Renal cancer

Nearly 30% of patients percent with denovo metastatic disease and almost 30% of those with initial localized disease will eventually develop metastasis after the surgical resection of the primary tumor.

In a localized setting a superior overall survival for patients with clear cell renal carcinoma is experienced in patients who were overweight and obese.

70% of patients are diagnosed with stage I RCC and 11% of patients with stage IV.

In patients  with obesity there is a lower risk of lymph node metastases and other poor prognostic factors such as renal vein invasion in male patients with obesity.

Aoround 16% of patients with renal cancer have metastatic involvement upon initial diagnosis with a recurrence rate of 30% in five years survival rate of approximately 14%.

Risk is weight dependent as an increase in BMI by 1 is associated with a rising risk of renal cell cancer by 4%.

Incidence over the last several decades steadily risen by approximately 2-4% annually.

Most renal cell carcinomas originate in the renal cortex-80-85%.

Despite early detection of smaller kidney lesions, the rate of renal cell carcinoma related mortality has increased, this suggesting that recurrence and advanced disease are responsible for mortality.

Steady increase in of approximately 2-4% per year in incidence over the last 2 decades, without explanation.

Associated with oncogenic pathways there include an activation of the von Hippel Lindau gene, mutations in the chromatin modifying genes polyp romo-1 and BRCA1 associated proteins and alterations in the tumor immune micro environment.

RCC arises from epithelial cells of the renal cortex and diagnosis is determined by histological review of morphology, and chemistry.

Immunohistochemical markers suggest renal carcinoma include presence of renal lineage marker paired box protein 8 (PAX8) and carbonic anhydrase IX, a transmembrane protein, specific for clear cell renal cancer.

For patients with low risk disease, which is defined as T1N0, the risk of recurrence is approximately 1-8% after surgery.

Nearly 1 in 5 patients will have a distinct metastasis at the time of diagnosis.

About 16% of patients have evidence of regional lymph node spread.

Approximately 1/3 of patients treated with curative intent will develop metastatic disease and about 30% of patients have metastatic disease at their initial presentation.

50% of patients with high risk features will have disease recurrence after surgery with curative intent.

5 year survival for all patients is greater than 75%, and those with metastatic disease a 5 year survival rate less than 12%.

Patients with initially clinically localized renal cell cancer confined to the primary site have a five-year survival rate of greater than 92%.

Approximately  75% of patients with RCC survive five years and more after diagnosis.

Despite adequate resection of the primary tumor, 30-40% of patients with locally advanced disease will recur.

Increased use of imaging and incidental discovery of renal masses in asymptomatic patients has resulted in the downgrading in the staging of renal cancers with smaller size and less locally advanced lesions and fewer lesions with metastatic disease (Volpe A et al).

The increased detection of renal cell cancer and downward stage migration has not resulted in improved cancer specific outcomes, suggesting over diagnosis and overtreatment of clinically insignificant renal lesions.

Approximately 208,000 new cases and 102,000 deaths per year in the world.

When kidneys are examined at autopsy with serial 2-3 mm sectioning, the prevalence rate of kidney cancer exceeds 22%.

Current age-specific prevalence rate of kidney cancer is 0.03-0.06% in the general population and 0.3% in men more than 70 years old.

Makes up about 2.6% of cancer diagnoses and deaths in the U.S.

Seventh most frequent cancer in men and the twelfth most common in women.

Mean age 64 years.

Rare below 45 years.

Approximately twice as common among men than women.

The size of tumors that diagnosis has been decreasing, likely due to increased use of abdominal imaging and higher incidental detection rate of asymptomatic tumors.

Coincident with a higher incidence of kidney cancer there is a stage migration with increasing diagnosis of stage T1 tumors which are organ confined, 7 cm or less, and related decreases in stages T2-T4.

Incidence increasing each year since than 1970’s with greater increases among blacks than whites.

Incidence in African Americans increasing the fastest in the U.S. surpassing that of white Americans.

Blacks now represent the highest risk group in the U.S

In an analysis of 40,000 patients, the five year survival for patients with RCC was 72.6% for white patients and 68% for blacks (NCI).

Having a first degree relative with renal cancer associated with 2-4 fold increased risk.

Patients with her family history have a 2.8 times greater chance for developing renal cancer during their lifetimes and account for 4% of all renal cancer cases.

Associated with six hereditary renal cell cancer syndromes: Von Hippel-Lindau, hereditary papillary renal carcinoma, Birt-Hogg- Dube syndrome, hereditary leiomyomatosis renal cell cancer, succinate dehydrogenase associated familial cancer, and tuberous sclerosis complex.

At least 13 genes have been identified to predispose patients to development of kidney cancer.

Inactivation of the von Hippel (VHL) ) gene is the cardinal oncogenetic event in the pathogenesis of clear cell renal cell cancer.

Most renal cell tumors exhibit by allelic loss of the tumor suppressor, gene VHL, which regulates hypoxia signaling.

Approximately 85% of all kidney tumors are renal cell carcinoma, and approximately 70% of renal cell carcinomas are of clear cell histology.

Approximately 3% of RCC are hereditary.

Loss of function in this tumor suppressor gene results in high levels of hypoxia- inducible factor with activation of multiple downstream factors involved in angiogenesis and cell proliferation, most prominently in the vascular endothelial growth factor.

In the majority of patients with renal cell cancers a loss of heterozygosity at chromosome 3p can be detected.

Genes associated with these syndromes are VHL, MET, FLCN, FH, SDH, TSC1 and TSC2, respectively.

Additional driver genes involved in the pathogenesis of renal cell cancer include PBTM1, and BAP1, SETD2, two, TCEB1, and KDM5C.

Von Hippel-Lindau syndrome increases the risk for clear-cell renal carcinoma.

Brit-Hogg-Dube syndrome increases the risk the chromosomal for hybrid renal cell carcinoma.

Mutations in the microphthalmia transcription factor gene (MITF) increases the risk of papillary and clear cell renal carcinoma.

Hereditary papillary renal carcinoma, increases the risk for papillary type 1 renal cell carcinoma, and hereditary leiomyomatosis and renal cell carcinoma increases the risk of papillary type 2 renal cell carcinoma.

Metachronus renal tumors in either the ipsilateral or contralateral kidney found in as many as 20% of patients with papillary renal cancer or familial renal cancer.

