Path Neoplasm II (8)

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Path Neoplasm II (8)
2014-02-14 14:24:31
MBS Pathology
Exam 2
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  1. How can the evolution of benign adenomas to carcinomas be characterized?
    it's marked by increasing & additive effects of mutations
  2. Agents that cause genetic damage & induce neoplastic transformation
    • • Chemical carcinogens
    • • Radiation energy
    • • Oncogenic viruses & other microbes
    • genetic damage lies at the heart of carcinogenesis
  3. What are the 2 categories of chemicals that can initiate carcinogenesis?
    • 1. direct acting agents
    • 2. indirect acting agents
  4. Direct Acting Agents
    • chemicals that do NOT require metabolic conversion to become carcinogenic
    • eg. alkylating & acylating agents, some of which are cancer chemotherapeutic agents (alkylating drugs: cyclophosphamide, chlorambucil, nitrosoureas etc.)
    • aka therapeutic agents themselves can cause new or subsequent, second forms of cancer
  5. Indirect-Acting Agents
    • pro-carcinogens that require metabolic conversion to an ultimate carcinogen before they become active
    • enzyme polymorphisms (eg. CYP-450) can be the reason behind why some people do or don't get cancer
    • examples: polycyclic/heterocyclic aromatic hydrocarbons, aromatic amines, amides, azo dyes, some natural plant & microbial products
  6. Initiation: 1st Step of Chemical Carcinogenesis
    • 1. cells are exposed to a significant dose of an 'initiator' (carcinogenic agent)
    • 2. rapid, irreversible mutation in the cell genome
    • 3. cell changes are now permanent → have the potential to give rise to tumors
    • 4. a promoter augments the carcinogenicity of the chemical initiator
  7. Initiator
    • causes non-lethal damage to DNA that cannot be repaired
    • mutated cell then passes on the DNA lesion to its daughter cell
  8. Can carcinogenesis occur before exposure to a promoter?
    • NO, an organism must be exposed to the promoter before carcinogenesis can proceed
    • the sequence of application of chemicals is critical, must go initiator → promoter → carcinogenesis/neoplasm formation
    • tumor won't form if the substances are given out of order
    • however exposure to a promoter can occur long after exposure to an initiator b/c its effect is long-lasting & irreversible
  9. How can all initiating chemical carcinogens be categorized?
    • as highly reactive electrophiles (E+ → have electron deficient atoms) that can react w/ nucleophilic (Nu:- electron rich) sites in the cell
    • they target DNA, RNA, proteins
  10. Promotion: 2nd Step of Chemical Carcinogenesis
    • the process of tumor induction in previously initiated cells by promoters (chemicals)
    • the effect of a promoter is ~short-lived & reversible
    • promoters do NOT affect DNA directly & are non-tumorigenic alone
    • they induce cell proliferation
  11. Promotor
    • pleiotropic chemicals involved in cell proliferation, clonal expansion, & aberrant differentiation of initiated cells
    • must follow the initiator & in doing so, produce a pre-neoplastic clone by inducing clonal expansion
    • (eg. phorbol esters, hormones, phenols, drugs)
  12. Ultraviolet Rays
    • cause skin cancers (squamous & basal cell carcinoma, possibly melanoma) by damaging DNA through the formation of pyrimidine dimers
    • the nucleotide excision repair pathway should normally reverse such damage
    • UV rays don't directly cause DNA mutations however they can cause changes in DNA that can further lead to mutations which may possibly result in cancer
