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Kidney and Ureteral Carcinoma
Key Points
Incidence
In 2018, an estimated 65,340 new cases of cancers arising from the renal pelvis and kidney proper are expected in the United States, with approximately 14,970 deaths. It represents the sixth most common cancer in men and the tenth most common cancer in women. Most of these cancers of the kidney are classified as renal cell carcinoma (RCC). By comparison, upper urinary tract cancers (UUTCA) are relatively uncommon. The estimated number of new cases for UUTCA in 2018 is 3820, with 960 deaths.
Biologic Characteristics
Factors known to be associated with risk of relapse and death from RCC following surgery include tumor stage, nuclear and Fuhrman grade, tumor size, extension through the renal capsule, nodal involvement, renal vein involvement, histologic pattern, and presence of necrosis. Presence of a sarcomatoid component is also associated with a poor prognosis. Lymphovascular invasion (LVI) is an independent predictor of RCC relapse. No molecular marker is available for routine use in the clinic to predict outcome following surgery for localized RCC. For UUTCA the most important prognostic factors for survival are stage and histologic grade of tumor. The presence of LVI also is predictive of worse outcome.
Staging Evaluation
Evaluation of a patient with RCC includes a history and physical examination (H&P), complete blood cell count (CBC), serum chemistries, urinalysis, chest radiography (CXR), and computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen and pelvis. Magnetic resonance angiography may be used in some cases for preoperative mapping of vasculature. Evaluation of patients with renal pelvis and ureteral cancers includes an H&P, CBC, blood chemistries, urinalysis, urine cytology, CXR, and CT of the abdomen and pelvis. Selective urine cytology of the upper urinary tract (UUT) is more sensitive than routine urine cytology. CT or MR urography is performed to evaluate the UUT bilaterally. Cystoscopy and ureteroscopy are performed to obtain tissue diagnosis and rule out additional synchronous lesions. With any concern about the function of the contralateral kidney, a nuclear renal scan should be performed before removal of a kidney.
Primary Therapy
Surgical resection (partial or radical nephrectomy) is the primary treatment of RCC. The 5-year survival is about 90% for those patients whose tumor is confined to the kidney, about 60% if it has extended to nearby tissues, and about 9% if it has spread to distant sites. For medically inoperable early stage RCC, emerging data on stereotactic body radiation therapy (SBRT) suggest favorable local control with short-term follow-up. Radical nephroureterectomy (RNU),with resection of a bladder cuff at the ureterovesical junction, is the standard therapy for UUTCA. When preoperative evaluation or clinical suspicion is high for nodal involvement, lymphadenectomy is also recommended. Five-year survival is 80% or more for minimally invasive disease not having invaded through the wall of the collecting system (T1 and T2 lesions), 30% to 50% for deeply invasive disease without nodal involvement, and 10% to 15% for cases involving lymph nodes or distant metastases. For selected patients with distal ureteral tumors and marginal renal function, nephron-sparing surgery is an option. Endoscopic resection is an option for low-grade and low-stage tumors in patients with marginal renal function.
Adjuvant Therapy
Adjuvant therapy for RCC is indicated in selected patients on the basis of failure patterns and survival results with surgery alone. After a gross total resection of tumor, the risk of local failure is low. There is no proven role for routine use of adjuvant radiation or chemotherapy for patients with localized RCC. Although several randomized trials evaluating molecularly targeted therapy have been negative, one study shows that adjuvant sunitinib for 1 year improves the disease-free survival for patients with high-risk clear cell RCC. Studies are ongoing to define the role of adjuvant immunotherapy. Postoperative radiation therapy can be considered in patients with positive margins or positive lymph nodes. Patients with UUTCA that is high grade or locally advanced, or with lymph node involvement, are at significant risk for developing both distant and locoregional relapses. Adjuvant radiation decreases local failure rates and may be combined with concomitant chemotherapy. Early result of a randomized trial suggests that adjuvant chemotherapy may benefit patients with high-risk disease.
Locally Advanced Disease
For unresectable RCC, a combined treatment approach consisting of preoperative external beam irradiation EBRT and cytoreductive surgical resection with or without intraoperative irradiation has the greatest potential for local control of disease. For UUTCA, irradiation with or without chemotherapy may occasionally achieve long-term disease control in patients with gross residual or locally recurrent disease after surgery. For patients with nonresectable disease, combined EBRT and chemotherapy or EBRT alone may achieve downstaging of disease to facilitate surgical resection.
