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Epidemiology of neoplasma

EPIDEMIOLOGY OF NEOPLASM

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Epidemiology of neoplasma

  1. 1. Faculty of Medicine NEOPLSIA 2019 King Abdulaziz University Rabigh Branch EPIDEMOLOGY
  2. 2. Epidemiology
  3. 3. Neoplasia • Cancer is the 2nd leading cause of death in the United States, behind heart disease • More than 1.3 million estimated new cancer cases occur annually (female - 43.2% and male - 56.8%) resulting in more than 560,000 deaths (excluding non-melanoma skin cancer) • The probability of dying of cancer is estimated at 20-25% for individuals born in 1985, which has increased from ~15- 19% for those born in 1975
  4. 4. Why epidemiology is useful • It allows you to know what is common and what is rare. • It can provide clues to aetiology • Can facilitate planning of preventative measures • It underpins the development of screening methods for early diagnosis
  5. 5. A range of factors can influence the epidemiology of a disease Age variation Gender differences Historical variation Geographic variation Social and economic factors Occupational factors Dietary factors Genetic factors etc . . . . . . . .
  6. 6. Incidence may be related to ethnic & geographic differences in community: • Cervical Cancer: Hispanic women are significantly more likely to be diagnosed with cervical cancer than the general population • Multiple myeloma: is twice as common in African- Americans as it is in white Americans. • Chronic lymphocytic leukemia: is more common among the Jewish people of East European descent and is rather uncommon in Asia
  7. 7. Geographic Location • Gastric CA -- High in Japan • Skin CA------ High in New Zealand • Hepatocellular CA --- High in Africa, China • Breast CA ---- High in USA • Prostatic CA ---- High in USA • Colorectal CA ----High in USA • Nasopharyngeal CA--- Far East • Burkitt Lymphoma ----- Africa
  8. 8. Genetic polymorphism is responsible for : • Individual predisposition to disease • Individual response to environmental agents • Individual response to drugs
  9. 9. Environment * Diet * Occupation * Sunlight * Personal habits
  10. 10. Age • In general , cancer incidence ≈ AGE • However, certain cancers occur more in children * Acute Leukemia * Some Lymphoma * Some CNS Tumors * Bone & soft tissue Sarcomas
  11. 11. Heredity • 5-10% of tumors • Inherited Cancer Syndromes : Presence of defined genetic abnormality, usually AD, often specific phenotype e.g. – APC gene : Familial Adenomatous Polyposis Coli – MEN1 & RET genes : MEN syndrome – NF1 & NF2 genes : Neurofibromatosis – RB gene : Retinoblastoma • Familial cancers : No specific phenotype & multifactorial • Family members have higher incidence to common cancers – CA of COLON, BREAST, OVARY – Younger age groups, multiple or bilateral, two or more family members are affected. – Some linked to inheritance of mutant genes e.g. BRCA-1 & BRCA-2
  12. 12. Acquired Preneoplastic Syndromes • These are associated with increased risk for CA and most are related to rapid or abnormal cell proliferation. – Endometrial Hyperplasia & carcinoma – Cervical Dysplasia & Cervical CA – Bronchial dysplasia & lung CA – Liver Cirrhosis & Hepatocellular – Chronic healing proces – Ulcerative Colitis & Colorectal CA – Villous Adenoma & Colorectal CA – Leukoplakia & Squamous cell CA
  13. 13. Mortality statistics the big 5 in men and women Males Females Lung Lung Prostate Breast Colorectal Colorectal Oesophagus Ovary Pancreas Pancreas
  14. 14. Invasion and Metastasis • The two properties (Invasion and Metastasis) accounts for most of the serious (and lethal) consequences of neoplasia. • Metastasis is the process whereby malignant tumor cells spread from their site of origin (Primary site) to some other distant site in the body (Secondary site). • Size and differentiation of the primary neoplasm may play role in metastatic potential. • All tumors can potentially metastasize except – BASAL CELL CA ., GLIAL TUMORS
  15. 15. Invasion and Metastasis • Not all cancer have equivalent ability to metastasize: – basal cell carcinoma of the skin and most primary tumors of the CNS (glial) are highly invasive at their primary sites but rarely metastasize. – osteogenic sarcomas usually have metastasized to the lungs at the time of initial discovery.
