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  1. 1. Fe A. Bartolome, MD, FPASMAP Department of Pathology Our Lady of Fatima University
  2. 2. <ul><li>Neoplasia </li></ul><ul><ul><li>Process of “new growth” </li></ul></ul><ul><ul><li>State of poorly regulated cell growth in which the neoplastic cells are said to be transformed </li></ul></ul>
  3. 3. <ul><li>Neoplasm </li></ul><ul><ul><li>Abnormal mass or tissue  neoplastic mass of cells called tumor </li></ul></ul><ul><ul><ul><li>Composed of cells that grow in a poorly regulated manner </li></ul></ul></ul><ul><ul><ul><li>Cellular proliferation and growth occur in the absence of any continuing external stimulus </li></ul></ul></ul><ul><ul><ul><li>Each neoplastic cell has an alteration in its genome, responsible for abnormal growth </li></ul></ul></ul>
  4. 4. Neoplasm
  5. 5. Neoplasm Heritable genetic alterations Passed down from progeny of tumor cells Excessive and unregulated proliferation Becomes independent of physiologic growth stimuli (autonomous growth) PERSISTENCE OF TUMOR
  6. 6. Benign Tumors N O M E N C L A T U R E <ul><li>Suffix “oma” generally indicates a benign tumor  usually for tumors of mesenchymal origin </li></ul><ul><ul><li>Fibroma  fibroblastic cells </li></ul></ul><ul><ul><li>Chondroma  cartilage </li></ul></ul><ul><ul><li>Osteoma  osteoblasts </li></ul></ul>
  7. 7. Benign Tumors N O M E N C L A T U R E <ul><li>Nomenclature of benign epithelial tumors more complex  classification based on: </li></ul><ul><ul><li>Cells of origin </li></ul></ul><ul><ul><ul><li>Adenoma – derived from glands but not necessarily reproducing glandular patterns </li></ul></ul></ul><ul><ul><li>Microscopic architecture </li></ul></ul><ul><ul><li>Macroscopic patterns </li></ul></ul>
  8. 8. Benign Tumors N O M E N C L A T U R E <ul><li>Benign epithelial tumors  classification based on: </li></ul><ul><ul><li>Microscopic architecture </li></ul></ul><ul><ul><ul><li>Cystadenoma – form large cystic masses </li></ul></ul></ul><ul><ul><ul><li>Papilloma – produce papillary patterns that protrude into cystic spaces </li></ul></ul></ul><ul><ul><li>Macroscopic patterns </li></ul></ul>
  9. 9. Benign Tumors N O M E N C L A T U R E <ul><li>Benign epithelial tumors  classification based on: </li></ul><ul><ul><li>Macroscopic patterns </li></ul></ul><ul><ul><ul><li>Polyp – macroscopically visible projection above a mucosal surface </li></ul></ul></ul>
  10. 10. B Colonic polyp. A, This benign glandular tumor (adenoma) is projecting into the colonic lumen and is attached to the mucosa by a distinct stalk. B, Gross appearance of several colonic polyps.
  11. 11. Benign Tumors N O M E N C L A T U R E <ul><li>Benign tumors of connective tissue origin </li></ul><ul><ul><li>Arise from mesoderm </li></ul></ul><ul><ul><li>Example: lipoma from adipose tissue </li></ul></ul>
  12. 12. Benign Tumors N O M E N C L A T U R E <ul><li>Tumors that are usually benign: </li></ul><ul><ul><li>Mixed tumors </li></ul></ul><ul><ul><ul><li>Divergent differentiation of a single line of parenchymal cells into another tissue </li></ul></ul></ul><ul><ul><ul><li>Example: pleiomorphic adenoma of parotid gland  arise from epithelial and myoepithelial cells of salivary gland origin </li></ul></ul></ul>
  13. 13. This mixed tumor of the parotid gland contains epithelial cells forming ducts and myxoid stroma that resembles cartilage. (Courtesy of Dr. Trace Worrell, University of Texas Southwestern Medical School, Dallas, TX.)
  14. 14. Benign Tumors N O M E N C L A T U R E <ul><li>Tumors that are usually benign: </li></ul><ul><ul><li>Teratomas </li></ul></ul><ul><ul><ul><li>Arise from totipotent cells </li></ul></ul></ul><ul><ul><ul><li>Tumors that derive from more than one germ cell layer  contain tissue derived from ectoderm, endoderm, and mesoderm </li></ul></ul></ul><ul><ul><ul><li>Sites: ovaries, testes, anterior mediastinum, and pineal gland </li></ul></ul></ul>
  15. 15. A, Gross appearance of an opened cystic teratoma of the ovary. Note the presence of hair, sebaceous material, and tooth. B, A microscopic view of a similar tumor shows skin, sebaceous glands, fat cells, and a tract of neural tissue (arrow).
