Neoplasia PDF

Neoplasia By : Waleed.A.M.Suliman, MBBS (RNU) Registrar of histopathology SMSB Contents  Introduction.  Characteristics of Benign and malignant Neoplasms.  Molecular Basis of Neoplasia.  Hallmarks of cancer  Clinical aspects of Neoplasia. Introduction  Definition of Neoplasia: refers to a...

Neoplasia By : Waleed.A.M.Suliman, MBBS (RNU) Registrar of histopathology SMSB Contents  Introduction.  Characteristics of Benign and malignant Neoplasms.  Molecular Basis of Neoplasia.  Hallmarks of cancer  Clinical aspects of Neoplasia. Introduction  Definition of Neoplasia: refers to a clonal proliferation of cells that have abnormal growth control mechanisms because of the acquisition of genetic aberrations.  Neoplasia literally means new cell growth. Introduction  Generally, Benign neoplasms are well circumscribed and easily excised , in contrast of malignant neoplasms with infiltrate the surroundings and spread to distant sites( metastasis). Introduction  All tumors are made of two main components : 1- Neoplastic cells 2- Non neoplastic stroma.  All Benign tumors names consist of name of neoplastic cells or growth pattern attached by suffix “-oma”(e.g.: Leiomyoma - papilloma). Introduction.  Nomenclature of malignant neoplasms follows that of benign neoplasms with small differences: Carcinoma : Malignant neoplasm of epithelial tissue. (e.g.: squamous cell carcinoma). Sarcoma: Malignant neoplasm of mesenchymal tissue.(e.g.: Leiomyosarcoma). Characteristics of Benign and malignant Neoplasms.  Most benign and malignant tumors can be distinguished based on : 1- Degree of differentiation. 2- Local invasion. 3- Metastastasis. Degree of differentiation  Differentiationrefers to the extent to which tumor cells resemble their parenchymal cell of origin , both morphologically and functionally.  Anaplasia ( dedifferentiation): loss of the structural and functional characteristics of normal differentiated cells. Degree of differentiation  Anaplasia characterized by the following : 1- Pleomorphism: variation in size and shape of cells. 2- Nuclear abnormalities: Hyperchromatism, prominent neoclulous , increased cytoplasmic ratio. 3- Atypical mitosis : e.g.: Mercedes Benz shape. 4-Loss of polarity : lack of normal pattern. 5- Tumor giant cells. Degree of differentiation  Dysplasia: is disordered growth of epithelial cells that are abnormal but not malignant. Characterized by : cellular and nuclear Pleomorphism , Abnormal mitotic activity ,and architectural disarray. Local invasion  Isthe feature that most reliably distinguishes benign from cancers.  Benign tumors are encapsulated ,in contrast of malignant tumors which lack true capsule even if grossly apparent. Metastasis  Definition: The spread of primary tumor to sites that are physically discontinuous with the primary tumor.  Routes of metastasis include : 1. Seeding of body cavities (transcaelomic).e.g: ovarian carcinomas. 2. Lymphatic spread. (most of carcinomas) 3. Hematogenous spread. (most of sarcomas) Molecular Basis of Neoplasia  Cancer genes fall into four classes: 1. Oncogenes. 2. Tumor suppressor genes. 3. Genes that regulate apoptosis. 4. Genes that regulate interactions between tumor cells and host cells.( evasion of immune system). Molecular Basis of Neoplasia  Mutations that lead to development of cancer are called driver mutations.  There are few types of driver mutations include: 1. single nucleotide substitution , deletion, and insertion. 2. Large deletions 3. Gene Amplifications. 4. Chromosome rearrangements. Molecular Basis of Neoplasia  Carcinogenesis: is the development of tumor through stepwise acquisition of multiple genetic aberrations.  Cancer continue to evolve genetically and become more aggressive, this phenomenon called tumor progression.  Genetic heterogeneity has implication not only for cancer progression but also for the response to therapy. Molecular Basis of Neoplasia  Factors that contribute in oncogenic mutation include : 1. Age. 2. Exposure to mutagenic agents : fall into two classes : Direct acting agents and indirect agent. 3. Increased Cellular proliferation. 4. Regulated DNA rearrangement and mutagenesis. 5. Germ line mutation. 