NEOPLASIA, cancer, Benign and malignant tumor

NEOPLASIA, cancer, Benign and malignant tumor

1. NEOPLASIA Mithun Venugopal. A Assistant Professor Dept. Of Pathology

2. What is a Neoplasia? The term ‘neoplasia’ means new growth ; the new growth produced is called ‘neoplasm’ or ‘tumour’. All ‘new growths’ are not neoplasms. Embryogenesis, regeneration and repair, hyperplasia, hormonal stimulation.

3. NORMAL CELLS The proliferation and maturation of cells in normal adults is controlled. Cells proliferate throughout life (Labile Cells) (hematopoietic stem cells, skin cells, GIT) Cells with limited proliferation (Stable Cells) (liver, endocrine glands, kidney) Cells do not replicate (Permanent Cells) (neurons, heart cells, RBC) On the other hand, neoplastic cells lose control and regulation of replication and form an abnormal mass of tissue. 3 TYPES OF CELLS

4. Define Neoplasm A neoplasm or tumour is ‘a mass of tissue formed as a result of abnormal, excessive, uncoordinated, autonomous and purposeless proliferation of cells even after cessation of stimulus for growth which caused it’. The branch of science dealing with the study of neoplasms or tumors is called Oncology ( oncos =tumour, logos=study).

5. Neoplastic Cells differs from Normal Cells An abnormal mass of tissue differs from the normal in: Growth Differentiation Organization Function

6. COMPONENTS Neoplastic Cells: Constitutes tumour parenchyma. Classification and biologic behavior is based on this. Reactive Stroma: Constitutes connective tissue, blood vessels, cells of immune system. Growth and spread are dependent on stroma.

7. CLASSIFICATION Benign : When they are slow growing and localized without causing much difficulty to the host. Malignant : When they proliferate rapidly, spread throughout the body and may eventually cause death of the host. The common term used for all malignant tumors is cancer . The word ‘cancer’ means crab, thus reflecting the true character of cancer since ‘it sticks to the part stubbornly like a crab’.

8. BENIGN TUMOURS Nomenclature can be based on: Microscopic Pattern (Example: Adenoma (derived from glandular) epithelium, may or may not form gland) Cells of Origin (Example: Renal tubular adenoma) Macroscopic Architecture (Example: papilloma (tumour with finger like projections), cystadenoma (tumour is predominantly cystic), polyp ( tomour with visible projections) The nomenclature can be a combination of these three patterns. For example ‘adenomatous polyp’ when on microscopy it is gland forming and macroscopically it is a polyp structure.

9. MALIGNANT TUMOURS Sarcomas: Tumour arising from solid mesenchymal tissues . Example: fibrosarcoma (malignant tumour of fibrous tissue), chondrosarcoma (malignant tumour of cartilage), leiomyosarcoma (malignant tumour of smooth muscle). Carcinoma: Tumour of epithelial origin . Example: squamous cell carcinoma (malignant tumour of squamous cell epithelium), adeno carcinoma (malignant tumour of glandular epithelium). Leukemias : Tumour arising from blood forming cells . Example: AML, CML, ALL, CLL. Lymphomas: Tumour arising from the lymphoid cells . Example: Hodgkins and Non- hodgkins lymphoma.

10. CANCER Vs CARCINOMA Cancer is a common term used to describe all malignant neoplasm (epithelial as well as mesenchymal). Carcinoma is a specific term used to describe malignancies arising from epithelial cells .

11. OTHER TYPES OF TUMOURS Mixed tumours: single neoplastic cell can differentiate into different types of cells. Example: pleomorphic adenoma of salivary gland. Teratoma : tumours contain mature or immature cells which are derived from more than one germ cell layer (ectoderm, endoderm, mesoderm). These tumours originate from totipotential germ cells (ovary, testis, embryonic rests). Hamartoma : benign masses where the cells are disorganized. Contain cells indigenous to the involved site. Example: hamartoma of lung and heart.

