Chapter 7 Neoplasia 1-2: Pathologic Basis of Disease PDF

6. CHORISTOMA – have normal tissue, but not in normal place (ie. NEOPLASIA I...

6. CHORISTOMA – have normal tissue, but not in normal place (ie. NEOPLASIA I endometriosis) Nomenclature – For Benign heterotopic rest of normal tissue Introduction Characteristics BENIGN MALIGNANT nd st 2 leading cause of death in the US (1 = CVD) 1. MESENCHYMAL – organs lined with mesothelium Decreased mortality in the last decade of the 20th century and Attach the suffix “oma” to the cell of origin – Osteoma - bone Differentiation and Well differentiated Well to poorly/ in a downward course anaplasia undifferentiated/ – Chondroma - cartilagenous – Fibroma – fibrous tissue anaplastic Nomenclature Rate of growth Indolent/slow Rapid, erratic pace *Neoplasma = tumor – Lipoma lipid tissue (not fat/ adipose) growing/expansile- Neoplasia - new growth capsule Tumor - swelling 2. EPITHELIAL Oncology – study of tumors or neoplasms Attach the suffix “oma” to the cell of origin, microscopic pattern or macroscopic architecture Local invasion Absent Present-progressive NEOPLASM infiltration/destruction – Adenoma – glandular; forming glands Abnormal mass of tissue of Growth exceeds and uncoordinated with that of the normal – Papillomas – finger-like projections – Polyp – protrudes from the surface of the organs surrounding/adjacent tissue tissue Persists in the same manner after the cessation of stimuli – Cystadenomas, papillary cystadenomas Exception: Hepatoma, Lymphoma, Seminoma, Melanoma, which evoked the change Metastasis Absent Present Mesothelioma-malignant (found in pleura) Autonomous Clonal-arise from single cell that incurred genetic damage *all “-oma” are malignant BENIGN Nomenclature – Malignant 1. CARCINOMA-from epithelial Differentiation & Anaplasia Relatively innocent Adenocarcinoma DIFFERENTIATION Remain localized Squamous cell carcinoma, basal cell carcinoma Extent to which neoplastic parenchymal cells resemble the Cannot spread to other sites corresponding normal parenchymal cells both Amenable to surgical removal 2. SARCOMA-from mesenchymal morphologically and functionally Patient generally survives liposarcoma, leiomyosarcoma, osteosarcoma ANAPLASIA – poorly differentiated MALIGNANT fibrosarcoma, chondrosarcoma, angiosarcoma, lack/loss of differentiation, associated with other morphologic Cancer rhabdomyosarcoma changes Invade and destroy adjacent structures Spread to distant sites Cause death 3. MIXED TUMOR Changes in Anaplasia Divergent differentiation of a single neoplastic clone 1. PLEOMORPHISM – hallmark ok neoplasia 2 BASIC COMPONENTS Pleomorphic adenoma of salivary gland (parotid) Variation in size and shape – ex.big/small cells 2. ABNORMAL NUCLEAR MORPHOLOGY 1. parenchyma-clonal neoplastic cells 4. TERATOMA – from testis, embryo, ovarian increased N:C ratio (1:6è1:1) determines tumor’s behavior and pathologic totipotential cell that differentiate along 3 germ cell layer – hyperchromatic, large nucleoli consequences totipotent means it can make a whole body/anything 3. MITOSES – mitosis is normale in labile cells 2. stroma  supporting tissues; tells how fast will grow benign (mature) or malignant (immature) increased, atypical, bizarre growth & evolution-blood supply 4. LOSS OF POLARITY connective tissue-framework 5. HAMARTOMAS – not necessary a neoplasia, it does not grow bigger disturbed orientation – Scant-soft and fleshy ex. Lymphoma, Fibrosarcoma disorganized but benign appearing masses composed of 5. TUMOR GIANT CELLS – NOT macrophages (ie. Langhan cells in mature specialized cells or tissue indigenous to the particular TB) – Abundant-desmoplasia (excessive stroma), site Not macrophages stony hard ex. Scirrhous CA of breast pulmonary chondroid hamartoma, hemangioma 6. DYSPLASIA – if severe dysplasia, it is already equal in carcinoma in situ (lesions confined in basement/noninvasive) loss in uniformity & architectural orientation of the cells Prepared by: EGBautistaII  disordered growth, often occurs in metaplastic – More