Neoplasia & Carcinogenesis
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PY 202 Basic Pathology Dr Pritinesh Singh Department of Health Sciences Fiji School of Medicine
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 Æ DNA damage g Æ Neoplasm. p
Uncontrolled & Irreversible* Benign
Localized, li d non-invasive. i i
Malignant (Cancer)
Spreading, Invasive.
Normal N l Æ Hyperplasia H l i Æ Metaplasia M t l i Æ(DNA damage) Æ Dysplasia Æ (DNA damage) Æ (DNA damage) AnaplasiaÆ p ((DNA damage) g ) Infiltration Æ ((DNA damage) g ) Æ Metastasis…. Progressive DNA Damage – features of neoplasia. l i
Non leading N lethal l h l DNA Damage D l di to uncontrolled cell division.
Environmental causes: (Carcinogens) ¾Chemicals ¾Viruses Vi ¾Radiation Hereditary causes- Genetic defects. Combination – common. Obscure defects
Mechanism of Growth Disorders
P l l Polyclonal l
M Monoclonal l l
Neoplastic cells l ll parenchyma. Non Non-neoplastic neoplastic - stroma (Connective tissue & BV)
Fast ast g growth o t Æ less ess st stroma o a Less stroma Æ more necrosis,
Cell of origin Rate of g growth 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 Exceptions: p : Leukemia, Lymphoma, y p Glioma,
History of Clinical examination Radiographic analysis – X-Ray, US, CT, MRI Laboratory analysis – Tumor markers Cytology –Pap smear, FNAB Biopsy - Histopathology, Histopathology markers. markers Autopsy – Research, learning & teaching
Grading – Cellular Differentiation (Microscopic) Staging g g – Progression g or Spread 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 p beyond y primary organ but has not spread to lymphnodes or other sites.
Direct Di t Spread S d Body cavities Blood vessels Lymphatic y p vessels Lungs – Systemic Venous blood Liver – GIT venous return, nutrition. Brain – End arteries.
p g y structures Tumor Impingement on nearby
Ulceration/bleeding
Colon, Gastric, and Renal cell carcinomas
Infection (often due to obstruction)
Pancreatic ca on bile duct Æ Obst. Jaund.
P Pneumonia, i U Urinary i inf. i f
Rupture or Infarction
Ovarian Bladder, Ovarian, Bladder colon, colon
Progressive loss off appetite, P i weakness, k l 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
Adrenal, Lung Ca – ACTH
Inappropriate ADH syndrome (Hyponatremia) – lung ca Hypothalamic tumors (vasopressin) Hypercalcemia – Ca is the common cause. – lung. H Hypoglycemia l i - insulin i li or iinsulin li lik like activities Fibrosarcoma, Cerebellar hemangioma.
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, t t i responsiveness i tto th therapy, and d th 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, p-onc, v onc c-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 Proto-oncogenes oncogenes Inhibitors – Cancer-suppressor genes – p53 Genes regulating Apoptosis. DNA repair genes.
Loss/damage to suppressor genes, Duplication of promotor genes Loss/damage g to Apoptosis p p g 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) à carcinogenic only after being metabolised into active compounds (procarcinogen Æ ultimate carcinogen)
Polycyclinc hydrocarbons – Benzpyrene A Aromatic ti amines, i d dyes - Benzidine B idi Natural products: Aflotoxin Others: Vinyl chloride, chloride turpentine etc etc.
Insertion of viral nucleic acids Æ mutation Alterations in Oncogenes, cancer suppressor genes and genes regulating DNA repair resulting l in up-regulation l off cell ll d division Æ Carcinogenesis.
v-fes, f v-sis i Æ proto-oncogenes. t v-sis Æ sis Æ PDGF Æ Brain tumours.
RNA Retrovirus – produces DNA provirus à DNA provirus containing i t i i viral i l oncogene (v-onc) ( ) is i
introduced, or à DNA provirus without v-onc is inserted adjacent to c-onc in host cell DNA à RNA viruses is thought to have acquired v-onc sequence by recombinant mechanism from animal cells
DNA virus à Do not contain viral oncogenes à Act by blocking suppressor gene products à Examples – HPV, EBV,HBV
Human Papilloma Virus H P ill Vi
Epstein Barr virus – Epstein-Barr
Cervical neoplasia – warts, papilloma, ca cx Burkitts Lymphoma, Nasopharyngeal ca.
