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Neoplasia. Pathophysiology of tumors and cancer. Cells normally differentiate, grow, mature and divide. These are regulated processes, balanced in a healthy system such that cell birth is nearly equal to cell death. Regulation of cell division includes:

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  1. Neoplasia Pathophysiology of tumors and cancer

  2. Cells normally differentiate, grow, mature and divide. These are regulated processes, balanced in a healthy system such that cell birth is nearly equal to cell death

  3. Regulation of cell division includes: 1. Signaling by biochemicals released from one cell that interact with other cells growth factors or cytokines 2. Other external factors , such as contact inhibition

  4. 3. Genes and internal factors that promote and regulate cell division genes and chromosomal factors -telomeres

  5. A tumor cell’s growth is autonomous – independent of controls Neoplasm – a type of tumor – group of neoplasic cells Study of tumors is oncology from Greek for tumor

  6. Two major types: Benign and Malignant Benign: grow slowly low mitotic rate well differentiated not invasive; well-defined borders remain localized; do not metastasize

  7. Any increase in tissue size is not necessarily neoplasia. left ventricular cardiac hypertrophy due to hypertension.

  8. Hypertrophy: an increase in cell size. Increase in skeletal muscle fiber size is a physiologic response to exercise • Hyperplasia: an increase in the number of cells. Postpartum breast lobules undergo hyperplasia for lactation, but endometrial hyperplasia in a postmenopausal woman is abnormal.

  9. The endometrium seen in this uterus opened to reveal the endometrial cavity are a result of hyperplasia. However, the cells are normal in appearance. Sometimes hyperplasias can be "atypical" and the cells not completely normal. Such conditions can be premalignant.

  10. The first step toward neoplasia is cellular transformation. Metaplasia: the exchange of normal epithelium for another type of epithelium. Metaplasia is reversible when the stimulus for it is taken away. Dysplasia: a disordered growth and maturation of an epithelium, which is still reversible if the factors driving it are eliminated.

  11. This is the next step toward neoplasia. Here, there is normal cervical squamous epithelium at the left, but dysplastic squamous epithelium at the right. Dysplasia is a disorderly growth of epithelium, but still confined to the epithelium. Dysplasia is still reversible.

  12. Of course, neoplasms can be benign as well as malignant, though it is not always easy to tell how a neoplasm will act. Here is a benign lipoma on the serosal surface of the small intestine. It has the characteristics of a benign neoplasm: it is well circumscribed, slow growing, and resembles the tissue of origin (fat).

  13. At low power magnification, a lipoma of the small intestine is seen to be well demarcated from the mucosa at the lower center-right. This neoplasm is so well-differentiated that, except for its appearance as a localized mass, it is impossible to tell from normal adipose tissue.

  14. Remember that the most common neoplasm is a benign nevus (pigmented mole) of the skin, and most people have several, as seen here over the skin of the chest. As a general rule, benign neoplasms do not give rise to malignant neoplasms.

  15. Malignant – cancer Grow rapidly ; high mitotic index, poorly differentiated; do not have a capsule; invade surrounding structures; can metastasize from the primary to a secondary site (metastasis).

  16. Some epithelia are accessible enough, such as the cervix, that cancer screening can be done by sampling some of the cells and sending them to the laboratory. Here is a cervical Pap smear in which dysplastic cells are present that have much larger and darker nuclei than the normal squamous cells with small nuclei and large amounts of cytoplasm.

  17. When the entire epithelium is dysplastic and no normal epithelial cells are left, then the process is beyond dysplasia and is now neoplasia. If the basement membrane is still intact, as shown here, then the process is called "carcinoma in situ" because the carcinoma is still confined to the epithelium.

  18. This is a neoplasm. Neoplasia is uncontrolled new growth. Note the mass of abnormal tissue on the surface of the cervix. The term "tumor" is often used synonymously with neoplasm, but a "tumor" can mean any mass effect, whether it is inflammatory, hemodynamic, or neoplastic in origin. Once a neoplasm has started, it is not reversible.

  19. This is the microscopic appearance of neoplasia, or uncontrolled new growth. Here, the neoplasm is infiltrating into the underlying cervical stroma.

  20. This gastric adenocarcinoma is positive for cytokeratin by immunoperoxidase. This is a typical staining reaction for carcinomas and helps to distinguish carcinomas from sarcomas and lymphomas. Immunoperoxidase staining is helpful to determine the cell type of a neoplasm when the degree of differentiation, or morphology alone, does not allow an exact classification.