aggressive, more rapidly growing, larger size- – Women: significant decline in death rates from epithelium greater likelihood of metastasis cancer of breast & colorectal CA & most notably 7. METASTASIS – Approximately 30% of newly diagnosed individuals cervix-earlier diagnosis –Pap smear tumor implants discontinuous with the primary tumor with solid tumors present with metastasis – Men: nearly 80% of the total decrease in lung, Rate of Growth – something to do w/stroma, needs blood supply prostate & colorectal CA 1. Doubling time of tumor cells – multiplication time remains the same (3) Pathways of Spread – Cell cycle time not shortened – time it takes to Seeding of body cavities & surfaces divide – Carcinomas arising from the ovaries Pseudomyxoma Geographic & Environmental Factors 2. Fraction of tumor cell in the replicative pool peritonei, appendiceal CA Environmental > hereditary – Growth fraction – affects the G0 (ie. Stable cells) Lymphatics – carcinoma Cultural > racial low in breast & colon, high in some – Skip metastasis – coz’ the passageway is obstructed Environmental factors leukemia, lymphoma & small cell CA – Sentinal nodes – Home - Outdoors Correlate with level of differentiation Hematogenous – sarcoma – most common route – Work - Medication Hormonal stimulation, adequacy of blood – Veins>arteries *Look at table 7-3 supply, etc – Organ area for metastasis (liver & lung) = need to Most overweight individuals have a higher death rate from CA 3. Rate at which cells are shed or die check fist Alcohol abuse-increase the risk for oropharynx, larynx, Transplantation – rare esophagus, liver CANCER STEM CELLS & CANCER CELL LINEAGES – If undergo surgery = it will spread because same Smoking-mouth, pharynx, larynx, esophagus, pancreas, Cancer could arise from scalpel is used in making cuts bladder, kidney – normal tissue stem cells or Risk of cervical CA: age of first intercourse, number of sex – More differentiated cells that acquire the property Epidemiology partners-HPV of self-renewal Study of cancer patterns CML- from stem cells Contributes substantially to knowledge about origins of Age AML- differentiated myeloid precursors cancer Most CA occur in later years of life >55yrs Tumor initiating cells (T-ICs) Provides major insights on the cause of cancer Main cause of death among women aged 40-79 and men – Allow cells to grow indefinitely – environmental, racial (hereditary) & cultural aged 60-79 ….carcinomas – May represent 25% of the total cellularity influences Acute leukemia & neoplasm of the CNS-approx 60% of deaths Cancer incidence in children Local Invasion Male Female Common neoplasms of infancy & childhood-small round blue Most benign tumors develop a rim of compressed connective – 1. Prostate 1. Breast cell tumors, which includes: tissue called a capsule – this are normal tissue that are – 2. Lung 2. Lung – Neuroblastoma, Wilms tumor, retinoblastoma, pushed outside the lining forming capsule – 3. Colon 3. Colon acute leukemias, & rhabdomyosarcomas Cancers show infiltration, invasion and destruction of – 4. Bladder 4. Uterus Death - most people die w/lung ca surrounding tissue Genetic Predisposition – Invasiveness Male Female 1. Autosomal Dominant Inherited Cancer Syndromes most reliable feature that differentiates – 1. Lung (31%) 1. Lung (26%) 2. Defective DNA Repair Syndromes benign from malignant tumor next to – 2. Prostate (10%) 2. Breast (15%) 3. Familial Cancers development of metastasis – 3. Colon (8%) 3. Colon (9%) – 4. Pancreas (5%) 4. Pancreas & Ovary (6%) 1. Autosomal Dominant Cancer Syndromes Metastasis Inheritance of single autosomal dominant mutant gene Unequivocally marks a tumor malignant Cancer Incidence greatly increases the risk of developing a tumor With few exceptions, all malignant tumors can metastasize Increased death rate Usually a point mutation in single allele of tumor suppressor – Gliomas of CNS, basal cell carinoma of skin-locally – HCC (hepatocellular ca)-caused by HCV (hepa C) gene (RB) invasive but rarely metastasize Decreased death rate Defect