  16. 16. MalignantTumors N O M E N C L A T U R E <ul><li>Sarcoma - mesenchymal tissue; with little connective tissue stroma  fleshy </li></ul><ul><ul><li>Fibrosarcoma </li></ul></ul><ul><ul><li>Liposarcoma </li></ul></ul><ul><ul><li>Leiomyosarcoma </li></ul></ul><ul><ul><li>Rhabdomyosarcoma </li></ul></ul>
  17. 17. Anaplastic tumor of the skeletal muscle (rhabdomyosarcoma). Note the marked cellular and nuclear pleomorphism, hyperchromatic nuclei, and tumor giant cells. (Courtesy of Dr. Trace Worrell, University of Texas Southwestern Medical School, Dallas, TX.) NORMAL
  18. 18. MalignantTumors N O M E N C L A T U R E <ul><li>Carcinoma – epithelial cell origin </li></ul><ul><ul><li>Adenocarcinoma – glandular  lung, distal esophagus to rectum, pancreas, liver, breast, endometrium, ovaries, kidneys, prostate </li></ul></ul><ul><ul><li>Squamous cell CA – recognizable squamous cells  oropharynx, larynx, upper/middle esophagus, lung, cervix, skin </li></ul></ul><ul><ul><li>Transitional  urinary bladder, ureter, renal pelvis </li></ul></ul>
  19. 19. Malignant tumor (adenocarcinoma) of the colon. Note that compared with the well-formed and normal-looking glands characteristic of a benign tumor, the cancerous glands are irregular in shape and size and do not resemble the normal colonic glands. BENIGN MALIGNANT
  20. 20. MalignantTumors N O M E N C L A T U R E <ul><li>Nomenclatures of other tumors: </li></ul><ul><li>Lymphomas </li></ul><ul><ul><li>Lymphoid system </li></ul></ul><ul><li>Malignant melanoma </li></ul><ul><ul><li>Highly malignant tumor of melanocytes </li></ul></ul><ul><li>Leukemias </li></ul><ul><ul><li>Hematopoietic elements in BM </li></ul></ul><ul><li>Gliomas </li></ul><ul><ul><li>Non-neural support tissues of the brain (e.g. astrocytoma, oligodendroglioma) </li></ul></ul>
  21. 21. MalignantTumors N O M E N C L A T U R E <ul><li>Nomenclatures of other tumors: </li></ul><ul><li>Seminomas </li></ul><ul><ul><li>Testicular origin </li></ul></ul><ul><li>Hepatomas </li></ul><ul><ul><li>Hepatocellular carcinoma </li></ul></ul>
  22. 22. Tumor-like conditions N O M E N C L A T U R E <ul><li>Hamartoma </li></ul><ul><ul><li>Non-neoplastic overgrowth of disorganized tissue indigenous to a particular site  disorganized but mature specialized cells or tissues </li></ul></ul><ul><ul><li>Example: bronchial hamartoma, Peutz-Jeghers polyp </li></ul></ul>
  23. 23. Hamartoma of the spleen. The hamartoma is the dark circular object on the left that dominates the image. This is a cross-section, the growth being about 9cm in diameter, while the spleen is actually about 11cm.
  24. 24. Tumor-like conditions N O M E N C L A T U R E <ul><li>Choristoma </li></ul><ul><ul><li>Non-neoplastic tissue in a foreign location; ectopic rest of normal tissues </li></ul></ul><ul><ul><li>Examples: pancreatic tissue in the stomach wall; gastric mucosa in Meckel diverticulum </li></ul></ul>
  25. 25. Complex choristoma (epibulbar). Complex choristomas, in addition to having the features of a dermoid or dermolipoma, include other tissues such as cartilage, bone, and lacrimal gland. In the image above there is cartilage (arrow 1), adipose tissue (arrow 2) and lacrimal gland tissue (arrow 3).
  26. 26. <ul><li>Parenchyma </li></ul><ul><ul><li>Proliferating neoplastic cells </li></ul></ul><ul><ul><li>Determine behavior and pathologic consequences of tumor </li></ul></ul><ul><ul><li>Serve as basis for nomenclature </li></ul></ul><ul><li>Supportive stroma </li></ul><ul><ul><li>Connective tissue and blood vessels  due to failure of production of anti-angiogenic factors </li></ul></ul><ul><ul><li>Provides the framework of the parenchyma </li></ul></ul>P R O P E R T I E S Components of Benign & Malignant Tumors
  27. 27. P R O P E R T I E S <ul><li>Extent to which neoplastic cells resemble comparable normal cells, both morphologically and functionally </li></ul>Differentiation
  28. 28. P R O P E R T I E S <ul><li>IN GENERAL, BENIGN TUMORS ARE WELL-DIFFERENTIATED. </li></ul><ul><li>MALIGNANT NEOPLASMS RANGE FROM WELL-DIFFERENTIATED TO UNDIFFERENTIATED </li></ul><ul><ul><li>Malignant neoplasms composed of undifferentiated cells are said to be ANAPLASTIC </li></ul></ul>Differentiation
  29. 29. (A) Normal smooth muscle. (B) Leiomyoma of the uterus. This benign, well-differentiated tumor contains interlacing bundles of neoplastic smooth muscle cells that are virtually identical in appearance to normal smooth muscle cells in the myometrium. P R O P E R T I E S A B
