Renal Cell Carcinoma fs

Question 1

Renal cell carcinoma overview

Answer 1

CarcinomaAdenocarcinoma of the kidney
-50,000 new cases in US/yr
12,000 deaths
2:1 male preponderance…70 yrsold
-Tobacco…cigarettes…obesity ,HT ,estrogen therapy
-4% familial (Autosomal dominant form)
-Associated with Von Hippel–Lindausyndrome(VHL gene chromosome 3)Clinical-Usually Silent… costovertebralpain, palpable mass, hematuria
fever……weight loss………weakness………METASTASES in 25% at presentation
ParaneoplasticSyndromes….polycythemia, hypercalcemia, Cushing syndrome… ect.

Question 2

renal tumor numbers

Answer 2

51000 cases diagnosed and 12900 deaths annually

3% of adult malignancy

Question 3

sporadic papillary genomics

Answer 3

trisomy 7,16,17

mutated, activated MET>PRCC oncogenes

Question 4

Hereditary papillary genomics

Answer 4

Trisomy 7

mutated activated MET

Question 5

Sporadic Clear cell genomics

Answer 5

Translocations 3:6, 3:8, 2:11 and deletions on chromosome 3

loss of vhl
inactivated mutated vhl
hypermethylation of vhl

Question 6

Hereditary clear cell

Answer 6

Translocations 3:6, 3:8, 2:11 and deletions on chromosome 3

loss of vhl
inactivated mutated vhl
hypermethylation of vhl

Question 7

RCC

cell of origin
most common appearance
second most common apperaacne

Answer 7

tubule epithelial cell

clear cell carcinoma

papillary carcinoma

Question 8

VHL syndrome

Answer 8

von Hippel-Lindau (VHL) disease, or von Hippel-Lindau syndrome, is a rare genetic disorder characterized by visceral cysts and benign tumors in multiple organ systems that have subsequent potential for malignant change.

usually vascular tumors

cysts are seen that have become malignant for rcc

visceral cysts and benign tumors in multiple organ systems that have subsequent potential for malignant change.

Question 9

Where is the VHL gene located?

Answer 9

Cytogenetic Location: 3p25.3

Molecular Location on chromosome 3: base pairs 10,141,634 to 10,153,669

Question 10

other malignancies in vhl

Answer 10

retinal agniomata
pulmonary hemangiomas
liver hamangiomas
multiple pancreatic cysts
epididymal cysts
cerebellar hemangioblastoma
pheochromocytoma
rcc and cysts
cystadenomas of broad ligament

Question 11

vhl proteins

Answer 11

when vhl protein is notmal it binds to hifa and it is destroyed if it doesnt bind hifa binds hifb these products are created and you get a lot of vascularization

vegf pdgfb tgfa epo

Question 12

what causes rcc to appear clear

Answer 12

lipids and glycogen

Question 13

Renal Cell Carcinoma (RCC)(Hypernephroma) Major Clinical Characteristics

Answer 13

Classic triad of most common presenting signs/symptoms
Hematuria(60%)
Costovertebral pain(40%)
Palpable flank mass(30-40%)
All 3 present only in 10% of RCC patients

Important Characteristic
Tendency widespread metastasis before local signs/symptoms

25% RCC patients have radiologic evidence of metastatic disease at time of their initial diagnosis.

Question 14

Type: conventional clear cell

% Total RCC

% 5-year Survival

Answer 14

70 -75%

70% without mets (with mets 45%-with renal vein or perinephric fat invasion-15%)

Question 15

Type: papillary

% Total RCC

% 5-year Survival

Answer 15

15 -20%

86%

Question 16

Type: chromophobe

% Total RCC

% 5-year Survival

Answer 16

7%

95%

Question 17

Type: RCC unclassified

% Total RCC

% 5-year Survival

Answer 17

5%

18%

Question 18

Major Factors in Prognosisof Renal Cell Carcinoma

Answer 18

Stage(particularly size of tumor)
The bigger the tumor,
the worse the prognosis

Histologic Type

Mode of Spread
Hematogenous -not lymphatic

Question 19

Renal Carcinoma staging

Stage I

Answer 19

5 year survival 96%

Tumor

Question 20

Renal Carcinoma staging

Stage II

Answer 20

5 year survival 82%

tumore>7cm in greatest dimension and limited to kidney

Question 21

Renal Carcinoma staging

Stage III

Answer 21

5 yr survival 64% tumor in major veins adrenal gland or perinephric tissue and or 1 regional lymph node involved

