1. Hormone induced (eg. hypercalcemia)
2. Neuromyopathic (eg. limbic encephalitis)
3. Dermatologic (eg. acanthosis nigricans)
4. Osseous/periarticular (eg. hypertrophic osteoarthropathy)
5. Vascular/hematologic (eg. venous thrombosis, anemia)
6. Others (nephrotic syndrome)

The term "ectopic hormone production" has been applied to hormone producing non-endocrine or endocrine tumors whose putative cells of origin do not normally synthesize that particular hormonal product. With the use of increasingly more sensitive methods of analysis of hormone production, many hormones formerly considered to represent "ectopic" products are produced normally at very low levels and should be considered "eutopic". Despite these observations, this term "ectopic hormone production" continues to be used to describe these phenomena. A more accurate descriptor is "paraneoplastic endocrine syndrome".

Proteins/peptides, steroids and monoamines represent the three major classes of hormones. Most paraneoplastic endocrine syndromes are related to the production of protein/peptide hormones. (Table) Tumors frequently lack some components of the biosynthetic pathways leading from the production of prohormone to hormone. As a result, tumors often synthesize products that are related to the normal hormones but that have less biological activity. In these instances, clinical syndromes related to hormone excess may be absent or muted despite the fact that levels of immunoreactive hormones are increased. Paraneoplastic syndromes due to the production of steroid hormones is uncommon with the exception of 1,25 dihydroxyvitamin D by certain lymphomas. (Table) Monoamine production, on the other hand, has not been documented as being responsible for paraneoplastic endocrine syndrome.

Most paraneoplastic endocrine syndromes are present in association with tumors of neuroendocrine type, including small cell carcinoma of pulmonary and extrapulmonary origin, medullary thyroid carcinoma, pheochromocytoma, carcinoids and pancreatic endocrine tumors. Other syndromes, such as humoral hypercalcemia of malignancy (HHM), are associated primarily with squamous carcinomas of different primary sites.

Some of the parameters that have been used to identify a paraneoplastic endocrine syndrome include:

1. Demonstration of mRNA expression and protein production by tumor cells.
2. Resolution of the syndrome following surgical resection, radiotherapy or chemotherapy.
3. Demonstration of elevated hormone levels in the circulation
4. Ten-fold or greater concentration gradient in blood before and after it passes through the tumor.
5. Normal or suppressed endogenous hormone production.

A summary of paraneoplastic endocrine syndromes follows:

Table: Paraneoplastic Endocrine Syndromes

Hormone	Syndrome	Tumor Type
Parathyroid hormone related protein (PTHrP)	Hypercalcemia	Squamous cell carcinoma of lung, skin head and neck; renal carcinoma; myeloma
Parathyroid hormone (PTH) (rare)	Hypercalcemia (rare)	Small cell carcinoma of lung; ovarian carcinoma; thymoma
Prostaglandin E (PGE) TNF, TGF-β, IL-1, 1, 25 dihydroxycholecalciferol	Hypercalcemia	Some solid tumors, multiple myeloma, Hodgkin's and non-Hodgkin's lymphoma
Vasopressin	Inappropriate ADH (SIADH)	Small cell carcinoma of lung, prostate, other sites; adenocarcinoma of prostate, pancreas, etc.
ACTH	Typical Cushing's syndrome Florid Cushing's syndrome	Carcinoids, medullary thyroid carcinoma, pheochromocytoma, pancreatic endocrine tumors Small cell carcinoma of lung and other sites
Corticotropin releasing hormone (CRH)	Cushing's syndrome	Small cell carcinoma of lung and other sites; pancreatic endocrine tumors; medullary thyroid carcinoma; hypothalamic gangliocytoma; bronchial carcinoid
Growth hormone releasing hormone	Acromegaly (rare)	Small cell carcinoma of lung; carcinoids; pancreatic endocrine tumors; pheochromocytoma; adrenal cortical adenoma
Growth Hormone	Acromegaly	Carcinoma of lung; pancreatic endocrine tumors

Hormone	Syndrome	Tumor Type
Placental lactogen		Small cell carcinoma of lung; adenocarcinoma of lung; pheochromocytoma; hepatoma; gastrointestinal tumors; germ cell tumors; breast carcinoma
Human Chorionic Gonadotropin	Gynecomastia, precocious puberty	Carcinoma of lung, prostate, ovary, cervix, adrenal, breast, bladder, liver; osteogenic sarcoma; lymphoma
Prolactin	Galactorrhea (rare)	Carcinoma of lung and kidney
Thyrotropin (?)	Hyperthyroidism	Trophoblastic tumors
Renin	?	Wilms' tumor; carcinoma of lung, pancreas, ovary, liver; paraganglioma; hemangiopericytoma
Insulin-like growth factors (IGF-1, IGF-2)	Hypoglycemia	Sarcomas, Wilms' tumor; hepatocellular carcinoma
Calcitonin	? Flushing	Pancreatic endocrine tumors; pheochromocytoma; adrenal cortical carcinoma, small cell CA of esophagus and lung; cervical, prostatic, breast, renal and GI carcinomas
Luteinizing hormone	Oligomenorrhea Precocious puberty (males)	Pancreatic endocrine tumor; adrenocortical carcinoma
Vasoactive intestinal peptide	Pancreatic cholera	Pancreatic endocrine tumors; neuroblastic tumors
Gastrin	Zollinger Ellison syndrome	Pancreatic endocrine tumors; tumors of other sites (eg ovary)
Prolactin	Galactorrhea and amenorrhea in women; hypogonadism and gynecomastia in men	Lung and renal carcinoma