May produce multiple hormone-like or cytokine-like biologically active products leading to paraneoplastic syndromes.

Paraneoplastic syndrome occurs in 10 to 40% of patients with RCC.

Common paraneoplastic manifestations include fever at 8%, hypercalcemia 1 to 30%, anemia 22 to 52% and thrombocytopenia 3 to 18%, erythrocytosis at 2 to 4%, and hypertension at 3 to 18%.

Paraneoplastic erythrocytosis is associated upon RCC cell VHL inactivation.

Relative risks for associated renal cancer and hypertension ranges between 1.3 and 2 or greater.

Adjusted incidence rates among white men, white women, black men and black women during period of 1992-2002 were 13.8, 6.6, 16.8, and 8.0 per 100,000 person-years, respectively.

In the U.S. increase in incidence more rapid among females than males.

C-reactive protein associated with systemic inflammation response to tumor proliferation and renal cell carcinoma specific mortality.

Approximately 65% of patients are diagnosed when the cancer is only located in the kidney.

The five-year survival for patients with disease confined to the kidney is 93%.

Up to 30% of patients present with advanced disease at diagnosis.

10-20% of patients treated for early stage disease experience recurrence.

Lifetime risk is about one in 63 or 1.6%.

If kidney cancer has spread to surrounding tissues, organs, and or the regional lymph nodes, the five-year survival rate is 66% and if the cancer spread to a distant part of the body the 5 year survival is 12%.

Increased risk with acetaminophen use and NSAIDs excluding aspirin.

For patients using NSAID’s from 4-10 years have significant increase in risk of renal cell carcinoma.

Patients exposed to non-aspirin NSAIDs for over 10 years should be counseled to discontinue these meds because of strong association between the use and the risk of developing renal cancer.

C-reactive protein elevated levels predict survival for localized and metastatic renal cell cancer.

Inhaled tobacco smoke is implicated in the etiology of renal cancer.

Increased risk with the increase in number of cigarettes smoke per day and a substantial reduction in the risk of renal cancer occurs for long term former smokers.

Higher body mass index independently associated with long-term risk of renal cancer in men.

Reducing hypertension is associated with a reduced risk.

The three risk factors of smoking, high body mass index, and hypertension are associated with 49% of cases.

Established risk factors for RCC development include older age, male gender, African-American, or native American, smoking, hypertension, obesity, and some genetic predispositions.

Increasingly lesions have been identified by chance.

Only 30% of patients with renal cell cancer are diagnosed on the basis of symptoms.

Patients with metastatic disease who continue to smoke reduce their overall survival, and continuing to smoke reduces the benefits of targeted therapies.

Modifiable risk factors include exposure to asbestos, thiazides, acetaminophen or other analgesic drugs.

Renal carcinoma more common in chronic hepatitis C infection, end-stage renal disease, acquired renal cyst disease, and tuberous sclerosis than in the general population.

PD-L1 expression in most cases of RCC and is associated with unfavorable survival.

Renal cell cancer impairs tumor immunity through indirect effects on the proliferation of T regulatory cells and myeloid derived suppressor cells and shifting the Th-1/Th-2 bias toward a pro-inflammatory state.

Impaired immunity in renal cancer include the expression of B7-H4 on tumor cells, which upon binding their receptors, act as negative regulators of T-cell immune the mediation.

19% of patients diagnosed with metastatic disease, and metastases will develop a 20-40% of individuals following nephrectomy for localized RCC.

Risk factors for recurrence after nephrectomy are related to: disease stage, size, nuclear grade, regional lymph node involvement of the resected tumor, and all are associated with an increased likelihood of disease recurrence, as well as with a reduced duration of recurrence and metastasis free survival.

Highest rates in Scandinavia, northern Europe and North America.

Asian Americans and Pacific Islanders of the lowest incidence within the US.

Highest rates observed in the Czech Republic and North America.

Approximately 50% more common in men than in women.

Usually occurs between the sixth and eighth decades of life, with a median age 65 years.

Lowest rates in India, China, Japan and in areas of Central and South America.

The most common sites of distant metastases are lungs, bone, and brain, but adrenal glands, contralateral kidney, and liver may demonstrate metastases.

In metastastic disease the most frequent metastases are lung,69%, 43% lymph nodes, 34% bones, 195 to the liver and 8% to the brain.

Bone metastasis occur in more than a third of patients with advanced RCC.

Lesions can be sporadic or hereditary, but both both forms are associated generally with structural alterations of the short arm of chromosome 3.

Survival after nephrectomy dependent upon pathological T stage, tumor grade, lymph node status and performance status.

Initial treatment for localized renal cell cancer is surgery, but 20-30% typically relapse, with a median time to relapse 1-2 years.

The risk of recurrence in surgically treated renal-cell carcinoma (RCC) persists beyond five years after surgery.

 

The 36-month cumulative incidence of recurrence was 31.1%. It was 26.0% for patients who did not have recurrence at 12 months from surgery, 18.8% at 24 months, 16.1% at 36 months, 18.9% at 48 months, and 20.3% at 60 months, the researchers report in European Urology.

 

On multivariable analysis, age, pathological T3/4 stage, pathological N1/2 stage, Fuhrman grade 3, and Fuhrman grade 4 independently predicted disease recurrence at 0 months from surgery, but none of these variables predicted recurrence at 60 months from surgery.

 

The risk of recurrence at year 5 appears similar, if not higher, to that at years 2, 3, and 4 from surgery.

Patients in good medical condition should have tumor resection of stage I-III tumors.

Most postsurgical recurrences present within the first couple of years after surgery and approximately half of all distant recurrences occur in the lung, but late recurrences and non lung sites of metastases are not uncommon.

The most common sites of RCC metastases are lung at 70%, lymph node 45%, bone 32%, liver 18%, adrenal gland 10%, and brain 8%.

A small number of patients will develop recurrences >10 years after surgical resection, and some present with distant metastases > 20 years.

Only 2.8% of patients develop recurrences after 5 years.

The risk of recurrence in surgically treated renal-cell carcinoma (RCC) persists beyond five years after surgery.

 

The 36-month cumulative incidence of recurrence was 31.1%. It was 26.0% for patients who did not have recurrence at 12 months from surgery, 18.8% at 24 months, 16.1% at 36 months, 18.9% at 48 months, and 20.3% at 60 months, the researchers report in European Urology.

