Cancer of the Kidney, Renal Pelvis, and Ureter

GENERAL MANAGEMENT Renal Cell Carcinoma

· NCCN- Local disease: surgery (no radiation). If R0, · then AS. CT or MRI in 6 m and then imaging q12m.• PORT: controversial. Consider for +SM, + LN- Metastatic disease: surgery (palliative · nephrectomy), sunitinib (multi-TKI), temsiro- limus, bevacizumab and IFN, interleukin-2, sorafenib (Multi-TKI).

● Approximately 88% of SOLID renal masses are _________ ○ the probability of malignancy is proportional to the _____ of the lesion ● RCCs ○ comprise _______% of primary kidney tumors ● Urothelial (transitional cell) carcinomas of the renal pelvis ○ account for ____% of kidney tumors.

MALIGNANT SIZE 80% to 85 7%

superior for evaluating IVC and right atrium for tumor involvement

MRI

○ can be valuable when evaluating the extent of involvement of the collecting system or inferior vena cava, or radiographic contrast cannot be administered

MRI

Renal Pelvis and Ureter Carcinoma ● Flow cytometry may aid in estimating long-term prognosis ● In a multivariate analysis, Corrado et al. ○ demonstrated that, although stage and grade were the most important prognostic indices ■ DNA pattern (diploid vs. nondiploid) and the number of lesions (unifocal vs. multifocal) identified at initial diagnosis also determined prognosis ○ Patients with diploid tumors

■ had a 79% survival rate, compared with only 46% in patients with nondiploid tumors (P = .0003)

● The kidneys are mobile organs and move vertically within the retroperitoneum an average of

○ 0.9 to 1.3 cm and ○ as much as 4 cm during normal respiration

● The incidence of bilateral upper urinary tract tumors is

○ 1.5% to 2% for synchronous ○ 6 to 8% for asynchronous presentations

● Recently, the minimally invasive ablative technologies of cryoablation and radio-frequency ablation (RFA) have emerged as potential treatment options for clinically localized RCC, especially in the elderly, or patients with a solitary kidney or comorbidities impeding surgery. ● Long-term oncologic efficacy for these modalities remains to be established ● The most favorable lesions for this approach are ● Relative contraindications for RFA and cryoablation include

○ <4 cm and in the periphery of the kidney. ○ distant metastases ○ tumors > 5 cm ○ tumors in the hilum or central collecting system, and ○ life expectancy less than a year

● Other symptoms of RCC include

○ Anemia ○ hepatic dysfunction in the absence of liver metastases ■ called Stauffer syndrome and because of a paraneoplastic elevation in alkaline phosphatase ○ secondary (AA) amyloidosis ○ fever ○ hypercalcemia ○ cachexia ○ erythrocytosis ○ thrombocytosis, and ○ a syndrome resembling polymyalgia rheumatica

● Therenal pelvis and ureter have the following layers:

○ Epithelium ○ subepithelial connective tissue, and ○ muscularis ■ is continuous with a connective tissue adventitial layer.

CLINICAL PRESENTATION Renal Cell Carcinoma ● Patients with RCC may present with an occult primary tumor or with signs and symptoms attributable to a local mass or systemic paraneoplastic syndromes ● Describe a classic triad that occurs only in 5% to 10% of patients ● Indeed, a finding of the classic triad often suggests ADVANCED disease with a poor prognosis

○ Gross hematuria ○ palpable flank mass ○ pain

● The MOST FREQUENT symptom associated with RCC is

○ Hematuria ■ either gross or microscopic ■ when there is invasion of the collecting system

● Occupations associated with a higher risk of RCC are

○ employment in the blast-furnace, coke-oven, or the iron and steel industry ○ exposure to asbestos, cadmium, dry-cleaning solvents, gasoline, and other petroleum products

○ which occurs in up to 50% of patients on dialysis for more than 3 years ○ increases50-foldthe risk of developing RCC ○ The ACKD-associated RCC is seen mostly in males, occurs approximately 20 years earlier than in the general population, and is frequently bilateral (9%) and multicentric (50%)

● Acquired cystic kidney disease (ACKD)

Renal Pelvis and Ureter Carcinoma ● Tumors of the renal pelvis and ureter have a natural history that is not too dissimilar from that of other urothelial malignancies originating in the bladder ● Their prognoses are dependent on e

