Refractory paraneoplastic hypercalcaemia responding to cinacalcet
- 1 Endocrinology and Diabetes, Mid Yorkshire Hospitals NHS Trust, Wakefield, UK
- 2 Endocrinology and Diabetes, Harrogate District Hospital, Harrogate, UK
- 3 Endocrinology and Diabetes, St James's University Hospital, Leeds, UK
- Correspondence to Dr Preet Mukesh Shah; drpreetshah@gmail.com
Abstract
A woman in her late 70s presented with an increased frequency of micturition, suprapubic pain and weight loss. She was found to be having advanced cancer of the urinary bladder, coupled with bilateral hydronephrosis.Whilst undergoing surgical intervention for the latter, she was incidentally found to be having hypercalcaemia. This was found to be paraneoplastic in nature, possibly due to elevated parathyroid hormone related peptide with no evidence of bone metastasis. The histology of the resected tumour revealed squamous and sarcomatoid differentiation. Her hypercalcaemia initially responded to intravenous fluids, and later on zolendronate,but the problem recurred again, with the response to a repeat dose of zolendronate and even denosumab being unsatisfactory. As a last resort cinacalcet was started, and although there was a good response to it, our patient sadly died a few weeks later.
We believe our case to be the first case of hypercalcaemia associated with isolated bladder cancer which showed a successful response to cinacalcet.
Background
Hypercalcaemia of malignancy is a paraneoplastic endocrine phenomenon, commonly occurring due to a rise in the levels of parathyroid hormone (PTH) related peptide (PTHrP); and uncommonly due to 1,25-dihydroxy-vitamin D production or osteolytic hypercalcaemia. Very rarely, it could be due to ectopic production of PTH.1 The common cancers associated with this phenomenon are lung cancer, multiple myeloma and renal cell carcinoma, followed by breast and colorectal cancers. The lowest prevalence seems to occur in prostate cancer.2
PTHrP-mediated hypercalcaemia in association with bladder carcinoma is very rare and has only been reported in isolated case reports.3
Case presentation
A woman in her late 70s with no comorbidities, taking no regular medications, presented with a history of increased frequency of micturition, suprapubic pain and weight loss over the past month. She had recently been empirically treated for a suspected urinary infection by her General Practitioner(GP), but this had not helped. An ultrasound of the abdomen showed a large echogenic mass arising from the anterior bladder wall, measuring 10.7 cm × 8.5 cm × 6 cm in dimensions, with some vascularity noted within the mass. Both the kidneys measured nearly 11.5 cm in bipolar length, and there was evidence of moderate hydronephrosis bilaterally. Her investigations showed a significant reduction in her estimated glomerular filtration rate (eGFR) to 39 mL/min/1.73 m2 (from a baseline of between 75 and 80 mL/min/1.73 m2). The formula used to calculate eGFR was the chronic kidney disease-Epidemiology Collaboration Equation.4 She had a CT of the urinary tract, which showed a large urinary bladder malignancy with the dimensions being 10.8 cm craniocaudally, 9.0 cm anteroposteriorly and 9.0 cm mediolaterally, causing upstream obstruction, with para-aortic lymphadenopathy. The stage of the malignancy was T3a N2 M1a, considered advanced by the oncology team.
She underwent a right sided nephrostomy 18 months ago. It could not be performed on the left side due to technical difficulties. In the meantime, she was found to be having a high blood pressure, and was thus started on doxazosin for it. Coincidentally, she was also found to be having an albumin-adjusted total serum calcium of 3.09 mmol/L (normal range: 2.20–2.60 mmol/L) on the same day. She was thus started on intravenous fluids, and this reduced her albumin-adjusted total serum calcium to 2.99 mmol/L after 2 days. With further hydration, this further reduced to 2.88 mmol/L a day later. Her eGFR also improved to >90 mL/min/1.73 m2.
She underwent a transurethral resection of the bladder tumour 2 days later with incomplete resection of the tumour. She was discharged after 2 days.
