Neoplasia

Document Sample
Neoplasia Powered By Docstoc
					         Neoplasia

Sakchai Chitpakdee, M.D.
Contents
 Introduction: Needs and Prospects for Cancer
 Control
 Epidemiology of Cancer
 Nomenclature
 Characteristics of Benign and Malignant Neoplasms
 Carcinogenesis : The Molecular Basis of Cancer
 Etiology of Cancer: Carcinogenic Agents
 Host Defense Against Tumors: Tumor Immunity
 Clinical Aspects of Neoplasia
 Laboratory Diagnosis of Cancer
 Cancer Therapy, Prevention and Control
Introduction: Needs and Prospects for
Cancer Control
 Cancer is the second leading cause of death in the
 US
 Cancer and heart disease are the major diseases
 and causes of death in old age
 Increased life expectancy and better clinical
 diagnosis has led to more cases of cancer being
 diagnosed, a proportion of which would have
 previously been missed.
 There has undoubtedly been a real increase in the
 number of people who develop cancer due to an
 increased exposure to etiological agents.
Cancer is not a modern disease
 A tumour has been reported from the tail of a dinosaur; a
 true malignant tumour? or a callous of bone?
 The femur of a homo erectus (Pithecanthropus) dating
 from 450 000 BC initially gave the appearance of a
 tumour but likely to have been myositis ossificans
 A lesion found in the calvarium of a skeleton from the
 Twentieth Dynasty of Ancient Egypt (c. 1200 BC) exhibits
 malignant destruction of the jaw, sinus and palate
 Writings from ancient India (Ayuruedic books) suggest
 that cancer was able to be diagnosed correctly over 2500
 years ago but was considered incurable. Tumours of the
 oral cavity, pharynx, oesophagus, pelvis and rectum are
 described
Global cancer burden
 In 2008, there were 12.4 million new cancer cases and
 7.6 million cancer deaths worldwide (60%)
 Lung cancer burden, in terms of incidence and mortality,
 is among the highest in the world
 More than half of cancer cases and 60% of deaths occur
 in the less-developed countries
 There are striking variations of cancer patterns by site
 from region to region
 Future cancer burden will be influenced by trends in the
 elderly population of both the less-developed and more-
 developed areas
 The role of prevention in cancer control programmes
 (tobacco control, vaccination, screening) will increase in
 the coming decades
Epidemiology of cancer
 The incidence of cancer varies with age, race,
 geographic factors, and genetic backgrounds.
  Cancers are most common at the two extremes of age.
  The geographic variation results mostly from different
 environmental exposures.
 Most cancers are sporadic, but some are familial.
 Predisposition to hereditary cancers may be autosomal
 dominant or autosomal recessive. The former are usually
 linked to inheritance of a germ-line mutation of cancer
 suppressor genes, whereas the latter are typically
 associated with inherited defects in DNA repair.
 Familial cancers tend to be bilateral and arise earlier in
 life than their sporadic counterparts.
Nomenclature
 Neoplasia = “new growth” “The development of
 neoplasms” [neo-, neos = new][+plassein = to form]

 Neoplasm = “A new and abnormal formation of tissue, as
 a tumor or growth” [+plasma = form, mold]

 Tumor = “A swelling” “neoplasm”

 Oncology = “The study of tumors” [oncos = bulk, mass]

 Benign vs. Malignant tumor = “ ไมรายแรง ” “ รายแรง หรือ มะเร็ง ”

 Cancer = Malignant neoplasm [Karnikos = crab]
Definition of Neoplasm
 Willis:

 “A neoplasm is an abnormal mass of tissue, the
 growth of which exceeds and is uncoordinated with
 that of the normal tissues and persists in the same
 excessive manner after cessation of the stimuli
 which evoked the change”
Fundamental to the origin of neoplasms
Basic components of tumors
Terminology
 Benign tumors (suffix -oma)
   Mesenchymal tissue    fibroma (fibrous), chondroma (cartilage)
   Glandular epithelium  adenoma, cystadenoma (cystic mass)
   Squamous & transitional epithelium   acanthoma, papilloma
   (finger-like fronds)


