neoplasia and mechanism of carcinogenesis introductory
TRANSCRIPT
NEOPLASIA
DR A.O. OLUWASOLA
• Neoplasia literally means ‘’new growth” and the new growth is a neoplasm.
• Oncology (Greek oncos = tumour) is the study of tumours or neoplasms.
• Cancer is the common term for all malignant tumours (derived from the latin word for crab)
• “A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissue and persists in the same excessive manner after cessation of the stimuli that evoked the change”.
• Tumour can be benign or malignant and are made
up of two basic components: 1. Parenchyma: the proliferating neoplastic cells. 2. Supportive stroma: made up of connective tissue
and blood vessels.
NOMENCLATURE
• Based on parenchymal component– Cells of origin
• In general attach the suffix -oma to the cell of origin.
– Microscopic architecture &– Macroscopic patterns.
Epithelial tissue- -e.g. cysts, papillae & polyp. • Malignant Mesenchymal tissue are usually called
sarcomas (Greek sar = fleshy) because they have little connective tissue stroma
Papilloma
Colonic Polyp
Gross appearance of an opened cystic teratoma of the ovary
NOMENCLATURE CTD
• Degree of diferentiation : Well; Mod; Poorly differentiated or undifferentiated malignant tumor
• Non-classical designations:-• Melanomas, seminomas, hepatomas.• choristoma-as • hamartoma -Aberrant
differentiation/anomalous development • Specific designations have specific clinical
implications.
Nomenclature of Tumors
Tissue of Origin Benign Malignant
Composed of One Parenchymal Cell Type
Tumors of mesenchymal origin
Connective tissue and derivatives Fibroma Fibrosarcoma
Lipoma Liposarcoma
Chondroma Chondrosarcoma
Osteoma Osteogenic sarcoma
Endothelial and related tissues
Blood vessels Hemangioma Angiosarcoma
Lymph vessels Lymphangioma Lymphangiosarcoma
Synovium Synovial sarcoma
Mesothelium Mesothelioma
Brain coverings Meningioma Invasive meningioma
Blood cells and related cells
Hematopoietic cells Leukemias
Lymphoid tissue Lymphomas
Muscle
Smooth Leiomyoma Leiomyosarcoma
Striated Rhabdomyoma Rhabdomyosarcoma
Tumors of epithelial origin
Stratified squamous Squamous cell papilloma Squamous cell or epidermoid carcinoma
Basal cells of skin or adnexa
Basal cell carcinoma
Epithelial lining of glands or ducts
Adenoma Adenocarcinoma
Papilloma Papillary carcinomas
Cystadenoma Cystadenocarcinoma
Respiratory passages Bronchial adenoma Bronchogenic carcinoma
Renal epithelium Renal tubular adenoma Renal cell carcinoma
Liver cells Liver cell adenoma Hepatocellular carcinoma
Urinary tract epithelium (transitional)
Transitional cell papilloma Transitional cell carcinoma
Placental epithelium Hydatidiform mole Choriocarcinoma
Testicular epithelium (germ cells)
Seminoma
Tumors of melanocytes Nevus Malignant melanoma
More Than One Neoplastic Cell Type-Mixed Tumors, Usually Derived from One Germ Cell Layer
Salivary glands Pleomorphic adenoma (mixed tumor of salivary origin)
Malignant mixed tumor of salivary gland origin
Renal anlage Wilms tumor
More Than One Neoplastic Cell Type Derived from More Than One Germ Cell Layer-Teratogenous
Totipotential cells in gonads or in embryonic rests
Mature teratoma, dermoid cyst
Immature teratoma, teratocarcinoma
Comparisons Between Benign and Malignant Tumors
Characteristics Benign Malignant
Differentiation/anaplasia
Well differentiated; structure may be typical of tissue of origin
Some lack of differentiation with anaplasia; structure is often atypical
Rate of growth Usually progressive and slow; may come to a standstill or regress; mitotic figures are rare and normal
Erratic and may be slow to rapid; mitotic figures may be numerous and abnormal
Local invasion Usually cohesive and expansile well-demarcated masses that do not invade or infiltrate surrounding normal tissues; Encapsulation
Locally invasive, infiltrating the surrounding normal tissues; sometimes may be seemingly cohesive and expansile
Metastasis Absent Frequently present; the larger and more undifferentiated the primary, the more likely are metastases
Leiomyoma of the uterus
Benign tumor (adenoma) of the thyroid
Malignant tumor (adenocarcinoma) of the colon
Anaplastic tumor showing cellular and nuclear variation in size and
shape
Fibroadenoma of the Breast
Invasive carcinoma of the breast
Biology of Tumor Growth
• The natural history of most malignant tumors can be divided into four phases:
• (1) malignant change in the target cell, referred to as transformation;
• (2) growth of the transformed cells;
• (3) local invasion; and
• (4) distant metastases
DIFFERENTIATION AND ANAPLASIA
• Differentiation –extent of functional & morphologic resemblance to mature normal cell.
