renal tumors

Renal tumours are not rare all together and could be related to some of the disease that affect the kidney as possible complications As for any other organ we have benign and malignant forms. In this slide we refer to the epithelial forms, There are also have mesenchymal tumours like lipomas, fibromas, hemoangiomas etc. There are some forms that typically affect the kidney: Mixed tumour ● Angiomyolipoma ● Angio- Vessels ● Myo- Muscle cells ● Lipoma- Adipose tissue ● It is a benign tumour that could be very large and compromise the renal function. ● It is benign but it should be distinguished by more aggressive forms ○ It has typical radiological appearance due to vascularization ● It should be distinguished from other forms: sarcomatous or melanomas, because of immunohistochemical profile, because it has melanocytes markers As for epithelial forms we include: ● Benign forms: ▪ Oncocytoma ▪ Renal cell adenoma ● Malignant forms: ▪ Renal cells carcinoma ▪ Wilms tumour ▪ Urothelial carcinoma ▪ Canaffect the kidney starting from the pelvis or the major and minor calyces with secondary involvement of the kidney ▪ It can arise from any tract of the excretory apparatus (ureter, urinary bladder and sometimes the urethra) 434 The first consideration is that the malignancy is more probable to arise than the benign. RENAL CELL CARCINOMA ● An epithelial tumor that arises from the tubular epithelium ○ Represents 85% of the primary malignant tumours of the kidney. ● If you could consider all cancer affecting adult the % of the incident would be only 2-3% so it is not so frequent, but its not so exceptional ● Typically affects aged individuals between the 6th and 7th decade with more predisposition for men Which are the risk factors: ▪ Cigarette smoking ▪ Occupational exposure to cadmium ▪ Dialyzed individual ▪ Sporadic cases in which these factors are not needed. Etiology: 435 ● Sporadic, non-genetically inherited ● Tobacco smoking contributes to ¼ of renal carcinoma, and it increases the risk 2-fold. ● Occupational exposure to some heavy metal like asbestos as it occurs in mesothelioma or petroleum ● Obesity and chronic aspirin use ● Acquired polycystic kidney disease due to dialysis (Example of PKD during dialysis) with an image reproduction of nodules Symptoms Which are the symptoms associated? ● Gross hematuria ○ main symptoms that alarm the patient ● Flank pain ● Palpable mass ○ These tumors tend to become evident in advanced sages when the size of the mass is more than 10cm ● Paraneoplastic syndrome, in few cases it is associated with: ○ Unexplained and long-lasting fever ○ Polycythemia ○ Hypercalcemic syndrome ○ hypertension ○ Cushing syndrome ● Metastases to lung or bone ○ The primary location of the tumour could be not symptomatic. 436 As for the classification we can consider three types: 1. Conventional RCC (In the past clear cell carcinoma) 2. Papillary RCC 3. Chromophobe RCC It is quite important to distinguish between these forms because of the different clinical behavior and prognosis. Here we have 3 groups according to their origin ● Conventional RCC ▪ 75% of all cases of RCC ▪ Arises from proximal nephron and is associated with a mutation ○ 60% in VHL gene 437 ○ 26% Hypermethylation ○ Loss of heterozygosity of chromosome 3p45 ○ Other abnormalities ● Thepapillary carcinoma: ▪ 15% of all cases of RCC ▪ Also drive from the proximal nephron, Types-- Type 1 → Mutation in Met proto-oncogene Type 2 → Mutation in fumarate hydratases ● On such form trisomy or some chromosomal abnormalities are commonly seen From the distal nephron ▪ 5% Oncocytoma ▪ <2% Chromophobe carcinoma ▪ Rare collecting duct carcinoma ▪ <2% Undifferentiated carcinoma ○ In which we cannot identify a typical histological pattern Hereditary Papillary Renal Carcinoma (Type 1 Papillary Carcinoma) ▪ HPRC is a hereditary condition that increases the risk of a papillary type of renal cell carcinoma ▪ Such individuals have an increased risk of multiple kidney tumors in one or both ▪ Not metastatic but synchronous or metachronous due to this mutation ▪ Currently no other type of problems are related to this condition 438 Hereditary leiomyomatosis and renal cell cancer (Type 2 Papillary Carcinoma) ● Hereditary