MOD first 3 lectures Flashcards
Features of malignance
METASTATIC Invasive Anaplasia (poor differentiation) Pleomorphic (bizarre shaped) Tripolar/mercedes benz mitoses Disarray Enlarged nucleus (incr N:C ratio) Rapid growing (lots of mitoses), large Necrotic
What is cancer of the parenchyma? Cells involved?
CARCINOMA (cancer of epithelial origin)
Epith, liver, kidney, etc (fibrous, bc karkinos=hard)
(parenchyma=fxnl part of organ outside circulation)
What is cancer of the mesenchyme called? Cells?
SARCOMA
muscle, bone, fat, cartilage, vessels
(CT derives from mesoderm/mesenchyme)
What are neuro-endocrine cell tumors called
CARCINOID tumors (eg islets of langerhans, etc) All carcinoid tumors are malignant
What are tumors of germ cells of gonads?
testicle, 2/3 embryological tissue type
Testicle: SEMINOMA (still malig)
2/3 embryological tissue type (ecto/meso/endo) is
TERATOMA (ovarian teratoma common in younger women, forms cystic masses) (benign or malig)
What are cancers of WBCs?
LEUKEMIA
What is a mesothelioma
Tumor in cell of pleural/peritoneal cavity
Hematoma
Bruise
Granuloma
Collection of immune cells in inflamm, immune sys walls off (histiocytes aka dendritic cell macrophages)
Hamartoma
A developmental abnormality of disorg tissue of particular system (eg hamartoma of lung)
Choristoma
normal tissue found in wrong site (eg pancr tissue in esoph)
What level of differentiation is cancer?
POORLY differentiated! (hard to tell what kind of tissue tumor is derived from)
EPETHELIUM TUMORS: (parenchymal?)
Adenoma/ adenocarcinoma
Squamous carcinoma
Papilloma/ papillary carcinoma
Glands
Squamous cells/linings
Papilloma
MESENCHYME TUMORS Lipoma/ liposarcoma Angioma/angiosarcoma Chondroma/Chondrosarcoma Leiomyoma/ Leiomyosarcoma Rhabdomyoma/ rhabodmyosarcoma Osteoma/osteosarcoma
Fat Blood vessels Cartilage Smooth muscle Striated muscle (eg cardiac) Bone
Neuroma Meningioma Glioma/Glioblastoma Lymphoma/leukemia Nevus/ melanoma
Nerve (benign?) Meninges (benign?) Brain (glioblastoma is most aggressive of gliomas) Lymphocyte/WBC (always malig?) Melanocytes in skin
PARENCHYMAL MALIGNANT ONLY TUMORS
Urothelial carcinoma (transitional cell carcinoma)
Hepatocellular carcinoma
renal cell carcinoma
Neoplasia characteristics
Excessive uncontrolled growth/ self governing, irreversible
Monoclonal (cells come from single mother cell)
What 3 isoforms is clonality determined by, and what ratios characterize these?
G6PD Isoforms
(X-linked, 1:1 is hyperplasia, anything diff is neoplasia)
Androgen receptor isoforms
Ig Light-chain phenotype (for B cells; any K:L ratio different from 3:1 could mean neoplasia, prob lymphoma)
Suffixes that almost always indicate malignancy
- SARCOMA
- CARCINOMA
What are the 3 types of malignant spread/metastasis
1 Direct (seeding of body cavities)
2 Lymphatic spread (usu in carcinomas)
3 Hematogenous spread (usu in sarcomas)
Metaplasia
Dysplasia
Anaplasia
Meta: one cell type replaced w another (eg in esoph, bronchus)
Dysplasia: disordered cells, abnormal, pre-malig (eg in cervix, oropharynx, GI) (severe is full epith involvement, thick, may still be in situ ie not invading stroma yet)
Anaplasia: lack of differentiation, malig
Cancer definition
A genetic disease resulting from DNA mutations
WHAT 4 TYPES OF GENES ARE MUTATED IN CANCER GENESIS?
1) Promotors of proliferation (eg Ras)
2) Tumor suppressors (eg RB gene)
3) Apoptosis genes (eg p53)
4) DNA repair (eg BRCA
1) mutation in promotors or proliferation
eg RAS
protooncogene mutates to oncogene and causes continuous stim
-This is the only one that requires ONE HIT (mutation in one allele only), gain of fxn
2) mutation in TSG
eg RB
mutation means lose the brakes, causing cancer
3) mutation in apoptosis gene
eg p53
mutation means cells that are supposed to die via apoptosis DON’T, so defective cells still multiply
4) DNA repair mutation
eg BRCA
cannot fixed damaged DNA
Vogelstein’s multi-hit hypothesis for colorectal carcinogenesis
Need mutations in lots of types of genes!
