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Neoplasia

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									Neoplasia
Richard D. Boucher, MD
Clinical Medicine I
Adjunct Faculty, SCCO
Next to life itself,
God’s most precious gift is
sight,
and to the ministry of this
great gift,
the profession of Optometry
dedicates itself.
Introduction

   Cancer is the second leading cause of
    death in the United States
   #1 is cardiovascular diseases
   More important than the mortality
    rates are the emotional and physical
    components
   Will there ever be a cure?
Definitions
   Hypertrophy
    – Increase in cell size
    – Therefore increase in organ size
    – Occurs in cells incapable of dividing (permanent)
   Atrophy
    – Decrease in cell size
    – Decrease in organ size
    – Cells with diminished function but not dead
   Hyperplasia
    –   Increase in cell number in a controlled fashion
    –   Increase in organ size
    –   Occurs in cells capable of replicating (labile and stable)
    –   Reversible if the stimulus is removed
    –   If control is lost, may become a cancer
Definitions
   Metaplasia
    – One adult cell type is replaced by another adult cell type
    – Reversible
    – Examples – cigarettes, Vitamin A deficiency
   Dysplasia
    –   Disorderly but non-neoplastic proliferation
    –   Loss of cell uniformity and normal architecture
    –   Reversible but higher possibility to become cancer
    –   Cell size and shape varies, more mitosis, organelles
    –   PAP smear
Neoplasia

   Means “new growth”
   Growth exceeds and is uncoordinated with
    normal tissue even after the stimulus that
    caused the change is removed
   Due to heritable (genetic) changes that
    allow excessive and uncontrolled
    proliferation independent of growth-
    regulatory stimuli
Neoplasia
   Neoplasm
    – Also called a tumor
    – Two types
          Benign
            –   Relatively innocent, but depends on location
            –   Slow growing, remains localized, no metastasis
            –   Local surgical removal
            –   Patient survives
          Malignant
            –   Referred to as cancers
            –   Can invade and destroy adjacent structures
            –   Rapid growing, can metastasize
            –   Can cause death
Neoplasms

   Benign and malignant tumors
    – Two components
          Parenchyma
            – Transformed or neoplastic cells
            – Determines behavior of tumor
            – Used to name tumor
          Stroma
            –   Supporting tissue of tumor
            –   Non-neoplastic
            –   Connective tissue, blood vessels, inflammatory cells
            –   However, crucial to tumor growth
Nomenclature
   Benign tumors
    – Named from the parenchymal cell and add the suffix “-oma”.
      Benign tumor from:
           Fibrous tissue – fibroma
           Cartilaginous tissue – chondroma
           For glandular tissue add “adenoma”
   Malignant tumors
    – Named from the parenchymal cell
    – If derived from mesenchymal tissue (bone, cartilage,
      hematopoietic) name tissue and add “sarcoma”
           Fibrous tissue origin – fibrosarcoma
           Cartilaginous tissue – chondrosarcoma
    – If derived from epithelial tissue like squamous epithelium, renal
      cells, hepatocytes, name tissue and add “carcinoma”
           Glandular pattern – adenocarcinoma
           Squamous cells – squamous cell carcinoma
Nomenclature
   Teratoma
     – Contains recognizable mature or immature cells or tissues
       representative of more than one germ-cell layer and sometimes
       all three
     – Come from totipotential stem cells such as ovary and testis
     – May have bone, epithelium, muscle, fat, nerve and other tissues
   Differentiation
     – Extent to which the cell resembles its normal precursors
       morphologically and functionally
     – Well differentiated better than undifferentiated
   Anaplasia
     – Lack of differentiation, actually dedifferentiation, “to form
       backward”
     – Cells are undifferentiated, loss of structural and functional
       differentiation of normal cells
Characteristics of Benign
and Malignant Neoplasms
   “It is benign”
   Four fundamental features that
    distinguish benign and malignant
    – Differentiation and anaplasia
    – Rate of growth
    – Local invasion
    – Metastasis
Fundamental Features
   Differentiation and Anaplasia
    – Differentiation
          Refers to extent to which parenchymal cells resemble
           their normal precursors morphologically and
           functionally
          Stroma important for growth but not in separation of
           benign from malignant
    – Anaplasia
          Pleomorphism
          Multiple mitosis
          Undifferentiated cells of malignant neoplasms
Fundamental Features

   Rate of Growth
    – Benign
          Grow slowly – months to years
          Influenced by hormones, blood supply, surrounding
           pressure (space to grow)
    – Malignant
          Correlates with level of differentiation – the more
           poorly differentiated the more rapid the growth
          May have central areas of necrosis – failure of blood
           supply to keep pace with tumor growth
Fundamental Features
   Local Invasion
    – Benign
          Remains localized at site of origin
          Does not infiltrate, invade or metastasize
          Encapsulation
    – Malignant
          Progressive infiltration, invasion, destruction and
           penetration of surrounding tissue
          Lack well-defined capsules
          Have “crab-like” feet that penetrate surrounding tissue
          Next to metastasis, most reliable feature that
           distinguishes benign from malignant
Fundamental Features

