CARCINOGENESIS1. Cell Rest Theory of Conheim – during development of an individual, some embryonic cells did not develop into mature cells. They become activated later on, grow rapidly into cancer.2. Clone Theory – single cell has become abnormal and become the starting point of the tumor.3. Group of Cell Theory – several cells become abnormal and become cancer cells.4. Irritation Theory – some cells are damaged and become cancer cells.5. Microbial Theory – begin to grow because of microorganisms , i.e., Epstein Barr Virus (EPV) and Ewing’s sarcoma
1. Molecular Basis of Tumor• Nonlethal genetic damage lies at the core of carcinogenesis• Four classes of regulatory genes, protooncogene, cancer suppressor gene, regulated apoptosis gene, and DNA repair gene, are the principal targets of genetic damage.• Carcinogenesis is a multistep process at both the phenotypic and genetic levels.
(1) Oncogenes and cancer① Protein products of oncogenesa. Growth factorsb. Growth factors receptorsc. Signal transducing proteinsd. Nuclear transcription proteinse. Cyclones and cyclic-dependent kinases
② Activation of oncogenesa. Point mutationsb. Chromosome rearrangements Translocations Inversionsc. Amplification
(Quoted from Robbins 《 Pathology Basis ofdisease 》 )
Table Selected oncogenes their mode of activation and associated human tumors Category Protooncogene Mechanism Associated Human TumorGrowth Factors Sis Overexpression AstrocytomaPDGF-β chain Osteosarcoma Hst-1 Overexpression Stomach cancerFibroblast growth factors Int-2 Amplification Bladder cancer Breast cancer Melanoma
(2) Cancer suppressor genes ① Molecules that regulated nuclear transcription and cell cycleRb gene: 13q14, G1 × SP53 gene: 17p13.1, related to 50% of human tumorsBRCA- l gene: 17q12-21,BRCA-2 gene: 13q12-13
Molecules that regulated signal transduction NF-1 gene: 17q11.2 APC gene: 5q21
(4) Genes that regulate DNA repair Humans literally swim in a sea of environmental carcinogens. Although exposure to naturally occurring DNA- damaging agents, such as ionizing radiation, sunlight, and dietary carcinogens, is common, cancer is a relatively rare outcome of such encounters.
This happy state of affairs results fromthe ability of normal cells to repair DNA damagesand thus prevent mutations in genes thatregulate cell growth and apoptosis. In addition to possible DNA damagefrom environmental agents, the DNA of normaldividing cells is also susceptible to alterationsresulting from errors that occur spontaneouslyduring DNA replication. Such mistakes, if not repaired promptly,can also push the cells along the slippery slopeof neoplastic transformation.
The importance of DNA repair inmaintaining the integrity of the genome ishighlighted by several inherited disordersin which genes that encode proteinsinvolved in DNA repair are defective. Those born with such inheritedmutations of DNA repair proteins are at agreatly increased risk of developingcancer. Several examples are discussednext.
(5) Telomere and tumortelomerase activity increasedin majority of human tumors.
2. Carcinogenic agentsA large number of agents cause geneticdamage and inchece neoplastictransformation of cells(1) Chemical carcinogens Chemical carcinogenesis is also amultistep process.
① Initiation of carcinogenesis Chemical carcinogens are diverse in structure,but they fall into one of two categories:a. Direct-acting chemical carcinogenes b. Indirect-acting chemical carcinogens(procarcinogenes), Which require metabolic conversion in vivo toproduce. Ultimate carcinogens capable of transformingcells. HP Solution Center.lnk
Both of them are highly reactiveelectrophiles that can react withnucleophilic (electron-rich) sites in thecells. These reactions are nonenzymatic andresult in the formation of covalentadducts between the chemicalcarcinogen and nucleotide in DNA.
The carcinogenic potency of a chemicalis determined not only by the inherentreactivity of its electrophilic derivative,but also by the balance betweenmetabolic activation and inactivationreactions. If initiation occurs, carcinogen-alteredcells could be heritable.
② Promotion of carcinogenesis Promoters earn induce tumors in initiated cells, but they are nontumorigenic by them selves. Prompters render cells susceptible to additional mutations by causing cellular proliferation.
CARCINOGEN Metabolic activation Excretion Electrophilic intermediates DNA INITIATION repair Binding to DNA: Normal cell Adduct formation Cell death Permanent DNA lesion: Initiated cell Cell proliferaion: Altered differentiationPROMOTION PRENEOPLASTIC CLONE Additional mutations Proliferation MALIGNANT NEOPLASM (Quoted from Robbins 《 Pathology Basis of disease 》 )
STAGES OF CANCER1. First Stage – intraepithelial, primary, carcinoma-in-situ2. Second Stage – infiltrative, invasive, beyond the basement membrane3. Third Stage – metastasis present, with secondary growth
Nomenclature• Although parenchymal cells determine their nature, the growth and evolution of neoplasms are critically dependent on their stroma.• Sometimes the parenchymal cells stimulate the formation of an abundant collagenous stroma referred to as desmoplasia.• Papillomas are benign epitjelial neoplasms producing visible warty projections• Syringomas are tumors of sweat glands• Trichoepithelioma are tumors arising from hair follicles• Hemartoma is a disorganized, benign tumor-like nodule that contains differentiated cells and one cell type often predominates• Carcinoma-in-situ is an epithelial tumor that has not yet penetrated the basement membrane and thus has no current chance of metastasis• Choristoma is the presence of normal tissue in an abnormal location• Hidradenomas are tumors arising from the vulva.
