Pathology: Tumors Of Kidneys And Bladder

Front 1

What are the 2 main types of kidney/bladder tumors?

Back 1

*RCC accounts for 85%.
*Urothelial is the second most common. 10-15%.

*Renal cell carcinoma (RCC) is the most common primary malignant neoplasm of the kidney in adults (85% of renal cancers), but can occur in children.

*Urothelial carcinomas of the renal pelvis are the 2nd most common (5-10% of renal cancers).

Front 2

What are the 4 main types of RCC?

Back 2

Front 3

What is survival like in the different types of RCC?

Back 3

Front 4

Describe the Clinical Presentation of RCC:

Where may there be mets?

Back 4

*Classic Triad (but only presents in 10% of cases):
1) Hematuria.
2) Costovertebral pain.
3) Palpable mass.

*Often asymptomatic growth.

*In 25% of RCC, there are metastases at presentation:
-Lung (50%).
-Bone (33%).

*Patients can also present with Paraneoplastic syndromes:
-Polycythemia
-Hypercalcemia
-Hypertension
-Hepatic dysfunction
-Feminization
-Masculinization
-Cushing syndrome

Front 5

What cells do RCCs arise from? What part of the kidneys do they affect most?

At what age do they usually strike? What gender?

What are the risk factors?

Back 5

*Derives from renal tubular epithelium.
*Most commonly affects the poles.

*Most commonly 6th and 7th decades.
*M:F=2:1.

*Risk factors:
-Smoking.
-Hypertension.
-Obesity.
-Heavy metals (cadmium).
-Acquired polycystic kidney disease as a result of chronic dialysis (30x risk).
-Tuberous sclerosis.

Front 6

How do you distinguish between the different types of RCCs?

Back 6

*There are distinct histological subtypes with characteristic gross and microscopic appearance.
*Distinct histogenesis.

*Unique cytogenetic abnormalities (at the level of the chromosome).
*Chromosomal deletions, amplifications, translocations and/ or genetic abnormalities (at the level of the gene).
*There can be loss of function mutations in tumor suppressor genes (VHL, BHD).
*There can be activation mutations in oncogenes (MET).

Front 7

Back 7

*Different types of RCCs.
L: CCC.
TR:
Middle:

Front 8

Looking at the nephron, identify what parts give rise to different kinds of tumors:

Back 8

*Most common is CCC; arises from PCT.
*Chromophobe and Oncocytoma come from the intercalated cells of the CD.
*No one knows where papillary comes from; shares traits of PCT and DCT.

Front 9

Discuss the Clear cell RCC:

Back 9

*Most common type of RCC; ~70-80%.

*Arises from proximal tubular epithelium.

*Gross:
-Usually solitary, ranging from 3-15 cm.
-Yellow-orange (lipid).
-Hemorrhages.
-Can have cystic change.
-Well circumscribed.
-They show invasion into the renal vein.

Front 10

Back 10

*Gross specimens of CC RCC.
*Left pic shows tumor in the renal vein.

Front 11

Back 11

*Renal Vein Invasion in CC RCC. This can progress into the IVC and into the heart!

Front 12

How do we stage RCCs? Why is this important?

Back 12

*Renal vein involvement = stage 3.
*Staging correlates with survival.

*Tumor size, lymph node involvement, and mets are used to stage.

Front 13

What are the µscopic traits of Clear Cell RCC?

Back 13

*Clear cytoplasm (due to high lipid, glycogen), may have granular cytoplasm.

*Distinct cell membrane.

*Growth patterns:
1) Solid
2) Trabecular (cordlike)
3) Tubular

*Stroma usually scant.
*Highly vascularized stroma.

Front 14

Back 14

*Clear Cell RCC.
*Note clear cytoplasm and rich vasculature.

Front 15

Back 15

*Clear Cell RCC.
*L: Low grade. Better differentiated. Nuclei aren't so large.
*R: High grade. Poorly differentiated. Nuclei are huge.

Front 16

Back 16

L: Clear cytoplasm in CC RCC.
R: Granular cytoplasm in CC RCC.

*Cytoplasm doesn't HAVE to be clear!

Front 17

What are the different patterns we see in sporadic vs. inherited kidney cancers?
-Age of onset?
-Frequency of each?
-Pattern of kidney involvement?
-Type of mutation?

Back 17

Front 18

Discuss VHL disease:
-Inheritance?
-Where all do we see tumors?

Back 18

1) Hemangioblastoma
2) Pheochromocytoma
3) RCCs-- ALL CLEAR CELL!

*Each patient is different, and may not have all the involvement shown on this slide (VHL gene can have different kinds of mutations).

