04 - Neoplasia Flashcards
Hypertrophy
adaptation defined by increase in size of cell. May enlarge whole organ.
Hyperplasia
defined by increase in number of cells in a tissue or organ
Hamartoma
a developmental malformation consisting of a disorganized mass of tissue native to the site. A hamartoma stops growing when the host stops growing
Metaplasia
an adaptation defined by substitution of one type of “adult” cell for another
Dysplasia
a change in cell differentiation and morphology such that the atypical cells show loss of uniformity, abnormal cell to cell orientation, and loss of maturity
-oma
Suffix “oma” alone – indicates a benign neoplasm.
Sarcoma
a malignant neoplasm of mesenchymal origin (from mesoderm)
Carcinoma
indicates a malignant neoplasm of epithelial origin (from ectoderm or endoderm).
“adeno”
indicates neoplasm is derived from a gland.
a. Adenoma – indicates a benign epithelial neoplasm derived from glandular tissue.
b. Adenocarcinoma – indicates a malignant epithelial neoplasm with origin from a gland
Papillo
indicates a surface growth having finger-like projections
Cyst
indicates growth has a cavity lined by epithelium
Fibrous tissue
Fibroma
Fibrosarcoma
Myxomatous tissue
Myxoma
Myxosarcoma
Cartilage tissue
Condroma
Chondrosarcoma
Renal tubule adenoma
Benign tumor of renal parenchyma/tubular epithelium
Renal cell carcinoma
Malignant tumore of renal parenchyma/tubular epithelium
Liver cell adenoma
Benign tumor of liver parenchyma (hepatocytes)
Heptocellular carcinoma
Malignant tumor of liver parenchyma (hepatocytes)
Nevus
Benign tumor of Neuroectoderm (melanocytes)
Melanoma
Malignant tumor of Neuroectoderm (melanocytes)
Hydatidiform mole
Benign tumor of Placental epithelium (trophoblasts)
Choriocarcinoma
Malignant tumor of Placental epithelium (trophoblasts)
Seminoma
Malignant tumor of Testicular epithelium (germ cells)
Embryonal carcinoma
Malignant tumor of Testicular epithelium (germ cells)
Example of a mixed neoplasm, derived from one germ layer, composed of more than one morphilogical cell type
Pleomorphic adenoma
Malignant mixed tumor
Wilms tumor
Pleomorphic adenoma
Benign tumor of Salivary glands
Malignant mixed tumor
Malignant tumor of
Wilms tumor
Malignant tumor of Renal anlage
Example of a teratogenous neoplasm, derived from totipotential cells
Benign cystic teratoma Immature teratoma (teratocarcinoma)
Benign cystic teratoma
Benign tumor of gonads
Immature teratoma (teratocarcinoma)
Malignant tumor of gonads
Characteristics of tumor cells
- Unrestrained growth, with decreased requirements on growth control from host
- Derived from one cell
- Heterogeneous in genetic expression
- Altered morphology
- New surface antigens
- Can be invasive
- Can be metastatic
Bening vs Malignant
Benign
- Cytologic and gross characteristics are relatively innocent.
- Lesion remains localized.(CAPSULE)
- Lesion is very amenable to local surgical removal.
- Patient usually survives
Malignant
- Neoplasm has potential to invade and destroy surrounding tissue.
- Neoplasm growth is out of control.
- Neoplasm is capable of spreading to distant sites (metastasis).
- Neoplasm is capable of causing significant host morbidity and mortality.
Indicators of malignancy?
Ranked
Metastasis
Local invasion, mode of growth (expansive vs invasive)
Differentiation + altered cytologic features
Rate of growth (NOT used for dx)
Lymphatic metastasis
a. Carcinomas prefer this as the initial route of metastasis.
b. Metastasis is usually to regional lymph nodes first
Hematogenous Metastasis
a. Sarcomas prefer this route of metastasis.
b. The liver and lungs are the most frequently involved secondary sites for hematogenous dissemination
Most common cancers in men?
Top 3 deadliest in men?
Common: Prostate, Lung/bronchus, Colon + rectum
Deadliest: Lung/bronchus, prostate, colon + rectum
Most common cancers in women?
Top 3 deadliest in women?
Common: Breast, Lung/bronchus, Colon + rectum
Deadliest: Lung/bronchus, breast, colon + rectum
What is the fundamental principle of carcinogenesis?
Non-lethal genetic damage lies at the heart of carcinogenesis. These mutations may be acquired from the environment or may be inherited in the germ line.
What classes of regulatory genes are principle targets of genetic damage that can lead to carcinogenesis?
a. Growth-promoting proto-oncogenes – dominant mechanism – Mutant allele of a proto-oncogene will transform cells even when the other allele is normal.
b. Growth-inhibiting tumor suppressor genes (antioncogenes) – Both alleles of antioncogenes (tumor suppressor genes) must be mutant for malignant transformation to occur. Therefore, these are called recessive oncogenes.
c. Genes that regulate programmed cell death (apoptosis) – Genes that regulate apoptosis may be dominant, or may behave as cancer suppressor genes.
d. Genes involved in DNA repair – A disability in these genes can predispose to widespread mutations in the genome. DNA repair genes affect cell proliferation or survival indirectly.
