The concept that neoplasms may produce hormones and/or hormone-like substances has already been introduced. The parathyroid hormone–related protein (PTHRP, Chapter 17) that regulates calcium metabolism in peripheral tissues is an example. A number of neoplasms derived from tissues that, in the adult, normally produce this hormone have been described (Chapter 17). In addition, as pointed out below, neoplasms produce a number of as yet unidentified materials that exert significant effects on host tissues. However, the best-understood aspect of hormonal effects of neoplasms on the host involves functional neoplasms of endocrine tissues.
Effects of Functioning Neoplasms of the Endocrine System on the
It has been known since the nineteenth century that neoplasms derived from endocrine tissues can retain the function of their cell of origin. However, the extent of this phenomenon was not appreciated until the last four decades. Table 18.3 is a partial list of functional neoplasms of endocrine tissues in the human. These neoplasms elaborate the hormones normally produced by their cell of origin. However, the regulation of the production of one or more hormones normally produced by that tissue is clearly aberrant in all cases, many times to such a degree that the pathophysiological changes that result from the excess hormone give rise to specific clinical findings. Therefore such neoplasms reflect the relative autonomy characteristic of all neoplasia, but this aberrant regulation is manifest not so much in growth control as in the regulation of the elaboration of their secretory products. In most instances the production of the hormone shows little or no environmental regulation by the host. On the other hand, there are now specific in-
stances in which such regulation still occurs to some extent, as in the production of calcitonin by medullary carcinoma of the thyroid (Deftos et al., 1971). In this example, calcitonin secretion by the tumor can be regulated by the administration of calcium, glucagon, or hypocalcemic agents. This may be the reflection of the presence of receptors in the neoplastic cell. In support of this is the fact that the responsiveness of carcinoid neoplasms to the administration of the somatostatin analog, octreotide is dependent on the presence of somatostatin receptors in the neoplasm (Kvols and Reubi, 1993).
Just as with the pancreatic islet, the anterior pituitary consists of a variety of different hor- mone-secreting cell populations and thus gives rise to a variety of different functional neo- plasms, each producing primarily but not exclusively one of the polypeptide hormones of the pituitary. The three listed in Table 18.2 comprise the more common lesions, but in addition neo- plasms producing excessive amounts of adrenocorticotropic hormones as well as various gona- dotropins have been described (cf. Thapar et al., 1995). Thyrotropin-secreting pituitary adenomas have rarely been seen; the vast majority are not associated with hypersecretion of other anterior pituitary hormones (Beck-Peccoz et al., 1996). Similarly, in the adrenal cortex one finds cells producing either aldosterone, a hormone regulating potassium metabolism and blood pressure, or cortisone, the steroid hormone affecting sodium metabolism as well as gluconeo- genesis (Chapter 17). Conn syndrome resulting from hyperaldosteronism is associated with hy- pertension and hypokalemia; Cushing syndrome is associated with hypertension, sodium retention, and a peculiar form of truncal obesity and rounded facies as well as abdominal stria. Neoplasms of the adrenal medulla are mostly pheochromocytomas that secrete excessive amounts of catecholamines, primarily adrenalin (epinephrine), noradrenalin (norepinephrine), and dopamine, resulting in frequent severe bouts of hypertension. In the thyroid, medullary car- cinoma of the “C” cells (which normally produce calcitonin) results in diarrhea and dysphagia (difficulty in swallowing) when these cells produce excessive amounts of calcitonin (Cohen and Modigliani, 1993). The normal function of this hormone is to decrease levels of calcium in the blood. In contrast, as discussed in Chapter 17, parathormone, the product of the parathyroid gland, when produced in excess by parathyroid adenomas, produces excessive hypercalcemia, loss of bone, and renal kidney pathology. Carcinoid neoplasms may occur in a variety of tissues of the gastrointestinal tract and lungs developing from neuroendocrine cells in these tissues (see below). These neoplasms in their differentiated state produce excessive amounts of serotonin and other hormones, as noted, producing among other effects vasoactive changes that appear to be associated with episodic flushing, diarrhea, abdominal pain, and eventually right-sided valvular heart disease (Kulke and Mayer, 1999). An interesting functional process of neoplastic cells in Hodgkin lymphomas is their production of a variety of cytokines (Chapter 19). These hormone- like substances have a variety of effects on immune cells and, together with growth factors pro- duced by these malignant lymphocytes, apparently produce the changes seen in this disease as noted in the table (Gruss et al., 1994; Hsu et al., 1993; Teruya-Feldstein et al., 2000).