12. Blastoma : Blastomas or embryomas are a 193 group of malignant tumours which arise from embryonal or partially differentiated cells which would normally form blastema of the organs and tissue during embryogenesis. These tumours occur more frequently in infants and children. Example: neuroblastoma, nephroblastoma. Choristoma : excess of normal tissue in abnormal location. Example: pancreatic tissue mass found in stomach or small intestine. OTHER TYPES OF TUMOURS

13. BENIGN Vs MALIGNANT FEATURES BENIGN TUMOUR MALIGNANT TUMOUR 1. GROSS Boundaries Encapsulated/ well circumscribed Irregular/poorly circumscribed Surrounding tissue Often compressed Usually invaded by cancer cells Size Usually small Often larger Secondary changes (hemorrhage, necrosis, etc.) Less often More often

14. BENIGN Vs MALIGNANT FEATURES BENIGN TUMOUR MALIGNANT TUMOUR 2. MICROSCOPY Pattern Usually resembles the tissue of origin closely Often poor resemblance to tissue of origin Basal polarity Retained Often lost Pleomorphism Usually not present Often present Neucleo -Cytoplasmic ratio Normal Increased Aniso neucleosis Absent Generally present Hyper chromatism Absent Often present

15. BENIGN Vs MALIGNANT FEATURES BENIGN TUMOUR MALIGNANT TUMOUR Mitoses May be present but are always typical mitoses Mitotic figures increased and are generally atypical and abnormal Tumour giant cells May be present but without nuclear atypia Present with nuclear atypia Chromosomal abnormalities Infrequent Invariably present Function Usually well maintained May be retained, lost or become abnormal

16. BENIGN Vs MALIGNANT FEATURES BENIGN TUMOUR MALIGNANT TUMOUR 3. GROWTH RATE Usually slow Usually rapid 4. LOCAL INVASION Often compresses the surrounding tissues without invading or infiltrating them Usually infiltrates and invades the adjacent tissues 5. METASTASIS Absent Frequently present 6. PROGNOSIS Local complications Death by local and metastatic complications

17. Oncogenes An oncogene is a mutated gene that has the potential to cause cancer. Before an oncogene becomes mutated, it is called a proto-oncogene, and it plays a role in regulating normal cell division. Cancer can arise when a proto-oncogene is mutated into an oncogene and causing the cell to divide and multiply uncontrollably.

18. Oncogenes

19. Oncogenes Proto-oncogenes encode proteins that function to stimulate cell division, inhibit cell differentiation, and halt cell death. All of these processes are important for normal human development and for the maintenance of tissues and organs. Oncogenes, however, typically exhibit increased production of these proteins, thus leading to increased cell division, decreased cell differentiation, and inhibition of cell death; taken together, these phenotypes define cancer cells.

20. Oncogenes Examples: HER2 gene in breast cancer. BCR/ABL1 gene in chronic myeloid leukemia. CMYC gene in Burkitts lymphoma. NMYC gene in small cell lung cancer and neuroblastoma. EGFR and EML4AK genes in adenocarcinoma of the lung.

21. HALLMARKS OF CANCER Self sufficiency in the growth signals. Insensitivity to antigrowth/growth inhibitory signals. Evasion of apoptosis. Limitless replication potential. Sustained angiogenesis. Ability to invade and metastasize. Reprogramming energy metabolism. Evasion of immune system.

22. Self sufficiency in the growth signals Oncogenes: they promote unregulated proliferation /autonomous cell growth (Self sufficiency in the growth signals). Proto oncogenes: the unmutated genes from which the oncogenes develop after mutation.

23. Insensitivity to antigrowth/growth inhibitory signals Tumour suppressor genes produce tumour suppressor proteins which regulate the cell growth by applying breaks to cell proliferation (growth inhibition). Failure of growth inhibition is seen in carcinogenesis. Loss of function of these tumour suppressor genes is a key event in carcinogenesis.

24. TUMOUR SUPPRESSOR GENES AND ASSOCIATED TUMOURS GENE LOCATION FUNCTION ASSOCIATED TUMOURS RB Nucleus (13q14) Cell cycle Retinoblastoma, osteosarcoma TP53 Nucleus (17p13) DNA repair, apoptosis Carcinoma of lung colon, head, neck and breast APC Cytosole Cell-cell recognition Carcinoma of colon BRCA 2 Nucleus DNA repair Carcinoma of breast and ovary

25. Evasion of apoptosis Apoptosis is cell death. To divide and grow uncontrollably, the cancer cells has to escape the normal cell death. This is achieved by either disrupting the balance between pro-apoptotic and anti-apoptotic factors or by impairing the death receptor signaling.

