INTRODUCTION

Between 1928 and 1961 there appeared in the medicalliterature over 40 well-documented cases of hyperadrenocorticism associated with tumors arising from “nonendocrine― tissues (1, 2, 4). Whether the relationship betweenthe tumor and the endocrinologic disorder was causal ormerely coincidental remained obscure, however, until itwas discovered in 1961 that the plasma (5, 13) and tumors(8, 13) of such patients contained a substance having biologic activity indistinguishable from that of ACTH.These observations have since been confirmed in severallaboratories (6, 7, 10, 11, 14—18).

Through the generous collaboration of the phySicianslisted in Table 1, our own laboratory has had an opportunity to assemble data and measure the tumor ACTH activity of 37 patients having the disorder that we now referto as the “ectopicACTH syndrome.― The tumors wereof diverse origin. Histologically, they were of no uniformpattern and bore no particular resemblance to pituitarytissue. In all of the patients in whom appropriate studies were performed, plasma ACTH and plasma and unnary 17-hydroxycorticosteroids (17-OHCS) were elevatedand could not be suppressed by the administration of thepotent synthetic corticoid, dexamethasone. ACTH activity was found in extracts of each tumor but could notbe found in extracts of nontumorous tissues. The concentration of ACTH in the pituitary glands was subnormal

1 These studies were supported in part by grants-in-aid from

the NIH, USPHS (AM-05318, T1-AM-5092, 8M01-FR-95, and5-K6-AM-3782).

2 The abbreviations used are : ACTH, adrenocorticotropic hor

mone; MSH, melanocyte-stimulating hormone; 17-OHCS, 17-

hydroxycorticosteroids; 17-KS, 17-ketosteroids.

in all but one of the cases in which this determination wasperformed.

DIAGNOSTIC CRITERIA

It should not be assumed that every patient with atumor of “nonendocrine―tissue who has hyperadrenocorticism is an example of the ectopic ACTH syndrome. Inorder for an unequivocal diagnosis of the ectopic ACTHsyndrome to be established, it is essential that ACTH befound iii significant quantities in a tumor arising from sometissue other than the pituitary gland. In the absence ofpositive evidence of tumor ACTH, one can make only apresumptive diagnosis. The presumption is extremelystrong, however, if it is found that the patient has supernormal levels of ACTH in his plasma and that his secretionof cortisol cannot be diminished by the administration oflarge doses of dexamethasone. The combined use ofplasma ACTH assays and pituitary-adrenal suppressiontests (9) is of considerable value in arriving at a precisediagnosis of the cause of Cushing's syndrome (Table 2).Case No. 37, studied by Dr. Thomas B. Connor of Baltimore, illustrates the point very well. This man developedCushitig's syndrome early in 1963. When he was firststudied in August of that year his plasma ACTH levelswere distinctly elevated at 1.7 mU/100 ml and his plasmaand urinary 17-OHCS were unaffected by the administration of 4 mg of dexamethasone every 6 hr for 2 days. Thesella turcica was normal. Although a presumptive diagnosis of the ectopic ACTH syndrome could be made on thebasis of the combined abnormalities of high plasma ACTHand nonsuppressible 17-OHCS, thorough study revealedno other evidence of neoplastic disease. Because of theseverity of the Cushing's syndrome, it@ elected to per

1057

The Ectopic ACTH Syndrome1

GRANT W. LIDDLE, JAMES R. GIVENS, WENDELL E. NICHOLSON, DONALD P. ISLAND

(Department of Medicine, Vanderbilt Univer.@ity School of Medicine, Nashville, Tennes8ee)

SUMMARY

The clinicopathological entity to which we have attached the name of the “ectopicACTH syndrome―can no longer be considered a rarity. With increasing frequency itis recognized that certain tumors (arising in such diverse sites as the lung, liver, parotid,and even neural tissue) can sometimes produce a hormone that is biologically, physically, chemically, and immunologically indistinguishable from human pituitaryadrenocorticotropic hormone (ACTH).2 Through its action on the adrenal glands thisectopic hormone can cause all of the chemical and clinical abnormalities of Cushing'ssyndrome. Unlike pituitary ACTH, ectopic ACTH is not suppressible with dexamethasone. Ectopic ACTH is usually associated with a separate ectopic MSH, andoccasionally it is produced in association with other ectopic hormones similar togastrin, parathyroid hormone, or anti-diuretic hormone. It is tempting to speculatethat many of the now obscure manifestations of malignancy might someday be understood in terms of the noxious effects of tumor products which are carried like hormonesto other 1)art.S of the body where they exert unwanted effects.

