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1 5 NEOPLASIA
P THOLOGY
NEOPLASIA New growth
It is defined as abnormal mass of tissue, the grow th of which
exceeds and is uncoordinated with that of the normal tissue
and persists in the same manner after cessation of stimuli
w hich evoked the change Cancer- common term to all malignancies
All neoplasms ultimately depends on the host for their nutrition
and vascular supply.
Two basic components of Neoplasia:
1. Proliferating neoplastic cell-parenchyma
2. Supportive stroma- connective tissue and blood vessels.
INCIDENCE & MORTALITY DATA 10.1 Million new cases
6.2 Million deaths
22.4 Million living w ith Cancer year 2005
Increase of 19% in incidence
Increase of 18% in mortality since 1990
MOST COMMON CANCER CAUSING DEATHLung 17.8 %
Stomach 10.4 %Liver 8.8 %
MOST COMMON CANCER WORLDWIDELung Cancer 12.3 %
Breast CancerProstate Cancer
10.4 %
Colorectum 9.4 %
NOMENCLATUREParenchymaProliferating neoplastic cells
Stroma Connective tissue and blood vessels
Benign Tumors
suffix oma
Malignant Tumors
2 broad categories:
Carcinomas - epithelial cells
sarcomas - mesenchymal tissues
Some tumors w ith more than one parenchymal cell type: mixed
tumors & teratomas
Two non-neoplastic lesions bear the names that are
deceptively similar to tumors: choristomas& hamartomas
CLASSIFICATION OF NEOPLASMSA. Site
B. Biologic Behaviorbenign, borderline, malignant
C. Cell ( tissue of origin )
D. Embryologic derivation
E. Diff erentiation potential of cell of origintotipotent cellF. Etiology
Tumors are classified to 2 broad categories: benign and
malignant.
BENIGN MALIGNANTSlow grow ing Rapidly grow ingEncapsulated Not encapsulated
No infiltration/Expansile grow th Infiltrative grow thNo metastas is Metastas is
Well diff erentiated Well-poorly diff erentiatedHigh patient survival after
successful surgical removalPoor patient survival rate;
tendency for local and distantrecurrence
BENIGN MALIGNANT
GROSS FEATURESSmooth surface with a fibroticcapsule; compress surroundingtissue
Irregular surface withoutencapsulation; destruction tosurrounding tissue
Slow rate of growth Rapid rate of grow thRarely fatal Usually fatalSmall to large Small to large
MICROSCOPICGrowth by compression Growth by invasionHighly diff erentiated Well or poorly diff erentiatedCell similar to normal andresembling to one another
-Cytologic abnormalities(Pleiomorphism)- Anaplasia (MorphologicHALLMARK of malignancy)
No mitosis With mitosisWell formed blood vessel Poorly formed and numerous
blood vessel(-) Necrosis/Hemorrhage(-) Metastasis
(+) Necrosis & Hemorrhage(+) Metastasis
INVESTIGATIVE TECHNIQUEDNA content usually normal DNA content of cells usually
increasedKaryotype normal Aneuploidy
PolyploidyClonal GeneticAbnormality
Fig1. Comparison of Leiomyoma & Leiomyosarcoma
Fig 2. Choristoma: Ectopic rest of normal tissue
Fig 3 & 4. Hamartoma: mass of disorganized but mature
specialized cells or tissue native to the particular s ite
BENIGN TUMORS
Cell of origin + OMA
AdenomaBenign tumor arising from glandular cells
LeiomyomaBenign tumor arising from smooth muscle cells
ChrondromaBenign tumor arising from chondrocytes
Papilloma Has finger-like projections
PolypProjects upw ard, forming a lump
CystadenomaHas hollow spaces (cysts) inside
Fig 5 & 6. Tubular adenoma, colon
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Fig 7. Papillomas: architecture finger like projections
Fig 8 & 9. Polyp: macroscopic projection of mucosal surfaceMALIGNANT NEOPLASMS
Malignant tumors: Differentiation and anaplasia Dysplasia Rapid rate of grow th Widespread invasion Metastases
Carcinomasarise in epithelial tissue Adenocarcinomamalignant tumor of glandular cells Squamous cell carcinomamalignant tumor of