○ tumor invasiveness and ○ pathologic grad

● Papillary RCC can be subdivided into

○ type 1 ■ which tends to be low-grade and have a better prognosis ○ type 2 ■ which is the opposite, each biologically distinct

○ is autosomal dominant ○ caused by germ-line mutations of this tumor suppressor gene, located on chromosome 3p25-26 ○ The protein is involved in cell cycle regulation and angiogenesis ○ In patients with this disease, loss of the sole functioning allele in somatic tissues causes a situation similar to hypoxia, with elevated levels of HIF-1-α, despite the presence of normal oxygen tension ○ The renal manifestations of this are kidney cysts and CLEAR CELL RCC ○ The mean age onset for this-associated clear cell RCC is 37 years, and periodic screening with MRI should start after the age of 10 years

○ von Hippel-Lindau (VHL) disease

Risk factors for RCC: ● Several inherited cancer syndromes affect the kidney:

○ von Hippel-Lindau (VHL) disease ○ hereditary papillary renal cancer (HPRC) ○ hereditary leiomyomatosis renal cell carcinoma (HLRCC) ○ Birt-Hogg-Dubé (BHD) syndrome ○ constitutional chromosome 3 translocation

○ has been associated with a high incidence of upper urinary tract urothelial carcinoma in Taiwan. ○ Prolonged heavy phenacetin-containing analgesic use can lead to urothelial carcinomas of the renal pelvis, ureter, and bladder (which may be multiple and bilateral)

● Arsenic-contaminated water

○ DOES NOT APPEAR to increase the incidence of RCC ○ but the tumors are more often multicentric (28% vs. 6%), bilateral (12% vs. 1% to 5%), and SARCOMATOID in type (33% vs. 1% to 5%) than in the general population

● Autosomal dominant polycystic kidney disease

○ is a small molecule tyrosine kinase inhibitor targeting VEGF, c-KIT, and PDGFR.

● Axitinib

○ is a chronic tubulointerstitial disease of unknown etiology most commonly reported in southeastern Europe A high frequency of urothelial atypia, occasionally progressing to tumors of the renal pelvis and urethra, but also involving the bladder,

● Balkan endemic nephropathy (BEN)

○ is a recombinant monoclonal antibody that binds VEGF-A

● Bevacizumab

○ is autosomal dominant with incomplete penetrance ○ is associated with multiple chromophobe and clear cell RCCs, papillary RCCs, and oncocytomas

● Birt-Hogg-Dubé (BHD) syndrome

○ is a small molecule inhibitor of the tyrosine kinases c-Met and VEGFR2

● Cabozantinib

○ is the MOST IMPORTANT FACTOR contributing to the overall incidence of urothelial cancer in Western countries

● Cigarette smoking

PATHOLOGIC CLASSIFICATION Renal Cell Carcinoma ○ is the MOST COMMON histology (80% to 90% of tumors) ■ followed by ________ (10% to 15%) and ■ __________ (4% to 5%)

● Clear cell RCC papillary RCC chromophobe RCC

○ is associated with multiple, BILATERAL CLEAR CELL RCCs

● Constitutional chromosome 3 translocation

○ may predispose childhood cancer survivors to translocation RCC, bearing TFE3 or TFEB gene fusions

● Cytotoxic chemotherapy

urothelial carcinoma of the renal pelvis and ureter: ○ are considered standard neoadjuvant or adjuvant chemotherapy regimens

● Dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) for 3 or 4 cycles and gemcitabine and cisplatin for 4 cycles ● Standard MVAC ○ is NO LONGER USED because it is less efficacious and more toxic ddMVAC

○ is a receptor tyrosine kinase inhibitor of EGFR

● Erlotinib

○ has been associated with acute, near-end-stage renal disease ○ is commonly found in the family of plants commonly used in Chinese herbal medicine ○ A high incidence of cellular atypia and urothelial carcinoma of the renal pelvis, ureter, and bladder

● Exposure to aristolochic acid

● Fuhrman grade ○ is the most widely used grading system for RCC

● Fuhrman grade

Renal Pelvis and Ureter Carcinoma ○ occurs in 70% to 95% of patients with renal pelvis or ureter tumors ○ About 10% to 20% of patients may present with ● The other less common symptoms include:

● Gross or microscopic hematuria ● a flank mass secondary to tumor or hydronephrosis ○ pain (8% to 40%) ○ bladder irritation (5% to 10%), or ○ other constitutional symptoms (5%)

○ is autosomal dominant with high penetrance ○ is characterized by multiple, bilateral, late-onset PAPILLARY RCCs ○ is autosomal dominant with a predisposition to papillary type 2 RCC

● Hereditary papillary renal cancer (HPRC)

○ is an antibody that selectively blocks the interaction between PD-1 and its ligands.

