Principles of Neoplasia (Pathoma) Flashcards
Basic Principles of Neoplasia
Unregulated, irreversible, and monoclonal.
Distinct from hyperplasia and repair.
Monoclonal
Neoplastic cells are derived from a single mother cell
*Clonality can be determined by G6PD isoforms (or androgen receptor isoforms). –> ratio of A:B G6PD will not be 1:1 in neoplasia, but will be 1:1 in hyperplasia.
All tumors are monoclonal (benign and malignant)
Clonality of B cells is determined by Ig light chain phenotype (kappa to lambda). Ratio is normally 3:1 .
In infection hyperplasia occurs, and 3:1 ratio stays the same. In neoplasia (i.e. lymphoma) ratio will be changed (i.e. 20:1)
Adenoma
Benign tumor of the epithelium w/ glandular differentiation.
Papilloma
Benign tumor of the epithelium finger like projections.
Adenocarcinoma
Malignant tumor of the epithelium w/ glandular differentiation.
Papillary carcinoma
Malignant tumor of the epithelium w/ finger like projections.
Lipoma
Benign tumor mesenchyme
Liposarcoma
Malignant tumor of mesenchyme
Lymphoma/Leukemia
Malignant lymphocyte proliferation (automatically malignant)
Nevus
Benign melanocyte tumor (mole)
Melanoma
Malignant melanocyte tumor.
Causes of death in adults:
1 Cardiovascular disease
- Cancer
- Cerebrovascular disease
Causes of death in children
- accidents
- cancer
- congenital defects
MC cancers in adults (excluding skin)
- Breast/ Prostate
- Lung
- CRC
MC cancer killers in adults
- Lung
- Breast/prostate
- CRC
Shows principled of early detection –> Can screen for breast, prostate, crc. Not for lung –> thus the jump in mortality.
Cancer progression
Begins w/ a single mutated cell
Approximately 30 cell divisions occur before earliest sx arise.
Each division (doubling time) results in increased mutations.
Cancers that don’t produce sx until late in disease will have undergone additional divisions and mutations.
Cancers that are detected late tend to have a poor prognosis (ovarian, pancreatic, lung)
Goal of screening
Catch dysplasia before it becomes carcinoma (i.e. pap smear)
Detect carcinoma before clinical sx arise (before additional mutations have occured) (i.e. mammography to catch ductal carcinoma in situ or tumors that are only 1cm (1/2 the size that is clinically found)
Pap smear
Detect CIN dysplasia before it becomes carcinoma
Mammography
- Detect ductal carcinoma in situ before it has had the chance to invade locally
- Detect tumors that are smaller (1cm) than can be found clinically (2cm). thus lowering their propensity to metastasize.
PSA and DRE
Prostate cancer tends to grow in the posterior and peripheral prostate –> thus is often a clinically silent disease (vs. BPH which grows periurethral causing urinary sx).
Digital Rectal Exam allows for palpation of posterior peripheral prostate.
Hemoccult and colonoscopy.
Goal is to remove the adenomas before they progress to carcinoma
Or detect carcinoma before it is clinically symptomatic.
Carcinogens
Carcinogens damage cell DNA
Important carcinogens include chemicals, viruses, and radiation.
Aflatoxins
Carcinogen derived from Aspergillus which can contaminate stored grains.
Risk for hepatocellular carcinoma (MC cancer in some areas in the world Asia/Africa due to this)
Alkylating agents
Side effect of chemotherapy that increases risk for Leukemia/Lymphoma
Alcohol
Squamous cell carcinoma of oropharynx and upper esophagus, pancreatic carcinoma (chronic pancreatitis), and hepatocellular carcinoma (cirrhosis)
Arsenic
Squamous cell carcinoma of skin (women in England putting on arsenic to cover up tan)
Lung cancer
Angiosarcoma in liver
Asbestos
Lung cancer
Mesothelioma
Exposure to asbestos are FAR MORE LIKELY to develop LUNG CANCER than mesothelioma
Cigarrette smoke
Carcinoma of oropharynx
Esophagus
Lung
kidney
Bladder
MC carcinogen worldwide; polycyclic hydrocarbons are particularly carcinogenic.
Nitrosamines
Stomach carcinoma (intestinal adenocarcinoma)
Found in smoked foods; responsible for high rate of stomach CA in Japan.