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TABLE 1

STEROID AND ACTH DATA FROM 37 CASES OF “ECTOPICACTH SYNDROME―@

@ Smiom @.ss.&ys ACTH ASSAYS

PATIZNT COLLABORATOR TUMOR si@z

Normal adults5—253—125—20<0.5—39-105

1058 Cancer Research

Urinary17-KS(mg/day)

Plasma17.OHCS(pg %)

Urinaryl7.OH@S(mg/day)

Plasma(mU%)

Tumor(mU/gm)

Pituitary(mU/mg)

1234

56789

10111213141516171819202122232425262728293031323334353637

LungLungPancreasLungMediastinumLungLungParotidLungLungLungPheochromocytomaLungLungLungLungLungOvaryLiver (child)PancreasProstateGanglioma (infant)LungLungLungParagangliomaLungPancreasBreastEsophagusLungLungPancreasLungPancreasPheochromocytomaThymoma

2321480.13

1258.31.00.050.270.360.6

280.430.010.041.70.570.350.17

220.680.590.440.340.243.00.021.32.40.20.30.31220.100.238.7

5950

13590

12011642

>15010013061

28450734451

15210020048

>100638.4

69100

606348804241793640

115200

J. A. LuetscherC. K. MeadorD. M. KipnisF. L. EngelF. L. EngelD. M. KipnisD. A. ScholzD. M. KipnisR. P. DoeR. L. NeyR. L. NeyD. M. Kipnis0. P. SchumacherR. L. NeyR. L. NeyH. A. Tretbarw. S.NesbitJ. A. LuetscherP. H. HennemanJ. E. JohnsonL. Jarettw. T.DobbinsN. KaplanA. L. GraberA. LabhartC. R. MeloniI. JohnsonD. H. Laww.C.LivingstonF. N. LohrenzJ. A. Grauel

C. R. GhermanD. W. ElliottC. K. MeadorR. M. SalassaJ. BourgoignieT. B. Connor

445885

10626

>125316034

14150523738

110

775.6

>100362.5

5463

3672

119401239351242

5741

67

84

247771807130

118374061

54

576751

120

79

25035445177

62100

0.727

1.80.8

2.4

7013

18

19

4.56.0

132.90.71.32.01.01.71.30.40.881.2

0.47

120.59

11

0.94

1.4

1.1

25

3 Additional information has been published elsewhere with respect to the following patients : Nos. 1—13, Reference 10 and bibli

ography thereof; No. 16, Reference 18; No. 36, Reference 3.

formbilateraladrenalectomy.Bothglandswerehyperplastic. Postoperatively, although the patient felt welland was maintained on 50 mg of cortisone daily, his plasmaACTH levels rose to 10—20mU/100 ml, and he becamedeeply pigmented. One year after the adrenalectomy hadbeen performed, the patient was found by X-ray to have amediastinal tumor. The tumor, a thymoma, was removedsurgically and was found to contain a very high concentration of ACTH. Postoperatively the plasma ACTH levelsfell quickly. The hyperpigmentation faded noticeablywithin a week and almost disappeared within 2 months.A portion of the tumor was grown in tissue culture andcontinued to produce ACTH for several weeks.

