Host Defense Against Tumor Tumor Immunity

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Host Defense Against Tumor Tumor Immunity

• Definition
• coordinated biologic process designed to
  recognize tumor cells and their products and to
  kill or damage the offending cells.

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Host Defense Against Tumor Tumor Immunity

• Tumor Specific Antigens (TSA)
• Present only on tumor cells and not on any normal
  cells and can be recognized by cytotoxic
  T-lymphocytes.
• Tumor Associated Antigens (TAA)
• Not unique to tumors and are also see on
  normal cells.

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Tumor Antigens

• Tumor Specific Antigens (TSA)
• Cancer testis antigen
• Viral antigen
• Mucin
• Oncofetal antigens
• Antigens resulting from mutational in protein
• B catenin, RAS, P53,CDK4

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Tumor Antigens

• Tissue Associated AntigenTAA
• Present in normal cells tumor cells
• e.g. MART-1, gp100, tyrosinase expressed in
  melanomas normal melanocytes
• T-cells directed against melanomas will also
  destroy normal melanin containing cells

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Tumor Antigens

• Tumor Associated Antigens(TAA)
• MART-1, gp100, tyrosinase
• Over expressed antigens
• Differentiation- specific antigens

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Tumor Associated Antigens(TAA)

• Over expressed Antigens
• e.g HER-2 (neu) in 30 Breast cancer
• ( present in normal breast ovary)

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Tumor Associated Antigens(TAA)

• Differentiation- Specific Antigens
• e.g CD10 PSA
• Expressed in normal B cells Prostate
• Used as a marker for tumors arise from these
  cells

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ANTITUMOR EFFECTOR MECHANISM

• Cellular
• Cytotoxic T lymphocytes.
• Natural killer cells.
• Macrophages.
• Humoral mechanisms.complement mediated or ADCC.

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Mechanisms of Immunity to Tumors

• Cytotoxic T lymphocytes (CTL) - that are
  sensitized to TSA and perhaps other tumor
  antigens kill tumor cells. Play a role in virus
  induce malignancy
• Natural Killer (NK) cells - can attack tumor
  cells directly without antibody coating or by
  Antibody Dependent Cell Cytotoxicity (ADCC)
  utilizing the Fc receptor on the NK cells.

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Mechanisms of Immunity to Tumors

• Killer Macrophages - activated by IFN-g
  elaborated by Helper T lymphocytes. Participate
  in ADCC and can lyse tumor cells through release
  of TNF-a.

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Immune surveillance

• a constant monitoring process aimed at
  eliminating emerging cancers
• recognition and destruction of non-self tumor
  cells .

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Evidence for Immune Response to Tumors

• 1) Infiltrate of lymphocytes and macrophages
  associated with better prognosis in many tumors.
  
• 2) Peripheral blood NK activity correlates with
  survival.
• 3) Peripheral blood lymphocytes counts fall as
  cancer overwhelms host patients develop anergy
  to skin tests.

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Evidence for Immune Response to Tumors

• 4) Non-specific vaccines can stimulate
  macrophages and improve prognosis. IFN-g and
  IL-2 can stimulate NK cells and improve outcome.
• 5) High incidence of some tumors in
  immunosuppressed individuals.
• 6) Spontaneous regression in some tumors.

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Immunosurveillance

• Sporadic cancers occur in immune competent people
• HOW ???
• Escape mechanisms
• Growth of antigen-negative variants.
• HLA underexpression .
• No expression of costimulatory molecule .
• Immunosuppression .

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Clinical Features Of Neoplasia
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Clinical Features Of Neoplasia

• Effects of Tumor On Host
• Grading Clinical Staging Of Cancer
• The Laboratory Diagnosis of Cancer

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Effects of Tumor On Host

• Tumor Impingement on nearby structures
• Pituitary adenoma on normal gland---compression
  of normal tissue -----Hypopitutrism
• Pancreatic carcinoma on bile duct-----Produce
  fatal billiary tract obstruction
• Renal artery leiomyoma-------ischemia
  hypertention
• Hormones production-----B cell tumor produce
  hyperinsulinism
• Ulceration/bleeding
• Colon, Gastric, and Renal cell carcinomas
• Infection (often due to obstruction)
• Pulmonary infections due to blocked bronchi (lung
  carcinoma), Urinary infections due to blocked
  ureters (cervical carcinoma)
• Rupture or Infarction
• Ovarian, Hepatocellular, and Adrenal cortical
  carcinomas Melano-carcinoma metastases

