Tumors of the genitourinary tract are among the most common neoplastic diseases found in adults. Prostate cancer, for example, is the most common cancer in men (33%), and renal and bladder cancer account for nearly 10% of all malignant tumors in men, but only about 3% in women. Even though excellent diagnostic methods are available, one-third of all genitourinary tumors are not found until regional or distant spread has occurred. Advances in diagnosis and treatment of genitourinary tract tumors have occurred in recent years, and the prognosis has improved in conditions such as Wilms tumor, testicular cancer, and bladder cancer. The mainstay of diagnosis continues to be physical examination, complete urinalysis, CT urography and cystoscopy whenever indicated. Curative treatment of these tumors continues to be surgical in most instances.
RENAL ADENOCARCINOMA (RENAL CELL CARCINOMA)
Malignant tumors of the kidney account for approximately 3% of all tumors in adults. Often, the diagnosis is found incidentally on ultrasound, CT scan, or MRI. Microscopic or gross hematuria evaluation can also identify renal cell carcinoma (RCC). Advanced or metastatic disease can present with flank mass, weight loss, or pathologic fracture. rRisk factors for RCC include cigarette smoking, obesity, and hypertension. The disease occurs in men three times more commonly than in women. A suppressor gene on chromosome 3p has been shown to be present in von Hippel–Lindau renal cancers as well as in most sporadic RCC. The most common cell type is clear cell (also called conventional) carcinoma, accounting for 70%-80% of renal carcinomas. The cell of origin is in the proximal convoluted tubule. Other cell types include papillary (10%-15%), chromophobe (3%-5%), and collecting duct renal carcinoma (1%). The tumor metastasizes commonly to the lungs (50%-60%), adjacent renal hilar lymph nodes (25%), ipsilateral adrenal (12%), opposite kidney (2%), and lytic lesions in mainly long bones (30%-40%).
Numerous conditions predispose to renal cell cancer, including von Hippel–Lindau syndrome (cerebellar hemangioblastomas, retinal angiomatosis, and bilateral RCC), tuberous sclerosis, and acquired renal cystic disease developing in patients with end-stage renal disease. Paraneoplastic syndromes are common in RCC and are often what suggests the diagnosis, yet they rarely have prognostic significance. These syndromes include hypercalcemia, erythrocytosis, hypertension, fever of unknown origin, anemia, and elevated liver enzymes (Stauffer’s syndrome). RCC has a predilection for producing occlusive tumor thrombi in the renal vein and the inferior vena cava (particularly from the right kidney), manifested by signs of lower extremity edema and acute scrotal varicocele when occluding the left renal vein. This phenomenon of inferior vena cava thrombus occurs in approximately 5%-10% of patients. Occasionally, the tumor thrombus reaches up to the right atrium.
Painless gross or microscopic hematuria throughout the urinary stream (“total hematuria”) occurs in some patients. The degree of hematuria is not necessarily related to the size or stage of the tumor. Although a triad of hematuria, flank pain, and a palpable flank mass suggests RCC, fewer than 10% of patients will so present. Both pain and a palpable mass are late events occurring only with tumors that are very large or invade surrounding structures or when hemorrhage into the tumor has occurred. Symptoms due to metastases may be the initial complaint (eg, bone pain, respiratory distress). Localized disease is often identified incidentally on imaging.
Microscopic urinalysis reveals hematuria in most patients. The erythrocyte sedimentation rate may be elevated but is nonspecific. Elevation of the hematocrit and levels of serum calcium, alkaline phosphatase, and aminotransferases occur in fewer than 10% of patients. These findings nearly always resolve with curative nephrectomy and thus are not usually signs of metastases. Anemia unrelated to blood loss occurs in 20%-40% of patients, particularly those with advanced disease.
The diagnosis of RCC is often made by CT (and, less frequently, by intravenous urography) performed as an initial step in the workup of hematuria, an enigmatic metastatic lesion, or suspicious laboratory findings (Figure 38–12). Ultrasonography and CT scan often reveal incidental renal masses, which now account for 50% of the initial diagnoses of RCC in patients without manifestations of renal disease. Plain abdominal x-rays may reveal a calcified renal mass, but only 20% of renal masses contain demonstrable calcification. (Twenty percent of masses with peripheral calcification are malignant; more than 80% with central calcification are malignant.) The initial technique for workup of hematuria is currently CT urography which can accurately identify an enhancing renal mass which is diagnostic for RCC. CT scan is also helpful in local staging and can reveal tumor penetration of perinephric fat; enlargement of local hilar lymph nodes, indicating metastases; or tumor thrombi in the renal vein or inferior vena cava. CT angiography can delineate the renal vasculature, which is helpful in surgical planning for partial nephrectomies.
A: Adenocarcinoma of the left kidney. CT scan of the abdomen shows an exophytic lesion from the midpolar kidney (arrow). B: CT scan showing a large left renal mass (arrow) incidentally found on imaging done to evaluate nonspecific abdominal pain. Final pathology revealed clear cell renal carcinoma.
Occasionally, some masses detected on CT require further characterization by ultrasound. Abdominal ultrasonography can define the mass as a benign simple cyst or a solid mass in 90%-95% of cases. Abdominal ultrasound can also identify a vena caval tumor thrombus and its cephalad extent in the cava.
MRI is not more accurate than CT and is much more expensive. It is, however, the most accurate noninvasive means of detecting renal vein or vena caval thrombi. With the further refinement of pulse sequencing and the use of paramagnetic contrast agents, MRI has become one of the primary techniques for staging solid renal masses. Magnetic resonance angiography (MRA) has become particularly useful for mapping the blood supply and the relationship to adjacent structures in candidates for partial nephrectomy.
D. Other Diagnostic or Staging Techniques
Isotopic bone scanning is useful in patients with bone pain, elevated alkaline phosphatase, or known metastases. Chest x-ray is sufficient if negative, but if equivocal, then CT scan of the chest can be used to detect metastases. Identification of metastatic disease in the thorax warrants consideration of brain imaging to rule out occult disease. There are currently no tumor markers specific for RCC. Occasionally, biopsy of the mass can be useful in when imaging is not definitive, or when metastases from another primary malignancy are a possibility. Previously, such procedures were discouraged because of fear of disseminating the tumor along the needle tract, but this has proved to be rare, and the technique is safe. False negative results and insufficient tissue for diagnosis are limitations of renal mass biopsy. Fortunately, imaging is diagnostic in most cases.
A variety of lesions in the retroperitoneum and kidney other than renal cysts may simulate renal cancer. These include lesions due to hydronephrosis, adult polycystic kidney disease, tuberculosis, xanthogranulomatous pyelonephritis, metastatic cancer from another primary cancer, angiomyolipoma or other benign renal tumors, or adrenal cancer and retroperitoneal lipomas, sarcomas, or abscesses. In general, one or more imaging techniques described above should make the differentiation. Percutaneous biopsy is necessary in rare instances when imaging cannot make the diagnosis.
Hematuria may be caused by renal, ureteral, or bladder calculi; renal pelvis, ureteral, or bladder tumors; or many other benign conditions usually delineated by the studies described. Cystoscopy is obligatory in hematuric patients with a normal CT scan or intravenous urogram to rule out disease of the bladder and to determine the source of the hematuria.
Occasionally, patients may present with acute flank pain secondary to hemorrhage within a tumor or colic secondary to obstructing ureteral clots. Tumor in the renal vein or vena cava may cause an acute left varicocele or lower extremity edema associated with proteinuria. Pathologic fractures are due to osteolytic metastases in long bones. Brain metastases can present with seizure or other neurologic symptoms.
Staging is the key to designing the treatment plan (Table 38–1). Patients with disease confined within the renal fascia (Gerota’s fascia) or limited to nonadherent renal vein or vena caval tumor thrombi (stages T1, T2, and T3a) are best treated by surgical extirpation with either radical nephrectomy or partial nephrectomy. Radical nephrectomy traditionally includes en bloc removal of the kidney and surrounding Gerota fascia (including the ipsilateral adrenal), the renal hilar lymph nodes, and the proximal half of the ureter. However, adrenal-sparing radical nephrectomy is routinely performed for mid- and lower-pole renal tumors with equivalent outcomes.
