Chapter 78: Paraneoplastic Endocrine Syndromes

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 78-1). At the clinical level, ectopic hormone production is important for two reasons.

TABLE 78-1: Paraneoplastic Syndromes Caused by Ectopic Hormone Production
PARANEOPLASTIC SYNDROME	ECTOPIC HORMONE	TYPICAL TUMOR TYPES^a
Common
Hypercalcemia of malignancy	PTHrP	Squamous cell (head and neck, lung, skin), breast, genitourinary, gastrointestinal
	1,25 dihydroxyvitamin D	Lymphomas
	PTH (rare)	Lung, ovary
	PGE₂ (rare)	Renal, lung
SIADH	Vasopressin	Lung (squamous, small cell), gastrointestinal, genitourinary, ovary
Cushing’s syndrome	ACTH	Lung (small cell, bronchial carcinoid, adenocarcinoma, squamous), thymus, pancreatic islet, medullary thyroid carcinoma
	CRH (rare)	Pancreatic islet, carcinoid, lung, prostate
	Ectopic expression of GIP, LH/hCG, other G protein–coupled receptors (rare)	Macronodular adrenal hyperplasia
Less Common
Nonislet cell hypoglycemia	IGF-II	Mesenchymal tumors, sarcomas, adrenal, hepatic, gastrointestinal, kidney, prostate
	Insulin (rare)	Cervix (small cell carcinoma)
Male feminization	hCG^b	Testis (embryonal, seminomas), germinomas, choriocarcinoma, lung, hepatic, pancreatic islet
Diarrhea or intestinal hypermotility	Calcitonin^c	Lung, colon, breast, medullary thyroid carcinoma
	VIP	Pancreas, pheochromocytoma, esophagus
Rare
Oncogenic osteomalacia	Phosphatonin (FGF23)	Hemangiopericytomas, osteoblastomas, fibromas, sarcomas, giant cell tumors, prostate, lung
Acromegaly	GHRH	Pancreatic islet, bronchial and other carcinoids
	GH	Lung, pancreatic islet
Hyperthyroidism	TSH	Hydatidiform mole, embryonal tumors, struma ovarii
Hypertension	Renin	Juxtaglomerular tumors, kidney, lung, pancreas, ovary
Consumptive hypothyroidism	Type 3 deiodinase	Hepatic hemangiomas

^aOnly the most common tumor types are listed. For most ectopic hormone syndromes, an extensive list of tumors has been reported to produce one or more hormones.

^bhCG is produced eutopically by trophoblastic tumors. Certain tumors produce disproportionate amounts of the hCG α or hCG β subunit. High levels of hCG rarely cause hyperthyroidism because of weak binding to the TSH receptor.

^cCalcitonin is produced eutopically by medullary thyroid carcinoma and is used as a tumor marker.

Abbreviations: ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; FGF23, fibroblast growth factor 23; GH, growth hormone; GHRH, growth hormone–releasing hormone; GIP, gastric inhibitory peptide; hCG, human chorionic gonadotropin; IGF, insulin-like growth factor; LH, luteinizing hormone; PGE₂, prostaglandin E₂; PTH, parathyroid hormone; PTHrP, parathyroid hormone–related protein; SIADH, syndrome of inappropriate antidiuretic hormone secretion; TSH, thyroid-stimulating hormone; VIP, vasoactive intestinal peptide.

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 adrenocorticotropic hormone (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 treatment. 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 hormone measurements cannot be relied on as the sole evidence of tumor activity.

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