  30. 30. (a) Normal colonic epithelium. (b) Benign neoplasm of colon. The cells of a benign neoplasm (b) resemble those of the normal epithelium (a), in that they are columnar and have an orderly arrangement. Loss of some degree of differentiation is evident in that the neoplastic cells do not show mucin vacuolation. P R O P E R T I E S
  31. 31. (a) Normal colonic epithelium. (c) Well-differentiated malignant neoplasm of colon. Cells of the well differentiated malignant neoplasm (c) have a haphazard arrangement and, although gland lumina ( G ) are formed, they are architecturally abnormal and irregular. Nuclei vary in shape and size. P R O P E R T I E S
  32. 32. (a) Normal colonic epithelium. (d) Poorly differentiated malignant neoplasm of colon. Cells in the poorly differentiated malignant neoplasm (d) have an even more haphazard arrangement, with very poor formation of gland lumina ( G ). P R O P E R T I E S
  33. 33. <ul><li>Degree of differentiation of a neoplasm is generally related to its behavior </li></ul><ul><ul><li>Poorly-differentiated neoplasms tend to be more aggressive than well-differentiated ones </li></ul></ul>P R O P E R T I E S Differentiation
  34. 34. <ul><li>Lack of differentiation </li></ul><ul><li>“ to form backward”  reversion from a high level of differentiation to a lower level </li></ul><ul><li>Hallmark of malignant transformation </li></ul>P R O P E R T I E S Anaplasia
  35. 35. (a) Normal colonic epithelium. (e) Anaplastic malignant neoplasm of colon. Cells in anaplastic malignant neoplasm (e) bear no relation to the normal, with no attempt at gland formation. There is tremendous variation in the size of cells and of nuclei, with very intense staining (nuclear hyperchromatism) of the latter. Without knowing the site of origin it would be impossible to tell what sort of tumor this was by histology. P R O P E R T I E S
  36. 36. <ul><li>Morphologic Changes: Anaplasia </li></ul><ul><ul><li>Pleiomorphism </li></ul></ul><ul><ul><ul><li>Variation in cellular size and shape </li></ul></ul></ul><ul><ul><li>Abnormal nuclear morphology </li></ul></ul><ul><ul><ul><li>Abundant DNA </li></ul></ul></ul><ul><ul><ul><li>Extremely dark staining (hyperchromatic) </li></ul></ul></ul><ul><ul><ul><li>Nucleus disproportionately large for the cell  N:C ratio ~ 1:1 (normal = 1:4 or 1:6) </li></ul></ul></ul><ul><ul><ul><li>Variable nuclear shape; large nucleoli </li></ul></ul></ul><ul><ul><ul><li>Coarsely clumped chromatin </li></ul></ul></ul>P R O P E R T I E S
  37. 37. <ul><li>Morphologic Changes: Malignant Tumors </li></ul><ul><ul><li>Mitoses </li></ul></ul><ul><ul><ul><li>Higher proliferative activity </li></ul></ul></ul><ul><ul><ul><li>Atypical, bizarre mitotic figures </li></ul></ul></ul><ul><ul><li>Loss of polarity </li></ul></ul><ul><ul><ul><li>Markedly disturbed orientation of anaplastic cells </li></ul></ul></ul><ul><ul><ul><li>Sheets or large masses of cells grow in a disorganized manner </li></ul></ul></ul>P R O P E R T I E S
  38. 38. <ul><li>Morphologic Changes: Malignant Tumors </li></ul><ul><ul><li>Other changes </li></ul></ul><ul><ul><ul><li>Tumor giant cells – nuclei large in relation to cell and hyperchromatic </li></ul></ul></ul><ul><ul><ul><li>Scant vascular stroma </li></ul></ul></ul><ul><ul><ul><li>Large central areas undergo ischemic necrosis </li></ul></ul></ul>P R O P E R T I E S
  39. 39. P R O P E R T I E S
  40. 40. <ul><li>Disordered growth </li></ul><ul><li>Encountered principally in epithelia </li></ul><ul><li>Changes include: </li></ul><ul><ul><li>Loss in uniformity of individual cells with loss of architectural orientation </li></ul></ul><ul><ul><li>Pleiomorphism </li></ul></ul><ul><ul><li>Hyperchromatic, abnormally large nuclei </li></ul></ul><ul><ul><li>Abundant mitotic figures that appear in abnormal locations within the epithelium </li></ul></ul>P R O P E R T I E S Dysplasia
  41. 41. <ul><li>If changes are marked and involve the entire thickness of the epithelium but the lesion remains confined to the normal tissue  pre-invasive neoplasm  CARCINOMA-IN-SITU </li></ul><ul><li>Often found adjacent to foci of invasive carcinoma </li></ul><ul><li>Does not necessarily progress to cancer but may antedate the appearance of cancer </li></ul>P R O P E R T I E S Dysplasia
  42. 42. Progression of dysplasia to neoplasia. In the diagram, as in real life, the distinction between dysplasia and in situ neoplasia is difficult and emphasis is placed on loss of normal tissue architecture to signify the development of neoplasia. The altered cell turnover in dysplasia probably allows local environmental factors to cause genetic abnormalities leading to neoplasia.
