Ectopic hormones refer to hormones or hormone-like substances produced by tumors originating from non-endocrine tissues, as well as hormones secreted by endocrine tumors that are outside the spectrum of hormones normally produced by those endocrine tissues. The clinical syndrome caused by these hormones is termed ectopic hormone secretion syndrome or paraneoplastic syndrome.
Currently, the majority of cases of ectopic hormone secretion syndrome are associated with malignant tumors originating from non-endocrine tissues. Additionally, some tumors may secrete other related hormones, such as neurotensin, vasoactive intestinal peptide (VIP), and somatostatin, alongside those hormones responsible for endocrine syndromes. However, these additional hormones often do not give rise to obvious clinical symptoms.
Properties and Characteristics of Ectopic Hormones
Ectopic hormones are predominantly peptide hormones and are mostly produced by malignant tumors originating from non-endocrine tissues. Although ectopic hormone secretion by tumors is relatively common, only a small number lead to ectopic hormone secretion syndrome, likely due to low hormone quantities and limited biological activity. In addition, ectopic hormones commonly exhibit the following characteristics:
Due to the incomplete functionality of gene transcription, splicing, and protein processing in tumor cells, the precursor molecules, fragments, or subunits of these hormones often exhibit low biological activity. Some hormones, lacking the amino-terminal signal peptides, fail to be secreted from the cells.
In the absence of regulatory mechanisms for hormone secretion, ectopic hormones are often secreted in an unregulated manner and cannot be suppressed.
Certain ectopic hormones, such as pituitary glycoprotein hormones (e.g., FSH, LH, and TSH), are primarily produced by ectopic pituitary tissue and rarely by non-pituitary tumors. This is because the synthesis of such hormones requires the expression of both α and β subunits, glycosylation, and the proper assembly into biologically active dimers, processes that necessitate multiple enzymes and make the synthesis of structurally complete glycoprotein hormones particularly difficult.
Pathogenesis
Tumor cells capable of ectopic hormone secretion often belong to neuroendocrine cells, which originate from the neural crest of the ectoderm. Some of these cells can differentiate to form endocrine glands, such as the pituitary, thymus, thyroid, parathyroid, and pancreatic islets. Others are scattered within the mucosa of the gastrointestinal tract, forming clusters of cells that secrete gastrointestinal hormones. Additionally, these cells are distributed in other organs, such as the lungs, liver, kidneys, and sympathetic ganglia, and share similar histochemical characteristics.
Under normal conditions, these neuroendocrine cells and tissues do not possess hormone-secreting functions. However, during tumorigenesis, they can undergo ectopic synthesis and secretion of various hormones, a process referred to as the "atavism phenomenon."
Current research suggests several relationships between ectopic hormones and tumors:
- Certain cells inherently possess hormone secretion capabilities, and during tumorigenesis and cellular proliferation, the production and release of hormones are significantly increased.
- Certain oncogenes can directly activate the transcription and expression of hormone-related genes.
- Tumor tissues may abnormally overexpress certain transcription factors, which promote the production of ectopic hormones.
- Paraneoplastic hormones can stimulate tumor cell growth through autocrine or paracrine mechanisms.
Common Ectopic Hormone Secretion Syndromes
Ectopic ACTH Syndrome
Ectopic ACTH syndrome is one of the earliest discovered and extensively studied ectopic hormone secretion syndromes. It is commonly associated with APUD tumors (amine precursor uptake and decarboxylation cell tumors), which are frequently seen in small-cell lung cancer and carcinoid tumors in various locations. Additionally, ectopic ACTH syndrome can occur in cases such as islet cell carcinoma, medullary thyroid carcinoma, pheochromocytoma, neuroblastoma, melanoma, and hepatocellular carcinoma. Malignant tumors often express the ACTH precursor proopiomelanocortin (POMC), but due to the absence of enzymatic systems that cleave ACTH from its precursor POMC, the POMC/ACTH ratio is typically elevated.
