Pathology and Diagnostics: Tumors of the Kidney (PDF)

Pathology and diagnostic P. Colombo - Pathology - lecture 05 Tumors of the kidney 08/11/2024 - group 12 (Buelli, Capozza) Epidemiology:...

Pathology and diagnostic P. Colombo - Pathology - lecture 05 Tumors of the kidney 08/11/2024 - group 12 (Buelli, Capozza) Epidemiology: There are approximately 50,000 new cases per year, representing 5% of cases of all neoplastic diseases in men; 3% in women. The rate of death is 4% of all cases of tumor. Thus, with 5% of new cases and 4% of deaths of all cases of tumors, we can understand that renal tumor is a fatal disease. Classification: Renal tumors are mostly of epithelial origin. However, there are several other less common variants which are not epithelial; this is because the kidney is not only made by epithelial cells, but also by stromal, mesenchymal cells (vessels, muscle cells, fat). For example, a schwannoma of the kidney might occur. Epithelial tumors are the most common in the adult kidney, representing more than 95% of cases. In 2022, a new WHO classification was drawn from the old 2016 WHO classification due to increased knowledge of prognosis depending on certain variants; every 6 years the classification is re-evaluated. The 2022 WHO classification comprehends clear cell tumors, papillary tumors, eosinophilic or pink tumors, other rare and aggressive tumors and molecularly defined tumors. Some variants have been differently classified, such as the medullary carcinoma, which is now included in the molecularly defined tumor because of a specific mutation in the neoplastic cells. Additionally to epithelial tumors, there are rarer mesenchymal tumors which are mostly correlated to the age of the patient (ex, pediatric renal tumors). Angiomyolipoma is a mesenchymal tumor which is not so uncommon, the professor calls it the “Italian tumor of the kidney” as it was first discovered and named in Verona 40 years ago. Diagnostic and prognostic information: When there is a focal lesion in the kidney, we must define whether the tumor is primary or secondary (metastasis). In fact, the kidney is a common recipient for metastasis. If it is primary, we must define whether it is benign or malignant. Afterwards, we must define the histological type. Then we should define the grade of the tumor, meaning the differentiation of cells, and the TNM. Lastly, we should evaluate other histological features which have prognostic values: sarcomatoid differentiation, presence of necrosis, vascular invasion. Other prognostic variables are still a work in progress, such as the molecular profile of some specific variants. Renal cell carcinoma (RCC): 90% of renal tumors are renal cell carcinoma (RCC), so of epithelial origin. It is most common in older patients, with male predominance. The cell of origin is the tubular epithelium. It is mostly somatic and sporadic, but might sometimes be related to mutation in the VHL gene (Von Hippel - Lindau gene), included in the Von Hippel - Lindau syndrome which consists in the deletion or rearrangement of Chromosome 3, triggering the development of multiple nodules in the kidney. The symptoms are aspecific: fever, weakness, weight loss. Hematuria is also a common presentation and it may be intermittent and microscopic. One typical clinical feature is the tendency to give metastasis widely before the first diagnosis, commonly in lungs (50%), bone (33%), lymph nodes, brain and contralateral kidney. A diagnosis of pancreas metastasis is often achieved before the diagnosis of the kidney tumor. Resecting metastasis from the pancreas is beneficial, even if it is an aggressive surgery, as it allows better control of the primary kidney tumor. We can also have the three classic clinical triad (present in only 10% pts) costovertebral pain, palpable mass and hematuria, and it indicates an advanced disease. Clear cell RCC: 80-85% of malignant renal tumors are clear cell renal cell carcinoma (clear cell RCC). Clear cell carcinoma is one of the most aggressive tumors of the kidney. Gross features: spherical mass composed of bright yellow, gray, white tissue that distorts the outline of the kidney, common hemorrhages and necrosis. It commonly affects the upper people of the kidney. The margins are well demarcated by the renal capsule - small satellite nodules are often seen at the periphery.The tumor typically invades the perirenal fat, the sinus fat and the renal vein. The tumor has a high tendency of invading the renal vein 1st case (image below): The tumor appears yellow with a white scar of connective tissue, it has smooth borders. It is invading the fat outside the kidney, so it is a pT3. Remember that a pT2 tumor is inside the organ, while a pT3 tumor is outside. 