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Renal Neoplasms: An Enigma and a Challenge
THE JOURNAL OF UROLOGY
Vol. 69, No. 1, January 1953 Printed in U.S.A.
RENAL NEOPLASMS: AN ENIGMA AND A CHALLENGE CLYDE L. DEMING From the Department of Surgery, Section on Urology, Yale University School of Medicine, and the Grace-New Haven Community Hospital, New Haven, Conn.
The literature enfolding the subject matter of renal neoplasms reads like a novel of romance. The differences of opinion as to the names of the tumors, the specificity of sex, their accidental, unheralded discovery, and their behavior are tantalizing. The attempt has been futile to teach medical students and house officers more than three simple facts concerning renal neoplasms: 1) That they are highly malignant; 2) that the only treatment is surgical; and 3) that the results are 20 per cent controls for a five-year period. The classifications have been confusing, the surgery not well organized, and the results discouraging. Many of the classifications are so long and complicated that it is not possible to remember them. The many references to a "nephroid" tumor imply that such a tumor is associated with the kidney but not necessarily of renal origin, and the reader is often misled as to the anatomic origin of the tumor. Furthermore, the etiology of renal tumors is still not clear. The work of Lucke in 1938 demonstrated that cancer in the kidney of the tree frog was due to a virus. Leary, in 1950, was successful in producing adenomas in the kidneys of rabbits subsequent to the development of nephrosclerosis with local implantation of cholesterol. Cabot has demonstrated conclusively that adenocarcinomas are derived from adenomas; and Kirkman and Bacon claim that renal cancers can be produced in the hamster by the use of the female hormone, stilbestrol. Such demonstrations are significant and encourage us to continue our efforts to elicit the actual cause of neoplastic activation in the kidney. It is the author's ambition to clarify the subject of renal tumors by considering their anatomic origin and their behavior patterns in order that we may formulate a sound and logical basis for discussion. With this objective, the following classification is proposed: CLASSIFICATION OF RENAL TUMORS
1) Nephroma (Wilms') 2) Hypernephroma, adrenal origin 3) Carcinoma of the cortex: a) Embryonic b) Adult c) Scirrhus-pelvis 4) Papillary: a) Pelvis b) Cortex 5) N eurogenic: a) Neuroblastoma The William T. Belfield Memorial Lecture, delivered before the Chicago Urological Society, October 25, 1951.
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CLYDE L. DEMING
b) Ganglioneuroma c) Medulloblastoma d) Schwannoma 6) Sarcoma The kidney as an organ is a system of tubes and its physiology, though complex, is now quite well understood. From the standpoint of tumor development we may state that the kidney is composed of a capsule, epithelial tubes, a pelvis lined with transitional epithelium and a pedicle of blood vessels containing varying amounts of mesothelial tissue and nerve tissue. The only nephroma which we encounter is the so-called Wilms' tumor. This tumor contains all the histological elements of the kidney and is truly nephroid. To use terms such as "histoid," "organoid" and "hypernephroid mesothelial type of hypernephroma" confuses the issue and conveys nothing concrete. To disbar the use of "oids" in the classification of neoplasms in and on the kidney would greatly simplify our understanding of them and pave the way for a clearer conception of their behavior and their response to therapy. Hypernephroma.-The hypernephroma is not a true kidney tumor but is derived from congenitally misplaced suprarenal tissue. Such misplaced tissue has been found widely distributed within the abdomen and even along the spermatic cord in the inguinal canal. Wide distribution can also take place anywhere on or within the renal organ. The reports of Martland and O'Crowley on autopsies in accidental deaths give conclusive evidence in support of this possibility. The deposit of embryonic rests makes possible the development of a hypernephroma on, underneath or anywhere in the renal parenchyma, and to say that a hypernephroma develops only on the capsule of the kidney is untrue. It is the only neoplasm reportedly found associated with polycystic kidney disease and is the most common renal neoplasm in the pregnant woman, which suggests an hormonal factor as the activating agent. These tumors are most common in the 6th decade of life and are rarely reported in children. Other than Wilms' tumor, they are most frequently discovered accidentally by the physician. The early stage of their development is relatively slmv, they are encapsulated and sometimes grow to large size or become large by intratumoral hemorrhage. At other times the primary tumor is secondary in size to the metastatic lesion, and such a condition complicates the clinician's responsibility respective to a correct diagnosis. Nephroma (Wilms').-The 53 names applied to this tumor which is commonly found in children would be almost a day's assignment for a medical student to memorize. The vVilms' tumor may be a true embryoma, but it seems logical that since it is the only renal tumor which contains all the elements of the kidney it has justly earned the distinction of being called a nephroma after its name has been bandied about for 123 years. It will require some effort to make this term universal, but it is wise to make the effort in order to clarify the terminology. It is one of the largest renal neoplasms in children, grows rapidly and metastasizes relatively early either by direct invasion or blood stream. In children it makes no selection of side or sex; in the adult, it is rare but does occur
RENAL NEOPLASMS
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in every decade up to and including the eighth -with a high preference for the male sex. ]Many of these tumors are accidentally discovered on routine examination in children's clinics and hospitals. Ladd of Boston has had one of the largest experiences with children's renal tumors and reports (\0 to 70 per cent of renal tumors to be of this In our clinic of general urology only about 30 per cent of renal tumors in children belong to this the others being carcinoma, both embryonic: and adult, and neuroblastomas and sympathic:oblastomas. Several writers have reported bilateral involvement with nephroma. The fact that these tumors have been found in foetuses, have been removed surgically within the first three days of life and that 75 per cent are found before the fifth year leaves no doubt that they belong to the embryonic: group of neoplasms. Becam:e of the rapidity of their grmrth, their high degree of malignancy, and the uncertainty as to the results of surgical treatment they still present a challenge to 2\-Iedicine. tumors of the kidney.~Tumors derived from the neurogenic anlage include the neuroblastoma, sympathicoblastoma, medulloblastoma, ganglioneuroma, paraganglioma and schwannoma, and take their origin from the nerve structures about the kidney and adrenal gland. They used to be called sarcomas. Such tumors are found close to the kidney pelvis, anterior, posterior or below it. They cause an obstruction to the ureter and interfere with the pyelogrnphic to the extent that it is impossible to predict their origin preoperatively, The most embryonic, the nenroblastomas and meclulloblastomas, grmv rapidly, There can be but little significance in the so-called Pepper and Hutchison type,~. The difference is not in the histology of the tumor but in the mode of its dissemination. The avenues for metastatic development can be explained by Anson's work on the difference between the venous drainage of the right kidney and of the left kidney. The right perirenal lymphatic drainage is in close approximation to the liver, which accounts for the metastases to the liver; -while the dii:;semination from a left kidney tumor is directly through the renal vein to the prevertebral system and upper skeletal region. \Ve are indebted to Pepper and Hutchison for their differentiation of behavior with respect to the development of metastases but to Anson for a possible explanation of the biological behavior of the left renal tumor. The ganglioneuroma and paraganglioma are more adult forms of nerve tumors. The latter are chromaffin tumors and grossly are reddish in color, shmv a lesser degree of malignancy and do not possess any sex hormone. The sc:hwannoma is rare, as only six or seven tumors are reported. These develop below the kidney but their x-ray shado1rn often overlie the kidney shadow, and they are difficult to diagnose clinically. 1-Iowever, they can usually be removed without, disturbing the kidney and ureter and are not possessive of a high degree of malignancy. The clinician can conceive of these tumors of neuroectodermal origin as perirenal tumors possessing the behavior characteristics of the same types of tumors found in the brain and spinal cord. Sarcomas.-The differenc:e between sarcomas and neurogenic: tumors is nmv well recognized, and tissue strains have done much to segregate these tumors into proper categories. HmYever, sarcoma of the kidney does occur arising from st.rue-
