Adrenal cortical hyperfunction associated with bronchogenic carcinoma

Adrenal

Cortical

Hvperfunction J I

with Bronchogenic H. G. MCDANIEL,~

J. A. PITTMAN,

M.D.,

Birmingham,

I

N 1928 Brown described Cushing’s syndrome associated with a nonendocrine tumor [I], and since then there have been a number of such cases reported in association with many different ty.pcs of tumors. The most common concurrent malignancy is bronchogenic carcinoma, which in almost every case is of the oat cell type. The next most common tumor is thymoma, and the third is carcinoma of the pancreas [ 21. Cushing’s syndrome has also been reported in association with carcinoma of the gallbladder [3], prostate [JI], thyroid [S], kidney [S], colon [ 71, trachea [8], pheochromocytoma [6,9,/O], sympathicoblastoma [ 771 and bronchial adenoma [ /_?]. These reports have stimulated interest in the relationship between hyperactivity of the adrenal cortex and neoplasms. The following case, concerning a man with oat cell carcinoma of the lung and increased adrenal steroid production, resembles a number of others reported in that the patient lacked the classic physical findings of Cushing’s syndrome an increased urinary excretion of despite 17-hydroxycorticosteroids (17-011). The individual Cts and Csr steroids have been chromatographically separated and quantitated (see Chart I for nomenclature), and the results compared \yith those obtained in normal subjects before and after the administration of ACTH (adrcnocorticotropic

REPORT

The patient (E. V.) was a sixty-nine year ambulatory white man who was admitted to Birmingham Veterans Administration Hospital May 5, 1959, because of an episode of “heaviness” his arms and chest pain which had persisted for or three hours the night prior to admission.

Carcinoma* S. R.

HILL,

M.D. and W.

R.

STAKNES

Alabama administration of nitroglycerin did not relieve the pain and, during this episode, he had dyspnea, palpitations and hypotension. Past history revealed that he had had hypertension for seventeen years, and dyspnea on exertion and angina pectoris for four years. His blood pressure was in the range of 180/100 mm. Hg despite therapy with Serpasil,@ 0.5 mg. per day, for the past four years. One week before admission, his doctor had noticed bilateral pedal edema and had prescribed 1 gm. of chlorothiazide daily. The physical examination revealed a well developed, obese, white man. He was well oriented although somewhat dyspneic during questioning. The blood pressure was 220/104 mm. Hg, pulse 108 and regular, respirations 24 per minute. and the temperature was normal. Numerous senile keratoses were present over the trunk, fac:e and arms. The fundi showed nicking of the veins at arterial junctions but no hemorrhages or exudates. Moist inspiratory rales were heard over the bases of both lungs. l‘he cardiac point of maximal impulse was at the midclavicular line in the sixth intercostal space. A grade 1 systolic murmur was heard along the left sternal border. The femoral pulses were strong. ‘fhe liver edge was palpable 3 cm. below the right costal margin. No striae, pedal edema, buffalo hump, central obesity, rounding of the face or neurologic abnormalities were present. The hematocrit was 52 vol. per cent, white blood count 17,000 per cu. mm., blood urea nitrogen 32 mg. per cent and the venous pressure was I1 5 to 130 mm. of normal saline solution. The arm to tongue circulation time (Decholin’@) was eighteen to twrntytwo seconds. The serum electrolyte values were sodium 144 mEq. per L., chloride 113 mEq. per L., potassium 5.2 mEq. per L. and carbon dioxide combining power 24 mEq. per L. The serum transaminase level was 16 and 41 units on two occasions. An electrocardiogram obtained on admission showed no abnormality. Cardiomegaly and loculated fluid in the right minor fissure were noted on the chest film. A two-hour postprandial blood sugar was 93

hormone). CASE

Associated

old the on in two The

* From the Radioisotope and Medical Services, Veterans Administration Hospital, Birmingham, and the lIepartment of Medicine, University of Alabama Medical Center, Birmingham, Alabama. This work was support4 by funds from U. S. Public Health Service Grant CY-5301, the Veterans Administration Endocrine Cooperative Study, and a grant from the G. D. Scarlr Co. Manuscript received August 13, 1962. t CJ. S. I’. H. S. Post-Junior Research Fellow. VOI..

