Neoplasia Flashcards
What is neoplasia?
Tumor with an abnormal mass of tissue
Cell growth that is triggered by a series of acquired mutations affecting a single cell and its clonal progeny
What are characteristics of neoplasia?
- An abnormal mass of tissue
- Loss of responsiveness to normal growth controls
- Persists in the same excessive manner after the cessation of the stimulus which evoked the change
- Different from hyperplasia
Define parenchyma
Functional tissue of an organ.
Made up of neoplastic cells, determines its biologic behavior
Define reactive stroma
Made up of connective tissue, blood vessels and inflammatory cells, contributes to growth and spread
What are the classifications of a tumor and what are its two basic components?
Benign or malignant classifications
Components:
1. Parenchyma
2. Reactive Stroma
Which type of cell makes benign tumors?
Mesenchymal cells
What is the nomenclature of benign tumors? Give the name examples for:
- Fibrous Tissue
- Fatty Tissue
- Cartilage
- Smooth muscle
- Skeletal muscle
cell +(-oma)
- Fibroma
- Lipoma
- Chondroma
- Leiomyoma
- Rhabdomyoma
What are benign epithelial tumors classified on the basis of?
- Cell origin
- Microscopic pattern
- Macroscopic architecture
What is an adenoma? Give examples
Benign epithelial neoplasms derived from glands may or may not form glandular structures
Ie: Parathyroid Adenoma & Pituitary adenoma
What is a papilloma? Give an example
Benign epithelial neoplasms growing on any surface that produce microscopic or macroscopic finger like pattern
Ie: Squamous cell papilloma
What is a polyp? What is the name if it has glandular tissue?
Mass that projects above a mucosal surface to form a macroscopically visible structure, could be benign or malignant
-> adenomatous polyp
What is the name of malignant tumors arising in solid mesenchymal tissue?
Give examples for:
1. Fibrous Tissue
2. Bone
3. Cartilage
4. Fat
SARCOMA
1. Fibrosarcoma
2. Osteosarcoma
3. Chondrosarcoma
4. Liposarcoma
What is the name of malignant tumors from mesenchymal cells of blood and related cells?
Hematopoietic cells: Leukemias
Lymphoid Tissues: Lymphomas
What is the name of malignant tumors arising from epithelial origin?
What are examples for squamous cells and glandular pattern carcinomas?
CARCINOMA
- Squamous cell carcinomas
- Adenocarcinomas
What are the malignant tumor name exceptions?
- Melanoma
- Mesothelioma (mesothelium)
- Seminoma (testis)
- Lymphoma (lymphoid tissue)
What are mixed tumors? Give an example
Arises from a divergent differentiation of a single neoplastic clone but is always from ONE GERM layer
“Neoplastic cell with 2 different types of cells from one germ layer”
Ie: Salivary Gland tumors: Epithelial components scattered within a myxoid stroma that has cartilage or bone
What is a teratoma? Where does it originate from? What can a teratoma differentiate into?
Has recognizable mature or immature cells or tissues representative of more than one germ- cell layer (can be all three)
Origin: Totipotential cells
Can differentiate into any cell types found in the adult body ie: epithelium, muscle, fat, nerve and other tissues
Which type of teratoma tumor is usually benign? Which type can be malignant?
Benign: Mature tumor
Malignant: Immature (anaplastic) tumor
What is a hamartoma? List an example
Benign mass of disorganized cells indigenous to the particular site
ie: pulmonary hamartoma
What are examples of hamartomas in the eye?
CHRPE: Combined hamartoma of the retina and RPE
Congenital Simple Hamartoma of the RPE
Retinal Astrocytic hamartoma
What is a choristoma? List an example
Mass composed of normal cells in the wrong location
ie: Pancreatic choristoma in liver or stomach
What is an example of an ocular choristoma?
Limbal Dermoid Choristoma
What is the difference between a teratoma and a chroistoma?
Choristoma is normal cells while teratoma are neoplastic cells
What is dysplasia?