condition associated with development of multiple leiomyomas, which are smooth muscle tumors located to the skin and the uterus: fibroids ● Aggressive form of kidney cancer. ● Differently from previous one, we have skin metastasis and more aggressiveness ○ The skin tumours that occur on the chest, back, arms and legs in adulthood ○ Women can develop uterine fibroids, as young as their teen age or early 20s ○ The cancers can occur in adulthood, but it can also arise early in children or teenagers ● Insuch hereditary forms, the occurrence of renal tumors is early in respect to the normal described age for renal tumours. The peak of incident was mentioned to be 6-7th decade ○ In such syndromic forms, we know it’s a hereditary condition This picture illustrates the typical aspect of a RCC ● We can see a large nodule that in some cases like that can be well defined and well circumscribed (Not encapsulated) (Bottom picture) Here we can see the same that can infiltrate the capsule and the perinephric fat, which is an advanced stage. 439 (Left) we can see intrarenal invasion. Here are two examples of non-solid, well circumscribed of RCC. On the left ● Not solid, extensive areas of necrosis ● One affecting the top pole and the remaining is not affected ● We can understand why hematuria is a sign of this cancer, has a late onset, we have the erosion of the calyces which causes the hematuria. This occurs late in the history of this tumour, that's why the size of the tumour is large. On the right ● This is a different condition in which we have a very large tumor of which the surface is typically hemorrhagic ● This tumor typically expands outside the profile of the kidney, the lower pole, infiltrates rapidly the perinephric fat, compressing the calicles, pelvic and ureters. ● E extensively necrotic. Here another gross aspect of tumor arising in acquired PCKD for a dialyzed individual 440 Histological description of renal cell carcinoma The macroscopic view is not indicative of the feature of the origin of the tumour. Conventional renal cell carcinoma: ● Account 70-80% of all cases ● Familial or sporadic ● Can be associated with Hippel-Lindau syndrome ○ Mutation in the VHL gene ▪ Autosomal dominant syndrome ▪ Associated with multiple tumors of different types the main of which are the hemangioblastoma of the cerebellum and retina and renal cyst and renal cell carcinoma ○ Inthis syndrome we have a germline mutation in the gene locatedinchromosome 3 and due to the loss of the second alleles by somatic mutations ○ Theaffected individuals will have a germline mutation and the second is caused by somatic mutation ○ Such mutation is seen sporadically in RCC 441 These are two histological views of the conventional renal cell carcinoma. ● We can understand why it is called the clear cell. ● We canseetheglomerulus that isenvelopedbytumourproliferationof cells thatare enlarged, whitish and pale with a small nucleus organized in cord like structure. ● Ontherightwecanseethesamethingbutinahighpower,suchcells, typicallyenlarged, pale and nuclei are a bit enlarged with small nucleoli. Papillary Renal Cell Carcinoma ● Accounts of about 10-15% deriving from the proximal tubular epithelium. ● Multifocal, bilateral ○ This is the first feature to characterize this form 442 ○ When we make the diagnosis of papillary type RCC the urologist need to consider the localization to the same kidney or the other ● Could be familial and sporadic ● MET proto-oncogene mutation of type 1 is typically involved ● Trisomy of chromosome 7 or mutation of chromosome7 ● In sporadic cases trisomy 7, 16, 17 The histologic aspect Macroscopic aspect of Papillary type RCC ● You can appreciate the multifocality ● We can see a sort of convoluted excursions (not solid area as in the conventional RCC) ● The color is different. The conventional RCC is yellowish, but in this color the color is grayish ● Papillae with fibrotic core or pseudo papillae with the proliferation of epithelial neoplastic cells This is another possible expression ● Such papillae are present with different degree of atypia that can affect the epithelium. Again In the core of the papillae, we have a lot of foam cells probably macrophages. 