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CLYDE L. DEMING
tures at the hilum adjacent to the pelvis, from the capsule or even from the kidney itself. Such growths become fairly large and are more apt to invade the kidney than the neurogenic tumors. They occur in all age groups but are not common. They often appear fairly well encapsulated at first and may be associated with renal calculi. The roentgenograms of sarcoma may shmY spotty areas indicating fatty tissue -which often suggests their type. They usually grow rapidly and are locally invasive of the kidney and perirenal tissues. They can be removed without much difficulty unless they are invasive of the posterior abdominal wall, and they are not usually considered as malignant as the other tumors. Carcinoma.-The carcinomas of the kidney cortex are seen at all ages and may be divided into the embryonic and adult types. The embryonic tumor takes its origin in the renal blastema while the adult carcinoma may arise, according to Cabot, from an adenoma, which is not an uncommon finding in the kidney, or from any of the tubules. The adult types frequently present an adenomatous character and are apt to develop into large lobulated masses. The embryonic cancer grows rapidly, infiltrates the whole organ and metastasizes to the lungs through the blood stream. The embryonic tumor is more often found in the child or young adult. The adult type grows slowly, at first is encapsulated and may be accidentally found on routine physical examination before it has penetrated the pelvis and caused hematuria. It infiltrates the renal organ and may infiltrate the liver or spleen. The behavior of these tumors is much like the behavior of adenocarcinomas elsewhere in the body. The embryonic type is the more malignant of the two. Papillary carcinoma.-Papillary cancers of the kidney pelvis are similar to transitional cell papillomas of the urinary bladder. While it has been known for many years that papillomas of the kidney pelvis metastasize to the ureter and bladder it is only within the past few years that reports have been made concerning such metastatic lesions from papillary carcinomas of the renal cortex. vVe have made a study of cortical cancers which have showed a papillary character. They may include the papillary adenocancers. All cancers with papillary cellular structure, whether derived from the kidney cortex or pelvis, behave similarly. They are not encapsulated, they bleed readily, infiltrate the kidney, and metastasize not infrequently to the lower ureter and to the lung. One has a right to ask -whether all of these papillary tumors do not take their origin from the pelvis, some of whose embryonic cells have reached well within the component parts of the renal blastema. Twenty years ago we removed a cancer of the kidney and seven years later the patient had a tumor of the lower ureter. This was removed. Two years later he had bloody sputum and a radiogram positive for metastatic tumor in the chest. In review of the microscopic sections the primary tumor was found to be of papillary character. Three years ago the right kidney of a physician 42 years of age ,ms removed by a general surgeon for malignancy. Two years later the lower end of the ureter was removed because of bleeding. One year later the patient was referred to us for hematuria and dysuria. He was found to have an infiltrating tumor of the base of the
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bladder with no other evidence of cancer. Biopsy indicated the same microscopic: picture of papillary carcinoma in all the specimens. The origin of the primary tumor was cortical rather than pelvic:. A ureterosigmoidostomy was done on the remaining side and his whole bladder removed. He subsequently developed a metastatic lesion in his abdominal -Yvall and died of the disease. Time forbids a discussion of the theories of transmission of papillary renal tumors to the lmrer ureter and bladder, but other reporters have made observations like ours and we are in accord in advising complete ureterectomy including a portion of the hladder for all tumors of the kidney, whether cortical or pelvic, which present a papillomatous character. The other tumors of the kidney pelvis, such as the scirrhus and epidermoid types, belong to the same category as the papillary carcinomas, show the same biological behavior as the papillary carcinomas and demand the same serious consideration for treatment. A difference in degree of malignancy of a tumor of the kidney pelvis has little significance when all have such a high degree of potential grnwth and are ultimately fatal. J1 etastatic developments.~ :\r eoplasms of the kidney present as many, if not more, problems dealing with metastases than any other group of neoplasms. The surgeon many times removes renal neoplasms when the prognosis seem::s good only to find that some time within one year to t-Yrnnty years the patient has a metastasis. Beer wrote many years ago, "we do not know what biological forces delay the development of secondary tumors." All the reports containing the largest series of cases are in accord that renal tumors metastasize to the lungs, bones, liver, regional lymph nodes, spleen, adrenal, opposite kidney, heart, brain and seminal vesicles in that order of frequency. (Abeshouse and Wienberg; McDonald and Priestley; Smith, Deming.) Thus to recommend the resection of the para-aortic lymph glands, whether they are involved or not, in all cases of renal neoplasms does not appear sound. The hypernephroma, the nephroma (Wilms'), embryonic cancer, and the papillomas may by-pass the local lymph nodes and present their secondary grmYths in the lungs and bones; -while adult cancers, together ,,·ith the adenocarcinomas, the scirrhus cancers and sarcomas, do involve the local regional lymph glands at the hilum of the kidneys and may be considered for resection at the time of the nephrectomy. If one keeps in mind the behavior of the different types of renal tumors and follmrn each patient after nephrectomy to his death the real facts appear: that a good number survive five years but die of a metastatic lesion or lesions between the 5th and 10th years and some even later. Graves reports the case of a patient 11·ho died of metastasis 20 years after the original tumor was removed, and there are a number of patients in our series who died of the disease between the 10th and 15th years. So far, we do not know what forces check the grmYth of these tumors for many years. To go one step further, Bumpus, Beer, Hyman and :Mann have reported the spontaneous disappearance of lung metastases. Churchill and Barney report the successful removal of a solitary nodule in one lung, and a long follmY-up period indicated that the patient remained in good health without further evidence of the disease. The existence of a solitary metastasis must be an exceedingly rare condition, but these cases of spontaneous disap-
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CLYDE L. DEMING