A loss in uniformity of the individual cells and a loss in their architectural orientation
Where does dysplasia take place? Which type of cells have dysplasia?
Occurs in the epithelia
Non- neoplastic and dysplastic cells have dysplasia
What do dysplastic cells display?
Pleomorphism- Different cell shape
Hyperchromasia- Cells with darker pigment
Increased mitosis- More cells in the area
What are dysplastic changes that involve the entire thickness of the epithelium called?
Carcinoma in-situ
What are characteristics of carcinoma in situ? Which type of neoplasm does it occur in?
Displays cytological features of malignancy without invasion of the basement membrane thus it can still be benign
Epithelial neoplasms are the only cells with carcinoma in-situ
Does dysplasia mean cancer and if not is it reversible?
Dysplasia does not mean cancer nor does it have to progress into cancer
Dysplasia may be reversible
How does the risk of cancer and dysplasia correlate?
Risk of invasive cancer varies with:
- Grade of dysplasia (mild, moderate, severe)
- Duration of dysplasia
- Site of dysplasia
What is the difference between cancer and dysplasia?
Dysplasia does not invade the basement membrane and is reversible
How are benign and malignant tumors distinguished from one another?
- Degree of differentiation
- Rate of growth
- Local invasiveness
- Distant Spread
What is the connection between differentiation and anaplasia?
Differentiation is the extent to which the parenchymal cells of the tumor resemble their normal counterparts morphologically and functionally
Anaplasia will occur when you can no longer tell which type of cell the parenchymal cells originated from
What are the different degrees of differentiation?
- Well differentiated- closely resemble their normal counterparts
- Moderately differentiated
- Poorly differentiated
- Undifferentiated (Anaplasia)
Which type of differentiation do benign tumors have?
They are well differentiated
Which type of differentiation do malignant tumors have?
They are poorly differentiated and anaplastic
What is the rate of growth for benign and malignant tumors?
Benign tumors: Progressive/ slow they can come to a standstill or regress
Malignant tumors: Erratic and can be slow to rapid
Rate of growth is inversely correlated to level of differentiation
If a malignant tumor has a high degree of differentiation what will its rate of growth be?
The tumor will have a slow rate of growth
What are the local invasion characteristics of benign tumors?
- Remain localized
- Cannot invade but can grow
- Usually encapsulated
What are the local invasion characteristics of malignant tumors?
- Progressive infiltration
- Destruction
- Usually not encapsulated
What is distant spread (metastasis)?
The development of secondary implants discontinuous with the primary tumor, possibly in remote tissues
What percentage of patients present with clinically evident metastases?
30% of patients with newly diagnosed solid tumors (excluding skin cancers other than melanomas)
What increases a tumors chance to metastize?
The more anaplastic -> larger the primary tumor -> higher chance to metastasize
If a tumor can metastasize what type of tumor is it?
Malignant
What are the three pathways of metastasis?
- Seeding of body cavities
- Lymphatic Spread
- Hematogenous Spread
What are the body cavities that tumors can metastasize to?
Pleural cavities
Peritoneal cavities
Cerebral ventricles
What is lymphatic spread? Which type of malignancy favors this route?
What are examples?
The malignancy is spread via the route of drainage
Favored by Epithelial Carcinomas
ie:
- Breast Carcinoma -> axillary lymph nodes
- Lung Carcinoma -> bronchial lymph nodes
What is hematogenous spread? Which type of malignancy favors this route?
What are examples?
The malignancy is spread via blood
Favored by sarcomas and used by carcinomas
Which structure is most commonly invaded by with hematogenous spead?
Veins and the liver/ lungs are the most frequently involved secondary sites
What are characteristics of benign tumors?
Remain localized
Cannot spread to distant sites
Generally can be locally excised
Patient generally survives
What are characteristics of malignant neoplasms?
Can invade and destroy structure
Can spread to distant sites
Cause death (if not treated)
Are cancers more sporadic or familial?