● Nivolumab

○ an autosomal dominant genetic condition because of inherited mutations that impair DNA mismatch repair ○ have an increased risk of developing urinary tract cancer

● Patients with Lynch syndrome

○ is very aggressive malignancy ○ mostly associated with young black patients with sickle cell trait and, less commonly, sickle cell disease

● Renal medullary carcinoma

○ is a small inhibitor of several tyrosine protein kinases, such as VEGFR, PDGFR, and Raf family kinases

● Sorafenib

Renal Pelvis and Ureter Carcinoma ● The diagnostic workup for renal pelvis and ureter carcinoma is listed in Table 67.2

● Staging includes a complete history and physical examination, complete blood count, and liver and kidney function tests ● CT urography is now used to evaluate patients with renal pelvis carcinoma ● CT or MRI of the abdomen and pelvis before and after contrast administration gives useful information regarding the possible extension of tumor outside the collecting system. ● Ureteroscopic visualization of the tumor is desirable, and tissue biopsy through a ureteroscope should be performed if feasible ● Cystoscopy is very important because of the high incidence of multiple tumors ● Urine cytology may help determine tumor grade if tissue is not available, but false-negative rates can be high for upper tract and low-grade tumors.

○ is a multikinase inhibitor targeting c-KIT, FGFR, FLT-3, CSF-1R, PDGFR, VEGFR, and RET

● Sunitinib

○ is the therapeutic foundation for the management of renal pelvis and ureter carcinoma

● Surgery

○ is the therapeutic foundation for the management of kidney cancer ○ has an important and growing role in the palliative management of RCC

● Surgery ● Radiotherapy

● The American Joint Committee on Cancer (AJCC) system is currently being utilized to stage patients with RCC (Table 67.3)

● T1 and T2 cancers ○ are limited to the kidney (< or > 7cm) ● T3 tumors ○ extend into major veins or perinephric tissues, but not into the ipsilateral adrenal gland and not beyond Gerota fascia ○ This staging system underwent some modifications for the 8th edition: ■ For T3a disease, the word "grossly" was eliminated from the description of renal vein involvement, "muscle containing" was eliminated, and "invasion of the pelvicalyceal system" was added ● T4 tumors ○ invade beyond Gerota fascia (including contiguous extension into the ipsilateral adrenal gland)

○ are mTOR inhibitors

● Temsirolimus and everolimus

PROGNOSTIC FACTORS Renal Cell Carcinoma: ○ remains the MOST IMPORTANT PROGNOSTIC FACTORfor RCC survival ○ Next is _________

● The STAGE at initial presentation ○ Next is nuclear grade

● Adjuvant radiation therapy is NOT RECOMMENDED in RCC after complete resection ● Two prospective randomized studies testing the value of adjuvant radiation therapy DID NOT DEMONSTRATE an advantage to patients receiving RT after surgery (Table 67.6)

● The first study from New Castle, United Kingdom (Fugitt) ● A second randomized study conducted by the Copenhagen Renal Cancer Study Group (Kjaer)

RCC ● The overall risk of lymph node metastases is ____%

20

○ is a multikinase inhibitor targeting c-KIT, FGFR, PDGFR, and VEGFR

● Pazopanib

● Neoadjuvant radiotherapy is NOT RECOMMENDED in patients with resectable RCC ● Two European studies were undertaken to test the efficacy of neoadjuvant/preoperative RTin RCC (Table 67.5)

1. van der Werd-Messing et al 2. Juusela et al

● The mean liver dose ○ should be kept below ________ Gy, excluding patients with pre-existing liver disease or hepatocellular carcinoma who have a lower tolerance ○ Sparing at least _____ cc of the liver from radiation is another potential strategy to avoid complications