35 . SI’.PTI’MRK’.R

1963

427

428

Bronchogenic Carcinoma and Adrenocortical Hyperactivity-McDaniel TABLE

VALUES

FOR

TOTAL

URINARY

I

17-HYDROXYCORTICOSTEROIDS,

Date

Volume (ml. /24 hr.)

Creatinine (gm./24 hr.)

6/29/59 * 7/l /59 7/4/59

900 839 3,320

1.42 1.13 1.71

17-KETOSTEROIDS

ALDOSTERONE

(blue tetrazolium)

1 (mi.7/2yhr.)

26.2 25.86 23.46

18.0 16.7 18.33

6+5 I

AND

Aldosterone

1 (rn~7$?tr.)

Normal values + 1 S. D. t I

et al.

4.7 14.8 10.0

15 + 5

6.6

t

1.9

I

I

* Average of a forty-eight hour pool. This urine specimen was collected before spironolactone was started. The only medications the patient was receiving were a diuretic (acetazolamide) and digitalis. The second and third specimens were collected during spironolactone administration. The patient appeared comfortable during these periods despite his edema. 7 For this laboratory.

mg. per cent. An x-ray series of the gastrointestinal tract revealed a small sliding hiatal hernia and probable antral gastritis. Subsequent chest films revealed a peripheral homogenous density and hilar enlargement on the right, suggestive of carcinoma. While in the hospital the patient had numerous episodes of rapid heart rate, usually appearing thirty minutes after eating. Pedal edema developed (2 plus) refractory to therapy with digitalis, meralluride acetazolamide (Diamox@). (Mercuhydrin@) and Orthopnea occurred at the same time and he was

TABLE Co,

URINARY

II

STEROlD

PATTERN

- -iPer Cent of- Total Value Patient (E. V.) Steroid

Normal Subjects

*

/

Steroid

6,129/591 -7 ‘/4/5(

(2”“. tro1

ACTH

1.4 35 1.2 0.9 5.7 4.6

1.5 3.0 1.7 0.6 6.1 6.2

(day 2)

A THA (a and 0)

0 4.4

B THB E

0 37 0

(a and

6)

THE and a-THF F THF THS $HQ THF:THEratic.

,

30.9 5.4 40.3 77 0 0 1.30

0 32

10.6 0.1 il.6 7.3 7.2 4.6 4.87

A

THA a-THA B THB u-THB E THE F THF u-THF THS THF:THE rzItio

43 3 0.5 3.6 2 3.7 1 1.5 2.8 l.li

20 20.5 6.5 30.5 10 0 5.6 1.97

NOTE: The dates and conditions of collection of specimens are as given under Table I. The values durina ACTH stimulation. with their controls, were obtained on urine specimens obtained from fifteen healthy young and middle-aged men. After collecting the control urine, ACTH was given at eight hourlv intervals. 80 U.S.P. units of the eel intramusc&ly per inJ:ction, fdr two days, and the “ACTH ori& was collected the second day. * See Chart I for abbreviations. t Average of a forty-eight hour pool.