This syndrome is categorized into two types. Type I is primarily observed in small-cell lung cancer patients, most commonly in men, with severe symptoms and rapid disease progression. Unlike typical Cushing syndrome featuring central obesity and striae, these patients often present with hypertension, severe hypokalemia accompanied by muscle weakness, edema, and significant hyperpigmentation. Type II is associated with carcinoid tumors of the lung, pancreas, intestine, and pheochromocytoma. Patients with this type have a longer disease course, milder symptoms, and exhibit typical features of Cushing syndrome, requiring differentiation from pituitary-origin Cushing’s disease.
Ectopic Antidiuretic Hormone Syndrome
Ectopic antidiuretic hormone syndrome is among the most common causes of tumor-associated hyponatremia, frequently observed in lung cancers, particularly small-cell lung cancer. Malignant tumor cells secrete excessive arginine vasopressin (AVP), leading to syndrome of inappropriate antidiuretic hormone secretion (SIADH), which results in water retention, dilutional hyponatremia, and clinical manifestations such as elevated urine sodium and osmolality.
While mild hyponatremia may be asymptomatic, significant reductions in serum sodium concentration (<125 mmol/L) can lead to muscle weakness, loss of tendon reflexes, stupor, seizures, or even coma and require urgent treatment. Chronic hyponatremia triggers compensatory mechanisms that protect the brain from edema, making brain tissue highly sensitive to sodium increases. As a result, rapid sodium supplementation may lead to osmotic demyelination syndrome (OMS).
Tumor-Associated Hypercalcemia
Hypercalcemia is the most common endocrine complication in patients with malignant tumors, affecting approximately 10% of all cancer patients. The primary mechanisms responsible for hypercalcemia include:
Parathyroid hormone-related peptide (PTHrP), which is ectopically produced by tumors and highly homologous to parathyroid hormone (PTH), binds to PTH receptors on osteoblasts, exerting biological effects that enhance osteoclast differentiation, promote bone resorption, and subsequently elevate serum calcium levels.
Tumor tissues, such as those in lymphomas, may overexpress 1α-hydroxylase, which converts 25-(OH)D3 (vitamin D precursor) in circulation into active 1,25-(OH)2D3, further contributing to hypercalcemia.
Cancer cells metastasizing to bone (e.g., renal cancer) and multiple myeloma cells within bone can produce cytokines (e.g., tumor necrosis factor, IL-1, and IL-6) that stimulate bone resorption and cause hypercalcemia.
Hypercalcemia without bone metastasis is often associated with tumors such as squamous cell carcinoma of the lung, renal adenocarcinoma, breast cancer, cervical squamous carcinoma, ovarian cancer, and pancreatic tumors. Mild hypercalcemia may be uncovered incidentally during systemic examinations, while severe cases can manifest with anorexia, nausea, vomiting, constipation, fatigue, arrhythmias, lethargy, depression, confusion, and even coma, potentially mimicking brain metastases from malignant tumors.
Tumor-Associated Hypoglycemia
Tumor-associated hypoglycemia, also referred to as Doege-Potter syndrome, is characterized by hypoglycemia induced by non-islet solid fibrous tumors. The underlying factor is tumor cell secretion of insulin-like growth factor-2 (IGF-2), which binds to and activates insulin receptors, increasing glucose uptake by peripheral tissues and reducing hepatic glucose output, leading to hypoglycemia. Clinical symptoms resemble those of hypoglycemia caused by insulinomas but tend to be more severe and often emerge during fasting periods or in an autonomous secretion pattern. Low blood glucose levels are observed during episodes despite normal serum insulin levels, facilitating differentiation from insulinomas.
Ectopic Human Chorionic Gonadotropin (HCG) Syndrome
Human chorionic gonadotropin (HCG) is normally produced by trophoblast cells within the placenta, though normal tissues such as the liver and colon can also produce HCG. Choriocarcinomas and teratomas, which contain trophoblastic cells, are not considered sources of ectopic HCG production. Known tumors that produce ectopic HCG include lung tumors, hepatoblastomas, renal carcinomas, and adrenocortical carcinomas. Biologically active HCG can cause precocious puberty in children during adolescence or induce gynecomastia in adult males. In adult women, symptoms are typically absent, though some may experience irregular uterine bleeding.
