Neoplasia 4


Published on

Published in: Technology, Health & Medicine
  • Be the first to comment

  • Be the first to like this

Neoplasia 4

  1. 1. Neoplasia 4<br />Fe A. Bartolome, MD, FPASMAP<br />Department of Pathology<br />Our Lady of Fatima University<br />
  2. 2. Chemical <br />Carcinogenesis<br />
  3. 3.
  4. 4. Chemical <br />Carcinogenesis<br /><ul><li>Initiation results from exposure of cells to a sufficient dose of a carcinogenic agent (initiator).
  5. 5. Initiation alone is not sufficient for tumor formation.
  6. 6. Initiation causes permanent DNA damage (mutations). It is rapid and irreversible and has “memory.”</li></li></ul><li>Chemical <br />Carcinogenesis<br /><ul><li>Unrepaired alterations in the DNA are essential first steps in the process of initiation.
  7. 7. For the change to be heritable, the damaged DNA template must be replicated
  8. 8. For initiation to occur, altered cells must undergo at least one cycle of proliferation so that DNA change becomes fixed</li></li></ul><li>Chemical <br />Carcinogenesis<br /><ul><li>Promoters (e.g. Phorbol esters, hormones, phenols, and drugs) can induce tumors in initiated cells, but they are non-tumorigenic by themselves
  9. 9. Tumors do not result when the promoting agent is applied before, rather than after, the initiating agent.
  10. 10. The cellular changes resulting from application of promoters do not affect DNA directly and are reversible.</li></li></ul><li>Chemical <br />Carcinogenesis<br /><ul><li>Application of promoters leads to proliferation and clonal expansion of initiated (mutated) cells
  11. 11. Mutated cells with reduced growth factor requirements
  12. 12. Process of tumor promotion includes multiple steps: proliferation of pre-neoplastic cells, malignant conversion, and tumor progression</li></li></ul><li>
  13. 13.
  14. 14. Chemical Carcinogenesis: Initiators<br />Direct-Acting Agents<br /><ul><li>Require no metabolic conversion to become carcinogenic
  15. 15. Most are weak carcinogens; some are chemotherapeutic drugs (e.g. Alkylating drugs)
  16. 16. Risk of induced cancer is low.</li></li></ul><li>
  17. 17. Chemical Carcinogenesis: Initiators<br />Indirect-Acting Agents<br /><ul><li>Requires metabolic conversion to an ultimate carcinogen before they become active
  18. 18. Polycyclic hydrocarbons
  19. 19. present in fossil fuels; animal fats during process of broiling meats; smoked meat and fish
  20. 20. Principal active product: epoxides form adducts with DNA, RNA, and proteins</li></li></ul><li>Chemical Carcinogenesis: Initiators<br />Indirect-Acting Agents<br /><ul><li>Most of the known carcinogens are metabolized by the cytochrome P-450-dependent mono-ozygenases
  21. 21. Example: benzo[a]pyrene light smokers with the susceptible genotype CYP1A1 with 7x higher risk of developing lung cancer</li></li></ul><li>Chemical Carcinogenesis: Initiators<br />Molecular Targets<br /><ul><li>DNA is the primary target
  22. 22. Any gene may be the target  commonly mutated are RAS and p53
  23. 23. Aflatoxin B1  cause G:C  T:A transversion in codon 249 of p53</li></li></ul><li>Radiation Carcinogenesis<br />Ultraviolet Rays<br /><ul><li>UV rays derived from sun  increased incidence of SCCA, basal cell carcinoma, and skin melanoma
  24. 24. Degree of risk depends on:</li></ul>Type of UV ray<br />Intensity of exposure<br />Quantity of light-absorbing protective coat of melanin<br />
  25. 25.
  26. 26. UVB radiation is the main cause of sunburn and skin cancer although mounting evidence suggests UVA may also play a role. UVB does not penetrate the skin as deeply as UVA but has more energy and therefore does more damage to the skin. <br />
  27. 27. UVB sunlight is directly absorbed by DNA resulting in single strand breaks and the formation of pyrimidinedimers. <br />
  28. 28.
