72479869 Chapter 7 Neoplasia 1 2 Robbins and Cotran Pathologic Basis of Disease

NEOPLASIA I Introduction nd st • 2 leading cause of death in the US (1 = CVD) • Decreased mortality in the last decade of the 20th century and in a downward course Nomenclature *Neoplasma = tumor • Neoplasia - new growth • Tumor - swelling • Oncology – study of tumors or neoplasms NEOPLASM • Abnormal mass of tissue • Growth exceeds and uncoordinated with that of the normal tissue • Persists in the same manner after the cessation of stimuli which evoked the change • Autonomous • Clonal-arise from single cell that incurred genetic damage BENIGN • Relatively innocent • Remain localized • Cannot spread to other sites • Amenable to surgical removal • Patient generally survives MALIGNANT • Cancer • Invade and destroy adjacent structures • Spread to distant sites • Cause death 2 BASIC COMPONENTS 1. parenchyma-clonal neoplastic cells • determines tumor’s behavior and pathologic consequences 2. stroma  supporting tissues; tells how fast will grow • growth & evolution-blood supply • connective tissue-framework – Scant-soft and fleshy ex. Lymphoma, Fibrosarcoma – Abundant-desmoplasia (excessive stroma), stony hard ex. Scirrhous CA of breast

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Nomenclature – For Benign 1. MESENCHYMAL – organs lined with mesothelium • Attach the suffix “oma” to the cell of origin – Osteoma - bone – Chondroma - cartilagenous – Fibroma – fibrous tissue – Lipoma lipid tissue (not fat/ adipose) 2. EPITHELIAL • Attach the suffix “oma” to the cell of origin, microscopic pattern or macroscopic architecture – Adenoma – glandular; forming glands – Papillomas – finger-like projections – Polyp – protrudes from the surface of the organs – Cystadenomas, papillary cystadenomas • Exception: Hepatoma, Lymphoma, Seminoma, Melanoma, Mesothelioma-malignant (found in pleura) *all “-oma” are malignant Nomenclature – Malignant 1. CARCINOMA-from epithelial • Adenocarcinoma • Squamous cell carcinoma, basal cell carcinoma 2. SARCOMA-from mesenchymal • liposarcoma, leiomyosarcoma, osteosarcoma • fibrosarcoma, chondrosarcoma, angiosarcoma, rhabdomyosarcoma 3. MIXED TUMOR • Divergent differentiation of a single neoplastic clone • Pleomorphic adenoma of salivary gland (parotid) 4. TERATOMA – from testis, embryo, ovarian • totipotential cell that differentiate along 3 germ cell layer – totipotent means it can make a whole body/anything • benign (mature) or malignant (immature) 5. HAMARTOMAS – not necessary a neoplasia, it does not grow bigger • disorganized but benign appearing masses composed of mature specialized cells or tissue indigenous to the particular site • pulmonary chondroid hamartoma, hemangioma

6. CHORISTOMA – have normal tissue, but not in normal place (ie. endometriosis) • heterotopic rest of normal tissue Characteristics BENIGN MALIGNANT Differentiation and anaplasia

Well differentiated

Well to poorly/ undifferentiated/ anaplastic Rapid, erratic pace

Rate of growth

Indolent/slow growing/expansilecapsule

Local invasion

Absent

Present-progressive infiltration/destruction of surrounding/adjacent tissue

Metastasis

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Present

Differentiation & Anaplasia DIFFERENTIATION • Extent to which neoplastic parenchymal cells resemble the corresponding normal parenchymal cells both morphologically and functionally ANAPLASIA – poorly differentiated • lack/loss of differentiation, associated with other morphologic changes Changes in Anaplasia 1. PLEOMORPHISM – hallmark ok neoplasia • Variation in size and shape – ex.big/small cells 2. ABNORMAL NUCLEAR MORPHOLOGY • increased N:C ratio (1:6è1:1) • hyperchromatic, large nucleoli 3. MITOSES – mitosis is normale in labile cells • increased, atypical, bizarre 4. LOSS OF POLARITY • disturbed orientation 5. TUMOR GIANT CELLS – NOT macrophages (ie. Langhan cells in TB) • Not macrophages 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

