Dual-mediated PTH and Osteolytic Hypercalcemia in Metastatic Endometrial Carcinoma

Abstract

Hypercalcemia of malignancy (HCM) occurs frequently in advanced stage cancer and can be secondary to many different etiologies. This case illustrates a rare case of dual-mediated PTH and osteolytic HCM in the setting of metastatic endometrial carcinoma. The patient's hypercalcemia was refractory to initial treatment with IV hydration, calcitonin, and zoledronic acid, eventually requiring the addition of denosumab therapy and cinacalcet. After 15 days of treatment, the patient's calcium concentration returned to normal levels. Owing to elevated PTH levels, other etiologies of hypercalcemia were not initially investigated. Bone metastases, which were not observed on admission computed tomography, were incidentally identified on the technetium-99 m sestamibi scan. This case illustrates that although concurrent etiologies of hypercalcemia are uncommon, it is important to evaluate all possible contributing causes, especially in the clinical setting of malignancy.

Introduction

Hypercalcemia of malignancy (HCM) occurs in approximately 30% of advanced stage cancer patients [1]. The underlying pathophysiology must be determined to provide effective treatment. Etiologies include PTH-related peptide-mediated hypercalcemia in ∼80% of cases and osteolytic metastasis-mediated hypercalcemia in ∼20% of cases, with <1% due to overproduction of 1,25-dihydroxycholecalciferol or PTH-mediated metabolism [2]. These conditions may rarely present concurrently. Prompt recognition and correction of HCM is especially important given the high mortality rate associated with lack of treatment [3]. The median survival after HCM diagnosis is 68 days [4]. The clinical manifestations of severe hypercalcemia include cardiac arrhythmias, cardiac arrest, pancreatitis, acute kidney injury (AKI), renal failure, lethargy, confusion, weakness, and coma [2]. We report a rare case of both PTH-mediated and osteolytic metastasis-mediated hypercalcemia in the setting of metastatic endometrial carcinoma.

Case Presentation

A 57-year-old female with stage IVB endometrial cancer and multiple solid organ metastases presented to the emergency room with a 2-week history of progressively worsening oral intake, nausea, emesis, constipation, and right flank pain. The patient was originally diagnosed with endometrial cancer 3 years prior to presentation. She had known stable pulmonary and brain metastases, with a recently discovered right adrenal mass. One month prior to admission, a biopsy was performed on the new adrenal mass, and the pathology was consistent with metastatic carcinoma. Her oncological treatment course included multiple rounds of systemic chemoimmunotherapy, initial brain lesion surgical resection, and radiation therapy to the pelvis/brain/right adrenal gland. The patient's most recent systemic regimen included bevacizumab every 2 weeks and cyclophosphamide 50 mg daily. Bevacizumab was last administered 2 months prior to hospitalization; however, it was stopped due to the complication of deep vein thrombosis within the right internal jugular, axillary, brachial, and basilic veins. On hospital admission, the patient was found to have severe hypercalcemia and Kidney Disease | Improving Global Outcomes stage 1 AKI with a baseline creatinine level of 1.3 mg/dL (115 µmol/L) (normal range 0.7-1.2 mg/dL; 62-106 µmol/L). On review of the laboratory results prior to admission, the patient had chronic intermittent mild hypercalcemia starting 3 years prior, with a corrected calcium concentration ranging from 10.0 to 11.4 mg/dL (2.50-2.85 mmol/L) (normal range 8.6-10.2 mg/dL; 2.15-2.55 mmol/L) for the 6 months prior to admission. An elevated PTH level of 113 pg/mL (113 ng/L) (normal range 15.0-65.0 pg/mL; ng/L) was documented 2 months prior to admission. Before hospitalization, the patient had normal mobility and was able to walk without assistance. Vital signs on admission included a heart rate of 69 beats/minute, a blood pressure of 144/83 mmHg, a respiratory rate of 18 breaths/minute, an oxygen saturation of 99% on room air, a weight of 111 kg, a height of 157 cm, and a body mass index of 45 kg/m². The patient lost 10 kg of weight in the month prior to admission. The physical examination revealed lethargy, poor skin turgor, right costovertebral tenderness, and limited movement of all 4 extremities secondary to pain. The physical examination was otherwise unremarkable.

