Neoplasia Flashcards
Neoplasia
A heritably altered, relatively autonomous growth of tissue.
Heritably altered: when a cell acquires a growth advantage and is able to pass that advantage on to daughter cells, a clone is established that has a higher replicative rate or slower rate of death than surrounding cells.
The cell are replicating more and faster, so they are genetically unstable; there is not enough time for genetic repair machinery to fix errors in DNA before cell divides again, so they accumulate even more mutations.
Example os growth advantages: increased rate of mitosis, decreased rate of apoptosis, ability to evade the organism’s immune system, ability to use alternate sources of energy. Most neoplastic cells die, but because there are so many other proliferating, there is a net growth of tissue.
Relative Autonomy
The inherited genetically based growth advantage allows the cells to still respond, but to a lesser extent to their environment.
Benign vs Malignant (Sarcoma vs Carcinoma)
Benign neoplasms are slow growing and do not spread to other tissues; these can still cause morbidity and mortality by exerting local effects, such as erosion of bone leading to fracture, produce hormones, cause pain by pressure, induce bleeding.
Malignant neoplasms grow more rapidly and have the ability to spread beyond their tissue of origin; these are the cancers that cause so much morbidity and death.
Carcinoma refers to malignant neoplasm in which cells arise from an epithelium and are differentiating towards epithelial cells; most common forms-breast, lung, colon, prostate most common of tis type.
Sarcoma refers to malignant neoplasm arising from mesenchymal cells (connective tissue); osteosarcoma or chondrosarcoma (cartilage).
Histological characteristics if Malignancy
Characterizing benign vs malignant reflects degree of differentiation of cells and the degree to which they are growing in a relatively autonomous fashion.
Encapsulation of lesion implies it is growing slowly because the surrounding tissue has time to form a protective barrier around it. Malignant neoplasms may be partially encapsulated.
If the cells in the sample do not resemble the cells in the tissue of origin, their genetic machinery is much distorted. If the cells show no differentiation at all and you cannot tell what is the tissue of origin, they are called anaplastic; compare the tissue you are looking at to what the tissue SHOULD look like.
Invasive; malignancies grow beyond their site of origin into surrounding tissues.
Metastatic
Mitotic figures; indicative of active replication of cells –> more numerous in malignancies. Grade of a neoplasm is measured by how many are present; there are some malignant neoplasms that are not very mitotically active.
Large nuclei in comparison to scant cytoplasm (high N:C ratio)
Nuclei have irregular contours
Large nucleoli
Stage/TNM System
Stage refers to how widely the malignancy has spread, either by invasion or metastasis, in the body.
Stage is determined by assessing (TNM System)
1. extent of local growth, or characteristics of tumor itself. It is characterized by the size of the neoplasm, the extent to which it has invaded the surrounding tissue, or both. (T)
2. extension to lymph nodes. It is characterized by the presence of lymph node metastases, the number of lymph nodes involved, and/or the size of the metastatic deposit in the lymph nodes. (N)
3. presence of distant organ metastases. Usually simply recorded as presence or absence of metastasis. (M)
Stage correlates with survival and it determines treatment. Details of this classification vary from one specific type of malignancy to the next; stage 1 for breast cancer might be stage 2 in colon cancer.
Invasion
The contiguous growth of neoplastic cells beyond their site of origin.
If neoplastic cells stay within the tissue in which they arise, they are not frankly malignant-they are dysplastic-they have features of malignancy and a high likelihood of behaving malignant in the future.
Invasion requires the cells to be able to degrade the surrounding tissue with proteolytic enzymes:
Metalloproteinases: attack the basement membrane to which epithelial cells are anchored.
Serine proteinases/cysteine proteinases: attack extracellular matrix proteins in the tissues through which the malignant cells migrate.
Effects:
ulceration and/or infection
renal failure
obstructive bronchopneumonia
perforation of peritonitis of large bowl
Metastasis
The non-contiguous spread of malignant cells throughout the body; occurs family late in malignant neoplasms.
- Malignant cells must gain ability to invade into the surrounding tissues beyond their site of origin (must be able to produce enzymes capable of digesting membrane and extracellular proteins).
