renal cell carcinoma

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Renal cell carcinoma 1 Renal cell carcinoma Renal cell carcinoma Classification and external resources Micrograph of the most common type of renal cell carcinoma (clear cell) - on right of the image; non-tumour kidney is on the left of the image. Nephrectomy specimen. H&E stain. ICD-10 C64 [1] ICD-9 189.0 [2] ICD-O: M8312/3 [3] OMIM 144700 [4] 605074 [5] DiseasesDB 11245 [6] MedlinePlus 000516 [7] eMedicine med/2002 [8] Renal cell carcinoma (RCC, formerly known as hypernephroma) is a kidney cancer that originates in the lining of the proximal convoluted tubule, one type of very small tubes in the kidney that transport waste molecules from the blood to the urine. RCC is the most common type of kidney cancer in adults, responsible for approximately 90-95% of cases. It has been described as one of the deadliest of cancers affecting the genitourinary tract. Initial treatment is most commonly either partial or complete removal of the affected kidney(s) and remains the mainstay of curative treatment. Where the cancer is has not metastasised or invaded deeper into the kidney the 5-year survival rate is 60-70%, but this is lowered considerably when the cancer has spread. It is relatively resistant to radiation therapy and chemotherapy, although some cases respond to immunotherapy. Targeted cancer therapies such as sunitinib, temsirolimus, bevacizumab, interferon alfa and sorafenib have improved the outlook for RCC. Signs and symptoms Historically, medical practitioners expected a person to present with three findings. This classic triad is 1: hematuria, which is when there is blood present in the urine, 2: flank pain, which is pain on the side of the body between the hip and ribs, and 3: an abdominal mass, similar to bloating but larger. It is now known that this classic triad of symptoms only occurs in 10-15% of cases, and is usually indicative that the renal cell carcinoma (RCC) in an advanced stage. Today, RCC is often asymptomatic (meaning little to no symptoms) and is generally detected incidentally when a person is being examined for other ailments. Other signs and symptom may include hematuria; loin pain; abdominal mass; malaise, which is a general feeling of feeling unwell; weight loss and/or loss of appetite; anemia resulting from depression of erythropoietin;

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  • Renal cell carcinoma 1

    Renal cell carcinoma

    Renal cell carcinomaClassification and external resources

    Micrograph of the most common type of renal cell carcinoma (clear cell) - on right of the image; non-tumour kidney is on the left of the image.Nephrectomy specimen. H&E stain.

    ICD-10 C64 [1]

    ICD-9 189.0 [2]

    ICD-O: M8312/3 [3]

    OMIM 144700 [4] 605074 [5]

    DiseasesDB 11245 [6]

    MedlinePlus 000516 [7]

    eMedicine med/2002 [8]

    Renal cell carcinoma (RCC, formerly known as hypernephroma) is a kidney cancer that originates in the lining ofthe proximal convoluted tubule, one type of very small tubes in the kidney that transport waste molecules from theblood to the urine. RCC is the most common type of kidney cancer in adults, responsible for approximately 90-95%of cases. It has been described as one of the deadliest of cancers affecting the genitourinary tract. Initial treatment ismost commonly either partial or complete removal of the affected kidney(s) and remains the mainstay of curativetreatment. Where the cancer is has not metastasised or invaded deeper into the kidney the 5-year survival rate is60-70%, but this is lowered considerably when the cancer has spread. It is relatively resistant to radiation therapyand chemotherapy, although some cases respond to immunotherapy. Targeted cancer therapies such as sunitinib,temsirolimus, bevacizumab, interferon alfa and sorafenib have improved the outlook for RCC.

    Signs and symptomsHistorically, medical practitioners expected a person to present with three findings. This classic triad is 1: hematuria,which is when there is blood present in the urine, 2: flank pain, which is pain on the side of the body between the hipand ribs, and 3: an abdominal mass, similar to bloating but larger. It is now known that this classic triad of symptomsonly occurs in 10-15% of cases, and is usually indicative that the renal cell carcinoma (RCC) in an advanced stage.Today, RCC is often asymptomatic (meaning little to no symptoms) and is generally detected incidentally when aperson is being examined for other ailments.Other signs and symptom may include hematuria; loin pain; abdominal mass; malaise, which is a general feeling of feeling unwell; weight loss and/or loss of appetite; anemia resulting from depression of erythropoietin;

  • Renal cell carcinoma 2

    erythrocytosis (increased production of red blood cells) due to increased erythropoietin secretion; varicocele, whichis seen in males as an enlargement of the tissue at the testicle (more often the left testicle) hypertension (high bloodpressure) resulting from secretion of renin by the tumor; hypercalcemia, which is elevation of calcium levels in theblood; sleep disturbance or night sweats; recurrent fevers; and chronic fatigue.

    Cause

    LifestyleThe greatest risk factors for RCC are lifestyle related - smoking, obesity and hypertension (high blood pressure) havebeen estimated to account for up to 50% of cases. Occupational exposure to some chemicals such as asbestos,cadmium, lead, chlorinated solvents, petrochemicals and PAH (polycyclic aromatic hydrocarbon) has been examinedby multiple studies with inconclusive results. Another suspected risk factor is the long term use of non-steroidalanti-inflammatory drugs (NSAIDS).Finally, studies have found that women who have had a hysterectomy are at more than double the risk of developingRCC than those who have not. The reason for this remains unclear

    GeneticsHereditary factors have a minor impact on individual susceptibility with immediate relatives of people with RCChaving a two to fourfold increased risk of developing the condition. Other genetically linked conditions also increasethe risk of RCC, including hereditary papillary renal carcinoma, hereditary leiomyomatosis, Birt-Hogg-Dubesyndrome, hyperparathyroidism-jaw tumor syndrome, familial papillary thyroid carcinoma, von Hippel-Lindaudisease and sickle cell disease.The most significant disease affecting risk however is not genetically linked patients with acquired cystic diseaseof the kidney requiring dialysis are 30 times greater more likely than the general population to develop RCC.