Table 38–1.TNM staging classification and prognosis of renal cell cancer. ||Download (.pdf) Table 38–1. TNM staging classification and prognosis of renal cell cancer.
|Robson Stage ||T ||N ||M ||Five-Year Survival (%) |
|I. Tumor confined by renal capsule || |
T1 (< 7.0 cm tumor)
T2 (> 7.0 cm tumor)
|N0 (nodes negative) ||M0 (lack of distant metastases) ||80-100 |
|II. Tumor extension to perirenal fat or ipsilateral adrenal but confined by Gerota’s fascia ||T3a ||N0 ||M0 ||50-60 |
|IIIa. Renal vein or inferior vena cava involvement || |
T3b (renal vein involvement)
T3c (renal vein and caval involvement below the diaphragm)
T4b (caval involvement above the diaphragm)
|N0 ||M0 || |
50-60 (renal vein)
25-35 (vena cava)
|IIIb. Lymphatic involvement ||T1-3 || |
N1 (single regional node involved)
N2 (multiple regional, contralateral, or bilateral nodes involved)
|M0 ||15-35 |
|IIIc. Combination of IIIa and IIIb ||T3-4 ||N1-2 ||M0 ||15-35 |
|IVa. Spread to contiguous organs except ipsilateral adrenal ||T4 ||N1-2 ||M0 ||0-5 |
|IVb. Distant metastases ||T1-4 ||N0-2 ||M1 ||0-5 |
In patients with very large or central tumors and a normal contralateral kidney, radical nephrectomy is recommended. In all other cases, attempts should be made for nephron-sparing surgery. Successful partial nephrectomy with negative surgical margins offers the same survival benefit as radical nephrectomy. Typically hilar-vessel occlusion with bulldog or satinsky clamp(s) is performed to allow for resection in a relatively bloodless field.
Laparoscopic radical or partial nephrectomy has been advocated as a method equal to the open approach with the advantages of less blood loss, shorter hospitalization, and earlier return to normal function. It is the gold standard in institutions with appropriate expertise. Laparoscopic or percutaneous cryoablation of RCC has also shown considerable promise. Alternatively, radiofrequency ablation has been utilized for small renal tumors. These ablative technologies do not provide pathologic diagnosis; so percutaneous biopsy can be performed before the procedure or intraoperatively.
Nephrectomy has not been associated with improved survival rates in patients with multiple distant metastases (stage IV), and the procedure is not recommended unless patients are symptomatic or a promising therapeutic protocol is being studied. Flanigan and others have shown, however, that up to a 6-month improvement in survival can be achieved with nephrectomy—even with soft tissue metastasis—in selected patients who also receive interferon alpha systemic therapy. Patients with solitary pulmonary metastases have benefited from joint surgical removal of both the primary lesion and the metastatic lesion (30% survival at 5 years). Preoperative arterial embolization in patients with or without metastases does not improve survival rates, though it may be helpful as a single treatment measure in patients with symptomatic but nonresectable primary lesions. Radiation therapy is of little benefit except as treatment for symptomatic bone metastases. Medroxyprogesterone for metastatic RCC has given an equivocal 5%-10% response rate of short duration. Vinblastine has also had a response rate of approximately 20%, again of minimal duration. There are no other cytotoxic chemotherapeutic agents of benefit.
Immunotherapy with interferon alpha has had a 15%-20% response rate. Other interferons, alone (interferon beta, interferon gamma) or in combination with chemotherapeutic agents, have been less effective than interferon alpha. Adoptive immunotherapy—using lymphocytes (lymphokine-activated killer cells) from exposure of the patient’s own peripheral blood lymphocytes to interleukin-2 (IL-2) in vitro followed by reinfusion into the patient along with systemic IL-2 infusion—has shown up to 33% objective response rates. High-dose intravenous IL-2 causes a profound capillary leak syndrome and substantial toxicity. Subsequent studies have shown only a 16% response rate.
Recent advances in research on the von Hippel–Lindau tumor suppressor gene has led to identification of growth factors including vascular endothelial growth factor (VEGF) and platelet-derived growth factor as molecular targets in treating advanced renal cancer. Initial studies using bevacizumab, an anti-VEGF antibody, have shown promising results. Sorafenib, a tyrosine kinase inhibitor that blocks the pathway leading to the production of several growth factors, has been studied in patients with metastatic renal cancer and shown longer median progression-free survival than placebo (24 weeks vs. 6 weeks). Sunitinib, another tyrosine kinase inhibitor, has shown longer progression-free survival and higher response rates than interferon alpha in patients with metastatic renal cancer. These oral agents are currently used as first-line therapy in this group of patients.
Temsirolimus is another targeted agent that is a specific inhibitor of the mammalian target of rapamycin kinase (mTOR inhibitor) and has shown promising results. It is now used as first-line therapy in poor prognosis patients. Many other agents are currently being studied.
Patients with localized RCC (stages T1, T2, and T3a) treated surgically have 5-year survival rates of approximately 70%-80%, whereas rates for those with local nodal extension or distant metastases are 15%-25% and less than 10%, respectively. Most patients who present with multiple distant metastases succumb to disease within 15 months (Table 38–1). The advent of new agents for RCC may improve the outcome in these patients.
Renal sarcomas include rhabdomyosarcoma, liposarcoma, fibrosarcoma, and leiomyosarcoma; the latter is the most common, though all are very uncommon. Sarcomas are highly malignant and are usually detected at a late stage and thus have a poor prognosis. The diagnostic approach is similar to that of RCC. The histology of the lesion is rarely suspected preoperatively, although local invasion into surrounding retroperitoneal structures is more common than with RCC. These tumors have a tendency to surround the renal vasculature and do not exhibit neovascularity on MRA.
Treatment is surgical, with wide local excision; however, local recurrence and subsequent distant metastases are the rule. There is no therapy of proved benefit for metastatic disease.
SECONDARY MALIGNANT RENAL TUMORS
Metastatic tumors to the kidney are more common than primary renal tumors and often develop from primary tumors of distant sites, most commonly the lung, stomach, and breast. It is rare for the diagnosis to be made before autopsy; this suggests that renal metastasis is a late event. There are usually no symptoms, though microscopic hematuria occurs in 10%-20% of cases. Imaging reveals a renal mass, often difficult to distinguish from RCC. Contiguous spread of a tumor adjacent to the kidney is not infrequent (eg, tumors of the adrenal, colon, and pancreas and retroperitoneal sarcomas). Tumors such as lymphoma, leukemia, and multiple myeloma may also infiltrate the kidney. Routine radiologic, hematologic, and chemical examinations should demonstrate the primary tumor in most cases. Percutaneous biopsy may be appropriate in certain circumstances.
Renal oncocytomas are benign renal neoplasms. The tumors are generally asymptomatic and not associated with the paraneoplastic syndromes. The finding of a central stellate scar on CT or a spoke-wheel pattern of feeding arteries on angiography may suggest the diagnosis, although these findings have been found to be unreliable. Oncocytomas can coexist with renal carcinoma in the same lesion or in other lesions in the same kidney (7%-30%). This finding, along with difficulty differentiating oncocytoma from clear cell or chromophobe renal cancers on fine-needle aspirates, make it difficult to make a definitive diagnosis preoperatively. Consequently, definitive treatment of these lesions with radical or partial nephrectomy, or with ablation (cryoablation or RFA) has been recommended.
Mesoblastic nephroma is a benign congenital renal tumor seen in early childhood, which must be distinguished from the highly malignant nephroblastoma, or Wilms tumor. Unlike Wilms tumor, mesoblastic nephroma is commonly diagnosed within the first few months of life. Histologically, it is distinguished from Wilms tumor by cells resembling fibroblasts or smooth muscle cells and by the lack of epithelial elements. The prognosis is excellent; complete surgical resection is curative, and neither chemotherapy nor radiotherapy is required.
