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1 Dr. Johnny Tang Department of Applied Biology & Chemical Technology, HKPU Department of Pathology, HKU Room Y 851 Office Tel: 3400 8727

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Presentation on theme: "1 Dr. Johnny Tang Department of Applied Biology & Chemical Technology, HKPU Department of Pathology, HKU Room Y 851 Office Tel: 3400 8727"— Presentation transcript:

1 1 Dr. Johnny Tang Department of Applied Biology & Chemical Technology, HKPU Department of Pathology, HKU Room Y 851 Office Tel: Johnny’s Teaching and Learning Homepage: (or via Blackboard)

2 2 Introduction to General Pathology

3 3 Introduction to General Pathology: Objectives: (1)To learn the function of adaptation as it relates to health and disease; (2)To understand the disease processes in terms of etiology, pathogenesis, morphology, clinical manifestations and prognosis; (3)To learn the reliability, validity, sensitivity, specificity, and predictive value as they relate to observations and tests used in the diagnosis of disease; (4)To study the etiology of cancers, their properties, molecular bases, host and environmental factors, and the related clinical manifestations

4 4 Introduction to General Pathology Expected learning outcomes: (1)To explain the function of adaptation as it relates to health and disease; (2)To characterize the disease process in terms of etiology, pathogenesis, morphology, clinical manifestations and prognosis; (3)To explain the meanings of reliability, validity, sensitivity, specificity, and predictive value as they relate to observations and tests used in the diagnosis of disease; (4)To discuss the concepts associated with the etiology of cancer and the key features of clinical manifestations

5 5 Introduction to General Pathology Recommended Textbook Porth C. M. (2004 or newer). Pathophysiology. Concepts of Altered Health States. (5th or newer edition). Philadelphia: Lippincott Other Textbooks Nowak T.J. (2004 or newer). Pathophysiology: Concepts and applications for health care professionals (3 rd or newer edition). McGraw Hill Higher Education Carlson J. H. (1999 or newer). Pathophysiology (2 nd or newer edition). Philadelphia: Lippincott Mera S. L. (1997 or newer). Understanding disease: pathology and prevention. Cheltenham: Stanley Thomas Publishers Ltd. McCance K. L. & Huether S. E. (2002 or newer). Pathophysiology: The biologic basis for disease in adults and children. (3 rd or newer edition). St. Louis: Mosby

6 6 State of complete physical, mental, and social well- being and not merely the absence of disease and infirmity US Department of Health and Human Services: interaction between an individual’s biology and behavior, physical and social environments, government policies and interventions, and access to quality health care Health – WHO’s Definition

7 7 Body’s physical and psychological adaptation to many stresses Adaptation is affected by: Availability of adaptive responses Ability of body to select the most appropriate response Decreased capacity of adaptation: Immaturity of infant Elderly Health and Disease as States of Adaptation

8 8 Disease – any deviation from or interruption of the normal structure or function of a part, organ, or system of the body that is manifested by a characteristic set of symptoms or signs Pathophysiology – cellular and organ changes that occur with disease; effects on total body function; mechanisms of disease Aspects of disease processes – etiology, pathogenesis, morphological changes, clinical manifestations, diagnosis, and clinical course Disease and Pathophysiology – A Brief Review

9 9 Etiology Etiologic agents – biologic, physical forces, chemicals, nutritional excess or deficits Defective molecules – gene defects (e.g. sickle cell anemia) Multifactorial nature of diseases, e.g. cancer – predisposition of risk factors Congenital conditions - defects present at birth; genetic and/or environmental factors Acquired defects – acquired after birth; interaction with environment Disease and Pathophysiology – A Brief Review (cont’d)

10 10 Pathogenesis Sequence of cellular and tissue events that take place from the time of initial contact with an etiologic agent until the ultimate expression of a disease Related to how disease process evolves, e.g. development of cancer after consuming food contaminated with carcinogens Disease and Pathophysiology – A Brief Review (cont’d)

11 11 Morphology Foundational structure or form of cells and tissues Changes can involve both gross anatomic and microscopic features Use of histological sections – histopathology Detection of lesion – a pathologic or traumatic discontinuity of a body organ or tissue Disease and Pathophysiology – A Brief Review (cont’d)

12 12 Clinical Manifestations Signs – a manifestation that is noted by an observer, e.g. elevated temperature Symptoms – a subjective complaint that is noted by the person with a disorder, e.g. pain and dizziness Signs and symptoms can reflect primary disorders or compensatory changes (e.g. tachycardia that accompanies blood loss) A single sign and symptom can imply different disease state, e.g. elevated temperature – infection, brain tumor, heat stroke, and many other disorders Disease and Pathophysiology – A Brief Review (cont’d)

