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Comparative Aspects of Experimentally Induced and Spontaneously Observed Renal Tumors*
Vol. 07, ,J1mto _Printed ih U.S.A,
THr!: .Jou.nx.1..L oF UnoLoGY
Copyright
CD Hl67 by The \Vi11-iarns & \Vilkin,-; Co
COMPARATIVE ASPECTS OF EXPERIMENTALLY INDUCED AND SPONTANEOUSLY OBSERVED RENAL TUMORS* GERALD P. l\lURI'HY, GERALD S. JOHNSTONt
From the James Buchanan
AND
EDWARD C. MELBY, .Ht.
Urological Insl"itnLe, 'Phe Johns Hopkins Hos71ital and the Division of
J,aboralo!°y Ani1nal Jierhcine, The Johns Hopkins University, Baltinwre, lliarylancL, and the Waller Heed General Hospital, Washington, D.C.
Despite apparent limitations concerning the characterization and nnderstanding of hmnan renal cell carcinomas, certain aspects of experimentally induced or spontaneously observed animal renal tun1ors noted in the past 6 years ean aid in further clarification of the elinical understanding of renal cell carcinoma. Human renal cell carcinornas have been classified on the basis of the predominant appearance of the cellular cytoplasm, i.e. clear-vacuolated, dark-granular and or rnixed. 1 , 2 Such classifications seem warranted as significant differences in survival rates after treatment have been noted dependent on the characteristic cell type. 2 Renal sarcomas, on the other hand, are of rare and infrequent clinical occurrence; less than 10 cases have been observed at the Brady Urological Institute in the past IO yearn. However, it is generally true that sarcomas, or undifferentiated renal tumors, are more frequently obtained experimentally following exposure to various carcinogenic agents. Despite refinements in diagnosis and treatment, it has been the commonly aecepted clinical observation that the tria,d of presenting complaints and signs of abdominal mass, pain and hematuria are often late manifestations and are frequently associated ,vith metastatic lesions (table 1). Polycythe1nia or other specific endoc:rine-related effects have also been of rare and infrequent occurrence (table 1). Therefore, it is with interest that experimental manipulation of renal structure and function has been Accepted for pnblicatiot1 June 28, J9G6. Presented in part at the Endocrine Urologi_c Forum annual meeting of the American Urological As~ociation, Inc., Chicago, Illinois, May 30June 2, 19G6. t Current address: Reed General Hosuital, Viashington, D. 1 Foot, N, C,, Humphreys, G. A. and Whit11:or!', VV. }'.: Renal tumors: Pathology and prognosis rn 295 cases. J. Urol., 66: 190, 195L . z ::Vforphy, CL P. and Mostofi, _F. K.: The significance of cytoplasmic grnnnlarny m the prognosis of renal cell carcinoma. J, Urol., 94: 48, 196:5. *
SPECIFIC INTRARlcNAL ALTERATIONS
Various specific intrarenal lesions have been induced in kidneys as the results of honnonai injections or other manipulations. Hyperphsia of the parietal layer of Bowman's capsule has been noted in some inbred mice strains. 3 • 4 Thi.~ lesion is sex dependent, i.e. found in male subjects, abolished by early castration and restored testosterone injections.'1 VVe have also observed this lesion in rats of both sexes after chronic dietary exposure to 1 per cent lead acetate (fig. l). 5 Spec;ific renal tubular alterations can be seeu in the rat after radiation exposure and usually consist of tubular dilations. 6 • 7 More than lOCh total body exposure is usually required before the successful induction of focal renal cortical adenomas in the rat. 6 • 7 Sin1ilar lesions with infrequent metastases are induced by chronic dietary tion of lead. 5 , 8 The combination of radiation and dietary lead increases the tumor incidence. 5 Toxic agents such as the heavy metals, also induce characteristic tubular cell intranuclear inclusions or deposits of no apparent significance.' However, such lesions in regard to 3 Crabtee, C, E.: Structure of Bowman's capsuln as index of age and sex varrntion in normal mice. Anat. Rec., 79: 395, 1941. 4 Crahteee, C. E.: Structure of Bowma.n 1s capsnle in cast.rate and testosterone treated nrnle mice as an index of hormonal effects on the rcua,I cortex. Endocrinology, 29: 5 :Murphy, G. P., Sharp, J. Lawson, N. L,, Greer, R. ·B. and Johnston, G. _: The chrouic functional and morphologic alterat10ns cansed by prolonged experimental nephrotoxic states in th(o rat. Invest. Urol., 1: 529, 1964c 6 Rosen, V. J., Castanera, T. J., Kimeldorf, D, J. and Jones, D. C.: Renal neoplasms in the radiated and non-irradiated Sprague-Dmvley rat Amer. J. Path., 38: 3.59-369, 1961. 'Murphy, G. P. and Sharp, J.C.: The effects radiation and cold immersion upon cxperimenh1l nrolithiasis, renal function, and morphology Invest. Urol., 1: 282, 1963. s Boyland, EC, Dukes, C. :E!., Grover, P, L. and lVIitchley, B. C.: The induction o_f renal tumors feeding lead acetate to rats. Bnt, J.