  29. 29.
  30. 30. Radiation Carcinogenesis<br />Ionizing Radiation<br /><ul><li>Electromagnetic (x-rays, gamma rays) and particulate (αparticles, β particles, protons, neutrons) radiation are all carcinogenic
  31. 31. Lead to formation of reactive oxygen species or free radicals</li></li></ul><li>Radiation Carcinogenesis<br />Ionizing Radiation<br /><ul><li>High vulnerability: acute and chronic myeloid leukemia; thyroid cancer (only in the young)
  32. 32. Intermediate: breast, lungs, salivary glands
  33. 33. Resistant: skin, bone, GIT</li></li></ul><li>DNA is damaged due to ionization or excitation caused by radiation. Clustered DNA damage would be produced where the density of ionization/excitation is high, whereas the isolated damage would be generated where it is low.<br />
  34. 34.
  35. 35.
  36. 36. Microbial Carcinogenesis<br />
  37. 37. Microbial Carcinogenesis<br />
  38. 38.
  39. 39. Microbial Carcinogenesis<br />Oncogenic RNA Viruses: HTLV type 1<br /><ul><li>Only human retrovirus firmly implicated in causation of cancer in humans (T-cell leukemia/lymphoma)
  40. 40. Does not contain an oncogene
  41. 41. Viral integration shows clonal pattern  site of integration identical within all cells of a given cancer</li></li></ul><li>Microbial Carcinogenesis<br />Oncogenic RNA Viruses: HTLV type 1<br /><ul><li>With tax regulatory gene</li></ul>stimulates viral mRNA transcription <br />activate transcription of several host cell genes involved in proliferation and differentiation of T cells<br /><ul><li>FOS gene – immediate early gene
  42. 42. Genes encoding IL-2 & its receptor
  43. 43. Gene for myeloid growth factor granulocyte-macrophage colony-stimulating factor</li></li></ul><li>Microbial Carcinogenesis<br />Oncogenic RNA Viruses: HTLV type 1<br /><ul><li>With tax regulatory gene</li></ul>Inactivates the cell cycle inhibitor p16/INK4a and enhance cyclin D activation<br />Activate NFκβ  activation of anti-apoptotic genes<br />Interfere with DNA repair functions<br />Inhibits ATM-mediated cell cycle checkpoints activated by DNA damage<br />
  44. 44.
  45. 45.
  46. 46. Microbial Carcinogenesis<br />OncogenicDNAViruses: HPV<br /><ul><li>High-risk HPVs: types 16 and 18  squamous cell CA of cervix and anogenital region; penile cancer; oropharyngeal CA
  47. 47. HPV genome integrated into host genome  site of integration random but pattern of integration is clonal</li></li></ul><li>
  48. 48. Microbial Carcinogenesis<br />OncogenicDNAViruses: HPV<br /><ul><li>Viral genome integration  interruption of viral DNA within E1/E2 open reading frame  loss of E2 viral repressor and overexpression of oncoproteins E6 and E7</li></li></ul><li>
  49. 49.
