Path Neoplasm I (7)

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mse263
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261835
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Path Neoplasm I (7)
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2014-02-19 10:20:07
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Pathology
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MBS Pathology
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Exam 2
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  1. Neoplasia
    the uncontrolled proliferation of cells (clonal cellular proliferation)
  2. Neoplasm
    • the physical manifestation of pathologic new cell growth
    • may be a solid mass lesion or tumor (literally “swelling”, but now is used synonymously w/ a mass forming neoplasm)
    • may also be characterized by a diffuse (systemic) process (ex. leukemia)
    • an abnormal mass of tissue the growth of which exceeds & is uncoordinated with that of the normal tissues
    • it persists in the same excessive manner after the cessation of the stimuli which evoked the change
  3. How can each neoplastic cell be characterized?
    • it has an alteration in its genome (is transformed)
    • this is what's responsible for abnormal growth (excessive & unregulated proliferation that is independent of physiologic growth-regulatory stimuli)
  4. What are the 2 basic components of all tumors/neoplasms?
    • 1. transformed neoplastic (parenchymal) cells
    • 2. a supporting stroma composed of non-transformed elements (eg, CT, BVs)
  5. Cancer
    • a malignant neoplasm
    • a neoplasm ALONE is a tumor, NOT cancer
  6. Benign Neoplasm (Tumor)
    • remains localized, doesn't spread to distant sites
    • both epithelial (most common) & mesenchymal (less common) benign tumors have the suffix –oma
  7. Adenoma
    • gland-like or gland-derived benign tumor
    • benign tumor of epithelial tissue w/ glandular origin, glandular characteristics, or both
  8. Papilloma
    a benign epithelial tumor growing exophytically (outwardly projecting) in nipple-like & often finger-like fronds
  9. Polyps
    mass projecting from the mucosa into the lumen of a hollow viscus
  10. Cystadenoma
    large cystic mass
  11. Malignant Neoplasms
    • cancer is a consequence of genetic damage whose cumulative effects result in unrestrained cell growth, tissue invasion, & metastasis
    • has the suffix –sarcoma
    • if of epithelial origin: –carcinoma suffix
    • if of mesenchymal origin: –SARcoma suffix
  12. Mixed Tumors
    • derived from 1 germ cell layer through divergent differentiation
    • tumors are made up of w/ more than one/different parenchymal cell type
  13. Teratomas
    • derived from MORE than 1 (sometimes all 3) germ cell layers
    • consist of a variety of parenchymal cell types (tumors are made up of different parenchymal cell types)
    • originate from totipotential germ cells found principally in the testis & ovary
  14. Choristomas
    • non-neoplastic, ectopic/heterotopic rests of non-transformed tissues, histologically normal cells, ‘right tissue in wrong place’
    • benign tumors that contain normal tissues found in abnormal locations
    • aka an excess of tissue in an abnormal situation
    • (eg. pancreatic cells under the small bowl mucosa)
  15. Hamartomas
    • benign, focal malformation that resembles a neoplasm in the tissue of its origin
    • not a malignant tumor; grows at the same rate as the surrounding tissues
    • is composed of tissue elements normally found at that site, but which are growing in a disorganized mass