9li5
283, HlG2.
966
MURPHY, JOHNSTON AND MELBY
...
•"''
Fm. 1. Hyperplasia of parietal layer of Bowman's capsule in rat exposed to chronic dietary lead acetate. 5 H & E X346. 1. Presenting symptoms and signs in 90 patients with hypernephroma (1945 to 1957)
TABLE
Symptoms and Signs
No.
%
Fever Abdominal mass Hematuria Positive urine culture Polycythemia Elevated erythrocyte sedimentation rate 20 (corrected) Metastases Previous urolithiasis
30 33 43 14
33 37 48
Men Women
16
4
6
51
57
42 21
47 23
53 37
59 41
lead are usually noted before the detection of a generalized renal cortical atypism (fig. 2, A). 5 This microscopic atypism usually precedes the appearance of the characteristic focal cortical tumor. 5 Tumors produced by lead and radiation commonly have a pseudocapsule, rarely invade the renal substance and are usually composed of dark-staining cells (fig. 2, B). 5 When detected, the occasional metastatic lesions do not resemble the primary tumor and are usually totally undifferentiated. 5 Heavy metals, 5 radiation9 and toxic doses of 9 Murphy, G. P. and Lawson, N. L.: Experimental acute renal failure: Functional and morphologic alterations induced by serotonin. Invest. Urol., 1: 65, 1963.
serotonin9 will also induce a periglomerular fibrosis in the rat on a non-infective basis. Hypertension is usually associated with the widespread presence of the lesion. This amorphoric thickening of the glomerular capsule often extends to a close association with the juxtaglomerular apparatus, 5 which may explain the resultant hypertension (fig. 3). Because of the presence of atypical renal growths, plasma was obtained from rats exposed to lead or radiation. 5 This was used in an isolated tissue-culture system in order to detect possible growth-promoting factors related to the tumor formation (table 2). The results were entirely negative. Local and other unmonitored factors appear more related to the tumor growth. Additional attempts at successful tissue culture of other undifferentiated renal tumors have not been persistently successful. 10 Spontaneous tumors in the rat or arising in inbred mouse strains have also not been particularly frequent or pathogenic in behavior. 11 • 12 The European literature is replete with the occasional human case re10 Olcott, C. T.: Transplantable nephroblastoma (Wilm's tumor) and other spontaneous tumors in colony of rats. Cancer. Res., 10: 625, 1950. 11 Thompson, S. W., Huseby, R. A., Fox, M.A., Davis, C. L. and Hunt, R. D.: Spontaneous tumors in the Sprague-Dawley rat. J. Nat. Cancer Inst., 27: 1037, 1961. 12 Eker, R.: Familial renal adenomas in Wistar rats; preliminary report Acta Path. Microbial. Scand., 34: 554, 1954.
967
RENAL TUMORS
Fm. 2. A, geueraliied rellal lnbHlar atypism noted after chronic dietary lead E X.52. B, renal tumor induced in ra1 aft.er radiation expusun, ancJ luad iug;esLion. tumor cells above and psemlocap,sule in midliue. H & E X350.
port of a sarcoma arising in a kidney exposed to thorotrast years before.1" Few other species haYe been me
NJ•;WER STUllILS
Dimethylnitrosamine (D:\IX), an hepaJo-toxic agent, has been µreviously clem011stra1ed lo induce clear and dark cell, differentiated renal car cinomas in the rats.18 vVe have fournl with a mod.i fication, that in more than 20 per cent of rats given a single dose of DMN, renal tumors will deYelop.19 These lesions closely resemble their human counterparts 2 and readily im·ade the renal substance (fig. 4). Metastases to di~tant organs are frequent and the lesions closely resemble i.he renal primary. Other hormonal effects are associated with DMN treatment.19 Rats \Yith suc:h tumors become hypertensiYe, and demonstrate characteristic patterns of renal ischernia as clemorntrated by the excretion and renal uptake of radioactive mercury ( table 3) rn In addition, as,a,1 for erythropoietin (EPF) in DJ\I:X-treated ani18 Magee, P. N. and Barnes, J. ;\l.: Induction of kidney tumors in the rat with dirnethylnitrosamine (N-nitrosodimethyla.mine). J. l'aih. & Bact., 84: 19, 1962. 19 Mira.nd, E. A., Murphy, G. P., Johnston, G. S. a.nd Scott, W.W.: Presence of erythropoiet.in in plasma. of non-anemic rats with renal adenocarcinomas. Proc. 8oc. Exp. Biol. Med., 122: /'i28,
1966.
