Laboratory Studies
Laboratory studies that should be ordered include the following:
-
Urinalysis – To confirm hematuria and to rule out a coexistent urinary tract infection
-
Basic metabolic panel – To check serum creatinine (to assess kidney function by permitting calculation of the glomerular filtration rate) and electrolytes
-
Liver function tests including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase
-
Complete blood count
Imaging Studies
Excretory urography, commonly referred to as intravenous pyelography (IVP), has traditionally been used to evaluate the upper urothelial tract, but has been primarily replaced with multidetector computed tomography (CT). [14, 15] Approximately 50-75% of patients with urothelial tumors of the renal pelvis and ureters have a radiolucent filling defect that is characteristically irregular and in continuity with the wall of the collecting system. (See the image below.) Approximately 10-30% of such tumors cause obstruction or non-visualization of the collecting system.
Intravenous pyelogram (IVP) demonstrating an upper calyx filling defect characteristic of upper tract urothelial carcinoma (UTUC). Blunting of the involved calyx is noted. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
Noncontrast CT scanning can be performed, followed by a contrast study, with particular interest in the excretory phase — a so-called CT urogram. Plain radiography, which demonstrates drainage and anatomy, can also be performed after CT scanning. Upper tract urothelial carcinomas (UTUCs) are usually visible as an irregular filling defect. They tend to be hypovascular in comparison with the rest of the kidney and demonstrate minimal increased attenuation (enhancement) following intravenous contrast injection. See the images below.
CT scan demonstrating right renal pelvis upper tract urothelial carcinoma (UTUC). Contrast in the renal pelvis is displaced by the tumor. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
CT scan demonstrating left distal ureteral upper tract urothelial carcinoma (UTUC). The left ureter is dilated and a medial filling defect is noted. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
CT scanning sensitivities and specificities based on lesion size are as follows:
-
For lesions 5-10 mm in size - 96% sensitivity and 99% specificity
-
For lesions smaller than 5 mm in size - 89% sensitivity
-
For lesions smaller than 3 mm in size - 40% sensitivity
CT scanning has limited value in staging UTUC because stage Ta or superficial lesions cannot be differentiated from T2 or invasive lesions (see Staging). However, CT scanning is helpful in demonstrating peripelvic or periureteral tumor extension, thereby assisting with staging of aggressive disease. Hydronephrosis and obstruction are associated with a higher degree of invasiveness.
As with CT scanning, magnetic resonance imaging (MRI) is also of limited use in staging early UTUC; however, it may have greater utility in more advanced disease or in patients with limited renal function. European Association of Urology guidelines note that although CT urography is generally preferred to MRI urography for diagnosing and staging, MR urography is indicated in patients who cannot undergo CT urography, usually when radiation or iodinated contrast media are contraindicated. However, the use of MR urography with gadolinium-based contrast media should be limited in patients with severe renal impairment (creatinine clearance < 30 mL/min), due to the risk of nephrogenic systemic fibrosis. [1]
There is interest in fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/CT for staging in urothelial carcinoma, but, at present, this technique does not appear to have significant advantages over MRI. [16]
Other Tests
Cytopathology of voided urine samples yields low sensitivity, especially for low-grade tumors, which results in normal cytology results in up to 80% of cases. The sensitivity of cytopathology increases for higher-grade tumors, which tend to shed more tumor cells. Cytology yields an accuracy of 83% in patients with high-grade disease. Cytology is less sensitive for UTUC than for bladder cancer.
Cytology samples should be taken from as near the suspected lesion as possible (eg, within the calyceal system if the tumor is suspected in that region). Positive cytology has been associated with more advanced (invasive) disease. [17] Selective washings of both the upper tracts and the bladder can aid in tumor localization. Cytology plays a role in urothelial tumor surveillance in conjunction with cystoscopy/ureteroscopy.
Fluorescence in situ hybridization (FISH) can be performed using probes for altered genes on chromosomes 3, 7, 17, and 9p21. FISH (UroVysion) is a useful test for detecting urinary tract cancer, as it yields a greater sensitivity for lower-grade tumors than cytology and other tests (as high as 76.6-100% vs 21-24% for cytology). [18, 19] Ureteral cancer has been detected with FISH during evaluation for hematuria. [20] FISH has equal specificity when compared with cytology (as high as 100%).
