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.

Impact and predictors of readmission in hypercalcemia of malignancy: Findings of a nationwide analysis.

e18809 Background: Hypercalcemia of malignancy (HCM) is common in cancer. It is a sign of advanced malignancy and associated with poor outcomes. Although a well-known phenomenon, treatment options are limited and recurrence leading to readmissions is common, increasing morbidity and mortality. We attempt to explore the mortality, healthcare resource utilization, 30-day readmission rate and independent predictors of readmission for HCM. Methods: We queried the 2017 National Readmission Database (NRD) of adults readmitted within 30 days after index admission for HCM with a concomitant diagnosis of solid tumors. T test was used for continuous variables and chi square test was used for categorical variables. Multivariate regression was used to identify predictors for unplanned readmissions. Results: A total of 14,323 patients with solid tumors were admitted with HCM. The 30-day readmission rate was 24.9%. Common causes for readmission were sepsis, respiratory failure, hypercalcemia, distant metastases and AKI. At 30 days, readmitted patients were less likely to be discharged compared to patients admitted initially due to hypercalcemia (27.4 vs 30.8%; P<0.01). Readmitted patients had a higher in-hospital mortality at 30 days (1.5 vs. 0.1%; P<0.01), more incidence of chemotherapy induced pancytopenia (3.8 vs 2.5%; P<0.01), mechanical ventilation (5.8 vs 4.7%; P=0.05) and venous thromboembolism (8.3 vs 5.9%; P<0.01). Total economic burden of readmission was $251 million in total charges and $62.6 million in total costs. Adjusting for age and comorbidities, independent predictors of readmission were anemia of chronic disease, iron deficiency anemia and obesity. Conversely, predictors for lower odds of readmission were disposition to skilled facility and discharge with home health care services (Table). Conclusions: Nationally, HCM has a high rate of readmissions with increased morbidity and mortality making it a consequential healthcare burden. Among causes of readmission, potentially targetable include AKI and sepsis while among readmission predictors, iron deficiency anemia and anemia of chronic disease warrant further attention. Similarly, negative predictors highlight the importance of proper disposition planning and supportive care in malignancy.[Table: see text]

Treatment-Resistant Hypercalcemia Secondary to Ectopic PTH Hypersecretion From Disseminated Ovarian Cancer

Background: Hypercalcemia of malignancy (HCM) can present secondary to hypersecretion of parathyroid hormone (PTH)-related protein (PTHrP) from malignant tumors, but rare cases of HCM have also been documented due to inappropriate PTH secretion from ectopic neoplasms. Here, we report an unusual case of HCM due to hypersecretion of PTH from a disseminated mucinous ovarian adenocarcinoma. Case Presentation: A 45-year-old female presented with confusion, constipation, fatigue, and abdominal pain two weeks after total abdominal hysterectomy with bilateral salpingo-oophorectomy and suboptimal debulking of a newly discovered left ovarian mucinous adenocarcinoma with metastasis to the bladder, parametrium, vagina, right ovary, and rectosigmoid. Subsequent CT revealed numerous bilateral pulmonary nodules, hilar adenopathy, liver lesions, and abdominal adenopathy. On exam, she was tachycardic and hypertensive with diaphoresis, dry mucous membranes, respiratory distress, guarded abdominal tenderness, and altered mental status. Her labs were significant for a serum calcium of 21.7 mg/dL, creatinine of 1.93 mg/dL, ferritin of 2,379 ng/mL, leukocytosis of 21.9 bil/L, PTH of 1,061 pg/mL, and PTHrP of 29 pmol/L. Ectopic PTH secretion was highly suspected after negative parathyroid ultrasound. Pamidronate (60 mg IV), calcitonin (200 U IM), and fluid resuscitation were unable to normalize her serum calcium, resulting in the need for dialysis and subsequent continuous renal replacement therapy. Further intervention with denosumab (120 mg SQ), etelcalcetide (5 mg IV), and cinacalcet (60 mg PO) was also attempted. Serum calcium began to decline, but repeat PTH resulted greater than 2,500 pg/mL. Unfortunately, the patient died just one week into her hospital course from septic shock and multi-organ system failure. Discussion: Hypercalcemia of malignancy typically arises from tumor secretion of PTHrP, cytokine release from osteolytic metastases, or tumor production of calcitriol. In cases of hypercalcemia due to excess PTH secretion, primary parathyroid etiologies are typically considered while ectopic PTH-secreting tumors are rare. PTH staining of biopsy specimens and total body sestamibi scan may prove useful in the early detection and treatment of these tumors, but HCM offers a poor prognosis with mean survival of 2 to 3 months and in-hospital mortality of 6.8%. Currently, there are only three cases in the reported literature of ectopic PTH-induced hypercalcemia related to ovarian cancer. To our knowledge, this is the fourth reported case. Conclusion: Ectopic PTH-secreting tumors carry a poor prognosis and should be considered in cancer patients presenting with PTH-associated hypercalcemia. Biopsy staining for PTH and total body sestamibi scan may assist in the early detection of these tumors, but current treatment strategies offer suboptimal outcomes.