968
MURPHY, JOHNSTON AND MELBY
FIG. 3. Amorphous thickening of periglomerular capsule in region of juxtaglomerular apparatus in rat exposed to chronic dietary lead. 6 H & E Xl368. TABLE
Group
2. Lack of systemic renal growth factor in renal tumor induced rats 5
3 Months
G.R.
4 Months
5 Months
G.R.
G.R.
Lead Lead plus radiation Radiation Control
278,500* 223,600 244,700 211,400 107,600 124,400 106,100 213,400
1.96 1.58 1.72 1.49 0.76 0.87 0.74 1.50
104.500 Contaminated 204,500 242,800
269,900 235,000
0.73 1.44 1.71 1.90 1.66
7 Months
--
--
I
Contaminated Contaminated 279,900* 108,300 334,400 260,200 410,600 331,000
1. 97 0.76 2.36 1.83 2.90 2.33
352,400 243,000 Flask broken 261,300 254,900 239,800 368,700 337,100
G.R.
-2.49 1. 71
1.84 1.80 1.69 2.60 2.38
* Hemolytic plasma, disregard result. Baseline count is 141,500 cells per flask. Growth ratio (G.R.) is determined by dividing final cell count by initial cell count; e.g., G.R. of 2 indicates that cell population doubled during 3-day growth period. mals demonstrated that renal tumor bearing animals had significantly elevated EPF levels present (table 4). Twelve months after DMN exposure some non-tumor bearing animals also had EPF elevations.10 The prognostic significance of this is to date unknown. There is some species differences in tolerance to a single dose of DMN. In our hands the dog and monkey are quite sensitive and commonly exhibit evidence of severe renal and hepatic necrosis, while the rat does not. However, to date, DMN appears the most promising agent for use in experimental renal tumor induction at least in the rat. The tumors exert specific endocrine effects
and closely resemble cases of human renal cell carcinoma. SPONTANEOUS TUMORS IN OTHER ANIMAL SPECIES
Primary renal tumors are not common in domestic animals. Renal adenomas may attain large size in horses and cattle but are infrequent in other species. 20 Renal carcinomas are the commonest epithelial tumors in the dog and cat 20 Bloom, F.: Pathology of the Dog and Cat: The Genitourinary System, with Clinical Considerations. Evanston, Illinois: American Veterinary Publications, Inc., 1954, pp. 128-131.
RENAL 'l'UMORS
FrG. 4. H.enal tumor invading kidney substance in rat given 1 dose of dimethylnitrosamine. 19 H & E X20.
kidney. However, they are relatively rare and the jncidenee is considerably less in the eat than in the dog. In both species the incidence is greater in male animals and animals more than 5 years old are more frequently affected. 20 • 21 The average age in the clog when they are found to occur is 8 years, although renal turn.ors have been found in dogs as young as 3 years. Hematuria is common.22 Histologically the renal cell carcinomas in the dog closely resemble the clear and granular cell tumors of man (fig. 5, A). The tumors often metastasize apparently by way of the blood to the lungs, liver, adrenals and less often to the opposite kidney, peritoneum, spleen, heart and other organs. Bone rnetastases are exceptionally rare in animal.s 23 • 24 but do occur (fig. 5, B). Undifferentiated tumorn, or so called nephro21 Mulligan, R. l\1.: Neoplasms of the Dog. Baltimore: The Williams & Wilkins Co., 1949. "JVIoulton, J.E.: Tumors in Domestic Animals. Los Angeles: University of California Press, 1961. 23 De JVlene½eS, Z.: Bovine renal tumors, incidence and histopathology. J. Amer. Vet. Med. Ass., 112: 466, 1948. 24 Nielsen, R. W. aud Archibald, J.: Canine renal disorders. III. Renal carcinoma in three dogs, No ..Amer. Vet., 36: 36, HJ55.
3. Representative values of heu.rl/kiclne!J weight ratio and kidney and urine 203-Hg 11.ptakes of rats receivinJ climethulnilrosamine (D ZvLV) 19
TABLE
Group
DMN-induced renal tumor rats a1 14, 15, 16, 17 mos. Non-tumor rats receiving DMN": 14 and 15 mos. lo mos. 17 mos. Control rats, not injected
blastomas, are more common in the pig and fowl In histologic appearance they are tnmor.s of embryonic origin and are developmentally distinct. from teratomas. Boston terriers haYe been re-
970
MURPHY, JOHNSTON AND MELBY TABLE
4. Presence of erythropoietin in plasmas of non-anemic rats with dimethylnitrosamine (DMN) induced renal adenocarcinomas19 Polycythemic mouse assay
No.