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disordered growth, often occurs in metaplastic epithelium 7. METASTASIS • tumor implants discontinuous with the primary tumor Rate of Growth – something to do w/stroma, needs blood supply 1. Doubling time of tumor cells – multiplication time remains the same – Cell cycle time not shortened – time it takes to divide 2. Fraction of tumor cell in the replicative pool – Growth fraction – affects the G0 (ie. Stable cells) • low in breast & colon, high in some leukemia, lymphoma & small cell CA • Correlate with level of differentiation • Hormonal stimulation, adequacy of blood supply, etc 3. Rate at which cells are shed or die CANCER STEM CELLS & CANCER CELL LINEAGES • Cancer could arise from – normal tissue stem cells or – More differentiated cells that acquire the property of self-renewal • CML- from stem cells • AML- differentiated myeloid precursors • Tumor initiating cells (T-ICs) – Allow cells to grow indefinitely – May represent 25% of the total cellularity Local Invasion • Most benign tumors develop a rim of compressed connective tissue called a capsule – this are normal tissue that are pushed outside the lining forming capsule • Cancers show infiltration, invasion and destruction of surrounding tissue – Invasiveness • most reliable feature that differentiates benign from malignant tumor next to development of metastasis Metastasis • Unequivocally marks a tumor malignant • With few exceptions, all malignant tumors can metastasize – Gliomas of CNS, basal cell carinoma of skin-locally invasive but rarely metastasize

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More aggressive, more rapidly growing, larger sizegreater likelihood of metastasis Approximately 30% of newly diagnosed individuals with solid tumors present with metastasis

(3) Pathways of Spread • Seeding of body cavities & surfaces – Carcinomas arising from the ovaries Pseudomyxoma peritonei, appendiceal CA • Lymphatics – carcinoma – Skip metastasis – coz’ the passageway is obstructed – Sentinal nodes • Hematogenous – sarcoma – most common route – Veins>arteries – Organ area for metastasis (liver & lung) = need to check fist • Transplantation – rare – If undergo surgery = it will spread because same scalpel is used in making cuts Epidemiology • Study of cancer patterns • Contributes substantially to knowledge about origins of cancer • Provides major insights on the cause of cancer – environmental, racial (hereditary) & cultural influences • Cancer incidence Male Female – 1. Prostate 1. Breast – 2. Lung 2. Lung – 3. Colon 3. Colon – 4. Bladder 4. Uterus • Death - most people die w/lung ca Male Female – 1. Lung (31%) 1. Lung (26%) – 2. Prostate (10%) 2. Breast (15%) – 3. Colon (8%) 3. Colon (9%) – 4. Pancreas (5%) 4. Pancreas & Ovary (6%) Cancer Incidence • Increased death rate – HCC (hepatocellular ca)-caused by HCV (hepa C) • Decreased death rate

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Women: significant decline in death rates from cancer of breast & colorectal CA & most notably cervix-earlier diagnosis –Pap smear Men: nearly 80% of the total decrease in lung, prostate & colorectal CA

Geographic & Environmental Factors • Environmental > hereditary • Cultural > racial • Environmental factors – Home - Outdoors – Work - Medication *Look at table 7-3 • Most overweight individuals have a higher death rate from CA • Alcohol abuse-increase the risk for oropharynx, larynx, esophagus, liver • Smoking-mouth, pharynx, larynx, esophagus, pancreas, bladder, kidney • Risk of cervical CA: age of first intercourse, number of sex partners-HPV Age • • • •

Most CA occur in later years of life >55yrs Main cause of death among women aged 40-79 and men aged 60-79 ….carcinomas Acute leukemia & neoplasm of the CNS-approx 60% of deaths in children Common neoplasms of infancy & childhood-small round blue cell tumors, which includes: – Neuroblastoma, Wilms tumor, retinoblastoma, acute leukemias, & rhabdomyosarcomas

Genetic Predisposition 1. Autosomal Dominant Inherited Cancer Syndromes 2. Defective DNA Repair Syndromes 3. Familial Cancers 1. Autosomal Dominant Cancer Syndromes • Inheritance of single autosomal dominant mutant gene greatly increases the risk of developing a tumor • Usually a point mutation in single allele of tumor suppressor gene (RB) • Defect in the second allele occurs in somatic cells as a consequence of chromosome deletion or recombination

