, and the patient was hypocalcaemic and needed a high calcium intake.

The final diagnosis was a 1-84 PTH-secreting neuroendocrine tumour of the pancreas.



   Discussion
 Top
 Introduction
 Case report
 Discussion
 References
 
This patient had a neuroendocrine carcinoma of the pancreas revealed by a paraneoplastic hypercalcaemia and high levels of PTH. A Sestamibi radionuclide scan evidenced that PTH was secreted by liver metastases. In addition, the very high levels of PTH (up to 8000 pg/ml), the concomitant increase of PTH levels and tumoural lesions together with their parallel decrease after chemotherapy confirm the tumoural origin of the hormone. Paraneoplastic secretion of PTH is rare. Usually, paraneoplastic hypercalcaemia is present in two clinical settings [1]. (i) First, it is observed in neoplasia with bone metastases and multiple osteolytic lesions, as in breast cancer. In this case, hypercalcaemia is due to a peritumoural osteolysis linked to a paracrine mechanism mediated by PTHrP or by cytokines such as TGF-{alpha}, IL-1, IL-6 and TNF{alpha}. (ii) Second, paraneoplastic hypercalcaemia may be present in diffuse osteolysis without bone metastases. In this setting, three mechanisms can be involved. Secretion of PTHrP by the tumour is usually found in epidermoid malignancies of the lung, the neck, the head, adenocarcinoma of the kidney, the lung and the pancreas. Clinical expression of the neoplasia is often obvious. In myeloma and in lymphoma, hypercalcaemia is not related to PTHrP but rather to other tumour-secreting factors like cytokines or calcitriol. Very rarely, hypercalcaemia is due to PTH secretion by the tumour. Even if a high level of PTH is found in a patient with a malignancy, this is usually due to a parathyroid adenoma associated with the cancer. PTHrP dosage is not routinely realized by our laboratory on routine examination. Usually the diagnosis of paraneoplastic hypercalcaemia with PTHrP secretion is suggested when the PTH level is low, no other causes of hypercalcaemia are found and the patient has a cancer. It is possible that in this patient both PTH and PTHrP were produced by the tumour cells but the contribution of PTHrP to the hypercalcaemia is probably low. A PTH level to 8000 pg/ml is sufficient to induce an intractable malignant hypercalcaemia. PTH was not demonstrated in tumour tissue but the paraneoplastic PTH secretion is illustrated by the kinetic of PTH before and after chemotherapy.

To our knowledge, only eight patients with tumoural secretion of PTH have been reported in the literature [5–12]. Nussbaum et al. [5] reported a 74-year-old woman with a PTH-secreting ovarian carcinoma. Plasma calcium was 15.6 mg/dl and the serum levels of PTH were eight times above the normal range. The PTH level in the ovarian vein was five times higher than in the peripheral vein. After surgery, PTH levels and plasma calcium decreased. Rearrangement of the PTH gene and PTH mRNA were detected in tumoural cells. In three other cases, patients with lung cancer, two with small cell cancer and one with squamous cell carcinoma, had hypercalcaemia and high PTH. PTH mRNA synthesis in the tumoural cells was evidenced by northern blot; this mRNA sequence was identical to that of the PTH mRNA of parathyroid cells [6,7]. Immunocytochemical analysis of the tumour tissue as well as of cultured tumour cells revealed PTH-positive staining [8].

Godlewski et al. [9] reported a patient with a parathyroid adenoma and a PTH-secreting kidney oncocytome. Serum levels of PTH decreased after the nephrectomy and they normalized only after parathyroid adenoma ablation. In the kidney tumour, PTH-containing granules were found.

Strewler et al. [10] reported a patient with a PTH- and PTHrP-secreting neuroectodermal malignancy. The PTH and PTHrP levels were, respectively, 5–10 times above and double the normal range. Again, both PTH and PTHrP mRNA were present in the tumoural cells. Koyama et al. [11] reported a case of hepatocellular carcinoma with tumour producing intact PTH. The humoral hypercalcaemia was controlled by transcatheter arterial chemoembolization. The last case was a 25-year-old man with thymoma producing PTH, cured by excision of the retrosternal mass [12].

Among 25 tumours associated with paraneoplastic hypercalcaemia, Mundy et al. [13] found PTH mRNA synthesis in only one.

The biological pattern of PTH in hypercalcaemia secondary to hyperparathyroidism is different from paraneoplastic secretion of PTHrP. PTH increases osteoformation, as assessed by secretion of osteocalcine, and stimulates calcitriol synthesis. Conversely, in malignant hypercalcaemia, a decrease in osteoformation and in the synthesis of calcitriol is observed [14]. Two features explain this difference. First, although PTHrP binds to the PTH receptor, it also has a specific receptor with specific functions. Second, molecules other than PTHrP are involved in bone metabolism during humoral hypercalcaemia of malignancy. IL1{alpha}, IL6, TGFß and TNF{alpha} have been found elevated in malignant hypercalcaemia. These cytokines strongly increase osteoclast activity. In our patient, very high levels of 1-84 PTH were not associated with high levels of osteoclastin or of calcitriol. It is possible that, besides 1-84 PTH secretion, PTHrP was also secreted by the neoplasm leading to this unusual pattern. Managing hypercalcaemia secondary to a tumoural PTH secretion is difficult. In our case, all the treatments failed: only chemotherapy was efficient.

After chemotherapy, a hypocalcaemia appeared despite a serum level of PTH twice the normal range. The dramatic decrease in PTH secretion following chemotherapy allowed bone remineralization. This phenomenon usually occurs after surgical ablation of a parathyroid adenoma and is called the hungry-bone syndrome.

We describe a patient with ectopic production of PTH by a pancreas neuroendocrine malignancy. It is a very rare cause of PTH-induced hypercalcaemia in neoplastic patients that must be distinguished from other causes of hyperparathyroidism. Only an effective treatment of the cancer is capable of normalizing plasma calcium, a leading cause of death in these patients.

Conflict of interest statement. None declared.



   References
 Top
 Introduction
 Case report
 Discussion
 References
 

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Received for publication: 12. 5.05
Accepted in revised form: 19. 7.05





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