HYPERCALCEMIA IN MALIGNANCY

報告：PGY 林學群 │指導醫師：VS 吳家兆

Outline

• Introduction

• Clinical presentation

• Etiology and pathophysiology

• Diagnostic approach

• Management

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Introduction

• Defined as the level above the upper limit of the normal reference range (usually > 10.5 mg/dl)

• Among all patients presenting to the ER with hypercalcemia Malignancy

Primary hyperparathyroidism

• Among all cancers Multiple myeloma has the highest prevalence

Breast, renal, and SqCC of any origin

• Of the total liquid malignancies Multiple myeloma is the most prevalent

Leukemia and non-Hodgkin lymphoma

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Clinical presentation

Serum total calcium levels

• Mild (10.5-11.9 mg/dl): asymptomatic

• Moderate (12-13.9 mg/dl)

• Severe (≥ 14 mg/dl): often associated with malignancy

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Etiology and pathophysiology

There are four mechanisms:

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Humoral hypercalcemia of malignancy (HHM)

• Parathyroid hormone related peptide (PTHrP) Encoded by Parathyroid Hormone-like Hormone (PTHLH) gene

PTHLH and PTH genes have quite comparable structures The first 13 amino acids are almost identical

A similar secondary structure over the next 21 amino acids

Physiologic role Regulates osteoblast, osteoclast, and chondrocyte differentiation

Highly expressed in the placenta (Embryologic development)

Highly expressed in the breast during lactation (Mammary gland function)

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Humoral hypercalcemia of malignancy (HHM)

• Parathyroid hormone related peptide (PTHrP) Secreted by

SqCC of skin, head, lung, esophagus, cervix

Adenocarcinoma of breast, prostate, ovary

Renal cell carcinoma

Bind to PTH1R despite differences in protein structure Mimic the effects of PTH: trigger RANKL expression in osteoblast

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Humoral hypercalcemia of malignancy (HHM)

PTH PTHrP Same

• Increased bone turnover with greater increase in bone resorption than formation

• Increased Ca reabsorption in AL of Henle and DCT • Inhibition of P reabsorption in PCT

Difference • Increase renal 1α-hydroxylase activity Elevated level of 1,25 (OH)2D

• No native PTH secretion in patients with cancer, except parathyroid cancer

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Local osteolytic hypercalcemia

• Common causes Multiple myeloma

Metastatic breast and lung cancer

• Local cytokines released from the tumor and surrounding cells (e.g., macrophages or endothelial cells) Include IL-1, IL-3, IL-6, TNF-α, TNF-β, etc.

Act similarly to PTH and PTHrp Increased secretion of RANKL by osteoblasts

Inhibit osteoblast function

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Excess production of extra-renal 1,25-dihydroxyvitamin D • The cancer cells recruit the adjacent macrophages and stimulate

them to express 1α-hydroxylase Production by lymphomas (Hodgkin, non-Hodgkin, multiple myeloma)

Conversion of endogenous 25-hydroxyvitamin D into 1,25-dihydroxyvitamin D Bind to the receptors in the gut (increased intestine calcium absorption)

Normal to high phosphorus level

Suppressed level of PTH (negative feedback)

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Ectopic secretion of parathyroid hormone

• Malignant cells can also produce ectopic PTH Pulmonary, thyroid, ovarian, pancreatic malignancies

Parathyroid adenoma or hyperplasia can also occur concomitantly

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Diagnostic approach

• Verify with repeat measurement Albumin-calcium correction

Hyperalbuminemia (eg, severe dehydration): pseudohypercalcemia

Hypoalbuminemia (eg, chonic illness)

• Clinical clues Symptoms: more symptomatic in malignancy

Diet and Medication: thiazide, lithium, etc.

Family history: hyperparathyroidism

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Diagnostic approach

• Laboratory evaluation: to differentiate PTH or non-PTH mediated Check serum intact PTH (35 to 65 pg/mL)

Elevated or minimally elevated

Low-normal or low (<20 pg/mL)

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Diagnostic approach

• Non-PTH mediated

PTH related peptide: humoral hypercalcemia of malignancy

Serum phosphate concentration

1,25-dihydroxyvitamin D (calcitriol): lymphoma, granulomatous disease, etc.

