on an ether extract of HCl-hydrolyzed urine, purified by NaOH and NaHCO3 solutions (Pincus (2)). One milliliter of diluted formaldehyde solution (formalin, 40 per cent, diluted 1 to 5 with water) was enough to prevent color contamination of 50 ml. of urine. The part played by chromo- gens in the reaction was calculated by running a blank of each extract, in which alcohol was used instead of the m-dinitrobenzene solution. This blank showed 98 to 100 per cent light transmission (against water) for all the formaldehyde-treated extracts. A Coleman-Junior spectrophotometer was used for the measurements.
LUIS NÓRA ANTUNES, M.D.t
Rua Potiguar Medeiros 99, Pinheiros, São Paulo, Brasil
REFERENCES
1. HOLTORFF, A. F., and KOCH, F. C .: The colorimetric estimation of 17-ketosteroids and their application to urine extracts, J. Biol. Chem. 135: 377-392 (Sept.) 1940.
2. PINCUS, G .: The analysis of human urines for steroid substances, J. Clin. Endocrinol. 5: 291-300 (Sept.) 1945.
CHRONIC ADRENOCORTICAL INSUFFICIENCY AND CARCINOMA OF THE BREAST
TO THE EDITOR:
It has seemed possible to some investigators that steroid hormones of adrenal origin play an etiologic role in the development of carcinoma of the breast. This concept has led to many investigations of the urinary and blood steroids in cancerous patients. Furthermore, total or subtotal adren- alectomy has been advocated for patients with advanced cancer of the breast.
The fact that we have observed the appearance of cancer of the breast in a 32-year-old woman who had been adrenalectomized three and a half years previously for Cushing’s syndrome is, therefore, of interest. Because she had chronic adrenal insufficiency and had been maintained on constant small amounts of cortisone and desoxycorticosterone, adrenocortical dys- function or hypersecretion of normal hormones could hardly have been present when the tumor developed.
L. B. was 28 years of age when first seen by us in January 1952. At this time she pre- sented the classic clinical picture of Cushing’s syndrome. The blood pressure was 162 mm. Hg systolic and 116 mm. diastolic. Roentgenograms of the thoracic and lumbar
t Former assistant of the Faculdade de Medicina da Universidade de São Paulo, Physiology Department, Prof. F. A. Moura Campos.
spine revealed osteoporosis and compression and anterior wedging of three of the dorsal vertebrae. Results of other laboratory studies were unremarkable except for a diabetic type of glucose tolerance curve. The urinary 17-ketosteroids were 7.8 mg. per twenty- four hours. This finding suggested, but did not prove that the disorder was associated with bilateral adrenocortical hyperfunction rather than with an adrenal tumor.
On February 25, 1952 a right subtotal adrenalectomy was performed by one of us (C.M.S.) without difficulty. Over 90 per cent of the gland was removed and at the time it was questioned whether the small amount of remaining tissue would continue viable. On March 25, 1952 a total left adrenalectomy was performed after preoperative medi- cation with cortisone and desoxycorticosterone. In the postoperative period the blood pressure remained at about 130 mm. Hg systolic and 80 mm. diastolic. Postoperatively the patient was maintained on 25 mg. of cortisone per day, orally.
In an effort to ascertain whether or not she had chronic adrenal insufficiency, cortisone was discontinued on May 10, 1952; four days later she became anorexic, weak and de- pressed. Her blood pressure fell to 88 mm. systolic and 60 mm. diastolic and she appeared to be seriously ill. Analysis of a 24-hour urine specimen at this time revealed a low level of 17-ketosteroid excretion, viz., 1.2 mg. Cortisone was resumed in a dose of 25 mg. per day and she immediately improved. Thereafter, there was a gradual disappearance of the manifestations of Cushing’s syndrome. However increased melanin pigmentation of the skin became evident. In September, menstrual periods began. In October, treatment with 2 mg. of desoxycorticosterone daily (Linguets) was started, in addition to the cor- tisone. For the next three years her medication consisted of 25 mg. of cortisone and 2 mg. of desoxycorticosterone per day, and she was maintained in excellent health.
In July 1954, the diagnosis of chronic adrenal insufficiency was further substantiated by demonstrating that the low levels of urinary 17-ketosteroids were unaltered by eight- hour infusions of 25 units of adrenocorticotropic hormone daily for three days. When seen again in January and August 1955, she appeared to be in good health.
In early October 1955, i.e., three and a half years after the adrenalectomies, she noted a small mass in the left breast. Surgical removal of the mass was advised and on October 19, 1955 a right radical mastectomy was performed by one of us (C.M.S.). The specimen was examined by Dr. Dann B. Claudon and Dr. Gorton Ritchie, who reported as follows:
“Numerous sections of the biopsy specimen revealed breast tissue altered from nor- mal by the presence of neoplastic epithelial cells derived from ductal epithelium. The medium and small ducts frequently were plugged with solid masses of fairly well differ- entiated epithelial cells which were quite uniform in size and shape. Microscopic fields of many areas of the biopsy specimen showed that the tumor cells had frequently pene- trated the basement membrane of the ducts and had extended into the connective tissues of the breast. Growth in these regions was scirrhous in nature and was not accompanied by an appreciable inflammatory exudate.