443 Chromophobe Renal Cell Carcinoma ● Accounts for 5% of all RCC ● Derives from the collecting ducts ● The genetic abnormalities associated with this form are extremely variable ● You need to remember that this tumor has a good prognosis: ○ Apossible effect of the histopathological diagnosis of the chromophobe RCC this form of tumour is less aggressive ● Your histological diagnosis can impact the clinical course ○ The therapeutic approach can be variable by an oncologic point of view This is typically the macroscopic aspect of a chromophobe cell carcinoma ● In this case it is typically and extrinsic or extra renal extension ● Whatisimportantisthecolor: “brown tan” not the typical color of the conventional renal cell carcinoma. Typical morphological aspect ● Made by large cells and large nuclei with perinuclear hollow with an evident cell membrane. 444 Here there is the ultrastructure of such tumor ● The cytoplasm filled with macrovesicles, typically related to morphological aspect that we can see with light microscopy. Slides to summarize the main features of this form Clear cell (Conventional) RCC ● Solitary ● Large, >10 cm ● Cortical in origin, in its early phase ● Well defined: not encapsulated but the borders of the tumours are well defined ● Color is typically yellow with some variation: Yellow-Orange, Gray-white ● Cystic on cut section ● Extensively hemorrhagic or necrotic ● Can extent to the pelvis and ureters ● Typically, can invade the renal vein and subsequently the IVC ▪ high affinity to the vessels, it can invade the vessels and metastasize there. ▪ The invasion of renal vein is quite important to predict the behavior of these form ▪ Extended to the pelvis and ureter that may invade the renal vein Papillary RRC ● Bilateral: More probably the papillary form ● Multiple 445 Chromophobe RRC ● The most characteristic aspect of the chromophobes is the brown-tan color. Microscopic features Clear cell (Conventional) RCC ● Pale or clear because of lipids and glycogen that are not seen in routine staining ● Round nuclei ● Vascular: the tumour is highly vascularized Papillary RRC ● The occurrence of papillae is quite specific for this form ● In few cases also in conventional RCC, pseudo-papillae may be found Chromophobe RRC ● Perinuclear halo ● Macrovesicles in electron microscopy ● Well defined cell membrane 446 Sum of the three forms Grading of Renal Cell tumors with specific neoplastic characteristics For every type of tumor, we grade them, we usually use a 3-grade classification: well differentiated, moderately differentiated, poorly differentiated But for RCC we use the Fuhrman classification/grading (4 grades not 3) ● Grade 1 ○ Small tumor nuclei in the absence of nucleoli ○ If present are very small and not evaluable unless high magnification ● Grade 2 447 ○ Nucleoli can be found, but these are small and visible at high magnification ● Grade 3 ○ large nucleoli intensely eosinophilic, easily visible at low magnification ● Grade 4 ○ Nuclear pleomorphism and neoplastic giant cells. ○ In some cases, sarcomatoid or rhabdoid (de)differentiation ○ When you have the latter mentioned bizarre differentiations, we should make a diagnosis of grade 4 ▪ Different from typical cases of 1,2,3 where the diagnosis is based on the morphology of nuclei. It is not simply a classification of the morphology. Because based on this classification, the therapeutic options may be different. ● Chemotherapy can be used for the grade 4 but not the other. Synthetically we can see the Fuhrman’s grades ● Some proposed system or modified Fuhrman’s grading scheme ○ We need to have less degrees to have major reproducibility of this system 448 ○ If wecombine the Furman grade1and2,isitiseasiertodefine those form that are less aggressive from grade 3 and 4 that are more aggressive ● Classification scheme that includes only 2 levels ○ 1st combining grades 1 and 2 ○ 2nd combining grades 3 and 4 The reason for merging is to simplify or make easier the type of therapy ● E.g for grade 1 and 2 together, chemotherapy is not used, ● For grades 3 and 4, chemotherapy is useful This classification is not just a description, doesn't not only give useful info about the behavior of the tumor, but also gives info about the treatment of the tumor. Benign forms Oncocytoma