After a week, she was admitted to the urology department for an antegrade stent insertion, but according to the nephrostogram, a stent was not needed. Her albumin-adjusted total serum calcium at this instance was 3.39 mmol/L. Her investigations have been summarised in table 1.
Depicting a summary of the investigations
| Test performed | Result |
| Parathyroid hormone | 1.4 pmol/L (normal range: 1.6–6.9 pmol/L) |
| 25-hydroxy vitamin-D | 61 nmol/L (normal range: 50–75 nmol/L) |
| 1,25-dihydroxy vitamin-D | 58 pmol/L (normal range=20–120 pmol/L) |
| Myeloma screen | Normal |
| Bone scan | Normal |
She was aggressively hydrated again, and considering possible paraneoplastic hypercalcaemia secondary to PTHrP, (suppressed PTH with elevated calcium levels), she was given 4 mg intravenous zolendronate in addition to the intravenous fluids on the second day of her admission. 2 days later, her albumin-adjusted total serum calcium improved to 2.74 mmol/L (figure 1). She was subsequently discharged with her albumin-adjusted total serum calcium being 2.38 mmol/L.
Trend of the adjusted calcium levels and its response to various agents.
She was readmitted 3 weeks later under the endocrinology team in view of a new onset of confusion and with an albumin-adjusted total serum calcium level of 3.41 mmol/L. She was again started on intravenous fluids for the hypercalcaemia. Despite this, the calcium did not improve, and 3 days later the levels had reached 3.44 mmol/L. Her renal functions had been stable all this while. She was given 4 mg intravenous zolendronate the next day (her second dose in total and a month after the first dose). She continued to be aggressively hydrated. Two days after this dose was administered, her albumin-adjusted total serum calcium improved to 3.13 mmol/L, but the next day it rose to 3.39 mmol/L.
It was thus decided to treat her with denosumab and she received a cumulative dose of 120 mg the very same day. After this, her albumin-adjusted total serum calcium increased to 3.44 mmol/L the next day and further rose to 3.65 mmol/L after 5 days.
Investigations
The biopsy of the resected tumour showed a necrotic tumour with areas of conventional urothelial carcinoma of grade 3 (high-grade) morphology. Also present was squamous differentiation (intercellular bridges) as well as sarcomatoid differentiation (stromal mucin) representing divergent differentiation. On immunohistochemistry, the tumour showed the staining profile as follows: positive for CK7 (weak), CK14 (strong and diffuse) and GATA3 (strong but patchy) (figures 2–4 respectively). Staining was negative for CK20, uroplakin. The morphology, supported by the immunohistochemistry, was in favour of a high grade urothelial carcinoma showing divergent differentiation. The differential of a metastatic squamous carcinoma/sarcomatoid carcinoma was a less likely probability given the GATA3 positivity.
Tumour staining weakly positive for CK7 on immunostaining.
Tumour staining strongly positive for CK14 on immunostaining.
Tumour staining strongly positive for GATA3 on immunostaining.
Differential diagnosis
Initially, the differentials being considered were hypercalcaemia due to PTH, PTHrP, excessive 1,25-dihydroxy-vitamin D production or osteolytic hypercalcaemia. The low PTH levels, the normal 1,25-dihydroxy-vitamin D production, and the negative myeloma screen and bone scan indicated the problem to be secondary due to PTHrP.
Treatment
Because of the refractory hypercalcaemia, it was decided to start her on cinacalcet 30 mg (two times per day) following the last result of the albumin-adjusted total serum calcium. Dialysis was not considered to be appropriate in her case by the oncology team, considering the advanced nature of her cancer.
She was referred to the palliative team as her overall clinical condition was deteriorating, and the oncology team did not have any viable options for her tumour. 2 days after cinacalcet was initiated, her albumin-adjusted total serum calcium reduced to 3.22 mmol/L.
Outcome and follow-up
With a palliative intent, she was discharged after 2 days while remaining on the same dose of cinacalcet. 9 days post discharge, her albumin-adjusted total serum calcium levels had further declined to 2.79 mmol/L. Unfortunately, she died a few days after this test result.
