primary spontakeous tumors in the kidney and...

PRIMARY SPONTAKEOUS TUMORS IN THE KIDNEY AND ADRENAL OF MICE

STUDIES ON TRE INCIDENCE AND INHERITABILITY OF SPONTANEOUS TUMORS IN MICE

SEVENTEENTH COMMUNICATION

MAUD $LYE, HARRIET F. HOLMES, AND H. QIDEON WELLS From fhe 0th S. A . Sprague Memorial Institute and the Department of Pathology

of the Univereity of Chicago

Received for publication May 8, 1922

Primary tumors of the kidney occur not infrequently throughout the animal kingdom, and, in general, seem to exhibit the variations and peculiarities seen in human renal tumors. As an indication of the comparative pathology of renal tumors the following review of the literature is presented:

Mouse: Few casm of primary renal tumors have been described among the great numbers of other tumors found in this species. Tyzaer (1) found 4 renal growths, which he interprets as hypernephromas, among 83 primary tumors in mice. One of these mice, an old female, had also an adenoma of the lung, a carcinoma of the ovary, and a lymphoma infiltrating both kidneys; another had an adenoma in the lung. At the time this paper was written the interpretation of hypernephroma was more liberal than at present, and the illustrations might now be interpreted by many pathologists as papillary adenoma of the kidney, which was Tyzzer’s original diagnosis in two of his cases.

Among the 300 mice with spontaneous tumors described by Haaland (2), there were but two renal tumors. One was a large growth in the kidney of a twenty-two months old male mouse, and had invaded a vein but produced no metastases: mioro- scopically the structure was that of an adenocarcinoma. The seoond tumor, in a mouse of the same sex and age, resembled

305

306 MAUD SLYE, H. F. HOLME8 AND H. Q. WELL8

perfectly in structure a human hypernephroma; there were no metastases, although the lung contained an adenoma. Inocula- tion of the hypernephroma into 40 mice was without result.

Murray (3) a h described a spindle-cell growth surrounding the kidney without infiltrating it, apparently a primary retroperitoneal sarcoma and related to the kidney by position only.

Further than the above we can find no reports of primary renal tumors in mice, although Stumpf (4) has contributed a discussion of the behavior of carcinomas inoculated into the kidney.

Rats: Of 103 tumors found in 100,000 rats autopsied in plague work by McCoy (5 ) , 11 were in the kidney, and were classified as 4 adenomas, 6 carcinomas, and 1 papilloma. Woolley and Wherry (6) in 23,000 rats found 22 tumors, of which 3 were in the kidney; all were of renal-cell type. Bullock and Rohdenburg (7), in a compilation of the literature on rat tumors, found 123 (including those cited above) of which 7 were fibroadenomas5 1 a papilloma, and 8 carcinomas of the kidney. Among 32 c w s of their own in laboratory white rats, there were 10 adenomas of the kidney. Therefore, of 155 rat tumors 26 were of renal origin. A further case of caroinoma of the kidney in a wild rat was reported by Beatti (8). Loewenstein (9) described tumor-like papillary out- growths arising in the pelvis of the kidney, as well as in the ureter and bladder, of rats infected with Trichodes crassicauda specifica.

Since sarcomas are much more common than carcinomas in rats, the fact that all the renal tumors in rats are of epithelial structure is of interest.

Squirrebs: In 250,000 ground squirrels (Citellus beecheyi) autopsied in plague work, McCoy (10) found 8 tumors, of which one was described as an angiosarcoma of the kidney. A case of hypernephroma in the kidney of a grey squirrel (Sciurus caro- linensis pennsylvanicus) was reported by Fox (11).

Birds: Fowls are rarely subject to renal tumors. Of 880 examined by Curtis (12), 79 had tumors, 5 of which were in the kidneys; but these were not microscopically corroborated and there is reason to doubt their true neoplastic nature. In 35 cases of tumor in fowls compiled by Wernicke (13), not one was

TUMORS IN KIDNEY AND ADRENAL OF MICE 307

primary in the kidney although in 3 cases renal metastases were found. In 852 autopded fowls Burger (14) found 12 tumors of which none was in the kidney, although a sarcoma of the ovary had produced metastases in the kidney in one case.

The review of the literature on tumors in fowls and birds by Joqst and Ernesti (15) who collected 112 c a w and added about 50 more, reports no further renal tumors.

Other birds seem to have renal tumors perhaps more frequently, rn is indicated by the following reports: White (16) described a fibrosarcoma in the kidney of a goose. Fox (17) reported in the kidney of a male chestnut eared finch (Amadina castanotis) a medullary carcinoma, becoming scirrhous in places, with metastases to the lungs, and three cases of benign adenoma of the kidneys in undulated grass parrakeets (Melopsittacus undulatus) . He had previously reported (18) two cases of papillary cystadenoma and also a “cyst adeno-carcinoma papilliferum”(l9) in the same species; besides an adenocarcinoma of the kidney in a saffron finch (Sycalis flaveola), (20) and a spindle-cell sarcoma of the left kidney with metastasis into the left tibia in a scaly ground dove (Scardapells squamosa) (21). Seligmann (22) reported as a diffuse carcinoma a growth which involved both kidneys, with metastases in the liver and mesentery, in a Chilian pintail (Dafila spinicauda) which was twenty-six years old. Baird (23) reported a case of keratinizing epithelioma in the kidney of a fowl, and Borrel and Masson (24) also described a renal tumor in a fowl which showed both cylindrical and squamous elements.

Domesticated mammals. Rabbits, which are less subject to tumor than most mammals, seem to have a relatively large proportion in the kidney, for Scott (25) stated that of 39 new growths reported, 5 were benign renal adenomas, resembling Wilms’ tumors in structure.

Swine also seem to be partioularly subject to renal tumors, for of the 12 cases of tumors in swine collected by Sticker, 7 arose in the kidney, and other wses reported since then indicate the same tendency. Many of these tumors were of the mixed embryonal tumor type.

308 MAUD SLYE, H. F. HOLMES AND H. Q. WELLS

In horses renal tumors are far from rare. In Sticker’s (26) compilation, of 509 cases of malignant tumors in horses 37 were in the kidneys. McFadyean (27)’ in 63 cases of tumor in animals included 5 in the horse kidney, none with metastases. Of 142 equine neoplasms among 77,224 horses slaughtered in Japan, there were 9 in the kidney, as compared with 49 in the testicle (Kimura) (28).

According to Trotter’s (29) figures, renal tumors are much less frequent in cattle, for of 305 case8 but 1, a colloid cancer, arose in the kidney; but Sticker’s figures show 10 of 78 bovine tumors in the kidneys. Steinke (30) described as hypernephroma a tumor of the kidney in a cow. Roussy and Wolf (31) in their review on cancer in animals, gave a picture of a tumor from a bovine kidney resembling a hypernephroma, and stated that cancer of the kidney in horses resembles that in man, while in swine the adenomrcoma of the kidney is among the most common tumors. Cadiot (32) quoted a case of an enormous cancer of the kidney in a mare.