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Carriers of mutant RB tumor suppressor gene have 10,000 folds increased risk-bilateral retinoblastoma – Increased risk of developing second cancer, osteogenic sarcoma Familial adenomatous polyposis-inherit AD mutation of APC tumor suppressor gene (APC0adenomatous polycystic carcinoma) – innumerable adenomas in colon, virtually 100% fated to develop CA Li-Fraumeni syndrome-germ line mutation in p53 gene Multiple Endocrine Neoplasia (MEN) 1 & 2 mutation in menin and RET tyrosine kinase Hereditary Nonpolyposis colon cancer (HNPCC)-inactivation of mismatch repair gene (HNPCC is both AD&AR)

Inherited Cancer Syndromes GENERAL CHARACTERISTICS • Tumors tend to arise in specific sites and tissues – Except Li Fraumeni • Associated with a specific marker phenotype – Lisch nodule & café-au-lait spots 2. Defective DNA Repair Syndromes • Generally autosomal recessive • Defects in DNA repair  can cause DNA instability • Xeroderma pigmentosum, Ataxia telagiectasia, Bloom syndrome • ★HNPCC – AD w/DNA repair defect – colon CA, small int., endometrium, ovary – most common cancer predisposition syndrome 3. Familial Cancers • Breast, ovary, pancreas, …..colon, brain, melanomas, lymphomas • Characteristic features – early age at onset - AR – tumors arising in 2 or more close relatives – Multiple or bilateral tumors • Transmission pattern of familial cancers is not clear Interactions Genetic & Nongenetic Factors • Complex • Genotype can significantly influence the likelihood of developing environmentally induced cancers

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Inherited variations (polymorphisms) of enzymes that metabolize procarcinogens to their active carcinogenic forms can influence the susceptibility to cancer – cytochrome P-450 enzymes

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– Genes involved in DNA repair Haploinsufficiency-loss of gene function caused by damage to a single allele – Single cell is palpak but the other one is normal. A total of 2 alelles Carcinogenesis is a multistep process at both the phenotypic & genetic levels, resulting from the accumulation of multiple mutations – Tumor progression

Nonhereditary Predisposing Conditions CHRONIC INFLAMMATION –can lead to neoplastic • ex. Ulcerative colitis, Crohn disease, H. pylori gastritis, viral hepatitis, chronic pancreatitis • it is d/t Cytokines stimulate growth of transformed cells – that stimulate jak stat receptors • Increase pool of tissue stem cells • Production of Reactive Oxygen Species • Evidence: COX-2 increased in colon CA PRECANCEROUS CONDITIONS • non-neoplastic disorders – chronic atrophic gastritis of pernicious anemia, solar keratosis, skin chronic ulcerative colitis, & leukoplakia of oral vulva, penis & oral cavity • Neoplasic – Villous adenoma-increase in size, develops CA in 50% of cases Molecular Basis of Cancer FUNDAMENTAL PRINCIPLES 1. Nonlethal genetic damage lies in the heart of carcinogenesis – mutation may be acquired-action of environmental agents: chemicals, radiation, viruses – inherited in the germ line – if cells died, there will be no replication & thus, it must not be lethal 2. Tumor is formed by the clonal expansion of single precursor cell that has incurred the genetic damage – Tumors are monoclonal – Cells that gone crazy 3. Four classes of normal regulatory genes are the principal target of genetic damage – Protooncogenes-growth promoting – Tumor suppressor gene-growth inhibiting – Genes that regulate apoptosis

7 FUNDAMENTAL CHANGES 1. Self-sufficiency in growth factors 2. Insensitivity to growth inhibitory signals 3. Evasion of apoptosis 4. Defects in DNA repair 5. Limitless replicative potential 6. Sustained angiogenesis 7. Ability to invade and metastasize

SELF SUFFICIENCY IN GROWTH SIGNALS • ONCOGENES - Genes that promote autonomous growth • PROTONCOGENES - Normal cellular counterpart • ONCOPROTEINS - Products of genes without regulatory function *Proto-oncogenes  oncogene  secretes oncoproteins