13 13 Diagnosis Designation as to the nature or cause of a health problem Careful history and physical examination Weighing competing possibilities and selecting the most likely one – depending on age, sex, race, life-style, locality Normality of diagnostic tests; statistics Quality of data for diagnosis – reliability, validity, sensitivity, specificity and predictive value Disease and Pathophysiology – A Brief Review (cont’d)

14 14 Disease and Pathophysiology – A Brief Review (cont’d) Diagnosis (cont’d) Reliability – the accuracy for repeated observation Validity – measuring what is intended to measure? Sensitivity – how accurate is the true-positive result of a test or observation? Specificity – how accurate is the true-negative result of a test or observation? Predictive value – how good is a test or observation to predict the presence of a disease +ve predictive value – proportion of true-positive observations in a population -ve predictive value – proportion of true-negative observations in a population

15 15 Clinical Course Evolution of a disease Acute (severe), subacute and chronic (continuous; long term) course Preclinical stage of disease – not clinically evident, but destined to progress to clinical disease, e.g. hepatitis B – virus can be transmitted at preclinical stage Subclinical disease – not clinically apparent and not destined to become clinically apparent, e.g. some cases of tuberculosis; the presence is evidenced by skin test Clinical disease – with signs and symptoms Disease and Pathophysiology – A Brief Review (cont’d)

16 16 Etiology of Cancer Background of Cancer Top leading cause of death, (Dep’t of Health, HKSAR Gov’t)Dep’t of Health Affects all age groups Disorder of altered cell differentiation and growth; lacks normal regulatory controls – proliferation, differentiation, apoptosis Neoplasia – “new growth”; grows at the expense of the host The behaviors of different tumor types depend on their parachymal (functional) origins

17 17 Types of Neoplasms Benign and Malignant Neoplasms Benign tumor - well differentiated cells and clustered together in a single mass not lethal unless its size and location affect other vital functions Named with suffix –oma, e.g. adenoma, osteoma, papilloma * Malignant tumor – less differentiated and show metastasis to other sites to form secondary malignant tumor More lethal e.g. carcinoma (epithelial origin; e.g. adenocarcinoma), sarcoma (mesenchymal origin; e.g. osteosarcoma) * Etiology of Cancer

18 18 Examples of Benign and Malignant Tumors

19 19 Characteristics of Benign and Malignant Neoplasms

20 20 Benign Neoplasms Key features of benign neoplasms Slower growth than malignant tumors Inability to metastasize to distant sites Well-differentiated cells Enclosed in fibrous capsule – facilitates surgical removal, e.g. encapsulated fibroadenoma of the breast Interference on other vital functions may cause death, e.g. compressing brain structures Etiology of Cancer

21 21 Malignant Neoplasms Key features of malignant neoplasms Grow more rapidly Compress blood vessels and cause ischemia and tissue necrosis Loss of contact inhibition Metastasis Solid and hematologic (non-solid) tumors Malignancy is positively correlated to degree of anaplasia (lack of cell differentiation) *; histological assessment Altered gene expression profile; tumor markers Etiology of Cancer

22 22 Poorly and Well- differentiated Neoplasms

23 23 Malignant Neoplasms Invasion and Metastasis Invasion - spreading of cancer cells Seeding of cancer cells into body cavities, e.g. peritoneal, pleural, pericardial cavities Metastasis – development of secondary tumor in a location distant from the primary tumor; via lymph channels (lymphatic spread) or blood vessels (hematogenic spread) Metastatic sites can provide support to secondary tumor, e.g. transferrin (growth promoting) isolated from lung tissues Clonality of multiple-site tumors – metastatic tumors share common properties (molecular or chromosomal) to the primary tumor; use of clonal markers Etiology of Cancer

24 24 An Example of Detecting Chromosomal Abnormality in Cancer Cells ( Full-article is HERE ; for reference only ) HERE

25 25 Abnormal Karyotype of Esophageal Cancer Cells (SLMT-1) as Clonal Markers † † Tang JCO, et al. Cancer Genetics and Cytogenetics, 124(1), (2001)

26 26 An Example of Detecting Genetic Alterations in Esophageal Cancer ( Full-article is HERE ; for reference only) HERE

27 27 An Example of Altered Gene Expression in Esophageal Cancer ( Full-article is HERE ; for reference only ) HERE

28 28 Another Example of Applying the Knowledge of Tumor Biology in Health- related Study

29 29 Another Example of Applying the Knowledge of Cell Biology in Health- related Study (cont’d)

30 30 Another Example of Applying the Knowledge of Cell Biology in Health- related Study (cont’d) ( Full-article is HERE ; for reference only ) HERE