Palliation
Nephrectomy may alleviate local symptoms of RCC or enhance the effects of systemic therapy. Radiation therapy is effective in palliating painful bone metastases and in alleviating symptoms from brain metastases. Several molecularly targeted and immunotherapeutic drugs have been approved for metastatic RCC. For metastatic UUTCA, cisplatin-based chemotherapy regimens can achieve a response rate of 50% to 70% and should be considered in patients with good performance status. Immunotherapeutic agents are being vigorously studied for metastatic urothelial cancer. Radiation therapy provides palliation of local symptoms, such as pain or hematuria, and improves the quality of life in some patients.
Introduction
The classic triad of symptoms of RCC includes hematuria, abdominal pain, and a flank mass, although patients often manifest other signs and symptoms. For localized tumors, surgical resection is the primary treatment. Nephron-sparing surgery (NSS) is the preferred for small to medium-size tumors. RCC appears to be more resistant to standard fractionated radiation therapy than most epithelial tumors. Control rates with SBRT are superior to conventional fractionated radiation therapy. Immunomodulation and molecularly targeted treatment have a role in the systemic treatment of patients with metastatic disease, although their role as adjuvant therapy after surgery remains to be better defined.
Primary cancer of the UUT includes cancer of the renal pelvis and ureter. The most common pathology is urothelial carcinoma. If the disease is resectable, RNU with removal of the bladder cuff is the standard surgery. Less-invasive surgeries with laparoscopic or robotic approaches have become more widely available as alternatives to the open approach. For patients with low-risk UUTCA (low-grade and low-stage disease, small unifocal lesion), as well as for patients with solitary kidney or significant medical comorbidity, NSS may be an option. Patients with high-grade tumors or advanced stage disease are at significant risk of developing local and distant relapses. Because of the rarity of these cancers, there is a paucity of prospective trials that have evaluated the benefits of adjuvant systemic therapy and adjuvant radiation therapy. Available data suggest that adjuvant chemotherapy and radiation therapy may improve the treatment outcomes of these patients.
Etiology and Epidemiology
Renal Pelvis and Ureter
Epidemiology
In the United States, kidney and renal pelvis cancers comprise approximately 4% of new cancer cases and 3% of cancer deaths each year. In 2018, an estimated 65,340 new cases of kidney and renal pelvis cancer were diagnosed, and there were approximately 14,970 deaths. Most kidney cancers (> 90%) are classified as RCC: of these, the vast majority (> 80%) are clear cell RCC.
Renal cell carcinoma is most commonly diagnosed in the seventh decade of life, with a median age at diagnosis of 65 years. According to data from the Surveillance, Epidemiology and End Results (SEER) program, the overall incidence of RCC in the United States has increased at a rate of 2% to 3% per year since the early 1970s. Many of these new cases are detected incidentally during abdominal imaging performed for unrelated reasons. However, early detection of subclinical tumors cannot fully explain the rising incidence of RCC.
There is a strong gender preponderance of RCC, with incidence rates in men approximately twice that of women. The incidence of RCC also varies among racial and ethnic groups. The highest rates occur in whites and African Americans, whereas the lowest rates are reported for Asian Americans. Between 1999 and 2008, incidence rates among African American males increased by 3.1% compared with only 2.3% in white males and 2.0% in Hispanic and Latino males. Globally, the incidence rate of RCC is the highest in North America and Scandinavia and the lowest in Asia and South America.
Although urothelial carcinoma may develop anywhere along the urinary tract, most occur in the urinary bladder and UUTCA account for only about 5% of all urothelial carcinomas. The age-adjusted annual incidence of renal pelvic and ureteral cancers is 0.73 per 100,000 person-years. Renal pelvis tumors are about four times more common than ureteral tumors. In the United States, the incidence of UUTCA has increased from 1.88 to 2.06 cases per 100,000 person-years during 1973 to 2005. There is a strong male predominance, with a male-to-female ratio of 2 : 1. The peak age at diagnosis is in the 7th decade of life. Synchronous urothelial cancer of the bladder can be found in 17% of patients with UUTCA. Patients with UUTCA have a 36% to 50% risk of developing a second bladder cancer. The risk of developing UUTCA after treatment of bladder cancer is 0.75% to 6.4%, with a median time of 33 to 48 months. Contralateral metachronous UUTCA is relatively uncommon, occurring in 3% to 6% of patients.
