Evaluation of Diagnostic Workup and Etiology of Hypercalcemia of Malignancy in a Cohort of 167,551 Patients over 20 Years

Context Hypercalcemia of malignancy (HCM) has not been studied in a fashion to determine all possible mechanisms of hypercalcemia in any given patient. Objective The two objectives were to assess the completeness of evaluation and to determine the distribution of etiologies of HCM in a contemporary cohort of patients. Methods A retrospective analysis was performed of patients with cancer who developed hypercalcemia over 20 years at a single health system. Laboratory data were electronically captured from medical records to identify cases of parathyroid hormone (PTH)-independent hypercalcemia. The records were then manually reviewed to confirm the diagnosis of HCM, document the extent of evaluation, and determine underlying etiology(ies) of HCM in each patient. Results The initial dataset included 167,551 adult patients with malignancy, of which 11,589 developed hypercalcemia. Of these, only a quarter (25.4%) had assessment of PTH with a third of the latter (30.9%) indicating PTH-independent hypercalcemia. Of those with PTH-independent hypercalcemia, a third (31.6%) had assessment of PTH-related peptide (PTHrP) and/or 1,25-dihydroxy vitamin D (1,25-OH vitamin D) and constituted the one hundred and fifty three cases of HCM examined in this study. Eighty three of these patients had an incomplete evaluation of their HCM. The distribution of etiologies of HCM was therefore determined from the remaining 70 patients who had assessment of all three possible etiologies (PTHrP, 1,25-OH vitamin D and skeletal imaging) and was as follows: PTHrP 27%, osteolytic metastases 50% and 1,25-OH vitamin D 39%, with combinations of etiologies being common (approximately 20%). Conclusion HCM is incompletely evaluated in many patients. The distribution of etiologies of HCM in this report differs significantly from the previous literature warranting further study to determine if its causes have indeed changed over time.

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

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.

HYPERCALCEMIA OF MALIGNANCY IN A CASE OF PERIPHERAL NERVE SHEATH TUMOR: ELUCIDATING THE ROLES OF SIMULTANEOUS MECHANISMS

Objective: Hypercalcemia of malignancy (HCM) is caused by 1 of 5 known mechanisms including systemic release of ectopic parathyroid hormone (PTH)-related protein (PTHrP), calcitriol, PTH, cytokines, or destruction of bone by osteolytic metastases. We report the first case of 2 simultaneous mechanisms for HCM in a patient with a peripheral nerve sheath tumor (PNST) Methods: PubMed and Google Scholar searches were performed using “hypercalcemia of malignancy” as the search term. Results: A 26-year-old woman with neurofibromatosis presented with worsening left hip pain. Magnetic resonance imaging showed a large left paraspinal mass, subtotal resection of which confirmed PNST. Despite chemo-radiation therapy, the tumor progressed over 16 months, requiring tumor debulking and L3–4 lumbar laminectomy. The patient developed progressive bilateral lower extremity weakness due to direct tumor invasion of the lumbosacral vertebrae with concurrent hypercalcemia. Ionized calcium was 1.47 mmol/dL (reference range is 0.95 to 1.32 mmol/dL), PTH was <4.0 pg/mL (reference range is 8 to 85 pg/mL), 25-hydroxyvitamin D was 14 ng/mL, calcitriol was <8.0 pg/mL (reference range is 18 to 78 pg/mL), PTHrP was 40 pg/mL(reference range is 14 to 27 pg/mL), urinary calcium was <2.0 mg/24 hours, serum C-telopeptide was 1,008 pg/mL (reference range is 64 to 640 pg/mL), and bone-specific alkaline phosphatase was 15.7 μg/L (reference range is 4.7 to 17.8 μg/L). Her serum magnesium, phosphorus, and creatinine levels were normal. Intravenous zoledronic acid and hydration resulted in a normal ionized calcium. Additional imaging revealed extensive tumor invasion of L3-S1 vertebrae. Due to her poor response to all cancer therapies, the patient was discharged to home hospice services. Conclusion: HCM due to PTHrP and osteolytic metastases has not been independently reported to our knowledge in association with malignant PNST as in our patient. The therapeutic importance of characterizing the mechanism of HCM is further discussed in detail.

Bone Metastases in Medullary Thyroid Carcinoma: High Morbidity and Poor Prognosis Associated With Osteolytic Morphology

Context The clinical relevance of bone metastases (BM) in advanced medullary thyroid carcinoma (MTC) is poorly described. Objective The objectives of this work are to describe the prevalence of BM, frequency of skeletal related events (SREs), and impact of BM morphology and SREs on prognosis, and to assess the role of antiresorptive treatment (ART). Design A retrospective cohort study was conducted. Setting This study was conducted at 4 German referral centers. Patients A total of 1060 MTC patients were included. Main Outcome Measure Main outcome measures include descriptive statistics, overall survival (OS) by the Kaplan-Meier method, and risk factors by Cox proportional hazards modeling. Results A total of 120 of 416 patients (29%) with metastatic MTC had BM, of which 97% had concurrent nonosseous metastases. BM occurred 2.1 years (median, range –0.1 to 20.6 years) after initial diagnosis, were multifocal in 79%, and were located preferentially in the spine (86%) and pelvis (60%). BM morphology was osteolytic in 32%, osteoblastic in 25%, and mixed in 22% of cases (unknown: 21%). Within a median observation period of 26.6 months (range, 0-188 months) after BM diagnosis, 47% of patients experienced one or more SREs (bone radiation 50%, pathological fractures 32%), of which 42% occurred in osteolytic and 17% in osteoblastic BM (P = .047). Presence of osteolytic metastases (hazard ratio 3.85, 95% CI 1.52-9.77, P = .005) but not occurrence of SREs was associated with impaired OS. Among the 36 patients who received ART (no ART: n = 71), SREs were significantly less frequent than in untreated patients (P = .04). Conclusion BM are common in metastatic MTC and most often with an osteolytic morphology and an unfavorable prognosis. The majority of SREs occur in osteolytic metastases and may be prevented by ART.