Adrenal glands and malignancy

ADRENAL GLANDS AND MALIGNANCY *

BORIS SOKOLOFF, M.D., SC.D. AND ISIDORE ARONS, M.D.

NEW YORK CITY

F IFTEEN years ago, a general opinion prevailed among the carcinologists that the endocrine system had no di-

rect or even indirect connection with the evoIution of malignancy. At that time, only a few, and most notabIy Dr. Leo Loeb, suspected that some of the hormones might have carcinogenic properties. During the intervening period, however, considerable material has accumuIated strongly indicat- ing that the endocrine system may be di- rectly or indirectly involved in the process of neoplastic formation.

Lacassagne and Loeb, and after them nu- merous other investigators, demonstrated the carcinogenic activity of estrin. In cer- tain strains of mice in whom mammary cancer occurs spontaneousIy in only a very smaI1 proportion of the femaIes (2 to 3 per cent), the normal rate was increased by estrin injections to 60 per cent in both sexes.l An important observation has been recently reported by Geschickter, who was able to obtain, by injection of estrogenic substances, a large number of mammary adenocarcinomas in both male and femaIe rats of a strain in which since 1934 no spontaneous cancer had been registered in a coIony of 2000 animaIs.2

Corner suggested that the ovarian hormones act on the mammary gland through the intermediary of the anterior pituitary. Nelson3 injected estrin and noticed a diminution in the number of basophiles in the pituitary and the disappearance of castra- tion cells in the previousIy castrated animals of both sexes. He obtained a greater reaction in the female than in the male rats. Collip and his co-workers4 found that administration of Iarge doses of estrin to femaIe rats led to a hypertrophy of the anterior lobe within a few days-an effect which was less marked in maIes and

in castrates. Other observers5 found that estrin increased the weight of the pituitary in males, while McEuen, SeIye and Collip6 reported that adenoma formation sometimes occurred. According to Wolfe and co-workers,7~8 the change caused by estrin treatment in the anterior lobe of the rat’s pituitary is manifested in a degranura- tion of the eosinophiIe and basophile cells and in an increase in size and number of the chromophobe ceIIs.

B. Zondekg observed that foIIowing prolonged administration of estrin the function of the anterior pituitary is inhibited. The gIand becomes enlarged and increased in weight in males, while in femaIes pituitary tumors may be observed. Cramer and HorninglO reported that a proIonged application of estrin to mice resulted in functional inactivity, producing a condition resembling that following hypophysectomy; a hyperpIasia of the anterior lobe was observed with noticeable diminution of chromophiles and increase of chromophobe ceIIs. According to Burrow,” this hyperplasia occasioned by estrin could be observed in males onIy on rare occasions.

Halpern and D’Amour12 observed that the administration of estrin causes an increase of IOO to 200 per cent in the weight of the hypophysis, produces hypertrophy and hyperplasia of the chromophobe cells, with increased mitosis. These effects were interpreted as an indication that estrin causes a release of gonadotropic hormones, and that when the secreting capacity of the gIand is excelled by demand, compensating hyperplasia of the primary cells resuIts.

In general, a greater reaction takes place in the females than in the males. Thus, in large doses, hypertrophy of the anterior lobe is noted within a few days in femaIes. FolIowing prolonged administration of

* Report to the Annual Meeting of the North American RadiologicaI Society, November, 1938.

471

472 American JournaI of Surgery SokoIoff, Arons-AdrenaI GIands SEPTEMBER, ‘$340

estrin there appears an emargement of the pituitary with production of adenomata, an inhibition of the activity of the anterior Iobe and of the growth and sex hormones.