Angiomyolipoma is a benign hamartoma seen most often bilaterally in adults with tuberous sclerosis (which also includes adenoma sebaceum, epilepsy, and mental retardation). The tumor is also common in middle-aged women, but only unilaterally. These tumors can be detected following spontaneous retroperitoneal hemorrhage, though 50% of these lesions are currently diagnosed incidentally. CT scan can be diagnostic, with negative Hounsfield units detected in the fat-containing area of the tumor. Occasionally, an angiomyolipoma eludes diagnosis preoperatively and requires resection (especially the lipid-poor angiomyolipoma). Asymptomatic patients with small (< 4 cm) tumors and typical findings on CT scan of fat within the tumor do not require surgery, as the prognosis is excellent without treatment. These patients can be followed with serial imaging. Those presenting with a retroperitoneal hemorrhage or a size greater than 4 cm should have the tumor removed surgically with partial nephrectomy or embolized via angioinfarction, which has been shown to be effective.
Other Benign Renal Tumors
Other benign renal tumors include (1) fibroma, a renal parenchymal capsular or perinephric fibrous mass; (2) lipoma, an adipose deposit within or around the kidney, often perihilar or within the renal sinus; (3) leiomyoma, a common retroperitoneal tumor that may arise from the renal capsule or renal vascular walls; and (4) hemangioma, which is occasionally found to be the elusive cause of hematuria. Hemangiomas are generally quite small, and the diagnosis can be confirmed by direct vision of the lesion in the renal collecting system on ureteroscopy.
et al.: Temsirolimus
, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med
et al.: Sunitinib
versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med
M: Surgical management of localised renal cell carcinoma. Cochrane Database Syst Rev
2010 Mar 17 ;(3):CD006579. doi: 10.1002/14651858.CD006579.pub2. Review.
TUMORS OF THE RENAL PELVIS & CALICES
In over 90% of cases, tumors involving the collecting system of the kidney are urothelial (or transitional cell) carcinomas. Fewer than 5% of tumors in this location are squamous carcinomas (often in association with chronic inflammation and stone formation) or adenocarcinomas. The cause of urothelial carcinoma of the upper urinary tract is similar to that of epithelial tumors in the ureter or bladder; there is a strong association with cigarette smoking and exposure to industrial chemicals. Excessive use of phenacetin-containing analgesics and the presence of Balkan nephritis are also predisposing factors.
Gross or microscopic painless hematuria occurs in over 70% of patients. The lesions are usually asymptomatic unless bleeding causes acute flank pain secondary to obstructing clots. Presenting symptoms can often be due to metastases to bone, the liver, or the lungs. Physical examination is usually negative for any positive findings.
Microscopic hematuria on urinalysis is the rule. Pyuria is not seen. Cytologic examination of voided urine specimens may be diagnostic in high-grade tumors. Urine obtained from the ureter by retrograde catheterization or by brushing with specialized ureteral instruments can improve the diagnostic accuracy of cytologic examinations. Direct biopsy during ureteroscopy is the most accurate. There are no commonly associated paraneoplastic syndromes or diagnostic serum tumor markers in urothelial carcinoma. A large number of urine markers are currently being studied, but only in situ hybridization studies identifying abnormalities in chromosomes 3, 7, 17, and 9p21 can be recommended at present.
The diagnosis is commonly made on CT urography or intravenous urography and confirmed by retrograde pyelography and ureteroscopy with biopsy. Renal ultrasound or CT scan can be used to rule out calculus. CT scan is also useful in local staging of the tumor. The tumors metastasize to the lungs, liver, and bone, so chest x-ray, CT scan of the lungs and liver, and a bone scan are useful to determine the presence of metastases. Urothelial carcinoma tends to be multifocal in the urinary tract, involving the opposite kidney (1%-2%), ipsilateral ureter, or bladder (38%-50%). Surveillance of these potential sites is important.
Cystoscopy is necessary when gross hematuria is present to determine the location of the bleeding. Lateralizing hematuria can be identified with cystoscopy (bloody efflux from one ureteral orifice). Retrograde pyelography and ureteral cytologic studies or brushing, as described previously, can be useful, though mildly abnormal cytologic findings may occur in patients with upper tract inflammation or calculi. Rigid or flexible ureteroscopes can be used to view the upper ureter and renal pelvis directly. Biopsy of upper tract lesions is possible through these instruments. Although percutaneous approaches to the renal collecting system have been perfected, their use for diagnosis or treatment of suspected urothelial carcinoma in routine cases is not recommended, because of the possibility of spreading tumor cells outside the kidney.
A variety of conditions may mimic transitional cell carcinoma of the renal pelvis, including calculi, sloughed renal papillae, tuberculosis, and RCC with pelvic extension of the tumor. These can usually be ruled out by the diagnostic studies described previously.
Occasionally, bleeding may be severe enough to require immediate nephrectomy. Infection may develop, particularly when there is obstruction and hydronephrosis, requiring prompt use of systemic antibiotics.
Renal urothelial carcinoma is treated by nephroureterectomy (perifascial nephrectomy and removal of the entire ureter, down to and including the ureteral orifice within the bladder). Transureteral or percutaneous endoscopic techniques for resection of selected low-grade lesions have been successful, particularly in patient with significant chronic kidney disease and/or solitary renal units. Upper tract instillation of bacille Calmette-Guérin (BCG) or mitomycin C has been reported with modest results. High recurrence rates and the potential for local tumor spread would argue against this approach in high-grade or extensive lesions. Laparoscopic nephroureterectomy has become common practice, but management of the distal ureter and bladder cuff by this technique has been the subject of controversy. Regional lymph node dissections have not been traditionally performed, although recent reports have shown some benefit for patients with aggressive disease. Because 50% of these patients will develop urothelial carcinoma of the bladder, cystourethroscopy must be performed postoperatively; it is usually done quarterly during the first year, twice the second year, and then annually.
Because most of these tumors are low grade and noninvasive, the 5-year tumor-free survival rate is higher than 90% for lesions treated with complete removal of the ipsilateral upper urinary tract. Survival rates are much lower for lesions that invade the renal parenchyma or are of high histologic grade. A poor prognosis is associated with tumors having histologic features of squamous carcinoma or adenocarcinoma. These tumors are mildly radiosensitive, but preoperative or postoperative radiotherapy has not been particularly helpful. Metastatic lesions are particularly problematic, and survivors are rare. Chemotherapy combinations, which have shown benefit in urothelial carcinoma of the bladder (methotrexate, vinblastine, Adriamycin, and cisplatin [MVAC] or gemcitabine and cisplatin), are also efficacious in urothelial carcinoma of the upper urinary tract.
Ureteral tumors are rarely benign, but benign fibroepithelial polyps do occasionally occur within the ureter. More than 90% of ureteral tumors are urothelial carcinomas. The cause is unknown, but tobacco smoking and exposure to industrial chemicals are known to be associated. Ureteral urothelial carcinoma is often found in association with renal pelvis urothelial carcinoma and slightly less often with bladder urothelial carcinoma. The lesions develop in persons aged 60-70 years and are twice as common in men as in women. More than 60% of these tumors occur in the lower ureter.
Gross or microscopic hematuria is the rule (80% of cases). Because ureteral tumors grow slowly, they may not cause symptoms even though they completely obstruct the kidney. Occasionally, gross hematuria may cause acute obstruction because of clots. The initial presentation may be due to symptomatic metastases to bone, lungs, or liver.
Urinalysis commonly reveals hematuria. There are no biochemical markers specific to the diagnosis, though patients with metastases may have abnormal liver function tests or anemia. Serum creatinine levels may be elevated with complete unilateral obstruction in elderly patients. Cytologic studies of voided urine or ureteral urine or brush biopsy studies may be diagnostic.
