ADRENOCORTICAL FUNCTION IN CARCINOMA OF THE LUNG
EMILE E. WERK, JR., M.D., AND LEON J. SHOLITON, M.D.
A RELATIONSHIP between adrenocortical function and carcinoma of the lung is suggested by the following observations: (1) Bronchogenic carcinoma has a predilection for metastasizing to the adrenal glands and occasionally causes adrenal insufficiency.11, 31, 41 (2) In autopsy studies, an increased incidence of adrenocortical hyperplasia has been noted in patients with carcinoma of the lung.26, 34 (3) Adrenocortical hyperfunction has been ob- served in association with carcinoma of the lung and to date 19 such cases have been reported or mentioned.2-5, 12, 15-17, 19, 22, 28, 28, 29, 85, 86, 40
Our interest in this relationship was stim- ulated when we discovered a patient with bronchogenic carcinoma who had elevated plasma and urinary 17-hydroxycorticosteroid (17-OHCS) levels without clinical manifesta- tions of Cushing’s syndrome or hyperaldoster- onism. Autopsy revealed the presence of bi- lateral adrenal hyperplasia. A report of this case follows:
REPORT OF A CASE
R.S., a 65-year-old white retired factory worker, was admitted to the Veterans Admin- istration Hospital, Cincinnati, Ohio, on April 15, 1957, with the presumptive diagnosis of carcinoma of the lung and mental depression. The patient was confused and responded poorly to questioning. His wife stated that he had developed progressive weakness, for- getfulness, and depression and had had a 25-1b. weight loss over the previous 6 to 9 months. During the 3 weeks prior to admission he had anorexia and recurrent vomiting. One year previously he had experienced some breath-
From the Department of Medicine, Veterans Admin- istration Hospital, and the University of Cincinnati Col- lege of Medicine, Cincinnati, Ohio.
Especial thanks are owed to the following persons for technical assistance: Kenneth Allen, Theresa Hughes, John Lindsley, Carol Reeves, and Brandon Taylor.
Dr. Joseph Incze, Department of Pathology, Veterans Administration Hospital, kindly performed the patho- logical studies, and we are grateful for his co-operation. The free cortisol in 50% aqueous alcohol used in this study was generously supplied by Mr. J. Stultz of The Upjohn Company, Kalamazoo, Mich.
Received for publication June 15, 1959.
lessness and ankle edema, and digitalis had been prescribed. Examination in April re- vealed a blood pressure of 110 over 80 and a pulse of 84. The patient was awake, but he was almost catatonic in his responses and rarely spoke. He was well developed with evidence of recent weight loss. Scattered rhonchi could be heard throughout both lung fields. There was no edema. He moved his extremities only on painful stimulation. No localizing neurologi- cal signs were elicited. There was no sugges- tion of Cushing’s syndrome in his appearance.
Chest roentgenograms revealed a left hilar mass measuring 3x3 cm. in the posterior seg- ment of the left upper lobe. Roentgenograms of the skull, spine, and long bones were nor- mal, as was an intravenous pyelogram. The hemogram and urinalysis were normal. The serum sodium was 143. mEq. per liter; potas- sium was 4.6 mEq. per liter; and chlorides were 100. mEq. per liter. The blood carbon dioxide content was 45 volumes per 100 cc. The blood urea nitrogen was 15 mg. per 100 cc., and the fasting sugar was 76 mg. per 100 cc. The results of a glucose tolerance test (3 months after admission) were: fasting, 80 mg. per 100 cc .; at 1/2 hour, 143 mg. per 100 cc .; at 1 hour, 173 mg. per 100 cc .; at 2 hours, 106 mg. per 100 cc .; and at 3 hours, 100 mg. per 100 cc. Bronchoscopy and Papanicolaou ex- aminations of sputa and bronchial washings were negative. An electroencephalogram and a spinal fluid examination were normal.
The depression, anorexia, and vomiting per- sisted for 4 weeks after admission. Adrenal in- sufficiency was actually suspected, and adrenal function tests were performed. Unexpectedly the plasma free 17-OHCS and urinary steroids were elevated and showed an exaggerated re- sponse to adrenocorticotropic hormone (ACTH). The studies were repeated on 2 subsequent occasions with similar findings (Figs. 1 and 2, patient 1). The patient’s condition steadily deteriorated. He developed progressive leth- argy and bilateral Babinski signs that indi- cated, more clearly, brain metastases and pre- cluded surgery. He died on Oct. 31, 1957, with left lower lobe pneumonia.