    • aka an excess of normal tissue in a normal situation (eg. birthmark)
    • (non-neoplastic masses of disorganized tissue indigenous to a particular site)
  16. 4 Criteria Used to Classify Benign vs. Malignant Tumors
    • 1. malignant change (transformation) of the target cell (i.e. differentiation and anaplasia)
    • 2. rate of growth
    • 3. local invasion
    • 4. metastasis (spread)
    • is based on appearance (morphology) & behavior (clinical course)
  17. Malignant Transformation
    • the process by which cells acquire the properties of cancer
    • may occur as a primary process in normal tissue, or secondarily as malignant degeneration of a previously existing benign tumor
    • causes of primary malignancy: genetic mutation (inheritance OR by acquiring mutations in one's DNA over time), induced by inorganic toxic substances or viral infections (HPV)
  18. Differentiation
    the extent to which the transformed parenchymal cells in a tumor resemble comparable normal cells in morphology & in function
  19. Which type of tumor generally retinas more characteristics of the tissue of origin, benign or metastatic?
    • benign tumors usually retain MORE characteristics of the tissue of origin than metastatic tumors
    • benign tumors usually contain well differentiated cells that closely resemble their normal counterparts
  20. Malignant Neoplasms
    characterized by a wide range of transformed parenchymal cell differentiation, from well differentiated to moderately well differentiated to completely undifferentiated
  21. Differentiation v. Anaplasia
    • more differentiated, more functional capabilities as seen in normal counterparts
    • more anaplastic (rapidly multiplying), less likely to have specialized functional activity
  22. Anaplasia
    • lack of differentiation; a hallmark of malignant cells
    • literally means "to form backward"
    • it implies de-differentiation, or loss of structural & functional differentiation of normal cells
  23. Morphology of Anaplasia
    • nuclear & cellular pleomorphism
    • hyperchromasia
    • nuclear:cytoplasmic ratio increases (1:4 in normal, 1:1 in anaplasia)
    • abundant & atypical mitosis
    • chromosomal abnormalities
    • loss of polarity
    • tumor giant cells
  24. Dysplasia
    • the disordered (but non-neoplastic) growth & maturation of a tissue's cells
    • manifests as changes in mitotic rate of cells, loss of positional control, & loss in the uniformity of cell shape (pleiotropy), nuclear enlargement, irregularity & hyperchromatism, & disarray in the arrangement of the cells within the epithelium (instead of an orderly appearance of cells in a tissue)
    • IS reversible if the causative influence is removed
    • in a preneoplastic lesion
    • a preliminary stage in the multi-step cellular evolution of cancer
  25. Carcinoma in situ
    • an early form of cancer defined by the absence of tumor cell invasion into surrounding tissue, usually before penetration through the basement membrane
    • considered preinvasive neoplasm
    • mostly synonymous w/ high-grade dysplasia, meaning the risk of transforming into cancer is high
  26. Tumor Growth Fraction
    • the relationship between cancer cells proliferating & those cells resting
    • is an important consideration in therapeutic intervention
    • has an effect on tumor cells' susceptibility to chemotherapy & radiation
  27. Tumor Growth Rate
    • benign tumors mostly grow slowly, but may not be more innocuous b/c they can press against things & cause derangements