Pooled Plasmas
Wt.
Avg. Ht.
Avg. Blood 24-hr. Fe-59 Uptake
1.33 (1. 26-1. 43) SD ± 0.19, SE 0.01 0.39 (0.26-0.64) SD ± 0.22, SE 0.13 0.31 (0.22-0.39) SD ± 0.09, SE 0.05 1.24 (1.17-1.31) SD± 0.17, SE 0.08 0.31 (0.24-0.37) SD ± 0.06, SE 0.03
(gm.)
DMN-induced renal tumor rats at 14, 15, 16, 17 mos.
5
33
71.3
Non-tumor rats receiving DMN at 14, 15 mos.
3
33
65.0
16 mos.
5
34
67.3
17 mos.
7
33
69.6
4
34
60.0
Control rats at 14, 15, 16, 17 mos.
'
Assay Mice
Avg. Body
SD SE
= =
Standard deviation. Standard error.
FIG. 5. A, renal cell carcinoma in dog demonstrating clear cell morphology. H & E X550. B, renal cell carcinoma in dog with metastases to bone. H & E X400.
ported to have a high incidence of pheochromocytomas in the kidney, 21 and cats are frequently found to have primary and secondary renal involvement in the presence of lymphoma (figs. 6 and 7).
Secondary tumors are common since disseminated neoplasms of any type may be found in the kidney. These usually localize in the cortices and tend to be bilateral. Renal tumors have been reported in a few spe-
RENAL T'UIVIORS
Fm. 6. Lymphoma in cal with extemive mvolvement of rennJ parenchyma.
971
curring. 25 In the mouse, tumors of the urogenital system are most comrronly found in the kidney. Most are reported to be embryonal nephromas, although some sarcomas and lymphosarcornas have been reported. 25 Renal tumors of various types including adeno· mas, hypernephromas and adenocarci.nomas ha.ve been reported in certain wild animals,2 7 psittacine birds, 27 and in snakes, 28 but their true incidence i.s difficult to properly evaluate. Information currently available indicates that tumors of any type, either benign or malignant are rare in simian primates. 2 ' Those that have been reported, regardless of the duration or apparent degree of malignancy, seldom metastasize. Hovrnver, a familial occurrence of renal carcinoma in rhesus
Fw. 7. Lymphocytes invading renal parenchyma in cat with lymphoma, H & E X400
cies of the more commonly used laboratory animals. In the rabbit, they an, reported to be the second most common, exceeded by tumors of the uterus. 2" The turn.om are usually undifferentiated,26 but have been described by various investigators as including adenomas, adenosarcomas and aclenocarcinomas. 25 In the rat, cases of renal carcinoma, adenorn.a and embryonal nephroma have been reported as spontaneously oc25 Cohrs,P ., Jaffe, R. andMeessen, H.: Pathologie Der Laboratoriumstiere. Springer--Verlag, Berlin, Gottingen, Heidelberg, HJ58. 26 Scott, E.: Tumors of the kidney in rah bits. J. Cancer Res., 2: 367, 1917 .
monkeys was reported from one source, 3n 3,nd cases of renal tumors including rnalignant adenoma, sarcoma. and carcinoma, with 27 Wadsworth, J. R.: Some neoplasms of captive wild animals. J.A.M.A., 125: 121, 1954, 28 Wadsworth, J. R.: Neoplasms of snakeso Vet. Exten. Quart., 33: 63, 1954. 29 Habermann, R. T. and Williams, F. P.: Diseases seen at necropsy of 708 Macaca. mulattn (Rhesus monkey) and Macaca Philippineuis (Cynomolgus monkey). Amer. J. Vet. Res,, 18: 419, 1957. 30 Ratcliffe, H. L.: Familial occurrence of rena.1 carcinoma in Rhesus monkeys (l\!Iacaca rn ulattal. Amer. J. Pa.th., 16: 619, 1940.
972
MURPHY, JOHNSTON AND MELBY
metastases, 31 have been reported. These important features of sub-human primate and other non-human species thus have been of significant aid in the proper selection and design of animal species for renal tumor induction. SUMMARY
Clinical characteristics and histopathologic features of human renal cell carcinoma have been delineated on the basis of several studies. These 31 Scott, H. H.: Report on the deaths occurring in the Society's gardens during the year 1927. Proc. Zool. Soc., London, 1: 81, 1928.
features, which include the cellular morphology of the renal primary and metastatic lesions, have been compared to experimentally induced renal alterations in mice, rats and dogs. Comparative features of tumors induced by radiation, dietary lead or dimethylnitrosamine are described. Hypertension and increased erythropoietin levels are seen in animals bearing renal cell carcinomas induced by a single dose of dimethylnitrosamine. Pertinent aspects of the Syrian and frog renal tumors are noted. The present status of spontaneously occurring renal tumors in other animal species has also been reviewed and compared on a similar basis.