Sections of the sixteen axillary lymph nodes revealed the presence of metastatic tumor in each. The tumor had more or less completely destroyed the architecture of the glands and had elicited a considerable degree of desmoplastic reaction. The histological and cytological features of the neoplastic cells in the nodes were similar to those ob- served in the breast tumor.”
Although we can not be certain that this patient did not possess a small fragment of adrenal tissue or some accessory adrenal tissue, we feel that, if present, it was inadequate to maintain life. The darkening of the skin, the low 17-ketosteroid excretion, the prompt appearance of clinical signs
of acute adrenal insufficiency upon withdrawal of replacement therapy, their quick disappearance following small “physiologic” doses of cortisone and desoxycorticosterone, and the lack of a significant rise in urinary ster- oid excretion upon administration of adrenocorticotropin intravenously, all support the idea that she had either no adrenocortical tissue or an ex- tremely inadequate amount.
The fact that she was kept alive and well for three and a half years with small constant doses of cortisone and desoxycorticosterone suggests that if these hormones played any role with regard to the carcinoma, it was merely one of permitting it to develop. This point of view is supported by Ingle’s interpretation (1) of the “permissive” role of the adrenal hormones in stress. Whatever the cause or causes of carcinoma of the breast may be, in our patient they appeared to be sufficient in themselves to initiate the malignant process and to allow it to progress, without any change in adrenocortical secretion. That our case is not unique is supported by the observations (unpublished) of Dr. R. G. Sprague at the Mayo Clinic. He has noted the development of cancer of the breast in 2 women with Addi- son’s disease. Because of these findings, it seems that considerable caution must be exercised when hypotheses of adrenal dysfunction or hyperfunc- tion are considered in relation to the genesis of carcinoma of the breast.
This report bears only indirectly on the problem of the efficacy of bi- lateral adrenalectomy in the treatment of advanced breast cancer. Although adrenalectomy may exert a transitory beneficial effect in some cases, this response may be due to other consequences of the operation (e.g., the re- moval of a source of estrogen) rather than to removal of the primary cause of the disorder. Huggins and Dao (2) reported that the better differentiated carcinomas show a high incidence of response to adrenalectomy, whereas the more anaplastic lesions do not. Although Pearson and his associates (3) found a similar correlation in general, there were exceptions to this rule because “some fairly well-differentiated tumors failed to respond and some anaplastic tumors did respond.” In our case the tumor was rather well differentiated.
The fact that our patient had Cushing’s syndrome prior to the adren- alectomies may also be of interest, but its significance is unknown. In a re- view of Cushing’s syndrome, Plotz and associates (4) reported that 10 per cent of the patients suffered from neoplasms (thymus or pancreas) other than those involving the adrenal or pituitary glands. This may seem to be a rather high incidence of associated carcinoma but it may not be signifi- cant. For example, it has been found that in a series of 100 consecutive patients dying of myocardial infarction, 9 per cent had malignant tumors (5); yet so far as is known, there is no relationship between myocardial in- farction and malignancy. Thus, there is no secure basis for arguing that
associated neoplastic disease is more or less common in patients with Cush- ing’s syndrome or even in those with Addison’s disease. In any event, the present case illustrates that malignant ductal carcinoma of the breast can occur despite the absence or virtual absence of functioning adrenocortical tissue.
WILLIAM W. ENGSTROM, M.D. NORMAN H. ENGBRING, M.D. C. MORRISON SCHROEDER, M.D.
Departments of Medicine and Surgery, Marquette University School of Medicine, Milwaukee, Wisconsin
REFERENCES
1. INGLE, D. J .: The role of the adrenal cortex in homeostasis, J. Endocrinol. (British) 8: xxiii-xxxvii (Oct.) 1952.
2. HUGGINS, C., and DAO, T. L-Y .: Adrenalectomy and oophorectomy in treatment of advanced carcinoma of the breast, J.A.M.A. 151: 1388 (April 18), 1953.
3. PEARSON, O. H .; WEST, C. D .; HOLLANDER, V. P., and TREVES, N. E .: Evaluation of endocrine therapy for advanced breast cancer, J.A.M.A. 154: 234 (Jan. 16), 1954.
4. PLOTZ, C. M .; KNOWLTON, A. I., and RAGAN, C .: The natural history of Cushing’s syndrome, Am. J. Med. 8: 597 (Nov.) 1952.
5. SPAULDING, W. D .; OLLIE, W. A., and GORNALL, A. G .: Mineralocorticoid-like dis- turbance associated with adrenal metastasis from a bronchogenic carcinoma, Ann. Int. Med. 42: 444 (Feb.) 1955.
EM