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.

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.

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

Tumor Antigens Tissue Associated Antigen=TAA 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

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

Tumor Associated Antigens(TAA) Over expressed Antigens e.g HER-2 (neu) in 30 % Breast cancer ( present in normal breast & ovary)

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

ANTITUMOR EFFECTOR MECHANISM Cellular Cytotoxic T lymphocytes. Natural killer cells. Macrophages. Humoral mechanisms.complement mediated or ADCC.

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.

Mechanisms of Immunity to Tumors Killer Macrophages - activated by IFN-  elaborated by Helper T lymphocytes. Participate in ADCC and can lyse tumor cells through release of TNF- .

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

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.

Evidence for Immune Response to Tumors 4) Non-specific vaccines can stimulate macrophages and improve prognosis. IFN-  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.

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

Clinical Features Of Neoplasia

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

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

Effects of tumor on host Cancer Cachexia Paraneoplastic Syndromes –Endocrinopathies –Neuromyopathies –Osteochondral Disorders –Vascular Phenomena –Fever –Nephrotic Syndrome

Cancer Cachexia Progressive weakness, loss of appetite, anemia and profound weight loss (>20 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- 

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

Paraneoplastic Syndromes Cushing’s Syndrome –Small cell undifferentiated lung cancer (ACTH) like product. Nonbacterial thrombotic Endocarditis Hypercoagulability

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-  ) –Breast carcinoma, usually by bone metastasis

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

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

Paraneoplastic Syndromes Neuromyopathies 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

Paraneoplastic Syndromes Osteochondral 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.

Paraneoplastic Syndromes Vascular Phenomena Altered Coagulability - caused by the release of tumor products –Migratory Venous Thromboses (Trousseau’s 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.

Paraneoplastic Syndromes Fever 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.

Paraneoplastic Syndromes Nephrotic Syndrome Excessive loss of protein in the urine –probably caused by damage to renal glomeruli by tumor antigen-antibody complexes.

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.

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

In the diagram below utilizing an adenocarcinoma as an example, the principles of grading are illustrated: –Gradin g Staging and Grading

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

Staging and Grading In this diagram utilizing a lung carcinoma as an example, the principles of staging are illustrated:

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.

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.

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,β-HCG,α-FETOPROTEIN...etc )may help to determine the presence of specific neoplasms. not perfect screening tools in a general population.

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.

Pathological Diagnostic Procedures FNA (fine needle aspiration) cytological smears biopsy frozen sections

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.

Pap smear with dysplasia

cytology smear: adenocarcinoma

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.

frozen section

staining a frozen section

ancillary studies Imunohistochemistry electron microscopy cytogenetics flow cytometry

cytokeratin stain on a carcinoma

AFP stain on a yolk sac tumor

EM: neurosecretory granules

EM: microvilli, tight junction in an adenocarcinoma

Molecular studies PCR FISH Molecular profiling of tumor

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.