.^ •^c.a^^-^-,t.fiJ t' CANCER TRINDS ORSLEY, 111, MD, GERALD GOLDSTEIN. MD, and ANAS M. EL-MAHDI, MD. ;_,,.^ ^ y • .. r, , ^JV Kidney Neoplasms Paul F. Schellhammer, MD, Norfolk, Virginia The author reviews the di agnosis and treatment of carcinoma of the kidney. Surgery remains the most effective therapy. The management of metastatic disease is discussed. T HE TERM "kidney tumor" has been used to include both adenocarcinoma of the renal parenchyma and transitional cell carcinoma involving the urothelium of the renal pelvis. The former account for approximately 85% of "kidney tumors", the latter approximately 15%. Less than 1% of parenchymal tumors are sarcomas. The following discussion pertains to adenocarcinoma of the renal parenchyma only, as the etiology and natural history and treatment of urothelial renal pelvic tumors are different. Incidence Kidney neoplasms constitute 1-2% of all new neoplasms in the United States population yearly with an occurrence rate of six cases/100,000 population.' It is the third most common GU malignancy after cancer of the prostate and bladder. Although kidney neoplasms are more prevalent in the 50-70 year age group. there have been more frequent recent reports of their occurrence in children,= so that renal cell carcinoma should be considered along with Wilms' tumor, neuroblastoma, and hydronephrosis in the differentiai diaglt.osis of an abdominal mass in a child. The adult male to female ratio is approximately 3:1. From the Department of Urology, Eastern Virginia Medical School. Address Dr. Schellhammer at 400 West Brambleton Avenue, Norfolk VA 23510. Sponsored by the Professional Education Committee, Virginia Division. American Cancer Society. Submitted 2-7-79. VOLUME 106 Etiology Renal cell carcinoma may be induced in the Syrian male hamster with diethylstilbestrol (DES). If the male hamster is first castrated, DES will not result in the production of carcinoma; nor is DES successful in producing renal cell carcinoma in the female. These and other experimental data point to a possible hormonal etiology for renal cell carcinoma. Indeed the kidney may be considered an endocrine as well as an excretory organ in that it responds to hormones (steroids, aldosterone, ADH) and produces hormones (erythropoietin, renin). Cholesterol is found in increased concentration in the tubule cells and may have a carcinogenic effect' In support of this is the fact that the incidence of diabetes mellitus, which is associated with hypercholesteremia, is reported in 15% of patients with renal cell carcinoma, which is five times the incidence of diabetes in the general population. : Smoking and exposure to certain hydrocarbons have been implicated as increasing the risk of renal cell carcinoma but no conclusive relationship has been documented.' Renal adenoma will be mentioned here as it must be considered in the discussion of renal cell carcinoma. The renal adenoma has been identified as a premalignant lesion. The reasons for this are as follows: an association of renal adenomas with renal cell carcinoma, their identical cellular features, the fact that as in renal cell carcinoma the male to female ratio is 3 to 1, the age at risk is similar, they are more VIRGINIA MEDICAL/APRIL. 1979 289 T109750624 frequent in the diabetic and heavy smoker, and choiesterol is increased in the tubular cells of adenomas. A lesion is arbitrarily called an adenoma if it is less than 3 cm in size only because lesions less than 3 cm are rarely found to be associated with metastases. However, exceptions do inevitably exist, and, on the other hand, large renal carcinomas may not be associated with metastases. It therefore would seem more logical that a renal adenoma be considered a small renal cell carcinoma. As there is generally a straight line relationship between the size of a renal lesion and the incidence of metastases. it follows that a small renal cell carcinoma will have a better prognosis if properly treated. This does not, however, identify the small lesion as benign. Natural History The natural history of renal cell carcinoma is characterized by extreme variability. This may, represent differences among different neoplasms or may be a reflection of the variability of host resistance but most likely represents a combination of both. Some tumors progress rapidly, resulting in mortality within one to two years after being discovered, while some patients who present with metastases have documented 15 year survivals. As further support of the indolent course of some renal cell carcinomas is the fact that metastases have developed as long as 40 years after removal of a primary, and one must presume that such a