Neoplasia Chapter 7

Definitions Neoplasm Benign Malignant Transformation Autonomy Anaplasia

I. Neoplasia A. Characteristics of Benign vs. Malignant Benign B. Tumor Nomenclature Malignant tumor of connective tissue origin Exceptions C. Grading and Staging of Neoplasms Grading Staging

Neoplasia Means new growth, commonly used to mean abnormal cell growth and is sometimes used interchangeably with the term tumor. Characteristics of Benign vs. Malignant There are “gray” areas that exist when stating the characteristics

1. Benign Histology: Looks like tissue of origin (differentiation), few mitotic figures (not rapidly dividing, undergoing mitosis). Remains localized- does not infiltrate adjacent tissue or metastasize (to different locations). Often encapsulated by Connective Tissue (CT). Rarely becomes necrotic (death). Very little vascularization (new blood vessels).

Benign cont. Often retains function of normal tissue. Slow growing. Rarely recurs and the prognosis is good.

2. Malignant Histology: anaplasia (lack of differentiation), abnormal cell size and shape, enlarged nuclei, many mitotic figures, strange looking giant cells, more anaplasia usually means more aggressive (more malignant). Infiltrated adjacent tissue. Metastasizes -> spreads to distant sites via blood or lymphatics. Common for necrosis to occur.

Malignant cont. Often becomes vascular: Tumors can initiate vessel growth (angiogenesis, “vessel” “new growth”). Rapid growth rate. Dysfunctional (tissue unable to perform normal functions). Often recur. Prognosis poor if untreated.

B. Tumor Nomenclature General rules of naming indicate tissue of origin and benign or malignant. 1. Benign tumor -oma suffix usually indicated benign tumor Lipoma-benign tumor of fat tissue Chondroma- benign tumor of cartilage Adenoma- benign glandular tumor

2. Malignant tumor of epithelial tissue origin: “Carcinoma” is used to describe the tumor. Ex: Squamous cell carcinoma (where would this be found?) Skin Adenocarcinoma (glandular).

3. Malignant tumor of epithelial tissue origin: Uses term “sarcoma”. Examples: Chondrosarcoma- malignant tumor of cartilage tissue. Osteosarcoma- malignant tumor of bone tissue. Liposarcoma- malignant tumor of adipost. Angosarcoma- malignant tumor of blood vessels.

4. Exceptions: Lymphoma, melanoma, hepatomas are malignant (even though they use the –oma suffix.

C. Grading and Staging of Neoplasms Used to predict the behavior (prognosis) of a neoplasia and also used to help select treatment options. I, II, III, IV Higher grade=more malignant 1. Grading – refers to histological characteristics, how much anaplasia (lack of differentiation)

2. Staging: Describes the location and pattern of spread. Tumor size, extent of local infiltration, lymph node involvement, distant metastases Used to select Tx choice TNM System: Tumor Node Metastasis

TNM T -> size physically N -> extent of lymph node involvement M-> metastases (spreading) Used for treatment, prognosis, statistical data base

II. Mechanisms of Cancer A. Metastatic Processes B. Escape from Tissue of Origin C. Patterns of Spread D. Tumor Markers

A. Metastatic processes Metastatic cells have escaped the normal mechanisms that control their growth and how they interact with neighbor cells. Loss of contact inhibition Loss of anchorage dependence Reduced requirement for growth factors

Loss of contact inhibition Normal cells stop growing when space is limited or contact other cells contact inhibition – cancer cells continue to divide when they contact other cells

Loss of anchorage dependence Normal cells in culture must have a solid substance to grow on – cancer cells will grow in suspension (no anchorage dependency)

Reduced requirement for growth factors Growth factors are local (paracrine) peptides that bind on target cell starting a series of intracellular reactions that leads to cell growth- cancer cells may be able to make own growth factors

B. Escape from Tissue of Origin Cancer cells have the ability to gain access to blood and lymph Can breakthrough basement membranes and migrate by amoeboid movement into vessel (escape membrane, through extracellular space, penetrate basement membrane of the vessel

C. Patterns of Spread Most metastatic tumor cells don’t survive- the immune system removes the cancerous cells. Some tumors prefer specific organs- may be chemotactic factors involved (chemotaxis- “chemical attractant). Some patterns related to blood flow –GI to liver via portal circulation. Some patterns related to lymphatic flow- first in regional lymph nodes then node to node.

D. Tumor Markers Tumors have varying degrees of differentiation- or resemblance to tissue of origin. Tumor markers are substances that help identify the tissue of origin. Helps in prognosis and selection of Tx. Use enzymes and other proteins specific to that tissue type.

III. Oncogenesis A. Intro Proto-oncogenes Suppressor genes B. Effects of Proto-oncogenes Activity Production of abnormal growth factors Production of abnormal growth factor receptors Abnormal intracellular pathway Abnormal growth genes C. Oncogene Activation (4 points of interest)

A. Intro Cancer is a malfunction in cell division, due to altered genes (DNA) that allow for uncontrolled growth of a cell. Carcinogen – cancer causing substance. Mutagen – substance that causes gene mutations. Oncogenes – genes that cause cancer.

Proto-oncogenes Normal genes that are important for normal embryonic growth and differentiation of cell. In a normal cell they are Highly Regulated. If proto-oncogenes becomes “turned-on” the growth of the cell is unregulated. At this point they are now oncogenes. Proto-oncogenes are like the “accelerators” of cell division.