• Anaplasia is lack of differentiation • Hallmark of malignant transformation• Xrized by: Pleomorphism; Hyperchromasia;
frequent/atypical mitosis; loss of polarity; tumour giant cells; Necrosis
Anaplastic tumor of the skeletal muscle (rhabdomyosarcoma)
Carcinoma in situ
DYSPLASIA
• Loss in the uniformity of the individual cells as well as a loss in their architectural orientation
• Disorganized;Pleomorphism; Hyperchromasia; Mitosis
• Carcinoma in situ;
• Invasion
Factors influencing tumour development
• Tumour development is influenced by many factors that may be considered under three headings:
1. Kinetics of tumour cell growth
2. Tumour angiogenesis and
3. Tumour progression and heterogeneity
Schematic representation of tumor growth
METASTASIS
• Unequivocal marker of malignancy
• Exceptions: Gliomas & BCC
• Pathways of spread:1. Direct seeding of body cavities
2. Lymphatic spread
3. Haematogenous spread
Figure 7-42 The metastatic cascade. Schematic illustration of the sequential steps involved in the hematogenous spread of a tumor.
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 3 August 2005 11:45 PM)
© 2005 Elsevier
A liver studded with metastatic cancer.
EPIDEMIOLOGY
• Can give insight to the cause of cancer• Factors in patient & environment.• US residents have 1/5 chances of dying
from cancer.• In Nigeria 100,000 new cases occur each
year (T. F. Solanke, 2000)• 500,000 in the 21st century • Lung, Breast, prostate C/rectum-death/US
LEADING CAUSES OF CANCER IN UNITED STATES
MEN• PROSTATE • LUNG• COLORECTAL
WOMEN• BREAST • LUNG• COLORECTAL
LEADING CAUSES OF CANCER IN NIGERIA
MEN• PROSTATE • LIVER• LYMPHOMA
WOMEN• BREAST• CERVIX • LYMPHOMA
Geography and Environmental Factors
Factors Predisposing to Cancer
• Geog/Environ: Age, Sex, Diet, Lifestyle, Occupation, ambient environ
• Genetic: • Nonhereditary conditions: Cx infla; UC, Crohn`s dx, viral hep. Cx pan. Precancerous cond.- CAG/Pernicious
anaemia; Solar Keratosis; leukoplakia; adenoma
MECHANISM OF CARCINOGENESIS/MOLECULAR
BASIS OF CANCER
• Cancer is essentially a genetic disease at the cellular level.
• Carcinogenesis, • The process of development of cancer in living
tissues, is a complex multistage process at both the phenotypic and the genetic levels.
• A malignant neoplasm has several phenotypic attributes,
• Such as excessive growth,• Local invasiveness and the ability to form distant
metastases.
• These characteristics are acquired in a stepwise fashion,
• A phenomenon called tumour progression. • At the molecular level, progression results from
accumulation of genetic lesions. • Such genetic damage [or mutation] may be
acquired by the action of environmental agents,• Such as chemicals, Radiation or viruses or it
may be inherited in the germ line.
• The genetic hypothesis of cancer also implies that a tumour mass results from the clonal expansion of a single progenitor cell that has incurred the genetic damage –
• This is the basis of tumour monoclonality.
Biology of tumor growth
The cell cycle and regulation of cell growth:
Normal cell division is closely regulated. Phases of cell cycle include:• -Growth-G-phase-G1,G2;• Synthetic-S-phase and mitotic-M-phase. After cell division daughter cells may re-
enter the cycle; • Differentiate into its specialized forms or
undergo a programmed cell death (apoptosis).
© 2005 Elsevier
CONTROL OF CELL CYCLE
During the cell cycle, the cell must recognize, detect and repair any DNA alteration or defect that might occur.