metastatic lesion was present at surgery and did not become clinically significant until years elapsed. These factors make it difficult to evaluate therapy since long survival, while it may be on the basis of such therapy, might also be secondary to the indolent natural history of that particular tumor. Symptoms The classical symptom triad includes pain, hematuria, and a palpable mass. This may be referred to as the "too late triad" since it occurs late in the course of the disease and is associated with a poor prognosis. Pain is usually due to distention of the capsule on the basis of intraparenchymal bleeding or due to the passage of clots down the ureter causing colic. Gross hematuria is the initial symptom in 40-50% of cases. Microscopic hematuria is the earliest detectable sign of the disease in many cases. Renal cell carcinoma has been referred to as the internists' tumor since it may present with many diverse non-specific systemic symptoms unrelated to retroperitoneal location of the renal neoplasm.S Some of these may be grouped under the heading of paraneoplastic syndromes whereby systemic symptoms remote from the 290 VIRGINIA MEDICAL/APRIL.1979 tumor area are produced. Paraneoplastic syndromes are of importance because they may be the first symptomatic clue to the existence of a tumor and also in and of themselves may be responsible for significant morbidity and mortality if unrecognized and untreated. Erythrocytosis occurs in approximately 4% of patients with renal cell carcinoma. Hepatic dysfunction consisting specifically of elevation of BSP, alkaline phosphatase, alpha 2 globulin levels and prolonged prothrombin time may occur in the absence of liver metastases and may disappear on removal of the primary tumor.° The etiology of this nonmetastatic hepatopathy is at present unknown. The recurrence of abnormal liver functions after treatment often heralds recurrent disease. Hypercalcemia may be secondary to ectopic PTH production or prostaglandin production by the tumor as well as osseous metastases. Hypertension may result from direct renin production by the tumor or by compression of the renal artery causing ischemia with hyperreninemia. A-V fistulas may produce hypertension and cardiac failure. An enteropathy may be present secondary to glucagon production by the tumor; gynecomastia may result secondary to gonadotropin production. Thus hormonal aberrations (PTH, erythropoietin, renin, glucagon, gonadotropins) may contribute to the symptom complex associated with renal cell carcinoma.' Other systemic symptoms include anemia, which occurs in 25% of the patients and is often associated with a less favorable prognosis. Anemia may be secondary either to marrow replacement or to suppression of erythropoietin production. It is rarely secondary to hematuria or spontaneous retroperitoneal hemorrhage of the neoplasm. Unexplained fever presents as the initial symptom in l 1% of the patients, the sole symptom in 2% of patients and is at some time present in 30% of patients with renal cell carcinoma. Mechanical obstruction of the vena cava may lead to peripheral edema and varicocele formation. Renal cell carcinoma has the tendency to invade the renal vein and propagate tumor thrombus to the vena cava. It is important to emphasize that recognition of microhematuria and proper urological investigation enhance the possibility of earlier detection of localized lesions amenable to curative surgery. Diagnostic Evaluation The intravenous pyelogram is the initial study. followed as needed by nephrotomogram, selective arteriogram with epinephrine studies if necessary, and celiac injection for detection of visceral metastases. If a solid mass is suspected on intravenous pyelogram VOLUME 106 . T109750625 and tomograms, arteriography is indicated. The diagnostic accuracy of renal arteriography in identifying renal cell carcinoma is about 95%. If intravenous pyelogram and nephrotomograms suggest a cystic mass (renal cyst), this diagnosis is supported by ultrasound and confirmed by needle aspiration of clear fluid with negative cytology. If bloody or dark fluid is aspirated or if cytology is suspicious, the diagnosis of renal cell carcinoma must be considered and surgical exploration undertaken. Metastatic evaluation includes chest films to identify pulmonary metastases. Pulmonary tomograms are necessary to identify multiple small lesions not seen on routine chest films. Inferior venocavography (IVC) is used if signs of venous obstruction are present or if the arteriogram shows no renal vein filling on delayed films especially if the tumor is on the right side. Bone scans are used to evaluate the presence of osseous