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15
RENAL CANCER
I. Epidemiology and etiology
A. Incidence
Renal cancer constitutes 2 percent of all malignancies. The incidence has increased slowly in the past decade. Men are affected twice as often as women.
B. Etiology
The cause of renal cancer is unknown.
1. Factors that increase the risk of renal cancer include
a. Smoking
b. Urban living
c. Family history of renal cancer
2. Unproven factors that may increase the risk of renal cancer include polycystic kidney disease, diabetes mellitus, and chronic dialysis.
II. Pathology and natural history
A. Adenocarcinomas
Adenocarcinomas ("hypernephromas" or "Grawitz tumors") make up nearly all renal cancers in adults.
1. The histologic variants include papillary, clear cell, granular cell, and spindle cell subtypes.
2. These tumors originate in the kidney from proximal tubular cells, invade local structures, and metastasize by way of the lymphatics and bloodstream. The most common sites of distant metastases are the lungs, liver, bones, and brain. Adenocarcinomas may present with metastases to unusual sites such as the finger tips, eyelids, and nose. A primary renal cancer may be diagnosed based on the characteristic histology of a metastatic deposit.
3. The natural history of hypernephroma is more unpredictable than most solid tumors. The primary tumor has variable growth patterns and may remain localized for many years. Metastatic foci may have long periods of indolent or apparently arrested growth or may develop many years after removal of the primary tumor.
B. Transitional cell carcinomas
Transitional cell carcinomas are very uncommon tumors that arise in the renal pelvis and often affect multiple sites of urothelial mucosa, including the renal pelvis, ureters, and urinary bladder. These tumors usually are low grade and discovered late in the course of the disease. Transitional cell carcinomas occasionally have a peculiar disposition to spread over the posterior retroperitoneum in a sheetlike fashion, encasing vessels and producing urinary tract obstruction. Hematogenous dissemination occurs, particularly to lung and bone.
C. Rare renal tumors
1. Nephroblastomas (Wilms' tumors) appear as large, bulky masses in children, but rarely occur in adults.
2. Lymphomas and sarcomas arising in the kidney have clinical courses similar to their counterparts elsewhere in the abdomen.
3. Juxtaglomerular tumors (reninomas) are rare causes of hypertension and are usually benign.
4. Hemangiopericytomas are associated with hypertension and are occasionally malignant (15% of cases).
5. Benign renal adenomas. The existence of benign renal adenoma is controversial because it is not possible to determine malignant or benign biologic behavior only by histology on any lesion less than 3 cm in diameter.
III. Diagnosis
A. Symptoms and signs
Symptoms other than hematuria usually indicate large, advanced tumors. The classic triad of flank pain, a flank mass, and hematuria occurs in less than 10 percent of patients with hypernephroma. The combined picture of anemia, hematuria, and fever is rare but very suggestive of renal cancer.
1. Symptoms
a. Gross hematuria occurs in over 50 percent of patients.
b. A steady, dull flank pain occurs in 50 percent of patients. Colicky pain may develop if blood clots are passed into the ureter.
c. Weight loss is a presenting feature in 30 percent of patients.
d. Left-sided varicocele that develops suddenly is a presenting feature in less than 3 percent of patients with adenocarcinoma of the left kidney.
e. Leg edema is the result of locally advanced disease, which causes venous or lymphatic obstruction.
f. Fever, plethora, or symptoms of hypercalcemia or anemia may be presenting features.
2. Physical findings
a. A flank mass is palpable in 50 percent of patients.
b. Fever occurs in up to 20 percent of patients.
c. Pallor from anemia occurs in about 40 percent of patients.
B. Diagnostic studies
1. Urinalysis may reveal proteinuria and hematuria. One-third of patients have neither gross nor microscopic hematuria. All patients with macroscopic or microscopic hematuria of any degree must have a urologic evaluation.
2. Routine studies
a. CBC, liver and renal function studies.
b. Hyperglobulinemia is frequently present in patients with hypernephroma because acute phase reactant proteins (alpha1- and alpha2-globulins) are elevated.
c. Chest x-ray film may reveal multiple, large, round ("cannonball") metastatic deposits that are characteristic of metastatic genitourinary neoplasms.
3. Scans should be performed in the following situations:
a. Bone scan, if there is bone pain or elevated alkaline phosphatase levels
b. CT scan of the brain, if there are signs or symptoms of CNS abnormalities
c. Liver, CT scan, if there is hepatomegaly or abnormal LFTs
4. Nephrotomography is the first diagnostic procedure to delineate mass lesions. Space-occupying lesions found by pyelography may represent cancers, cysts, or hamartomas (angiomyolipomas).