26. Limitless replication potential Normal cell – limited cell division (due to the loss of telomere in each cell division). Telomere protect the chromosome from damage and once the telomere is completely loss, the cell undergoes death. Cancer cells - activate enzyme telomerase - make telomere long and prevent cell death.

27. Sustained Angiogenesis Angiogenesis - process by which new blood vessels form (delivery of oxygen and nutrients to the body’s tissues). The process of angiogenesis is controlled by chemical signals in the body (vascular endothelial growth factor (VEGF).   Solid tumors need a blood supply for their growth. Tumors promote angiogenesis by producing chemical signals. Tumors can also stimulate nearby normal cells to produce angiogenesis signaling molecules. The resulting new blood vessels “feed” growing tumors with oxygen and nutrients, allowing the tumor to enlarge and the cancer cells to invade nearby tissue, to move throughout the body, and to form new colonies of cancer cells, called metastases.

28. Ability to Invade and Metastasize Major cause of cancer related morbidity and mortality. This damage or destroy vital structures. Invasion: direct extension and penetration by tumour cells into neighboring tissues. Metastasis: spread tumour to sites that are physically discontinuous with the primary tumour .

29. Reprogramming energy metabolism Normally energy (ATP) is produced by 2 mechanisms: Oxidative phosphorylation in mitochondria (oxygen dependent process) - production of 36 ATP. Glycolysis in cytoplasm (oxygen independent process) - production of 2ATP. So in the presence of adequate oxygen ATP is generated by oxidative phosphorylation and as oxygen decreases this shifts to glycolysis (anaerobic glycolysis).

30. In early 20 th century a German physiologist ‘Otto Heinerich Warburg’ observed that the cancer cells had increased rates of glycolysis despite the availability of adequate oxygen levels. He called that effect as aerobic glycolysis or Warburg effect . The metabolic intermediates of aerobic glycolysis provides raw material for the synthesis of cellular components in these rapidly dividing tumour cells. Release of lactic acid lowers the extracellular pH which favors the tumour invasion and suppresses the immune effectors. Reprogramming energy metabolism Cont.

31. Evasion of Immune System

32. MORPHOLOGY OF NEOPLASTIC CELLS DIFFERENTIATION: It is defined as the extent of morphological and functional resemblance of parenchymal tumour cells to corresponding normal cells. If the deviation of neoplastic cell in structure and function is minimal as compared to normal cell, the tumour is described as ‘well-differentiated’ such as most benign and low-grade malignant tumours. ‘Poorly differentiated’ , ‘undifferentiated’ or ‘dedifferentiated’ are synonymous terms for poor structural and functional resemblance to corresponding normal cell.

33. ANAPLASIA: Anaplasia is the lack of differentiation and is a characteristic feature of most malignant tumours . Depending upon the degree of differentiation, the extent of anaplasia is also variable i.e. poorly differentiated malignant tumours have high degree of anaplasia. MORPHOLOGY OF NEOPLASTIC CELLS

34. As a result of anaplasia, following noticeable morphological and functional alterations in the neoplastic cells are observed. Loss of polarity Pleomorphism N:C ratio Anisonucleosis Hyperchromatism Nucleolar changes Mitotic figures Functional (Cytoplasmic) changes MORPHOLOGY OF NEOPLASTIC CELLS

35. Loss of polarity Normally, the nuclei of epithelial cells are oriented along the basement membrane which is termed as basal polarity. This property is based on cell adhesion molecules, particularly selectins. Early in malignancy, tumour cells lose their basal polarity so that the nuclei tend to lie away from the basement membrane.

36. Pleomorphism The term pleomorphism means variation in size and shape of the tumour cells. The extent of cellular pleomorphism generally correlates with the degree of anaplasia. Tumour cells are often bigger than normal but in some tumours they can be of normal size or smaller than normal.