Hypercalcemia of Malignancy
Hypercalcemia of malignancy is the most common of all paraneoplastic endocrine syndromes and is present in up to 30% or more (depending on the series) of all patients with hypercalcemia. There are 2 major groups of malignancy associated hypercalcemia. Humoral hypercalcemia of malignancy (HHM) is related to the presence of circulating hormones (predominantly parathyroid hormone related peptide, PTHrP). So-called localized osteolytic hypercalcemia (LOH) is caused by paracrine factors secreted by the tumor cells. These categories, however, form a spectrum since in some cases of LOH, the mediator of hypercalcemia is PTHrP.

PTHrP shows considerable homology with PTH at the amino terminus. Eight of the first 13 amino acids are identical, 3 represent conservative changes and the two proteins show considerable conformational similarity through residue 34. This homology accounts for the ability of PTHrP to bind to and activate classical PTH receptors in bone and kidney. The PTHrP gene maps to the short arm of chromosome 12 where it is flanked by the genes for lactic dehydrogenase B and K-ras while the PTH gene is present on a homologous region of chromosome 11 where it is flanked by the genes for lactic dehydrogenase A and H-ras. The PTHrP gene spans more than 15 kilobases and contains 8 exons. PTHrP undergoes endoproteolytic post-translational processing that results in: (1) an amino terminal PTHrP (1-36); (2) a mid-region species that begins at amino acid 38 with an unidentified carboxyl terminus; (3) a carboxy-terminal product recognized by antibody against the 109-138 region.

While PTH is present only in the parathyroid glands, PTHrP is found in a wide variety of fetal and adult tissues including various epithelia, mesenchymal tissue, endocrine glands and CNS. PTHrP is involved with a wide variety of local tissue functions while PTH has a systemic hormonal function. Some of the major functions of PTHrP are summarized below:

Site	Action
Cartilage	Promotes proliferation of chondrocytes; inhibits terminal differentiation and apoptosis of chondrocytes
Bone	Stimulates or inhibits bone resorption
Smooth muscle	Relaxes smooth muscle
Cardiac muscle	Positive chronotropic stimulus
Mammary gland	Induces branching morphogenesis; possible role in lactation
Epidermis	Unknown
Hair follicle	Inhibits anagen
Tooth follicle	Induces osteoclastic resorption of bone
Parathyroid gland	Stimulates placental transport of calcium
Pancreatic islet	Stimulates insulin secretion
Pituitary	Unknown
Placenta	Calcium transport (?)
CNS	Released from cerebellar granular neurons in response to activation of L-type calcium channels; receptors in cerebellum, hippocampus, hypothalamus.

Malignancies associated with HHM include non-small cell lung cancer and cancers of the breast, kidney, head and neck and bladder. Most of the tumors associated with this syndrome are squamous cell carcinomas. Hypercalcemia is present in less than 1% of patients at presentation while up to 20% have hypercalcemia at the time of death.

In addition to PTHrP which has been implicated in some cases of LOH, other factors that play a major role include TGF-α, TL-1, INF-β, lymphotoxins, PGE and 1,25-dihydroxycholecalciferol. The latter factors may be responsible for other paraneoplastic syndromes in patients with HHM, including leukocytosis and cachexia.

Molecular Mechanisms
The molecular mechanisms responsible for paraneoplastic endocrine syndromes are largely unknown. In the case of PTHrP, it has been shown that receptor tyrosine kinases mediate their effects on expression of this gene by Ras dependent pathways. Moreover, many stimulators of PTHrP gene expression are also activators of Ras. Aklilu and coworkers have shown that PTHrP expression is induced both by Raf-ERK and Rac-JNK mediated pathways. These pathways may, therefore, provide specific targets to reduce PTHrP expression in patients with HHM. Studies of small cell carcinomas have suggested that disturbances in certain differentiation factors (hASH, HES-1) may be involved not only in the development of the transformed phenotype but also in the expression of aberrantly produced small peptide hormones.