  16. 16. Local invasion • Benign tumors remain localized at its site of origin • They expand slowly and develop an enclosing fibrous capsule (adenomas and fibromas). – Exception: leiomyoma of the uterus separated from the surroundings by a zone of compressed normal myometrium • Cancers grow by progressive infiltration, invasion, destruction, and penetration of the surrounding tissue. • Local invasiveness is the most reliable feature that distinguishes malignant from benign tumors.
  17. 17. Basal cell carcinoma of the skin • Basal cell carcinomas of the skin, the most common malignant tumor in the human body. • It is a locally invasive malignant tumor, which, if untreated, could ultimately kill the host. • These tumors are usually diagnosed early and removed adequately, so that they almost never metastasize • The neoplastic cells extend downward into the dermis. Note the pleomorphism of the cells, and there is little keratinization. Compare with the normal skin at the right. An intense inflammatory infiltrate is present.
  18. 18. Microscopic view of fibroadenoma of the breast . The fibrous capsule (below) sharply delimits the tumor from the surrounding tissue.
  19. 19. breast carcinoma illustrates the invasion of breast stroma and fat by nests and cords of tumor cells. The absence of a well-defined capsule should be noted.
  20. 20. Routes of spread • Seeding within body cavities • Lymphatic spread (typical of carcinoma) • Haematogenous spread (favored by sarcomas) • Direct transplantation of tumor cells (artificial mode of dissemination) – surgical instruments or the surgeon’s gloves
  21. 21. • Peritoneal surfaces (colon carcinoma, ovary cancers) • Pleural cavities (lung cancers) • Cerebral ventricles and then be carried by cerebrospinal fluid to reimplant on the meningeal surfaces (medulloblastoma) Seeding within body cavities Transcoelomic Spread
  22. 22. Pseudomyxoma Peritonei • Pseudomyxoma of the ovary usually results (as a complication) from peritoneal seeding of mucin- secreting tumors of the ovary (Mucinous cystadenoma of the ovary) or the gastrointestinal tract, and most often the appendix. • Although the ovarian tumor is benign, the implants of the tumor cells seeding the peritoneal cavity can be difficult to eradicate. • The cells continue to secrete mucin and fill the abdominal cavity, colloquially known as "jelly-belly."
  23. 23. Lymphatic spread (typical of carcinoma) lymph node involvement depends on : • The site of the primary • The natural lymphatic pathways of drainage of the site. Examples: • lung carcinomas: regional bronchial lymph nodes then tracheobronchial and hilar nodes. • breast carcinoma: axillary nodes then supraclavicular and infraclavicular Nodes.
  24. 24. Haematogenous spread (favored by sarcomas) Penetration of arteries are less readily than are veins. In venous invasion, • The bloodborne cells follow the venous flow, draining the site of the neoplasm. • The liver and lungs are the most frequently involved secondary sites. • Certain carcinomas invade veins early e.g. RENAL Carcinoma  renal vein IVA Hepatocellular Carcinoma Portal & Hepatic v.