5. Renal angiography is the most accurate study for distinguishing malignant from benign lesions prior to biopsy.
a. Both renal cancers and hamartomas are vascular and both mandate surgical exploration. Renal cysts are hypovascular. The angiographic appearance of hamartomas may make preoperative diagnosis possible. Neovascularization and vascular parasitization are characteristic of cancer.
b. Up to 25 percent of renal cancers, however, are hypovascular and resemble cysts on angiography. Epinephrine administered during angiography causes normal arterial smooth muscles to contract. Tumor vessels lack well-developed musculature and will produce a "tumor blush" after epinephrine is given; this may make previously obscure lesions more readily detectable.
6. Ultrasonography of the kidney is relatively insensitive but may suggest the presence of a cyst; it may be used as an adjunct in the diagnosis of renal mass lesions but never as the final step.
7. CT scans of the kidneys help to define cystic lesions and to determine the extent of tumor and adjacent organ involvement.
8. MRI may be as accurate as CT and defines renal vein and caval extension more reliably in preparation for surgery.
9. Inferior vena cavography is performed to locate tumor thrombi in all patients with large tumor masses, but has recently been replaced by MRI.
10. Percutaneous thin-needle aspiration biopsy of a renal mass may result in tumor seeding in the needle track. This procedure should be restricted to patients with medical conditions that make angiography or surgery unduly hazardous, patients with metastatic disease where a tissue diagnosis is necessary, or patients who have findings strongly suggestive of a benign cyst.
11. Exploratory surgery or nephrectomy may be necessary to define renal masses that cannot be accurately assessed by noninvasive methods, IVP, angiography, or aspiration.
IV. Staging system and prognostic factors
A. Staging system
The TNM system is commonly used to stage renal cancer.
B. Prognostic factors
The survival rate for untreated patients is less than 5 percent at three years and less than 2 percent at five years.
1. Histology. Patients with clear cell carcinoma appear to have a better prognosis. Patients with ndifferentiated and spindle cell cancers have five-year survival rates of less than 25 percent.
2. Venous extension. Renal vein or vena cava involvement is not associated with a hopeless prognosis if managed properly; 25 to 50 percent of patients survive for five years.
3. Disease-free interval. The length of time between nephrectomy and the development of metastases affects the survival of patients with metastatic disease.
a. Nearly all patients who have metastases at the time of surgery or who develop metastases within one year of surgery die within two years if untreated.
b. Patients who develop metastases more than two years after nephrectomy have a 20 percent five-year survival from the time metastases are recognized.
4. Spontaneous regression of renal cancer following resection of the primary tumor is very rare and occurs in less than 1 percent of patients.
V. Prevention and early detection
The incidence of renal cancer might be reduced if tobacco smoking habits could be controlled. Early detection depends on prompt attention to hematuria and other symptoms suggestive of these cancers.
VI. Management
A. Early disease
1. Surgery
a. Nephrectomy with removal of Gerota's fascia, the adrenal gland, and tumor in the renal vein or vena cava is the treatment of choice.
b. Partial nephrectomy is sometimes adequate for small peripheral or polar lesions, even when the opposite kidney is normal. Patients with bilateral cancer and only one functional kidney may undergo partial nephrectomy. It is occasionally necessary to remove the kidney entirely, excise the tumor ("bench nephrectomy"), and then perform autotransplantation.
c. Preoperative occlusion of the renal artery using angiographic techniques has been advocated by some urologists but is seldom indicated. The hypervascular nature of renal cancer often results in hemorrhage during surgery, particularly with large, bulky tumors. Occlusion procedures make the operation technically easier but the patient may suffer considerable discomfort from pain, fever, and nausea.
d. Contraindications to surgery include high surgical risk due to unrelated medical diseases or evidence of distant metastases.
2. RT has no established role in the management of early renal cancers.
3. Chemotherapy has no established role in the management of early renal cancers.
B. Advanced disease
1. Surgery
a. Nephrectomy. The chance of a spontaneous regression of metastases following nephrectomy is well known but is far exceeded by the surgical morbidity and mortality. The hope for spontaneous regression is never an indication for surgery. Nephrectomy for the palliation of pain or hematuria can be considered in patients with metastatic disease if all of the following criteria are met:
(1) The performance status of the patient is at least 30 percent on the Karnofsky scale (100% is good general condition of patient) or is expected to improve substantially if hemorrhage was controlled.
(2) The only symptoms are in the area of the primary tumor. Sites of metastatic disease must be asymptomatic.
(3) The tumor should have a reasonable chance of being resectable as evaluated by the renal angiogram.
b. Resection of metastases. Metastases of hypernephroma can be considered for resection only if the following criteria are met:
(1) The interval from nephrectomy to the detection of metastases is at least two years.