    • a type of radiation carcinogenesis
  13. UV Ray Ranges
    • UVA: 320-400nm
    • UVB: 280-320nm
    • UVC: 200-280 nm
  14. What factors can effect the possible negative outcomes of exposure to UV rays?
    • 1. the type of UV (uvB light causes T base pairs next to each other to bond together into pyrimidine dimers)
    • 2. the intensity of exposure
    • 3. amount of melanin in skin
  15. Ionizing Radiation
    • electromagnetic (x & γ-rays) & particulate (α & β particles, protons, neutrons) radiation are all a type of radiation carcinogenesis
    • they cause mutations by Direct effect of radiation energy & an Indirect effect mediated by the generation of free radicals from H2O or O2
    • resulting damage to chromosomes by breakage, translocation, or point mutations → genetic damage + carcinogenesis
  16. Hierarchy of Cellular Vulnerability to Radiation- Induced Neoplasms
    • 1. myeloid leukemias, thyroid cancer in children
    • 2. breast, lungs, & salivary gland cancer
    • 3. skin, bone, GI tract cancer
  17. Viral & Microbial Carcinogenesis
    • a variety of DNA & RNA viruses are implicated in human cancer
    • oncogenic DNA Viruses encode proteins that bind regulatory proteins (eg. HPV, Epstein-Barr, Hep B)
    • oncogenic RNA Viruses (eg. human T-cell lymphotropic virus)
    • oncogenic microbes (eg. H.pylori is implicated in gastric adenocarcinoma & MALT lymphoma)
  18. Human Papillomavirus (HPV)
    • certain strands of an oncogenic DNA virus encode proteins that bind regulatory human proteins
    • are over 70 genetically distinct types of
    • HPV
    • some types (1, 2, 4, & 7) cause benign squamous papillomas (warts)
    • types 6 & 11 cause genital warts w/ low malignant potential
    • however types 16 & 18 are implicated in over 90% of squamous cell cancers of the uterine cervix & anorectal region as well as at least 20% of oropharyngeal cancers (high-risk types)
  19. How can papillomaviruses be oncogenic/cause malignancy?
    • by a rare events during which a portion of the viral DNA including E1 & E6, but NOT E2, integrates into the host cell genome
    • in these cells, continued expression of the early genes will enable the cell to divide continuously out of control & become a cancer cell (the genetic change becomes heritable)
    • infection by high-risk HPV types simulates the loss of tumor suppressor genes, activates cyclins, inhibits apoptosis, & combats cellular senescence
  20. Human T-cell Lymphotropic Virus (HTLV-1)
    • an oncogenic RNA Virus associated with a form of T-cell leukemia/lymphomas endemic in parts of Japan & Caribbean basin
    • is sporadic elsewhere, including the US
  21. What is HTLV-1's mechanism of carcinogenesis ?
    • it's not clear - the virus doesn't contain an oncogene nor is it integrated near a proto-oncogene
    • HTLV-1 encodes a viral transcription activation factor, TAX, which turns on genes for cytokines & their receptors in infected T-cells
    • a signaling loop is formed stimulating T-cell proliferation
    • polyclonal expansion of T-cells puts person at increased risk of developing additional mutations that can eventually give rise to a monoclonal T-cell tumor
  22. What was the 1st bacteria classified as a carcinogen?
    • Helicobacter pylori
    • is implicated in gastric adenocarcinoma & gastric lymphomas b/c it causes increased epithelial proliferation in combination w/ chronic inflammation
    • chronic inflammation/gastritis → gastric atrophy → intestinal metaplasia → dysplasia → cancer
  23. Cancer Cachexia (a clinical aspect of neoplasia)
    • progressive loss of body fat & lean body mass, profound weakness, anorexia, & anemia
    • may be caused by soluble factors such as cytokines produced by the tumor & the host
    • eg. macrophages secrete TNF in response to tumor cells, which themselves may release it
    • an imbalance in homeostatic mechanisms → cachexia
  24. Paraneoplastic Syndrome
    • when cancers produce remote effects that are not attributable to tumor invasion or to metastasis but are related to the synthesis of bioactive compounds by the tumor
    • found in 10-15% of cancer patients
  25. Cushing Syndrome
    • an endocrinopathic paraneoplastic syndrome associated w/
    • 1. small cell carcinoma of the lung
    • 2. pancreatic carcinoma
    • 3. neural tumors
    • results from prolonged exposure to high levels of ectopic ACTH (made by tumor)
  26. Hypercalcemia
    • another endocrinopathy w/ ectopic hormone production, specifically PTHrP (parathyroid hormone-related protein), TGF-α, TNF, & IL-1
    • may be seen in
    • 1. lung cancer (squamous cell carcinoma)
    • 2. breast carcinoma
    • 3. renal carcinoma
    • 4. ovarian carcinoma
    • 5. adult T-cell leukemia/lymphoma
  27. Nonbacterial Thrombotic Endocarditis
    • a hematological paraneoplastic syndrome seen in advanced cancers
    • it causes hypercoagulability
  28. Grading of Tumors
    • reflects cellular characteristics
    • is based on the degree of differentiation of the tumor cells & architectural features (aka does the tumor architecture look like its tissue of origin)
    • higher grade tumors are generally more aggressive
  29. Staging of Tumors
    • reflects the extent of spread
    • is based on the size of the primary lesion, its extent of spread to regional lymph nodes, & the presence or absence of vascular metastasis
  30. TNM system
    • T: site & extent of primary tumor
    • N: involvement of regional lymph nodes
    • M: distant metastasis
  31. Virtual Microscopy
    a method of posting microscope images on, & transmitting them over, computer networks allowing for independent viewing of images by large numbers of people in diverse locations