considered attempt

to was

be

made

in

congestive

to induce

heart

diuresis

failure. with

the

An oral

administration of spironolactone (Aldactone@), 100 mg. every six hours. Control urine samples were collected for determination of baseline steroid excretion levels before spironolactone was administered. He was then given spironolactone for five days (June 30 to July 4), then it was discontinued because of the development of a pruritic rash. He was given 1 ml. of meralluride sodium intramuscularly with the last dose of spironolactone, and over the following eighteen hours diuresis occurred and he lost 7 pounds. On the following night he complained of severe chest pain and shortness of breath. A few minutes later he was found pulseless; he died despite all efforts to resuscitate him. No anticoagulants were administered. The autopsy revealed an anaplastic bronchogenic carcinoma, oat cell type, arising from the bronchus of the lower lobe of the right lung. The tumor had spread to the hilar area, periaortic nodes and adrenal glands. Distal to the carcinoma were multiple abscesses of the lung. There was a small organizing infarct in the lower lobe of the right lung, near the minor fissure. The heart weighed 620 gm., and both ventricles were hypertrophied. There was moderate atherosclerosis of the coronary arteries. White fibrous patches were present in the myocardium of the left ventricle. No recent infarct was detectable. The right adrenal weighed 23 gm., the left 50 gm. after trimming. Both adrenal glands had extensive matastases, with only a rim of normal adrenal tissue remaining. Microscopically the architecture of the cortex was distorted and it was difficult to be sure whether or not it was hyperplastic. The calyces and pelves were not dilated. There was no obstruction of the inferior vena cava by tumor growth. The head was not included in the autopsy. Urinary steroid levels are given in Tables I, II and III. AMERICAN

JOURNAL

OF

MEDICINE

Bronchogenic

Carcinoma

and Adrenocortical

Hyperactivity-McDaniel

CHART STEROID

429

et al.

I

NOMENCLATURE

Etiocholan-3cu-o&17-one Androsten, 3or-01, 17-one 5-Androsten-38-01, 17-one Etiocholan-3cu-ol, 11,17-dione Androstan-3or-ol, 11,17-dione Androstan-3q IlP-diol, 17-one Etiochoian-3@, llp-diol, 17-one

(Etiocholanolone) (Androsterone) (Dehydroepiandrosterone) (11 -ketoetiocholanolone) (11-ketoandrosterone) (1 lp-hydroxyandrostcrone) (IlP-hydroxyetiochoianolone) CZI Steroids

A THA allo-THA B THB allo-‘I’HB E THE allo-THE F THF allo-‘1’HF S TSH ?&IQ allo-THQ

4-Pregnene-21-01, 3,11,20-trione 58 pregnane-3rw, 21-diol-118, 20-dione 5a pregnane-3or, 21-diol-1 I@, 20-dione 4-Pregnene-116, 21-diol-3, ZO-dione 5@ pregnane-3m, 118, 21 -triol-20-one 5cu pregnane-3ol, llp, Zl-trio]-20-one 4-Pregnene-1701, 21-dial-3,11,20-trione 58 pregnane-3or, 1 SLY,21 -triol-11,20-dione 50( pregnane-3ol, 17a, 21-triol-11,20-dione 4-Pregnene-II@, 17~u, 21-triol-3,20-dione 5p pregnane-3ol, 118, 17ru, 2l-tetrol-20-one 5~ypregnane-3cu, 118, 1701, 21-tetrol-ZO-one 4-Pregnene-17rr, 21-dial-3, 20-dione 50 pregnane-3ol, 17a, 21-triol-20-one 4-Pregnene-21-01-3, 20-dione 5p pregnane-3cu, 21-dial, 20-dione 5a: pregnane-3cr, 21-dial, 20-dione

COMMENTS

The clinical picture seen in patients with hyperadrenalcorticism and a nonendocrine tumor is variable. Edema, polyuria and polydipsia are usually present. Diabetes mellitus is almost always found, as is hypertension. The classic physical findings of Cushing’s syndrome have been present in only about half the cases reported. This is said to be due to the fact that hyperadrenocorticism was not present long enough for the classic signs of Cushing’s syndrome to have deveIoped, since most of these patients have a rapidly fatal course. In fact there is some evidence indicating that the administration of cortisone accelerates the course of bronchogenic carcinoma [ 731. These patients are usually older than those with ordinary Cushing’s syndrome, and there is no female predominance. The tumors found in association with Cushing’s syndrome have already been mentioned. It is of interest that oat cell carcinoma of the lung, which makes up only 9 per cent of bronchogenic carcinomas [Id], has been found in case of Gushing’s syndrome almost every VOL. 35 . SEPTEMBER 1963