The postmortem examination revealed a well differentiated squamous cell carcinoma of the left upper lobe bronchus with metastases to both adrenal glands and the left frontal, right parietal, and right cerebellar lobes of
| Pt. | Age, yr. | Wt., kg. | Ap- prox. wt. loss, kg. | Ac- tiv- ityt | Pulmon. statusţ | Site metast. | Type ca. § | Treatment | Complications & remarks | Interv. studies to death wk. |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 67 | 60. | 11 | Br. | Density lul | Brain | Sq. | None | Lethargy, | 25 |
| periodic fever | 23 | |||||||||
| 10 | ||||||||||
| 2 | 65 | 36.6 | 18 | Br. | Mass lul | Rib | Oat cell | None | Old hip frac., fever, hypotension | 1 |
| 3 | 61 | 60.7 | 7 | Br. | Mass rml & mediastinum | Bladder, kidney, pleura | Sq. | Thoracot. 5 mo. prior study (inop.), X ray | None | 2 |
| 4 | 67 | 41.4 | 9 | Br. | Density lul | Bone, lymph | Sq. | X ray | Fever | 5 |
| nodes | ||||||||||
| 5 | 37 | 44.5 | 14 | Br. | Mediastinal mass | Brain, abdom. | Ad. | X ray | Pulmonary osteo- arthropathy | 6 |
| viscera | ||||||||||
| 6 | 65 | 54.0 | 23 | Amb. | Density Ill, atelectasis, hilar nodes | Skull | Ana. | X ray | Hypertensive cardiovascular dis. | 4 |
| 7 | 62 | 59.9 | 11 | Amb. | Nodule rml | ?liver | Sq. | X ray | Arteriosclerotic heart dis., ca. colon resec. | 3 |
| 8 | 63 | 43.1 | 17 | L. amb. | Mass lul | ?liver | Un- diff. | Thoracot. 6 mo. prior study (inop.), X ray | Pulmonary osteo- arthropathy | 7 |
| 9 | 66 | 74.5 | 4 | Amb. | Mass & atelec- tasis rul | Skin | Un- diff. | X ray | Low grade fever | 8 |
| 10 | 62 | 75.4 | 4 | Amb. | Bilateral hilar masses, infil- trate lul | Liver, skin | Ana. | None | Hypertension | 12 |
| 11 | 55 | 58.1 | 23 | Amb. | Density & ate- lectasis rul | Skin, bone | Sq. | X ray | None | 14 |
*The patients are numbered and arranged in the order of the severity of the illness as determined mainly by the interval between the time of study and death and the activity status and clinical evaluation at the time of study. The numbering is the same on subsequent tables. Patients I through 5 were not included in the statistical comparisons. The mean age for the cancer patients was 59.3 years, with a range of from 37. to 69. years and a standard error of ±1.66 (sick group P>0.1; controls P>0.1). The mean weight for the cancer patients was 60.3 kg., with a range of from 36.6 to 78.2 kg. and a standard error of ±2.29 (sick group P>0.5; controls P <0.05). The mean weight loss for the cancer patients was 10.2 kg., with a range of from 4. to 23. kg. and a standard error of ±1.45 (sick group P>0.1).
the brain. Grossly the left adrenal was en- larged, whereas the right was obscured by metastases. Microscopically both adrenal cor- tices were hyperplastic with a tendency to- ward adenoma formation in 2 areas in the left. The right adrenal cortex measured 2.17 mm., and the left 2.52 mm. The larger adeno- matous area in the left measured 6 mm. in diameter. There was also a small microscopic metastasis in the left adrenal cortex.
On the basis of this information, it seemed appropriate to study adrenocortical function in a group of patients with carcinoma of the lung and to compare them to hospital patients without cancer. The findings herein reported indicate that the group of male patients with carcinoma of the lung had adrenal hyperac- tivity.
MATERIAL AND METHODS
Subjects. The carcinoma of the lung group was comprised of 22 male patients at varying stages of illness. Eighteen had clinical evidence of metastases at the time the studies were per- formed. Pertinent clinical data concerning these patients are presented in Table 1. The first patient was the previously mentioned pa- tient with bronchogenic carcinoma and as- sociated adrenal hyperplasia. The remaining patients were selected at random. They were numbered and arranged in the order of the severity of the illness as determined mainly by the interval between the time of study and death and the activity status and clinical evalu- ation at the time of study. Patients 2, 3, 4, and 5 were considered preterminal and were bed-
| Pt. | Age, yr. | Wt., kg. | Ap- prox. wt. loss, kg. | Ac- tiv- ityt | Pulmon. statusţ | Site metast. | Type ca. § | Treatment | Complications & remarks | Interv. studies to death wk. |
|---|---|---|---|---|---|---|---|---|---|---|
| 12 | 49 | 53.6 | 7 | Amb. | Lt. hilar density, ate- | Pleura | Sq. | Nitrogen mustard | None | 11|| |
| lectasis Ill | ||||||||||
| 13 | 47 | 54.5 | 11 | Amb. | Atelectasis rml, effus. rll | Brain | Sq. | Nitrogen mustard | None | 16 |
| 14 | 47 | 57.7 | 7 | Amb. | Lt. hilar den- sity, atelectasis 111, effus. | Lymph nodes | Sq. | X ray | None | 19 |
| 15 | 67 | 53.6 | 9 | W.c. | Mass lul | Spinal cord, | Ad. | X ray | Hypertension, paraplegia | 21 |
| bone | ||||||||||
| 16 | 69 | 67.3 | 4 | Amb. | Atelectasis lul | Bone | Sq. | X ray | Prev. ca. buccal mucosa | 22 |
| 17 | 61 | 57.4 | 4 | Amb. | Infiltrate & atelectasis 111 | Lymph nodes, | Ana. | X ray | None | 22 |
| liver | ||||||||||
| 18 | 60 | 61.3 | 11 | Amb. | Density 111 with effus. | Lymph nodes | Ad. | Nitrogen mustard | Diabetes mellitus, albuminuria, | 23 |
| 19 | 60 | 78.2 | 9 | Amb. | Infiltrate & mass rul | None | Un- diff. | Thoracot. 6 wk. prior study (inop.), X ray | hepatomegaly None | 27 |
| 20 | 59 | 55.9 | 12 | Amb. | Lt. hilar density | None | Un- diff. | Not op. because poor | Chr. lung dis., skeletal de- | 56|| |
| 21 | 53 | 51.8 | 7 | Amb. | Density 111 | None | Ad. | respir. func. Pneumo- nect. after study | mineralization None | 53 |
| 22 | 63 | 68.1 | 11 | Amb. | Mass 111 with atelectasis | None | Sq. | Pneumo- nect. after study | Rheumatic heart dis. | 11|| |
tIn this column, the following abbreviations are used: br., bedridden; amb., ambulatory; 1. amb., limited ambulation; and w.c., wheelchair.