  25. 25. Metastatic Pathway
  26. 26. Metastases occurs in two phases • 1- Invasion of Extracellular Matrix (ECM) • 2- Vascular dissemination
  27. 27. The main steps in the formation of a metastasis
  28. 28. 1- Mechanism of invasion of ECM 1- Detachment of tumor cells Inactivation of E-Cadherin OR activation of  catenin detachment of tumor cells Loss of function E-Cadherin in most CAs 2- Degradation of ECM by proteases :e.g. Matrix Metalloproteinase (MMPs) such as Cathepsin D, Type IV collagenase
  29. 29. 1- Mechanism of invasion of ECM 3- Attachment of tumor cells to matrix components by laminin & integrin receptors to basement membrane & ECM 4- Migration of tumor cells : Tumor derived cytokines e.g. Autocrine motility factor * Cleavage products of matrix & GF have chemotactic activity for more tumor cells
  30. 30. 2- Vascular dissemination 1- Invasion of the circulation : Adhesion to endothelium retraction of endothelium  vessel 2- Attack by NK cells, some escape by formation of a thrombus 3- Escape from circulation : Adhesion to endothelium retraction of endothelium  escape to tissue
  31. 31. What influences site of metastases ? • Anatomical Location • Complimentary adhesion molecule between tumor cells & target organs • Chemoatractants liberated by target organs • Protease inhibitors present in certain tissues
  32. 32. Examples of Tropism (Homing) • Prostatic Carcinoma  Bone • Lung Carcinoma  Adrenals & Brain • Neuroblastoma  Liver & Bone – Less common sites of metastases include skin, muscle, thyroid, breast….etc. – Spleen, Cartilage, Heart are almost never involved by metastatic tumors.
  33. 33. CARCINOGENESIS IS A MULTISTEP PROCESS
  34. 34. Cancer is a disease of the cell cycle Do you agree
  35. 35. What Is the Connection Among Cancer, the Cell Cycle, and Genetics? Cells either grow and divide with control ...or not! All kinds of malignant growth that the term "cancer" represents, all have one lethal attribute in common: The cells of the malignancy go through the cell cycle without control. These cells disobey control mechanisms that lie with them.
  36. 36. What Is the Connection Among Cancer, the Cell Cycle, and Genetics?  Many protein molecules involved in the cell cycle, each is the product of a single gene.  When there is a mutation in one of these genes, it can:  increase the likelihood that a cell will become cancerous and eventually, through repeated, unrestrained division, overtake the normal cells, become malignant;  possibly spread, or metastasise throughout the body
  37. 37. What Is the Connection Among Cancer, the Cell Cycle, and Genetics? Cancer can develop at almost any stage in life. Some forms of cancer develop very early, such as retinoblastoma (a cancer of the eye) Others tend to develop in childhood, such as various forms of leukaemia, a cancer of the blood There are many forms that develop during adulthood. In each case, cancer is the result of a mutated gene, or a series of mutated genes, that lead to unregulated cell growth and haphazard controls over cell proliferation.
  38. 38. MALIGNANT NEOPLASM (CANCER) • Is multifactorial disease (genetic, environmental) – Types of genes which may mutate to cause cancer: (tumour suppressor genes, oncogenes, DNA repair genes, telomerase, p53) – Environmental agents associated with cancer such as viruses, tobacco smoke, food, radiation, chemicals, pollution
  39. 39. • Cancer is considered as a genetic disease; occurs sporadically (somatic mutations), or as a hereditary trait. • Genes in which mutations cause cancer fall into two distinct categories: – Oncogenes – Tumor suppressor genes (TSGs) fall into two types Gatekeepers and Caretakers GENETIC BASIS OF CANCER
  40. 40. • Oncogene is a mutant allele of a proto-oncogene, whose altered function or expression results in abnormal stimulation of cell division and proliferation. – Proto-oncogene is normal gene that has physiologic function via its protein that regulate cell growth (proliferation & apoptosis) and differentiation ONCOGENES
  41. 41. ONCOGENES • Oncogenes facilitate malignant transformation by stimulating proliferation or inhibiting apoptosis. • Oncogenes have a dominant effect at the cellular level – when it is activated or overexpressed, a single mutant allele is sufficient to initiate the change in phenotype of a cell from normal to malignant.
  42. 42. ONCOGENES • The mutation can be an activating gain-of- function mutation in the coding sequence of the oncogene itself, a mutation in its regulatory elements, or an increase in its genomic copy number, leading to unregulated ectopic function of the oncogene product.
