ACTH Production by Non-Pituitary Tumors A Review STEPHEN A. GELLER, M.D .* Howard University College of Medicine Washington, D.C.
A DRENOCORTICOTROPHIC hormone (ACTH) is one of the seven hormones (thyroid-stimu- lating hormones, TSH; follicle-stimulating hor- mone, FHS; luteinizing hormone or interstitial- cell-stimulating hormone, LH or ICSH; luteotro- phic hormone or prolactin, LTH; somatotrophic or growth hormone; and melanocyte-stimulating hor- mone, MSH) normally secreted by the anterior pituitary gland. These hormones, all of which are proteins or polypeptides, act to stimulate various target organs and glands. In general, the hormones elaborated by the target glands act in a “feed-back” manner to inhibit the production of the stimulat- ing hormone by the pituitary.
ACTH increases the liberation of the adrenal cortical hormones by stimulating the cells of the adrenal cortex. Following removal or destruction of the anterior pituitary, the adrenal cortex under- goes marked atrophy with almost complete sup- pression of its secretory activity. Exogenously ad- ministered ACTH can restore the atrophic cortex to normal size and activity. Clinical evidence of hyperactivity of the adrenal cortex can be produced by prolonged and excessive administration of ACTH. Many pathologic conditions may af- fect the production of this and other hormones. Clinically, these derangements become manifest because of deficiencies or excesses of the involved hormones. Indeed, the importance of the endo- crine glands and their products has only become known in the past two or three decades as the many clinical conditions associated with impaired endocrine function have been studied.
The syndrome due to excess production of the hormones of the adrenal cortex was described, in 1932, by Harvey Cushing.1 His classic report concerned the signs and symptoms produced by a basophilic adenoma of the anterior pituitary gland. However, the most common form of Cushing’s syndrome is due to hyperplasia of both adrenal
cortices, with a functioning adenoma of one- adrenal as the next most common. The syndrome may also be produced by adrenal-rest tumors of the ovary, carcinoma of the adrenal or the anterior pituitary, as well as by the exogenous admini- stration of ACTH or adrenal cortical hormones. such as cortisone. Cushing’s syndrome is mani- fested by “moon face” and “buffalo hump” obes- ity with protuberant abdomen and thin extremi- ties, hirsutism, purple striae, a plethoric appear- ance, hypertension, easy bruisability and facial pigmentation. The patients often complain of backache, headache, weakness, oligomenorrhea or amenorrhea in the female; and impotence in the male. Mental symptoms ranging .to frank psy- chosis may be seen.
Insulin resistant glycosuria, with low glucose tolerance, is seen. Urinary 17-hydroxycorticoids and blood corticoids are high. Urinary 17-keto- steroids are often low or normal in the benign form of Cushing’s syndrome, but usually elevated when associated with carcinoma or excess ACTH production. Both the red and white blood cell counts are often elevated with an eosinopenia. Serum CO2 is high and serum chloride and potas- sium are low in many cases, particularly when associated with malignancy.
Four years prior to Cushing’s article, W. Hurst Brown, an assistant chemical pathologist at the St. Mary’s Hospital in London, reported a case2 presenting the cardinal features of the condition. now known as Cushing’s syndrome. Brown de- scribed a 45-year-old hypertensive, diabetic female who was irregularly responsive to insulin. The patient complained of increasing drowsiness, as- thenia, painful cramps of the legs and back, scalp alopecia, chin and lip hirsutism, hyperpigmented patches on the face and breasts, and purpuric spots. She bruised easily and was obese at the back of the neck, the breasts, abdomen, and upper part of the arms. She had polycythemia, albu- minuria, hematuria, and a basal metabolism rate
* Graduate in the Class of 1964.
of +20. Roentgenograms failed to show enlarge- ment of the pituitary fossa. Five months after her initial examination she died of heart failure and nephritis. At necropsy, “one typical oat-celled carcinoma one centimeter in diameter” was found in one lung. Bilaterally “enlarged suprarenals” were also described.
In the 30 years following Brown’s discussion only a few cases of Cushing’s syndrome associated with non-endocrine neoplastic disease were re- ported, but many cases have reached the literature in the past five or six years. Excess adrenal cortical activity, both with and without the clinical syn- drome, has been associated with a number of neo- plastic processes, most commonly intrathoracic thy- momas and bronchogenic carcinomas, as well as pancreatic carcinomas. 3-19 In addition, a malignant carcinoid tumor of the bronchus20 and two cases of apparently benign bronchial adenoma21 have been linked with Cushing’s syndrome.