  43. 43. <ul><li>Rate of growth of tumor determined by three main factors: </li></ul><ul><ul><li>Doubling time of tumor cells </li></ul></ul><ul><ul><li>Fraction of tumor cells that are in the replicative pool </li></ul></ul><ul><ul><li>Rate at which cells are shed and lost in the growing lesion </li></ul></ul>Rates of Growth P R O P E R T I E S
  44. 44. <ul><li>Doubling time of tumor cells </li></ul><ul><ul><li>Original transformed cell must undergo at least 30 population doublings to produce 10 9 cells (weight approx. 1 gram)  smallest clinically detectable mass </li></ul></ul><ul><ul><li>10 further doublings  10 12 cells (approx. 1 kg) </li></ul></ul>P R O P E R T I E S Rates of Growth
  45. 45. P R O P E R T I E S Rates of Growth Normal cell Single tumor cell 30 doublings 1 gm – 10 9 cells Smallest clinically detectable mass 10 doublings Microscopic metastases (?) 1 kg – 10 12 cells Maximum mass compatible with life Metastases
  46. 46. <ul><li>Doubling time of tumor cells </li></ul><ul><ul><li>Range of doubling time varies from < 1 month for some childhood cancers to > 1 year for some salivary gland tumors </li></ul></ul>P R O P E R T I E S Rates of Growth
  47. 47. <ul><li>Fraction of tumor cells in the replicative pool </li></ul><ul><ul><li>Growth fraction - proportion of cells within the replicative pool </li></ul></ul><ul><ul><li>Vast majority of transformed cells are in the proliferative pool during the early, submicroscopic phase of tumor growth </li></ul></ul>Rates of Growth P R O P E R T I E S
  48. 48. <ul><li>Rate at which cells are shed and lost in the growing lesions </li></ul><ul><ul><li>As tumors continue to grow, cells leave the proliferative pool due to: </li></ul></ul><ul><ul><ul><li>Shedding </li></ul></ul></ul><ul><ul><ul><li>Lack of nutrients </li></ul></ul></ul><ul><ul><ul><li>Apoptosis </li></ul></ul></ul><ul><ul><li>Most cancer cells remain in the G0 or G1 phases  not in the replicative pool by the time tumor is clinically detectable </li></ul></ul>P R O P E R T I E S Rates of Growth
  49. 49. Schematic representation of tumor growth. As the cell population expands, a progressively higher percentage of tumor cells leaves the replicative pool by reversion to G 0 , differentiation, and death.
  50. 50. <ul><li>Rate at which cells are shed and lost in the growing lesions </li></ul><ul><ul><li>Progressive growth of tumors and the rate at which they grow are determined by an excess of cell production over cell loss </li></ul></ul><ul><ul><li>If with high growth fraction  greater cell production  more rapid growth (e.g. Small cell CA of lungs) </li></ul></ul><ul><ul><li>Low growth fraction  cell production > cell loss by 10%  slow growth </li></ul></ul>P R O P E R T I E S
  51. 51. <ul><ul><li>Fast-growing tumors may have a high cell turnover  rate of proliferation > apoptosis </li></ul></ul><ul><ul><li>Growth fraction of tumor cells has a profound effect on their susceptibility to cancer chemotherapy </li></ul></ul><ul><ul><ul><li>Low growth fraction  slow growth  refractory to treatment with drugs that kill dividing cells </li></ul></ul></ul>P R O P E R T I E S
  52. 52. <ul><ul><li>Latent period before which a tumor becomes clinically detectable is unpredictable </li></ul></ul><ul><ul><ul><li>Usually > 90 days, up to many years for solid tumors  late diagnosis </li></ul></ul></ul><ul><ul><li>Growth rate of tumors correlates with their level of differentiation </li></ul></ul><ul><ul><ul><li>Malignant tumors grow more rapidly than benign tumors </li></ul></ul></ul><ul><ul><ul><li>Rate of growth of benign and malignant tumors may not be constant over time </li></ul></ul></ul>P R O P E R T I E S
  53. 53. <ul><li>Growth rate of tumors may be affected by factors such as hormonal stimulation, adequacy of blood supply, and other influences. </li></ul>P R O P E R T I E S
  54. 54. <ul><li>Nearly all benign tumors do not have the capacity to infiltrate, invade, or metastasize to distant sites. </li></ul><ul><ul><li>Due to slow growth, develop a rim of compressed connective tissue  fibrous capsule (except leiomyoma)  keeps the tumor discrete, readily palpable, and easily movable  easy to remove surgically </li></ul></ul>P R O P E R T I E S Local Invasion
  55. 55. Benign neoplasm of thyroid gland. This low-power micrograph shows the features of a benign epithelial neoplasm. The tumor is very well circumscribed, and although it compresses adjacent tissue it does not grow into it.