(II-dehydrocorticosterone) (Tetrahydro-ll-dehydrocorticosterone) (allo-Tetrahydro-ll-hydrocorticosteronc) (Corticosterone) (Tetrahydrocorticosterone) (allo-Tetrahydrocorticosterone) (Cortisone) (Tetrahydrocortisonc) (allo-Tetrahydrocortisone) (Cortisol) (Tetrahydrocortisol) (allo-Tetrahydrocortisol)

(11-Deoxycortisone) (Tetrahydro-1 I-deoxycortisone:) (11 -Deoxycorticosterone) (Tetrahydro-11-deoxycorticosterone) (allo-Tetrahydro-11 -deoxycorticosterone)

reported in association with cancer of the lung. Cohen et al. reported that the thymomas seen with Cushing’s syndrome are composed entirely of epithelial cells [ 121. They found that two TABLE CI~ URINARY

III

STEROID

PATTERN

(Per Cent of Total Value) 7-

Patient (E. V.)

Normal

Subjects

Steroid 6 /29/55 l/4/51

OHE OHA OE OA CL903 total DHEA E A Cl.302 total E : A ratio

15.8 10.4 18.3 11.8 56.3 0 11.2 6.4 17.6 1.75

16.6 59.0 0 0 75.6 0 10.2 4.7 14.9 2.1(

Zontrol

7.6 7.0 8.1 7.3 30.0 15.2 27.0 17.9 60.1 1.50

/I 9CT13 (day 2) 11 .‘) 9.4 15.4 6. 1 42.8 13.0 22.7 13.6 49 .3

1.67

Nom: See legends of previous tables and Chart I for abbreviations.

430

Bronchogenic

Carcinoma

and Adrenocortical

bronchial adenomas in patients with Cushing’s syndrome closely resembled the thymomas associated with Cushing’s syndrome, and also had some histologic similarities with oat cell carcinoma of the lung. They suggested that these three types of neoplastic cells originate in a common cell type. The pancreatic malignancies have been both islet cell tumors (functioning and nonfunctioning) [ 75-771, and adenocarcinema [ 781. The autopsy findings in the cases reported have revealed bilateral hyperplasia of the adrenal glands. These are usually very hyperplastic, weighing 10 to 20 gm. per gland. One of the patients of Billinghurst et al. [79] had an adrenal cortical adenoma. Metastases to the adrenal glands have been present in about half of the patients with lung cancers and associated Cushing’s syndrome. Histologic examinations of the adrenal glands have shown hyperplasia of the zona fasciculata with encroachment on the zona glomerulosa. Large, peculiar, eosinophilic, vacuolated cells are seen in the zona fasiculata [8,77,20]. Metastatic lesions may or may not be present in the liver and anterior pituitary. Hyaline changes in the basophils of the anterior pituitary have been reported [3,20]. Hypokalemic alkalosis has been present in a large number of these cases [27] and may be accompanied by marked weakness. It has been seen in several patients with none of the physical stigmata of Cushing’s syndrome. The hypokalemia has been shown to be due to the loss of potassium through the kidneys. Because of the severe potassium wasting, which is fairly uncommon in uncomplicated Cushing’s disease, the aldosterone excretion has been measured and found to be normal in many cases and increased in only a few [4,20,22]. The edema in the patient described herein did not respond to therapy with a potent aldosterone antagonist alone, and his urinary aldosterone values were normal even though he had congestive heart failure and increased 17-hydroxycorticosteroid values. Bagshawe [27] noted a close correlation between the occurrence of hypokalemic alkalosis and the presence of neoplasms associated with Cushing’s syndrome. In a series of 111 patients with Cushing’s syndrome he found twenty-three patients with hypokalemic alkalosis, and twenty-one of these had either an endocrine or nonendocrine malignancy. Christy

Hyperactivity-McDaniel

et al.