THr!: .Jou.nx.1..L oF UnoLoGY
Copyright
CD Hl67 by The \Vi11-iarns & \Vilkin,-; Co
COMPARATIVE ASPECTS OF EXPERIMENTALLY INDUCED AND SPONTANEOUSLY OBSERVED RENAL TUMORS* GERALD P. l\lURI'HY, GERALD S. JOHNSTONt
From the James Buchanan
AND
EDWARD C. MELBY, .Ht.
Urological Insl"itnLe, 'Phe Johns Hopkins Hos71ital and the Division of
J,aboralo!°y Ani1nal Jierhcine, The Johns Hopkins University, Baltinwre, lliarylancL, and the Waller Heed General Hospital, Washington, D.C.
Despite apparent limitations concerning the characterization and nnderstanding of hmnan renal cell carcinomas, certain aspects of experimentally induced or spontaneously observed animal renal tun1ors noted in the past 6 years ean aid in further clarification of the elinical understanding of renal cell carcinoma. Human renal cell carcinornas have been classified on the basis of the predominant appearance of the cellular cytoplasm, i.e. clear-vacuolated, dark-granular and or rnixed. 1 , 2 Such classifications seem warranted as significant differences in survival rates after treatment have been noted dependent on the characteristic cell type. 2 Renal sarcomas, on the other hand, are of rare and infrequent clinical occurrence; less than 10 cases have been observed at the Brady Urological Institute in the past IO yearn. However, it is generally true that sarcomas, or undifferentiated renal tumors, are more frequently obtained experimentally following exposure to various carcinogenic agents. Despite refinements in diagnosis and treatment, it has been the commonly aecepted clinical observation that the tria,d of presenting complaints and signs of abdominal mass, pain and hematuria are often late manifestations and are frequently associated ,vith metastatic lesions (table 1). Polycythe1nia or other specific endoc:rine-related effects have also been of rare and infrequent occurrence (table 1). Therefore, it is with interest that experimental manipulation of renal structure and function has been Accepted for pnblicatiot1 June 28, J9G6. Presented in part at the Endocrine Urologi_c Forum annual meeting of the American Urological As~ociation, Inc., Chicago, Illinois, May 30June 2, 19G6. t Current address: Reed General Hosuital, Viashington, D. 1 Foot, N, C,, Humphreys, G. A. and Whit11:or!', VV. }'.: Renal tumors: Pathology and prognosis rn 295 cases. J. Urol., 66: 190, 195L . z ::Vforphy, CL P. and Mostofi, _F. K.: The significance of cytoplasmic grnnnlarny m the prognosis of renal cell carcinoma. J, Urol., 94: 48, 196:5. *
SPECIFIC INTRARlcNAL ALTERATIONS
Various specific intrarenal lesions have been induced in kidneys as the results of honnonai injections or other manipulations. Hyperphsia of the parietal layer of Bowman's capsule has been noted in some inbred mice strains. 3 • 4 Thi.~ lesion is sex dependent, i.e. found in male subjects, abolished by early castration and restored testosterone injections.'1 VVe have also observed this lesion in rats of both sexes after chronic dietary exposure to 1 per cent lead acetate (fig. l). 5 Spec;ific renal tubular alterations can be seeu in the rat after radiation exposure and usually consist of tubular dilations. 6 • 7 More than lOCh total body exposure is usually required before the successful induction of focal renal cortical adenomas in the rat. 6 • 7 Sin1ilar lesions with infrequent metastases are induced by chronic dietary tion of lead. 5 , 8 The combination of radiation and dietary lead increases the tumor incidence. 5 Toxic agents such as the heavy metals, also induce characteristic tubular cell intranuclear inclusions or deposits of no apparent significance.' However, such lesions in regard to 3 Crabtee, C, E.: Structure of Bowman's capsuln as index of age and sex varrntion in normal mice. Anat. Rec., 79: 395, 1941. 4 Crahteee, C. E.: Structure of Bowma.n 1s capsnle in cast.rate and testosterone treated nrnle mice as an index of hormonal effects on the rcua,I cortex. Endocrinology, 29: 5 :Murphy, G. P., Sharp, J. Lawson, N. L,, Greer, R. ·B. and Johnston, G. _: The chrouic functional and morphologic alterat10ns cansed by prolonged experimental nephrotoxic states in th(o rat. Invest. Urol., 1: 529, 1964c 6 Rosen, V. J., Castanera, T. J., Kimeldorf, D, J. and Jones, D. C.: Renal neoplasms in the radiated and non-irradiated Sprague-Dmvley rat Amer. J. Path., 38: 3.59-369, 1961. 'Murphy, G. P. and Sharp, J.C.: The effects radiation and cold immersion upon cxperimenh1l nrolithiasis, renal function, and morphology Invest. Urol., 1: 282, 1963. s Boyland, EC, Dukes, C. :E!., Grover, P, L. and lVIitchley, B. C.: The induction o_f renal tumors feeding lead acetate to rats. Bnt, J.