Etiology
Two well-established risk factors for RCC are cigarette smoking and obesity. Meta-analyses of studies suggest that each of these factors doubles the risk of RCC. Hypertension has emerged as a third risk factor for RCC. Several studies suggested an 80% increase in the risk of RCC for individuals with a history of hypertension. These three factors may account for approximately 50% of all RCCs diagnosed in the United States.
There are few consistent associations of RCC and dietary factors. Consumption of vegetables may be associated with reduced risk, whereas red meat consumption may slightly increase the risk of RCC. However, a meta-analysis did not support an independent association of red meat consumption and RCC. A number of studies, including a pooled analysis of several large population-based cohort studies, support an inverse association between alcohol consumption and risk of RCC. Some studies also support an inverse association with physical activity, as well as a positive association with a history of urinary tract infections.
Other factors that have been associated with an increased risk of RCC include occupational exposures to asbestos, gasoline, lead, and cadmium; use of Thorotrast; and a history of end-stage renal disease or acquired cystic kidney disease.
A positive family history increases the risk of RCC as much as twofold. Although inherited forms of RCC have been identified (e.g. VHL ), it is less clear whether individuals carrying single nucleotide polymorphisms in specific genes may be at increased risk of sporadic RCC.
Many risk factors and environmental agents that cause bladder cancer play similar roles in the development of UUTCA. Conversely, there are genetic and environmental factors specific for the promotion of UUTCA and not bladder cancer. Examples include hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome), Balkan endemic nephropathy, or Chinese herb nephropathy.
Tobacco is a major risk factor for the development of UUTCA. Cigarette smokers have a 2.6- to 7.2-fold increased risk of UUTCA. The relative risk of developing UUTCA is 4.8 for smoking more than 40 cigarettes daily. Occupational exposure to aromatic amines is associated with a higher risk of UUTCA for workers in the chemical or plastic industries. Chronic use of phenacetin causes papillary necrosis, which promotes carcinogenesis and increases the risk of UUTCA.
Aristolochic acid (AA) contained in Aristolochia fangchi and Aristolochia clematis plants causes kidney damage and leads to the development of UUTCA. These tumors have a distinct p53 mutation involving A:T→T:A transversion at codon 139. In some Balkan countries, Balkan endemic nephropathy (BEN) is associated with a 57- to 100-fold increase in risk of UUTCA. BEN is characterized by an interstitial nephritis. Consumption of bread made from grain contaminated with seeds of Aristolochia clematitis is a significant risk factor for BEN. DNA adducts derived from AA are present in patients with BEN and are also detected in their UUTCA. These patients more often present with higher-grade disease, solid growth pattern, and bilateral kidney involvement (8% to 10%) compared with nonendemic cases. The incidence of UUTCA in Taiwan is among the highest in the world and accounts for 20% to 25% of all urothelial cancers. It is associated with the use of Aristolochia herbal remedies. One study estimated that one-third of the Taiwanese population has ingested AA. These patients develop a nephropathy characterized by progressive renal fibrosis with an increased risk of urothelial cancer. The p53 mutation in UUTCA of these patients is identical to that seen in UUTCA associated with BEN.
Patients with a history of kidney or ureteral stones have a 2.5-fold increase in risk of renal and ureteral cancers, suggesting that chronic irritation and infection may play a role.
Familial UUTCA have been reported. HNPCC (Lynch syndrome) is an autosomal-dominant genetic disease caused by germline mutations in one of six mismatch repair (MMR) genes, resulting in microsatellite instability (MSI) and DNA replication fidelity. UUTCA risk is greatest in carriers of the MSH2 mutation compared with other MMR mutations. UUTCA is the third most common malignancy (5%) in patients with HNPCC, after colon (63%) and endometrial (9%) cancers. The risk is 22-fold compared with the general population, and the median age of onset is 56 years, which is 10 to 15 years earlier than usual. HNPCC should be suspected when a patient presents with UUTCA before age 60 years or meets the 3-2-1 rule using the Amsterdam II criteria (three relatives affected with specified cancer in at least two successive generations with one a first-degree relative of the other two, and at least one diagnosed at less than 50 years of age).