In this column, the following abbreviations are used: lul, left upper lobe; rul, right upper lobe; rml, right middle lobe; Ill, left lower lobe; and rll, right lower lobe.
§As determined from biopsy, or operation, or subsequent postmortem examination. In this column, the fol- lowing abbreviations are used: sq., squamous; ad., adenocarcinoma; ana., anaplastic; and undiff., undiffer- entiated.
||Still living when the manuscript was prepared.
ridden. The remainder were ambulatory. A comparable age group, referred to as the sick group, consisted of ill patients with subacute and chronic disease states. Patients were se- lected who had lost considerable amounts of weight and did not have cancer. The majority of these patients were afflicted with chronic lung diseases and/or arteriosclerotic heart dis- ease. The clinical data concerning these pa- tients are presented in Table 2, which is also arranged according to the severity of illness based on a clinical evaluation. The third group, referred to as the control group, was made up of the healthiest hospital patients of comparable age available for study. Most of these patients had been admitted to the hos- pital for minor surgical conditions, and the studies were completed in advance of surgery.
The data concerning these subjects are in- cluded in Table 2.
Adrenal Function Studies. Plasma samples were obtained between 8 a.m. and 9 a.m. for the basal level of free 17-OHCS. Twenty-five units of ACTH in 1 liter of normal saline was then administered intravenously over an 8- hour period, and a second sample of plasma was obtained at the end of the infusion. Twenty-four-hour urine collections for steroid determinations were obtained before the day of the ACTH infusion and also on the day en- compassing the ACTH infusion. Plasma and urinary creatinine concentrations were also determined, and the 24-hour creatinine out- puts and endogenous creatinine clearances were calculated. Approximately 1 week later cortisol removal tests were performed using a
technique similar to that described by Brown and his colleagues.1 Free cortisol in 50% aque- ous alcohol (5 mg. per ml.) was diluted in 250 ml. of saline and infused intravenously over 30 minutes. The dosage for each patient was 1.25 mg. of cortisol per kilogram of body weight. Blood samples for the estimation of free 17- OHCS were obtained at approximately 1, 2, 3, and 4 hours after the end of the infusion. The
biological half time (T1/2) of the disappear- ance of cortisol from the plasma was calcu- lated according to the least squares method. At autopsy, special attention was given to the adrenal glands of patients who had been stud- ied. The total adrenal cortical thickness was estimated using a calibrated microscopic linear scale. Only satisfactory sections were read, and areas adjacent to metastases were avoided. The
| Pt. | Age, yrs. | Wt., kg. | Approx. wt. loss, kg. | Activityt | Diagnosis |
|---|---|---|---|---|---|
| Sick t | |||||
| 1 | 67 | 38.4 | 11 | Br. | Pulmonary emphysema, cor |
| 2 | 65 | 50.8 | 7 | Br. | pulmonale Bronchiectasis, cor pulmonale, asthma |
| 3 | 66 | 88.5 | 0 | Br. | Myocardial infarct., pulmonary emphysema |
| 4 | 67 | 65.8 | 7 | L. amb. | Pneumonia, pulmonary emphysema, cor pulmonale |
| 5 | 63 | 65. | 7 | Amb. | Arteriosclerot. heart dis., duodenal |
| 6 | 60 | 57.6 | 9 | Amb. | ulcer, pulmonary emphysema Pulmonary emphysema, cor pulmonale |
| 7 | 69 | 54.9 | 2 | L. amb. | Pyelonephritis, epilepsy |
| 8 | 69 | 61.7 | 7 | Br. | Bronchiectasis, varicose leg ulcers |
| 9 | 51 | 49.9 | 30 | Amb. | Pulmonary emphysema, cor pulmonale, asthma |
| 10 | 67 | 75.8 | 0 | L. amb. | Myocardial infarct. |
| 11 | 52 | 51.8 | 7 | Amb. | GI bleeding, arteriosclerot. heart dis. |
| 12 | 54 | 67.6 | 7 | Amb. | Pulmonary emphysema, cor pulmonale, asthma |
| 13 | 55 | 79.4 | 0 | Amb. | Hypertensive cardiovascular dis., asthma |
| 14 | 63 | 60.4 | 7 | Amb. | Myocardial infarct., congestive heart failure |
| 15 | 68 | 57.6 | 18 | L. amb. | Myocardial infarct., syphilitic hypertension |
| 16 | 70 | 65.4 | 0 | L. amb. | aortitis, Myocardial infarct., pulmonary |
| 17 | 60 | 60.5 | 9 | Amb. | emphysema Bronchiectasis, pulmonary rheumatoid arthritis |
| 18 | 63 | 67.7 | 18 | Amb. | emphysema, Pneumonia, bronchiectasis |
| Control'§ | |||||
| 1 | 66 | 61.7 | ... | ... | Inguinal hernia |
| 2 | 64 | 66.7 | ... | Cervical spondylosis | |
| 3 | 63 | 65.4 | ... | ... | Chronic leg ulcer, peripheral vascular dis. |
| 4 | 72 | 62.2 | ... | ... | Dupuytren's contracture |
| 5 | 60 | 76.3 | ... | Hemorrhoids | |
| 6 | 57 | 66.3 | ... | ... | Inguinal hernia |
| 7 | 55 | 71.3 | ... | ... | Old perianal abscess |
| 8 | 67 | 68.6 | ... | ... | Hemorrhoids |
| 9 | 65 | 62.6 | ... | Hemorrhoids, chronic prostatitis | |
| 10 | 52 | 72.3 | ... | ... | Inguinal hernia |
| 11 | 61 | 60.9 | ... | Hemorrhoids, polyposis colon |
*The sick patients are numbered and arranged in the order of the severity of their illness based on clinical evaluation. The control patients are arranged in chronological order of studies. The numbering is the same on subsequent tables.