squamous cells Sarcomasarise in mesenchymal tissue
ChrondrosarcomaMalignant tumor ofchondrocytes
AngiosarcomaMalignant tumor of blood vessels RhabdomyosarcomaMalignant tumor of skeletal
muscle cellsANAPLASIA
Lack of differentiation Hallmark of malignant transformation Numerous morphologic changes
Fig 10. Pleomorphism: variation in size and shape
Fig 11. Abnormal nuclear morphology: hyperchormatic
(abundant DNA), increased N:C ratio (normal 1:4- 1:6)
Fig 12. Mitoses: Increased, bizarre
Fig 13. Loss of polarity
Fig 14. Tumor giant cells
Fig 15 & 16. Dysplasia : Disordered grow thCELL (TISSUE OF ORIGIN)
I. Composed of One Parenchymal Cell type:
A. EpithelialB. Mesenchymal
II. More than one Neoplastic Cell Type derived from one germ layer:A. Salivary GlandB. BreastC. Renal Anlage
III. More than one Neoplastic Cell Type derived from more than one germlayer: Teratoma
TISSUE OF ORIGIN BENIGN MALIGNANTMesenchymal/
connective tissueFibromaLipoma
ChondromaOsteoma
FibrosarcomaLiposarcoma
ChondrosarcomaOsteogenic sarcoma
Endothelial & relaxedtissue
HemangiomaLymphangioma
Meningioma
AngiosarcomaLymphangiosarcoma
Synovial sarcomaMesotheliomaInvasive meningioma
Hematopoietic LeukemiasLymphoma
Muscle LeiomyomaRhabdomyoma
LeiomyosarcomaRhabdomyosarcoma
Epithelial Squamous papillomaAdenomaPapilloma
CystadenomaBronchial adenoma
Renal tubularadenoma
Liver cell adenomaTransititonal cell
papillomaHydatiform mole
SCC or epidermoidCABCC
AdenocarcinomaPapillary carcinoma
CystadenocarcinomaBronchogenic
carcinomaRenal cell carc inoma
Transitional cellcarcinoma
ChoriocarcinomaSeminoma
Embryonal CAMelanocytes Nevus Malignant Melanoma
MIXED TUMOR Mixed tumors show divergent differentiation Examples
o Pleiomorphic adenomaglands + f ibromyoid stroma Teratomas
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MORE THAN ONE NEOPLASTIC CELL MIXEDSalivary gland Pleomorphic
AdenomaMalignant mixedtumor of salivarygland origin
Renal Wilms tumorTERATOGENOUS (FROM MORE THAN ONE GERM CELL LAYER)Totipotential cells Mature
teratoma/dermoid cystImmature tertoma,teratocarcinoma
CONFUSING TERMS Malignant tumors that sound benign
o Lymphomao Mesotheliomao Melanomao Seminoma
Non tumors that sound like tumorso Hamartoma mass of disorganized indigenous
tissueo ChoristomaHeterotopic rest of cells
Names that seem to come out of now hereo Nevuso Leukemiao Hyatidiform mole
BORDERLINE TUMORS Variable grow th rate Locally infiltrative Low or no metastatic potential Intermediate patient survival rate; tendency for local recurrence
after successful surgical removal INTACT BASEMENT MEMBRANE
PRE-MALIGNANT (PRE CANCEROUS) LESIONSA. Hyperplasia
-Endometrial Hyperplasia-Lobular and Ductal Hyperplasia-Cirrhosis of the liver
B. DysplasiaC. Metaplasia
-Barrets EsophagusD. Inflammatory Lesions
-Ulcerative Colitis, Atrophic Gastritis-Autoimmune (Hashimotos) Thyroiditis
E. Benign neoplasms- Colonic Adenoma
MECHANISMS & CAUSES OF NEOPLASIA At MOLECULAR LEVEL , neoplasia is defined as disorder of grow th
regulatory genes ( proto-oncogenes and tumor suppressor genes ). Origin of Neoplasia: Monoclonal Origin Field Origin MONOCLONAL THEORY- The initial neoplastic change aff ects a single cell, w hich then
multiplies and give r ise to neoplasm. FIELD THEORY- A carcinogenic agent acting on a large number of s imilar cells mayproduce a filed potentially neoplas tic cells. Then neoplasms may then
arise from one or more cells within this field.MOLECULAR BASIS OF CANCER Inherited cancer syndrome, usually involving germ-line mutation in
tumor suppressor or DNA repair genes, accounts f or 4 % of allCancer
Genetic susceptibility significantly alter the risk from environmentalexposures
