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Neoplastic cells can produce a variety of substances that can alter the physiology of hormonal, hematologic, dermatologic, rheumatologic, renal, and neurologic systems. Paraneoplastic syndromes 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 are common causes of paraneoplastic syndromes, but they have been associated with many types of tumors that produce peptide hormones, cytokines, and growth factors and induce the production of antibodies. 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 are easily 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 hormonal 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 tissues other than 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 is often characterized by abnormal regulation of hormone production (e.g., defective feedback control in ectopic ACTH) and peptide processing (resulting in large, unprocessed precursor peptide such as proopiomelanocortin [POMC]).

Many different molecular mechanisms can cause ectopic hormone production. In rare instances, genetic rearrangements account for 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 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. Although genetic rearrangements cause selected cases of ectopic hormone production, this mechanism is 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), PTH–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 ...

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