Adrenal Weight-Maintaining Corticotropin in Carcinoma of Lung
John Nichols, MD, and William Gourley, MD, Kansas City, Kan.
In two cases of carcinoma of the lung without Cushing’s syndrome but with bi- lateral adrenal cortical hypertrophy, the tumor was found to be devoid of cortico- tropin with corticosteroid-releasing ca- pacity. Both tumors, however, had an extractable “corticotropin-like material” with adrenal weight-maintaining capacity. These findings, suggesting two different kinds of corticotropin, may explain the bilateral cortical hypertrophy not in- frequently found in patients with tumors but without Cushing’s syndrome.
R ECENTLY CUSHING’S SYNDROME in cases of carcinoma of the lung has been attributed to a corticotropin-like material extractable from the primary tumor.1-4 Cushing’s syndrome in a case of ovarian tumor 5 and mediastinal tumor ” likewise has been attributed to a corticotropin-like material extractable from the primary tumor. At autopsy bilateral adrenal cortical hypertrophy is not infre- quent in cases of carcinoma of the lung without Cushing’s syndrome. The following two cases dem- onstrate the presence of a substance extractable from the primary tumor of such patients which par- tially maintains the adrenal weight of hypophysec- tomized rats.
Report of Cases
CASE 1 .- A 56-year-old male with a 2-month history of weight loss, increasing dyspnea, and a productive cough was referred from another hospital for x-ray therapy. Anaplastic carcinoma of the lung had been diagnosed from a lymph node biopsy and mechlorethamine hydrochloride therapy had been started. The patient had smoked two packages of cigarettes daily for 40 years. Serum sodium was 135 mEq/ liter, potassium 4.6 mEq/liter, and chloride 101 mEq/liter. Corticosteroid studies were not done. The patient died 3 days after admission, without receiving radiation treatment. Cushing’s disease was not present.
Autopsy done 3 hours after death revealed a tumor mass that occluded the left lower lobe bronchus. There were metastases to the pleurae, mediastinal lymph nodes, pericar- dium, and liver. Microscopically, the neoplasm was of the
“oat cell” type of bronchogenie carcinoma. The right adrenal gland weighed 15 gm and the left one 17 gm, the adrenal cortex being uniformly hypertophied. Microscopically, the zona glomerulosa was irregularly thickened but the bulk of the hyperplasia was in the zona fasciculata where broad areas of vacuolated fat-laden cells alternated with narrower areas of cells with denser cytoplasm. Metastases were absent. Examination of the head was not permitted.
CASE 2 .- The patient, not treated at this hospital, was a 46-year-old male who presented with a 3-month history of cough, weight loss, and increasing dyspnea. He had smoked two packages of cigarettes daily for the past 30 years. Physical examination revealed signs compatible with tumor of the right lower lobe of the lung. Because of religious persuasion he declined hospitalization, further ex- amination, or treatment. Two weeks later, in acute respira- tory distress, he entered a hospital. Turbid serosanguinous fluid, 1,100 ml, containing tumor cells was removed from the right pleural cavity, and x-rays were interpreted as revealing tumor at the hilus of the right lung with ex- tensive involvement of the lower lobe. On two successive days serum sodium was 132 and 128 mEq/liter, and potassium was 4.2 and 4.2 mEq/liter. On two successive days, 17-hydroxycorticosteroids ( Porter-Silber method ) were 20.8 and 22.1ug/100 ml. Naked eye and microscopic examination of the urine revealed red blood cells with marked proteinuria. Urine collections were not quantitative and corticosteroid excretions were not done. The patient died on the third hospital day with only oxygen therapy having been administered. No signs of Cushing’s disease were seen.
Postmortem examination done 5 hours after death was limited severely and the head was not examined. Extensive neoplasia was found in the hilum of the right lung and involving the parenchyma as an irregular mass measuring about 3-5 cm. Metastases were noted in the liver and both kidneys. Microscopic examination revealed the tumor to be a highly anaplastic, poorly differentiated adenocarcinoma. ’ Many microscopic fields were histologically identical with the so-called oat cell carcinoma. Both adrenal glands were diffusely enlarged, the right weighed 21 gm and the left 23 gm. A few microscopic clusters of tumor cells were found in both adrenal cortices. The hypertrophy of the adrenals was confined to the cortex, the cells of which showed cytomegaly with poorly staining cytoplasm con- taining abundant lipid material. The pituitary gland was not examined.