in the second allele occurs in somatic cells as a consequence of chromosome deletion or recombination Prepared by: EGBautistaII  Inherited variations (polymorphisms) of enzymes that – Genes involved in DNA repair 1. Carriers of mutant RB tumor suppressor gene have 10,000 metabolize procarcinogens to their active carcinogenic forms 4. Haploinsufficiency-loss of gene function caused by damage to folds increased risk-bilateral retinoblastoma can influence the susceptibility to cancer a single allele – Increased risk of developing second cancer, osteogenic – cytochrome P-450 enzymes – Single cell is palpak but the other one is normal. A sarcoma total of 2 alelles 2. Familial adenomatous polyposis-inherit AD mutation of APC 5. Carcinogenesis is a multistep process at both the phenotypic tumor suppressor gene (APC0adenomatous polycystic & genetic levels, resulting from the accumulation of multiple carcinoma) mutations – innumerable adenomas in colon, virtually 100% fated to – Tumor progression develop CA 3. Li-Fraumeni syndrome-germ line mutation in p53 gene 4. Multiple Endocrine Neoplasia (MEN) 1 & 2 mutation in menin Nonhereditary Predisposing Conditions and RET tyrosine kinase CHRONIC INFLAMMATION –can lead to neoplastic 5. Hereditary Nonpolyposis colon cancer (HNPCC)-inactivation of ex. Ulcerative colitis, Crohn disease, H. pylori gastritis, viral mismatch repair gene (HNPCC is both AD&AR) hepatitis, chronic pancreatitis it is d/t Cytokines stimulate growth of transformed cells – that Inherited Cancer Syndromes stimulate jak stat receptors GENERAL CHARACTERISTICS Increase pool of tissue stem cells Tumors tend to arise in specific sites and tissues Production of Reactive Oxygen Species – Except Li Fraumeni Evidence: COX-2 increased in colon CA Associated with a specific marker phenotype – Lisch nodule & café-au-lait spots PRECANCEROUS CONDITIONS 7 FUNDAMENTAL CHANGES non-neoplastic disorders 2. Defective DNA Repair Syndromes – chronic atrophic gastritis of pernicious anemia, solar 1. Self-sufficiency in growth factors Generally autosomal recessive keratosis, skin chronic ulcerative colitis, & 2. Insensitivity to growth inhibitory signals Defects in DNA repair  can cause DNA instability leukoplakia of oral vulva, penis & oral cavity 3. Evasion of apoptosis Xeroderma pigmentosum, Ataxia telagiectasia, Bloom Neoplasic 4. Defects in DNA repair syndrome – Villous adenoma-increase in size, develops CA in 5. Limitless replicative potential ★HNPCC – AD w/DNA repair defect 50% of cases 6. Sustained angiogenesis 7. Ability to invade and metastasize – colon CA, small int., endometrium, ovary Molecular Basis of Cancer – most common cancer predisposition syndrome FUNDAMENTAL PRINCIPLES 1. Nonlethal genetic damage lies in the heart of carcinogenesis 3. Familial Cancers – mutation may be acquired-action of environmental Breast, ovary, pancreas, …..colon, brain, melanomas, agents: chemicals, radiation, viruses lymphomas – inherited in the germ line Characteristic features – if cells died, there will be no replication & thus, it – early age at onset - AR must not be lethal – tumors arising in 2 or more close relatives 2. Tumor is formed by the clonal expansion of single precursor – Multiple or bilateral tumors cell that has incurred the genetic damage Transmission pattern of familial cancers is not clear – Tumors are monoclonal – Cells that gone crazy Interactions Genetic & Nongenetic Factors 3. Four classes of normal regulatory genes are the principal Complex target of genetic damage Genotype can significantly influence the likelihood of – Protooncogenes-growth promoting developing environmentally induced cancers – Tumor suppressor gene-growth inhibiting – Genes that regulate apoptosis Prepared by: EGBautistaII SELF SUFFICIENCY IN GROWTH SIGNALS – kinase is transiently activated by binding of the Can act in concert to reprogram somatic cells into ONCOGENES - Genes that promote autonomous growth specific GF, followed rapidly by receptor pluripotent stem cells PROTONCOGENES - Normal cellular counterpart