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 (e.g., 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...
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Chapter 096. Paraneoplastic Syndromes: Endocrinologic/Hematologic (Part 3) Chapter 096. Paraneoplastic Syndromes: Endocrinologic/Hematologic (Part 3) Etiology Humoral hypercalcemia of malignancy (HHM) occurs in up to 20% ofpatients with cancer. HHM is most common in cancers of the lung, head and neck,skin, esophagus, breast, genitourinary tract, and in multiple myeloma andlymphomas. Several distinct humoral causes of HHM occur, most commonlyoverproduction of PTHrP. In addition to acting as a circulating humoral factor,bone metastases (e.g., breast, multiple myeloma) may produce PTHrP, leading tolocal 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 proliferationand differentiation in other tissues including skin, bone marrow, breast, and hairfollicles. The mechanism of PTHrP induction in malignancy is incompletelyunderstood; however, tumor-bearing tissues commonly associated with HHMnormally produce PTHrP during development or cell renewal. Mutations in certainoncogenes, 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 morelikely to produce PTHrP than are metastases in other tissues, suggesting that boneproduces factors that enhance PTHrP production, or that PTHrP-producingmetastases have a selective growth advantage in bone. Thus, PTHrP productioncan be stimulated by mutations in oncogenes, by altered expression of viral orcellular 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 withhypercalcemia, lymphomas can produce an enzyme that converts 25-hydroxyvitamin D to the more active 1,25-dihydroxyvitamin D, leading toenhanced gastrointestinal calcium absorption. Other causes of HHM includetumor-mediated production of osteolytic cytokines and inflammatory mediators. Clinical Manifestations The typical presentation of HHM is a patient with a known malignancywho is found to be hypercalcemic on routine laboratory tests. Less often,hypercalcemia is the initial presenting feature of malignancy. Particularly whencalcium levels are markedly increased [>3.5 mmol/L (>14 mg/dL)], patients mayexperience fatigue, mental status changes, dehydration, or symptoms ofnephrolithiasis. Diagnosis Features that favor HHM, as opposed to primary hyperparathyroidism,include known malignancy, recent onset of hypercalcemia, and very high serumcalcium levels. Like hyperparathyroidism, hypercalcemia caused by PTHrP isaccompanied by hypercalciuria and hypophosphatemia. Measurement of PTH isuseful to exclude primary hyperparathyroidism; the PTH level should besuppressed in HHM. An elevated PTHrP level confirms the diagnosis, and it isincreased in ~80% of hypercalcemic patients with cancer. 1,25-DihydroxyvitaminD levels may be increased in patients with lymphoma. Humoral Hypercalcemia of Malignancy: Treatment The management of HHM begins with removal of excess calcium in thediet, medications, or IV solutions. Oral phosphorus (e.g., 250 mg Neutra-Phos 3–4times daily) should be given until serum phosphorus is >1.0 mmol/L (>3 mg/dL).Saline rehydration is used to dilute serum calcium and promote calciuresis. Forceddiuresis with furosemide or other loop diuretics can enhance calcium excretion butprovides relatively little value except in life-threatening hypercalcemia. Whenused, loop diuretics should be administered only after complete rehydration andwith careful monitoring of fluid balance. Bisphosphonates such as pamidronate(30–90 mg IV), zolendronate (4–8 mg IV), or etidronate (7.5 mg/kg per day POfor 3–7 consecutive days) can reduce serum calcium within 1–2 days and suppresscalcium release for several weeks. Bisphosphonate infusions can be repeated ororal bisphosphonates can be used for chronic treatment. Dialysis should beconsidered in severe hypercalcemia when saline hydration and bisphosphonatetreatments are not possible or are too slow in onset. Previously used agents, suchas calcitonin and mithramycin, have little utility now that bisphosphonates areavailable. Calcitonin (2–8 U/kg SC every 6–12 h) should be considered whenrapid correction of severe hypercalcemia is needed. Hypercalcemia associatedwith lymphomas, multiple myeloma, or leukemia may respond to glucocorticoidtreatment (e.g., prednisone 40–100 mg PO in fou ...