Hepatitis B & C virus
Hepatocellular carcinoma.
Radiation Oncogenesis g
Types of oncogenic radiation à à à à
Ultraviolet X X-ray Radioisotopes Nuclear Fallout
Mode of oncogenesis à Direct effect on DNA à Activation of cellular oncogenes
g radiation Æ dysjunction y j Ionizing Æ random fusion Æ mutation. Neoplasia Mutations
X Ray workers – Leukemia R di i Radio-isotopes – Thyroid Th id carcinoma i Atomic explosion – Skin cancer, Leukemia
UV Radiation
à Solar UV radiation associated with skin
cancers – squamous q CA, basal cell CA, malignant melanoma à Fair-skinned and elderly are susceptible à UV light is believed to induce crosslinkages between DNA molecules and CA occurs when repair mechanisms are not efficient
X-ray radiation à Earlier use of X-rays X rays caused skin cancer, cancer
leukemia and papillary thyroid CA à Radiotherapy causes radiation-induced malignancy 10-30 yrs later – usually sarcomas à Diagnostic X-rays are considered to have no increased risk except p in abdominal xrays which increase incidence of leukemia in the fetus
Radioisotopes p
à Osteosarcoma common among factory
workers who use radium-containing gp paints à Radioactive mineral mining in Europe and USA associated with lung cancer à Thorium increases risk of liver cancer – hepatocellular, angiosarcoma, cholangiocarcinoma à Radioactive iodine – increased risk of cancer 15-25 15 25 years later l
Nuclear Fallout à Hiroshima, Nagasaki (atomic blasts) à Marshall M h ll islands i l d (atmospheric ( h i testing i of nuclear divide containing radioactive di i iodine) i di ) à Chernobyl, 1986
Genetic Oncogenesis (Role of Inheritance)
Types
à Mendelian M d li inheritance i h it à Polygenic inheritance à Association with inherited diseases
Mendelian Inheritance
à Dominant à Recessive
Due to inhereted abnormal genes. genes FAP – gene C5, polyposis Æ Adenocarcinoma colon Retinoblastoma – Rb gene – (C13) N ur bla t ma – (C17) Neuroblastoma Trisomy 21 – Down’s syndrome – Leukemias in infants. infants
Polygenic Inheritance à Neoplasms occuring in related individuals more often than expected on the basis of chance Breast B CA Colon CA
Association with Inherited Diseases à Many inherited diseases are associated with higher risk of neoplasia à Types yp : Syndromes characterised by increased chromosomal fragility Syndromes of immunodeficiency
Proto--oncogene Proto
Oncogene g
Tumor initiation and progression results from stepwise accumulation of DNA mutations. Several characters of malignant g neoplasm p are the result of multiple genetic defects. Initial steps p reversible(e.g. ( g dysplasia), y p ) but final 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 p p by yp p53 g gene. “P53 is a guardian of the genome. Its homozygous yg loss leads to accumulation of damaged DNA may result in malignancy” Homozygous yg loss of p p53 is seen in virtually y every type of cancer. Over half of human malignant g cells show loss 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 chemicals, radiation radiation, viruses Growth autonomy from activation of growth factors or by suppression of tumour suppressor genes
g - loss of control over cell DNA damage division. Radiation, Chemicals & Viral infections are some known k causes off cancers. Cancer evolves in multiple steps by sequentially acquiring different DNA damages. damages Initiation, Latent stage, Promotion and Malignant g transformation are recognizable g stages in carcinogenesis. Each character of malignancy depends on unique i DNA alteration. l i
Acquired environmental factors radiation ,viruses viruses chemicals ,radiation Changes in Ch i genome of somatic cells Activation of growth promoting oncogenes
G Genetic ti factors f t
Inactivation of cancer supressor genes
Expression all altered gene products and loss of regular gene products
MALIGNANT NEOPLASM
Surgical therapy – early stage/debulk Chemotherapy Radiotherapy Immunotherapy
Most anticancer treatment is directed towards killing killi actively ti l dividing di idi cells. ll Complications: Marrow aplasia, alopecia, sterility, t ilit GIT, GIT lung, l kidney kid damage). 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 p papilloma? p Adenoma? 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 p named? 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 p of familial neoplasms. p Write a short note on chemical/viral/radiation carcinogenesis.