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Effects of tumor on host

• Cancer Cachexia
• Paraneoplastic Syndromes
• Endocrinopathies
• Neuromyopathies
• Osteochondral Disorders
• Vascular Phenomena
• Fever
• Nephrotic Syndrome

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Cancer Cachexia

• Progressive weakness, loss of appetite, anemia
  and profound weight loss (gt20 lbs.)
• Often correlates with tumor size and extent of
  metastases
• Etiology includes a generalized increase in
  metabolism and central effects of tumor on
  hypothalamus
• Probably related to macrophage production of TNF-a

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• PARANEOPLASTIC SYNDROMES Symptom complexes other
  than cachexia that appear in patients with cancer
  and cannot be readily explained either by the
  local or distal spread of the tumor or by the
  elaboration of hormones indigenous to the tissue
  of origin of the tumor .
• Occur in 10-15 of tumors

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Paraneoplastic Syndromes

• Cushings Syndrome
• Small cell undifferentiated lung cancer (ACTH)
  like product.
• Nonbacterial thrombotic Endocarditis
• Hypercoagulability

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Paraneoplastic Syndromes

• Hypercalcemia (Cancer is the most common cause of
  hypercalcemia by either humoral or metastatic
  mechanisms)
• Squamous cell carcinoma of lung (PTH-like
  peptide)
• Renal cell carcinoma (prostaglandins)
• Parathyroid carcinoma (PTH)
• Multiple myeloma and T-cell lymphoma (IL-1 and
  perhaps TNF-a)
• Breast carcinoma, usually by bone metastasis

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Paraneoplastic Syndromes

• Hypoglycemia - caused by tumor over-production of
  insulin or insulin like activities
• Fibrosarcoma, Cerebellar hemangioma,
  Hepatocarcinoma
• Carcinoid syndrome - Caused by serotonin,
  bradykinin or ?histamine produced by the tumor
• Bronchial carcinoids, Pancreatic carcinoma,
  Carcinoid tumors of the bowel

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Paraneoplastic Syndromes

• Polycythemia - caused by tumor production of
  erythropoietin's
• Renal cell carcinoma, Cerebellar hemangioma,
  Hepatocarcinoma
• WDHA syndrome (watery diarrhea, hypokalemia, and
  achlorhydria) - caused by tumor production of
  vasoactive intestinal polypeptide (VIP).
• Islet cell tumors, Intestinal carcinoid tumors

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Paraneoplastic SyndromesNeuromyopathies

• Myasthenia Gravis- A block in neuromuscular
  transmission possibly caused by host antibodies
  against the tumor cells that cross react with
  neuronal cells or perhaps caused by toxins.
• Bronchogenic carcinoma, Breast cancer
• Carcinomatous Myopathy - probably immune-mediated

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Paraneoplastic SyndromesOsteochondral Disorders

• Hypertrophic Osteoarthropy - clubbing, periosteal
  new bone, and arthritis
• Isolated clubbing occurs in chronic obstructive
  pulmonary disease and in cyanotic congenital
  heart disease, but the full-blown syndrome is
  limited to lung cancer.

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Paraneoplastic SyndromesVascular Phenomena

• Altered Coagulability - caused by the release of
  tumor products
• Migratory Venous Thromboses (Trousseaus sign)
  Pancreatic, gastric, colon, and bronchogenic
  carcinomas particularly adenocarcinoma of the
  lung.
• Marantic endocarditis - Small thrombotic
  vegetations on mitral or aortic valves that occur
  with advanced carcinomas.

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Paraneoplastic SyndromesFever

• Associated with bacterial infections
• Common where blockage of drainage occurs
• Decreased immunity may play a role
• Not associated with infection
• Episodic as in Bar-Epstein fever with Hodgkin's
  lymphoma poor prognostic seen in sarcomas,
  indicates dissemination
• Likely caused by response to necrotic tumor cells
  and/or immune response to necrotic tumor
  proteins.