  56. 56. Fibroadenoma of the breast . The tan-colored, encapsulated small tumor is sharply demarcated from the whiter breast tissue (A). Microscopic view of fibroadenoma of the breast (B). The fibrous capsule (right) delimits the tumor from the surrounding tissue. (Courtesy of Dr. Trace Worrell, University of Texas Southwestern Medical School, Dallas, TX.) A A B
  57. 57. <ul><li>Most malignant tumors are invasive. </li></ul><ul><ul><li>Next to metastasis, invasion is the second most important criterion for malignancy </li></ul></ul><ul><li>Malignant tumors are poorly demarcated from the surrounding normal tissue. </li></ul><ul><li>In situ epithelial cancers display the cytologic features of malignancy without invasion of the basement membrane. </li></ul>P R O P E R T I E S Local Invasion
  58. 58. (A) Cut section of an invasive ductal carcinoma of the breast. The lesion is retracted, infiltrating the surrounding breast substance, and would be stony hard on palpation. (B) The microscopic view of the breast carcinoma seen in (A) illustrates the invasion of breast stroma and fat by nests and cords of tumor cells. The absence of a well-defined capsule should be noted. (Courtesy of Dr. Trace Worrell, University of Texas Southwestern Medical School, Dallas, TX.) A B
  59. 59. <ul><li>Metastases - tumor implants discontinuous with the primary tumor </li></ul><ul><li>All cancers can metastasize. Major exceptions are: gliomas (glial cells of CNS) and basal cell carcinoma of skin </li></ul><ul><li>The more aggressive, the more rapidly growing, and the larger the primary neoplasm, the greater the likelihood of metastasis. </li></ul>P R O P E R T I E S Metastasis
  60. 61. Pathways of Spread <ul><li>Lymphatic Spread </li></ul><ul><ul><li>Most common pathway for initial spread of carcinomas </li></ul></ul><ul><ul><li>Tumors without functional lymphatics  lymphatic vessels at tumor margins sufficient for lymphatic spread </li></ul></ul>P R O P E R T I E S
  61. 62. Pathways of Spread <ul><li>Lymphatic Spread </li></ul><ul><ul><li>Regional lymph nodes are the first line of defense against the spread of a carcinoma </li></ul></ul><ul><ul><ul><li>If nodal architecture is destroyed  malignant cells enter efferent lymphatics  empty into the bloodstream  metastasis to different organs </li></ul></ul></ul>P R O P E R T I E S
  62. 63. Pathways of Spread <ul><li>Lymphatic Spread </li></ul><ul><ul><li>Pattern of LN involvement follows the natural routes of lymphatic drainage </li></ul></ul><ul><ul><ul><li>Breast CA usually arise in the upper outer quadrants  spread first to axillary LN </li></ul></ul></ul><ul><ul><ul><li>Lung CA  perihilar tracheo-bronchial and mediastinal nodes </li></ul></ul></ul>P R O P E R T I E S
  63. 64. Pathways of Spread <ul><li>Lymphatic Spread </li></ul><ul><ul><li>Nodal enlargement in proximity to a cancer does not necessarily mean dissemination of the primary lesion </li></ul></ul><ul><ul><ul><li>Enlargement of nodes may be caused by: </li></ul></ul></ul><ul><ul><ul><ul><li>Spread and growth of cancer cells </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Reactive hyperplasia </li></ul></ul></ul></ul>P R O P E R T I E S
  64. 65. Lymphatic invasion by tumor. (a) Histology of invasion of lymphatic vessel. (b) Tumor in para-aortic lymph nodes. Micrograph (a) shows malignant cells ( M ) in a small lymphatic vessel. Cells break off from the primary tumor, enter small lymphatics and are carried to lymph nodes, where they frequently grow as metastases. The macroscopic appearance of tumor in nodes is shown in (b); the nodes ( N ) are enlarged and replaced by tumor which, in this instance, originated from the testis.
  65. 66. Pathways of Spread <ul><li>Hematogenous Spread </li></ul><ul><ul><li>Typical of sarcomas but also seen with carcinomas </li></ul></ul><ul><ul><li>Arteries less readily penetrated as veins due to thicker walls </li></ul></ul><ul><ul><ul><li>Arterial spread may occur when tumor cells pass through pulm. capillary beds or pulmonary A-V shunts </li></ul></ul></ul>P R O P E R T I E S
  66. 67. Pathways of Spread <ul><li>Hematogenous Spread </li></ul><ul><ul><li>Tumor cells can spread via the veins draining the primary lesion </li></ul></ul><ul><ul><ul><li>Gastrointestinal tumors  portal vein  liver metastasis </li></ul></ul></ul><ul><ul><li>Tumor cells that enter systemic veins most frequently form metastases in the lungs, BM, brain, and adrenal glands </li></ul></ul>P R O P E R T I E S
  67. 68. Pathways of Spread <ul><li>Hematogenous Spread </li></ul><ul><ul><li>Renal cell carcinoma  branches of the renal vein  IVC  right side of heart </li></ul></ul><ul><ul><li>Hepatocellular carcinoma  portal and hepatic radicles  main venous channels </li></ul></ul>P R O P E R T I E S
  68. 69. Main sites of blood-borne metastasis. (a) Sites of hematogenous metastasis. (b) Metastasis in bone. (c) Metastasis in brain. (d) Metastasis in liver. (e) Metastasis in adrenals. (f) Metastasis in lungs. P R O P E R T I E S
  69. 70. Pathways of Spread <ul><li>Direct Seeding of Body Cavities & Surfaces </li></ul><ul><ul><li>May occur whenever a malignant neoplasm penetrates into a natural “open field”  most often involves peritoneal cavity </li></ul></ul><ul><ul><ul><li>Serous cystadenocarcinoma of ovaries  omentum </li></ul></ul></ul><ul><ul><ul><li>Peripherally located lung CA  parietal and visceral pleura </li></ul></ul></ul><ul><ul><ul><li>Glioblastoma multiforme  CSF  brain and spinal cord </li></ul></ul></ul>P R O P E R T I E S
  70. 71. Monoclonality <ul><ul><li>Benign and malignant tumors derive from a single precursor cell </li></ul></ul><ul><ul><li>Non-neoplastic proliferations derive from multiple cells (polyclonal) </li></ul></ul>P R O P E R T I E S