et al. [23] believe that the presence or absence of hypokalemic alkalosis depends upon the amount of cortisol (hydrocortisone) produced by the adrenals. This may be correlated with Bagshawe’s report in that most of his patients with malignancies had very high levels of steroid production, unlike the patient in the present report. Some patients with bronchogenic carcinoma have had increased 30 metabolites in the urine, suggesting an adrenal carcinoma. A few patients have had a steroid suppression test. The output of steroids decreased in some, showing that the adrenals were under control of a stimulus still to blood levels of glucocorticoid responsive [24,25]. In most patients treated by pituitary radiation or adrenalectomy there has been some regression of the signs and symptoms of adrenal hyperfunction but no patient has lived long enough following removal of his tumor to see whether the symptoms would disappear. In studying the relationship between nonendocrine cancer and adrenal function, a number of interesting observations have been made. In 1952, Dobriner found ll,&hydroxyetiocholanolone (OHE) in the urine of patients with cancer, but in only two of twenty normal persons. He believed that gonadal and adrenal dysfunction was present in patients with various types of cancer [26]. Subsequent technical improvements have shown that this metabolite is present in the urine of most normal persons. (Table III.) It was, however, present in this patient in abnormally large quantities. Slaunwhite et al. [27] found increased conversion of exogenous cortisone to 11-ketoetiocholanolone (OE) and 1 l/Ghydroxyetiocholanolone (OHE) in three patients with prostatic cancer and one of three patients with bronchogenic carcinoma. Sholiton et al. [28] have reported loss of the normal diurnal variation in 17-hydroxycorticosteroids in patients with bronchogenic carcinoma, similar to that seen in patients with uncomplicated Cushing’s syndrome. Sommers [29-371 has made extensive autopsy studies in patients with cancer and found histologic changes in the pituitary, adrenals and gonads. Parker and Sommers [32] and Sholiton et al. [33] found an increased incidence of adrenal hyperplasia in patients dying of cancer, using a cortical width of 2 mm. or more as the criterion of adrenocortical hyperplasia. Many others have reported finding high AMERICAN Jo”RNAI_

OF MEDICINE

Rronchogenic

Carcinoma

and Adrenocortical

steroid levels in patients with various types of cancers [.3/J-.%‘]. Cortisone has been shown numerous times to increase the number of takes of transplanted tumors in mice and the incidencc~ of widespread metastases (37~401. T‘his is thought to be related to the decreased antit&? response to tumor tissue and to changes in the ground substance and connecti1.e tissue allowing a morr rapid spread to tumor cells in tissues. These findings raise a number of interesting question,s. (1) Is the association fortuitous? (2~ Is there some common factor which produces both disorders in the same patient? (3) I>oes the adrenal abnormality come first, then the increased steroid production which induces formation or growth of cancer in a susceptible person? (4) Or does the tumor come first and evoke increased adrenal activity? In the case of bronchogenic carcinoma it seems unlikely that the association is simply fortuitous, Ijecausc of the high incidence of oat cell carcinoma in these patients compared with other patients with bronchogenic carcinoma. At autopsy the o\,cr-all incidence of carcinoma in patients with C:ushing:-‘s syndrome is about the same as it is for those with myocardial infarction [J/l. The t,est evidence to date indicates that the increased steroid output in patients with nonendocrine tumors and associated Gushing’s syndrome is the result of adrenal cortical stimulation by an ACTH-like substance formed by the tumor. Some neoplasms appear to make substances similar to parathyroid hormone, insulin, antidiuretic hormone or erythropoietin. Incrcxasccl blood levels of ACTH-like activityhave been reported in patients with malignancies and Gushing’s syndrome [L?-&‘1], and corticotropin-like activity was found in one oat cell carcinoma of the lung associated with C!ushing’s syndrome [44]. The pituitary of this same patient (uninvolved with tumor) showed an unusually low concentration of ACTH, consistent with the postulate that the tumor was producinq a similar substance. Furthermore, the urinar\- steroid level was not suppressecl by the administration of 8 mg. of dexamethasone per da)-. The urinary steroid patterns presented in ‘TalJes I and II are consistent with this postulate, since they most closely resemble those seen in normal subjects after ACTH stimulation. They do not resemble those seen in the presence of

Hyperactivity-McDaniel

et 01.