pearance of the secondary lesions relate entirely to the hypernephromas and not to the other types of renal tumors. Radiation of renal neoplasms.-Radiation of renal neoplasms has been applied in a desultory manner. vVaves of enthusiasm have been followed by waves of defeatism, and it would seem that no one has really crystallized this form of treatment for clinicians. Radiation has been used as the last straw or because it was thought that it might play some part in preventing metastases. The only sound basis for radiation is the sensitivity of the tumor. It is known that the nephroma (vVilms'), the hypernephroma, embryonic carcinoma and the sarcoma respond to radiation. vVharton suggests radiation of nephroma (Wilms'), while Ladd deprecates its value; Munger believes that radiation does only temporary damage to neoplasms. To radiate large kidney neoplasms or deepseated metastases with the hope of full control is folly. Radiation will reduce the size of the responsive tumors but as far as complete control of the growth is concerned ,rn can not yet expect full control of the tumor growth by radiation alone. One can expect cessation of bleeding, and we have used x-ray therapy in conjunction with ligation of the ureter to stop bleeding and for palliation in patients who have an inoperable tumor. However, proof that roentgen therapy ·will control the growth of renal tumors has not yet been given. Certainly, it should not be employed until a microscopic study has been made to determine the tumor's type and hence its probable sensitivity to radiation. Treatment of renal neoplasms.-~ephrectomy has always been and still is the treatment for malignant disease of the kidney provided the growth can be removed. Much interest has been shm;-n with regard to the operative approach to the tumor. The loin incision has for many years maintained its popularity, but during the last 3 years Chute and others have favored the transthoracic approach as giving an unexcelled exposure of the tumor and the pedicle of the kidney. No doubt thoracic surgery has influenced and stimulated this method of approach, and numerous operators in various countries have successfully performed nephrectomies by this route. More recently, N agamatsu has suggested a dorsolumbar approach with subperiosteal resection of segments of the tenth, eleventh and twelfth ribs to avoid traversing the thoracic cavity. Both incisions have been used in our clinic and have given equal satisfaction in exposure of the pedicle. Ladd advises the transabdominal approach and ligation of the vessels before mobilizing the tumor and shows statistically superior results. This is possible in children but more difficult in adults. There is no doubt that much is to be said in favor of ligating the pedicle before freeing the kidney and tumor for in so doing the many tumor cells which might be scattered through the blood and lymph streams are held in check. When the tumor is inoperable a biopsy should be taken and the ureter ligated, provided the kidney is not infected; and supplemental x-ray therapy may be given if the tumor is radiosensitive. It would seem unnecessary to resect the peri-aortic lymph glands in those tumors whose metastases ordinarily occur through the venous blood stream to the lungs and bones. Surely patients with papillary tumors of the renal cortex and all patients with tumors of the pelvis should routinely have a
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removal of the ureter and segment of the bladder. 1Ve belie-:e that the surgical technique concerning renal tumors is now clearly defined but we urge that the surgeon at the time of nephrectomy ascertain by immediate biopsy the of tumor with -which he is dealing. Results.---The control of renal neoplasms, except for the nephroma and neurogeuic tumors, can not be determined by a 5-year follow-up or e\·en by a follow-up. \Ve have iu our clinic recordc1 of 132 consecuti,·e renal tumors in the past 25 years. All have a microscopic section. All haYe a complete follo\\°-up to date or to the death of the patient. The control of the renal tumorn in the a.hove series by nephrectomy is 9.0 per cent. This is humiliating, but if one compares these results -with the results of treatment of malignancies of other internal organs it is not too bad \\·hen compared with lung cancer at 2 per cent, gastric cancer at 6 per cent and prostatic cancer at 5 per cent. The author feels that om past conception of control of renal malignaneie::, has been incorrect and that ,rn have been far too optimistic regarding the actual results. The only true determination is the complete follow-up of every caseo In e,·cry case, a microscopic study of the tumor should be made and its character noted. The report::, by Foot, Humphreys and vVhitmor0 of 29:S cases arc instructiYe hut there are too many indeterminate cases, although they ha-:e made allmrnnces for the <'a1:,es which haYe not been followed to the end. Ladd presents a remarkable report 011 the treatment of children's renal tumors. Priestley and Broders add another farnrable list. The many individual reports of a few succe::,sful controls add mterest but do not help us arrive at an absolute eonclusiou. The author does not place much credence in the difference bet,rnen a granular cell or clear cell hypernephroma because both tun1ors prove to be lethal if left in place. Tumors do vary in degree of malignancy and patients vary in theJX defense to malignant growth, but the surgeon should not take credit for lhe control of a renal malignancy ,vhich he has removed until the patient has survived 15 to 20 years without a recurrence or autopsy reveals no evidence of tumor. We have taken the challenge of the problem of renal tumors seriously and attempted to disclose why we can not obtain better results. 1Ve ha.ve not,ed the delay in diagnosis and treatment as applied to the doctor and patient, Lhe doctor alone and the patient alone. vVe would like to lay some of the blame upon /he procrastination element, but we can not do it. Patients who refused treat-· rnent and patients II hose doctors prescribed stypt,ics and pink pills to stop bleeding have the same reem·ery record as the 45 per cent whose tumors gave no symptoms, 1rnre accidentally found and were immediately treated. The might truly argue that the delayed cases had time to develop a defense mechanisn, to the tumor growth. The typing of these tumors ha::, not been of any particular adyantage in ::,olving this problem of control. Is the tumor malignant or i::, it not? Will it metastasize lymphatic channels or by ,my of the blood stream? ls it radio-sensitive? VVe have no ,Yay to measure a patient's resistance to tumor gro,,th. We have ad-nrneed in our knowledge of the behavior of renal tumors and haYe developed a sound surgical approach to their remm·al, but even with the
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CLYDE L. DEMING
Papanicolaou stain of the urines, new serological tests for cancer and cystoscopy and x-ray procedures by means of which an early diagnosis can be made, the enigmas of the problem seem almost insurmountable and the challenge to raise the actual percentage of control of renal tumors and their metastatic lesions is as great as ever. This challenge the author begs the urologist to accept and to make another effort to improve the percentage of control by the use of radioactive isotopes in association with surgery. The research of Moore and his coworkers in Minneapolis, Davis in Chicago and Selverstone and White in Boston indicates not only a high degree of accuracy in determining the presence of nerve and epithelial tumors and sarcomas with radioactive isotopes but a precise focal localization in 95 per cent. Malignant tumors of the kidney contain these tissue elements. The isotope diiodofluorescein has a special affinity for tumor cells so that not only the primary tumor but the metastatic transplants to lymph nodes and peritoneum are readily detected. The technical procedure is not difficult in its application and would add but a few minutes additional time for the operating surgeon with the assurance of localizing tumor tissue and recognizing the lymph glands involved in metastatic renal tumor so that such tissues which might otherwise be left behind can be removed if operable. Sufficient work with tumors using radioactive isotopes has already been done to conclude that their use in conjunction with the surgical treatment of renal tumors is well within the realm of our present-day consideration. vVe are living in the atomic age. '\Ve must be atomic urologists and invoke the use of the radioactive isotope, for it is reasonable to expect that it will provide the next cog in the chain of our efforts to control renal malignancies. SUMMARY
A plea is made for a simple classification of renal tumors based on their tissue origins and biological behavior. The exposure of large renal tumors by the transthoracic route or N agamatsu incision offers technical advantages in the adult patient. Biopsy of every renal tumor should be made at operation. Lymph node resection of para-aortic nodes is necessary only in those tumors which biologically metastasize to local lymph nodes rather than through the blood stream to distant organs. The enigmas of renal tumors will persist until the cause of renal malignancy is divulged. The challenge for an improved percentage of control of renal malignancy may reasonably be found in the use of radioactive isotopes.