Flexible or rigid ureteroscopy can be used for direct visualization of a tumor. Important to note is that it can be used to obtain tissue (biopsy) for a diagnosis (histology) and grade in 90% of cases. [21] Staging information regarding depth of invasion, however, is more difficult to obtain.
Diagnostic Procedures
Each of the following should be obtained in a suspected case of UTUC:
-
Cystoscopy – To rule out bladder tumor
-
Urinary cytology
-
CT urography
For cystoscopy, a small fiberoptic scope is inserted through the urethra in order to visualize the bladder. This ambulatory/clinical procedure is usually well tolerated by both women and men. A 16F flexible cystoscope is typically used. This procedure is mandatory to rule out coexistent bladder lesions, which occur with a frequency of 8-13%. [1] Cystoscopy is also essential for postoperative surveillance to monitor for bladder tumor development; bladder recurrence occurs in 15-51% of patients with UTUC. [22]
In retrograde urography (see image below), contrast is injected into the ureteral orifice with the aid of a cystoscope and a ureteral access catheter. This can be performed with fluoroscopic guidance or with standard radiography plates. Retrograde urography allows better visualization of the collecting system than excretory urography by increasing the distention of the urinary collecting system. Retrograde pyelography is preferable in patients with azotemia and/or contrast allergy. Overall, retrograde urography is more than 75% accurate in establishing a diagnosis of urothelial cancer.
Left retrograde ureterogram demonstrating the classic "goblet" sign of ureteral upper tract urothelial carcinoma (UTUC). Ureteral dilation distally and proximally to the tumor is present. The narrowed wall of the ureter is irregular. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
Since the advent of rigid and flexible ureteroscopes, ureteropyeloscopy is used increasingly for the diagnosis of upper tract urothelial tumors. Biopsy forceps or cytology brushings can be used to collect tissue. This procedure yields an accuracy of 86% in diagnosing renal pelvis tumors and 90% in diagnosing ureteral tumors. Large size, broad base, and nonpapillary pattern favor tumor invasiveness. Studies have demonstrated that 85% of urothelial lesions in the renal pelvis are papillary papillary in morphology. The complication rate associated with ureteropyeloscopy is approximately 7%; these include perforation, complete disruption, and ureteral stricture.
Percutaneous nephroscopy is not indicated for the diagnosis of urothelial tumors of the renal pelvis and ureters because of the theoretical risk of tumor cell implantation in the retroperitoneum and nephrostomy tube tract. It is used for treatment in selected situations when nephron-sparing approaches are necessary.
Nevertheless, Huang et al concluded that percutaneous biopsy is safe and effective for diagnosis of upper tract urothelial lesions that are not amenable to endoscopic biopsy. In their study of 26 upper tract lesions in 24 patients, percutaneous biopsy provided tissue diagnosis in 85% of cases; the three recurrences in the nephrectomy bed developed at sites remote from the biopsy site and thus were not attributed to tract seeding. [23]
Staging
The distribution of tumor stages and grades differs from study to study. Stage and grade yield the greatest prognostic value.
The National Comprehensive Cancer Network (NCCN) guidelines grade urothelial histologies according to the World Health Organization (WHO)/International Society of Urological Pathology (ISUP) classification, as follows [24] :
-
Low grade
-
High grade
Squamous cell carcinoma and adenocarcinoma use the following grading classifications [24] :
-
GX—Grade cannot be assessed
-
G1—Well differentiated
-
G2—Moderately differentiated
-
G3—Poorly differentiated
Staging is based on the depth of tumor invasion and classified using the tumor, node, metastases (TNM) system. [25]
Primary tumor categories are as follows:
-
TX - Primary tumor cannot be assessed
-
T0 - No evidence of primary tumor
-
Ta - Papillary noninvasive carcinoma
-
Tis - Carcinoma in situ
-
T1 - Subepithelial connective tissue invasion (lamina propria invasion)
-
T2 - Muscularis invasion
-
T3 – For renal pelvis only: Tumor invades beyond muscularis into peripelvic fat or the renal parenchyma
-
T3 - For ureter only - Tumor invades beyond muscularis into periureteric fat
-
T4 - Tumor invades adjacent organs, or through the kidney into the perinephric fat
Regional lymph node categories are as follows:
-
NX - Regional lymph nodes cannot be assessed
-
N0 - Negative nodes
-
N1 - Metastasis ≤2 cm in greatest dimension in a single lymph node
-
N2 - Metastasis > 2 cm in a single lymph node, or multiple lymph nodes
Distant metastasis categories are as follows:
-
M0 - No distant metastasis
-
M1 - Distant metastasis
The location of the tumor can affect the findings. Renal pelvis tumors are more commonly invasive than bladder tumors, possibly because of delayed diagnosis and a less well-developed muscle layer.