tSee Table 1 for explanation of abbreviations.
¿The mean age for the sick group was 62.7 years, with a range of from 51. to 70. years and a standard error of ±1.44 (controls P>0.1). The mean weight for the sick group was 62.4 kg., with a range of from 38.4 to 88.5 kg. and a standard error of ±2.76 (controls P>0.1). The mean weight loss for the sick group was 8.1 kg., with a range of from 0. to 30. kg. and a standard error of ±1.81.
§The mean age for the controls was 62.0 years, with a range of from 52. to 72. years and a standard error of ±1.75. The mean weight for the controls was 66.8 kg., with a range of from 60.9 kg. to 76.3 kg., and a standard error of ±1.50.
| COMPARISON OF RESULTS | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| BEFORE ACTH | AFTER ACTH | RISE | |||||||
| CARCIN- OMA OF LUNG | SICK | CONTROL | CARCIN OMA OF LUNG | SICK | CONTROL | CARCIN- OMA OF LUNG | SICK | CONTROL | |
| MEAN | 21.1 | 13.0 | 12.0 | 62.2 | 46.6 | 44.7 | 39.3 | 35.4 | 31.9 |
| 5.E. | 1.54 | 1.47 | 1.39 | 1.54 | 3.92 | 2.79 | 5.23 | 3.83 | 2.54 |
| P SICK | $0.01 | >0.05 | >0.5 | ||||||
| ₱ CONTROL | <0.01 | >0.50 | .0.02 | >0.50 | >0.1 | >0.1 | |||
130
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SICK
CONTROL
average of 2 separate readings is reported.
Chemical Methods. The plasma was re- moved from the heparinized blood samples within 45 minutes after drawing the blood. It was frozen and subsequently analyzed for free 17-OHCS by a modification of the Nelson and Samuels method.24 The urine samples were collected on ice and at the end of the 24-hour period, aliquots were taken and frozen for subsequent analyses. The urinary 17-OHCS were determined according to the method of Glenn and Nelson.10 Total blue tetrazolium- reacting (BTR) steroids were determined color- imetrically25 on the 25% methanol-in-chloro- form chromatographic fraction and are re- ferred to as the total BTR steroids. The method used by Weichselbaum and Margraf39 was utilized for the estimation of 17-deoxycortico- steroids (17-Dos), which employs standards of both cortisol and corticosterone and corrects for the slight difference in color intensity of these 2 compounds. The urinary 17-ketoster-
oids were analyzed by a modification of Drek- ter et al.‘s8 method. The plasma and urinary creatinine were determined by a modification of the Folin and Wu method.º The accuracy of the various steroid methods as performed in this laboratory-according to the formula, per- centage error of reproducibility equals (mean difference plus 2 standard deviations between duplicates) times 100 divided by the mean-is as follows: for plasma free 17-OHCS, 21% at a level of less than 30 µg. per 100 ml. and 10% at a level greater than 30 µg. per 100 ml .; urinary 17-OHCS, 8%; urinary total BTR ster- oids, 6%; urinary 17-Dos, 14%; and urinary 17-ketosteroids, 5%.
RESULTS
The concentrations of plasma and outputs of urinary steroids per gram of creatinine, be- fore and after ACTH, are presented in Figs. 1 and 2. Expressing the urinary steroid values
using creatinine output as a reference base brought out additional differences among the results of the 3 groups. The mean urinary ster- oid excretions, not related to creatinine out- put, are shown in Table 3. The number shown
under each vertical bar in Figs. 1 and 2 refers to the individual patient as described in Tables 1 and 2.
Patient 1 of the carcinoma group was the patient with adrenal hyperplasia described in
URINARY 17- HYDROXYSTEROIDS 24hrs. mgms/Gm.