  43. 43. ONCOGENES • Activated oncogenes encode proteins such as: – proteins in signaling transduction pathways for cell proliferation (K-Ras, H-Ras, N-Ras) – receptors and cytoplasmic proteins that transduce signals – transcription factors that respond to the transduced signals and control the expression of growth-promoting genes (myc) – inhibitors of programmed cell death machinery
  44. 44. Proto-oncogene activation
  45. 45. Proto-oncogene activation • Point mutation: Ras oncogene point mutation results in decreased GTPase activity. – GTPase: enzyme that hydrolyze guanosine triphosphate. • Chromosomal rearrangement: (translocation and inversion) Philadelphia chromosomes, Burkitt’s lymphoma gene arrangement • Gene amplification
  46. 46. • Fig 16-3. Mechanisms of tumorigenesis by oncogenes of various classes. Unregulated growth factor signaling may be due to mutations in genes encoding growth factors themselves (1), their receptors (2), or intracellular signaling pathways (3). Downstream targets of growth factors include transcription factors (4), whose expression may become unregulated. Both telomerase (5) and antiapoptotic proteins that act at the mitochondria (6) may interfere with cell death and lead to tumorigenesis.
  47. 47. • TSGs are normal genes and their normal function is to regulate cell division, so can suppress the development of cancer – TSGs encode a proteins which are part of the system that regulates cell division (keeping cell division in check). • When mutated, TSGs lose their function, and as a result uncontrolled cell growth may occur – This may contribute to the development of a cancer • Both alleles need to be mutated or removed in order to lose the gene activity. – The first mutation may be inherited or somatic. – The second mutation will often be a gross event leading to loss of heterozygosity TUMOR SUPPRESSOR GENES (TSGS)
  48. 48. Knudsen’s “two hit” hypothesis explain why certain tumors can occur in both hereditary and sporadic forms
  49. 49. The Two-Hit Origin of Cancer • For example, it was suggested that the hereditary form of the childhood cancer retinoblastoma might be initiated when a cell in a person heterozygous for a germline mutation in a tumor-suppressor retinoblastoma gene, required to prevent the development of the cancer, undergoes a second, somatic event that inactivates the other allele.
  50. 50. The Two-Hit Origin of Cancer • As a consequence of this second somatic event, the cell loses function of both alleles, giving rise to a tumor. The second hit is most often a somatic mutation, although loss of function without mutation, such as occurs with transcriptional silencing (epigenetic changes), has also been observed in some cancer cells.
  51. 51. The Two-Hit Origin of Cancer • In the sporadic form of retinoblastoma, both alleles are also inactivated (two somatic events occurring in the same cell). • familial polyposis coli, familial breast cancer, neurofibromatosis type 1 (NF1), hereditary nonpolyposis colon carcinoma, and a rare form of familial cancer known as Li-Fraumeni syndrome.