Prevention and Early Detection
Kidney
Cessation of cigarette smoking is the most effective method of preventing RCC. A large case-control study in Iowa reported that the risk of RCC development decreases steadily from the time of smoking cessation. After 15 years of cessation the risk of developing RCC returns to that of nonsmokers. It is unclear whether reduction in weight would decrease the risk for RCC.
Early diagnosis of RCC is challenging. Of patients, 25% to 40% are asymptomatic at the time of diagnosis. The increased use of imaging modalities, including CT, MRI, and ultrasonography (US), for other medical conditions often incidentally detects RCC at earlier stages.
Renal Pelvis and Ureter
Smoking cessation is the most important life style modification to prevent UUTCA. The risk of UUTCA in smokers is reduced by 60% to 70% after 10 years of smoking cessation. Current smokers have an increased risk of cancer recurrence and death after treatment of UUTCA. Diet with frequent intake of both green and yellow vegetables may reduce the risk of urothelial cancers. Screening urine cytology is not sensitive to detect UUTCA and has not been used routinely, even in populations at increased risk of developing these diseases (e.g., occupational exposure to organic chemicals or history of BEN). For individuals with Lynch syndrome, there is no consensus policy on screening for UUTCA. Cytology alone or together with cystoscopy has a sensitivity of 29%. Frequent urinalysis has been proposed as a screening method. Owing to increased risks of other malignancies, these patients should have screening colonoscopy and genetic counselling. For patients with a prior history of bladder cancer, routine follow-up examination with pyelography in any form (CT, MRI, or intravenous pyelography) remains controversial.
Biologic Characteristics and Molecular Biology
Kidney
Renal cell carcinoma occurs both familially and sporadically. Several hereditary syndromes are associated with the development of RCC, including the von Hippel-Lindau syndrome, tuberous sclerosis, hereditary papillary renal carcinoma, Birt-Hogg-Dubé (BHD) syndrome, and hereditary renal carcinoma. The von Hippel-Lindau syndrome, an autosomal-dominant disorder affecting 1 in 40,000 individuals, is caused by a mutation of the VHL tumor-suppressor gene located on chromosome 3p. Silencing of the VHL gene by either somatic mutation or hypermethylation plays a role in 50% to 60% of sporadic cases of clear cell RCC. Tuberous sclerosis is an autosomal-dominant disorder affecting 1 in 10,000 individuals and results from mutations of either the TSC1 gene on chromosome 9q or the TSC2 gene on chromosome 6p. Hereditary papillary renal carcinoma is also an autosomal-dominant disorder in which patients develop bilateral, multifocal lesions with associated germline mutations of the MET protooncogene located on chromosome 7q. BHD syndrome is a dominantly inherited predisposition to benign fibrofolliculomas and other skin and soft-tissue tumors, including RCC. The gene for BHD syndrome has been mapped to chromosome 17p12-q11.2.
There are currently no molecular markers (either tumor based or otherwise) for routine clinical use to predict outcome following surgery for localized RCC. Many studies analyzed single candidate biomarkers within RCC tumor tissue for their association with prognosis following nephrectomy. Candidate biomarkers, such as B7H1, survivin, CAIX, IMP, BAP1, PBRM1, SETD2, and IMP3, have been proposed as molecular alterations that are associated with RCC aggressiveness and risk of cancer-specific death. However, none of these biomarkers are sensitive or specific enough for postoperative surveillance to detect recurrence. Some investigators have combined individual biomarkers into multi-marker panels that can provide more robust forecasting for patients with RCC; however, the accuracy of these panels is still not at the level to warrant routine clinical use. In recent years, next-generation sequencing technology has been used to broaden the scope of our understanding of the genomic landscape of kidney cancer. These genome-wide studies may provide the benchmark for the next iteration of biomarker discovery in RCC that can be used as prognosticators of disease outcome.