KarIefors13 in 1920 reported that in cancer (in man) the chromophobe ceIIs of the pituitary were increased in size. RSssIer14 observed an increase in the eosinophiles in case of chorionepitheIioma. Guyer and CIaus15 described changes in the anterior pituitary in rats who were bearers of FIexner carcinoma. The anterior pituitary was found to resembIe that of castrated animaIs, with an increase in basophiIes and with hyperactivity. These investigators concIuded that changes are brought about by the influence of the growing tumor on the gIand. When carcinoma is transpIanted to the uterus, there is an increase in acido- phiIe ceIIs in the pituitary, resembIing the phenomenon observed foIIowing estrin injections. Wyeth16 found an increase in the eosinophiIe ceIIs in the presence of human cancer. The gIand is aIso heavier than nor- ma1 (weight increase of 0.60 to I .80 Gm.). EngeIl’ recorded loose structure of pituitary in the majority of tumor mice. Mende- Ieefls concludes that pituitary hormona1 activity increases during the evoIution of a tumor and that the hypophyseal growth hormone is responsibIe for the continued proliferation of a neopIasm once this has been initiated. Lacassagne and Nykalg observed that after the hypophysis has been destroyed, rabbits appeared to be Iess sus- ceptibIe to carcinogenic action of both tar and benzopyrine, as we11 as to inocuIation with Shope papiIIoma. SamueIs and BaI120 confirmed this observation. They found that the pituitary is a factor in tumor growth, since hypophysectomy retards the growth rate of WaIker carcinoma in rats and aIso sIows the rate of growth of subcutaneous tumor induced by debenzanthracene.

Summarizing these observations we may say that there seems to be a definite increase of basophiIes, as we11 as of pituitary hormone activity in maIignancy, the re- verse of which is observed under estrin therapy. Gonadectomy aIso Ieads to hyper-

trophy of the pituitary, with an increase of basophiIe ceIIs and an increase in the gonadotropic hormones.

These observations are receiving particu- IarIy interesting interpretation in the Iight of the recentIy pubIished work by Loeb and Kirtz.21 The transpIantation of anterior Iobes of the hypophysis causes a marked deveIopment and secretory activity in the mammary gIand tissue, both in strains with a high and with a Iow incidence of spontaneous mammary gIand carcinoma. These transpIants aIso cause a considerable increase in the cancer rate. The authors point out that the mechanism depends upon the co6peration of functioning ovaries, transpIantation being entirely ineffective in ovariectomized mice. There is a possibiIity that the suppression of the IuteaI hormona1 activity and the foIIicuIar hormona1 over- activity is a contributing factor directIy promoting growth processes in the mammary gIands. In a number of mice which had received anterior Iobe transpIants there occurred, in addition to the mammary gIand changes, precancerous proliferations in the vaginaI-cervica1 tract.

In his previous work Loeb,22123 has estab- Iished that ovariectomy causes a marked reduction in the incidence of mammary cancer. If in mice beIonging to strains with a high incidence (aImost IOO per cent) of mammary adenocarcinoma, the ovaries are extirpated at the age of 3 or 4 months, the cancer incidence faIIs to zero. These lind- ings, confirmed by other workers (Cori, Laccasagne) are now interpreted as indicat- ing that excess of foIIicuIar hormone, acting on the mammary gIand, causes the transformation of norma mammary gland tissue into cancerous tissue.

GIanduIar imbaIance, observed in mammary cancer, is not Iimited to the anterior pituitary and the ovaries. In 1929, SokoI- offz4 found that the adrenaIs of chickens who were bearers of Rous sarcoma, increased to from three to four times their normal weight. Some increase in the weight of adrenaIs was found in FIexner carcinoma rats and in sarcoma #r$o mice. In 1934,

NEW SERIES VOL. XLIX, No. 3 SokoIoff, Arons-Adrenai Glands A rnerican .Iourn:dofsilr~~r~ 473

Tamuraz5 confirmed these observations. whether spontaneous1-y in the females or More recentIy, Sure, Theis and HarreIsonz6 in response to estrin- in the maIes. This found that ” in WaIker carcinosarcoma phenomenon was confirmed subsequentIy

FIG. I. Adrenal cortex of normal chicken FIG. 2. AdrenaI cortex of Rous sarcom:) (Sudan III).

the weight of the adrena is aImost doubIed.

