Neoplasia Flashcards
Choristoma
Heterotopia
Normal tissues in abnormal location
Ectopic Tissue
developmental abnormality, results in a lesion
Hyperplasia
increase in cell number in response to a stimulus
only in cells with capacity to divide
epithelial cells in breast during pregnancy
hepatocytes to regenerate liver parenchyma after partial resection
prostatic hyperplasia in older men from androgens
endometrial hyperplasia in postmenopausal women receiving estrogens
Metaplasia
replacement of one type of normal adult cell/tissue by another normal cell/tissue
squamous metaplasia in bronchial epithelium (smoking…)
intestinal metaplasia in stomach (H.pylori)
Epithelial tissues
Squamous, urothelium, glandular
Nomenclature of Neoplasms
Epithelial (most common)
Squamous
squamous papilloma - squamous cell carcinoma
Nomenclature of Neoplasms
Epithelial (most common)
urothelium
urothelial papilloma - urothelial carcinoma
Nomenclature of Neoplasms
Epithelial (most common)
glandular
adenoma, papillary adenoma - adenocarcinoma
Nomenclature of Neoplasms
Melanocytes
Nevus - melanoma
Nomenclature of Neoplasms
Germ Cells
benign cystic teratoma - dysgerminoma
Nomenclature of Neoplasms
Mesenchymal (solid tissues)
Fibroblasts
fibroma - fibrosarcoma
Nomenclature of Neoplasms
Mesenchymal (solid tissues)
Adipocytes (fat cells)
lipoma - liposarcoma
Nomenclature of Neoplasms
Mesenchymal (solid tissues)
Smooth muscle cells:
leiomyoma - leiomyosarcoma
Nomenclature of Neoplasms
Mesenchymal (solid tissues)
Endothelium
hemangioma - angiosarcoma
Nomenclature of Neoplasms
Mesenchymal (solid tissues)
Osteocytes
Osteoma- osteosarcoma
What are the mesenchymal tissues?
Fibroblasts, adipocytes, smooth muscle cells, endothelium, osteocytes
Nomenclature of Neoplasms
Bone marrow/lymphoid
Hematopoietic cells
None - leukemia
Nomenclature of Neoplasms
Bone marrow/lymphoid
Lymphoid cells
None - lymphoma
Nomenclature of Neoplasms
Mixed Tumours
Breast
Fibroadenoma - phyllodes tumor
Microscopic morphology of neoplasias
Abnormal cytology/ cellular atypia or pleomorphism
Nucleus: hyperchromasia, increased size and N/C ratio, increased and abnormal mitoses (e.g.,tripolar), more prominent nucleoli
Cytoplasm: loss of normal features, more basophilic (more RNA)
Malignant neoplasms = cancers characteristics
aggressive and fast growing
- invasion (infiltrate and destroy surrounding tissues)
- metastatic potential
Nomenclature for neoplasms
oma = suffix for neoplasm
carcinoma = malignant epithelial neoplasm
sarcoma = malignant mesenchymal neoplasm
lymphoma, melanoma, seminoma, dygerminoma = malignant by definition
some carcinomas have VERY low metastasic potential, like basal cell carcinoma of the skin
Carcinoma vs Sarcoma
Incidence
Carcinoma: More common
Sarcoma: Less Common
Carcinoma vs Sarcoma
Age
Carcinoma: Increase with age
Sarcoma: Younger, bimodal
Carcinoma vs Sarcoma
Etiology
Carcinoma: generally known, environmental (drinking, smoking…) , viral
Sarcoma: viral unknown (maybe genetic?)
Carcinoma vs Sarcoma
Metastatic Spread
Carcinoma: Lymphatics, then hematogenous
Sarcoma: Hematogenous (BLOOD)
Carcinoma vs Sarcoma (morphology)
Macroscopy
Carcinoma: Variably hard
Sarcoma: Fleshy, firm
Carcinoma vs Sarcoma (morphology)
Microscopy
Histology
Carcinoma: Form islands of cells separated by stroma
Sarcoma: Sheets of spindle cells admixed with stroma between cells
Carcinoma vs Sarcoma (morphology)
Microscopy
Histochemistry
Carcinoma: Epithelial: e.g., mucin
Sarcoma: mesenchymal: fat, etc.
Carcinoma vs Sarcoma (morphology)
Microscopy
Immunohistochemistry
Carcinoma: Keratins
Sarcoma: Vimentin, muscle actin
How do we measure proliferation rates?
Using Ki67 proliferation marker
follicular lymphoma is SLOW
Burkitt lymphoma is FAST
Sequence of development of carcinoma of the cervix
well-defined sequence of development of carcinomas!