The diagnosis may be made on CT or intravenous urography, though the tumor often obstructs the ureter completely, so that cystoscopy and retrograde pyelography are required for definition of the lesion. These studies often reveal a filling defect in the ureter (classically described as a goblet sign). The ureter is dilated proximal to the lesion. CT scan is useful in ruling out nonopaque calculi and in abdominal tumor staging. Chest x-ray, CT scans, and bone scans are helpful in determining the presence of metastases.
Cystoscopy is necessary when gross hematuria is present to determine the site of bleeding. Retrograde pyelography may then be necessary. Ureteroscopy may provide a direct view of the tumor and access for biopsy.
Nonopaque calculi, sloughed renal papillae, blood clots, or extrinsic compression by retroperitoneal masses or nodes may all produce signs, symptoms, and x-ray findings similar to those with ureteral tumors. The radiographic, cytologic, and endourologic studies listed above should make the distinction, but surgical exploration is required occasionally.
Most ureteral transitional cell carcinomas are not associated with metastases and can be definitively treated with nephroureterectomy. Selected patients with noninvasive low-grade lesions may be treated by segmental ureteral resection with end-to-end anastomosis (ureteroureterostomy), or ureteral reimplanation for lesions in the distal one-third of the ureter. In some patients carefully selected with low-grade noninvasive tumors, resection or laser ablation can be considered. Regional lymph node dissections have not been traditionally performed, although recent reports have shown some benefit. Preoperative or postoperative radiation therapy appears to be of no benefit. As with renal pelvis and bladder urothelial carcinoma, cystoscopy should be performed periodically postoperatively. Patients with metastases are rarely helped by removal of the primary tumor. These tumors are responsive to chemotherapy. Traditional agents that have been used include cisplatin with gemcitabine or MVAC. These have shown reasonable response rates but poor long-term outcomes.
The 5-year survival rate for patients with low-grade noninvasive lesions treated surgically approaches 100%. Those with high-grade or invasive lesions have a poorer prognosis, and those with metastases have a 5-year survival rate of less than 10%.
Vesical neoplasms account for nearly 6% of all cancers in men and are the second-most common cancer of the genitourinary tract in men. In women, these tumors account for 2% of all cancers and are the most common cancer of the genitourinary tract. Men are affected twice as often as women. More than 90% of tumors are urothelial carcinomas, while a few are squamous cell carcinomas (associated with chronic inflammation, as in bilharziasis) or adenocarcinomas (often seen at the dome of the bladder in patients with a urachal remnant).
Most urothelial carcinomas (70%-80%) are nonmuscle invasive (not invasive into the bladder detrusor musculature) when recognized. Only 10%-15% of recurrent tumors become invasive.
The cause of urothelial carcinoma is unknown; there is a strong association with chronic cigarette smoking and exposure to chemicals prevalent in dye, rubber, leather, paint, and other chemical industries.
The treatment and prognosis depend entirely on the degree of anaplasia (grade) and the depth of penetration of the bladder wall or beyond (Table 38–2). Most of these tumors develop on the trigone and the adjacent posterolateral wall; thus, ureteral involvement with obstruction is a possibility. Tumors tend to be multifocal within the bladder. Approximately 5% of patients develop upper urinary tract urothelial carcinoma as well.
Table 38–2.Treatment and prognosis of tumors related to stage of disease. ||Download (.pdf) Table 38–2. Treatment and prognosis of tumors related to stage of disease.
|Conventional Stage ||TNM Stage ||Tumor Involvement ||Treatment ||Five-Year Survival (%) |
|O ||Ta ||Mucosa only ||Transurethral resection ||85-90 |
|A ||T1 ||Submucosal invasion (lamina propria) ||Transurethral resection and intravesical chemoimmunotherapy ||60-80 |
Superficial muscle invasion
Deep muscle invasion
Perivesical fat invasion
|Total cystectomy and pelvic lymphadenectomy || |
Regional lymph node invasion
|Systemic chemotherapy || |
Gross or microscopic hematuria is a common finding that leads to the diagnosis. Patients with diffuse noninvasive tumors, particularly carcinoma in situ, may have urinary frequency and urgency. Occasionally, large necrotic tumors become secondarily infected, and patients exhibit symptoms of cystitis. Pain secondary to clot retention, tumor extension into the bony pelvis, or ureteral obstruction may occur but are not frequent presenting complaints. When both ureters are obstructed, azotemia with attendant secondary symptoms may be the finding that requires diagnostic studies.
External physical examination is not generally revealing, though occasionally a suprapubic mass may be palpable. Rectal examination may reveal large tumors, particularly when they have invaded the pelvic sidewalls. Thus, bimanual examination is a necessary part of staging evaluation.
Microscopic hematuria is the only consistent diagnostic finding. Patients with bilateral ureteral obstruction may have azotemia and anemia. Liver metastases may cause elevation of serum transaminases and alkaline phosphatase. There are no paraneoplastic syndromes or tumor markers consistently present in patients with urothelial carcinoma. Urinary markers currently being studied are various tumor-associated antigens, growth factors, and nuclear matrix proteins, but none are proved to be accurate enough to obviate cystoscopy for diagnosis.
Small bladder tumors are not seen on intravenous urography but may be seen on CT. Larger tumors usually produce filling defects in the bladder on both urography or CT (Figure 38–13). Ureteral obstruction with hydroureteronephrosis may occur as well. Invasion of the bladder wall may be predicted in patients with asymmetry or marked irregularity of the bladder wall. Noninvasive lesions seen on CT or intravenous urography tend to be exophytic within the bladder, without evidence of bladder wall distortion.
Noncontrast CT scan showing space-occupying lesion (transitional cell carcinoma) on the posteroinferior of the bladder (arrow).
Ultrasonography by external, transrectal, or transurethral routes can accurately define moderate-sized bladder tumors and can often depict deep invasion.
CT scan can be useful for staging, but the depth of bladder wall penetration and delineation of tumor deposits in adjacent nonenlarged lymph nodes are not accurately defined. In patients with nodal metastases suspected on CT scans, fine-needle aspiration and cytologic studies may confirm the diagnosis and eliminate the need for surgical exploration. MRI is helpful in the pelvis, where motion artifacts are minor and the scant pelvic fat is just enough to provide organ differentiation. However, the information is not superior to that obtained with CT.
D. Urinary Cytologic Studies
Urothelial tumors shed neoplastic cells into the urine in large numbers. Low-grade tumor cells may not appear abnormal on cytologic examination, but higher-grade tumor cells can be detected by cytologic study with high specificity. These studies are most useful in checking for recurrence of urothelial carcinoma. Flow cytometry (differential staining of DNA and RNA within urine cells to measure the amount of nuclear protein and thus the relative number of aneuploid [abnormal] cells) has been used to screen patients with some success. This technique may be useful for early diagnosis of recurrence. The urinary fluorescence in situ hybridization assay is more sensitive and comparably specific for bladder cancer cells as compared to cytology.
Cystoscopy is mandatory in any adult patient with unexplained hematuria and a normal upper-tract imaging study. Many urothelial carcinomas are not identified on CT or intravenous urography. Cystoscopic examination should detect nearly all tumors in the bladder (Figure 38–14). Only a few patients will have carcinoma in situ (high-grade noninvasive tumor) that is not visible. Any tumor seen should be biopsied and preferably resected to completion if the patient is under anesthesia. The entire bladder, including the bladder neck, should be routinely scrutinized in all patients with microscopic hematuria. In patients without visible tumor and no other causes of hematuria, random biopsies may be diagnostic of carcinoma in situ. A bimanual examination should be done during cystoscopy in all patients with urothelial carcinoma to be certain that the bladder is not fixed, signifying extensive extravesical extension.
Transitional cell (papillary) carcinoma of the bladder with minimal invasion of the bladder wall.
Therapy depends on the stage of the tumor as seen on histologic sections and examinations for metastases. Table 38–2 sets forth the stage, treatment, and prognosis of patients with urothelial carcinoma of the bladder. The histologic grade of the tumor is also important in determining treatment and prognosis, but in general, low- and high-grade histologic characteristics tend to occur in low- and high-stage tumors, respectively.