Basic Components of TumorThere are 2 basic components of a tumor:1. Parenchyma – made up of proliferating neoplastic cells. It is the component from which the tumor derives its name. It determines the biologic behavior of the tumor.2. Stroma – is the supporting tissue of the tumor made u of CT, blood vessels and possibly lymphatics.
Choristoma• An ectopic rest of normal tissue is called a choristoma.• Example is a rest of adrenal cells under the kidney capsule• Analogously, aberrant differentiation may produce a mass of disorganized mature specialized cells or tissue indigenous to the particular site, referred to as hamartoma.• Types are: Salivary gland chorsitoma, cartilaginous choristoma,oral osseous choristoma, lingual thyroid choristoma, lingual sebaceous chorsitoma, and glial choristoma
HAMARTOMA• Hamartoma is a developmental abnormality, tumor-like but non- neoplastic malformation consisting of a mixture of tissues normally found at a particular site.• The commonest forms are those composed of blood vessels and those involving cells of the skin.
Fibroma• A benign neoplasm arising from fibroblast• The tumor is discrete, encapsulated, spherical ovoid nodules; about 15-20 cm particularly in the ovary, CT sheaths of nerves, and of muscles• They are soft, rubbery, pliable masses.• They occur at any age, the cut surface discloses a firm, white glistening surface• Microscopically, typical spindle cell fibrocytes and fibroblasts are present.• Scant to large amounts of collages are found between the fibroblasts
Leiomyoma• Also called “myoma” or “fibroid”.• Tumor is composed on intertwining bundles of smooth muscle cells that more or less resemble of uninvolved myometrium.• They are sharply circumscribed, unencapsulated but discrete, firm, gray-white masses with a characteristic whorled appearance on cut surface.• This tumor may have an increase of the CT with dense hyalinization of the stroma
Types of Nevus• Intradermal nevus – is the common, flat or elevated type composed of sheets of nevus cells, many of which contain melanin pigment.• Compound nevus – exhibit features of both the intradermal and junctional nevus• Blue nevus – is a smooth blue to blue-black lesion located in the CT and composed of spindle-shaped melanoblasts.• Juvenile nevus – found in children that is histologically similar to malignant melanoma but is clinically benign• Junctional nevus – appears to be dropping off from the overlying epithelium. It is of particular clinical significance, since it may undergo malignant transformation to malignant melanoma.
Adenoma• Adenoma is the term applied to the benign epithelial neoplasm that forms glandular patterns• Cystadenoma- those that form large cystic masses in the ovary• Papillary cystadenoma – protrude into cystic spaces• Papilloma – finger-like or warty projections from epithelial surfaces• Desmoplasia – result when parenchymal cells stimulate the formation of an abundant stroma.
QuestionA tumor composed of tissuesrepresenting all three embryonic germlayers commonly seen either in theovary or in the testis is called A. adenocarcinoma B. choristoma C. hamartoma D. teratoma E. mixed mesodermal tumor
ADENOMATOUS POLYPS COLIAPC is an inherited disorder characterized by the development of myriad polyps in the colon beginning in late adolescence or early childhood.If untreated, the condition may lead to colon cancer.The gene is located on chromosome 5.
HODGKIN’S LYMPHOMA • Also called benign lymphoblastoma • Affects the lymph nodes, spleen, liver and bone marrow • Diagnostic feature in the RS giant cell (Reed-Sternberg giant cell)
Question• On Southern Blot examination the DNA of a malignant tumor is found to have a clonal immunoglobulin gene rearrangement. From what type of cell is the tumor derived? A. fibroblast B. T lymphocyte C. squamous epithelial cell D. smooth muscle cell E. B lymphocyte
FIBROADENOMA - FEMALE BREAST Fibroadenoma is the most coomon benign Tumor of the breast. It developed as a result of increased sensitivity to estrogen. Types of fibroadenoma: 1. Intracanalicular fibroadenoma – the proliferating comonents into the parenchymal channels are large polysoid masses 2. Pericanalicular fibroadenoma – the proliferating components are both the epithelium and CT stroma. Varieties of fibroadenocarcinoma: 1. Scirrhous and medullary carcinomas 2. Adenocarcinomas 3. Intraductal carcinomas 4. Paget’s disease of the nipple
Giant cell Tumor or Osteoclastoma or Codmon’s Tumor• This is a tumor of the epiphyses of long bones• Males and females are equally affected.• It involves the proximal tibia, distal femur and distal radius.• It consists of destruction and replacement of original bone matrix• Extensive production of new bone trabeculae• Filling of all cancellous bone spaces with proliferating bone forming tumor cells.• It recur after curettage.