metastasis. Histology and Staging Tumors may be predominantly clear cell or granular cell, or a combination of the two. There is some evidence that granular cell tumors have a worse prognosis. Patients with higher grade tumors have a poorer 5-year survival. Survival rates largely depend upon the surgical and pathological staging of a tumor. Stages of renal cell carcinoma and anticipated survival within each stage are as follows: Stage 1: Neoplasm limited to renal parenchyma-5-year survival 60-70%. Stage 2: Invasion of the capsule of the kidney. the perirenal fascia, and fat, the intraparenchymal vessels-5-year survival rate 50%. Stage 3: Involvement of the hilar and periaortic lymph nodes, penetration through Gerotas fascia, involvement of the renal vein or inferior vena cava-5year survival 30%. Stage 4: Distant metastases, involvement of adjacent organs-5-year survival less than 10%. Treatment A number of treatment modalities are used, but surgery constitutes the mainstay for the treatment of renal cell carcinoma. Treatment of Stage 1, 2, and 3 neoplasms includes radical nephrectomy with or without lymph node dissection. The term "radical nephrectomy" refers to the removal of the kidney and adrenal and all their investing fascia and fat. The renal artery and vein are immediately isolated and ligated prior to manipulation of the primary tumor in order to limit vascular emboli during removal. It has been demonstrated by Robson that lymph node metastases are present in 25% of patients undergoing nephrectomy; and on the basis of this, a VOLUME 106 node dissection is advisable." However, improvement of survival by lymph node dissection is still a matter of uncertainty. Recommendation for lymph node dissection is based on the fact that it may improve survival and does not add significantly to morbidity. The boundary of the lymph node dissection varies greatly depending on the surgeon's technique but in general extends from the diaphragm to the level of the inferior mesenteric artery encircling the great vessel on the side of the neoplasm. Radiotherapy is not of proven efficacy for primary treatment. Preoperative radiation therapy may decrease the size of a renal tumor, alter the vascularity, and kill the viable tumor cell, thus reducing metastases stemming from tumor manipulation at surgery. However, preoperative radiotherapy has not been uniformly shown to increase the 5-year survival postnephrectomy and radiation and, when directed to right renal tumors, can cause significant morbidity secondary to radiation hepatitis' Radiation is very helpful in palliation of painful osseous metastases. If nephrectomy is not performed because of the presence of dissseminated disease or medical contraindication to surgery, radiation may be delivered to the primary if necessary to control bleeding and/ or pain. Chemotherapy may be hormonal or cytotoxic. A progestationat agent medroxyprogesterone acetate (Provera&), in large doses (300 mg a day orally or 400-800 mg 2X week IM) has produced subjective responses in a majority of patients and an occasional dramatic objective response.'° The response is most common in young males. There has also been an apparent prolongation of survival as well as an improvement in the quality of survival in some patients. Cytotoxic chemotherapy has been uniformly ineffective in offering significant palliation or objective control of disease." Therefore, medroxyprogesterone acetate is recommended for patients with metastatic disease in that there is little alternative choice of other chemotherapy, it is non-toxic. and it will usually demonstrate an effect within a 6-12 week period. Also there is experimental evidence that the drug does have a direct effect on renal cell epithelium grown in tissue culture.'= Cryosurgery, largely experimental in primary tumors, has been used with success in the few cases where solitarv bone metastasis have been found. In such instances freezing has resulted in alleviation of pain and regression of disease by exam, arteriographic and biopsy analysis." Spontaneous tumor regression. although a rare event, can occur with renal cell carcinoma. Such occurrences, together with in vitro studies documenting VIRGINIA MEDIC.4L/APRIL. 