As previously discussed, CT scan, MRI, or both may be helpful in predicting the stage of the tumor. Isotope bone scanning, chest x-ray, and chest CT scan evaluate the possibility of bone or pulmonary metastases and should be done before determining therapy in patients with invasive lesions.
A. Transurethral Resection, Fulguration, and Laser Therapy
Endoscopic transurethral resection of superficial and submucosally invasive low-grade tumors can be curative. Nevertheless, because the tumor recurs in more than 50% of patients, cystoscopy should be performed periodically. Quarterly examinations are recommended during the first year following tumor resection, every 6 months during the second year, and annually thereafter. Periodic urinary cytologic examinations can be helpful as well. Upper tract surveillance with CT urography is recommended for high-grade tumors, typically every 2 years. Low-grade tumors do not require upper tract surveillance unless hematuria recurs without evidence for tumor recurrence in the bladder. Recurrent small tumors without obvious invasion may be treated by fulguration only, though biopsy is recommended to document the stage and grade.
Neodymium:YAG lasers have been used for desiccation of low-grade, low-stage tumors. There is as yet no proven advantage to this approach except that patients can be treated under local anesthesia as outpatients and perhaps that tumor cells are rendered nonviable and thus incapable of reimplantation elsewhere in the bladder or urethra. Biopsies for diagnosis and staging are still required.
A variety of chemotherapeutic agents have been used in patients with recurrent low-grade, low-stage tumors. Mitomycin C is instilled into the bladder by catheter (40 mg in 40 mL of water) and left indwelling for 1-2 hours. Patients are treated once a week for 6 weeks and may undergo a less frequent maintenance regimen. Treatment results in decreased frequency of recurrence or no recurrence in nearly 50% of patients. Other agents include thiotepa and doxorubicin.
Immunotherapeutic drugs, which include BCG, are effective in prophylaxis (60%) of recurrent papillary tumors and curative (70%) in carcinoma in situ, a highly malignant lesion less responsive to the cytotoxic agents described earlier. Intravesical BCG is the gold-standard first line therapy for carcinoma in situ of the bladder. Side effects of BCG include vesical irritability (90%), low-grade fever, and systemic BCG-osis (1%). Although the mechanism of action of BCG is not entirely known, it is suspected to induce T-cell recruitment and subsequent cytokine release locally at the tumor site. It is the most effective agent currently used. Interferon alpha has also been studied and is effective (nearly 50% of cases) for carcinoma in situ, with less toxicity than BCG; however, its durability as a single agent is poor. The combination of BCG and interferon alpha has shown nearly 50% response rates and is occasionally used in patients who have failed BCG. BCG is contraindicated in immunocompromised patients due to risk of systemic BCG infection and the likely decreased efficacy.
Immediate instillation of Mitomycin C after transurethral resection has shown a substantial decrease in recurrence rates and is now standard of care.
Definitive radiation therapy should be reserved for patients who have inoperable muscle-invasive bladder cancer localized to the pelvis or who refuse surgical treatment, as the 5-year survival rate is only 30%. In some patients with recurrence after radiation therapy, salvage cystectomy can be curative (in at least 30% of cases), though surgical morbidity rates are high. Radiation, when used, is combined with systemic chemotherapy.
Occasional patients are seen with muscle-invasive lesions (T2) localized to an area in the bladder well away from the bladder base or orifices and without tumor in other sites of the bladder (proved by multiple biopsies) or beyond. Partial cystectomy (removal of the tumor with a cuff of normal bladder) may be appropriate in these patients. Such tumors are rare, and patients must be selected carefully for partial cystectomy. All other patients with high-grade or invasive (T2 and T3) lesions without distant spread or a fixed pelvis on bimanual examination are best treated by radical cystectomy and pelvic lymph node dissection. This includes removal of the bladder and the prostate in men. Removal of the entire urethra may be necessary in selected patients with tumors at the bladder neck or in the prostate or in those with diffuse carcinoma in situ in the bladder. In women, the uterus, ovaries, fallopian tubes, urethra, and the anterior vaginal wall are usually removed en bloc with the bladder. Vaginal-sparing cystectomy can be performed as well.
Urinary diversion is required and is accomplished with the use of intestinal conduits, pouches or neobladders. Ileal conduit urinary diversion creates a urostomy on the skin and requires continuous bag drainage. This is the most common urinary diversion with the lowest complication rates. Continent cutaneous urinary diversions requiring intermittent cutaneous catheterization rather than cutaneous bag drainage became popular in the late 1980s. The basic principles are large-volume reservoirs with detubularization of bowel to maintain low intrapouch pressures and construction of an intussuscepted or plicated ileal segment to provide cutaneous continence. Orthotopic neobladder reservoirs also have been devised using bowel configurations similar to those described above to connect directly to the membranous urethra in men and in the distal two thirds of the female urethra, permitting the patient to void normally. These procedures are appropriate in both men and women and have been shown to be safe, with minimal increase in morbidity over cutaneous diversions.
Robotic cystectomy has been done in large numbers at select centers in the United States and Europe. With short-term follow up, oncologic outcomes appear equivalent to open surgery with potentially less blood loss and faster convalescence postoperatively. In most cases, the urinary diversion is done via open surgery, but more recently, ileal conduit and neobladder urinary diversions have been performed intracorporeally with robotic assistance.
Chemotherapy in the form of CMV (cisplatin, methotrexate, and vinblastine) or MVAC (CMV plus doxorubicin [Adriamycin]) has been used precystectomy (neoadjuvant) or postcystectomy (adjuvant) for muscle-invasive tumors or as treatment of metastatic urothelial cancer. More recently, gemcitabine and cisplatin have become standard of care after a randomized trial showed similar efficacy to MVAC with fewer side effects. A recent randomized trial showed improved survival in patients with locally advanced bladder cancer who received neoadjuvant chemotherapy and cystectomy compared to those who underwent cystectomy alone. Adjuvant chemotherapy has been shown in randomized trials to help patients with locoregional disease but not patients with localized disease (stage T1-T2). Several reports of efficacy with either CMV or MVAC for treatment of metastatic disease have shown a 60% overall objective response rate with a 30% complete response rate. A few long-term survivors with apparent cure have been reported (10%-15%), and either of these regimens thus appears to be a definite advance in the treatment of urothelial cancer. Other chemotherapeutic agents used in urothelial cancer include paclitaxel and carboplatin in various regimens that appear to have similar efficacy with less toxicity.
Approximately half of the low-grade superficial tumors are controlled by transurethral surgery or intracavitary use of chemotherapeutic agents (Table 38–2). Following radical cystectomy, the 5-year survival rate varies with the extent, stage, and grade of the tumor, but with T2N0M0 tumors averages about 50%-70%. The complications of urinary diversion (ureteral obstruction with hydronephrosis, pyelonephritis, and nephrolithiasis) also influence the outcome.
CARCINOMA OF THE PROSTATE
In adult men, prostate cancer is the most common neoplasm (after skin cancer) and the second-most common (after lung cancer) cause of death due to cancer. The tumor is more prevalent in black men than in any other group in the United States. The tumor rarely occurs before age 40, and the incidence increases with age such that more than 75% of men older than age 85 have prostate cancer on autopsy. In most of these older men, however, the disease is not clinically apparent; only 10% of men over age 65 develop clinical evidence of the disease. Ninety-five percent of tumors are adenocarcinomas. The tumor arises primarily in the peripheral zone (85%), an area that differs in embryologic derivation from the periurethral (transition) zone, which is the site of formation of benign prostatic hyperplasia. The cause of prostate cancer is unknown, but many factors appear to be involved, including genetic, hormonal, dietary (particular high-fat diets), and perhaps environmental carcinogenic influences.
Screening with PSA monitoring and digital rectal examination (DRE) has been controversial due to conflicting evidence regarding a decrease in mortality. Two very large randomized controlled trials examining the effects of PSA screening on mortality have recently been completed, one in the United States and one in Europe. The US trial did not show a survival benefit in the screening group, although the control group was significant contaminated with men who had some previous PSA testing. The European study showed a relative survival benefit of 20% in the screening group after 10 years of follow-up, and the data will be reanalyzed with longer follow-up.