The macroscopic appearance is quite typical ● Large nodular mass 449 ● Well circumscribed ● Brownish color ● Solitary mass ● Central scar Almost invariably all these features occur. Synthesis of the features of an oncocytoma ● Benign renal oncolytic neoplasm ● Cell are packed with mitochondria under electron microscopy ○ The morphological aspect is due to this accumulation ○ It is essential to differentiate from mimicker of oncolytic tumours. ○ Also, in some cases we can have multiple tumours in syndromic conditions ○ Some cases can have hybrid oncolytic chromophobe renal cell carcinoma Typical histological oncocytoma aspect of the ● Benign renal epithelial cells with round eosinophilic cells ● Cytoplasm is intensely eosinophilic ● The nuclei are small and regular they have an edematous component 450 These were the predominant histological feature: ● Well circumscribed lesions (not infiltrative pattern) ▪ No pseudo-capsules ● Solid nest with loose connective tissue or edematous stroma ▪ Could be also tubular or microcytic form. ● The predominant feature is the large round eosinophilic cells with dense granular cytoplasm known as Oncocytes ● Papillary aspect is not a feature of this tumor. ▪ When we have papillary proliferation, it is not compatible with oncocytoma diagnosis, but rather a papillary tumor of the kidney ● Nuclei uniform, round and are regular with even chromatin ● Notcommonly, Bizarre pleomorphic hyperchromatic cells are present, but they have to be considered degenerative. ▪ Not a sign of malignancy but simply a degenerative effect ● Mitosis is rare, atypical mitosis are not described ● Could be hemorrhagic by coagulative necrosis is not present ● We can have areas of cytoplasmic clearing around scar areas ▪ Aspect of clear cells but not the same as clear cell carcinoma 451 Papillary Adenoma Last for form benign tumour ● You can see a low magnification view of a kidney with a small subcapsular nodule, the adenoma ● Well circumscribed, very small ● Small papillae Definition ● It is defined adenoma not on the bases of histologic features, because the same features are visible in a well differentiated papillary carcinoma ● It is based on size of the tumor, because the risk of developing metastasis is very low ● Size of the tumor and good differentiation. ● Benign kidney lesion defined by WHO classification in 2016 as an unencapsulated tumor with papillary or tubular architecture, low grade of differentiation, diameter of no more than 15mm 452 The criteria to define it as benign ● Unencapsulated Tubular or papillary architecture ● Dimension do no exceed 15mm In other words, if we find an incidental small tumour that has clear cells and with 2cm size it is a precursor of a RCC. If we found a tumor of about 1 cm, papillary or tubular structure, and low grade of differentiation it should be defined as a benign tumour or papillary adenoma. You could find such lesions in the kidney to be transplanted. The occurrence of an adenoma makes this kidney able to be transplanted, but obviously a true carcinoma should not be transplanted. So, the histological diagnosis is crucial to define the consequences that could influence therapy This is the histological view of the tubular papillary adenoma. ● Low nuclear grade lesions, similar in morphology to papillary RCC (type 1) but smaller and lack a pseudo-capsule. ● These lesions cannot metastasize, and the risk is very small. ● It was postulated that they are precursors for papillary RCC, and the limit is fixed to 15 mm (Used to be 3cm) ● The adenoma prevalence is much higher than carcinomas; meaning that not all of them can progress into carcinomas. ● The transplantation practice has increased with this type of adenoma ○ The problem is to decide if this kidney should be transplanted or not. ○ That’s the reason why WHO established a method to decide if the kidney is transplantable or not. 453 WILMS TUMOUR or Nephroblastoma The most common primary kidney tumor in children, the others are syndromic RCC that we saw before. ● Common between 2-5 year, some forms can be present at birth ● WT1 gene or WT2 gene mutation ● Can be associated with other congenital malformation like: ▪ WAGR syndrome ▪ Denys-Drash syndrome ▪ Beckwith Wiedemann syndrome 