2nd case: The tumor is invading the fat of the sinus of the kidney, without invading the perirenal fat. 3rd case: The tumor has pushing borders; it is very large but it is not infiltrating the perirenal fat. It is a pT2. Again, it shows as a yellow area with connective tissues and some oedema. The clear appearance of cells (histologically), that corresponds to the yellow aspect (grossly), is made by glycogen. 4th case: The tumor appears with hemorrhages and areas of necrosis. It is not infiltrating the fat outside. 5th case: The tumor is infiltrating the outside fat. 6th case: The tumor is very small, it is infiltrating the fat of the sinus but it also developed a lymph node metastasis. 7th case: This is a 35cm tumor that has destroyed all the kidney with outside infiltration (pT3). When the tumor is infiltrating the renal vein, a thrombotic lesion is visible inside the vein. The tumor has destroyed the wall of the renal vein and is entering the lumen, possibly causing embolic disease of the lung. Histological features: proliferation of clear (white) cells due to deposit of glycogen inside the cells. In other types of tumors, the clear appearance is given by the presence of fat, such as in lipoma or liposarcoma. Clear cell RCC has a high vascularity given by vessel proliferation causing hemorrhages (seen grossly) as the tumor itself destroys the vessels. The cells between clear cells are endothelial cells of small capillary structures. The tumor is commonly solid, but might be cystic. The cystic version is low grade, well differentiated, and has a low aggressiveness. So a cystic tumor is good news for the patient. Cysts are covered by a monolayer of clear cells. When the tumor is almost all cystic, it can be considered to not be malignant (not a carcinoma) as it is not able to give metastasis. So this type of tumor is a clear cell RCC that however is not malignant. Grading system: In the past the Fuhrman grading system was used, now we use the ISUP system based on the presence and size of nucleoli in the nucleus of cells. - Grade 1: no nucleoli are visible, only small nuclei similar to lymphocytes - Grade 2 and 3: increasing number of visible nucleoli, easily seen in grade 3 (seen even at low power field) - Grade 4: polymorphic cells Patients must be stratified based on grading to evaluate mortality and prognosis. Grade 3 and 4 have a worse prognosis with respect to grade 1 and 2. Grade 4 indicates 50% survival after 10 years. Other features defining prognosis: - Sarcomatoid change of cells: epithelial cells acquire a sarcomatous, mesenchymal differentiation (cells “forget” to be epithelial and “believe” to be sarcomatous). Cytokeratin, a protein typical of epithelial cells, is still present in these cells. When this occurs in a renal tumor, it will look like a spindle cell sarcoma. The sarcomatoid change negatively impacts prognosis as it is associated with a high grade tumor (grade 4): clear cell carcinoma with sarcomatoid areas will never be grade 1, as grade 1  means that the cells are well differentiated while sarcomatoid changes indicate de-differentiation of cells. The survival of a patient with sarcomatoid areas in the tumor is less than 20% in less than 5 years (80% of patients with sarcomatoid changes die within 5 years). The image shows an example of a chromophobe carcinoma (see later) with sarcomatoid areas. The areas circled in yellow are well differentiated neoplastic cells of chromophobe carcinoma while the rest are sarcomatoid changes of cells which are not epithelioid in shape but rather spindle. In histology, spindle cells indicate mesenchymal cells which can either be smooth muscle cells, fibroblasts or neurogenic cells; so in general, spindle shape describes mesenchymal cells while epithelioid shape describes epithelial cells. Rhabdoid cells are an exception of sarcomatoid changes. A rhabdoid cell is an epithelial cell that acquires sarcomatoid features, specifically similar to rhabdomyoblastic cells. “Rhabdo” means skeletal differentiation; rhabdomyoblastic cells are undifferentiated, totipotent cells capable of differentiating into skeletal muscle cells. So sometimes instead of acquiring a spindle-like differentiation the cells look epithelioid, but it still has to be considered a sarcomatoid differentiation because cells have rhabdoid features. Notice that sarcomatoid changes are most commonly seen in clear cell RCC, but also in chromophobe carcinoma or any other type of malignant