    PathophysiologyThe tumour arises from the cells of the proximal renal tubular epithelium. It is considered an adenocarcinoma. Thereare two subtypes: sporadic (that is, non-hereditary) and hereditary. Both such subtypes are associated with mutationsin the short-arm of chromosome 3, with the implicated genes being either tumour suppressor genes (VHL and TSC)or oncogenes (like c-Met).

    DiagnosisThe first steps taken in order to diagnose this condition are observing any of the signs and symptoms, and ananamnesis (the detailed medical review of past health state) to evaluate any risk factors. Based on the symptomspresented, a range of biochemical tests (using blood and/or urine samples) are generally also considered as part ofscreening process to provide sufficient quantitative analysis of any differences in electrolytes, renal and liverfunction, and blood clotting times. Upon physical examination, palpation of the abdomen may reveal the presence ofa mass or an organ enlargement.Although this disease lacks characterisation in the early stages of tumour development, considerations based ondiverse clinical manifestations, as well as resistance to radiation and chemotherapy are important. The maindiagnostic tools for detecting renal cell carcinoma are ultrasound, computed tomography (CT) scanning andmagnetic resonance imaging (MRI) of the kidneys.

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    ClassificationRenal cell carcinoma (RCC) is not a single entity, but rather a collection of different types of tumours, each derivedfrom the various parts of the nephron (epithelium or renal tubules) and possessing distinct genetic characteristics,histological features, and, to some extent, clinical phenotypes.Classification of the Common Histological Subtypes of Renal Cell Carcinoma

    Renal Cell Carcinoma Subtype Frequency Genetic Abnormalities Characteristics

    Clear Cell Renal Cell Carcinoma(CCRCC)

    Generally the cells have a clear cytoplasm,are surrounded by a distinct cell membrane

    and contain round and uniform nuclei.

    60-70% Alterations of chromosome 3p segmentsoccurs in 70 90% of CCRCCs

    Inactivation of von Hippel-Lindau (VHL)gene by mutation and promoterhypermethylation

    Gain of chromosome 5q Loss of chromosomes 8p, 9p, and 14q In 2009-2010, five new frequently mutated

    genes were discovered in CCRCC;KDM6A/UTX, SETD2,KDM5C/JARID1C, and MLL2

    CCRCC is derived from theproximal convoluted tubule

    Most commonly affects malepatients in their sixties and seventies

    Majority of CCRCC arisesporadically

    Only 2 4% of the cases presentingas part of an inherited cancersyndrome

    Papillary Renal Cell Carcinoma (PRCC)

    Type 1 PRCC consist of papillae coveredwith a single or double layer of small cuboid

    cells with scanty cytoplasm and Type 2PRCC consist of papillae covered by large

    eosinophilic cells arranged in an irregular orpseudostratified manner.

    1015% Trisomy or tetrasomy of chromosomes 7and 17

    Loss of chromosome Y in men Gain of chromosomes 12, 16, and 20 Rare mutations of Metproto-oncogene

    PRCC is derived from the proximalconvoluted tubule

    PRCCs most commonly affect malesin their sixties and seventies

    Less aggressive tumour than clearcell RCC, with 5-year survival ratesof 80% to 85%.

    Majority of tumours occursporadically, but some may developin members of families withhereditary PRCC

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    Chromophobe Renal Cell Carcinoma(ChRCC)

    ChRCC consists of tumor cells withabundant eosinophilic cytoplasm (pale

    cells and eosinophilic cells with aperinuclear halo) and show mainly a

    solid structure.

    35% Loss of chromosomes Y, 1, 2, 6, 10, 13,17, and 21

    ChRCC is derived from the corticalcollecting duct

    ChRCC has a much better prognosisthan clear cell and papillary RCC,with 5-year survival rate of greaterthan 90%.

    Most cases arise sporadically, whilesome familial cases are associatedwith Birt-Hogg-Dube (BHD)syndrome

    Clinical, Pathological and Genetic Features of Uncommon RCC Subtypes Included in the 2004 WHOClassification of RCC Pathology

    RCC subtype Clinical features Cell/TissueCharacteristics

    Genetics Prognosis

    Multilocular CysticRCC

    Variant of CCRCC (5% ofCCRCC)

    Mean age 51 years (range2076)

    Male:female = 23:1

    Clear cytoplasm, smalldark nuclei

    3p deletion as observed inCCRCC

    Favorable No local or distant

    metastasis aftercomplete surgicalremoval

    Carcinoma of theCollecting Ducts ofBellini

    Less than 1% of all renaltumors; arising in thecollecting ducts of Bellini

    Mean age 55 years (range40-70)

    Male:female = 2:1

    High-grade tumour cellswith eosinophiliccytoplasm

    Variable results: LOH onchromosomes 1q, 6p, 8p,9p, 13q,19q32 and 21q; c-erB2amplification associated withunfavorable outcome

    Poor prognosis 1/3 presenting

    with metastasis 2/3 patients

    succumb to thedisease within 2years of diagnosis

    Medullary Carcinoma Exceedingly rare; almostexclusively in patients withsickle cellhemoglobinopathies or traits

    Majority areAfrican-Americans

    Mean age 19 years (569) Male:female = 2:1

    Haemorrhage andnecrosis, high-gradetumour cells witheosinophilic cytoplasm

    Not well defined Highly aggressive 95% presenting

    with metastasis Often succumb to

    the disease within6 months ofdiagnosis

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    Xp11.2 TranslocationCarcinoma