(2) The metastasis is proved to be solitary by all of the following studies:
(a) Physical examination
(b) Normal LFTs (normal CT scan if LFTs are abnormal)
(c) Bone scan
(d) Chest CT scan
(e) CT scan of the brain if the patient has neurologic symptoms
2. RT is used to control bleeding and pain from the primary tumor and to palliate symptoms from metastases to the CNS and bone. Generally, renal tumors are relatively radioresistant.
3. Drug therapy
a. IL-2 administered alone in high-dose regimens produces a response rate of 15 to 20 percent in good risk patients and durable remissions often lasting years.
b. alpha-IFN has been reported to have a response rate of 15 to 20 percent (particularly for intrathoracic metastases) but no effect on survival.
c. Progestins have been used to treat patients with metastatic adenocarcinomas. Medroxyprogesterone acetate (Depo-Provera), 500 mg IM weekly for four weeks and monthly thereafter, and megestrol acetate (Megace), 40 to 80 mg PO q.i.d., have been used. Tumor responses have been reported in less than 15 percent of patients with progestin therapy, and no improvement in survival has been reported.
d. Cytotoxic agents have produced negligible effects on metastatic hypernephroma and no improvement in survival. Agents reported to produce occasional responses (15-20% of patients) include the fluoropyrimidines and vinblastine.
e. Transitional cell cancers of the renal pelvis and ureters may respond to cisplatin, Adriamycin, cyclophosphamide, or fluorouracil.
URINARY BLADDER CANCER
I. Epidemiology and etiology
A. Incidence
Bladder cancers constitute 4 percent of visceral cancers in the United States. The disease is 2.5 times more frequent in men than women and is most frequent in industrial northeastern cities. The average age of onset is the sixth to seventh decade.
B. Risk factors and carcinogens
1. Industry. Aniline dye workers are 30 times more likely to develop bladder cancer than the general population. Aromatic amines that are chemical intermediates of anilines, rather than the aniline dyes themselves, have been shown to be etiologic. Leather, paint, and rubber industry workers also appear to have an increased risk of bladder cancer. Proven chemical carcinogens in these industries are 2-naphthylamine, benzidine, 4-amino-biphenyl, and 4-nitro-biphenyl.
2. Schistosoma haematobium infection of the bladder is associated with bladder cancer, particularly with squamous cell histology, in endemic regions of Africa and the Middle East.
3. Smoking increases the risk of bladder cancer twofold. Eighty-five percent of men who die of bladder cancer have a history of smoking.
4. Pelvic irradiation increases the risk of bladder cancer by a factor of four.
5. Drugs. Cyclophosphamide unequivocally increases the risk of bladder cancer. Other drugs that have been implicated in animal studies but not proved in human beings are phenacetin, sodium saccharin, and sodium cyclamate.
6. Abnormal tryptophan metabolism has been found in up to 50 percent of patients with bladder cancer. Certain metabolites are carcinogenic in animals.
II. Pathology and natural history
A. Pathology
1. Histology. Ninety percent of bladder cancers are transitional cell (urothelial) and 8 percent are squamous cell types. Adenocarcinomas, sarcomas, lymphomas, and carcinoid tumors are rare.
2. Sites of involvement. Bladder tumors often involve the posterior and lateral walls and involve the superior wall least often. Patients with bladder carcinoma also frequently have carcinomas in other urinary tract sites.
3. Types of bladder cancer
a. Single papillary cancers are the most common type and the least likely to show infiltration
b. Diffuse papillary growths with minimal invasion
c. Sessile cancers are often high grade and invasive
B. Natural history
1. Low-grade superficial carcinomas have a better prognosis than CIS. Even though the recurrence rate is 80 percent, 80 percent of patients with these tumors survive five years. Invasive cancer develops in only 10 percent of patients with superficial tumors, often in association with CIS. More than 80 percent of patients with both superficial cancers and CIS develop invasive malignancies.
2. High-grade or invasive tumors are associated with adjacent areas of CIS in 85 percent of cases. Squamous cell cancers are usually high grade and are the most aggressive carcinomas of the bladder.
3. Mode of spread. Bladder cancers spread both by lymphatic channels and the bloodstream. High-grade lesions are more likely to metastasize. Thirty percent of patients with distant metastases do not have involvement of the draining lymph nodes. Distant sites of metastases include bone, liver, lung, and, less commonly, skin and other organs. Uremia from local extension into pelvic organs, inanition from advancing cancer, and liver failure are the usual causes of death.
4. Role of instrumentation. Bladder cancer cells exfoliated by cystoscopy, brushing, transurethral biopsy, or resection may seed other areas of the bladder. Mucosal sites damaged by inflammation or instrumentation appear to be most receptive to such implants. Implanted tumors may become invasive.