Diagnostic Assessment

The patient had multiple myeloma evaluations with negative urine and serum protein electrophoresis results 1 month prior to admission. Computed tomography of the chest/abdomen/pelvis without contrast revealed increased sizes of known right adrenal metastases, new left adrenal lesions, periaortic lymphadenopathy, and scattered nodules in the subcutaneous tissues of the abdomen and chest. However, new bone metastases were not noted. With a history of chronic hypercalcemia and elevated PTH, there was concern for PTH-mediated hypercalcemia during admission. Subsequent staining of the right adrenal metastasis biopsy was negative for PTH. Pertinent admission labs are shown in Table 1. Morning cortisol levels were obtained for the evaluation of adrenal insufficiency contributing to hypercalcemia; however, cortisol levels were normal at 17.3 µg/dL (477 nmol/L) (normal range 8-24 µg/dL; 221-662 nmol/L). A technetium-99 m sestamibi scan was obtained for the localization of possible parathyroid adenoma or carcinoma. The scan did not localize a focal parathyroid lesion; however, it did show numerous new lytic lesions in the skull, sternum (Fig. 1), spine (Fig. 2), rib cage, and right humerus (Fig. 2). Only some of these lesions demonstrated increased sestamibi uptake, which was likely attributable to a pathologic fracture rather than increased mitochondrial activity from the underlying malignancy. Most lesions were apparent only on the single photon emission computed tomography-computed tomography portion acquired with the sestamibi scan. The patient's renal function continued to decline throughout admission, with creatinine peaking at 6.9 mg/dL (610 µmol/L). Nephrology suggested that the decline in renal function was due to acute tubular necrosis in the context of renal vasoconstriction and volume depletion.

Treatment

On admission, the patient was aggressively resuscitated with IV fluids, 4 mg of zoledronic acid administered by IV, and 4 mg/kg calcitonin administered subcutaneously every 12 hours. The corrected calcium concentration decreased to 19.3 mg/dL (4.83 mmol/L) on day 2, and her calcitonin dosage was increased to 8 mg/kg every 12 hours for days 2 to 3. On day 4, the corrected calcium concentration decreased to 15.6 mg/dL (3.90 mmol/L). Owing to concerns about PTH-mediated causes, oral cinacalcet (30 mg twice daily) was started. On day 5, the corrected calcium concentration decreased to 14.5 mg/dL (3.63 mmol/L), lytic lesions were observed on a technetium-99 m sestamibi scan, and the patient was administered a dose of 120 mg of denosumab subcutaneously. Figure 3 summarizes the calcium levels with the associated treatments during hospitalization.

Outcome and Follow-up

In addition to hypercalcemia, the patient's hospital course was complicated by progressively worsening renal function, anemia, and thrombocytopenia. Nephrology evaluated the patient and determined there were no indications for renal replacement therapy. Palliative medicine was consulted because of acutely worsened malignancy and complications with poor prognosis. The patient declined hospice care and preferred discharge to rehabilitation. After 16 days of treatment, the patient was discharged to a long-term acute rehabilitation facility off hypercalcemia treatment. Laboratory results at discharge were notable for a corrected calcium concentration of 10.0 mg/dL (2.50 mmol/L) and a creatinine concentration of 6.9 mg/dL (610 µmol/L). The patient passed away within 1 week of hospital discharge.

Discussion

The evaluation of hypercalcemia includes verifying that hypercalcemia is present, considering possible causative diseases or medications, and measuring PTH levels [5]. If the PTH level is inappropriately normal or high, it is considered PTH-mediated hypercalcemia, and the cause of PTH elevation is investigated. The causes of elevated PTH hypercalcemia include hyperparathyroidism, familial hypocalciuric hypercalcemia, and ectopic PTH production in tumors [6, 7]. Ectopic production of PTH by nonparathyroid tumors is rare and has been observed in only a small number of endometrial cancer patients [7, 8]. The patient had a biopsy of her right adrenal metastasis 1 month prior to admission, and staining was negative for PTH, making ectopic production of PTH unlikely in this case. Previously resected endometrial cancer tissue could not be used for PTH staining, as the last tissue sample was collected more than 2 years prior. The patient had primary hyperparathyroidism that was nonlocalizing to a single adenoma on a technetium-99 m sestamibi scan. Additional localization imaging for surgical intervention was not considered given the patient's prognosis and improvement in serum calcium levels with medical therapy.