37. N:C Ratio Generally, the nuclei of malignant tumour cells show more conspicuous changes. Nuclei are enlarged disproportionate to the cell size so that the nucleocytoplasmic ratio is increased from normal 1:5 to 1:1.

38. Anisonucleosis Just like cellular pleomorphism, the nuclei too, show variation in size and shape in malignant tumour cells.

39. Hyperchromatism Characteristically, the nuclear chromatin of malignant cell is increased and coarsely clumped. This is due to increase in the amount of nucleoprotein resulting in dark-staining nuclei, referred to as hyperchromatism. Nuclear shape may vary, nuclear membrane may be irregular and nuclear chromatin is clumped along the nuclear membrane.

40. Nucleolar changes Malignant cells frequently have a prominent nucleolus or nucleoli in the nucleus reflecting increased nucleoprotein synthesis.

41. Mitotic figures The parenchymal cells of poorly- differentiated tumours often show large number of mitoses as compared with benign tumours and well-differentiated malignant tumours. As stated above, these appear as either normal or abnormal mitotic figures.

42. Tumour Giant Cells Multinucleate tumour giant cells or giant cells containing a single large and bizarre nucleus, possessing nuclear characters of the adjacent tumour cells, are another important feature of anaplasia in malignant tumours.

43. Functional (Cytoplasmic) changes Structural anaplasia in tumours is accompanied with functional anaplasia as appreciated from the cytoplasmic constituents of the tumour cells.

44. GRADING AND STAGING OF CANCER ‘Grading’ and ‘staging’ are the two systems to predict tumour behaviour and guide therapy after a malignant tumour is detected. Grading is defined as the gross and microscopic degree of differentiation of the tumour, while staging means extent of spread of the tumour within the patient. Thus, grading is histologic while staging is clinical.

45. GRADING Cancers may be graded grossly and microscopically. Gross features like exophytic or fungating appearance are indicative of less malignant growth than diffusely infiltrating tumours . However, grading is largely based on 2 important histologic features: the degree of anaplasia, and the rate of growth. Based on these features, cancers are categorised from grade I as the most differentiated, to grade III or IV as the most undifferentiated or anaplastic.

46. Many systems of grading have been proposed but the one described by Broders for dividing squamous cell carcinoma into 4 grades depending upon the degree of differentiation is followed for other malignant tumours as well. Broders ’ grading is as under: Grade I: Well-differentiated (less than 25% anaplastic cells). Grade II: Moderately-differentiated (25-50% anaplastic cells). Grade III: Moderately-differentiated (50-75% anaplastic cells). Grade IV: Poorly-differentiated or anaplastic (more than 75% anaplastic cells). GRADING

47. STAGING The extent of spread of cancers can be assessed by 3 ways— by clinical examination, by investigations, and by pathologic examination of the tissue removed. Two important staging systems currently followed are: TNM staging and AJC staging .

48. TNM Staging T for primary tumour, N for regional nodal involvement, and M for distant metastases. Was developed by the UICC (Union Internationale Contre Cancer, Geneva). For each of the 3 components namely T, N and M, numbers are added to indicate the extent of involvement, as under: T0 to T4: In situ lesion to largest and most extensive primary tumour . N0 to N3: No nodal involvement to widespread lymph node involvement. M0 to M2: No metastasis to disseminated haematogenous metastases.

49. AJC Staging American Joint Committee staging divides all cancers into stage to IV , and takes into account all the 3 components of the preceding system (primary tumour, nodal involvement and distant metastases) in each stage. TNM and AJC staging systems can be applied for staging most malignant tumours.