III. Diagnosis
A. Symptoms and signs
1. Symptoms
a. Hematuria occurs as a presenting feature in 90 percent of patients.
b. Bladder irritability occurs in 25 percent of patients. Hesitancy, urgency, frequency, dysuria, and postvoiding pelvic discomfort may mimic prostatitis or cystitis. These symptoms occur in patients with CIS, as well as with tumors that are large, extensive, or near the bladder neck.
c. Pain in the pelvis or flank is associated with locally advanced disease.
d. Edema of the lower extremities and genitalia develops from venous or lymphatic obstruction.
2. Physical findings. The patient is carefully examined for metastatic sites. Bimanual examination is performed by the urologist through the rectum while the patient is under general anesthesia for cystoscopy.
B. Special diagnostic studies
1. Routine studies
a. CBC, renal and liver function tests
b. Urinalysis
c. Chest x-ray
2. Cystoscopy is the cornerstone for diagnosing bladder cancer. Grossly abnormal areas are biopsied. Biopsies of both suspected areas and normal areas at random are also taken to search for CIS. Cystoscopy is followed by bimanual pelvic examination under anesthesia in both men and women. Cystoscopy is indicated for patients with
a. Hematuria
b. Unexplained or chronic lower urinary tract symptoms
c. Urine cytology positive for cancer
d. A history of bladder cancer
3. Urography. An IVP is performed on all patients with unexplained hematuria or cystoscopic or cytologic evidence of tumor. To search for primary sites in the ureters or renal pelves, the IVP is performed before cystoscopy in patients with positive urine cytology.
4. Urine cytology, often accompanied by flow cytometry, detects about 70 percent of bladder cancers that are subsequently diagnosed by cystoscopy. Cytologic evaluation should not be the primary diagnostic method for patients suspected of having bladder cancer. Urine cytologies are useful for
a. Following patients with a history of bladder cancer
b. Screening asymptomatic patients who are exposed to environmental carcinogens
c. Evaluating patients with chronic irritative bladder symptoms before cystoscopy is done
5. Scans. Abdominal CT and bone scans should be performed in patients with bone pain or elevated serum alkaline phosphatase or transaminase levels.
IV. Staging system and prognostic factors
A. Staging system
The staging system for bladder cancer is based on clinical findings rather than on pathologic data obtained at surgery.
B. Prognostic factors
Untreated patients have a two-year survival of less than 15 percent and a median survival of 16 months.
1. Histology. Squamous cancers and adenocarcinomas have poorer prognoses than transitional cell carcinoma.
2. Invasion of muscle, lymphatic, or perivesical fat is associated with a poor prognosis. Invasive cancer is associated with a 50 percent mortality in the first 18 months after diagnosis.
3. Ca is progresses to invasive carcinoma in 80 percent of patients within 10 years of diagnosis.
4. Tumor grade
a. The close relationship of tumor grade and stage of disease is shown in Table 13-2Table 13-2.
b. Tumor grade alone affects survival in patients with superficial tumors. The five-year survival is 85 percent with low-grade lesions and 30 percent with high-grade lesions. Virtually all high-grade superficial tumors become invasive if left untreated.
5. Size of the primary tumor does not correlate with the risk of dissemination. Large superficial lesions, however, are more likely to recur after therapy than small lesions.
V. Prevention and early detection
A. Prevention
Protecting factory workers in certain industries from continuous exposure to bladder carcinogens (e.g., with protective clothing) may be beneficial. The benefit gained by reducing the intake of coffee or artificial sweetener has not been determined. All persons should be discouraged from smoking.
B. Early detection
Early detection depends on prompt evaluation of all patients with hematuria or chronic irritative bladder symptoms.
VI. Management
A. Early disease
1. Overview
a. Superficial low-grade tumors not associated with CIS are managed by transurethral resection and intravesical chemotherapy. Although the recurrence rate is 80 percent with this management, the prognosis is good. Fulguration is added if there are excessive numbers of small lesions.
b. Invasive tumors or superficial tumors with CIS are best treated by pelvic lymph node dissection and radical cystectomy in females and radical cystoprostatectomy in males. Segmental resections of the bladder may be used in highly selected cases. Radiotherapy and chemotherapy may be appropriate in some cases.
2. Surgery
a. Transurethral resection or fulguration is used for superficial low-grade carcinomas (stage A) and borderline urothelial atypia.
b. Segmental resection is associated with a high risk of recurrence. Only about 5 percent of patients are candidates for this procedure. Segmental resection can be considered if the tumor
(1) Is solitary, and
(2) Is localized to the bladder dome, and
(3) Is not associated with areas of CIS sought by multiple biopsies of urothelial mucosa, and
(4) Can be removed with a 3-cm margin of healthy tissue
c. Radical cystectomy includes excision of the bladder, pericystic fat, and attached peritoneum; ureters are diverted through a loop of ileum that functions as a bladder to an abdominal stoma (Bricker's procedure). In addition, males undergo removal of the entire prostate and seminal vesicles; females undergo en bloc removal of the uterus, adnexa, and cuff of the vagina. Alternative urinary drainage procedures include direct cutaneous implantation of the ureters and ureterosigmoidostomy. Continent urinary reservoirs, such as the Kock pouch or an ileal bladder anastomosed directly to the urethra, may be offered to selected patients. Lymphadenectomy is controversial; it does not improve survival, but adds little morbidity and provides information for staging.