30 to 32 700

● In UNRESECTABLE lesions, ______ Gy neoadjuvant radiation therapy (1.8 to 2 Gy/fraction) directed to the kidney tumor and regional lymphatics MAY IMPROVE resectability

40 to 50 Gy

● About ______ of patients with upper urinary tract tumors will have a synchronousor metachronousbladder cancer

40% to 50%

● Total radiation doses of _______ Gy (1.8 to 2 Gy/fraction) to the nephrectomy bed and regional lymph nodes ○ with a boost to small volumes of microscopic or gross residual disease of ________ are appropriate

45 to 50 Gy 10 to 15 Gy (total dose 50 to 60 Gy

Renal Pelvis and Ureter Carcinoma ● Radiation doses of _____ Gy at 1.8 to 2 Gy per dayare appropriate to treat subclinical and microscopic disease ● For more extensive disease (e.g., multiple positive nodes), R1 (microscopic positive margins) or R2 (macroscopic residual margins) resections ○ a boost of ______ should be considered

45 to 50 Gy 5 to 10 Gy

● Approximately ○ ___% of patients with RCC have localized disease ○ ___% have regional disease ○ about __% have evidence of distant metastases at the time of diagnosis

45% 25% 30%

Renal Pelvis and Ureter Carcinoma ● More than _____% of malignant tumors arising from the renal pelvis and ureter are urothelial (also called transitional cell) carcinomas

90%

● RCC is a group of malignancies arising from the epithelium of the renal tubules and comprises ____% of all malignancies in the kidney

90%

DIAGNOSTIC WORKUP Renal Cell Carcinoma ● Renal masses are not uncommon, and MOST of them are ______ ● A _________ renal mass ○ may suggest the presence of UROTHELIAL carcinoma; ○ if so, urine cytology, ureteroscopy, and biopsy should be considered

BENIGN CENTRAL

Ureteral tumors tend to occur in the _______ of the ureter

DISTAL THIRD

● Papillary RCC ○ has a 5-year survival rate that approaches 90% ○ metastasizes __________ than clear cell RCC

LESS FREQUENTLY

International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) Criteriab 1. Prognostic factors 2. Prognostic risk groups

Prognostic factors 1. Less than one year from time of diagnosis to systemic therapy 2. Performance status <80% (Karnofsky) 3. Hemoglobin < lower limit of normal (Normal: 120 g/L or 12 g/dL) 4. Calcium > upper limit of normal (Normal: 8.5-10.2 mg/dL) 5. Neutrophil > upper limit of normal (Normal: 2.0-7.0×109/L) 6. Platelets > upper limit of normal (Normal: 150,000-400,000) Prognostic risk groups• Favorable-risk group: no prognostic factors• Intermediate-risk group: one or two prognostic factors • Poor-risk group: three to six prognostic factors

Memorial Sloan Kettering Cancer Center (MSKCC) Prognostic Model (RCC) 1. Prognostic factors 2. Prognostic risk groups

Prognostic factors • Interval from diagnosis to treatment of less than 1 year • Karnofsky performance status less than 80% • Serum lactate dehydrogenase (LDH) greater than 1.5 times the upper limit of normal (ULN) • Corrected serum calcium greater than the ULN • Serum hemoglobin less than the lower limit of normal (LLN) Prognostic risk groups • Low-risk group: no prognostic factors • Intermediate-risk group: one or two prognostic factors • Poor-risk group: three or more prognostic factors

○ carries a significantly POORER PROGNOSIS than the clear cell or granular cell subtypes ○ Almost half of patients have bone metastases at presentation. ○ The median survival time of patients is only 6.6 months, compared with 19 months for other histologic types

Sarcomatoid differentiation

● Danish workers exposed to ________, an industrial solvent used as a metal degreaser ○ had an 8-fold higher incidence of kidney cancer.

TRICHLOROETHYLENE

True or False ● Thereis NO SIGNIFICANT DIFFERENCE in prognosis between urothelial carcinomas originating in the ureter compared to those arising in the renal pelvis.

