CASE REPORTS
CARCINOMA OF THE LUNG ASSOCIATED WITH MARKED ADRENOCORTICAL HYPERPLASIA AND ADRENAL HYPER-RESPONSIVENESS TO ACTH IN THE ABSENCE OF CUSHING’S SYNDROME*
By LEON J. MARKS, M.D., ALBERT E. ANDERSON, M.D., and HARVEY LIBERMAN, M.D., Boston, Massachusetts
THE role of pituitary corticotropin in the regulation of the adrenal secretion of cortisol during the basal state, as well as during periods of stress, has been well documented.1 The work of several investigators has suggested the exist- ence of a pituitary factor which is separate from conventional ACTH and which primarily affects adrenal growth and weight maintenance without causing the secretion of adrenal hormones.2,3 Although Jailer et al.” have demonstrated the presence of an adrenal weight-maintaining substance in patients with Cushing’s disease due to bilateral adrenal hyperplasia by assaying their plasma in hypophy- sectomized rats, the clinical significance of a human adrenal growth factor thus far has remained uncertain. The purpose of this paper is to report the case of a patient with carcinoma of the lung who, while alive, had a markedly exaggerated adrenocortical response to conventional ACTH in the complete absence of clinical evidence of Cushing’s snydrome and who, at autopsy, had extremely large adrenal glands with adrenocortical hyperplasia.
CASE REPORT
J. M., a 64-year-old white male, entered the Boston Veterans Administration Hospital July 8, 1959, with the chief complaint of a persistent cough of four months’ duration. He had lost 10 pounds within the previous six months. Significant physical findings included blood pressure of 110/80 mm. Hg, bilateral Herberden’s nodes on the distal interphalangeal joints of the fingers, impaired hearing bilaterally, and dullness to percussion and diminished breath sounds over the left upper chest.
The hematologic data were as follows : hemoglobin, 14.3 gm.%; hematocrit, 45%; white cells, 10,600/cu. mm .; differential count: stab forms, 7%; segmented forms, 63%; lymphocytes, 28%; eosinophils, 2%. Corrected sedimentation rate was 33 mm./hr. Urine examination was normal. Blood chemical findings were: nonprotein nitrogen, 28 mg.%; fasting blood sugar, 81 mg.% Roentgenograms of the chest revealed bilateral emphysema and nodular consolidation of the left upper lobe. An electrocardiogram was within normal limits.
At exploratory thoracotomy on August 4, 1959, a carcinoma of the superior segment of the left upper lobe was observed to extend to the left parietal pleura. A
* Received for publication June 8, 1960.
From Steroid Research Laboratory and Department of Pathology, Boston Veterans Administration Hospital, Boston, Mass.
Requests for reprints should be addressed to Leon J. Marks, M.D., Director, Steroid Research Laboratory, Veterans Administration Hospital, 150 S. Huntington Ave., Boston 30, Mass.
left pneumonectomy was performed, the patient tolerating the operative procedure without incident. Two weeks postoperatively, a total tumor dose of 3,430 roentgens was administered to the left parietal pleura over a 16-day period, following which the patient was discharged.
The patient was readmitted on December 22, 1959, because of left chest pain and dyspnea of five days’ duration. He had lost six pounds since his operation. Physical examination revealed the presence of an effusion in the left hemithorax. A thoracocentesis was performed and 250 ml. of cloudy yellow sterile fluid were removed. A cell block of this fluid was positive for malignant cells. The patient improved on supportive therapy and was discharged to a nursing home.
He was readmitted on January 21, 1960 because of persistent left chest pain and weakness. It was evident on physical examination that fluid had reaccumulated in the left hemithorax. His blood pressure was 105/76 mm. Hg. The hematologic data were as follows : hemoglobin, 13.1 gm.% ; hematocrit, 41% ; white cells, 13,800/cu. mm .; differential count: stab forms, 11%; segmented forms, 76%; lymphocytes, 12%; eosinophils, 1%. An eosinophil count was 102/cu. mm. Blood chemical values were: urea nitrogen, 12 mg.%; fasting blood sugar, 89 mg.%; total bilirubin, 0.6 mg.%; cephalin flocculation, 2-plus; thymol turbidity, 3.4 U .; total protein, 4.4 gm.%; albumin, 3.1 gm.%; globulin, 1.3 gm%. Serum electrolytes were: sodium, 139 mEq./L .; potassium, 4.2 mEq./L .; carbon dioxide, 29 mEq./L .; and chloride, 100 mEq./L.
| Type of Plasma Steroid | Control Plasma 17-OHCS (ag./100 ml.) 6 Hours* | |
|---|---|---|
| Free | 18.4 ± 2.1} | 46.1 ± 3.6 |
| Conjugated | 14.9 ± 1.8 | 30.7 ± 2.9 |
* All patients received a six-hour infusion of ACTH.
t Standard errors of the means are shown.
