NEOPLASIA V & ENVIROMENTAL DISEASES

Host Defense Against Tumor

Immune surveillance a normal function of the immune system (emerging malignant cells) idea supported by many observations -lymphocytic infiltrates around tumors -increased incidence of some cancers in immunodeficient individuals immune Surveillance is imperfect and often cannot control rapidly growing tumors

Immune surveillance
Immune surveillance also the effect of the immune system in selecting for tumor variants. These variants have reduced immunogenicity

TUMOR ANTIGENS
Classified into two categories based on their patterns of expression: 1.-tumor-specific antigens, which are present only on tumor cells and not on any normal cells. 2.-tumor-associated antigens, which are present on tumor cells and also on some normal cells.

TUMOR ANTIGENS
Cytotoxic T lymphocytes (CTLs, CD8+)are the major immune defense mechanism against tumors. Recognize peptides bound to class I major histocompatibility complex (MHC) molecules

The modern classification of tumor antigens is based on their molecular structure and source

1.-Products of Mutated Genes Oncogenes: RAS mutated, Bcr/Abl Tumor Suppressor Genes: p53 mutated 2.-Overexpressed or Aberrantly Expressed Cellular Proteins: Tyrosinase, an enzyme involved in melanin biosynthesis that is expressed only in normal melanocytes and melanomas Melanoma antigen (MAGE) genes

classification of tumor antigens

3.-Tumor Antigens Produced by Oncogenic Viruses: Human papilloma virus E6 &E7 proteins in cervical cancer. EBNA proteins in EBV Lymphoma 4.-Oncofetal Antigens. Carcinoembryonic antigen (CEA) alpha-fetoprotein (AFP). (Tumor Markers) 5.-Cell Type-Specific Differentiation Antigens. lymphomas may be diagnosed as B cell-derived tumors by the detection of surface markers characteristic of this lineage, such as CD10 (previously called common acute lymphoblastic leukemia antigen, or CALLA) and CD20

ANTITUMOR EFFECTOR MECHANISMS

Cytotoxic T lymphocytes Natural killer cells Macrophages Antibodies

Mechanisms by which tumors evade the immune system.

Selective outgrowth of antigen-negative variants: Lack of costimulation (costimulatory molecule B7-1) Immunosuppression: Tumors or tumor products may also be immunosuppressive. For example, TGF- Antigen masking (glycocalyx molecules) Apoptosis of cytotoxic T cells: Some melanomas and hepatocellular carcinomas express Fas ligand

DIAGNOSTICO DE LABORATORIO DEL CANCER

Marcadores tumorales bioqumicos (suero, orina heces) Mtodos morfolgicos
Frotis citolgico Biopsia por aspiracin con aguja delgada (forma de frotis citolgico) Biopsia tisular con aguja gruesa o incisional (tincin HE y especiales) Inmunohistoqumica Citometra de flujo Diagnstico molecular

MARCADORES TUMORALES BIOQUIMICOS

HORMONAS ANTGENOS ONCOFETALES PROTENAS ESPECFICAS (Igs, Ag prost especfico) CARBOHIDRATOS (CA-19-9 Ca pncreas) MUCINAS Y GLUCOPROTENAS (CA125 Ca ovario,) NUEVOS MARCADORES (p53 y RAS mutante en suero, orina, heces etc. )

Hormonas
Gonadotrofina corinica humana Epitelio placentario Mola hidatidiforme Coriocarcinoma Catecolaminas Feocromocitoma (mdula suprarrenal)

Antgenos oncofetales
Antgeno carcinoembrionario ACE CEA GLUCOPROTENA TEJIDO EMBRIONARIO DE INTESTINO PNCREAS HGADO CANCERRES COLORRECTALES, DE PNCREAS Y GSTRICOS PATOLOGA NO NEOPLSICA

Antgenos oncofetales
Alfa feto-protena GLUCOPROTENA Normalmente en SACO EMBRIONARIO CA HGADO Y CLULAS GERMINALES TESTICULARES CA COLON, PULMN ,PANCREAS Y CA HEPATOCELULARES. NO NEOPLSICAS