True

True or False: Adjuvant Radiation Therapy ● There are NO RANDOMIZED TRIALS on the role of postoperative RT in patients who have had a complete resection of an upper urinary tract cancer

True

True or False: · - Renal pelvis 3-4x more common than ureter. · - UUT have worse stage-for-stage prognosis than bladder

True

True or False: ● A patient with a solitary bone metastasis may have a long survival time, and a sufficient radiation dose should be administered to allow durable pain relief ● If surgery is used to remove a metastatic lesion, postoperative radiotherapy IS INDICATED to prevent its recurrence

True

True or False: ● Eachpapilla opens in the minor calices, which unite in the major calices and drain into the renal pelvis

True

True or False: ● Men are TWICE as likely as women to be diagnosed with kidney cancer ● The median age of RCC diagnosis is 65 years

True

True or False: ● Patients with a solitary metastatic lesion have a 5-year survival rate of 24% (compared with 4% for those with more than one metastatic focus), and they may benefit from aggressive therapy ● The resection of one or a limited number of metastases in combination with nephrectomy or at relapse has been associated with a 13% to 50% 5-year survival in small series of selected patients

True

True or False: ● Renal pelvis tumors are found two to three times more commonly in MEN than in women, ● The peak incidence is in the fifth and sixth decades of life

True

True or False: ● Chemotherapy has LIMITED USE in RCC because it is one of the most chemotherapy-resistant solid tumors

True

True or False; ● Because the mucosal surfaces of the renal pelvis, ureter, and bladder have the same embryologic origin, many of the etiologic factors in renal pelvis and ureter tumors also apply to tumors of the urinary bladder ● Urothelial carcinomas of the upper urinary tract tend to be MULTIFOCAL because of "field cancerization" ○ which may be caused by exposure of the urothelium to potential carcinogens.

True

● The __________ is variable in position but serves as the LANDMARK to separate the renal pelvis and the ureter

URETEROPELVIC JUNCTION

● Recent data suggest that HYPERMETHYLATIONof the promoter region of patients with urothelial cancers of the urothelium ○ is associated with a ________ prognosis

WORSE ○ was also associated with higher tumor stage, tumor progression, and mortality.

preferred in Dx workup of RCC because it shows calcification and better visualization of other body parts

abdominal +/-pelvic CT scan

● For both renal pelvis and ureter tumors, once the pathologic staging is obtained, patients with pathologic stage pT2, pT3, pT4, or N+ ○ should be considered for

adjuvant chemotherapy with or without radiotherapy ○ See NCCN Guidelines

Renal Cell Carcinoma ● Primary renal cell tumors may spread by local infiltrationthrough the renal capsule to involve the perinephric fat and Gerota fascia ● The tumor may grow directly along the venous channels to the renal vein or vena cava. ● Lymph node metastases occur with an incidence of 9% to 27% ○ most often involve the

renal hilar, para-aortic, and paracaval lymph nodes

● A meta-analysis comparing cryoablation and RFA suggested that

cryoablation results in fewer retreatments and improved local tumor control and that cryoablation may be associated with a lower risk of metastatic progression compared with RFA

● Thespindle cell or sarcomatoid variants of RCC ○ are associated with STATISTICALLY SIGNIFICANT ______ 5-year survival rates, compared with pure clear or clear and granular histologic variants

inferior

● Patients who have local symptoms, such as hematuria, pain, hypertension, or other paraneoplastic syndromes ○ may benefit from a _________ nephrectomy

palliative

● The lymphaticsof the kidney and renal pelvis ○ drain along the renal vessels ● The right kidney ○ drains predominantly into the _____________ lymph nodes ● theleftkidney ○ drains exclusively to the ____________

paracaval and interaortocaval para-aortic lymph nodes

● The ureters course POSTERIORLY and INFERIORLY, paralleling the lateral border of the _________ until they curve anteriorly to join the bladder at the trigone

psoas muscle

● The 2017 AJCC 8th edition staging classification for renal pelvis and ureter carcinoma is shown in Table 67.4

see reviewer

True or False ● Upper urinary tract carcinoma is frequently a MULTIFOCAL process ● Patients with cancer at one site in the upper urinary tract are at significant risk for development of tumors elsewhere along the urothelium. ● The probability of multifocal occurrence is greatest in:

true ○ patients with large tumors and ○ those with carcinoma in situ

● In Sweden, a second prospective randomized clinical trial was also UNABLE to demonstrate an advantage for neoadjuvant radiotherapy in RCC