Physiological Studies
In Case 1, portions of the primary tumor, normal liver, and liver metastases were placed in a refrig- erator at -70 C (-137 F) for subsequent corti- cotropin assay. In Case 2, only portions of the pri- mary tumor were saved for assay. Tumor from
From the Department of Pathology and Oncology, University of Kansas School of Medicine.
three other cases of anaplastic “oat cell” carcinoma of lung without Cushing’s syndrome and without adrenal hypertrophy were also assayed for cortico- tropin. These were considered as “controls.” All tissues were extracted by the method of Birming- ham et al7 for corticotropin content. Aliquots of the primary tumor extracts in all cases were assayed in the hypophysectomized adrenal-vein-cannulated dog by the method of Nelson and Hume.8 Three assays, each assay on a different dog, were done on each tumor extract; no corticosteroid releasing (corticotropin-like) effect was detected in any ex- tract. The several extracts were next assayed for adrenal weight-maintaining capacity in the hypo- physectomized rat by a modification of the method of Simpson and associates.9 Fifty-gram rats were hypophysectomized and kept untreated for 2 weeks. They were then injected subcutaneously twice daily for 10 days with a saline suspension of tissue ex- tract. Each injection represented 0.1 gm of tissue. The animals were killed, and the adrenals were re- moved and placed in 10% formalin for a day. They were then weighed on an analytical balance after the surrounding fat was removed with iris forceps and the aid of a steroscopic microscope. The results are shown in the Table, where it can be seen that extracts from the primary tumors in Patients 1 and 2 had the capacity to partially maintain the weight of the adrenal in the hypophysectomized rat. The metastases, normal liver from Patient 1, and control tumors without adrenal hypertrophy did not have this capacity. Although the dose administered to the hypophysectomized rats and the treatment of the rats are different, data of Marks and associ- ates 2, ” are included for comparisons. It appears that the weight-maintaining capacity of our tumors is
Effects on Adrenal Weight of Tumor Extract Compared with Saline Injection* in Hypophysectomized Ratest
| Material Injected | No. of Rats | Mean Paired Adrenal Weight in Mg ± VEd2/N | |
|---|---|---|---|
| (1) Saline | 10 | 6.8±0.5 | |
| (2) Extract of primary tumor (Case 1) | 8 | 8.8±1.19 | |
| (3) Extract of liver free of tumor (Case 1) | 9 | 6.8±0.34 | |
| (4) Extract of liver metastases (Case 1) | 8 | 6.9±0.40 | |
| (5) Extract of primary tumor (Case 2) | 10 | 8.6±0.44 | |
| (6) Extract of first control lung tumor | 8 | 6.6±0.20 | |
| (7) Extract of second control lung tumor | 10 | 6.9±0.21 | |
| (8) Extract of third control lung tumor | 10 | 6.9±0.25 | |
| Marks, Russfield, & Rosenbaum 2: | |||
| Tumor | 4 | 15.4 | |
| Saline control | 4 | 10.9 | |
| Marks, Rosenbaum, & Russfield 8: | |||
| Tumor | 4 | 15.4 | |
| Saline control | 4 | 10.9 | |
Note: It can be seen that extracts of the primary tumor in Patients 1 and 2 with hypertrophy of the human adrenals significantly in- hibit atropny of the adrenal gland of the hypophysectomized rat, while corresponding extracts from similar tumors in patients with normal adrenals do not have this capacity. Comparing (1) and (2), t = 4.02, degrees of freedom = 14, P<0.01; comparing (1) and (5), t = 7.39, degrees of freedom = 16, P<0.01. The difference in fre- quency of injection, amount of substrate, and time after hypophys- ectomy make comparison of our data and that of Marks and associates difficult.
*Twice daily for 10 days.
tMean paired adrenal weight of ten nonhypophysectomized rats was 39.2 ±3.0 mg.
less than that of theirs. Apparently both of their papers are based on the response of the same four hypophysectomized rats to the same tumor from a single patient.