 

On multivariable analysis, age, pathological T3/4 stage, pathological N1/2 stage, Fuhrman grade 3, and Fuhrman grade 4 independently predicted disease recurrence at 0 months from surgery, but none of these variables predicted recurrence at 60 months from surgery.

 

The risk of recurrence at year 5 appears similar, if not higher, to that at years 2, 3, and 4 from surgery.

 

Patients included in this study are those with intermediate- and high-risk disease with negative surgical margins.

Patients with low stage, low grade and incidentally noted kidney cancers have a more favorable long term prognosis.

Most important prognostic determinants are tumor stage, grade, local extent of the tumor, presence of regional nodal metastases, the presence of sarcomatoid features, and evidence of metastases at presentation.

The use of ctDNA  and MRD is efficacious in following patients with renal cell cancer management.

ctDNA Assay is prognostic of recurrence, in patients with resected renal cell carcinoma.

Medical evaluation prior to surgery include: CBC, chemistry profile, CT of abdomen, CXR although CT of chest is better for staging.

Preoperative evaluation includes assessing the inferior vena cava for tumor involvement, and bone scan or CT brain studies are performed only if clinical signs or symptoms are present.

PET scan is still not standard for evaluation.

Median survival for patients with metastatic disease is 10 months, with less than 2% with long term survival.

5 year survival rate has increased over time for localized disease from 88.4% during 1992-1995-91.8% during 2004-2010 and advanced disease from 7.3% during 1992-1995-12.3% during 2004 2010 (SEER).

With targeted therapies median survival is increased from approximately 12 months in the interferon era up to 40 months (Escudier B et al).

CARMENA Trial demonstrated that the initial cytoreductive nephrectomy in metastatic renal cell cancer is not more beneficial than starting with targeted therapy.

Cytoreductive nephrectomy management is reserved in the a upfront setting for those with more favorable features, such as minimal extra renal disease and few metastatic risk factors and can be considered in the deferred setting for patients who have exceptional systemic disease responses following systemic therapy.

Given the toxicity and general non-curative nature of systemic therapy, asymptomatic patients whose disease is expected to follow a more indolent course could benefit from active surveillance.

TARGET study with sorafenib doubled the median progression free survival from 2.8 months with placebo to 5.5 months with this drug in patients with advanced RCC with a 56% reduction in the risk of progression of disease (Treatment Approaches in Renal cancer Global Evaluation Trial, Escudier B et al).

TARGET study sorafenib associated with 78% stable disease and 2% partial response, compared to 55% and 0%, respectively for placebo, and a median survival of 17.8 months compared with 15.2 in the placebo arm.

Among 670 patients with metastatic disease factors predictive of survival include: Performance status, serum calcium level, hemoglobin level, serum LDH level and nephrectomy status (Motzer RJ et al).

The 5-year survival rate for localized cancer is greater than 90%.

5-year survival is less than 10% for patients with metastastic disease.

Unlike other genitourinary cancers renal cell cancer tends to the unifocal with no field defect as is seen in prostate and bladder malignancies.

The incidence of multifocality ranges from 10-to 13% in the non-hereditary population.

Represents different histological subtypes with variable metastatic potential and penetrance in different populations.

Nephrectomy in patients with metastatic disease increases median survival: Nephrectomy followed by interferon treatment as a median survival of 13.6 months compared to 7.8 months in patients assigned to interferon alone (Flanigan RC et al).

There is an improved overall survival in patients with metastatic renal cancer treated with cytoreductive nephrectomy and immunotherapy compared to immunotherapy alone.

Improved survival in cytoreductive therapy due to possibly that the primary tumor may sequester antibodies, immune cells, allow immunotherapy to work on metastases to a greater degree and the reduction of VEGF, platelet-derived growth factor, fibroblast growth factor and transforming growth factor secreted by the primary tumor.

Patients that may benefit from cytoreductive nephrectomy: those with 75% tumor burden reduction, absence of CNS, bone or liver metastases , and have adequate pulmonary and cardiac function, good performance status and predominantly clear cell histology.

The median survival for patients with metastatic RCC treated with cytoreductive nephrectomy and the above characteristics have a median overall survival of 20.5 months (Fallick ML et al).

A meta-analysis of patients treated with cytoreductive surgery and targeted therapy showed that such surgery adds to a reduction in risk of death of 50% compared to patients treated with targeted therapy alone (Petrelli Fausto et al),

Immunotherapy based interventions prior to cytoreductive nephrectomy in patients with advanced or metastatic renal cell cancer demonstrates efficacy with the small fraction of patient showing complete response (Panian J).

Prognosis showing slow improvement with 5 year relative survival rates as high as 64% by 2002 compared to 40% in the early 1960�s.

Kidney cancer reflects the presence of a number of different types with different histology, clinical course, caused by different genetic abnormalities and responding differently to therapy.

Memorial Sloan-Kettering Cancer Center system for evaluating metastatic renal cancer include 5 clinical features predicting survival: low Karnofsky performance status, LDH >1.5 times normal, low serum hemoglobin, high serum calcium and time from diagnosis to the start of treatment: survival ranging from 30 months in patients with no risk factors to 14 months in patients with 1-2 risk factors and to 5 months in patients with 2 or more risk factors.

Risk factors include systolic hypertension, diastolic hypertension, smoking, kidney disease, patients undergoing dialysis, environmental exposures to heavy metals, industrial solvents, obesity, and hereditary cancer syndromes.

85% are adenocarcinomas.

10% of derived from the renal pelvis, a urothelial cancer.

Histologic diagnosis is typically established after surgical removal of lesions or after biopsy.

One fifth-one third of patients present with metastatic disease.

About 11% cases are transitional cell cancers of the renal pelvis and sarcomas and other soft tissue malignancies make up about 2% of cases.

65-70% of cases clear cell type derived from proximal convoluted tubules.

Predominant types of kidney cancer include clear cell 75%, papillary 15%, chromophobe 5%, and oncocytic type tumors.

Non-clear cell malignant tumors of the kidney account for approximately 25% of cases.

The most common non-clear renal cancer subtype is papillary, and include chromophobe, sarcomatoid, collecting duct, medullary, and various hereditary forms.