(1) Indications
(a) Superficial low-grade (stage A) tumors that are diffuse, multiple, and frequently recurring
(b) True, severe CIS
(c) High-grade tumors
(d) Invasive tumors
(2) Complications of cystectomy
(a) Mortality of 3 to 8 percent.
(b) Impotence in men; potency can be preserved in some men by sparing the corporal nerves.
(c) Ureterocutaneous fistulae, wound dehiscence or infection, or small bowel obstructions or fistulae occur in about 30 percent of patients. Small bowel fistulae are associated with a 50 percent mortality.
(3) Complications of urinary diversion
(a) Urinary tract infection.
(b) Obstruction due to stenosis.
(c) Urinary calculi occasionally occur after Bricker's procedure; calcium stones are most common.
(d) Hyperchloremic acidosis from the rapid reabsorption of chloride by the sigmoid colon may become a problem after ureterosigmoidostomy.
3. RT.
a. Indications
(1) Preoperative radiation is seldom employed. RT does not appear to improve expected survival beyond that achieved by radical surgery alone, although local recurrence is reduced.
(2) Postoperative radiation has no proven role in bladder cancer.
(3) RT alone is an alternative to surgery in patients who desire to retain their bladder and potency and are willing to accept a 20 percent lower cure rate.
(4) RT combined with cisplatin alone or M-VAC may spare the bladder in patients who are not candidates for cystectomy.
4. Chemotherapy
a. Topical therapy. Superficial low-grade bladder cancers may be treated with intravesical chemotherapy after sites of gross disease are resected transurethrally. The incidence of tumor recurrence is reduced with topical therapy, but how much topical therapy improves survival is not known. Thiotepa, mitomycin C, BCG, and Adriamycin are effective. Thiotepa is the most commonly used topical agent: 30 to 60 mg in 100 ml of sterile water or saline is instilled through a catheter into the previously emptied bladder and retained for two hours. A widely used method is to repeat the instillation weekly for six months, then monthly for one year, and bimonthly for three years from the start of therapy. Repeat cystoscopic examinations with biopsy of questionable areas are performed every three months for the three-year period; evidence of progression or invasive carcinoma indicates the need for radical cystectomy.
b. Adjuvant therapy with systemic cytotoxic agents (cyclophosphamide, doxorubicin, cisplatin) for patients undergoing cystectomy has been associated with a delay in time to progression and improved survival time. Confirmatory studies are in progress.
c. Neoadjuvant therapy is an attempt to provide the earliest possible treatment of micrometastatic disease and to facilitate definitive local therapy.
B. Advanced disease
1. Surgery
a. Large, bleeding tumors can occasionally be fulgurated.
b. Urinary diversion with a ureterocutaneous conduit is indicated in the patient with severe hemorrhage or voiding symptoms.
2. RT ameliorates hemorrhage in about 50 percent of patients and provides substantial local pain relief in areas of bone involvement. Tumor masses that threaten extension through the skin, particularly in the perineum, should be irradiated early. Bacterial cystitis should be treated effectively before the institution of RT if possible.
3. Chemotherapy. Combinations of methotrexate, vinblastine, Adriamycin, and cisplatin (M-VAC) have produced sustained complete responses in up to 40 percent of patients and represent the best current therapy for advanced bladder cancer.
C. Patient follow-up
1. Patients with severe urothelial dysplasia should have urine cytology repeated every two to three months, and cystoscopy with random biopsies every three to six months.
2. Patients with superficial low-grade cancer treated with intravesical chemotherapy should have cystoscopy performed at three-month intervals.
3. Patients who have undergone cystectomy should be evaluated every three months for the first two years, every six months for the next three years, and yearly thereafter. Urinalysis and urine cytology should be performed at six-month intervals to search for the development of new primary cancers in the upper urinary tract. Hematuria or a positive cytology should be evaluated with intravenous urography.
PROSTATE CANCER
I. Epidemiology and etiology
A. Incidence
1. Clinically evident cancer of the prostate. The risk of clinically detectable prostate cancer increases with age from 0.02 percent at the age of 50 years to 0.8 percent at age 80. The risk of prostate cancer in black men increases at a faster rate than in whites.