No reports of cases of renal tumors in sheep can be found. Of 766 primary cancers in dogs in Sticker’s tables 19 were in

the kidney. McFadyean also described two renal tumors in dogs, each caw exhibiting metastasis. No renal tumors appeared in the 21 cats with tumors in Sticker’s lists, nor in Roffo’s 7 cases (33) nor in Murray’s 11 cases (34) but Teutschlaender mentioned the cat (Kater) on his list of animals in which carcinoma of the kidney has been report,ed. Murray also described 48 case8 of tumors in dogs, 12 in horses, and 18 in cows, with none arising in the kidneys.

We are indebted to Dr. L. E. Day for his summary of 316 tumors found among 2000 animal specimens eent to the Chicago Laboratory of the Bureau of Animal Industry. These do not represent all the tumors that are observed in the slaughter house, but merely specimens sent to the laboratory by the inspectors when in doubt concerning the diagnosis. Among 175 tumors of oattle there were no renal tumors although there were four adrenal tumors, two diagnosed as sarcomas and two as hypernephromas. Among 93 tumors in pigs no less than 52 were in the kidney,

TUMORS IN KIDXEY Ah-D ADREh‘AL OF MICE 309

47 being diagnosed as embryonal adenosarcomas and 5 as sarcomas; there were no adrenal tumors. In considering the tumors in swine i t is to remembered that nearly all swine are slaughtcrcd before thtby are two years old, so that not many of the slaughtered, animals have reached an age for developing c~arcinomas. Among 48 tumors from sheep none whatever were found in the kidney or adrenal. These figures emphasize the infrequency of rcwd tumors in caattlc and sheep and the frequency of mixed tumors of the kidney in swine, which resemble the typical mixcd tumors of the human kidncy.

Other incidental cases are: Sarcoma of the kidney in a swine (Hamburger) (35), the report of which leaves some uncertainty whether the growth may not have been leukemic.

Papillary adenoma in the left kidney in a mongoos lemur (White) (36). -1 tumor involving the kidneys, liver, lungs, and ovaries of a python, the primary site not being determined (Bland-Yutton) (37). -1 leioniyorna in the kidney of a horse, described by Wells (38). Pick (30) described a soft adenoma involving both kidncys of an eel. JYilliams (40) stated “A malignant renal tumor (drrived from an adrcnal ‘rest’) has been described by Bland-Sutton in a marmot,.” In Teutschlaender’s compilation (44) wcre listed the following cases from thc litcrnture: Heniangioma of the kidncy in a horse: carcinoma of the kidney in fowl, frog, pike, and buzzard.

While the above compilation is certainly not entirely complete, it serves to bring together much of the literature on the comparative pathology of renal turnors, and to indicate their general distribution and frcquency.

We can find no reports of primary adrenal tumors in mice, despite the great nurnt)crh of mice that havebeen examined a t :tutopsy and the not infrequent occurrence of adrenal tumors in other spccics. Thus, Kimura (42) found in the literature recortls of adrenal tumors in 24 horses and 46 c:tttle, and hc himself found 5 adrenal tuniors among 46 tumors from horses. The cxtcnsive discushion of the comparative pathology of adrenal tumors by Steinkc (43) mentioned tumors only in horses and cow, commenting on the absence of such tumors in

Adrenal tumors.

310 MAUI) SLY]':, 11. F. HOLMES A S I ) H. G . WELLS

other species excvpt for an adrenal tumor of parasympathetic-cell chtiracter in :L tn-o-year-old swine, reportcd by K1iiwittc.r.

There is, howver, the intcrcsting case reported by Smalln-ood (44) as a carcinoma of the kitlncy of a frog and believed to I)(> derivcvl from the adrenal tissues. hlurray, who rciixaminetl this specimen, corroborated its carcinomatous nature, but his statement suggests that he was not convinced that it developed from atlrcnal rathrr th:m rend ccll.;. The illustrations in Smallvwotl's article suggest :I papillary rend tunior.

Fox (45) dchcrit)ccl :is a hypcrnephromn a tunior that arose in the sdrennl of u Chlifornia hair seal (Zalophus californianus) , and also described a hypernephroma in the adrenal of a brown ccbus (Cchus fat ucllus) (46).

.\s statcd previously, in thc 316 animal tumors examined by Day in the Chicago Stock Ymls , but 4 arose in thc adrenal, all in cattle, 2 being diagriosccl as sarcoma and 2 as adenoma.

ItENhIi TUMORS IN MICE I S TIIE SLYE STOCK

In 33,000 autopsies pcrformcd on mice of thc Slye stock, but 16 cases of unquestionablc prirn:iry tumor arising in thc kidncy have been observcd, supporting the imprcssion that the kidney of tho mouse is not among the comnion sites of priiriary neoplasm. These renal tumors are, according to the histological evidence, to be classified as follows : 1 carcinoma, 3 adcnomas, 1 hypernephroma, 7 sarcomas, 3 mesotheliomas, and 1 sarcoma in the renal pelvis. I t will be noted that we havc obsprved no instances of the mixed tumors of the kidncy that are so common in irian and somc: other species, nor have we had any papillary tumors of the renal pelvis. Thc features presented by these several types of renal tumor are best dcwribed by giving bricfly the findings in wch of the several cases that we havc observcd.

EPITIII"LI;\L TUJIORS O F THE KIDNEY

1. Primwy carcinoma of thc kidney (fig. 1). Female mouse This mouse showed a white solid muss in the right kidney

Heyond this there were no (1034). about the size of ti normal kidney.

r 3 lLAlOl{S T IS K I D S E Y AlYD ADRESAI. 01” MICE 311

sbnorrnalitics found, exccpt that the spleen was about three times thc normal size. The left kidney was normal, :tilt1 no 1wtastasc.s were found. illicroscopically thc tumor is composed of cells of epithelial type, but without, the c1h:iracteristics of cit her adrenal cells or of tiibu1:ir epitht3liuin of t hc kiclncy. Thcy :irc :irr:inged

F I G . 1. PliIJ1.41iY ( ~ A l 1 C I S O M : i OF THI? I < I l ) S E Y

The jiinction of the compressed rerial tissue nntl the t,uinor is shown. Appnr- eiitly this tnrnor is tlrrived from rctnal epithcliuin. 3Iouse 1034. X 110.

in large, pscudo-alvc.oli with much central necrosis, so that the persistence of the tumor cells near the b:inds of stroxna givcs in places the impresion of a papilloma. Although the growth docs not infiltrate the kidney ~ ~ r y much, it has no capsule of its own, infiltrates the renal capsule in places, and is iindoubtedly

312 M-ICD SLTI:, 11. F. HOLMES A S D H e G . WELLS

malignant. Evidently it is a tumor derived from the rerial epit heliurii arid niay be properly designated as a carcinoma, although the term mcsothclioma might also be appropriately used. Presumably it is in an early stage of riialignaricy in view of thc relatively sinall amount of extension of the growth.