Sporadic
Which disease is known to be associated with an increased risk for development of cancer?
Preneoplastic disorders
What is a benign tumor in the ovaries associated with and what is another name for it?
Leiomyoma
-Small
- Well demarcated
- Slow growing
- Noninvasive
-Nonmetastatic
- Well differentiated
What is a malignant tumor in the ovaries associated with and what is another name for it?
Leiomyosarcoma
- Large
- Poorly demarcated
- Rapidly growing w/ hemorrhage and necrosis
- Locally invasive
- Metastatic
- Poorly differentiated
What are the #1 and #2 leading causes of death in the US?
- Heart Disease
- Cancer
What are the most common cancers for men?
- Prostate
- Lung
- Colorectal
What are the most common cancers for women?
- Breast
- Lung
- Colorectal
How many new cancer cases were there in 2020 and how many people died from cancer?
1.8 million new cancer cases
606,520 died of cancer
What are the top risk factors for cancer?
- Age
- Genetic predisposition
- Gender
- Geographic/ environmental
- Occupational/ exposure
- Nonhereditary predisposing conditions
What are common associated cancers with young age?
Neuroblastoma
Retinoblastoma
Wilms Tumor
What are common associated cancers with older age?
Prostate cancer
Thyroid Cancer
Colon Cancer
What is an example of exclusive gender cancer?
Prostate cancer in men and ovarian cancer in women
What is an example of preferred gender cancer?
Breast cancer in women
What are examples of geographic/ environmental risk factors for cancer?
Name a specific country example
Infectious agents
Smoking
Alcohol consumption
Diet
Obesity
Reproductive history
Environmental carcinogens
Japan -> gastric cancer
US -> colon cancer
What are examples of occupational/ exposure cancers?
Asbestos -> mesothelioma
Radiation -> Thyroid Cancer
What are example of nonhereditary predisposing conditions?
- Chronic inflammation: Ulcerative colitis -> color cancer
- Precancerous Lesions: Adenoma -> colon cancer
- Immunodeficiency State
- Important because T cells kill cancer and can detect abnormal cancer so if they’re not functioning correctly then cancer can invade.
- If immune system is normal then cancer can still learn how to invade/ escape the immune system
What are four classes of normal regulatory genes?
- Proto-oncogenes- normal cellular genes whose products promote cell proliferation
- Growth inhibiting tumor suppressor genes
- DNA repair genes
- Apoptosis genes
What is the molecular basis of Cancer?
- Nonlethal genetic damage (if lethal cell would have died -> no cancer)
- Tumor formed by clonal expansion of a single precursor cell (monoclonal)
- Mutations/ over expression of the normal regulatory genes
Can one oncogene cause cancer?
NO
Several oncogenes and several tumor suppressor genes must be involved
What is an oncogene?
Mutated or over expressed version of proto-oncogenes
What is tumor progression?
⭐Heterogeneity⭐ from original single cell
What is angiogenesis?
Blood vessel growth
What is the pathway to a malignant neoplasm?
What are carcinogenic agents?
- Chemicals
- Radiant Energy
- Microbial Agents
What are the first two steps of carcinogenesis?
- Initiation
- Promotion
Can just an initiator cause cancer?
NO
Both initiators and promoters are needed and promotion must occur after initiation
What do initiators do?
They are carcinogens that inflict nonlethal damage to the DNA that cannot be repaired
What do promoters do?
Enhance proliferation of initiated cells and can induce tumors to arise from initiated cells
What do indirect acting compounds require? And what are they?
Pro carcinogens that leads to mutations in cells by affecting the functions of oncogenes, tumor suppressor genes and apoptotic genes.
- Require metabolic conversion IN VIVO to produce carcinogens that can transform cells
What are the promoters of chemical carcinogenes?
- Hormones
- Phorbol esters
- Phenols
- Drugs
What are examples of radiation carcinogens?
Which type of mutations does it produce?
Which type of cancers does it produce?