  21. Here is a small hepatic adenoma, an uncommon benign neoplasm, but one that shows how well-demarcated an benign neoplasm is. It also illustrates how function of the normal tissue is maintained, because the adenoma is making bile pigment, giving it a green color.

  22. In contrast, this hepatocellular carcinoma is not as well circumscribed (note the infiltration of tumor off to the lower right) nor as uniform in consistency. It is also arising in a cirrhotic (nodular) liver.

  23. Malignant neoplasms are also characterized by the tendency to invade surrounding tissues. Here, a lung cancer is seen to be spreading along the bronchi into the surrounding lung.

  24. This is an example of metastases to the liver. Note that the tan-white masses are multiple and irregularly sized. A primary neoplasm is more likely to be a solitary mass. Metastasis is the best indication that a neoplasm is malignant.

  25. Here are three abnormal mitoses. Mitoses by themselves are not indicators of malignancy. However, abnormal mitoses are highly indicative of malignancy. The marked pleomorphism and hyperchromatism of surrounding cells also favors malignancy.

  26. Malignant tumors – use embryonic origin of tissue Carcinomas come from ectoderm and Endoderm - epithelial and glandular tissue Sarcomas arise from mesoderm connective tissue, muscle, nerve and endothelial tissues

  27. Oncogenes in non-mutant state called proto-oncogenes stimulate cell growth and replication when turned “on” by mutation cause uncontrolled growth

  28. Tumor suppressor genes negatively regulate proliferation - antioncogenes want these to remain intact takes two “hits” to remove both genes

  29. Gene silencing regions of genes normally turned off can spread without mutation and turn off tumor suppressor genes drugs that demethylate DNA may turn genes back on

  30. Angiogenesis angiogenic factors or vascular endothelial growth factor (VEGF) possible source of new therapies

  31. Telomerase Other factors: decreased cell-to-cell adhesion secretions of proteases ability to grow in new locations

  32. Genetics and cancer prone families to be passed down, mutations must occur in germ cells inherited mutations almost always in tumor suppressor genes these individuals are targets for cancer screening

  33. Viral causes of cancer: viruses assoc. with about 15 % of cancers world wide – us. Cervix or liver hepatitis B or C in chronic form Human papilloma virus spread through sexual contact HPV integrates into DNA and uses viral oncogenes

  34. Epstein-Barr and Kaposi sarcoma both herpes viruses Human T cell leukemia-lymphoma virus blood transfusions, needles, sex and breast feeding infections may be asymptomatic may have high incidence, but low #’s of cancer cofactors increase the risk of cancer

  35. Bacterial causes of Cancer Helicobacter pylori infects >1/2 world’s population assoc. with B cell lymphomas of the stomach treatment with antibiotics can cause regression of lymphoma

  36. Environmental factors Tobacco use Diet Alcohol use Sexual and reproductive behavior Air pollution Occupation hazards – asbestos UV radiation and other radiation hormones

  37. Gene-Environment Interactions: Exposure to environmental agents can cause increased risk of cancer cancer in lab animals – carcinogens Comparisons of populations genetics vs. lifestyle

  38. “Genetics loads the gun; the environment pulls the trigger.” director of Nat’l Institute of Environmental Health & Safety

  39. Diagnosis: screening procedures and blood tests: Tumor markers substances on plasma membranes in blood, spinal fluid or urine hormones, genes antigens or antibodies

  40. Markers can be used: to screen and identify individuals at high risk to help diagnose the specific type of tumor to follow the course of the cancer

  41. Tumor spread Local spread Cellular multiplication Function of generation time Growth if cell reproduction > cell death

  42. Mechanical invasion • along path of least resistance • compresses blood vessels, leading to tissue death and increased space

  43. Lytic enzymes • proteases, collagenases, plasminogen activators, lysosomal enzymes • some involved in producing new blood vessels

  44. Decreased cell adhesion • loss of anchoring molecules allows cancer to slip between normal cells

  45. Stages of cancer spread: Stage 1 – confined to site of origin Stage 2- cancer is locally invasive Stage 3 – cancer has spread to regional structures Stage 4- cancer has spread to distant sites

  46. TNM system: tumor spread node involvement presence of distant metastasis Staging may influence choice of treatment

  47. Staging TNM system • Size of tumor – T0, T1, T2,T3 • Degree of local invasion – lymph node involvement • Extent of spread – metastasis

  48. Patterns of spread: Metastasis Direct or continuous extension By lymphatics or blood stream As clumps or as single cells Lymphatics most common

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