    • most cancers grow quickly, spreading locally then metastasizing → death

    • progression of tumors & their growth rates are determined by rate of cell proliferation vs. rate of cell death
  28. How many population doublings must an original transformed cell undergo to produce 109 cells (~1g aka a clinically detectable mass)?
    • at least 30 population doublings
    • now the population of transformed cells must only undergo 10 more doubling cycles before a tumor w/ 1012 cells (about 1 kg) is produced (usually the maximal size compatible w/ life)
    • by the time a solid tumor is clinically detected, it has already completed a major portion of its life cycle
  29. Circumscribed
    • to restrict within limits
    • benign tumors: circumscribed, possibly encapsulated, easier to remove, & localized at its site of origin
    • malignant tumors: poorly circumscribed, doesn't develop well-defined capsules, infiltrates, invades, & destroys tissue surrounding site of origin
  30. Fibroadenoma of the Breast
    • lumps composed of fibrous & glandular tissue
    • is a benign tumor with a fibrous capsule that sharply delineates the tumor from surrounding tissue
    • is easy to move w/ clearly defined edges
  31. Invasive Ductal Carcinoma of the Breast (IDC)
    • an infiltrating, malignant, & abnormal proliferation of neoplastic cells in the breast tissue
    • there is an invasion of breast stromal fat by nest & cords of tumor cells w/ a notable absence of a well-defined capsule
  32. Metastasis
    • metastatic spread is the most commonly cause of cancer death
    • the property of metastasis identifies a neoplasm as malignant
    • benign tumors DON'T metastasize
    • malignant tumors are invasive & can spread (by local invasion or seeding) from a primary site to other locations
  33. *Transcoelomic Spread
    • the spread of a malignancy into body cavities can occur via seeding the surface of the peritoneal, pleural, pericardial, or subarachnoid spaces
    • eg. melanomas or (ovarian) carcinomas can spread transperitoneally to the liver surface
  34. *Lymphatic Spread
    • invasion into the lymphatic system allows the transport of tumor cells to regional & distant lymph nodes + ultimately to other parts of the body
    • is the most common route of metastasis for CARCINOMAS (is uncommon for a sarcoma to metastasize via this route)
  35. Sentinel Lymph Node
    the first lymph node in a regional lymphatic drainage that receives lymph flow from a primary tumor
  36. *Hematogenous Spread
    • typical route of metastasis for sarcomas
    • the liver & lungs are the most frequently involved secondary sites
    • b/c of the thinner walls, veins are more frequently invaded than arteries, so metastasis tends to follow the pattern of venous flow
  37. What is an example of Direct Tumor Invasion?
    squamous cell carcinoma
  38. Benign Leiomyoma vs. Malignant Leiomyosarcoma
    • benign = a very rarely premalignant smooth muscle neoplasm that can occur in any organ but is most commonly found in the uterus, small bowel, or esophagus
    • malignant = LMS, is a malignant cancer of smooth muscle
  39. Cancer Stem Cells (CSCs)
    • cancer cells (found w/in tumors or hematological cancers) that possess characteristics associated w/ normal stem cells, eg. the ability to give rise to all cell types found in a particular cancer sample
    • CSCs are tumorigenic (tumor-forming); have the capacity to initiate & sustain a tumor
    • might explain why chemo/radiation failed to treat a cancer
  40. *Cancer Incidence
    the number of NEW cancers of a specific site/ type expressed as the number of cancers per 100,000 population at risk
  41. *Cancer Prevalence
    • the number of new AND pre-existing cancer cases alive on a certain date
    • identifies the level of burden of a disease on a population
  42. What types of cancers are more commonly seen in people ages 15 years or younger?
    • leukemias, lymphomas, neuroblastomas, Wilms tumors, retinoblastomas, sarcomas of bone & skeletal muscle
    • cancer in general tends to affect people over the age of 55
  43. *6 Hallmarks of Cancer
    • 1. Self-sufficiency through growth signals (eg. RAS activation)
    • 2. Insensitivity to anti-growth signals (eg. loss of pRB, retinoblastoma suppressor)
    • 3. Evasion of apoptosis (produce IGF survival factor, or missing/mutated p53)
    • 4. Limitless replicative potential (eg. telomerase activation)
    • 5. Sustained angiogenesis (constant blood supply to tumor; VEGF)
    • 6. Tissue invasion & metastasis
    • cancer cells acquire these properties during their development typically through relevant gene mutations
  44. Molecular Basis of Cancer
    • a genetic disorder caused by DNA mutations that are non-lethal & heritable (able to be passed onto daughter cells during cell division)

    • the non-lethal genetic damage may be acquired from the environment or inherited in the germ line
  45. Monoclonality of Neoplasms
    • tumors are monoclonal: a tumor mass results from the clonal expansion of a single progenitor cell that has incurred genetic damages

    • while most malignant tumors are monoclonal in origin, by the time they become clinically evident their constituent cells are extremely heterogeneous
  46. Carcinogenesis
    • process by which normal cells are transformed into cancer cells (the creation of cancer)
    • abnormalities in genes that regulate cell proliferation underlie neoplastic transformation
  47. When do the phenotypic attributes characteristic of malignancy develop?
    • when multiple mutations involving multiple genes accumulate
    • subclones of tumor cells evolve during neoplastic progression
  48. Protooncogenes
    normal genes encoding proteins which regulate normal cell growth, proliferation, & differentiation
  49. Oncogenes
    • mutated counterparts of normal protooncogenes
    • they encode oncoproteins & promote autonomous cell growth
    • such a mutation is a “gain of function”, activating mutation & it only has to affect 1 allele for there to be a phenotypic effect
  50. Mechanisms by which oncogenes promote uncontrolled cell proliferation
    1. Stimulus-independent expression of growth factors + its receptor, setting up an autocrine loop of proliferation