789 Howard Ave., New Haven, Conn. REFERENCES ABESHOUSE, B. S. AND WEINBERG, TOBIAS: Malignant renal neoplasms. Arch. Surg., 50: 46, 1945. ANSON, B. J., CAULDWELL, E.W., PrcK, J. W. AXD BEATON, L. E.: The anatomy of the pararenal system of veins, with comments on the renal arteries. J. Urol., 60: 714, 1948 BEER, EDWIN: Some aspects of malignant tumors of the kidney. Surg., Gynec. and Obst., 65: 433, 1937.
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BuMPus, H. C., JR.: The apparent disappearance of pulmonary metastases in a case of hypernephroma following nephrectomy. Trans. Am. Ass'n G. U. Surg., 21: 19, 1928. CABOT, H. AXD MIDDLETON, A. W.: Relation of so-called adenoma of kidney to carcinoma of kidney. Trans. Am. Ass'n G. U. Surg., 31: 91, 1938. CHURCHILL, E. D. AXD BARX:BJY, J. D.: Adenocarcinoma of the kidney with metastasis to the lung. Trans. Am. Ass'n G. U. Surg., 31: 71, 1938. · CHUTE, RICHARD, SouTTER, L,UIAR AND KERR, W. S., JR.: The value of the thoraco-abdominal incision in the removal of kidney tumors. New Eng. J. Med., 241: 951, 1949. DAVIS, LOYAL, l\1ARTIN, JOHN, AsHKEXAZY, l\1osEs, LEROY, G. V. A:\D FIELDS, THEODORE: Radioactive diiodofluoresceiu in diagnosis and localization of central nervous system tumors. J.A.M.A., 144: 1424, 1950. L.: The prognosis and problems in renal tumors. J. Urol., 55: 571, 1946. DEMING, Foo'r, N. AXD P APA:\ICOLAOU: Early renal carcinoma in situ detected by means of smears of fixed urinary sediment. J.A.M.A., 139: 356, 1949. FooT, N. C., HUMPHREYS, G. A. A:-iD WHITMORE, W. F.: Renal tumors. J. Urol., 66: 190, 1951. HIKMA:-S, FRANK: Principles and Practice of Urology. Philadelphia: W. B. Saunders Co., 1935. (Pepper and Hutchinson) GRAVES, R. C. AND MABREY, R. E.: Adenocarcinoma of kidney recurrent after twenty years. New Eng. J. Med., 212: 416, 1935. HYMAN, A.: A clinical study of malignant tumors of the kidney. Surg. Clinics Xorth Am,, 13: 347, 1933. KIRKMAN, HADLEY AND BAcox, R. L.: :Malignant renal tumors in male hamsters treated with estrogen. Cancer Research, 10: 122, 1950. LADD, W. E.: Embryoma of the kidney (Wilms' tumor). Ann. Surg., 108: 885, 1938. LADD, W. E. AND WHITE, R.R.: Embryoma of the kidney (Wilms' tumor). J. A. l'vi. A,, 117: 1858, 1941, LEARY, TIMOTHY: Crystalline ester cholesterol and adult cortical re1rnl tumors. Arch Path., 50: 151, 1950. LucKJil, BALDUIN: Carcinoma of the kidney in the leopard frog: occurrence and significance of metastasis. Am. J. Cancer, 34: 15, 1938. LUCKE, BALDUIN: Physical factors influencing the growth of cancer (experimental studies based on renal adenocarcinoma in animals). J. Urol., 44: 545, 1940. MANN, L. T.: Spontaneous disappearance of pulmonary metastases after nephrectomy for hypernephroma. Four-year follow-up. J. Uro\., 59: 564, 1948. McDONALD, J. R. AND PRIESTLEY, J. T.: Malignant tumors of the kidney. Surg., Gynec. & Obst., 77: 295, 1943. MooRE, G. E.: Fluorescein as an agent in the differentiation of normal and malignant tissues. Science, 106: 130, 1947. MooRE, G. E., Hu;-;TER, S. W. AND I-I-GBBARD, T. B.: Clinical and experimental studies of fluorescein dyes with special reference to their use for the diagnosis of central nervous system tumors. Ann. Surg. 130: 637, 1949. l'v1uNc+ER, A. D.: Irradiation of malignant renal neoplasms. J. Urol., 37: 680, 1937. NAGAMA'l'Su, GEORGE: Dorsolumbar approach to the kidney and adrenal with osteoplastic Hap. J. Urol., 63: 569, 1950, O'CROWLEY, C. R. AND l\L,RTLAND, H. S.: Adrenal heterotopia, rests, and the so-called Grawitz tumor. J. Urol., 50: 756, 1943. PRIESTLEY, J. T.: Survival following removal of malignant renal neoplasms. J.A.1\I.A .. 113: 902, 1939. PRIESTLIDY, J. T. AKD BRODERS, A, C.: Wilms' tumor; a clinical and pathologic study. J, Urol., 33: 544, 1935. SELVERSTONE, BERTRAM AND WHITE, JA,IES C.: Evaluation of the radioactive mapping technic in the surgery of brain tumors. Ann. Surg., 134: 387, 1951. SMITH, G. G.: ;'\eoplasms of the kidney and ureter. Am. J. Surg., 30: 130, 1935. WATERS, C. A.: Preoperative irradiation of cortical renal tumors. Am. Jour. Roentgenol. and Radium Therapy, 33: 149, 1935. WHARTON, L. R.: Preoperative irradiation of massive tumors of the kidney. Arch. Surg., 30: 35, 1935.