Table 1. American Joint Committee on Cancer Prognostic Groups (Open Table in a new window)
Stage |
Tumor |
Node |
Metastasis |
0a |
Ta |
N0 |
M0 |
0is |
Tis |
N0 |
M0 |
I |
T1 |
N0 |
M0 |
II |
T2 |
N0 |
M0 |
III |
T3 |
N0 |
M0 |
IV |
T4 |
NX, N0 |
M0 |
Any T |
N1 |
M0 |
|
Any T |
N2 |
M0 |
|
Any T |
Any N |
M1 |
-
Intravenous pyelogram (IVP) demonstrating an upper calyx filling defect characteristic of upper tract urothelial carcinoma (UTUC). Blunting of the involved calyx is noted. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
-
CT scan demonstrating right renal pelvis upper tract urothelial carcinoma (UTUC). Contrast in the renal pelvis is displaced by the tumor. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
-
CT scan demonstrating left distal ureteral upper tract urothelial carcinoma (UTUC). The left ureter is dilated and a medial filling defect is noted. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
-
Left retrograde ureterogram demonstrating the classic "goblet" sign of ureteral upper tract urothelial carcinoma (UTUC). Ureteral dilation distally and proximally to the tumor is present. The narrowed wall of the ureter is irregular. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
-
CT scan demonstrating bulky right renal pelvis upper tract urothelial carcinoma (UTUC) replacing the majority of the renal parenchyma. A pericaval lymph node metastasis is noted. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
-
CT scan demonstrating metastatic upper tract urothelial carcinoma (UTUC) of the right adrenal gland. A heterogeneous adrenal mass is noted adjacent to the spine. The superior portion of the right kidney is observed. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
-
Graphic representation of templates for lymph node dissection in patients with upper tract urothelial carcinoma, as proposed by Matin et al. For tumors in the right pelvis and upper ureter, dissection encompassing the right hilar, paracaval, and retrocaval regions (orange) will remove 82.9% of the involved lymph nodes. Adding the inter-aortocaval region (green) will improve coverage to 95.8%. For left-sided pelvic tumors, removal of hilar and para-aortic lymph nodes (violet) will ensure removal of 86.9% of the involved nodes. Adding inter-aortocaval lymph nodes (green) will increase the coverage to 90.2% of involved nodes. The level of dissection along the great vessels varies for pelvic tumors. The lower limit is the inferior mesenteric artery. For upper ureteric tumors, dissection should extend up to the aortic bifurcation. For distal ureteric tumors, pelvic template dissection involving the common iliac, external iliac, obturator, and internal iliac nodes will remove 75% of involved nodes on the right side and 83.3% of involved nodes on the left side (orange and violet circles). However, adding paracaval groups for tumors on the left side (orange rectangle) and para-aortic groups for those on the right side (violet rectangle) will improve coverage to almost 100%.