Immunohistochemistry algorithm for poorly differentiated tumores

Carcinoma Pankeratain Leu Comm Antigen(LCA) Prot S/199 HMB/45 Desmin Vimentin Lymphoma Melanoma Sarcoma

+ -

+ -

+ +

+ +

BIOLOGIA MOLECULAR PATOLOGIA DIAGNOSTICA MOLECULAR

PCR RT-PCR Hibridacin in situ

PATOLOGIA DIAGNOSTICA MOLECULAR

El material para el PCR y sus variantes se puede obtener de los tejidos conservados en el Servicio de Patologa, ya sea en formol o de los bloques de parafina

HIBRIDACION IN SITU (ISH)

La hibridacin in situ es la tcnica molecular ms usada en la patologa diagnstica 2 variantes 1.- Fluorescencia 2.- Cromgenos

FISH
Sondas de oligonucleticos marcadas con fluorescencia 3 tipos generales 1.- Cromosoma entero 2.- Sondas centromricas ( enumeran copias de cromosoma especfico) 3.- Sondas de alelos especficos (gene supresor tumoral p53 o el oncogen HER2/neu )

Aplicaciones FISH
1.- Diagnstico, pronstico y monitoreo de neoplasias hematolgicas (leucemias y linfomas) 2.- Pruebas para blanco teraputico Ej: HER2/neu (del oncogen del receptor del factor de crecimiento epidrmico humano del cncer de mama)

Fluorescence in situ hybridization analysis for BCR-ABL chromosomal translocations. (Chronic myeloid leukemia)

HER2 FISH signal is red orange and CEN 17 FISH signal is green in the blue

Brightfield in situ hybridization and dual color fluorescence in situ hybridization (FISH) for HER2 and CEN 17.

ENVIRONMENTAL DISEASES

Environmental Pathology
The overall fatality rate for occupational exposures is 4.8 per 100,000 workers; the highest rates occur in the mining, agricultural, construction, transportation, and public utility industries. In addition it may lead to premature death . The magnitude of occupational diseases is most likely underestimated

Reported Occupational Diseases in the United States in 1997

Repeated trauma Skin disorders Lung conditions due to toxic exposures Physical injury Poisoning Lung disease due to dusts

Organ-Specific Carcinogens in Tobacco Smoke

Organ Lung, larynx Esophagus Pancreas Bladder Oral cavity (smoking) Oral cavity (snuff)

Deaths Attributable to Cigarette Smoking in the United States

Cancer Cardiovascular disease Respiratory disease Residential fires Perinatal deaths Lung cancer and heart disease attributable to passive smoking

Alcohol Abuse
Liver (Fatty change,Acute hepatitis Alcoholic cirrhosis) Central Nervous system (S. de Wernicke y de Korsakoff) Peripheral neuropathy Cardiovascular system (Cardiomyopathy) Hypertension Vasopressor Gastrointestinal tract (Gastritis) Pancreatitis

Alcohol Abuse
Skeletal muscle ( Rhabdomyolysis) Reproductive system (Testicular atrophy, Spontaneous abortion) Fetal alcohol syndrome (Growth retardation, Mental retardation, Birth defects ) Cancer ( oral cavity, pharynx, esophagus, liver, and possibly the breast )

Alcohol Abuse
One of its metabolites, acetaldehyde, may act as a tumor promoter Ethanol inhibits the detoxification of chemical carcinogens such as nitrosamines, which have been associated with tumors of the upper gastrointestinal tract. Heavy alcohol use synergizes with chronic hepatitis B or C infection in predisposing to the development of hepatocellular carcinoma

Obesity and cancer

In 2001, experts concluded that cancers of the colon, breast (postmenopausal), endometrium, kidney, and esophagus are associated with obesity. Some studies have also reported links between obesity and cancers of the gallbladder, ovaries, and pancreas.

Combined use interacts in a multiplicative way on cancer risk.

Alcohol drinking and smoking are independent risk factors for upper aerodigestive tract cancers. Convincing evidence that acetaldehyde, the first metabolite of ethanol and a constituent of tobacco smoke, is a local carcinogen in humans. Int J Cancer. 2004 Sep 10;111(4):480-3