Clinical Differences Between Benign and Malignant NeoplasmsGrow slowly Grow rapidlyExpansive growth Invasive growthUsually encapsulated Not capsulatedDo not recur after careful Recur after removalremovalDo not metastasize Often metastasizeDo not kill unless they Do killcompress vital organsRarely show metastasis Often show necrosis and ulcerationNo cachexia Cachexia and anemia
Histological Differences between Benign and Malignant Neoplasms Benign MalignantConsist of well-differentiated cells Consist of poorly-differentiated anaplastic cellsCells are rather uniform in size and Pleomorphism of cellsshapeNuclei take up stain normally Hyperchromatic nucleiFew mitosis Numerous multipolar mitosisCells do not infiltrate Cells do infiltrateFairly good imitation of the Unsuccessful imitation of thearrangement of the tissue from tissue of the originwhich they are derived
Differences Between Carcinoma and SarcomaPoints of Differences Carcinoma SarcomaCell origin Epithelial MesenchymalCellular arrangement Alveolar or glandular SinglySize Less in size MoreBlood vessels Less MoreHemorrhages Less MoreNecrosis Less MoreAge incidence Older (may also occur in the Younger (may also affect young) the older)Mode of metastases Commonly through the Commonly through the lymphatics blood but may also involve the lymphaticsSite of first metastasis Regional lymph nodes Lungs
ROUTES OF METASTASIS• LOCAL INVASION• LYMPHATIC SPREAD• BLOOD OR HEMATOGENOUS SPREAD• TRANSCOELOMIC SPREAD• PERINEURAL SPREAD• INTRAEPITHELIAL SPREAD
Pathways of Spread (Metastasis)• Direct seeding of body cavities – most often involve the peritoneal cavity• Transplantation – refers to the mechanical transport of tumor fragments by instruments of gloved hands during surgical procedures.• Lymphatic spread – is the transport through the lymphatics and it is the most common pathway for the initial dissemination of carcinomas but sarcomas may also use these routes.• Hematogenous spread – this pathway is typical with sarcomas but may also found in carcinomas.
Mechanisms of Cancer Invasiveness• Physical pressure• Reduced adhesiveness and cohesiveness of tumor cells• Increased motility of tumor cells• Loss of contact inhibition• Release of destructive enzymes• Reduced immune response inducing inflammatory reaction
SCC or Epidermoid carcinoma• Account for 90% of all malignant oral tumors• Arise at any site normally covered by stratified squamous epithelium – skin, mouth, esophagus• Develop following conditions like leukoplakia, senile keratosis, arsenic keratosis, burns, scar or foci of radiodermatitis• Two Macroscopic types: 1. Papillary or exophytic types- appears as a warty outgrowth with an infiltrating base 2. Nodular or endophytic types – produces a hard, nodular mass beneath the surface and shows more raid infiltration and dissemination
MULTIPLE MYELOMA• Multiple myeloma is a malignant neoplasm of the bone marrow. The tumor, composed of plasma cells destroys osseous tissue, especially in flat bones, causing pain, fractures, hypercalcemia and skeletal deformities.• Characteristically, there is hyperglobulinemia, Bence Jones proteinuria, anemia, weight loss, pulmonary complications secondary to rib fractures and kidney failures are present.
Bone Lesions in MM• The tumor cells produce lytic lesions in bone, especially in the skull and axial skeleton,• Bone lesions: - appear lucent on X-ray exam, with characteristic sharp borders, referred to as punched out lesions - diffuse demineralization of bone (osteopenia) - severe bone pain and spontaneous fractures
Ameloblastoma• A highly destructive, malignant, rapidly growing tumor of the jaw.• Also called adamantinoma.• The histologic pattern is quite variable and recapitulates the enamel organ of the tooth.• Microscopically, nests or cords of stratified squamous or columnar epithelium are embedded in a loose fibrous stroma.
Arrhenoblastoma• An ovarian neoplasm whose cells mimic those in testicular tubules and secrete male sex hormome, causing virilization in females.• Also called andreoblastoma or Sertoli- Leydig cell tumor
TNM• GRADING of cancer is a system for describing the size and extent of spread of a malignant tumor, used to plan treatment and predict prognosis.• T is used to represent the tumor size• N denotes the regional lymph node involvement• M indicates distant metastases• Numeric subscripts-in each category indicates the degree of dissemination
TNM• T1N0M0 - is a small, localized tumor• T2N1M0 - is larger primary tumor that has extended to regional nodes• T4N3M3 – is a very large lesion involving regional nodes and distant sites