Etiology Humoral hypercalcemia of malignancy (HHM) occurs in up to 20% of patients with cancer. HHM is most common in cancers of the lung, head and neck, skin, esophagus, breast, genitourinary tract, and in multiple myeloma and lymphomas. Several distinct humoral causes of HHM occur, most commonly overproduction of PTHrP. In addition to acting as a circulating humoral factor, bone metastases (., breast, multiple myeloma) may produce PTHrP, leading to local osteolysis and hypercalcemia. PTHrP is structurally related to PTH and it binds to the PTH receptor, explaining the similar biochemical features of HHM and hyperparathyroidism. PTHrP plays a key. | Chapter 096. Paraneoplastic Syndromes Endocrinologic Hematologic Part 3 Etiology Humoral hypercalcemia of malignancy HHM occurs in up to 20 of patients with cancer. HHM is most common in cancers of the lung head and neck skin esophagus breast genitourinary tract and in multiple myeloma and lymphomas. Several distinct humoral causes of HHM occur most commonly overproduction of PTHrP. In addition to acting as a circulating humoral factor bone metastases . breast multiple myeloma may produce PTHrP leading to local osteolysis and hypercalcemia. PTHrP is structurally related to PTH and it binds to the PTH receptor explaining the similar biochemical features of HHM and hyperparathyroidism. PTHrP plays a key role in skeletal development and regulates cellular proliferation and differentiation in other tissues including skin bone marrow breast and hair follicles. The mechanism of PTHrP induction in malignancy is incompletely understood however tumor-bearing tissues commonly associated with HHM normally produce PTHrP during development or cell renewal. Mutations in certain oncogenes such as Ras can activate PTHrP expression. In adult T cell lymphoma the transactivating Tax protein produced by human T-cell lymphotropic virus I HTLV-I stimulates PTHrP promoter activity. Metastatic lesions to bone are more likely to produce PTHrP than are metastases in other tissues suggesting that bone produces factors that enhance PTHrP production or that PTHrP-producing metastases have a selective growth advantage in bone. Thus PTHrP production can be stimulated by mutations in oncogenes by altered expression of viral or cellular transcription factors and by local growth factors. Another relatively common cause of HHM is excess production of 1 25-dihydroxyvitamin D. Like granulomatous disorders associated with hypercalcemia lymphomas can produce an enzyme that converts 25-hydroxyvitamin D to the more active 1 25-dihydroxyvitamin D leading to enhanced gastrointestinal calcium absorption.
