Lec10 Neoplasia Flashcards
Is histopathological diagnosis necessary for neoplasia?
Yes
What is common etiology of neoplasia?
Cacinogens/hereditary
Definition of neoplasm
abnormal mass of tissue whose uncoordinated and excessive growth exceeds normal tissue and persists after cessation of stimuli that evoked change. Genetic changes allow excessive and unregulated proliferation that become autonomous [independent of physio stimuli] but tumors are dependent on host for nutrition and blood supply
6 Characteristics of neoplsam
- autonomous growth
- monoclonality
- histology phenotype
- genetic mutations
- mutagens/carcingoens [initiating cause]
- benign or malignant
Benign tumor characteristics
- cohesive, expansile [slow limited growth]
- well circumscribe, lobulated, encapsulated
- discrete, mobile [easily removed]
What are two examples of benign tumors than can be lethal
- brain meningioma
- atrial myxoma
Malignant tumor characteristics
- progressive infiltration [limitless growth]
- invasion/destruction of adjacent structures
- poorly demarcated [not clear margins]
- unfavorable prognosis
What is hamartoma?
Disorganized growth/mass of indigenous tissue
- excess of normal tissue in normal place
- usually benign
ex. extra bile duct tissue in liver
What is choristoma?
Congenital anomaly [heterotropic rest of cells]
- excess of normal tissue in abnormal place
- ex. pancreatic tissue in duodenum
Definition of Parenchyma
The tumor = transformed neoplastic cells
Definition of stroma
The host = surrounding supportive connective tissue
Definition of hyperplasia
increase in number of cells
Definition of metaplasia
replacement of one mature cell type by another
Definition of Dysplasia
loss of cell uniformity/orientation [epithelial]
disordered proliferation, lack of progressiver maturation, differentiation
Definision of Desmoplasia
Stromal reactions [fibrosis-collagen] to invasion
Definition of Anaplasia
Complete lack of differentiation [malignancy]
Only in malignant tumor
What are 4 histologic criteria of tumor?
- uniformity of cells
- nuclei
- mitosis
- architecture
Pleomorphism
variation in size and shape
Cells and nuclei become less uniform
How do nuclei change in cancer
abnormal nuclear morphology
large nuclei, irregular, hyperchromatic
How does proliferative activity change in cancer?
- higher proliferative activity
- more cells undergoing mitosis, atypical shapes
How does architecture change in cancer?
Loss of architecture
haphazard growth
irregular glands
How to measure differentiation in tumor cell
- extent of resemblance to normal
- evaluated on histologic sections
- morphologically and functionally
Grading of tumors
- quantitative evaluation of differentiation
- predicts future behavior [prognosis]
grade from 1-4
1-2 = low grade
3-4 = high grade
Benign tumor differentiation
- very well differentiated
- difficult to distinguish from normal
- mass may be only sign of neoplasia
Malignant tumor differentiation
- range of differentiation
- grading: well, moderately, poorly
- anaplasia: lack of differentiation
How is rate of tumor growth measured
- doubling time
- growth fraction
- rate of cell loss
[cell production > cell loss, malignant > benign]
At what stage clinically detectable? Incompatible with life?
clinically detectable: 10^9 cells [1gm], 30 doublings
incompatible with life: 10^12 [1kg], + 10 doublings
Local growth and invasion in benign vs malignant tumors
benign: remain localized in tissue of origin, have well-defined cleavage plane [enucleation]
malignant: invade host stroma and desmoplasia, wider margin needed for complete resection
What is carcinoma in situ? What is it characterized by?
- marked dysplasia involving entire thickness of epithelium
- pre-invasive
3 forms of metastatic spread
- lymphatic spread: regional lymph nodes
[carcinomas] - hematogenous: liver, lungs
[carcinomas, sarcomas] - seeding of cavities: peritoneum, pleura
[carcinomas]
Tumor staging
T = primary tumor: size or extent
– T0-T4 [T0 = in situ]
N = regional node: number, location
– N0-N3 [N0 = negative]
M = metastases: number, sites
– M0-M2 [M0 = negative
Is staging or grading more important for prognosis?