Napthylamine
Urothelial of carcinoma of bladder.
Derived from cig. smoke
Vinyl chloride
Angiosarcoma of the liver.
Occupational exposure to make PVC for use in pipes.
Nickel, chromium, beryllium, of silica
Lung CA
Occupational exposure.
EBV
Nasopharyngeal carcinoma (chinese male or African child)
Burkitt lymphoma
CNS lymphoma in AIDS
HHV-8
Kaposi Sarcoma
- Older eastern European males (rx w/ excision)
- ) AIDS patients (antiretrovirals –> immune system kills tumor)
- ) Transplant patients (reduce immonsuppression)
HBV and HCV
Hepatocellular carcinoma
HTLV-1
Adult T cell leukemia/lymphoma
HPV (16,18,31,33)
SCC of vulva, vagina, anus, and cervix.
Adenocarcinoma of cervix
Ionizing radiation (nuclear reactors and radiotherapy)
AML, CML, and papillary carcinoma of the thyroid
Generates hydroxyl free radicals
Nonionizing radiation (UVB sunlight is MC source)
Basal Cell, SCC, and Melanoma of skin
Results in formation of pyrimidine dimers in DNA, which are normally excised by restriction endonuclease (mutated in Xeroderma Pigmentosum!)
Systems disrupted by carcinogens
Proto-oncogenes
TS genes
Regulators of apoptosis
Proto-oncogenes
Genes that are essential for cell growth and differentiations
Mutations form oncogenes which leads to unregulated cell growth.
Categories:
- ) Growth factors (PDGFB)
- ) Growth Factor Receptors
- ) Signal transducers
- ) Cell cycle regulators
Platelet Derived Growth Factor B (PDGFB)
Overexpression due to mutation causing an autocrine loop (PDGF binds to its own PDGFR causing overgrowth of astrocytes).
Drives creation of Astrocytoma
ERBB2 (HER2/NEU)
Epidermal growth factor receptor
Causes Amplification of normal signal –> increased cell growth
Subset of breast cancers
Treatable with Trastuzumab.
RET
Neural Growth Factor Receptor
Point mutation
MEN 2A; MEN 2B and sporadic medullary carcinoma of thyroid. (test if concerned of MEN –> prophylactic removal of thyroid)
KIT
Stem cell growth factor receptor
Point mutation
Gastrointestinal stromal tumor (GIST)
Can treat w/ Imatinib
RAS gene family
Signal transducer
*GTP-binding protein
Point mutation –> GAP (GTPase Associated Protein) mutation –> RAS doesn’t shut itself off –> uncontrolled growth
Carcinomas, melanoma, and lymphoma
Mutated in 70% of cancers
ABL
Signal Transducer
Tyrosine kinase
t(9:22) with BCR –> BCR:ABL aka Philadelphia chromosome
CML and some types of AML (poor prognosis AML)
c-MYC
Nuclear regulator
Transcription factor
t(8;14) involving IgH causes Burkitt’s lymphoma (massive overproduction of MYC due to being translocated onto IgH which is constitually on)
Massive cell ovegrowth –> Burkitt’s lymphoma –> Starry Sky –> White is
N-MYC
Nuclear regulator
Transcription factor
Amplification
Neuroblastoma (N-myc = Neuroblastoma)
L-MYC
Nuclear regulator
Trascription factor
Amplification
Small cell carcinoma of the Lung (L-myc = Lung)
CCND1 (Cyclin D1)
Cell cycle regulator
Cyclin (key regulator of G1 –> S phase).
t(11;14) –> Mantle Cell (region next to the follicle) Lymphoma. Translocation of cyclin D(11) to IgH (14) (which is constituitively active)
CDK4
Cell Cycle Regulator
Amplification of Cyclin Dependent Kinase (CDK4).
Causes Melanoma
p53
Regulates cell cycle progression from G1–>S.
Monitors for DNA damage and can signal DNA repair or apoptosis (via BAX destroying Bcl-2)
Both copies of p53 must be knocked out for tumor formation (two brakes)
Loss is seen in >50% of cancer
Germline mutation in Li-Fraumeni sydrome; increased risk for multiple carcinomas and sarcomas
RB
RB binds E2F.
If RB is phosphorylated by Cyclin D/CDK4 it releases E2F allowing E2F to facilitate G1 to S.