Treatment for severe HCM includes adequate IV hydration, calcitonin, and either IV bisphosphonate or denosumab [9]. The patient was initially treated with IV fluids, a dose of zoledronic acid, and calcitonin for up to 72 hours. Although calcitonin helps to lower calcium, its use is limited to 48 to 72 hours because of tachyphylaxis [9]. Calcimimetic treatment is recommended for hypercalcemia due to parathyroid carcinoma. Because the patient had an unknown PTH-mediated cause of unresolving hypercalcemia, cinacalcet was started on day 4. A previous study revealed corrected serum calcium normalization by day 4 of zoledronic acid treatment in approximately 45% of patients and a complete response by day 10 in 88% of patients [10]. Owing to worsening kidney function and corrected calcium levels remaining at 14.5 mg/dL (3.63 mmol/L) 4 days after zoledronic acid dosing, the decision was made to add denosumab. Prior studies have shown the efficacy of denosumab for IV bisphosphonate refractory hypercalcemia, with a median response time of 9 days [11]. The patient's hypercalcemia finally normalized 15 days after zoledronic acid therapy and 11 days after denosumab therapy, but she remained on cinacalcet until discharge.

Osteolytic metastasis-mediated hypercalcemia occurs in ∼20% of HCM patients and <1% of HCM patients have PTH-mediated causes [2]. These conditions rarely present concurrently, but they were both present in this patient. Owing to the patient's AKI on admission, initial imaging was noncontrasted, and some subtle bone metastases were not observed. In most cases of HCM, PTH is normal or suppressed [2]. PTH elevation was found early in the patient's hospital course; therefore, other non-PTH-mediated causes of hypercalcemia were not pursued until later. The patient's elevated PTH level was discordant with her high degree of hypercalcemia and prolonged treatment course. If the bone findings were not incidentally discovered on the technetium-99 m sestamibi scan, it would not have been known the patient had widespread osteolytic metastases contributing to hypercalcemia. On review of the initial computed tomography images of the chest, abdomen, and pelvis after the sestamibi scan, many of the lytic lesions were not in the field of view (skull, C2, and humerus). However, subtle sternal lesions were missed. Although multiple etiologies of hypercalcemia can be rare, it is important to evaluate all contributing causes, especially in the setting of clinical conditions such as malignancy.

Learning Points

• PTH-mediated hypercalcemia is a rare cause of hypercalcemia of malignancy. PTH levels are typically low or low-normal in patients with osteolytic-mediated hypercalcemia.

• Although multiple etiologies of hypercalcemia can be rare, it is important to evaluate all contributing causes, especially in the setting of clinical conditions such as malignancy.

• Additional therapy with denosumab should be considered for hypercalcemia of malignancy that is refractory to IV bisphosphonate therapy.

Contributors

All authors made individual contributions to authorship. N.S.T. and Z.K.M. were involved in the diagnosis and management of the patient. C.K.P., N.S.T., and Z.K.M. were involved in writing and editing the manuscript. C.K.P. was involved in the literature review, preparation, and manuscript submission. R.S.G reviewed the radiology and edited the manuscript. D.J.B. edited the manuscript, provided overall supervision, and approved the work. All authors reviewed and approved the final draft.

Funding

No public or commercial funding.

Disclosures

The views expressed in this manuscript are those of the author(s) and do not necessarily reflect the official policy or position of the Defense Health Agency, Brooke Army Medical Center, the Department of Defense, or any agencies under the US government.

Informed Patient Consent for Publication

Signed informed consent could not be obtained from the patient or a proxy but has been approved by the treating institution.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

References