Front 19

Back 19

*Gross kidney in VHL. Shows multiple cysts and multiple tumors. You can see the yellow color that's characteristic of CC RCC.

Front 20

Back 20

*CC RCC in VHL disease.
*Note small size of the tumor on the right; this tumor is likely 1-2mm in diameter. Remember that in VHL disease the patient can have HUNDREDS of these.

Front 21

How is the mutation for CC RCC acquired in VHL (like from the perspective of "hits")?

Back 21

*Short arm of chromosome 3.
*There's a GERMline, universal mutation.
*There's a loss of function mutation in the VHL tumor suppressor gene in the kidneys--> bilateral tumors.

Front 22

How is the mutation for CC RCC acquired in sporadic cases (like from the perspective of "hits")?

Back 22

*Kind of similar; still involves short arm of chromosome 3, and 80% of cases still involve the VHL gene.
*NO GERMLINE MUTATION.
*First event: deletion of 3p.
*Second event: somatic mutation or epigenetic silencing; loss of VHL function.
*Tumors are SINGLE AND UNILATERAL.

Front 23

What is the function of VHL gene? What goes wrong when it gets mutated?

Back 23

*Abnormal VHL Protein Causes Accumulation of Hypoxia Inducible Factor-a.
*VHL PRO is normally part of the ubiquitin system. When the ubiquitin system doesn't work, HIF accumulates.

Front 24

What's the significance of HIF accumulation in VHL mutations?

Back 24

*HIF Stimulates Tumor Cell Growth and Angiogenesis--> VEGF.
*There's a pathway of steps involved (PDGF, TGF, etc.).

Front 25

Discuss Papillary RCC:
How common?
What forms are there?
Where are the tumors?
Who gets this?

Back 25

*15% of RCCs.

*Familial and sporadic forms.

*Frequently multifocal and bilateral.

*Share phenotype of distal and proximal tubules.

*The most common type of RCC in patients who develop dialysis-associated cystic disease.

Front 26

Back 26

*Papillary RCC.
*Good example of a gross specimen:
-Well circumscribed
-Encapsulated
-Hemorrhagic
-Cystic

*If there's any yellow color present, it's from macrophages.

Front 27

What are the µscopic features of Papillary RCC?

Back 27

*Papillary formations.
*Cuboidal to low columnar cells.
*Foamy macrophages in papillary cores.
*Psammoma bodies (concentric calcifications) may present.
*Highly vascularized stroma.

Front 28

Back 28

*Papillary RCC. On the left you see normal kidney tubules. Tumor is well-cirumscribed and encapsulated.
*Note papillae (with white space between).
*Pale cells in the middle are foamy macrophages.

Front 29

Back 29

*Papillary RCC, high power.
*Foamy macrophages are the light objects located within the papilla.

Front 30

Back 30

*Hereditary Papillary Renal Cell Carcinoma (HPRCC).
*Bilateral. Multiple tumors.

Front 31

Discuss HPRCC:

Back 31

*Autosomal dominant.
*Late onset.
*Germline ACTIVATING mutations in Met protooncogene (7q31).

*Tumors: selective duplication of mutant allele in chromosome 7.
*Multifocal (may be >100 tumors).
*No extrarenal manifestations.

Front 32

How are mutations acquired in HPRCC?

Back 32

*Becomes activated without hepatocyte growth factor, which is normally required to activate it.
*Starts with a GERMline mutation (trisomy 7), followed by a gain of function of MET.

Front 33

What are the cytogenetic differences between the sporadic and inherited forms of HPRCC?

Back 33

*Sporadic is rare, but look at all the trisomies plus loss of Y.

Front 34

Discuss Chromophobe RCC:
Where does it originate?
Gross traits?

Back 34

*5% of RCC
*Originate from intercallated cells of collecting ducts.

*Excellent prognosis.

*Gross:
-Well circumscribed.
-Tan/ Mahogany.
-Rarely, hemorrhage or necrosis.

Front 35

Back 35

*Chromophobe RCC. Well circumscribed.

Front 36

Back 36

*Chromophobe RCC. Cells are LARGE, and they contain some eosinophilic cytoplasm. They line up along capillaries.

Front 37

Discuss the µscopic characteristics of Chromophobe RCC:

Back 37

*Solid sheets.
*Concentration of large cells around blood vessels.
*Prominent cell membranes.
*Pale eosinophilic cytoplasm.
*Irregular, wrinkled, rasinoid nuclei.
*Perinuclear halo.

