Mayo Clinic Proceedings, Volume 72, Issue 12, December 1997, Pages 1111-1115
To report the high prevalence of increased parathyroid hormone-related peptide (PTHrP) in patients with islet cell carcinoma and associated hypercalcemia.
We conducted a retrospective study of PTHrP levels in patients with hypercalcemia and eucalcemia associated with islet cell carcinoma and compared these findings with those in healthy subjects.
Using a sensitive PTHrP immunochemiluminometric assay, we measured PTHrP levels in 17 patients with islet cell carcinoma and 110 healthy subjects. The differences between PTHrP levels in patients with normal and those with high serum calcium concentrations were analyzed statistically.
PTHrP levels were significantly higher (P less than 0.01) in 10 patients with hypercalcemia and islet cell carcinoma (median, 14.0 pmol/L; range, undetectable to 40.1) than in 7 patients with eucalcemia and islet cell carcinoma (median, undetectable; range, undetectable to 1.3 pmol/L) or in the 110 healthy subjects (median, undetectable; range, undetectable to 4.2 pmol/L). The range of increased PTHrP levels in hypercalcemic islet cell carcinoma was 2 to 20 times the upper normal limit (2.0 pmol/L). Decreased PTHrP and serum calcium and increased parathyroid hormone levels were demonstrated in two patients after effective therapy. For all seven eucalcemic patients with islet cell carcinoma, PTHrP levels did not differ significantly from those in healthy subjects.
PTHrP levels are increased in a substantial proportion of patients with hypercalcemia and islet cell carcinoma and seem to decrease after treatment of the underlying tumor. Measurement of PTHrP levels may be useful for confirming the diagnosis of hypercalcemia associated with malignant disease and for monitoring of therapy.
Study Subjects.—Plasma levels of PTHrP were determined in 110 normal subjects (19 to 72 years of age). These study participants were volunteers from a pool of normal subjects (primarily Mayo Clinic employees) who had provided in-formed consent. In addition, during a 2-year period (1994 and 1995), 17 patients with islet cell carcinoma (10 with hypercalcemia, including 1 with type I multiple endocrine neoplasia [MEN I], and 7 with eucalcemia, in whom carcinoma was subsequently diagnosed in the pancreas, liver, or lymph nodes) were studied. The diagnosis of islet cell carcinoma was confirmed by histologic examination. The study was approved by the Mayo Clinic Institutional Review Board.
Healthy Subjects.—The 110 healthy subjects had a plasma PTHrP median level of less than 0.5 pmol/L (undetectable) (range, undetectable to 4.2). Of the 110 healthy subjects, 82 (75%) had undetectable PTHrP levels. The 95th percentile of the upper limit was 2.0 pmol/L. Provisionally, 2.0 pmol/L was set as the upper reference limit for PTHrP (Fig. 1).
Islet Cell Carcinoma.—Of the 17 patients with islet cell carcinoma, 10 (59%) had complications of hypercalcemia. Statistically, PTHrP levels in the hypercalcemic group were significantly higher (P less than 0.01) than those in the eucalcemic group or in the healthy subjects. In the hypercalcemic group, 9 of the 10 patients (90%) had increased PTHrP levels (greater than 2.0 pmol/L). The median PTHrP level in the hypercalcemic group was 14.0 pmol/L (range, undetectable to 40.1). In the eucalcemic group, all 7 patients had PTHrP levels within the reference range (median, undetectable; range, undetectable to 1.3 pmol/L).
The major findings in this study were that a substantial proportion of patients with islet cell carcinoma and associated hypercalcemia had increased plasma PTHrP levels (2 to 20 times the upper normal limit). The prevalence rate of increased PTHrP levels was 89% among the group with hypercalcemia and islet cell carcinoma (with exclusion of the patient ultimately found to have MEN I). In comparison, previous reports of HHM associated with other malignant conditions have shown a prevalence of increased PTHrP levels ranging from 50 to 90%.
PTHrP levels are increased in a considerable proportion of patients with hypercalcemia and islet cell carcinoma and seem to decrease with treatment of the underlying tumor. In selected situations, measurement of a PTHrP level may be useful to confirm the diagnosis of HHM. The decreased PTHrP level in association with normalized PTH and serum calcium levels may be useful for monitoring response to therapy.
We gratefully acknowledge Peter C. O'Brien, Ph.D., for his statistical consultation and helpful suggestions for presentation of data.