0kamottoz7 found that Kato rabbit sarcoma eIicits proliferative changes in the adrena cortex of rabbits and according to 0ike28 in tar cancer the adrenaIs of rabbits are greatly enIarged.

McEuen and SeIye2g and SaIa and Stein30 described a Ieucocytic infiltration of the ad- renaIs of tumor-bearing rats, particuIarIy in the zona fascicuIata. This was thought to be due to the necrosis of adrenaIs.

Cramer and Horning31 observed a brown degeneration in the adrenaIs of mice of mixed strains which had been painted with estrin. IsoIated Iipoid-containing ceIIs in the zona reticuIaris were enIarged and their contents were transformed into a brown materia1. Degeneration became more extensive during proIonged administration of estrogenic substances. AIthough brown degeneration did not occur in norma mice, it occurred spontaneousIy in male and femaIe mice where there was a high incidence of mammary carcinoma among the females. The important point, according to these authors, is that these adrenal Iesions fuIIy deveIoped before mammary cancer occurred,

chicken showing fatty degeneration (Sudan III).

by Lacassagne and Raynaud,“2 Burrows,33 and DobrovoIskaia-Zavadskaia.34-35 In a recent pubIication, Cramer and Horning36 reported that in the two high cancer strains the brown degeneration began very earIy and after six months was present in a11 mice. MaIes and femaIes of equal ages were found to be about equaIIy affected. The brown degeneration affected not onIy the cortex but the meduIIary cells of the gIand as weI1. They believe that “an impairment of the functiona activity of the adrena meduIIa favors the action of the ovarian estrogens on the mamma.” Experiments on adrenaIectomized mice had Ied them to the concIusion that “the hormona1 functions of the adrena cortex are synergic with the estrogenic functions of the ovary.”

BaII and SamueIs37 found that the adrenals are enIarged in tumor-bearing rats. But in hypophysectomized rats bearing WaIker carcinoma this hypertrophy of the adrenaIs was absent and, as is usual in hypophysectomized animaIs, atrophy of the adrenaIs was present. The authors conclude that the reaction of the adrenaIs to tumor growth is not a direct one but a reflection

474 American Journal of Surgery SokoIoff, Arons-AdrenaI GIands SEPTEMBER, 19‘%0

of modification in pituitary hormona1 activity in case of mahgnancy.

Reviewing these observations Ieads to an

FIG. 3. Adrenal cortex of Rous sarcoma showing vacuolation of spongiocytes.

indication that in maIignancy, as we11 as under estrin apphcation, there occur his- toIogic changes in the adrenaIs which seem to have a cIose interreIation with the reaction of the anterior pituitary.

Our study on this subject has been con- ducted for over a period of years, embrac- ing extensive materia1. We have examined the adrenals of chickens, bearing Rous sarcoma; of rats, bearing Flexner carcinoma, sarcoma #39 and #IO; and of mice, bearers of sarcoma #I 80. *

TABLE I ADRENAL WEIGHT IN CHICKENS

Types

Average No. Weight,

Mg.

NormaI............................ 5 100.8 SmaII tumor.. . . . Medium tumor. , . . . . . . 1:

136.0 169.0

Largetumor........................ ro 332. o

The most striking changes were observed in the adrenaIs of Rous sarcoma chickens. With the progress and growth of t.umor the

*A Iarge part of this work was done by one of us (B. S.) in Dr. Leo Loeb’s Laboratory at Washington University Medical School, St. Louis,

weight of adrenaIs steadiIy increased, reach- ing as high as four times the norma weight. (TabIe I.)

The adrena hypertrophy in tumor-bear- . ing chickens affects chiefIy the cortica1 part of the gIand. (Figs. I and 2.) The cortica1 ceIIs in mahgnancy are increased in voIume, lose their typical structure and become fiIIed with fat. The spongiocytes are in a state of vacuoIization (Fig. 3), with picnotic nucIeus and modified ceIIuIar structure.

The adrenaIs of tumor mice and rats show Iess pronounced increase in weight than in chickens. The average increase is about 80 to 90 per cent of the normal rate. Here there are two distinct stages of glan- dular reaction: cellular hyperactivity in the beginning of tumor growth, and hypoactiv- ity and pathologic Iesions in advanced mahgnancy.