Two important classes of genes control cell growth:
• Proto-oncogenes;• Tumour suppressor genes. Many of the cellular changes associated
with cancer affect this vital process.
Multiple-hit concept of carcinogenesis
• This involves primary and secondary genetic abnormalities:-
• 1. Primary abnormalities: Consistent changes essential in establishing
the neoplasm, Strongly correlated with tumour type.• Features that contribute to their development
include: • Environmental factors and genetic factors
[hereditary].
These primary abnormalities [or mutations] effect phenotypic transformation in tumour cells.
• Such as:• – loss of capacity for growth arrest.• –loss of contact inhibition of movement• –change in cell morphology and growth habits
[anchorage independence] and • - Capacity for indefinite replication
[immortality]
Secondary abnormalities:
• These are additional mutations that confer an evolutionary edge on the new clones of tumour cells possessing them,
• Causing them to proliferate more vigorously; • Have longer life span and eventually outgrow their
neighbours. • These new subsets [tumour heterogeneity] differ in
their karyotype, invasiveness, growth rate, hormonal responsiveness,
• Metastatic abilities and susceptibility to antineoplastic drugs.
• These secondary genetic changes underlie the phenomenom of tumour progression –
• Defined as “the acquisition of permanent irreversible qualitative change in one or more characteristics of a neoplasm”
• Environmental factors: 1. Physical, 2. Chemical & 3. Biological.
Genetic factors.
• Genetic alterations can occur sporadically or may be inherited.
• The types of genetic changes seen in tumouriogenes are:
• 1. Gene amplification • 2. Gene re-arrangement [e.g. translocations]• 3. Gene mutations and• 4. Deletion of specific genes.
Causes of mutation:
• Exposure to environmental genotoxic agents and stresses,
• Gene classes• 5 main classes of genes are involved in the genetic
changes underlying carcinogenesis.• i. Oncogenes• ii. Tumour suppressor genes• iii. Metastasis genes• iv. Apoptosis gene . v. DNA repair genes
ONCOGENES
• 1. ONCOGENES Cancer causing genes are
derived from proto-oncogenes.• Proto-oncogenes can exert their functions
through production of:1. Growth factors, 2. Growth factor receptors, 3. Signal tranducers and 4. Transcriptional factors.
Mechanisms of activation of Oncogenes
• a. Gene amplification – e.g. • Small cell lung cancer [L-myc]; • b. Loss of control mechanism – e.g. • Burkitt’s lymphoma [C-myc] t[8,14]; • c. Structural alteration – CML t[9,22] →
abl-bcr hybrid gene → a fusion protein.• d. Point mutation in k-ras gene –
colorectal cancer
(ii) TUMOUR SUPPRESSOR GENES [TSG]
• Their gene products are involved in the negative control of cell proliferation and differentiation,
• And their loss or inactivation is associated with carcinogenesis.
• E.g. P53, a TSG is the most common genetic alteration found in cancers.-
• Li fraumeni syndrome, Rb, BRCA, APC genes.
(iii) METASTASIS GENES:
• Ezrin- ERMS & Osteosarcoma
• Metastasis Suppressors: NM23 & KAI-1 genes.
• The loss or decreases expression of nm23 genes located on 17q 21.3 is associated with high metastatic potential
• And poor survival in breast carcinoma.
(iv) APOPTOSIS GENES:
• Bcl-2 oncogene may rescue cells from apoptosis thus potentiating cellular genetic alteration.
(v) DNA REPAIR GENES
• Mutation in DNA repair genes are known to lead to some cancers e.g.
• HNPCC[Hmsh2-(2p16) & Hmlh1-(3p21)] and lymphoid malignancies.
• Failure of DNA repair is associated with a group of autosomal recessive disorders comprising:
• Bloom syndrome, Xeroderma pigmentosum, Ataxia telangiectasia and Fanconi’s anaemia, all of which are also associated with increased predisposition to cancer.
HEREDITY AND CANCER:
• A large number of types of cancer, [5-10% or more] including the most common forms show hereditary predisposition in addition to environmental influences.
• These include:• 1. Inherited cancer syndromes (Autosomal
Dominant):• Retinoblastoma, • Li fraumeni syndrome and FAP,• All associated with TSG.
• 2. Familial cancers – evident familial clustering of cancer, but role of inherited predisposition may not be clear in each case. e.g.
• BRCA 1 and 2.
• 3. Autosomal recessive syndromes of defective DNA repair [as above]