    Predominantly affectingchildren and young adults

    Accounts for 40% of RCCs inthis age group

    Affects adult patients with astriking female predominance

    May resemblePRCC

    Clear andeosinophilic cells

    Chromosomal translocationinvolving TFE3 gene on Xp11.2resulting in overexpression of theTFE3 protein

    Present atadvanced stage,but with indolentclinical course inchildren

    Adult patients maypursue moreaggressive course

    Mucinous TubularSpindle CellCarcinoma

    Mean age 53 years (range1382)

    Affects predominantly femalepatients (male:female = 1:4)incidental finding in mostcases

    Tubules, extracellularmucin and spindle cells

    Not well defined; Lossesinvolving chromosomes 1, 4, 6,8, 9, 11, 13, 14, 15, 18, 22reported; 3p alterations and gainof chromosome 7, and 17 notpresent

    Favourable Majority of

    patients remaindisease free aftersurgical resection

    Post-NeuroblastomaRenal Cell Carcinoma

    Mean age of RCC diagnosisis 13.5 years (range 235)

    Eosinophilic cells withoncocytoid features(same as CCRCC)

    Not well defined; Loss ofmultiple chromosomal lociobserved

    Similar to othercommon RCCsubtypes

    Array-based karyotyping can be used to identify characteristic chromosomal aberrations in renal tumors withchallenging morphology. Array-based karyotyping performs well on paraffin embedded tumors and is amenable toroutine clinical use. See also Virtual Karyotype for CLIA certified laboratories offering array-based karyotyping ofsolid tumors.The 2004 World Health Organization (WHO) classification of genitourinary tumors recognizes over 40 subtypes ofrenal neoplasms. Since the publication of the latest iteration of the WHO classification in 2004, several novel renaltumor subtypes have been described: Clear cell papillary renal cell carcinoma and Clear cell renal cell carcinoma with smooth muscle stroma Mucinous tubular and spindle cell carcinoma (MTSCC) Multilocular cystic clear cell renal cell carcinoma Tubulocystic renal cell carcinoma Thyroid-like follicular renal cell carcinoma Acquired cystic kidney disease-associated renal cell carcinoma Renal cell carcinoma with t(6;11) translocation (TFEB) Hybrid oncocytoma/chromophobe renal cell carcinoma Hereditary leiomyomatosis and renal cell carcinoma(HLRCC)

    Laboratory testsLaboratory tests are generally conducted when the patient presents signs and symptoms that may be characteristic ofkidney impairment. They are not primarily used to diagnose kidney cancer, due to its asymptomatic nature and aregenerally found incidentally during tests for other illnesses such as gallbladder disease. In other words, these cancersare not detected usually because they do not cause pain or discomfort when they are discovered. Laboratory analysiscan provide an assessment on the overall health of the patient and can provide information in determining the stagingand degree of metastasis to other parts of the body (if a renal lesion has been identified) before treatment is given.

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    Urine analysis

    The presence of blood in urine is a common presumptive sign of renal cell carcinoma. The haemoglobin of the bloodcauses the urine to be rusty, brown or red in colour. Alternatively, urinalysis can test for sugar, protein and bacteriawhich can also serve as indicators for cancer. A complete blood cell count can also provide additional informationregarding the severity and spreading of the cancer.

    Complete blood cell count

    The CBC test provides a quantified measure of the different cells in the whole blood sample from the patient. Suchcells examined for in this test include red blood cells (erythrocytes), white blood cells (leukocytes) and platelets(thrombocytes). A common sign of renal cell carcinoma is anaemia whereby the patient exhibits deficiency in redblood cells. CBC tests are vital as a screening tool for examination the health of patient prior to surgery.Inconsistencies with platelet counts are also common amongst these cancer patients and further coagulation tests,including Erythrocyte Sedimentation Rate (ESR), Prothrombin Time (PT), Activated Partial Thromboplastin Time(APTT) should be considered.

    Blood chemistry

    Blood chemistry tests are conducted if renal cell carcinoma is suspected as cancer has the potential to elevate levelsof particular chemicals in blood. For example, liver enzymes such as aspartate aminotransferase [AST] and alanineaminotransferase [ALT] are found to be at abnormally high levels. The staging of the cancer can also be determinedby abnormal elevated levels of calcium, which suggests that the cancer may have metastasised to the bones. In thiscase, a doctor should be prompted for a CT scan. Blood chemistry tests also assess the overall function of thekidneys and can allow the doctor to decide upon further radiological tests.

    RadiologyThe characteristic appearance of renal cell carcinoma (RCC) is a solid renal lesion which disturbs the renal contour.It will frequently have an irregular or lobulated margin and may be seen as a lump on the lower pelvic or abdomenregion. Traditionally, 85 to 90% of solid renal masses will turn out to be RCC but cystic renal mass mass may alsobe due to RCC. However, the advances of diagnostic modalities are able to incidentally diagnose a great proportionof patients with renal lesions that may appear to be small in size and of benign state. Ten percent of RCC willcontain calcifications, and some contain macroscopic fat (likely due to invasion and encasement of the perirenal fat.Deciding on the benign or malignant nature of the renal mass on the basis of its localised size is an issue as renal cellcarcinoma may also be cystic. As there are several benign cystic renal lesions (simple renal cyst, haemorrhagic renalcyst, multilocular cystic nephroma, polycystic kidney disease), it may occasionally be difficult for the radiologist todifferentiate a benign cystic lesion from a malignant one. The Bosniak classification system for cystic renal lesionsthat classifies them based specific imaging features into groups that are benign and those that need surgical resectionis available.The main imaging tests performed in order to identify renal cell carcinoma are pelvic and abdominal CT scans,ultrasound tests of the kidneys (ultrasonography), MRI scan, intravenous pyelogram (IVP) or renal angiography.Among these main diagnostic tests, other radiologic tests such as excretory urography, positron-emissiontomography (PET) scanning, ultrasonography, arteriography, venography, and bone scanning can also used to aid inthe evaluation of staging renal masses and to differentiate non-malignant tumours from malignant tumours.