  52. 52. • Gatekeeper TSGs regulate the cell cycle and control cell growth directly – they block tumor development by regulating the transition of cells through checkpoints ("gates") in the cell cycle or by promoting apoptosis and, thereby, controlling cell division and survival. – loss-of-function mutations of gatekeeper genes lead to uncontrolled cell proliferation. TUMOR SUPPRESSOR GENES (TSGS)
  53. 53. TUMOR SUPPRESSOR GENES (TSGS) • Gatekeeper TSGs encode: – regulators of various cell-cycle checkpoints – mediators of programmed cell death
  54. 54. • Caretaker TSGs are involved in repairing DNA damage and maintaining genomic integrity. – Loss of function of caretaker genes permits mutations to accumulate in proto-oncogenes and gatekeeper genes, which, in concert, go on to initiate and promote cancer. TUMOR SUPPRESSOR GENES (TSGS)
  55. 55. • Caretaker TSGs encode: – proteins responsible for detecting and repairing mutations – proteins involved in normal chromosome disjunction during mitosis – components of programmed cell death machinery TUMOR SUPPRESSOR GENES (TSGS)
  56. 56. • Loss of both alleles of genes that are involved in repairing DNA damage or chromosome breakage leads to cancer indirectly by allowing additional secondary mutations to accumulate either in proto-oncogenes or in other TSGs. TUMOR SUPPRESSOR GENES (TSGS)
  57. 57. Gene Gene product and possible function sporadic DISORDERS IN WHICH THE GENE IS AFFECTED Gatekeepers Familial Sporadic RB1 p110 Cell cycle regulation Retinoblasto ma Retinoblastoma, small cell lung carcinomas, breast cancer TP53 p53 Cell cycle regulation Li-Fraumeni syndrome Lung cancer, breast cancer, many others Selected Tumor-Suppressor Genes Caretakers Familial Sporadic BRCA1, BRCA2 Brca1, Brca2 Chromosome repair in response to double- stranded DNA breaks Transcriptional regulation and DNA repair Familial breast and ovarian cancer Breast cancer, ovarian cancer MLH1, MSH2 Mlh1, Msh2 Repair nucleotide mismatches between strands of DNA (Microsatellite instability, a marker of DNA mismatch repair) Hereditary nonpolyposis colon cancer Colorectal cancer
  58. 58. • The p53 protein is a DNA-binding protein that appears to be an important component of the cellular response to DNA damage. • In addition to being a transcription factor that activates the transcription of genes that stop cell division and allow repair of DNA damage, p53 also appears to be involved in inducing apoptosis in cells that have experienced irreparable DNA damage. TP53
  59. 59. TP53 • Loss of p53 function, therefore, allows cells with damaged DNA to survive and divide, thereby propagating potentially oncogenic mutations. The TP53 gene can therefore be considered to also be a gatekeeper TSG.
  60. 60. • Different types of genetic alterations are responsible for initiating cancer. These include mutations such as: – activating or gain-of-function mutations, including gene amplification, point mutations, and promoter mutations, that turn one allele of a proto-oncogene into an oncogene – chromosome translocations that cause misexpression of genes or create chimeric genes encoding proteins with novel functional properties – loss of function of both alleles, or a dominant negative mutation of one allele, of TSGs. Tumor Initiation & Progression
  61. 61. • Once initiated, a cancer progresses by accumulating additional genetic damage, through mutations or epigenetic silencing, of caretaker genes that encode the cellular machinery that repairs damaged DNA and maintains cytogenetic normality. • A further consequence of genetic damage is altered expression of genes that promote vascularization and the spread of the tumor through local invasion and distant metastasis. Tumor Initiation & Progression
  62. 62. • Stages in the evolution of cancer. Increasing degrees of abnormality are associated with sequential loss of tumor- suppressor genes from several chromosomes and activation of proto-oncogenes, with or without a concomitant defect in DNA repair. • Multiple lineages carrying somewhat different mutational spectra and epigenetic changes are likely, particularly once metastatic disease appears.
  63. 63. Transformation is a multistep process
  64. 64. • Some tumor-suppressor genes directly regulate proto-oncogene function (gatekeepers); others act more indirectly by maintaining genome integrity and correcting mutations during DNA replication and cell division (caretakers). Activation of an antiapoptotic gene allows excessive accumulation of cells, whereas loss of function of apoptotic genes has the same effect. • Activation of oncogenes or antiapoptotic genes is dominant. Mutations in tumor-suppressor genes are recessive; when both alleles are mutated or inactivated, cell growth is unregulated or genomic integrity is compromised. Loss of pro-apoptotic genes may occur through loss of both alleles or through a dominant negative mutation in one allele.
  65. 65. Tumor Initiation & Progression • The development of cancer (oncogenesis) results from mutations in one or more of the vast array of genes that regulate cell growth and programmed cell death.