Several types of RCC are related to a hereditary process with von Hippel Landau (VHL) disease being the most common.

VHL is caused by an autosomal dominant constitutional mutation in the VHL gene that predisposes to benign and malignant cysts or tumors.

Chromophobe renal cell carcinoma is the third most frequent kidney cancer histologic subtype, accounting for proximally 5% of all renal cell cancers.

At diagnosis chromophobe renal cell cancers are generally confined to the kidney but can metastasize.

The median survival for patients with chromophobe renal cell cancer treated with targeted drugs ranges between 25 and 32 months.

Oncocytoma and chromophobe tumors cluster together and suggest origins from distal cells of the nephron.

In a surgical series of renal cell tumors involving 1600 consecutive patients benign neoplasms comprised 7% of tumors with papillary adenoma, renal oncocytoma and metanephric adenoma, with 93% malignant tumors, 82% clear cell, 11% papillary, 5% chromophobe, less than 1% collecting duct and 2% unclassified (UCLA).

Non-clear renal cancers are less responsive to drugs active with clear cell cancers of the kidney.

The number of benign renal tumors treated annually is estimated to be a 5600, an approximately 80% increase over the last decade.

Clear cell cancer develops from activation of pseudohypoxic pathways within the proximal tubules as a result of loss of function of the von Hippel Lindau tumor suppressor gene and leading to protein expression of the hypoxia-inducible factors (HIF).

Clear cell renal cell cancer produces proangiogenic growth factors and has hosted immune dysfunction.

Von Hippel Landau protein loss accounts for transcription factors HIF 1 and 2 to accumulate and transcriptionally activate genes including VEGF and PDGF mediators of angiogenesis of renal cell cancer.

m-TOR complex promotes HIF synthesis during cellular stress.

M-TOR biology is a driver of aggressive poor risk cancer.

In renal cell carcinoma m-TOR pathway activation correlates with survival and poor pathologic prognostic features.

Clear cell type tumors usually are unilateral, sporadic and unifocal.

Approximately 85% of kidney tumors are renal cell carcinoma, and approximately 20% of these are clear RCC.

Clear cell makes up 60-70% of all lesions.

Clear cell tumor cells have clear cytoplasm, acinar growth pattern and increased lipid and glycogen.

An aggressive RCC variant almost exclusively arises in patients who have sickle cell trade, or hemoglobin SC disease, or, rarely, sickle cell disease.

The most recent pathologic classification suggest there are close to 20 types of RCC.

Low-grade tumors have more clearing than high grade lesions where the cytoplasm may be partially clear or eosinophilic.

Sarcomatoid carcinoma may be present in clear cell, collecting duct, chromophobe, and papillary types.

The presence of sarcomatoid changes regardless of tumor type of origin suggests high grade disease.

Sarcomatoid renal cancer is associated with resistance to established therapies, and most cases have metastatic disease upon presentation.

In the CheckMate 214 study the use of ipilimubab and nivolumab resulted in a 56% overall response rate in sarcomatoid renal cancers.

In the Checkmate 214 study the combination of ipilimubab and nivolumab significantly improved overall survival and quality life over sunitunib as first line treatment.

Among patients with previously untreated, advanced renal cell carcinoma, who had intermediate or poor prognosis, treatment with cabozantinib plus Nivolumab and ipilimumab, resulted in significantly longer progression free survival than treatment with Nivolumab and ipilimumab alone( COSMIC-313 Investigators).

Granular cell features may be seen in papillary, oncocytic, collecting duct and clear cell carcinomas.

Majority of lesions are sporadic and a small percentage may be hereditary, such as those of clear cell type associated with the VHL gene

Many cases of clear cell cancer related to inactivation of the von Hippel Lindau tumor suppressor protein.

Renal cancers arise from biallelic VHL a gene inactivation.

One of the alleles is inactivated to a deletion as observed in more than 90% of noninherited, sporadic) clear cell renal cell carcinoma.

The remaining VHL a lead held is inactivated flu gene mutation involving approximately 50% of clear cell renal cell cancers, or through gene silencing by methylation in 5 to 10% of cases.

For carcinogenesis to take place alterations and other gene loci other then VHL are probably required

Inherited forms of cancer likely to be diagnosed earlier in age, more likely to be multifocal and bilateral.

At least 60% of these tumors are associated with von Hippel Lindau tumor suppressor gene inactivation.

Loss of the Von  Hippel Lindau tumor suppressor gene occurs in up to 90% of clear cell, renal cell tumors, and VHL inactivation leads to activation of hypoxia and angiogenesis pathways.

von Hippel Landau protein is a critical component of a pathway that couple changes in oxygen availability to gene expression through the regulation of a hypoxia inducible factor (HIF).

von Hippel Lindau (VHL) protein degrades the HIF-alpha subunit when oxygen abundant, coupling oxygen needs to HIF activity.

Cells deficient in VHL accumulate HIF-alpha under normal oxygen tension and have an increased expression of HIF regulated genes including those that encode for angiogenesis and tumorigenesis.

von Hippel Lindau (VHL) gene responsible for hyperphosphorylating and causing ubiquitization of HIF-alpha inducible factor leading to its degradation, with its mutation HIF-? not degraded and leads to the transcription of genes that increases vascularization.

Inactivation of VHL increases HIF activity and increases VEGF, PDGF�, and TGF-?.

Immune dysfunction exists with a shift from a type-1-mediated CD4+ T cell response reducing interferon- gamma, to a type-2 cytokine response there is important in mediating humoral immunity.

VEGF pathway is the primary driver of renal cell cancer due to defects in the VHL gene.

Increased vascular endothelial growth factor (VEGF) and transforming growth factor-alpha (TGF-alpha) and loss of VHL tumor suppressing gene suspected to lead to progression of clear cell renal carcinoma.

VHL inactivation results in highly vascular tumors with a high risk of bleeding.

the VHL Gene is part of the complex of hypoxia inducible factor family of transcription factors for degradation.

More common in patients with chronic hepatitis C infection, end-stage renal disease, acquired renal cystic disease and tuberous sclerosis.

Patients with a positive family history of RCC account for about 4% of cases.

Studies have revealed 6 hereditary RCC syndromes: von hippel-Lindau, hereditary papillary renal carcinoma,Birt-Hogg-Dube syndrome, hereditary leiomyomatosis RCC, succinate dehydrogenase-associated familial cancer, and tuberous sclerosis complex.