Apparently, biochemical evidence of hyper- adrenocorticism, with increased plasma and urinary corticosteroids and ketosteroids, is present more often than clinical Cushing’s syndrome in these cases.10 When the clinical entity is present it is often acute and fulminant, with severe hypokale- mic alkalosis the rule rather than the exception,9 and invariably associated with an oat-cell type of carcinoma.3,6,7 These patients have generally been middle-aged males rather than the young females usually associated with the benign Cushing’s syn- drome. The alkalosis and potassium deficit sug- gest an accompanying aldosteronism, but this has not been borne out by these investigators who measured aldosterone. Indeed, low values were often obtained.4 This disease pattern may be due to an aldosterone-like property of the glucocorti- coids, but the question has not been resolved at this time. Exogenous potassium is somewhat ef- fective in the management of this fulminant form of the syndrome.
Biochemical studies of this group of patients have revealed consistently elevated 24 hour plasma and urine levels of 17-ketosteroids, 17-ketogenic steroids, and 17-hydroxycorticosteroids, often to a greater degree than seen in the benign form of Cushing’s syndrome.9,10,16
Hynes and Doe10 studied adrenal function in two patients with clinical Cushing’s syndrome as- sociated with bronchogenic carcinoma and 55 un-
selected patients with the malignancy, and com- pared these two groups with control groups with other malignancies as well as with “normal” pa- tients having no known neoplastic or endocrine disease. They reported elevated mean levels of 17-hydroxycorticoids as well as hyper-responsive- ness to ACTH administration in most of the pa- tients afflicted with bronchogenic carcinoma and the absence of this response in the control groups. They further studied the patients in terms of the histologic cell types of the malignancies and showed mean plasma levels of plasma 17-hydroxy- corticosteroids, both before and after ACTH ad- ministration, to be significantly lower in those patients with well-differentiated cancers as opposed to those with undifferentiated or anaplastic cancers. This confirmed the work of Riggs and Sprague18 who had also pointed to the markedly decreased survival time in those patients exhibiting increased adrenocortical activity. Hynes and Does also show- ed, as did Wolf,22 that patients receiving exogen- ous cortisone chemotherapy for inoperable bron- chogenic carcinoma had a shortened survival time. A clinical paradox evident in many of the patients with bronchogenic carcinoma and Cushing’s syn- drome is the gaining, or at least maintenance, of weight in the face of a rapidly spreading carci- noma.12
Lung and thymus tumors predominate among the intrathoracic neoplasms particularly associated with hyperadrenocorticism. In these instances the neoplasms are almost always of the undifferen- tiated oat-cell variety.7 Bornstein6 describes an oat- cell carcinoma of the trachea with this association and Meador16 recently reported a case of a widely disseminated, anaplastic, oat-cell-like malignancy whose primary site was not determined.
An unusual case linking the Cushing and car- cinoid syndromes was described by Escovitz and Reingold,20 with the carcinoid manifested by flushing, elevated serotonin levels in cutaneous metastases and elevated 5-hydroxy-indole-acetic acid (5-HIAA). The primary tumor was of bronchial origin and liver metastases were not demonstrated. The patient expired because of re- current sinus arrests secondary to cardiac metas- tases, with a short interval between the onset of the Cushing’s syndrome and death. At necropsy, the adrenal glands exhibited the characteristic hyperplasia.
Benign tumors have also been associated with Cushing’s syndrome.21 Grossly, and histologically, identical benign pulmonary epithelial tumors were discovered in two unrelated patients, each suffer- ing from Cushing’s syndrome. The lesions in both cases were found in the lingula and were classi- fied as peripheral bronchial adenomas, histologic- ally similar to the thymomas often associated with hyperadrenocorticism. Indeed, the frozen section of one of these tumors was originally interpreted as thymoma.