   Metastasis
    – Found in malignant tumors
    – Secondary implants in remote tissues
    – More unequivocally identify a neoplasm
      as malignant
    – Yet not all metastasize
    – Examples – basal cell carcinoma vs.
      osteogenic sarcoma
Dissemination of
Malignant Neoplasms
   Three pathways
    – Spread by seeding
          Invades a body cavity
    – Lymphatic spread
          Favored by carcinomas
          Depends on tumor site and lymphatic drainage
          Skip metastases
          “Sentinal lymph node”
    – Hematogenous spread
          Favored by sarcoma
          Tumor cells stop at first capillary bed they encounter
Epidemiology

   Cigarette smoking
   Dietary differences in countries
    – Dietary fat and fiber
   Cancer incidence
    – Men – death rate from lung cancer has dropped
    – Women – death rate slightly dropped due to
      decline in death rate from cervix, stomach and
      large bowel cancer. Yet lung cancer has
      increased
Epidemiology

   Geographic and Environmental Variables
    – Predominant cause of most common sporadic
      cancers
    – Breast cancer higher in US and Europe than
      Japan
    – Stomach cancer higher in Japan than US
    – Liver cell carcinoma higher in Africa
    – Cervical cancer linked to age of first intercourse
      and number of sex partners
Epidemiology
   Age
    – Cancer frequency increases with age
    – Chance for more mutations and decline in immune
      competence
   Heredity (autosomal dominant)
    – Inherited Cancer Syndromes
             Retinoblastoma, melanoma, breast and ovarian tumors and
              colon cancer
    – Familial Cancers
             Clustered in families
             Breast, ovarian and pancreatic
    – Defective DNA repair (autosomal recessive)
Epidemiology
   Acquired Preneoplastic Disorders
    – Persistent regenerative cell replication
          Long unhealed skin wound
          Cirrhosis of the liver
    – Hyperplastic and dysplastic proliferations
          Endometrial carcinoma/bronchogenic carcinoma
    – Chronic atrophic gastritis
          Pernicious anemia/Helicobacter pylori
    – Chronic ulcerative colitis
    – Leukoplakia
          Oral cavity
Carcinogenesis
   Four classes of normal regulatory genes
    – Growth promoting proto-oncogenes
    – Growth-inhibiting tumor suppressor genes
    – Genes that regulate programmed cell death
      (apoptosis)
    – Genes involved in DNA repair
   Multi-step process of multiple mutations
    – Tumor progression is more than increase in size
    – Each mutation contributes a different
      characteristic
    – “survival of the fittest”
Molecular Pathogenesis
of Cancer
   Fundamental changes in cell physiology
    –   Self-sufficiency in growth signals
    –   Insensitivity to growth-inhibitory signals
    –   Evasion of apoptosis
    –   Limitless replicative potential
    –   Development of sustained angiogenesis
    –   Ability to invade and metastasize
    –   Genomic instability resulting from defects in DNA
        repair
Cell Physiology
   Self-sufficiency in growth signals
    – Proto-oncogenes
          Normal growth
    – Oncogenes
          Uncontrolled synthesis of growth factors (paracrine)
          Overexpression of growth factor (autocrine)
          Mutant receptor proteins deliver continuous mitogenic
           signals to cells in the absence of growth factor (causes
           growth)
          Signal-transducing proteins couple growth factor
           receptors to nucleus
          Nuclear transcription factors
Cell Physiology

   Insensitivity to growth-inhibitory
    signals
    – Products of tumor suppressor genes
      apply brakes to cell proliferation
    – Disruption (insensitivity) to these
      products allows for growth
    – Retinoblastoma
        Sporadic – two-hit hypothesis
        Familial – inherited and then one mutation
Learning is never over, it
has no end.
Indeed, each day is it’s
beginning
Cell Physiology

   Evasion of Apoptosis
    – Accumulation of neoplastic cells may
      result not only from activation of growth-
      promoting oncogenes or inactivation of
      growth-suppressing tumor suppressor
      genes but also from mutations in the
      genes that regulate apoptosis
Cell Physiology
   Limitless Replicative Potential
    – Most normal human cells double 60-70 times
    – Normal cells lack expression of telomerase
    – Shortened telomeres activate cell cycle
      checkpoints
    – Cell division is limited – senescence
    – Cells with disabled checkpoints lead to
      chromosome instability and mitotic crisis
    – Tumor cells avoid both cellular senescence and
      mitotic catastrophe
    – Telomerase is reactivated by tumor cells
Cell Physiology
   Development of Sustained Angiogenesis
    – Without vascular supply tumor size limited to 1-2
      mm diameter
    – Tumors can stimulate neo-angiogenesis or
      vasculogenesis
    – Tumor vasculature is leaky, dilated and
      haphazard in pattern
    – Duel effect
          Perfusion delivers nutrients and oxygen
          Newly formed endothelial cells secrete growth factors
    – Allows for tumor growth and metastasis
Cell Physiology