dimerization & tyrosine phosphorylation of several May also enhance self-renewal, block differentiation or ONCOPROTEINS - Products of genes without regulatory substrate that are part of signaling cascade both function Oncogenic/mutant receptors Amplified in breast, colon, lung and many other *Proto-oncogenes  oncogene  secretes oncoproteins – associated with constitutive dimerization & carcinomas activation without binding to the GF, deliver N-MYC & L-MYC in neuroblastomas & small cell CA of continuous mitogenic signals to the cell even in the lungs respectively absence of GF in the environment Translocation-Burkitts lymphoma Can be constitutively activated in tumors by different STEPS IN CELL PROLIFERATION mechanisms CYCLINS Binding of growth factor to cell membrane receptor – Mutations Activation of signal transducing proteins – gene rearrangements Transmission of signal to nucleus – overexpression Activation of nuclear factors Ex. RET proto-oncogene : mutation with gene rearrangement Entry into cell cycle – MEN-2A & MEN-2B Over expression of normal forms of GF receptors – By gene amplification and other unknown mechanisms Ex. EGFR ERBB1-overexpressed in SCCA of the lung, glioblastomas, head & neck tumors  Control orderly progression of cells thru the phases of the cell cycle Signal Transducing Proteins CDK Inhibitors Oncoprotein can mimic signal transducing proteins CIP/WAF ex. RAS family of guanine triphosphate (GTP)-binding proteins – p21,p27,p57 (G proteins)-RAS genes – Inhibit all stages INK4 RAS Oncogene – p15, p16, p18, p19 Point mutation of RAS family genes-single most common – Inhibit cyclin D abnormality of protooncogene in human tumors-approx. CDK4 & CDK6 15-20% of all human tumors Check points at G1/S and G2/M mediated 90% in pancreatic adenoCA & cholangioCA by p53, p21 50% in colon, endometrial, thyroid Growth Factors Major cause of genetic instability 30% in lung adenoCA & myeloid leukemia Normal cells KRAS-colon & pancreas, HRAS-bladder, NRAS- – need GF to stimulate proliferation SELF SUFFICIENCY OF GROWTH SIGNALS hematopoeitic tumors – paracrine action Overexpression of growth factor genes Many cancer cells – PDGF & TGF Activated RAS stimulates downstream regulators of – acquire the ability to synthesize the same GF to Altered growth factor receptors proliferation such as the mitogen-activated protein (MAP) which they are responsive – RET kinase cascade-floods the nucleus with signals for cell – autocrine loop Minicry of signal transducing proteins proliferation Ex. Glioblastoma-express PDGF &PDGFR – RAS Mutated RAs is trapped in its activated GTP-bound form, and Sarcomas-TGFα Oncoproteins as transcription factors the cell is forced into continuously proliferating state – MYC Growth Factor Receptors Dysregulation of cyclins MYC Oncogene Normal Prepared by: EGBautistaII INSENSITIVITY TO GROWTH INHIBITORY SIGNALS  PTCH- “Gorlin syndrome”, basal cell carcinoma TUMOR SUPPRESSORS – Stop cell proliferation RB gene NEOPLASIA PART II P53 protein APC and NF-1 EVASION OF APOPTOSIS Reduced levels of CD95/Fas – inhibit extrinsic pathway Knudson’s Hypothesis Inactivation of caspase 8 by FLIP – inhibit extrinsic path. “two hits” required Protection of tumor cells by BCL2 – First hit - inherited, all somatic cells – Second hit- inherited or acquired, particular cell “loss of heterozygosity” LIMITLESS REPLICATIVE POTENTIAL – Heterozygotes-no expression of cancer Replicative senescence lies in telomere shortening – Homozygotes-cancer Short telomere activation of p53 checkpoint apoptosis Telomerase-prevents shortening of telomere RB GENE About 90% of tumors have telomerase activity RB protein regulates cell growth at G1/S Some have alternative lengthening of telomeres Cyclin E- CDK2 and Cyclin D CDK 4,6 required Mutation associated with retinoblastoma and osteosarcoma SUSTAINED ANGIOGENESIS Loss of normal cell cycle control is central to malignant Tumors >2mm require new blood supply transformation and that at least 1 of 4 key regulators of the Angiogenic switch- change in phenotype that