○ In this trial, patients were randomly assigned to receive neoadjuvant RT to 33 Gy in 15 fractions administered to the flank with a betatron unit followed by nephrectomy or nephrectomy alone ○ Patients receiving neoadjuvant RT had a 5- year survival rate of 47%, compared with 63% for patients undergoing surgery alone

● Among patients presenting with metastatic RCC, the sites of distributioninclude the: ● RCC can metastasize to unusual sites like

○ Lung ○ Bone ○ Brain ○ Liver ○ adrenal gland ○ distant lymph nodes ○ nasal sinuses, skin, penis, etc

● A prospective randomized study of neoadjuvant RT and nephrectomy versus nephrectomy alone was conducted in Rotterdam:

○ NO ADVANTAGE was demonstrated in patients receiving 30 Gy RT in 2 Gy fractions with respect to OVERALL SURVIVAL or SURVIVAL FREE OF DISTANT METASTASIS ○ Neoadjuvant radiotherapy did appear to increase the rate of complete resectability in patients with locally advanced tumors ○ Subsequent patients received 40 Gy in 2 Gy fractions ○ NO BENEFIT was demonstrated at the higher radiation dose

● This is the most important prognostic feature of clear cell carcinoma, after stage:

○ Nuclear grade

● These increase the likelihood of lymph node involvement:

○ Nuclear grade ○ sarcomatoid component ○ tumor size ○ stage ○ the presence of tumor necrosis

● At the renal hilus are the

○ Pelvis ○ Ureter ○ renal artery, and ○ vein

PROGNOSTIC FACTORS Renal Cell Carcinoma: ● Tumor-related prognostic factors include:

○ Stage ○ tumor size ○ tumor grade ○ histologic type ○ tumor necrosis ○ sarcomatoid transformation ○ ≥2 sites of organ metastases

● The kidney cancer NCCN guidelines (version 2.2017) offer the following surgical options depending on the stage:

○ Stage I (pT1a): partial (preferred) or radical nephrectomy (if partial not feasible or central location), active surveillance, or ablative techniques in selected patients ○ Stage I (pT1b): partial or radical nephrectomy ○ Stage II and III: radical nephrectomy or partial nephrectomy if clinically indicated ○ Stage IV: nephrectomy and surgical metastasectomy if potentially resectable primary with solitary metastatic site, followed by systemic first-line therapy; cytoreductive nephrectomy if potentially resectable primary with solitary metastatic site, followed by systemic first-line therapy; or systemic first-line therapy if surgically unresectable

● Radical nephrectomy-induced chronic renal insufficiency is associated with an increased risk of cardiovascular death and death from any cause ● For this reason, nephron-sparing surgery is PREFERRED in

○ T1a and T1b tumors ○ patients with hereditary RCC ■ to preserve renal function and decrease the risk of cardiovascular events **● Bilateral RCC occurs in 2% to 3% of patients In these patients,nephron-sparing surgery is an attractive option because bilateral radical nephrectomy sentences the patient to a lifetime of renal dialysis or the need for a renal transplant

● The organs adjacent to the right kidney include ● On the left, the kidney

○ The liver superiorly ○ the duodenum and the vertebral bodies medially, and ○ the transverse colon and small bowel anteriorly ○ abuts the spleen laterally; ○ the stomach, pancreas, and vertebral bodies medially; and ○ the small bowel and colon anteriorly.

PROGNOSTIC FACTORS Renal Cell Carcinoma: ● Laboratory prognosticfactors include

○ Thrombocytosis ○ elevated ESR or CR

● There are NO ESTABLISHED dose constraints for sparing the remaining kidney after nephrectomy or in the palliative setting when both kidneys are present ● In the context of two normal kidneys, the QUANTEC kidney panel recommended

○ a mean bilateral kidney dose of <15 to 18 Gy and ○ a bilateral kidney DVH with a ■ V12 < 55% ■ V20 < 32% ■ V23 < 30%, and ■ V28 < 20%

● Nevertheless, based on the spleen's exquisite radiosensitivity and experience with palliative radiotherapy for myeloproliferative disorders,it seems prudent to limit the spleen to