    2. Mutations in genes encoding growth factor receptors, leading to over-expression or constitutive signaling by the receptor

    3. Mutations in genes encoding signaling molecules

    4. Overproduction or unregulated activity of transcription factors

    5. Mutations that activate cyclin genes or inactivate cyclin & CDKs regulators
  51. RAS protein
    • a type of G protein (cytoplasmic signaling molecule) that when bound to GTP, RAS activates protein kinase cascades
    • it can normally hydrolyze bound GTP → switching itself into its inactive GDP-bound form
  52. When bound to GTP, RAS is in its ______ form
    ACTIVE
  53. How does a mutation of the ras gene affect the signaling activity of its protein product, RAS?
    • mutations in the GTPase domain of RAS will reduce the protein's ability to hydrolyze GTP
    • this results in constitutively active RAS & constantly occurring protein kinase cascades, which results in constitutive transcription & progression through the cell cycle
  54. Retinoblastoma
    • rare tumors that arise from neural precursor cells in the immature retina caused by missing Rb gene (tumor suppressor gene)
    • only a small number of mutations are required to form retinoblastomas
    • disease can either be hereditary or not
  55. Knudson’s Two Hit Hypothesis
    • 2 mutations (2 hits) are required to produce a tumor (eg. retinoblastoma); both the normal alleles of a tumor suppressor gene (TSG) must be inactivated
    • inheriting 1 defective copy of a gene (1st hit) predisposes you to the condition
    • acquisition of a 2nd mutation (2nd hit) of the same gene renders the condition homozygous → tumor develops (familial form)
    • or 2 mutations at a locus may be acquired after birth (sporadic form)
  56. RB
    • a phosphoprotein encoded by the Rb gene (a TSG) that exists in the nucleus & regulates the G1-S checkpoint of the cell cycle
    • it blocks progression through the cell cycle in its un-phosphorylated state
    • having one functional allele of Rb is protective against cancer
  57. What are the 4 key regulators of the cell cycle that become mutated in most human cancers?
    • 1. CDKN2A (p16)
    • 2. cyclin D
    • 3. CDK4
    • 4. RB
  58. p53 tumor suppressor gene
    • one of the most commonly mutated genes in human cancers (~70%)
    • is a central monitor of cellular stress activated by DNA damage, anoxia, inappropriate oncogene signaling etc.
    • causes G1 arrest & induces DNA repair genes
    • if DNA damage cannot be repaired p53 induces apoptosis
  59. What are the 3 3 mechanism p53 uses to prevent neoplastic transformation?
    • 1. Quiescence: activation of temporary cell cycle arrest (“breathing time” for DNA repair)
    • 2. Senescence: induction of permanent cell cycle arrest
    • 3. Apoptosis: programmed cell death
  60. Li-Fraumeni syndrome
    • a rare inherited cancer condition caused by germline mutations of the p53 gene
    • 1 defective copy inherited in the germ line, 2nd copy acquired in somatic tissues
    • characterized by a wide variety of tumors
    • a person may develop multiple primary tumors
  61. BCL-2 Family Mutations
    can help tumor cells evade cell death
  62. *What are the 4 principle regulatory genes that when targeted by genetic damage can cause malignancy?
    • 1. Growth promoting proto-oncogenes (Ras)
    • 2. Growth inhibiting tumor suppressor genes (RB)
    • 3. Genes involved in DNA repair (p53)
    • 4. Genes that regulate apoptosis (BCL-2)
  63. What role does Telomerase play in cancer?
    • tumor cells have enhanced telomerase activity, usually due to up-regulation, that gives such cells limitless replicative potential
    • normal cells have none or very low levels of telomerase activity
  64. HIF1α (hypoxia-inducible factor 1-α)
    a protein that triggers angiogenesis in response to hypoxia
  65. VHL (von Hippel-Lindau protein)
    • has E3 ubiquitin ligase activity that acts to degrade HIF1α (they work in opposition)
    • therefore it acts as a tumor suppressor gene by decreasing angiogenesis

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