Discussion
Hypercalcaemia associated with carcinoma of the bladder is related to the presence of high-grade undifferentiated carcinoma or squamous cell carcinoma (SCC) component.5 Our patient had the variety which had squamous and sarcomatoid differentiation. Furthermore, her PTH levels were low, thus suggesting that the problem could be secondary to PTHrP production by the tumour. The mainstay of treatment of hypercalcaemia is aggressive hydration.6 The next line of treatment is bisphosphonates, namely zolendronate, which is the drug of choice. Interestingly, this drug had been administered to her 1 month ago, after which there had been a transient improvement in the adjusted calcium levels. But the adjusted calcium levels started rising again after a few weeks, and she started getting symptomatic with this. On this occasion, she again received intravenous zolendronate, but there was no improvement in her calcium levels. Because bisphosphonates are unable to inhibit PTHrP-induced calcium reabsorption in the kidneys, the hypercalcaemia may be refractory to the bisphosphonates.6 We believe this may have been the case with our patient.
It was thus decided to proceed to the next line of treatment-denosumab. This drug is a human monoclonal antibody to receptor activator of nuclear factor kappa-Β ligand that inhibits osteoclast activity and bone resorption, and had been approved in 2014 for the treatment of hypercalcaemia of malignancy.6 It is worth noting, that these drugs were given to her in addition to intravenous fluids, so as to prevent her from getting dehydrated. Calcitonin is a drug that can rapidly lower the calcium levels, but its efficacy is limited to the first 48 hours after initiation, owing to the development of tachyphylaxis, and was thus not used.7 Since the response to denosumab was unsatisfactory, cinacalcet was started. This agent has calcimimetic properties, and activates the calcium-sensing receptor (CaSR). Cinacalcet is used for the reduction of hypercalcaemia in those with severe primary hyperparathyroidism who are unable to undergo parathyroidectomy, for the treatment of secondary hyperparathyroidism in patients with end-stage renal disease on maintenance dialysis therapy, and additionally, to treat hypercalcaemia in those suffering from parathyroid carcinoma.8 Cinacalcet has been used very rarely to treat hypercalcaemia of malignancy, and there are only a handful of case reports available with regard to the same.9 CaSR is expressed in bone cells as well (contributing to bone homeostasis), in addition to the parathyroid glands and kidneys. In animal studies, activation of osteoclastic-CaSR has been shown to inhibit bone resorption, leading to an increase in bone anabolism.10 Even in the absence of CaSR, cinacalcet has been found to attenuate PTHrP-mediated increase in serum calcium, in mice bearing Rice H-500 Leydig cells or C26-DCT colon tumours and this effect was accompanied by an increase in plasma calcitonin levels.11 Surprisingly, our patient started responding to cinacalcet, with a reduction in her albumin-adjusted total serum calcium levels to 2.79 mmol/L. In the other reports in which cinacalcet has been used for the treatment of paraneoplastic hypercalcaemia, the tumours involved have been neuroendocrine tumours, breast cancer, lung cancer and renal cell carcinoma.6 12–15
We believe our case to be the first case of hypercalcaemia associated with isolated bladder cancer which showed a successful response to cinacalcet. With a limited number of modalities currently available for treating hypercalcaemia of malignancy, further research would be useful to explore the use and benefits of using cinacalcet in this scenario.
Patient’s perspective
It was disheartening to see my wife have one problem after another. The medical team did their best to solve these issues.
Learning points
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Bladder cancer is an uncommon, and yet an important cause of paraneoplastic hypercalcaemia.
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In addition to the squamous cell variety of bladder cancer, even the relatively less common sarcomatoid variety may be associated with paraneoplastic hypercalcaemia.
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It would be indispensable to conduct further studies in humans, examining the mechanisms of action of cinacalcet in cases of paraneoplastic hypercalcaemia.
Ethics statements
Patient consent for publication
Acknowledgments
We would like to thank and acknowledge Dr Elza Tjio for providing the histopathological images.
Footnotes
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Contributors IR contributed to the case description. PMS and DM contributed to the discussion of the case.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
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