Parathyroid Hormone-Related Protein Causing Hypercalcemia in a Patient with Large Cell Lung Cancer

Secretion of parathyroid hormone-related protein (PTHrP) accounts for up to 80% of cases with hypercalcemia of malignancy. It is most commonly associated with lung cancer, with a reported incidence up to 12.5% in those at advanced stages. While elevated PTHrP levels have been reported with all histologic types of lung cancer, it is rare in large cell carcinoma, with only 3 previously reported cases.

Case Description:

A 59-year-old man with 40 pack-year smoking history and stage IV large cell lung cancer, on Gemcitabine, was admitted with altered mental status and new onset hypercalcemia with a corrected calcium of 13.8 mg/dL (reference range 8.7-10.5). He had previously undergone 2 cycles of chemotherapy (Cisplatin/Etoposide) with concurrent radiation therapy, 2 cycles of consolidation therapy with Durvalumab (stopped due to pneumonitis), followed by disease progression with metastases to liver, spleen, pancreatic tail, abdominal nodes, and a couple of ribs. CT head was unremarkable on admission. He received IV fluids and calcitonin for 2 days, and one dose of zoledronic acid prior to Endocrine consultation. Labs at that time showed uncorrected calcium 9.1 mg/dL, albumin 2.0 g/dL (3.5-5.2), vitamin D 20.8 ng/mL (30-100), calcitriol 62 pg/mL (20-79), PTH 27.7 pg/ml (9-77), PTHrP 14 pmol/L ( <4.2) and creatinine 0.65 mg/dL (0.5-1.4). His calcium normalized over the next 2 days. Due to his overall poor prognosis, he transitioned to hospice care and passed away a few days later.

Discussion:

Hypercalcemia is reported in 3.4 to 12.7% of patients with large cell carcinoma, mostly due to osteolytic metastases and rarely humoral hypercalcemia of malignancy. With bone metastatic lesions, calcium rises due to bone destruction mediated by osteoclasts and not a direct effect of the tumor cells. Although bone metastases may secrete PTHrP locally, it is not usually measurable in a serum assay. Additionally, hypercalcemia of this etiology typically requires extensive skeletal tumor burden far beyond that seen in our patient. For humoral hypercalcemia of malignancy, as in the presented case, typical lab findings include an elevated PTHrP, low PTH, and a normal or low calcitriol level. The inappropriately normal PTH in this patient may be due to vitamin D insufficiency; PTH at the time of initial severe hypercalcemia was not available. In conclusion, PTHrP mediated humoral hypercalcemia should be considered in patients with large cell lung cancer, though it is a rare finding.