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Title: NEOPLASIA


1
NEOPLASIA
Core Pathology
Spencer B. Gilbert, M.D.
2
OBJECTIVES
  • To understand and study
  • General Aspects of Neoplasia
  • Properties of Cancer Cells
  • Clinical Aspects of Neoplasia
  • Carcinogenic Agents and Pathogeneses

Reading assignment Robbins Pathologic Basis of
Disease, Chapter 8
3
GENERAL ASPECTS Definitions
  • Neoplasm ( new growth ) - Two related
    definitions
  • A mass of tissue that results from irreversible
    and inheritable transformation in a somatic cell
    or cells leading to their uncontrolled
    proliferation. The resulting neoplastic tissue is
    purposeless, preys on the host, and to some
    extent is autonomous.

4
GENERAL ASPECTS Definitions (continued)
  • Neoplasm ( new growth ) - (continued)
  • 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 caused the change. -- Rupert Willis

5
GENERAL ASPECTS Definitions (continued)
  • Neoplasia - The disease process that results from
    neoplasms. ( benign or malignant )
  • Cancer - the disease produced by malignant
    neoplasms.

6
GENERAL ASPECTS Definitions (continued)
  • Tumor - literally means any mass or swelling. At
    present this is mostly used to mean malignant or
    benign neoplastic growths. In the old ( clinical
    ) definition, an abscess or a hematoma, or a
    non-neoplastic growth are also referred to as
    tumors.

7
Nomenclature
  • All tumors, benign or malignant, have two basic
    components
  • parenchyma - the proliferating neoplastic
    cells
  • supportive stroma - connective tissue and
    blood vessels
  • desmoplasia - abundant collagenous stroma
  • scirrhous - dense, fibrous stroma stony hard

8
Nomenclature and Classification of Neoplasms
(continued)
  • The cell type or tissue of origin is used to name
    the tumor. Examples of cell or tissue types
  • Epithelial Cells
  • squamous epithelium ( squamous cell )
  • glandular epithelium ( adeno )
  • transitional epithelium ( transitional cell )

9
Nomenclature and Classification of Neoplasms
(continued)
  • Examples of cell or tissue types (continued)
  • Mesenchymal Cells
  • fibroblast ( fibro )
  • muscle
  • (1) skeletal ( rhabdomyo )
  • (2) smooth ( leiomyo )
  • fat cell ( lipo )

10
Nomenclature and Classification of Neoplasms
(continued)
  • Examples of cell or tissue types (continued)
  • Mesenchymal Cells
  • cartilage (chondro)
  • bone (osteo)
  • endothelium (hemangiopericytoma)
  • vascular (angio)
  • lymphatic (lymphangio)

11
Benign tumors
  • In general, benign tumors have the suffix -oma to
    the cell of origin.
  • Fibroma - from fibroblastic cells
  • Chondroma - from cartilage
  • Osteoma - from bone

12
Benign tumors
  • Tumors may also be classified because of their
    microscopic architecture or macroscopic patterns.
  • Adenoma - glandular pattern
  • Papillomas - finger-like projections (fig. 8-1)
  • Cystadenomas - cystic masses
  • Papillary cystadenoma - papillary patterns that
    protrude into cystic spaces
  • Polyp -projection above a mucosal surface
    (fig. 8-2)

13
Benign tumorPapilloma of the colon
14
Benign tumors
  • Tumors may also be classified because of their
    microscopic architecture or macroscopic patterns.
  • Adenoma - glandular pattern
  • Papillomas - finger-like projections (fig. 8-1)
  • Cystadenomas - cystic masses
  • Papillary cystadenoma - papillary patterns that
    protrude into cystic spaces
  • Polyp -projection above a mucosal surface
    (fig. 8-2)

15
Benign tumorColonic polyp Adenoma. Gross
16
Benign tumorColonic polyp Adenoma. Micro
17
Benign Tumors
  • Gross Appearance
  • Benign tumors are usually surrounded by a fibrous
    capsule, otherwise they have well-defined smooth
    margins.
  • Benign Micro
  • Benign tumors - all are well differentiated.
    Their parenchymal cell component resemble closely
    the normal cell in morphology and function.

18
Malignant tumors
  • Malignant tumors that arise from mesenchymal
    tissue are usually called sarcomas
  • fibrosarcoma - fibrous tissue
  • liposarcoma - fat tissue
  • leiomyosarcoma - smooth muscle
  • rhabdomyosarcoma - striated muscle

19
Malignant tumors
  • Malignant tumors that arise from epithelial cell
    origin (three germ layers) are called carcinomas
  • Adenocarcinomas - glandular origin
  • Squamous cell carcinomas - from epithelium

20
Malignant Tumors
  • Gross Appearance
  • Malignant tumors, most of the time, do not have
    capsules. Their tumor margins are irregular due
    to "fingers" of malignant cells growing into
    adjacent normal tissue. Hemorrhage, necrosis,
    and ulceration are usually present.