tumor in the kidney. These types of tumors are aggressive, although less aggressive than an actual sarcoma, and some might respond to chemotherapy (the reason is unknown but it might be because they are more proliferative with respect to the counterpart without sarcomatoid change and thus more cells are most commonly in the S phase, and as such are more vulnerable to chemotherapy). - Presence of necrosis: necrosis is common in RCC and is able to stratify patients, as necrosis means the tumor is fastly proliferating and thus more aggressive. Survival is reduced if necrosis is present. Papillary RCC: Papillary RCC is the second most common tumor in the kidney. It is called “papillary” because of the papillary structures visible histologically. It is the second cancer, after clear cell carcinoma, in prognosis. It can be solitary or multiple. Necrosis is very common. As in clear cell RCC, grading is done through ISUP grading system. Papillary RCC is commonly characterized by chromosome 7 and 17 gains producing trisomy and loss of Y chromosome. Sometimes it is difficult to diagnose this tumor at biopsy, but we can use the FISH technique which easily detects the presence of Chr 7 and 17 trisomy. Gross features: common hemorrhages and smooth borders of the tumor. The tumor is commonly large with pushing borders but with no infiltrations. This is in contrast with clear cell carcinoma: a clear cell carcinoma might be 1cm large and infiltrate the fat, while a papillary carcinoma might be 20cm large and not infiltrative. This is essential for prognosis: if the tumor is not infiltrative, it might be very large but still prognosis is good after resection (malignancy is established by evaluating both metastasis and the infiltration of nearby structures). 1st case: The tumor is large (pushing borders), with hemorrhages. No infiltrations. 2nd case: The tumor is almost all necrotic, with hemorrhages. It is difficult to identify alive neoplastic structures. Histological features: multiple polypoid, papillary structures with a complex architecture and inside connective stalk protruding in the lumen. Most commonly, deposits of histiocytes (chronic inflammatory cells) are present in the core of the papilla, the reason is unknown. Carcinoma of the kidney develops in the tubules of the cortex of the kidney. If the tumor develops in an area of the cortex in the polar region of the kidney (polar tumors), close to the sinus fat, the tumor is more dangerous as it can more easily infiltrate the sinus fat and successively the nearby vessels. A trick to recognise tumoral areas with respect to normal areas in histological images is to look at the color. In the image below, on the right the cells are stained pink while on the left the cells are stained of a darker, bluish color; this is because the nucleus is stained blue. The left area is the tumor as it has a higher cellularity, so more nuclei, so at a low power field the tissue appears blue. For example, connective tissue has a much lower cellularity and thus appears pink at a low power field. The normal cortex of the kidney tends to appear pink also because of the presence of connective tissue. The image also shows a piece of tumor inside the renal pelvis (recognisable as it is lined by umbrella cells and transitional cells) which is given by a contamination during tissue processing. Papillary adenoma: The difference between papillary adenoma and carcinoma is the size. A focal lesion with papillary features at histology is considered an adenoma (benign tumor) if it is less than 1.5cm. However, remember that a papillary adenoma often presents with multiple papillary lesions, one of which could be malignant. Histologically, it is similar to its malignant counterpart but with low nucleolar features, meaning nucleoli are not visible (low grade). Chromophobe RCC: Chromophobe RCC is the third most common tumor in the kidney. It is the less aggressive malignant tumor in the kidney, only rare cases with metastasis. It is mostly solitary, and most commonly in the renal cortex. Grading is not recommended as polymorphic and atypicality are not related to prognosis. Thus, grading to stratify patients to evaluate prognosis is not recommended in chromophobe RCC. Gross features: brownish mass, commonly with smooth margins. Histological features: epithelioid and polygonal cells characterized by a peri-nuclear halo (white ring around nucleus where the cytoplasm is not stained). Reinforcement of cell membrane might be visible (increased staining of cell membrane). Under a microscope, a leaf has a similar cytological appearance