- Normal mucosa
- Dysplasia (some abnormality), aka CIN = cervical intraepithelial neoplasia
- Carcinoma-in-situ (whole layer is abnormal)
- Invasive squamous cell carcinoma (broken through basement membrane, can go to lymphatics and metastasize)
Grading of MALIGNANT neoplasms, purpose
determines degree of differentiation
differentiation = resemblance to normal
de-differentation: loss of resemblance, to a variable degree
anaplasia = complete de-differentation – no resemblance
prognostic and therapeutic implications
Grading of MALIGNANT neoplasms, HOW
light microscopy, based on cytology and histology
Grade 1: >75%
Grade 2: 50-75%
Grade 3: 25-50%
Grade 4: <25% differentiated
low grade = grade 1 = well differentiated= better prognosis
Grading parameters to assess in…
- Squamous CA
- Adenocarcinoma
- amount keratin, intercellular bridges
- quantity of glands, mucin
Routes of metastases (3)
- Lymphatic vessels to lymph nodes
- Blood vessels (hematogenous)
- Transcoelomic (seeding via body cavities)
Staging of neoplasms
Determination of size and extent of spread
correlates to survival
TNM system
Staging
Primary TUMOR size, characteristics
presence of absence of lymph NODE metastases
presence or absence of distant METASTASES
Distant metastases == automatically stage 4
Tumor markers
CA in blood
CEA (carcinoembryonic antigen) in colon carcinoma
AFP (alpha-fetoprotein) in hepatocellular carcinoma, germ cell tumours
PSA (prostate specific antigen) in prostate carcinoma
types of cancers with highest incidence in males
- Prostate
- Lung and Bronchus
- Colon and rectum
types of cancers with highest incidence in females
- breast
- Lung and Bronchus
- Colon and rectum
Cancer deaths
- Lung and Bronchus
- Prostate (males) and Breast (females)
- Colon and Rectum
Exogenous Cancer Etiologies
- Chemical carcinogens
- Physical agents: radiation – electromagnetic, UV, and ionizing
- Biological agents: Viruses (e.g., HPV), bacteria, parasites
Endogenous cancer etiologies
- Heredity
- Gender and Hormones
- Altered Immunity (Age, immunosuppressant drugs, immune deficiency states (e.g., AIDS…))
Principal Causes of human cancer
(Top 3 are most important)
25% - Tobacco
25% - Diet
20% - Sexual behaviour, infections
7% - Industrial occupation, pollution
3% - Alcohol
3% - Radiation
Chemical carcinogenesis
- Initiator - mutagenic and induce potentially heritable DNA damage
they can be direct, requiring NO metabolic conversion, or indirect, the opposite
- Promoters - not mutagenic, increase proliferation, including of cells with DNA mutations, favouring tumor growth
What are the 3 classes of Medicinal Drugs that can act as carcinogens
- Anti-cancer drugs
- Horomones/related
- Immunosuppressants
What are the 4 groups to classify carcinogens?
Group 1: carcinogenic to human (128)
Group 2: A(95)/B(323)- probably carcinogenic to humans
Group 3: not classifiable as to carcinogenicity in humans (500)
Medicinal Drugs as carcinogens
Anti-cancer drugs
busulphan, chlorambucil, cyclophosphamide, etopside: leukemia ± bladder carcinoma
Medicinal Drugs as carcinogens
Horomones/related
estrogens: breast, uterus…
tamoxifen: uterus
DES: cervix, vagina
Medicinal Drugs as carcinogens
Immunosuppressants
cyclosporine: lymphoma, kaposi sarcoma
azathioprine: lymphoma, skin tumours
Ionizing radiation and cancer
x rays, gamma rays, alpha and beta particles
hiroshima/nagasake = leukemia, breast, thyroid
radionuclides in occupation: lung, thyroid, liver CA, sarcomas and leukemias
Chernobyl = thyroid
how? through damaging chromosomes, translocations, mutations
UV radiation
skin basal cell and squamous cell CA, melanomas
forming pyrimidine dimers, damaging DNA, overwhelming DNA repair mechanisms
Electromagnetic fields (low frequency)
possibly carcinogenic (group 2bB): leukemia in children, data in adults is questionable
Chronic infections and cancer
First link discovered by Rous, chicken sarcoma
18% of cancers worldwide, mostly developing countries
carcinogenicity may be: direct via oncogenic protein, indirect via inflammation, cell damage and regeneration with ensuing proliferation
Asbestos
Occupational chemical carcinogen
causes lung and mesothelium cancer
lung: coetiological with smoking
mesothelium: good, they can get worker’s comp
industry: insulation, textiles
Arsenic
occupational chemical carcinogen
causes skin and ling cancer
in glass, pesticides and metals
HPV
Cervix, oral Ca, etc
HBV and HCV
Liver CA
EBV
lymphoma, nasopharyngeal CA
HHV-8
Kaposi SA, lymphoma
HTLV-1
Leukemia
Merkel CA polyoma virus
Merkel cell carcinoma
Schistomiasis
Bladder CA
indirect effect
H. pylori
Gastric CA, lymphoma
indirect effect - bacteria, causing cell damage, inflammation, cytokines
Liver flukes
cholangioCA
indirect effect
HIV
lymphoma, Kaposi
indirect effect - immunosuppression
Cancer stem cells
capable of self-renewal
potentially arise from transformation of normal or differentiated stem cells
must be eliminated to cure a cancer but are resistant to therapy: low rate of replication (bad with drugs that target rapidly diving cells), multiple drug resistance 1 expression (MDR-1) that counter drug effects
Driver versus passenger mutations
Driver: alter function of cancer genes, with direct control, clustered
passenger: random, do not affect behaviour, but may provide a selective advantage e.g., after therapy
Hallmarks of Cancer (8)
- Unrestricted proliferation w/o external stimuli - ONCOGENES
- Insensitivity to growth inhibitory signals
- TUMOR SUPPRESSOR GENES - Altered Cell Metabolism
- Evasion of Apoptosis
alterations in tumor suppressor (p53) and anti-apoptotic genes (BCL2) - Unlimited replicative potential
activation of telomerase
5.Sustained angiogenesis - Invasion and metastasis
- Evasion of immune surveillance
- Defects in DNA repair, leading to genomic instability, facilitating mutations
What is an autocrine loop? Provide an example
Cancer cells make their own growth factor to stimulate their own surface receptors
example: PDGF (platelet-derived growth factor) secreted by glioblastomas
What can oncogenes be?
