THE INCIDENCE OF OF MALIGNANT TUMORS TO THE ADRENALS

DANIEL A. GLOMSET, B.S. (From the Department 01 Pathology, University 01 Chicago)

The frequency with which adrenal metastases from malignant tumors are observed is striking, in view of the relative infrequency of secondary neoplastic deposits in many larger organs receiving a similar arterial supply. This great susceptibility of the adrenals to secondary tumor growth is not generally emphasized in the literature, though in some statistical studies figures are found indicating the predilection of certain tumors for metastasis to these or­ gans. Willis (4) in his monograph on metastatic tumors gives the following figures: In 323 autopsies on patients dying of malignant , blood­ borne secondary growths were present in the adrenals in 27 (8.3 per cent). Of these, 7 came from carcinomas of the breast, 3 from the , 3 from the colon, 2 from the thyroid, and 12 from miscellaneous sources. Willis found the incidence of metastatic growth in the adrenals to be greatest from carci­ nomas of the lung (20-30 per cent) and from malignant melanoblastomas. Warren and Witham (11) found the adrenals involved in 50 out of 162 cases of malignant tumors of the breast. In their series only the , , and bone were more frequently the site of organic metastases. Clark and Rowntree (10) report a series of 25,000 consecutive autopsies done at the Philadelphia General Hospital, in only 2 per cent of which were the adrenals examined histologically. They list 202 neoplasms of the adrenal, benign and malignant, of which 42 were metastatic-16 from the gastrointestinal tract, 8 from the breast, 4 from , 3 from lung carcinomas, and 3 from epi­ dermoid carcinomas. Ewing quotes Offergeld as finding the adrenals involved in 0.85 per cent of metastasizing carcinomas of the uterus, following the liver, lungs, and . Arkin and Wagner (1) found the adrenals to be involved more frequently than any other organ by metastases of pulmonary carcinoma (43 per cent), but Fried (6) lists the adrenals as following the liver, brain, and lungs as the site of metastases from lung carcinomas. Warren (13) reported the adrenals involved in only 0.2 per cent of malignant neoplasms of the stom­ ach and in 8 of 156 cases of carcinoma of the large bowel, following the liver and lung in incidence of metastases (12). Price (3), reviewing 158 cases of squamous-cell carcinoma, found metastases in 19, with adrenal involvement in only one. Mintz and Smith (2) in 100 cases of carcinoma of the prostate found a single case of adrenal metastasis. Apparently there has been no previous discussion of the relative suscepti­ bility of the adrenals to metastases in comparison with other organs having a similar blood supply. An analysis has therefore been made of 4000 consecu­ tive autopsies performed by the staff of the Department of Pathology of the University of Chicago up to and including 1936. These autopsies were per­ formed principally at Cook County Hospital and at Billings Memorial Hospital 57 58 DANIEL A. GLOMSET in Chicago. Brain tumors, Hodgkin's disease, , and leu­ kemias were excluded as instances of malignant growth because of their indi­ vidual peculiarities in form and metastasis. Cases of direct extension of a tumor from one organ to another, metastases to lymph nodes, and cases in which tumor emboli did not appear to be definitely lodged and growing in the tissues, were not regarded as instances of true organic metastasis. Finally, spread through the serous cavities was not considered as organic metastasis, since it does not lend itself to a study of the comparative incidence of organic spread and since most of these metastases were intracapsular and not growing in the organ itself. In this series of 4000 autopsies, 821 (20.5 per cent) showed evidence of malignant neoplastic growth, and in 445 (54 per cent) of these there were organic metastases. In 275 cases (34 per cent of all malignant tumors) there was metastasis to the liver. Forty-six per cent of these metastases, however, came from tumors whose primary site was in the portal area. In addition, 224 cases (27 per cent) metastasized to the lung, 110 cases (13 per cent) to the adrenals, 49 cases (6 per cent) to the kidneys, and 30 cases (3.7 per cent) to the spleen. Metastases to other organs were not enumerated.