Vol. 69, No. 1, January 1953 Printed in U.S.A.
RENAL NEOPLASMS: AN ENIGMA AND A CHALLENGE CLYDE L. DEMING From the Department of Surgery, Section on Urology, Yale University School of Medicine, and the Grace-New Haven Community Hospital, New Haven, Conn.
The literature enfolding the subject matter of renal neoplasms reads like a novel of romance. The differences of opinion as to the names of the tumors, the specificity of sex, their accidental, unheralded discovery, and their behavior are tantalizing. The attempt has been futile to teach medical students and house officers more than three simple facts concerning renal neoplasms: 1) That they are highly malignant; 2) that the only treatment is surgical; and 3) that the results are 20 per cent controls for a five-year period. The classifications have been confusing, the surgery not well organized, and the results discouraging. Many of the classifications are so long and complicated that it is not possible to remember them. The many references to a "nephroid" tumor imply that such a tumor is associated with the kidney but not necessarily of renal origin, and the reader is often misled as to the anatomic origin of the tumor. Furthermore, the etiology of renal tumors is still not clear. The work of Lucke in 1938 demonstrated that cancer in the kidney of the tree frog was due to a virus. Leary, in 1950, was successful in producing adenomas in the kidneys of rabbits subsequent to the development of nephrosclerosis with local implantation of cholesterol. Cabot has demonstrated conclusively that adenocarcinomas are derived from adenomas; and Kirkman and Bacon claim that renal cancers can be produced in the hamster by the use of the female hormone, stilbestrol. Such demonstrations are significant and encourage us to continue our efforts to elicit the actual cause of neoplastic activation in the kidney. It is the author's ambition to clarify the subject of renal tumors by considering their anatomic origin and their behavior patterns in order that we may formulate a sound and logical basis for discussion. With this objective, the following classification is proposed: CLASSIFICATION OF RENAL TUMORS
1) Nephroma (Wilms') 2) Hypernephroma, adrenal origin 3) Carcinoma of the cortex: a) Embryonic b) Adult c) Scirrhus-pelvis 4) Papillary: a) Pelvis b) Cortex 5) N eurogenic: a) Neuroblastoma The William T. Belfield Memorial Lecture, delivered before the Chicago Urological Society, October 25, 1951.
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CLYDE L. DEMING
b) Ganglioneuroma c) Medulloblastoma d) Schwannoma 6) Sarcoma The kidney as an organ is a system of tubes and its physiology, though complex, is now quite well understood. From the standpoint of tumor development we may state that the kidney is composed of a capsule, epithelial tubes, a pelvis lined with transitional epithelium and a pedicle of blood vessels containing varying amounts of mesothelial tissue and nerve tissue. The only nephroma which we encounter is the so-called Wilms' tumor. This tumor contains all the histological elements of the kidney and is truly nephroid. To use terms such as "histoid," "organoid" and "hypernephroid mesothelial type of hypernephroma" confuses the issue and conveys nothing concrete. To disbar the use of "oids" in the classification of neoplasms in and on the kidney would greatly simplify our understanding of them and pave the way for a clearer conception of their behavior and their response to therapy. Hypernephroma.-The hypernephroma is not a true kidney tumor but is derived from congenitally misplaced suprarenal tissue. Such misplaced tissue has been found widely distributed within the abdomen and even along the spermatic cord in the inguinal canal. Wide distribution can also take place anywhere on or within the renal organ. The reports of Martland and O'Crowley on autopsies in accidental deaths give conclusive evidence in support of this possibility. The deposit of embryonic rests makes possible the development of a hypernephroma on, underneath or anywhere in the renal parenchyma, and to say that a hypernephroma develops only on the capsule of the kidney is untrue. It is the only neoplasm reportedly found associated with polycystic kidney disease and is the most common renal neoplasm in the pregnant woman, which suggests an hormonal factor as the activating agent. These tumors are most common in the 6th decade of life and are rarely reported in children. Other than Wilms' tumor, they are most frequently discovered accidentally by the physician. The early stage of their development is relatively slmv, they are encapsulated and sometimes grow to large size or become large by intratumoral hemorrhage. At other times the primary tumor is secondary in size to the metastatic lesion, and such a condition complicates the clinician's responsibility respective to a correct diagnosis. Nephroma (Wilms').-The 53 names applied to this tumor which is commonly found in children would be almost a day's assignment for a medical student to memorize. The vVilms' tumor may be a true embryoma, but it seems logical that since it is the only renal tumor which contains all the elements of the kidney it has justly earned the distinction of being called a nephroma after its name has been bandied about for 123 years. It will require some effort to make this term universal, but it is wise to make the effort in order to clarify the terminology. It is one of the largest renal neoplasms in children, grows rapidly and metastasizes relatively early either by direct invasion or blood stream. In children it makes no selection of side or sex; in the adult, it is rare but does occur
RENAL NEOPLASMS
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in every decade up to and including the eighth -with a high preference for the male sex. ]Many of these tumors are accidentally discovered on routine examination in children's clinics and hospitals. Ladd of Boston has had one of the largest experiences with children's renal tumors and reports (\0 to 70 per cent of renal tumors to be of this In our clinic of general urology only about 30 per cent of renal tumors in children belong to this the others being carcinoma, both embryonic: and adult, and neuroblastomas and sympathic:oblastomas. Several writers have reported bilateral involvement with nephroma. The fact that these tumors have been found in foetuses, have been removed surgically within the first three days of life and that 75 per cent are found before the fifth year leaves no doubt that they belong to the embryonic: group of neoplasms. Becam:e of the rapidity of their grmrth, their high degree of malignancy, and the uncertainty as to the results of surgical treatment they still present a challenge to 2\-Iedicine. tumors of the kidney.~Tumors derived from the neurogenic anlage include the neuroblastoma, sympathicoblastoma, medulloblastoma, ganglioneuroma, paraganglioma and schwannoma, and take their origin from the nerve structures about the kidney and adrenal gland. They used to be called sarcomas. Such tumors are found close to the kidney pelvis, anterior, posterior or below it. They cause an obstruction to the ureter and interfere with the pyelogrnphic to the extent that it is impossible to predict their origin preoperatively, The most embryonic, the nenroblastomas and meclulloblastomas, grmv rapidly, There can be but little significance in the so-called Pepper and Hutchison type,~. The difference is not in the histology of the tumor but in the mode of its dissemination. The avenues for metastatic development can be explained by Anson's work on the difference between the venous drainage of the right kidney and of the left kidney. The right perirenal lymphatic drainage is in close approximation to the liver, which accounts for the metastases to the liver; -while the dii:;semination from a left kidney tumor is directly through the renal vein to the prevertebral system and upper skeletal region. \Ve are indebted to Pepper and Hutchison for their differentiation of behavior with respect to the development of metastases but to Anson for a possible explanation of the biological behavior of the left renal tumor. The ganglioneuroma and paraganglioma are more adult forms of nerve tumors. The latter are chromaffin tumors and grossly are reddish in color, shmv a lesser degree of malignancy and do not possess any sex hormone. The sc:hwannoma is rare, as only six or seven tumors are reported. These develop below the kidney but their x-ray shado1rn often overlie the kidney shadow, and they are difficult to diagnose clinically. 1-Iowever, they can usually be removed without, disturbing the kidney and ureter and are not possessive of a high degree of malignancy. The clinician can conceive of these tumors of neuroectodermal origin as perirenal tumors possessing the behavior characteristics of the same types of tumors found in the brain and spinal cord. Sarcomas.-The differenc:e between sarcomas and neurogenic: tumors is nmv well recognized, and tissue strains have done much to segregate these tumors into proper categories. HmYever, sarcoma of the kidney does occur arising from st.rue-