induces cell cycle is dysregulated in the vast majority of human APC/ CATENIN angiogenesis mostly controlled by hypoxia cancers APC protein down regulates catenin Neovascularization (adult) or vasculogenesis – this 2 both Loss of APC causes continuous WNT signaling and -catenin occur in neoplasia p53 (p63,p73) enters nucleus cell proliferation Vasculature is abnormal- leaky, haphazard Most common target for genetic alteration Vasculogenic mimicry – tumor cells resemble capillaries Located on chromosome 17p13.1 The only difference is that there is no blood inside Stops neoplastic transformation by Notes: – Cell cycle arrest (quiescence and senescence) Decreased angiogenesis inhibitors – angiostatin, endostatin, – initiation of apoptosis vasculostatin One mutant p53 = Li Fraumeni syndrome Loss of p53 provides more permissive environment for – 25 % increased risk of neoplasia angiogenesis – Sarcomas, breast, leukemia Vegf expressed on tumor cells – culprit in angiogenesis Vasculogenic mimiccry no longer in book! METASTATIC CASCADE Two phases 1. Invasion of the extracellular matrix 2. Vascular dissemination, homing of tumor cells and colonization TUMOR SUPPRESSORS  NF1-Neurofibroma, glioma 1. INVASION  NF2- Schwannoma Detachment of tumor cells from one another  VHL – renal cell ca, pheochromocytoma – Down regulation of E cadherins – becomes loose  PTEN- “Cowden Syndrome” epithelial cancers Degradation of ECM  WTI- Wilms Prepared by: EGBautistaII  – Secrete proteolytic enzymes: MMPs, cathepsin D, – Snail and twist promote EMT epithelial to mesenchymal – Loss of tumor suppressor genes urokinase, plasminogen transition.which favors migration Non hematopoietic solid tumors Attachment to matrix components RB in retinoblastoma – Intergrins attach to fibronectin, laminin Genomic Instability Migration of tumor cells or locomotion Where DNA become vulnerable for mutations (irreversible) Gene Amplification – Directed by cell derived cytokines/ amoeboid mov’t Inherited defects in DNA repair genes allow mutations in Two patterns are seen other genes – double minutes (dms) Notes: DNA repair systems – Homogeneous Staining Regions (HSR) Down regulation of E catherins or mutation in catenin needed – Mismatch - can cause: – Ex. N-MYC – neuroblastoma, both patterns seen for linkage HHPCC – microsatellite instability – Ex. ERBB2 – breast ca Matrix metalloproteinases – remodelng insoluble components – Nucleotide excision repair and release of growth factors Xeroderma pigmentosa (AR) – sensitive to Epigenetic Changes Ameoboid migration- a second method of migration using uv light – Reversible, heritable changes in gene expression collagen fibers – Recombination repair – Post translational modification Bloom, etc – hypersensitivity to DNA – Genome imprinting / loss of imprinting d/t damaging agents – Methylation causes inactivation BRCA 1 &BRCA 2 breast cancer Ex BRCA 1 in breast cancer Notes: Genonic instability occurs when both DNA repair genes are MiRNAs and Cancer lost Small non-coding single stranded RNA Microsatellite instability- tandems are shorter or longer Mediate post-transcriptional gene silence UV radiation causes cross-linkage of pyrimidine residues that now cannot be excised Multistep Carcinogenesis Cancer must result from the accumulation of multiple Warburg Effect – a metabolic alterations mutations Does not want yo breakdown glucose; inhibit kreb’s cycle Tumors shift to aerobic glycolysis Not on Oxygen-hunger  more onn Glucose hunger Possible explanation – Increased need for energy of dividing cell 2. VASCULAR DISSEMINATION – Abnormal vasculature Tumor cells -clump, form emboli, adhere to target (emboli is – Reduction in autophagy filled with platelet & metabolite) Notes: At site -proliferate, develop a vascular supply, evade host Used to visualize tumors in PET defenses Gives 2 ATP rather than 20 Organ trophism – – Adhesion molecules on the endothelial cells of the target organ Chromosomal Abnormalities – Chemokine receptors – Translocation – Some tissues are unfavorable to metastasis ( where – Overexpression of protooncogenes we do not see metastasis, ex.skeletal muscles) MYC of Burkitt Lymphoma Notes: Carcinogenesis – Hybrid “chimaric” genes – Some tissues, like skeletal muscles have an unfavorable Initiation-promotion sequence – Constitutive tyrosine kinase activity environment for growth 1. Initiation results from exposure of cells to a sufficient dose of BCR-ABL (Philadelphia chromosome 9) of CML – CD44 – are adhesion molecule expressed on T cells; carcinogen BCR( 22) to ABL (9) overexpression favors metatasis – Permanent DNA damage is rapid and irreversible – Deletions Prepared by: EGBautistaII  2. Promoters induce tumors in initiated cell without affecting Bile salts HPV also activate cyclins, inhibit apoptosis and combat cell DNA directly and are reversible High levels of dietary fat aging – Not tumorigenic themselves; only cause cell phenols EBV uses CD 21 receptor to attach to B cells proliferation 2. RADIATION CARCINOGENS Tumor Immunity CARCINOGENS Ultra Violet rays Immune surveillance 1. Chemical – UV B in sunlight linked to all forms of skin cancer – – Guards against tumor development 2. Radiant energy can cause squamous cell Ca - melanoma Cancer immunoediting 3. Microbial – Formation of pyrimidine dimers – Sculpting the immunogenic properties of tumors to Ionizing Electromagnetic Forces select tumor cells that escape immune elimination 1. CHEMICAL CARCINOGENS – X rays and gamma rays Initiation –  and  particles Tumor Antigens – Exposure and mutation – linked to leukemias, thyroid ca etc 1. Products of mutated genes Promotion – Mutated tumor suppressor genes – Reversible enhancement of proliferation Notes: – Mutated self protein Accumulated even exposure (SCC), short bursts of Notes: INITIATORS – cause damage; direct (alkalyting agent); or indirect exposure (melanoma) – Tumor specific or tumor associated antigen no Direct acting UVC more carcinogenic but filtered by ozone longer used!! – Highly reactive electrophils – Antigens must be recognized by CTLs – Weak carcinogens 3. MICROBIAL CARCINOGENS – Products of mutated genes become tumor antigens Indirect acting 1. RNA viruses - HTLV-1 – Require metabolic activation – T –cell leukemia, lymphoma 2. Overexpressed or aberrantly expressed cellular proteins – Vary among individuals – tax genone causes proliferation and instabiity – Ex – tyrosinase and cancer testis antigen 2. Bacteria - Helicobacter pylori – Normal cellular proteins that are abnormally  DNA is primary target – Gastric adenocarcinomas and MALTomas expressed!  Altered cells must be able to undergo at least one cycle so – CagA cytotoxin gene and cytokines (Chronic 3. Produced by Oncogenic viruses change can be made permanent inflammation) 4. Oncofetal antigens found on fetal and cancer cells CARCINOGENIC CHEMICALS 5. Altered cell surface glycolipids and glycoproteins * Liver cancer caused by Aflatoxin B has a signature mutation in (p53) – Higher concentration Alkylating agents Naturally occurring Notes: – Abnormal forms Weak - direct acting Aflatoxin B Tax has transforming activity 6. Cell type specific differentiation antigens Therapeutic agents Stored corn, rice, peanuts H pylori – 1st bacteria called a carcinogen – Do not induce immune response – target for immunotherapy Polycyclic hydrocarbons Nitrosamines and amides 3. DNA viruses Most potent Preservatives – Human Papilloma Virus (16 & 18) Anti Tumor Mechanisms Tobacco, smoked meat/fish Squamous cell ca of cervix d/t Cytotoxic T lymphocytes – cell mediated Overexpression of E6 & E7 oncogenes Natural killer cells Aromatic amines/Azo dyes Others: – Epstein – Barr Virus Macrophages Mainly affect liver asbestos, vinyl chloride, arsenic Burkitt lymphoma, B cell (coz’ CD21) Antibodies - humoral Food coloring Industrial exposure, insecticides lymphoma in HIV, Hodgkin, Notes: Nasopharyngeal Ca, gastric Ca,NK Mostly cell mediated lymphoma Antibody against CD20 for B cell lymphoma PROMOTERS LMP-1 is oncogene Phorbol esters – Hepatitis B & C Viruses Tumor Evasion of the Immune System Viral infection Liver