This action might not be possible to undo. Are you sure you want to continue?
Progressive, Purposeless, Pathologic, P i P l P th l i Proliferation of cells characterized by loss of control over cell division division. DNA damage at growth control genes is central to development of neoplasm. Carcinogens – Chemical, physical & genetic DNA damage Neoplasm. g p
Uncontrolled & Irreversible* Benign
Localized, non-invasive. li d i i
Normal N l
Hyperplasia Metaplasia (DNA H l i M t l i damage) Dysplasia (DNA damage) (DNA damage) Anaplasia (DNA damage)) Infiltration (DNA damage)) p ( g ( g Metastasis…. Progressive DNA Damage – features of neoplasia. l i
Non lethal DNA Damage leading to N l h l D l di uncontrolled cell division.
Environmental causes: (Carcinogens) Chemicals Viruses Vi Radiation Hereditary causes- Genetic defects. Combination – common. Obscure defects
Mechanism of Growth Disorders
Polyclonal P l l l
Monoclonal M l l
Neoplastic cells parenchyma. l ll Non neoplastic Non-neoplastic - stroma (Connective tissue & BV) Fast growth ast g o t Less stroma less stroma ess st o a more necrosis,
Cell of origin Rate of growth g Differentiation Local Invasion Metastasis
Lung cancer Grade - low, high , g Well, Mod, P, Un. Staging Staging
Lung cancer: Squamus cell carcinoma. Poorly differentiated, high grade, stage 4, Liver+
Slow growing, capsulated, Non-invasive do not metastasize, , well differentiated, suffix “oma” eg. g Fibroma.
Fast growing, non capsulated, p Invasive & Infiltrate Metastasize. poorly differentiated, Suffix “Carcinoma” or “Sarcoma”
Suffix - oma Fibroma Osteoma Adenoma Papilloma Chondroma
Carcinoma / Sarcoma Fibrosarcoma Osteosarcoma Adencarcinoma Squamous cell carcinoma Chondrosarcoma
Exceptions: Leukemia, Lymphoma, Glioma, Exceptions: p y p
History of Clinical examination Radiographic analysis – X-Ray, US, CT, MRI Laboratory analysis – Tumor markers Cytology –Pap smear, FNAB Biopsy - Histopathology markers. Histopathology, markers Autopsy – Research, learning & teaching
Grading – Cellular Differentiation (Microscopic) Staging – Progression or Spread ( g g g p (clinical) )
T1N1M0 – Means primary tumor is within the organ but cancer cells have spread to local lymphnodes, there is no metastasis. T3N0Mo - Means tumor has spread beyond p y primary organ but has not spread to lymphnodes or other sites.
Direct Spread Di t S d Body cavities Blood vessels Lymphatic vessels y p
Lungs – Systemic Venous blood Liver – GIT venous return, nutrition. Brain – End arteries.
p g y Tumor Impingement on nearby structures
Pancreatic ca on bile duct Obst. Jaund.
Colon, Gastric, and Renal cell carcinomas
Infection (often due to obstruction)
Pneumonia, U i P i Urinary inf. i f
Rupture or Infarction
Ovarian, Bladder colon Ovarian Bladder, colon,
Progressive weakness, loss of appetite, P i k l f i anemia and profound weight loss (>20%) Often correlates with tumor mass & spread Etiology includes a generalized increase in metabolism and central effects of tumor on hypothalamus Probably related to macrophage production of TNF-a TNF
Due to Products released by tumor Cushing’s Syndrome Inappropriate ADH syndrome (Hyponatremia) – lung ca Hypothalamic tumors (vasopressin) Hypercalcemia – Ca is the common cause. – lung. Hypoglycemia - i H l i insulin or i li insulin lik li like activities Fibrosarcoma, Cerebellar hemangioma.
Adrenal, Lung Ca – ACTH
The prognosis of a patient with any type of neoplasm depends on a number of factors including: the rate of growth of the tumor, the size of the tumor, the tumor site, the cell type and degree of differentiation, the presence of metastasis, responsiveness t th t t i i to therapy, and th d the general health of the patient.