Fundamental Principles: Non-lethal genetic damage lies at the heart of carc inogenesis. A tumor is formed by the clonal expansion of a single precursor
cell that has incurred genetic damage. Carcinogenesis is a multistep process hence multiple
mutations. The 7 key changes are the ff : (Essentials for malignant
transformation) Self-suf ficiency in growth signals Insensitivity to grow th inhibitory signals
Evasion of apoptosis Limitless replicative potential Sustained angiogenesis Ability to invade and metastas ize
Defects in DNA repair
Fig 17. Events in neoplastic transformation Oncogenes and Cancer
Oncogenes Proto-oncogenes
Protein products of Oncogenes Activation of Oncogenes
Point mutations Chromosomal rearrangements Gene amplifications
Oncogenes are genes capable of causing cancer. The genes are activated by mutation, amplification, or
translocation. Activation can lead to the loss of normalregulation and differentiation, increased proliferation.
Activationis the functional concept whereby the normal
action of grow th regulation is diverted into oncogenesis.
Mechanisms of Occurrence:
1. Mutation
2. Translocation
3. Insertion
MOLECULAR BASIS OF NEOPLASIA Basic unde rlying cause of cancer:
DISORDER IN THE GROWTH REGULATORY GENE Four kinds of normal genes are damaged:
1. Genes that promote grow th (protooncogenes)2. Genes that inhibit grow th (tumor-suppressor genes)
3. Genes that regulate apoptosis4. Genes involved in DNA repair
Cancers develop in multiple steps
Fig.18 Transformation of NeoplasiaHALLMARKS OF CANCER
Fig. 19. Hallmarks of Cancer
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GROWTH FACTOR SIGNALING PATHWAYS IN CANCER
Fig 20. Growth Factor Signaling pathways in Cancer
Fig 21. Escape from senescence and mitotic catastropheSELF RENEWING CAPACITY IN CANCER CELLS
PATHOGENESIS IN RETINOBLASTOMA
Fig 22.Retinoblastoma PathogenesisEVASION OF IMMUNE SURVEILLANCE
Different classes of tumor antigens are products of:1. Mutated proto-oncogenes2. Tumor suppressor genes3. Overexpressed or aberrantly expressed proteins4. Tumor antigens produced by oncogenic viruses5. Oncofetal antigens6. Altered glycolipids and glycoproteins7. Cell types specific diff erentiation antigens
Tumors may avoid the immune system by:1. Selective outgrow th of antigennegative variants2. Loss or reduced expression of histocompatibility antigens3. Immunosuppression mediated by expression of certain factors
(ex. TGF-B, PD-1 ligand, galectins) by the tumor cells.
HOST DEFENSE AGAINST TUMOR IMMUNITY
Fig 23. Tumor antigens recognized by CD8+ T cells
Fig.24. Mechanisms by w hich tumors evade the immune system.GENETIC LESIONS IN CANCER
Oncogenic mutations, including point mutations and othernonrandom chromosomal abnormalities, such astranslocations, deletions, and gene amplifications.
Balanced translocations. Deletions Gene amplification Numerous cryptic(subcytogenetic) rearrangements.
TUMOR EVOLUTION
Fig 25.
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MOLECULAR MODEL FOR CANCER EVOLUTION
Fig 26. Molecular model for the evolution of colorectal cancersthrough the adenoma-carcinoma sequence.
Each cancer must result from the accumulation of multiplemutations.
CARCINOGENIC AGENTS AND THEIR CELLULAR INTERACTIONS Steps involved in Chemical Carcinogenesis
1. Initiation results from exposure of cells to a suff icient dose of acarcinogenic agent. (initiator)
2. Initiation causes permanent DNA damage. (mutations)3. Promoters can induce tumors in initiated cells, but they are non
tumorigenic by themselves.CHEMICAL CARCINOGENESIS
Chemical carc inogens have highly reactive electrophile groupsthat directly damage DNA, leading to mutations and eventuallycancer.