UVB and Ionizing Radiation (X-rays, Gamma rays, alpha/beta particles, protons, neutrons)
Mutations via UVB: Pyrimidine dimers in DNA and Xeroderma pigmentosum
Mutations via ionizing radiation: Chromosome breaks, translocations, point mutations
UVB Cancers: Basal cell carcinoma, squamous cell carcinoma, melanoma
Ionization radiation Cancers: Thyroid cancer, lung cancer, leukemia
What are examples of viral carcinogens (6) and which type of cancer do they produce?
- Human Papillovirus (HPV)- Cervical Carcinoma
- Epstein- Barr Virus (EBV) Burkitt Lymphoma
- Hepatitis B&C (HBV & HCV)- Liver Cancer
- Human T cell leukemia (HTLV1-> T cell leukemia/ lymphoma)
- Kaposi’s sarcoma herpes (KSHV)- Kaposi Sarcoma
- Merkel Cell Polyomavirus (MCPyV)- Merkel Cell Carcinoma
Which bacteria are associated with cancer?
Only 1
- H. Pylori-> gastric carcinomas/ gastric lymphomas
- Stomach Ulcers
What are the different type of gene mutations?
Which mutation is most associated with cancer?
- Point
- Translocation
- Deletions
- Amplifications
- Overexpression
What are the genetic lesions that lead to cancer?
- miRNA involvement- Negative regulators of genes
- Epigenetic changes
What occurs with miRNA to cause cancer development?
Overexpression of miRNA -> reduces tumor suppressor proteins-> increases risk of cancer
Deletion/ loss of expression of miRNA -> overexpression of oncogenes-> increases risk of cancer
What are epigenetic changes?
Hypermethylation of promoter sequences for tumor suppressing genes and DNA repair genes -> inhibits transcription of TUMOR SUPRESSING GENES -> increases risk of cancer
What is the common mutation that leads to cancer?
Which cancer has this mechanism?
What is the mutation called?
What is given as treatment?
Which two chromosomes are involved?
Chromosomal translocation
Found in Chronic Myelogenous Leukemia
Philadelphia chromosome- shortened chromosome #22 that causes phosphorylation of RAS -> Cancer
Tx= Tyrosine Kinase Inhibitors
Chromosomes 9 and 22
What all do oncogenes involve?
Mutations in:
Growth factors
Growth factor receptors
Signal Transduction Proteins
Nuclear Regulatory Factors
Cell Cycle Regulators
What are the steps of the normal cell cycle? What occurs if their is corruption in one of these cells?
- Binding of growth factor to receptor
- Transient, limited activation of receptor, initiating signal transduction on plasma membrane
- Transmission of signal through second messengers to nucleus
- Entry and progression into cell cycle with induction and activation of nuclear regulatory factors that initiate DNA transcription
- Mitosis and cell division
Cancer!!
Which types of cells release growth factors to neighboring cells? And what is the action called?
Which types of cells release growth factors to themselves? And what is the action called?- What are examples of this action?
Normal Cells- Paracrine Action
Cancer Cells- Autocrine Action
Ie: Glioblastomas secreting PDGF with PDGF receptor
- Sarcomas with transforming growth factor-a (TGF-a) and its receptor
What are modes of activation of proto-oncogenes for growth factors?
Overexpression
Amplification
What are modes of activation of proto-oncogenes for growth factor receptors?
Overexpression
Amplification
Point Mutation
What happens during receptor tyrosine kinase signaling in cancer?
Which types of mutations cause this?
What enzyme can inhibit this process?
Ras is normally transient between being action & inactive due to the hydrolysis of GTP -> GDP via GAP (GTPase activating protein) but during cancer tyrosine kinase phosphorylates RAS and keeps it active which leads to activation of transcription
Mutation of GAP or RAS
What is the single most common abnormality of dominant oncogenes in human tumors?
Which is the most common popular signal transduction protein?
