Introduction to Neoplasia: Understanding Tumor Growth and Development

1. ATM 3357 Pathology and Physiopathologyพยาธิวิทยาและสรีรวิทยาสำหรับการแพทย์แผนไทยประยุกต์ ผศ.(พิเศษ) ดร.นพ.ธวัชชัย กมลธรรม วท.ม. พ.บ. ส.ด. Assist.Prof.Dr.Thavatchai Kamoltham MSc.MD.FICS.FRCST.Dr.PH หน่วยกิต3 หน่วยกิต บรรยาย - ปฏิบัติ - ศึกษาด้วยตนเอง : 2– 2– 5 ชั่วโมง/สัปดาห์ ภาคเรียนภาคเรียนที่ 2 ปี 2559 ผู้เรียน นักศึกษาแพทย์แผนไทยประยุกต์ ชั้นปีที่ 3

2. คำอธิบายรายวิชา (Course Description) • Introduction to pathology • Cellular Reaction to Injury • Principal Pathology of Infection • Inflammation • Healing • Neoplasia • Hemodynamic Disorder • Hematopoiesis • Genetic Diseases • Immunopathology • Metabolic disorder • Environmental Disease • Tropical Disease

3. Neoplasia

4. WHAT IS A TUMOUR? a swelling inflammatory – abscess neoplasm - growth

5. NEOPLASM • Abnormal growth of cells which persists after initiating stimulus has been removed • Cell growth has escaped from normal regulatory mechanisms • Benign • Malignant

6. BENIGN NEOPLASM Cells grow as a compact mass and remain at their site of origin

7. MALIGNANT NEOPLASM Growth of cells is uncontrolled Cells can spread into surrounding tissue and spread to distant sites Cancer = a malignant growth

8. INTRODUCTION & DEFINITIONS • Neoplasia(Latin, new growth) is an abnormality of cellular differentiation, maturation, and control of growth. • Neoplasms are commonly recognized by the formation of masses of abnormal tissue (tumors). • The term tumor can be applied to any swelling-and in that context is one of the cardinal signs of inflammation-but today it is used most commonly to denote suspected neoplasm.

9. Neoplasms are benignormalignant depending on several features, chiefly the ability of malignant neoplasms to spread from the site of origin. • Benign neoplasms grow but remain localized. • Cancerdenotes a malignant neoplasm (the term is thought to derive from the way in which the tumor grips the surrounding tissues with claw-like extensions, much like a crab). This feature led Hippocrates to call such tumors karkinoma after karkinos.

10. "Oncology" is the study of tumors. In current usage, an oncologist is an internist or surgeon who specializes in the administration of cancer chemotherapy. • In modern usage, a tumor/neoplasm may be thought of as an attempt by the body under some stimulus to make some new sort of organ. (It develops in the wrong shape, in the wrong place, and it persists after the initiating stimulus is removed.) Tumors are like organs: • All have parenchyma and stroma. • Cells usually look similar to cells in the organ where the tumor arose. • Cells will continue to perform some of the functions of the parent organ. Tumors are different from organs: • They don't contribute to the homeostasis of the body. • They usually grow more rapidly than surrounding tissues. • Some benign and all malignant tumors never cease to grow.

11. INCIDENCE & DISTRIBUTION OF CANCER IN HUMANS • Incidence & Mortality Rates • Cancer is the second overall leading cause of death (after ischemic heart disease) in the world. The incidence continues to rise, probably reflecting the increasing average age of the population. • Major Factors Affecting Incidence • The presence or absence of any of the many factors influencing the incidence of cancer must be established during history taking and physical examination of a patient thought to have cancer.

13. Sex: • Prostate cancer in men and uterine cancer and breast cancer in women are obviously sex-specific. • In other types of cancer, the reasons for the difference in incidence between the sexes are less evident. • For example, cancer of the oropharynx, esophagus, and stomach is more than twice as common in men, but cancers of the gallbladder and thyroid and malignant melanoma are more frequent in women.

14. Age: • The frequency of occurrence of most types of cancer varies greatly at different ages. • Carcinoma is rare in children, but some leukemias, primitive neoplasms (blastomas) of the brain, kidney, and adrenal, malignant lymphomas, and some types of connective tissue tumors are relatively common. Most of these childhood neoplasms grow rapidly and are composed of small, very primitive cells with large, hyperchromatic nuclei, scant cytoplasm, and a high mitotic rate.

15. In adults, carcinomas make up the largest group of malignant tumors; they result from neoplastic change occurring in mature adult-type epithelial tissues. Sarcomas occur in adults but are less common than carcinomas. • Neoplasms of the hematopoietic and lymphoid cells (leukemias and lymphomas) occur at all ages. The incidence of different types of these neoplasms varies with age; acute lymphoblastic leukemia is common in children, whereas chronic lymphocytic leukemia occurs more often in the elderly.

16. Occupational, Social, and Geographic Factors: • Occupational factors have been mentioned with reference to an increased risk of bladder cancer in workers in the dye industry and lung cancer in certain miners. • Because the risk is so high in certain industries, an occupational history is an essential part of a full medical examination. • Similarly, such social habits as cigarette smoking represent risk factors for development of several types of cancer, and the physician must evaluate the amount of exposure to these factors during history taking.

17. Childbearing • Circumcision • Socioeconomic status • Geographic area or country • Eating and drinking habbits, • Foodstufs... are the other factors affecting the development of specific types of cancer

19. Family History: • A few cancers have a simple pattern of genetic inheritance and those that do are so striking that they warrant careful study of relatives of known cases • (eg, retinoblastoma, polyposis coli and carcinoma of the colon, medullary carcinoma of the thyroid, hereditary breast-ovary carcinoma syndromes).

