75 PARANEOPLASTIC ENDOCRINE SYNDROMES
Harrison’s Manual of Medicine
PARANEOPLASTIC ENDOCRINE SYNDROMES
Ectopic ACTH Syndrome
Both benign and malignant tumors of nonendocrine tissue can secrete a variety of hormones, principally peptide hormones, and many tumors produce more than one hormone (Table 75-1). At the clinical level, ectopic hormone production is important for two reasons.
Table 75-1 Common Paraneoplastic Endocrine Syndromes
First, endocrine syndromes that result may either be the presenting manifestations of the neoplasm or occur late in the course. The endocrine manifestations in some instances are of greater significance than the tumor itself, as in pts with benign or slowly growing malignancies that secrete corticotropin-releasing hormone and cause fulminant Cushing’s syndrome. The frequency with which ectopic hormone production is recognized varies with the criteria used for diagnosis. The most common syndromes of clinical import are those of ACTH hypersecretion, hypercalcemia, and hypoglycemia. Indeed, ectopic ACTH secretion is responsible for 15–20% of pts with Cushing’s syndrome, and ~50% of pts with persistent hypercalcemia have a malignancy rather than hyperparathyroidism. Because of the rapidity of development of hormone secretion in some rapidly growing tumors, diagnosis may require a high index of suspicion, and hormone levels may be elevated out of proportion to the manifestations.
Second, ectopic hormones serve as valuable peripheral markers for neoplasia. Because of the broad spectrum of ectopic hormone secretion, screening measurements of plasma hormone levels for diagnostic purposes are not cost- effective. However, in pts with malignancies that are known to secrete hormones, serial measurements of circulating hormone levels can serve as markers for completeness of tumor excision and for effectiveness of radiation therapy or chemotherapy. Likewise, tumor recurrence may be heralded by reappearance of elevated plasma hormone levels before mass effects of the tumor are evident. However, some tumors at recurrence do not secrete hormones, so that hormone measurements cannot be relied on as the sole evidence of tumor activity.
Therapy of ectopic hormone-secreting tumors should be directed when possible toward removal of the tumor. When the tumor cannot be removed or is incurable, specific therapy can be directed toward inhibiting hormone secretion (octreotide for ectopic acromegaly or mitotane to inhibit adrenal steroidogenesis in the ectopic ACTH syndrome) or blocking the action of the hormone at the tissue level (demeclocycline for inappropriate vasopressin secretion).
The most common paraneoplastic syndrome, hypercalcemia of malignancy accounts for 40% of all hypercalcemia. 80% of cancer pts with hypercalcemia have humoral hypercalcemia mediated by parathyroid hormone–related peptide; 20% have local osteolytic hypercalcemia mediated by cytokines such as interleukin-1 and tumor necrosis factor. Many tumor types may produce hypercalcemia (Table 75-1). Pts may have malaise, fatigue, confusion, anorexia, bone pain, polyuria, weakness, constipation, nausea, and vomiting. At high calcium levels, confusion, lethargy, coma, and death may ensue. Median survival of hypercalcemic cancer pts is 1–3 months. Treatment with saline hydration, furosemide diuresis, and pamidronate (60–90 mg IV) controls calcium levels within 7 days in 80% of cases.
Most commonly discovered in asymptomatic individuals as a result of serum electrolyte measurements, hyponatremia is usually due to tumor secretion of arginine vasopressin and is called syndrome of inappropriate antidiuretic hormone (SIADH). Atrial natriuretic hormone may also produce hyponatremia. SIADH occurs most commonly in small cell lung cancer (15%) and head and neck cancer (3%). A number of drugs may produce the syndrome. Symptoms of fatigue, poor attention span, nausea, weakness, anorexia, and headache may be controlled by restricting fluid intake to 500 mL/d or blocking the effects of the hormone with 600–1200 mg demeclocycline a day.
Ectopic ACTH Syndrome
When pro-opiomelanocortin mRNA in the tumor is processed into ACTH, excessive secretion of glucocorticoids and mineralocorticoids may ensue. Pts develop Cushing’s syndrome with hypokalemic alkalosis, weakness, hypertension, and hyperglycemia. About half the cases occur in small cell lung cancer. ACTH production adversely affects prognosis. Ketoconazole (400–1200 mg/d) or metyrapone (1–4 g/d) may be used to inhibit adrenal steroid synthesis.
For a more detailed discussion, see Johnson BE: Paraneoplastic Syndromes, Chap. 100, p. 632, in HPIM-15.