Ectopic GHRH/GH Secretion Syndrome
Tumors outside the pituitary can produce growth hormone-releasing hormone (GHRH), and in rare cases, growth hormone (GH), leading to acromegaly. Tumors secreting GHRH are primarily carcinoid tumors, followed by islet cell tumors, and less commonly pheochromocytomas or paragangliomas. Elevated levels of GHRH, GH, and IGF-1 are often observed, with the diurnal rhythm of GH secretion disrupted. Clinical presentation is indistinguishable from pituitary-origin acromegaly. Approximately 90% of carcinoids that secrete GHRH are located within the thoracic cavity, while rare cases suggest that islet cell tumors can also produce GH, inducing acromegaly.
Other Ectopic Hormone Secretion Syndromes
Tumor-Produced Renin Leading to Hypertension
Renin production by tumors, such as renal tumors, small-cell lung cancer, lung adenocarcinoma, liver cancer, pancreatic cancer, and ovarian cancer, can result in increased aldosterone secretion accompanied by hypertension and hypokalemia. Management typically involves the use of spironolactone or angiotensin-converting enzyme inhibitors.
Tumor-Induced Osteomalacia
Mesenchymal tumors, prostate cancer, and lung cancer can cause osteomalacia associated with severe hypophosphatemia and muscle weakness. Phosphate supplementation, either orally or intravenously, along with increased vitamin D intake, is recommended. Surgical removal of the tumor should be considered after evaluation.
Prolactin Release by Non-Pituitary Tumors
This condition is relatively rare, with some cases involving prolactin production and release by lung cancer and renal cancer. In female patients, this can cause galactorrhea and amenorrhea, while male patients may experience reduced sexual function and gynecomastia.
Laboratory Tests and Diagnosis
Laboratory Tests
In addition to assessing the levels of ectopically secreted hormones, the following tests are useful for diagnosing ectopic hormone secretion syndrome:
Imaging Studies
X-ray, ultrasound, CT, and MRI examinations can be performed to identify tumors and achieve tumor localization in specific areas such as the chest, abdomen, and adrenal glands.
Blood Chromogranin A Measurement
Chromogranin A, present in the chromaffin granules of neuroendocrine cells, can be produced by cells secreting peptide hormones. Testing for chromogranin A can aid in the localization of neuroendocrine-related tumors in different systems.
111In-Labelled Octreotide Scanning
Neuroendocrine cells that produce peptide hormones commonly express somatostatin receptors. Imaging with radiolabeled somatostatin analogs can assist in tumor localization.
Diagnostic Criteria
The key diagnostic criteria for ectopic hormone secretion syndrome include:
- The simultaneous presence of a tumor and endocrine syndrome, where the tumor arises from an endocrine tissue that does not normally secrete the specific hormone.
- Abnormally elevated levels of a hormone in the blood or urine in tumor patients, accompanied by corresponding clinical syndromes, while the tissue or cells in question do not typically synthesize or secrete that hormone under normal conditions.
- Autonomous hormone secretion that is not suppressed by normal feedback mechanisms.
- Specific treatment of the tumor (e.g., surgical resection, radiotherapy, or chemotherapy) leads to a reduction in the hormone level, with corresponding symptoms of the endocrine syndrome gradually alleviating or disappearing.
- Exclusion of other potential causes for the associated syndrome.
Treatment and Prognosis
The primary treatment strategies for ectopic hormone secretion syndrome include surgical resection of the primary tumor and anti-ectopic hormone therapy. For resectable tumors, it is important to identify the tumor's function and type and to select appropriate interventions, such as surgery, radiotherapy, chemotherapy, or combination therapy, based on the specific condition. This approach aims to control excessive ectopic hormone secretion and alleviate related symptoms effectively.
For tumors that cannot be definitively localized or are not amenable to complete removal, anti-ectopic hormone therapy is the focus, primarily aiming to alleviate symptoms. This involves using appropriate medications to inhibit or block the synthesis and secretion of hormones, including both ectopic hormones and related hormones produced by target tissue glands.
Additionally, surgical removal of target gland tissues affected by ectopic hormonal actions represents an alternative strategy to manage symptoms effectively.