In the adrena of the female mouse the meduIIa and cortex are not separated by a defined band of connective tissue, as they are in the maIe. The juxtameduhary zone of reticuIar cells almost completely disap- pears when the males reach the age of two months but in the femaIes it continues to growth until puberty, but it is here that the first ceIIuIar reaction to tumor growth is observed. The reticular ceIIs, normally free of pigmentation, show the first signs of granuIation and mitochondrial activity. The number of AItmann granuIes, which are considered as representing preIipoids, are aIso increased. GraduaIIy, with growth of the tumor, the fatty degeneration is more pronounced, the AItmann granuIes disappear almost compIeteIy and the spongiocytes are filIed with fat.

Soon after the transpIantation of a tumor and with the first sign of the tumor growth there is an increase in the number of Iarge reticuIo-endothelia1 ceIIs, particuIarly in the zone outside the meduha. With the progress of mahgnancy these ceIIs disappear aImost compIeteIy from the zona reticularis and onIy a few pIasma ceIIs are found. Intensive vacuoIization of cytopIasm around the nucleus in plasma ceIIs indi- cates a specific regressive process (Stoerk).

tin\\ St RI,:!2 vo.. 41.1x, No. 3 SokoIoff, Arons-Adrenal Glands A ,ll‘liC‘lI1 01111,:11 (II sulg(.iy ,.' J 475

GraduaIly, the zone fascicmata aIso shows BiIateraI adrenaIectomy was performed a sign of degeneration. (Figs. 4 and 3.) on thirty rats. Ten days after the opera-

Cortical Extract. In 1930, ArIoing, Jos- tion, tumors were grafted (twelve rats with

FIG. 4. FIG. j.

FIGS. 4 AND 5. Adrenal cortex of mouse with sarcoma.

serand and Charchon3* found that adrena cortex extract had inhibiting and even cu- rative effects in mahgnancy, but a number of other authors3g-41 could not achieve these resuIts. More recentIy, Beard42 using concentrated cortica1 extract and supracorsin was abIe to obtain some inhibiting effect on the growth of WaIker carcinosarcoma. We have found that Wilson corticaI extract had no effect on sarcoma #18o. Large doses of the same extract produced a slight inhibiting effect on FIexner rat carcinoma.

Adrenalectorny. Rogoff and others have demonstrated that biIatera1 adrenaIectomy has a pronounced inhibiting effect on the growth of transpIanted tumor. Tamura,41 however, found onIy sIight inhibition from destruction of both adrena gIands.

According to our experiments on twenty rats, uniIatera1 adrenaIectomy had no effect on the growth of sarcoma #3g. The opera- tion was performed at the same time when the graft of tumor was made. BiIateraI adrenaIectomy had a definiteIy inhibiting effect on the growth of FIexner carcinoma and sarcoma 39, if the graft folIowed the adrenaIectomy.

Flexner carcinoma, eighteen rats with sarcoma #39). The animaIs were maintained on smal1 amounts of suprarenal extract, injected subcutaneousIy. The adrenalectomized animaIs were rather apathetic and Iacking in their usua1 vitaIity. Two animals died, probabIy from Iarge tumors (sarcoma 3g), and two others from infection. The rest seemed to show a strong resistance towards grafts. In the contro1 animaIs, two rats out of eighteen showed regression of tumors, the remaining sixteen dying from malignancy.

Similar resuIts have been obtained with FIexner carcinoma. OnIy in two instances out of tweIve did the adrenalectomized ani- maIs die from malignancy.

In other series of experiments, in which the graft preceded adrenalectomy, the inhibition of the tumor growth was much less pronounced.