Direct acting agents do not require metabolic conversion tobecome carcinogenic.
Indirect-acting agents arent active until converted to anultimate carcinogen by endogenous metabolic pathways.
DEVELOPMENT OF A CANCER
Fig 27. Tumor progression and generation of heterogeneity.CARCINOGENIC AGENTS AND THEIR CELLULAR INTERACTIONS Radiation Carcinogenesis
o UV rayso Ionizing radiation
Microbial Carcinogenesiso Onconegenic RNA viruses
Human T cell Leukemia Virus Type Io Onconegenic DNA viruses
Human papilloma virus Epstein Barr virus Hepatitis B & C virus
Bacterial Carcinogenesiso Helicobacter pylori
RADIATION CARCINOGENESIS Ionizing radiation causes chromosome breakage,
translocations, band, less frequently, point mutations, leadingtobgenetic damage and carcinogenesis. (X-rays, gamma rays,alpha, beta, positrons, protons, neutrons and primary cosmicradiation)
UV rays induce formation of pyrimidine dimers w ithin DNA,
leading to mutations.GENES CANCER GENES
Autonomous grow th Insensitivity to grow th-inhibitory signals Evasion of apoptosis Limitless replication Sustained angiogenesis Invasion and metastasis
PROTO-ONCOGENES (CELLULAR ONCOGENES) Code for a variety of growth factors, receptors, and signal-relay
or transcr iption factors which act in concert to control entry intothe cell cycle.
PROTO-ONCOGENES code for a number of protein products(grow th factors, kinases, etc). The expression is w ell controlled,playing a role in normal grow th and development.
o Normal cellular genes w hose products promote cellproliferation.
Ras- proto-oncogene: a G protein defect. SRC proto-oncogene: tyrosine kinase deficiency.
Sis proto-oncogene: platelet derived grow th factor receptordefect.
Erb B proto-oncogene- epidermal grow th factor receptor defect. Myc (c-myc, n-myc, l-myc) proto-oncogenes- nuclear factors. HER-2/neu over expression in 15-30% of pts w ith breast
cancer. LiFraumeni syndrome: defect in p53 gene. Patients get
childhood sarcomas, breast cancer, brain tumors, leukemia,adrenal cancer.
Medullary thyroid cancer: associated with Ret proto-oncogeneon chr 10. Patients w ith Ret oncogene defect plus familyhistory- 90% get medullary cancer of thyroid, need totalthyroidectomy.
MENIN a product of MEN1 gene also associated withmedullary cancer of thyroid.
ONCOPROTEIN: A protein encoded by an oncogene that
drives increased cell proliferation through one of severalmechanisms. ONCOGENES: Mutated or overexpressed versions of proto-
oncogenes that function autonomously.ONCOGENES, THEIR MOA & ASSOCIATED HUMAN TUMORS
CATEGORY PROTOCONCOGENES MECHANISM A.TUMORGrowth factors
PDGF- chain sis Ov erexpression Astrocy toma
Growth Factor Receptors
EGF-receptorfamily
erb-B1 Ov erexpression Squamouscell CA ofthe lungs
Proteins involved in Signal Transduction pathway
GTP-binding ras Pt mutations CA ofLung,colon,pancreas;manyleukemias
Nuclear Regulatory proteins
Transcriptionalactivators
myc Translocation Burkittlymphoma
Cell Cycle Regulators
Cyclins cyclin D Translocation Mantle celllymphoma
TUMOR SUPPRESOR GENES (ANTI ONCOGENES)Which serve to dow n-regulate the cell cycle.
Note: a net increase in the production of s timulatory (promoter) factors , adecrease in inhibitory (suppressor) growth factors may lead touncontrolled cell grow th.