9li5
283, HlG2.
966
MURPHY, JOHNSTON AND MELBY
...
•"''
Fm. 1. Hyperplasia of parietal layer of Bowman's capsule in rat exposed to chronic dietary lead acetate. 5 H & E X346. 1. Presenting symptoms and signs in 90 patients with hypernephroma (1945 to 1957)
TABLE
Symptoms and Signs
No.
%
Fever Abdominal mass Hematuria Positive urine culture Polycythemia Elevated erythrocyte sedimentation rate 20 (corrected) Metastases Previous urolithiasis
30 33 43 14
33 37 48
Men Women
16
4
6
51
57
42 21
47 23
53 37
59 41
lead are usually noted before the detection of a generalized renal cortical atypism (fig. 2, A). 5 This microscopic atypism usually precedes the appearance of the characteristic focal cortical tumor. 5 Tumors produced by lead and radiation commonly have a pseudocapsule, rarely invade the renal substance and are usually composed of dark-staining cells (fig. 2, B). 5 When detected, the occasional metastatic lesions do not resemble the primary tumor and are usually totally undifferentiated. 5 Heavy metals, 5 radiation9 and toxic doses of 9 Murphy, G. P. and Lawson, N. L.: Experimental acute renal failure: Functional and morphologic alterations induced by serotonin. Invest. Urol., 1: 65, 1963.
serotonin9 will also induce a periglomerular fibrosis in the rat on a non-infective basis. Hypertension is usually associated with the widespread presence of the lesion. This amorphoric thickening of the glomerular capsule often extends to a close association with the juxtaglomerular apparatus, 5 which may explain the resultant hypertension (fig. 3). Because of the presence of atypical renal growths, plasma was obtained from rats exposed to lead or radiation. 5 This was used in an isolated tissue-culture system in order to detect possible growth-promoting factors related to the tumor formation (table 2). The results were entirely negative. Local and other unmonitored factors appear more related to the tumor growth. Additional attempts at successful tissue culture of other undifferentiated renal tumors have not been persistently successful. 10 Spontaneous tumors in the rat or arising in inbred mouse strains have also not been particularly frequent or pathogenic in behavior. 11 • 12 The European literature is replete with the occasional human case re10 Olcott, C. T.: Transplantable nephroblastoma (Wilm's tumor) and other spontaneous tumors in colony of rats. Cancer. Res., 10: 625, 1950. 11 Thompson, S. W., Huseby, R. A., Fox, M.A., Davis, C. L. and Hunt, R. D.: Spontaneous tumors in the Sprague-Dawley rat. J. Nat. Cancer Inst., 27: 1037, 1961. 12 Eker, R.: Familial renal adenomas in Wistar rats; preliminary report Acta Path. Microbial. Scand., 34: 554, 1954.
967
RENAL TUMORS
Fm. 2. A, geueraliied rellal lnbHlar atypism noted after chronic dietary lead E X.52. B, renal tumor induced in ra1 aft.er radiation expusun, ancJ luad iug;esLion. tumor cells above and psemlocap,sule in midliue. H & E X350.
port of a sarcoma arising in a kidney exposed to thorotrast years before.1" Few other species haYe been me
NJ•;WER STUllILS
Dimethylnitrosamine (D:\IX), an hepaJo-toxic agent, has been µreviously clem011stra1ed lo induce clear and dark cell, differentiated renal car cinomas in the rats.18 vVe have fournl with a mod.i fication, that in more than 20 per cent of rats given a single dose of DMN, renal tumors will deYelop.19 These lesions closely resemble their human counterparts 2 and readily im·ade the renal substance (fig. 4). Metastases to di~tant organs are frequent and the lesions closely resemble i.he renal primary. Other hormonal effects are associated with DMN treatment.19 Rats \Yith suc:h tumors become hypertensiYe, and demonstrate characteristic patterns of renal ischernia as clemorntrated by the excretion and renal uptake of radioactive mercury ( table 3) rn In addition, as,a,1 for erythropoietin (EPF) in DJ\I:X-treated ani18 Magee, P. N. and Barnes, J. ;\l.: Induction of kidney tumors in the rat with dirnethylnitrosamine (N-nitrosodimethyla.mine). J. l'aih. & Bact., 84: 19, 1962. 19 Mira.nd, E. A., Murphy, G. P., Johnston, G. S. a.nd Scott, W.W.: Presence of erythropoiet.in in plasma. of non-anemic rats with renal adenocarcinomas. Proc. 8oc. Exp. Biol. Med., 122: /'i28,
1966.