6. Infectious agents. Molecular Basis of Neoplasia  Passenger mutations: Do not alter growth properties but influence host response to tumor. Are important in several ways : 1. Resistance to therapeutic agents. 2. Create tumor neoantigens. Hallmarks of cancer 1. Self-sufficiency in growth signals 2. Insensitivity to growth –inhibitory signals. 3. Altered Cellular metabolism. 4. Evasion of cell death. 5. Limitless replicative potential (immortality). 6. Sustained Angiogenesis. 7. Invasion and metastasis. 8. Evasion of immune surveillance. Hallmarks of cancer  Two enabling factors include: 1. Genomic instability. 2. Tumor inflammation. Self-sufficiency in growth signals  Growth factor –induced signaling can be resolved in the following steps: 1. Binding of a growth to it’s specific receptor. 2. Transient activation of the growth factor receptor. 3. Transmission of transduced signal across cytosol to the nucleus. 4. Activation of transcription factors. 5. Progression of the cell through cell cycle. Self-sufficiency in growth signals  The genes that normally regulate growth factors , receptors , transcriptional factors and singling pathway components are called proto-oncogenes.  Gain of function mutations of proto- oncogenes form oncogenes ,leading to self – sufficiency in growth in cancer cells. Insensitivity to growth – inhibitory signals  Mutation in tumor suppressor genes.  The most common two tumor suppressor genes are RB (Governor of the cellular proliferation ) TP53(Guardian of the genome). Insensitivity to growth – inhibitory signals  RB: The governor of cellular proliferation Cell cycle: G1,S,G2, M Cell cycle progression depends on three factors : Cyclins , Cyclin dependent kinases(CDK), and Cyclin dependent kinases inhibitors (CDKI). RB regulates the G1/S checkpoint. Insensitivity to growth – inhibitory signals  Earlyin G1 RB is hypo phosphorylated active form binds and inhibits transcription factors of E2F family ( a transcription factors regulate gene of S phase).  CDK4 ,CDK6 inactivate RB releasing EF2 and permitting cell to through S phase.  Phosphatases remove the phosphate group from RB during mitoses. M phase. Insensitivity to growth – inhibitory signals  Mutation in RB is either Sporadic or familial (most of the cases )  Familial mutation is by two hit hypothesis.  Gain of function mutation in D/CDK 4 inactivate RB leading E2F protein.  HPV virus E7 protein inactivate RB and prevents E2F inhibition. Insensitivity to growth – inhibitory signals  TP53: Guardian of the genome.  Stresses that activate P53 include the following : DNA damage , inappropriate regrowth stimuli , and hypoxia.  In nonstressed cells P53 has a short life because of it’s association with MDM2,(a protein targets and destruct P53). Insensitivity to growth – inhibitory signals  When P53 activated , it derives cell into one the three following pathways: 1. Cell cycle arrest by: CDKI P21 family which inhibits D-CKD4 complexes. 2. Cellular senescence: epigenetic changes leads to permanent changes in genes of cell growth. 3. Apoptosis. Insensitivity to growth – inhibitory signals  70% of human cancers are have defects in TP53. Both alleles are required to develop phenotype.  Li – fraumeni syndrome : germ line mutation in TP53. 25 – fold greater chance to develop wide spectrum of cancers by the age of 50.  HPV E6 oncoprotein binds to and inhibit P53. Insensitivity to growth – inhibitory signals  Other tumor suppressor genes include: APC : Which produce APC protein the degrades B-Catenin.( transcription factor). Familial mutation in one allele of APC produce adenomatous polyposis. Colon cancer requires both alleles to defected. Altered Cellular metabolism  Even in the presence of abundant oxygen, cancer uptake high level of glucose and undergo fermentation (glucose to lactose ) , thin called aerobic glycolysis or Warburg effect.  In PET scan this phenomenon is an evidence of malignancy. Altered Cellular metabolism  The Warburg effect (aerobic glycolysis) provides growing or tumor cells with metabolic intermediates that are needed for synthesis of cellular components.  Autophagy is suppressed in cancer cells.  