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    Computed tomography

    Contrast-enhanced Computed tomography (CT) scanning is a routinely used imaging procedure in determining thestage of the renal cell carcinoma in the abdominal and pelvic regions of the patient. CT scans have the potential todistinguish solid masses from cystic masses and may provide information on the localisation, stage or spread of thecancer to other organs of the patient. Key parts of the human body which are examined for metastatic involvement ofrenal cell carcinoma may include the renal vein, lymph node and the involvement of the inferior vena cava.According to a study conducted by Sauk et al., multidetector CT imaging characteristics have applications indiagnosing patients with clear renal cell carcinoma by depicting the differences of these cells at the cytogenic level.

    Ultrasound

    Ultrasonographic examination can be useful in evaluating questionable asymptomatic kidney tumours and cysticrenal lesions if Computed Tomography imaging is inconclusive. This radiologic procedure is a safe and non-invasivewhich uses high frequency sound waves to generate an interior image of the body on a computer monitor. The imagegenerated by the ultrasound can help diagnose renal cell carcinoma based on the differences of sound reflections onthe surface of organs and the abnormal tissue masses. Essentially, ultrasound tests can determine whether thecomposition of the kidney mass is mainly solid or filled with fluid.Percutaneous biopsy can be performed by a radiologist using ultrasound or computed tomography to guide samplingof the tumour for the purpose of diagnosis by pathology. However this is not routinely performed because when thetypical imaging features of renal cell carcinoma are present, the possibility of an incorrectly negative result togetherwith the risk of a medical complication to the patient may make it unfavourable from a risk-benefit perspective.However, biopsy tests for molecular analysis to distinguish benign from malignant renal tumours is of investigativeinterest.

    Magnetic resonance imaging

    Magnetic Resonance Imaging (MRI) scans provide an image of the soft tissues in the body using radio waves andstrong magnets. MRI can be used in replacement of CT if the patient exhibits an allergy to the contrast media cannotbe administered. Sometimes prior to the MRI scan, an intravenous injection of a contrasting material calledgadolinium to allow for a more detailed image. Patients on dialysis or have renal insufficiency should avoid thiscontrasting material as it may induce a rare, yet severe, side effect known as nephrogenic systemic fibrosis. A bonescan or brain imaging is not routinely performed unless signs or symptoms suggest potential metastatic involvementof these areas. MRI scans should also be considered to evaluate tumour extension which has grown in major bloodvessels, including the vena cava, in the abdomen. MRI can be used to observe the possible spread of cancer to thebrain or spinal cord should the patient present symptoms that suggest this might be the case.

    Intravenous pyelogram

    Intravenous pyelogram (IVP) is a useful procedure in detecting the presence of abnormal renal mass in the urinarytract. This procedure involves the injection of a contrasting dye into the arm of the patient. The dye travels from theblood stream and into the kidneys which in time, passes into the kidneys and bladder. This test is not necessary if aCT or MRI scan has been conducted.

    Renal angiography

    Renal angiography uses the same principle as IVP, as this type of X-ray also uses a contrasting dye. This radiologictest serves importance in diagnosing renal cell carcinoma as an aid for examining blood vessels in the kidneys. Thisdiagnostic test relies on the contrasting agent which is injected in the renal artery to be absorbed by the cancerouscells. The contrasting dye provides a clearer outline of abnormally-oriented blood vessels believed to be involvedwith the tumour. This is imperative for surgeons as it allows the patients blood vessels to be mapped prior tooperation.

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    StagingThe staging of renal cell carcinoma is the most important factor in predicting its prognosis.[9] Staging can follow theTNM staging system, where the size and extent of the tumour (T), involvement of lymph nodes (N) and metastases(M) are classified separately. Also, it can use overall stage grouping into stage I-IV, with the 1997 revision of AJCCdescribed below:

    Stage I Tumour of a diameter of 7cm (approx. 234 inches) or smaller, and limited to the kidney. No lymph node involvement ormetastases to distant organs.

    Stage II Tumour larger than 7.0cm but still limited to the kidney. No lymph node involvement or metastases to distant organs.

    Stage IIIany of thefollowing

    Tumor of any size with involvement of a nearby lymph node but no metastases to distant organs. Tumour of this stage may be withor without spread to fatty tissue around the kidney, with or without spread into the large veins leading from the kidney to the heart.

    Tumour with spread to fatty tissue around the kidney and/or spread into the large veins leading from the kidney to the heart, butwithout spread to any lymph nodes or other organs.

    Stage IVany of thefollowing

    Tumour that has spread directly through the fatty tissue and the fascia ligament-like tissue that surrounds the kidney.

    Involvement of more than one lymph node near the kidney

    Involvement of any lymph node not near the kidney

    Distant metastases, such as in the lungs, bone, or brain.

    At diagnosis, 30% of renal cell carcinomas have spread to the ipsilateral renal vein, and 5-10% have continued intothe inferior vena cava.