968
MURPHY, JOHNSTON AND MELBY
FIG. 3. Amorphous thickening of periglomerular capsule in region of juxtaglomerular apparatus in rat exposed to chronic dietary lead. 6 H & E Xl368. TABLE
Group
2. Lack of systemic renal growth factor in renal tumor induced rats 5
3 Months
G.R.
4 Months
5 Months
G.R.
G.R.
Lead Lead plus radiation Radiation Control
278,500* 223,600 244,700 211,400 107,600 124,400 106,100 213,400
1.96 1.58 1.72 1.49 0.76 0.87 0.74 1.50
104.500 Contaminated 204,500 242,800
269,900 235,000
0.73 1.44 1.71 1.90 1.66
7 Months
--
--
I
Contaminated Contaminated 279,900* 108,300 334,400 260,200 410,600 331,000
1. 97 0.76 2.36 1.83 2.90 2.33
352,400 243,000 Flask broken 261,300 254,900 239,800 368,700 337,100
G.R.
-2.49 1. 71
1.84 1.80 1.69 2.60 2.38
* Hemolytic plasma, disregard result. Baseline count is 141,500 cells per flask. Growth ratio (G.R.) is determined by dividing final cell count by initial cell count; e.g., G.R. of 2 indicates that cell population doubled during 3-day growth period. mals demonstrated that renal tumor bearing animals had significantly elevated EPF levels present (table 4). Twelve months after DMN exposure some non-tumor bearing animals also had EPF elevations.10 The prognostic significance of this is to date unknown. There is some species differences in tolerance to a single dose of DMN. In our hands the dog and monkey are quite sensitive and commonly exhibit evidence of severe renal and hepatic necrosis, while the rat does not. However, to date, DMN appears the most promising agent for use in experimental renal tumor induction at least in the rat. The tumors exert specific endocrine effects
and closely resemble cases of human renal cell carcinoma. SPONTANEOUS TUMORS IN OTHER ANIMAL SPECIES
Primary renal tumors are not common in domestic animals. Renal adenomas may attain large size in horses and cattle but are infrequent in other species. 20 Renal carcinomas are the commonest epithelial tumors in the dog and cat 20 Bloom, F.: Pathology of the Dog and Cat: The Genitourinary System, with Clinical Considerations. Evanston, Illinois: American Veterinary Publications, Inc., 1954, pp. 128-131.
RENAL 'l'UMORS
FrG. 4. H.enal tumor invading kidney substance in rat given 1 dose of dimethylnitrosamine. 19 H & E X20.
kidney. However, they are relatively rare and the jncidenee is considerably less in the eat than in the dog. In both species the incidence is greater in male animals and animals more than 5 years old are more frequently affected. 20 • 21 The average age in the clog when they are found to occur is 8 years, although renal turn.ors have been found in dogs as young as 3 years. Hematuria is common.22 Histologically the renal cell carcinomas in the dog closely resemble the clear and granular cell tumors of man (fig. 5, A). The tumors often metastasize apparently by way of the blood to the lungs, liver, adrenals and less often to the opposite kidney, peritoneum, spleen, heart and other organs. Bone rnetastases are exceptionally rare in animal.s 23 • 24 but do occur (fig. 5, B). Undifferentiated tumorn, or so called nephro21 Mulligan, R. l\1.: Neoplasms of the Dog. Baltimore: The Williams & Wilkins Co., 1949. "JVIoulton, J.E.: Tumors in Domestic Animals. Los Angeles: University of California Press, 1961. 23 De JVlene½eS, Z.: Bovine renal tumors, incidence and histopathology. J. Amer. Vet. Med. Ass., 112: 466, 1948. 24 Nielsen, R. W. aud Archibald, J.: Canine renal disorders. III. Renal carcinoma in three dogs, No ..Amer. Vet., 36: 36, HJ55.
3. Representative values of heu.rl/kiclne!J weight ratio and kidney and urine 203-Hg 11.ptakes of rats receivinJ climethulnilrosamine (D ZvLV) 19
TABLE
Group
DMN-induced renal tumor rats a1 14, 15, 16, 17 mos. Non-tumor rats receiving DMN": 14 and 15 mos. lo mos. 17 mos. Control rats, not injected
blastomas, are more common in the pig and fowl In histologic appearance they are tnmor.s of embryonic origin and are developmentally distinct. from teratomas. Boston terriers haYe been re-
970
MURPHY, JOHNSTON AND MELBY TABLE
4. Presence of erythropoietin in plasmas of non-anemic rats with dimethylnitrosamine (DMN) induced renal adenocarcinomas19 Polycythemic mouse assay
No.
Pooled Plasmas
Wt.
Avg. Ht.