Clinical features of the syndrome.—The clinical featuresof the ectopic ACTH syndrome are sometimes subtle, andthe diagnosis is undoubtedly missed with considerable frequency. The condition is not rare, however. Of 36 casesof Cushing's syndrome studied at Vanderbilt UniversityMedical Center between 1961 and 1964, 19 were due toexcess pituitary ACTH, 8 were due to primary adrenocortical tumor, and 9 were due to ectopic ACTH. Of the9 cases, only 2 had the classical clinical appearance ofCushing's syndrome. The others were diagnosed onlybecause the physicians in the local community had beenalerted to the possibility that their patients with neoplasticdiseases might have occult hyperadrenocorticism. When

Vol. 25, August 1965

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Plasma ACTH,basal017.OHCS, basale17-OHCS

in response todexamethasone(O.Smgq6hr)17-OHCS

in responsetodexamethasone

(2—8mgq6hr)NormalNormalNormalCompletely

suppressedCompletelysuppressedCushing'ssyndrome dueHighHighUnsuppressed orPartially or com

to excess pituitarypartiallypletelysuppressedACTHsuppressedCushing's

syndromedueLowHighUnsuppressedUnsuppressedtoautonomousadrenaltumorCushing's

syndromedueHighHighUnsuppressedUnsuppressedtoectopic ACTH

LIDDLE et al.—Ectopic ACTH Syndrome

TABLE 2CHARACTERISTICPATTERNSOF ACTH AND17-OHCS IN PATIENTS WITH VARIOUSDISORDERSLEADING

TO CUSHING'S SYNDROME

1059

a Individual basal values can overlap with normal, and one must take into consideration the normalcircadian rhythm of ACTH and 17-OHCS production if the statements made in this table are to betaken literally.

cancer patients have been found to have edema, hypokalemia, or impaired glucose tolerance, an effort has beenmade to obtain measurements of their plasma and urinary17-OHCS. When the 17-OHCS have been elevated, anattempt has been made to perform pituitary-adrenal suppression tests and assays of plasma and tissues for ACTH.

Compared with patients with other varieties of Cushing's syndrome, those with the ectopic ACTH syndromeare more likely to exhibit extreme elevations of plasma andurinary 17-OHCS, and they are more likely to have hypokalemia and edema. They are less likely to exhibit obesity, striae, and osteoporosis. They are about equallylikely to exhibit impaired carbohydrate tolerance and ecchymoses.

The probable explanation for the above differences canbe found in the facts that the patients with the ectopicACTH syndrome tend to have higher levels of plasmaACTH, poorer food intake, and shorter periods of survivalthan do patients with other varieties of Cushing's syndrome. Those who survive long enough and eat enoughdo develop florid Cushing's syndrome. Only a minorityof patients with the ectopic ACTH syndrome are females,but among them the manifestations of androgen excesssuch as hirsutism, acne, and oligomenorrhea are at leastas frequent as in women with Cushing's syndrome due toexcess pituitary ACTH or to primary adrenocortical tumors.

RESPONSES TO TREATMENT

With a few salubrious exceptions the treatment of theectopic ACTH syndrome has been unrewarding. Theendocrinologic aspect of the problem is manageable, butthe great majority of tumors that secrete ectopic ACTHarise in or metastasize to locations that are surgically inaccessible. Of the 37 patients listed in Table 1, 34 diedwithin 1 month to 6 years of the initial onset of symptoms.

Surgical removal of the neopla.sm.—This has been accomplished with apparent cure of the ectopic ACTH syndromein Cases 12, 26, and 37. Still another patient (No. 5) wastemporarily benefited by subtotal excision of an ACTHproducing mediastinal carcinoma. The fact that removal

of such a tumor corrects the metabolic disorder has morethan clinical significance; it provides an essential link inthe chain of reasoning which holds that the tumor is ofprimary etiologic importance and not merely coincidentalwith the metabolic disorder.

Surgical removal of the pituitary gland.—This has beenaccomplished in 2 cases without correcting the hyperadrenocorticism. One patient was studied by Dr. Frank H.Tyler of the University of Utah (personal communication),the other by Drs. Mattingly et al. of Great Britain (12).These important observations offer strong evidence in support of the idea that the tumor rather than the pituitarygland is the source of the ACTH in this syndrome.