Genes associated with the above syndromes are VHL, MET, FLCN, FH, SDH, TSC1 and TSC2, respecively (Lineham WM et al).

The three dominant histological subtypes are clear cell (75–80%), papillary ( 10–15%) , and chromophobe ( (5%)).

10-15% of cases are papillary cancers derived from distal convoluted tubules and have a better prognosis than those with clear cell type.

Clear cell renal cancer is named for its golden yellow clear cytoplasm.

Papillary cancers more likely to be bilateral and multifocal than clear cell types of cancer.

Papillary cancer are the most common type to present with bilateral disease.

There are two and possible three types of papillary renal cancer with morphologic, genetic and distinct clinical behaviors

Papillary cancers often have abundant lipid laden macrophages within the interstitium of fibrovascular cores.

Papillary renal cancers have a better prognosis than clear cell cancers.

Approximately 10% of sporadic papillary renal cancers have mutations in c-MET gene.

MET and AXL are involved with resistance development to VEGFR targeting therapy.

Majority of sporadic papillary renal cancers characterized by trisomy of chromosomes 7 and 17 in type I tumors, as well as loss of chromosome Y.

Type 2 papillary renal cancers associated with mutations in the fumarate hydratase (FH) gene.

Chromophobe cancers make up 5-10% of renal cancers and tend to be indolent.

Chromophobe cancers have a cobblestone appearance.

Chromophobe cancers of the kidney characterized by loss of chromosomes 1 and Y and chromosomal losses affecting chromosomes 1, 6, 10, 13, 17, and 21.

Chromophobe cancers associated with loss of multiple chromosomes leads to hypodiploid tumor cells.

Chromophobe renal cancers have prognosis that is much better than clear cell renal cancers with a 5-year disease free survival rates near 90%.

Collecting duct tumors make up fewer than 1% of renal cancers.

Collecting duct cancer tends the occur in younger patients.

Collecting duct cancers arise from such ducts within the renal medulla and exhibit papillary and tubular growth patterns.

Collecting duct cancers are aggressive tumors with one third of patients presenting with metastases and most die within 3 years of diagnosis.

Medullary cancer of the kidney is a variant of collecting duct carcinoma and found mainly in patients with sickle cell trait.

Oncocytic tumors make up 2-5% of tumors.

Up to 7% of renal cancers are unclassifiable based on architecture.

Cigarette smoking a risk factor with a range of 1.2-2.3.

Smoking estimated to account for approximately 20-30% of such lesions among men and 10-20% among women.

Strong dose dependent increase in risk with smoking with a relative risk of 2.0 among heavy male smokers and 1.6 for heavy female smokers.

Risk of renal cancer decreases as period of smoking cessation increases, with a 15-30% reduction in risk by 10-15 years after quitting.

Obesity an associated causative factor as is hypertension.

Exposure of ionizing radiation weakly increases risk for patients treated for ankylosing spondylitis and cervical cancer.

Relative risk for renal cancer of 1.07 per unit increase of body mass index.

Hypertension an independent risk factor.

A reduction in blood pressure associated with reduced risk of RCC.

Smoking, elevated body mass index and hypertension associated with 49% of cases (Benichou J et al).

Longer duration of nonaspirin NSAIDs may increase risk (Cho E et al).

Use of aspirin and acetaminophen not associated with renal cancer.

Rising incidence may partly be accounted for by increasing rate of obesity (40%).

About 40% of patients present with hematuria.

Typical presentation is with local disease at 65% of cases.

Pain, hematuria and a palpable mass are the most common presenting findings.

Classic clinical presentation of flank pain, hematuria and mass is uncommon and seen in about 10% of patients and reflects advanced disease.

Because of its retroperitoneal space location, only large renal cell cancers are detected by palpation, and abdominal imaging now leads to incidental RCC detection in 37 to 61% of cases.

With increased incidental detection of RCC, gross hematuria is found in less than 25% of patients and occurs more often in advanced disease.

Approximately 1.3% of patients with gross hematuria are eventually diagnosed with RCC.

25-39% of patients are asymptomatic and are diagnosed incidentally on radiographic studies for other diagnostic purposes.

Fewer than 5% associated with erythrocytosis.

With a cure rate of approximately 50% only 1% of the adult population develops potentially lethal renal cancer.

Metachronous metastases will develop in approximately 1/3 of patients in whom renal cell carcinoma is initially local.

With improved treatment renal cancer has emerged as an necessity and is used to establish diagnosis of indeterminate renal masses, obtain histology of incidentally detected renal masses in patients who are candidates for active surveillance, and select the most suitable targeted therapy for patients with metastases.

A needle biopsy is not necessary if imaging studies indicate clear findings.

Needle biopsy may be indicated for small lesions or central lesions to rule out urothelial cancer.

Messenger RNA for human protein survivin is over expressed in aggressive cancers compared to un-aggressive renal cell cancers.

Patients with metastases median survival less than 1 year.

Advanced renal cell carcinoma 5-year overall survival is less than 5%.

Metastatic disease that is untreated is associated with overall survival rates at 3 and 5 years of less than 10% and 2%, respectively.

Approximately 50% higher incidence in males than in females.

Most rapidly increasing of all types of tumors in the U.S.

About 25-30% of patients initially diagnosed have metastatic disease.

60-70% of patients present with localized cancer.

For localized disease the 5-year relative survival rate is approximately 90%, indicating stage the diagnosis is the most important prognostic factor.

15-20% present with regional spread of the cancer.

Forty percent of patients present with localized disease but develop metastases after nephrectomy.

Approximately 2-11% of patients will initially present with or develop brain metastases.

About 10% of patients with brain metastases initially present with seizure activity (Culine S et al).

An interim analysis of the CheckMate 920 phase IIIb/IV trial indicates that the combination of nivolumab and ipilimumab is safe and effective in advanced renal cell carcinoma (RCC) patients with brain metastases, with encouraging antitumor activity.

Only curative therapy for localized disease is radical nephrectomy.

Radical nephrectomy involves removal of the kidney, Gerota�s fascia, perirenal fat and the ipsilateral adrenal gland with or without ipsilateral lymph node dissection.