 Malignant tumors (suffix –sarcoma, -carcinoma, or prefix
 with malignant)
   Epithelium   carcinoma (general), adenocarcinoma
   (glandular),
   Mesenchymal tissue     fibrosarcoma (fibrous)
   Others    malignant lymphoma, malignant melanoma
Terminology (continued)
 Tumors with mixed component = mixed tumors
  e.g. pleomorphic adenoma (salivary gland), fibroadenoma
  (breast)

 Teratoma     totipotent stem cells (germ layers)
  Mature vs. immature teratoma


 Malignant tumors : lymphoma, melanoma, seminoma,
 hepatoma, mesothelioma

 Tumor-like mass
  Hamartoma = mass of disorganized indigenous tissue
  Choristoma (heterotopic rest) = ectopic tissue
Characteristics of Benign and Malignant
Neoplasms
Differentiation and Anaplasia
 The extent of resemblance of the parenchymal cells
 to their normal original cells morphologically and
 functionally
   Well differentiated   moderately        poorly differentiated
   Undifferentiated (lack of differentiation) = anaplasia
   Dedifferentiated (loss of differentiation)
   Benign tumors (well differentiated)
   Malignant tumors (well differentiated to anaplasia)
 Anaplastic cells: pleomorphism, hyperchromatic,
 bizarre nuclei, numerous mitoses, atypical mitosis
 Dysplasia : loss in the uniformity of cells and their
 architectural orientation (non-neoplastic)
Rate of growth and extension
 Benign tumors: slowly grow, localized, form capsule,
 not invade, and not metastasize

 Malignant tumors: fast grow, infiltrate, invade, and
 metastasize
  Poorly differentiated tumor   rapidly grow

 Metastasis = development of secondary implants
  Malignant tumors     metastasis and local invasion
  Anaplastic and large tumor     likely metastasis
  1) seeding within body cavities 2) lymphatic 3)
  hematogenous
Carcinogenesis : The molecular basis of
cancer
 Nonlethal genetic damage (mutation) lies at the
 heart of carcinogenesis

 Tumor mass : clonal expansion of a single progenitor
 cells that has incurred genetic damage
  Tumor = monoclonal