Cancer Cytokines and reactive oxygen species Selective outgrowth of antigen-negative variants Hormones Loss or reduced expression of MHC molecules Notes: Prepared by: EGBautistaII  Lack of costimulation Tumor antigen cross reaction "The stage is T-3, N-1, M-0" which means "the cancer has spread Immunosuppression – ex. HIV 7. Acanthosis Nigricans – hyperpigmentation of the skin through the stomach wall, there is some spread to local lymph nodes, Antigen masking but no metastases in other parts of the body". Apoptosis of cytotoxic T cells 8. Hypertrophic osteoarthropathy (from bronchogenic) *Cancers more common in immunocompromised – New bone formation Laboratory Diagnosis – Arthritis 1. Histologic & cytologic methods Clinical Features of Tumors – Clubbing – Biopsy, needle aspiration (FNAB) & cytologic smears Effects of Tumors on the Host 9. Vascular and hematologic (PAP) – stain not only for cervix Location & impingement on adjacent structures Migratory thrombophlebitis (pancreas, lung) 2. Immunohistochemistry Functional activity such as hormone synthesis Thrombotic endocarditis (adenocarcinoma) – Categorization of undifferentaiated malignancies Bleeding & secondary infection-ulcerate to surface DIC (leukemia, prostate) – Determination of site of origin (PSA) Initiation of acute symptoms-rupture or infarction – Detection of molecules that have prognostic or Cachexia – 10% body weight loss Grading and Staging therapeutic value (ERBB2/ HER2-neu) Grading-degree of differentiation of the tumor cells and the * Cannot see loss of polarity, invasion, in FNAB and PAP Local and Hormonal Effects number of mitosis within the tumor Destruction of remaining tissue-pituitary adenoma- – Usually 4 grades 3. Flow cytometry – give 3D view endocrinopathies ie hypofunction Staging is based on size of primary lesion, extent of regional – Individual cell characteristics Obstruction & intussuception lymph nodes, & presence or absence of blood borne 4. Molecular diagnosis – FISH & PCR, to look for cancer genes Fatal hypoglycemia-Beta cell adenoma metastasis. – Diagnosis Hematuria-renal – 2 staging system: UICC (TNM) & AJCC – Prognosis Melena-GIT – Detection of residual disease * Stage more clinically significant than grade – Hereditary disposition Cancer Cachexia *spread & size is important Progressive loss of body fat & lean body mass Weakness, anorexia and anemia  T stands for tumour - how far the primary tumour has grown Increased basal metabolic rate locally. Action of soluble factors-cytokines-TNF, IL-1, IFN-gamma,  N stands for nodes - if the cancer has spread to the local Leukemia Inhibitory Factor (LIF) lymph nodes.  M stands for metastases - if the cancer has spread to other parts of the body. Paraneoplastic Syndromes s/sx no connection with neoplastic T0 – carcinoma in situ; do not invade yet 1. May present the earliest manifestation of an occult neoplasm N0 – no lymph node involved Tumor Markers* 2. May represent significant clinical problems and may even be M0 – no metastasis HCG lethal – choriocarcinoma 3. May mimic metastatic disease and therefore confound Example: stomach cancer AFP treatment  T-1 means the primary tumour is still in the stomach wall. T-3 – HCC means the primary tumour has grown right through the CEA 4. Endocrinopathies stomach wall and T-4 means it is invading nearby structures – colon, pancreas Cushing syndrome (most common endocrine), such as the pancreas. PSA, PAP ectopic hormone production in lung – prostate  N-0 means there is no spread to lymph nodes. N-1 means that 5. Hypercalcemia (most common paraneoplastic) NSE some local lymph nodes are affected. N-2 means more Osteolysis – SCCL and neuroblastoma extensive spread to local lymph nodes. Calcemic humoral substances (PTHRP) CA 125 NOT due to skeletal metastasis  M-0 means there are no metastases. M-1 means that there – ovarian 6. Neuromyopathic syndromes are metastases to some other area of the body such as the CA-19-9 liver or brain. Prepared by: EGBautistaII  – colon, pancreas CA-15-3 – breast Prepared by: EGBautistaII