    Histopathology

    Renal cell carcinoma

    The gross and microscopic appearance of renal cell carcinomas ishighly variable. The renal cell carcinoma may present reddened areaswhere blood vessels have bled, and cysts containing watery fluids. Thebody of the tumour shows large blood vessels that have wallscomposed of cancerous cells. Gross examination often shows ayellowish, multilobulated tumor in the renal cortex, which frequentlycontains zones of necrosis, haemorrhage and scarring. In a microscopiccontext, there are four major histologic subtypes of renal cell cancer:clear cell (conventional RCC, 75%), papillary (15%), chromophobic(5%), and collecting duct (2%). Sarcomatoid changes (morphologyshowing spindle cells) can be observed within any RCC subtype.Under light microscopy, these tumour cells can exhibit papillae,tubules or nests, and are quite large, atypical, and polygonal.

    Recent studies have brought attention to the close association of thetype of cancerous cells to the aggressiveness of the condition. Somestudies suggest that these cancerous cells accumulate glycogen andlipids, their cytoplasm appear "clear", the nuclei remain in the middleof the cells, and the cellular membrane is evident. Some cells may be smaller, with eosinophilic cytoplasm,resembling normal tubular cells. The stroma is reduced, but well vascularized. The tumour compresses thesurrounding parenchyma, producing a pseudocapsule.

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    Renal cell carcinoma

    The most common cell type exhibited by renal cell carcinoma is theclear cell, which is named by the dissolving of the cells high lipidcontent in the cytoplasm. The clear cells are thought to be the leastlikely to spread and usually respond more favourably to treatment.However, most of the tumours contain a mixture of cells. The mostaggressive stage of renal cancer is believed to be the one in which thetumour is mixed, containing both clear and granular cells.

    The recommended histologic grading schema for RCC is the Fuhrmansystem (1982), which is an assessment based on the microscopicmorphology of a neoplasm with haematoxylin and eosin (H&Estaining). This system categorises renal cell carcinoma with grades 1,2, 3, 4 based on nuclear characteristics. The details of the Fuhrmangrading system for RCC are shown below:

    Grade Level Nuclear Characteristics

    Grade I Nuclei appears round and uniform, 10 m; nucleoli are inconspicuous or absent.

    Grade II Nuclei has an irregular appearance with signs of lobe formation, 15 m; nucleoli are evident.

    Grade III Nuclei appears very irregular, 20 m; nucleoli are large and prominent.

    Grade IV Nuclei appear bizarre and multilobated, 20 m or more; nucleoli are prominent.

    Nuclear grade is believed to be one of the most imperative prognostic factors in patients with renal cell carcinoma.However, a study by Delahunt et al. (2007) has shown that the Fuhrman grading is ideal for clear cell carcinoma butmay not be appropriate chromophobe renal cell carcinomas and that the staging of cancer (accomplished by CT scan)is a more favourable predictor of the prognosis of this disease. In relation to renal cancer staging, the Heidelbergclassification system of renal tumours was introduced in 1976 as a means of more completely correlating thehistopathological features with the identified genetic defects.

    PrognosisThe prognosis for renal cell carcinoma is largely influenced by a variety of factors, including tumour size, degree ofinvasion and metastasis, histologic type, and nuclear grade. For metastatic renal cell carcinoma, factors which maypresent a poor prognosis include a low Karnofsky performance-status score (a standard way of measuring functionalimpairment in patients with cancer), a low hemoglobin level, a high level of serum lactate dehydrogenase, and a highcorrected level of serum calcium. For non-metastatic cases, the Leibovich scoring algorithm may be used to predictpost-operative disease progression.Renal cell carcinoma is a potential source of ectopic hormone production and presents "great mimic" effects. Fewpatients with prominent sarcomatoid features survive for more than 1 year. By contrast, 1-year overall survival afternephrectomy for clear cell renal cell carcinoma is 50%. The papillary and chromophobe types have a betterprognosis than the clear cell type.[citation needed] Tumour spreads most frequently to the lungs and bones.A study in Turkey that used the 1997 AJCC staging system estimated the five-year survival rate to be 90% for stageI, 51% for stage II, 22% for stage III and 4.6% for stage IV. The same study estimated the median survival time to be7.7 years for stage I, 5.0 years for stage II, 3.1 years for stage III and 1.1 years for stage IV.

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    For those that have tumour recurrence after surgery, the prognosis is generally poor. Renal cell carcinoma does notgenerally respond to chemotherapy or radiation. Immunotherapy, which attempts to induce the body to attack theremaining cancer cells, has shown promise. Recent trials are testing newer agents, though the current completeremission rate with these approaches are still low, around 12-20% in most series. Most recently, treatment withtyrosine kinase inhibitors including nexavar, pazopanib, and rapamycin have shown promise in improving theprognosis for advanced RCC.

    ManagementThe type of treatment depends on multiple factors and the individual, some of which include: Which stage the renal cell carcinoma is in Which organs and parts of the body are affected or unaffected What type of Renal cell carcinoma (RCC) Any pre-existing or comorbid conditions the person has Overall health and Age of the personEvery form of treatment does have both risks and benefits involved, a health care professional will provide the bestoptions that suit the individual circumstances.

    Active surveillanceActive surveillance or "Watchful waiting" is becoming more common as small renal masses or tumours are beingdetected and also within the older generation surgery is not always suitable. Active surveillance involves completingvarious diagnostic procedures, tests and imaging to monitor the progression of the RCC before embarking on a morehigh risk treatment option like surgery. In the elderly, patients with co-morbidities and in poor surgical candidates,this is especially useful.