TABLE I: The Incidence of Metastasis to the Adrenals

Percentage No. Per- No. Per- adrenal No. of centage of centage metastases Type of tumor of organic organic adrenal adrenal in cases met as- met as- metas- rnetas- organically tases tases tases tases metastasizing tumors ------Adrenal 7 6 86 5 72 83 Breast 43 37 86 25 58 68 Bladder 28 10 36 1 33.6 10 Colon 63 30 48 3 4.8 10 Esophagus 42 13 31 2 4.8 15 Gallbladder 28 19 68 2 7.1 11 Hypernephroma 14 10 91 3 21 33 Kidney. carcinoma 11 10 91 5 45 50 Larynx 15 5 33 0 0 0 Liver 12 5 4 1 8.3 20 Lung 66 49 74 24 36 49 Malignant melanoblastoma 10 10 100 6 60 60 Mouth and pharynx 37 11 30 0 0 0 Ovary 21 9 43 0 0 0 40 31 78 7 18 23 Prostate 40 22 55 2 5 9 Rectum 45 8 18 0 0 0 Retroperitoneal sarcoma 10 7 70 0 0 0 Stomach 140 66 43 7 5 11 Tongue 13 1 8 0 0 0 Uterus 29 14 48 1 3.5 7

The five primary malignant tumors most frequently encountered were, in order of their frequency, carcinomas of the stomach, large bowel and rectum, lung, breast, and esophagus (Table I). Forty-one per cent of the 140 cases of gastric carcinoma had metastases to other organs; 33 per cent of the 108 INCIDENCE OF METASTASIS TO THE ADRENALS 59 cases of carcinoma of the large bowel and rectum, 74 per cent of the 66 cases of carcinoma of the lung, 86 per cent of the 43 cases of carcinoma of the breast, and 31 per cent of the 42 cases of carcinoma of the esophagus. Tumors me­ tastasizing most commonly to other organs were the malignant melanoblas­ tomas (100 per cent) and the carcinomas of the kidney (91 per cent). Those metastasizing least frequently were tumors of the tongue, liver, and rectum. The tumors which metastasized to the adrenals most frequently were those which are well known to metastasize through the blood stream. Of the 20 tumors most often encountered in our series (Table I) those which metas­ tasized most frequently to the adrenals were: the malignant melanoblastomas (60 per cent), carcinomas of the breast (58 per cent), kidney (45 per cent) and lung (36 per cent).' If the instances of malignancy revealing no organic spread are excluded, the incidence of adrenal metastasis becomes even more striking. Sixty-eight per cent of those carcinomas of the breast with metas­ tasis to other organs, metastasized to the adrenals as well. The same holds for 50 per cent of carcinomas of the kidney and 49 per cent of carcinomas of the lung. In one case of carcinoma of the lung and one of carcinoma of the esoph­ agus the only organic metastasis was in the adrenal. Those tumors which metastasized less frequently to the adrenals were tumors of the oral cavity and pelvis. No metastases to the adrenals occurred in carcinomas of the tongue, mouth and pharynx, larynx, rectum, ovaries, or in the retroperitoneal sar­ comas. Carcinomas of the uterus, bladder, prostate, colon, stomach, esopha­ gus, liver and biliary system showed but a smaIl percentage of adrenal metas­ tases. In the 445 cases with organic metastases there were 20 cases with no record of either gross or microscopic examination of the adrenals. If these 20 cases are excluded, 25.9 per cent of organicaIly metastasizing tumors metastasized to the adrenals, The incidence may be even higher, for in 307 of the 821 cases of malignant neoplasms there was no microscopic description of the adrenals, and in 13 of the 110 cases of adrenal metastasis the metastasis was discovered only on routine microscopic section of the adrenal. This high incidence of metastasis to the adrenal is interesting in view of the claims that have been made that adrenal extract injections have an antagonistic effect on growth of human . Of the 110 tumors with adrenal metastases, there were 62 cases in which the secondary growths were bilateral, 31 in which they were unilateral; in 17 the location in the glands was not mentioned. Of the 31 unilateral metastases, 20 were in the left adrenal and 11 in the right. A similar difference has been noticed by WiIIis, who in a series of 69 cases of unilateral metastases collected from the literature found the left adrenal involved in 40 and the right in 29 instances. This he attributes to the larger size of the left adrenal. Among the 821 malignant tumors, there were 26 instances of direct growth into the adrenals and 7 primary adrenal tumors. One of these primary growths, a , was the largest adrenal tumor found, weighing 230 grams. The largest metastatic tumor had its primary site in the breast. In this case the left adrenal weighed 80 grams and the right 30 grams. In another