31 31 Other Suggested Journal Articles (Related to the Tumor Progression) 1.Novell PC. Mechanisms of Tumor Progression. Cancer Research 46: (1986)Novell PC 2.Tang JCO, et al. Progression of spontaneous lymphomas in SJL mice: monitoring in vivo clonal evolution with molecular markers in sequential splenic samples. Laboratory Investigation 78: (1998)Tang JCO

32 32 Related findings (our previous and on-going work) Genomic Instability:Comparative DNA profiling (Tang et al.) and aCGH (Law et al.) analyses Molecular Targets:GAEC1 (Law et al.) & GAEC2 (chr 7q) JS-1 (Fatima et al.) & JK-1 (Tang WK et al.) (chr 5p)JK-1 Timm22, NM3585 & NP3694 (chr 17p) ESCC Cell Lines (HK): SLMT-1 (Tang et al.), HKESC-1, HKESC-2, HKESC-3 (Hu et al.), HKESC-4 (Cheung et al.)

33 33 Invasion and Metastasis (cont’d) Primary tumors secrete enzymes to break extracellular matrix and get access to blood vessels Escape from the host immune response, e.g. forming tumor emboli with blood platelets * Express cell surface attachment factors, e.g. laminin receptors, for anchoring to capillary basement membrane Collagenase for degrading the basement membrane and migration to interstitial area to form secondary tumor Metastatic tumors secrete angiogenic factors to enable growth of new vessels – angiogenesis Malignant Neoplasms Etiology of Cancer

34 34 The Pathogenesis of Metastasis

35 35 Malignant Neoplasms Tumor Growth More cells enter cell cycle than the normal counterparts; faster growth of cancerous tissues (greater value of growth fraction and shorter doubling time) Undetectable until there are about 1 billion cells (~ 1cm in diameter) in a solid tumor * Etiology of Cancer

36 36 Growth Curve of a Tumor

37 37 Molecular Basis of Cancer Molecular mechanisms of oncogenesis Cause the transformation (changes) of normal cell physiology (functions) into cancer Involve changes of genes which control cell growth and replication: proto-oncogenes, tumor suppressor genes, genes for controlling apoptosis and DNA repairing Oncogenesis is a multi-factorial event at molecular level Oncogenes – promote growth of cancer cells; derived from mutated proto-oncogenes (e.g. change in DNA sequence, amplification, overexpression) ; targets of therapeutic agents Etiology of Cancer

38 38 Oncogenes in ESCC Growth factors, e.g. EGF, TGF, hst-1/int-2 Growth factor receptors, e.g. erbB-1 & -2, EGFR Signal transducers, e.g. c-ras, frat1 Nuclear factors, e.g. c-myc, cyclinD1, mdm-2 Epidermal growth factor receptor (EGFR) signal transduction pathways Clinical anti-epidermal growth factor receptor (EGFR) therapies Adopted from Claudia Mar´ıa Valverde C, et al. Critical Reviews in Oncology/Hematology 59, pp129, 2006

39 39 Molecular Basis of Cancer Molecular mechanisms of oncogenesis (cont’d) Tumor suppressor genes – inhibit cell proliferation in normal cells; related to normal signaling pathways* e.g. TP53 genes in chromosome 17p13 region encode p53 protein (a cell cycle regulator protein; regulator of apoptosis) mutation correlates with development of many cancers and suggested as a prognostic marker for chemo- and radiotherapy p53 also inhibits angiogenesis through induction of anti- angiogeneic factors, e.g. thrombospondin-1 Etiology of Cancer

40 40 Controls of Cell Growth and Replication

41 41 Molecular Basis of Cancer Molecular mechanisms of oncogenesis (cont’d) Three stages of cell transformation leading to malignant tumors: initiation, promotion, progression Initiation – exposure of cells to appropriate doses of carcinogenic agents; more susceptible to malignant transformation Chemical, physical or biological factors; irreversible changes of genome of normal cells Promotion – induction of accelerated growth in initiated cells Chemicals or growth factors Progression – tumor cells acquired malignant phenotypes are further promoted to increase invasiveness, metastatic competence, growth tendencies * Etiology of Cancer

42 42 Clonal Evolution of Malignant Tumors

43 43 Host and Environmental Factors for Carcinogenesis Interactions among multiple risk factors to host’s cells Risk factors: heredity, hormones, immunologic mechanisms, chemical carcinogens, radiation, oncogenic viruses Heredity Implicated in most cancer types; family history; carrier of gene mutations in cancer-related genes (oncogenes and tumor suppressor genes) Hormones Usually associated with tumors which are responsive to sex hormones, e.g. breast, ovarian, endometrial and prostate cancers Implications on hormone supplements to the cancer risk Etiology of Cancer