2. Subclinical (latent) cancer of the prostate is a common incidental finding in autopsies. Latent cancer increases by 1 percent per year of age starting at the age of 50 years; the incidence is 10 percent at 50 years and 30 percent at 70 years.
B. Etiology
The cause of prostate cancer is unknown. Several factors are associated with an increased risk.
1. Demography. The risk of developing prostate cancer is highest in Sweden, intermediate in the United States and Europe (and Japanese men who migrated to the United States), and lowest in Taiwan and Japan. Jews of all age groups appear to be at low risk.
2. Marital status. The risk is lowest for single men and increases, in order of increasing risk, for married, widowed, and divorced men. The risk also appears to increase with the number of children parented.
3. Occupation. Higher rates of prostate cancer are reported in workers exposed to cadmium, loggers, chemists, farmers, textile workers, painters, and rubber tire workers.
4. Hormones. Altered estrogen and androgen metabolite levels have been detected in patients with prostate cancer or hyperplasia. The association of liver cirrhosis with increased risk of prostate cancer further suggests that an altered hormonal milieu plays a role in the etiology.
II. Pathology and natural history
A. Histology
Almost all prostate cancers are adenocarcinomas. Sarcomas and transitional, small, and squamous cell carcinomas are rare. The prostate may be the site of metastases from bladder, colon, or lung cancer or from the melanomas, lymphomas, or other malignancies.
B. Location
Prostate cancer tends to be multifocal and frequently involves the gland's capsule. Both of these characteristics make removal by transuretheral resection unfeasible.
C. Mode of spread
The biology of adenocarcinomas of the prostate is strongly influenced by tumor grade. Low-grade tumors may remain localized for long periods of time. The disease metastasizes along nerve sheaths, through lymphatic chains, and hematogenously. Distant metastases may occur without evidence of nodal involvement. Distant metastases are nearly always present when lymph nodes are involved.
D. Metastatic sites
Bone is the most common site of prostate cancer metastases, almost always producing dense osteoblastic metastases. Occasionally, patients demonstrate uncharacteristic osteolytic lesions. Liver involvement also occurs, but metastases to the brain, lung, and other soft tissues are rare.
E. Associated paraneoplastic syndromes
1. Systemic fibrinolysis
2. Neuromuscular abnormalities
III. Diagnosis
A. Symptoms and signs
1. Symptoms
a. Early prostatic cancer is usually asymptomatic and can only be detected by the routine rectal examination. The presence of symptoms indicates advanced disease. Symptoms include hesitancy, urgency, nocturia, poor urine stream, dribbling, and terminal hematuria.
b. The sudden onset and rapid progression of symptoms of urinary tract obstruction in men of the appropriate age is most likely to be caused by prostate cancer.
c. Pain in the back, pelvis, shoulders, or over multiple bony sites is the most common presenting complaint in patients with distant metastases.
d. The sudden onset of paraplegia and incontinence resulting from extradural spinal metastases may be a presenting feature or may develop during the course of the disease.
2. Physical examination
a. Check for induration or nodularity of the prostate, which often represents prostatic cancer. Approximately two-thirds of patients with malignancy found on biopsy have palpable induration. Nodules of prostatic cancer are typically stony hard and not tender.
b. Examine for normal lateral sulci and palpable (i.e., abnormal) seminal vesicles.
c. Evaluate inguinal nodes for metastatic disease.
d. Evaluate for distant metastases.
B. Differential diagnosis of the enlarged prostate
1. Acute prostatitis. Bacterial infection causes dysuria, pain, and, often, fever. The prostate is tender and enlarged but not hard. Examination and culture of prostatic fluid obtained by prostate massage reveal the infectious agent.
2. Chronic and granulomatous prostatitis caused by bacterial, tuberculous, fungal, or protozoan infection may produce a mass that cannot be clinically distinguished from cancer. Biopsy may be necessary to make the diagnosis.
3. Nodular hyperplasia (benign prostatic hypertrophy) is found in men 30 years of age and over and in 80 percent of men by 80 years of age. Urinary obstructive symptoms are common. Palpable nodules that are indistinguishable from cancer necessitate biopsy.
4. Other possibilities. Rarely, calculi, amyloidosis, benign adenomas, or infarction of a hyperplastic nodule may cause obstruction or a mass suggestive of cancer.
C. Laboratory studies
1. Routine studies. Urinalysis; CBC, renal and liver function tests; alkaline phosphatase, calcium, and phorphorous levels; chest x-ray film.
2. Tumor markers
a. Acid phosphatase (AP) levels in the serum are increased in 70 to 80 percent of patients with disseminated disease. AP is not sensitive enough for screening of patients with localized disease. Blood levels should be assayed before digital rectal examination and prostate manipulation, which result in elevated serum concentrations.