Dr. Pritinesh Singh PY 202 Basic Pathology Pathology Lecturer Fiji School of Medicine
Oncogenesis: Pathogenesis of neoplasm (b/m) Carcinogenesis: Pathogenesis of cancer (m) Carcinogen - agent causing cancer cancer. Oncogen - agent causing neoplasm. Mutagen - agent causing mutation mutation. Oncogenes – genes causing cancer p-onc, v-onc, c-onc p onc v onc c onc – Proto/viral/cell - naming of oncogenes.
Genes control cell division by cytokines. Four classes of regulatory genes.
1. 2. 3. 4.
Promotors – Proto-oncogenes Proto oncogenes Inhibitors – Cancer-suppressor genes – p53 Genes regulating Apoptosis. DNA repair genes.
Loss/damage to suppressor genes, Duplication of promotor genes Loss/damage to Apoptosis g g p p genes Loss/damage of DNA repair genes.
Initiation DNA damage eg.Benzpyrene d B Promotion Histologic change – eg eg. Turpentine (co-carcinogens) Malignant transformation: Visible tumor formation – further DNA damage.
Direct Acting Carcinogens: Acts locally without metabolic change g
Alkylating Agents: Cyclophosphamide
Procarcinogenes (needs activation) carcinogenic only after being metabolised into active compounds (procarcinogen ultimate carcinogen)
Polycyclinc hydrocarbons – Benzpyrene Aromatic amines, d A ti i dyes - B Benzidine idi Natural products: Aflotoxin Others: Vinyl chloride, turpentine etc chloride etc.
Insertion of viral nucleic acids mutation Alterations in Oncogenes, cancer suppressor genes and genes regulating DNA repair resulting in up-regulation of cell d l l f ll division Carcinogenesis.
v-fes, v-sis f i v-sis sis proto-oncogenes. t PDGF Brain tumours.
RNA Retrovirus – produces DNA provirus
DNA provirus containing viral oncogene (v-onc) is i t i i i l ( )i introduced, or DNA provirus without v-onc is inserted adjacent to c-onc in host cell DNA RNA viruses is thought to have acquired v-onc sequence by recombinant mechanism from animal cells
Do not contain viral oncogenes Act by blocking suppressor gene products Examples – HPV, EBV,HBV
Human Papilloma Virus H P ill Vi
Cervical neoplasia – warts, papilloma, ca cx
Epstein-Barr Epstein Barr virus –
Burkitts Lymphoma, Nasopharyngeal ca.
Hepatitis B & C virus
Radiation Oncogenesis g
Types of oncogenic radiation
Ultraviolet X-ray X Radioisotopes Nuclear Fallout
Mode of oncogenesis
Direct effect on DNA Activation of cellular oncogenes
g y j Ionizing radiation dysjunction fusion mutation.
X Ray workers – Leukemia Radio-isotopes – Th id carcinoma R di i Thyroid i Atomic explosion – Skin cancer, Leukemia
Solar UV radiation associated with skin cancers – squamous CA, basal cell CA, q malignant melanoma Fair-skinned and elderly are susceptible UV light is believed to induce crosslinkages between DNA molecules and CA occurs when repair mechanisms are not efficient
Earlier use of X rays caused skin cancer X-rays cancer, leukemia and papillary thyroid CA Radiotherapy causes radiation-induced malignancy 10-30 yrs later – usually sarcomas Diagnostic X-rays are considered to have no increased risk except in abdominal xp rays which increase incidence of leukemia in the fetus
Osteosarcoma common among factory workers who use radium-containing p g paints Radioactive mineral mining in Europe and USA associated with lung cancer Thorium increases risk of liver cancer – hepatocellular, angiosarcoma, cholangiocarcinoma Radioactive iodine – increased risk of cancer 15 25 years later 15-25 l
Nuclear Fallout Hiroshima, Nagasaki (atomic blasts) Marshall i l d ( M h ll islands (atmospheric testing h i i of nuclear divide containing radioactive iodine) di i i di ) Chernobyl, 1986
Genetic Oncogenesis (Role of Inheritance)
Mendelian i h it M d li inheritance Polygenic inheritance Association with inherited diseases
Due to inhereted abnormal genes. genes FAP – gene C5, polyposis Adenocarcinoma colon Retinoblastoma – Rb gene – (C13) Neuroblastoma N ur bla t ma – (C17) Trisomy 21 – Down’s syndrome – Leukemias in infants infants.