The pathophysiology involved in the overall syndrome has only recently been well studied. Werk and Sholiton19 compared a group of pa- tients having lung cancer and Cushing’s syndrome with a group of sub-acute and chronic non-neo- plastic diseased patients as well as with “normal” controls. They found similarly elevated basal levels of 17-hydroxycorticoids in the non-neoplastic as well as the neoplastic patients. They concluded that the syndrome of neoplasia and hyperadrenocor- ticism was due to the stress factor of the disease acting over a prolonged period of time, and also suggested that these patients might have a predis- position to increased adrenal activity which might or might not be related to cancer. Cohen, Toll, and Castleman,21 in 1960, suggested that an un- usual secretion of the adrenal cortex may act to stimulate the production of thoracic neoplasms. They stated that there was no evidence that thy- moma, pulmonary carcinoma or pulmonary ade- noma had the ability to secrete a corticotrophic or ACTH-like substance. Marks et al,14 in 1961, pos- tulated an adrenocortical factor that influenced adrenal growth but not secretions. They described a case of epidermoid carcinoma associated with marked bilateral adrenal hyperplasia. In 1963, however, Marks15 discussed a patient with fulmi- nant Cushing’s syndrome and oat-cell carcinoma of the lung and concluded that the tumor could stimulate pituitary secretion of ACTH. He also suggested that the tumor itself might be the source of a corticotrophic agent of either a growth or function stimulating nature.
In 1961, Christy8 measured the plasma cortico- trophin in two patients evidencing adrenal cortical hyperplasia following the appearance of broncho- genic carcinoma, and also studied a patient with a proven carcinoma of the adrenal gland. His assays demonstrated an adrenal-weight-maintaining
corticotrophin functional in hypophysectomized rats in the patients with bronchogenic carcinoma, whereas the plasma from the patient with primary adrenal cancer failed to show this capacity. Meador16 studied five patients with “non-endo- crine” tumors, bilateral adrenal hyperplasia, bio- chemical hyperadrenocorticism, and hypokalemia. He demonstrated an ACTH-like substance in the plasma, the primary and the metastatic tumors of all the patients, as well as an associated subnormal pituitary ACTH content. Corticosteroid suppres- sion with dexamethasone was unsuccessful in the five patients, all of whom exhibited urinary cortico- steroid levels greater that those usually seen in benign Cushing’s syndrome. Meador concluded that certain tumors have the ability to elaborate autonomously an ACTH-like substance that has the property of stimulating the adrenal glands to secrete large quantities of corticosteroids which, in turn, suppress normal ACTH-secreting mech- anisms and, in addition, may induce major metabolic aberrations. Liddle et al13 confirmed this study and further pointed to the presence of the abnormal ACTH-like substance ‘in all primary and metastatic lesions, as well as demonstrating the low pituitary ACTH activity and non-suppres- sion with large doses of dexamethasone. Liddle and his co-workers stated that henceforth a sine qua non in the diagnosis of this entity must be the demonstration of ACTH-like material in tumor tissue obtained at surgery or necropsy. Nichols and Gourley17 have also shown the presence of an ACTH-like substance extractable from primary lung tumors which partially maintained the adrenal weight of hypophysectomized rats. They postu- lated two forms of corticotrophin elaborated by the neoplasms: a steroid releasing type causing Cushing’s syndrome and a weight-maintaining type resulting in bilateral adrenal hyperplasia and bio- chemical hyperadrenocorticism. In 1963, how- ever, Jarrett, Lacy, and Kipnis11 demonsrated sub- stances immunologically similar to ACTH in two cases: one, an undifferentiated carcinoma of the parotid and, the other, a pancreatic islet cell tumor with an associated Zollinger-Ellison syndrome.
A recent report by Amatruda et al23 reviewed the association of oat-cell carcinoma and anti- diuretic activity. The authors point to the remark- able association of a syndrome of inappropriate anti-diuresis, not modifiable by known therapy,
and oat-cell carcinoma, as further strengthening, the likelihood that certain tumors may elaborate polypeptides of biologic importance.
Any case of Cushing’s syndrome with bilaterally hyperplastic adrenals occurring in a mature male, which is abrupt in onset and rapidly becomes severe, or is accompanied by hypokalemic al- kalosis or high urinary levels of 17-hydroxycorti- costeroids and 17-ketosteroids, should alert the physician to suspect a neoplasm, particularly an intrathoracic tumor. In many cases the severe hypo- kalemia and alkalosis associated with the Cush- ing’s syndrome may precede the finding of a carcinoma by a considerable time, from a few months to a few years.4 Further, the existence of a syndrome of neoplastic disease of various organs, but particularly intrathoracic malignancy, in association with clinical or biochemical hyper- adrenocorticism obliges the physician to be alert to the possibility of disturbed adrenal function.