Considering the fact that bilateral ad- renaIectomy reflects considerably on the genera1 condition of animals, the inhibiting effect of destruction of adrenaIs on tumor growth should be minimized. We know that the genera1 welI-being of the animal is an essentia1 factor for successful transplanta-

476 * merican Journal of Surgery SokoIoff, Arons-AdrenaI GIands SEPTEMBER , 1940

tion of cancer. NevertheIess, adrenaIectomy to seventy-two hours after the operat Zion. seems to have some inhibiting effect on InitiaI necrosis manifested itseIf in the tumor growth. center of the gIand, then graduahy ex-

FIG. 6. FIG. 7.

FIGS. 6 AND 7. Transplanted adrena cortex showing initial necrosis (mouse).

Adrenal Grafts. AdrenaIs extirpated from brothers or sisters were transpIanted to rats which had abeady been inoculated

FIG. 8. InitiaI necrosis.

with sarcoma #3g (thirty rats) or FIexner carcinoma (twenty rats). The adrena gIand was transpIanted either to ovaries or intracutaneousIy.

As a ruIe, degeneration of the trans- pIanted gland fohowed within forty-eight

tended ‘peripheraIIy. (Figs. 6 and 7,) Three days after grafting, the adrena gIand, ex- cept for the capsule and the exterior portion of the zona gIomeruIosa, was destroyed.

At about this stage the first signs of regeneration of the cortica1 tissue were noticed, but this regenerative activity of the cortica1 tissue was very smaI1 and the amount of restored cortex was rather insignificant.

We couId not observe any noticeabIe effect of the grafting on the growth of the tumor. In three cases there was some inhibition of tumor growth, but this was onIy temporary.

Studying the regeneration of cortica1 tissue of grafting adrenaIs, we found con- siderabIe difference in regenerative power, depending on the progress of maIignancy. In those cases where the animaIs had smaI1 incipient tumors, the adrenal transplant showed much Iess regenerative activity. In cases where the adrenaIs were grafted in animaIs with Iarge tumors, the regenerative process was much more extended.. The organism of animaIs affected with advanced maIignancy must have some physiologic

Nru SFR~PS Var.. XI.IX. No. 3 SokoIoff, Arons-AdrenaI Glands A m&can Journal l,T\nrpery J.7’

need for the biologic principIe eIaborated by the adrenal grand. The function of the adrenal cortex seems to be in a suppressed stage in cases of advanced malignancy.

Recently Wyman and turn Suden43 con- cluded from a series of their studies on adrena grafts that surviva1 of a graft de- pended on the presence of the pituitary adrenotropic principIe. They expressed the belief that this was used in the growth and maintenance of the norma adrenaIs, and thus adrena grafts without avaiIabIe adrenotropic principIe faiIed to survive. Their theory finds conlirmation in the recent work of Ingle.44

DISCUSSION

Regaud pointed out that in a11 probability a state of hyperactivity of some glands precedes the appearance of maIignancy. Yet the nature and character of this glan- dular dysfunction has not been cIearIy de- lined. However, it is a we11 estabIished fact that prolonged appIication of estrin inhibits the activity of anterior pituitary, including the production of the growth and sex hormones. Should we therefore consider estrin over-production as a potentia1 precancerous state, since estrin has definite carcinogenic properties?*

Some evidence in support of this theory was brought out in the recent work of Leo Loeb, who found that anterior pituitary transplants increased the incidence of mammary gIand carcinoma in inbred strains of mice. However, the transplants of hypophysis were completeIy ineffective when the ovariectomy preceded the trans- plantation. Thus, Loeb conchrdes, the growth-stimulating effect of anterior pituitary transplant on the mammary gland is not direct but through the ovaries, in a11 probability through the corpus Iuteum.

Corpus Iuteum seems to have an inhibiting effect on the growth properties of es-

* Biologically, the suppression of growth hormone could be responsible for abnormat ceIIuIar multipli- cation. Suppression of the growth of cell increased the dynamic properties of its nucleus. According to Sokol- ~ff,*~ the nucIeocytoplasmic ratio of cancer cells of incipient growth is considerabIy increased.

trin. Thus we may visuaIize that an increase of anterior pituitary’s activity may resuIt in suppression of corpus Iuteum and deliberation of estrin-growth-stimulating factor.