2. Solid adcnorna arising in 1)ilatcr:tl cystic kidncys. RIale mouse (0907), age two years, thirteen days. noth kidncys were converted into niasscs of sniall cysts of various sizcs, resembling the congenital cystic kidneys, although no cysts were found in the liver. Sonic of the cysts contain colloid masses, and between them arc occasional foci of srnall round cells. Thcre remains niorc kidney tissue in a functional condition than is usually seen in fatal human cases of congenital cystic kidncy, but this tissue is far from normal, the tubules containing many hynlinc casts, the interstitial tissue being infiltrated with round cells, arid many of the glomeruli being more or less hyalinized. In the lowcr pole of each kidney was a fleshy nodule about, 3 to 4 mm. in diameter. Microscopically these nodules are corriposcd of a solid tissuc, made up of groups of largc epithelial cells somewhat rcwmbling renal epithelium. .\bout theso is a delicate strorna containing some collections of small round cells. The nodule is distinctly encapsulated :mi seems to be in thc renal substance rather than within one of the cysts. In niany respects the structure resembles that of the benign ovarian adenomas of niice (47). KO abnormalities of importance were noted in the othcr organs.

hlalc mouse ( 1 0220), which died with advanced sarcosporitliosis ; had marked chronic ncphri- tis, both kitlncys being large nnd nodular, with atrophic areas alternating with :ireas of swollcn and dilated tubules, some of the lattw being distinctly cystic. 13ene:ith the capsule of one kidney was :I nodule 4 mn. i n diameter, with a well cicafirietl capsule. It consists of :L mass of largcl epithelial cells with solid cytoplasiri, a r m ~ i g ~ d in large cords with a very delicate stroma bctwen t hein. ‘I’hc arrangement of the cells rcwmbles that of the aclrenal :idenoni:is, and a diagnosis of benign hypcrnephroma might readily bc iiiatle. ‘l’he (*ells are less wcuolzlted than those

3. ,ldcnoma of the kidnc.y (fig. 2).

TUJIORS IN K I D S E Y AND ADRESAL O F M I C E 313

of the typical adrenal cortex, having n denser cytoplasm, and are riot dis+imilur to the epithelial cells found lining thc distended renal t~ib~il(’s; it swms prohnblc, therefore, that this adenoma is dcrived from renal epithelium. There are some clefts containing

1;IG. 2. ADISSO\l . \ O F I < I l ) S K Y

Tliis sorricn.h:lt rcscnit,lcs n tumor dcrived frorn :drcnal (:ells, 1)ut is bclievcd to have h e i i tlcriwtl froiii r c i d c1)itliclium.

colloid innterinl, and n u r n e r o ~ ~ cnlcific grnnules in thc form of calcosphcri t es. 4. A(leiionin of the kidney. 3T:ilc mouse (24073, with a

large livw cyst cont nining a t.:ipcinorni, exhibiting in one kidney a solid sul)c!:ipsular nodule 5 niin. in tlialndcr, with a delicatc but definito capsule. This is oornposed of n solid mass of large

~ I o u s c 10?”0. x 63.

314 IIAUL) SLY&:, 11. F. I I O I X E S AXD IT. G . WELLS

epit hclial cc4s \\.it11 n1)untlant foariiy cytoplasm and small dark nuclci. The cclls are in large cords or :dveoli with a very delicate stroin:L lwt \ w w thcrn. There are numerous srriall foci of calcification of thc tiiinor tissuc. The foamy character of the tuinor ccIIs, togScthcr with thcii. ;irr:inprrimt, supgrsts an adrenal

1.‘ I I i. 3. I?XNAL I IT I’ I.: II s I’ t I 111 )>I A

This growtli oiitirci!y rrpl:tc:ctl on(: kidncby, h i i t protliic:otl no 1nct:ist:isc:s; i t c iorrc~sp~~i i t l s i i i striicttiirc to hiini:m h~~)criictl)hroin:i~. 3huso 3(i3!). X 110.

origin for t.liis groivt h , hut the post-niortcrn chnnges have so altctrccl the nuctlc:~r and cytoplasniic details that this cannot be dct crniinecl positivcly. In pl:ic~!s there is a tcritlericy to tuhultir arrangenient. of t h c t timior co11s, suggesting a renal origin. Out- side the tunior thc: kitlncy shows an advanced chronic nephritis with many hyaline and fibroid glomeruli.

TUMORS I N K I D S E Y AND ADRENAL O F MICE 315

5. Hyperncphroma in tho kidney (fig. 3). Male mouse (3639) with no other lesions of significance. The left kidney was rcplaced by an encapsulated, heinorrhagic mass, measuring 22 x 22 x 18 Trim. T h e right kidney was slightly enlarged arid soft, and showed a moderate d e g r c ~ of rhronic nephritis. KO remains of rcrial tissue are found in the turnor muss, which prwents the typical appearance of a hypernephroma. Nore than half the mass contains no cells, being coinposcd of the rwidue of old hemorrhages and nerrosis. The living portions consist of large foamy cells arranged in cords and alveoli with a delicate stroma. It is coniplctcly surrouridcd by a capsule which shows no invasion by tumor cells. In all respects this growth corresponds perfectly to the human renal hypernephromas. S o metastases can be found.

I n the hilum of the right kidney, attached to a large artery, is tt nodule about 2 mm. in diametcr which, in tho cctnter, resembles a small leiornyoma, but about it is a mass of granulation tissuc. I t bears no resemblance to the hypernephrorna arid its nature is unknown.

In view of the fact that chronic nephritis is one of the commonest diseases in miw, and appears in forms often quite similar to nephritis in man, i t is strange that we have found so few instances of epithelial neoplasms in mice, especially the benign adenomas which are so often found in hurnari kidneys showing chronic nephritis.

S i\RCOhfb OF THE KIDNKY

The diagnosis of sarcoma, always difficult and often unsafe, is particularly dubious in the case of the kidney which presents so many non-sarcomatous growths that resemble sarcoma, and especially in the facc of the statement made by Ewing (48): “Birch-Hirschfcld’s group of adeno-angiosarcomtt, derived from Wolffian rerniiants, and the liponiyosarcomas remain, however, the only wcll-defined varieties of roiial sarcoma which have been fully divorced from a pro1)able epithelial origin.” Severtheless, since the kidney contains connective tissue it is perfectly possible for sarcomas to arisc therein, and in this mouse material we have

316 M A U D SI,YE, H. F. HOLMES AND H. G . WlCLLS

soveral specinlens for which only the diagnosis of sarcoma can bc made, after excluding all other possihilitiw. In doing this we h a w carefully cliniinatcd numerous growths of doubtful character, sornc of which also may really be sarcomas.1 These eases are briefly descrihccl as follows:

(i. I3ilaternl sarconia of kidneys. Male mouse (i(i(ii), with both kidneys symnict.ricnlly enlarged to equal size, about 17 x 10 x 0 mm. ‘l’hcy contained little recognizable kidney t.issuc, and werc for the niost part infiltrated by R fleshy, pinkish white t.issue which involved equally the cortical : i d niedullnry portions. So lesions werc fouricl elscwhcrc. 1Iicroseopicdly both kidneys show infiltration rcplnoing nhout 80 to 90 per writ of the renal elcmcnts. The neoplasm is composed everywhere of slightly o w l cdls, a little larger than Iginphocytcs, with deeply staining niwlci nnd wry little cytop1:isrn. No evidencc! of neoplastic epit hc1i:d o r inixctl tumor elcnicnts can be found. ‘I’his tissue infilt rutcs bet weeii the tubulcs niuch as (lo t.he cclls in leukemic infilt r:it ions, arid the capsule is also invaded. l‘he cliff useness of this infiltrut.ive growth ant1 its equal involvement, of both kidneys makes it resemble :t leukcrnia or pseudoleukernin, but this dingnosis is uritenublc in view of the lack of involvement of other organs or lymph-nodes. ‘l’hc diiignosis of sarcoma is made largely by exclusion.