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the case report given previously. The levels of plasma free 17-OHCS and urinary 17-OHCS and total BTR steroids were elevated before and particularly after ACTH. The elevations of the urinary 17-Dos and 17-ketosteroids were
only slight. Only the urinary values in terms of creatinine excretion are shown (Fig. 2). Patients 2, 3, 4, and 5 were terminal and had elevated plasma free 17-OHCS. The uri- nary values for the most part were also
| COMPARISON OF RESULTS | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| BEFORE ACTH | AFTER ACTH | RISE | |||||||
| CARCINOMA OF LUNG | SICK | CONTROL | CARCINOMA OF LUNG | SICK | CONTROL | CARCINOMA OF LUNG | SICK | CONTROL | |
| MEAN | 6.2 | 4.4 | 3.7 | 21.2 | 15.8 | 13.6 | 15.0 | 11.5 | ... |
| S.E. | 0.80 | 0.40 | 0.40 | 2.76 | 1.29 | 1.35 | 2.24 | 1.14 | 1.23 |
| P SICK | >0.05 | >0.05 | >0. 1 | ||||||
| CONTROL | ≤0.05 | >0.1 | <0.05 | >0.1 | >0.5 | >0.1 | |||
| MEAN | 11.0 | 8.0 | 6.9 | 32.7 | 25.7 | 19.3 | 21.7 | 17.4 | 12.3 |
| S. E. | 1. 52 | 0.60 | 0.70 | 3.94 | 2.05 | 2.23 | 2.82 | 1.03 | 1.99 |
| › SICK | >0.05 | >0.1 | >0.1 | ||||||
| P CONTROL | >0.05 | >0.1 | <0.02 | ≤0.05 | 30.05 | >0.5 | |||
| MEAN S.E. | 4.5 0.71 | 3.3 0.28 | 3.0 0.31 | 10.8 1.53 | .. 3 0.67 | 6.4 0.99 | 6.4 0.99 | 6.0 0.74 | 3.5 0.00 |
| P SICK | >0.1 | >0.1 | >0.5 | ||||||
| CONTROL | >0.1 | >0.t | $0.05 | $0.05 | 30.05 | $0.05 | |||
| MEAN | 10.1 | 10.2 | 11.2 | 19.4 | 14.6 | 13.9 | 7.7 | 4.6 | 3.3 |
| S.E. | 0.01 | 0.01 | 0.91 | 1.47 | 0.09 | 1.07 | .... | 0.61 | 0.46 |
| D SICK | >0.1 | 30.02 | ≤0.01 | ||||||
| CONTROL | >0.1 | >0.1 | <0.02 | >0.1 | 30.01 | >0.5 | |||
represents the control value, and the upper triangle the value encompassing the 8-hour 25-I.U. ACTH infusion. 2, 4, and 5 of the carcinoma of the lung group are not included in the statistical comparison of results at the
| COMPARISON OF RESULTS OF URINARY | ||||||||
|---|---|---|---|---|---|---|---|---|
| Group | 17-Hydroxysteroids | Total BTR steroids | ||||||
| Mean | S.E. | P sick | P control | Mean | S.E. | P sick | P control | |
| Before ACTH | ||||||||
| Ca. lung | 6.1 | ±0.41 | <0.02 | <0.02 | 10.7 | ±0.67 | <0.02 | <0.05 |
| Sick | 4.4 | ±0.54 | ... | >0.50 | 8.0 | ±0.82 | ... | >0.50 |
| Control | 4.6 | ±0.41 | ... | ... | 8.6 | ±0.64 | ... | ... |
| After ACTH | ||||||||
| Ca. lung | 18.9 | ±1.73 | >0.5 | >0.5 | 29.1 | ±2.47 | >0.5 | >0.1 |
| Sick | 17.7 | ±1.67 | ... | >0.5 | 28.6 | ±2.72 | ... | >0.1 |
| Control | 18.6 | ±2.07 | ... | ... | 26.1 | ±3.27 | ... | ... |
| Rise | ||||||||
| Ca. lung | 12.9 | ±1.52 | >0.5 | >0.5 | 19.3 | ±2.39 | >0.5 | >0.1 |
| Sick | 13.2 | ±1.3 | ... | >0.5 | 20.7 | ±2.13 | ... | >0.1 |
| Control | 14.0 | ±1.92 | ... | ... | 17.5 | ±2.91 | ... | ... |
*Urinary steroid values are not expressed in terms of creatinine output. Patients 1 through 5 of the carcinoma
high. The responses to ACTH were variable. Patient 2 who had very high basal levels of both plasma and urinary steroids showed very little rise of the urinary steroids after ACTH, whereas the plasma level rose from 49 ug. to 82 µg. per 100 ml. This discrepancy may be ex- plained by terminally diminished hepatic and renal function. Patient 3 displayed a decreased plasma steroid rise from 36 ug. to 48 ug. per 100 ml., and it is noteworthy that almost complete destruction of the adrenals by metas- tases was found at autopsy. It should be em- phasized that these first 5 patients of the can- cer group are not included in the statistical comparison of results depicted in Figs. 1 and 2, or in Table 3, or in the text to follow.
The principal results from hereon refer to the patients with carcinoma of the lung who were essentially still ambulatory (patients 6 through 22). The basal plasma free 17-OHCS levels ranged from 12 ug. to 29 ug. per 100 ml. and were significantly higher (P<0.01) than those in both the sick and control groups, the means being 21.1 for the carcinoma group, 13.8 for the sick group, and 12.8 for the con- trol group. After ACTH infusion, the mean plasma steroid level for the cancer group was 62.2 ug. per 100 ml., a concentration signifi- cantly higher than that of the control group (P=0.02) but not that of the sick group (P>0.05). The mean increment produced by ACTH was not significantly different among the 3 groups. However, 2 patients of the cancer series, patients 8 and 18, had exceptionally marked responses to ACTH, particularly the latter whose plasma free 17-OHCS concentra- tion rose from 27 ug. to 120 µg. per 100 ml.
