tumors of the kidney

THE FOURTH SUBTYPE OF RCC - GENERAL features - prognosis - treatment- which gene is important - macrosco-micros apearence

(4) Sarcomatoid (renal cell) carcinoma v Finally, secondary dedifferentiation of all these previous 3 categories is leading to the development of sarcomatoid renal cell carcinoma Ø So, it is the result of transformation of previous subtypes of renal cell carcinomas v Very rare Ø Saying that this tumor is rare simply means that this transformation is not very common, but it exists, so you should be aware of that Ø Because when this transformation appears, the median survival is shortened to approx. 1,5 year (19 months) Ø So, really when you compare it with the previous ones, this is a very cruel prognosis Ø Don't forget this v Also called spindle cell carcinoma, carcinosarcoma v 1% of renal tumors in adults v Not a distinct histologic entity, but the common pathway of transformation of different subtypes of RCC = Secondary, not primary v Occurs in <10% of all subtypes; however, most sarcomatoid carcinomas are derived from clear cell carcinomas since they are most common v Mean age 60 years; metastases to lungs common v Aggressive with median survival of 19 months; 5/10 year survival is 22%/13% vs. 79%/76% for other RCC Ø Prognosis is poor v Why do we call it sarcomatoid? Ø Because the histological appearance is really resembling sarcoma § It has spindle cell type morphology Ø It is very important to do a very proper analysis of this tumor to find out if it is primary sarcoma of the kidney (it theoretically does exist) or whether it is secondary transformation/dedifferentiation of previous categories of renal cell carcinoma v Activation of MET (mesenchymal epithelial transition) gene v There exists a gene, which is called MET gene, it is abbreviation for mesenchymal epithelial transition/transformation Ø This gene is switched on in the process of dedifferentiation to sarcomatoid RCC v It also reflects the therapy, by blocking the MET gene, we can try to cure this patient v Macroscopical picture of sarcomatoid renal cell carcinoma: Ø Fleshy, gray-white Ø Infiltrative margins Ø Mean 9 cm Ø May have clear cell component (yellow, hemorrhagic, necrotic parts) v Microscopical picture of sarcomatoid renal cell carcinoma: Ø Atypical spindle or giant cells with marked nuclear pleomorphism and abnormal mitotic figure Ø May resemble sarcoma with poorly formed fascicles Ø Occasionally undifferentiated with rhabdomyosarcomatous component, bone, cartilage

FIRST SUBTYPE OF RCC(renal cell carcinoma) - general information - the risk factors - metastases to which organs -macro-microscopic features/appearence

1. Clear cell type (renal cell) carcinoma / or just conventional or classic type v Conventional / classic type (Grawitz tumor) - 70% of adult renal epithelial tumors v Risk factors: Ø It is associated with known risk factors, among the risk factors of this kind of cancer is smoking, obesity and hypertension (HT) Ø This is true, but majority of these patients develop cancer as a result of bad luck § Although we know that these risk factors are playing a role, they are not directly associated formation of this tumor Ø Adult polycystic disease, acquired kidney cystic disease, smoking, obesity in women, HT, von Hippel Lindau disease, tuberous sclerosis (von Hippel Lindau disease: AD, hemangioblastomas of retina and cerebellum, cysts of pancreas, liver and kidney, clear cell tumors of other sites, pheochromocytoma; bilateral or multiple RCC) Ø Compare to the other 2 types, clear cell type has the worst prognosis v Metastases: Ø Lung, LN, liver, bone, adrenal glands, kidney, brain, heart, spleen, intestine, skin v Why is it called "clear cell type"? Ø Because the typical morphology of these cells is clear cell appearance Ø Maybe you remember when we studied about necrosis and dystrophy Ø One of the examples which you had about dystrophy of glycogen, was this cancer § That means simply the cytoplasm of the cells is rich in glycogen and lipids, therefore it gives rise to this clear cell appearance, and also gives rise to this peculiar yellowish macroscopical color of this tumor v Macroscopical picture of clear cell type renal cell carcinoma: Ø Orange/ yellow (from lipid) Ø Well circumscribed Ø Hemorrhage, necrosis and calcification are common Ø Frequent renal vein involvement Ø May undergo cystic degeneration v Microscopical picture of clear cell type renal cell carcinoma: Ø Compact, tubulocystic, alveolar or rarely papillary architecture of cells with clear cytoplasm (from glycogen/ lipid) Ø Distinct but delicate cell boundaries Ø Often glassy hyaline globules