I \Ye ivisli t o qiiotc Iirrt. I L st:rtenient of the vritcriir usc:d in oiir consit1cr:ition of s:irvoiii:i tliroiighoiit 1 his work its culire~actl in o w pnpcr on I’riinary Sporitiiiic- oils Siirromi i i i Alice (,lour. Cnnccr Ilcs. , 1917, i i , 1 ) . “\re rrcogriize fully the difiiciilt ics tli:it iit.t.rntl t Iic tliffcrcntiiition of s:ircoiii:i, i i n t l fnr tlic purlinsc of t l i i3 stiitlg h:ivc c*scliitl(vl every forin of new grinvtli conwrning t lie n:tt iirc o f which t ticre scc~iiicd niiy po3rit)lc room for qwstion. Therefort:, we hirvtr not inf,lutkd niiiiicrniis (‘nws in which I\(! think thnt t lie Rrmvths tire prti\~id)Iy siirconiiitous, m t l ninny l i m e in which \vc cannot bc siirc t l i i i t the ncoplanin is not silrvoiii:i. 0 1 1 t l w otlicr Iinntl. t lie stilt ist ical virliie of oiir figiircs is Icss;cwvl I)y t!ic f:irt. thnt \vc h n w uritloiil~(ctlly ornittell sonic growths tliitt, :Ire I r i i c snrroiiiirr. I:rorn t he st:uitlpoint of invest iR:rt ions in hcrctlit y, with which our work is partit:iiltrrly conrcrnctl, it i.; just ns uiitlcsirnblc to cirll :L snri:oinn somet hing elsc ns to inclutle :L yrnnulornn niiiorig thc s:ii-(’oiiins, i r i i t l hencc thr rigid cliissilicirt ion iitloptctl in this study ( I f

siirrnnins is no iiiiirc s:rtisfiwtury for niir hcrcility stirtist ics th:iii woulcl he n Inu cliissilicnt ion thilt inc~lutlctl SOIIIC growths of t1oiit)tful nntiirc. ‘I’hercfore, in chnrting the ht:rdity stntisfivs i t is ncccsarrry to recognize tt ic :rtJscncc of pwit.ive criterin for tlic clifTc.rc:nt iiit.ion of s:rrconi:i, :md to irdmit thc tmrderlinc c:tscs w i t h n iiinrk of intcrrogntion t o intlicntc this fsllihility.”

()iir figiircs rcprcwnt iiiiniiniil V : ~ I I P S oiily.

TUMORS IN K I D S E Y AND ADRENAL OF MICE 317

7. Sarcoma of kidney. Old male mouse (24979), with the right kidncy cntircly rcplaccd by a turnor, 16 x 12 x 10 mm., which infiltrated thc adjacent tissues, including the ureter and the pelvis of the opposite kidricy. The regional lymph-nodes were also invaded, arid there was a mass in the root of the mcsen- tcry about 20 rnrri. in diameter, which seemed also to infiltrate the pancreas.

Mcroscopically, the right kidricy is found to be almost corn- plotely rcplaccd by a growth of large round cells, uniform in size, with very little cytoplasm, but with nuclei much larger than those of lymphocytes. Thcre is no tendency to structural arrangemcrit, the tumor cells infiltratirig freely the tissues about the kidney, including the adjacent muscles arid the pelvis of the opposite kidncy, the uretcr of which is surrounded by a mass of tumor. The regional lymph-nodes are rcplaced by tissue of the same character, but the mesenteric mass is c*ompletcly necrotic, with few cells resembling those of the tumor. By virtue of its highly infiltrative character and the large size of the cells, this seeins to be an undoubted sarcoma. The other tissues showed no evidence of either leukemia or pseudoleukemia.

Female mouse (26867) with much sarcosporidiosis, showed a marked enlargement of the left kidney, which was betwecn two arid three times the normal size, and infiltrated diffusely with a pink, floshy tissue. Elsewhere in the body there vIwe no important changes. Microscopically it is found that the enlarged kidney is infiltrated extensively, nearly all the rend elemcnts being replaced by a tissue composed of round and elongated wlls, considerably larger than lymphocytcis and with more cytoplasm. They tend to be arrangcd in wide bands, grouing out from the blood-vessels, but this arrangeriierit is not constant or w4l drveloped. The neoplastic tissue grows out from tho pelvis and tends to invado the adjacent tissues and the hiluin of the opposite kidney. S o similar tissue is t o be found clsowherc? in the mouse. The probable diagnosis is pri- iuary s:irc.orna of thc kidxwy.

!I. Snrcorna of the kidney. Female mouse (27148), with the right kidney much enlargc4 (18 x 15 x 32 mm.) and consisting of

8. Sarcoma of the kidney.

318 MIAUD SLPE, H. F. HOLMES AS11 H. G . TVELLR

a firm tissue ovorlaid with softer port.ions. i’,licroscopicall>- . .s found that, thc kidney is tliffusely intiltratcd n-ilh a growth ‘@on- sisting of pol. ’ 4ral cells, sninllcr than epit liclial ( ~ 4 s usu:dly arc, but, with I inor(: cytoplasm than lymphoid cells. ‘These cells exhibit ;)I), st.ructurti1 org:iiiization and have rcplaccd all but a few of the original rcnal c1cment.s. ;\bout one-third of the tissue is ncwot ic. A small timount of thc nctoplastic tissue infi1tr:it.w the hiluni of the left kitlncy, which ulso shows timy- loitlosis. KO sirnilar t.issue is found elsewht~re in the body, and thcre arc no cvidenct:s of diffuse I~rnphoid hypcrp1asi:i or similar c.ondit,ions.

T h c turnor shows 1nuc11 variat,ion i n thc sizc of the nuclei, hyperchrolnntism being common, and occ!,zsional very large cells are soen. Irnfortunat.ely there is too rriuch post-mortem change for exact details to be seen. The general character of the growth and thc? absence of sirnilw chanpes in other t.issucs make a diagnosis of sarcoma sewn inevitable.

10. M a t e r d sarcoma of kidneys, with metastasis in splectn. Female rnoiiso (3!N), with the uterus enormously distcndod with fluid because of vaginal obstruction by a seminal mass, and with great enlargoinent of both kidneys by a unifonn white t,issuc. The right kitlncy measured 18 x 13 mni., t.he left 15 x 13 mm. On the anterior surface of the left, kidney is a depressed scar. In the spleen there is a turnor nodule, 4 x 5 mm. KO other turnor growths were found.

Nicroscopically, both kidneys arc found to be infiltrated diffusely, with rqdaccment, of 80 t.o !10 per cent of the renal tissue by a gronth unifornily composed of srriall oval cclls in solid ni:isscs, without any pnrtioular organizst.ion. So similar tissue can bc found in any othcr organ cxoctpt the spleen, which has a turnor nodule of thc same structure as the rcnal t.umor. The aclrcnnls are in contnct with, but not invaded by tumor. The tuinor forms largc niassos in tht? hiluni o f one of t,hc kidneys, or within t.he kidney itself. l’he left. kidney is more itivolvcd than thc right,, :tiid probably was t.lic st.arting point of the sarcoina.

l~cmale rnousc (1S124), wit.h two separate mammary carcinomas, and in t.he left kidney a

‘1’11~ lung contains a siiiall benign utfenoma.

Thc adrenals were normal.