RAS mutation occurs in 1/3 of all cancers
- RAS is a member of small G proteins that binds guanosine nucleotides and flips between resting GDP to active GTP
RAS
What are modes of activation of proto-oncogenes for signal transduction proteins?
Point mutation
Translocation ie: Nonreceptor Tyrosine Kinase
What is a nuclear regulatory factor seen in cancer?
What is activated with this factor?
What is repressed with this factor?
MYC transcription factor
- MYC encodes a gene that can activate or repress the transcription of genes due to its role in cell cycle progression and apoptosis
MYC activates cyclin dependent kinases (CDK) -> promote cell proliferation
MYC inhibits CDK inhibitors (CDKIs) > promotes cell proliferation
What are modes of activation of proto-oncogenes for nuclear regulatory proteins?
Translocation
Amplification
What are cell cycle regulators? (Slide skipped)
Cyclins and cyclin dependent kinases
What are examples of cell cycle checkpoints?
Which inhibitors occur between G1 and S phase?
Which inhibitors occur between S and G2 phase?
Which inhibitors occur between G2 and M phase?
What is mutation that leads to cancer?
CDK inhibitors and RB
RB, CDK4 & CDK6
CDK2 and CDK1
CDK1
Phosphorylation of RB
What is the function of tumor suppressor genes?
What is the difference in destruction of tumor suppressor genes vs oncogenes?
Encode proteins which inhibit cellular proliferation by regulating the cell cycle
In tumor suppressor genes BOTH copies of the gene must be dysfunctional for tumor development to occur
What are some examples of common tumor suppressor mutations that can lead to cancer?
RB- stops cell proliferation -> retinoblastoma and other cancers
p53- stops cell proliferation-> all cancers
BRCA-1,2 -> Breast Cancer
What is the RB gene known as?
What type of RB loss leads to cancer? Which type of cancers are seen with RB?
Governor of cell cycle
Homozygous loss of this gene causes retinoblastoma
Breast cancer, small cell cancer, and bladder cancer seen
What is the mechanism of RB?
Rb has antiproliferative effects by controlling G1-> S transition
- When inactive Rb binds to E2F transcription factor which prevents transcription of genes like Cyclin E which is needed for DNA replication leading to cells being arrested in G1
What a common mutated tumor suppressor gene ?
-What is its role?
How common (%) is it found in human cancers?
What is capable of incapacitating TP53?
TP53
- Senses internal stress
TP53 is mutated in more than 70% of all human cancers
p53 is incapacitated by binding to proteins encoded by oncogenic DNA viruses ie: HPV
What are the 3 mechanisms TP53 performs on the cell cycle in response to internal stress?
- Activates temporary cell cycle arrest (Quiescence)
- Induces permanent cell cycle arrest (Senescence)
- Triggers programmed cell death (apoptosis)
What are common apoptosis gene mutations found in cancer?
What is the common anti apoptotic gene found in B lymphomas? What is its mutation mode?
BAX, BAK, BCL2, BCL-X, P53, MYC gene mutations lead to evasion of cell death
BCL2 found in follicular B cell lymphomas by translocation
Which enzyme causes limitless replication?
How common is it in cancer (%)?
Telomerase changes telomeres so they have unlimited replicative potential
Found in 90% of human cancers
Which is the mechanism of sustained angiogenesis?
Which genes can inhibit this mechanism?
Hypoxia triggers angiogenesis via HIF-1a on the transcription of pro-angiogenic factor VEGF.
- Von Hippel- Lindau (VHL) is a tumor suppressor that can degrade HIF-1a and prevent angiogenesis
- Angiogenesis inhibitor TSP-1 activated by p53 regulates angiogenesis
What are antitumor effector mechansisms?
Cytotoxic T Lymphocytes (CTL)
Natural Killer Cells
Macrophages- elicited by secretion of IFNy
How do tumor cells escape immune surveillance?
- Selective outgrowth of antigen negative variants (T cells can’t detect them)
- Loss or reduced expression of MHC molecules
- Activation of immunoregulatory pathways
- Secretion of immunosuppressive factors by cancer cells
- Induction of regulatory T cells
What are invasion factors? What are they involved in?