 Regulatory genes targeting for genetic damage
  Proto-oncogenes
  Tumor suppressor genes
  Genes regulating apoptosis
  Genes involving DNA repair
Alterations for malignant
transformation
 Self-sufficiency in growth signals (oncogenes)
 Insensitivity to growth-inhibitory signals (tumor
 suppressor genes)
 Evasion of apoptosis
 Limitless replicative potential
 Sustained angiogenesis
 Ability of invade and metastasis
 Defects in DNA repair (mutator phenotype)
 Escape from immune attack
Self-sufficiency in Growth signals
Oncogenes
 Oncogenes can promote uncontrolled cell proliferation by
 several mechanisms:
 Stimulus-independent expression of growth factor and its
 receptor, setting up an autocrine loop of cell proliferation
   PDGF-PDGF-receptor in brain tumors
 Mutations in genes encoding growth factor receptors,
 leading to overexpression or constitutive signaling by the
 receptor (e.g., EGF receptors)
   EGF-receptor family members, including HER2/NEU (breast,
   lung, and other tumors)
 Mutations in genes encoding signaling molecules
   RAS mutations (15-20% of all tumors)
   Fusion of ABL tyrosine kinase with BCR protein in certain
   leukemias generates a hybrid protein with constitutive kinase
   activity
Oncogenes
 Overproduction or unregulated activity of transcription
 factors
   Translocation of MYC in some lymphomas leads to
   overexpression and unregulated expression of its target genes
   controlling cell cycling and survival
 Mutations that activate cyclin genes or inactivate normal
 regulators of cyclins and cyclin-dependent kinases
   Complexes of cyclins with cyclin-dependent kinases (CDKs)
   drive the cell cycle by phosphorylating various substrates
   CDKs are controlled by inhibitors;
   Mutations in genes encoding cyclins, CDKs, and CDK inhibitors
   result in uncontrolled cell cycle progression
   Such mutations are found in wide variety of cancers including
   melanomas, brain, lung, and pancreatic cancer.
Insensitivity to Growth-Inhibitory Signals
 Tumor suppressor genes encode proteins that inhibit
 cellular proliferation by regulating the cell cycle.
 Both copies of the gene must be lost for tumor
 development, leading to loss of heterozygosity
 (LOH) at the gene locus.
 In cases with familial predisposition to develop
 tumors, the affected individuals inherit one defective
 (nonfunctional) copy of a tumor suppressor gene and
 lose the second one through somatic mutation.
 In sporadic cases both copies are lost through
 somatic mutations.
Insensitivity to Growth-Inhibitory Signals
 RB Gene and Cell Cycle
   RB exerts antiproliferative effects by controlling the G1-to-
   S transition of the cell cycle.
   In its active form RB is hypophosphorylated and binds to
   E2F transcription factor. This interaction prevents
   transcription of genes like cyclin E that are needed for
   DNA replication, and so the cells are arrested in G1.
   Growth factor signaling leads to cyclin D expression,
   activation of the cyclin D-CDK4/6 complexes, inactivation
   of RB by phosphorylation, and thus release of E2F.
   Almost all cancers will have disabled the G1 checkpoint,
   by mutation of either RB or genes that affect RB function,
   like cyclin D, CDK4, and CDKIs.
   Many oncogenic DNA viruses, like HPV, encode proteins
   (e.g., E7) that bind to RB and render it nonfunctional.
Insensitivity to Growth-Inhibitory Signals
 p53 Gene: Guardian of the Genome
   p53 is the central monitor of stress in the cell and can be
   activated by anoxia, inappropriate oncogene signaling, or
   DNA damage.
   Activated p53 controls the expression and activity of
   genes involved in cell cycle arrest, DNA repair, cellular
   senescence, and apoptosis.
   DNA damage leads to activation of p53 by
   phosphorylation.
   Activated p53 drives transcription of CDKN1A (p21) that
   prevents RB phosphorylation and therefore causes a G1-
   S block in the cell cycle. This pause allows the cells to
   repair DNA damage.
Insensitivity to Growth-Inhibitory Signals
 p53 Gene: Guardian of the Genome (continued)
   If DNA damage cannot be repaired, p53 induces cellular
   senescence or apoptosis.
   Of human tumors, 70% have homozygous loss of p53.
   Patients with the rare Li-Fraumeni syndrome inherit one
   defective copy in the germ line and lose the second one
   in somatic tissues; such individuals develop a variety of
   tumors.
   As with RB, p53 can be incapacitated by binding to
   proteins encoded by oncogenic DNA viruses like HPV
   (E6), and possibly EBV and HBV.
Evasion of Apoptosis
 Apoptosis can be initiated through the extrinsic or
 intrinsic pathways.
 Both pathways result in the activation of a proteolytic
 cascade of caspases that destroys the cell.
