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hypercalcemia of malignancy

Etiology: 1) local osteolytic hypercalcemia a) breast carcinoma b) multiple myeloma c) non-Hodgkin's lymphoma 2) humoral hypercalcemia of malignancy a) squamous cell carcinoma of the lung, head & neck, oresophagus b) breast carcinoma c) cervical carcinoma d) ovarian carcinoma e) renal cell carcinoma f) bladder carcinoma g) pheochromocytoma h) islet cell neoplasms of the pancreas i) T-cell lymphoma j) B-cell lymphoma* k) multiple myeloma 3) increased calcitriol - B-cell lymphoma 4) immobilization worsens hypercalcemia Epidemiology: 1) often discovered in hospitalized patients - the most common cause of hypercalcemia in hospitalized patients [1] 2) often occurs as an end-stage complication Pathology: 1) local osteolytic hypercalcemia a) cytokines produced by tumor cells act locally to stimulate bone resorption b) extensive bone involvement of tumor, especially in breast carcinoma, myeloma & lymphoma 2) humoral hypercalcemia of malignancy a) PTH-related peptide or other related peptides secreted by tumor cells act systemically to stimulate bone resorption &/or inhibit Ca+2 excretion b) *unregulated production of 1,25 (OH)2 vit D3 (generally B-cell lymphoma*) c) other implicated proteins - C19orf53 Clinical manifestations: 1) a diagnosis of malignancy is generally already established 2) manifestations of volume depletion & general debility may dominate the clinical picture 3) manifestations of hypercalcemia a) gastrointestinal: - nausea/vomiting, constipation b) renal: - polyuria, polydipsia, dehydration c) central nervous system - cognitive difficulties, confusion, apathy, somnolence, coma d) cardiovascular: - hypertension, enhanced sensitivity to digitalis e) diffuse muscle weakness [1] Laboratory: 1) hypercalcemia moderate to severe -> serum Ca+2 > 12 mg/dL virtually assures diagnosis 2) 24 hour urinary Ca+2 excretion is markedly elevated (> 4 mg/kg) 3) serum PTH: endogenous PTH is suppressed 4) immunoassay for serum PTH-related peptide - diagnostic test of choice for humoral hypercalcemia of malignancy - squamous cell carcinoma of the lung, lymphomas, breast cancer ... 5) serum calcitriol a) low or normal b) indications: - multiple myeloma - B-cell lymphoma - hormone sensitive breast cancer 5) serum phosphate is normal or low 6) serum sodium: hypernatremia if patient is dehydrated Special laboratory: - electrocardiogram: shortened QT-interval Radiology: 1) plain radiographs as indicated 2) CT scan of the chest, abdomen & pelvis 2) bone scan Management: 1) treatment of underlying malignancy 2) intravenous volume expansion with normal saline increases urinary Ca+2 excretion (& Na+ excretion) 3) loop diuretics after volume expansion if needed - loop diuretics only if hypervolemia & heart failure or renal failure [1] - furosemide inhibits Ca+2 resorption in the thick ascending loop of Henle - cinacalcet is not indicated with furosemide [12] 4) hemodialysis for severe hypercalcemia (> 18 mg/dL) or refractory hypercalcemia, especially if associated with renal failure [1] 5) calcitonin recommended for immediate management of symptomatic hypercalcemia - results in a rapid but short-lived drop in serum Ca+2 & serum phosphate by promoting incorporation of calcium into bone 6) intravenous bisphosphonate pamidronate 60-90 mg IV over 24 hours most appropriate step after volume expansion [12] - zoledronate also acceptable [NEJM Knowledge+] - denosumab suggested vs bisphosphonate [15] 7) bisphosphonate for chronic treatment [1] a) zoledronate (Zometa) over 15 minutes [3] - treatment of choice (GRS9) [9] b) etidronate c) denosumab [10,11]; not indicated (GRS9, MKSAP19) [1,9] - indicated for hypercalcemia refractory to bisphosphates [15] 8) plicamycin (mithramycin) 25 ug/kg IV over 4 hours 9) gallium nitrate 200 mg/m2/day IV infusion for 5 days 10) glucocorticoids a) calcitriol-mediated hypercalcemia 1] multiple myeloma 2] B-cell lymphoma 3] hormone sensitive breast cancer 4] sarcoidosis b) prednisone c) methylprednisolone d) IV bisphosphonate or denosumab if glucocorticoid-refractory [15] 11) ketoconazole blocks 1,25 (OH)2 vit D-mediated hypercalcemia 12) parathyroid carcinoma may be treated with calcimimetic &/or antiresorptive therapy [15] 13) hypercalcemia of malignancy is often a pre-terminal event & aggressive management may not be indicated - median survival for humoral hypercalcemia of malignancy is 52 days from date of serum PTH-related peptide measurement [6]