21
Malignant Tumors (continued)
  • Malignant Micro
  • Nuclear Changes
  • Enlargement - increased nucleocytoplasmic ratio
    (NC ratio)
  • Hyperchromasia - darkly staining due to increased
    DNA content
  • Coarsely clumped chromatin
  • Nucleoli are prominent, may be multiple
  • Increased number of mitoses (not always present)
  • Abnormal mitotic forms (tripolar, quadripolar)

22
Malignant Tumors (continued)
  • Malignant Micro
  • Pleomorphism - variation in size and shape of the
    cells and nuclei.
  • Formation of tumor giant cells

23
Benign or Malignant Tumors
  • Mixed tumor (pleomorphic adenoma) - tumor
    contains epithelial components scattered within a
    myxoid stroma (fig 8-3)
  • Teratoma - contains parenchymal cells of all 3
    germ layers (hair, sebaceous glands, a tooth,
    etc.) (fig. 8-4)

24
Benign tumorMixed tumor, parotid gland
25
Benign or Malignant Tumors
  • Mixed tumor (pleomorphic adenoma) - tumor
    contains epithelial components scattered within a
    myxoid stroma (fig 8-3)
  • Teratoma - contains parenchymal cells of all 3
    germ layers (hair, sebaceous glands, a tooth,
    etc.) (fig. 8-4)

26
Benign tumorCystic teratoma (dermoid cyst),
ovary. Gross
27
Benign tumorCystic teratoma (dermoid cyst),
ovary. Micro
28
Other Tumors
  • Non-Neoplastic growths that produce tumor-like
    lesions
  • Hamartoma - ( coined from the Greek words
    meaning error and tumor ) an overgrowth of mature
    tissue or tissues normally present in an organ
    resulting in disorderly histomorphology. Just
    like any normal tissue neoplasms may develop in
    hamartomas, but rarely.

29
Other Tumors
  • Hamartoma - ( continued )
    Examples

    skin hemangiomas
    lung hamartomas - a
    mass of tissues mostly consisting of normal
    cartilage and bronchial epithelium. These are
    often present at birth and may regress in time.

30
Other Tumors
  • Choristomas - normal cells or tissues that are
    present in abnormal locations.
  • Examples normal pancreatic tissue present in
    the intestinal mucosa, adrenal cells present in
    the kidney or elsewhere.
  • The terms aberrant or heterotopic
    tissues or ectopic rest are applied to the
    same conditions.

31
Old terminology
  • In the old terminology, the terms melanoma,
    hepatoma, and hypernephroma were used to denote
    malignant tumors of melanocytes, liver, and
    kidney, respectively. Presently, the use of
    these terms are discouraged. A more specific
    terminology would be malignant melanoma,
    hepatocellular carcinoma, and renal cell
    carcinoma, respectively.

32
Eponyms
  • People's names are also used to name certain
    tumors. Although this is discouraged, some have
    their merits since the nature of some tumors are
    not exactly clear.

33
Eponyms (examples)
  • Name of Tumor
  • Brenner's Tumor
  • Burkitt's Lymphoma
  • Ewing's Sarcoma
  • Grawitz's Tumor
  • Kaposi's Sarcoma
  • Cell Tissue of Origin
  • Ovary
  • Lymph Node
  • Bone
  • Kidney
  • Blood Vessels

34
Eponyms (examples)
  • Name of Tumor
  • Krukenberg's Tumor
  • Warthin's Tumor
  • Wilm's Tumor
  • Hodgkin's Disease
  • Cell Tissue of Origin
  • Carcinoma of ovary (usually metastatic from
    stomach)
  • Tumor of salivary gland
  • Adenomyosarcoma of kidney
  • Lymph Nodes

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Characteristics of Benign Malignant Neoplasms
  • Differentiation and Anaplasia
  • Rate of growth
  • Local invasion
  • Metastasis

39
Differentiation and Anaplasia
  • Differentiation -the extent to which parenchymal
    cells resemble comparable normal cells, both
    morphologically and functionally.
  • In general, benign tumors are well differentiated
  • fig. 8-5 - leiomyoma of the uterus
  • fig. 8-6 - adenoma of the thyroid

40
Benign tumorLeimyoma (fibroid), uterus.
41
Benign tumorAdenoma, thyroid
42
Differentiation
  • METAPLASIA - a REVERSIBLE change in which one
    adult cell type ( epithelial or mesenchymal ) is
    replaced by another adult cell type.
  • DYSPLASIA - deranged development. Proliferation
    and atypical cytologic alterations involving cell
    size, shape, and organization.
  • Carcinoma-in-situ
  • cervical lesions (fig. 8-11)

43
Carcinoma-in-situ TumorCervix
44
Carcinoma-in-situ TumorCervix
45
Differentiation and Anaplasia
  • Malignant tumors are invasive /or metastatic and
    range from well differentiated to
    undifferentiated.
  • Well differentiated adenoCA , colon (fig. 8-7)
  • Well differentiated squamous cell carcinoma of
    the skin (fig. 8-10)
  • Anaplasia - lack of differentiation.
  • Anaplastic tumor - rhabdomyosarcoma (8-8)
  • Anaplastic tumor - ( fig. 8-9)
  • Pleomorphism - variation in size shape

46
Malignant TumorAdenocarcinoma, colon, micro
47
Malignant TumorWell-differentiated squamous cell
carcinoma, skin
48
Malignant TumorRhabdomyosarcoma, skeletal muscle
49
Malignant TumorAnaplastic tumor, site unknown
50
Rate of Growth
  • In general, malignant tumors grow more rapidly
    than benign lesions.
  • Factors such as hormone dependence, adequacy of
    blood supply, genetics, etc., influence growth.