(1) AP is produced by several tissues, including the prostate, kidney, breast, granulocytes, and platelets. Elevated blood levels of the enzyme are found in 80 percent of prostate cancer cases with skeletal metastases, 60 percent of untreated cases, and 20 percent of cases apparently without extracapsular extension.
(2) Elevated levels of serum AP are also found in patients with thrombocytosis, Gaucher's disease, osteitis deformans, breast cancer, and bony involvement from other tumors (particularly breast cancer and osteosarcoma).
(3) The AP produced by the prostate, both normal and cancerous, is tartrate resistant. Radioimmunoassay of the enzyme has a high rate of false-positive results and is not yet recommended for routine screening or follow-up.
b. Prostatic-specific antigen (PSA) is a specific marker for prostate carcinoma and is more sensitive than AP.
(1) Approximately 15 percent of patients with nodular hyperplasia have elevated PSA levels, but elevation usually indicates carcinoma. PSA values can also be increased with prostatic inflammation, surgery, or endoscopy, but not with rectal examination. PSA values have occasionally been elevated in patients with cancer that did not originate in the prostate.
(2) PSA can detect primary or recurrent tumors of very low volume and is useful in diagnosis and follow-up. When PSA is combined with transrectal ultrasound and prostatic biopsies, cancer is detected in 20 percent of patients with PSA values between 4.0 ng/ml and 10 ng/ml and in 60 percent of patients with values exceeding 10 ng/ml. Although PSA is not sensitive enough to be the sole screening method for prostate cancer, it is useful when combined with digital rectal examination and transrectal ultrasound.
(3) About 10 percent of patients with biopsy-proven prostate cancer have normal PSA levels. About 10 percent of patients with metastatic prostate cancer have elevated AP levels with normal PSA levels.
(4) PSA values may show a progressive increase several years before metastatic disease becomes evident. Such a rise is an indication to look for local recurrence in previously treated patients using physical examination or transrectal ultrasound but not an indication to conduct a detailed, unbeneficial search for metastatic disease.
c. CEA is increased in too few patients with prostate carcinoma and in too many other conditions to be clinically useful.
3. Needle biopsy is the standard method to diagnose prostate cancer. Biopsy of nodules, suspect indurations, and multiple random areas detects cancer in only one-half of patients with induration of the prostate. Biopsy also helps determine whether the cancer is multifocal. Needle biopsy fails to detect cancers found by other surgical techniques in up to 30 percent of patients. The fine-needle aspiration biopsy is less painful and has less morbidity than the standard large needle and is the method of choice in many institutions with pathologists skilled in its interpretation.
4. Transurethral resection of the prostate for benign hyperplasia is the most common means of diagnosing patients with stage A prostate cancer.
5. Bone scans should be performed in all patients with a histologic diagnosis of prostate cancer even if the disease appears to be localized.
6. IVPs with cross-table lateral views are routinely obtained in all patients except those with stage A1 lesions.
7. CT scans and ultrasonography are used to demonstrate pelvic and abdominal lymph node enlargements in patients with scrotal and lower extremity edema.
IV. Staging and prognostic factors
A. Staging system
A system based on clinical findings.
B. Prognostic factors
1. Tumor grade strongly affects prognosis. Higher tumor grades are more frequently associated with lymph node and distant metastases.
2. Involvement of seminal vesicles is associated with a poor prognosis even in apparently early disease.
V. Prevention and early detection
Early detection of prostate cancer necessitates careful examination of the prostate. Although screening for prostate cancer remains controversial the use of transrectal ultrasound, serum PSA, and biopsy with ultrasound-guided automatic gun hold promise and are the subjects of large clinical trials. Patients with any questionable induration or mass should be referred to a urologist for biopsy.
VI. Management
The management of all stages of prostate cancer is highly controversial. This disease has a long natural history and substantial numbers of patients survive 15 or more years after the diagnosis. Investigators and clinicians vary widely in their use of surgery, RT, and hormonal manipulation for treating each stage of disease. Most clinicians agree, however, that treatment of early-stage disease with either surgery or radiation therapy results in comparable survival.
A. Early disease
Early disease (stages A, B, and C)
1. Surgery
a. Stage A1 prostate cancer is discovered by histologic evaluation of specimens taken from transurethral resection for prostatic hyperplasia. Once a focus of cancer is discovered, random needle biopsies are obtained to look for other areas of cancer. If none is found, no further therapy is necessary since patients with this stage of disease have the same survival expectancy as normal age-matched controls. The extent of disease is followed with frequent digital examinations. Needle biopsies are performed for changes noted on rectal examination (some urologists perform a repeat transurethral resection three months after the first surgery). If the biopsy shows cancer, the patient is reclassified as stage A2 and managed accordingly.
b. Stages A2, B1, B2, and C. These patients are offered either RT or radical prostatectomy. Urologists may recommend that patients with these clinical stages undergo pelvic lymphadenectomy for pathologic staging before prostatectomy is done. The results of staging would then determine subsequent therapy.
c. Complications of prostatectomy and lymphadenectomy
(1) Prostatectomy causes incontinence in 4 percent and stress incontinence in up to 30 percent. Potency can be spared by a skilled surgeon in 60 to 80 percent of patients with small B1, B2, or with A2 tumors.
