Principles of Neoplasia Flashcards
Basic principles of neoplasia
Neoplasia: new tissue growth that is unregulated, irreversible, and monoclonal –> these features distinguish it from hyperplasia and repair
- monoclonal = neoplastic cells are derived from a single mother cell
- clonality was historically determined by G6PD enzyme isoforms –> only 1 isoform is present in neoplasia, which is monoclonal
- clonality of B lymphocytes is determined by Ig light chain phenotype
- -> normal kapp to lambda light chain ration is 3:1 - this ratio is maintained in hyperplasia which is polyclonal but increases to >6:1 or is inverted (1:3) in lymphoma, which is monoclonal
Tumor nomenclature
Epithlium
- benign = adenoma/papilloma
- malignant = adenocarcinoma/papillocarcinoma
Mesenchyme
- benign = lipoma
- malignant = liposarcoma
Lymphocyte = lymphoma/leukemia
Melanocyte
- benign = nevus/mole
- malignant = melanoma
Cancer epidemiology
Cancer is the second leading cause of death in both adults and children
- leading causes of death in adults = 1) cardiovascular disease 2) cancer 3) chronic respiratory disease
- leading causes of death in children = 1) accidents 2) cancer 3) congenital defects
Most common cancers by incidence in adults:
1) breast/prostrate
2) lung
3) colorectal
Most common causes of cancer mortality in adults:
1) lung
2) breast/prostate
3) colorectal
Role of screening
- cancer begins as a single mutated cell - approximately 30 divisions occur before the earliest clinical symptoms arise
- each division/doubling time results in increased mutations
- cancers that do not produce symptoms until late in disease will have undergone additional divisions and mutations
- cancers that are detected late have a poor prognosis
- goal of screening is to catch dysplasia before it becomes carcinoma, or carcinoma before clinical symptoms arise
Basic principles of carcinogenesis
- cancer formation is initiated by damage to DNA of stem cells - the damage overcomes DNA repair mechanisms but is not lethal
- carcinogens are agents that damage DNA, increasing the risk for cancer
- DNA mutations eventually disrupt key regulatory systems, allowing for tumor promotion (growth) and progression (spread)
Aflatoxins
Hepatocellular carcinoma
- derived from aspergillus, which can contaminate stored rice and grains
Alkylating agents
Leukemia/lymphoma
- side effect of chemotherapy
Alcohol
Squamous cell carcinoma of oropharynx and upper esophagus + hepatocellular carcinoma
Arsenic
Squamous cell carcinoma of skin, lung cancer + angiosarcoma of liver
- present in cigarette smoke
Asbestos
Lung carcinoma + mesothelioma
- exposure to asbestos is more likely to lead to lung cancer than mesothelioma
Cigarette smoke
Carcinoma of oropharynx, esophagus, lung, kidney, bladder + pancreas
- most common carcinogen worldwide
- polycyclic hydrocarbons are particularly carcinogenic
Nitrosamines
Stomach carcinoma
- found in smoked foods
- responsible for high rate of stomach carcinoma in Japan
Naphthylamine
Urothelial carcinoma of bladder
- derived from cigarette smoke
Vinyl chloride
Angiosarcoma of liver
- occupational exposure
- usesd to make polyvinyl chloride for use in pipes
Nickel, chromium, beryllium, or silica
Lung carcinoma
- occupational exposure
EBV
- nasopharyngeal carcinoma
- burkitt lymphoma
- CNS lymphoma in AIDS
HHV-8
Kaposi sarcoma
HBV + HCV
Hepatocellular carcinoma
HTLV-1
Adults T-cell leukemia/lymphoma
HPV
Squamous cell carcinoma of vulva, vagina, anus and cervix
Adenocarcinoma of the cervix
Ionizing radiation
Generates hydroxyl free radicals
- AML
- CML
- papillary carcinoma of the thyroid
Non-ionizing radiation (UVB sunlight)
Results in formation of pyrimidine dimers in DNA, which are normally excised by restriction endonuclease
- basal cell carcinoma
- squamous cell carcinoma
- melanoma of skin
Oncogenes
Proto-oncogenes are essential for cell growth and differentiation; mutations form oncogenes that lead to unregulated cellular growth
Categories of oncogenes:
- growth factors - induce cell growth
- growth factor receptors - mediate signals from growth factors
- signal transducers - relay receptor activation to the nucleus