compared to chromophobe carcinoma. Polynucleated cells might be present. Some nuclei might be shrunken and are called resinoid nuclei; resinoid nuclei are almost always associated with the peri-nuclear white halo. Why is it called chromophobe? Years ago some authors described tumors as chromophilic (“philic to stain”), such as almost half of clear cell carcinoma cases which usually lose differentiation and thus lose the glycogen inside them, increasing the eosinophilic stain, and chromophobe (“phobic to stain”), in which there is no staining of the cytoplasm. Collecting duct carcinoma: Collecting duct carcinoma is the less common tumor of the kidney but the most aggressive. More people die from clear cell carcinoma because it is much more frequent, while collecting duct carcinoma is rarer, but all patients with a collecting duct carcinoma will die. High mortality of collecting duct carcinoma (median survival 12-30 months) is due to: high stage at diagnosis, extra-renal spread at diagnosis with node metastasis, peri-renal and sinus fat invasion at diagnosis, common distant metastasis… The age range is from 6 to 87 years old, with male predominance, as in clear cell carcinoma. Presentation with hematuria (most common), abdominal mass, pain, weight loss, fever. It generally takes its origin in the medullary region of the kidney. Gross features: It is important to understand where the tumor took origin: 1st case: The tumor has developed from the medulla. 2nd case: It is not possible to determine where the tumor developed from. 3rd case: The tumor developed from the cortex, which is very rare. When the tumor is high stage and high size, it is impossible to define it grossly as a collecting duct carcinoma. It is easier histologically. Infiltrative growth pattern with irregular borders between non neoplastic renal tubules and preserved glomeruli Histological features: It is an adeno-carcinoma, which is a malignant proliferation of glandular structures. We must search for tubulo-papillary, glandular structures. Histological images show neoplastic tubules which proliferate around preserved normal glomeruli; the tumor grows from the medulla to the cortex, preserving glomeruli. At a higher power field, atypicality of cells is visible.Since there are tubulo-papillary structures, the differential diagnosis is papillary carcinoma. It is essential to differentiate collecting duct carcinoma from papillary carcinoma because of the difference in prognosis. There may be a sawtooth appearance of ducts, which is a neoplastic feature. When viewing these histological images, we can immediately exclude clear cell and chromophobe carcinoma. We might mistake it for papillary carcinoma; however, in papillary carcinoma there is no connective tissue around papillary structures. From a statistical point of view, a papillary carcinoma is more common. Before diagnosing a collecting duct carcinoma, be sure to exclude the papillary carcinoma. We have finished with the malignant tumors of the kidney, now we will focus on other variants. Oncocytoma: The oncocytoma is the most common benign tumor of the kidney, it does not have a malignant counterpart (no possibility to progress into a malignant cancer). Clear cell RCC and papillary RCC have a benign counterpart, while oncocytoma, although histologically similar to chromophobe carcinoma, does not have a malignant counterpart. After resection, prognosis is excellent (no possibility of metastasis). Gross features: The tumor has a scar in the central area (visible in CT and US), has smooth borders, and is characterized by an eosinophilic proliferation of cells that produce the brownish gross appearance. Necrosis is not visible. Hemorrhages might be present. Sometimes the tumor infiltrates the fat with no impact on prognosis. The tumor might present with a cystic degeneration. Histological features: The tumor is characterized by eosinophilic cells in tubules or small nests. Oedema, water in the stroma, is also common (white areas). Notice that eosinophilic cells are cells which are stained pink due to the presence of a huge number of mitochondria in the cytoplasm. The eosinophilic appearance of every cell is based on mitochondria. Mixed epithelial and stromal tumor: We have seen epithelial tumors and now we are transitioning from epithelial to mesenchymal tumors, and this entity has both features. Sometimes, in CT or US, multiple cystic lesions are visible which are usually simple cysts but might be a mixed epithelial and stromal tumor. The medulla is the common location. It is asymptomatic, especially in early stages. It is