Based on all available evidence, the US Preventive Services Task Force released a recommendation against routine screening for prostate cancer in 2011. The American Urological Association recommends a shared decision making discussion about prostate cancer screening with men between the ages 55-69, and at a younger age for those men with a positive family history in a first degree relative or for African Americans. If screening is agreed upon, serum PSA level and DRE are performed annually or every two years based on the clinician’s discretion.
Nonpalpable (T1) carcinoma of the prostate presents without physical signs and is only diagnosed by the pathologist when prostate tissue is removed as treatment for symptomatic bladder outlet obstruction presumed to be caused by benign prostatic hyperplasia or is found by an elevated PSA (T1c). Patients T2 or higher disease have a hard nodule on the prostate that can be felt during rectal examination (Table 38–3). T3 disease is palpable (or visible by imaging) beyond the capsule of the prostate or demonstrates seminal vesicle involvement. T4 disease invades adjacent organs including the rectum and pelvic sidewall. Previously, 50% of patients presented with evidence of metastases, including weight loss, anemia, bone pain (commonly in the lumbosacral area), or acute neurologic deficit in the lower limbs. Today, however, fewer than 20% of patients present in this way because of earlier diagnosis due to wide use of PSA screening (stage migration).
Table 38–3.Treatment and prognosis of prostate cancer related to tumor stage. ||Download (.pdf) Table 38–3. Treatment and prognosis of prostate cancer related to tumor stage.
|Conventional Stage ||TNM Stage 1997 ||Clinical Findings ||Treatment ||Fifteen-Year Recurrence-Free Survival (%) |
|A1 ||T1a ||Nonpalpable tumor; incidental finding at transurethral prostatectomy (low-grade cancer seen in < 5% of prostate) ||Observation ||100 |
|A2 ||T1b ||Same as above except tumor is high-grade, or > 5% of prostate is involved, or both ||Radical prostatectomy with pelvic lymphadenectomy ||70-80 |
|B1 ||T2a ||Tumor involves one lobe or less ||External beam radiation ||85 |
|B2 ||T2b ||Tumor involves more than one lobe ||Brachytherapy ||60-70 |
|C ||T3a ||Unilateral extraprostatic extension ||Radiation with or without pelvic lymphadenectomy ||20-60 |
|C2 || |
Bilateral extraprostatic extension
Seminal vesicle invasion
Invades bladder neck or rectum
Invades levator muscle and/or fixed to pelvic sidewall
Hormonal therapy (orchiectomy or LHRH/antiandrogen) when symptomatic
Irradiation for isolated bone pain
|D ||N+ or M+ ||Pelvic lymph node involvement or distant metastases || |
Hormonal therapy (orchiectomy or LHRH/antiandrogen) when symptomatic
Irradiation for isolated bone pain
Patients with extensive metastases may have anemia due to bone marrow replacement by tumor. Those with bilateral ureteral obstruction secondary to trigonal compression by tumor may exhibit azotemia and uremia. Serum alkaline phosphatase is often elevated in patients with bone metastases but not in those with localized disease.
PSA is elevated in the serum of most men with prostate cancer, but high-grade (Gleason 8-10) cancers and ductal variant adenocarcinomas can present with normal PSA levels. Values above 4 ng/mL are considered abnormal but rise normally with age and significant benign prostatic hypertrophy. PSA can also be falsely elevated due to cystoscopy, prostate biopsy, urethral catheterization, and urinary tract infection. Routine DRE does not usually affect PSA levels.
Methods for enhancing PSA specificity include the following: (1) age-specific PSA (younger men [< age 50 years], normal < 2.5 ng/mL; older men [> age 70 years], normal > 6.5 ng/mL); (2) PSA density (PSA divided by prostate volume), where less than 0.15 ng/mL suggests cancer; (3) percent-free PSA (total PSA minus complexed PSA), where lower values signify an increased risk of cancer (useful for total PSA levels between 4 and 10). While total PSA is useful for staging, it is not absolute. PSA appears to be most helpful in following up on patients after treatment, as levels fall to undetectable after surgery and decrease dramatically after radiation therapy when there is a complete response. There are several new prostate cancer markers currently being investigated, but none have become widely used to date. PCA3 urinary assay shows promise in men with persistently elevated PSA levels and previous negative biopsies.
Transrectal ultrasound has become very useful for evaluating prostate volume and guiding biopsy needles into the peripheral zone and other specific areas, such as the base, the apex, and the transition zone of the prostate. The study can also reveal typical hypoechoic peripheral zone lesions in 70% of patients with palpable lesions. Because many prostate cancers are not hypoechoic and not all hypoechoic lesions are cancer, transrectal ultrasound alone for screening for prostate cancer is not recommended. CT scan may reveal urinary retention, distal ureteral obstruction with resultant hydronephrosis, and pelvic lymphadenopathy. Locally advanced disease and bony metastases can also be visualized on CT scan. A chest x-ray or CT may help in identifying the uncommon lung metastases but more often shows typical osteoblastic metastases in the thoracic spine or ribs. An abdominal x-ray may reveal metastases in the lumbosacral spine or ilium. Abdominopelvic CT is not usually recommended unless the disease is palpable, Gleason score is 7 or more, or PSA level is more than 20 ng/mL.
Endorectal MRI (eMRI) appears to be more helpful than CT scan in the staging of prostate cancer. This study allows for localization of malignant lesions within the prostate as well as assessment for extracapsular extension, seminal vesical invasion, involvement of adjacent organs, and lymph node involvement. eMRI is useful for clinical staging and preoperative planning but is reliant upon having a radiologist with expertise in this field.
Positron emission tomography is not typically utilized for prostate cancer staging.
The diagnosis is established by transrectal ultrasound–guided biopsies in most instances. Because the great majority of patients have biopsies due to an elevated serum PSA (stage T1c) and no abnormal findings on exam or imaging, biopsies of the base, middle, and apex of the prostate—concentrating on the peripheral zone, with 6 biopsies per side of the prostate—are required for accurate diagnosis.
Differentiation of the tumor is graded by the pathologist using the Gleason score, which assigns a grade of 1-5 (low to high grade) for both the primary and secondary forms of the tumor. The two numbers are added, and the cancer can thus be Gleason sum 2-10, with 10 being the most poorly differentiated cancer. Gleason score is an independent predictor of disease recurrence. Typically, pathologists give Gleason scores between 6 and 10.
Rectal examination can provide initial staging in patients with palpable tumors (Table 38–3). Needle biopsy is confirmatory, and histologic grading (Gleason score) can fairly accurately predict the metastatic potential of the tumor. Imaging as described above can be useful for staging of the primary tumor (eMRI) and to rule out metastatic disease (eMRI, bone scan).
Nodules caused by benign prostatic hyperplasia may be difficult to distinguish from cancer; benign nodules are usually rubbery, whereas cancerous nodules have a much harder consistency. Fibrosis following a prior prostatectomy for benign disease or secondary to chronic prostatitis or prior biopsies may be associated with lesions indistinguishable from cancerous nodules and require biopsy for definition. Occasionally, phleboliths or prostatic calculi on the surface of the prostate may be confusing; however, transrectal ultrasound can be helpful in the differentiation and for biopsy guidance.
Curative treatment for localized prostate cancer includes radical prostatectomy and various forms of radiation therapy (external beam radiation therapy, transperineal radioactive seed placement [brachytherapy with 125I, 103Pd, or 192Ir], and cyberknife). Complete staging is important so that appropriate candidates will be selected. Patients with localized prostate cancer are stratified into three risk groups (Table 38–4). Low-risk patients have similar 5-year recurrence survival rates irrespective of the curative treatment modality. Intermediate-risk and high-risk patients have better recurrence-free rates with prostatectomy or external beam radiation compared to brachytherapy. None of these modalities have been compared in randomized trials. The only reported randomized trial compared watchful waiting to radical prostatectomy and showed improved disease-free as well as overall survival in the prostatectomy group. Studies have shown that compared to external beam radiotherapy alone, combined androgen deprivation (for 6 months to 3 years) and external beam radiation improve survival in patients with localized prostate cancer, especially patients in the intermediate and high-risk groups. Patients with grossly positive pelvic lymph nodes are not candidates for curative therapy. Recent advances in surgical technique have led to a low incidence of incontinence (1%-4%) and preservation of potency in up to 70% of patients. Alternative procedures include external beam pelvic irradiation plus brachytherapy and transperineal cryoablation of the prostate for primary and recurrent disease after radiation.
