W.J. Jeffcoate and Lesley H. Rees,     Department of Chemical Pathology, St. Bartholomew’s Hospital, London, England

Publisher Summary

This chapter focuses on adrenocorticotropin and related peptides in nonendocrine tumors. The ectopic adrenocorticotropic hormone (ACTH) syndrome is usually defined as the secretion of ACTH and/or of closely related peptides, by a tumor comprised of cells that are not normally engaged in their production. It is the syndrome that results from ACTH secretion by a nonpituitary tumor. It has been established beyond doubt that tumors of certain groups of cells frequently synthesize and secrete ACTH, its precursor forms, or its fragments. The synthesis of ACTH in such tumors is common and includes at least 50% of all oat cell carcinomas of the lung. The formation and secretion of ectopic ACTH is probably invariably accompanied by the formation of βn-LPH-related peptides. The chapter discusses the diagnosis, clinical features, and incidence of ectopic ACTH syndrome, characterization of ectopic ACTH and related peptides, tumor types associated with ectopic ACTH secretion, and ACTH and related peptides in control tumors.

I Introduction

Initially, an association was noted between certain nonendocrine tumors and the clinical features of Cushing’s syndrome. Later, it was realized that the association arose because such tumors were capable of the biosynthesis and secretion of adrenocorticotropic substances. These substances were thought at first to be identical to pituitary ACTH (αh1-39ACTH), but it is now known that a variety of ACTH-related peptides may be produced, including both larger precursor molecules and ACTH-like fragments. In addition, the ectopic synthesis of ACTH-like peptides appears to be accompanied, invariably, by the synthesis of a second group of peptides, related to β-lipotropin (β-LPH). The first member of this group identified was the 22-amino acid fragment βh-melanocyte-stimulating hormone (MSH),1 and for this reason the term ectopic ACTH/MSH syndrome came into use. We shall refer to the clinical condition simply as the ectopic ACTH syndrome.

II History

Although the classical description of Cushing’s syndrome was not to be made until 1932 (Cushing, 1932), it is possible to identify earlier reports of the condition. One of these was that by Gabcke (1896) whose patient with a nonendocrine tumor, pigmentation, and hypertrophy of the adrenal glands probably represents the first reported case of the ectopic ACTH syndrome. Then Achard and Thiers (1921) described patients with a condition they termed “le diabete des femmes a barbe” and in 1928 Brown found that one of six cases of “diabetes of bearded women” had an oat cell carcinoma of the lung. Such early studies assumed no causal relationship between the tumors and adrenal hyperplasia, merely calling then pluriglandular syndromes (Leyton et al., 1931; Keppler, 1933). Crooke (1946) noted the relationship between Cushing’s syndrome and carcinoma of the pancreas and commented that “basophilism is a disorder usually associated with tumor formation.” Some assumed that Cushing’s syndrome predisposed to cancer. But it was not until 1952 that Thorne first suggested that these tumors secreted an adrenocorticotropic substance, although he concluded that there was no evidence to support the theory. Ten years later this evidence was forthcoming when Christy (1961) described raised adrenal weight-maintaining activity in the plasma of two patients with lung tumors, and Meador and his colleagues (1962) published their elegant study of five patients with nonpituitary tumors and Cushing’s syndrome and later Liddle et al. (1965) coined the phrase “ectopic ACTH.”

In the last 15 years the ectopic ACTH syndrome has been extensively studied and reviewed (Liddle et al., 1969; Ratcliffe et al., 1972; Rees and Ratcliffe, 1974; Rees, 1975, 1977a). With increasing awareness on the part of physicians and with the increasing availability of sensitive immunoassay and bioassay techniques for the measurement of ACTH and related peptides, the diagnosis is made more frequently. For example, there is good evidence that ectopic ACTH secretion occurs in between one-third and half of all patients with oat cell carcinoma of the lung (Gilby et al., 1975) and that most, if not all, the remainder have the potential for ACTH synthesis.

The realization that the ectopic secretion of ACTH is associated with the ectopic elaboration of other related peptides followed, and the presence of a melanocyte-stimulating factor (called β-MSH at the time) was observed in the plasma and tumor extracts of some patients (Island et al., 1965; Shimizu et al., 1965; Abe et al., 1967a). At the same time Abe described the ectopic secretion of α-MSH (Abe et al., 1967b) in association with ACTH, and it has since become apparent that coincident secretion of many different related and nonrelated peptides may occur (Rees and Landon, 1975).

III Definition of Ectopic Adrenocorticotropic Hormone (ACTH) Syndrome

The ectopic ACTH syndrome is usually defined as the secretion of ACTH, and/or of closely related peptides, by a tumor comprised of cells not normally engaged in their production (Liddle et al., 1969; Ellison and Neville, 1973). Although traditional, this definition is far from perfect for it implies that all the normal sites of ACTH secretion are known, which is probably not true (Rees, 1976; Bloomfield et al., 1977). It is better to say simply that it is the syndrome that results from ACTH secretion by a nonpituitary tumor.

IV Evidence for Existence of Ectopic Humoral Syndromes

The coexistence of a tumor and Cushing’s syndrome does not prove that the former is the cause of the latter. To establish that any hormone is secreted ectopically a number of criteria must be satisfied, listed in Table I. This subject has been discussed in detail elsewhere (Omenn, 1970; Rees, 1977a). In the case of ACTH all but the last of these features have been demonstrated.

V Diagnosis of Ectopic ACTH Syndrome

This depends initially on clinical suspicion for, if a condition is thought to be rare, it is only rarely diagnosed. The patient may present only one or two of the clinical features listed below and the classical appearance of Cushing’s syndrome may not occur. However, in any patient with a tumor and associated hypokalemia, the diagnosis should be seriously entertained. Similarly, if a patient with clinical or biochemical features of Cushing’s syndrome has either high ACTH and Cortisol levels or hypokalemia, he may well have ectopic ACTH secretion. In such circumstances the tumor may well be occult and occasionally not become clinically obvious until several years after initial presentation (Bagshawe, 1960).

However, in a suspected case of ectopic ACTH secretion it may well be difficult to find definite...