Document 5626

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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.
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.
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.
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
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.
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
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
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
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 .
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%.
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
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
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."
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,
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,
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