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Title: Basic aspects of tumour pathology


1
Basic outlines of Tumour Pathology
  • Dr. D.Gomathinayagam, M.D (path)

2
cancer
  • Hippocrates (460-377 BC) coined the term karkinos
    for Ca breast
  • Sticks to the part stubbornly like a crab

3
NEOPLASM
  • SIR RUPERT WILLIS
  • ABNORMAL MASS OF TISSUE, THE GROWTH OF WHICH
    EXCEEDS AND IS UNCOORDINATED WITH THAT OF THE
    NORMAL TISSUES AND PERSISTS IN THE SAME MANNER
    AFTER CESSATION OF THE STIMULUS WHICH EVOKED THE
    CHANGE.

4
characteristics of cancer
  • Clonality Originates from a SINGLE STEM CELL
    (Tumour initiating cells T-ICs)Analysis of
    methylation pattern adjacent to HUMARA (human
    androgen receptor gene) is the most common method
    to prove monoclonality)
  • Autonomy The growth rate is unrestricted
  • Anaplasia Lack of differentiation.
  • Local invasionInfiltrate the surrounding zone
  • Metastasis Dissemination to other parts of the
    body.

5
7 key changes in malignant cell
  • Self-sufficiency in growth signals due to
    oncogene activation.
  • Insensitivity to growth-inhibiting signals TGF-ß
    inhibitors of cyclin dep.kinases
  • Evasion of apoptosis due to inactivation of p-53
    or activation of anti apoptic genes( FLIP
    (FLICE-inhibitory protein), anti-apoptotic
    members of the Bcl2 family and inhibitors of
    apoptosis (IAP) are the main three groups of
    anti-apoptotic genes)
  • Defects in DNA repair Spell checker
  • Limitless replicative potential Telomerase
  • Angiogenesis
  • Invasive and metastatic ability
  • 8th one Warburgs aerobic glycolysis

6
ONCOLOGY DEFINITIONS
  • ENCAPSULATION Induction of peripheral fibrosis,
    characteristic of benign neoplasm
  • DIFFERENTIATION Degree of morphologic and
    functional resemblance to comparable normal cell.
  • ANAPLASIA Lack of differentiation, is
    considered as a cancer marker.

7
ONCOLOGY DEFINITIONS
  • INVASION/INFILTRATION Unrestricted permeation
    into contiguous structures, characteristic of
    malignant neoplasms.
  • METASTASES Remote /distant, tumor- implants,
    from the primary neoplasm.
  • LOSS OF contact inhibition of growth . grow in
    an uncontrolled manner even when in contact with
    neighbouring cells. They aren't motivated to
    change direction upon contact, so they pile up
    and grow over each other.
  • DOUBLING TIME Time required by the tumor to
    double in size.

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Cancer incidence
10
Key words
  • Carcinogenesis Pathogenesis of cancer
  • Carcinogen - agent causing cancer.
  • Oncogen - agent causing neoplasm.
  • Mutagen - agent causing mutation.
  • p-oncogene - proto oncogene. (Normal)(Herald
    varmus and Michael Bishop)
  • Oncogenes genes causing cancer (Pathological)
  • v-oncogene viral oncogene (pathological)