  71. 72. Telomerase activity <ul><ul><li>Telomerase preserves length of telomeres (sequences of non-transcribed DNA at the ends of chromosomes)  prevent gene loss after multiple cell divisions </li></ul></ul>P R O P E R T I E S
  72. 73. Telomerase activity <ul><ul><li>Benign tumors have normal telomerase activity </li></ul></ul><ul><ul><li>Malignant tumors have increased telomerase activity  do not lose genetic material after multiple cell divisions </li></ul></ul>P R O P E R T I E S
  73. 74. Comparisons Between Benign & Malignant Tumors Characteristics Benign Malignant Differentiation/ anaplasia Well-differentiated; structure may be typical of tissue of origin Some lack of differentiation with anaplasia; structure is often atypical Rate of growth Usually progressive & slow; may come to a standstill or regress; mitotic figures rare and normal Erratic (may be slow to rapid); mitotic figures may be numerous and abnormal Local invasion Usually cohesive and expansile well-demarcated masses that do not invade or infiltrate surrounding normal tissues Locally invasive, infiltrating the surrounding normal tissues; sometimes may be seemingly cohesive and expansile Metastasis Absent Frequently present Telomerase activity Normal Increased
  74. 75. Comparisons Between Benign & Malignant Tumors Characteristics Benign Malignant Histology Resembles cell of origin Shows failure of cellular differentiation Few mitoses Many mitoses, some of which are abnormal forms Normal or slight increase in nuclear/cytoplasmic ratio High nuclear/cytoplasmic ratio Cells are uniform throughout the tumor Cellular and nuclear pleiomorphism
  75. 76. E P I D E M I O L O G Y Cancer Incidence <ul><li>Most common tumors in men (in decreasing order): </li></ul><ul><ul><li>Prostate </li></ul></ul><ul><ul><li>Lung </li></ul></ul><ul><ul><li>Colorectal </li></ul></ul><ul><li>Most common tumors in women (in decreasing order): </li></ul><ul><ul><li>Breast </li></ul></ul><ul><ul><li>Lung </li></ul></ul><ul><ul><li>Colon and rectum </li></ul></ul>
  76. 77. E P I D E M I O L O G Y Cancer Incidence <ul><li>Most common tumors in children (in decreasing order): </li></ul><ul><ul><li>Acute lymphoblastic leukemia </li></ul></ul><ul><ul><li>CNS tumors (e.g. Cerebellar astrocytoma) </li></ul></ul><ul><ul><li>Burkitt’s lymphoma </li></ul></ul>
  77. 79. E P I D E M I O L O G Y Cancer Mortality Rate <ul><li>Cancers of the lung, female breast, prostate and colon/rectum constitute > 50% of cancer diagnosis and deaths (U.S. population) </li></ul><ul><li>Overall age-adjusted cancer death rate has increased in men  attributed to lung cancer </li></ul>
  78. 80. E P I D E M I O L O G Y Cancer Mortality Rate <ul><li>Overall age-adjusted cancer death rate has decreased in women  attributed to decline in death rates from cancers of the uterus, stomach, liver, and cervix </li></ul><ul><ul><li>CA of the breast 2.5x more common than lung cancer </li></ul></ul><ul><li>Striking increase in death from cancer of the lungs for both sexes </li></ul>
  79. 81. E P I D E M I O L O G Y Cancer and Geography <ul><li>Worldwide </li></ul><ul><ul><li>Malignant melanoma increasing at the most rapid rate of all cancers </li></ul></ul><ul><li>China </li></ul><ul><ul><li>Nasopharyngeal CA due to EBV </li></ul></ul><ul><li>Japan </li></ul><ul><ul><li>Gastric adenocarcinoma due to smoked foods </li></ul></ul><ul><li>Southeast Asia </li></ul><ul><ul><li>Hepatocellular CA due to HBV + aflatoxin in food </li></ul></ul><ul><li>Africa </li></ul><ul><ul><li>Burkitt’s lymphoma due to EBV & Kaposi’s sarcoma due to HHV8 </li></ul></ul>
  80. 82. E P I D E M I O L O G Y Cancer and Geography Most of the geographic differences are due to environmental and cultural factors rather than genetic predisposition.
  81. 83. E P I D E M I O L O G Y Cancer & Environmental Factors <ul><li>Lifestyles & personal exposures </li></ul><ul><ul><li>Overweight & obese  higher death rate from cancer as compared to slim individuals </li></ul></ul><ul><ul><li>Alcohol abuse  CA of oropharynx, larynx, esophagus, pancreas, liver </li></ul></ul><ul><ul><li>Cigarette smoking  CA of mouth, pharynx, larynx, esophagus, pancreas, lungs, and bladder </li></ul></ul><ul><ul><li>Age at first intercourse & number of sex partners  cervical cancer </li></ul></ul>
  82. 84. E P I D E M I O L O G Y Age <ul><li>Most cancers occur in the later years of life ( > 55 years)  40 – 79 y/o in women; 60 – 79 y/o in men </li></ul><ul><li>Children under 15 y/o </li></ul><ul><ul><li>10% of all cancer deaths in the U.S. second only to accidents </li></ul></ul><ul><ul><li>Acute leukemia & neoplasms of CNS = 60% of all cancer deaths in children </li></ul></ul><ul><ul><li>Neuroblastoma, Wilms tumor, retinoblastoma, acute leukemia, rhabdomyosarcoma </li></ul></ul>
  83. 85. E P I D E M I O L O G Y Reported Deaths for the 5 Leading Cancer Types for Males by Age (US, 2000) All ages < 20 20 – 39 40 – 59 60 – 70 80+ Lung & bronchus Leukemia Brain and CNS Lung and bronchus Lung and bronchus Lung and bronchus Prostate Brain and CNS Leukemia Colon and rectum Colon and rectum Prostate Colon & rectum Bones & joints Lung and bronchus Pancreas Prostate Colon and rectum Pancreas Endocrine system NHL Esophagus Pancreas Urinary bladder NHL NHL Colon & rectum Liver NHL Leukemia
  84. 86. E P I D E M I O L O G Y Reported Deaths for the 5 Leading Cancer Types for Females by Age (US, 2000) All ages < 20 20 – 39 40 – 59 60 – 70 80+ Lung & bronchus Leukemia Breast Breast Lung and bronchus Lung and bronchus Breast Brain and CNS Uterine cervix Lung and bronchus Breast Colon and rectum Colon & rectum Endocrine system Leukemia Colon and rectum Colon and rectum Breast Pancreas Bones & joints Lung and bronchus Ovary Pancreas Pancreas Ovary Soft tissue Brain and CNS Pancreas Ovary NHL
  85. 87. Average 5-year survival rates for common neoplasms . The chances of surviving for 5 years after diagnosis vary greatly according to the type of neoplasm.
