in this video we will study the pathology of renal cell carcinoma firstly we will study its origin risk factors and its types then we will study the pathogenesis and morphology of each of the types in details so let's begin firstly you need to learn that the origin of renal cell carcinoma is from renal tubular epithelium as implied by the name renal cell carcinoma secondly the risk factors for renal cell carcinoma are smoking and obesity you know that these two factors are commonly the risk factors of many types of cancers now the third very surprising risk factor for renal cell carcinoma is hypertension and it's quite surprising because hypertension is a vascular disorder and logically a vascular disorder does not make sense to have association with the neoplastic disorder but still this is considered as a risk factor the fourth risk factor is exposure to amateur cadmium and the last risk factors is acquired polycystic kidney disease that commonly occurs in patients who are on chronic dialysis those patients who are on chronic dialysis have tendency to develop multiple cysts on the kidney and along with the development of cysts they may develop prenatal carcinomas so the risk factors for renal cell carcinoma are smoking obesity hypertension cadmium exporter and acquired polycystic kidney disease now based on the histopathological features there are three types of renal cell carcinomas first is clear cell carcinoma second is papillary cell carcinoma and the third is chromophobe cell carcinoma out of all these types clear cell carcinoma is the most common and chromophobe renal carcinoma is the least common we will study each of these types in details now let's start with the clear cell carcinoma firstly we will study its pathogenesis so basically clear cell carcinoma occurs when there are mutations in vhlg on chromosome number three vhl stands for one hippodendo and this vhl gene is a tumor suppressor gene whose function is to suppress the formation of cancers but when this tumor suppressor gene is itself mutated there is tendency to develop clear cell carcinomas now let's study it in a little bit details you know that in our cells there is pair of each chromosome and on each member of one pair of chromosome there are two corresponding alleles so vhl gene is also in form of two alleles one on each chromosome number three now in clear cell carcinoma what happens is that one of the vhl allele undergoes deletion by some cytogenetic abnormalities and the other vhlg at the vhl elite undergoes somatic mutation due to chemical carcinogens like cigarettes chemicals or other carcinogenic elements or alternatively it may become silenced due to hypermethylation now when both copies of vhl alleles are inactivated this way that this loss of vhl results in increased production of hif that is known as hypoxia and usable factor now this hif or hypoxia and usable factor acts as a transcription factor and increases the transcription of vascular endothelial growth factor as well as other growth factors such as insulin growth factor one now this vascular endothelial growth factor and other growth factors stimulate the growth of renal tubular cells which result in uncontrolled cell division this uncontrolled cell division results in formation of clear cell carcinomas so this is the pathogenesis of clear cell carcinomas let's review its once again in clear cell carcinomas there is mutation in vhlg which results in increased formation of a transcription factor known as hif this hypoxia inducible factor or hif increases the transcription of vascular endothelial growth factor and other growth factors these growth factors provoke uncontrollable cell division resulting in clear cell carcinomas now here we also need to understand an additional point regarding one hippo endowed disease this is an autosomal dominant trait in which one of the vhl gene is inherited as a germline mutation so these people need only one additional mutation in the second allele to develop cancers resultantly these patients are at increased risk of neoplasia so if people with bhl disease who already have one mutated gene develop somatic mutations in the other genes in the cells of kidney they develop clear cell carcinomas and other than clear cell carcinomas they are also at increased risk of developing multiple renal cysts human geoplastromas of the cerebellum and retina and other variety of tumors so people with vhl disease can develop all these tumors now let's come to the morphology of clear cell carcinomas on gross specimen clear cell carcinoma appears as a solitary mess the word solitary means single so instead of multiple masses there is a single mass in clear cell carcinoma secondly the cut surface of the tumor shows cystic areas or hemorrhage thirdly this tumor has a very classical tendency to invade the renal veins and when it invades the renal veins the tumor grows as a solid column of cells that extend from renal vein into the inferior vena cava such extension into renal vein and then into inferior vena cava occurs in the serpent time fashion serpentine means snake so the gross features are solitary mass whose cut surface shows cystic areas or hemorrhage and the tumor sometimes invades renal vein and grow as a solid column of cells in inferior vena cava now let's come to the microscopic features for microscopic features we will mainly focus on three points that how do the cells look like how do the cells arrange and how does the stroma surrounding the cells appear so firstly as far as the cellular structure is concerned the cells in clear cell carcinoma do not stand eosinophilic rather they are clear in color with empty cytoplasm secondly along with these clear cells that have clear cytoplasm there are other type of cells that appear intensely eosinophilic and granular but these cells are very few most of the cells are those that are with clear cytoplasm so you can see in this diagram when the