  66. 66. Tumor Initiation & Progression • When cancer occurs as part of a hereditary cancer syndrome, the initial cancer-causing mutation is inherited through the germline and is therefore already present in every cell of the body. • Most cancers, however, are sporadic because the mutations occur in a single somatic cell, which then divides and proceeds to develop into the cancer.
  67. 67. Micro-RNA Genes • The catalogue of genes involved in cancer also includes genes that are transcribed into noncoding RNAs from which regulatory microRNAs (miRNAs) are generated. • There are at least 250 miRNAs in the human genome that carry out RNA-mediated inhibition of the expression of their target protein-coding genes, either by inducing the degradation of their targets' mRNAs or by blocking their translation.
  68. 68. Micro-RNA Genes • Approximately 10% of miRNAs have been found to be either greatly overexpressed or down- regulated in various tumors, and are referred to as oncomirs. • One example is the 100-fold overexpression of the miRNA miR-21 in glioblastoma multiforme, a highly malignant form of brain cancer.
  69. 69. Micro-RNA Genes • Overexpression of some miRNAs can suppress the expression of tumor-suppressor gene targets, whereas loss of function of other miRNAs may allow overexpression of the oncogenes they regulate. • Since each miRNA may regulate as many as 200 different gene targets, overexpression or loss of function of miRNAs may have widespread oncogenic effects because many genes will be dysregulated.
  70. 70. Carcinogenic agents (carcinogens) Three Major types of Carcinogens – Chemical – Radiation – Viral and Microbial
  71. 71. Chemical Carcinogens • Direct Carcinogens :Directly produce damage without prior metabolic conversion • Indirect Carcinogens (Procarcinogen): Metabolic conversion in liver by microsomal cytochrome P- 450 dependent mono-oxygenases (found in the smooth endoplasmic reticulum of hepatocytes)  ultimate carcinogen
  72. 72. Action of chemical carcinogens • Initiator - Chemical inducing irreversible DNA damage • Promoter -Augment effect of initiator by promoting cell growth, e.g. phorbol ester (PTA) activate signal transduction or GF secretion, hormones, saccharine …..etc • No tumor develops unless the promoter is applied AFTER the initiator.
  73. 73. Mode of action in chemical Carcinogens • Chemical carcinogens contain highly reactive electrophil groups that combine to DNA, RNA, or proteins producing mutations • Genes commonly affected are RAS & P53 • May be very specific‘ Signature Mutation’ • Some strong chemicals act as Initiator & Promoter e.g. polycyclic hydrocarbon
  74. 74. CHEMICAL CARCINOGENS • Alkylating Agents: Direct, used in chemotherapy of cancer – Cyclophosphamide: can cause leukemia, lymphoma • Polycyclic aromatic hydrocarbons: Indirect & very strong, can cause cancer in the region of contact (lung and bladder cancer), it is found in tobacco smoke, smoked meats and fish. • Aflatoxin B1: Naturally occurring carcinogen present in fungus (Aspergillus flavus  Hepatocellular CA)
  75. 75. CHEMICAL CARCINOGENS • Nitrosamines: Endogenous or food preservatives, it is converted to nitrites in the GI tract, which may cause gastric cancer and other GI cancers. • Aromatic Amines & Azo dyes: Rubber & Food Industry e.g.  naphthylamine  Bladder CA • Asbestos (ships insulation): lung Ca, mesotheliomas, GI Ca • Vinyl chloride - rare type of liver Ca • Chromium, nickel - lung Ca • Arsenic - skin cancer
  76. 76. PHYSICAL CARCINOGENS • U-V light: – Effect depends on intensity of exposure & quantity of melanin – Production of pyrimidine dimers in DNA  MUTATION in RAS, P 53 – Failed repair  Skin CA • Skin cancer includes: Squamous Cell CA, Basal Cell CA, Melanoma
