Unusual behaviour of an unusual tumour: calcitriol-induced hypercalcaemia in metastatic oesophageal neuroendocrine carcinoma

Abstract

Hypercalcaemia in malignancy is most commonly caused by paraneoplastic secretion of parathyroid hormone-related protein or osteolytic metastases. Very rarely (<1% of cases), the mechanism behind increased serum calcium is increased production of calcitriol (1,25-dihydroxyvitamin D) and even rarer is the occurrence of this phenomenon in solid malignancies, with few such instances reported in the literature. We present a case of a neuroendocrine malignancy originating in the oesophagus associated with calcitriol-induced hypercalcaemia, a phenomenon that has not been previously described. We review the pathophysiology of calcitriol-induced hypercalcaemia and previously reported cases of solid tumours with this presentation.

Background

Hypercalcaemia is frequent in malignancy and can arise from three well-established mechanisms, which generally correlate well with tumour histology and stage. Most common in non-metastatic solid tumours is paraneoplastic secretion of parathyroid hormone-related protein (PTHrP), whereas osseous metastatic disease accounts for the remainder of cases. A third mechanism involving excessive endogenous production of calcitriol, while prevalent in lymphomas, has only very rarely been described in solid tumours. We report a case of calcitriol-induced hypercalcaemia in a patient with metastatic oesophageal neuroendocrine tumour, a novel association to the best of our knowledge.

Case presentation

A 45-year-old man with a recent diagnosis of neuroendocrine carcinoma (NEC) of the oesophagus was admitted for 1 day of confusion, dyspnoea and palpitations. His malignancy had been diagnosed 1 month prior, when he presented with chest pain and nausea without vomiting. He also reported unintentional weight loss (13 kg) over the past year. Contrast CT revealed dilatation of the oesophagus, bilateral pulmonary and hepatic and peritoneal masses suspicious for metastatic disease (figure 1); there was no radiographic evidence of bone lesions. Upper endoscopy found a large mass involving over 75% of the length of the oesophagus distally. Microscopic examination evidenced a small cell population with prominent nuclear atypia and a high mitotic index; immunohistochemistry was positive for pancytokeratin, neuron-specific enolase and synaptophysin, and negative for p63 and thyroid transcription factor 1. Findings were consistent with high-grade NEC (small cell type) of oesophageal origin. Subsequent biopsies of the pulmonary and hepatic lesions demonstrated metastatic spread. At diagnosis, he had significant bleeding from his primary tumour site, requiring transfusion and palliative external-beam radiation therapy for haemostasis. Treatment was initiated with carboplatin and etoposide, which were stopped after one cycle because of lethargy and dyspnoea. He was discharged 2 weeks prior to the current encounter with plans to continue management of his malignancy on an outpatient basis.

Figure 1.

CT of the chest showing a distal oesophageal mass (orange arrow) and multiple pulmonary masses representing metastatic disease (green arrows).

On arrival in the emergency department, in addition to the above complaints, he reported severe nausea with occasional vomiting, but denied fever, cough, sputum production, dysuria or diarrhoea. He had taken two doses of ergocalciferol (50,000 IUs) prescribed for treatment of vitamin D deficiency (25-hydroxyvitamin D level of 6 ng/mL during prior admission). He reported no sick contacts or recent travel outside the northern USA. His vital signs were notable for sinus tachycardia (140 bpm) and tachypnoea (27 rpm), with normal peripheral oxygen saturation (95%), blood pressure (103/67 mm Hg) and body temperature (36°C). Examination revealed a cachectic, middle-aged Caucasian man; he was lethargic, but answered questions appropriately. The abdomen was distended, mildly tender in the right upper quadrant and epigastrium, with no discernible fluid wave. Bilateral pitting oedema was observed in the lower extremities. Skin examination revealed no jaundice.

Laboratory studies (table 1) were remarkable for significant neutrophilic leucocytosis, moderate normocytic anaemia and thrombocytosis, severe lactic acidosis (14.9 mmol/L), as well as elevated transaminases compared with baseline. These findings were suggestive of multiple organ dysfunction in the setting of sepsis. He received fluid resuscitation (supplemented with albumin) and broad spectrum antibiotics (vancomycin and piperacillin–tazobactam) before transfer to the intensive care unit. Repeat thoracic and abdominal imaging showed progression of metastatic disease involving the lungs and the liver, but no suspicious focus of infection. After stabilisation, further review of serum chemistry revealed hypercalcaemia (corrected total calcium 12.9 mg/dL in the setting of hypoalbuminaemia of 2.6 mg/dL) and mild hyperphosphatemia (4.6 mg/dL).

