BRONCHIAL ADENOMAS IN CUSHING’S SYNDROME: THEIR RELATION TO THYMOMAS AND OAT CELL CARCINOMAS ASSOCIATED WITH HYPERADRENOCORTICISM
RICHARD B. COHEN, M.D., GILES D. TOLL, M.D., AND BENJAMIN CASTLEMAN, M.D.
T WO CASES of apparently benign pulmo- nary epithelial tumors of an unusual type have been studied. Both tumors, which were identical in location and histological pattern, developed in patients with known Cushing’s syndrome. An attempt is made to relate these neoplasms to the thymomas and undifferenti- ated pulmonary carcinomas that have been reported in association with hyperadrenocor- ticism.1, 2
CASE REPORTS
Case 1. A 33-year-old white man entered the hospital in October, 1953, complaining of flushing of the cheeks and emotional insta- bility of 1 year’s duration. Shortly after the onset of these symptoms he experienced facial and ankle edema, with a shift of tissue mass from the extremities to the trunk and a weight loss of 20 1b. He also had symptoms suggestive of a peptic ulcer that were controlled by diet. Physical examination revealed a blood pres- sure of 170 over 110 mm. of mercury, a “moon face” with acne, a “buffalo hump,” wasted extremities, and slight ankle edema. Labora- tory studies showed normal serum electrolytes and hemoglobin. Separate subtotal adrenalec- tomies were done, and both glands showed hyperplasia. The manifestations of the Cush- ing syndrome gradually subsided in 2 years. A follow-up roentgenographic examination 2 years after the operation revealed a mass in the left lung at the level of the third rib. At operation a well circumscribed, light gray, spherical mass, 1.4 cm. in diameter, was found 1. cm. from the resection edge and 0.3 cm. from a small bronchus, and a lingulectomy was done (Fig. 1). The nodule was easily shelled out of the surrounding parenchyma,
From the Department of Pathology, Harvard Medical School, and the James Homer Wright Pathology Lab- oratories, Massachusetts General Hospital, Boston, Mass.
This study was supported by a research grant (C-3424) from the National Cancer Institute, of the National Institutes of Health, Public Health Service. Received for publication Aug. 14, 1959.
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and cut sections revealed a trabeculated light- yellow tissue. Three years later there were no further pulmonary abnormalities and no evi- dence of recurrent Cushing’s syndrome.
Case 2. A mother of 1 child was first ad- mitted to the hospital in 1951 at the age of 25 years with a history of 1 month’s duration
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of “moon face,” acne, increasing obesity of the trunk, hirsutism, muscular weakness, easy bruisability, and amenorrhea. Bilateral sub- total adrenalectomies were performed in 2 separate procedures, and cortical hyperplasia was found on each side. The postoperative course was complicated by mental depression but was otherwise unremarkable. Three months later the Cushing’s syndrome had largely cleared, and she seemed cheerful. In 1954, a frontal lobotomy was performed at another hospital because of severe depression. Shortly afterward, the symptoms of Cushing’s syndrome recurred, and adrenal hyperactivity was confirmed by laboratory data. One year later an adenoma of adrenal cortical tissue was removed from the right side. At that time a chest roentgenogram showed multiple cir- cular densities that were thought to represent calluses forming about rib fractures secondary to osteoporosis. During the next 2 years the manifestations of Cushing’s syndrome sub- sided, as did the chest densities except for a small circular lesion in the left upper lobe that seemed unrelated to the ribs. A review of previous films revealed that this density had been present several years earlier. This mass doubled in size during the subsequent year (Fig. 2), and a left upper lobectomy was done. Examination of the resected lobe showed a 1.5-cm., loosely encapsulated, soft, light-yellow, circular mass in the inferior portion of the apicoposterior segment, 2.5 cm. beneath the pleura. The mass appeared contiguous with a small bronchiole.
HISTOLOGICAL FINDINGS
These neoplasms were identical histologi- cally. The tumor was composed of nests and sheets of uniform cells, round to polyhedral in shape, with moderate quantities of eosin- ophilic cytoplasm (Figs. 3 and 4). The nuclei were located centrally and were uniform and round to oval, with occasional nucleoli. A rare mitotic figure was noted. The stroma was scanty, composed largely of thin septa of loose connective tissue that incompletely separated cell nests. Large areas of the tumor showed little or no connective tissue between the cells. Vascularity was not a conspicuous character- istic, and there was no necrosis or calcification. The tumor was circumscribed (Fig. 5) but had infiltrated alveoli focally at its periphery. Re- ticulin was largely confined to the scattered septa and perivascular areas (Fig. 6). In both cases the neoplasm was located directly be- neath the epithelium of a small bronchus (Figs. 7 and 8). No metachromasia was dem- onstrated when toluidine blue was utilized, and the cells were uniformly negative to the periodic acid-Schiff and mucicarmine reac- tions. An argentaffin reaction was negative in case 2; none was done in case I.
RELATION TO BRONCHIAL ADENOMA
On the basis of the morphological findings and the short clinical observation, these tu-
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FIG. 9. A thymoma removed surgically from a patient with Cushing’s disease.
FIG. 10. The adenoma in case 2. (x400.)
FIG. 11. A section of a metastatic nodule in the liver from a pulmonary oat cell carcinoma removed from a patient with Cushing’s syndrome. (x400.)