1 Malignant tumors primary In one adrenal metastasized in 72 per cent of cases to the opposite adrenal, but are not included in the above list because this was not one of the 20 most common primary sites. 60 DANIEL A. GLOMSET

case, a metastasis from a primary carcinoma of the lung was found in the right gland, weighing 72 grams. Apparently, however, metastatic growths fail to destroy enough adrenal tissue to produce clinical symptoms of insufficiency. In no instance in our series were there such, nor in a series of 42 secondary neoplasms of the adrenal studied by Clark and Rowntree (10). The liver and lung are, of course especially often the site of metastatic tumors, since they are the filters for the entire portal circulation and systemic venous blood. Despite the great opportunity for tumor emboli to be filtered off in these two organs, they are still behind the adrenal as a site for metastatic growth if the weight of the organ as well as the number of cases of metastasis is taken into account, for on this basis the adrenals are found to have the great­ est incidence of any organ studied. Our figures show for the adrenals an inci­ dence of 0.87 (this figure is obtained by dividing the percentage of adrenal metastases in all cases of malignancy, 13 per cent, by an arbitrary average weight of 15 grams), compared with 0.05 for the lungs (27 per cent, arbitrary average weight 600 grams), 0.02 per cent for the liver (34 per cent, arbitrary weight 1600 grams) , 0.02 per cent for the spleen (3.7 per cent, arbitrary weight 180 grams), and 0.02 per cent for the kidneys (6 per cent, arbitrary weight 300 grams). According to Willis' figures, the thyroid showed metastases in 4.6 per cent of malignant neoplasms (4). This gives to the only other organ in the body with a blood supply (per unit weight) greater than the adrenals an incidence of 0.15 (4.6 per cent, arhitrary weight 30 grams). These figures may be somewhat misleading in so far as they fail to take into account the number of metastases present in any given case in any given organ, and as the computative error is great, but they show that the adrenals, for their weight, catch and hold a large number of tumor emboli which find there a favorable soil for growth. The relative tendency of the adrenals to hold metastases is further empha­ sized when one contrasts them with the kidney and spleen, which receive blood from similar sources. Although the blood supply of the adrenals per unit weight is higher than that of either the kidney or spleen, the total amount of blood per minute flowing into the latter organs is much greater than in the adrenals, and one would expect, from purely mechanical considerations, that they would have a much greater chance to catch tumor emboli than the adrenals. Also, it would be expected, if the sinusoidal type of circulation were the only factor, that the spleen would hold more tumor emboli than the adrenal. The situation, however, is reversed. The adrenals showed 110 cases of met­ astatic tumor growth, whereas the spleen had only 30 and the kidneys 49.

CONCLUSIONS (1) In a series of 4000 autopsies there were 821 malignant neoplasms, of which 445 had organic metastases. Of the 821 cases, 34 per cent metastasized to the liver, 27 per cent to the lungs, 13 per cent to the adrenals, 6 per cent to the kidneys, and 3.7 per cent to the spleen. It is especially noteworthy that, although the kidneys, spleen, and adrenals are situated close together and have a similar blood supply, the adrenals have more metastases than either spleen or kidney, despite their much smaller size. INCIDENCE OF METASTASIS TO THE ADRENALS 61

(2) Of all organically metastasizing tumors, 24.7 per cent metastasized to the adrenals. If those cases in which no description of the adrenal is given are eliminated, this percentage rises to 25.9 per cent. This makes the adrenal incidence, per unit weight, higher than that of the thyroid, lung, spleen, liver, or kidney. (3) The high incidence of tumors which metastasize to the adrenals that have their primary site in the lung and breast, or in a malignant melanoblas­ toma, lead one to surmise that most adrenal metastases are blood borne. (4) These figures are in accord with those of Willis, which show that adrenal metastases are most commonly bilateral, but when unilateral are more prevalent in the left than in the right gland. (5) Tumors which only occasionally metastasize to the adrenals are those of the gastro-intestinal tract and the pelvic organs.

BIBLIOGRAPHY 1. ARKIN, A., AND WAGNER, D. H.: J. A. M. A. 106: 587, 1936. 2. MINTZ, E. R., AND SMITH, G. G.: New England J. Merl. 211: 479,1934. 3. PRICE, L. W.: Am. J. Cancer 22: 1, 1934. 4. WILLIS, R. A.: Spread of Tumours in the Human Body, Churchill, London, 1934. 5. BARNEY, J. D., AND MINTZ, E. R.: Tr. Assn. of Genito-Urin. Surg. 26: 233, 1933. 6. FRIED, B. M.: Medicine 2: 373, 1931. 7. EWING, J.: Neoplastic Diseases, W. B. Saunders Co., Philadelphia, Ed. 3, 1928. 8. MILLER, J. K.: Am. J. Surg. 32: 527,1936. 9. POLLIA, J. A., AND GOGOL, L. J.: Am. J. Cancer 27: 329, 1936. 10. CLARK, J. H., AND ROWNTREE, L. G.: Endocrinology 18: 256, 1934. 11. WARREN, S., AND WITHAM, E. M.: Surg. Gynec. & Obst. 57: 81, 1933. 12. WARREN, S.: New England J. Med. 209: 167, 1933. 13. WARREN, S.: New England J. Med. 209: 825.1933.