What are the seven fundamental physiologic changes that dictate the malignant phenotype?
- Self-sufficiency in Growth Signals
- Insensitivity to Growth Inhibitory Signals
- Evasion of Cell Death
- Limitless Replicative Potential
- Development of Sustained Angiogenesis
- Ability to Invade and Metastasize
- Genomic instability
What strategies are used by cancer cells to acquire self-sufficiency in growth signals?
1) Growth factors – some cancer cells acquire the ability to synthesize growth factors they need for self-sufficiency. Examples: PDGF, TGF-α
2) Growth factor receptors
a) Mutations in these receptors may allow continuous mitogenic signals.
b) Over expression of growth factor receptors may allow cancer cells to proliferate in presence of only small amounts of growth factor.
c) Examples: ERBB1, a receptor for EGF
3) Signal transducing proteins – common mechanism allowing growth autonomy
a) Example: RAS – the most commonly mutated proto-oncogene in humans
4) Nuclear transcription factors – mutations affecting genes that regulate transcription of DNA. Example: MYC
5) Cyclin and cyclin-dependent kinases
a) Mutations that dysregulate activity of cyclins and CDKs favor cell proliferation.
b) Examples: Abnormal expression of cyclin D, CDK4
How do cancer cells become insensitive to growth inhibitory signals?
a. Disruption of growth inhibitory cancer suppressor genes has growth promoting effects.
b. Two mutations are required to inactivate effects of tumor suppressor genes.
c. Examples:
1) RB gene – the first cancer suppressor gene identified
2) p53 gene – one of most commonly mutated cancer suppressor genes
a) p53 arrests the cell cycle and induces apoptosis in cells with damaged DNA.
b) Mutations in p53 allows cells with damaged DNA to live and replicate.
c) Proteins encoded by oncogenic viruses (such as HPV, HBV and EBV) can bind to normal p53 proteins and nullify their protective functions.
What are some features of chemical carcinogens?
b. Direct-reacting agents require no chemical transformation to induce carcinogenicity.
c. Indirect-reacting agents become active only after metabolic conversion. They are called procarcinogens and their products are called ultimate carcinogens.
d. All direct-acting and ultimate chemical carcinogens are highly reactive electrophiles that react with the electron-rich atoms in RNA, cellular proteins, and DNA.
e. Carcinogenicity of some chemical can be augmented by promoters.
What are examples of known chemical carcinogens?
a. Benz[a]anthracene
b. Benzo[a]pyrene
c. β-naphthylamine
d. Nitrosamines
e. Aflatoxin B1
Give an example of an RNA virus that is linked to cancer (oncogenic)
Human T-cell leukemia virus-1 (HTLV-1)
Hep C virus
Give an example of an DNA virus that is linked to cancer (oncogenic)
a. Human papilloma virus (HPV) is associated with squamous cell carcinoma.
b. Epstein-Barr virus (EBV) is implicated in the pathogenesis of Burkitt lymphoma and nasopharyngeal cancer.
c. Human herpes virus 8 (HHV-8) is associated with Kaposi sarcoma.
d. Hepatitis B virus (HBV) is linked with hepatocellular carcinoma. Hepatitis C virus (HCV) is linked with hepatocellular carcinoma through similar mechanisms, but is not a DNA virus.
Example of a microbial organism that is linked to cancer
Helicobacter pylori infection is implicated in development of gastric carcinoma and gastric lymphoma.
What are the main classes of tumor antigens?
a. Antigens Which Are Products of Mutated Oncogenes And Tumor Suppressor Genes
b. Antigens Which Are Products of Other Mutated Genes
c. Antigens Derived from Overexpressed or Aberrantly Expressed Cellular Proteins
d. Tumor Antigens Produced by Oncogenic Viruses
e. Oncofetal Antigens
f. Antigens Derived from Altered Cell Surface Gycolipids and Glycoproteins
g. Cell Type-Specific Differentiation Antigens
Antigens Which Are Products of Mutated Oncogenes And Tumor Suppressor Genes
1) Expressed as surface antigens
2) Do not appear to elicit protective responses
3) Examples: products from mutated p53, RAS
Antigens Which Are Products of Other Mutated Genes
1) Very diverse
2) Can be targeted by the immune system
Antigens Derived from Overexpressed or Aberrantly Expressed Cellular Proteins
1) Normal cellular proteins
2) Elicit immune responses
3) Example: MAGE family of gene products in melanomas
Tumor Antigens Produced by Oncogenic Viruses
1) CTLs can recognize these viral products.
2) These antigens generally elicit the strongest immune responses.
3) Vaccines can be developed against these oncogenic viruses
4) Examples: Antigens induced by EBV, HPV HBV, HTLV-1
Oncofetal Antigens
1) These antigens which are normally expressed during fetal development, but not in adults. They reappear in some malignant cells.
2) Do not elicit antitumor responses in the host with the tumor
3) Can serve as serum markers for certain cancers.