Effective control of cancer with no statistical differences between open and laparoscopic radical nephrectomy.

Radical nephrectomy is the preferred tretment if the tumor extends to the inferior vena cava.

A study comparing outcomes for thermal ablation versus nephrectomy for renal cell carcinoma found that thermal ablation provided superior outcomes.

Using the National Cancer Database, 4,817 of 56,065 patients (8.6%) who underwent thermal ablation and 51,248 of 56,065 patients (91.4%) who were treated with nephrectomy, and all patients had biopsy-proven T1aN0M0 renal cell carcinoma.

Older patients with more comorbidities tended to receive thermal ablation.

Perioperative outcomes are superior for thermal ablation: including unplanned hospital readmission (2% vs 3.3%), mean hospital stay (1.3 days vs 4.3 days), and 30- and 90-day postoperative mortality (0% vs 0.9%, and 0% vs 1.4%, respectively).

Nephron sparing surgery is now replacing radical nephrectomy as the surgical treatment of choice.

5-year disease free rate for T1 to T2-N0-M0 patients was 91% for laparoscopic surgery.

In the absence of enlarged lymph nodes there is no clinical benefit to adding regional lymph node dissection to radical nephrectomy.

5 year survival rates as low as 5% in patients with nodal metastases.

Estimated cancer specific survival rates of nodal involvement following radical nephrectomy at 1, 5, and 10 years for patients with pN0/pNx clear cell disease is 95.5%, 82.1% and 72.5%, respectively, compared with 52.2%, 20.9% and 11.4% for patients with pN1/pN2 disease (Blute).

In a EORTC 30904 study randomized patients with renal cell cancer to partial nephrectomy or radical nephrectomy in more than 500 patients with small renal tumors of less than 5 cm and a normal contralateral kidney: Partial nephrectomy associated with more perioperative morbidity and a 10 year overall survival better in the radical nephrectomy group 81% versus 76%, and cardiovascular events more common in the partial nephrectomy group.

Adrenalectomy in the context of radical nephrectomy is no longer felt to be necessary for most tumors and is reserved for upper pole lesions.

Features that are associated with increased risk for positive lymph nodes are nuclear grade 3 or 4, presence of a sarcomatoid component, presence of tumor necrosis, tumor greater than 10 cm in size and tumor stage pT3 or pT4.

Computerized tomography has a sensitivity of 94% for the detection of renal masses 3 cm or greater in diameter.

Differential diagnosis of incidentally detected solid renal masses include oncocytoma, angiomyolipoma, transitional cell carcinoma, complex cyst or a hypertrophied column of Bertin.

Solid lesions that enhance with radiographic intravenous contrast are considered renal cell carcinomas, until proven otherwise.

Biopsy is not required prior to surgical resection for tumors larger than 4 cm and radiologic findings consistent with renal cell carcinoma.

The average growth rate of clinically significant renal carcinomas was 2.13 cm/year.

 

The growth rate of clinically significant renal cancer appears to be higher than the rate reported in surveillance trials. 

 

Renal tumors tend to grow faster in young patients.

15% of enhancing solid lesions are oncocytomas.

Hysterectomy for benign reasons associated with renal cancer (Altman D et al).

Increases risk of renal cancer after hysterectomy by 50%.

Women undergoing hysterectomy at an earlier age have a higher risk of developing renal cancer.

It is suggested that uteropelvic junction obstruction and persistent subclinical hydronephrosis after hysterectomy may predispose to renal proliferation and cancer transition (Gago-Dominguez M et al).

Approximately 23% of patients will have extension of the tumor into the renal vein and 7% into the inferior vena cava.

Partial nephrectomy appropriate for patients with bilateral renal cancers, tumors that involve a single functioning kidney, in patients with chronic renal insufficiency and in patients with potential dysfunction of the opposite kidney.

Previously partial nephrectomy, or nephron sparing surgery, was limited to patients with solitary kidneys, hereditary renal cell cancer producing syndromes, or severe renal insufficiency.

Retrospective studies of radical nephrectomy have shown and incremental increases in renal insufficiency was associated with increased all cause hospitalization, cardiovascular morbidity and at all-cause mortality, And this has led to the expansion of indications for nephron sparing surgery.(Lebovich BC et al).

Nephron-sparing surgery for tumors less than 4 cm the five-year survival is comparable to radical nephrectomy.

Hereditary and non-hereditary renal cancers are associated with chromosome 3p alterations.

40% of patients with von Hippel-Lindau syndrome develop renal cell carcinoma and is a major cause of death in such patients.

Most metastatic clear cell renal carcinomas harbor mutations in the von Hippel Lindau tumor suppressor genes.

Treatment for metastatic disease: inhibitor of mammalian target of rapamycin (mTOR) or VEGF receptor inhibitors in the first line.

Metastatic renal cell cancer highly refractive to chemotherapy with a response rate of 0-14%.

5-FU response rate 5-10%.

Gemcitabine response rate 6-8%.

Resistance to chemotherapy related to high expression of multidrug resistance gene MDR1, which encodes protein P-glycoprotein.

Approximately 100 cases of spontaneous remission have been reported.

Overall response rate for metastatic disease with alpha-interferon is 12% with longer survival in patients with high performance status and previous nephrectomy (30%).

High-dose IL-2 produces a significant increase in response rate compared to conventional dose IL-2 or alpha interferon (23.9% vs. 9.9%).

No trial has shown survival advantage of IL-2, but the durability of patient responses has made the drug useful in low-volume disease states, good performance status and lung/mediastinal disease only cases.

High-dose IL-2 is administered as an infusion of 600,000 IU/kilogram every eight hours a with 15 min. on days one through five, and 15 through 19, every cycle, and 2-3 cycles are usually considered for patients who experience a response.

High-dose IL-2 responses have a median duration of 19 months and durable complete responses are noted in up to 7% of patients with a median of 30 months.

AVOREN trial of 649 randomized metastatic patients to Interferon-alpha with placebo or bevacizumab 10 mg/kg every 2 weeks: progressive free survival in the combination group 10.2 months vs. 5.4 months for the Interferon-placebo group, response rate 30.6% vs. 12.4% for the interferon-placebo group with a trend toward improved overall survival as well.

Bevacizumab binds to VEGF and inhibits vascular endothelial growth.

Sutinib and sorafenib bind to VEGF receptor and platelet derived growth factor receptor.

