TUMORS OF THE RENAL PELVIS AND URETER
A vast majority of the tumors that originate in the renal pelvis and ureter develop from urothelial cells, which line the renal calices, ureters, and bladder. Urothelial carcinomas (also known as transitional cell carcinomas) of the upper urinary tract represent less than 10% of all renal tumors and only 5% of all urothelial carcinomas.
Approximately 5% of ureteral tumors are in the proximal ureter, 25% are in the midureter, and 70% are in the distal ureter. Moreover, patients with an upper tract tumor are much more likely to develop a bladder tumor than vice versa. The reason for this apparent downstream effect is not clear; however, it has been hypothesized to reﬂect downstream seeding or longer exposure of bladder urothelium to carcinogens.
Upper tract urothelial carcinomas tumors occur on average in the seventh decade. Men and Caucasians are twice as likely to develop these tumors as women and African Americans.
Several genetic and environmental risk factors are known. Many are shared with urothelial carcinoma of the bladder, including cigarette smoking, aromatic amine (e.g., aniline) exposure, cyclophosphamide exposure, and mutations in certain genes (e.g., TP53 and RB).
Other factors, however, appear to increase the risk of upper tract carcinomas in particular. Phenacetin abuse, for example, has been associated not only with analgesic nephropathy (see Plate 4-30) but also with upper tract urothelial carcinomas. In addition, the interstitial nephropathy known as Balkan nephropathy (seen primarily in populations near the Danube River and its tributaries) increases the risk of upper tract urothelial carcinomas. Finally, hereditary nonpolyposis colorectal cancer (HNPCC, or Lynch syndrome) is an autosomal dominant condition characterized by altered DNA mismatch repair genes (MLH1, MSH2, MSH6) and increased risk of cancer in the stomach, small intestine, colon, liver, endometrium, ovary, and upper urinary tract (urothelial type).
PRESENTATION AND DIAGNOSIS
The major presenting symptom of an upper tract urothelial carcinoma is gross or microscopic hematuria. If there is obstruction of the ureter, dull ﬂank pain may also occur.
Patients suspected of having upper tract malignancies should be evaluated using contrast-enhanced CT, which may reveal a visible mass or ﬁlling defect on delayed urographic phase. If there is a chronic obstruction to urine outﬂow, dilation of the renal pelvis and ureter may be seen, depending on the level of the mass.
The presence of regional extension or metastases may also be assessed using various radiographic modalities. Urothelial carcinomas of the upper tract, like those of the bladder, may metastasize to lymph nodes, liver, lung, and bone. CT can be used to assess for the presence of abdominal or pelvic metastases. Chest radio- graph is often adequate to screen for the presence of lung metastases. A bone scan may be performed to evaluate for bone metastases in the setting of suggestive symptoms or elevated serum alkaline phosphatase concentration.
Once the presence of an upper tract tumor has been established, cystoureteroscopy should be performed to examine the entire urine collecting system. A retro-grade pyeloureterogram performed during this procedure often reveals a ﬁlling defect in the area of the tumor. All abnormal-appearing areas should undergo directed biopsy. The histopathologic ﬁndings of upper tract urothelial carcinomas are similar to those of the lower tract and are classiﬁed in a similar manner. Once the tumor has been radiographically and pathologically characterized, initial staging can be performed according to TNM criteria.
APPEARANCE (URETEROSCOPIC, GROSS, AND MICROSCOPIC) AND STAGING OF TUMORS OF THE RENAL PELVIS AND URETER
Surgery is the therapy for localized disease. The optimal approach depends on characteristics of both the patient and tumor.
For a patient with a normally functioning contralateral kidney, the gold-standard treatment is radical nephroureterectomy, in which the entire kidney and ureter on the affected side are removed, along with a cuff of normal-appearing bladder. Removal of the entire urothelial tract is essential because there is a high risk of recurrent disease if a ureteral stump is left behind.
Radical nephroureterectomy can be performed from either an open or laparoscopic approach. Regional lymphadenectomy is usually performed simultaneously. For proximal tumors, the ipsilateral renal hilar, para-aortic, and paracaval nodes are removed; for distal tumors, the ipsilateral pelvic lymph node chains are removed. The main beneﬁt to lymph node dissection is more accurate staging of the tumor, which may provide prognostic information and determine eligibility for trials of adjuvant chemotherapy. There is no evidence, however, that there is any survival beneﬁt to lymphadenectomy itself because patients with node-positive disease often have distant metastasis at the time of node dissection.
For a patient with a small, localized, low-grade tumor, or with a relative contraindication to nephroureterectomy (solitary functional kidney, bilateral upper tract tumors, chronic kidney disease, severe comorbid illness), a nephron-sparing approach may be used instead. In most cases, the tumor is accessed using retrograde ureteroscopy. After initial debulking with a basket, forceps, or other device, the tumor is ablated using a laser or monopolar electrocautery. If the tumor cannot be adequately treated from a retrograde approach, a percutaneous anterograde approach using a nephroscope may be undertaken.
For a patient with a tumor conﬁned to the distal ureter, selective distal ureterectomy with ureter reimplantation may be an option if there is a relative contraindication to nephroureterectomy (see previous list) or the tumor is small and low grade.
Systemic chemotherapy may be administered either before surgery (neoadjuvant) or after extirpation (adjuvant). Because urothelial carcinomas of the upper tract are relatively rare, however, there are no randomized controlled trials that substantiate the beneﬁt of chemotherapy in patients with advanced or metastatic lesions. Nonetheless, in patients with known metastasis, chemotherapy regimens are typically employed and are similar to those used for urothelial carcinomas of the bladder (i.e., cisplatin-based). In general, however, patients with metastatic upper tract tumors have a poor outcome no matter the treatment strategy.
Tumor stage and grade are critical factors when determining an individual patient’s prognosis. Following radical nephroureterectomy, one series noted 5-year disease-speciﬁc survival rates of 100% with Ta/Tis disease, 92% with T1 disease, 73% for T2 disease, 40% for T3 disease, and 0% for T4 disease. Another series noted 5-year disease-speciﬁc survival rates of 94% with Ta/Tis disease, 91% with T1 disease, 75% with T2 disease, 54% with T3 disease, and 12% with T4 disease. In addition, this series found 5-year disease-speciﬁc survival rates to be 89% with low-grade disease and 63% with high-grade disease. The type of surgical intervention also affects outcomes because a higher risk of recurrence has been observed among those treated using an endourologic approach.
A signiﬁcant subset of the patients treated for urothelial carcinoma of the upper tract will subsequently develop bladder cancer. Thus it is essential to perform surveillance of all patients with regular examination, cytoscopy, urine cytology, and CT of the abdomen and pelvis for several years after initial treatment. In patients who have undergone nephron-sparing treatment, surveillance ureteroscopy is often indicated as well.