Table 38–4.Localized prostate cancer risk groups. ||Download (.pdf) Table 38–4. Localized prostate cancer risk groups.
|Low risk || |
PSA ≤10 ng/mL
Clinical stage T1c-T2a
Gleason score 2-6
|Intermediate risk || |
PSA 10-20 ng/mL
Clinical stage T2b
Gleason score 7
|High risk || |
PSA >20 ng/mL
Clinical stage ≥T2c
For the past decade, robotic-assisted radical prostatectomy has increased in popularity and has been shown to have decreased blood loss and length of hospital stay and more rapid return to normal activity than open surgery. Oncological and functional (continence and potency) outcomes are equivalent to open surgery. More than 80% of prostatectomies in the United States are now performed with the da Vinci™ Robot.
Patients with metastatic disease cannot be cured, but significant palliation can be offered. Androgen deprivation therapy in the form of luteinizing hormone–releasing hormone (LHRH agonist or bilateral orchiectomy) is effective in 70%-80% of symptomatic patients. Estrogen-based treatments are less commonly used due to the numerous side effects (in about 25% of patients), including congestive heart failure, thrombophlebitis, and myocardial infarction, and thus should not be used except in selected patients. These hormonal treatments are not additive, and use of both treatments simultaneously has no advantages over use of either alone. LHRH agonists have shown efficacy comparable to that of estrogen or orchiectomy, with reduced side effects, and are preferred by patients who find bilateral orchiectomy unacceptable. The drug must be given by injection every 1-6 months (depending on dosage) or via subcutaneous pellet annually. Studies have also shown that if an LHRH agonist is used, concomitant administration of an antiandrogen (flutamide or bicalutamide) may slightly improve survival. Studies to determine if orchiectomy plus an antiandrogen is more effective than orchiectomy alone have not shown an advantage to the combination. Antiandrogens should be administered for at least one week prior to inception of LHRH agonists to prevent the short-term flare that occurs with initiation of LHRH monotherapy. LHRH antagonists have more recently become available and have a faster onset to castration, and do not require pre-treatment with antiandrogens.
Hot flashes, osteoporosis, cardiac disease, and cognitive impairment are all potential long-term side effect of androgen deprivation.
Controversy continues concerning whether to treat asymptomatic patients at the time of diagnosis or to wait until symptoms develop. Because either approach is palliative only and there are no definitive studies showing survival advantages with early treatment, it is recommended that treatment be withheld until PSA is relatively high (> 20 ng/mL) or symptoms occur except in patients who cannot accept a no-treatment philosophy. Recent studies do show that patients who have had a radical prostatectomy and have node-positive disease do have a slight survival advantage with early hormonal treatment.
Patients whose prostate cancer becomes hormone refractory (median of 18 months after starting treatment) can be treated by ketoconazole (which inhibits adrenal androgen production) with oral corticosteroids for short-term response. Radiation therapy for symptomatic bone lesions can be helpful, as can local irradiation for an obstructing or bleeding prostate tumor. On occasion, transurethral prostatectomy is required to relieve bladder outlet obstruction. Chemotherapy with docetaxel and prednisone has shown a slight survival advantage in phase III trials.
Prostate Cancer Prevention
Because the etiology of prostate cancer is not known, prevention is difficult to determine. However, there is evidence that a low-fat diet and lycopene (found in processed tomatoes) decrease the growth of prostate cancer cells in vitro and in vivo in animals. Further large-scale epidemiologic studies suggest a decrease in prostate cancer in humans who consumed vitamin E and selenium. However, these studies were not planned specifically for this purpose, and thus the results were questionable. A current randomized trial comparing selenium and vitamin E (SELECT) was recently halted due to the lack of evidence of prostate cancer prevention. The largest chemoprevention trial (Prostate Cancer Prevention Trial [PCPT]), with over 18,000 men, compared finasteride (5α-reductase) to placebo and found a 25% reduction in prostate cancer with finasteride but also showed an increased risk of high-grade cancer in the finasteride-treated patients. While this is thought to be an artifact of the study, these results have limited enthusiasm for recommending prevention therapy with finasteride routinely.
Radical prostatectomy cures 70%-80% of the patients suitable for that operation, but its use should be limited to those with a reasonable life expectancy (Table 38–3). Currently, about 60%-70% of patients with prostatic cancer are amenable to curative therapy when their disease is discovered.
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Malignant tumors of the urethra are rare. The disease is more common in women than in men (4:1). Squamous cell types are seen most often in both sexes.
In women, urethral bleeding is the most common symptom. Distal urethral lesions of low grade and without extension can be treated by radiotherapy or wide local excision. Advanced disease is best treated by combination radiotherapy, chemotherapy, and surgery to achieve good local and distant disease control. Surgery includes anterior exenteration (removal of the bladder, uterus, adnexa, and urethra with the anterior vaginal wall), including pelvic lymphadenectomy and urinary diversion. The prognosis is excellent for distal lesions without extension, but 5-year survival rates are less than 50% for those with proximal lesions.
In men, the lesion is most commonly in the bulbomembranous urethra and is associated with a history of chronic urethral strictures, often secondary to gonorrheal infection. Patients present with urethral bleeding, a weak urinary stream, and a perineal mass. The diagnosis is made by urethroscopy and biopsy. Distal penile urethral lesions can be treated by partial or total penectomy. Lesions in the bulbous urethra or more proximal lesions require extensive surgical resection, including en bloc removal of the penis, urethra, prostate, bladder, pelvic lymph nodes, and urinary diversion. In both men and women with distal lesions, inguinal lymphatics may be involved, but node dissection is required only when gross disease is palpable. Prophylactic node dissection is controversial. Five-year survival rates are 60% for distal urethral tumors but less than 40% for the more common proximal lesions.
Primary irradiation—other than to distal lesions in the female—is rarely helpful. Patients with metastatic disease may respond to methotrexate or cisplatin alone or in combination, but objective remissions are usually of short duration.
Most testicular tumors are malignant germ-cell tumors. Non–germ-cell tumors such as Sertoli cell tumors and Leydig cell tumors are rare and usually benign. Germ-cell tumors are categorized as either seminomatous (35%) or nonseminomatous (embryonal, 20%; teratocarcinoma, 38%; teratoma, 5%; and choriocarcinoma, 2%). Cryptorchidism predisposes to testicular cancer, with the incidence increasing inversely with the level of testicular descent (ie, testicles remaining in the abdomen have a much higher incidence of cancer). Metastases first develop in the retroperitoneal nodes; right-sided tumors metastasize primarily to the interaortocaval region just below the renal vessels and left-sided tumors primarily to the left para-aortic area at the same level. Distant spread is to supraclavicular areas (left, primarily) and the lungs. Almost 50% of patients have metastases when first evaluated, and this is more common for nonseminomatous tumors.
Testicular tumors present as a painless firm mass within the testicular substance. They often have been present for several months before the patient seeks consultation. Occasionally (10%), a hydrocele is present, obscuring palpation of the mass. A few patients have spontaneous bleeding into the mass, causing pain. Patients with high serum levels of hCG may have gynecomastia. Patients with extensive abdominal metastases may present with abdominal pain, anorexia, and weight loss. Examination may reveal palpable retroperitoneal nodes when spread is extensive or palpable supraclavicular nodes, particularly on the left side.