Question 22

Renal Carcinoma staging

Stage IV

Answer 22

5 year survival 23%

tumor beyond gerotas fascia

more than 1 lymph node involved and more than 1 distant metastasis

Question 23

cannon ball mets

Answer 23

rcc spread to lung

Question 24

erythematous-violaceious lobulated mass on skin

Answer 24

rcc spread to skin

Question 25

bone mets

Answer 25

rcc spread to bone

Question 26

Rcc clinical presentation second card

Answer 26

silent for most of course classic triad 5-10% of pts flank pain hematuria palapable abdominal mass hematuria present 40% of pts ``` systemic symptoms anaemia fatigue cachexia wt loss hypercalcemia hepatic dysfunction ``` paraneoplastic syndrome parathyroid like hormones epo renin gonadotropins palacenal lactogen prolactin enteroglucagon insulin like homrones adrenocorticotropic hormone and prostaglandins identified in rcc pt

Question 27

RCC Diagnostic workup

Answer 27

General - history pe lab studies - cbc lfts alkaline phosphatase bun creatinine ua radiographic studies

Question 28

RCC radiographic studies

Answer 28

xray kub region ultrasound - distinguish cysts from solid masses iv urography - starting point for hematuria avaluations and function of contralateral kidney ct - provide an excellent assessment of the parenchyma and nodal status mri - excellent demonstration of solid renal masses and is image test of choice to demonstrate extent of vena caval involvement with tumor, useful in patients with renal insufficiency

Question 29

general concept of interstitial space

Answer 29

Fluid filters and diffuses (O2) out of blood capillaries and enters into the interstitial space Starling’s Equation Fluid is drained from the interstitial space by absorption into lymphatic capillaries. Oncotic/hydrostatic pressures, valves and contractions move the fluid along.

Question 30

Lymphovascular invasion and metastasis:

Answer 30

Tumor metastasis involves a coordinated series of complex events that include promotion of angiogenesis and lymphangiogenesis, detachment of malignant cells from the primary tumor, microinvasion of the surrounding stroma, blood and/or lymphatic vessel invasion, survival of the malignant cells in the blood and/or lymphatic flow, and extravasion and growth in secondary sites. Because the large lymphatic vessels reenter the blood vascular system, malignant cells spread via the lymphatic system to the regional lymph nodes and, from this point, to distant organs (Fig. 3). Follow-up data have shown that 80% of the tumors, mainly those of epithelial origin, disseminate through the lymphatic vasculature; the remaining 20% use the blood circulation to colonize secondary organs. The blood vessels are not the best route for the success of malignant dissemination. Although their disorganized structure may contribute to the intravasion of malignant cells or emboli, in the bloodstream these cells experience serum toxicity, high shear stresses and mechanical deformation. Consequently, the viability of the tumor cells is seriously compromised. Conversely, the success rate of lymphogenous spread is high. As previously referred, the structure and function of the lymphatic capillaries facilitates intravasion of tumor cells or emboli. On the other hand, the composition of the lymph is similar to interstitial fluid, which provides an optimal medium for the survival of malignant cells. In collecting lymphatic vessels, muscle fibers assure lymph propulsion, that flows slowly, and valves prevent its backflow. Lymph nodes are areas of flow stagnation that represent ideal “incubators” for malignant cells’ growth. Some cells exit the lymph node through the efferent channels or high endothelial venules. Other cells may remain mechanically entrapped for long periods of time, originating micrometastases. Martens and colleagues described the expression of a gene signature of scavenger and lectin-like receptors in the lymph node sinus, which are known mediators of tumour cell adhesion and, therefore, can contribute to selective metastasis in an organ-specific context. Probably, tumor-cell-specific characteristics, microenvironmental factors and crosstalk between tumor and host cells have a pivotal role in determining survival and growth of micrometastasis. Moreover, lymph node lymphangiogenesis may provide an additional mechanism to facilitate further metastatic spread throughout the lymphatic system. The occurrence of lymphangiogenesis prior to arrival of tumor cells indicates that signals derived from the primary tumor are transported to the draining lymph nodes. Pathways of dissemination of malignant cells: Different tumors metastasize preferentially to different organs, suggesting that tumor spread is a guided process. It has been reported that malignant cells may use chemokine receptor ligand interactions to guide the colonization of target organs. Chemokines are a family of chemoattractant cytokines that bind to G protein-coupled receptors expressed on target cells, namely malignant cells . For instance, breast cancer cells, that normally choose regional lymph nodes, bone marrow, lung and liver as their first sites of destination, overexpress CCR7 (chemokine, CC motif, receptor 7) and CXCR4 (chemokine, CXC motif, receptor 4). Their ligands, SLC/CCL2 (secondary lymphoid chemokine / CC- type chemokine ligand 21) and SDF-1 CXCL12/ (stromal cell-derived factor 1 / chemokine, CXC motif, ligand 12) are expressed at high levels by isolated lymphatic endothelial cells and lymphatic endothelium from vessels present in the preferred sites of metastasis. This guides chemoattraction and migration of tumor cells, and characterizes lymphatic vessel invasion as an active event.