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IN CELL PROLIFERATION Binding of growth factor to cell membrane receptor Activation of signal transducing proteins Transmission of signal to nucleus Activation of nuclear factors Entry into cell cycle

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kinase is transiently activated by binding of the specific GF, followed rapidly by receptor dimerization & tyrosine phosphorylation of several substrate that are part of signaling cascade Oncogenic/mutant receptors – associated with constitutive dimerization & activation without binding to the GF, deliver continuous mitogenic signals to the cell even in the absence of GF in the environment Can be constitutively activated in tumors by different mechanisms – Mutations – gene rearrangements – overexpression Ex. RET proto-oncogene : mutation with gene rearrangement – 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

Signal Transducing Proteins • Oncoprotein can mimic signal transducing proteins • ex. RAS family of guanine triphosphate (GTP)-binding proteins (G proteins)-RAS genes

Growth Factors • Normal cells – need GF to stimulate proliferation – paracrine action • Many cancer cells – acquire the ability to synthesize the same GF to which they are responsive – autocrine loop Ex. Glioblastoma-express PDGF &PDGFR Sarcomas-TGFα Growth Factor Receptors • Normal Prepared by: EGBautistaII

RAS Oncogene • Point mutation of RAS family genes-single most common abnormality of protooncogene in human tumors-approx. 15-20% of all human tumors • 90% in pancreatic adenoCA & cholangioCA • 50% in colon, endometrial, thyroid • 30% in lung adenoCA & myeloid leukemia • KRAS-colon & pancreas, HRAS-bladder, NRAShematopoeitic tumors •

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Activated RAS stimulates downstream regulators of proliferation such as the mitogen-activated protein (MAP) kinase cascade-floods the nucleus with signals for cell proliferation Mutated RAs is trapped in its activated GTP-bound form, and the cell is forced into continuously proliferating state MYC Oncogene

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Can act in concert to reprogram somatic cells into pluripotent stem cells May also enhance self-renewal, block differentiation or both Amplified in breast, colon, lung and many other carcinomas N-MYC & L-MYC in neuroblastomas & small cell CA of lungs respectively Translocation-Burkitts lymphoma

CYCLINS

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Control orderly progression of cells thru the phases of the cell cycle

CDK Inhibitors • CIP/WAF – – • INK4 – –

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p21,p27,p57 Inhibit all stages

p15, p16, p18, p19 Inhibit cyclin D • CDK4 & CDK6 • Check points at G1/S and G2/M mediated by p53, p21 Major cause of genetic instability

SELF SUFFICIENCY OF GROWTH SIGNALS • Overexpression of growth factor genes – PDGF & TGF • Altered growth factor receptors – RET • Minicry of signal transducing proteins – RAS • Oncoproteins as transcription factors – MYC • Dysregulation of cyclins

INSENSITIVITY TO GROWTH INHIBITORY SIGNALS • TUMOR SUPPRESSORS – Stop cell proliferation • RB gene • P53 protein • APC and NF-1

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NEOPLASIA PART II EVASION OF APOPTOSIS • Reduced levels of CD95/Fas – inhibit extrinsic pathway • Inactivation of caspase 8 by FLIP – inhibit extrinsic path. • Protection of tumor cells by BCL2

Knudson’s Hypothesis • “two hits” required – First hit - inherited, all somatic cells – Second hit- inherited or acquired, particular cell • “loss of heterozygosity” – Heterozygotes-no expression of cancer – Homozygotes-cancer RB GENE • • • •

RB protein regulates cell growth at G1/S Cyclin E- CDK2 and Cyclin D CDK 4,6 required Mutation associated with retinoblastoma and osteosarcoma Loss of normal cell cycle control is central to malignant transformation and that at least 1 of 4 key regulators of the cell cycle is dysregulated in the vast majority of human cancers

p53 (p63,p73) • Most common target for genetic alteration • Located on chromosome 17p13.1 • Stops neoplastic transformation by – Cell cycle arrest (quiescence and senescence) – initiation of apoptosis • One mutant p53 = Li Fraumeni syndrome – 25 % increased risk of neoplasia – Sarcomas, breast, leukemia

