In addition to local tissue invasion and metastasis, neoplastic cells can produce a variety of products that can stimulate hormonal, hematologic, dermatologic, and neurologic responses. Paraneoplastic syndromes is the term used to refer to the disorders that accompany benign or malignant tumors but are not directly related to mass effects or invasion. Tumors of neuroendocrine origin, such as small cell lung carcinoma (SCLC) and carcinoids, produce a wide array of peptide hormones and are common causes of paraneoplastic syndromes. However, almost every type of tumor has the potential to produce hormones or cytokines or to induce immunologic responses. Careful studies of the prevalence of paraneoplastic syndromes indicate that they are more common than is generally appreciated. The signs, symptoms, and metabolic alterations associated with paraneoplastic disorders may be overlooked in the context of a malignancy and its treatment. Consequently, atypical clinical manifestations in a patient with cancer should prompt consideration of a paraneoplastic syndrome. The most common endocrinologic and hematologic syndromes associated with underlying neoplasia will be discussed here.
Hormones can be produced from eutopic or ectopic sources. Eutopic refers to the expression of a hormone from its normal tissue of origin, whereas ectopic refers to hormone production from an atypical tissue source. For example, adrenocorticotropic hormone (ACTH) is expressed eutopically by the corticotrope cells of the anterior pituitary, but it can be expressed ectopically in SCLC. Many hormones are produced at low levels from a wide array of tissues in addition to the classic endocrine source. Thus, ectopic expression is often a quantitative change rather than an absolute change in tissue expression. Nevertheless, the term ectopic expression is firmly entrenched and conveys the abnormal physiology associated with hormone production by neoplastic cells. In addition to high levels of hormones, ectopic expression typically is characterized by abnormal regulation of hormone production (e.g., defective feedback control) and peptide processing (resulting in large, unprocessed precursors).
A diverse array of molecular mechanisms has been suggested to cause ectopic hormone production. In rare instances, genetic rearrangements explain aberrant hormone expression. For example, translocation of the parathyroid hormone (PTH) gene can result in high levels of PTH expression in tissues other than the parathyroid gland, apparently because the genetic rearrangement brings the PTH gene under the control of atypical regulatory elements. A related phenomenon is well documented in many forms of leukemia and lymphoma, in which somatic genetic rearrangements confer a growth advantage and alter cellular differentiation and function (Chap. 110). Although genetic rearrangements may cause selected cases of ectopic hormone production, this mechanism is probably rare, as many tumors are associated with excessive production of numerous peptides. Cellular dedifferentiation probably underlies most cases of ectopic hormone production. Many cancers are poorly differentiated, and certain tumor products, such as human chorionic gonadotropin (hCG), parathyroid hormone–related protein (PTHrP), and α fetoprotein, are characteristic of gene expression at earlier developmental stages. In contrast, the propensity of certain cancers to produce particular hormones (e.g., squamous cell carcinomas produce PTHrP) suggests that dedifferentiation is partial or that selective pathways are derepressed. These expression profiles probably reflect alterations in transcriptional repression, changes in DNA methylation, or other factors that govern cell differentiation.
In SCLC, the pathway of differentiation has been relatively well defined. The neuroendocrine phenotype is dictated in part by the basic-helix-loop-helix (bHLH) transcription factor human achaete-scute homologue 1 (hASH-1), which is expressed at abnormally high levels in SCLC associated with ectopic ACTH. The activity of hASH-1 is inhibited by hairy enhancer of split 1 (HES-1) and by Notch proteins, which also are capable of inducing growth arrest. Thus, abnormal expression of these developmental transcription factors appears to provide a link between cell proliferation and differentiation.
Ectopic hormone production would only be an epiphenomenon associated with cancer if it did not result in clinical manifestations. Excessive and unregulated production of hormones such as ACTH, PTHrP, and vasopressin can lead to substantial morbidity and complicate the cancer treatment plan. Moreover, the paraneoplastic endocrinopathies are sometimes the presenting feature of underlying malignancy and may prompt the search for an unrecognized tumor.
A large number of paraneoplastic endocrine syndromes have been described, linking overproduction of particular hormones with specific types of tumors. However, certain recurring syndromes emerge from this group (Table 100–1). The most common paraneoplastic endocrine syndromes include hypercalcemia from overproduction of PTHrP and other factors, hyponatremia from excess vasopressin, and Cushing's syndrome from ectopic ACTH.
Table 100–1 Paraneoplastic Syndromes Caused by Ectopic Hormone Production
| Save Table
Table 100–1 Paraneoplastic Syndromes Caused by Ectopic Hormone Production
|Paraneoplastic Syndrome||Ectopic Hormone||Typical Tumor Typesa|
|Hypercalcemia of malignancy||Parathyroid hormone-related protein (PTHrP)||Squamous cell (head and neck, lung, skin), breast, genitourinary, gastrointestinal|
|1,25 dihydroxyvitamin D||Lymphomas|
|Parathyroid hormone (PTH) (rare)||Lung, ovary|
|Prostaglandin E2 (PGE2) (rare)||Renal, lung|
|Syndrome of inappropriate antidiuretic hormone secretion (SIADH)||Vasopressin||Lung (squamous, small cell), gastrointestinal, genitourinary, ovary|
|Cushing's syndrome||Adrenocorticotropic hormone (ACTH)||Lung (small cell, bronchial carcinoid, adenocarcinoma, squamous), thymus, pancreatic islet, medullary thyroid carcinoma|
|Corticotropin-releasing hormone (CRH) (rare)||Pancreatic islet, carcinoid, lung, prostate|
|Ectopic expression of gastric inhibitory peptide (GIP), luteinizing hormone (LH)/human chorionic gonadotropin (hCG), other G protein–coupled receptors (rare)||Macronodular adrenal hyperplasia|
|Non-islet cell hypoglycemia||Insulin-like growth factor (IGF-II)||Mesenchymal tumors, sarcomas, adrenal, hepatic, gastrointestinal, kidney, prostate|
|Insulin (rare)||Cervix (small cell carcinoma)|
|Male feminization||hCGb||Testis (embryonal, seminomas), germinomas, choriocarcinoma, lung, hepatic, pancreatic islet|
|Diarrhea or intestinal hypermotility||Calcitoninc||Lung, colon, breast, medullary thyroid carcinoma|
|Vasoactive intestinal peptide (VIP)||Pancreas, pheochromocytoma, esophagus|
|Oncogenic osteomalacia||Phosphatonin [fibroblast growth factor 23 (FGF23)]||Hemangiopericytomas, osteoblastomas, fibromas, sarcomas, giant cell tumors, prostate, lung|
|Acromegaly||Growth hormone–releasing hormone (GHRH)||Pancreatic islet, bronchial and other carcinoids|
|Growth hormone (GH)||Lung, pancreatic islet|
|Hyperthyroidism||Thyroid-stimulating hormone (TSH)...|
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