Cancer-Suppressor Genes Protein Products of Tumor Suppressor Genes
Gene amplifications p53 BRCA-1 and BRCA-2 APC gene NF-1 gene cell surface receptors WT-1
Genes That Regulate Apoptos is bcl-2
Genes That Regulate DNA Repair hMSH2 and hMLH1
Molecular Basis of Multistep Carcinogenesis gatekeeper genes- APC, NF-1, and Rb caretaker genes- DNA repair genes
Retinoblastoma (RB1)- chr 13: involved in cell cycle. P53- chr 17: involved in cell cycle (normal gene induces cell
cyc le arrest and apoptosis, abnormal gene allows unrestrainedcell grow th.
APC- chr 5; involved w ith cell adhesion and cytoskeletonfunction.
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BRCA I and IIRB
Governor the cell cyc le When hypophosphorylated, RB exerts antiproliferative Normal grow th factor signaling leads to RB
hyperphosphorylation and inactivation.1. Loss of function mutations aff ecting RB2. Gene amplifications of CDK4 and cyclin 0 genes3. Loss of cyclin-dependent kinase inhibitors (p16/INK4a)4. Viral oncoproteins that bind and inhibit RB (E7 protein of
HPV)P53
Guardian of the genome The p53 protein is the central monitor of stress in the cell. Involved in cell cycle arres t, DNA repair, cellular senescence
and apoptosis. Kinases phosphorylate p53, liberating it from inhibitors causing
cell-cycle arrest at the G1-S checkpoint. This pause allows cells to repair DNA damage. The majority of human cancers demonstrates biallelic loss of
function mutations in TP53.
Fig 28. Role of p53 in maintaining the integrity of the genome.KARYOTYPIC CHANGES IN TUMOR CELLS
Three types of nonrandom chromosomal abnormalities have beendescribed:
(1) translocation (2) deletions (3) amplification
CYTOGENETIC ABNORMALITIES IN HUMAN NEOPLASMSTUMOR CYTOGENETIC
ABNORMALITYEFFECTS
Chronic myeloidleukemia
Translocationbetw een chromosome9 & 22 (Philadelphia
chromosome)
Forms a protein w ithtyrosine kinaseactivity (bcr-abi
protein)Follicular lymphoma Translocation
betweenchoromosome 14 &
18
Production of protein
that prevents celldeath (bcl 2 product)
Neuroblastoma Homogenous regionsand double minute
chromosomes
Amplification of n-mycin poor prognosis type
Ew ings tumor Translocationbetw een chromosome
11 & 22
Uncertain
CHARACTERIZED HERITABLE NEOPLASIA SYNDROMESYNDROME TUMOR CAUSED DEFECT
MEN syndrome Multiple tumor inendocrine organs
Mutations onchromosomes 10 &11
Polyposis coli Adenomata and
carcinomas of thecolon
Absnt tumor
suppressor gene
Li-Fraumeni Breast cancer andsarcomas
Mutated tumorsuppressor gene
XerodermaPigmentosum
Skin cancer Abnormal DNA repair
Familialretinoblastoma
Malignant tumor of theretina
Absent tumorsuppressor gene
NeurofibromatosisType I
Benign and malignanttumors of peripheralnerves
Abnormal tumorsuppressor gene
Neoplasia Associated with Constant Genetic Abnormality:a. Philadelphia Chromosome- CMLb. Retinoblastoma-Rb genec. Wilms Tumor-WT-1d. Familial Polyposis Coli-APC
There is increasing recognition of the causative role of li festyle
factors, including diet, physical activity and alcoholconsumption.
The most important human carcinogens include tobacco,asbestos, aflatoxins and ultraviolet light.