50. Currently, clinical staging of tumours does not rest on routine radiography (X-ray, ultrasound) and exploratory surgery but more modern techniques are available by which it is possible to ‘stage’ a malignant tumour by non-invasive techniques. These include use of computed tomography (CT) and magnetic resonance imaging (MRI) scan based on tissue density for locating the local extent of tumour and its spread to other organs. More recently, availability of positron emission tomography (PET) scan has overcome the limitation of CT and MRI scan because PET scan facilitates distinction of benign and malignant tumour on the basis of biochemical and molecular processes in tumours. DIAGNOSIS

51. PREDISPOSING FACTORS OF CANCER FAMILIAL AND GENETIC FACTORS: It has long been suspected that familial predisposition and heredity play a role in the development of cancers. E xample: Retinoblastoma, Familial polyposis coli, Cancer of the breast,

52. RACIAL AND GEOGRAPHIC FACTOR: Differences in racial incidence of some cancers may be partly attributed to the role of genetic composition but are largely due to influence of the environment and geographic differences affecting the whole population such as climate, soil, water, diet, habits, customs etc. White Europeans and Americans develop most commonly malignancies of the lung, breast, and colon. Black Africans, on the other hand, have more commonly cancers of the skin, penis, cervix and liver. Indians of both sexes have higher incidence of carcinoma of the oral cavity and upper aero-digestive tract, while in females carcinoma of uterine cervix and of the breast run parallel in incidence. PREDISPOSING FACTORS OF CANCER

53. ENVIRONMENTAL AND CULTURAL FACTORS: Cigarette smoking Alcohol abuse Cancer of the cervix is linked to a number of factors such as age at first coitus, frequency of coitus, multiplicity of partners, parity etc. Certain constituents of diet have also been implicated in the causation of cancer. Overweight individuals, deficiency of vitamin A and people consuming diet rich in animal fats and low in fibre content are more at risk of developing certain cancers such as colonic cancer. PREDISPOSING FACTORS OF CANCER

54. AGE: The most significant risk factor for cancer is age. Generally, cancers occur in older individuals past 5th decade of life (two-third of all cancers occur above 65 years of age), though there are variations in age incidence in different forms of cancers. Tumours in infancy and childhood are: neuroblastoma, nephroblastoma, retinoblastoma, hepatoblastoma, rhabdomyo - sarcoma, teratoma and CNS tumors. SEX: Apart from the malignant tumours of organs peculiar to each sex, most tumours are generally more common in men than in women except cancer of the breast, gall bladder, thyroid and hypopharynx. PREDISPOSING FACTORS OF CANCER

55. CARCINOGENS A carcinogen is any substance, agent, or organism that has the potential to cause cancer. Some carcinogens, such as UV rays from sunlight, occur naturally. Others originate from artificial sources, such as cigarette smoke. Most carcinogens cause cancer by producing mutations in a cell’s DNA. Different carcinogens can cause different types of cancer. Carcinogens do not necessarily cause cancer every time someone interacts with them. However, exposure to a carcinogen can raise a person’s risk of developing certain cancers.

56. Types of Carcinogens Carcinogens are divided into three main categories. Chemical carcinogens : These are carcinogens that release into the environment through pollution, such as through car exhaust fumes, industrial by-products, and cigarette smoke. Physical or environmental carcinogens : These carcinogens come from the environment. UV rays from sunlight and radiation from X-rays or other radioactive materials are examples of physical carcinogens. Biological carcinogens : These are microbial agents that can cause cancer. Examples include human papillomavirus (HPV), Epstein-Barr, and hepatitis B.

57. Examples of Carcinogens Alcohol Asbestos Formaldehyde Processed meat Tobacco UV rays Arsenic Chloroform Coal dust and emissions Nickel Epstein-Barr virus Hepatitis B virus Hepatitis C virus Human Papilloma Virus HIV type-1 Helicobacter pylori Aspergillus flavus Oral contraceptives X-rays and gamma rays

58. CARCINOGENESIS Carcinogenesis or oncogenesis or tumorigenesis means mechanism of induction of tumours (pathogenesis of cancer) and agents which can induce tumours are called carcinogens (etiology of cancer).

59. Etiology & Pathogenesis of Cancer Molecular pathogenesis of cancer (genes and cancer) Chemical carcinogens and chemical carcinogenesis Physical carcinogens and radiation carcinogenesis Biologic carcinogens and viral oncogenesis.

60. Radiation agents Non-radiation agents UV light Mechanical injury to the tissue X-rays Healed scars following burns or trauma Radioactive isotopes Protons

61. Parasites Fungus Bacteria Schistosoma haematobium Aspergillus flavus Helicobacter pylori Clonorchis sinensis

62. TH AN K YO U…