Chapter 096. Paraneoplastic Syndromes: Endocrinologic/Hematologic (Part 1)

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Harrison's Internal Medicine Chapter 96. Paraneoplastic Syndromes: Endocrinologic/Hematologic Paraneoplastic Syndromes: Endocrinologic/Hematologic: Introduction In addition to local tissue invasion and metastasis, neoplastic cells can produce a variety of peptides that that can stimulate hormonal, hematologic, dermatologic, or neurologic responses. 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, produce a wide array of peptide hormones and are common causes of paraneoplastic syndromes. ...

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Chapter 096. Paraneoplastic Syndromes: Endocrinologic/Hematologic (Part 1) Harrison's Internal Medicine > Chapter 96. Paraneoplastic Syndromes: Endocrinologic/Hematologic Paraneoplastic Syndromes: Endocrinologic/Hematologic: Introduction In addition to local tissue invasion and metastasis, neoplastic cells can produce a variety of peptides that that can stimulate hormonal, hematologic, dermatologic, or neurologic responses. 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, produce a wide array of peptide hormones and are common causes of paraneoplastic syndromes.
However, almost every type of malignancy 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. Etiology 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 neoplastic hormone production. In addition to high levels of hormones, ectopic expression is typically 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, but this process remains incompletely understood. In rare instances, genetic rearrangements explain aberrant hormone expression. For example, translocation of the parathyroid hormone (PTH) gene resulted in high levels of PTH expression in an ovarian carcinoma, presumably because the genetic rearrangement brings the PTH gene under the control of ovary-specific 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. 105). Although genetic rearrangements may cause selected cases of ectopic hormone production, this mechanism is probably unusual, as many tumors are associated with excessive
production of numerous peptides. It is likely that cellular dedifferentiation underlies most cases of ectopic hormone production. In support of this idea, many cancers are poorly differentiated histologically, and certain tumor products, such as human chorionic gonadotropin (hCG), parathyroid hormone–related protein (PTHrP), and αfetoprotein, are characteristic of gene expression at earlier developmental stages. On the other hand, 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 are likely to be driven by alterations in transcriptional repression, changes in DNA methylation, or other factors that govern cell differentiation. Consistent with this idea, many solid tumors harbor poorly differentiated "cancer stem cells," a subpopulation of cells that are capable of initiating new tumors. In SCLC, the pathway of differentiation has been 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 are also capable of inducing growth arrest. Thus, abnormal expression of these developmental transcription factors appears to provide a link between cell proliferation and differentiation.