SECOND SUBTYPE OF RENAL CELL CARCINOMA - prognosis - micros-macroscopical appearence -survival rate

2. Papillary (renal cell) carcinoma v Representing 15% of all renal cell carcinoma v It has a little bit better prognosis than clear cell carcinoma v It is called papillary because the morphology here is clearly papillary v In reality we distinguish type I and type II, but we should not be studying that v This is all what we should know about this tumor according to Plank v Macroscopical picture of papillary renal cell carcinoma: Ø Red/brown color (from hemorrhage) Ø Multifocal (80% of tumors), occasionally bilateral Ø Well circumscribed, often with distinct fibrous capsule v Microscopical picture of papillary renal cell carcinoma: Ø Papillary or tubulopapillary pattern Ø Papillary fibrovascular cores, papillae may have foamy macrophages Ø Variable psammoma bodies v Associated with adenomatous changes in adjacent kidney v Survival: Ø 5 years 82-90% Ø Better prognosis than clear cell carcinoma Ø Metastases to regional LNs

THIRD SUBTYPE OF THE RCC - its common feature - micro and macroscopical picture

3. Chromophobe (renal cell) carcinoma v The 3rd major type is chromophobe v "Chromophobe" means expression of the histological t

KIDNEY TUMORS - what you should first focus on when this tumor of this organ is mentioned

Kidney tumors v Tumors of the renal parenchyme can be divided: v Of adults v Of children (= pediatric neoplasias) v Primary v Secondary (MTS) Ø As in any other organ v You can also follow the COO, cell of origin concept, or has we call is "histogenetical" concept, if the tumor is epithelial, mesenchymal or any other origin v Tumors: Ø Epithelial Ø Mesenchymal Ø Mixed Ø Secondary (MTS) Ø à Epithelial + mixed = are most common

Nephroblastoma (Wilms tumor) - mention general information - metastases & spreding of the tumors to which organs - survival rate

Nephroblastoma = 99% of pediatric renal tumors v Typical story is that from full health, the parents are bringing the baby to the hospital, saying that by e.g. bathing their baby, they have found a tumorous mass in the abdominal cavity v Most common kidney tumor of childhood v One of the most common tumors of infancy v 90% occur before age of 6 years (It appears mostly in very young babies) v Presents as large abdominal mass, may present with lung metastases or traumatic rupture Ø Unfortunately, in very many cases, this is already in very advanced stage, and the patient may already be present with lung metastasis Ø Or when this is very large tumor, then it may undergo traumatic rupture by falling of the baby v Spreads into perirenal soft tissue; may invade renal vein, metastasizes to regional lymph nodes (15%), lung, peritoneum; rarely to bone (1%) Ø The tumor may spread into the perirenal soft tissue (pararenal = through renal capsule) Ø Therefore, it is very important to recognize this tumor as early as possible Ø Because, in the proper condition, you see 90% of these babies are showing very good long-term survival and they are cured § When it is recognized properly v 90% long term survival

RENAL CELL CARCINOMA (histologically was known as aadenocarcinoma) - explain the general imortant features - clinical signs - where does this tumor metastases to