4
CLYDE L. DEMING
tures at the hilum adjacent to the pelvis, from the capsule or even from the kidney itself. Such growths become fairly large and are more apt to invade the kidney than the neurogenic tumors. They occur in all age groups but are not common. They often appear fairly well encapsulated at first and may be associated with renal calculi. The roentgenograms of sarcoma may shmY spotty areas indicating fatty tissue -which often suggests their type. They usually grow rapidly and are locally invasive of the kidney and perirenal tissues. They can be removed without much difficulty unless they are invasive of the posterior abdominal wall, and they are not usually considered as malignant as the other tumors. Carcinoma.-The carcinomas of the kidney cortex are seen at all ages and may be divided into the embryonic and adult types. The embryonic tumor takes its origin in the renal blastema while the adult carcinoma may arise, according to Cabot, from an adenoma, which is not an uncommon finding in the kidney, or from any of the tubules. The adult types frequently present an adenomatous character and are apt to develop into large lobulated masses. The embryonic cancer grows rapidly, infiltrates the whole organ and metastasizes to the lungs through the blood stream. The embryonic tumor is more often found in the child or young adult. The adult type grows slowly, at first is encapsulated and may be accidentally found on routine physical examination before it has penetrated the pelvis and caused hematuria. It infiltrates the renal organ and may infiltrate the liver or spleen. The behavior of these tumors is much like the behavior of adenocarcinomas elsewhere in the body. The embryonic type is the more malignant of the two. Papillary carcinoma.-Papillary cancers of the kidney pelvis are similar to transitional cell papillomas of the urinary bladder. While it has been known for many years that papillomas of the kidney pelvis metastasize to the ureter and bladder it is only within the past few years that reports have been made concerning such metastatic lesions from papillary carcinomas of the renal cortex. vVe have made a study of cortical cancers which have showed a papillary character. They may include the papillary adenocancers. All cancers with papillary cellular structure, whether derived from the kidney cortex or pelvis, behave similarly. They are not encapsulated, they bleed readily, infiltrate the kidney, and metastasize not infrequently to the lower ureter and to the lung. One has a right to ask -whether all of these papillary tumors do not take their origin from the pelvis, some of whose embryonic cells have reached well within the component parts of the renal blastema. Twenty years ago we removed a cancer of the kidney and seven years later the patient had a tumor of the lower ureter. This was removed. Two years later he had bloody sputum and a radiogram positive for metastatic tumor in the chest. In review of the microscopic sections the primary tumor was found to be of papillary character. Three years ago the right kidney of a physician 42 years of age ,ms removed by a general surgeon for malignancy. Two years later the lower end of the ureter was removed because of bleeding. One year later the patient was referred to us for hematuria and dysuria. He was found to have an infiltrating tumor of the base of the
RENAL NEOPLASMS
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bladder with no other evidence of cancer. Biopsy indicated the same microscopic: picture of papillary carcinoma in all the specimens. The origin of the primary tumor was cortical rather than pelvic:. A ureterosigmoidostomy was done on the remaining side and his whole bladder removed. He subsequently developed a metastatic lesion in his abdominal -Yvall and died of the disease. Time forbids a discussion of the theories of transmission of papillary renal tumors to the lmrer ureter and bladder, but other reporters have made observations like ours and we are in accord in advising complete ureterectomy including a portion of the hladder for all tumors of the kidney, whether cortical or pelvic, which present a papillomatous character. The other tumors of the kidney pelvis, such as the scirrhus and epidermoid types, belong to the same category as the papillary carcinomas, show the same biological behavior as the papillary carcinomas and demand the same serious consideration for treatment. A difference in degree of malignancy of a tumor of the kidney pelvis has little significance when all have such a high degree of potential grnwth and are ultimately fatal. J1 etastatic developments.~ :\r eoplasms of the kidney present as many, if not more, problems dealing with metastases than any other group of neoplasms. The surgeon many times removes renal neoplasms when the prognosis seem::s good only to find that some time within one year to t-Yrnnty years the patient has a metastasis. Beer wrote many years ago, "we do not know what biological forces delay the development of secondary tumors." All the reports containing the largest series of cases are in accord that renal tumors metastasize to the lungs, bones, liver, regional lymph nodes, spleen, adrenal, opposite kidney, heart, brain and seminal vesicles in that order of frequency. (Abeshouse and Wienberg; McDonald and Priestley; Smith, Deming.) Thus to recommend the resection of the para-aortic lymph glands, whether they are involved or not, in all cases of renal neoplasms does not appear sound. The hypernephroma, the nephroma (Wilms'), embryonic cancer, and the papillomas may by-pass the local lymph nodes and present their secondary grmYths in the lungs and bones; -while adult cancers, together ,,·ith the adenocarcinomas, the scirrhus cancers and sarcomas, do involve the local regional lymph glands at the hilum of the kidneys and may be considered for resection at the time of the nephrectomy. If one keeps in mind the behavior of the different types of renal tumors and follmrn each patient after nephrectomy to his death the real facts appear: that a good number survive five years but die of a metastatic lesion or lesions between the 5th and 10th years and some even later. Graves reports the case of a patient 11·ho died of metastasis 20 years after the original tumor was removed, and there are a number of patients in our series who died of the disease between the 10th and 15th years. So far, we do not know what forces check the grmYth of these tumors for many years. To go one step further, Bumpus, Beer, Hyman and :Mann have reported the spontaneous disappearance of lung metastases. Churchill and Barney report the successful removal of a solitary nodule in one lung, and a long follmY-up period indicated that the patient remained in good health without further evidence of the disease. The existence of a solitary metastasis must be an exceedingly rare condition, but these cases of spontaneous disap-
6
CLYDE L. DEMING
