Renal Cell Carcinoma fs Flashcards
Renal cell carcinoma overview
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.
renal tumor numbers
51000 cases diagnosed and 12900 deaths annually
3% of adult malignancy
sporadic papillary genomics
trisomy 7,16,17
mutated, activated MET>PRCC oncogenes
Hereditary papillary genomics
Trisomy 7
mutated activated MET
Sporadic Clear cell genomics
Translocations 3:6, 3:8, 2:11 and deletions on chromosome 3
loss of vhl
inactivated mutated vhl
hypermethylation of vhl
Hereditary clear cell
Translocations 3:6, 3:8, 2:11 and deletions on chromosome 3
loss of vhl
inactivated mutated vhl
hypermethylation of vhl
RCC
cell of origin
most common appearance
second most common apperaacne
tubule epithelial cell
clear cell carcinoma
papillary carcinoma
VHL syndrome
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.
Where is the VHL gene located?
Cytogenetic Location: 3p25.3
Molecular Location on chromosome 3: base pairs 10,141,634 to 10,153,669
other malignancies in vhl
retinal agniomata pulmonary hemangiomas liver hamangiomas multiple pancreatic cysts epididymal cysts cerebellar hemangioblastoma pheochromocytoma rcc and cysts cystadenomas of broad ligament
vhl proteins
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
what causes rcc to appear clear
lipids and glycogen
Renal Cell Carcinoma (RCC)(Hypernephroma) Major Clinical Characteristics
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.
Type: conventional clear cell
% Total RCC
% 5-year Survival
70 -75%
70% without mets (with mets 45%-with renal vein or perinephric fat invasion-15%)
Type: papillary
% Total RCC
% 5-year Survival
15 -20%
86%
Type: chromophobe
% Total RCC
% 5-year Survival
7%
95%
Type: RCC unclassified
% Total RCC
% 5-year Survival
5%
18%
Major Factors in Prognosisof Renal Cell Carcinoma
Stage(particularly size of tumor)
The bigger the tumor,
the worse the prognosis
Histologic Type
Mode of Spread
Hematogenous -not lymphatic
Renal Carcinoma staging
Stage I
5 year survival 96%
Tumor
Renal Carcinoma staging
Stage II
5 year survival 82%
tumore>7cm in greatest dimension and limited to kidney
Renal Carcinoma staging
Stage III
5 yr survival 64% tumor in major veins adrenal gland or perinephric tissue and or 1 regional lymph node involved
Renal Carcinoma staging
Stage IV
5 year survival 23%
tumor beyond gerotas fascia
more than 1 lymph node involved and more than 1 distant metastasis
cannon ball mets
rcc spread to lung
erythematous-violaceious lobulated mass on skin
rcc spread to skin
bone mets
rcc spread to bone
Rcc clinical presentation second card
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
RCC Diagnostic workup
General - history pe
lab studies - cbc lfts alkaline phosphatase bun creatinine ua
radiographic studies
RCC radiographic studies
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
general concept of interstitial space
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.
Lymphovascular invasion and metastasis:
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.
new way to track malignancy
tumor dna and rna in blood
Clinical presentations of neoplasms
Local effects
mass effect (eg leiomyoma>menorrhagia)
invasion (eg SCC of cervix>renal failure secondary to ureteric obstruction)
Clinical presentations of neoplasms
metastases
Mesothelial surface (eg ovarian serious carcinoma>malignant ascites)
lymph node (eg pancreatic adenoca>lymphadenopathy(virchows node)
organ
Liver, lung, bone, cns
Clinical presentations of neoplasms
Paranelioplastic syndromes
Endocrine
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)
Clinical presentations of neoplasms
Paraneoplastic syndromes
Migratory Thrombphlebitis
(pancreatic adenocarcinoma)
Clinical presentations of neoplasms
Paraneoplastic syndromes
Neruologic (onconeural antibodies)
Myasthenia gravis (thymoma)
eaton-lambers mg (multiple)
CNS, PNS, ANS (multiple)
Clinical presentations of neoplasms
Paraneoplastic syndromes
skin and joints
acanthosis nigricans
dermatomyositis
Clinical presentations of neoplasms
Paraneoplastic syndromes
kidney
membranous glomerulopathy
Low grade papillary urothelial
papillomas
- Exophytic or endophytic (inverted)
* Benign, cured by resection
low grade papillary urothelial
carcinoma
–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
urothelial low grade tumors
hyperplasia>fgfr3/raas activation>papillary carcinoma ta
urothelial muscle-invasive tumors
dysplasia>p53 signaling pathway>CIS invasive carcinoma T2, metastasis
Progression of carcinoma: a schema
Precancer (dysplasia)
squamous metaplasia:
low grade papillary TCC - mild
high grade papillary - moderate
CIS - severe
Progression of carcinoma: a schema
Carcinoma
Squamas metaplasia:
invasive urothelial carcinoma (invasion, LVI)
Progression of carcinoma: a schema
Metastasis
Squamos metaplasia:
Perivesicle nodes
(sentinel lymph node, regional lymph nodes, systemic)
normal urothelium
umbrella cell
cis
full thickness abnormalities
non-invasive in-situ cancer
No lymphatic vessels or blood vessels in mucosa
invasive in situ cancer
Tumor cells have access to lymphatic channel as soon as the tumor has invaded through the basement membrane.
Staging: superficial
Stage:ois, os, I
TNM: tis, ta, t1
L nodes:
5 year survival: 90%
Staging infiltrating
Stage: II, III
TNM: t2, t3a, t3b,
L nodes: 26, 50
5 year survival: 70%
Staging invasion of adjacent structures
Stage: III, IV
TNM: t4a, t4b
L nodes: 70
5 year survival: 10-20%
Staging lymph node invasion
Stage: IV
TNM: N+
L nodes: 100%
5 year survival: 10-20%
staging distant extension
Stage: IV
TNM: M+
L nodes: 100%
5 year survival:10-20%
Tissue biopsy
sample of cells form the body
liquid biopsy is useful when there is
not enough tissue sample available
note enough tumor tissue in the sample
a hard to reach tumor
need for regular monitoring
liquid biopsy steps
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
liquid biopsy potential applications
monitoring treatment response, drug resistance, disease recurrence
detection of genomic mutations to guide treatment decisions, various tumors of an earlier stage