Philadelphia chromosome in CML
CML is associated with the philadelphia chromosome. this is when BCR from chromosome 9 translocates to ABL on chromosome 22, forming the Bcr-abl fusion on chrom 9:22 (bcr abl is an oncogene, and expresses an abnormal tyrosine kinase which cues abnormal growth signal)
What viruses can cause cancer?
- HPV 16 and 18 can cause squam cell carcin of uterine and oropharynx (most common)
- Epstein barr virus (EBV, a herpes virus) can cause nasophar carcin and lymphoma (like burkitt)
- HHV8 (human herpes virus 8) can cause kaposi sarcoma and lymphomas in AIDS pts
- Hep B&C: hepatocell carcinoma
Bacteria and parasites that can cause cancer?
- H pylori: gastric MALT lymphoma and gastric adenocarcinoma
- Clonorchis sinesnsis: fluke that can cause bile duct carcinoma
What is a lymphoma
WBC cancer! (can include enlarged lymph nodes etc)
What is Familial Adenomatous Polypsis (FAP) syndrome?
germline mutation in APC (adenomatous polypsis coli) gene, a TSG), develop many colorectal ademonas early, need colectomy or eventually dev carcinoma
Diff b/n labile, permanent, and quiescent stable cells?
- Labile always profli (eg marrow)
- permanent: non-dividing, dont give rise to neoplasms (eg neurons and cardiac myocytes)
- quiesecent stable: in g0 phase, not dividing normally but can enter cell cycle or acquire mutations to give neoplasm (eg liver and renal tube cells)
Tumor detectable size
1cm (palpation, xray), 1 billion cells, takes 30 divisions (exponential amplification)
What is growth fraction and what can decrease this
proliferative pool, can be decr by chemo
What is the mitotic figure count (histo, eqn)
# mitoses/fields= grade (proliferation/mitotic index PI and flow cyometry not done as much anymore)
What is immunohistochemistry in measuring cancer prolif rate?
What marker is impt in breast cancer?
Use antibodies to prolifreration markers, eg PCNA
Ki-67 (MIB-1) is impt marker in BC (use an ab to this, so if ab binding shows 20% are ki-67 positive, this means theres 20% growth fraction, and these cells are prolif)
-used to determine type of tumor, her-2 also
Neoplasia sx
asymptomatic
high WBC count
painless lump, fatigue, wasting (cachexia), paraneoplastic syndromes (sx of immune resp against tumor)
What are some examples of paraneoplastic sydnromes?
any sx really,
carcinoid syndrome, hypercalcemia
Carcinoid syndrome?
Tumor cells rel serotonin, diarrh, bronchospasm, flushing/sweating, heart failure, GI tract and can flow to liver
Hypercalcemia in cancer?
squamous cell carcinoma in lung
PTH like hormone rel by tumor cells
abnormal clotting (trosseau’s sign), clot, DIC (small vessel clots)
GRADE vs STAGE?
grade: differentation and number of mitoses, necrosis (higher grade =more aggro)
Stage: tumor size/spread (MORE impt for prognosis!), higher stage means more extensive spread
What are 3 ways of dx neoplasia?
- Monoclonal protein (immunoglobulin, myeloma (plasma cell cancer)/lymphoma)
- Endocrine/hormones: increased lvls may mean tumor is secreting excess hormones
- Serum tumor markers (elevated, shed into circ often by tumor in later stage)
Examples of serum tumor markers?
CEA (carcinoembryonic ag; colon/pancr/lung carcin)
AFP (alpha fetoprot; liver carcin, and testis/ovary/yolk sac tumors)
PSA (prostate specific ag; prostate carcin)
CA-19-9 (cancer ag; pancr adenocarcin)
CA-125 (ovarian carcinomas)
Biopsy methods
Look @ histology from frozen section
Look @ cytology from needle aspiration or pap smear (less invasive)
What does brown stain cytokeratin positive on histo mean
carcinoma (keratin, int filament in epith cells)
Is meningioma benign?
Yes, but can still be fatal (so can hormone producing tumors)
Most important prognostic factor of malignant tumor
STAGE!
Driver vs passenger mutations?
DNA mutations that promote tumor development (mutations w no effect are passenger)
Primary, immortal, and transformed cells?