TOBACCO SMOKING Accounts for 30 % of all malignant tumors 25 % of all Cancers in Men 4 % of all Cancers in Women 16 % both, in w ell developed countries 10 % in less developed countries
ALCOHOL Accounts for 3 % of all cancers 4% of Cancer in Men 2% of Cancer in Women Analytical epidemiological studies of cohort and case-control
type conducted, the causal association of drinking alcohol has
been established in oral, esophageal and liver cancer Risk for cancer is a linear function of the level of consumption,
up to an intake of about 80 g/day.OCCUPATIONAL EXPOSURE
20 % - proportion of cancer attributable to occupationalcarcinogen exposure
4.5% - estimated proportion of Cancer in developed countries Lung Cancer is the most frequent
ENVIRONMENTAL EXPOSURE 1-4% of all Cancer are attributed to pollution of air, soil and
w ater Asbestos is one of the best characterized cause Less than 5 %, a small proportion of Lung Cancer is attributed
to air pollutionCHRONIC INFECTION
Infections agents are one of the main causes of cancer
accounting for 18 %(1.6 million) of cases worldwide Approximately 9 million new cases of Cancer attributed to
infectious agents 23 % in developing countries 9 % in developed countries EBV
- 65% for Burkitts Lymphoma and Nasopharyngeal CA Hepatitis B virus
-60% of cases of Primary Liver CA w orldwide-67 % in developing countries
Hepatitis C virus-25 % of cases of Liver CA
HPV- 80 % of Cervical CA- 35 % of Cancers of the Vulva, Vagina, Penis & Anus
BIOLOGY OF TUMOR GROWTH
Kinetics of Tumor Cell Growth variables influence tumor cell grow th:
doubling time of tumor cells grow th fraction cell production and loss
Tumor Angiogenesis 2 most important tumor angiogenic factors are:
vascula r endo thelial growth factor(VEGF)
basic fi broblast gr owth factor (bFGF). Tumor Progression and Heterogeneity Me chanisms of Invasion and Metastasis
Invasion of Extracellular Matrix Detachment of tumor cells attachment to matrix components degradation of extracellular matrix Migration of tumor cells
Vascular Dissemination and Homing of Tumor Cells
METASTASIS Establishment of a second neoplastic mass thru transfer of
neoplastic cells from the first neoplasm to a secondary locationseparate from the original tumor
Tumor not contiguous to its primary site. Definitive proof of malignancy1. Lymphatic Spread: Occurs early in carc inomas and melanomas but is an unusual
occurrence in most sarcomas. Malignant cells are carried by the lymphatics to the regional
lymph nodesw here their advance may be temporarilyarres ted by immune response.
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2. Hematogenous Spread:
Believed to occur during the early clinical course. Malignant cells are destroyed by the immune system, but some
become ocated w ith fibrin and entrapped in the capillaries. Metastasis occur only if enough cancer cells survive in the
tissue and proliferate. TAF ( tumor angiogenesis fac tor )3. Direct Seeding or Metastasis via body cavities (pleura,
peritoneum, preicardium): Entry of malignant cells into the body cavities may be followed
by dissemination of the cells elsew here.METASTATIC PROCESS
Ineff icient, multistep process called the metastatic cascade. Detachment and invasion: pass in to lymphatic or venous
system. Transport: to a distant site of grow th. Has to survive a bunch of
host defenses on the w ay. Arrest and extravasation: Stuck up in target organ. Digestion of
BM to invade. Establishment of new growth.
METASTATIC CASCADE1. Primary tumor w ill undergo donal expansion , grow th,
diversification
2. Metastatic subclone3. Adhes ion to and invasion of basement membrane4. Intravasation5. Interaction w ith host lymphoid cells6. Tumor cell rmbolus7. Adhes ion to basement membrane8. Extravasation9. Metastatic deposit
Fig 29. Cellular events needed for metastasis
HOST DEFENSE AGAINST TUMORS
Fig 30. Main routes for tumor spread
Fig 31. Main sites of blood borne metastasis
CANCER SPREAD Supraclavicular: breast, lung, stomach (Virchows), pancreas. Ax illary: lymphoma (#1), breast, melanoma. Periumbilical: pancreas (SMJ node). Ovarian: stomach (Krukenberg tumor), colon. Bone mets: Breast (#1), prostate. Skin mets: breast, melanoma.