- Growth factors (PGDF)
- Growth factor receptors (Her2)
- Signal transduction proteins (Ras)
- Nuclear TFs (Myc)
- Cyclins and CDKs (breast hepatic and esophageal cancers and mantle cell lymphomas have cyclin D over expression)
Burkitt lymphoma translocation
Translocation between chromosomes 8 and 14
MYC activity is regulated by IgH regulatory region = thus always on in the lymphocytes
Roles of Wild p53 protein
Arrests cell cycle in late G1 via CDK inhibitor p21
Assists in DNA repair
Apoptosis if DNA cannot be repaired
Angiogenesis inhibitor via thrombospondin-1
Mutated p53
Genetic: Li-Fraumeni syndrome, SAs, leukemias, breast and adrenal cortical CAs
Somatic, homozygous, in breast, lung and colon CAs
Follicular lymphoma translocation
Translocation between chromosomes 18 and 14
BCL2 activity is regulated by IgH regulatory region = thus always on in the lymphocytes
BCL2 inhibits apoptosis = overexpression leads to rescue of lymphocytes == malignancy
helpful to identify follicular lymphoma versus follicular hyperplasia
What is angiogenesis? What is it required for?
Process of BV neoformation from preexisting vasculature
Required for tumor to grow beyond 1-2mm in diameter
Occurs by disruption in balance between angiogenic factors and angiogenic inhibitors
Angiogenic factors include…
Growth factors (VEGF, FGF2, PDGF)
Mutated p53
Angiogenic inhibitors include…
Thrombospondin-1, endostatin, angiostatin
Wild p53
5 stimuli for angiogenesis
- Tissue ischemia
- Tissue hypoxia
- Tissue injury
- Inflammation
- Shear stress
chronology of neovasculatization (8 steps)
- basement membrane of parent vessel is DEGRADED
- ECs move to angiogenic stimulus (chemotaxis)
- elongation and alignment of ECs: capillary sprout
- EC proloferation in parent and offspring
- Lumen formation
- Anastomosis of 2 hollow sprouts to form loop
- Onset of blood flow
- Basement membrane produced, pericytes added
Vascular endothelial growth factor (VEGF)
What is it?
growth factor acting on surface of endothelial cells via surface receptors (mains is VEGFR-2)
Vascular endothelial growth factor (VEGF)
Sources?
Inflammatory cells, various neoplasms
Vascular endothelial growth factor (VEGF)
Unregulated by?
Hypoxia (analogous to EPO)
Cytokines, hormones, other growth factors.
Vascular endothelial growth factor (VEGF)
Actions?
Mitogenesis and maintenance ECS
Anti-immune: decrease maturation of dendritic cells
Vascular: vasodilation via NO pathways, fenestrations in EC
Clinical applications of angiogenesis
- Radiologists use their properties to visualize them on angiograms, CT scans, etc
- abnormally permeable vessels explain high protein content (exudate) and hemorrhagic nature of malignant effusions in peritoneal, pericardial and pleural cavities – ascites in ovarian cancer
- inhibitor Avastin used in treatment
DNA repair defects (3)
- mismatch excision repair (MMR) (MSH2, MLH1, PMS1, PMS2) - hereditary non-polyposis colon cancer
- nucleotide excision repair
- recombination repair
Multistep carcinogenic sequence in gastric carcinoma
- Infection with H. pylori or pernicious anemia (immunologic)
- Chronic gastritis
- Intestinal metaplasia
- Dysplasia/CIS
- Adenocarcinoma