Inhibitors of VEGF receptors sunitinib, sorafenib, pazopanib, axitinib, cabozantinib associated with clinical benefit in RCC as well as angiogenesis agent bevacizumab.

Nivolumab plus cabozantinib versus sunitinib in  first line treatment for advanced tenal carcinoma found combination demonstrated improved efficacy versus sunitinib..

Small molecule tyrosine knase inhibitors block the intracelllar domain of the VEGF recetor, hile evacizumab binds with circulating VEGF and prevents activation of the VEGF receptor.

VEGF inhibitors can control disease for less than a year on average, and do not cure the disease as all patients will eventually progress.

VEGF inhibitors have double the median survival time in kidney cancer from approximately 12-14 months to 26-28 months, doubling survival.

Complete remission rate for high-dose IL-2 8% with a durable response rate of 7.4% and a response duration of 24 months.

<5% have a durable response to high dose IL-2.

Majority of patients do not benefit from alpha interferon or IL-2 with only 10% of patients remaining progression free at 3 years.

Duration of response to alpha-interferon is rarely longer than 2 years.

VEGF and EGFR are both overexpressed.

Angiogenesis inhibitors now are the backbone of treatment for metastatic renal cancer.

Targeted therapies offer benefits of treatment maintained periods of disease stabilization for the majority of patients rather than durable remissions off treatment for a small minority of patients.

Phase III trials with bevacizumab, sunitinib, sorafenib, pazopanib, and temsirolimus have shown clinical benefit for patients treatment naïve or previously treated with cytokines by prolonging progression free survival.

In a randomized, open labeled clinical study of 723 patients whose disease progressed on or after treatment with one prior systemic therapy: Median progression free survival was 6.7 months in those treated with axitinib, compared with 4.7 months in those treated with sorafenib.

Axitinib 5 mg twice a day in the second line setting has a greater objective response compared with sorafenib 400 mg twice daily.

Axitinib in combination with pembrolizumab in advanced renal cell carcinoma in treatment naive patients the response rate was 73% and median progression free survival exceeded 20 months (Atkins M): considered standard first line therapy for advanced renal cell carcinoma.

Axitinib combined with Avelumab resulted in a significantly longer progression free survival among patients with sunitinib for first line treatment of advanced renal cancer.

Axitinib with Pembrolizumab in advanced renal carcinoma resulted in significantly longer overall survival and progression free survival and a high response rate in treatment with sunitinib (Rini B).

In the Keynote 564 study Pembrolizumab treatment led to a significant improvement in disease free survival as compared with placebo after surgery among patients with kidney cancer who were high risk for recurrence (77.3 vs 68.1% at 24 months.

In the above stay the estimated percentage of patients who remained alive a 24 months was 96.6% in the Pembrolizumab Group and 93.5% in the placebo group.

Keynote-564 showed that adjuvant Pembrolizumab versus placebo as post-nephrectomy therapy for high risk clear cell renal carcinoma showed a benefit-hazard ratio 0.63.

Adjuvant pembrolizumab is associated with a significant and clinically meaningful improvement in overall survival, as compared with placebo,  among participants with clear cell renal cell carcinoma at increased risk for recurrence after surgery.

Everolimus as a second line therapy after failure of sunitinib or sorafenib more than doubled median progression free survival time compared to placebo.

Progression free survival in patients with advanced kidney cancer was 47.3 weeks for patients receiving sunitinib and 24.9 weeks for those treated with alpha-interferon with response rates of 24.8% versus 4.9%. respectively.

Phase II studies of sunitinib in pooled analysis had a response rate of 42% in patients who had failed cytokines.

Sunitinib increases the percentage of interferon gamma producing T cells, which is typically diminished in renal cell cancer patients relative to type-1 response to normal individuals.

Most clear cell renal cancers have a mutation in the VHL gene.

Mutations, deletions, or methylation of the VHL gene occur in more than 90% of clear cell renal cell carcinoma tumors, resulting in dysregulation of the hypoxia – inducible factor (HIF) pathway through accumulation of HIF – two alpha, which leads to tumorogenesis, angiogenesis, and metastasis.

HIF-2α is a transcription factor that up regulates hundreds of genes, including for VEGF, platelet derived growth factor, transforming growth, factor, CXC chemokine receptor, erythropoietin, and cyclin D1, all of which play a potential role in the growth and progression of clear cell renal carcinoma.

Clear cells type of cancers characterized by loss of genetic material from the short arm of chromosome 3 (3p) and mutations in the VHL gene.

VHL gene controls the breakdown of cellular hypoxia inducible factor and with a gene mutation it accumulates and results in the overproduction of VEGF.

In the absence of functional VHL genes, hypoxia-inducible factor accumulates and leads to the over production of VEGF and other signaling protiens.

Increased transcription of VEGF helps explain the vascularity of renal cell carcinoma.

C-met proto-oncogene mutations associated with papillary carcinoma.

Incidence of isolated renal fossa recurrence is rare and ranges from 1-3%.

TREATMENT:

Surgery with partial or radical nephrectomy is the preferred treatment for RCC confined to the kidney.

Radical nephrectomy includes resection of the kidney, perirenal fat, and sometimes includes resection of the ipsilateral adrenal gland and the regional lymph node dissection.

Partial nephrectomy is a nephron sparing approach that involves tumor resection and preservation of the remaining non-malignant portion of the kidney.

Both radical and partial nephrectomy can be performed using open, laparoscopic or robotic surgical techniques.

Radical nephrectomy is preferred for tumors with extension to the inferior vena cava.

The management of metastatic renal cell cancer has evolve from high-dose interleukin – two and interferon-alpha to target therapies such as vascular endothelial growth factor receptor inhibitors, mammalian target of rapamycin inhibitors, and immunotherapy with checkpoint inhibitors.

The median survival for metastatic renal cell cancer has improved from less than one year in the 1990s to over four years in recent trials.

IL-2 and interferon alfa treatments result in median survival of 12-17 months.

Trial of sunitinib vs alfa-interferon as first line treatment in patients with favorable and intermediate profiles: sunitinib response rate 39% vs 8% for alfa-interferon, median progression free time 11 vs. 5 months, respectively and quality of life favored sunitinib (Motzer).