Prior to ACTH, the mean 24-hour urinary outputs of 17-OHCS, in milligrams per gram of creatinine, was 6.2 for the cancer series, 4.4
for the sick series, and 3.7 for the control series (Fig. 2). The difference was significant (P<0.05) between the cancer and control groups but not significant (P>0.05) between the cancer and sick groups. The total BTR ster- oids and 17-Dos were slightly higher in the cancer series than in the other 2 groups but the differences were not significant. The 17- ketosteroids were similar in all 3 groups. The variation of the steroid outputs was greater among the cancer patients, with values for 3 cancer patients (patients 7, 8, and 18) being elevated above the ranges of the 2 other groups.
After ACTH the mean outputs of all the urinary steroid fractions per gram of creati- nine were significantly higher in the carcinoma patients than in the control group. The 24- hour outputs of 17-OHCS per gram of creat- inine were 21.2 mg. for the cancer patients and 13.6 mg. for the control group (P<0.05). The mean 24-hour urinary outputs of 17-DOS per gram of creatinine were 10.8 mg. for the cancer group and 6.4 for the control series (P<0.05). The 17-ketosteroids were signifi- cantly higher in the carcinoma patients versus both other groups, the mean 24-hour outputs per gram of creatinine being 19.4 mg. for the cancer group, 14.8 for the sick group, and 13.9 for the control group (P<0.02). The mean rise was significantly higher in the carcinoma group as compared to the control group for the total BTR steroids, the 17-Dos, and the 17-ketoster- oids per gram of creatinine respectively. Only the rise of the last type was higher in the cancer group versus the sick group, the mean values being 7.7 and 4.6 respectively (P<0.01). Again the variation was more marked in the cancer series, with the values in patients 7, 8, and 18 being elevated above the ranges of the other 2 groups.
| 17-Deoxysteroids | 17-Ketosteroids | ||||||
|---|---|---|---|---|---|---|---|
| Mean | S.E. | P sick | P control | Mean | S.E. | P sick | P control |
| 4.3 | ±0.33 | <0.05 | >0.1 | 12.7 | ±1.05 | >0.05 | >0.1 |
| 3.3 | ±0.36 | ... | >0.5 | 10.2 | ±0.95 | ... | <0.05 |
| 3.6 | ±0.26 | ... | ... | 13.8 | ±1.24 | ... | ... |
| 9.6 | ±1.22 | >0.5 | >0.5 | 18.2 | ±1.71 | >0.5 | >0.5 |
| 10.4 | ±1.13 | ... | >0.1 | 16.8 | ±1.29 | ... | >0.1 |
| 8.8 | ±1.54 | ... | ... | 19.3 | ±2.12 | ... | ... |
| 5.4 | ±0.97 | >0.5 | >0.1 | 5.9 | ±1.05 | >0.5 | >0.5 |
| 7.1 | ±0.9 | ... | >0.1 | 6.6 | ±0.65 | ... | >0.5 |
| 5.2 | ±1.4 | ... | ... | 5.4 | ±1.63 | .... | ... |
of the lung group are not included. The P values that indicate significant differences are italicized.
When the urinary steroid values were com- pared directly, without employing the creat- inine ratio (Table 3), the basal 17-OHCS and total BTR steroids, in milligrams per 24 hours, were significantly higher (P<0.02) in the can- cer group than in either of the other series, the means being respectively 6.1 and 10.7 for the cancer group, 4.4 and 8.0 for the sick group, and 4.6 and 8.6 for the control group. The mean urinary outputs of 17-Dos, in milli- grams per 24 hours, were 4.3 for the cancer, 3.3 for the sick, and 3.6 for the control pa- tients. The difference between the cancer and sick groups was significant (P<0.05). None of the outputs after ACTH showed any significant difference in contrast to the results obtained in terms of creatinine excretion. In this re- gard it should be pointed out that the mean 24-hour creatinine output for the control day and ACTH day were as follows: the carcinoma group 1.11 and 1.0 gm .; the sick group 1.01 and 1.13 gm .; and the control group 1.26 and 1.39 gm. respectively. Thus, using the creat- inine ratio changed the mean results very little for the former 2 groups but decreased the figure for the control group.
There was no significant difference in the endogenous creatinine clearance among the 3 groups, indicating that renal function was ap- proximately similar; the means (plus or minus standard errors) being 90.3 (±9.9) ml. per minute for the carcinoma group, 80.1 (±5.02) ml. per minute for the sick group, and 88.2 (±5.54) ml. per minute for the control group.
Cortisol removal tests were performed in 10 of the carcinoma group (patients 7, 8, 10, 11, 12, 13, 14, 15, 21, and 22), 13 of the sick group (patients 1, 3, 4, 6, 7, 8, 9, 10, 12, 13, 14, 15, and 16) and all 11 of the control group. The individual T1/2 in the carcinoma group ranged
from 107 to 172 minutes, in the sick group from 103 to 173 minutes, and in the control group from 104 to 175 minutes. The mean T1/2’s of the 3 groups were 138, 142, and 128 minutes respectively, without any significant difference among the 3 by the t test (Fig. 3).