- nuclear regulators
- cell cycle regulators - mediate progression through the cell cycle
–> ex: cyclin + cyclin dependant kinases = form a complex which phosphorylates proteins that drive the cell through the cell cycle
–> cyclinD/CDK4 complex phosphorylates the rb protein, which promotes progression through the G1/S checkpoint
Ras
- ras is associated with growth factor receptors in an inactive GDP-bound state
- receptor binding causes GDP to be replaced with GTP –> activates ras
- activated ras sends growth signals to the nucleus
- ras inactivates itself by cleaving GTP to GDP –> augmented by GTPase activating protein (GAP)
- mutated ras inhibits the activity of GAP –> prolongs the activated state of ras = increased growth signals
p53
Regulates the progression of the cell cycle from G1 - S phase
- in response to DNA damage, p53 slows the cell cycle and upregulates DNA repair enzymes
- If DNA repair is not possible, p53 induces apoptosis –> upregulates BAX = disrupts bcl2 –> causes cyt c to leak from the mitochondria = activates apoptosis
Both copies of p53 gene must be knocked out for tumor formation = knudson two-hit hypothesis
- loss is seen in >50% of cancers
- germline mutation results in Li-Fraumeni syndrome –> characterized by propensity to develop multiple types of carcinomas and sarcomas
Rb
Regulates progression from G1 - S phase
- Rb holds the E2F transcription factor, which is necessary for transition to the S phase
- E2F is released when Rb is phosphorylated by the cyclinD/CDK4 complex
- Rb mutation results in constitutively free E2F –> allows progression through cell cycle and uncontrolled cell growth
Both copies of Rb gene must be knocked out for tumor formation
- sporadic mutation when both hits are somatic is characterized by unilateral retinoblastoma
- germline mutation results in familial retinoblastoma where second his is somatic –> characterized by bilateral retinoblastoma and osteosarcoma
Regulators of apoptosis
Prevent apoptosis in normal cells, but promote apoptosis in mutated cells whose DNA cannot be repaired - eg. Bcl2
- Bcl2 normally stabilizes the mitochondrial membrane, blocking release of cyt c
- disruption of Bcl2 allows cyt c to leave the mitochondria and activate apoptosis
Bcl2 is overexpressed in follicular lymphoma
- 14:18 translocation moves Bcl2 from chromosome 18 to the Ig heavy chain locus on chromosome 14 = increased Bcl2 expression –> mitochondrial membrane is further stabilized, prohibiting apoptosis
- B cells that would normally undergo apoptosis during somatic hypermutation in the lymph node germinal center accumulate –> lymphoma
Other important features of tumor development
Telomerase is necessary for cell immortality
- normally telomeres shorted with serial cell divisions –> eventually results in cellular senescence
- cancers often have upregulated telomerase –> preserves telomeres
Angiogenesis is necessary for tumor survival and growth
- GFG and VEGF = angiogenic factors –> commonly produced by tumor cells
Avoiding immune surveillance is necessary for tumor survival
- mutations often result in production of abnormal proteins –> expressed on MHC I
- cd8 t cells detect and destroy such mutated cells
- tumor cells can evade immune surveillance by downregulating expression of MHC I
- immudeficiency increases risk for cancer
Tumor invasion and spread
Accumulation of mutations eventually results in tumor invasion and spread
- epithelial tuomr cells are normally attached to one another by cellular adhesion molecules = E cadherin
- downregulation of E- cadherin leads to dissociation of attached cells
- cells attach to laminin and destroy basement membrane (collagen type 4) via collagenase
- cells attach to fibronectin in the ECM and spread locally
- entrance into vascular or lymphatic spaces allows for metastasis
Routes of metastasis
Lymphatic spread is characteristic of carcinomas –> initially spready to regional draining lymph nodes
Hematogenous spready is characteristic of sarcomas and some carcinomas
- renal cell carcinoma –> often invadesrenal vein
- hepatocellular carcinoma –> often invades hepatic vein
- follicular carcinoma of the thyroid
