ANNALS O F CLINICAL AND LABORATORY SCIENCE, Vol. 9, No. 4 Copyright © 1979, Institute for Clinical Science, Inc. Ectopic Hormone Production by Malignant Tumors IRWIN J. HOLLANDER, M.D. and GONZALO E. APONTE, M.D. Department of Pathology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA 19107 ABSTRACT Malignant tumors of nonendocrine tissues may produce ectopic hor­ mones. The most likely mechanism is depression of genes which code for hormones. Ectopic hormones are invariably peptides, and each is identical to some peptide product of an endocrine gland. However, the majority of ectopic hormones occur as biologically inactive precursors or subunits and therefore remain occult unless they are specifically sought. When appropri­ ate assays are made for such inactive forms, it is found that ectopic produc­ tion of hormone-like peptides occurs frequently. Clinical syndromes result only in the relatively rare patients in whom a biologically active form is synthesized in large quantities. Laboratory research in this area improves our understanding of genetic control mechanisms in neoplasia. Ectopic hormones may be of limited use in diagnosis of cancer, especially when multiple markers are measured simultaneously. Introduction Ectopic hormone production is synthe­ sis of a hormone by tissues which do not To most of us, the ectopic synthesis of normally produce that hormone. This def­ hormones by malignant tumors brings to inition implies, of course, that all of the mind a rare patient whose vigorous normal sites of origin of the hormone are workup by an enthusiastic endocrin­ known, but this assumption conceals ologist merited a case report. The complexities to which we will return later. phenomenon is neither new nor all that The organ in which the ectopic synthesis rare, but our awareness of it has increased occurs may or may not have an endocrine with the advent of radioimmunoassay function in healthy persons. In the great techniques which have improved the majority of cases, it is tissue not consid­ sensitivity and availability of hormone ered endocrine until neoplasia endows it measurements. Recent work has greatly with that capacity. advanced our understanding of ectopic The four glycopeptide hormones are hormones and has indicated that they human chorionic gonadotrophin (HCG), may provide a tool for exploring the mo­ luteinizing hormone (LH), follicle stimu­ lecular biology of neoplasia. lating hormone (FSH) and thyrotropin 268 0091-7370/79/0700-0268 $01.20 © Institute for Clinical Science, Inc. ECTOPIC HORMONES 269 stimulating hormone (TSH). They are In most cases, of course, plasma hor­ each composed of an alpha chain and a mone concentrations are the only data beta chain which lack biologic effect available. Since most hormones are subject when separated but which, when bound to a negative-feedback-physiologic regu­ as a dimer, form a biologically active mol­ lation, production of ordinary quantities ecule. The alpha chains of all four are of hormone ectopically succeeds only in nearly identical, and the biological and shutting off eutopic synthesis, and the net immunological specificity of these hor­ result is a non-diagnostic blood level in mones is conferred by their beta chains. In the normal range. The diagnosis ofectopic addition to the peptide structures, each production by this approach must often hormone has a carbohydrate component wait until the plasma hormone concentra­ which, if removed, leaves a molecule tion clearly exceeds normal levels, which which retains immunologic reactivity in lowers the rate of detection to the point assays but is of greatly reduced biological where this phenomenon becomes a medi­ potency because of an enormous decrease cal curiosity. in metabolic half-life.9 Placental hormones such as HCG and Until quite recently, HCG could be as­ human placental lactogen (HPL) assume sayed only as the sum of HCG and LH special importance as ectopic products because the beta chains of these two hor­ because they are not found in the sera of mones are sufficiently similar to cause healthy non-pregnant persons and are not immunologic cross-reaction. The produc­ subject to any feedback-loop control, so tion of small amounts of HCG had escaped that they are almost specific for cancer detection because it could not be sepa­ when present in serum in any measurable rated from the relatively large normal quantity. With the great sensitivity al­ levels of LH. The fairly recent develop­ lowed by this low level of significant ment of the so-called beta-subunit assay production, the placental hormones are which is highly specific for HCG was the found early and relatively frequently, and technical advance which made possible much of the most interesting and impor­ much of the current