  50. 50. Microbial Carcinogenesis<br />OncogenicDNAViruses: EBV<br /><ul><li>Associated with African form of Burkitt’s lymphoma, a subset of Hodgkin lymphoma, nasopharyngeal Ca and some gastric carcinoma
  51. 51. Infects B cells and possibly epithelial cells of the oropharynx via complement receptor CD21</li></li></ul><li>Microbial Carcinogenesis<br />OncogenicDNAViruses: EBV<br /><ul><li>Infection of B cells is latent  no viral replication and destruction of cells
  52. 52. Involves the “hijacking” of several normal signalling pathways</li></li></ul><li>Microbial Carcinogenesis<br />OncogenicDNAViruses: EBV<br /><ul><li>EBV gene LMP-1 (latent membrane protein-1):</li></ul>acts as oncogene  behaves like a constitutively active CD40 receptor  stimulate B cell growth<br />Activate NFκβ and JAK/STAT signalling pathways<br />Promote B cell survival and proliferation<br />Activate BCL2 – prevent apoptosis<br />Induce expression of pro-angiogenic factors (VEGF, FGF-2, MMP9, COX2)<br />
  53. 53. Microbial Carcinogenesis<br />OncogenicDNAViruses: EBV<br /><ul><li>EBV gene EBNA-2 </li></ul>Encodes a nuclear protein that mimics a constitutively active Notch receptor<br />Transactivates several host genes  cyclin D and src family of proto-oncogenes<br />
  54. 54. Microbial Carcinogenesis<br />OncogenicDNAViruses: EBV<br /><ul><li>EBV genome contains a viral cytokine vIL-10 hijacked from the host genome  prevent macrophages and monocytes from activating T cells
  55. 55. Impair immune competence  allow sustained B-cell proliferation
  56. 56. Cause translocations that activate c-MYC oncogene</li></li></ul><li>Microbial Carcinogenesis<br />OncogenicDNAViruses: HBV and HCV<br /><ul><li>Genomes do not encode any viral oncoproteins
  57. 57. No consistent pattern of integration in liver cells
  58. 58. Immunologically-mediated chronic inflammation with hepatocyte death  regeneration and genomic damage</li></li></ul><li>
  59. 59.
  60. 60.
  61. 61.
  62. 62. Microbial Carcinogenesis<br />Helicobacter pylori<br /><ul><li>First bacterium classified as a carcinogen
  63. 63. Implicated in gastric adenocarcinoma and gastric lymphomas
  64. 64. Involves increased epithelial cell proliferation in a background of chronic inflammation  contain genotoxic agents such as ROS</li></li></ul><li>Microbial Carcinogenesis<br />Helicobacter pylori<br /><ul><li>Contains a “pathogenicity island” that contains cytotoxin-associated A (CagA) gene
  65. 65. Penetrates into gastric epithelial cells  initiate signalling cascade that mimics unregulated growth factor stimulation
  66. 66. Additional mutations may be acquired (e.g. (11:18) translocation)  cause constitutive activation of NF-κβ</li></li></ul><li>
  67. 67.
  68. 68.
  69. 69. Tumor Immunity<br />Immune surveillance<br /><ul><li>A normal function of the immune system is to survey the body for emerging malignant cells and destroy them
  70. 70. (+) lymphocytic infiltrates around tumors and in LN draining sites of cancer
  71. 71. Increased incidence of cancer in immunocompromised individuals
  72. 72. Demonstration of tumor-specific T cells and antibodies</li></li></ul><li>Tumor Immunity<br />Tumor antigens<br /><ul><li>Poorly immunogenic
  73. 73. Initially classified as:</li></ul>Tumor-specific antigens<br /><ul><li>Present only on tumor cells and not on any normal cells</li></ul>Tumor-associated antigens<br /><ul><li>Present on tumor cells and also on some normal cells</li></li></ul><li>Tumor Immunity<br />Tumor antigens<br /><ul><li>Modern classification based on molecular structure and source</li></ul>Products of mutated genes<br /><ul><li>Synthesized in cytoplasm of tumor cells  enter class I or class II MHC pathways
  74. 74. Not present in normal cells  do not induce self-tolerance</li></li></ul><li>Tumor Immunity<br />Tumor antigens<br />Overexpressed or aberrantly expressed cellular proteins<br /><ul><li>May be normal cellular proteins abnormally expressed in tumor cells  elicit immune response</li></li></ul><li>Tumor Immunity<br />Tumor antigens<br />Antigens produced by oncogenic viruses<br /><ul><li>Most potent: proteins produced by latent DNA viruses (e.g. HPV and EBV)</li></li></ul><li>Tumor Immunity<br />Tumor antigens<br />Oncofetal antigens (CEA, AFP)<br /><ul><li>Proteins that are expressed at high levels on cancer cells and in normal developing (fetal) but not adult tissues
  75. 75. Genes silenced during development and activated during malignant transformation</li></li></ul><li>
  76. 76. Tumor Immunity<br />Tumor antigens<br />Altered cell surface glycolipids and glycoproteins<br /><ul><li>Include gangliosodes, blood group antigens, and mucins present at higher levels in cancer cells than on normal cells