Total bilateral adrenalectomy.—When performed in 2cases (Nos. 3 and 37), this operation resulted in correctionof hypercorticism without altering the plasma ACTH level.A 3rd patient (No. 5) experiencedtemporary alleviation ofher hypercorticism following subtotal adrenalectomy.Whether, in a given case, adrenalectomy is worthwhile depends upon the severity of the hypercorticism and theprognosis of the neoplastic disease. It is obvious that theonly way to cure both the neoplastic and metabolic disorders is to remove the neoplasm. Nevertheless certainpatients, even though not cured by adrenalectomy, candoubtless be helped temporarily by this procedure. Furthermore, it should be pointed out that 2 of the apparent“cures―cited above were achieved when, in the course ofadrenal surgery, ACTH-secreting tumors were found arising from the adrenal medulla.

Other therapeutic measures, such as roentgen ray therapy and cytotoxic agents directed toward the neoplasm or0 ,p'-DDD and Metopirone used to reduce adrenal synthe

sis of cortisol, have been ineffective in altering the downhill courses of the patients listed in Table 1.

CHARACTERIZATION OF TUMOR “ACTH―

Because of the very limited quantity of the ectopicACTH available for study, it has not been possible to perform an analysis of its amino acid composition. However,in a wide variety of test systems the tumor ACTH has beenfound to be indistinguishable from pituitary ACTH. The

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1060 Cancer Research Vol. 25, August 1965

the serum of a rabbit immunized with human pituitaryACTH (Raben) has been found to neutralize human pituitary ACTH (Raben) and tumor ACTH, while failing toneutralize porcine ACTH and rabbit ACTH. These observations suggest that the tumor ACTH might have achemical structure very similar to that of human pituitaryACTH.

MULTIPLE ECTOPIC HORMONES

That tumors which produce ectopic ACTH often produce other ectopic hormones as well has received littleemphasis.

Whenever adequate studies have been performed, all ofthe ACTH-producing tumors have been found to containa separate fraction that is chemically and biologically similar to pituitary melanocyte-stimulating hormone (MSH).A method recently developed for separating pituitaryMSH from pituitary ACTH has also proved to be of value111 separating “tumor MSH― from “tumor ACTH.―Briefly, the technic is one of applying the hormone mixtureto a column of SE-Sephadex in acid solution, theti elutingwith progressively more alkaline solvents. In this procedure, MSH (human or nonhuman) appears in Fraction I(pH 4.8—6.2),while pituitary ACTH (human or nonhuman) appears in Fraction III (pH 8.1—10.0). Similarly,tumor MSH activity is recovered largely in Fraction I andtumor ACTH activity in Fraction III.

Evidence for the production of still other ectopic hoemones has beeti found in the following patients from theVanderbilt University Hospital series.

Patient No. 28 was a woman with pancreatic carcinomaand severe hyperadrenocorticism. Plasma ACTH washigh and was not suppressible with large doses of dexamethasone. Both “ACTH―and “MSH―were found inthe tumor. Of additional interest, this patient also hadsevere and dramatic manifestations of the Zollinger-Ellisonsyndrome. A very high concentration of a material whichwas biologically and chemically indistinguishable from gas

triti was extracted from the tumor and partially characterized by Dr. Stuart Tauber of Dallas.

Patient No. 15 was a man with oat-cell carcinoma of thelung, hypercortisolism, and high nonsuppressible levels ofl)la.sma ACTH. Both “ACTH―and “MSH―were cxtracted from the tumor. Indirect evidence suggested thatthe tumor was also elaborating an anti-diuretic hormone.Unless fluid intake was i-igidly restricted, the patient'sserum osmolality fell to 250 mOsm/kg (serum Na@115mEijliter) while his urine remained very concentrated atapproximately 1000 mOsm/kg. Although attempts todemonstrate vasopressin in the tumor tissue of this patientwere unsuccessful, it. is conceivable that the tumor mighthave elaborated anti-diuretic substances other than vasopres.sin.