454 Included in this slide we can see some symptoms: ● Mostly the nephroblastoma are not associated with this syndrome and occur sporadically. Clinical they occur as a mass ● If you consider the age of the patient, the mass can be large and easily palpable ● Across the midline ● Could be associated with hematuria if it involves the urinary system ● Could provoke obstruction due to its dimensions ● The prognosis is generally good, and the 2-years survival is around 90% Here you can see two possible examples in these kidney On the Left: ● Large mass in the upper pole ▪ Solid area homogenous, grayish ● Wecansee another nodule in lower pole of the kidney ● Insome cases,wecanhavemultipletumour and one possible precursor of the nephroblastoma is the nephroblastomatosis, not a neoplastic condition, but accumulation of a nest of immature tissues along the cortex of the kidney ▪ Tumours may then develop from these nests ▪ One of the cases in which we can have a bifocal tumour On the R ● Different aspect of the tumor: extensive hemorrhagic areas or necrotic infiltration of the tumour itself Small remaining functional area of the kidney ● In this case only a small part of the kidney remains (top left) as the rest is replaced by the tumor ● It’s about 13-14 cm and therefore It was palpable externally 455 The same can be said for this one ● We can recognize a crescent ● Wecansee the pelvis, the ureter, and the tumor, which is solid, homogenous some lobulation due to septa ● The typical morphology of this kidney affecting the infancy Here we can see the typical histological view. ● We can see immature cells and tissue like the pancreaticoblastoma or hepatoblastoma ● It is tubular, we can see primitive tubules and primitive glomeruli (or immature glomeruli); so, we have an immature component of the epithelial cells ● Solid nest of small round cells, these cells represent blastematous cells or blastemocytes that are immature and not differentiated. ● Stroma is edematous, made of connective collagen fibers, fibroblasts. ● In the stroma we may also heterotopic tissue, like; bone, cartilage or striated muscles, a mix of different tissues. At higher magnification ● we can see a blastematous nest with foci of neoplasia because some of the tubules and cells are enlarged and we can see mitoses ● Someofthemmaybeatypicalwithamoreaggressivecytological pattern 456 Sum-up of aspects: Grossly tumour appearance ● large well circumscribed ● In 10% of cases, it can be bilateral, or multiple ● Soft tan gray color ▪ It can also be hemorrhagic with cystic excavations, necrotic ● Histologically: we can find 3 main components ▪ Epithelium: Tubules ▪ Stroma: fibroid and myxoid ▪ Blastematous component: Small blue cell ● Foci of anaplasia indicative of the aggressiveness and behavior of the cells in the therapeutic approach ● Nephrogenic rests should be noted, which may be precursor lesions. Their occurrence is needed to evaluate the contralateral kidney to see if there is risk on the other kidney too. Anaplasia

-present in 5-20% of tumors

-defined as the presence of enlarged, atypical, tripolar or multipolar mitotic figures, marked nuclear enlargement and hyperchromasia

-all 3 features need to be present

-may occur in any of the components

-focal anaplasia is defined as a clearly defined focus within a primary intrarenal tumor.

-In SIOP: up to 2 foci of up to 15mm in size

-In COG: up to 4 small foci, size not specified

-Diffuse anaplasia is defined as nonlocalized anaplasia; focal anaplasia with marked nuclear unrest in the remaining tumor; anaplasia beyond the tumor capsule; anaplastic cells in intrarenal or extrarenal vessels, renal sinus, ...

Staging 

Stage 1: confined to kidney; complete excision with renal capsule intact and negative resection margins; lymph nodes negative for Wilms tumor spread.

Stage 2: regional extension beyond kidney capsule, but confined to flank; may include: tumor penetration through capsule but confined to Gerota's fascia, infiltration into renal vein, complete excision with negative resection margins, lymph nodes negative for WIlms tumor spread

Stage 3: residual tumor, but confined to abdomen; may include: regional lymph node involvement, peripheral contamination (biopsy....