Oncometabolism: By mutation in enzymes that participate in Krebs cycle. Evasion of cell death  Mutation in genes of apoptosis. By : 1. Overexpression of BCL2. E.g. : follicular lymphoma. 2. TP53 loss of function mutation.. Limitless replicative potential (immortality)  Normally cells divide 60 to 70 time and then enter senescence due to shortening of telomeres.  Shortening of telomeres leads to activation of TP53 leading to apoptosis or cell cycle arrest (senescence).  Cancer maintains telomere length by up regulation of enzyme called telomerase.  Sustained Angiogenesis.  Cancer generate new blood vessels to increase in size beyond the limits of preexisting vessels.  VEGF (vascular endothelial growth factor) is the key proangiogenic factor. Sustained Angiogenesis  HIF (hypoxia – induced factor) up regulates expression of VEGF.  P53 represses VEGF , thus loss of mutation in TP53 means more availability of VEGF.  Gain of function in growth factor – receptor signaling and MYC also stimulate.  Bevacizumab is an antibody drug that inhibits angiogenesis by VEGF degradation. Invasion and Metastasis  Results from complex interactions involving cancer cells , stromal cells , and the extracellular matrix.  The process of invasion and metastasis into : 1. Invasion of the extracellular matrix. 2. Vascular Dissemination and Homing of Tumor cells. Invasion and Metastasis 1. Invasion of the Extracellular Matrix :  Loosening of intercellular connections between tumor cells( loss of function mutation in E- Cadherin ).  Local degradation of the basement membrane and interstitial connective tissue. (Metalloproteases MMPs).  Locomotion ( by chemokines) Invasion and Metastasis 2- Vascular Dissemination and Homing of Tumor cells:  The sites of metastases are related to two factors: the anatomic location and vascular or lymphatic drainage of the primary tumor, and the tropism of particular tumors for specific tissues.  In general, large tumors are more likely to metastasize than small tumors. Evasion of immune surveillance.  All tumor antigens expressed as class I MHC associated peptides to CD8+ T cells.  The most important mechanism of tumor elimination is the killing of tumor cells by CD8+ Cytotoxic T lymphocytes. Evasion of immune surveillance.  Tumor cells evade the immune system either by being invisible to lymphoid cells or by hijacking inhibitory pathways designed for regulation of immunity. Evasion of immune surveillance  Two of mechanisms of immune evasion has been described : 1-Antigen loss variants 2- Inhibition of T-cells using checkpoint receptors. (CTLA-4 OR PD-1). Genomic instability  Defects in DNA repair genes.  Allow accumulation of mutations in cancer genes.  HNPCC. (Hereditary non polyposis colon cancer syndrome).Mutation of miss match repair genes. Characterized by microsatellite instability (MSI). Genomic instability  Xeroderma pigmentosum : UV light cross linking pyrimidine residues. Defect in nucleotide repair system. Increased risk to develop cancer. Tumor promoting inflammation  Cancer provokes chronic inflammatory reaction.  Inflammatory cells produce factors that promote tumor growth, including : growth factors – factors promotes angiogenesis – suppressing antitumor factors. Treatment of cancer Clinical aspects of Neoplasia  Benign and malignant tumors may cause local and systemic problems through a variety of direct and indirect effects.  Some of the effects include : Compression – bleeding – Tumor cachexia – Para neoplastic syndrome. Clinical aspects of Neoplasia  Grading : is based on the degree of differentiation of the tumor cells to judge the aggressiveness of the tumor cells.  Staging: Depends on clinical , radiological and , histological features using TNM system.It is more of prognostic value more than grading. Clinical aspects of Neoplasia  Cancer diagnosis: Morphological methods : open biopsy- fine needle aspiration- Cryptologic (papanicoloaou preparation ). Protein markers : Immunohistochemistry – flow cytometry- Circulating tumor markers. Clinical aspects of Neoplasia  Cytogenetic markers: Conventional karyotyping – fluorescence in situ hybridization FISH.  Nucleic acid Markers: Molecular profiling of cancers. THANK YOU