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

Harrisons Internal Medicine Chapter 96. Paraneoplastic Syndromes: Endocrinologic/HematologicParaneoplastic Syndromes: Endocrinologic/Hematologic: IntroductionIn 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) Chapter 096. Paraneoplastic Syndromes: Endocrinologic/Hematologic (Part 1) Harrisons Internal Medicine > Chapter 96. Paraneoplastic Syndromes:Endocrinologic/Hematologic Paraneoplastic Syndromes: Endocrinologic/Hematologic: Introduction In addition to local tissue invasion and metastasis, neoplastic cells canproduce a variety of peptides that that can stimulate hormonal, hematologic,dermatologic, or neurologic responses. Paraneoplastic syndromes refer to the disorders that accompany benign ormalignant tumors but are not directly related to mass effects or invasion. Tumorsof neuroendocrine origin, such as small cell lung carcinoma (SCLC) andcarcinoids, produce a wide array of peptide hormones and are common causes ofparaneoplastic syndromes. However, almost every type of malignancy has the potential to producehormones or cytokines, or to induce immunologic responses. Careful studies of theprevalence of paraneoplastic syndromes indicate that they are more common thanis generally appreciated. The signs, symptoms, and metabolic alterations associated withparaneoplastic disorders may be overlooked in the context of a malignancy and itstreatment. Consequently, atypical clinical manifestations in a patient with cancershould prompt consideration of a paraneoplastic syndrome. The most commonendocrinologic and hematologic syndromes associated with underlying neoplasiawill be discussed here. Etiology Hormones can be produced from eutopic or ectopic sources. Eutopic refersto the expression of a hormone from its normal tissue of origin, whereas ectopicrefers to hormone production from an atypical tissue source. For example, adrenocorticotropic hormone (ACTH) is expressedeutopically by the corticotrope cells of the anterior pituitary but it can beexpressed ectopically in SCLC. Many hormones are produced at low levels from awide array of tissues, in addition to the classic endocrine source. Thus, ectopicexpression is often a quantitative change rather than an absolute change in tissueexpression. Nevertheless, the term ectopic expression is firmly entrenched and conveysthe abnormal physiology associated with neoplastic hormone production. Inaddition to high levels of hormones, ectopic expression is typically characterizedby 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 causeectopic hormone production, but this process remains incompletely understood. Inrare instances, genetic rearrangements explain aberrant hormone expression. For example, translocation of the parathyroid hormone (PTH) generesulted in high levels of PTH expression in an ovarian carcinoma, presumablybecause the genetic rearrangement brings the PTH gene under the control ofovary-specific regulatory elements. A related phenomenon is well documented in many forms of leukemia andlymphoma, in which somatic genetic rearrangements confer a growth advantageand alter cellular differentiation and function (Chap. 105). Although geneticrearrangements may cause selected cases of ectopic hormone production, thismechanism is probably unusual, as many tumors are associated with excessiveproduction of numerous peptides. It is likely that cellular dedifferentiationunderlies most cases of ectopic hormone production. In support of this idea, manycancers are poorly differentiated histologically, and certain tumor products, suchas human chorionic gonadotropin (hCG), parathyroid hormone–related protein(PTHrP), and αfetoprotein, are characteristic of gene expression at earlierdevelopmental stages. On the other hand, the propensity of certain cancers toproduce 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 transcriptionalrepression, changes in DNA methylation, or other factors that govern celldifferentiation. Consistent with this idea, many solid tumors harbor poorlydifferentiated cancer stem cells, a subpopulation of cells that are capable ofinitiating new tumors. In SCLC, the pathway of differentiation has been defined. Theneuroendocrine phenotype is dictated in part by the basic-helix-loop-helix (bHLH)transcription factor human achaete-scute homologue 1 (hASH-1), which isexpressed at abnormally high levels in SCLC associated with ectopic ACTH. Theactivity of hASH-1 is inhibited by hairy enhancer of split 1 (HES-1) and by Notchprot ...