Selected References

1. Case Records of the Massachusetts General Hospital (Case 27461). N Eng J Med. 1941; 225: 789-791.
2. Akliliu, F. Gladu, J, Goltzman, D, Rabbani, SA, Role of mitogen activated protein kinase in the induction of parathyroid hormone related peptide. Cancer Res. 2000;60: 1753-1760.
3. Chen, H, Thiagalingham, A, Chopra, H. et al. Conservation of the Drosophila lateral inhibition pathway in human lung cancer: A hairy related protein (HES-1) directly represses achete-scute homolog-1 expression. Proc Nat'l Acad Sci. 1997; 94: 5355-5360.
4. Gagel, RF. Endocrine Manifestations of Tumors: "Ectopic" Hormone Production. (Chapter 194). Goldman, L. Cecil textbook of Medicine, 21^st edition. On-line. WB Saunders. 2000.
5. Johnson, BE. Paraneoplastic syndromes. Part 6, Section 1, Chapter 100. Harrison: On-Line. McGraw-Hill. 2001-2003.
6. Linnoila, RI, Zaho, B, DeMayo, JL. et al. Constitutive achete-scute homologue-1 promotes airway dysplasia and lung neuroendocrine tumors in transgenic mice. Cancer Res. 2000; 60; 4005-4009.
7. Mundy, G, Guise, TA. Hypercalcemia of malignancy. Am J Med. 1997; 103; 134-145.
8. Philbrick, WM. Parathyroid hormone related protein: Gene structure, biosynthesis, metabolism and regulation. In: The Parathyroid, Basic and Clinical Concepts. 2^nd ed. Edited by JP Bilezekian. Academic Press. 2000(p. 31-52)
9. Rubbani, SA. Molecular mechanism of action of parathyroid hormone related peptide in hypercalcemia of malignancy: therapeutic strategies (review). Int J Oncol. 2000; 16: 197-206.
10. Strewler, GJ. The physiology of parathyroid hormone related protein. N Engl J Med. 2000; 342: 177-185.
11. Turner, He, Wass, JAH. Ectopic Hormone Syndromes. Chapter 192. In: Endocrinology 4^th ed. Edited by LJ DeGroot and JL Jameson. WB Saunders. 2001. Vol. 3, (p. 2559-2573).

"Ectopic" Hormone Syndrome

Hormone	Syndrome	Tumor Type
Parathyroid hormone related protein (PTHrP)	Hypercalcemia	Squamous cell carcinoma of lung, skin head and neck; renal carcinoma; myeloma
Parathyroid hormone (PTH) (rare)	Hypercalcemia (rare)	Small cell carcinoma of lung; ovarian carcinoma; thymoma
Prostaglandin E (PGE) TNF, TGF-B, IL-1, 1, 25 dihydroxycholecalciferol	Hypercalcemia	Some solid tumors, multiple myeloma, Hodgkin's and non-Hodgkin's lymphoma
Vasopressin	Inappropriate ADH (SIADH)	Small cell carcinoma of lung, prostate, other sites; adenocarcinoma of prostate, pancreas, etc.
ACTH	Typical Cushing's syndrome Florid Cushing's syndrome	Carcinoids, medullary thyroid carcinoma, pheochromocytoma, pancreatic endocrine tumors Small cell carcinoma of lung and other sites
Corticotropin releasing hormone (CRH)	Cushing's syndrome	Small cell carcinoma of lung and other sites; pancreatic endocrine tumors; medullary thyroid carcinoma; hypothalamic gangliocytoma; bronchial carcinoid
Growth hormone releasing hormone	Acromegaly (rare)	Small cell carcinoma of lung; carcinoids; pancreatic endocrine tumors; pheochromocytoma; adrenal cortical adenoma
Growth Hormone	Acromegaly	Carcinoma of lung; pancreatic endocrine tumors

Hormone	Syndrome	Tumor Type
Placental lactogen		Small cell carcinoma of lung; adenocarcinoma of lung; pheochromocytoma; hepatoma; gastrointestinal tumors; germ cell tumors; breast carcinoma
Human Chorionic Gonadotropin	Gynecomastia, precocious puberty	Carcinoma of lung, prostate, ovary, cervix, adrenal, breast, bladder, liver; osteogenic sarcoma; lymphoma
Prolactin	Galactorrhea (rare)	Carcinoma of lung and kidney
Thyrotropin/?	Hyperthyroidism	Trophoblastic tumors
Renin	?	Wilms' tumor; carcinoma of lung, pancreas, ovary, liver; paraganglioma; hemangiopericytoma
Insulin-like growth factors (IGF-1, IGF-2)	Hypoglycemia	Sarcomas, Wilms' tumor; hepatocellular carcinoma
Calcitonin	? Flushing	Pancreatic endocrine tumors; pheochromocytoma; adrenal cortical carcinoma, small cell CA of esophagus and lung; cervical, prostatic, breast, renal and GI carcinomas
Luteinizing hormone	Oligomenorrhea Precocious puberty (males)	Pancreatic endocrine tumor; adrenocortical carcinoma
Vasoactive intestinal peptide	Pancreatic cholera	Pancreatic endocrine tumors; neuroblastic tumors
Gastrin	Zollinger Ellison syndrome	Pancreatic endocrine tumors; tumors of other sites (eg ovary)