Patient No. 2, previously reported by Meador el al. (14),had an oat-cell carcinoma of the lung, nonsuppressihiehypersecretion of cortisol, and high concentrations ofplasma “ACTH.―Both “ACTH―and “MSH―were cxtracted from the tumor. This patient also had markedand persistent hypercalceniia, hypophosphatemia, hypercalciuria, and hyperphosphaturia. At postmortem examination, the parathyroid glands were normal in appearance,

TABLE 3PROPERTIES COMMON TO PITUITARY ACTITI AND TUMOR ACTH

1. Stimulation of adrenocortical enlargement.2. Stimulation of corticosterone secretion in hypophysectomized

rat.3. Stimulation of adrenal ascorbic acid depletion in hypophysec

tomized rat.4. Stimulation of cortisol, corticosterotie, and 17-ketosteroid

production in man.5. Melanocyte-stimulating activity in in vitro frog skin prepa

ration and in hypophysectomized frog.6. Release of free fatty acids in adipose tissue incubates.7. Extractable from tissue with glacial acetic acid.8. Precipitable from acetic acid with acetone-plus-ether.9. Adsorbable onto IRC-50 from dilute acetic acid.

10. Can be eluted from IRC-50 with 50% acetic acid.11. Adsorbable onto oxycellulose from dilute acetic acid.12. Can be eluted front oxycellulose with 0.1 N IICl.13. Behavior during counter current distribution.14. Separable from MSH by chromatography on SE-Sephadex.15. Dialyzable only in acid medium.16. Inactivation by trypsin and chymotrypsin.17. Lability in unheated human plasma.18. Relative stability in acid and lability in alkali.19. Inactivated by hydrogen peroxide; reactivated by cysteine.20. Irreversibly inactivated by periodate.21. Neutralization by ACTH antisera.

common properties of ectopic ACTH and pituitary ACTHare suflTlmalized in Table 3.

Recent immunologic studies have been especially informative in suggesting a close similarity between tumorACTH and human pituitary ACTH. Using as antigensporcine Ol@human ACTH @)altiallypurified on oxycellulose,it has beeii possible to develop a series of antisera in bothguinea pigs and rabbits. The capacity of antiserum toneutralize ACTH activity has been tested by incubatingan ACTH preparation with the antiserum in a phosphatebuffer, then injecting the mixtui-e into hypophysectomizedrats and observing the ensuing effect on corticosteronesecret ion . As a control, serum from a nonimmunizedguilleit pig oi rabbit has been incubated with identical(luatitities of the same ACTH preparation and then assayed in the same manner.

In our experience, the antisera from guinea pigs have notbeen highly specific in their neutralizing activity. Althoughthey have not neutralized short-chain ACTH preparationsSUCh as C. H. Li's at-'9ACTH or a'26-ACTH, they have

indiscriminately neutralized all of the longer chain preparations such a-s R. Schwyzer's synthetic j9'@-corticotropin,porcine ACTH, monkey ACTH, human pituitary ACTHprepared by M. Raben, and tumor ACTH. These antisera have also beeii found to neutralize the ACTH foundin the pla.sma of 1 patient with the ectopic ACTH syndrome and of 2 patients who developed pituitary tumorsand hyperpigmentation after undergoing bilateral adrenalectomy as treatment for Cushing's disease.

On the other hand, certain rabbit antisera have beenmuch more specific. The serum of a rabbit immunizedwith porcine ACTH has been found to neutralize the activity of porcine ACTH while failing to neutralize eitherhuman pituitary ACTH or tumor ACTH. Conversely,

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LIDDLE et al.—Ectopic ACTH Syndrome 1061

hut extracts of the lung tumor have since been found byDr. Armen Ta.shjian of Boston to contain a material thatbehaves serologically Iike parathyroid hormone.

ACKNOWLEDGMENTThe authors are deeply grateful to all of the collaborators listed

in Table 1 for providing the clinical data and specimens for thepresent study. The cooperation of Dr. H. C. Meng in performingthe assays of free fatty acid-releasing activity is gratefully acknowledged.

ItEFEHENCES1. Allott, E. N., and Skelton, M. 0. Increased Adrenocortical

Activity Associated with Malignant Disease. Lancet, @:278—83,1960.