Question 31

new way to track malignancy

Answer 31

tumor dna and rna in blood

Question 32

Clinical presentations of neoplasms Local effects

Answer 32

mass effect (eg leiomyoma>menorrhagia) invasion (eg SCC of cervix>renal failure secondary to ureteric obstruction)

Question 33

Clinical presentations of neoplasms metastases

Answer 33

Mesothelial surface (eg ovarian serious carcinoma>malignant ascites) lymph node (eg pancreatic adenoca>lymphadenopathy(virchows node) organ Liver, lung, bone, cns

Question 34

Clinical presentations of neoplasms Paranelioplastic syndromes Endocrine

Answer 34

Epo>polycythemia (rcc, hepatocellular Ca) siadh>hyponatremia (small cell ca lung) acth> cushing (small cell ca lung, scc lung) PTHrp and pth>hyercalcemia (myeloma, breast, lymphomas) Insulin>hypoglycemia (islet cell tumors) also IGF2 (other tumors) Serotonin>carcinoid syndrome (mid-gutwith metastasis to liver) Catecholamines>episodic sympathetic system (pheochromocytomas)

Question 35

Clinical presentations of neoplasms Paraneoplastic syndromes Migratory Thrombphlebitis

Answer 35

(pancreatic adenocarcinoma)

Question 36

Clinical presentations of neoplasms Paraneoplastic syndromes Neruologic (onconeural antibodies)

Answer 36

Myasthenia gravis (thymoma) eaton-lambers mg (multiple) CNS, PNS, ANS (multiple)

Question 37

Clinical presentations of neoplasms Paraneoplastic syndromes skin and joints

Answer 37

acanthosis nigricans dermatomyositis

Question 38

Clinical presentations of neoplasms Paraneoplastic syndromes kidney

Answer 38

membranous glomerulopathy

Question 39

Low grade papillary urothelial papillomas

Answer 39

* Exophytic or endophytic (inverted) | * Benign, cured by resection

Question 40

low grade papillary urothelial carcinoma

Answer 40

–PAPILLARY UROTHELIAL NEOPLASMS OF LOW MALIGNANT POTENTIAL –LOW GRADE PAPILLARY UROTHELIAL CARCINOMA •Larger than papillomas, thicker epithelium, •Recur after resection, but don't become high grade or invade •Orderly architecture; mildly atypical cytology, few mitoses •Recur but only invade infrequently •Treat by TURBT; 98% 10 year survival

Question 41

urothelial low grade tumors

Answer 41

hyperplasia>fgfr3/raas activation>papillary carcinoma ta

Question 42

urothelial muscle-invasive tumors

Answer 42

dysplasia>p53 signaling pathway>CIS invasive carcinoma T2, metastasis

Question 43

Progression of carcinoma: a schema Precancer (dysplasia)

Answer 43

squamous metaplasia: low grade papillary TCC - mild high grade papillary - moderate CIS - severe

Question 44

Progression of carcinoma: a schema Carcinoma

Answer 44

Squamas metaplasia: invasive urothelial carcinoma (invasion, LVI)

Question 45

Progression of carcinoma: a schema Metastasis

Answer 45

Squamos metaplasia: Perivesicle nodes (sentinel lymph node, regional lymph nodes, systemic)

Question 46

normal urothelium

Answer 46

umbrella cell

Question 47

cis

Answer 47

full thickness abnormalities

Question 48

non-invasive in-situ cancer

Answer 48

No lymphatic vessels or blood vessels in mucosa

Question 49

invasive in situ cancer

Answer 49

Tumor cells have access to lymphatic channel as soon as the tumor has invaded through the basement membrane.

Question 50

Staging: superficial

Answer 50

Stage:ois, os, I TNM: tis, ta, t1 L nodes: 5 year survival: 90%

Question 51

Staging infiltrating

Answer 51

Stage: II, III TNM: t2, t3a, t3b, L nodes: 26, 50 5 year survival: 70%

Question 52

Staging invasion of adjacent structures

Answer 52

Stage: III, IV TNM: t4a, t4b L nodes: 70 5 year survival: 10-20%

Question 53

Staging lymph node invasion

Answer 53

Stage: IV TNM: N+ L nodes: 100% 5 year survival: 10-20%

Question 54

staging distant extension

Answer 54

Stage: IV TNM: M+ L nodes: 100% 5 year survival:10-20%

Question 55

Tissue biopsy

Answer 55

sample of cells form the body

Question 56

liquid biopsy is useful when there is

Answer 56

not enough tissue sample available note enough tumor tissue in the sample a hard to reach tumor need for regular monitoring

Question 57

liquid biopsy steps

Answer 57

free circulating nucleic acids come mainly from dead cells and ncan contain cancer related mutations rna from exosomes, microvesicles that are used to transport genetic instructions between cells circulating tumor cells result from cancers that shed cells from the primary tumor into the blood stream

Question 58

liquid biopsy potential applications

Answer 58

monitoring treatment response, drug resistance, disease recurrence detection of genomic mutations to guide treatment decisions, various tumors of an earlier stage