    SurgeryDifferent procedures may be most appropriate, depending on circumstances.Radical nephrectomy is the removal of the entire affected kidney including Gerota's fascia, the adrenal gland whichis on the same side as the affected kidney, and the regional lymph nodes all at the same time. This method althoughsevere is effective. But it is not always appropriate, as it is a major surgery that contains the risk of complication bothduring and after the surgery and can have a longer recovery time. It is important to note that the other kidney must befully functional, and this technique is most often used when there is a large tumour present in only one kidney.Nephron-sparing partial nephrectomy is used when the tumor is small (less than 4cm in diameter) or when thepatient has other medical concerns such as diabetes or hypertension. The partial nephrectomy involves the removalof the affected tissue only, sparing the rest of the kidney, Gerota's fascia and the regional lymph nodes. This allowsfor more renal preservation as compared to the radical nephrectomy, and this can have positive long term healthbenefits. Larger and more complex tumors can also be treated with partial nephrectomy by surgeons with a lot ofkidney surgery experience.Laprascopic nephrectomy uses laparoscopic surgery, with minimally invasive surgical techniques. Commonlyreferred to as key hole surgery, this surgery does not have the large incisions seen in a classically performed radicalor partial nephrectomy, but still successfully removes either all or part of the kidney. Laprascopic surgery isassociated with shorter stays in hospital and quicker recovery time but there are still risks associated with thesurgical procedure.Surgery for metastatic disease: If metastatic disease is present surgical treatment may still a viable option. Radicaland partial nephrectomy can still occur, and in some cases if the metastasis is small this can also be surgicallyremoved. This depends on what stage of growth and how far the disease has spread.

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    Targeted ablative therapiesTargeted ablative therapies are also known as percutaneous ablative therapies. Although the development oflaprascopic surgical techniques that are used to complete nephrectomies has reduced some of the risks associatedwith surgery, surgery of any sort in some cases will still not be feasible. For example, the elderly, people alreadysuffering from severe renal dysfunction or people who have several comorbidities surgery of any sort is notwarranted. Instead there are targeted therapies which do not involve the removal of any organs or serious surgery.Rather, these therapies involve the ablation of the tumor or the affected area. Ablative treatments use imaging suchas computed tomography (CT) or magnetic resonance imaging (MRI) to identify the location of the tumors, whichideally are smaller than 3.5cm in size and to guide the treatment. However there are some cases where ablation canbe used on tumors that are larger.The two main types of ablation techniques that are used for renal cell carcinoma are radio frequency ablation andcryoablation.Radio frequency ablation uses an electrode probe which is inserted into the affected tissue, to send radiofrequencies to the tissue to generate heat through the friction of water molecules. The heat destroys the tumor tissue.Cell death will generally occur within minutes of being exposed to temperatures of or above 50C.Cryoablation also involves the insertion of a probe in to the affected area. However in this case instead of heatbeing used to kill the tumor cold is. The probe is cooled with chemical fluids which are very cold. The freezingtemperatures cause the tumor cells to die by causing osmotic dehydration, which pulls the water out of the celldestroying the enzyme, organelles, cell membrane and freezing the cytoplasm.

    Targeted drug treatmentsImmunotherapy is a method that targets the persons immune system and uses it to their own advantage, this wasdeveloped after the observation was made that in some cases there was spontaneous regression. That is, the renal cellcarcinoma improved or reverted to a lower phase with no other therapies. Immunotherapy capitalises on thisphenomenon and aims to build up a persons immune response to particular cancer cells or agents. Other medicationsthat have been developed target things such as growth factors that have been shown to promote the growth andspread of tumours. They inhibit the growth factor which promotes the growth of tumours to prevent tumours fromforming. There have been many different medications developed and most have only been approved in the last 7 orso years.Some of the most recently developed treatments are listed below: Axitinib (been found to be superior to sorafenib and pazopanib in terms of progression-free survival) Bevacizumab Carfilzomib Everolimus Interferon- Interleukin-2 Lenalidomide (research into this treatment is ongoing) Pazopanib Sirolimus (Rapamycin) Sorafenib Sunitinib Temsirolimus Thalidomide (results with this agent have been largely disappointing) Tivozanib

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    Each of the treatments listed above are slightly different, some only work for a little while and others need to be usedin conjunction with other therapies.There are also different side effects and risks associated with different forms ofmedication. As always the advice of a Health Care professional should be sought if considering any of the therapiesmentioned.

    ChemotherapyChemotherapy and radiotherapy are not as successful in the case of RCC. RCC is resistant in most cases but there isabout a 4-5% success rate sometimes, but this is often short lived with more tumours and growths developing later.

    VaccineCancer vaccines are being developed but so far have been found to be effective for only certain forms of the RCC.The vaccines are being designed to "prime" the immune system to provide tumour specific immunity. They are stillbeing developed but the present another treatment possibility.

    Adjuvant therapyAdjuvant therapy is a form of treatment that is given after a primary treatment has already been administered. In theexample of RCC the adjuvant therapies tend to be the medications such as Interleukin-2 which are given after therenal nephrectomy surgery. The idea behind this method is that the adjuvant therapy will prevent the cancer fromreturning as sometimes cancerous cells can remain in the body after the primary tumour has been removed. A newerform of adjuvant therapy is Neoadjuvant therapy this is similar to adjuvant therapy but in this case the treatment isadministered before the intended primary or main treatment. In some cases neoadjuvant therapy has been shown todecrease the size and stage of the RCC to then allow it to be surgically removed. This is a very new form oftreatment and the effectiveness is still being assessed. There are not RCC specific Adjuvant or Neoadjuvanttherapies, but trials are still ongoing.