11. 1,ymphosarcorn:i of kidney.

TUMORS IN KIDNEY r\SD ADRENAI, O F MICE 319

r. Fphcricol rl*iss about 14 mm. in diameter, whidi was pal y necrotic. hIic*roscopically this growth is (winposed of a dense m a s of siiinll rouiid c d s n-ithout v’ .? cytoplasm, packed closely togcthcr without att cwpt a. ,,tion of any structure. It inii1tr:ttcs the adjac*ent renal tissue I I ~ * l y , and there is a smsll amount of infiltration of thch hiluin ot’ t h r opposite kidney. The struvture is of distinctly iieoplastic ch,zractc.r, and there is no similar iiifiltration of othrr orgins, or lymph-node enlnrgernen t , such as charactcrizchs pseudoleukemia. The diagnosis of swcomn, in struvture corresponding to lyrriphosarcoma, is the only oiie that can be n1:tdc on the features presented.

This seems to be similar to case 1 1 , but unfortunatdy post-rnorteni dwoiriposition has advanced so fnr that accwrntc microscopic study is not possible. Such tissue as rcbmains st sinable rescmblcs a lyinphosarcorna. The inoiise was a feinale (12353) with no other tumors, and the right kidney was repl:tccd by a soft pink mass measuring 14 x 12 x 12 mrn. -1 small amount of the same tissue invaded the hilum of the left kidney.

J-

12. Lymphosnrcoma of kidnchy.

MESOTHELI0M.i OF THE K I D S E Y

In our previous papers on turnors in the ovary (49) and testicle (-50) of mice we have called attcntion to the not infrequent occwrrence of tiirriors composd of polyhedral cells, presenting some characteristics resembling carcinoma and some resembling sarcoma, (figs. 4, 0 , 7 and 8) and hence suitably designated meso- theliorna, in accordance with Adanii. Thcse tumors arc characteristic of the urogenital anlage, and hence it is riot surprising that growths of thc same structure are found in the adrenal and kidnc.y. Wc. have observed the following cases of r t ~ a l tumors that sceiri to hclong to this group.

13. This is a rcmarknble caw i i i that a fcmalc mouse (21W3), when bit1 oiic niontli old (3xhihitcd two iritlepentlcnt cawirioinas of the rriamirinry gland, and ostcosarcomntous growths in the spinnl columii iiwr the pelvis :tnd in the: left fifth rib. It lived but eighteen days more and at autopsy showed its loft kidney :dso almost completely replawd hy a tumor rnoasuring 18 x 12 x

320 MAUD SLTE, 11. F. IlOI,M.IE:S AKD H. G . \YELLS

10 mm.; the right kidney, similarly in\-ol\wl, nicasuntd 10 x (i x t i rnni. (fig. 4 ) . These ronal growt.hs are entirely different in st.ructure from t.hc other four t.uinors. 'Thcy arc: aliko and vary in appearanw in diff eront parts, some portions rcsc~rribling

spindle-ccll sarcoma whilc others are composed of larger, more polyhedral cells, twanged in a somcwhat :dvcolar fashion, often separated hy highly vascular septa. l'liis structure corresponds to thc type of grcwth ofton wen in tumors of thc ovaries, tcsticks,

TUMORS IX K I D S K Y A S I ) ADRENAL OF MICE 321

and adrenals in mice, and agrees with the turnors called meso- theliorna by .ldarni and Woollcy. Since, except for this cats(’, there haw: bcen vcry few other cases of malignant tumors arising in mice less than six nionths of age, the occurrence in so young an animal of at least four independcnt primary growths representing three distinct types of malignant neoplasm, is a most remarable condition, without, as far as we know, a parallel in either mouse cancers or in those of any other animal.

14. hlale mouse (10011), with no other lesions of importance, had its right kidney largely replacwl by a whitish tumor, forming a mass mcasuring 14 x 12 x 10 mm. Microscopically the tumor has largely replaced the kidney arid has infiltrated the capshle in places. I t is composed of small cells with a dark, round nucleus and a small amount of cytoplasm. These cells tend to form bands or pseudo-alveoli in some places, hut for the most part the growth is composed of cells in a structureless mass. The left kidney was riot involved by the tumor.

hlale mouse (0779) had an enlarged left kidney without other lesions of note. Micro- scopically the kidney is largely replaced by a mass composed of small cells slightly larger than lymphocytes and with more cytoplasm, showing no structural arrangement. The main neoplastic mass lies at onc side of the kidnt.y, which it infiltrates slightly. The kidney itself shows some foci of round-cell infiltration. Some of these areas slightly rescmblc the tumor, but probably are not a part of it,. There are some small areas of calcification, some scars, and numerous hyaline casts. Post- mortem changes are too advanved for more awurate study. The opposite kidney contains no tumor, but there is the same amourit of amyloid and calcification.

15. This seems to be similar to case 14.

S 4RCOJI?\ OF RENAL PEL\ IS

We have excluded numerous cases in which a retropcritoneal tumor of sarcomatous character has invaded the kidncy hilum, but there is one vase in which both the gross arid microscopical findings distinctly indicate that the tumor had its origin in the tissues of the pelvis itself.

322 M?\UD SLYE, H. F. IIOLBIES A S D H. G . TVELLS

Female niousc (348) had a pale swelling extending downward ttnd inlvard fro111 t.he pelvis, composed of t.issuc of a h i t the same consistency as the kidney and of uniform yellow color. On cross section the pelvis of the kidncy was in the center of t,hc mass formcd by the tumor and t.hc kidney, which measures 12 x 0 rnm. 'I'ho lcft kidney was of normal size with a pale area of swlliiig on the anterior surface. Ko other chanpts of iniportitrice were found exwpt. severe edema of the lungs.

Microscopically the growth is found t o lie symmetrically about the pelvis of t,lic kidncy and the upper end of the ureter, invading thc wall of t . h e st ruvtures extensivcly. From hcre it passes along thc vessels deeply into the kidncy, hut docs not extend far into the cortcx. Thct kidney is about one half :is large as t.he tumor, t.hc t,ubules being much dilated and t,hc glomeruli more or less hyalinized. The tunior also extends some distance along the rcmi.1 capsulc as a thin layer. A s no growths are found elsewhere it is evident, t,hat this growth arose in t.he t.issues about the hilutn of the right kidncy. There is only a sniall amount of invasion of the left. kidncty hilum. The growth is cornposed of large round cells with a ctc1icat.e rcticulum. 'l'hcre are several delicate vessels packed with lymphoid cells, but no other evi- dences of lymphatic origin in this tumor. The cclls of the tumor itre polymorplious with considerable cytoplasm, and deeply st.airiing nuclci much larger than those of the ordinary lymph- cell, and usually larger than the nuclei of t,he rcrial epithelium. KO mitoscs are sectn. KO changes of importance are found in the other orgms.

This tumor is much less cornplex in structure than the cascs of sarcoma of t;he renal pelvis in children described by de Vccchi and Salomori (51).

ADItENAL TUMORS

As mentioned above, no cases of adrenal tumors have hitherto been described i r i mice. We arc nMe to rctport a few unqucstion- able instanccs of such tumors. Despite the frequency of benign cortical adenomas of the adrerial in man, we liavc found but one such turnor in micc. It may be recalled that adrenal tumors have not. bccn found frequently in other spccicts of animals.

