Evaluation of Diagnostic Workup and Etiology of Hypercalcemia of Malignancy in a Cohort of 167 551 Patients Over 20 Years

Michael T. Sheehan; Ya-Huei Li; Suhail A. Doi; Adedayo A. Onitilo


J Endo Soc. 2021;5(11) 

In This Article

Abstract and Introduction


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 2 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 data set 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 (1,25-OH) vitamin D and constituted the 153 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 3 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 whether its causes have indeed changed over time.


Hypercalcemia of malignancy (HCM) occurs in 10% to 30% of patients with malignancy.[1–4] The underlying pathophysiology of this condition is almost always parathyroid hormone (PTH)-independent because PTH-dependent HCM occurs only in parathyroid carcinoma and in very rare cases of ectopic PTH secretion.[1–4] HCM can, therefore, be divided into 3 main categories: humoral hypercalcemia of malignancy [induced by PTH-related peptide ([PTHrP)], which the literature suggests makes up the majority of cases (80%); osteolytic metastases (OM), estimated to make up another 20% of cases; and excess 1,25-dihydroxy (1,25-OH) vitamin D, estimated to contribute to <1% of cases (most of these reported in lymphomas).[1–4] The previously mentioned prevalence estimates have been commonly cited in the literature since the seminal review article by Stewart in the New England Journal of Medicine published in 2005.[1] However, the classical distribution of etiologies listed in this article is mainly based on several studies between 1980 and 1990 at a time when PTHrP was just being identified and characterized.[5–7] Notably, 2 of the leading publications in this regard contained findings from small studies involving 50[5] and 38 patients,[7] respectively. While several other publications in the 1990s confirmed this 80% contribution of PTHrP,[8–10] other publications around the same time showed a much lower prevalence of PTHrP-mediated HCM between 44% and 69%.[11–13] In a more recent study published in 2016, PTHrP contributed to only 38% of 242 cases of HCM, with OM contributing to approximately 27% (this number included both PTHrP and OM contributing in combination in 10% of cases), and the cause was undetermined in 40%.[14] Although these studies reported PTHrP levels in all subjects, many, but not all, patients also underwent skeletal imaging to assess for OM. However, virtually no assessment of 1,25-OH vitamin D levels was undertaken in most of these studies.[6–14]

More recent literature has continued to challenge conventional thinking about the etiology of HCM, especially regarding the contribution of 1,25-OH vitamin D. In a review of 101 cases of 1,25-OH vitamin D–mediated hypercalcemia, 22% were related to malignancy.[15] In a 2020 publication by Chukir et al, 45% of 101 patients with HCM and solid tumors in whom 1,25-OH vitamin D was assessed had an elevated or inappropriately high-normal level of that hormone.[16] Thus, the long-standing belief as to the etiology of HCM is based largely on decades-old data obtained from incompletely evaluated patients.

Furthermore, HCM now appears to be less common in clinical practice than the often-quoted 10% to 30% in many reviews on the subject and is currently on the order of just 0.67% to 2.0% of patients with cancer.[17,18] To further characterize this apparent trend in HCM diagnosis, we undertook a retrospective chart review to identify the etiology, or combinations of etiologies, in patients with HCM at Marshfield Clinic Health System (Weston, WI, USA) over a contemporary 20-year time span (2000–2019). We had 2 goals: (1) to assess the degree of completeness of the diagnostic workup for HCM and (2) to review a cohort of patients that had undergone a conclusive evaluation with regards to the etiology of their HCM according to assessments of PTHrP levels, skeletal imaging, and 1,25-OH vitamin D levels.