CARCINOGENIC SITES Chemical Carcinogenesis
Initiation Promotion
Molecular Targets of Chemical Carcinogens DNA
Carcinogenic Chemicals alkylating agents, aromatic hydrocarbons, azo dyes
etc
Radiation Carcinogenesis UV rays and ionizing radiations
Viral and Microbiological Carcinogenesis DNA Viruses
(1) HPV, Epstein-Barr virus (EBV) andHepatitis B virus (HBV)
RNA Oncogenic Viruses (HTLV-1)
VIRUSES IMPLICATED IN HUMAN NEOPLASIAVIRUS NEOPLASMEpsetin-barr virus Burketts lymphoma
Nasopharyngeal carcinomaOther B cell lymphomas and somecases of Hodgkins disease
Hepatitis B virus Hepatocellular carc inoma
Human papilloma virus Cervical carcinomaSome forms f carcinoma of theskin
HTLV-I T-cell leukemia / lymphoma Immunosurveillance
Increased frequency of cancers in patientsw ith congenital or acquiredimmunodeficiency
increased susceptibility to EBV infectionsand EBV-associated lymphoma in boysw ith X-linked immunodeficiency
Tumors may escape immunosurveillance selective outgrowths of antigen-negative
variants loss or reduced expression of
histocompatibility antigens tumor-induced immunosuppress ion failure of sensitization apoptosis of cytotoxic T cells
CLINICAL FEATURES OF TUMORS Local and Hormonal Effects
related to location hormone production
Cancer Cachexia Paraneoplastic Syndromes
endocrinopathies Hypercalcemia Acanthosis nigricans clubbing of fingers and hypertrophic osteoarthopy thr om boembolic diatheses
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APPROACH TO CANCER DIAGNOSISI. Clinical SuspicionII. Screening TestsIII. Tumor MarkersIV .Definitive Diagnosis
- tissue biopsy ( most accurate )1.Ordinary H and E stain2. Immunohistochemistry3. Electron Microscopy
LABORATORY DIAGNOSIS OF CANCER Histologic and Cytologic Methods Immunohistochemistry and flow cytometry Molecular diagnosis Molecular prof ile of tumors Proteomics Fine-Needle Aspiration Cytologic (Papinacolaou Smears) DNA Probe Analysis Tumor Markers Assays of circulating tumor cells and of DNA
GRADING & STAGING OF TUMORS GradingDetermined by cytologic appearance; based on the
idea that behavior and differentiation are related, w ith poorly
differentiated tumors having more aggressive behavior. Grades I to IV w ith increasing anaplasia Imperfect because
(1) the differentiated parts of the sametumor may display diff erent degrees ofdifferentiation
(2) the grade of tumor may change as thetumor grows
StagingDetermined by surgical exploration or imaging, isbased on size, local and regional lymph node spread, anddistant metastases; of greater clinical value than grading.
anatomic extent of the tumor TNM
Information Provided by Pathologic Diagnosis:1. Type of Neoplasm - name of the neoplasm2. Biologic Behavior- benign or malignant3. Histologic Gradedegree of diff erentiation4. Degree of Invasion- depth5. Staging - size of the mass/depth of involvement
- involvement of nodes- +/- metastasis
OTHER CLINICAL ASPECTS OF TUMORS CachexiaProgressive loss of body fat and lean body mass,
accompanied by profound weakness, anorexia and anemia. Paraneoplastic syndromesSymptom complexes in
individuals w ith cancer that cannot be explained by tumorspread or release of hormones that are indigenous to the tumorcell of origin.
PARANEOPLASTIC SYNDROMES Endocrinopathies (Cushing syndrome, hypercalcemia) Neuropathic syndromes (polymyopathy, peripheral
neuropathies, neural degeneration, myasthenic syndrome) Skin disorders (acanthosis nigricans)
Skeletal and joint abnormalities (hypertrophicosteoarthritis)Hypercoagulability (migratory thrombophlebitis,disseminated intravascular coagulation, nonbacterialthrombotic endocarditis)
TREATMENT OF NEOPLASMSA. Benign
Surgical removalB. Malignant
- Surgery ( radical, w ide excision, palliative surgery )- Lymph node removal- Palliative:
a. Chemotherapyb. Radiotherapyc. Immunotherapy
The goal of primary prevention is to avoid the development ofCancer by reducing or el iminating exposure to cancer-causingfactors and by frequent medical check-ups and populationbased-screening programs
World Cancer Report
World Health Organization2003
IMPORTANT DEFINITION RELATED TO CANCER SCREENINGSCREENING
Testing people who have no symptoms and have not noticed anyproblems suggestive of disease.
A particular screening test may be suggested for everyone or onlyfor people with certain risk factors.