Autopsy Studies. Postmortem examinations were performed on 11 of the 19 carcinoma pa- tients who died. The first patient was the one with the adrenal hyperplasia, and this case has been described. Of the remaining 10 pa- tients, 6 had metastases to the adrenals. The types of carcinoma are shown in Table 1. The total individual thicknesses of the adrenal cortices are listed in Table 4. It will be noted that none of the total thicknesses was greater than 2 mm., which was the criterion for adre- nal hyperplasia employed by Parker and Som- mers.26 However the mean cortical thickness, 1.73 mm., for the 10 cancer patients, was sig- nificantly greater (P<0.01) than the mean thickness, 1.42 mm., of glands from 10 random patients of comparable age without cancer. Unfortunately postmortem examinations were not performed in patients 7, 8, and 18 who had manifested high plasma and/or urinary steroid values.
DISCUSSION
The purpose of this study was to evaluate adrenocortical function in a group of men afflicted with carcinoma of the lung by em- ploying direct steroid measurements. The re- sults in the cancer patients have been com- pared to those in patients with (1) subacute and chronic non-neoplastic medical diseases (sick group) and (2) minor elective surgical conditions (control group). It should not be inferred that the men in the sick group were
160
CORTISOL REMOVAL CURVES
140
120
110
100
PLASMA 17 - HYDROXYSTEROIDS mc qs. /100 ml.
90
00
70
60
50
40
30
CARCINOMA OF LUNG (IO) 11/2 : 138 Min.
* -* CONTROL (II) 11/2 : 128 Min.
P >0.
P>0.5
· SICK (13) 11/2 : 142 Min.
>> >0.1
60
120
180
240
MINUTES
necessarily as “ill” as were the cancer patients. From the standpoint of survival they certainly were different, but they did constitute a com- parable hospital group, and furthermore many had chronic lung diseases that are frequently associated with carcinoma of the lung.
The most significant finding was that of elevated basal plasma free 17-OHCS in the patients with carcinoma of the lung. It was expected that these levels would be elevated in terminal patients,32 but the ambulatory pa- tients surviving for 6 to 12 months also had distinctly higher values than did the patients in the sick or control groups. Furthermore, patients 19, 20, 21, and 22 had no evidence of metastases at the time the studies were per- formed. None of the patients investigated, however, represented early asymptomatic cases.
Elevated basal plasma 17-OHCS levels could be caused by (1) decreased cortisol removal from plasma, (2) increased cortisol produc- tion, (3) a combination thereof, or (4) possibly a chromagen that is not cortisol. The last pos- sibility has not been completely investigated though the evidence so far20 indicates that the 17-OHCS measured by the method employed is actually cortisol. Since the cortisol removal rates were similar in the 3 groups, the most likely conclusion is that the elevated plasma
levels reflect increased cortisol production by the adrenal glands. The fact that the plasma free 17-OHCS levels did not rise to a greater extent in most of the carcinoma patients after ACTH need not alter this conclusion as many patients with Cushing’s syndrome do not have an exaggerated plasma 17-OHCS response to ACTH.
The urinary steroid values were slightly higher in the cancer patients, which is con- sistent with increased adrenal production. The differences were not as distinct as were those of the plasma values, and the mean elevations in the cancer series were mainly attributable to only a few patients. The basal urinary 17- OHCS levels were significantly higher in the cancer group and were correlated with the elevated basal plasma free 17-OHCS. The urinary steroid outputs after ACTH were similar in the 3 series, but the values related to creat- inine excretion were higher in the cancer series. Creatinine excretion reflects muscle mass, and it has been used as a steroid refer- ence point to elucidate mild Cushing’s syn- drome18 and to emphasize changes in steroid output with aging.27 The application of the creatinine ratio to the present data seemed appropriate since the cancer patients and the sick patients, particularly the former, had lost muscle mass in contrast to the control patients. It is noteworthy that the application of the creatinine ratio to the 17-ketosteroid excretion after ACTH demonstrated distinctly higher values in the carcinoma patients. This finding might suggest that the fractional increment of 11-oxygenated 17-ketosteroids, which were de- rived from endogenous cortisol, was relatively greater in the carcinoma patients. In this re- gard it is noteworthy that Slaunwhite and his colleagues described an increased conversion of exogenous cortisone to 11-ketoetiocholano- lone and 11ß-hydroxyetiocholanolone in 1 of 3 patients with carcinoma of the lung and 3 patients with carcinoma of the prostate.33
An attempt was made to gain further infor- mation on adrenal secretion by determining the total BTR steroids. The 17-Dos values, which mainly reflect corticosterone and its deriva- tives, were calculated as essentially the differ- ence between the total BTR steroids and the 17-OHCS. In general the calculated 17-DOS correlated with the 17-OHCS, suggesting that the increased adrenal production in the cancer patients included corticosterone as well as cortisol.
The findings in patients 8 and 18 were of
particular interest. All the plasma and urinary steroid values of these 2 patients were excep- tionally elevated, suggesting that they might have had specific adrenal hyperplasia. Patient 18 had had diabetes mellitus for 12 years but otherwise there was no evidence of Cushing’s syndrome or hyperaldosteronism in either pa- tient.