Suppressor genes Anti-oncogenes Normal genes that inhibit growth by suppressing proto-oncogenes activity. Cancer can occur when these are “turned off” They are the “brakes” of cell division.

B. Effects of Proto-oncogenes Activity Pro-o’s become activated oncogenes when normal controls that keep them in check are disrupted. Activated oncogenes can influence the cell in the following ways: (4 ways)

1. Production of abnormal growth factors Normally a differentiated cell does not produce growth factors to which it can also respond to – they don’t have the receptor for their own growth factors. Mutation may cause the production of a growth factor for which the cell also has receptors for and caused self-stimulation of growth (autocrine)

2. Production of abnormal growth factor receptors Gene mutation may allow for the production of receptors that should not be present. May cause excessive number of receptors (breast carcinomas) Receptor may have high affinity for growth factors or even active in their absence.

3. Abnormal intracellular pathway Gene mutation may cause production of excessive or abnormal components of the intracellular growth-signaling pathway. Normally transmit a growth signal from a surface receptor to the nucleus (work as a second messenger) Pathway is normally only activated when stimulated at cell receptors, therefore by- passes the receptors.

4. Abnormal growth genes (transcription factors) Normal growth pathway ultimately affects the transcription of growth genes in the nucleus, if these genes become activated a cell grows in absence of any outside growth factor stimulus. Called: Growth Factor Independence

C. Oncogene activation (4 ways to activate oncogene) Proto-oncogenes become activated when normal controls that keep them in check are disrupted.

1. Oncogenes may be introduced into the host cell by a retrovirus Examples: HIV- Kaposi’s sarcoma Epstein-Barr virus Burkitt’s lymphoma

2. Proto-oncogene within cell undergoes mutation due to mutagen. 2. Proto-oncogenss within cell undergo a mutation due to a mutagen: Examples: UV radiation X-Rays Chemical radiation 2. Proto-oncogene within cell undergoes mutation due to mutagen.

3. Loss of suppressor gene activity- gene may be damaged or lost. Allows the proto-oncogenes to become abnormally active. 3. Loss of suppressor gene activity- gene may be damaged or lost.

4. Amplification of proto-oncogene (extra copies). 4. Amplification of a proto-oncogene Proto-oncogene is released from normal regulation allowing excessive production leading to unregulated cell growth (extra copies) 4. Amplification of proto-oncogene (extra copies).

IV. Multisteps of Carcinogenesis (not a single event that occurs, cancer requires many cell accidents). A. Initiation- mutation of genes.

B. Promotion- cell must proliferate or divide for cancer to develop May require several mutations to cause promotion. (Fully differentiated cardiac muscle cells or neurons do not become cancerous b/c they typically lack the ability to divide).

C. Progression- Cells show malignant behavior. As proliferation continues, evolved tumor cells are generated that differ significantly from original parent cells.

V. Effects of Cancer on Host A. Asymptomatic B. Benign C. Malignant Pain Cachexia Bone marrow suppression Complications due to treatment

A. Asymptomatic No symptoms/signs. During early stages or with benign tumors, doesn't’ interfere with anything.

B. Benign Can cause harm as a space occupying lesion. Ex: The impaired function of brain, nerve, or vessel as tumor presses on these structures. Gets bigger start to press against surrounding structures. Physical problems.

C. Malignant Pain- from invasion into organs or bone which activated pain receptors Tx: analgesics (pain killers/relievers) Cachexia- “wasting away” Weight loss and weakness Can be caused by: anorexia (not eating) or the increased metabolic rate of tumor cells (tumor cells out compete normal cells for nutrients).

Bone marrow suppression Anemia-decreased ability to transport oxygen Leukopenia-decrease in WBC’s impairs immune system ability to fight infection which is a major cause of morbidity and mortality in cancer patients (decrease platelets) Bone marrow suppression may be due to metastasis to bone marrow, poor nutrition, or from Tx

Complications due to Tx Hair loss, sloughing of mucosal cells **Rapidly dividing cells die because that is how most chemotherapeutics work, they interfere with cell division. **Mucosal cell loss also causes pain, anorexia and makes it easier to acquire infections.

VI. Cancer Treatment A. Surgery B. Radiation C. Chemotherapy

A. Surgery Can cure a large portion of localized cancers. Main advantage: remove cancer cells with min. damage to normal cells. Important to remove the margin or normal tissue as well to assure you get all cells. Check lymph nodes for metastasis. Often patients have undetectable metastases at time of surgery, May follow with radiation or chemotherapy

B. Radiation Used to: Kill tumor cells that can’t be removed surgically because of location, kill cells that may have escaped removal, reduce size of tumor – prior to removal or to relieve pain (such as brain tumor) Most effective at killing small groups of tumor cells. Kills cells by damaging their DNA Cells that are rapidly dividing are more susceptible because less time for DNA repair and damaged DNA passed to daughter cell which then dies.

Radiation cont. Some destruction of normal cells is expected. Give maximum dose normal tissue can tolerate and hope that it kills the tumor.

C. Chemotherapy IV or Oral Systemic administration of anticancer drugs. Used to Tx cancers that have disseminated in body. Unlike surgery or radiation – these drugs go EVERYWHERE!

Chemo cont. Most chemotherapeutics are cytotoxic b/c they interfere with cell division. Rapidly dividing cells most susceptible to killing effects. Some normal cells will also be killed- especially rapidly dividing such as bone marrow, GI mucosal epithelium, hair follicles.