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.
ENDOCRINE PARANEOPLASTIC SYNDROMES
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. 15). 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 ...