25-hydroxyvitamin D: vitamin D intoxication

Urinary calcium excretion < 100 mg/day [2.5 mmol/day]

Milk-alkali syndrome

Thiazide diuretics

Familial hypocalciuric hypercalcemia

Multiple myeloma: SPEP, UPEP

Thyrotoxicosis: TSH

Vitamin A intoxication

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Management

• Primary goal: treatment of underlying malignancy

• The type and timing of therapy Mild, asymptomatic: delay until a diagnosis has been made

Moderate to severe: start immediately Especially severe renal and neurologic symptoms

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Management

Isotonic saline • Initial treatment of choice

Restore renal perfusion and increase renal calcium excretion

• The addition of furosemide is not recommended Reserved for symptoms of volume overload or oliguric renal failure

• The rate: depend on the severity, the age, and the comorbidities (eg, CHF) Usually, bolus 1-2 L followed by maintenance 100-150ml/hr titrated to ensure urine output of

100ml/hr

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Management

Calcitonin • Adjunctive initial therapy

Inhibit osteoclastic bone resorption and renal calcium reabsorption

• The addition of bisphosphonate: lower calcium level more rapidly

• The addition of glucocorticoids: enhance the effect (upregulating surface receptors)

• Disadvantage: Tachyphylaxis within 3 days (downregulation of receptors)

• Minimal side effects

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Management

Bisphosphonates (pyrophosphate analogues) • First line therapy and should be given within 48h of diagnosis (2-4 days to take

effect) Target osteoclasts inducing their apoptosis

Proliferation and differentiation of osteoblast

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Management

Corticosteroid • Clinical effect in multiple myeloma and other hematological malignancies

associated with 1, 25(OH)2D overproduction Inhibit conversion of 1α-hydroxylase

Decrease tumor production of locally active cytokines

Inhibit osteoclast resorption

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Management

Denosumab (human monoclonal antibody to RANKL) • Inhibits osteoclasts activity

• More pronounced in patients with renal failure

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Management

Cinacalcet (calcimimetic agent) • Increase the sensitivity of the calcium sensing receptor (CaSR) to extracellular

calcium level Effect a reduction in PTH and therefore a reduction in serum calcium level

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Management

Hemodialysis

• Recommended for GFR < 10-20ml/min

Severe congestive heart failure

Treatment failure (hydration, bisphosphonates)

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Management

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Take home message

• Hypercalcemia of malignancy is a common finding in patients with advanced stage cancers.

• There are four mechanisms which are responsible for the development of hypercalcemia of malignancy.

Humoral hypercalcemia of malignancy

Local osteolytic hypercalcemia

Excess production of extra-renal 1,25-dihydroxyvitamin D

Ectopic secretion of parathyroid hormone

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Take home message

• Clinical evaluation, including presence or absence of symptoms, family history, and medications, may help determine the etiology of hypercalcemia.

• Measurement of intact PTH is important to distinguish PTH-mediated from non-PTH-mediated causes of hypercalcemia.

• Treatment includes i. v. hydration, calcitonin, bisphosphonates, denosumab, corticosteroids, and cinacalcet depending on the cause of hypercalcemia. Hemodialysis should be considered for advanced underlying kidney disease and/or refractory

severe hypercalcemia

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References

• Diagnosis, Pathophysiology and Management of Hypercalcemia in Malignancy: A Review of the Literature

- Horm Metab Res. 2019 Dec -

• Hypercalcemia and Cancer: Differential Diagnosis and Treatment - CA Cancer J Clin. 2018 Sep -

• Diagnostic approach to hypercalcemia - UpToDate -

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Progression of a Solitary

Plasmacytoma to Multiple Myeloma Left pelvic mass in this patient

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Plasmacytomas

A mass composed of neoplastic monoclonal plasma cells

• Solitary plasmacytoma of bone (SBP): Occur solely in the bone

• Extramedullary plasmacytoma (EMP): arise outside bone in soft tissues

Differentiation criteria for both SBP and EMP from myeloma

• Lack of CRAB features (not systemic)

• Normal bone marrow with no evidence of clonal plasma cells BM may show <10% plasma cells in 4% of patients due to patchy BM involvement

• Normal imaging except for the primary lesion

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SBP versus EMP

SBP EMP

Presentation A single, typically painful bone lesion Space-occupying lesions

Site • Axial skeleton (83%) • Appendicular skeleton (17%) (e.g,

pelvic bones)

• Soft tissue (usually in nasal cavity and nasopharynx)

Treatment RT (highly radiosensitive disease) even after gross total excision

RT instead of radical surgery due to head and neck region

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Our case

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• Biopsy of soft tissue, left pelvis: Plasma cell myeloma, with kappa monoclonality

• Biopsy of bone marrow: Slightly increased small T cells without aggregation

No increase or clusters of B cells

• Abdomen CT: multiple osteolytic lesions involving the T-L vertebrae, pelvic bones and bilateral femurs

• Bone scan: suspected multiple bony metastasis

• Lab tests: no significant biomarker of malignancy

Suspicion: SBP progresses to MM

References

• Plasmacytoma (Solitary bone plasmacytoma, extramedullary plasmacytoma) - Atlas Genet Cytogenet Oncol Haematol. 2019 -

• A Review for Solitary Plasmacytoma of Bone and Extramedullary Plasmacytoma - The Scientific World Journal 2012 -

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Thanks for your attention

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