Tables
Stage |
Tumor |
Node |
Metastasis |
0a |
Ta |
N0 |
M0 |
0is |
Tis |
N0 |
M0 |
I |
T1 |
N0 |
M0 |
II |
T2 |
N0 |
M0 |
III |
T3 |
N0 |
M0 |
IV |
T4 |
NX, N0 |
M0 |
Any T |
N1 |
M0 |
|
Any T |
N2 |
M0 |
|
Any T |
Any N |
M1 |
Reference |
Study design |
Outcome |
Number of patients enrolled |
Leow JJ, Martin-Doyle W, Fay AP, et al. 2014
|
Systematic review and meta-analysis |
Pooled hazard ratio (HR) for overall survival (OS) was 0.43 (95% confidence interval [CI], 0.21–0.89; P = 0.023) for adjuvant therapy group compared with controls without adjuvant therapy |
Prospective study (n = 36) investigating adjuvant carboplatin–paclitaxel and nine retrospective studies, with a total of 482 patients receiving cisplatin-based or non-cisplatin–based AC after nephroureterectomy |
Porten S, Siefker-Radtke AO, Xiao L, et al. 2014
|
Retrospective review between neoadjuvant chemotherapy group and initial surgery group |
Neoadjuvant chemotherapy had improved OS and disease-specific survival (DSS) with a 5-year DSS rate of 90.1% and a 5-year OS rate of 80.2% versus DSS and OS rates of 57.6% for those who underwent initial surgery (P = 0.0204 and P = 0.0015, respectively |
Neoadjuvant chemotherapy +surgery (n =31) and surgery only (n= 81)
|
Huang YC, Chen MF, Shi CS, et al. 2015
|
Retrospective review of patient records with pT3N0M0 upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy and adjuvant therapy versus control group |
Statistically significant differences were found between the adjuvant and control groups in 5-year cancer-specific survival rates (80.5% vs 57.6%, P = 0.010) and recurrence-free survival rates (74.4% vs 52.9%, P = 0.026), but no statistically significant difference in overall survival (71.9% vs 49.0%, P = 0.072) |
Postoperative adjuvant chemotherapy (n= 60) vs surgery only (n=111) |
Urakami S, Yuasa T, Yamamoto S, et al. 2015 |
Retrospective analysis of clinicopathological response to induction chemotherapy and identification of prognostic factors for OS |
Clinically objective response to the induction chemotherapy occurred in 75% of patients. Histopathological analysis indicated pT0 status in 20% and pN0 in 33%. Clinical tumor response correlated significantly with achievement of pathological complete response |
60 urothelial cancer patients; primary cancer site was the urinary bladder (n= 31; 52%) and upper urinary tract (n=29; 48%) |
Lucca I, Kassouf W, Kapoor A, et al. 2015
|
Retrospective analysis of data of patients with lymph node (LN)–positive UTUC, who underwent full surgical resection followed by adjuvant chemotherapy (AC) |
In all patients (T(all) N+), administration of AC had no significant impact on UTUC-related mortality on univariable (P = 0.49) and multivariable (P = 0.11) analysis. Further stratified analyses showed that only N+ patients with pT3-4 disease benefited from AC. In this subgroup, AC reduced UTUC-related mortality by 34% (P = 0.019). |
263 patients with LN-positive UTUC underwent full surgical resection. Study group (n=107, 41%) received three to six cycles of AC, while controls (n=156; 59.3%) were treated with RNU alone |
Kim DK, Kim JW, Jung HD, et al. 2019 |
Systematic review and meta-analysis of adjuvant therapy after radical nephroureterectomy (RNU) in patients with locally advanced UTUC
|
Compared with patients who underwent RNU only, those who received adjuvant chemotherapy after RNU had HRs for disease-free survival of 0.59 (P = 0.001), cancer-specific survival of 0.73 (P = 0.02), and OS of 0.84 (P = 0.02) |
11 studies, comprising 1496 patients who underwent RNU alone and 798 patients who received ACH after RNU |
Margulis V, Puligandla M, Trabulsi EJ, et al. 2020
|
Prospective phase II trial of neoadjuvant systemic chemotherapy followed by extirpative surgery for patients with high-grade UTUC
|
Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin neoadjuvant chemotherapy in patients with high-grade UTUC and creatinine clearance > 50 mL/min was safe and demonstrated predefined activity with a 14% pathologic complete response rate. |
23 men and 6 women with a median age of 65 years (range 40 to 84); 80% completed all planned treatments |
NCT01261728 |
Prospective phase II study of gemcitabine and cisplatin as neoadjuvant chemotherapy in patients with high-grade UTUC |
Expected to complete by Dec 2023 |
NA |