In general, testicular tumors do not alter the usual laboratory parameters, but serum tumor markers are diagnostically helpful. Patients with extensive retroperitoneal metastases may have bilateral ureteral obstruction that causes azotemia and anemia.
Serum lactic dehydrogenase, particularly isoenzyme I, is elevated in approximately 60% of patients. β-HCG, a particularly sensitive marker, is a glycoprotein produced by 65% of nonseminomatous testicular tumors but only 10% of seminomas. The alpha-subunit of the molecule is identical to LH, but the beta-subunit is unique to testicular tumors in adult men. There is cross-reactivity in some assays between the alpha- and beta-subunits; treated patients who develop modest elevations should have simultaneous assay of LH to be certain the marker detected is β-hCG.
α-Fetoprotein is elevated in 70% of patients with nonseminomatous testicular cancer but is not elevated in patients with seminoma. Patients in whom histologic study has shown seminoma but in whom serum AFP is elevated should be suspected of having nonseminomatous elements in the primary specimen or metastatic lesions.
Approximately 85% of patients demonstrate elevation of one of these markers at presentation. Serum levels decrease when the tumor is completely removed or regresses. Markers are used mainly to follow tumor regression or predict recrudescence, as even minute amounts of tumor may cause serum elevations; however, tumor may be present without elevation of serum markers.
Abdominal CT scan defines enlarged lymph nodes in approximately 90% of cases when they are present. Chest x-ray and CT scan will detect most pulmonary metastases.
Scrotal ultrasound is useful for identifying the typical hypoechoic lesion in the testicle. Regardless of the findings on ultrasound, however, a young man with an intratesticular mass on palpation requires surgical definition of the mass.
Testicular masses in men aged 18-40 are frequently malignant and should be treated accordingly. Confusion can occur with scrotal hydroceles, cord hydroceles, epididymal masses or cysts, or epididymitis. Most of these can be differentiated from masses within the testicle by palpation, but if not, scrotal ultrasound is usually helpful.
Table 38–5.Treatment and prognosis of testicular cancer related to tumor stage. ||Download (.pdf) Table 38–5. Treatment and prognosis of testicular cancer related to tumor stage.
|Conventional Stage ||TNM Stage ||Clinical Findings ||Treatment ||Five-Year Survival (%) |
|I ||T1 ||Confined to testicle ||Nonseminoma: RPLND vs. surveillance; Seminoma: irradiation ||>95 |
|IIA ||N1 ||Regional nodes < 2 cm || |
Nonseminoma: RPLND or chemotherapy; Seminoma: XRT or chemotherapy
|IIB ||N2 ||Nodes 2-5 cm || |
Nonseminoma; RPLND or adjuvant chemotherapy; Seminoma: XRT or chemotherapy
Nodes > 5 cm
|Chemotherapy followed by resection of residual disease ||~70 |
Inguinal orchiectomy with high ligation of the cord at the internal ring is proper initial treatment for all subtypes of testicular cancer. Rarely is incisional biopsy of the testicle advisable. Recommendations for further therapy (retroperitoneal node dissection, chemotherapy, radiation therapy) are then based on the pathologic findings. A staging workup, including postoperative measurement of serum markers, chest x-ray, and chest and abdominal CT scan, is conducted to determine the extent of disease.
A. Nonseminomatous Tumors
Following orchiectomy, three management options are available: (i) active surveillance, (ii) retroperitoneal lymph node dissection (RPLND), and (iii) systemic chemotherapy. Treatment is based on clinical staging and pathology from the orchiectomy specimen. Patients with no evidence of metastatic disease on imaging and normal serum tumor markers postorchiectomy are candidates for close surveillance with the knowledge that about 20% will relapse and require salvage therapy. This strategy avoids the adverse effects of RPLND and/or systemic chemotherapy. Surveillance, however, is rigorous and should only be offered to motivated and reliable patients.
RPLND is recommended for clinical stage I patients (no evidence of metastatic disease on imaging) or for those with retroperitoneal lymphadenopathy that is not bulky (stage IIA-IIB). The extent of lymphadenectomy depends on the testicle involved but in general includes para-aortic and paracaval nodes from the renal vessels down to the aortic bifurcation and along the external iliac artery to the internal inguinal ring on the involved side. Adverse effects of RPLND include severe hemorrhage from vascular injury to the vena cava, aorta or major branches, chylous ascites, loss of seminal emission, and damage to surrounding structures. If necessary, adjacent organs involved are removed en bloc with the lymph node tissue (eg, nephrectomy). Seminal emission can be preserved with modified templates or nerve sparing techniques that prospectively identify and preserve the sympathetic fibers that coalesce near the bifurcation of the aorta.
Patients with any nonseminomatous cell type who have extensive retroperitoneal or chest metastases are best treated after orchiectomy by multiagent chemotherapy—typically bleomycin, etoposide, and cisplatin. Residual masses postchemotherapy are surgically excised. Combination chemotherapy with bleomycin, etoposide, and cisplatin achieves over a 90% cure rate in stage II patients and a 70% cure rate in stage III patients. Patients who do not respond may be treated with ifosfamide, doxorubicin, or both, with some expectation of success.
In the absence of extensive distant spread, patients with pure seminoma should be treated with external beam radiation therapy (2500 cGy) to the retroperitoneum following orchiectomy. A recent study showed that one cycle of carboplatin is equivalent to radiation therapy for stage I seminoma. In the presence of bulky abdominal disease or more distant metastases, survival rates are better with multiagent chemotherapy (described earlier) given initially in lieu of radiation therapy. Patients with substantial residual retroperitoneal tumor (> 3 cm) after chemotherapy may benefit from surgical removal of the remaining tumor.
Even in the presence of metastases, many of these patients can be cured, with overall survival rates more than 90%. The only exception is patients with pure choriocarcinoma, who still have a poor survival rate (35% at 5 years) despite extensive chemotherapy.
Cancer of the penis is a rare disease occurring in the fifth to sixth decades. The cause is uncertain. The disease is rarely seen in circumcised men. The lesion commonly is on the glans penis or foreskin. Early cases may exhibit a painless red, velvety lesion, but most often the lesion is an exophytic nodular or wart-like growth with secondary infection. The initial diagnosis is made by a generous incisional biopsy of the lesion, which reveals squamous cell carcinoma in over 95% of cases. The tumors tend to metastasize to superficial or deep inguinal nodes, though the attendant infection may cause enlarged, tender nodes, which may be difficult to differentiate from metastatic cancer.
The differential diagnosis includes syphilitic chancre, soft chancre due to Haemophilus ducreyi infection, and simple or giant condyloma. Biopsy usually differentiates among these conditions.
Small, noninfiltrating lesions (carcinoma in situ) can be treated with fluorouracil cream, external beam radiation, or laser therapy. However, close follow-up is mandatory in patients so treated. Larger lesions not involving deep structures that are limited to the distal penis are treated by partial penile amputation at least 2 cm proximal to the lesion, leaving enough of the penis for adequate direction of the urinary stream. Deeply infiltrating and proximal lesions require total penectomy, with formation of a perineal urethrostomy.
Patients with high-risk features (high T stage, high grade, or presence of lymphovascular invasion) are at risk of inguinal nodal metastases. Prophylactic node dissection has been associated with improved survival.
Palpable inguinal nodes should be treated with antibiotics for 6 weeks following treatment of the primary lesion to eliminate infection. Persistently palpable nodes require bilateral ilioinguinal lymphadenectomy. An alternative would be fine-needle aspiration of the palpable nodes and node dissection if positive for metastases. Even those who undergo delayed node dissection when the nodes become palpable can be cured, though this is a lower percentage. Radiation therapy for palpable nodes or as prophylaxis for nonpalpable nodes has been occasionally effective, but mostly in the palliative setting.
Patients with distant metastases (to the pelvic nodes, lungs, or bone) have a poor prognosis, though cisplatin and methotrexate have shown objective but not durable responses. Five-year survival rates for patients with noninvasive lesions localized to the penis are 80%; for those with inguinal node involvement, 50%; and for those with distant metastases, nil.
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