  77. 77. PHYSICAL CARCINOGENS • Ionizing Radiation – Explosions  Leukemia after 7 yrs, Latent period  Breast, colon, thyroid, lung CA • Leukemias (for example Chronic lymphocytic leukemia) represent the most common radiation- induced cancer in humans – Therapeutic exposure  Thyroid CA, Leukemia – Mechanism: Free radical injury  Mutations in RAS, RB. P53
  78. 78. VIRAL & MICROBIAL CARCINOGENESIS • Emerging Field – DNA viruses – RNA viruses – other organisms
  79. 79. Viral & Microbial Carcinogenesis Viruses RNA Oncogenic viruses Human T-Cell Leukemia Virus type 1 (HTLV-1) • RNA retrovirus targets / transforms T-cells causing T-Cell leukemia/Lymphoma • Transmitted like HIV but only 1% of infected develop T-Cell leukemia/Lymphoma • No cure or vaccine exists for HTLV-I, treatable with chemotherapy, but relapse is common
  80. 80. Viral & Microbial Carcinogenesis Viruses DNA Oncogenic Viruses such as: • Human Papilloma Viruses (HPV). – sexually transmitted – Two types: Benign HPV and Malignant HPV • Low risk groups (6, 11)  Genital Squamous Cell Papilloma • High risk group ( 16, 18 )  Squamous Cell CA in cervix, vulva, perianal & oropharyngeal regions
  81. 81. Viral & Microbial Carcinogenesis Viruses • Epstein-Barr (EBV) infects B lymphocytes and epithelial cells of oropharynx and may result in malignancy • Burkitt’s Lymphoma • B cell lymphoma in immunosuppressed • Nasopharyngeal carcinoma • Hepatitis B virus (HBV) has strong association with Liver Cancer. • Herpes virus 8 causes Kaposi sarcoma
  82. 82. Viral & Microbial Carcinogenesis Helicobacter Pylori • Bacteria infecting stomach implicated in: – peptic ulcers – gastric carcinoma – marginal zone lymphomas (mucosa- associated B-cell lymphomas (MALTomas) ) • The best and strongest evidence links Helicobacter pylori infection with the onset of mucosa-associated B-cell lymphomas (MALTomas) of the stomach, which are also known as marginal zone lymphomas.
  83. 83. Viral & Microbial Carcinogenesis Helicobacter Pylori • It is thought that H. pylori activates T cells, which in turn promote polyclonal proliferation of B cells in the gastric mucosa. In this process, some cells obviously become malignant and give rise to T-cell independent low-grade monoclonal lymphomas
  84. 84. Tumor’s Effects on host Tumours cause problems because of: • Location and effects on adjacent structures: – 1cm pituitary adenoma can compress and destroy the surrounding and cause hypopituitarism). – 0.5 cm leiomyoma in the wall of the renal artery may lead to renal ischemia and serious hypertension). • Tumors may cause bleeding and secondary infections (lesion ulcerates adjacent natural surfaces)
  85. 85. Tumor’s Effects on host • Effects on functional activity such as Hormone synthesis – adenomas and carcinomas of B cells of the islets of the pancreas produce hyperinsulinism. • Cancer cachexia (wasting due to cancer): manifests with weakness, weight loss, anorexia, anemia and infection. – The principal cytokine responsible for such changes is Tumor necrosis factor-a.
  86. 86. Tumor’s Effects on host Paraneoplastic syndromes • They are diverse symptoms associated with many different tumors that occur in patients and cannot be explained. – Could be earliest manifestation of hidden cancer in some cases • Bronchogenic and breast cancers and hematologic malignancies are the most often neoplasms associated with these syndromes.
  87. 87. Examples of Paraneoplastic Syndromes • Small Cell CA lung increased ACTH (Cushing syndrome), increased ADH, Bone changes, nervous system disorders • Squamous Cell CA lung & Breast CA  Parathormone related & others  Hypercalcemia • Hepatic & Renal CA  Polycythemia • Pancreatic, Gastric CA  Carcinoid S.