  86. 88. G E N E T I C S <ul><li>For a large number of cancer types, there exist not only environmental influences but also hereditary predisposition. </li></ul><ul><li>Less than 10% of cancer patients have inherited mutations that predispose to cancer. </li></ul><ul><li>Genes that are causally associated with cancers that have a strong hereditary component are generally also involved in the more common sporadic forms of the same tumor. </li></ul>
  87. 89. G E N E T I C S Categories of Genetic Predispositions to Cancer <ul><li>Autosomal Dominant Cancer Syndromes </li></ul><ul><li>Inheritance of a single mutant gene greatly increases the risk of developing a tumor </li></ul><ul><li>Inherited mutation usually a point mutation occurring in a single allele of a tumor suppressor gene </li></ul><ul><ul><li>Childhood retinoblastoma  RB tumor suppressor gene </li></ul></ul><ul><ul><li>Familial adenomatous polyposis  adenomatous polyposis coli ( APC ) gene </li></ul></ul>
  88. 90. G E N E T I C S <ul><li>Autosomal Dominant Inherited – FEATURES: </li></ul><ul><ul><li>In each syndrome, tumors involve specific sites & tissues, although they may involve more than one site. </li></ul></ul><ul><ul><ul><li>MEN-2  RET protooncogene  thyroid, parathyroid, and adrenals </li></ul></ul></ul><ul><ul><li>Tumors are often associated with a specific marker phenotype. </li></ul></ul><ul><ul><ul><li>e.g. With multiple benign tumors in the affected tissue in MEN </li></ul></ul></ul><ul><ul><li>As in other autosomal dominant conditions, both incomplete penetrance and variable expressivity occur. </li></ul></ul>
  89. 91. G E N E T I C S Selected Autosomal Dominant Cancer Syndromes Syndrome Gene involved Features Retinoblastoma RB suppressor gene on chr. 13 Malignancy of eye in children; with predisposition for osteogenic sarcoma in adolescence Familial adenomatous polyposis APC suppressor gene Malignant transformation of polyps by age 50 Li-Fraumeni synd. TP53 suppressor gene Inc. risk for sarcomas, leukemia, carcinomas (e.g. Breast) before age 50
  90. 92. G E N E T I C S Inherited Predisposition to Cancer Inherited Cancer Syndromes (Autosomal Dominant) Gene Inherited Predisposition RB p53 p161NK4A APC NF1, NF2 BRCA1, BRCA2 MEN-1, RET MSH2, MLH1, MSH6 PATCH Retinoblastoma Li-Fraumeni Synd. (various tumors) Melanoma Familial adenomatous polyposis/colon cancer Neurofibromatosis 1 and 2 Breast and ovarian tumors MEN-1, MEN-2 Hereditary nonpolyposis colon cancer Nevoid basal cell carcinoma syndrome
  91. 93. G E N E T I C S <ul><li>Defective DNA Repair Syndromes </li></ul><ul><li>Defects in DNA repair lead to DNA instability </li></ul><ul><li>Generally autosomal recessive </li></ul><ul><li>Includes: </li></ul><ul><ul><li>Xeroderma pigmentosum </li></ul></ul><ul><ul><ul><li>Increased risk for developing skin cancers due to UVL (produce pyrimidine dimers) </li></ul></ul></ul><ul><ul><ul><li>Includes basal cell CA, squamous cell carcinoma </li></ul></ul></ul>
  92. 95. G E N E T I C S <ul><li>Defective DNA Repair Syndromes </li></ul><ul><li>Includes: </li></ul><ul><ul><li>Chromosome instability syndromes </li></ul></ul><ul><ul><ul><li>Chromosomes susceptible to damage by ionizing radiation and drugs; predisposition to cancer </li></ul></ul></ul><ul><ul><ul><li>Includes: Fanconi anemia, ataxia telangiectasia, Bloom syndrome </li></ul></ul></ul>
  93. 96. Telangiectasia
  94. 97. G E N E T I C S <ul><li>Defective DNA Repair Syndromes </li></ul><ul><li>Includes: </li></ul><ul><ul><li>Hereditary non-polypoid colon cancer (HNPCC) </li></ul></ul><ul><ul><ul><li>most common cancer predisposition syndrome  CA in colon, small intestine, endometrium, ovary </li></ul></ul></ul>
  95. 98. G E N E T I C S <ul><li>Familial Cancers </li></ul><ul><li>No clearly defined pattern of transmission; increased frequency in families </li></ul><ul><li>Seen in virtually all the common types of cancers that occur sporadically </li></ul><ul><li>Not associated with specific marker phenotypes </li></ul><ul><li>Features: </li></ul><ul><ul><li>Early age at onset </li></ul></ul><ul><ul><li>Tumors arise in 2 or more close relatives of the index case </li></ul></ul><ul><ul><li>Multiple or bilateral tumors </li></ul></ul>