 Mitochondrial outer membrane permeabilization is
 regulated by the balance between pro-apoptotic (e.g.,
 BAX, BAK) and anti-apoptotic molecules (BCL2, BCL-
 XL).
 BH-3-only molecules activate apoptosis by tilting the
 balance in favor of the pro-apoptotic molecules.
 In 85% of follicular B-cell lymphomas the anti-apoptotic
 gene BCL2 is activated by the t(8;14) translocation.
Limitless Replicative Potential
 In normal cells, which lack expression of telomerase,
 the shortened telomeres generated by cell division
 eventually activate cell cycle checkpoints, leading to
 senescence and placing a limit on the number of
 divisions a cell may undergo.
 In cells that have disabled checkpoints, DNA repair
 pathways are inappropriately activated by shortened
 telomeres, leading to massive chromosomal
 instability and mitotic crisis.
 Tumor cells reactivate telomerase, thus staving off
 mitotic catastrophe and achieving immortality.
Development of Sustained Angiogenesis
 Vascularization of tumors is essential for their growth
 and is controlled by the balance between angiogenic
 and anti-angiogenic factors that are produced by
 tumor and stromal cells.
 Hypoxia triggers angiogenesis through the actions of
 HIF1α.
 Because of its ability to degrade HIF1α and thus
 prevent angiogenesis, VHL acts as a tumor
 suppressor gene.
 Many other factors regulate angiogenesis; for
 example, p53 induces synthesis of the angiogenesis
 inhibitor thrombospondin-1.
Ability to Invade and Metastasize
 Ability to invade tissues, a hallmark of malignancy,
 occurs in four steps: loosening of cell-cell contacts,
 degradation of ECM, attachment to novel ECM
 components, and migration of tumor cells.
 Cell-cell contacts are lost by the inactivation of E-
 cadherin through a variety of pathways.
 Basement membranes and interstitial matrix degradation
 is mediated by proteolytic enzymes secreted by tumor
 cells and stromal cells, such as MMPs and cathepsins.
 Proteolytic enzymes also release growth factors
 sequestered in the ECM and generate chemotactic and
 angiogenic fragments from cleavage of ECM
 glycoproteins.
Ability to Invade and Metastasize
 The metastatic site of many tumors can be predicted
 by the location of the primary tumor.
 Many tumors arrest in the first capillary bed they
 encounter (lung and liver, most commonly).
 Some tumors show organ tropism, probably due to
 expression of adhesion or chemokine receptors
 whose ligands are expressed by the metastatic site.
Genomic Instability –Enabler of Malignancy
 Individuals with inherited mutations of genes
 involved in DNA repair systems are at a greatly
 increased risk of developing cancer.
 Patients with HNPCC syndrome have defects in the
 mismatch repair system and develop carcinomas of
 the colon. These patients show microsatellite
 instability (MSI), in which short repeats throughout
 the genome change in length.
 Patients with xeroderma pigmentosum have a defect
 in the nucleotide excision repair pathway and are at
 increased risk for the development of cancers of the
 skin exposed to UV light, because of an inability to
 repair pyrimidine dimers.
Genomic Instability –Enabler of Malignancy
 Syndromes involving defects in the homologous
 recombination DNA repair system compose a group
 of disorders (Bloom syndrome, ataxia-telangiectasia,
 and Fanconi anemia) that are characterized by
 hypersensitivity to DNA-damaging agents, such as
 ionizing radiation.
 BRCA1 and BRCA2, which are mutated in familial
 breast cancers, are involved in DNA repair.
Molecular Basis of Multistep Carcinogenesis
Karyotypic changes in Tumors
 Tumor cells may develop a variety of nonrandom
 chromosomal abnormalities; these include balanced
 translocations, deletions, and gene amplification.
 Balanced translocations contribute to carcinogenesis by
 overexpression of oncogenes or generation of novel
 fusion proteins with altered signaling capacity.
 Deletions frequently affect tumor suppressor genes,
 whereas gene amplification increases the expression of
 oncogenes.
 Tumor suppressor genes and DNA repair genes may
 also be silenced by epigenetic changes, which involve
 reversible, heritable changes in gene expression that
 occur, not by mutation, but by methylation of the
 promoter.
miRNA and cancers
 miRNA = small noncoding SS-RNAs, approximately
 22 nucleotides in length, incorporated into the RNA-
 induced silencing complex (post-transscriptional
 gene silencing)
 Control cell growth, differentiation, and cell survival
 Changes in expression in cancer cells: amplication
 and deletion of miRNA loci
 Target gene if oncogene       miRNA act as TS genes;
 if TS genes     miRNA act as oncogene
 miRNA profiling     classification of tumor