Comment
An adrenal weight-maintaining factor in blood of patients with Cushing’s syndrome from pulmonary neoplasms has been reported.1º Therefore, our find- ing of an adrenal weight-maintaining factor in cases of carcinoma of the lung without Cushing’s syn- drome but with adrenal hypertrophy is not unex- pected. It affords an explanation for the large adrenal glands occasionally found in these patients. It does, however, require recognition that there are possibly two types of corticotropin, viz, a steroid- releasing type to cause the Cushing’s syndrome and a second weight-maintaining corticotropin to cause the adrenal cortical hypertrophy. There is good evi- dence that at least two separate corticotropins do exist, because Stack-Dunne and Young 11 have found a dichotomy in the adrenal weight-main- taining and adrenal ascorbic acid-depleting capacity of several corticotropin preparations. The latter method is the basis for USP assay for corticotropin. Hume and Egdahl 12 have succeeded in placing lesions in the hypothalamus of dogs, which resulted in histologically normal adrenals and pituitaries but very low secretory rates of 17-hydroxycorticoste- roids. They postulate that the neurocenter for regu- lating steroid releasing corticotropin had been destroyed, while that for the adrenal weight-main- taining corticotropin was unaffected.
Marks et al 13 report a case of epidermoid carci- noma of the lung without Cushing’s syndrome but with an exaggerated plasma corticoid response to corticotropin. At autopsy bilateral adrenal cortical hypertrophy was found. They postulate an adrenal growth factor. Belsky and Marks 14 report an exag- gerated plasma corticoid response to corticotropin of patients with carcinoma of the lung, some of whom at autopsy had adrenal cortical hypertrophy and diminished pituitary corticotropin content. Sim- ilar hyperresponse to corticotropin of patients with- out Cushing’s syndrome but with lung cancer has been reported by Hymes and Doe 15 and Werk and associates.16 The findings of these investigators would be in accord with those of this study if we assume that an increased amount of adrenal weight-maintaining corticotropin were present to cause the adrenal cortical hypertrophy, thereby al- lowing a hyperresponse to exogenously administered (steroid-releasing) corticotropin. This postulation concurrently would require steroid releasing cor- ticotropin to be diminished in the patient, otherwise Cushing’s syndrome would develop. Support for such a theory could come from finding a dimin- ished amount of corticotropin in the pituitary glands which were not assayed in our two cases.
The foregoing considerations are based on the
presumption of two distinct types of corticotropin. When we consider that Cushing’s syndrome can arise from such diverse tumor origins as parotid gland,17 lung, and anterior pituitary, it is apparent that the protein moiety of the corticotropin from these diverse tumors may differ slightly. Slight dif- ferences in amino acid construction of the cortico- tropin may affect different facets of adrenocortical function, this possibility having been considered more fully by Liddle and associates.18 It is also possible that both of the tumors presented here may have a slight content of corticosteroid-releas- ing corticotropin not detected by the method used. It
does seem that many patients without Cushing’s syndrome but with lung tumors do have slightly higher than normal plasma corticosteroid values.19 Final answers to these problems must await devel- opment of more sensitive and more specific assay methods.
Rainbow Blvd at 39th St, Kansas City 3, Kan. (Dr. Nichols).
This study was supported in part by a grant from the US Public Health Service.
Generic and Trade Names of Drugs
Mechlorethamine hydrochloride-Mustargen Hydrochloride. Corticotropin-Acth, Acthar, Corticotropin.
References
1. Meador, C., et al: Cause of Cushing’s Syndrome in Patients with Tumors Arising from “Nonendocrine” Tissue, J. Clin Endocr 22:693-703 (July) 1962.
2. Marks, L. J .; Russfield, A. B .; and Rosenbaum, D. L .: Corticotropin-Secreting Carcinoma, JAMA 183:115-117 (Jan) 1963.
3. Marks, L. J .; Rosenbaum, D. L .; and Russfield, A. B .: Cushing’s Syndrome and Corticotropin-Secreting Carcinoma of Lung, Ann Intern Med 58:143-149 (Jan) 1963.
