8/11/2019 1.5 Neoplasia

1/9

`

Page 1 of 9

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

8/11/2019 1.5 Neoplasia

2/9

Page 2 of 9

1 5 NEOPLASIA

Pathology

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

8/11/2019 1.5 Neoplasia

3/9

Page 3 of 9

1 5 NEOPLASIA

Pathology

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

8/11/2019 1.5 Neoplasia

4/9

Page 4 of 9

1 5 NEOPLASIA

Pathology

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.

8/11/2019 1.5 Neoplasia

5/9

Page 5 of 9

1 5 NEOPLASIA

Pathology

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.

8/11/2019 1.5 Neoplasia

6/9

Page 6 of 9

1 5 NEOPLASIA

Pathology

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.

8/11/2019 1.5 Neoplasia

7/9

Page 7 of 9

1 5 NEOPLASIA

Pathology

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

8/11/2019 1.5 Neoplasia

8/9

Page 8 of 9

1 5 NEOPLASIA

Pathology

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

8/11/2019 1.5 Neoplasia

9/9

Page 9 of 9

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

END OF TRANS