Etiology of Cancer: Carcinogenic Agents
Chemical carcinogens
 Chemical carcinogens have highly reactive
 eletrophile groups that directly damage DNA, leading
 to mutations and eventually cancer.
 Direct-acting agents do not require metabolic
 conversion to become carcinogenic
 Indirect-acting agents are not active until converted
 to an ultimate carcinogen by endogenous metabolic
 pathways.
 Polymorphisms of endogenous enzymes like
 cytochrome P-450 may influence carcinogenesis.
Chemical carcinogens
 Following exposure of a cell to a mutagen or an
 initiator, tumorigenesis can be enhanced by
 exposure to promoters, which stimulate proliferation
 of the mutated cells.
 Examples of human carcinogens include direct-
 acting (e.g., alkylating agents used for
 chemotherapy), indirect-acting (e.g., benzopyrene,
 azo dyes, and aflatoxin), and promoters/agents that
 cause pathologic hyperplasias of liver, endometrium.
Radiation Carcinogenesis
 Ionizing radiation causes chromosome breakage,
 translocations, and, less frequently, point mutations,
 leading to genetic damage and carcinogenesis.
 UV rays induce the formation of pyrimidine dimers
 within DNA, leading to mutations.
 Therefore UV rays can give rise to squamous cell
 carcinomas, basal cell carcinoma and melanomas of
 the skin.
Oncogenic Viruses
 HTLV-1 causes a T-cell leukemia that is endemic in
 Japan and the Caribbean.
 HPV has been associated with benign warts, as well
 as cervical cancer.
 The oncogenic ability of HPV is related to the
 expression of two viral oncoproteins, E6 and E7;
 they bind to p53 and RB, respectively, neutralizing
 their function; they also activate cyclins.
 E6 and E7 from high-risk HPV (that give rise to
 cancers) have higher affinity for their targets than E6
 and E7 from low-risk HPV (that give rise to low-grade
 tumors).
Oncogenic Viruses
 EBV has been implicated in the pathogenesis of Burkitt
 lymphomas, lymphomas in immunosuppressed
 individuals with HIV infection or organ transplantation,
 some forms of Hodgkin lymphoma, and nasopharyngeal
 carcinoma. All except the nasopharyngeal cancers are B-
 cell tumors.
 Certain EBV gene products contribute to oncogenesis by
 stimulating a normal B-cell proliferation pathway.
 Concomitant compromise of immune competence allows
 sustained B-cell proliferation and eventually development
 of lymphoma with occurrence of additional mutations
 such as t(8 ; 14), leading to activation of the MYC gene.
 KSHV/HHV-8 is associated with Kaposi’s sarcoma
Hepatitis B and Hepatitis C Viruses
 Between 70% and 85% of hepatocellular carcinomas
 worldwide are due to infection with HBV or HCV.
 The oncogenic effects of HBV and HCV are
 multifactorial, but the dominant effect seems to be
 immunologically mediated chronic inflammation,
 hepatocellular injury, stimulation of hepatocyte
 proliferation, and production of reactive oxygen
 species that can damage DNA.
 The HBx protein of HBV and the HCV core protein
 can activate a variety of signal transduction
 pathways that may also contribute to carcinogenesis.
Helicobacter pylori (H. pylori)
 H. pylori infection has been implicated in both gastric
 adenocarcinoma and MALT lymphoma.
 The mechanism of H. pylori-induced gastric cancers
 is multifactorial, including immunologically mediated
 chronic inflammation, stimulation of gastric cell
 proliferation, and production of reactive oxygen
 species that damage DNA.
 It is thought that H. pylori infection leads to
 polyclonal B-cell proliferations and that eventually a
 monoclonal B-cell tumor (MALT lymphoma) emerges
 as a result of accumulation of mutations.
Host defense against tumors
 Tumor antigens
  Tumor-specific antigens: only present on tumor cells
  Tumor-associated antigens: present on both tumor and
  normals cells
 Main classes of tumor antigens:
  Products of mutated oncogenes and tumor suppressor
  genes
  Products of other mutated genes
  Overexpressed or aberrantly expressed cellular proteins
  Tumor antigens produced by oncogenic viruses
  Oncofetal antogens: CEA, alpha-fetoprotein
  Altered cell surface glycolipids and glycoproteins: CA-
  125, CA19-9
Cell Type-Specific Differentiation antigens
 Specific for particular lineages or differentiation
 stages of various cell types
 Potential targets for immunotherapy and for
 identifying the tissue of origin if tumors
 (immunohistochemistry)
 CD10 and CD20 are surface markers for B-cell-
 derived tumors, antibodies against CD20 are used
 for B-cell lymphoma chemotherapy
 Example of cellular marker for tumors: CD3 (T-cell),
 CD20 (B-cell), cytokeratin (carcinoma), HMB-45
 (melanoma), CD31 (endothelium), desmin (muscle)
Immune surveillence