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 Æ DNA damage g Æ Neoplasm. p
Uncontrolled & Irreversible* Benign
Localized, li d non-invasive. i i
Malignant (Cancer)
Spreading, Invasive.
Normal N l Æ Hyperplasia H l i Æ Metaplasia M t l i Æ(DNA damage) Æ Dysplasia Æ (DNA damage) Æ (DNA damage) AnaplasiaÆ p ((DNA damage) g ) Infiltration Æ ((DNA damage) g ) Æ Metastasis…. Progressive DNA Damage – features of neoplasia. l i
Non leading N lethal l h l DNA Damage D l di to uncontrolled cell division.
Environmental causes: (Carcinogens) ¾Chemicals ¾Viruses Vi ¾Radiation Hereditary causes- Genetic defects. Combination – common. Obscure defects
Mechanism of Growth Disorders
P l l Polyclonal l
M Monoclonal l l
Neoplastic cells l ll parenchyma. Non Non-neoplastic neoplastic - stroma (Connective tissue & BV)
Fast ast g growth o t Æ less ess st stroma o a Less stroma Æ more necrosis,
Cell of origin Rate of g growth 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 Exceptions: p : Leukemia, Lymphoma, y p Glioma,
History of Clinical examination Radiographic analysis – X-Ray, US, CT, MRI Laboratory analysis – Tumor markers Cytology –Pap smear, FNAB Biopsy - Histopathology, Histopathology markers. markers Autopsy – Research, learning & teaching
Grading – Cellular Differentiation (Microscopic) Staging g g – Progression g or Spread 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 p beyond y primary organ but has not spread to lymphnodes or other sites.
Direct Di t Spread S d Body cavities Blood vessels Lymphatic y p vessels Lungs – Systemic Venous blood Liver – GIT venous return, nutrition. Brain – End arteries.
p g y structures Tumor Impingement on nearby
Ulceration/bleeding
Colon, Gastric, and Renal cell carcinomas
Infection (often due to obstruction)
Pancreatic ca on bile duct Æ Obst. Jaund.
P Pneumonia, i U Urinary i inf. i f
Rupture or Infarction
Ovarian Bladder, Ovarian, Bladder colon, colon
Progressive loss off appetite, P i weakness, k l 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
Adrenal, Lung Ca – ACTH
Inappropriate ADH syndrome (Hyponatremia) – lung ca Hypothalamic tumors (vasopressin) Hypercalcemia – Ca is the common cause. – lung. H Hypoglycemia l i - insulin i li or iinsulin li lik like activities Fibrosarcoma, Cerebellar hemangioma.
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, t t i responsiveness i tto th therapy, and d th 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, p-onc, v onc c-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 Proto-oncogenes oncogenes Inhibitors – Cancer-suppressor genes – p53 Genes regulating Apoptosis. DNA repair genes.
Loss/damage to suppressor genes, Duplication of promotor genes Loss/damage g to Apoptosis p p g 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) à carcinogenic only after being metabolised into active compounds (procarcinogen Æ ultimate carcinogen)
Polycyclinc hydrocarbons – Benzpyrene A Aromatic ti amines, i d dyes - Benzidine B idi Natural products: Aflotoxin Others: Vinyl chloride, chloride turpentine etc etc.
Insertion of viral nucleic acids Æ mutation Alterations in Oncogenes, cancer suppressor genes and genes regulating DNA repair resulting l in up-regulation l off cell ll d division Æ Carcinogenesis.
v-fes, f v-sis i Æ proto-oncogenes. t v-sis Æ sis Æ PDGF Æ Brain tumours.
RNA Retrovirus – produces DNA provirus à DNA provirus containing i t i i viral i l oncogene (v-onc) ( ) is i
introduced, or à DNA provirus without v-onc is inserted adjacent to c-onc in host cell DNA à RNA viruses is thought to have acquired v-onc sequence by recombinant mechanism from animal cells
DNA virus à Do not contain viral oncogenes à Act by blocking suppressor gene products à Examples – HPV, EBV,HBV
Human Papilloma Virus H P ill Vi
Epstein Barr virus – Epstein-Barr
Cervical neoplasia – warts, papilloma, ca cx Burkitts Lymphoma, Nasopharyngeal ca.