    Metastatic renal cell carcinomaMetastatic renal cell carcinoma (mRCC) is the spread of the primary renal cell carcinoma from the kidney to otherorgans. 25-30% of people have this metastatic spread by the time they are diagnosed with renal cell carcinoma. Thishigh proportion is explained by the fact that clinical signs are generally mild until the disease progresses to a moresevere state. The most common sites for metastasis are the lymph nodes, lung, bones, liver and brain. How thisspread affects the staging of the disease and hence prognosis is discussed in the Diagnosis and Prognosis section.MRCC has a poor prognosis compared to other cancers although average survival times have increased in the lastfew years due to treatment advances. Average survival time in 2008 for the metastatic form of the disease was undera year and by 2013 this improved to an average of 22 months. Despite this improvement the 5 year survival rate formRCC remains under 10% and 20-25% of suffers remain unresponsive to all treatments and in these cases, thedisease has a rapid progression.The available treatments for RCC discussed in the Treatment section are also relevant for the metastatic form of thedisease. The most relevant of these is Interleukin-2 which is the standard therapy for advanced renal cell carcinoma.In the past six years, seven new treatments have been approved specifically for mRCC (Sunitinib, Temsirolimus,Bevacizumab, Sorafenib, Everolimus, Pazopanib and Axitinib). These new treatments are based on the fact that renalcell carcinomas are very vascular tumors they contain a large number of blood vessels. The drugs aim to inhibit thegrowth of new blood vessels in the tumors, hence slowing growth and in some cases reducing the size of the tumors.Side effects unfortunately are quite common with these treatments and include: Gastrointestinal effects - nausea, vomiting, diarrhea, anorexia Respiratory effects - coughing, dyspnea (difficulty breathing)

  • Renal cell carcinoma 13

    Cardiovascular effects -hypertension(high blood pressure) Neurological effects - intracranial hemorrhage (bleeding into the brain), thrombosis (blood clots) in the brain Effects on the skin and mucus membranes - rashes, hand-foot syndrome, stomatitis Bone marrow suppression -resulting in reduced white blood cells, increasing the risk of infections plus anemia

    and reduced platelets Renal effects - impaired kidney function Fatigue.Radiotherapy and chemotherapy are more commonly used in the metastatic form of RCC to target the secondarytumors in the bones, liver, brain and other organs. While not curative, these treatments do provide relief for suffersfrom symptoms associated with the spread of tumors. Other potential treatments are still being developed, includingtumor vaccines and small molecule inhibitors.

    EpidemiologyThe Epidemiology of RCC is complex. It is known that the incidence of the disease varies according to geographic,demographic and, to a lesser extent, hereditary factors. There are some known risk factors, however the significanceof other potential risk factors remains more controversial. The incidence of the cancer has been increasing infrequency worldwide at a rate of approximately 2-3% per decade until the last few years where the number of newcases has stabilised.The incidence of RCC varies between sexes, ages, races and geographic location around the world. Men have ahigher incidence than women (approximately 1.6:1) and the vast majority of sufferers are diagnosed after 65 years ofage. Asians reportedly have a significantly lower incidence of RCC than whites and while African countries have thelowest reported incidences, African Americans have the highest incidence of the population in the United States.Developed countries have a higher incidence than developing countries, with the highest rates found in NorthAmerica, Europe and Australia / New Zealand

    HistoryDaniel Sennert made the first reference suggesting a tumour arising in the kidney in his textPracticae Medicinae,first published in 1613.Miril published the earliest unequivocal case of renal carcinoma in 1810. He described the case of Franoise Levelly,a 35 year old woman, who presented to Brest Civic Hospital on April 6, 1809, supposedly in the late stages ofpregnancy.Koenig published the first classification of renal tumours based on macroscopic morphology in 1826. Koenigdivided the tumors into scirrhous, steatomatous, fungoid and medullary forms.

    Hypernephroma controversyFollowing the classification of the tumour, researchers attempted to identify the tissue of origin for renal carcinoma.The pathogenesis of renal epithelial tumours has provided one of the most enduring controversies of modern surgicalpathology. The debate was initiated by Paul Grawitz when in 1883, he published his observations on the morphologyof small, yellow renal tumours. Grawitz concluded that only alveolar tumours were of adrenal origin, whereaspapillary tumours were derived from renal tissue.In 1893, Paul Sudeck challenged the theory postulated by Grawitz by publishing descriptions of renal tumours inwhich he identified atypical features withinrenal tubules and noted a gradation of these atypical features between thetubules and neighboring malignant tumour. In 1894, Otto Lubarsch, who supported the theory postulated by Grawitzcoined the term hypernephroid tumor, which was amended tohypernephroma by Felix Victor Birch-Hirschfeld todescribe these tumours.

  • Renal cell carcinoma 14

    Vigorous criticism of Grawitz was provided by Oskar Stoerk in 1908, who considered the adrenalorigin of renaltumours to be unproved. Despite the compelling arguments against the theory postulated by Grawitz, the termhypernephroma, with its associated adrenal connotation, persisted in the literature.Foot and Humphreys, and Foote et al. introduced the term Renal Celled Carcinoma to emphasize a renal tubularorigin for these tumours. Their designation was slightly altered by Fetter to the now widely accepted term Renal CellCarcinoma.Convincing evidence to settle the debate was offered by Oberling et al. in 1959 who studied the ultrastructure ofclear cells from eight renal carcinomas. They found that the tumour cellcytoplasm contained numerous mitochondriaand deposits of glycogen and fat. They identifiedcytoplasmic membranes inserted perpendicularly onto basementmembrane with occasional cells containing microvilli along the free borders. They concluded that these featuresindicated that the tumours arose from the epithelial cells of the renal convoluted tubule, thus finally settling one ofthe most debated issues in tumour pathology.