431

specific adrenal defects, such as adrrnogenital syndrome or hyperaldosteronism, although the finding of compounds S and THQ in OIII: urine specimen is of interest. These metabolites are not normall!. present e\-cn after XC’I’I I stimulation and might reflect a re1atiL.c‘ drficienq of I 18 h)-drosylasc activit),. However, the prc~nc~ of large quantities of E, F, THE and ‘I‘HF is against this simple cxplanatiori. It is of inttarest that in patients with Gushing’s s)-ndromc due to bilateral adrenal hyperplasia the urinary steroid patterns rcsemt)lc those of this patient in several respects [d5]: namely, a low pcrcentagc of CL1 metabolites of compounds A and B (including intact A and B) and elevated mctal)olitrs of rompouncl F (not including 1; itself, the perccyntaqe of \vhich remains approxima telv normal). The very high level of OHA in the second specimen is certainly abnormal. A pussi t)lc eflect of spironolactonc on the biosynth(G or metabolism of the steroids in this second spccimen cannot bc excluded, even thou,ch chrc matographic studies indicate that this is not a metabolite of spironolactone. The complete absence of DHEA is also noteworthy, q~ecially in connection with the values for S, ‘I’IHS and THQ in the Czl steroid pattern. Although the over-all pattern of the 17-ketvsteroids (17-U) is consistent with XCTH-like stimulation, the total \,alue was not increased. This might be explained by the fact that nonc of the urinary steroid levels were extremely clevatcd in this patient so that these values (about 18 mg. per da).), which ma)- have been abo\.e his basal level, did not exceed the normal range. In some of the other patients described the urinary 17-kctosteroid levels also \vere rlcvatec’.

.4 patient is described with oat cc11 carcinoma of thr lung who had increased total 17-hydroxycorticosteroids and normal total 17-ketosteroids in the urine. The urinary steroid pattc-rns lvere found to resemble those seen in C:ushin,y:‘s S\Xdrome from bilateral adrenal cortical hypersubjects after S’\C:TH plasia and in normal stimulation. The relationships t)ctwc%en nonendocrine tumors and Gushing’s syndrome, and between cancer and adrenocortical 11,:perfunction, are discussed. It is concluded that the tnost reasonable explanation for the adrenocortical hyperactivity, in the light of existing knowledge,

432

Bronchogenic

Carcinoma

is that the “nonendocrine” substance with ACTH-like

tumor activity.