○ a total of 5 to 10 Gy

PROGNOSTIC FACTORS Renal Cell Carcinoma: ● Patient-relatedfactors include

○ asymptomatic versus local symptoms versus systemic symptoms ○ weight loss ○ paraneoplastic syndromes ○ an interval of less than a year from original diagnosis to start of systemic therapy

● The World Health Organization (WHO) classifies renal cell tumors as

○ clear cell RCC ○ multilocular cystic renal neoplasm of low malignant potential ○ papillary RCC ○ HLRCC-associated RCC ○ chromophobe RCC ○ collecting duct RCC ○ Renal medullary carcinoma ○ MiT family translocation RCC ○ succinate dehydrogenase (SDH)- deficient RCC ○ mucinous tubular and spindle cell carcinoma ○ tubulocystic RCC ○ acquired cystic disease-associated RCC ○ clear cell papillary RCC ○ unclassified RCC

● A second randomized study conducted by the Copenhagen Renal Cancer Study Group (Kjaer)

○ compared patients with stage II or III renal cell cancer treated with nephrectomy alone with patients who received nephrectomy and adjuvant RT to 50 Gy in 20 fractions to the kidney bed and regional ipsilateral and contralateral lymph nodes ○ No difference in the relapse rate was found between the two study groups ○ There were significant complications involving the stomach, duodenum, and liver in 44% of patients receiving adjuvant RT ○ Specifically, 19% of deaths in the RT group were attributed to RT-induced complications.

Renal Pelvis and Ureter Carcinoma ● Because patients with urothelial carcinoma of the upper urinary tract are at a high risk of urothelial tumors of the bladder, monitoring with cystoscopy at periodic intervals is necessary ● For patients who underwent a renal-sparing procedure, imaging with CT or MRI and/or ureteroscopy may be necessary ● The NCCN Bladder Cancer Panel recommends a

○ cystoscopy every 3 months for 1 year ○ and then at increasing intervals

● The first study from New Castle, United Kingdom (Fugitt)

○ demonstrated an INFERIOR SURVIVAL for patients receiving adjuvant RT compared with those treated by surgery alone ○ Local tumor recurrence rates were not affected by adjuvant RT ○ Four patients died of fatal hepatotoxicity after RT to a right-sided nephrectomy bed. ○ Patients in this study received 55 Gy in 2.04-Gy daily fractions

● A number of other factors have been associated with the development of RCC

○ environmental (e.g., exposure to thorium dioxide) ○ hormonal (e.g., diethylstilbestrol) ○ dietary (e.g., high total energy intake and fried meats increase the risk, whereas vegetables, fruits, and alcohol are protective) ○ cellular ○ genetic factors ● Long-term cigarette smoking ○ is associated with an increased risk of developing RCC ● Obesity, diabetes, hepatitis C, and hypertension are also associated with a higher relative risk for development of these tumors

FOLLOW-UP Renal Cell Carcinoma ● The NCCN Kidney Cancer Panel recommends patients be seen

○ every 6 months for the first 2 years after surgery ○ and then annually up to 5 years after diagnosis

● The greatest risk of recurrence following surgery for RCC is

○ in the first 1 to 2 years ○ with most relapses occurring within 3 years ○ but recurrences can occur more than a decade later

● The WHO classifies urothelial tumors as

○ infiltrating urothelial carcinoma or ○ infiltrating urothelial carcinoma with the following variants: ■ with squamous differentiation ■ with glandular differentiation ■ and with trophoblastic differentiation ■ nested ■ microcystic ■ micropapillary ■ lymphoepithelioma-like ■ plasmacytoid ■ sarcomatoid ■ giant cell ■ undifferentiated

Renal Pelvis and Ureter Carcinoma ● The major prognostic factors in patients with renal pelvis or ureter carcinoma are

○ initial stage ○ grade of the tumor

● The lymphatic drainage of the ureter

○ is segmentedand diffuseand may involve any of the renal hilar, abdominal para-aortic, paracaval, common iliac, internal iliac, or external iliac lymph nodes.