Front 38

Discuss the characteristics of Chromophobe RCC on EM:

Back 38

*Cytoplasm is filled with abundant microvesicles (maybe from degradation of mitochondria).

*The few mitochondria are localized near to the cell membrane.

Front 39

Discuss the ∆ b/t the inherited and sporadic forms of chromophobe RCC:

Back 39

*Inherited is rare. Associated with BHD mutation.
*Sporadic RARELY involves BHD mutation; usually involves chromosomal abnormalities. Don't have to remember which ones are involved.

Front 40

Discuss oncocytoma:

What might it get confused with?

Back 40

*5% of renal neoplasms. Rare.

*Originates from intercalated cells of collecting ducts (just like chromophobe RCC).

*BENIGN tumor with excellent prognosis.

*Main differential diagnosis with chromophobe RCC.

Front 41

Back 41

*Oncocytoma.
*Mahogany brown with a central scar.

Front 42

What are the µscopic traits of oncocytoma?

Back 42

*Nesting pattern
*Round to polygonal cells
*Eosinophilic cytoplasm
*Small round nuclei
*Large nucleoli
*Mitotic figures only rarely identified

Front 43

Back 43

Front 44

Back 44

*Oncocytoma.
L: Shows Granular eosinophilic cytoplasm. Granularity is due to huge amounts of mitochondria.
R: Mitochondria on EM.

Front 45

Describe the significance of Birt-Hogg-Dube Syndrome :

What organs are involved?

Back 45

*Caused by Mutations in BHD Gene.

*Benign skin tumors:
-Fibrofolliculoma
-Trichodiscoma
-Acrochordon

*Pulmonary cysts.

*Renal cell tumors (Chromophobe RCC, oncocytoma, hybrid tumors with features of both.)

*BHD gene is on chromosome 17l produces the protein folliculin.

Front 46

ID these tumors and their gene association:

Back 46

Front 47

ID and discuss this tumor:

Back 47

*Collecting Duct (Bellini Duct) RCC.
*RARE, 1% of all RCC.
*Arise from collecting duct cells in medulla
*Gray-white and firm
*Poor prognosis

Front 48

ID this tumor and discuss the features that are present:

Back 48

*Tubulopapillary architecture.
*Single cuboidal layer with hobnails.
*Marked nuclear pleomorphism.
*Desmoplastic and inflamed stroma (distinguishes this tumor).
*Dysplasia of adjacent tubules.
*HE SAYS THIS WON'T BE ON THE EXAM*

Front 49

Discuss Renal medullary carcinoma:
Who gets them?
What's the gene association?
How does the tumor behave?

Back 49

Young African American males (mean age 22 y).

*Sickle cell trait (HbAS) in 85% (may be a board question).

*Located in medulla.
*Originates in collecting ducts.
*Highly aggressive; patients die in a couple of months.

*May be a subtype of collecting duct carcinoma.

Front 50

ID and discuss this tumor:

Back 50

*Renal Papillary Adenoma.
*Benign.
*Small (<0.5 cm...if you saw this same tumor and it was >0.5cm, this would by definition be a papillary renal cell carcinoma).

*Histologically indistinguishable from papillary RCC.

*NOTE: Clear cell, chromophobe, collecting duct-- these are never called adenomas even if they are small.

Front 51

ID and discuss this tumor:
*Who gets these?

Back 51

*Angiomyolipoma (composed of vessels, muscle, and fat).
*Benign.

*Sporadic or syndromic.

*Present in 25-50% of patients with tuberous sclerosis (seizures, mental retardation, autism, and tumors in many organ systems, including the brain, retina, heart, kidney, and skin).

*Susceptible to spontaneous hemorrhage.

Front 52

Back 52

Angiomyolipoma

Front 53

Back 53

*This is NORMAL!

Front 54

Discuss Tumors of the Urinary Bladder:

Back 54

*Bladder is the most common site of urinary tract tumors.

*Older patients (median age 65 y).
*M>F (3:1)

*Almost always sporadic (familial is extremely rare).

*90% are urothelial carcinomas (SEE ROBBINS 976).
*Often multifocal.

Front 55

What are the Risk Factors for bladder cancer? 5

Back 55

*Cigarette smoking (3-7 fold increased risk).

*Occcupational carcinogens (arylamines).

*Schistosoma hematobium (Egypt, Sudan, other African countries) --> SCC.

*Drugs (cyclophosphamide and analgesics).

*Radiation therapy.

Front 56

How does bladder CA present?

Back 56

*Painless hematuria is the dominant clinical presentation.

*Lesions that invade the ureteral or urethral orifices cause urinary tract obstruction.