 Tumor cells can be recognized by the immune system as
 non-self and destroyed.
 Antitumor activity is mediated by predominantly cell-
 mediated mechanisms.
 Tumor antigens are presented on the cell surface by
 MHC class I molecules and are recognized by CD8+
 CTLs.
 The different classes of tumor antigens include products
 of mutated proto-oncogenes, tumor suppressor genes,
 overexpressed or aberrantly expressed proteins, tumor
 antigens produced by oncogenic viruses, oncofetal
 antigens, altered glycolipids and glycoproteins, and cell
 type-specific differentiation antigens.
Immune Surveillance
 Immunosuppressed patients have an increased risk
 of cancer.
 In immunocompetent patients, tumors may avoid the
 immune system by several mechanisms, including
  selective outgrowth of antigen-negative variants,
  loss or reduced expression of histocompatibility antigens,
  and
  immunosuppression mediated by secretion of factors
  (e.g., TGF-β) from the tumor.
Clinical aspects of neoplasia
 Location and impingment on adjacent structures
 Functional activity such as hormone synthesis or the
 development of paraneoplastic syndromes
 Bleeding and infections when the tumor ulcerates
 through adjacent surfaces
 Symptoms that result from ruptured or infarction
 Cachexia or wasting
Clinical aspects of tumors
 Cachexia, defined by progressive loss of body fat
 and lean body mass, accompanied by profound
 weakness, anorexia, and anemia, is caused by
 release of cytokines (IL-1, TNF) by the tumor or host.
 Paraneoplastic syndromes, defined by systemic
 symptoms that cannot be explained by tumor spread
 or by hormones appropriate to the tissue, are caused
 by the ectopic production and secretion of bioactive
 substances, such as ACTH, PTHrP, or TGF-α.
Grading and Staging
 Grading of tumors is determined by cytologic
 appearance and is based on the idea that behavior
 and differentiation are related, with poorly
 differentiated tumors having more aggressive
 behavior. (Grade I-IV; high- or low-grade)
 Staging, determined by surgical exploration or
 imaging, is based on size, local and regional lymph
 node spread, and distant metastases. Staging has
 greater clinical value than grading.
  AJC (American Joint Committee): Stage I-IV
  TNM (T = primary tumor; N = regional lymph nodes; M =
  metastases)
Laboratory Diagnosis of cancers:
Morphological methods
 Histology of tissue
  Tissue biopsy: Incisional biopsy and Excisional biopsy
  Tissue processes : Frozen and paraffin section
  Tumor classification and grading : WHO classification
  (WHO blue books): morphology code (ICD-O)
 Cytology of smear or fluid
  Fine-needle aspirations: breast, thyroid, lymph nodes,
  salivary glands
  Exfoliative specimens:
    Papanicolaou (PAP) smear: cervicovaginal smear
    Body fluid: ascites, pleural effusion
Tumor markers
 Immunohistochemistry and flow cytometry help in the
 diagnosis and classification of tumors, because
 distinct protein expression patterns define different
 entities.
 Proteins released by tumors into the serum, such as
 PSA, can be used to screen populations for cancer
 and to monitor recurrence following treatment.
Molecular Diagnosis
 Molecular analyses are used to determine diagnosis,
 prognosis, the detection of minimal residual disease,
 and the diagnosis of hereditary predisposition to
 cancer.
 Molecular profiling of tumors by cDNA arrays can
 determine expression of large segments of the
 genome at once and can be useful in molecular
 stratification of otherwise identical tumors for the
 purpose of treatment and prognostication.
Principles of cancer therapy
 Surgery
 Chemotherapy
 Radiotherapy
 Supportive and
 palliative care
Medical Oncology
 There are 20–30 cytotoxic drugs commonly used in the
 treatment of malignant disease
 These drugs are often administered in combination, using
 multiple mechanisms to induce cancer cell death
 Cytotoxic drugs can be associated with a range of side
 effects (neutropenia, oral ulceration, diarrhoea, hair loss,
 and nerve and kidney damage)
 Chemotherapy has significantly improved survival of
 breast, colorectal, testicular and ovarian cancer, sarcoma
 and a range of haematological malignancies
 Molecular biological insights have given us a range of
 new targets based on growth factors and their receptors
 which have already begun to yield new drugs
Cancer Prevention and Control
 Surveillance
 Primary prevention
 Secondary prevention
 Diagnosis and
 treatment
 Palliative care
References
 World Cancer Report 2008 : WHO IARC
 Hospital-based Cancer Registry 2007: National
 Cancer Institute, Thailand
 Robbins Basic Pathology, 8th edition

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:10
posted:10/14/2012
language:English
pages:106