  77. 77. Melanomas: high levels of gangliosides GM2, GD2, and GD3
  78. 78. Target for cancer therapy with specific antibodies</li></li></ul><li>Loss of normal topology and polarization of epithelial cells in cancer results in secretion of mucins into the bloodstream. The tumor cells invading the tissues and bloodstream also present such mucins on their cell surfaces<br />
  79. 79. Cancer cells entering the bloodstream form complex thromboemboli with platelets and leukocytes, which are thought to facilitate arrest at ectopic sites, assist interactions with the endothelium, and help in evasion of the immune system. Current data suggest that this phenomenon can be explained by interactions between platelet and/or endothelial P-selectin and carcinoma mucins. <br />
  80. 80. Tumor Immunity<br />Tumor antigens<br />Cell type-specific differentiation antigens<br /><ul><li>Specific for particular lineages or differentiation stages of various cell types
  81. 81. Typically normal self-antigens  do not induce immune response
  82. 82. Potential targets for immunotherapy and for identifying the tissue of origin of tumors</li></li></ul><li>
  83. 83.
  84. 84. Tumor Immunity<br />Anti-tumorEffector Mechanisms<br />Cytotoxic T lymphocytes<br /><ul><li>Play a protective role against virus-associated neoplasms
  85. 85. Demonstrated in blood and tumor infiltrates of cancer patients</li></li></ul><li>In this diagram the various mechanisms elicited by stress for stimulating innate and adaptive immunity against cancer are illustrated. <br />
  86. 86. Tumor Immunity<br />Anti-tumorEffector Mechanisms<br />Natural killer cells<br /><ul><li>Capable of destroying tumor cells without prior sensitization  may form first line of defense vs. Tumor
  87. 87. Activated by IL-2 and IL-5; may be activated by tumors that fail to express MHC class I antigens
  88. 88. NKG2D proteins  activating receptors; recognize stress-induced antigens expressed on tumor cells</li></li></ul><li>
  89. 89. Tumor Immunity<br />Anti-tumorEffector Mechanisms<br />Macrophages <br /><ul><li>Activated by interferon-gamma secreted by T cells and NK cells
  90. 90. Kill tumors by mechanisms similar to those used to kill microbes or by secretion of TNF</li></li></ul><li>
  91. 91. Tumor Immunity<br />Anti-tumorEffector Mechanisms<br />Antibodies <br /><ul><li>No evidence of protective effects of antitumor antibodies against spontaneous tumors
  92. 92. Monoclonal antibody vs. CD20 (B-cell surface antigen)  treatment of lymphomas</li></li></ul><li>Tumor Immunity<br />Tumor Evasion of Immune System<br />Selective outgrowth of antigen-negative variants<br /><ul><li>Elimination of strongly immunogenic subclones during tumor progression</li></li></ul><li>Tumor Immunity<br />Tumor Evasion of Immune System<br />Loss or reduced expression of MHC molecules<br /><ul><li>Failure to express normal levels of class I MHC molecules  escape CTLs but may trigger NK cells</li></li></ul><li>Tumor Immunity<br />Tumor Evasion of Immune System<br />Lack of co-stimulation<br /><ul><li>Express peptide antigens with class I molecules but without co-stimulatory molecules  prevent sensitization and render T cells anergic or undergo apoptosis
  93. 93. Express arginase arginine essential component of TCR  loss of T cell recognition</li></li></ul><li>Tumor Immunity<br />Tumor Evasion of Immune System<br />Immunosuppression<br /><ul><li>TGF-β secreted in large quantities by many tumors potent immuno-suppressant
  94. 94. Immune response induced by the tumor may inhibit tumor immunity by activation of T-cell inhibitory receptor CTLA4</li></li></ul><li>Tumor Immunity<br />Tumor Evasion of Immune System<br />Immunosuppression<br /><ul><li>Production of COX2  decreased IL-10 and increased IL-12  immunosuppression and promotion of metastasis</li></li></ul><li>Tumor Immunity<br />Tumor Evasion of Immune System<br />Antigen masking<br /><ul><li>Cell surface antigens of tumors may be hidden, or masked, by glycocalyx molecules expressed in greater amounts in tumor cells</li></li></ul><li>Tumor Immunity<br />Tumor Evasion of Immune System<br />Apoptosis of CTLs<br /><ul><li>Some melanomas and hepatomas express FasL kill Fas-expressing T lymphocytes that come in contact with them</li></li></ul><li>Tumor Immunity<br />Tumor Evasion of Immune System<br />Dendritic cell defects<br />Tumor secretion of growth factors  inhibit formation of DCs in bone marrow<br />Increased IL-10 levels  decreased expression of CD80 and CD86  decreased T cell activation<br />Tumor secretion of nitric oxide and hydrogen peroxide  DCs undergo cell death<br />
  95. 95.