FIG. 12. The primary oat cell carcinoma from the lung of the patient in Fig. 11. Note the dense hyalinized stroma and the lack of differentiation. (x125.)
FIG. 13. Liver metastasis from the tumor noted in Fig. 12. The metastasis appears more differentiated than does the primary tumor. Compressed liver cells are seen in the upper left. (x125.)
FIG. 14. A thymoma obtained from a patient with Cushing’s syndrome. Note the similarity to the tumor in Fig. 13. (×125.)
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(For captions see opposite page.)
mors may be tentatively classified as a form of peripheral bronchial adenoma.3 They did not resemble the classic carcinoid or cylindroma- tous varieties.
RELATION TO THYMOMAS FOUND IN CUSHING’S DISEASE
We have had the opportunity to study 9 of these interesting tumors collected from many institutions. The thymomas associated with Cushing’s disease observed by us are unusual and resemble none of the other varieties of thymoma.1
These tumors are composed entirely of cells that are clearly epithelial and not ad- mixed with lymphocytes. The histological similarities between the tumors described in the present study and these thymomas is strik- ing. The cell type and arrangement were often identical, as were the reticulin pattern and the reaction to other special stains (Figs. 9, 10, and 11).
RELATION TO UNDIFFERENTIATED PULMONARY CARCINOMAS (OAT CELL) ASSOCIATED WITH HYPERADRENOCORTICISM
We have observed 2 cases of this type of tumor; in both it had metastasized extensively. In these cases the tumors in the lung resem- bled oat cell carcinomas with a tendency to- ward hyalinization of tumor stroma (Fig. 12). In the metastases, the tumor appear more dif- ferentiated, and the cell type and arrange- ment closely resembled those observed in the adenomas and thymomas previously discussed (Figs. 9, 10, 11, 13, and 14) although, as might be expected in a malignant tumor, much more atypicality was found. This observation was not made in the original study of these tumors, but only became apparent in retro- spect after review of the thymomas and ade- nomas.
DISCUSSION
In the past few years particular attention has been drawn to 2 groups of neoplasm of intrathoracic origin that apparently occur in a more than coincidental relation to hyper- adrenocorticism: one type arises in the thymus and is considered a variety of thymoma, but is unique in that it is composed entirely of plump epithelial cells and is devoid of lympho- cytes; the other is a pulmonary neoplasm re-
sembling oat cell carcinoma. In this paper we present 2 tumors that we believe represent a third group, a peculiar type of bronchial ade- noma, and it seems likely that its association with Cushing’s disease is based on more than chance.
If the tumors had been bronchial adenomas of the common type, the association would be less impressive. The fact that they are his- tologically identical seems particularly signifi- cant, and their common location in the lingula is interesting. There is a striking similarity between these 2 tumors and the thymomas associated with Cushing’s disease. The resem- blance is such that a frozen section done on the tumor in case 1 was at first interpreted as a thymoma. The hints of histological simi- larity between these peculiar adenomas and the clearly malignant pulmonary oat cell carci- nomas are also provocative. Caution must be exercised in interpreting functional signifi- cance on the basis of morphological similari- ties, but we suggest that these 3 varieties of intrathoracic tumor associated with hyper- adrenocorticism arise from a common cell type, which may, as a result of unusual stimu- lation, become neoplastic. The ultimate sig- nificance of the association of the endocrine syndrome with any of these neoplasms is not known.
Although all of the cases have been associ- ated with adrenocortical hyperplasia and 1 (case 2, this report) with an adrenocortical adenoma, there is no evidence that a thy- moma, pulmonary carcinoma, or pulmonary adenoma has the capacity to secrete a sub- stance that directly or indirectly stimulates the cortex. It is unlikely that the tumor itself secretes an adrenocortical-like hormone, but unusual secretion of the adrenal cortex may stimulate the production of the thoracic neo- plasms.
The possibility that a common stimulus is responsible for both the neoplasms and the adrenocortical hyperplasia must also be con- sidered. Definitive explanation of this inter- esting phenomenon awaits study of accumu- lated cases with chemical and biological in- vestigations of the tumors and the patients in whom they develop.
SUMMARY
Two cases are reported in which a bron- chial adenoma developed in a patient with Cushing’s syndrome. The adenomas were
identical in size, location, histology, and re- action to special stains. These tumors were of unusual pattern and cannot be classified with the carcinoid or cylindromatous bron- chial adenomas. A distinct histological resem- blance of these bronchial adenomas to the thy- momas and the oat cell carcinomas that arise in association with hyperadrenocorticism was observed.
Cohen et al. REFERENCES
1. CASTLEMAN, B .: Tumors of the Thymus Gland; Atlas of Tumor Pathology, sect. 5, fasc. 19. Washing- ton, D.C. Armed Forces Institute of Pathology. 1955; p. 65.
2. KOVACH, R. D., and KYLE, L. H .: Cushing’s syn- drome and bronchogenic carcinoma. Am. J. Med. 24: 981-988, 1958.
3. LIEBOW, A. A .: Tumors of the Lower Respiratory Tract; Atlas of Tumor Pathology, sect. 5, fasc. 17. Washington, D.C. Armed Forces Institute of Pathol- ogy. 1952; pp. 38, 39.
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