Staging is more important
Risk factors for cancer
- geography and environment - ambient carcinogens
- diet and lifestyle - tobacco, obesity, alcohol
- age (>55 yrs) - more mutations, less immunity
- genetic predisposition (hereditary)
- cancer syndromes, familial clustering
- chronic inflammation
- pre-malignant leisions
cancer cachexia
- loss of body fat, lean muscle
- weakness, anorexia, anemia
- high BMR, catabolic rate
paraneoplastic syndromes
- unexplained by local/distant spread of indigenous hormones
- 10-15% of malignancies
- can precede cancer diagnosis
- significant morbidity/mortality
- can be hematologic, endocrinopathy, neuropathy/myopathy
Direct effects of cancer
- pressure atrophy [glands]
- obstruction/occlusion [tract]
- destruction [rupture]
- bleeding
- ulcer [secondary infection]
- infarction
Cause of molecular carcinogenesis
- mutations either inherited [germline] or acquired
Main targets of mutations
- oncogenes [gain of function, dominant]
- tumor suppressors [LOF, recessive]
- genes that regulated cell death
- genes involved in DNA repair
Haploinsufficiency
one allele loss
8 steps of malignant transformation
- self sufficient growth [oncogenes]
- insensitivity to growth inhibition [tumor suppressor]
- evasion cell death/apoptosis [p53, BCL2, BAX]
- Limitless replicative potential [telomerase]
- sustained growth/angiogenesis [VEGF, bFGF]
- capacity for invasion/metastasis
- reprogrammed metabolic pathways
- ability to evade immune system
retinoblastoma mech
- due to point mutation/deletion
- gene = RB1 tumor suppressor
chronic myelogenous leukemia mech
- due to chromosome translocation
- gene = BRC-ABL proto-oncogene
neuroblastoma mech
- due to gene amplification
- gene = N-myc proto-oncogene
breast/ovarian carcinoma
- due to epigenetic mutagenesis
- gene = BRCA1 tumor suppressor
Mech and Effect of DNA mismatch repair [MMR] defect?
- due to mismatched base pairs, microsatellite instability
- neoplasm = colon, endometrial
- gene = MSH2, MLH1
- syndrom = Lynch [HNPCC]
Mech and Effect of Homologous recombination defect?
- due to double stranded break, ionizing radiation
- neoplasm = leukemia, lymphoma
- gene = FANCA, ATM]
- syndrome = Fanconi anemia, ataxia-telangiectasia
Mech and Effect of Nucleotide excision repair [NER] defect?
- due to cross linking, UV radiation
- neoplasm: basal cell melanoma
- gene: XPA, XPB
- syndrome: xeroderma pigementosum [XP]
Steps of multi-step carcinogenis in colon
- normal colon
- mucosa at risk
- adenoma
- carcinoma
Steps of invasion and metastasis
- loss of cell interactions [E-cadherins]
- ECM degradation [metalloproteinases]
- Attachment and migration [integrins]
- Intravasation [access to vessels]
- Dissemination and homing [chemokines]
- Adhesion and extravasation
- Metastatic deposition
- Interaction with stroma
- Angiogenesis and growth [VEGF]
Effect of UV rays
- UVB exposure –> pyrimidine dimers
- can cause melanoma
Disease associated with HPV
Cervical squamous cell carcinoma
Disease associated with HBV/HCV?
Hepatocellular carcinoma
Disease[s] associated with H pylori
gastric lymphoma/adenocarcinoma
Venous thrombosis
- trousseau syndrome
- underlying neoplasm: pancreatic carcinoma
- mech: hypercoaguable state
sarcoma
maglinant neoplasm of mesenchymal cells
carcinoma
– malignant neoplasm of cells differentiating toward epithelial cells
What is doubling time
time it takes for a cell to divide
What is growth fraction?
percent of neoplastic cells dividing
one of most important factors
what grows faster malignant or benign
malignant
What is most deadly disease? most prevalent?
most deadly = lung cancer
most prevalent = breast and prostate
how can surgery change susceptibility to chemotherapy?
- surgery pushes down growth fraction so can increase susceptibility to chemo
What is adenoma?
- benign epithelial neoplasm of glandular tissue
Most common early mutation in colorectal adenoma?
APC!