As proved by patient 1, adrenal hyper- plasia may be present with markedly elevated 17-OHCS levels over several months without clinical evidence of adrenal hyperfunction. Unfortunately autopsies were not performed on patients 8 and 18. The incidence of 2 suspected hyperplasia cases out of 21 studied (not including patient 1) correlates with the 12.3% incidence of adrenal hyperplasia in respiratory cancer found by Parker and Som- mers.26
The results of the steroid measurements con- firm in part and extend earlier studies of Voigt and Kny37 who measured urinary 17-ketoster- oids and reducing corticoids in 27 patients with carcinoma of the lung. Four of their pa- tients had increased levels. On the other hand, 4 of their patients had very low levels, which none of our patients demonstrated except for the urinary 17-ketosteroids in patient 4 who was terminal.
The slightly increased adrenal cortical thick- ness in the patients with carcinoma of the lung is additional evidence for a greater ster- oid production and is consistent with the ob- servations of Parker and Sommers.26 However
| Cancer pt.t | Adrenal cortical thickness in pt. with: | |
|---|---|---|
| Ca. lung, mm. | No cancer, mm.# | |
| 2 | 1.54 | 1.36 |
| 3 | 1.89 | 1.47 |
| 5 | 1.61 | 1.44 |
| 6 | 1.68 | 1.42 |
| 10 | 1.92 | 1.48 |
| 11 | 1.62 | 1.54 |
| 15 | 1.68 | 1.26 |
| 16 | 1.80 | 1.33 |
| 17 | 1.72 | 1.38 |
| 21 | 1.82 | 1.48 |
| MEAN | 1.73 | 1.42 |
| S.E. | 0.040 | 0.026 |
| P | <0.01 | ... |
*Each figure represents the average of 2 separate readings (error of reproducibility 11%).
“The numbers for the cancer patients correspond to those in Table 1 and in Figs. 2 and 3.
At autopsy the sections were selected at random from patients of ages comparable to those of the carcinoma of the lung group. The control patients did not have cancer or any known endocrine disease.
there are difficulties involved in this finding, namely, the variations of thickness of an in- dividual cortex, the differences in sectioning, and the influence of adjacent metastases. Fur- ther studies are necessary for adequate con- firmation.
The explanation for increased adrenal ster- oid output in carcinoma of the lung is purely speculative at this time. Two basic lines of reasoning may be considered: (1) that the “stress” of the cancer over a prolonged period serves as a stimulus to the pituitary-adrenal system or (2) that there is a predisposition to increased adrenal activity that may or may not be related to the development of the cancer. Probably most of the studies currently made on adrenal function would favor the former explanation, but it is indeed unsettled.
Finally, attention should be drawn to ster- oid measurements in neoplastic diseases in sites other than the lung. Dobriner and his col- leagues7 initially reported diminished urinary steroids in patients with carcinoma of the larynx, prostate, stomach, breast, and in those with lymphatic leukemia. However, they often found an increased amount of 11-hydroxyetio- cholanolone, a derivative of cortisol, and later they reported elevated formaldehydogenic ster- oids in subjects with various neoplastic dis- eases.” Rozenbojm et al.30 found normal levels of plasma free 17-OHCS and slightly elevated urinary 17-OHCS in patients with gastric car- cinoma, whereas Jabbour18 reported low uri- nary 17-ketosteroids in this disease. Weichsel- baum et al.38 studied 8 patients with “terminal mammary cancer,” and many of them were found to have elevated plasma free 17-OHCS. Jepson et al.14 mentioned a patient with gas- tric carcinoma who had very high urinary 17- ketogenic steroids, and Moore et al.21 reported a woman with carcinoma of the breast with elevated urinary 17-OHCS. The latter authors stated that similar levels were not found in other cases of “widespread malignancy.” It seems likely that carcinomas other than lung may be associated with elevated adrenal ster- oid levels, but whether there is a quantitative or qualitative difference remains to be ascer- tained.
SUMMARY
1. Adrenocortical function has been evalu- ated in a group of male patients with carci- noma of the lung at various intervals before death; this was compared to adrenocortical
function in sick medical patients and in essen- tially well patients with minor surgical con- ditions.
2. The basal plasma free 17-hydroxycorti- costeroids were distinctly higher in the car- cinoma of the lung group than in the other 2 groups. After ACTH, the mean values were slightly higher in the cancer group. The basal urinary 17-hydroxycorticosteroids and 17-de- oxycorticosteroids were slightly higher in the cancer group. After ACTH, the urinary steroid outputs were similar in all groups. However, related to creatinine excretion, the urinary 17- ketosteroids after ACTH were significantly greater in the cancer group as compared to the other 2 groups, and the 17-hydroxycorticos- teroids and 17-deoxycorticosteroids were sig-
nificantly greater in the cancer group versus the mildly ill control patients. The rate of disappearance of infused cortisol from plasma was the same for all groups.
3. The combined findings are compatible with adrenal hyperactivity in the carcinoma of the lung patients as compared to the non- cancer patients. The observation microscopi- cally at autopsy of increased adrenal cortical thicknesses of glands from the cancer patients tends to confirm this contention.
4. A patient with squamous cell broncho- genic carcinoma and adrenal hyperplasia is reported who during life had markedly ele- vated plasma and urinary steroid values with- out any clinical manifestations of Cushing’s syndrome or hyperaldosteronism.
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