Avg. Blood 24-hr. Fe-59 Uptake
1.33 (1. 26-1. 43) SD ± 0.19, SE 0.01 0.39 (0.26-0.64) SD ± 0.22, SE 0.13 0.31 (0.22-0.39) SD ± 0.09, SE 0.05 1.24 (1.17-1.31) SD± 0.17, SE 0.08 0.31 (0.24-0.37) SD ± 0.06, SE 0.03
(gm.)
DMN-induced renal tumor rats at 14, 15, 16, 17 mos.
5
33
71.3
Non-tumor rats receiving DMN at 14, 15 mos.
3
33
65.0
16 mos.
5
34
67.3
17 mos.
7
33
69.6
4
34
60.0
Control rats at 14, 15, 16, 17 mos.
'
Assay Mice
Avg. Body
SD SE
= =
Standard deviation. Standard error.
FIG. 5. A, renal cell carcinoma in dog demonstrating clear cell morphology. H & E X550. B, renal cell carcinoma in dog with metastases to bone. H & E X400.
ported to have a high incidence of pheochromocytomas in the kidney, 21 and cats are frequently found to have primary and secondary renal involvement in the presence of lymphoma (figs. 6 and 7).
Secondary tumors are common since disseminated neoplasms of any type may be found in the kidney. These usually localize in the cortices and tend to be bilateral. Renal tumors have been reported in a few spe-
RENAL T'UIVIORS
Fm. 6. Lymphoma in cal with extemive mvolvement of rennJ parenchyma.
971
curring. 25 In the mouse, tumors of the urogenital system are most comrronly found in the kidney. Most are reported to be embryonal nephromas, although some sarcomas and lymphosarcornas have been reported. 25 Renal tumors of various types including adeno· mas, hypernephromas and adenocarci.nomas ha.ve been reported in certain wild animals,2 7 psittacine birds, 27 and in snakes, 28 but their true incidence i.s difficult to properly evaluate. Information currently available indicates that tumors of any type, either benign or malignant are rare in simian primates. 2 ' Those that have been reported, regardless of the duration or apparent degree of malignancy, seldom metastasize. Hovrnver, a familial occurrence of renal carcinoma in rhesus
Fw. 7. Lymphocytes invading renal parenchyma in cat with lymphoma, H & E X400
cies of the more commonly used laboratory animals. In the rabbit, they an, reported to be the second most common, exceeded by tumors of the uterus. 2" The turn.om are usually undifferentiated,26 but have been described by various investigators as including adenomas, adenosarcomas and aclenocarcinomas. 25 In the rat, cases of renal carcinoma, adenorn.a and embryonal nephroma have been reported as spontaneously oc25 Cohrs,P ., Jaffe, R. andMeessen, H.: Pathologie Der Laboratoriumstiere. Springer--Verlag, Berlin, Gottingen, Heidelberg, HJ58. 26 Scott, E.: Tumors of the kidney in rah bits. J. Cancer Res., 2: 367, 1917 .
monkeys was reported from one source, 3n 3,nd cases of renal tumors including rnalignant adenoma, sarcoma. and carcinoma, with 27 Wadsworth, J. R.: Some neoplasms of captive wild animals. J.A.M.A., 125: 121, 1954, 28 Wadsworth, J. R.: Neoplasms of snakeso Vet. Exten. Quart., 33: 63, 1954. 29 Habermann, R. T. and Williams, F. P.: Diseases seen at necropsy of 708 Macaca. mulattn (Rhesus monkey) and Macaca Philippineuis (Cynomolgus monkey). Amer. J. Vet. Res,, 18: 419, 1957. 30 Ratcliffe, H. L.: Familial occurrence of rena.1 carcinoma in Rhesus monkeys (l\!Iacaca rn ulattal. Amer. J. Pa.th., 16: 619, 1940.
972
MURPHY, JOHNSTON AND MELBY
metastases, 31 have been reported. These important features of sub-human primate and other non-human species thus have been of significant aid in the proper selection and design of animal species for renal tumor induction. SUMMARY
Clinical characteristics and histopathologic features of human renal cell carcinoma have been delineated on the basis of several studies. These 31 Scott, H. H.: Report on the deaths occurring in the Society's gardens during the year 1927. Proc. Zool. Soc., London, 1: 81, 1928.
features, which include the cellular morphology of the renal primary and metastatic lesions, have been compared to experimentally induced renal alterations in mice, rats and dogs. Comparative features of tumors induced by radiation, dietary lead or dimethylnitrosamine are described. Hypertension and increased erythropoietin levels are seen in animals bearing renal cell carcinomas induced by a single dose of dimethylnitrosamine. Pertinent aspects of the Syrian and frog renal tumors are noted. The present status of spontaneously occurring renal tumors in other animal species has also been reviewed and compared on a similar basis.