cells do not appear eosinophilic rather they are with clear cytoplasm now secondly coming to the arrangement of the cells in clear cell carcinoma the cells are arranged in form of tubules or chords as you can see here in this diagram where the clear cells are in form of tubules but they can also be in form of cords now thirdly the stroman cases of clear cell carcinomas is scanty but vascular which means that the stroma is not abundant because the cells are over proliferating so the relative amount of stroma remains very small that's why we call it as scanty but even despite being scanty the stroma is highly vascular this high vascularity corresponds to increased blood supply demand of the tumor cells so one light microscopic picture of clear cell carcinomas using clear cells with empty cytoplasm you see few cells that are in density eosinophilic and granular and you see that that they're the cells that arrange in form of tubules or quartz and you see stroma that is candy but vascular now let's come to capillary renal cell carcinomas firstly we will study its pathogenesis so papillary renal cell carcinomas are caused by activating mutations in matte proton cogene on chromosome number seven now this matte proto oncogene and quartz for receptor tyrosine kinase so when there is activating mutation of mac proton oncogene there will be increased activity of receptor tyrosine kinase which will cause uncontrolled cell division resulting in cancer so the main point to learn here is that in papillary carcinomas the mutations in the mac proton co gene on chromosome number seven so the mutation is in macro to oncogene on chromosome number seven now let's come to the morphology of papillary carcinomas one gross specimen papillary inner cell carcinomas appear as bilateral or multiple masses which means that it can be present in both the kidneys and there can be multiple tumor masses instead of a solitary mass that we studied in clear circarcinoma this presence of multiple masses is a point of difference between clear cell carcinomas and papillary carcinomas secondly in papillary carcinomas similar to clear cell carcinoma the cut surface will show cysts and hemorrhages now for microscopic features the keyword to focus is papillary the word papillary indicates that in this cancer the light microscopic picture will show finger like projections called papilla which will be lined by proliferating neoplastic epithelial cells now let's come to the pathology of last type of renal cell carcinomas that is chromophobial cell carcinomas these chromophobina cell carcinomas arise from intercalated cells of collecting ducts and the unique feature about them is that they are caused not by mutations in one or few genes rather they have multiple losses of entire chromosomes this deficiency of multiple chromosomes is known as extreme hypoploidy so remember this point that extreme hypoploidy is a feature of chromophobia carcinomas now let's move to the morphology on gross specimen chromophobial cell carcinomas appear as ten brown messes tan brown messes for microscopic features the mnemonic to remember is p p p or triple p out of these three p's the first p stands for pale straining cytoplasm so that's why it is called as chromophobe chroma means color and fob means hating or existing as this tumor stains lightly eosinophilic that's why we call it as chromophobe but this cytoplasm is not totally clear like clear cell carcinomas it just stained lightly eoxinophilic the second piece stands for pairy nuclear clearing so what does it mean you remember that we have just studied that in chroma for grenache carcinomas the cytoplasm stains slightly eosinophilic but just around the nucleus there is central zone where it's where instead of light eosinophilic staining there is completely colorless or clear zone you can see here in this diagram that there is a clear area just around the nucleus this clear zone around the nucleus is in form of link and is known as perinuclear clearing now the third p stands for prominent cell membranes so the cell membranes of this tumor appear very distinct with prominent margins so overall you will see pale cytoplasm you will see perinuclear clearing and you will see prominent cell membranes now let's discuss the clinical features of all greener cell carcinomas we will divide clinical features into linear manifestations and extraordinary manifestations as far as the renal manifestations are concerned there is a classical triad for clinical features of renal cell carcinoma this triad includes palpable mass flank pain and hematuria palpable mass flank pain and hematuria now this sounds logical because when a tumor is blowing from the kidney it will appear as a palpable mass in that dormant secondly as the tumor of the kidney grows it will stretch the capsule of the kidney this stimulates the pain receptors in the capsule resulting in localized frank pain thirdly as the tumor cells invade surrounding vascular stoma this invasion will cause leakage of blood into urinary system this leakage of blood is called hematuria so the classical triad consists of palpable mass flank pain and hematuria now the extra renal manifestations are in the form of paraneoplastic syndromes these paraneoplastic syndromes are in form of polycythemia that is caused by secretion of erythropoietin by tumor cells cushing's syndrome that is caused by secretion of acth-like substances by tumor cells and hypercalcemia that is caused by secretion of parathyroid hormone-related protein by the tumor cells so the extraordinary manifestation or pioneer plastic syndromes in renal cell carcinomas are polycythemia cushing syndrome and hypercalcemia now the last point is that you know all the cancers have a tendency to measure size to other distant organs so the common sites of metastasis in renal cell carcinomas are lungs and bones lungs and bones so this concludes our discussion on renal cell carcinomas