Primary: divide a limited amoutn of times before senescence
Immortal: divide indefinitely
Transformed: divide indef and other abnormal things like are indep of GFs, anchorage indep; immortal cells can become transformed and cause tumors
Evidence that cancer is multistep>?
Incidence incr with age (so multiple events req)
Transfection expts (introduce foregin DNA to transform cells and growth)
Oncogene synergy (tumors dev faster if multiple oncogenes activated, eg both myc and fos)
(cancer genes were also ID’d with transforming retroviruses, and genetic sequencing etc)
Protooncogene
TSG
definitions
Protooncogene is normal gene that becomes oncogene when mutated
TSG prevents tumor formation when activated
Diff between proto-oncogene and TSG
protoonco: need ONE mutation, gain of fxn (dominant), mutated allele not inherited (eg in germline)
TSG: req TWO mutations, loss of fxn (recessive), often inherited (thru germline), if inherited usu has tissue preference
Examples of TSGs
RB, APC
two mutations in these can cause inherited cancer syndromes
What can mutations in Ras oncogenes do?
Can cause it to stay active in GTP-bound form and continually transmit growth signal
(single base substitutions v common)
May be issue with GAP (GTPase activating prot) causing issue with GTPase (which normally conv GTP to GDP)
Amplification can occur where on chrom?
extra chrom dna called double minutes, or in HSR (homogenously stained region)
Burkitts lymphoma mutation
c-myc 8:14 translocation, expressed constitutively
TYPES OF MUTATIONS in cancer
Point mutation (eg ras, SBS’s)
Amplification
Translocation on chrom (eg bcr-abl)
Insertion (Retroviruses ingtegrate near proto-onco, causing synth of abnormal prot, but rare)
6 CLASSES OF PROTO-ONCOGENES
1) Growth factors
2) Growth factor receptors
3) Signal transducers
4) Transcription factors
5) Inhibitors of apoptosis
6) Cell cycle regulatory proteins
1) growth factors
overexpression of PDGF, TGF-a of EGF family, etc causing increased cell growth
2) growth factor receptors
bind growth factors and transmit growth signals via tyrosine kinase activity, eg Her2 receptor can mutate and be const activated, EGF R can have deletion etc
3) signal transducers
inner memb, transmit growth signals to cytoplasm prots
eg Ras, activated by GNFRF/GEFs and GTP, inactivated by GAPs (???), and Akt (tyrosine kinase which prevents apoptosis and can increase activity if activated)
4) Transcription factors
const active transcription of cell cycle stuff
eg Myc TF if increased then increases cell cycle prots and cancer
5) Inhibitors of apoptosis
eg Bcl-2 overexpr decreases apoptosis, (preventing cytochrome C rel from mito, Bax induces apop)
6) Cell cycle regulatory proteins
eg cyclins combine with CDKs for cell cycle to progress, if cyclin D is overexpressed then faster cell cycle
TSG can be inactivated by
point mut chrom transloc deletion/insertion DNA METHYLATION (whereas oncogenes are activated by above stuff and amplification), eg p16 TSG deleted/silenced
4 CLASSES OF TUMOR SUPPRESSORS
1) cell adhesion
2) Signal transduction
3) transcription regulators
4) DNA repair proteins
1) cell adhesion
eg e-cadherin loss of fxn allows tumor cells to escape and metast (common in epith cancers)
2) signal transduction (3)
NF-1 GAP that inactivates RAS by inr GTP hydrolysis, if lost then Ras is const active, icnr cell prolif
Beta-catenin incr transcr /cell cycle w/ Wnt, where APC binds to beta-cat then causes degrad, loss of APC incr transcription and cell cycle progression)
3) transcription regulators (2)
Rb binds and inactivates TF E2F
CDK can inactiv8 Rb to activate E2F by phosphorylating Rb (loss of Rb fxn inc transcr and cell cycle)
Loss of p53 results in incr survival (normally would prevent dna dmg, incr p21 and bax
-activates mdm-2, a protooncogene that inhibits own p53 fxn
4) DNA repair proteins (and cell cycle prots?)
- p16 is CDK inhibitor (inhibits cell cycle), loss of this causes cell cycle incr
- ATM is a protein kinase activated by double strand breaks in dna, which phosphorylates and activates p53 causing cell cycle arrest, loss of ATM decr p53 activation
- hMSH2 is dna MMR prot, loss causes accum of mutations
STUDY TIPS
CLICKER Q’s (molec aspects lecture)
This year’s notesets-review
Practice q’s (canvas, etc?)
IMAGES (gross and histo) in neoplasia 1 lecture