Renal Pelvis and Ureter
Upper urinary tract cancers and bladder cancer have many common chromosomal and genomic alterations. The karyotypic profile of UUTCA has been shown to be similar to that of bladder cancers. Loss of the entire chromosome or partial loss of the short arm of chromosome 9 is a common finding, suggesting that it may be an early important event in tumorigenesis. Deletions at 2q, 8p, 9q, 11p, 13q, 17p, 18q, and gains at 1q, 6p, 8q, and 17q are seen in UUTCA as well as in bladder cancer. UUTCA also has many genetic and epigenetic abnormalities that are unique and different from bladder cancer. In a study using next generation sequencing assay, significant differences in the prevalence of somatic mutations between UUTCA and bladder cancer are seen. Compared with bladder cancer, alterations in FGFR3, HRAS, and CDKN2B are more common, whereas mutations in TP53, RB1, and ARID1A are less common in UUTCA. Microsatellite instability is frequently present in UUTCA. High levels of MSI are seen in 13% of UUTCA, compared with 1% of bladder cancer. Patients with HNPCC have MSI secondary to germline mutations in the MMR system and have a significant increased risk of developing UUTCA. Alterations in protein expression in many pathways of cell cycle regulation, proliferation, and apoptosis have been associated with prognosis. The expression of survivin, an inhibitor of apoptosis, and the apoptotic index are associated with shorter disease-specific survival (DSS). Ki-67 is a protein that is involved in cell proliferation. It is overexpressed in 24% of cases and is an independent predictor of progression and DSS. 105| Upregulation of nuclear factor-kB, a transcription factor involved in antiapoptosis, invasion, and angiogenesis, plays a role in the carcinogenesis of UUTCA and is a predictor of DSS. Upregulation of signaling through the PI3K/AKT/mTOR pathway promotes cell proliferation and growth. Activating mutations of the PI3K/AKT pathway and loss of heterozygosity at the PTEN locus are involved in the development of UUTCA. E-cadherin is a transmembranous cell-cell adhesion receptor responsible for the maintenance of tissue architecture. Loss of E-cadherin expression promotes invasion and metastases, and is associated with an increased risk of recurrence. Overexpression of TP53, cyclin A, and cyclin E is seen in 24% to 30% of UUTCA and is associated with advanced stage and grade, as well as worse prognosis. In a study using immunohistochemical staining of tumor tissues, expression of p21, p27, p53, cyclin E, and ki-67 were altered in 19%, 49%, 45%, 11%, and 89% of the specimens, respectively. A significant association was found between the number of altered markers and unfavorable clinicopathologic findings (e.g., nonorgan-confined disease, sessile architecture). Patients with two or fewer marker alterations had much better survival. In a study of 423 patients, PD-1 and PD-L1 expression was evaluated via immunohistochemistry. PD-1 and PD-L1 were positive in 37% and 26% of patients, respectively. PD-1 positivity was associated with adverse pathologic features and survival, whereas PD-L1 positivity was associated with favorable T-stage and outcome.
Pathology and Pathways of Spread
Kidney
Pathology
The classification of RCC was established in 1997 by an international consensus conference on RCC sponsored by the Union Internationale Contre le Cancer and the American Joint Committee on Cancer (AJCC). The classification system originally proposed at the Heidelberg conference in 1996 was adopted. There are four categories of RCC: clear cell, papillary, chromophobe, or collecting duct subtypes. RCC that does not fall into one of these four groups is classified as “renal cell carcinoma, not otherwise specified.” Granular cell RCC was excluded from the classification because it encompassed oncocytoma (benign kidney tumor) as well as chromophobe and clear-cell RCC and was not specific to a single subtype. This classification system recognizes that RCC consists of several histologic subtypes with distinct morphologic and genetic characteristics. There are significant differences in patient outcome based on histologic subtypes. Patients with clear-cell RCC have a worse prognosis compared with patients with papillary and chromophobe RCC. There is no statistically significant difference in outcome between patients with papillary RCC and those with chromophobe RCC.
Pathologic features predictive of a poorer prognosis, including histologic tumor necrosis and sarcomatoid differentiation, have been shown to differ by subtype. Histologic tumor necrosis is noted in 20% to 45% of patients with RCC, whereas sarcomatoid differentiation occurs in 5% to 15% of patients.
Fuhrman et al. developed a nuclear grading system based on the size and appearance of nuclei and nucleoli. The Fuhrman nuclear grade is predictive of disease outcome. A large cohort study reported that LVI is an independent marker of RCC recurrence more than 5 years following nephrectomy.
