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.

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

10 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.

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12 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.

13 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.

14 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).

15 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.

16 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.

17 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).

18 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.

19 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.

20 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.

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

22 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.

23 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.

24 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.

25 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.

26 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.

27 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.

28 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

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

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

31 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

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

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

34 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

35 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 usesviral oncogenes

36 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

37 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

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

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

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

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

42 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

43 Tumor spread Local spread Local spread –Cellular multiplication Function of generation time Function of generation time Growth if cell reproduction > cell death Growth if cell reproduction > cell death

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

45 Lytic enzymes proteases, collagenases, plasminogen activators, lysosomal enzymes some involved in producing new blood vessels

46 Decreased cell adhesion loss of anchoring molecules allows cancer to slip between normal cells

47 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

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

49 Staging TNM system 1.Size of tumor – T 0, T 1, T 2,T 3 2.Degree of local invasion – lymph node involvement 3.Extent of spread – metastasis

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

51 Patterns of spread: Metastasis Angiogenesis Angiogenesis –Due to production of angiogenic factors –Due to drop in antiangiogenic factors

52 A metastasis grows when: vascular network is developed host defenses are evaded a compatible environment is available

53 Distribution and common sites of distant metastases often occurs in the first capillary bed encountered Others show “organ tropism” Due to: Local growth factors or hormones Preferential adherence to the surface Presence of chemotactic factors

54 Clinical manifestations of Cancer Pain Pain –Usually not in early stages –60 – 80 % of terminally ill –Psychogenic, cultural and physiologic components –Due to pressure, obstruction, stretching, tissue damage or inflammation

55 Branches of peripheral nerve are invaded by nests of malignant cells. This is often why pain associated with cancers is unrelenting.

56 Clinical manifestations of Cancer Fatigue sleep disturbances biochemical changes loss of muscle function

57 Clinical manifestations of Cancer Cachexia – wasting anorexia early satiety weight loss anemia marked weakness taste alterations altered metabolism

58 Clinical manifestations of Cancer Anemia chronic bleeding malnutrition medical therapies malignancy in blood forming organs Administer erythropoietin

59 Clinical manifestations of Cancer Leukopenia and thrombocytopenia tumor invasion of bone marrow chemotherapy or radiation

Paraneoplastic Syndromes Paraneoplastic Syndromes –Release of hormones by cancer cells –Hematological complications such as procoagulation factors –Causes weakness by attacking neuromuscular junction (similar to myasthenia gravis) 60 Clinical manifestations of Cancer

Infection Infection most significant cause of complications and death most significant cause of complications and death 61

62 Cancer Treatment Chemotherapy Chemotherapy –Cytotoxic drugs + body defenses Single agent Single agent Combination chemotherapy Combination chemotherapy –Avoids single agent resistance –Can use lower dose –Better remission and cure rate

63 Cancer Treatment Radiation targets DNA kill tumor without damage to surrounding tissues tumor must be accessible

64 Cancer Treatment Surgery method of choice can remove entire tumor debulking adjuvant chemotherapy or radiation palliation

65 Cancer Treatment Immunotherapy Nonspecific enhancement of the immune system – interferons or interleukins protect against recurrence eliminates cancer cells only T- cell based or antibody responses Conjugated antibodies

Cancer Treatment Targeted Therapies Targeted Therapies –Drugs that target the processes of cancer cells specifically Thalidomide Thalidomide –Vaccines 66

67 Side effects of treatment Gastrointestinal tract: Gastrointestinal tract: –Oral ulcers –Malabsorption –Diarrhea –Vomiting – caused by effects on CNS

68 Side effects of treatment Bone marrow: chemo and radiation suppress bone marrow decrease in red blood cells, white blood cells and platelets

69 Side effects of treatment Hair and skin: alopecia skin breakdown and dryness

70 Side effects of treatment Reproductive tract: affects gametes premature menopause also due to damage of hypothalamus and/or pituitary sperm or embryo bank