Cytokine therapy of limited value in patients with advanced disease and with adverse prognostic markers.

Median survival of patients with advanced metastatic disease is 4-8 months.

Recent trials suggest therapy to use mTOR followed by VEGF inhibitors for metastatic disease.

Most patients treated with VEGF receptor inhibitors eventually develop drug resistance and exhibit disease progression.

Nivolumab, a fully human IgG4 PD-1 immune checkpoint-inhibitor monoclonal antibody that selectively blocks the PD-1 and PD-L1/PD-L2 interaction.

Durable responses were obtained with the immune checkpoint inhibitor nivolumab in a phase II dose-ranging trial conducted in patients with previously treated metastatic renal cell carcinoma (mRCC).

Among patients with advanced renal cell ca that failed treatment, overall survival and fewer adverse events occurred with nivolumab than with everolimus (Motzer RJ et al).

In CheckMate 025 trial in patients with advanced renal cell carcinoma nivolumab demonstrated superior overall survival versus Everiolimus-25 months versus 19.6 months and a higher objective response rate 25% versus 5% in previously treated patients with advanced renal carcinoma.

No apparent dose-response relationship observed for progression-free survival (PFS) in treatment of renal cancer.

Objective responses in refractory renal cell carcinoma is about 20%, with a median duration of response for the 10-mg/kg dosage arm of 22.3 months.

The median overall survival (OS) for renal cell cancer was 18.2 months, 25.5 months, and 24.7 months in the 0.3-mg/kg, 2-mg/kg, and 10-mg/kg arms, respectively.

The median PFS and median ORR were greater in patients with renal cell cancer who had PD-L1 expression >5% in their tumors, but meaningful responses were observed even in patients without PD-L1 expression.

The median PFS at the time of the analysis was 2.7 months in patients randomized to 0.3 mg/kg of nivolumab, 4.0 months in those randomized to 2 mg/kg, and 4.2 months in those randomized to 10 mg/kg.

The rate of objective responses was similar between the three arms.

In a trial of 821 patients with advanced clear-cell renal cell cancer who had previously received treatment with one or two regimens of anti-angiogenesis therapy randomized to receive 3 mg per kilogram of nivolUmab IV every two weeks or 10 mg of everolimus tablet once daily: overall survival was longer with fewer toxic events with nivolumab than with everolimus (Motzer RJ et al).

Nivolumab and ipilimubab in metastatic renal cell cancer decrease risk of death by 32% compared with sunitinib with a median overall survival that has not been reached, versus 32.9 months with sunitinib (CheckMate-214).

In the above study the combination of ipilimumab and nivolumab had an objective response rate of 39% vs 32% for sunitinib.

The above combination approved as treatment for renal cell cancer.

Lenvatinib Approved for the treatment of patients with advanced metastatic renal cell carcinoma previously treated with a vascular endothelial growth factor targeted therapy.

In a phase II trial of 153 patients with renal cancer previously treated with VEGF targeted therapy: Patients were randomized to Everiolimus or lenvatinib alone, or a combination of these 2 drugs-the median duration of response was longest inthe drug combination at 13.1 months compared to Levatinib alone at 7-1/2 months and Everiolimus alone at 8.5 months.

The difference among VEGFR TKIs is minimal as single agent treatment for metastatic renal cell carcinoma.

VEGF targeted therapy produces limited responses in patients with metastatic renal cell carcinoma.

The overall response rate to single agent VGFR inhibitors is just 30%, and complete responses in durable responses are very rare.

VEGFR targeted therapy progression free survival is rarely longer than 12 months.

Because renal cell carcinoma considered an immunogenic tumor with high numbers of immune cells, targeted immunotherapy is the best alternative to anti-antiangiogenics.

Systemic therapy is currently used adjuvant therapy after nephrectomy for a localized renal cell cancer.

Pembrolizumab demonstrated a disease free and overall survival benefit with patients with intermediate and high risk renal carcinoma.

S-TRAC trial 2016 showed that adjuvant sunitinib improved disease-free survival following one year of adjuvant therapy in patients at risk for recurrence.

Pembrolizumab in randomized control trials is effective as adjuvant therapy after nephrectomy on high risk renal cell cancer patients.

In a randomized trial of 658 patients who received cabozantinib at dose is 60 mg a day or everolimus at a dose of 10 mg a day: the medium progression free survival was 7.4 months for cabozantinib and was 3.8 months for everolimus (Choueiri TK et al).

Cabozantinib superior to sunitinib in advanced renal cell carcinoma with a median PFS of 8.6 months vs 5.3 months for sunitinib.

The FDA has approved the combination of avelumab (Bavencio) and axitinib (Inlyta) for the frontline treatment of patients with advanced renal cell carcinoma.

The approval is based on results from the pivotal phase III JAVELIN Renal 101 trial, which showed that the combination was associated with a 31% reduction in disease progression or death compared with sunitinib (Sutent) in patients with treatment-naive advanced RCC, regardless of PD-L1 expression.

A first-line treatment option that combines a PD-L1 immunotherapy with a well-known VEGFR TKI to provide a significant reduction in the risk of disease progression or death and doubling of the response rate compared with sunitinib.

In the JAVELIN Renal 101 study, patients with advanced or metastatic RCC were randomized 1:1 to receive 10 mg/kg of avelumab intravenously every 2 weeks plus 5 mg of oral axitinib twice daily in 6-week cycles or 50 mg of oral sunitinib once daily for a 4-weeks-on/2-weeks-off schedule: in the PD-L1 positive population, the median PFS was 13.8 months with avelumab/axitinib compared with 7.2 months with sunitinib, leading to a 39% reduction in the risk of disease progression or death.

The ORR with the combination was 55.2%, and the ORR with sunitinib was 25.5%.

The median PFS with the combination of avelumab and axitinib versus sunitinib was 13.8 months and 8.4 months, respectively.

Lenvatinib plus Pembrolizumab  is associated with a significantly longer progressive free survival and overall survival in advanced renal cell carcinoma than sutinib:it is the preferred treatment option for patients with clear cell renal cancer across all groups.

Patients with primary renal cell carcinoma who are unable to undergo surgery can be effectively treated with stereotactic ablative radiotherapy with good long-term outcomes.

Axitinib plus pembrolizumab is the preferred first line therapy in patients with metastatic renal cell carcinoma.