1979 295 T109750626 active cell mediated immunity against renal cell carcinoma extract, supports the concept that at times immune competence or resistance of the host is active in eliminating neoplasia." Immune therapy with non-specific stimulants of the immune system. i.e., BCG,15 immune RNA,16 are under investigation." Metastases are present in approximately one-third of patients at the time of presentation and diagnosis." Only 2% are found to have a single or solitary metastatic lesion. If a patient has a solitary metastasis, he should be treated by excision of the primary and the metastasis as a very respectable (30-35%) 5year survival will result." For lung metastases a lobectomy or wedge resection is usually undertaken. For a bone metastases, cryosurgery, as mentioned above, or amputation is advisable. It should be mentioned that in the case of a solitary pulmonary nodule in association with a renal cell carcinoma, the possibility of dealing with a second primary. i.e., a lung cancer, or a benign lesion, i.e., a granuloma, should always be considered and adds support for thoracotomy and excision. As with any neoplasm, multiple factors must be considered when evaluating metastatic disease. For instance, in the case of renal cell carcinoma. metastases which appear simultaneously with the primary have a poorer prognosis than those which appear years later. Solitary metastasis in one organ system are associated with better survival than multiple metastases, and metastases limited to one organ sys:em are associated with longer survival than when metastases are present in multiple organ systems. There may be certain indications for surgical treatment of a renal cell primary even when multiple metastases are present- Nephrectomy is recommended in such a situation if local symtoms, i.e., bleeding or pain, or systemic symptoms. i.e., anemia, hvpercalcemia, hypertension, exist. A recent development in the treatment of metastatic renal cell carcinoma has been the use of pre-nephrectomy arteriographic tumor infarction. The renal artery is occluded under angio;r::*:hic control with gelfoam or synthetic microspLerc!s. Nephrectomy is undertaken 3-7 days subsequent to infarction followed by administration of inedroxyprogesterone acetate. A series of patients thus treated at M. D. Anderson Hospital and Tumor Institute, Houston, Texas, have demonstrated prolonged survial and a higher than anticipated regression of metastatic disease using this sequence of treatment. The mechanism of such regressions is unclear but perhaps is secondary to release of antigen and stimulation of the host immune system." 296 VIRGINIA MEDICAL/APRIL 1979 References l. End Results in Cancer, Report No. 4, edited by Lillian M. Axtell, M. A., Sidney J. Cutler, Sc.D.; Max H. Myers, Ph.D. U.S. Department of Health, Education, and Welfare. Public Health Service, National Institutes of Health. Bethesda, Maryland, National Cancer Institute, 1972 2. Schellhammer PF, Smith MJV: Renal cell carcinoma in children. South Med J 66:1345-1350, 1973 3. Gonzalez R, Goldberg ME: Origin of intracellular cholesterol in renal cell carcinoma. Lancet 1:912, 1977 4. Bennington JL: Cancer of the kidney--etiology, epidemiology and pathology. Cancer 32:1017-1029, 1973 5. Kiely JM: Hypernephroma: the internist's tumor. Med Clin NA 50:1067, 1966 6. Utz DC, Warren MM, Gregg JA et aL• Reversible hepatic dysfunction associated with hypernephroma. Mayo Clinic Proc 45:161, 1970 7. Holland JM: Cancer of the kidney-natural history and staging. Cancer 32:1030, 1973 8. Robson Cl, Churchill BM, Anderson W. The results of radical nephrectomy for renal cell carcinoma. J Urol 101:197-30L, 1968 9. Finney R: The value of radiotherapy in the treatment of hypernephroma-a clinical trial. Br J Urol 45:258, 1973 10. Bloom HJG: Hormone-induced and spontaneous regression of metastatic carcinoma. Cancer 32:10661071, 1973 11. Talley Robert W: Chemotherapy of adenocarcinoma of the kidney. Cancer 32:1062-1065, 1973 12. Bloom HJG, Jukes CE, Mitchley BCV: Hormone-dependent tumors of the kidney. Br J Cancer 17:611-645, 1963 13. Marcove RC, Sadrieh J, Huvos AG et al: Cryosurgery in the treatment of solitary or multiple bone metastases from renal cell carcinoma. J Urol 108:540, 1972 14. Wright GL, Schellhammer PF, Rosato FE et al: Cell mediated immunity in patients with renal cell carcinoma as measured by the leukocyte migration inhibition test. Urology XII (#5):525-53 1, November 1978 15. Morales A, Eidinger D: Bacillus Calmette-Guerin in the treatment of adenocarcinoma of the kidney. J Urol 115:377, 1976 16. Skinner DG, deKernion JB, Pilch YH: Advanced renal cell carcinoma: treatment with xenogeneic immune ribonuceli acid (RNA) and appropriate surgery. J Urol 115:246, 1976 17. Middleton RJ: Surgery of metastatic renal cell carcinoma. J Urol 97:973, 1973 18. Tolia BM, Whitmore WF, Jr. Solitary metastasis from renal cell carcinoma. J Urol 114:836, 1975 19. Bracken RB, Johnson DE, Goldstein HM et al: Experience with percutaneous transfemoral renal artery occlusion in patients with renal carcinoma: a preliminary report. Urol 6:6. 1975 VOLUME 106 T109750627