- The malignant cells must be able to grow through the wall of a vessel, either a blood vessel or lymph capillary (intravasation); requires additional enzymes capable of breaking apart basement membrane to which endothelial cells are anchored and the junctions between the endothelial cells of the vessel wall.
- The cells must be able to evade the host’s immune system once in the vessel. If the embolus is capable of surrounding itself with platelets, it evades immune detection. The liver and lungs, which filter body’s blood through vast expanses of capillaries and sinusoids, are the organs in which metastases most frequently occur.
- Tumor embolus must adhere to vessel wall and a distant site and migrate back out of it (extravasation).
- The tumor cell must be able to establish themselves in the new location.
- May require the ability to stimulate growth of its own blood supply (angiogenesis).
CANCER IS A DISEASE OF GENES
The basic pathogenic alteration involved the genetic machinery of the cell. It takes a series of alterations to the genes for cancer to arise.
Genes can be altered in germ cells-affecting the person from the time of conception and be present in every cell int he body (risk of developing cancer at a younger age).
Genes can be altered during the lifetime of a person, and the mutation will ONLY effect a subset of cells in the body-somatic mutations-most cancers caused by these.
CANCER IS CLONAL
The altered genes are passed to the daughter cells of the originally mutated cell, conferring them a growth and/or survival advantage.
Each of the daughter cells can accumulate even more mutations that give it a greater growth advantage that they can pass on to their daughter cells-subclones within a clone.
The pop of malignant cells is ultimately derived from a single mutated cell.
CARCINOGENESIS IS A MULTIPSTEP PROCESS
No single genetic alteration will cause a cell to become neoplastic. Genetic machinery takes many “hits,” involving mutations, deletions, translocations, activation or suppression of genes that encode proteins that involved in several critical cell functions; may be why most cancers occur in older people.
It is the cumulative effect of the genetic alterations that leads to the malignant phenotype.
Retinoblastoma: childhood cancer that arises from minimum of two “hits.”
Self-sufficiency in growth signals
Physiologic function in cell commonly corrupted in pathway to cancer.
USUALLY: growth factors bind to growth factor receptors, which undergo a conformational change that activates RAS protein, which releases raf protein, which travels to nucleus to activate transcription.
The genes encoding these proteins are called photo-oncogene. An oncogene is the mutated and activated form of the photo-oncogene.
CANCER: If proteins involved in messaging are constantly active, the communication system that controls growth becomes dysregulated-if proteins that are transcribed at a higher rate are proteins that drive the cell through the cell cycle, the cell replicates more rapidly than normal, giving rise to a clonal, expanded population of cells.
Mutations that cause proto-oncogene to become an oncogene are activating mutations, and it only takes a mutation in one of the two alleles of the photo-oncogene to cause altered protein function (autosomal dominant).
Insensitivity to growth-inhibitory stimuli
Growth is usually inhibited by various regulatory proteins: these can detect and repair damaged DNA before the cell can proliferate-these proteins are usually present in the cell in an activated state, and are called tumor suppressor genes.
Mutations in tumor suppressor genes can result in the cell progressing through the cell cycle with altered DNA-which then becomes fixed in the daughter cell.
Deactivating mutations, both alleles have to be mutated for the regulatory function of tumor suppressor genes to be lost.
Example: p53
ONCOGENE AND TUMOR SUPPRESSOR GENES ARE THE MOST COMMON DEFECTIVE GENES IN THE DEVELOPMENT OF CANCER.
Evasion of Apoptosis
Defects in any proteins involved in apoptosis can cause process to go awry so that the cell persists and proliferates-even in the presence of DNA damage.
Example: bcl-2; when this molecule is produced in excess, apoptosis is inhibited (many indolent B cell lymphomas); tumors grow because of a slow addition of malignant cells rather than their rapid proliferation.
Defective DNA repair
Genes being repaired are not oncogenes or tumor suppressor genes.
When the repair mechanisms do not function properly, the cell accumulates damage throughout the genome, including oncogenes and tumor suppressor genes.
Most cancers develop defective DNA repair at some point during oncogenesis.
Limitless replicative potential
Normal somatic cells can undergo about 60-80 cell cycles before they die-some cells or subclasses within a cancer are immortal: they can go through cell cycles indefinitely.
