INTRODUCTION
Hypercalcemia of malignancy is a serious condition that can lead to various symptoms such as nausea, vomiting, abdominal pain, confusion, electrolyte disturbances, and even cardiac arrhythmias. Studies report that it affects about 30% of patients with cancer and is associated with poor prognosis in this population. Mechanisms of hypercalcemia in malignancy include paraneoplastic syndrome, osteolytic bone metastases, calcitriol production, and ectopic hyperparathyroidism. 1 While documented significantly in patients with esophageal cancer of squamous cell origin, hypercalcemia in adenocarcinoma of the esophagus is a lesser-known entity. Presented below is a patient who had hypercalcemia and abdominal pain as the presenting symptoms for esophageal carcinoma without apparent bone metastasis.
CASE REPORT
A 73-year-old White man with a medical history of hypertension, chronic obstructive pulmonary disease, gastroesophageal reflux disease, history of tobacco use, and alcohol dependence presented to his primary care provider with symptoms of generalized fatigue, abdominal pain, and decreased oral intake, resulting in 20 to 30 lbs weight loss. Further history revealed that he had asbestos exposure from previously working in a plastics factory and no significant family history. Outpatient laboratory work revealed hypercalcemia, and he was instructed to present to the emergency department.
On arrival at the hospital, laboratory results revealed a leukocytosis of 18.2, acute kidney injury with creatinine of 3.25, elevated calcium of 13.9, and mildly elevated aspartate aminotransferase/alanine transaminase. Parathyroid hormone (PTH) was elevated at 205 (normal range: 12–88 pg/mL), and PTH-related protein (PTHrP) at 42.3 (normal range: 0–2.3 pmol/L). Phosphorus levels returned to normal, and vitamin D level was 23.7. To investigate the abdominal pain, a computed tomography (CT) of the abdomen and pelvis was performed and showed circumferential esophageal thickening, diffuse hepatic masses, and upper abdominal metastatic lymphadenopathy. Chest CT showed evidence for asbestos exposure with bilateral diffuse calcified pleural plaques with an associated pleural plaque in the right middle lobe measuring 3.4 cm × 1.8 cm and a more rounded nodular density which appeared to be in the right upper lobe anteriorly measuring 6.5 mm. CT angiogram redemonstrated the extensive bilateral calcified and noncalcified pleural plaques along with circumferential mural thickening of the distal esophagus with adjacent periesophageal lymphadenopathy and bulky lymphadenopathy throughout the upper abdomen.
There was no improvement of calcium with intravenous fluids, so the patient was started on calcitonin and zoledronic acid, eventually resulting in normocalcemia. An esophagogastroduodenoscopy with endoscopic ultrasound was performed, showing evidence of a low-grade stricture within the distal esophagus, associated with a friable, circumferential 5 cm mass; biopsies were obtained. Liver biopsy was also performed. Esophageal biopsies revealed poorly differentiated carcinoma, preferentially adenocarcinoma. Liver biopsy was compatible with a metastatic, poorly differentiated adenocarcinoma of the esophagus.
Concurrently, the patient was initiated on dialysis for worsening acute kidney injury resulting in end-stage renal disease, as well as suffering from acute on chronic hypoxic respiratory failure secondary to a chronic obstructive pulmonary disease exacerbation. Given the patient's clinical deterioration during his month long hospitalization and complications of concurrent comorbidities, after ongoing discussions regarding goals of care, the family and the patient elected to change the patient's code status to Do-Not-Resuscitate Comfort Care. The patient was eventually transitioned to Hospice care.
DISCUSSION
Hypercalcemia is a relatively common and serious metabolic disorder seen in malignancy, affecting approximately 10% to 20% of patients with cancer, particularly those with advanced disease. It is also the most common life-threatening metabolic disorder in patients with cancer. 2 The causes of hypercalcemia in patients with cancer can be divided into 3 main mechanisms: bony metastases with release of osteoclast activating factors, increased production of 1,25-dihydroxy vitamin D (calcitriol), and excessive secretion of PTHrP. Osteolytic metastases, frequently seen in cancers such as breast cancer and multiple myeloma, account for approximately 20% of malignancy-associated hypercalcemia. Typical findings of osteolytic metastases include skeletal metastasis with low to low-normal PTH, PTHrP, and 1,25-dihydroxy vitamin D levels. Most cases of Hodgkin lymphoma and one-third of non-Hodgkin lymphoma cases cause hypercalcemia by increasing 1,25-dihydroxy vitamin D production. Excessive secretion of PTHrP is the most common cause of hypercalcemia of malignancy, which is known as humoral hypercalcemia of malignancy (HHM) and accounts for 80% of cases. HHM is often associated with squamous cell carcinomas of the lung, head, neck, and esophagus, but it can also occur in other malignancies such as renal cancer, breast cancer, and leukemia. 3 While there are multiple case reports identifying hypercalcemia in the context of squamous cell carcinoma of the esophagus, the incidence of adenocarcinoma is not well reported and, to the best of our knowledge, is one of the only case reports that demonstrates hypercalcemia as a consequence esophageal adenocarcinoma without bony involvement. 4 – 6 In a study investigating the incidence and prognostic importance of hypercalcemia in patients with esophageal cancer, it was found that 46 patients had squamous cell carcinoma, and only one had adenosquamous cell carcinoma. 7
HHM is mediated by the secretion of PTHrP, which mimics the action of PTH by increasing osteoclastic bone resorption and renal tubular reabsorption of calcium. Treatment options for hypercalcemia of malignancy include aggressive hydration with intravenous saline to restore renal calcium excretion, bisphosphonates (such as zoledronic acid or pamidronate) to inhibit bone resorption, and calcitonin for short-term effects. Denosumab, a monoclonal antibody, may be used if bisphosphonates are ineffective, and glucocorticoids are helpful in specific malignancies such as lymphoma. Definitive treatment involves addressing the underlying tumor through surgery or chemotherapy. Prognosis depends on the underlying malignancy but is often poor, as hypercalcemia generally indicates advanced cancer and is associated with a median survival of 3 to 4 months in untreated cases. 3
In this case, the patient had asbestos exposure, which manifested as asymptomatic pleural plaques without contributing to his hypercalcemia. His hypercalcemia was related to metastatic esophageal adenocarcinoma with liver and lymph node involvement. The elevated serum PTHrP levels pointed to paraneoplastic hypercalcemia, which is uncommon in esophageal adenocarcinoma and occurs without bone metastases. This makes the case noteworthy as a rare association between esophageal adenocarcinoma and PTHrP-mediated hypercalcemia, adding valuable insight to the literature on hypercalcemia in malignancy.
DISCLOSURES
Author contributions: R. Patel, S. Chinnam, M. Karrick, and A. Kobeissy: contributed to the conception and design of the case report, data collection, analysis, literature review, drafted and edited the manuscript. A. Kobeissy is the article guarantor.
Financial disclosure: None to report.
Informed consent was obtained for this case report.
Contributor Information
Sahithi Chinnam, Email: sahithi.chinnam@utoledo.edu.
Megan Karrick, Email: megan.karrick@utoledo.edu.
Abdallah Kobeissy, Email: Abdallah.Kobeissy@utoledo.edu.
REFERENCES
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