Hepatitis B & C virus
Hepatocellular carcinoma.
Radiation Oncogenesis g
Types of oncogenic radiation à à à à
Ultraviolet X X-ray Radioisotopes Nuclear Fallout
Mode of oncogenesis à Direct effect on DNA à Activation of cellular oncogenes
g radiation Æ dysjunction y j Ionizing Æ random fusion Æ mutation. Neoplasia Mutations
X Ray workers – Leukemia R di i Radio-isotopes – Thyroid Th id carcinoma i Atomic explosion – Skin cancer, Leukemia
UV Radiation
à Solar UV radiation associated with skin
cancers – squamous q CA, basal cell CA, malignant melanoma à Fair-skinned and elderly are susceptible à UV light is believed to induce crosslinkages between DNA molecules and CA occurs when repair mechanisms are not efficient
X-ray radiation à Earlier use of X-rays X rays caused skin cancer, cancer
leukemia and papillary thyroid CA à Radiotherapy causes radiation-induced malignancy 10-30 yrs later – usually sarcomas à Diagnostic X-rays are considered to have no increased risk except p in abdominal xrays which increase incidence of leukemia in the fetus
Radioisotopes p
à Osteosarcoma common among factory
workers who use radium-containing gp paints à Radioactive mineral mining in Europe and USA associated with lung cancer à Thorium increases risk of liver cancer – hepatocellular, angiosarcoma, cholangiocarcinoma à Radioactive iodine – increased risk of cancer 15-25 15 25 years later l
Nuclear Fallout à Hiroshima, Nagasaki (atomic blasts) à Marshall M h ll islands i l d (atmospheric ( h i testing i of nuclear divide containing radioactive di i iodine) i di ) à Chernobyl, 1986
Genetic Oncogenesis (Role of Inheritance)
Types
à Mendelian M d li inheritance i h it à Polygenic inheritance à Association with inherited diseases
Mendelian Inheritance
à Dominant à Recessive
Due to inhereted abnormal genes. genes FAP – gene C5, polyposis Æ Adenocarcinoma colon Retinoblastoma – Rb gene – (C13) N ur bla t ma – (C17) Neuroblastoma Trisomy 21 – Down’s syndrome – Leukemias in infants. infants
Polygenic Inheritance à Neoplasms occuring in related individuals more often than expected on the basis of chance Breast B CA Colon CA
Association with Inherited Diseases à Many inherited diseases are associated with higher risk of neoplasia à Types yp : Syndromes characterised by increased chromosomal fragility Syndromes of immunodeficiency
Proto--oncogene Proto
Oncogene g
Tumor initiation and progression results from stepwise accumulation of DNA mutations. Several characters of malignant g neoplasm p are the result of multiple genetic defects. Initial steps p reversible(e.g. ( g dysplasia), y p ) but final 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 p p by yp p53 g gene. “P53 is a guardian of the genome. Its homozygous yg loss leads to accumulation of damaged DNA may result in malignancy” Homozygous yg loss of p p53 is seen in virtually y every type of cancer. Over half of human malignant g cells show loss 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 chemicals, radiation radiation, viruses Growth autonomy from activation of growth factors or by suppression of tumour suppressor genes
g - loss of control over cell DNA damage division. Radiation, Chemicals & Viral infections are some known k causes off cancers. Cancer evolves in multiple steps by sequentially acquiring different DNA damages. damages Initiation, Latent stage, Promotion and Malignant g transformation are recognizable g stages in carcinogenesis. Each character of malignancy depends on unique i DNA alteration. l i
Acquired environmental factors radiation ,viruses viruses chemicals ,radiation Changes in Ch i genome of somatic cells Activation of growth promoting oncogenes
G Genetic ti factors f t
Inactivation of cancer supressor genes
Expression all altered gene products and loss of regular gene products
MALIGNANT NEOPLASM
Surgical therapy – early stage/debulk Chemotherapy Radiotherapy Immunotherapy
Most anticancer treatment is directed towards killing killi actively ti l dividing di idi cells. ll Complications: Marrow aplasia, alopecia, sterility, t ilit GIT, GIT lung, l kidney kid damage). 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 p papilloma? p Adenoma? 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 p named? 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 p of familial neoplasms. p Write a short note on chemical/viral/radiation carcinogenesis.