Front 57

What are the 2 shapes of urothelial lesions?

What's the difference between them clinically?

Back 57

*Papillary urethelial carcinomas are never called carcinoma "in situ." We call them "non-invasive papillary carcinoma."

Front 58

ID and discuss this entity:

Back 58

*This is Papillary Hyperplasia.
*Urothelium is thicker on the left (>7 layers), but no need to count the number of cell layers.
*There are undulating folds.
*There are no fibrovascular cores.

Front 59

ID and discuss this lesion:

Back 59

*Urothelial Papilloma.
*<1% of bladder tumors
*Younger patients
*Usually single lesions
*Discrete papillary growth
*Central fibrovascular cores
*No atypia
*Rare recurrences or progression. Benign.

Front 60

What's the difference?

Back 60

*These are the 2 types of urothelial papilloma.
*Left: Exophytic (growing up within the lumen of the ureter).
*Right: Endophytic (inverted papilloma; growing down).

Front 61

*Discuss this entity:

Back 61

*PUNLMP.
*Somewhere in b/t malignant and benign.
*Thickened urothelium (> 7 layers).
*Orderly arrangement of cells within papillae.
*Minimal architectural abnormalities.
*Minimal nuclear atypia.
*Mitotic figures rare.
*May recur or rarely progress to high- grade tumors.

Front 62

Back 62

Low-Grade Papillary Urothelial Carcinoma

Front 63

ID this and describe the features that you are seeing:

Back 63

*Low-Grade Papillary Urothelial Carcinoma.
*Thickened layers (>7).
*Orderly appearance.
*Minimal but definitive cytologic atypia. You see SOME mitoses and some signs of malignancy.
*OFTEN recur.
*USUALLY non-invasive (90%).

Front 64

ID this and describe the features that you are seeing:

Back 64

*High power view of Low-Grade Papillary Urothelial Carcinoma.
*Cells maintain polarity.
*Scattered hyperchromatic nuclei.
*Infrequent mitotic figures.
*Mild variation in nuclear size and shape.

Front 65

ID and discuss this tumor:

Back 65

*High-Grade Papillary Urothelial Carcinoma.
-High incidence of invasion into muscularis (detrusor muscle).
-Higher risk of progression than low-grade lesions.
-Significant metastatic potential.

Front 66

ID this and describe the features that you are seeing:

Back 66

*High-Grade Papillary Urothelial Carcinoma.
*Architectural disarray and loss of polarity.
*Nuclear atypia, some huge nuclei.
*Frequent mitotic figures.

Front 67

Papilloma:
PUNLMP:
LGPUC:
HGPUC:

1) What's the recurrence of each?
2) How likely are each to invade?
3) How likely are each to kill you?

Back 67

Front 68

How do we stage bladder cancers?

Back 68

*Based on DEPTH of INVASION, not on tumor size.
*Papillary is called Ta, not Tis.
*Note the layers involved with different stages.

Front 69

ID and give approximate staging:

Back 69

Top: Has invaded muscularis-- T2.
Bottom: Has invaded fat--T3.

Front 70

ID this and gives its approximate staging:

Back 70

*Invasive Urothelial Carcinoma. Invading the uterus.

Front 71

What is the survival of Urothelial Carcinomas, based on staging?

Back 71

*The extent of spread (staging) at the time of initial diagnosis is the most important prognostic factor.

Front 72

ID and discuss this entity:

Back 72

*Urothelial Carcinoma In-Situ.
*FLAT; no gross mass.
*You see mucosal reddening, granularity, or thickening.
*Commonly these tumors are multifocal.
*May involve most of the bladder surface.

Front 73

ID and discuss features:

Back 73

Front 74

ID and discuss:

Back 74

*Urothelial Carcinoma In-Situ.
*Left shows denuding CIS.
*Right shows shedding of malignant cells into urine.
*THESE ARE AGGRESSIVE TUMORS; 50% OF THEM WILL PROGRESS.
*Urine samples can be used to track the tumor growth; it's difficult to do this in low grade ones.

Front 75

What's the genetic association of Urothelial Carcinoma In-Situ?

Back 75

*Deletion of chromosome 9!!!! p16 gene is lost.
*Note difference in progression with low grade and high grade tumors.
*Note that 15% of low grades INVADE; this is due to an additional mutation of p53 and Rb!! Low grade becomes high grade this way.
*SEE ROBBINS 980.

Front 76

What are these variants of? Discuss.

Back 76

*Variants of urothelial carcinoma.
*These aren't terribly important for the test.

Front 77

What are these? One of them has a connection to micro/ID.

Back 77