Cortical aderionia of misplaced inter-renal adrenal rest (fig. 5 ) . Between the kidneys of a fcm:tla mouse (1 921), with marked aniyloidosis and vhwnic iicphritis, was found a sphcricnl inass about 5 riiiii . in diaiiicltc.r, :it t:ic*hod nctit her t o tht: kidneys nor to tht: intcstines. I h t h ndrennls were present st thcir noriii:tl site

and were of normal structure and size, except for some peripheral round-cell infilt ri ‘1 t’ ion.

1 he turnor riodulc is composed of n solid ninss of caells rescmb- ling those of the ndrend cortclx ctxccpt i n lack of orderly nrrnnge- nient, closely packed togetht.r, and flattcniiig out a thin shell of

r ,

324 MihUI) SLI’E, €I. F. HOLMES A S D H. G . WELLS

adrenal cortex, evidently all that remains of an adrenal rest, since no medullary eleineiits are to be found. I n all rospects this tumor corresponds t o the simple adenoma of the adrenal cortex seen in man.

JIESOTfIEI~IOM:\. O F THE ADRENAL

This seems to he the commonest turnor of the adrenal, as also of the t.ctsticle, o f mice, and it. is quit.e iiiipossiblc to distinguish on the basis of microscopic appearance between the mesotheliomas arising in the different organs derived from the urogenital anlage. The cases in which the diagnosis seems certain are the following:

1. Male mouse (10.390) had in place of the right adrenal a spherical inass 5 mni. in diameter, which is completely encnpsu- lnted and does not inyolvc the kidney. S o other nodules or findings of importance cIsewhcre. Microscopically t.he nodule contains 110 remains of adrenal tissue, but consists of a solid tumor made up of niasses of large cells with considerable cytoplasm and large o w l o r sphericrtl nuclei, arranged in atypical alveoli or broad hands with a very small amount, of stroma containing thin-walled blood-vctssels. .I 11 i1uincrous places the capsule is infilt.rat(td with tumor cells and there is some invasion of the areolar tissues about the adrenal, but no invasion of the adjacent kidiicy. This seenis to he a typical mesothclioma of the adrenal in an ctarly stttgc of Inalignancy.

2. hlcsothelioma of adrenal with peritonea’ metastasis. Fe- male niousc (1Z44), with abdomen greatly distended by a bloody exudate, prctsctntcd at the site of the left adrenal a whitish mass about the sizc of t,lie kidney. All t.hrough the abdominal cavity are masses of partially newotic: whit.ish tissue, especially attached to the liver and uterus, which (lo not s w m to be involved by this growth. Thcrc are enlarged rctroperitoncal lymph-nodes, b u t elsewhere no lympliatic involvement. There are no tumors in the lungs.

-\Iicroscopioally the tumor shows the usual features of the typical nicsot heliorixis, :LS descri1)ecl in the other cases, with slight tendcnc.y to alveolar :irrtingcrnent. It do(?s not. seem t o have

TUMORS IS KIDNEY A S D AI)RENAI, OF M I C E 325

infiltrated or produccd metastases in the viscera. The right adrenal is surrounded, but not invaded, by thc tumor and seems nornial. The retroperitoncttl nodes are rcplaced entirely by tumor tissuc.

I

3. Jlilnteral malignant nicsotheliornn of adrcnals (fig. 6). Female inowe (7699) with much suhcutnncous cdcmn, showed numerous enlargcd suhcutancous lymph-nodcs, soill(! rcd and some palc, the largest measuring as much as 8 x 10 rnm. There was a milky fluid in the pcritoncal cavity, vresumably hecause of pressure of enlarged lymph-nodes on the thoracic duct, for

326 XIAUD SI,YlC:, H. F. IIOLhIES A S D H. G . WELLS

the rotroperitoneal nodes werc greatly enlarged, up to (i x 12 mm. The rnesenteric nodes were :ilso enormously enlarged, one mass at t.he root, of the niescntery measuring 40 x 20 x 20 mm. I3oth adrends i v c w groatly enlrtrged, cach being about thc sizc of the kidney, which was adherent, to the adrenal h i t , not enlarged or infiltrated by rictoplastic t.issue. Tho ut orus seemcd to be infiltrated 1)y t,umor. The l i \ w was riot :~fferted, and the lungs showed only a singlc small nodule, although t.here was some tissue increase ill thc upper mt?diastinum; both lungs showed a bloody edcina, ant1 therc was a bilateral hydrot horax.

.-\lt.hough the gross appearancc suggested a general lyrnpho- sarcomatosis or psctudolcukemia, yet. the microscopic structurc is of an entirely cliffcrent. charact.er. Every\vhctre the ncoplastic tissue presents t,he same appcnrance, tieing composed of a solid growth of cells with considerable cytoplasm, so that they look much like epit.heliurri. The nuclei, which vary grct:ttly in size, arc: much more solid t.hnn those of epithelial c!olls usually are. Mitotic figurcts WP abundant.. The invaded lymph-nodes arc largctly rcpl:tcwl hy tunior rells, which are also found in t.he lymph-vessels of the lungs, but not. in thc liver. 130th adrenals seem to be cntircly replaced by t.hc tumor, which lies upon the capsulc of t.he adjacent kidney without. any invasion of this organ. There arc some arcas of hemorrhage, but riot. much necrosis. The oells show no attempt at definite arrangement., but, simply form a solid mass with numerous, poorly defined blood spaces.

This tumor resenihles in structure ot,hcr growths found arising in the urogenital anlage, and in view of this and of the complete replacement of both :ttlrenals it is most. probable that i t did arise in thcsc tissues, although thc extensive lymph-node involvemcnt is unusual in atirctnal tumors. The structure is not essent.ially dissimilar t o that of the adrenal turnor 10390, exccpt for the amount of ctxtcnsion.

7~1iOGEXlT.iI~ MJ3SOTHEIJIOM.\S OF UN(’EEtT.iIN ORIGIN

13ecause of the identity in appearance of mesotheliomas from all organs originating in the urogcnital anlage, i t is not always

TUMORS IN KIDNEY AND ADRESAL OF MICE 327

possible to decide the place of origin of some tumors which in- volve two or more of these orgaris, as shown by the following cases.

12307. 1Irsothclioma of cithrr adrenal or ovary. I t is riot possible to deterinine the origin of this tumor, which we have described in our papcr on tuiriors of the ovary in the following words :

The :~ldomin:il cavit,y shows scbvcr:il notlriles whose cxact origin is difficult to t l ~ t . c ~ r i t i i n c ~ :is the. matc 1i:is pirt ly cL~vourcv1 the I)otly. The right awry is, how(wr , (wi ly clist.iriguislict1. It, iricasur(1s 18 x 12 x 12 m n . %%it swiiis t.o he tht1 left. 0v:u.y is 10 x 8 x ti 111111.

Thcrc :ir(’ 8 ot.lict’ simil:w iiotli~los in t.lic1 :ihtlornin:d cavity, oiic being in t.lic position of tlir lvft :itlrrn:d, inc:tcuririg 10 x 8 x 8 riiiii. The othc’r notlulw arc :ipparc>iit.ly in t.hv ~ncw~i t~c~ry . On(? l o h of t hc livor is convcrtc~cl int.0 :i tunior notlalo 1 1 x 10 x 18 i i i i i i . , irrogn1:rr and lurnpy in out,liiict, pink in c~)lol-.