  88. 88. Examples of Paraneoplastic Syndromes • Advanced Cancers Nonbacterial thrombotic endocarditis. • Colonic Adenocarcinoma  Acanthosis nigricans • Pancreatic & lung CA  clotting factors  Deep vein thrombosis – N.B. Hypercalcemia is commonly produced by lytic bone metastases
  89. 89. Tumor Diagnosis: • History and Clinical examination • Imaging: X-Ray, US, CT, MRI • Biochemical assays – Tumor markers Laboratory analysis • Morphologic methodes (Histological diagnosis) – Cytology: Pap smear, FNAB – Biopsy: Histopathology, markers. • Molecular Tech: Gene detection.
  90. 90. Histological diagnosis Microscopic tissue examination is the gold standard of cancer diagnosis. • The specimen must be adequate, representative and properly preserved. Several sampling approaches are available: • Excision or biopsy • fine-needle aspiration • Cytologic (papanicolaou) smears • Immunocytochemistry • Flow cytometry
  91. 91. Excision or biopsy • Awareness in selecting appropriate site for biopsy • In case of large mass: the margins may not be representative and the center may be largely necrotic. • Frozen-section: quick technique permits histologic evaluation within minutes – determining the nature of lesion – Evaluating the margins of an excised cancer to ascertain that the entire neoplasm has been removed.
  92. 92. Excision or biopsy • in breast biopsy, frozen-section allows determination of whether the lesion is malignant and may require wider excision or sampling of axillary lymph nodes for possible spread
  93. 93. Fine-needle aspiration • It involves aspiration of cells from a mass, followed by cytologic examination of the smears. • Useful for palpable lesions affecting the breast, thyroid, lymph nodes, and salivary glands • With modern imaging techniques it can be extended to deeper structures (liver, pancreas, and pelvic lymph nodes)
  94. 94. Cytologic (papanicolaou) smears • It is used widely for detecting cervix carcinoma at an in situ stage. • It is also used for endometrial carcinoma, bronchogenic carcinoma, bladder and prostate tumors. • Neoplastic cells are less cohesive than others and so are shed into fluid or secretion • The shed cells are evaluated for anaplastic features
  95. 95. Immunocytochemistry tumor markers • Monoclonal antibodies against cytokeratin present in epithelial cells (undifferentiated tumor rather than large cell lymphoma) • PSA for prostatic metastasis • Estrogen receptor and Her2 in breast cancer • Carcinoembryonic antigen (CEA): abnormal increase are seen in colorectal Ca, Gastric CA, Pancreatic Ca, Breast Ca. • Alpha fetoprotein: increased in liver cancer, colorectal Ca, pancreatic Ca, lung Ca, and cancer arised from germ cells of testes.
  96. 96. Flow cytometry • Routine classification of leukemias and lymphomas • Fluorescent antibodies against cell surface molecules and differentiation antigens. • Assessing DNA content of the tumor cell
  97. 97. Biochemical assays • Useful for measuring the levels of tumor associated enzymes, hormones, and tumor markers in serum. • Useful in determining the effectiveness of therapy and detection of recurrences after excision
  98. 98. Molecular diagnosis • Polymerase chain reaction (PCR) example: detection of BCR-ABL transcripts in chronic myeloid leukemia. • Fluorescent in situ hybridization (fish) it is useful for detecting translocation characteristic of many tumors • Both PCR and Fish can show amplification of oncogenes (HER2 and N-MYC)
  99. 99. Bilateral Cystadenoma Ovary
  100. 100. Lipoma Intestine
  101. 101. Meningioma
  102. 102. Lung carcinoma
  103. 103. Hepatic Adenoma
  104. 104. Carcinoma Breast
  105. 105. Carcinoma Lung
  106. 106. Osteo-sarcoma
  107. 107. Colon Polyp
  108. 108. Hepatic Adenoma Normal Adenoma
  109. 109. Metastatic Adenocarcinoma
  110. 110. Hepatic Adenocarcinoma

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