Basic aspects of tumour pathology

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Basic outlines of Tumour Pathology

• Dr. D.Gomathinayagam, M.D (path)

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cancer

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

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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.

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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.

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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

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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.

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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
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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)

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• Nomenclature and classification

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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
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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
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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
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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
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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
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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 -
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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

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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

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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

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Tumor Growth
Radiation and chemotherapy work on dividing
cells, so the size of the non-proliferative pool
is important.
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AETIOPATHOGENESIS OF CANCER
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Environmental vs. Hereditary Cancer
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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

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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

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

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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.

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Normal CELL CYCLE Phases
INHIBITORS Cip/Kip, INK4/ARF Tumor (really
growth) suppressor genes p53
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NORMAL CELL
Growth factor Growth factor receptor
cytoplasm
Signal transduction
Activation of transcription
nucleus
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Growth factor receptors
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Signal transduction
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Nuclear and cell cycle regulators
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Cancer supressor genes and cancer
P53 Ch 17p RB gene in Ch 13 LOH leads to
retinoblastoma
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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

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Genes inhibiting DNA repair
Defective DNA repair increases DNA instability

• Nucleotide excision repair X.Pigmen.
• Mismatch repairHNPCC
• Recombination repairBloom,AT,Fanconi

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NEOPLASTIC CELLS
Increased In growth factor receptors
Increased In growth factor
Increased in signal transduction
Increase in activation of transcription
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FOR PERMANENT FIX IN YOUR MIND
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Initiation and Promotion
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Multi step carcinogenesis
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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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Effects of TUMOR on the HOST

• Location? anatomic ENCROACHMENT
• HORMONE production
• Bleeding, Infection
• ACUTE symptoms, e.g., rupture, infarction
• METASTASES

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CACHEXIA

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

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LAB DIAGNOSIS

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

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IMMUNOHISTOCHEMISTRY

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

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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
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Thank you
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Thank you all for patient listening