  96. 96. Clinical Aspects of Neoplasia<br /><ul><li>Both malignant and benign tumors cause problems because of:</li></ul>Location and impingement on adjacent structures<br />Functional activity (e.g. Hormone synthesis or development of para-neoplastic syndrome)<br />Bleeding and infections due to ulceration of tumor through adjacent surfaces<br />Symptoms due to rupture or infarction<br />Cachexia or wasting<br />
  97. 97. Clinical Aspects of Neoplasia<br />Local and Hormonal Effects<br /><ul><li>Cancers arising within or metastatic to an endocrine gland  endocrine insufficiency
  98. 98. Hormone production seen in neoplasms arising in endocrine glands  more typical of benign tumor
  99. 99. Neoplasms in the gut  obstruction or intussusception</li></li></ul><li>Clinical Aspects of Neoplasia<br />Local and Hormonal Effects<br /><ul><li>Non-endocrine tumors may elaborate hormones or hormone-like products  paraneoplastic syndromes
  100. 100. Melena and hematuria characteristic of neoplasms of the gut and urinary tract</li></li></ul><li>Clinical Aspects of Neoplasia<br />Paraneoplastic Syndromes<br /><ul><li>Symptom complexes in cancer-bearing individuals that cannot readily be explained, either by the local or distant spread of the tumor or by the elaboration of hormones indigenous to the tissue from which the tumor arose</li></li></ul><li>Clinical Aspects of Neoplasia<br />Paraneoplastic Syndromes<br /><ul><li>Significance:</li></ul>May present the earliest manifestation of an occult neoplasm<br />May represent significant clinical problems in the affected patients<br />May mimic metastatic disease which may complicate treatment<br />
  101. 101. Clinical Aspects of Neoplasia<br />Paraneoplastic Syndromes<br />Endocrinopathies<br /><ul><li>Ectopic hormone production
  102. 102. Cushing syndrome – most common endocrinopathy 50% with small cell CA of lungs; due to excessive corticotropin production</li></li></ul><li>Clinical Aspects of Neoplasia<br />Paraneoplastic Syndromes<br />Hypercalcemia<br /><ul><li>Most common paraneoplastic synd.
  103. 103. Two processes involved:</li></ul>Osteolysis induced by cancer<br />Production of calcemichumoral substances in extra-osseous neoplasms<br />
  104. 104. Clinical Aspects of Neoplasia<br />Paraneoplastic Syndromes<br />Acanthosisnigricans<br /><ul><li>Gray-black patches of verrucous hyperkeratosis on the skin
  105. 105. Genetically determined; juveniles or adults</li></li></ul><li>
  106. 106. Clinical Aspects of Neoplasia<br />Cancer Cachexia<br /><ul><li>Progressive loss of body fat and lean body mass accompanied by profound weakness, anorexia, and anemia
  107. 107. Weight loss results equally from loss of fat and lean muscle
  108. 108. Due to increased basal metabolic rate despite reduced food intake</li></li></ul><li>LMF – lipid-mobilizing factor  induce breakdown of adipose into fatty acids; PIF – proteolysis-inducing factor  induce protein degradation in skeletal muscles. Tumours convert glucose to lactate, which is transferred to the liver, where it is converted back into glucose. This cycle uses a large amount of energy, and might contribute to cachexia.<br />
  109. 109. Grading and Staging<br />Cancer Grading<br /><ul><li>Based on degree of differentiation of the tumor cells and, in some cancers, the number of mitoses or architectural features
  110. 110. Provides information about potential behavior of tumor
  111. 111. Of less clinical value than staging</li></li></ul><li>
  112. 112.