44 44 Host and Environmental Factors for Carcinogenesis Immunologic mechanisms Cancer development is associated with impaired immune system Increased cancer incidence found in: Patients with immunodeficiency diseases; Patients with organ transplants who received immunosuppressant drugs; Elderly in whom the immune activities have declined; B- and T-lymphocytes, antibodies, macrophages and NK cells are all involved in suppressing the growth of antigenic tumor cells Etiology of Cancer

45 45 Host and Environmental Factors for Carcinogenesis Chemical Carcinogens Dose and exposure-time dependent Two groups: direct-reacting agents and indirect-reacting agents Direct-reacting agents – no activation is required to become carcinogenic Indirect-reacting agents – become carcinogenic after metabolic conversion, e.g. a flatoxins Bind to DNA, RNA and proteins of cells to cause mutation and alterations of enzyme and structural proteins synthesis; altered cell replication and regulatory controls Life style: smoking, dietary factors, alcohol consumption Etiology of Cancer

46 46 Host and Environmental Factors for Carcinogenesis Radiation Exposure to ionizing radiation has been well correlated to cancer risk in different professions Time related - children exposed to ionizing radiation in utero increased the risk of early (2-3 yr-old) childhood leukemia; longer latency period (5 to 10 years) if exposed after birth. Exposure of sunlight (ultraviolet radiation) to risk of skin cancer – intensity, body-site and melanin dependent Etiology of Cancer

47 47 Host and Environmental Factors for Carcinogenesis Oncogenic viruses Infection related to cancer development and etiology Common examples: human papillomavirus (HPV), Epstein- Barr virus (EBV), hepatitis B virus (HBV), human herpevirus-8 (HHV-8) HPV -- squamous cell carcinoma of cervix EBV -- lymphoma, nasopharyngeal carcinoma (NPC) HBV -- hepatocellular carcinoma HHV-8 – Kaposi’s sarcoma (malignancy of endothelial cells of small blood vessels) Etiology of Cancer

48 48 Clinical Manifestations of Cancer Initial manifestations can reflect the primary site of involvement, e.g. impaired pulmonary function for lung cancer patients Other generalized manifestations are also found, e.g. fatigue, anorexia, weight loss, anemia Tissue Integrity Cancers disrupt tissue integrity, compress and erode blood vessels, leading ulceration, necrosis and possible hemorrhage Tissues damaged by cancer growth do not heal normally Obstruction of adjacent structures, e.g. abdominal cancers can cause bowel obstruction Obstruct lymph node and penetrate serous cavities, e.g. pleural effusion, ascites

49 49 Clinical Manifestations of Cancer Cancer Cachexia Weight loss, wasting of body fat and proteins, weakness, anorexia and anaemia; decrease in survival time Also called cancer anorexia-cachexia syndrome; severity increased with progression Anorexigenic factors (from damaging cells, host cells and tumors) act on the satiety centers of hypothalamus Cytokines (e.g. TNF-  from macrophages) suppress the satiety centre, induce inflammatory responses, suppress bone marrow stem cell division Hypermetabolic state – large amount lactate produced by tumors activates gluconeogenesis in liver to make more glucose to support tumor’s metabolic needs; over use of amino acids for gluconeogenesis leading to decreased muscle mass

50 50 Clinical Manifestations of Cancer Paraneoplastic Syndromes Manifestations in sites which are not directly affected by tumors Endocrinologic, hematologic, neurologic and dermatologic nature* Can be the early indications of cancer Endocrinologic type - abnormal biochemical pathways of hormone synthesis in tumors Abnormality due to changes in hormonal levels

51 51 Clinical Manifestations of Cancer Paraneoplastic Syndromes (cont’d) Hematologic type - abnormal levels of circulating mediators, e.g. procoagulation factors High risk of venous thrombosis and thrombotic endocarditis Unexplained thrombotic event may be the early indicator of malignancy Neurologic type – expression of onconeural antigens by cancer cells, leading to autoimmune destruction of nervous system Dermatologic type – growth factors produced by cancer cells Pigmented hyperkeratosis in skin

52 52 Paraneoplastic Syndromes

53 53 Diagnosis and Treatment Diagnostic methods Papanicolaou test - microscopic examination for cancer cells in secretion, e.g. nipple drainage, pleural fluid Biopsy sampling – removal of tissue specimen for microscopic examination by needle aspiration, endoscopic and laparoscopic Detection of tumor markers – proteins (antigens) overexpressed in the presence of tumor e.g. prostate-specific antigen, alpha-fetoprotein, carcinoembryonic antigen Novel markers remain to be identified

54 54 ~ END ~

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