● The dose to the stomach should be ● the small bowel

○ kept below 45 Gy ○ V45 < 195 cc ○ **when it is contoured as a bowel bag (Fig. 67.3)

● For patients with METASTATIC RCC, the following factors were predictive of SURVIVAL in a retrospective study of 670 patients:

○ low Karnofsky performance status (<80) ○ high LDH (>1.5 times upper limit of normal) ○ low hemoglobin (less than lower limit of normal) ○ high "corrected" serum calcium (>10 mg/dL or 2.5 mmol/L) ○ absence of prior nephrectomy

● Conservative surgical excision should be considered only in patients with ● Conservative surgical options in selected cases include

○ low-grade, low-stage, solitary tumors in whom radical nephrectomy is not indicated because of poor kidney function or an absent contralateral kidney ○ laparoscopic nephroureterectomy ○ nephrectomy and partial ureterectomy ○ endoscopic resection, and fulguration

● Retrospective studies suggest that adjuvant RT in urothelial Ca of upper urinary tract

○ may diminish the likelihood of local tumor recurrence ○ but it DOES NOT APPEAR to have an impact on overall survival or reducing future distant metastases

● High-grade renal pelvis tumors, large tumors, or tumors that invade the renal parenchyma have the following management options:

○ nephroureterectomy with a cuff of bladder and regional lymphadenectomy, with consideration of neoadjuvant chemotherapy in selected patients.

● The bladder cancer NCCN guidelines (version 2.2017) recommend the following treatment options for renal pelvis low-grade tumors:

○ nephroureterectomy with a cuff of bladder or ○ endoscopic resection ± postsurgical intrapelvic chemotherapy or BCG

● Most contrast-enhancing masses tend to be malignant, and the odds ratio of malignancy increases with increasing size. ● If computed tomography (CT) or ultrasound clearly identifies the mass as a cyst ● If a solid lesion is identified ● In the case of small lesions,

○ no further workup is necessary ○ then tumor removal by nephrectomy should be considered ○ a follow-up CT scan to evaluate potential growth of the mass may raise the suspicion of malignancy

● The NCCN guidelines list the following first-line systemic therapies for CLEAR CELL histology:

○ pazopanib (Category 1, preferred) ○ sunitinib (Category 1, preferred) ○ bevacizumab + interferon (Category 1) ○ temsirolimus (Category 1 for poor-prognosis patients and Category 2B for selected patients of other groups) ○ axitinib ○ high-dose IL-2 for selected patients ○ sorafenib for selected patients ● Subsequent therapy includes ○ cabozantinib (Category 1, preferred) ○ nivolumab (Category 1, preferred) ○ axitinib (Category 1) ○ everolimus ○ pazopanib ○ sorafenib ○ sunitinib ○ bevacizumab (Category 2B)\ ○ high-dose IL-2 for selected patients, or ○ temsirolimus (Category 2B)

● A radical nephrectomy includes a:

○ perifascial resection of the kidney ○ perirenal fat ○ regional lymph nodes, and ○ ipsilateral adrenal gland ● Adrenalectomy ○ is NOT indicatedwhen imaging shows a normal adrenal gland or if the tumor is not high-risk

● The mucosal surfaces of these all have the same embryologic origin

○ renal collecting tubules ○ calyces ○ renal pelvis ○ ureter ○ bladder ○ urethra

● For non-clear cell histology, the NCCN guidelines list the following first-line systemic therapies:

○ sunitinib, axitinib, bevacizumab, cabozantinib, erlotinib, everolimus, lenvatinib + everolimus, nivolumab, pazopanib, sorafenib, and temsirolimus (Category 1 for poor-prognosis patients and Category 2A for other risk groups)

● The kidneys are retroperitoneal structures located at the level between ● Each kidney is approximately ________ in length ● The kidney is encased by a fibrous capsule and surrounded by perinephric fat, which is enveloped by Gerota fascia

○ the 11th rib and the transverse process of the 3rd lumbar vertebral body 11 to 12 cm in length

Renal Pelvis and Ureter Carcinoma ● Adjuvant radiation therapy has been used in the management of renal pelvis and ureter cancers ● For elective radiotherapy, the clinical target volume should include

○ the renal fossa ○ the course of the ureter to the bladder ○ the entire bladder, and ○ the paracaval and para-aortic lymph nodes (Fig. 67.3)

● The EORTC conducted a randomized trial of radical nephrectomy with or without an elective lymph node dissection

○ there was NO SURVIVAL ADVANTAGE between the two study groups ○ The incidence of unsuspected lymph node metastases was low (4%) ● Nevertheless, the lymph node dissection does provide valuable prognostic information.