LIMITLESS REPLICATIVE POTENTIAL • Replicative senescence lies in telomere shortening • Short telomere  activation of p53 checkpoint  apoptosis • Telomerase-prevents shortening of telomere • About 90% of tumors have telomerase activity • Some have alternative lengthening of telomeres

APC/ CATENIN • APC protein down regulates catenin • Loss of APC causes continuous WNT signaling and -catenin enters nucleus  cell proliferation

TUMOR SUPPRESSORS  NF1-Neurofibroma, glioma  NF2- Schwannoma  VHL – renal cell ca, pheochromocytoma  PTEN- “Cowden Syndrome” epithelial cancers  WTI- Wilms Prepared by: EGBautistaII

PTCH- “Gorlin syndrome”, basal cell carcinoma

SUSTAINED ANGIOGENESIS • Tumors >2mm require new blood supply • Angiogenic switch- change in phenotype that induces angiogenesis mostly controlled by hypoxia • Neovascularization (adult) or vasculogenesis – this 2 both occur in neoplasia • Vasculature is abnormal- leaky, haphazard • Vasculogenic mimicry – tumor cells resemble capillaries • The only difference is that there is no blood inside Notes: • Decreased angiogenesis inhibitors – angiostatin, endostatin, vasculostatin • Loss of p53 provides more permissive environment for angiogenesis • 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 1. • •

INVASION Detachment of tumor cells from one another – Down regulation of E cadherins – becomes loose Degradation of ECM

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Secrete proteolytic enzymes: MMPs, cathepsin D, urokinase, plasminogen Attachment to matrix components – Intergrins attach to fibronectin, laminin Migration of tumor cells or locomotion – Directed by cell derived cytokines/ amoeboid mov’t

Notes: • Down regulation of E catherins or mutation in catenin needed for linkage • Matrix metalloproteinases – remodelng insoluble components and release of growth factors • Ameoboid migration- a second method of migration using collagen fibers

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VASCULAR DISSEMINATION Tumor cells -clump, form emboli, adhere to target (emboli is filled with platelet & metabolite) • At site -proliferate, develop a vascular supply, evade host defenses • Organ trophism – Adhesion molecules on the endothelial cells of the target organ – Chemokine receptors – Some tissues are unfavorable to metastasis ( where we do not see metastasis, ex.skeletal muscles) Notes: – Some tissues, like skeletal muscles have an unfavorable environment for growth – CD44 – are adhesion molecule expressed on T cells; overexpression favors metatasis

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Snail and twist promote EMT epithelial to mesenchymal transition.which favors migration

Genomic Instability • Where DNA become vulnerable for mutations (irreversible) • Inherited defects in DNA repair genes allow mutations in other genes • DNA repair systems – Mismatch - can cause: • HHPCC – microsatellite instability – Nucleotide excision repair • Xeroderma pigmentosa (AR) – sensitive to uv light – Recombination repair • Bloom, etc – hypersensitivity to DNA damaging agents • BRCA 1 &BRCA 2 breast cancer Notes: • Genonic instability occurs when both DNA repair genes are lost • Microsatellite instability- tandems are shorter or longer • UV radiation causes cross-linkage of pyrimidine residues that now cannot be excised Warburg Effect – a metabolic alterations • 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 – Abnormal vasculature – Reduction in autophagy Notes: • Used to visualize tumors in PET • Gives 2 ATP rather than 20 – Chromosomal Abnormalities – Translocation – Overexpression of protooncogenes • MYC of Burkitt Lymphoma – Hybrid “chimaric” genes – Constitutive tyrosine kinase activity • BCR-ABL (Philadelphia chromosome 9) of CML • BCR( 22) to ABL (9) – Deletions

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Loss of tumor suppressor genes • Non hematopoietic solid tumors • RB in retinoblastoma

Gene Amplification • Two patterns are seen – double minutes (dms) – Homogeneous Staining Regions (HSR) – Ex. N-MYC – neuroblastoma, both patterns seen – Ex. ERBB2 – breast ca Epigenetic Changes – Reversible, heritable changes in gene expression – Post translational modification – Genome imprinting / loss of imprinting d/t – Methylation causes inactivation Ex BRCA 1 in breast cancer MiRNAs and Cancer • Small non-coding single stranded RNA • Mediate post-transcriptional gene silence Multistep Carcinogenesis • Cancer must result from the accumulation of multiple mutations