understanding of the tant recent research in ectopic hormone ectopic production of this hormone. production has centered about these hor­ mones.12 These placental hormones are The Special Role of Placental Hormones not to be confused with fetal proteins, such as alpha fetoprotein or carcino- One of the first problems encountered embryonic antigen, which are normally in considering ectopic hormones is how to present in sera of healthy adults in small prove that they are synthesized ectopi- quantities. cally by tumors rather than produced eutopically at a normal site of origin. The Genetic Derepression most elegant and definitive methods are a demonstration of an arteriovenous gra­ The mechanism of polypeptide produc­ dient in hormone concentration across the tion by nonendocrine tumors has been the tumor or in vitro production of hormone subject of controversy ever since the by tumor explants. These studies, while phenomenon was first described. One optimal, are rarely done. Direct analysis of theory has been that it is part of the chaos tumor tissue for hormone is somewhat of malignancy, in which a peptide corre­ more practical, but it cannot distinguish sponding to the active site of a hormone is genuine synthesis of hormone by tumor fortuitously synthesized by an occasional from mere concentration or “trapping” of tumor. There is now much evidence, hormone in tumor tissue. however, that ectopic synthesis is not ran­ 270 HOLLANDER AND APONTE dom, and that it is of very basic signifi­ may have an element of selectivity. This cance in tumor biology. has fostered an additional hypothesis in An hypothesis termed “genetic dere­ which there is a hierarchy of availability pression” explains the observations in a for derepression of DNA, ranging from much more satisfactory way than does any DNA which is inaccessible through vari­ previous theory. Essentially, it states that ous degrees of reversible repression to all tissues contain the same genetic infor­ DNA which is actively coding messenger mation in the nuclei of all cells, but much ribonucleic acid (RNA). In this theory, the of it is repressed as cellular and tissue synthesis of ectopic hormones by tumors differentiation advances. In the neoplas­ is governed by DNA which is in those tic process, some of these repressed genes middle levels of reversible repression, may be activated, leading to production of and the frequency with which a peptide is normal peptides by tissues other than synthesized ectopically should correlate their natural sources. with the ease of derepression of the DNA If this theory is true, then ectopic hor­ which codes for it.18 mones should all be polypeptides and Research using tissue cultures of never steroids or thyroid hormones, and malignant tumors has made significant this is in fact what has been found. All contributions to our understanding of the ectopic hormones which have been mechanism of ectopic hormone produc­ studied are peptides. In those patients tion. The well-known HeLa cell line was who have appeared to produce steroid or derived from a carcinoma of the uterine thyroid hormones ectopically, the tumor cervix and has been maintained in cell makes only the tropic hormone, which is a culture for over 25 years. HeLa cells have peptide, while the steroid or thyroid hor­ been demonstrated to secrete the alpha mones are secondary products of eutopic subunit of HCG ectopically in significant origin. To believe otherwise would be to amounts, and the fact that alpha subunit ignore what is known from ultrastructure was synthesized by all of the HeLa cell and biochemistry, since all nucleated strains studied by one laboratory suggests cells possess the organelles and enzymes that transcription of this peptide may be for making peptides, but only certain cells relatively easily derepressed.7 in the body have the long and complex Variability in expression of this dere­ pathways necessary for steroid synthesis. pressed genetic information has been Additional support for this theory elegantly demonstrated in another cell comes from the finding that those ectopic culture system. In 1971 a subcutaneous hormones which have been isolated and metastasis was excised from a 45-year-old characterized are structurally identical to man with an HCG-producing broncho­ eutopic hormones and their precursors genic carcinoma. A number of clonal and subunits. Not only the active site but strains from single cells of this tumor, an entire polypeptide is faithfully dupli­ designated ChaGo, were established in cated by the tumor. Such fidelity would be long-term tissue cultures. Secretion of most unlikely if ectopic hormones arise HCG and its subunits into the culture from chaos, but it is the expected result if media of three of these clones has