more common in women, there is no genetic link but might be hormone related (ex. men taking hormones for prostate hyperplasia, or patients abusing of hormone therapy). It is benign. However the professor says that years ago he had found a case of mixed epithelial and stromal tumor in a patient, but after partial resection of the kidney it recurred and radical nephrectomy had to be performed. So, based on his experience, he is not completely sure that the tumor is completely benign, it could have a very low malignancy; in general it must be considered benign. Histological features: Multiple cysts proliferation, similar to multiple cystic clear cell carcinoma, but cells are eosinophilic (pink) rather than clear and in the stroma, between the cysts, is a spindle cell proliferation. This is in fact a transition tumor between an epithelial tumor and a mesenchymal tumor. Spindle cells are mostly fibroblasts positive for estrogens or progesterone. Angiomyolipoma: We have concluded the transition as we will now talk about the mesenchymal counterpart of kidney tumors. Angiomyolipoma is the most common mesenchymal tumor of the kidney. It is quite a common tumor, occurring in 0.3% of the total population. It is sometimes associated to the Tuberosic Sclerosis syndrome. Angiomyolipoma consists in the proliferation of vessels, smooth muscle cells and fat. The stem cell of origin is common for all the cell types; the stem cell can differentiate into a smooth muscle cell, an adipocyte or a vessel cell. All these 3 cell types possess a common feature: a melanocytic protein in the cytoplasm, the reason is unknown but it might be because they all come from the same stem cell (common melanocytic differentiation). This melanocytic differentiation is easily identified with the HMB45 protein in immuno-histochemistry, also used for other melanocytic proliferations (ex. melanoma). The same immunophenotype of renal angiomyolipoma can also occur in the liver, uterus, lungs, pancreas… In some cases, rather than spindle the cells are epithelioid and thus the angiomyolipoma is to be considered an epithelioid angiomyolipoma. In this variant, the tumor might be malignant. All angiomyolipomas are benign, with the exception of cases with epithelioid features. A malignant epithelioid angiomyolipoma might mimic at presentation a classic clear cell renal cell carcinoma. TNM: - pT1: less than 7cm in size, inside the kidney - pT2: 7-10cm in size, inside the kidney - pT3: outside the kidney (peri-renal fat, sinus fat, renal vein) Also evaluate multifocality and presence of local regional lymph node metastasis (N1). Distant metastasis is almost never observed at presentation, but if so it is indicated with M1. Staging is important to stratify patients based on their survival probability. A pT4 at presentation indicates a probability of survival of less than 10% at 15 years. A peri-renal invasion means the tumor is invading the fat close to the Gerota’s fascia. A small tumor of 1cm can be a pT3 if it infiltrates the peri-renal fat. These two images below show 2 pT3s: one is much larger than the other, but classification-wise these two tumors are considered the same. Statistically, a carcinoma of more than 7 cm in size is a pT3: the great majority of clear cell carcinomas more than 7 cm in size are pT3 because of invasion of renal sinus fat, sinus vessels or perirenal fat. A tumor might have a good prognosis based on size, but the topographical extension of the lesions in the sinus fat negatively impacts survival. Approach to renal mass: Sometimes urologists resect the kidney due to a carcinoma without having a histological diagnosis as CT scan is usually very clear. Sometimes instead, before resection, a core biopsy is required to correctly type the tumor (histological diagnosis) in order to perform chemotherapy prior to surgery (cytoreduction of the tumor before resection). In other cases, after diagnosis at core biopsy, the patient will undergo active surveillance. Limitations of core biopsy is due to the small fragment of tissue: no staging of the tumor, excessive necrosis preventing the definition of the histotype, grading heterogeneity in different tumor areas. The following images are examples of heterogeneity in grading: For the oral exam: type of tumor (general classification), gross and microscopic features of clear cell RCC, impact of sarcomatoid change and necrosis, difference between clear cell carcinoma with and without cystic changes, describe papillary carcinoma, describe common features of chromophobe carcinoma and oncocytoma, use of grading in common histotypes.