LITERATURE CITED
1. CUSHING, H. The Basophil Adenomas of the Pitu- itary Body and Their Clinical Manifestations (Pitu- itary Basophilism), Bull., Johns Hopkins Hosp., 50: 137, 1932.
2. BROWN, W. H. A Case of Pluriglandular Syndrome: “Diabetes of Bearded Women,” Lancet, 2:1022, 1928.
3. ALLOTT, E. N., and M. O. SKELTON. Increased Adrenocortical Activity Associated with Malignant Disease, Lancet, 2:278, 1960.
4. BAGSHAWE, K. D. Hypokalemia, Carcinoma and Cushing’s Syndrome, Lancet, 2:284, 1960.
5. BELSKY, J. L., and L. J. MARKS. Plasma 17-Hydro- xycorticosterol Responses to ACTH in Patients with Bronchogenic Carcinoma, Metabolism 11:435, 1962.
6. BORNSTEIN, P. et al. Adrenocortical Hyperfunction in Association with Anaplastic Carcinoma of the Respiratory Tract, N.E.J.M., 264:363, 1961.
7. CHAFFEE, W. R., et al. Cushing’s Syndrome with Accessory Adrenocortical Tissue, J.A.M.A., 186:799, 1963.
8. CHRISTY, N. F. Adrenocorticotrophic Activity in the Plasma of Patients with Cushing’s Syndrome Asso-
ciated with Pulmonary Neoplasms, Lancet, 1:85, 1961.
9. Editorial: The Syndrome of Intrathoracic Neoplasia with Bilateral Hyperfunction of the Adrenal Cortex, Ann. Int. Med., 54:1295, 1961.
10. HYNES, A. C., and R. P. DOE. Adrenal Function in Cancer of the Lung, With and Without Cushing’s Syndrome, Am. J. Med., 33:398, 1962.
11. JARRETT, L., P. E. LACY and D. M. KIPNIS. Char- acterization by Immunoflourescence of an “ACTH- like” Substance Produced by Non-Pituitary Tumors, (Abstract) Am. J. Path., 43:11a, 1963 .
12. KOVATCH, R. D. and L. H. KYLE. Cushing’s Syn- dome and Bronchogenic Carcinoma, Am. J. Med., 24:981, 1958.
13. LIDDLE, G. W. et al. Nonpituitary Neoplasms and Cushing’s Syndrome, Ann. Int. Med., 111:471, 1963.
14. MARKS, L. J. et al. Carcinoma of the Lung Asso- ciated with Marked Adrenocortical Hyperplasia and Adrenal Hyper-responsiveness to ACTH in the Ab- sence of Cushing’s Syndrome, Ann. Int. Med., 54: 1243, 1961.
15. MARKS, L. J. et al. Corticotrophin-secreting Car- cinoma, J.A.M.A., 183:115, 1963.
16. MEADOR, C. K. Cause of Cushing’s Syndrome in Patients with Tumors Arising from “Non-endo- crine” Tissue, J. Clin. Endocrin., 22:693, 1962.
17. NICHOLS, J. and W. GOURLEY. Adrenal. Weight- Maintaining Corticotrophin in Carcinoma of Lung, J.A.M.A., 185:696, 1963.
18. RIGGS, B. L. and R. G. SPRAGUE. Association of Cushing’s Syndrome and Neoplastic Diseases, Arch. Int. Med., 108:841, 1961.
19. WERK, E. E. and L. J. SHOLITON. Adrenocortical Function in Carcinoma of the Lung, Cancer, 13:469, 1960.
20. ESCOVITZ, W. E. and I. M. REINGOLD. Functioning Malignant Bronchial Carcinoid with Cushing’s Syn- drome and Recurrent Sinus Arrests, Ann. Int. Med., 54:1248, 1961.
21. COHEN, R. B., G. D. TOLL and B. CASTLEMAN. Bronchial Adenomas in Cushing’s Syndrome: Their Relation to Thymomas and Oat-Cell Carcinoma Associated with Hyperadrenocorticism, Cancer, 13: 812, 1960.
22. WOLF, J. et al. Nitrogen Mustard and the Steroid Hormones in the Treatment of Inoperable Bron- chogenic Carcinoma, Am. J. Med., 29:1008, 1960.
23. AMATRUDA, T. T. et al. Carcinoma of the Lung with an Inappropriate Anti-diuresis, N.E.J.M., 269: 544, 1963.
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