Polygenic Inheritance Neoplasms occuring in related individuals more often than expected on the basis of chance Breast CA B Colon CA
Association with Inherited Diseases Many inherited diseases are associated with higher risk of neoplasia Types : yp Syndromes characterised by increased chromosomal fragility Syndromes of immunodeficiency
Tumor initiation and progression results from stepwise accumulation of DNA mutations. Several characters of malignant neoplasm are g p the result of multiple genetic defects. Initial steps reversible(e.g. dysplasia), but final p ( g y p ) Malignant transformation is irreversible.
Stage of initiation Latent stage Stage of promotion Stage of malignant transformation
p53 senses DNA damage, and induces G1 arrest and induces DNA repair p p process. Cell with un-repairable DNA is directed to apoptosis by p g p p y p53 gene. “P53 is a guardian of the genome. Its homozygous loss leads to accumulation of yg damaged DNA may result in malignancy” Homozygous loss of p is seen in virtually yg p53 y every type of cancer. Over half of human malignant cells show loss g of p53 gene by special tests.
Pathogenesis of cancer is complex it is a genetic disease- either acquired genetic abnormality or inherited genetic abnormality It arises when several mutations accumulate within genome Added insults from the environmental exposures to carcinogens : chemicals radiation viruses chemicals, radiation, Growth autonomy from activation of growth factors or by suppression of tumour suppressor genes
g DNA damage - loss of control over cell division. Radiation, Chemicals & Viral infections are some k known causes of cancers. f Cancer evolves in multiple steps by sequentially acquiring different DNA damages damages. Initiation, Latent stage, Promotion and Malignant transformation are recognizable g g stages in carcinogenesis. Each character of malignancy depends on unique DNA alteration. i l i
Acquired environmental factors chemicals ,radiation ,viruses radiation viruses Changes in genome Ch i of somatic cells Activation of growth promoting oncogenes
Genetic factors G ti f t
Inactivation of cancer supressor genes
Expression all altered gene products and loss of regular gene products
Surgical therapy – early stage/debulk Chemotherapy Radiotherapy Immunotherapy
Most anticancer treatment is directed towards killing actively dividing cells. killi ti l di idi ll Complications: Marrow aplasia, alopecia, sterility, GIT, lung, kidney damage). t ilit GIT l kid d ) Newer drugs target tumor cells by immune mechanisms or hormones hormones.
I AM YAWNING!!
What is a neoplasm? Write two special characters? What is a papilloma? Adenoma? p p What is dysplasia and anaplasia? Mention examples. Mention major classes of neoplasms with five differentiating features? Mention three features of a malignant tumor?
What is carcinoma-in-situ? What is grading? And staging? How are neoplasms named? p What is CIN? Classify What are the common routes of cancer spread? How do we diagnose cancer? Brief note of tumor markers?
Briefly describe molecular basis of g carcinogenesis. What are Oncogenes? Give examples. Write a brief note on p53 gene / carcinogenesis. Briefly describe the multistep theory of carcinogenesis Briefly describe the hereditary causes of cancer with an example example. What are oncogenic viruses? Give examples. Give two examples of familial neoplasms. p p Write a short note on chemical/viral/radiation carcinogenesis.
This action might not be possible to undo. Are you sure you want to continue?
We've moved you to where you read on your other device.
Get the full title to continue reading from where you left off, or restart the preview.