(2) Complications of staging lymphadenectomy occur in approximately 20 percent of patients and include lymphocele, pulmonary embolus, wound infection, and lymphedema.
d. Contraindications to prostatectomy and lymphadenectomy
(1) Physiologic age over 75
(2) High-grade cancers
(3) Invasion of the seminal vesicles (stage C2)
(4) Metastases to pelvic nodes (stage D1)
(5) Disseminated cancer (stage D2)
2. RT
a. Indications. RT is widely employed in the treatment of patients with stage A2, B1, B2, and C2 tumors. Therapy of patients with stage C disease is also controversial, but most authorities recommend RT. Other indications for RT include
(1) The patient's medical condition precludes surgery.
(2) Node involvement is found at staging lymphadenectomy (radical prostatectomy is not performed).
(3) Residual malignant pelvic disease after prostate surgery.
3. Systemic therapy. Neither hormonal manipulation nor chemotherapy clearly improves the survival of patients with early prostate cancer.
B. Advanced disease
Advanced disease (stage D)
1. Surgery. Transurethral resection of the prostate may be used to relieve bladder outlet obstruction even in the presence of advanced disease; however, orchiectomy alone is usually effective.
2. RT is useful in treating the following problems commonly encountered in cancer of the prostate:
a. Isolated, painful bony metastatic sites after endocrine therapy has ceased to be effective.
b. Pelvic pain syndromes, urinary tract obstruction, and gross hematuria.
c. Metastases to retroperitoneal lymph nodes, which produce back pain and scrotal and lower extremity edema.
d. Spinal cord compression from vertebral and extradural metastases is a common and rapidly progressive complication of prostate cancer. Cord compression is an emergency; myelography and definitive therapy must be undertaken within a few hours after onset of symptoms.
3. Endocrine therapy is the mainstay of treatment for symptomatic advanced prostate cancer. Asymptomatic patients with advanced disease do not appear to have improved survival with treatment when compared to untreated patients; treatment of asymptomatic patients with advanced disease is not essential. Orchiectomy, LHRH agonists, antiandrogen, or DES is the treatment of choice. Each produces symptomatic relief in 80 percent of patients. Improvement is often dramatic; many bedridden patients crippled with bone pain return to a more functional status in a few days.
a. DES (3 mg/day PO). Testosterone is produced by the testes and is the only natural androgen that has a substantial stimulatory effect on the prostate. The 3-mg dose of DES reduces plasma testesterone levels to those produced by orchiectomy. Patients should be given a brief course of RT to the breasts before starting DES to prevent painful gynecomastia. Patients being treated with DES must be observed for the development of congestive heart failure and thrombophlebitis.
b. Orchiectomy is preferred for treatment of patients with a history of cardiovascular disease (particularly congestive heart failure), stroke, or thromboembolic phenomena. These conditions are potentially aggravated by DES therapy.
c. LHRH agonists, such as leuprolide, appear to be as effective as orchiectomy or DES and do not produce the cardiovascular, mammary, or GI side effects of DES. The cost of treatment with leuprolide is substantially greater than with either DES or orchiectomy.
d. Antiandrogens combined with LHRH agonists are superior to LHRH agonists alone and result in a small but significant survival benefit for "total androgen blockade." Flutamide, an antiandrogen, is given at a dosage of 250 mg PO t.i.d. Leuprolide is given at a dose of 7.5 mg IM monthly.
e. Diethylstilbestrol diphosphate (Stilphostrol) may be tried (50-200 mg PO t.i.d.) in patients failing orchiectomy or DES. This drug is a high-dose equivalent form of DES, which is presumably activated by acid phosphatase inside prostate cancer cells.
f. Other endocrine agents that may be helpful
(1) The long-acting estrogen, chlorotrianisene (TACE), 12 to 25 mg PO each day (same precautions as for short-acting estrogens).
(2) Progestins such as megestrol acetate, 40 mg PO q.i.d.
(3) Drugs that inhibit androgen synthesis (aminoglutethimide, ketoconazole) have also been shown to be effective.
4. Chemotherapy provides symptomatic relief in 20 to 30 percent of patients with prostate cancer. Effective agents include cyclophosphamide, fluorouracil, Adriamycin, and dacarbazine.