Renal cell carcinoma v 85% are renal cell carcinoma (adults over 50 years, 2/3 male) only 1/3 females v Renal cell carcinoma is a very dangerous tumor, it is dangerous due to 2 conditions: Ø 1. Firstly because this tumor is detected mostly incidentally, How is it possible that malignant tumor is in very many patients found incidentally? § Incidentally means coming to the hospital, he is at certain age, and he checked for all changes in all organ and then this tumor is found § It is due to the anatomy and histological anatomy of the kidney, because the kidney parenchyme itself is not innervated § Therefore, the tumor which grows here, is not causing any pain § The manifestation of this tumor may appear in 2 conditions: · A. First when the tumor attaches and opens into urinary flow tract, and then the hemorrhage is appearing in urine, so blood in urine may be first sign of the tumor, however, when it is only microscopical presence of blood, you don't recognize it macroscopically, when it is more aggressive, and more severe, then it is showing macroscopical changes and patient will come and says "okay I have something wrong with my urine" · B. Second possibility is when the patient is lucky enough and this tumor starts to grow very closely to the renal capsule. Renal capsule is pushed away by the growth of this tumor and renal capsule is innervated ¨ Therefore, it causes, not yet pain but some strange feeling for the patients which can bring the patient to the hospital § Very commonly the patients do not recognize it as something very bad, because they are mostly older, they feel the pain in back area very commonly, so they underestimate the value of the information that they find some strange pain in their back area § So very often, these tumors are very large at the time of diagnosis Ø 2. The second risk of this tumor is that it is so-called "great mimic" of any other conditions, because very commonly these tumors are producing some neuroendocrine active substance, which are causing paraneoplastic syndrome § The patient may show hypercalcemia, Cushing's syndrome, amyloidosis § And thus, the attention of the medical staff is orientated to this presentation, and not at the tumor of the kidney Ø Be aware of this, many paraneoplastic conditions may be caused by renal cell carcinoma v Clinically: Ø "Great mimic" due to associated paraneoplastic syndromes (hypercalcemia, hypertension, gynecomastia, Cushing's syndrome, systemic amyloidosis, polyneuropathy) Ø "Classic" clinical features of costovertebral pain, palpable mass and hematuria are present in only 10% Ø Tumors now usually detected incidentally; historically were often large (10cm) at the time of Dx v Metastases (lungs, bones, LN, adrenals, liver, brain), often solitary and detected after removal of primary tumor Ø This tumor likes to metastasize elsewhere, very commonly Ø It is not rare that we do diagnosis of renal cell carcinoma from metastasis, while the primary tumor was up to this moment not recognized clinically

ADULT KIDNEY TUMOURS - DIFFERENCE BETWEEN adult and pediatric kidney tumors - how to approch adult kidney tumors - the types of primary and secondary tumors (metastasis to the kidney)

Tumors of adult v The tumors of adults represent a completely different clinical situation than the pediatric v The first approach is primary vs. secondary Ø Although the majority of the kidney tumors are primary, kidney, because it is situated centrally in the blood circulation, it is not surprising that like liver, the kidney parenchyme, although lower incidence, it may show a lot of metastatic cancers, spreading into the kidney parenchyme v The primary are; epithelial, mesenchymal and mixed And nr.3 is the metastasis, meaning secondary

First type of primary tumors of kidney in adult is ... - list the different tumors in this category

v 1. Epithelial tumors Ø Basically, renal cell epithelium, appearing in the tubules, is glandular epithelium histogenetically § So, basically, we could speak about adenocarcinoma of the kidney, because histogenetically it is glandular type of epithelium Ø However, since few years ago the terminology has changed to renal cell carcinoma § So, we no longer use adenocarcinoma, but instead renal cell carcinoma § But still technically it is adenocarcinoma à and therefore, the benign counterpart is simply adenoma Ø Benign tumors: = relatively rare § Papillary cortical adenoma · Glandular epithelium = adenoma § Oncocytoma (subtype of adenoma) · When this adenoma is showing peculiar oncocytoma changes, then we call it oncocytoma, a subtype of adenoma · But it is rare Ø Malignant tumors: § Renal cell carcinoma (conventional / classic type) · (We don't use adenocarcinoma here, even though it is glandular epithelium) · 1) Clear cell carcinoma (KUNNA) · 2) Papillary carcinoma (RCC) (KUNNA) · 3) Chromophobe carcinoma (RCC) (KUNNA) · Sarcomatoid carcinoma (dedifferentiated type of 1,2 and 3) (KUNNA) · Collecting duct or Bellini duct carcinoma (rare)