Carcinogenesis Initiation-promotion sequence 1. Initiation results from exposure of cells to a sufficient dose of carcinogen – Permanent DNA damage is rapid and irreversible

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Promoters induce tumors in initiated cell without affecting DNA directly and are reversible – Not tumorigenic themselves; only cause cell proliferation

CARCINOGENS 1. Chemical 2. Radiant energy 3. Microbial 1. CHEMICAL CARCINOGENS • Initiation – Exposure and mutation • Promotion – Reversible enhancement of proliferation INITIATORS – cause damage; direct (alkalyting agent); or indirect • Direct acting – Highly reactive electrophils – Weak carcinogens • Indirect acting – Require metabolic activation – Vary among individuals  

DNA is primary target Altered cells must be able to undergo at least one cycle so change can be made permanent CARCINOGENIC CHEMICALS * Liver cancer caused by Aflatoxin B has a signature mutation in (p53) Alkylating agents Naturally occurring Weak - direct acting Aflatoxin B Therapeutic agents Stored corn, rice, peanuts Polycyclic hydrocarbons Most potent Tobacco, smoked meat/fish

Nitrosamines and amides Preservatives

Aromatic amines/Azo dyes Mainly affect liver Food coloring

Others: asbestos, vinyl chloride, arsenic Industrial exposure, insecticides

PROMOTERS • Phorbol esters • Viral infection • Hormones Prepared by: EGBautistaII

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Bile salts High levels of dietary fat phenols

2. RADIATION CARCINOGENS • Ultra Violet rays – UV B in sunlight linked to all forms of skin cancer – can cause squamous cell Ca - melanoma – Formation of pyrimidine dimers • Ionizing Electromagnetic Forces – X rays and gamma rays –  and  particles – linked to leukemias, thyroid ca etc Notes: • •

Accumulated even exposure (SCC), short bursts of exposure (melanoma) UVC more carcinogenic but filtered by ozone

3. MICROBIAL CARCINOGENS 1. RNA viruses - HTLV-1 – T –cell leukemia, lymphoma – tax genone causes proliferation and instabiity 2. Bacteria - Helicobacter pylori – Gastric adenocarcinomas and MALTomas – CagA cytotoxin gene and cytokines (Chronic inflammation)

Notes: • Tax has transforming activity • H pylori – 1st bacteria called a carcinogen 3.

DNA viruses – Human Papilloma Virus (16 & 18) • Squamous cell ca of cervix d/t • Overexpression of E6 & E7 oncogenes – Epstein – Barr Virus • Burkitt lymphoma, B cell (coz’ CD21) lymphoma in HIV, Hodgkin, Nasopharyngeal Ca, gastric Ca,NK lymphoma • LMP-1 is oncogene – Hepatitis B & C Viruses • Liver Cancer • Cytokines and reactive oxygen species Notes:

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HPV also activate cyclins, inhibit apoptosis and combat cell aging EBV uses CD 21 receptor to attach to B cells

Tumor Immunity • Immune surveillance – Guards against tumor development • Cancer immunoediting – Sculpting the immunogenic properties of tumors to select tumor cells that escape immune elimination Tumor Antigens 1. Products of mutated genes – Mutated tumor suppressor genes – Mutated self protein Notes: – Tumor specific or tumor associated antigen no longer used!! – Antigens must be recognized by CTLs – Products of mutated genes become tumor antigens 2.