  96. 99. G E N E T I C S Inherited Predisposition to Cancer Familial Cancers Familial clustering of cases, but role of inherited predisposition not clear for each individual Breast cancer Ovarian cancer Pancreatic cancer Inherited Autosomal Recessive Syndromes of Defective DNA Repair Xeroderma pigmentosa Ataxia-telangiectasia Bloom syndrome Fanconi anemia
  97. 100. Nonhereditary Predisposing Conditions <ul><li>Chronic Inflammation </li></ul><ul><li>Cancer develops at sites of chronic inflammation (Virchow, 1863) </li></ul><ul><ul><li>Chronic gastritis  carcinoma of stomach </li></ul></ul><ul><ul><li>Chronic colitis  carcinoma of colon </li></ul></ul><ul><ul><li>Liver cirrhosis  hepatocellular CA </li></ul></ul><ul><ul><li>Celiac disease  gut lymphoma </li></ul></ul><ul><ul><li>Autoimmune thyroiditis  thyroid lymphoma </li></ul></ul>
  98. 101. Nonhereditary Predisposing Conditions <ul><li>Mechanisms: </li></ul><ul><ul><li>Chronic inflammation  cytokine release  growth of transformed cells </li></ul></ul><ul><ul><li>Chronic inflammation  increased pool of tissue stem cells  affected by mutagens </li></ul></ul><ul><ul><li>Chronic inflammation  production of reactive oxygen species (ROS)  predispose to malignant transformation </li></ul></ul>
  99. 102. Nonhereditary Predisposing Conditions <ul><li>Precancerous Conditions </li></ul><ul><li>Non-neoplastic diseases that carry an increased risk of later development of neoplasia </li></ul><ul><ul><li>Villous adenoma  colonic CA (50%) </li></ul></ul><ul><ul><li>Cervical intraepithelial neoplasia (CIN)  cervical carcinoma </li></ul></ul><ul><ul><li>Endometrial hyperplasia  endometrial carcinoma </li></ul></ul>
  100. 103. Villous adenoma
  101. 105. Endometrial hyperplasia
  102. 106. Nonhereditary Predisposing Conditions <ul><li>Precancerous Conditions </li></ul><ul><li>MOST BENIGN NEOPLASMS DO NOT BECOME CANCEROUS ! </li></ul>
  103. 107. Acquired Preneoplastic Disorders Precursor Lesion Cancer Actinic (solar) keratosis Atypical hyperplasia of ductal epithelium of breast Third degree burn scars Chronic ulcerative colitis Complete H-mole Dysplastic nevus Endometrial hyperplasia Barrett’s esophagus Glandular metaplasia of stomach (H. pylori) Scar tissue in lung Villous adenoma of rectum Squamous cell carcinoma Adenocarcinoma Squamous cell carcinoma Adenocarcinoma Choriocarcinoma Malignant melanoma Adenocarcinoma Adenocarcinoma Adenocarcinoma Adenocarcinoma Adenocarcinoma
  104. 108. Prevention Modalities in Cancer <ul><li>Lifestyle modifications </li></ul><ul><ul><li>Stop smoking cigarettes </li></ul></ul><ul><ul><li>Increase fiber/decrease dietary saturated fat </li></ul></ul><ul><ul><li>Reduce alcohol intake </li></ul></ul><ul><ul><li>Reduce weight </li></ul></ul><ul><ul><ul><li>Increased adipose tissue  increased aromatase conversion of androgens to estrogen </li></ul></ul></ul><ul><ul><ul><li>Increased estrogen  increased risk for endometrial and breast cancer </li></ul></ul></ul>
  105. 109. Prevention Modalities in Cancer <ul><li>Hepatitis B vaccination </li></ul><ul><ul><li>Decreases risk for hepatocellular carcinoma due to hepatitis B-induced post-necrotic cirrhosis </li></ul></ul>
  106. 110. Prevention Modalities in Cancer <ul><li>Screening procedures </li></ul><ul><li>Cervical Papanicolau smears </li></ul><ul><li>Colonoscopy </li></ul><ul><li>Mammography </li></ul><ul><li>Prostate-specific antigen – also increased in benign prostatic hyperplasia </li></ul>
  107. 111. Prevention Modalities in Cancer <ul><li>Treatment of conditions that predispose to cancer: </li></ul><ul><li>Treatment of Helicobacter pylori infection  decrease risk for developing malignant lymphoma and adenocarcinoma of stomach </li></ul><ul><li>Treatment of GERD  decrease risk for developing distal adenocarcinomas arising from Barrett’s esophagus </li></ul>
  108. 112. E N D of P A R T 1