Table 1.

Laboratory values on admission

Haematology
White blood cells	49.2	3.5–10.1×109/L
Red blood cells	3.41	4.31–5.48×1012/L
Haemoglobin	99	135–170 g/L
Haematocrit	32.5	40.1%–50.1%
MCV	95	80–100 fL
RDW	23	12%–15%
Platelets	590	150–400 × 109/L
Neutrophils	43.8	1.6–7.2×109/L
Lymphocytes	0.7	1.1–4.0×109/L
Monocytes	2.4	0.0–0.9×109/L
Eosinophils	0.0	0.0–0.4×109/L
Basophils	0.1	0.0–0.1×109/L
Immature granulocytes	2.26	0.00–0.04×109/L
Chemistry
Sodium	134	135–145 mmol/L
Potassium	5.1	3.5–5.2 mmol/L
Chloride	94	98–111 mmol/L
Bicarbonate	9	20–29 mmol/L
Anion gap	25	5–17
Glucose	102	60–99 mg/dL
Urea nitrogen	43	7–25 mg/dL
Creatinine	1.24	0.60–1.30 mg/dL
Glomerular filtration rate	87	>59 mL/min/1.73 m2
Calcium	11.8	8.5–10.5 mg/dL
Phosphorus	4.6	2.3–4.4 mg/dL
Albumin	1.8	3.5–5.1 g/dL
Alkaline phosphatase	667	33–120 U/L
Aspartate aminotransferase	410	<35 U/L
Alanine aminotransferase	337	<45 U/L
Bilirubin total	1.9	0.3–1.2 mg/dL
Endocrine
Intact parathyroid hormone	7	8–72 pg/mL
PTH-related protein	0.6	<4.2 pmol/L
25-Hydroxyvitamin D	8	30–100 ng/mL
1,25-Hydroxyvitamin D	>200	19.9–79.3 pg/mL

MCV, mean corpuscular volume; PTH, parathyroid hormone; RDW, red cell distribution width.

Investigations

During the prior hospitalisation, corrected total calcium had been low–normal (8.5–8.9 mg/dL) and moderate hypercalcaemia was a new, acute finding. Work-up included measurement of intact parathyroid hormone (PTH) level, PTHrP and vitamin D metabolites (1,25-dihydroxyvitamin D and 25-hydroxyvitamin D). The results of the studies are summarised in table 1 and showed an appropriately suppressed PTH (7 pg/mL, and subsequently <4 pg/mL) and low PTHrP (0.6 pmol/L) and 25-hydroxyvitamin D level (8 ng/mL). The level of 1,25-dihydoxyvitamin D was surprisingly elevated (197 pg/mL) and was confirmed with repeat testing (>200 pg/mL). Repeat imaging showed no new lesions localised to the bone or that could harbour granulomatous inflammation.

Differential diagnosis

The suppressed PTH ruled out primary hyperparathyroidism. Vitamin D toxicity was considered, but the patient reported correctly taking his supplements and the 25-hydroxyvitamin D level was low. PTHrP was similarly low and there was no evidence of osteolytic metastases. His hypercalcaemia was attributed to the very high 1,25-dihydoxyvitamin D, a very infrequent mechanism in solid malignancies. Imaging findings, the time course of his illness and lack of infectious exposures ruled out granulomatous and lymphoproliferative disease as a cause of the elevated vitamin D metabolite.

Treatment

The patient was initially treated with aggressive intravenous fluids and furosemide was later added, resulting in a significant decrease in corrected total calcium. On the fourth day of hospitalisation, the ionised calcium was measured and was high at 6.18 mg/dL, which prompted administration of intravenous zoledronic acid. Based on prior reports of success in the treatment of calcitriol-induced hypercalcaemia in sarcoidosis, daily hydroxychloroquine was initiated. Calcium levels failed to improve over the next 3 days, and intravenous calcitonin was administered while awaiting peak effect of the intravenous bisphosphonate. Ionised serum calcium was normalised over the ensuing 12 days when it again began to increase and a second dose of zoledronic acid was administered.

Outcome and follow-up

The second dose of bisphosphonate was followed by a brief period of hypocalcaemia after which the calcium level normalised and remained stable for the rest of the hospital stay. The aetiology of the initial septic episode was not identified, but it resolved and the patient was able to leave the intensive care unit after 4 days. He remained hospitalised because of persistent lactic acidosis, likely a consequence of metastatic disease and liver failure. On day 19 of hospitalisation, he again became septic and required vasopressor support, intubation with mechanical ventilation and continuous renal replacement therapy for acute kidney injury and control of severe acidosis. Despite aggressive supportive management, he continued to decompensate and the family withdrew care after 38 days from his initial presentation.