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Overexpressed or aberrantly expressed cellular proteins – Ex – tyrosinase and cancer testis antigen – Normal cellular proteins that are abnormally expressed! Produced by Oncogenic viruses Oncofetal antigens found on fetal and cancer cells Altered cell surface glycolipids and glycoproteins – Higher concentration – Abnormal forms Cell type specific differentiation antigens – Do not induce immune response – target for immunotherapy

Anti Tumor Mechanisms • Cytotoxic T lymphocytes – cell mediated • Natural killer cells • Macrophages • Antibodies - humoral Notes: • Mostly cell mediated • Antibody against CD20 for B cell lymphoma Tumor Evasion of the Immune System • Selective outgrowth of antigen-negative variants • Loss or reduced expression of MHC molecules

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Lack of costimulation Immunosuppression – ex. HIV Antigen masking Apoptosis of cytotoxic T cells *Cancers more common in immunocompromised

Clinical Features of Tumors Effects of Tumors on the Host • Location & impingement on adjacent structures • Functional activity such as hormone synthesis • Bleeding & secondary infection-ulcerate to surface • Initiation of acute symptoms-rupture or infarction • Cachexia – 10% body weight loss Local and Hormonal Effects • Destruction of remaining tissue-pituitary adenomaendocrinopathies ie hypofunction • Obstruction & intussuception • Fatal hypoglycemia-Beta cell adenoma • Hematuria-renal • Melena-GIT Cancer Cachexia • Progressive loss of body fat & lean body mass • Weakness, anorexia and anemia • Increased basal metabolic rate • Action of soluble factors-cytokines-TNF, IL-1, IFN-gamma, Leukemia Inhibitory Factor (LIF)

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Endocrinopathies • Cushing syndrome (most common endocrine), ectopic hormone production in lung Hypercalcemia (most common paraneoplastic) • Osteolysis • Calcemic humoral substances (PTHRP) • NOT due to skeletal metastasis Neuromyopathic syndromes

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Hypertrophic osteoarthropathy (from bronchogenic) – New bone formation – Arthritis – Clubbing Vascular and hematologic • Migratory thrombophlebitis (pancreas, lung) • Thrombotic endocarditis (adenocarcinoma) • DIC (leukemia, prostate)

Grading and Staging • Grading-degree of differentiation of the tumor cells and the number of mitosis within the tumor – Usually 4 grades • Staging is based on size of primary lesion, extent of regional lymph nodes, & presence or absence of blood borne metastasis. – 2 staging system: UICC (TNM) & AJCC * Stage more clinically significant than grade *spread & size is important

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Paraneoplastic Syndromes s/sx no connection with neoplastic 1. May present the earliest manifestation of an occult neoplasm 2. May represent significant clinical problems and may even be lethal 3. May mimic metastatic disease and therefore confound treatment

• Tumor antigen cross reaction Acanthosis Nigricans – hyperpigmentation of the skin

"The stage is T-3, N-1, M-0" which means "the cancer has spread through the stomach wall, there is some spread to local lymph nodes, but no metastases in other parts of the body". Laboratory Diagnosis 1. Histologic & cytologic methods – Biopsy, needle aspiration (FNAB) & cytologic smears (PAP) – stain not only for cervix 2. Immunohistochemistry – Categorization of undifferentaiated malignancies – Determination of site of origin (PSA) – Detection of molecules that have prognostic or therapeutic value (ERBB2/ HER2-neu) * Cannot see loss of polarity, invasion, in FNAB and PAP 3. 4.

Flow cytometry – give 3D view – Individual cell characteristics Molecular diagnosis – FISH & PCR, to look for cancer genes – Diagnosis – Prognosis – Detection of residual disease – Hereditary disposition

T stands for tumour - how far the primary tumour has grown locally. N stands for nodes - if the cancer has spread to the local lymph nodes. M stands for metastases - if the cancer has spread to other parts of the body.

T0 – carcinoma in situ; do not invade yet N0 – no lymph node involved M0 – no metastasis Example: stomach cancer  T-1 means the primary tumour is still in the stomach wall. T-3 means the primary tumour has grown right through the stomach wall and T-4 means it is invading nearby structures such as the pancreas.  N-0 means there is no spread to lymph nodes. N-1 means that some local lymph nodes are affected. N-2 means more extensive spread to local lymph nodes.  M-0 means there are no metastases. M-1 means that there are metastases to some other area of the body such as the liver or brain.

Tumor Markers* • HCG – choriocarcinoma • AFP – HCC • CEA – colon, pancreas • PSA, PAP – prostate • NSE – SCCL and neuroblastoma • CA 125 – ovarian • CA-19-9

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– colon, pancreas CA-15-3 – breast

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