pearance of the secondary lesions relate entirely to the hypernephromas and not to the other types of renal tumors. Radiation of renal neoplasms.-Radiation of renal neoplasms has been applied in a desultory manner. vVaves of enthusiasm have been followed by waves of defeatism, and it would seem that no one has really crystallized this form of treatment for clinicians. Radiation has been used as the last straw or because it was thought that it might play some part in preventing metastases. The only sound basis for radiation is the sensitivity of the tumor. It is known that the nephroma (vVilms'), the hypernephroma, embryonic carcinoma and the sarcoma respond to radiation. vVharton suggests radiation of nephroma (Wilms'), while Ladd deprecates its value; Munger believes that radiation does only temporary damage to neoplasms. To radiate large kidney neoplasms or deepseated metastases with the hope of full control is folly. Radiation will reduce the size of the responsive tumors but as far as complete control of the growth is concerned ,rn can not yet expect full control of the tumor growth by radiation alone. One can expect cessation of bleeding, and we have used x-ray therapy in conjunction with ligation of the ureter to stop bleeding and for palliation in patients who have an inoperable tumor. However, proof that roentgen therapy ·will control the growth of renal tumors has not yet been given. Certainly, it should not be employed until a microscopic study has been made to determine the tumor's type and hence its probable sensitivity to radiation. Treatment of renal neoplasms.-~ephrectomy has always been and still is the treatment for malignant disease of the kidney provided the growth can be removed. Much interest has been shm;-n with regard to the operative approach to the tumor. The loin incision has for many years maintained its popularity, but during the last 3 years Chute and others have favored the transthoracic approach as giving an unexcelled exposure of the tumor and the pedicle of the kidney. No doubt thoracic surgery has influenced and stimulated this method of approach, and numerous operators in various countries have successfully performed nephrectomies by this route. More recently, N agamatsu has suggested a dorsolumbar approach with subperiosteal resection of segments of the tenth, eleventh and twelfth ribs to avoid traversing the thoracic cavity. Both incisions have been used in our clinic and have given equal satisfaction in exposure of the pedicle. Ladd advises the transabdominal approach and ligation of the vessels before mobilizing the tumor and shows statistically superior results. This is possible in children but more difficult in adults. There is no doubt that much is to be said in favor of ligating the pedicle before freeing the kidney and tumor for in so doing the many tumor cells which might be scattered through the blood and lymph streams are held in check. When the tumor is inoperable a biopsy should be taken and the ureter ligated, provided the kidney is not infected; and supplemental x-ray therapy may be given if the tumor is radiosensitive. It would seem unnecessary to resect the peri-aortic lymph glands in those tumors whose metastases ordinarily occur through the venous blood stream to the lungs and bones. Surely patients with papillary tumors of the renal cortex and all patients with tumors of the pelvis should routinely have a
RENAL NEOPLASMS
.., I
removal of the ureter and segment of the bladder. 1Ve belie-:e that the surgical technique concerning renal tumors is now clearly defined but we urge that the surgeon at the time of nephrectomy ascertain by immediate biopsy the of tumor with -which he is dealing. Results.---The control of renal neoplasms, except for the nephroma and neurogeuic tumors, can not be determined by a 5-year follow-up or e\·en by a follow-up. \Ve have iu our clinic recordc1 of 132 consecuti,·e renal tumors in the past 25 years. All have a microscopic section. All haYe a complete follo\\°-up to date or to the death of the patient. The control of the renal tumorn in the a.hove series by nephrectomy is 9.0 per cent. This is humiliating, but if one compares these results -with the results of treatment of malignancies of other internal organs it is not too bad \\·hen compared with lung cancer at 2 per cent, gastric cancer at 6 per cent and prostatic cancer at 5 per cent. The author feels that om past conception of control of renal malignaneie::, has been incorrect and that ,rn have been far too optimistic regarding the actual results. The only true determination is the complete follow-up of every caseo In e,·cry case, a microscopic study of the tumor should be made and its character noted. The report::, by Foot, Humphreys and vVhitmor0 of 29:S cases arc instructiYe hut there are too many indeterminate cases, although they ha-:e made allmrnnces for the <'a1:,es which haYe not been followed to the end. Ladd presents a remarkable report 011 the treatment of children's renal tumors. Priestley and Broders add another farnrable list. The many individual reports of a few succe::,sful controls add mterest but do not help us arrive at an absolute eonclusiou. The author does not place much credence in the difference bet,rnen a granular cell or clear cell hypernephroma because both tun1ors prove to be lethal if left in place. Tumors do vary in degree of malignancy and patients vary in theJX defense to malignant growth, but the surgeon should not take credit for lhe control of a renal malignancy ,vhich he has removed until the patient has survived 15 to 20 years without a recurrence or autopsy reveals no evidence of tumor. We have taken the challenge of the problem of renal tumors seriously and attempted to disclose why we can not obtain better results. 1Ve ha.ve not,ed the delay in diagnosis and treatment as applied to the doctor and patient, Lhe doctor alone and the patient alone. vVe would like to lay some of the blame upon /he procrastination element, but we can not do it. Patients who refused treat-· rnent and patients II hose doctors prescribed stypt,ics and pink pills to stop bleeding have the same reem·ery record as the 45 per cent whose tumors gave no symptoms, 1rnre accidentally found and were immediately treated. The might truly argue that the delayed cases had time to develop a defense mechanisn, to the tumor growth. The typing of these tumors ha::, not been of any particular adyantage in ::,olving this problem of control. Is the tumor malignant or i::, it not? Will it metastasize lymphatic channels or by ,my of the blood stream? ls it radio-sensitive? VVe have no ,Yay to measure a patient's resistance to tumor gro,,th. We have ad-nrneed in our knowledge of the behavior of renal tumors and haYe developed a sound surgical approach to their remm·al, but even with the
8
CLYDE L. DEMING
Papanicolaou stain of the urines, new serological tests for cancer and cystoscopy and x-ray procedures by means of which an early diagnosis can be made, the enigmas of the problem seem almost insurmountable and the challenge to raise the actual percentage of control of renal tumors and their metastatic lesions is as great as ever. This challenge the author begs the urologist to accept and to make another effort to improve the percentage of control by the use of radioactive isotopes in association with surgery. The research of Moore and his coworkers in Minneapolis, Davis in Chicago and Selverstone and White in Boston indicates not only a high degree of accuracy in determining the presence of nerve and epithelial tumors and sarcomas with radioactive isotopes but a precise focal localization in 95 per cent. Malignant tumors of the kidney contain these tissue elements. The isotope diiodofluorescein has a special affinity for tumor cells so that not only the primary tumor but the metastatic transplants to lymph nodes and peritoneum are readily detected. The technical procedure is not difficult in its application and would add but a few minutes additional time for the operating surgeon with the assurance of localizing tumor tissue and recognizing the lymph glands involved in metastatic renal tumor so that such tissues which might otherwise be left behind can be removed if operable. Sufficient work with tumors using radioactive isotopes has already been done to conclude that their use in conjunction with the surgical treatment of renal tumors is well within the realm of our present-day consideration. vVe are living in the atomic age. '\Ve must be atomic urologists and invoke the use of the radioactive isotope, for it is reasonable to expect that it will provide the next cog in the chain of our efforts to control renal malignancies. SUMMARY
A plea is made for a simple classification of renal tumors based on their tissue origins and biological behavior. The exposure of large renal tumors by the transthoracic route or N agamatsu incision offers technical advantages in the adult patient. Biopsy of every renal tumor should be made at operation. Lymph node resection of para-aortic nodes is necessary only in those tumors which biologically metastasize to local lymph nodes rather than through the blood stream to distant organs. The enigmas of renal tumors will persist until the cause of renal malignancy is divulged. The challenge for an improved percentage of control of renal malignancy may reasonably be found in the use of radioactive isotopes.