11
  • Nomenclature and classification

12
Nomenclature of tumors
Tissue of Origin Benign Malignant
Composed of One parenchymal cell Type Mesenchymal tumors Connective tissue and derivatives     Fibroma Lipoma Chondroma Osteoma     Fibrosarcoma Liposarcoma Chondrosarcoma Osteogenic sarcoma
Endothelial and related tissues Blood vessels Lymph vessels Synovium Mesothelium Brain coverings   Hemangioma Lymphangioma     Meningioma Angiosarcoma Lymphangiosarcoma Synovial sarcoma Mesothelioma Invasive meningioma
13
Nomenclature of tumors
Tissue of Origin Benign Malignant
Blood cells and related cells Hematopoietic cells Lymphoid tissue Muscle Smooth Striated Leiomyoma Rhabdomyoma Leukaemia Lymphoma Leiomyosarcoma Rhabdomyosarcoma
Epihelial tumors Stratified squamous Basal cells of skin or adnexa Epithelial lining Glands or ducts   Squamous cell papilloma     Adenoma Papilloma Cystadenoma Squamous cell or epidermoid carcinoma Basal cell carcinoma Adenocarcinoma Papillary carcinoma Cystadenocarcinoma
14
Nomenclature of tumors
Tissue of Origin Benign Malignant
Respiratory passages Neuroectoderm Renal epithelium Liver cells Urinary tract epithelium (transitional) Placental epithelium (trophoblast) Testicular epithelium (germ cells) Nevus Renal tubular adenoma Liver cell adenoma Transitional cell papilloma Hydatidiform mole Bronchogenic carcinoma Bronchial adenoma (carcinoid) Malignant melanoma Renal cell carcinoma Hepatocellular carcinoma Transitional cell carcinoma Choriocarcinoma Seminoma Embryonal carcinoma
15
Nomenclature of tumors
Tissue of Origin Benign Malignant
More Than One Neoplastic Cell Type- Mixed Tumors, Usually Derived From One Germ Layer Endometrium Adenosquamous carcinoma Adenoacanthoma
Salivary glands Pleomorphic adenoma (mixed tumor of salivary origin) Malignant mixed tumor of salivary gland origin
Breast Renal anlage Fibroadenoma Malignant cystosarcoma phyllodes Wilms tumor
16
Nomenclature of tumors
Tissue of Origin Benign Malignant
More Than One Neoplastic Cell Type Derived From More Than One Germ Layer- Teratogenous More Than One Neoplastic Cell Type Derived From More Than One Germ Layer- Teratogenous More Than One Neoplastic Cell Type Derived From More Than One Germ Layer- Teratogenous
Totipotential cells in gonads or in embryonic rests Mature teratoma, dermoid cyst Immature teratoma, teratocarcinoma
17
Differences between benign and malignant tumor
Characteristics Benign Malignant
Nature of growth Expansile (Capsule) Slow Infiltrative (No capsule) Fast
Vascularity Less More
Ulceration Uncommon Common
Light microscopy Low N/C ratio (14) low mitosis High N/C ratio (11) more mitotic activity
Well differentiated WD to anaplastic
Degenerative changes less common More common
Tumor giant cells - Tumor giant cells
EM Normal Less mitochondria and endoplasmic reticulum
Metastasis -
18
Differentiation (Basis for Grading)
  • Well differentiated neoplasm
  • Resembles mature cells of tissue of origin
  • Moderately differentiated Neoplasm
  • Poorly differentiated neoplasm
  • Composed of primitive cells with little
    differerentiation
  • Undifferentiated or anaplastic tumor
  • Correlation with biologic behavior
  • Benign tumors are well differentiated
  • Poorly differentiated malignant tumors usually
    have worse prognosis

19
significance of Grading
  • Differentiation often provides clues as to the
    clinical aggressiveness of the tumor
  • Tumors often lose differentiation features over
    time as they become more malignant and as they
    acquire more cumulative genetic mutations
  • Differentiation often predicts responsiveness to
    certain therapies, eg estrogen receptors and
    Tamoxifen in breast cancers

20
ANAPLASIA
  • Pleomorphism
  • Size
  • shape
  • Abnormal nuclear morphology
  • Hyperchromasia
  • High nuclear cytoplasmic ratio
  • Chromatin clumping
  • Prominent nucleoli
  • Mitoses
  • Mitotic rate
  • Location of mitoses
  • Loss of polarity

21
Tumor Growth
Radiation and chemotherapy work on dividing
cells, so the size of the non-proliferative pool
is important.
22
AETIOPATHOGENESIS OF CANCER
23
Environmental vs. Hereditary Cancer
24
Oncogenes
  • Oncogenes are activated, unregulated versions of
    protooncogenes
  • Acts as dominant genes
  • Proto oncogenes normal genes encoding for protein
    kinase and other growth signals
  • Their gene products stimulate cell growth
  • Viral oncogenes are altered copies of
    protooncogenes

25
Tumour Suppressor Genes
  • Genes that block neoplastic growth,
    e.g. p53
  • Functional opposites of oncogenes, hence
    originally named anti-oncogenes
  • Characteristic double allelic activity
  • both alleles must be damaged for malignant
    activity
  • retinoblastoma follows two hit model

26
  • Carcinogens
  • Chemicals
  • Viruses
  • Radiation
  • Hereditary causes- Genetic defects.
  • Combination common.