- choriocarcinoma
Seeding of body cavities is characteristic of ovarian carcinoma –> often involves the peritoneum = omental caking
PDGFB
Platelet derived growth factor
Oncogene mechanism: Overexpression, autocrine loop
Associated tumor: Astrocytoma
ERBB2 (HER2/Neu)
Epidermal growth factor receptor
Oncogene mechanism: Amplification
Associated tumor: Subset of breat carcinomas
RET
Neural growth factor receptor
Oncogene mechanism: Point mutation
Associated tumors:
- MEN2A
- MEN 2B
- sporadic medullary carcinoma of thyroid
KIT
Stem cell growth factor receptor
Oncogene mechanism: Point mutation
Associated tumor: GI stromal tumor
RAS gene family
GTP binding protein
Oncogene mechanism: Point mutation
Associated tumors:
- carcinomas
- melanoma
- lymphoma
ABL
Tyrosine kinase
Oncogene mechanism: 9:22 translocation with BCR
Associated tumors:
- CML
- some types of ALL
c-MYC
Transcription factor
Oncogene mechanism: 8:14 translocation involving IgH
Associated tumor: Burkitt lymphoma
N-MYC
Transcription factor
Oncogene mechanism: Amplification
Associated tumor: Neuroblastoma
L-MYC
Transcription factor
Oncogene mechanism: Amplification
Associated tumor: Lung carcinoma (small cell)
CCND1 (cyclin D1)
Cyclin (cell cycle regulator)
Oncogene mechanism: 11:14 translocation involving IgH
Associated tumor: Mantle cell lymphoma
CDK4
Cyclin dependent kinase
Oncogene mechanism: Amplification
Associated tumor: Melanoma
General clinical features of neoplasia
- benign tumors tend to be slow growing, well circumscribed, distinct and mobile
- malignant tumors are usually rapid growing, poorly circumscribed, infiltrative and fixed to surrounding tissues and local structures
- biopsy or excision is generally required before a tumor can be classified as benign or malignant with certainty
- some benign tumors can grow in a malignant like fashion, and some malignant tumors can grow in a benign like fashion
Histologic features of benign tumors
- usually well differentiated
- organized growht
- uniform nuclei
- low nuclear to cytoplasmic ration
- minimal mitotic activity
- lack of invasion of basement membrane or local tissue
- no metastatic potential
Histologic features of malignant tumors
- classically poorly differentiated = anaplastic
- disorganized growth/loss of polarity
- nuclear pleomorphism and hyperchromasia
- high nuclear to cytoplasmic ratio
- high mitotic activity with atypical mitosis
- invasion through basement membrane or into local tissue
- metastatic potential is the hallmark of malignancy - benign tumors never metastasize
Immunohistochemical stains for intermediates:
- epithelium
- mesenchyme
- muscle
- neuroglia
- neurons
- epithelium = keratin
- mesenchyme = vimentin
- muscle = desmin
- neuroglia = GFAP
- neurons = neurofilaments
Immunohistochemical stains for:
- prostatic epithelium
- breast epithelium
- thyroid follicular cells
- neuroendocrine cells
- melanoma, schwannoma and langerhans cell histiocytosis
- prostatic epithelium = PSA
- breast epithelium = ER
- thyroid follicular cells = thyroglobulin
- neuroendocrine cells = chromogranin (eg small cell carcinoma of lung and carcinoid tumors)
- melanoma, schwannoma and langerhans cell histiocytosis = S-100
Serum tumor markers
- proteins released by tumor into serum (eg PSA)
- useful for screening, monitoring response to tx and monitoring recurrence
- elevated levels require tissue biopsy for dx of carcinoma
Grading of cancer
Microscopic assessment of differentiation - how much a cancer resembles the tissue in which it grows –> takes into account architectural and nuclear features
- well differentiated = low grade –> resembles normal parent tissue
- poorly differentiated = high grade –> does not resemble parent tissue
Important for determining prognosis –> well differentiated cancers have better prognosis
Staging of cancer
Assessment of size and spread of a cancer –> key prognostic factor, more important than grade
- determined after final surgical resection of the tumor
Utilizes TNM staging
- T = tumor size/depth of invasion
- N = spread to regional lymph nodes, second most important prognostic factor
- M = metastasis, single most important prognostic factor