If mutated E2F constituitively active.
Rb mutation results in constituitvely free E2F and uncontrolled G1–>S progression.
Sporadic mutation - unilateral retinoblastoma
Germline mutation (familial) - bilateral RB and osteosarcoma
Need two hits!
Bcl2
Normally stabilized mitochondrial membrane blocking release of cytochrome C
Disruption of Bcl2 allows cytochrome c to leave mitochondria and activate apoptosis
Overexpressed in follicular lymphoma t(14:18) moves Bcl2 (18) to IgH (14); results in increased Bcl2
Need B-cell apoptosis in follicle where somatic hypermuation is occuring.
Telomerase
Normally telomeres shorten w/ serial cell divisions resulting in senescence
Cancers have upregulated telomerase –> preserves telomeres.
Angiogenesis
FGF and VEGF are commonly produced by tumor cells to supply needed nutrients
Avoiding immune surveillance
Tumor cells can evade immune surveillance by downregulation of expression of MHC I.
Immunodeficiency (primary and secondary) increases the risk for cancer.
Characteristics of Progression of Malignant Neoplasia and Metastasis
Downregulation of E-cadherin –> cadherins normally keep cells attached to each other.
Tumor cells attach to laminin and destroy BM (collegniase type IV)
Attaches to fibronecting –> spreads locally.
Gains access into vascular/lymphatic space.
Lymphatic spread
Characteristic of carcinomas.
Intitial spread is to regional draining lymph nodes (sentinel node)
Hematogenous spread
Characteristic of sarcomas and some carcinomas
Exceptions: Renal Cell carcinoma (renal vein) Hepatocellular carcinoma (hepatic vein) Follicular carcinoma of Thyroid Choriocarcinoma (malignancy of trophoblasts --> cells programmed to find vasculature)
Seeding of body cavities
Characteristic of ovarian carcinoma
Results in “caking” of omentum
Benign tumor clinical features
Slow growing
Well circumscribed
Distinct
Mobile (can move it upon palpation)
Biopsy or excision is required for confirmation
Malignant tumors clinical features
Rapid growing
Poorly circumscribed
Infiltrative (i.e. nerve involvement)
Fixed to surrounding structures.
Biopsy or excision is required for confirmation
Benign tumor histologic features
Well differentiated
Organized growth
Uniform Nuclei
Low nuclear to cytoplasmic ratio
Minimal mitotic activity
Lack of invasion
No metastatic potential
Malignant tumors histologic features
Poorly differentiated
Disorganized growth
Nuclera pleomorphism w/ hyperchromasia
High nuclear to cytoplasmic ratio
High mitotic activity
Invavsion
The absolute distinction between benign and malignant?
Ability to metastasize = malignant.
Immunohistochemistry
Used to characterize malignant tumors that are difficult to classify.
Add antibodies and brown stains for specific cell types.
Keratin Positive
Carcinoma (Malignant epithelium)
Vimentin Positive
Sarcoma (Malignant mesenchyme)
Desmin positive
Muscle
GFAP positive
Neuroglia
Neurofilament positive
Neurons
PSA positive
Prostatic eptihelium
Estrogen Receptor positive
Breast epithelium
Thyroglobulin positive
Thyroid follicular cells
Chromogranin positive
**Neuroendocrine cells (i.e. small cell CA of lung and carcinoid tumors)
S-100 positive
Melanoma
Serum tumor markers
Proteins released by the tumor that can be useful as:
- ) Screening (PSA)
- ) Monitoring response to treatment (PSA CA-19)
- ) Monitoring for recurrence (prostate cancer w/ bone pain after remission –> PSA elevated)
Elevated levels require tissue biopsy for dx of carcinoma because other things can elevate tumor marker.
Grading of cancer
Microscopic assessment of differentiation
Takes into account architectural and nuclear features.
Well differentiated: resembles parent tissue (good prognosis)
Poorly differentiated: does not resemble parent tissue.(poor prognosis)
Important for determining prognosis
Staging of cancer
Key prognostic factor (more important than grading)
Determined after final resection of tumor.
Uses TNM system
T - tumor size (solid organs) or depth (hollow organs)
N - Spread to regional lymph nodes; second most important prognostic factor*
M- Metastasis; MOST IMPORTANT PROGNOSTIC FACTOR**