2. Bagshawe, K. 1). Hypokalemia, Carcinoma and Cushing'sSyndrome. Ibid., @:284-87, 1960.

3. Bourgoigne, J., l)upont, .J. C., and Noiret, H. Association d'unpheochromocytome et d'utt hypercorticisme du type Cushingavec hyperaldosterontLrie. Ann. Endocrinol. Paris, @5:269—84,1964.

4. Brown, W. H. A Case of Pitiriglandular Syndrome: “J)iahetesof Bearded Women.― Lancet, 2: 1022—23, 1928.

,5. Christy, N. P. Adrenocorticotropic Activity in the Plasma ofPatients with Cushing's Syndrome Associated with PulmonaryNeoplasms. Ibid., 1: 85—86,1961.

6. Engel, F. L., and Kahana, L. Cushing's Syndrome withMalignant Corticotropin-producing Tumor. Am. J. Med.,34: 726—34,1963.

7. Hallwright, G. P., North, K. A. K., and Reid, J. D. Pigmentation and Cushing's Syndrome Due to Malignant Tumor of thePancreas. J. Clin. Endocrinol. Metab., 24: 496—500,1964.

8. Holub, D. A., and Katz, F. H. A Possible Etiologic Link hetween Cushing's Syndrome and Visceral Malignancy. Clin.Ees.,9: 194,1961.

9. Liddle, G. W. Tests of Pituitary-Adrenal Suppressibility inthe Diagnosis of Cushing's Syndrome. J. Clin. Endocrinol.Metab., 50: 1539-60, 1960.

10. Liddle, G. W., Island, D. P., Ney, H. L., Nicholson, W. E.,and Shimizu, N. Nonpituitary Neoplasms and Cushing'sSyndrome. Arch. Internal Med., 3: 471—75,1963.

11. Marks, L. J., Rosenbaum, D. L., and Russfield, A. D. Cushing's Syndrome and Corticotropin-secreting Carcinoma ofthe Lung. Ann. Internal Med., 58: 143—49,1963.

12. Mattingly, I)., Keane, P. M., McCarthy, C. F., and Read,A. E . Adrenocortical Hyperfiinctioii and Oat-Cell Carcinomaof the Bronchus. Bristol Medico-Chirurgical J., 79: 6—14, 1964.

13. Meador, C. K., Island, I). P., Nicholson, W. E., Nuckton,j. G. , Lucas, C. P., Luetscher, J. A., and Liddle, G. W. SevereCushing's Syndrome Apparently l)ue to Corticotropin Seereting Oat Cell Carcinoma. Proc. of The Endocrine Society,

Abstract162,1961.14. Meador, C. K., Liddle, U. W., Island, 1). P., Nicholson, W. E.,

Lucas, C. P., Nuckton, J. U., and Luetscher, J. A. Cause ofCushing's Syndrome in Patients with Tumors Arising from“Nonendocrine― Tissue. J. Cliii. Endocrinol. Metab., @5:693—703,1962.

15. Nichols, J., Warren, J. C., and Mantz, F. A. ACTH-Iike Excretion from Carcinoma of the Ovary. J. Am. Med. Assoc.,182: 713—18,1962

16. Pfohl, R. A., and Doe, H. P. Adrenal-Pituitary Studies in aPatient with Bronchogenic Carcinoma and Cushing's Syndrome. Ann. Internal Med., 58: 993—1002,1963.

17. Scholz, D. A., Riggs, B. L., Bahn, R. C., and Liddle, G. W.Adrenocortical Hyperfunction Associated with a Corticotropin Secreting Bronchogenic Carcinoma. Proc. Staff Meetings Mayo Clinic 58: 45-66, 1963.

18. Tretbar, H. A., and Cawley, L. P. Ctishing's Syndrome. J.Kansas Med. Soc.,64:487—90,1963.

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1965;25:1057-1061. Cancer Res   Grant W. Liddle, James R. Givens, Wendell E. Nicholson, et al.   The Ectopic ACTH Syndrome

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