These experimenta data might be of considerabIe importance in cancer therapy, particuIarIy in the case of malignancy of the mammary gland or uterus. They would suggest a sterilization in the earliest stage of malignancy as the most rationa method of prevention of recurrence of growth.

The functional relations between the ad- renaI cortex and gonads are very close. The most striking fact in this relationship was brought out by Rogoff46 who showed that pregnancy has a marked influence in dogs in proIonging the period of surviva1 and maintaining good heaIth after the removal of adrenaIs. The corpus Iuteum can pre- sumabIy contribute something to make up for the loss of the adrenaIs. Goormachtich4’ recentIy suggested that the juxtameduhary celIs of the adrena and the JuteaI cells of the ovaries have something in common. Every change in the activity of the gonads reflects on the adrenal cortex, and vice versa. In n-avitaminosis, the adrenaIs may be enIarged from five to seven times, there may aIso be a striking atrophy of the gonads (in pigeon).

Thus the question arises, what role, if any, does the adrena gland pIay in maIignancy? Cramer found that the ad- renaI cortex of mice with a high incidence of mammary carcinoma has pathoIogic le- sions which couId not be observed in norma mice and which preceded the appearance of malignancy. Tamura confirmed the observation of one of us (Sokoloff) pub- lished some years ago, that the weight of the adrenal gland is increased in mahgnancy. A number of other authors have re- centIy described various histologic changes in the adrenal cortex of cancerous rats and mice.

AnaIyzing our materiaI on this subject, we found that there are at Ieast two different ceIIuIar reactions of adrenal cortex to tumor growth. In the precancerous state

4?8 American Journal of Surgery SokoIoff, Arons-AdrenaI GIands SEPTEMBER, 1940

there exists in the reticuIar zone of the adrena ceIIuIar stimuIation and gIanduIar hyperactivity. In advanced maIignancy, there is ceIIuIar degeneration and gIanduIar hypofunction.

These experimenta findings seem to be in accord with cIinica1 observations on cancer patients. The feeIing of weII-being and even of unusua1 energy, which has often been noticed in patients with incipient cancer, is soon repIaced by a feeIing of extreme fatigue which often cannot be expIained by anemia or toxemia, but may we11 be ac- counted for by the presence of Iesions in the adrenal. We have, however, no proof that these adrena Iesions are contributing fac- tors to the progress of maIignancy. They may be nothing but a reflection of gonado- pituitary dysfunction. And even the fact that biIatera1 adrenaIectomy considerabIy inhibits the growth of transpIanted tumor does not necessariIy prove that the adrena pIays an active rBIe in cancer. OnIy one statement may be made safeIy at present: that in maIignancy cortico-adrena imbaI- ante is present.

SUMMARY

The interreIation between tumor growth, the anterior pituitary, and the adrena glands is discussed.

The histoIogic changes in the adrenals of chickens, rats, and mice, bearing tumor, have been studied. The weight of adrena gIands is increased in cancerous animaIs, particularIy in chickens with Rous sarcoma.

Two stages of cellular reaction have been found in the adrena cortex, hyperactivity of the zona reticuIaris, in incipient maIig- nancy, and Iipoid accumuIation and fatty degeneration of the cortica1 part, simiIar to B-avitaminosis in Iarge tumors. These two stages probabIy correspond to two different stages of gIanduIar activity : hyperactivity of the adrena cortex in the beginning of maIignancy and hypofunction with the progress of tumor growth.

UniIateraI adrenaIectomy seems to have no effect on the growth of transplanted

tumor. BiIateraI adrenaIectomy has a definite inhibiting effect upon it.

Grafting of adrena tissue does not pro- duce any noticeabIe effect on tumor growth.

The regenerative power of the cortica1 tissue is more pronounced in grafts in rats with Iarge tumors than in non-cancerous rats. This suggests that the organism affected by cancer must have some physi- oIogic need for the bioIogic principIe eIabo- rated by the adrena gIand.

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Adrenal glands and malignancy