Single Dose of Denosumab Effective for Management of Bisphosphonate-Refractory Hypercalcemia of Malignancy Related to Non-Small Cell Lung Cancer

Background: First line therapy for hypercalcemia of malignancy (HCM) includes cancer directed treatment and bisphosphonate therapy. Denosumab is effective in bisphosphonate-refractory HCM (BR-HCM), approved for treatment with dosing schedule at 1, 8, 15, and 29 days and then monthly. Clinical Case: We present the case of a 64 year-old man with Stage IIIA squamous cell lung carcinoma diagnosed 5/2019 with corrected serum calcium (CSC) of 11.2 mg/dL (8.4–10.2) at presentation. Prior to treatment, he developed symptomatic CSC 14.0 mg/dL, treated with IV pamidronate 90mg and IV fluids (IVF) 6/28/2019 with improvement to CSC 9.7 mg/dL. Hypercalcemia recurred 8/2019 while undergoing radiation therapy with CSC 14.7 mg/dL, phosphorus 2.5 mg/dL (2.7–4.5), PTH 7 pg/mL (15–65), PTHrP 2.2 pmol/L (&lt;2.0), 25-OH vitamin D 30.16 ng/mL (30–100), and 1,25-OH2 vitamin D 98.7 pg/mL (19.9–79.3). He was treated with IVF and 4mg zoledronic acid (ZA) on 8/20 and 8/29/2019. CSC normalized 9/30/2019 and he subsequently received three cycles of pembrolizumab 11/25/2019 to 1/6/2020, discontinued for associated pneumonitis He again developed HCM 6/5/2020 with CSC 12.6 mg/dL. He was treated with ZA 4mg on 6/16 and 6/29/2020 with persistent, symptomatic hypercalcemia to 13.7 mg/dL 7/9/2020 with ongoing confusion, constipation, and lethargy. Endocrinology was consulted 7/9/2020 and initiated IVF, calcitonin SQ 4U/kg q12h for 48 hours, and prednisone 30mg daily for 5 days. Chemotherapy was initiated 7/14/2020. CSC remained stable &lt;11.5 mg/dL until 8/3/2020 with recurrent calcium to 13.0 mg/dL despite cancer-directed therapy. He was then given 120mg SQ denosumab on 8/7/2020. CSC improved to 10.6 mg/dL on 8/11/2020 and has remained &lt;11 mg/dL at 70 days after a single dose of denosumab. Conclusion: Denosumab was approved for BR-HCM with a complex treatment schedule based on a single-arm study of 33 patients, of whom 39% had treatment-related adverse events.1 We present a case of successful management of BR-HCM with a single dose of 120mg denosumab with CSC &lt;11.5 mg/dL at day 4 after treatment and persistent control of calcium at day 70 without further treatment. Further investigation is warranted to determine the most effective treatment schedule of denosumab for BR-HCM to reduce adverse events including hypocalcemia and overtreatment. References: 1. Hu MI, Glezerman IG, Leboulleux S, et al. Denosumab for treatment of hypercalcemia of malignancy. J Clin Endocrinol Metab. 2014 Sep;99(9):3144–52

A Case Report of Patient With Mysterious Hypercalcemia

Background: Non-parathyroid hormone related hypercalcemia has a broad differential diagnosis. One of the key diagnosis to exclude is malignancy. Case: A 41 yo male with paraplegia due to an accident at age 21, b/l BKA, stage 4 sacral pressure ulcer complicated by vesico-cutanous fistula status post ileal conduit and chronic osteomyelitis of the ischia, sacrum and pelvis was admitted with sepsis secondary to infected sacral pressure ulcer. He was noted to be hypercalcemic with corrected calcium of 13.4mg/dl. He had no previous history of hypercalcemia, kidney stones, head or neck radiation. Work up showed appropriately suppressed PTH with normal PTHrp, 1,25-dihydroxy vitamin D, 25-dihydroxy vitamin D, SPEP, UPEP and TSH. Drug induced hypercalcemia was ruled out. CT abdomen/pelvis was done and showed chronic osteomyelitis; destruction of the sacrum, ischia, pubic bones and femoral heads with enlarged inguinal lymph nodes. Review of records showed a NM bone scan done the year prior to admission to evaluate the chronic destruction of pelvic bones was negative for malignancy. Chest imaging was unremarkable. Patient underwent debridement and wash out of sacral and bilateral lower extremity wounds with bone biopsy. Pathology showed necrotic bone, chronic and acute inflammatory tissue. Calcium peaked at 17mg/dl prior to bisphosphonate, calcitonin and IVF becoming effective. Given the severity of hypercalcemia there was concern for malignancy despitethe negative work up thus Interventional Radiology was consulted for lymph node biopsy. Inguinal lymph node FNA was positive for metastatic squamous cell cancer prompting an exam under anesthesia which was negative for anal lesions. He underwent a cystoscopy which showed a large fungating mass involving the bulbar and membranous urethra with biopsies consistent with invasive and moderately differentiated keratinizing squamous cell carcinoma. Hypercalcemia resolved with treatment and he was discharged home to complete an antibiotic course prior to anticipated chemotherapy. Unfortunately, patient died prior to starting chemotherapy. Conclusion: Hypercalcemia has been found to be associated with 30% of late stage malignancies and is a marker of poor prognosis. It is most commonly associated with hematological malignancies, such as multiple myeloma and leukemias as well solid tumors like breast carcinomas. In Hypercalcemia of malignancy, PTHrp is the causal agent in over 80% of cases with 20% of cases attributed to osteolytic mechanisms mediated by inflammatory cytokines. Less than 1% of hypercalcemia of malignancy is attributed to excess 1,25-dihydroxy vitamin D. High level of suspicion for malignancy should be presentwhen patients present moderate/severe non-PTH mediated hypercalcemia. Workup for malignancy should be pursued even with normal PTHrp.