1 hc tunior sliows ovc~ywlicrc the samr striictur(:, consist,ing of irrcyy1:ir dveoli composctl of I:trg(t cc~lls with u1)unclant cytop1:isin with well tlefincd 1)ortLw ant1 dccply staining nuc l ( i RTitotic figures :irc nuiii(troiis. ‘h chnract.rr is that usu:~l t.o nicsothr1i:d growths. The ovary c:innot lw posit ivoly idcntific~l, but, orio inass c.xhil)it.ccl in thc capsulc striictuw suggests coinpr~~ssctl ov:iri:iii t.issuc with clcgctncr- ntcxtl ow. In :dl rcspwts t.his t.uinor is i(lrritica1 with thc ni:ilignnnt ov:iri:in tiiriiors just dcscritwd.

It s(:(!ins probnt)lc t1i:it t.liis truiior nrosc in t.he ovary which cxliibitcd t.ho 1nrgw:t growth, but. it is not possiblc to exclude thc! adrcn:d as the prit iiary sit.c .

r 7

T h e indignant tuiiiors of the adrenal, ovary, and t.esticle commonly exhibit identically the same histological picture as that seen in this case.

\\re have also ohserved two othcr cases, dcscribed in the paper on ovarian tumors in which we cannot. state whet.her t.he renal growth was primary or secondary.

12870. The left kidney ctontained a mass of pink, fleshy tissue, 18 x 14 x 14 mm. The right kidney, which was slightly enlarged, contained no tunior, The right ovary consisted of a pinkish tissue resembling that in thc kidney, and measured

328 MAUD SLYE, H. F. HOLMES AND 11. G . WELLS

12 x 8 x 8 nirn. I n the mesentery was a similar, slightly paler mass, 16 x 8 x 8 nim. The rctroperitoneal and subcutaneous nodes werc not. enlarged and no nodules were found in the lungs.

llioroscopirally tho tumor is alike in all three places, consisting of a diffuse infltrnt.ing growth of large round cells, which also invade the connect.ivo tissues about. the kidney and ovary. It does riot at all rctsemblc the typical ovarian tumors, being ap- parcntly a round-coll sarcorna. We have no way of t,elling which of the three turnors wis primary. The ricxt. case presents similar difficulties.

26. This niouse had a tumor mass about 8 x 10 n m . in the upper portion of t.hc livcr, with other smaller nodulcs near it. A similar small nodule was found in the right kidney. The right ovary was enlarged to two-thirds the size of a kidney, and was solid. h.licroscopically all thme growt.hs arc composed of round cells, apparently a round-cell sarcoma. It is impossible t.o say which growth was primary.

:Itnong swerrtl tumors arising in the retroperitoncal tissues, mostly of s:ircoinntous type, are n few of :I st,ructure identical 1vit.h tht? characteristic mesothclioinu t.ype of growth that arises i l l

the urogenital alilngc. 111 the t .w) c'ascs described \)elow this ch,zract.er of growth was so Inurlied t.hat it seems prot)a\)lc that the tumors havc arisen in some misplaced crribryonic rest., since the organs of this series were distinctly not. the starting point of the growths. Nuiii(!rous tumors of this sort have heell described in man.

(22:MO) RIalignant retroperitoncal mctsothelioma with extension through the body wall. Male mouse prescnting extttrnally a su1)cut:uicous tumor, involving t,hc left, hip and extending t.o tho anus, the external measurements being 30 x 25 x 25 rnm. When the hotly was opened it was found that this mass was an c.xt.oiision of ,z huge iriftss (41) x 20 x 18 min.) which had surrounded tho lc!ft, kidney and pushed it to the ventral midline, invaded the spleen and pushed it niostly to the right of the midline by forniation of a mass that measured 20 x 15 x 13 mm., and cxt.cnded downward t,hrough the pelvic caL4t.y where i t surrounded the rectum and seminril vesicles and broke out through the

TUMORS I S KIDNEY .4SD ADRESAL OF hIICE 329

body wall. There was slight infiltration of the lower pole of the right kidney. The liver was slightly enlarged and mottled with arcas of infilt,ration. There was some tumor in the lower part of the medinstinum, arid the lungs show inany small spots of neoplastic tissue. Thcrc sccnied to be no involvement of the

I:IG. 7 . SE(:OSI)AIIY ~ ~ I M ) T H L L I U M A IS I,IYKII Tlie primtry growth ~ 1 1 s cither i n the :ulrennl or iii :i rctroperitoiicnl embryonic:

rest,; i t infiltr:itetl the body w:dl mid retrol)c.ritoiiciil tissiics, and prodiicictl innii- Incrable metnst:ises in the luiigs :tnd livcr. Ttik section shows the inasses of tuinor cells coinpressing nncl replacing the lnrgcr liver cclls. hIoiise 22380. x 110.

lymph-nodes, &her subcut.aneous or abdominal. The testicles wcrc not involved.

hIicroscopically the tumor everywhere consists of masses of largc cells with much deeply st.aining cytoplasm, sorncwhat resembling liver cells, wit.h a slight tendency to arrangement in

330 hIAUD SLTE, H. F. HOLLIES AN11 11. G . WELLS

cords or t)aiick. Where thc tuinor invades the livcr it can be sceii that the cells arc a little smaller and paler than the liver wlls (fig. i ) .

The growth infiltrates the livcr nidctly, invndcs the niusele of thci body wall, iiiv:ich~s tlw rcnal capsulc Init not thc kidney,

1'1(;. 8. sECOSDAR1' ~ f E S O T I I I ~ ~ I . I O ~ ~ A OF 1,lJSc:S

I h i n tlic siiiric c:isc ns figrirc 7 . l'hc sectinri shows the cxtcnt, of irivolvcmcnt of tho lung. Aloiisa "L':BO. X GO.

infilt.ratc?s t.hc nbdominal sympathetic ganglia, surrounds densely thc rcctuni and sprcads into the seminal vesicle, invades the spleen, and in the lung appears as multiple Ournor cell emboli wit.hin the vessels and as large tumor nodules largely replacing portions of t.he liing (fig. 8 ) . The lcft adrenal was found entirely einbeddcd in but not infiltrated by the turnor.

TUMORS I S KIDKEY AND A D R E S X L OF MICE 33 1

The microscopic appearances are idcntical with those usual in inaligriant adrenal tuniors, h i t the :idrenal was not involved; and in view of the retroperitoiieal origin, the growth may be presumed to have ariscn in an cmbryoiitrl rest of the urogenital anlage.

(9079) JIalignant retroperitoiical mesothclioma infiltrating kidneys. Small fciiiale niousc with extensive infiltration of the right thigh by a typical spindle-cell sarcoma, and with a mass above the left kidney, about as large as the kidney itself, which was infiltrated by the growth. The entirc mass nieasured 20 x 14 x 10 mni. The growth sccnied to have arisen a t the site of the lcft adrenal, and to have pushed the kidney forward. The liver was invaded by tumor and enlarged. S o metastascs wcre found clsewherc. Micro- scopically thc tumor about the kidney bears no rcscmblarice to the spindle-cell sarcoma of the thigh, being composed of a mass of polyhedral cells arranged in solid masses, with a slight tendency to form bands or cords. The nuclei are not much larger than those of lymphocytes, but thc cells have much more cytoplasm. The chief mass lies abovc and behind the lcft kidney, which shows considerable invasion through the capsule and about the blood vessels. Therc is a similar invasion of the right kidney but much less tumor about it. The right adrenal cannot bc located; t,he left is free from tumor although thcre is a necrotic area between it and the kidney. The liver shows a large nodule of the same sort of tumor.