the other types of primary tumors of the kidney in adults

v 2. Mesenchymal and mixed tumors Ø Angiomyolipoma § The most common mesenchymal tumor, a mixed tumor § A very peculiar and complex tumor which we will this end this lecture on Ø Leiomyoma Ø Lipoma Ø Mixed epithelial and stromal tumor Ø Primitive neuroendocrine tumor (PNET)

the secondary types of kidney tumors in adult

v 3. Metastasis to the kidney (!) Ø Usually small, multiple, bilateral, intracortical localization Ø The primary tumors may be: § Lung tumors, malignant melanoma, breast carcinoma, tumors of GIT, pancreas, ovary, testis Ø It is not absolute criterium, but a support criterium. when you see small, multiple bilateral tumors, (more than 2-3) than you can think about metastasis, when you see 1 single tumor, think about epithelial cell tumors

the mesenchymal and mixed tumor of the RCC is.... -its general features - its dignity

v Benign, mesenchymal, but more correct, to say mesenchymal MIXED tumor of the kidney v In majority of patients, this tumor does not arise in the kidney Ø But it arises in vicinity, in the capsular and pericapsular region of the kidney Ø However, it interferes with kidney parenchyme by a very peculiar way (we will come back to this) v Less than 1% of renal tumors (usually adults) Ø Very rare, it is mostly in adult patients v It benign, (almost always) Ø Why this bracket, why almost always? Either the tumor should be benign or not Ø But in these carcinomas, the classification into benign and malignant is maybe not so good § There are some fans of changing this classification and distinguish the tumor of different degrees of malignancy (of risk of malignancy and risk of metastasis) v Because, what we have learned in the past 10-20 years is that many tumors traditionally included into the benign tumors are in reality not benign, because the patient may develop metastasis 20-30 years after the primary diagnosis Ø The best example leiomyoma of the uterus v Back to the angiomyolipoma: Ø As you can see by the name, it is containing: § Angiomatous component § Leiomyomatous component - this is this "myo" in the middle § And Lipomatous component v Benign (almost always) neoplasm composed of thick-walled blood vessels, smooth muscle and fat; includes spindle and epithelioid cells v Usually one large mass; multiple masses suggests tuberous sclerosis

Nephroblastoma (Wilms tumor) - macroscopical picture of the tumor - microscopical picture of the tumor

v Macroscopical picture of nephroblastoma: Ø Large, solitary, at beginning well-circumscribed mass Ø 10% bilateral or multicentric Ø Soft, homogenous appearance Ø Tan-grey tumor Ø Hemorrhage, necrosis, cysts are common Ø Soft and myxoid consistency v Microscopical picture of nephroblastoma: Ø Triphasic tumor: § 1. Undifferentiated blastema (small blue primitive cells with scanty cytoplasm, patterns are diffuse, nodular, cordlike) · Because the origin of these tumor cells are derived from nephrogenic blastema cells, these are very undifferentiated and primitive tumor cells of blastema origin § 2. Fibroblast-like stroma, may have smooth muscle, cartilage, adipose tissue, squamous/ mucinous epithelium, bone, neural tissue § 3. Epithelium (abortive tubules, glomeruli)