4. Jarett, L .; Lacy, P. E .; and Kipnis, D. M .: Character- ization by Immunofluorescence of “ACTH-Like” Substance Produced by Non-pituitary Tumors, Amer J Path 43:11a (July)
5. Nichols, J .; Warren, J. C .; and Mantz, F. A .: ACTH- Like Excretion from Carcinoma of Ovary, JAMA 182:713- 718 (Nov) 1962.
6. Engel, F. L., and Kahana, L .: Cushing’s Syndrome with Malignant Corticotropin Producing Tumor: Remission and Relapse Following Subtotal Adrenalectomy and Tumor Resection, Amer J Med 34:726-734 (May) 1963.
7. Birmingham, M. K., et al: ACTH Content of Rat Pituitary Glands, Endocrinology 59:677-680 (Dec) 1956.
8. Nelson, D. H., and Hume, D. M .: Corticosteroid Se- cretion in Adrenal Venous Blood of Hypophysectomized Dog as Assay for ACTH, Endocrinology 57:184-192 (Aug) 1955.
9. Simpson, M.E .; Evans, H.M .; and Li, C.H .: Bioassay of Adrenocorticotrophic Hormone, Endocrinology 33:261- 268 (Nov) 1943.
10. Christy, N. P .: Adrenocorticotrophic Activity in Plas-
ma of Patients with Cushing’s Syndrome Associated with Pulmonary Neoplasms, Lancet 1:85-86 (Jan) 1961.
11. Stack-Dunne, M., and Young, F. G .: Properties of ACTH, J Endocr 7:1xvi-lxix (May) 1951.
12. Hume, D. M., and Egdahl, R. H .: Importance of Brain in Endocrine Response to Injury, Ann Surg 150: 697-712 (Oct) 1959.
13. Marks, L. J .; Anderson, A. E .; and Liberman, H .: Carcinoma of Lung Associated with Marked Adrenocortical Hyperplasia and Adrenal Hyper-Responsiveness to ACTH in Absence of Cushing’s Syndrome, Ann Intern Med 54: 1243-1248 (June) 1961.
14. Belsky, J. L., and Marks, L. J .: Plasma 17-Hydroxy- corticosteroid Responsiveness to ACTH in Patients with Bron- chogenic Carcinoma, Metabolism 11:435-442 (April) 1962.
15. Hymes, A. C., and Doe, R. P .: Adrenal Function in Cancer of Lung, With and Without Cushing’s Syndrome, Amer J Med 33:398-407 (Sept) 1962.
16. Werk, E. E .; Sholiton, L. J .; and Marnell, R. T .: Further Studies of Adrenocortical Function in Patients with Carcinoma of Lung, Amer J Med 34:192-212 (Feb) 1963.
17. Clinicopathological Conference: Cushing’s Syndrome Associated with Parotid Gland Tumor, Amer J Med 34:394- 406 (March) 1963.
18. Liddle, G. W., et al: Nonpituitary Neoplasms and Cushing’s Syndrome, Arch Intern Med (Chicago) 111:471- 475 (April) 1963.
19. Segaloff, A .; Hatch, H. B .; and Rongone, E. L .: Elevated Plasma Corticoids Associated with Lung Cancer, Cancer Chemother Rep 16:343-344 (Feb) 1962.
BERZELIUS 10
SVERIGE
SWEDISH PHYSICIAN PATHFINDER IN CHEMISTRY .-
Jöns Jacob Berzelius (1779-1848) was a Swedish physician but his reputation was established as a chemist. He introduced the modern system of writing chemical symbols and formulas and gave the world an alphabet of chemistry. Thus, he is regarded as founder of modern inorganic chemistry.
Berzelius was born in Westerlosa, Sweden. After his gradua- tion in medicine from the University of Upsala in 1809, he be- came a professor at the College of Surgery, Stockholm. He concentrated his re- search in the field of chemistry. Among his discoveries were the elements selenium, thorium and cerium. In 1804, he isolated biliverdin, a dark green bile pigment, formed in the body from hemoglobin but largely reduced in the liver to bilirubin, main pigment of bile.
He also served as professor of medicine at the Stockholm University and for 30 years as the secretary of the Stockholm Academy of Science .- Mirt, J.A .: Medical Pathfinders on Postage Stamps, an exhibit.