and Adrenocortical produces

a

REFERENCES 1. BROWN, 1V. II. A case of pluriglandular syndrome “diabetes of bearded women.” Lancet, 2: 1022, 1928. 2. SCIIOLZ, D. A. and BOIIN, R. C. Thymic tumors associated with Cushing’s syndrome. Kevicw of three casts. Proc. St+8 Meert. Mqo C/in., 34: 433, 1959. 3. BRICKNER, P. W., LYONS, M. and LANDAU. S. J. Gushing’s syndrome associated with non-endocrine neoplasms. Am. J. Med., 31: 632, 1961. 4. WEBSTER, G. D., JR., TOUCHSTONE, J. C. and Suzu~r, M. Adrenocortical hyperplasia occurring with metastatic carcinoma of the prostate. Report of a case exhibiting increased urinary aldosterone and glucocorticoid excretion. J. Clm. Endocrinol., 19: 967, 1959. 5. DYSON, B. C. Cushing’s disease: report of a case associated with carcinoma of the thyroid gland and cryptococcosis. hTew England J. Med., 261: 169, 1959. 6. RIGGS, B. L. and SPRAGUE, R. E. Association of Cushing’s syndrome and neoplastic disease. Arch. Int. Med., 108: 841, 1961. 7. WARREN, F. L. Estimation of urinary 17-ketosteroids in diagnosis of adrenal cortical tumors. Cancer Res., 5: 49, 1945. 8. BORNSTEIN,P., NOLAN, J. P. and BERNANKE, D. Adrenocortical hyperfunction in association with anaplastic carcinoma of the respiratory tract. n’ew England J. Med., 264: 363, 1961. 9. CI~ENAULT,S. B., GAUTNEY, M. G., MCNEIL, J. II. and HILL, S. R., JR. Interrelationships between adrenal cortical and medullary secretory activity in patients with pheochromocytoma. (Abstract.) Clin. Res. Pm.: 6: 258, 1958. 10. COPE, O., LABBE, J. P., RAKER, J. LV. and BLAND, E. F. Phcochromocytoma and adrenal cortical adenoma. Report of a case with both tumors and discussion of their relation. J. Clin. Endocrinol., 12: 875, 1952. 11. KAPLAN, L. I., SOKOLOFF, L., MURRAY, F. and STEVENSON, L. D. Sympathicoblastoma with metastases, associated with the clinical picture of Cushing’s syndrome. Report of a case. Arc/z. h’eurol. &f Psych&., 62: 696, 1949. 12. COHEN, R. B., GILES, D. T. and CASTLEMAN,B. Bronchial adenomas in Gushing’s syndrome. Their relationship to thymomas and oat cell carcinoma associated with hyperadrenocorticism. Cancer, 13: 812, 1960. 13. WOLFF, J., SPEAR, P., YESNER,R. and PATNO, M. E. Nitrogen mustard and the steroid hormones in the treatment of inoperable bronchogenic carcinoma. Am. J. Med., 29: 1008, 1960. 14. MCBURNEY, R. P., MCDONALD, J. R. and CLAoErr, 0. T. Bronchogenic small cell carcinoma. J. Thoracic Surg., 22: 63, 1951. 15. BALLS, K. F., NICKOLSON,J. T. L., GOODMAN,H. I,. and TOUCHSTONE,J. C. Functioning islet cell carcinoma of the pancreas with Gushing’s syndrome. J. Clin. Endocrinol., 19: 1134, 1959.

Hyperactivity-McDaniel

et al.

16. DEL CASTILLO, E. B., TRUCCO, E. and MANGUOLI,J. Maladic de Cushing et cancer de pancreas. Prem mbd., 2: 783, 1950. adrenocortical 17. ROSENBERG, A. A. Fulminating hyperfunction associated with i&t-cell carcinoma of the pancreas. Case report. J. Clin. Endocrinol., 16: 1364, 1956. 18. CROOKE, A. C. Basophilism and carcinoma of the pancreas. J. Path. & Back, 58: 667, 1946. 19. BILLINGHURST, J. Ii., THOULD, A. K., GALPIN, 0. P. and HINTON, J. N. Carcinoma and Cushing’s syndrome. Brit. M. J., 2: 490, 1961. 20. LOCKWOOD, C. H. Studies of adrenal cortical function in three cases of carcinoma. Canad. itl. A. J., 79: 728, 1958. 21. BAG~~IAWE, K. D. Hypokalemia. carcinoma and Cushing’s syndrome. Lancet, 2: 284, 1960. 22. FURRANT, P. C. and INSLEY, J. Increased adrenocortical activity and malignant disease. Letters to the Editor. Lancet, 2: 434, 1960. 23. GIIKISTY, N. P. and L.AR~GII, J. H. Pathogenesis of hypokalcmic alkalosis in Gushing’s syndrome. ~Vezeru England J. Med., 265: 1083, 1961. 24. ALLOTT, E. N. and SKELTON, M. 0. Increased adrenocortical activity associated with malignant disease. Lance& 2: 278, 1960. 25. MLTZLER, C. and FLINK, E. B. Adrenal cortical hypcrfunction associated with metastatic bronchogcnic carcinoma. J.-Lam&, 76: 242, 1956. 26. DOBKINER,K. Adrenal function and steroid excretion in ncoplastic disease. In: Steroid Hormones and Enzymes. Ciba Foundation Colloquia on Endocrinolgy, vol. 1, p. 210. Edited by Wolstenholme, G. E. W. Philadelphia, 1952. The Blakiston Co. 27. SLAUNWHITE,\V. I~., JR., LIST, B. and SOKAL, J. E. Conversion of cortisone to 17-ketosteroids in patients with carcinoma of the prostate and of the lung. J. Lab. & C&n. Med., 53: 737, 1959. 28. SIIOLITON, L. J., WERK, E. E., JR. and MARNEL, R. I. Diurnal variation of adrenocortical function in non-endocrine disease states. Metabolism, 10:

632, 1961. 29. SOMMERS,S. C. Endocrine changes with prostatic carcinoma. Cancer, 10: 345, 1957. 30. SOMMERS,S. C. and MEISSNER, W. A. Endocrine abnormalities accompanying endomctrial cancer. Cancer, 10: 516, 1957. 31. SOMMERS,S. C. Host factors in fatal human lung cancer. Arch. Path., 65: 104, 1958. 32. PARKER, T. G. and SOMMERS,S. C. Adrenal cortical hyperplasia accompanying cancer. Arch. Surg., 72: 495, 1956. 33. SHOLITON,L. J., INCZE, J. S. and WERK, E. E., JR. Adrenocortical width in carcinoma of the lung. Cancer, 14: 105, 1961. 34. JEPSON, R. P., JORDAN, A. and LEVELL, M. J. Urinary steroid response to operation. Brit. J. Surg., 43: 390, 1955-56. 35. MOORE, F. D., STEENBERG,R. W., BALL, M. R., WILSON, G. M. and MYRDEN, J. A. Studies in surgical endocrinology. I. Urinary excretion of 17_hydroxycorticosteroids, and associated metabolic changes in cases of soft tissue trauma of varying severity and in bone trauma. Ann. Surg.,

141: 145,1955. 36. ROZENBOJM,J., KRAKAUER, L. J. and GRAY, S. J. AMERICAN

JOURNAL

OF

MEDICINE

Bronchogenic

37.

38.

39. 40.

41.

Carcinoma

and Adrenocortical

Adrenal cortical activity in gastric carcinoma. Studies of plasma 17-hydroxycorticostrroid levels. Arch. Id. ,Zid..98: 266, 1956. KALTSS, N., Ro~c~ss, P. R. F. and DAY, E. n. Survival and mctastatic spread of homografts of mollsr tnmors in miw, prctreatrd with lyophilized tiswc and cortisone. Cawer Krr., 14: 210, 1954. I’OMXROY, ‘7‘. (:. Studiw on mechanism of cortisoneinduced mctastascs of transplantable mo~sc tumors. CUICP~Kc:., 14: 201, 1954. (GREEN, I-1. N. and \YIIITEI.EY, H. J. Cortisone and tnrnor growth. Rd. -14. J., 2: 538, 1952. IVERSON, 1-I. G. and HJORT, G. II. The inlluence of corticoid steroids on the frequency of splenic mctastascs in patients with breast rancrr. ,4cta path. rt microhinl. scmdinnz~., 44: 205, 1958. SPAULDISG, \I-. FL, OLLIE, Tz'. -4. and (~BRNALL,

42.

43. 44.

45.

Hyperactivity-McDaniel

et

171.

433

A. G. Mineralocorticoid-like disturbance associated with adrenal metastases from .a bronchogcnic carcinoma. /Inn. Int. Mod., 42: 444, 1’155. Hor.u~, n. h. and KATZ, F. H. ‘5. possihle vtiologic link betwm Gushing‘s syndrome and viswral malignancy. (Abstract.) Clin. Rcs.. ‘9: 194. 1061. NF:LSON:11. II. Uisorders of AGTI-I sccrction in man. .Ifctnbolism, 10: 894, 1961. MEADoR, c:., 1SI.AND,n., NICIIOI.SO~, It’.., NI CKTON, J., I,uK.\s, C:., ILJETSCHER, J. and I,ro~rr.~:, G. Scvcrc 0xhing’s syndrome apparently dur to corticotropin secreting oat ccl1 carcinoma. In: Prog-ram of the Forty-Third Annual Mwting of the Endocrine Society, 1961. (Abstract No. 162.) SWIFT, J. P.. SVARNES, \V. R. and HILL, S. R. Urinary steroid patterns in adrmocortical hypcrplasia. In preparation.