123 Overview of Upper Tract Urothelial Cancers
Upper tract urothelial cancers (UTUC) include cancers arising from the urothelial lining anywhere between the renal calyces to the distal ureter. They are characterized by multifocality and share some similarities with urothelial carcinoma of the bladder. However, they tend to be much less common and pose a diagnostic challenge.
UTUC involving the renal pelvis and ureter are relatively uncommon (5%–7% of all renal tumors). However, there is a higher incidence of UTUC in Balkan countries and Taiwan due to the specific risk factors (1,2).
The disease tends to be more common in White males, but disease-specific mortality rates are higher in African Americans and women (3). The mean age at diagnosis is 73, with peak incidence at 75 to 79 years. The incidence of renal pelvis tumors has been stable but the incidence of ureteral tumors has been steadily increasing, with a trend toward earlier stage at diagnosis. Multifocal involvement of the entire urinary tract is common, with 17% of patients having concurrent bladder tumors at presentation. The incidence of bilateral UTUC is 1.6%–6%.
• Balkan nephropathy is a familial (but not hereditary) cause for multiple and bilateral UTUC cancers, which tend to be 124low grade. A possible association with dietary aristolochic acid consumption has been postulated. Surprisingly, bladder cancer incidence is unaffected (1).
• Smoking is the most important modifiable risk factor, with a 4- to 11-fold increased risk. The risk tends to be dose-related and declines after quitting, but never completely normalizes. Smokers are at increased risk for recurrence in the operative bed and have increased mortality (4).
• Phenacetin use with renal papillary necrosis has been associated with a 20-fold increased risk for UTUC together, but both are independent risk factors (5).
• There is increased incidence in Taiwan with artisan-well water use, which has high arsenic content. Arsenic-related UTUC is associated with increased mortality, but causality is yet to be identified (2).
• Hereditary UTUC has been noted to be associated with Lynch syndrome (6).
• The incidence of UTUC after prior bladder cancer is 2% to 4%. Factors that predict a higher risk for UTUC include grade, stage, TIS, multifocality, and tumors at the ureteral orifice. The incidence increases with bladder cancer follow-up duration. Patients with bladder carcinoma in situ (CIS) were noted to have more bilateral and lower ureteral involvement (7).
Signs and Symptoms
The most common presenting symptom of UTUC is hematuria, which is present at diagnosis in the majority of patients. This may be either grossly visible to the patient or microscopic on urinalysis (8). The patient may also complain of flank pain, although this is seen in less than half of cases. It is also possible for the patient to experience systemic “B” symptoms such as fever, night sweats, anorexia, weight loss, or fatigue. The presence of such symptoms should alert one to the increased possibility of metastatic disease (9).
125Physical Examination, Laboratory Examination, and Imaging
On physical exam, an abdominal mass may be palpable in large tumors (8). In addition to microscopic hematuria, there may be decreased renal function in cases where the tumor is causing obstructive uropathy. While patients with normal contralateral renal function often compensate for obstruction, patients with the rare bilaterally obstructing tumors, solitary kidney, or chronic kidney disease will demonstrate a rise in creatinine. Imaging findings of hydronephrosis or a mass within the collecting system or the ureter could indicate UTUC. Although symptoms such as pain or presence of a mass are unrelated to prognosis, the presence of hydronephrosis is itself an independent indicator of more invasive disease (9,10).
A CT urogram, which includes a delayed contrast phase in order to better visualize the collecting system, is the gold standard for assessing UTUC (11). It is between 67% and 100% sensitive and between 93% and 99% specific for detecting tumors in the collecting system and ureter (12). A reason for the high variability in sensitivity is due to decreased sensitivity in detecting CIS. This entity is flat and generally not visible on imaging, although urothelial thickening may be seen (13). CT is also used to assess for lymphadenopathy, which is highly predictive of metastatic disease in the context of UTUC (14). Hydronephrosis can also be assessed on CT urogram. Renal ultrasound can be used as a screening modality for obstruction (Figure 19.1a–c).
In cases where CT is contraindicated, MRI may be used; however the sensitivity of the exam decreases to 75% in tumors less than 2 cm (15). Additionally, one must use caution with gadolinium in patients with chronic kidney disease, as patients with a glomerular filtration rate (GFR) of less than 30 are at increased risk for nephrogenic systemic fibrosis.
Figure 19.1 (A) Normal CT coronal urogram. (B) CT coronal showing a filling defect in the left collecting system corresponding to an upper tract high-grade urothelial carcinoma. (C) CT urogram reconstruction demonstrating a right UPJ obstruction from a kinking at the UPJ and a normal left collecting system and ureter.
UPJ, ureteropelvic junction.
Cytology and Tumor Markers
Cytology for UTUC is generally less sensitive than it is for bladder cancer. However, if UTUC is suspected, in situ washings of the collecting system should be performed in order to maximize diagnostic yield (16). The use of fluorescence in situ hybridization (FISH) seems to be more sensitive for UTUC than urine cytology (54% vs. 18% sensitive when bladder tumors were excluded) (17). However, it is still less sensitive than endoscopic evaluation and therefore has had little added value as a diagnostic tool.
Cystoscopy should always be performed in cases of UTUC to assess for concomitant bladder tumors (12). Positive urine cytology in the context of a negative cystoscopic exam might suggest UTUC, although CIS of the bladder is a possibility as well. Blue-light technology has increased our ability to detect flat lesions and might assist in detecting subtle bladder lesions, and will be discussed in more depth in Chapter 6A, Non Muscle Invasive Bladder Cancer.
In addition to direct visualization and biopsy of the bladder specimen, cystoscopy offers the opportunity to conduct retrograde pyelograms in order to further evaluate the upper tracts. Due to their high negative predictive value (92% vs. a 60% positive predictive value), they are particularly helpful in ruling out upper tract disease in cases where imaging is ambiguous (18). In the case of obstruction or poor visualization by this modality, percutaneous anterograde pyelograms may be considered. This method is preferred by some for larger tumors of the renal pelvis and proximal ureter (19).
Ureteroscopy has demonstrated a higher sensitivity and specificity for the diagnosis of UTUC when compared with other methods, and is becoming the gold standard for diagnosis of UTUC (20). However, some clinicians may prefer to reserve ureteroscopy for times when management will be affected, such as when previous work-up is ambiguous or to avoid under-staging in the event that nephron-sparing management is being considered.
In addition to allowing for the direct visualization of upper tract lesions, ureteroscopy provides the opportunity for biopsy. Ureteroscopic biopsy is able to accurately determine tumor grade in greater than 90% of cases (20), although taken alone it is unreliable in the determination of tumor stage. Visualization is greatly aided by blue light technology, allowing for detection of flat lesions which would otherwise be missed (21,22). Ureteroscopy can also be used to collect in situ washings for cytology to increase yield in cases of CIS or otherwise difficult to visualize tumors (11).
The majority (90%) of primary tumors arising in the renal pelvis and ureter are urothelial in origin. Squamous cell carcinoma makes up under 10% of these tumors, and less than 1% are adenocarcinoma (11). Small cell carcinoma has been described but is very rare.
Cancers of the upper tract urothelial area are staged using the tumor, node, metastasis (TNM) system (Table 19.1).