    References[1] http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ C64[2] http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=189. 0[3] http:/ / www. progenetix. net/ progenetix/ I83123/[4] http:/ / omim. org/ entry/ 144700[5] http:/ / omim. org/ entry/ 605074[6] http:/ / www. diseasesdatabase. com/ ddb11245. htm[7] http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 000516. htm[8] http:/ / www. emedicine. com/ med/ topic2002. htm[9] Kidney Cancer / General Information (http:/ / www. cornellurology. com/ kidney/ gi/ rcc. shtml) at Weill Cornell Medical College, James

    Buchanan Brady Foundation, Department of Urology

  • Article Sources and Contributors 15

    Article Sources and ContributorsRenal cell carcinoma Source: http://en.wikipedia.org/w/index.php?oldid=598522082 Contributors: 1ForTheMoney, Af1523, Alexbrn, Alexius08, Allyoop09, Alpha30, AltheaJ, Anaxial,Anchroo, Andrew73, Anypodetos, Arcadian, Avaron676, BD2412, Bender235, Bobblewik, Brysonborg, Bunnyhop11, Camelotchic, Ccacsmss, Ceccomaster, Cenarium, Chicago2009, Chowbok,Chris Capoccia, CimanyD, CommonsDelinker, Coralmizu, Cweight, Cyclonenim, DanMS, Danny, Davodd, Debronkart, Derwig, Diademodon, Diberri, Dl2000, Dom Kaos, Dougtischler,Download, DrJos, Dragonfire2384, Drf5n, DropDeadGorgias, ESL2010, Ec4gt, Emiellaiendiay, Emmanuelm, Erebus Morgaine, Erinperin, Faisal0786, FeatherPluma, Fuse809, GG The Fly,Gabbe, Gaius Cornelius, GermanX, Giftlite, Gilo1969, Giovanni Codacci-Pisanelli, Gogo Dodo, GoingBatty, Gor n bein, Gregorme, Ground Zero, Haddendaddendoedenda, Hancong,Harrisd5917, Hovea, Hu12, Ian Glenn, Igor.stevan, Immunize, JaGa, JamesAM, Jbsykes, Jfdwolff, Jhagenk, Jjasi, Jmh649, Joseph Solis in Australia, Jwy, Katalaveno, Keilana,Ken-train19890106, Kenny1973uk, Kevin B12, Khazar2, Klemen Kocjancic, Knownot, Krebiozen, L Kensington, Lappleman, LilHelpa, Lomn, Lybbar12, Mandarax, Manojkkashyap, Marek69,Mba123, Mdanciu, Middayexpress, Mikael Hggstrm, Miketm, MistyMorn, MnemosynesMusings, Mohammad ahmad, N5iln, Nbauman, Nephron, Nesta333, Niceguyedc, Nono64, OrangeSuede Sofa, PC-XT, PHaze, Palltrast, Patho, PhilKnight, RDBrown, Reinyday, Rich Farmbrough, Richiez, Rixster69, Rjwilmsi, Rmenikoff, Robert Ewing, Roberta F., Rod57, Runt, SJP,Salamurai, Seans Potato Business, Sgibbel23, Shingra, Spannell, Speciate, Squids and Chips, SteinbDJ, StephP, Stevenfruitsmaak, Stormie, Tangotango, Tarquilu, Tikiwont, Timjcuster,Titamary97, Ulric1313, Una Smith, Valmataro, Vojtech.dostal, Wouterstomp, Yobol, Yourskeptic, Zalgo, ZayZayEM, 211 anonymous edits

    Image Sources, Licenses and ContributorsFile:Clear cell renal cell carcinoma high mag.jpg Source: http://en.wikipedia.org/w/index.php?title=File:Clear_cell_renal_cell_carcinoma_high_mag.jpg License: Creative CommonsAttribution-Sharealike 3.0 Contributors: NephronFile:Renal clear cell ca (1) Nephrectomy.jpg Source: http://en.wikipedia.org/w/index.php?title=File:Renal_clear_cell_ca_(1)_Nephrectomy.jpg License: GNU Free Documentation LicenseContributors: Alex brollo, Ares.it, IGEL, KGH, Rosenzweig, 1 anonymous editsFile:Papillary renal cell carcinoma 1.jpg Source: http://en.wikipedia.org/w/index.php?title=File:Papillary_renal_cell_carcinoma_1.jpg License: Creative Commons Attribution-Sharealike 3.0Contributors: NephronFile:Oncocytic chromophobe rcc high mag.jpg Source: http://en.wikipedia.org/w/index.php?title=File:Oncocytic_chromophobe_rcc_high_mag.jpg License: Creative CommonsAttribution-Sharealike 3.0 Contributors: NephronImage:Renal cell carcinoma.jpg Source: http://en.wikipedia.org/w/index.php?title=File:Renal_cell_carcinoma.jpg License: Public Domain Contributors: Ed Uthman, MD (1953 )Image:Kidney cancer.jpg Source: http://en.wikipedia.org/w/index.php?title=File:Kidney_cancer.jpg License: Creative Commons Attribution 3.0 Contributors: Emmanuelm (talk)

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    Renal cell carcinomaSigns and symptoms Cause Lifestyle Genetics

    PathophysiologyDiagnosis Classification Laboratory tests Urine analysis Complete blood cell count Blood chemistry

    Radiology Computed tomography Ultrasound Magnetic resonance imaging Intravenous pyelogram Renal angiography

    Staging Histopathology

    Prognosis Management Active surveillance Surgery Targeted ablative therapies Targeted drug treatments Chemotherapy Vaccine Adjuvant therapy

    Metastatic renal cell carcinoma Epidemiology History Hypernephroma controversy

    References

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