Ideally, a screening test would stage or be able to detect cancerat an early before cancer has developed.
PREVENTION Removing the cause or risk for a certain type of cancer. Prevention often consists of life-style changes like quitting
smoking or using sunscreen properly Screening is not considered prevention. Screening involves checking for cancer or cancerous
conditions in persons w ithout symptoms Screening for some cancers is eff ective in detecting
precancerous cells or f inding cancer at an early stage w hentreatment is more eff ective.
Screening procedures include visual exams, laboratory tests,or procedures such as mammography or colonoscopy that testfor internal cancers.
TUMOR MARKERS Secreted into the blood in measurable concentration only after
the cells produce it had undergone malignant transformation. Adjunct tow ards correct diagnosis. Marker for prognostic and risk factors
QUALITY INDEX SENSITIVITY percentage of test results w hich are correctly
positive in the presence of a tumor
SPECIFICITY percentage of healthy persons or persons withbenign conditions in w hom the test correctly gives a negativeresult
* The signifi cance of the data on the diagnostic specificity and sensitivityof a tumor marker is critically dependent upon tumor stage and selectionof control groups
POINTERS IN USING TUMOR MARKERS1. Never rely on the result of a s ingle test.2. When ordering serial testing, be certain to order every test f romlaboratory using same assay kit.3. Be certain that the tumor marker selected for monitoring recurrencew as elevated in patient prior to surgery4. Consider the half-life of the tumor marker w hen interpreting the result.5. Consider how the tumor marker w as removed or metabolized f rom theblood circulation.6. Consider order ing multiple tumor markers to improve both thesensitivity and specificity of the diagnosis.7. Be aw are of the presence of ectopic tumor marker. (AFP, Calcitonin,Chromogranin A HCG, Thyroglobulin).8. Be aw are of the possibility of hook eff ect.- Takes place w hen the assay tends to give a falsely low value when
the tumor marker concentration in the specimen rises above a certainhighly elevated concentration.
CARCINOEMBRYONIEC ANTIGEN (CEA) Glycoprotein Oncofetal antigen produced during embryonic and fetal life Scarcely detectable in normal adults (2.5-5 ng/ml) Found mostly in the gastrointestinal tract and serum of fetus Small quantities in the intestinal, pancreatic, and liver tissues of
healthy adultsALPHA-FETOPROTEIN (AFP)
Glycoprotein
Formed phys iologically in the yolk sac, fetal liver and fetal GItract.
Hepatocellular carc inoma, germ cell tumors Maybe elevated in breast, bronchial and colorectal carc inomas
CANCER ANTIGEN 19-9 (CA 19-9) Glycolipid Fetal stomach, intestine and pancreas Reference range 37 U/ml Marker of choice for pancreatic carcinoma
CANCER ANTIGEN 125 (CA 125) Differentiation antigen that arises in fetal tissue from coelomic
epithelial derivatives. Applicable for ovarian neoplasms. Maybe elevated in benign gynecologic tumors and
inflammation of adnexa.
NEURON SPECIFIC ENOLASE (NSE)
Glucose splitting enzyme identified in neurons of the brain andperipheral nervous system.
Also found in neuroendocrine tissue and APUD cells. False positive: hemolysis and delayed centrifugation of blood. Neuroblastoma, Carcinoid
HUMAN CHORIONIC GONADOTROPIN (HCG) Glycoprotein Formed physiologically in syncytiotrophoblast Diagnosing and monitoring GTD. Monitoring germ cell tumor of the testis and ovaries
ESTROGEN RECEPTOR & PROGESTERONE ASSAY Used to identify patients who are to benefit from endocrine
therapy. Indicate good prognosis, longer disease-f ree survival
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1 5 NEOPLASIA
Pathology
55-60% patients are positive to eER or PR only 85% positive to both.
WHAT ARE THE FINAL COMPLICATIONS OF MALIGNANCY(CAUSES OF DEATH)
Pneumonia Cachexia Renal Failure Bleeding Severe anemia, Thrombocytopenia Infections Hypercoagulability DIC Pain more of devastating symptom than a complication. It has
to be controlled Multiple Organ Failure
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