Discussion

We report a case of calcitriol-induced hypercalcaemia in a patient with poorly differentiated NEC of the oesophagus. Although the main driver of increased serum calcium in lymphomas, this mechanism is rarely encountered in solid malignancies and is a very rare cause of malignant hypercalcaemia overall, accounting for <1% of cases.¹ Our review of the literature identified seven cases of solid tumours associated with excess production of 1,25-dihydoxyvitamin D. There were four reports of germ cell malignancies: one seminoma in a 49-year-old man² and three ovarian dysgerminomas in the paediatric population^3–5; of these, only two confirmed the mechanism of hypercalcaemia by a low measurement of PTHrP. Increased calcitriol production has also been described in cases of metastatic cancers of non-germ cell origin: neuroendocrine pancreatic tumour⁶ and small cell cervical carcinoma⁷; in both cases, measured PTHrP was low–normal. One case of clear cell renal cell carcinoma had both elevated 1,25-dihydroxyvitamin D and PTHrP.⁸ In addition to individual cases, one large retrospective analysis (101 adult patients) investigating the causes of calcitriol-induced hypercalcaemia found solid malignancies as the cause in 5% of patients; these included seminoma, ovarian clear cell cystadenocarcinoma, non-small cell lung cancer and metastatic squamous carcinoma of the tongue and adenocarcinoma of unknown origin.⁹ All had undetectably low PTHrP.

Though calcitriol-mediated hypercalcaemia has been previously described in at least two cases of neuroendocrine tumours, ours is the first to report the association with a neuroendocrine tumour of oesophageal origin. NECs of the oesophagus are very rare, with only approximately 4000 cases reported over the past 70 years.¹⁰ Histologically, NECs are composed of small cells with nuclear atypia and a high mitotic index, which stain positively for the common neuroendocrine markers: neuron-specific enolase and synaptophysin. Many (31%–90%) are metastatic at presentation. An ideal treatment algorithm has not been established and they are generally treated with platinum-based chemotherapy similarly to neuroenodocrine tumours of the lung. In our patient with confirmed NEC, more common causes of malignant hypercalcaemia such as PTHrP production and osteolytic metastases were ruled out based on biochemical and imaging studies. The possibility of a concurrent granulomatous disease or haematological malignancy was also considered, but the patient’s clinical course and imaging findings made these unlikely.

Antitumour therapy, either medical or surgical, represents the mainstay of treatment of malignant hypercalcaemia.¹ In the interim, non-specific therapies are warranted to control calcium levels if elevation is severe or symptomatic. These have no long-term mortality benefit.¹ Modalities include discontinuation of medication that can increase calcium levels, intravenous hydration with or without later addition of loop diuretics, calcitonin for immediate decrease in serum calcium and intravenous bisphosphonates, which usually achieve peak effect after 2–4 days. Denosumab, an osteoclast inhibitor, is an option for patients with severe renal impairment or hypercalcaemia refractory to bisphosphonates. Establishing the exact mechanism for hypercalcaemia may be important when choosing additional therapy. Normally, production of calcitriol (1,25-dihydoxyvitamin D) from calcidiol (25-hydroxyvitamin D) is catalysed by the enzyme 1-hydroxylase located in the renal cortex and the process is controlled by PTH. In the setting of granulomatous disease or lymphoma, the unregulated synthesis of calcitriol occurs extrarenally in activated macrophages or malignant lymphocytes. When this has been established as the cause of hypercalcaemia, treatment can directly target these inflammatory cells. The antimalarial drugs chloroquine and hydroxychloroquine have been successfully used to decrease calcium levels in patients with sarcoidosis,¹¹ but this approach failed to achieve control in our patient. Glucocorticoids are another recognised option, and there is one report of their efficacy in calcitriol-mediated hypercalcaemia associated with renal cell carcinoma.⁸ However, in the setting of active infection, their profound immunosuppressant effect prohibited their use in our patient and control was eventually achieved with bisphosphonates.

Learning points.

• Hypercalcaemia of malignancy can result from several mechanisms and an effort should be made to identify the main cause.

• 1,25-hydroxyvitamin D levels should be measured in all patients with hypercalcaemia regardless of measured parathyroid hormone (PTH), PTH-related protein and 25-hydroxyvitamin D levels.

• Calcitriol-induced hypercalcaemia is a rare cause of hypercalcaemia in solid tumours.

• Establishing the mechanism of hypercalcaemia may have therapeutic implications.