The mesenchymal and mixed tumor type of KIDNEY - risk factors - micro and macroscopical features - histologically -dignity - prognosis

v Risk factors: tuberous sclerosis (50% of Angiomyolipoma occur in these patients) Ø Tuberous sclerosis: Ø AD neurocutaneous disorder of 1 per 6-11.000 individually with hamartomas/ tumors of brain (subependymal giant cells tumor), retina, skin (cutaneous angiofibroma's), heat (rhabdomyomas), bone, lung, (lymphangioleiomyomatosis), kidney (angiolipoma in 40-80%, RCC, cysts, clinically mental retardation) Ø Now we are proceeding to the classification of this tumors, based on genetics Ø We know that the risk factor for this tumor à Tuberous sclerosis § At least half of the patient with this tumor have this hereditary disease, so therefore from the genetic point of view may distinguish: § 1. Sporadic angiomyolipoma · The prognosis is much better here § 2. Associated with tuberous sclerosis · The prognosis is worse due to this underlaying conditions of tuberous sclerosis v Macro: Ø Red, gray-white, yellow Ø Resembles clear cell carcinoma Ø May invade local LNs and renal vein even though benign Ø Capsular invasion in 25% Ø Tumors often multiple (1/3) and bilateral (15%) v Micro: Ø Triphasic tumor with myoid spindle cells, islands of mature lipid-distended cells, thick walled blood vessels without elastic lamina Ø Smooth muscle component appears to spin off from vessel walls Ø Adipose tissue may be scanty Ø Sometime atypical cells - epithelioid cells v Histologically: Ø This pink area, are thick walled vessels, which are proliferating here § This is the "angiomatous" component Ø These spindle cell areas between is "leiomyomatous" component § It can be proven by immunohistochemistry Ø And last is mature fatty adipose tissue - the "lipomatous" component Ø Thus; angio-myo-lipoma Ø However, when you look closer, you can see that this leiomyomatous component is infiltrating into the septa between the adipose cells? § Yes, this leiomyomatous component is also infiltrating into these vessels v So, it is benign mesenchymal mixed tumor, showing basically infiltrative growth pattern à Makes no sense but it is true v Here you see the tumor which is infiltrating the kidney (capsular invasion) Ø Clinical story, unfortunately, is that patient has some problems, mostly pain, because the capsule is here infiltrative, so it's painful Ø What the clinicians will find by radiological examination is tumor, infiltrating the kidney, what follows is nephrectomy, and what follows after that we are sitting by the microscope and calling the clinician and saying "I am deeply sorry, but this tumor is NOT malignant it is benign" Ø Then people will think we are crazy because they know that it was infiltrating the kidney, the surgeon even saw it v Therefore, when it is possible, again, nephron-sparing surgery is the solution, this tumor must be resected, because it would continue the grow into kidney parenchyme, but basically it is benign, therefore, partial nephrectomy is enough to remove this tumor Ø So, this tumor may even show capsular invasion in certain percentage v Therefore, it is an open question, for the future: Ø Is it better to keep the old fashioned benign vs. malignant and semi-malignant, these dignities or whether we should switch to this newly updated version of this assessment of the tumors? Ø It is an open question, it is not so clear, he is not saying that benign and malignant does not exist, but there are exceptions of every rule v In this case the exception is presented by the beautiful angiomyolipoma Ø The benign, infiltrative tumor Prognosis: v Classic AML: benign v Risk of retroperitoneal hemorrhage (if size > 4 cm, or in pregnant woman) v Multiple AMLs = risk of renal failure v Minority of AML: mortality