20. Inherited cancer syndromes • Li-Fraumeni syndrome - p53, breast, bladder, sarcoma • Familial retinoblastoma - Rb, retinoblastoma • Xeroderma pigmentosum - XPAC, skin cancer • Hereditary Breast-OvaryCancer(HBOC)- BRCA1, BRCA2

21. History of Associated Diseases: • Perhaps the most important finding in the history of a patient with suspected cancer is a record of diagnosis or treatment of previous cancer. • A positive history of cancer greatly increases the chances that the current illness represents either a metastasis (which may be delayed many years) or a second primary tumor.

22. HOW DO TUMOURS DEVELOP? • There has to be a change to DNA • The change must cause an alteration in cell growth and behaviour • The change must be non-lethal and be passed onto daughter cells

23. 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

24. HOW DO TUMOURS DEVELOP? • Alteration is to more than one gene • Genes concerned are oncogenes/tumour suppressor genes • Sequence of gene alterations from normal to benign to malignant • Intrinsic and extrinsic / inheritance and environment key factors

25. A A A A A A B B B B B B CLONALITY Alterations in genes regulating growth and behaviour occur in every cell – monoclonal population Evidence from studying G6PD In heterozygotes cells contain either G6PD A or G6PD B, but tumours in those people consist of cells that all have the same enzyme OR NORMAL CANCER

26. HOW DO NEOPLASTIC CELLS DIFFER FROM NORMAL CELLS? Alterations in growth control • proliferation • cell death • factors regulating growth and response Alterations in cellular interactions • cell-cell • cell-stroma

27. GROWTH CONTROL • Increased cell proliferation more cells enter cell cycle cell cycle “speeded up” • Cells have changed life span • Alterations in cell death-decreased apoptosis • Modification of cell metabolism • Angiogenesis

28. GROWTH CONTROL • Increased or decreased growth factor receptors or altered receptors • Synthesis of growth factors – autocrine or paracrine effect • Excess/modified growth control proteins e.g. oncoproteins

29. Autocrine Increased DNA synthesis and proliferation Growth factor receptor = Growth factor Paracrine

30. CELLULAR INTERACTIONS Cell-cell interactions Cell-stromal interactions with basement membrane Important for cell and tissue differentiation, embryogenesis, growth regulation

31. Desmosomes Ordered Cytoskeleton Basement membrane Cell receptors Disorganised Cytoskeleton Loss of cell receptors

32. DYSPLASIA • Premalignant condition • Increased cell growth • Cellular atypia • Altered differentiation • Can range from mild to severe • Sites -cervix -bladder -stomach

33. IN-SITU MALIGNANCY Epithelial neoplasm with features of malignancy • altered cell growth • cytological atypia • altered differentiation BUT-no invasion through basement membrane

36. POSSIBLE EVENTS Benign Benign Benign Dysplasia Benign Dysplasia In-situ Benign Dysplasia In-situ Invasive Dysplasia In-situ Invasive In-situ Invasive Invasive Invasive

37. Biology of tumor growth

38. Terms to know about when discussing neoplasia • Metastasis - spread of a malignant tumor from one site to another via blood or lymph • Benign – typically refers to those tumors incapable of metastasis and having a good clinical outcome (prognosis) • Malignant – those tumors capable of invasive growth and/or metastasis, often fatal if not treated effectively

39. More terms…. • Parenchyma – these are the tumor cells themselves, usually referring to epithelial cells in organs. • Stroma – connective tissue cells that support the parenchymal cells – not actually tumor cells, but are stimulated to grow by the tumor via growth factors, eg angiogenesis

40. Cellular differentiation • Tumors are often “graded” as to how closely they resemble the normal parent tissue that they are derived from. • Well-differentiated means the cells are very similar in appearance and architectural arrangement to normal tissue of that organ

41. Normal cervical “Pap smear”

42. Malignant cervical “Pap smear”

43. Colonic “adenoma” illustrating a “well-differentiated” neoplasm similar to normal colon mucosa

44. Differentiation • “Poorly-differentiated” refers to tumors that show only minimal resemblance to the normal parent tissue they are derived from. • “Anaplastic” means the tumor shows no obvious similarity to it’s parent tissue, usually associated with aggressive behavior

45. So what?????? • Differentiation often provides clues as to the clinical aggressiveness of the tumor • Tumors often lose differentiation features over time as they become more “malignant” and as they acquire more cumulative genetic mutations • Differentiation often predicts responsiveness to certain therapies, eg estrogen receptors and Tamoxifen in breast cancers

46. Gross (macroscopic) features of two breast neoplasms Benign – circumscribed, often encapsulated, pushes normal tissue aside Malignant – infiltrative growth, no capsule, destructive of normal tissues

47. Classification of neoplasms • Epithelial tumors • Benign forms – adenoma , papilloma • Malignant forms – carcinoma, eg adenocarcinoma, squamous cell carcinoma • Mesenchymal tumors • Benign forms – fibroma, leiomyoma, • Malignant forms – sarcoma, eg fibrosarcoma, leiomyosarcoma

48. Classification continued • Tumors of lymphocytes are always malignant – called lymphoma • Tumors of melanocytes • Benign – nevus • Malignant - melanoma

49. Microscopic features of tumors • Loss of normal architectural arrangement –

50. Microscopic features of tumors • Pleomorphism – variation in size and shape of cells within the neoplasm