The right kidney was riot, so much enlarged.

SE(’0SDARY TUMORS O F THE: K I D S E Y S i\ND .\DRISSALS

The mouse kidneys seem to be cxtrcmely insusceptible to metastatic iiivasion by tumors. Tn our entire series of primary tumors of micc, now in thc neighborhood of 5000 cases, of which tht? prc~lominating form is carcinoma of the mammary gland, we have nevcr met with a metastatic growth from one of these tumors into the kidneys, with one possible exception, despite the frequency of pulmonary metastates, which often replaco most of the lung. The only metastatic carcinomas of the kidney that we have seen have bcen found

332 MAUD SLYE, H. F. HOLMES A S D H. G . WELLS

in four cases of primary carcinoma in the lung (3098, 11777, 12373, 14242). .I photograph of the first of these four cases appears in our paper on lung tumor (52). These carcinomas of the lung are especially likcaly to produce extensive riietastasw, and the suggestion of some authors that these pulmonary growths in mice should not be included arnong thc true tumors is evidently based on ignorance of their character. The fact that they have furnished our only instancos of metastatic carcinoma in the kidney is sufficient evidence of thcir true neoplastic character and the high malignancy of some types.

Although we have seen many instances of widespread metastasis in sarcoma, the kidneys are almost immune from vascular sarcoma embolism. In our series of 87 cases of sarcoma in mice, although 23 showed metastasis but onc hematogenous secondary nodule was found in the kidney, this coming from a rnediastinal sar(’oma (11791). Since thcm wo have seen one other case of vascular metastasis of sarcoma into the kidney, from a sarcoma of the uterus (12058), with a large nodule of the same structure almost replacing the lower pole of the right kidney, and metastasis in the right ovary. Even the widespread growths of small round cells, which rescrnble the condition culled lymphosarco- matosis in man, sccm to affect the kidney but little, for among a considerable numbcr of such cases we have but one with a distinct metastatic nodule in the kidney (7572), although several cases show extension from retropcritoncal nietastases into the capsule, and thcn into thc kidney. On the other hand, the kidneys exhibit extensive diffuse infiltration in leukemia arid massive pcrivascular growths in pseudoleukemia in mice as in man.

Thc malignant rctropcritoneal growths, most of which resemble lyrnphosarcoiiia, atid t hc rnalignant tumors derived from the adrenltls, commonly invade the kidriey by direct extension into the hilum, often very cxtensively. The sarcomas primary in one kidney also tend to spread into the hilum of the opposite kidney. This ready invasion of thc hiliini of the kidney is a point of similarity of human and mouse ncoplasms.


No instance of tumor metastasis into the adrenal has ever been observed, except possibly in the few cases of widespread mesotheliomatous growths invading both the ovaries and adrenale, the origin of which is uncertain.

SUMMARY

In a series of 33,000 autopsies on mice of the Slye stock, dying natural deaths at all ages, but as far as possible living out their natural span of life, there have been observed the following cases of true primary neoplasm arising from renal or adrenal tissues: First, from the kidney, 16 twors , classified as follows: 1 carcinoma, 3 adenomaa, 1 hypernephroma, 7 sarcomas, 3 mesotheliomas, and 1 sarcoma of the renal pelvis. Second, from the adrenal, 4 tumors, as follows: 1 cortical adenoma from a misplaced inter-renal adrenal rest, 3 mesothelial tumors. Third, five cases of tumors of the mesothelial structure characteristic of urogenital anlage neoplasms, but of which the exact origin could not be determined because of their widespread growth at the time of death. As these 25 tumors occurred in 33,000 mice presenting not far from 5000 other tumors, they are evidently uncommon tumors of mice, at least in this particular atock.

It will be noted that in this series there has been no instance of a mixed renal tumor of the Wilms type, which is so common a type of renal tumor in man and apparently also in swine. Al- though inflammatory conditions are very prevalent in the kidneys of mice, epithelial tumors are rare, and especially to be noted is the absence of even a single case of typical malignant hypernephroma, although one benign growth of this type was found. No epithelial tumors of the renal pelvis were found, although there was one case of sarcoma that seemed to take its origin in the pelvis.

Several instances of malignant retroperitoneal tumors have been observed, mostly of sarcomatous structure, which usually invade the kidney. These have not been included in this series, except two cases in which the structure resembled that of the

334 MAUD SLYE, H. F. HOLbfES AND H. 0. WELLS

mesotheliomas, suggesting that the tumor had its origin in misplaced rests of the urogenital anlage.

Secondary tumors have never been found in the adrenals, and but rarely in the kidneys. Although this series includes at least 3000 cases of mammary carcinoma, often with widespread metastases in the lungs, we have never seen a secondary carcinomatous growth in the kidney. The only secondary carcinomas of the kidney as yet observed are four cases in which the primary carcinoma was in the lung, thus establishing the true neoplastic nature of these lung growths. In but two cases have metastatic sarcomas been seen in the kidney, if we exclude the numerous cases of invasion of the kidney by direct extension from para-renal growths.

As to sex: In the entire group of renal and adrenal tumors, we have equal numbers in males and females, agreeing with the observation made on other tumors in mice that, in tumors not peculiar to the sex glands, there is usually little difference in the incidence in the two sexes.

Differing from the tumors previously studied, coincidence of other tumors with the renal and adrenal tumors is uncommon. One mouse in this series had a spindle-cell sarcoma of the thigh. One mouse had a small, benign papillary adenoma of the lung. Only two mice had a mammary carcinoma, and one of these (21663) was a remarkable case, for this animal, when but one month old, was found with two independent mammary carcinomas, and with osteosarcomas in the spinal column and in a rib. It lived eighteen days more, and at autopsy there was also found a mesotheliomatous type of growth involving both kidneys. Except for this unique case there have been practically no instances of malignant tumors in mice less than four months of age, and few under six months, Most of the renal sarcomas occurred between the ages of seven months and one year, which is somewhat earlier than the usual time of appearance of epithelial growths; this, of course, corresponds to experience with human neoplasms.

The epithelial renal and adrenal tumors furnished no illustm tion of metastasis, but in three cases of sarcomatous or meso-


theliomatous growths there was noted involvement of the adjacent lymph-nodes; in two there were pulmonary, in two hepatic, and in one splenic metastasis, and in one case there were numerous peritoneal growths. The mesothelial type of growths produced the most extensive metastasis and the most widespread infiltration of the body wall.

A review of the literature on renal tumors throughout the animal kingdom, which constitutes the introductory part of this article, discloses but six other cases of renal tumors in mice, all epithelial, and no other adrenal tumors.

REFERENCES

(1) TYZZER: Jour. Med. Res., 1907, xvii, 166; 1909, xxi, 479. (2) HAALAND: Fourth Sci. Report, Imperial Cancer Research Fund, London,

(3) MURRAY: Third Sci. Report, Imperial Cancer Research Fund, London,

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336 MAUD SLYE, H. F. HOLMES AND H. G. WELLS

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