THE SUBTYPES PF KIDNEY TUMORS IN ADULT

v Subtypes to know: - YOU HAVE TO KNOW THIS Ø 1. Clear cell carcinoma § The most malignant tumor of these 3 conditions § This is also the most common type Ø 2. Papillary carcinoma § Papillary carcinoma is something like intermediate malignancy Ø 3. Chromophobe carcinoma § This is the less malignant of renal cell carcinoma = so the prognosis is the best here § However, this carcinoma is showing the highest risk of recidives (recurring), by recidivization of this tumor, it may show to the sarcomatoid type § This is paradox, on one side it relatively good prognosis, on the other side this tumor bears the risk of secondary transformation Ø 4. Sarcomatoid carcinoma (false category) Ø These are the subtypes of renal cell carcinoma, which you have to know! Ø At least you have to know the classification and something more about these tumors Ø To be more exact, these are not 4 types of tumors, in reality these are only 3 types of tumors § Because clear cell carcinoma, papillary carcinoma and chromophobe carcinoma may undergo the dedifferentiation into this 4th category (sarcomatoid) § That means that this 4th category, sarcomatoid carcinoma, is not a tumor itself, it is secondary dedifferentiation of the primary recognized other categories of the tumors § The clinical study is rather typical, the patient shows something of these 3 types, by metastasis and when we take biopsy sample, we suddenly see that the morphology of one of these three types is changed into this 4th type v We have to know this classification; Plank highly respects this classification Ø Because this classification was first published 150 years ago Ø And todays molecular pathology has proved that this classification was correct

Pediatrics tumors - list all of them and mention which one is the most common

v This is the list of all pediatric neoplasias which may appear in the kidney Ø But in reality, 99% of all these tumors are represent by nephroblastoma (Wilms tumor) v Nephroblastoma (Wilms tumor) Ø You have to know this one, NEPHROBLASTOMA IS the most common tumor of kidney in children § Not only the most common kidney tumor of childhood, but one of the most common tumors of children generally! KIDNEY TUMORS IN CHILDREN ARE: v Congenial mesoblastic nephroma v Neuroblastoma v Metanephric stromal tumor v "Clear cell "sarcoma v Ossifying renal tumor of infancy v Renal cell carcinoma in children v Rhabdoid tumor

Nephroblastoma (Wilms tumor) - treatment - defferenciation, grading of the tumor

v Very sensitive for chemotherapy (80-90% overall are cured, a small percentage develop second neoplasms) Ø Once you have a baby, which shows in the renal area, a tumor Ø You can be almost 100% sure that it cannot be anything else than nephroblastoma Ø Then you simply can do a small punctional biopsy, and pathologist will confirm that this is nephroblastoma Ø What follows is now is NOT operation, but neoadjuvant chemotherapy Ø Because this tumor is very sensitive for chemotherapy Ø By this approach, you can reduce very dramatically the size of this tumor Ø After this therapeutical reduction of the tumor mass, the patient undergoes surgical operation Ø Remember: blastic cells are very sensitive to chemotherapy v Why is it so important? Ø Because the tumor is very probably sitting on one pole of the kidney, and another part of the kidney, when the baby is lucky enough in this situation, then the pelvic region and ureter remains intact Ø Then what the surgeons do is not total nephrectomy, but partial nephrectomy Ø Generally, not only in pediatric urology, but generally in urology, nowadays, there is a trend of operations which are called "nephron-sparing" surgery § That means operations which spares as much kidney as possible, because it is better to have 1,5 kidneys than only 1 kidney v The origin of tumor is related to the nephrogenic blastema (nephrogenic blastema cells) Ø It is the embryological structure, appearing in the age of approx. from 6-12 weeks, in the localization where the future kidney should be formed v Apparently derives from nephrogenic blastema cells Ø These nephrogenic blastema are represented by these small blue cells and what you can see are glandular structures, these are very primitive tubular and glomerular morphological changes § This means that in this tumor, this blastema component is trying to mimic/resemble or to form the structures which are resembling the normal tubular epithelium of kidney Ø The more of this better differentiation is present, the better is the differentiation of the tumor § So, the role of pathologist after the operation is to establish a ratio between these epithelial structures vs. these primitive blastema structure · This is grading of this tumor! § The worst situation is when the tumor contains only, or predominance of these immature blastema cells § A better situation is when this tumor shows more differentiation