789 Howard Ave., New Haven, Conn. REFERENCES ABESHOUSE, B. S. AND WEINBERG, TOBIAS: Malignant renal neoplasms. Arch. Surg., 50: 46, 1945. ANSON, B. J., CAULDWELL, E.W., PrcK, J. W. AXD BEATON, L. E.: The anatomy of the pararenal system of veins, with comments on the renal arteries. J. Urol., 60: 714, 1948 BEER, EDWIN: Some aspects of malignant tumors of the kidney. Surg., Gynec. and Obst., 65: 433, 1937.
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BuMPus, H. C., JR.: The apparent disappearance of pulmonary metastases in a case of hypernephroma following nephrectomy. Trans. Am. Ass'n G. U. Surg., 21: 19, 1928. CABOT, H. AXD MIDDLETON, A. W.: Relation of so-called adenoma of kidney to carcinoma of kidney. Trans. Am. Ass'n G. U. Surg., 31: 91, 1938. CHURCHILL, E. D. AXD BARX:BJY, J. D.: Adenocarcinoma of the kidney with metastasis to the lung. Trans. Am. Ass'n G. U. Surg., 31: 71, 1938. · CHUTE, RICHARD, SouTTER, L,UIAR AND KERR, W. S., JR.: The value of the thoraco-abdominal incision in the removal of kidney tumors. New Eng. J. Med., 241: 951, 1949. DAVIS, LOYAL, l\1ARTIN, JOHN, AsHKEXAZY, l\1osEs, LEROY, G. V. A:\D FIELDS, THEODORE: Radioactive diiodofluoresceiu in diagnosis and localization of central nervous system tumors. J.A.M.A., 144: 1424, 1950. L.: The prognosis and problems in renal tumors. J. Urol., 55: 571, 1946. DEMING, Foo'r, N. AXD P APA:\ICOLAOU: Early renal carcinoma in situ detected by means of smears of fixed urinary sediment. J.A.M.A., 139: 356, 1949. FooT, N. C., HUMPHREYS, G. A. A:-iD WHITMORE, W. F.: Renal tumors. J. Urol., 66: 190, 1951. HIKMA:-S, FRANK: Principles and Practice of Urology. Philadelphia: W. B. Saunders Co., 1935. (Pepper and Hutchinson) GRAVES, R. C. AND MABREY, R. E.: Adenocarcinoma of kidney recurrent after twenty years. New Eng. J. Med., 212: 416, 1935. HYMAN, A.: A clinical study of malignant tumors of the kidney. Surg. Clinics Xorth Am,, 13: 347, 1933. KIRKMAN, HADLEY AND BAcox, R. L.: :Malignant renal tumors in male hamsters treated with estrogen. Cancer Research, 10: 122, 1950. LADD, W. E.: Embryoma of the kidney (Wilms' tumor). Ann. Surg., 108: 885, 1938. LADD, W. E. AND WHITE, R.R.: Embryoma of the kidney (Wilms' tumor). J. A. l'vi. A,, 117: 1858, 1941, LEARY, TIMOTHY: Crystalline ester cholesterol and adult cortical re1rnl tumors. Arch Path., 50: 151, 1950. LucKJil, BALDUIN: Carcinoma of the kidney in the leopard frog: occurrence and significance of metastasis. Am. J. Cancer, 34: 15, 1938. LUCKE, BALDUIN: Physical factors influencing the growth of cancer (experimental studies based on renal adenocarcinoma in animals). J. Urol., 44: 545, 1940. MANN, L. T.: Spontaneous disappearance of pulmonary metastases after nephrectomy for hypernephroma. Four-year follow-up. J. Uro\., 59: 564, 1948. McDONALD, J. R. AND PRIESTLEY, J. T.: Malignant tumors of the kidney. Surg., Gynec. & Obst., 77: 295, 1943. MooRE, G. E.: Fluorescein as an agent in the differentiation of normal and malignant tissues. Science, 106: 130, 1947. MooRE, G. E., Hu;-;TER, S. W. AND I-I-GBBARD, T. B.: Clinical and experimental studies of fluorescein dyes with special reference to their use for the diagnosis of central nervous system tumors. Ann. Surg. 130: 637, 1949. l'v1uNc+ER, A. D.: Irradiation of malignant renal neoplasms. J. Urol., 37: 680, 1937. NAGAMA'l'Su, GEORGE: Dorsolumbar approach to the kidney and adrenal with osteoplastic Hap. J. Urol., 63: 569, 1950, O'CROWLEY, C. R. AND l\L,RTLAND, H. S.: Adrenal heterotopia, rests, and the so-called Grawitz tumor. J. Urol., 50: 756, 1943. PRIESTLEY, J. T.: Survival following removal of malignant renal neoplasms. J.A.1\I.A .. 113: 902, 1939. PRIESTLIDY, J. T. AKD BRODERS, A, C.: Wilms' tumor; a clinical and pathologic study. J, Urol., 33: 544, 1935. SELVERSTONE, BERTRAM AND WHITE, JA,IES C.: Evaluation of the radioactive mapping technic in the surgery of brain tumors. Ann. Surg., 134: 387, 1951. SMITH, G. G.: ;'\eoplasms of the kidney and ureter. Am. J. Surg., 30: 130, 1935. WATERS, C. A.: Preoperative irradiation of cortical renal tumors. Am. Jour. Roentgenol. and Radium Therapy, 33: 149, 1935. WHARTON, L. R.: Preoperative irradiation of massive tumors of the kidney. Arch. Surg., 30: 35, 1935.