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Paraneoplastic SyndromesNephrotic Syndrome

• Excessive loss of protein in the urine
• probably caused by damage to renal glomeruli by
  tumor antigen-antibody complexes.

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Grading And Staging

• Grading is based on the microscopic features of
  the cells which compose a tumor and is specific
  for the tumor type.
• Staging is based on clinical, radiological, and
  surgical criteria, such as, tumor size,
  involvement of regional lymph nodes, and presence
  of metastases. Staging usually has prognostic
  value.

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Grading

• Estimate of aggressiveness of tumor or level of
  malignancy based on
• -cytological differentiation
• -number of mitosis
• Tumors are classified as grad 1,2,3,4 in order
  of increasing anaplasia

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Grading
Staging and Grading

• In the diagram below utilizing an adenocarcinoma
  as an example, the principles of grading are
  illustrated

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Staging

• Anatomical spread of tumor based on
• -size of tumor
• -spread to regional L.N
• -presence or absence of metastasis
• TNM staging system AJC

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Staging and Grading

• In this diagram utilizing a lung carcinoma as an
  example, the principles of staging are
  illustrated

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Diagnostic Methods for Neoplasia

• History and Physical Examination
• learning from
• talking to the patient .
  direct examination
  clues to the presence
  of a neoplasm. Signs and symptoms
  such as weight loss, fatigue, and pain may be
  present. A mass may be palpable or visible.

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Diagnostic Methods for Neoplasia

• Radiographic Techniques The use of plain films
  (x-rays), computed tomography (CT), magnetic
  resonance imaging (MRI), mammography, and
  ultrasonography (US) may be very helpful to
  detect the presence and location of mass lesions.
  The findings from these methods may aid in
  staging and determination of therapy.

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biochemical assays

• tumor markers sometimes diagnostic or
  prognostic
• can be helpful in monitoring effectiveness of
  therapy or in detecting relapses/recurrences
• Serum tumor markers prostate specific
  antigen,CEA ,ß-HCG ,a-FETOPROTEIN...etc )may help
  to determine the presence of specific neoplasms .
  not perfect screening tools in a general
  population.

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Laboratory Diagnostic Methods for Neoplasia

• Laboratory Analyses
• General findings ( anemia, enzyme abnormalities
  (alkaline phosphatase,LDH), URIN (hematuria)
  ,stool occult blood further workup.
• Detection of specific genes (such as BRCA-1 for
  breast cancer) may suggest an increased risk for
  some malignancies.

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Pathological Diagnostic Procedures

• FNA (fine needle aspiration)
• cytological smears
• biopsy
• frozen sections

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Diagnostic Methods for Neoplasia

• Cytology
• sample cells
• simple
• cost-effective
• minimally invasive.
• e.g Pap smear for the diagnosis of cervical
  dysplasias and neoplasms.
• Cells exfoliated into body fluids can be
  examined.
• Fine needle aspiration (FNA) can be used also.

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Pap smear with dysplasia
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cytology smear adenocarcinoma
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Diagnostic Methods for Neoplasia

• Tissue Biopsy and Surgery Methods that sample
  small pieces of tissue (biopsy) from a particular
  site, often via endoscopic techniques (such as
  colonoscopy, upper endoscopy, or bronchoscopy)
  can often yield a specific diagnosis of
  malignancy. At surgery, portions of an organ or
  tissue can be sampled, or the diseased tissue(s)
  removed and examined in surgical pathology to
  determine the stage and grade of the neoplasm.

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frozen section
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staining a frozen section
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ancillary studies

• Imunohistochemistry
• electron microscopy
• cytogenetics
• flow cytometry

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cytokeratin stain on a carcinoma
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AFP stain on a yolk sac tumor
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EM neurosecretory granules
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EM microvilli, tight junction in an
adenocarcinoma
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Molecular studies

• PCR
• FISH
• Molecular profiling of tumor

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Diagnostic Methods for Neoplasia

• Autopsy Sometimes neoplasms are not detected or
  completely diagnosed during life. The autopsy
  serves as a means of quality assurance for
  clinical diagnostic methods, as a way of
  confirming diagnoses helpful in establishing
  risks for family members, as a means for
  gathering statistics for decision making about
  how to approach diagnosis and treatment of
  neoplasms, and to provide material for future
  research.

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Thank You