In endocrine tissues with multiple cellular populations—such as the pituitary, adrenal, thy- roid, and islets of Langerhans—separate and distinct clinical syndromes are produced, the spe- cific kind depending on which of the cell types of the gland becomes neoplastic. The spectrum of hormones produced by the various cell types of neoplasms of the islets of Langerhans is shown in Figure 18.4 (cf. review by Friesen, 1982). The β cell classically produces insulin and presumably is the neoplastic element found in insulinomas. The δ or α1 cell of the islet produces gastrin, and neoplasms derived from this cell are responsible for the peptic ulceration of the stomach and duodenum found in the Zollinger-Ellison syndrome. In addition, other cellular spe- cies of the islets have been found to be producers of amines and the hormone secretin. Neo- plasms of the α cells may produce glucagon, giving rise to hyperglycemia. As a result, these individuals express clinical diabetes as well as a peculiar necrolytic migratory erythema appear-
Figure 18.4 Spectrum of neoplasms derived from the islets of Langherans of the pancreas. The hormones produced by each of the neoplasms are noted, together with the syndromes resulting from excessive production of these hormones. (Modified from Schein, 1973, with permission of the author and publisher.)
ing as a skin rash–like phenomenon, with healing and reappearance (Wermers et al., 1996). Sev- eral neoplasms producing the hormone somatostatin, a polypeptide also produced in the hypothalamus (Pimstone et al., 1979), have been reported (Vinik et al., 1987). As this hormone regulates the secretion of a number of other hormones including insulin, glucagon, gastrin, and pituitary polypeptides, neoplasms of the D cell appear to result in a syndrome indistinguishable from mild diabetes. Such interrelationships of hormones have been known for some time and play a role in the pathophysiology of syndromes resulting in the excessive production of other hormones of endocrine neoplasms. Furthermore, a number of these hormones are produced in precursor forms, such as those noted in Figure 18.5. Of the pre-pro forms, only those shaded in the diagram actually are the functional components, although a number of neoplasms secrete the pro hormones, whereas their tissues of origin seldom secrete significant amounts of such struc- tures (cf. Rehfeld et al., 1996). Since processing of the pre-pro forms of these proteins is post- translational, their secretion is a further indication of the altered regulatory mechanisms present in such neoplasms.
Another group of neoplasms of endocrine tissues that appear to be related are those of the amine precursor uptake and decarboxylation (APUD) system (cf. Baylin, 1975; Pearse, 1968). Cells of the APUD system include pancreatic islet cells, pituitary cells producing adreno- corticotropic hormone (ACTH) and melanotropin, C cells of the thyroid, gastrointestinal ar- gentaffin cells, and adrenal medullary cells. This concept, which was first proposed by Pearse (1968), relates functional cell types to their synthesis and storage of polypeptide and amine hormones. Such cell types are thought to arise from the neural crest. A diagram of the APUD system is seen in Figure 18.6. This concept not only links various neoplasms by their embryo- logical origin, but also accounts for the production of amine and polypeptide hormones by some neoplasms that arise in tissues where APUD cells were thought to be absent or in the minority, such as in the lung, thymus, and urogenital tract. Today the term “neuroendocrine” is used more frequently than “APUD” to characterize neoplasms that produce polypeptide hormones as well as amines in which identical or similar forms are secreted by cells of the nervous system (Capella et al., 1994). A number of members of this group produce more than a single hormone (cf. Weil, 1985).