4) Examples: Carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP)
Antigens Derived from Altered Cell Surface Gycolipids and Glycoproteins
1) Cell surface glycolipids/glycoproteins may be altered in tumor cells or expressed at higher levels.
2) These antigens may be used as diagnostic tumor markers.
3) These antigens may be used as targets for cancer therapy with specific antibodies.
4) Examples: MUC-1 in breast carcinomas, CA-125 in ovarian carcinomas
Cell Type-Specific Differentiation Antigens
1) Antigens expressed by tumor cells that are specific to the tumor cell of origin
2) These antigens are sometimes specific for a stage of cell/tumor differentiation.
3) Used in tumor diagnostics to establish cell of origin
4) Specific antibodies to these antigens may be used for cancer immunotherapy.
5) Examples: CD10 and CD20 which are B-cell markers for lymphomas
Give an example of a tumor marker?
a. Carcinoembryonic Antigen (CEA)
b. Alpha-fetoprotein (AFP)
c. Prostate-specific Antigen (PSA)
Carcinoembryonic Antigen (CEA)
1) Best characterized of all tumor markers
2) An oncofetal antigen found in alimentary tract, liver and pancreas of the fetus at 2-6 months gestation
3) Elevated in colorectal, lung, pancreatic, breast cancers
4) Elevated in several non-neoplastic diseases, such as ulcerative colitis and COPD
5) Often used to monitor response to cancer therapy and evaluate for tumor recurrence
Alpha-fetoprotein (AFP)
1) An oncofetal antigen present in fetal circulation
2) Elevated in hepatocellular carcinoma, some testicular germ cell cancers
3) Not particularly useful for early detection of cancer, but may be used to monitor cancer patients for therapy and progression of disease
Prostate-specific Antigen (PSA)
1) A glycoprotein that is present in normal prostate gland
2) Elevated in prostatic cancer
3) Used in screening for prostate cancer, but has low sensitivity and specificity
4) Elevation may also be due to benign prostatic hyperplasia (BPH), or even a non-prostate type of tumor (ovary, kidney, salivary gland).
What is the dominant mechanism in antitumor effector mechanisms?
Cell-mediated immunity is the dominant mechanism
What are the cells/responses involved in antitumor effector mechanisms?
- Cytotoxic T Lymphocytes (CTL or Tc) – MAJOR importance
- Natural Killer (NK) Cells
- T Helper Lymphocytes (Th)
- Macrophages
- Humoral Responses – minor importance
Cytotoxic T Lymphocytes (CTL or Tc)
MAJOR importance
a. Well-demonstrated against a variety of tumors
b. Tumor recognition is highly specific and MHC class I restricted, i.e., sensitized CTLs recognize tumor antigens (peptides from cytoplasmic proteins) expressed bound to class I MHC molecules.
c. Kill tumor cells by release of perforins or induction of apoptosis.
d. Specifically sensitized CTLs are the major immune defense mechanism against tumors
Natural Killer (NK) Cells
a. NK cells are capable of killing tumor cells without prior sensitization.
b. Kill a variety of different tumor targets (non-specific, non-MHC restricted).
c. Kill when MHC class I is lost or mutated.
d. Kill by direct contact and release of toxic substances and by antibody-dependent cell cytotoxicity (ADCC).
e. Are most important early in tumor growth before development of CTLs.
f. Likely to be involved in immune surveillance.
T Helper Lymphocytes (Th)
a. Participate in induction and regulation of antitumor responses.
b. Secrete cytokines that recruit and activate cells with antitumor potential.
c. Highly specific and MHC class II restricted.
Macrophages
a. May collaborate with other cells (CTLs and NK cells) to kill tumor cells.
b. Kill tumor cells when activated by cytokines (especially interferon-γ).
c. Kill tumor cells by phagocytosis, secretion of TNF, or via reactive oxygen species.
d. May be most important in control of metastases.
Humoral Responses
minor importance
a. Tumor-specific (monoclonal) antibody may be used to kill tumor cells through complement activation.
b. Opsonization of tumor cells (via antibody or components of complement) targets tumor cell for destruction by phagocytic cells.
c. Antibodies against antigens on tumor cell surface may interfere with adhesive properties of tumor cells and thus reduce metastatic activity by preventing adherence to surrounding tissue.
Mendelian disorders
Disorders related to mutation of a single gene of large effect
Disorders with Multifactorial Inheritance
Disorders where phenotypic expression of disease is related to the combined effects of environmental influences and multiple gene mutations of small effect (polygenic inheritance)
Cytogenetic Disorders
(AKA Chromosomal Disorders) – Diseases arising from chromosomal aberrations that are identifiable on a karyotype
Single-gene Disorders with Atypical Patterns of Inheritance
Triplet repeat mutations, mutations in mitochondrial genes, and genomic imprinting
Example of disorder with multifactorial inheritance
- Diabetes Mellitus – to be studied in General and Systemic Pathology
- Hypertension – to be studied in General and Systemic Pathology
- Gout
- Schizophrenia
- Bipolar disorder (PKA manic depression)
- Some congenital heart malformations
Example of Single-gene Disorders with Atypical Patterns of Inheritance
Fragile X Syndrome