Related

parathyroid hormone [PTH]-related protein

General

hypercalcemia

References

  1. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2015, 2018, 2021 - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  2. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 680-681
  3. Prescriber's Letter 8(9):53 2001
  4. Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med. 2005 Jan 27;352(4):373-9. PMID: 15673803
  5. Clines GA. Mechanisms and treatment of hypercalcemia of malignancy. Curr Opin Endocrinol Diabetes Obes. 2011 Dec;18(6):339-46 PMID: 21897221
  6. Donovan PJ et al. PTHrP-mediated hypercalcemia: Causes and survival in 138 patients. J Clin Endocrinol Metab 2015 May; 100:2024. PMID: 25719931
  7. Ziegler R Hypercalcemic crisis. J Am Soc Nephrol. 2001 Feb;12 Suppl 17:S3-9. PMID: 11251025
  8. Rosner MH, Dalkin AC. Onco-nephrology: the pathophysiology and treatment of malignancy-associated hypercalcemia. Clin J Am Soc Nephrol. 2012 Oct;7(10):1722-9. Review. PMID: 22879438 Free Article
  9. Geriatric Review Syllabus, 9th edition (GRS9) Medinal-Walpole A, Pacala JT, Porter JF (eds) American Geriatrics Society, 2016
  10. Mirrakhimov AE.3. Hypercalcemia of Malignancy: An Update on Pathogenesis and Management. N Am J Med Sci. 2015 Nov;7(11):483-93. Review. PMID: 26713296 Free PMC Article
  11. Sternlicht H, Glezerman IG. Hypercalcemia of malignancy and new treatment options. Ther Clin Risk Manag. 2015 Dec 4;11:1779-88. Review. PMID: 26675713 Free PMC Article
  12. NEJM Knowledge+ Question of the Week June 13, 2017 https://knowledgeplus.nejm.org/question-of-week/1011/
  13. NEJM Knowledge+ Question of the Week March 19, 2019 https://knowledgeplus.nejm.org/question-of-week/938/ - Broadus AE, Mangin M, Ikeda K et al. Humoral hypercalcemia of cancer. Identification of a novel parathyroid hormone-like peptide. N Engl J Med 1988 Sep 1; 319:556 PMID: 3043221 https://www.nejm.org/doi/full/10.1056/NEJM198809013190906 - Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med 2005 Jan 27; 352:373 PMID: 15673803 https://www.nejm.org/doi/full/10.1056/NEJMcp042806
  14. NEJM Knowledge+ Question of the Week May 14, 2019 https://knowledgeplus.nejm.org/question-of-week/887/ - Mirrakhimov AE. Hypercalcemia of malignancy: an update on pathogenesis and management. N Am J Med Sci 2015 Nov; 7:483. PMID: 26713296 Free PMC Article
  15. Dickens LT, Derman B, Alexander JT Endocrine Society Hypercalcemia of Malignancy Guidelines. JAMA Oncol. Published online January 13, 2023 PMID: 36637830 https://jamanetwork.com/journals/jamaoncology/fullarticle/2800546
  16. El-Hajj Fuleihan G, Clines GA Treatment of Hypercalcemia of Malignancy in Adults: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2023 Feb 15;108(3):507-528. PMID: 36545746
  17. Guise TA, Wysolmerski JJ Cancer-Associated Hypercalcemia. N Engl J Med. 2022 Apr 14;386(15):1443-1451. PMID: 35417639 Review. No abstract available. https://www.nejm.org/doi/pdf/10.1056/NEJMcp2113128
  18. Zagzag J, Hu MI, Fisher SB, Perrier ND. Hypercalcemia and cancer: Differential diagnosis and treatment. CA Cancer J Clin. 2018 Sep;68(5):377-386. PMID: 30240520 Free article. Review.