Algorithms have been developed to predict outcomes for patients with RCC. Using retrospective data from 1801 patients with clear-cell RCC, investigators from the Mayo Clinic developed a predictive model using a scoring system that incorporated s tage, tumor si ze, nuclear g rade, and histologic tumor n ecrosis (acronym: SSIGN). Ten-year cancer-specific survival (CSS) could be estimated based on a patient's SSIGN score. Kattan et al. developed a nomogram to predict 5-year probability of treatment failure using presenting symptoms, histology, tumor size, and stage. Zisman et al. developed a clinical outcome algorithm based on 814 patients, using stage, Fuhrman grade, and performance status. This algorithm has been validated by two international multicenter studies. Similar algorithms have also been developed and validated for predicting time to death for patients with metastatic RCC. Overall, these robust prognostic tools have become widely accepted in the clinic.
Renal Pelvis and Ureter
Urothelial carcinoma accounts for the majority of renal pelvis and ureter neoplasms. Histologic variants have been reported in 24% of the pathologic specimens. These include differentiations, such as squamous cell, glandular, micropapillary, clear-cell, sarcomatoid, lymphoepithelial, and plasmacytoid features. Histologic variants are associated with advanced tumor stage, LVI, and nodal metastasis compared with pure UUTCA. Nonurothelial histology is uncommon. Squamous cell carcinoma (SCC) accounts for about 4% of all cases. Patients with SCC tend to present with more advanced-stage diseases and worse prognosis; however, there is no significant difference in prognosis between urothelial and SCC stage for stage. Other rare cell types include adenocarcinoma, neuroendocrine carcinoma, and sarcoma.
Pathologic features that predicts worse prognosis include high tumor grade and LVI. LVI is associated with higher stage and tumor grade and lymph node metastasis.
Gross tumor architecture (sessile versus papillary growth pattern) is an independent predictor of tumor relapse and cancer-specific mortality. Sessile growth pattern is associated with higher tumor grade, more advanced stage, and nodal metastasis.
Pathways of Spread
Renal cell carcinoma may spread by local extension through the renal capsule into the perinephric fat or the adrenal gland, or by direct extension through the renal vein to the inferior vena cava (occasionally reaching the right atrium). Regional lymphatic drainage includes renal hilar, paracaval, aortic, and retroperitoneal lymph nodes. RCC may also spread hematogenously to the lung, soft tissue, bone, and brain, or by retrograde venous drainage to the ovary or testis.
Involvement of multiple areas of the urothelial epithelium by urothelial carcinoma, either synchronously or metachronously, is common in patients with UUTCA. As the tumor progresses, it invades the surrounding tissues with direct extension through the ureteral wall into periureteral tissues or to adjacent renal parenchyma as well as extrarenal tissues. Lymph node metastasis is the most common site of metastasis. In a multi-institutional series of 1363 patients, lymph node metastasis was shown to increase with advancing pathologic stage: less than 1% for T0/Ta/Tis, 2% for T1, 8% for T2, 17% for T3, and 46% for T4. High-grade tumors were more likely to have nodal involvement (15% for high-grade, 2% for low-grade).
Kondo et al. outline the distribution of nodal metastatic sites. For tumors of the right renal pelvis, the primary metastatic sites are the right renal hilar, paracaval, and retrocaval nodes. Tumors of the upper two-thirds of the right ureter primarily metastasize to the retrocaval and interaortocaval nodes. Tumors of the left renal pelvis metastasize to the left renal hilar and paraaortic nodes. Tumors of the upper two-thirds of the left ureter primarily metastasize to the paraaortic nodes. Tumors of the lower ureter primarily metastasize inferiorly to the aortic bifurcation. The finding of LVI in the tumor is predictive of regional lymph node metastasis. Nodal metastasis is a predictor for distant metastasis and worse survival.
The pattern of recurrence of UUTCA varies depending on the primary tumor location. Recurrence in the abdomen is more with primary sites in the renal pelvis, upper and middle ureter. Pelvic recurrence is more common in lower ureteral primaries. Patients with high grade or advanced stage disease are at significant risk of developing distant metastasis. The predominant sites of distant failure include lung, liver, and bone.
Clinical Manifestations, Patient Evaluation, and Staging
Kidney
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