   Ability to Invade and Metastasize
    – Divided into two phases
        Invasion of the Extracellular Matrix (ECM) and
         vascular dissemination
        Homing of tumor cells
Invasion of ECM
   Two types
    – Basement membrane
    – Interstitial connective tissue
   Carcinoma must breach these two to reach the vasculature
    and then repeat the cycle to reach the distant site
   This is an active process that has four steps
    – Detachment of tumor cells from each other
           Intercellular “glues” are loosened
    – Degradation of ECM
           Proteolytic enzymes from tumor cells or stromal cells
    – Attachment to novel ECM components
           Stimulates migration
    – Migration of tumor cells
           Autocrine motility factor
           Stromal cell paracrine effect on tumor cell
Vascular Dissemination and
Homing of Tumor Cells
   In the circulation, tumor cells susceptible to
    host immune response
   Some form emboli adhering to leukocytes or
    platelets
   Location of metastasis predicted by location
    of primary site, usually first capillary bed
    they encounter
    – Not always true though
    – Some organs/tumors have affinity for each other
    – After extravasation, tumor cells depends on
      receptive stroma
Cell Physiology
   Genomic Instability – Enabler of Malignancy
    – There is constant exposure to agents that are
      mutagenic – chemicals, radiation, sunlight
    – But cancers are relatively rare outcomes of these
      encounters. Why?
    – Normal cells can repair DNA damage
    – Those born with inherited defects in DNA repair
      are at increased risk
          Mismatch repair – “proofreaders” (spell check)
          Nucleotide excision repair
          Recombination repair
Multistep Carcinogenesis

   Cancers result from an accumulation
    of multiple mutations
   Breast and colon cancers reveal an
    average of 90 mutant genes
   Must have mutations in genes that
    regulate apoptosis and senescence
Etiology of Cancer
   Genetic damage lies at the heart of
    carcinogenesis
   There are three classes of carcinogenic
    agents
    – Chemicals
    – Radiant energy
    – Microbial agents
   They may act separately, in concert or
    sequentially
Carcinogenic Agents
   Chemical Carcinogens
    – Direct-Acting agents
          No metabolic conversion needed
          In general weak but important as they are cancer
           chemotherapeutic agents
    – Indirect-Acting agents
          Require metabolic conversion to an ultimate carcinogen to
           become active
          Examples
             – High-temperature combustion of tobacco in cigarette smoking
             – Polycyclic hydrocarbons produced from animal fats in broiling
               meats and in smoked meats and fish
             – Aflatoxin B1 produced by the Aspergillus mold that grows on
               improperly stored grains and nuts (hepatocellular carcinoma in
               Africa and the Far East)
Carcinogenic Agents

   Radiation Carcinogenesis
    – UV rays of sunlight
          Melanomas
          Squamous cell carcinomas
          Basal cell carcinomas
    – X-rays
          Therapeutic radiation of the head and neck
    – Nuclear fission
          Nuclear power
    – Radionuclides
Carcinogenic Agents
   Viral and Microbial Oncogenesis
    – RNA viruses
           HTLV-3
    – DNA viruses
           Human papillomavirus (HPV)
           Epstein-Barr virus
              – Lymphomas in immunosuppressed individuals with HIV infection
                or organ transplant
           Hepatitis B
    – Hepatitis C
    – Microbial
           Helicobacter pylori
              – Immunologically mediated chronic inflammation, stimulation of
                gastric cell proliferation and damage to DNA
Clinical Aspects of
Neoplasia
   Morbidity and mortality due to
    – Location and impingement on adjacent
      structures
    – Functional activity such as hormone synthesis or
      development of paraneoplastic syndromes
    – Bleeding and infection when the tumor ulcerates
      through the adjacent tissue
    – Symptoms that result from rupture or infarction
    – Cachexia or wasting
Laboratory Diagnosis of
Cancer
   Gold standard is tissue biopsy with review by a
    pathologist
    – Excision or biopsy
    – Fine-needle aspiration
    – Cytologic smears
   Clinical data from clinicians are invaluable for
    optimal pathologic diagnosis
   Tumor Markers
    – PSA – prostate cancer
    – CEA – carcinoembryonic antigen – colon, pancreas,
      stomach, and breast cancers
    – Alpha-fetoprotein – hepatocellular carcinoma
I don’t know what your
destiny will be,
but one thing I know;
the only ones among you
who will be really happy are
those who will have sought
and found how to serve.

          Albert Schweitzer

								
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