  113. 113. Grading and Staging<br />Cancer Staging<br /><ul><li>Based on:</li></ul>Size of primary lesion<br />Extent of spread to regional LN<br />Presence or absence of blood-borne metastases<br /><ul><li>Gives an idea of how extensive or widespread the cancer is
  114. 114. Determines treatment and outlook for recovery</li></li></ul><li>
  115. 115.
  116. 116. Laboratory Diagnosis<br />Histologic and Cytologic Methods<br /><ul><li>Sampling approaches:</li></ul>Excision or biopsy<br /><ul><li>Quick-frozen section desirable  determine the nature of a mass lesion or in evaluating the margins of an excised cancer</li></li></ul><li>Laboratory Diagnosis<br />Histologic and Cytologic Methods<br /><ul><li>Sampling approaches:</li></ul>Fine-needle aspiration<br /><ul><li>Aspirating cells and attendant fluid with a small-bore needle
  117. 117. Used for more readily palpable lesions in breast, thyroid, and LN
  118. 118. Less invasive and more rapidly performed</li></li></ul><li>
  119. 119. Laboratory Diagnosis<br />Histologic and Cytologic Methods<br /><ul><li>Sampling approaches:</li></ul>Cytologic (Papanicolau) smears<br /><ul><li>Screen for cervical carcinoma and also endometrial CA, bron-chogenic CA, bladder and prostatic tumors, and gastric CA
  120. 120. For ID of tumor cells in abdominal, pleural, joint, and cerebrospinal fluids</li></li></ul><li>
  121. 121. Laboratory Diagnosis<br />Immunohistochemistry<br /><ul><li>Uses:</li></ul>Categorization of undifferentiated malignant tumors<br /><ul><li>(+) cytokeratins carcinoma
  122. 122. (+) desmin  muscle cell origin</li></li></ul><li>Laboratory Diagnosis<br />Immunohistochemistry<br /><ul><li>Uses:</li></ul>Determination of site of origin of metastatic tumors<br /><ul><li>Detect tissue-specific or organ-specific antigens in a biopsy specimen of the metastatic deposit (e.g. PSA)</li></li></ul><li>Laboratory Diagnosis<br />Immunohistochemistry<br /><ul><li>Uses:</li></ul>Detection of molecules that have prognostic or therapeutic significance<br /><ul><li>e.g. Detection of hormone receptors in breast cancer cells of prognostic and therapeutic value</li></li></ul><li>Laboratory Diagnosis<br />Flow Cytometry<br /><ul><li>Rapidly and quantitatively measure individual cell characteristics (e.g. Membrane antigens, DNA content of tumor cells)
  123. 123. Useful in ID and classification of tumor arising from T and B cells, and from mononuclear-phagocytic cells</li></li></ul><li>Laboratory Diagnosis<br />Molecular Techniques<br />Diagnosis of malignant neoplasms<br />Prognosis of malignant neoplasms<br />Detection of minimal residual disease<br />Diagnosis of hereditary predisposition to cancer<br />
  124. 124. Tumor Markers<br /><ul><li>Biochemical assays for tumor-associated enzymes, hormones, and other tumor markers in the blood
  125. 125. Contribute to detection of cancer
  126. 126. Useful in determining the effectiveness of therapy or appearance of recurrence</li></li></ul><li>