- Detachment (loosening of cell-cell contacts)
- Attachment to ECM components
- Degradation of ECM
- Migration of tumor cells
- Invasion factors invade and metastasize
What is the invasion/ metasis pathway?
- Transformation
- Growth
- BM invasion
- Angiogenesis
- Intravasation
- Embolization
- Adhesion
- Extravasation
- Metastatic Growth
How do tumor cells invade and metastasize?
-What are examples?
Proteolytic enzymes are secreted by tumor cells and stromal cells which degrade the basement membrane and interstitial matrix
MMPs- break down the ECM
Cathepsins- Proteins that break down the stroma
How can the metastatic site be predicted?
What are the two most common sites?
Metastatic site is predicted by the location of the primary tumor and its blood flow.
Many tumors arrest in the first capillary bed they encounter
Lung and Liver are most common
What are the hallmarks of cancer?
- Insensitivity to anti-growth signals
- Tissue invasion and metastasis
- Limitless replicative potential
- Sustained angiogenesis
- Evading apoptosis
- Self sufficiency in growth signals
What causes variation of the effects of a tumor on a host?
What is an eye related example
- Location -> anatomic encroachment
- Hormone
- Infection, Bleeding
- ACUTE symptoms ie: rupture, infarction
- Metastases
Ie: A benign pituitary tumor can affect the optic nerve and cause visual field defects
What is cachexia?
What contributes to cachexia?
Equal loss of both fat and lean muscle
Profound weakness, anorexia and anemia which provides evidence of systemic inflammation
- Release of TNFa contributes to cachexia
- PIF (Proteolysis inducing factor) released from tumor cells -> loss of muscle mass
What is the difference between grading and staging?
Which is most important?
Grading is how differentiated the cells are
Staging is how much anatomic extension (TNM) there is
Staging
What is TNM? What are the values?
T= primary tumor size (0-4)
N= regional lymph node involvement (0-3)
M= Metastases (0-2)
- Scale is 0-4 in general
What are paraneoplastic syndromes?
What is an example?
Is metastasis involved?
Syndromes not typical of the original tumor that can’t be explained by tumor spread or release of hormones that are indigenous to the tumor.
The symptoms will mimic another disease so knowing a tumor’s paraneoplastic syndromes can help you detect the original tumor’s location.
Cushing syndrome
No METASTASIS
What are the retinopathies from paraneoplastic syndromes that involve the visual system?
- Cancer- Associated Retinopathy (CAR)
- Melanoma- Associated Retinopathy (MAR)
- Paraneoplastic vitelliform maculopathy (PVM)
- Bilateral diffuse uveal melanocytic proliferation (BDUMP)
- Paraneoplastic Optic Neuropathy
- These cancers release something which in turn affects the eye. Not from METASTASIS to the eye
What are the lab processes for sampling a tumor?
- Excision/ Biopsy
- Fine needle aspiration- If palpable tumor
- Cytologic Smears
How can immunochemistry be useful for detecting a tumor?
It can be used to find antigens on the tumor that correspond to the metastatic tumors origin since the cells were so undifferentiated
It is also used for detection of molecules that can have prognostic or therapeutic significance ie: Estrogen/ Progesterone receptor
What are the molecular diagnostic tests for tumors?
Molecular analyses are used to determine diagnosis, prognosis, and the detection of minimal residual disease, and the hereditary predisposition to cancer
Ie: PCR & DNA microarrays
What is the benefit of micro-arrays?
You can test multiple DNAs at one time
- Thousands of genes identified from the tumors give their cells their own FINGERPRINT which can help with therapy guidelines
What type of test is used for tumor markers?
What occurs in this test?
Biochemical assays
- Proteins released by tumors into serum can be used to screen populations for cancer and to monitor the chance of cancer coming back after treatment
-Certain proteins are elevated in certain cancers