27
Molecular Basis of Carcinogenesis
  • Genes control cell division by cytokines.
  • Four important classes of regulatory genes (for
    cell division)
  • Promoters Proto-oncogenes
  • Inhibitors Tumor or Cancer-suppressor genes
    p53
  • Genes regulating Apoptosis.
  • DNA repair genes.

28
Normal CELL CYCLE Phases
INHIBITORS Cip/Kip, INK4/ARF Tumor (really
growth) suppressor genes p53
29
NORMAL CELL
Growth factor Growth factor receptor
cytoplasm
Signal transduction
Activation of transcription
nucleus
30
Growth factor receptors
31
Signal transduction
32
Nuclear and cell cycle regulators
33
Cancer supressor genes and cancer
P53 Ch 17p RB gene in Ch 13 LOH leads to
retinoblastoma
34
Genes regulating apoptosis
  • Promoters of Apoptosisbax, bad, bcl- and p53
  • Inhibitor bcl -2Eg- Ch 14 has Ig heavy chain
    gene and ch18 has bcl-2 gene. In follicular
    lymphoma (t 1418) increased expression of bcl-2
    prevents apoptosis

35
Genes inhibiting DNA repair
Defective DNA repair increases DNA instability
  • Nucleotide excision repair X.Pigmen.
  • Mismatch repairHNPCC
  • Recombination repairBloom,AT,Fanconi

36
NEOPLASTIC CELLS
Increased In growth factor receptors
Increased In growth factor
Increased in signal transduction
Increase in activation of transcription
37
FOR PERMANENT FIX IN YOUR MIND
38
Initiation and Promotion
39
Multi step carcinogenesis
40
How do tumor cellsescape immune surveillance?
  • Mutation, like microbes
  • ? MHC molecules on tumor cell surface
  • Lack of CO-stimulation molecules, e.g., (CD28,
    ICOS), not just Ag-Ab recognition
  • Immunosuppressive agents
  • Antigen masking
  • Apoptosis of cytotoxic T-Cells (CD8), i.e., the
    damn tumor cell KILLS the T-cell!

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42
Effects of TUMOR on the HOST
  • Location? anatomic ENCROACHMENT
  • HORMONE production
  • Bleeding, Infection
  • ACUTE symptoms, e.g., rupture, infarction
  • METASTASES

43
CACHEXIA
  • Reduced diet Fat lossgtMuscle loss
  • Cachexia Fat lost Muscle loss
  • TNF (a by default)
  • IL-1
  • PIF (Proteolysis Inducing Factor)

44
LAB DIAGNOSIS
  • Cytology Exfoliative in space/fluid FNA Imprint
    Crush
  • Biopsy Tru cut Incision Excision

45
IMMUNOHISTOCHEMISTRY
  • Categorization of undifferentiated tumors
  • Leukemias/Lymphomas
  • Site of origin
  • Receptors, e.g., ER, PR

46
TUMOR MARKERS
  • HORMONES (Paraneoplastic Syndromes)
  • ONCOFETAL AFP, CEA
  • ISOENZYMES PAP, NSE
  • PROTEINS PSA, PSMA (M membrane)
  • GLYCOPROTEINS CA-125, CA-19-5, CA-15-3
  • MOLECULAR p53, RAS

NOTE These substances which can be measured in
the blood, also can be stained by immunochemical
methods in tissue
47
Thank you
48
Thank you all for patient listening
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