On January 26, 1960, the adrenal cortical capacity to respond to a six-hour in- fusion of 30 USP units of ACTH was tested. Blood samples were obtained before and at the end of the infusion for plasma 17-hydroxycorticosteroid (17-OHCS) determi- nations. Plasma free 17-OHCS were measured by the method of Nelson and Samuels.5 Plasma conjugated 17-OHCS were analyzed by the method of Bongio- vanni and Eberlein.” The mean values and the standard error of the mean of free and conjugated plasma 17-OHCS of 15 normal subjects both before and after ACTH infusion are presented in Table 1.
The control free and conjugated plasma 17-OHCS levels of the patient were 18 ug.% and 7 ng.%, respectively. Following ACTH administration, free and con- jugated plasma 17-OHCS values rose to 93 ng.% and 42 ng.%, respectively (Figure 1).
Three days following the completion of the ACTH test, the patient developed bronchopneumonia in his right lung and died within 36 hours.
Pathologic Findings: The surgical specimen of the left lung revealed the presence of a carcinoma which arose in the superior bronchus of the left upper lobe. Tumor was present in several of the hilar lymph nodes resected at operation. On microscopic examination the tumor was a grade 2 epidermoid carcinoma.
The significant pathologic processes at post-mortem examination were con- fined to the thorax and to the adrenals. A moderate amount of cloudy yellow
fluid was found in both pleural cavities from which alpha and beta streptococci were cultured. Diffuse bronchopneumonia was present in the right lung. Tumor was observed in the resected margin of the left lung, the main bronchus of the right lung, the left pleura, the posterior mediastinal, periaortic, and right hilar lymph nodes, and in the bodies of the seventh and eighth thoracic vertebrae. There was a moderate degree of coronary arteriosclerosis. The central venous system was not examined.
Both adrenal glands were greatly enlarged and after careful removal of periadrenal fat, the right adrenal weighed 21 gm. and the left adrenal weighed 33 gm. The cortices of both adrenals were thickened and measured from
NORMAL (IS SUBJECTS)
J.M. AGE 64
ID AGE 42
100
90
80
70
PLASMA
17-OHCS
60
/100 ML
50
40
A
4
30
4
20
10
· · FREE A-A CONJUGATES
ADRENAL HYPERPLASIA
CUSHING’S SYNDROME ADRENAL HYPERPLASIA
Y
0
ACTH
30 1.0. 1V
30 14. IV
30 1.V. 1V
TIME (HOURS) 0
2
4
6
0 2 4 6 0 2 4 6
0.4 to 0.7 cm. The external surfaces were corrugated with a suggestion of nodule formation. On cut section, bright yellow radial streaking was seen in a brown cortical parenchyma. The medullae of both adrenals were a waxy gray and of average size.
Microscopic examination revealed marked bilateral adrenocortical hyper- plasia, involving all three zones of the cortex. There was considerable hyper- trophy of the cells of the zona glomerulosa and fasciculata. Multiple nodule formation could be seen within the fasciculata. An occasional nucleus of the cells of the fasciculata was enlarged and hyperchromatic. Focal lipid depletion was present in the zona fasciculata and reticularis.
DISCUSSION
The marked adrenocortical hyperplasia observed in our patient at autopsy was in striking contrast to the complete absence of clinical signs suggestive of adrenal hyperfunction during the seven months of careful clinical observa- tion prior to his death. The demonstration of normal control values of both free and conjugated plasma 17-hydroxycorticosteroids are in agreement with the patient’s clinical state.
In Figure 1 may be seen both the free and conjugated plasma 17-OHCS response to a six-hour infusion of ACTH in a group of 15 normal subjects, in our patient, J. M., and in a 42-year-old male, I. D., with full-blown Cushing’s syndrome. Although the control pre-ACTH free and conjugated plasma 17-OHCS values in patient I. D. are considerably higher than those of patient J. M., the increment rises both in free and conjugated plasma 17-OHCS in response to ACTH are indentical in both patients and are significantly greater than those observed in normal subjects.
An exaggerated free plasma 17-OHCS response to ACTH has been demon- strated by Sandberg et al. in moribund patients,” whose pre-ACTH plasma 17-OHCS levels were elevated. This observation was confirmed by Christy et al.,8 who suggested that the elevated resting and post-ACTH free plasma 17-OHCS values seen in severely ill patients were due in part to the delayed disappearance of cortisol from plasma. They commented that two of their patients with a hyper-response to ACTH had adrenal glands which were normal in weight and morphology at post-mortem examination.
We should like to emphasize that our patient J. M. should not be placed in the foregoing category for the following reasons. First, on the day the ACTH test was performed, he was not critically ill and was being considered for discharge to a nursing home. Second, his resting pre-ACTH free and conjugated plasma levels were not elevated. Third, the marked increase of his conjugated plasma 17-OHCS in response to ACTH is evidence against the thesis that the high value of free plasma 17-OHCS observed after ACTH was due primarily to impaired metabolism of circulating cortisol.
The authors favor the concept that the adrenal glands of the patient were exposed to unidentified growth factor over a long period of time. The primary action of this X substance was to increase the size of the adrenal cortex without affecting the adrenal secretion of corticosteroids. If one assumes that these large adrenals remained responsive to conventional ACTH during their growth, then endogenous ACTH secretion must have diminished as adrenal hyperplasia developed. If pituitary ACTH secretion did not decrease, then the adrenal output of cortisol should have risen and Cushing’s syndrome would have appeared. Indeed Cushing’s syndrome has been reported in a few patients dying with oat-cell carcinoma of the lung who had bilateral adrenal cortical hyperplasia at autopsy.9, 10
Adrenal weight-maintaining effects have been found in growth hormone fractions by Reinhardt, Geschwind, and Li,11 by Young.12 and by Cater and Stack-Dunne.3 Jailer et al. observed that plasma from two patients with “active acromegaly” possessed significant adrenal weight-maintaining activity in hypophysectomized rats.” Although patients with acromegaly may have en- larged adrenal glands at autopsy,13 acromegalic patients have not been observed
to have an exaggerated plasma 17-OHCS response to ACTH.’ Liddle et al.14 administered a highly purified beef growth hormone preparation to two patients for five successive days and did not observe any change in adrenocortical responsiveness to conventional ACTH.
Thus, at the present time it appears that the chemical identity of any specific adrenal growth hormone in man remains unresolved. It is our hope that the reporting of the present case in detail will stimulate further investigation in this complex field.
SUMMARY
A case is reported of epidermoid carcinoma of the lung associated with extreme bilateral adrenocortical hyperplasia. Although this patient exhibited a markedly exaggerated free and conjugated plasma 17-hydroxycorticosteroid response to conventional ACTH, no objective evidence of either hyper- or hypoadrenocorticism was present during his entire clinical course. It is postulated that these large adrenals were due to the action of an unidentified adrenal growth factor, which did not affect adrenocortical secretion.
SUMMARIO IN INTERLINGUA
Es reportate un caso de carcinoma epidermoide del pulmon, associate con extreme hyperplasia adrenocortical bilateral. Ben que iste patiente exhibiva un marcatemente exaggerate responsa del libere e del conjugate 17-hydroxycorticosteroides del plasma a ACTH conventional, nulle signo objective de hyper- o hypoadrenocorticismo esseva presente durante su integre curso clinic. Es postulate que iste grande adrenales esseva causate per le action de un non identificate factor de crescentia adrenal que non afficeva le secretion adrenocortical.
BIBLIOGRAPHY
1. Sayers, G .: The adrenal cortex and homeostasis. Physiol. Rev. 30: 24, 1950.
2. Dixon, H. B., Stack-Dunne, M. P., Young, F. G., Cater, D. B .: Influence of adreno- corticotropic hormone fractions on “adrenal repair” and on adrenal ascorbic acid. Nature 168: 1084, 1951.
3. Cater, D. B., Stack-Dunne, M. P .: Mitotic activity in the adrenal cortex studied in the rat. Ciba Foundation Colloquia on Endocrinology 8: 31, 1955.
4. Jailer, J. W., Longson, D., Christy, N. P .: Studies in Cushing’s syndrome. II. Adrenal weight-maintaining activity in the plasma of patients with Cushing’s syndrome. J. Clin. Invest. 36: 1608, 1957.
5. Nelson, D. H., Samuels, L. T .: A method for the determination of 17-hydroxycorti- costeroids in blood: 17-hydroxycorticosterone in the peripheral circulation. J. Clin. Endocr. 12: 519, 1952.
6. Bongiovanni, A. M., Eberlein, W. R .: The determination, recovery, identification, and renal clearance of conjugated adrenal corticoids in human peripheral blood. Proc. Soc. Exp. Biol. Med. 89: 281, 1955.
7. Sandberg, A. A., Eik-Nes, K., Migeon, C. J., Samuels, L. T .: Metabolism of adrenal steroids in dying patients. J. Clin. Endocr. 16: 1001, 1956.
8. Christy, N. P., Longson, D., Jailer, J. W .: Studies in Cushing’s syndrome. I. Observa- tions on the response of plasma 17-hydroxycorticosteroid levels to corticotropin. Amer. J. Med. 23: 910, 1957.
9. Thorne, M. G .: Cushing’s syndrome associated with bronchial carcinoma. Guy. Hosp. Rep. 101 : 251, 1952.
10. Kovach, R. D., Kyle, L. H .: Cushing’s syndrome and bronchogenic carcinoma. Amer. J. Med. 24: 981, 1958.
11. Reinhardt, W. O., Geschwind, I. I., Li, C. H .: On the evidence suggesting a multiplicity of adrenocorticotropic hormones. Acta Endocr. 8: 393, 1951.
12. Young, F. G .: ACTH-a single substance or a mixture of hormones. Adrenal Cortex, Transactions of the Fifth Conference, Josiah Macy, Jr. Foundation, 1954, p. 97.
13. Goldberg, M. B., Lisser, H .: Acromegaly : a consideration of its course and treatment. J. Clin. Endocr. 2: 477, 1942.
14. Liddle, G. W., Island, D., Rinfret, A. P., Forsham, P. H .: Factors enhancing response of human adrenal to ACTH: is there an adrenal growth factor? J. Clin. Endocr. 14: 839, 1954.