51
Local Invasion
  • Almost all benign tumors grow as cohesive
    expansile masses.
  • They develop a rim of compressed connective
    tissue, a fibrous capsule, a discrete, easily
    movable mass. Benign fibroadenoma of the
    breast (figs. 8-12, 8-13)

52
Benign tumorFibroadenoma, breast. Gross
53
Benign tumorFibroadenoma, breast. Micro
54
Local Invasion
  • Malignant lesions infiltrate, invade and destroy
    surrounding tissue.
  • Invasiveness is a reliable feature of malignancy.
    Carcinoma of the
    breast (figs. 8-14, 8-15)

55
Malignant TumorInfiltrating duct carcinoma,
breast. Gross
56
Malignant TumorInfiltrating duct carcinoma,
breast. Micro
57
Metastasis
  • Metastasis unequivocally implies malignancy.
  • With few exceptions, all cancers can metastasize.
  • About 30 of newly diagnosed patients with solid
    tumors (excludes most skin cancer) present with
    metastases.

58
Pathways of Spread
  • Seeding of body cavities and surfaces
  • ex. Ovary - pseudomyxoma peritonei
  • Lymphatic spread - most common follows the
    natural routes of drainage. (fig.8-16)
  • Hematogenous spread - venous most common drain
    to liver and lung (figs.8-17, 8-18)

59
Malignant Tumor. MetastaticLymph node, breast
60
Malignant Tumor. MetastaticAdenocarcinoma,
liver. Gross
61
Malignant Tumor. MetastaticAdenocarcinoma,
liver. Micro
62
SUMMARY
  • Comparisons between benign and malignant tumors
    (table 8-2)
  • Comparisons between benign and malignant tumors
    of the myometrium (Fig. 8-19)

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Cancer StatisticsFigures 8-20 21 p. 272
  • Incidence
  • Most common male - PROSTATE
  • Most common female - BREAST
  • Deaths
  • Most common male - LUNG
  • Most common female - LUNG

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Geographic Environmental Factors
  • Stomach cancer - Japan (smoked fish)
  • Melanomas - fair skin (sun exposure)
  • Occupational exposure - table 8-3, p. 274
  • Alcohol abuse - cancer of GI tract
  • Smoking - cancer of lung, bladder, etc.
  • Cervical cancer - promiscuity STDs

70
Age
  • Most cancers occur in the later years of life,
    especially 55-74.
  • No age group is spared

71
Heredity
table 8-6, p. 275
  • Inherited cancer syndromes (autosomal dominant)
  • familial retinoblastoma
  • Familial cancers
  • breast ovarian colon
  • Autosomal recessive syndromes of defective DNA
    repair
  • xeroderma pigmentosum

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Acquired Preneoplastic Disorders
  • Metaplasia leads to dysplasia, carcinoma-in-situ
    and then cancer.
  • Lung, cervix, etc.
  • Chronic inflammatory diseases
  • ulcerative colitis, hepatitis
  • Non-neoplastic disorders
  • solar keratosis, leukoplakia
  • Benign tumors
  • most do not become cancer, BUT...

74
Molecular Basis of Cancer
  • Nonlethal genetic damage
  • Regulatory genes
  • growth-promoting protooncogenes (oncogenes)
  • growth-inhibiting cancer-suppressor genes
    (antioncogenes)
  • apoptosis (programmed cell death)
  • DNA repair genes
  • Carcinogenisis is a multistep process at the
    phenotypic and genetic level.

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ONCOGENES
  • Cancer-causing genes.
  • Derived from protooncogenes (v-onc)which promote
    normal growth and differentiation.
  • DNA of spontaneously arising cancers contains
    oncogenes.
  • Protooncogenes may become oncogenic by retroviral
    transduction (v-oncs) or by influences that alter
    their behavior in situ, thereby converting them
    into cellular oncogenes (c-oncs).

77
Protein Products of Oncogenes
  • Growth factors
  • Growth factor receptors
  • Proteins involved in Signal Transduction
  • Nuclear regulatory proteins
  • Cell cycle regulators

78
Protein Products of Oncogenesmode of
activation
  • Fig. 8-25 page 281
  • Growth factors
  • overexpression c-sis
  • amplification
  • Growth factor receptors
  • overexpression c-erb B2
  • amplification
  • point mutation

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Protein Products of Oncogenes mode of activation
  • Proteins involved in Signal Transduction
  • point mutations ras (mutation of the ras gene
    is the single most common abnormality of dominant
    oncogenes in human tumors)
  • translocation
  • Nuclear regulatory proteins
  • translocation c-myc
  • amplification

81
Protein Products of Oncogenes mode of activation
  • Cell cycle regulators Cyclin-dependent kinases
    drive the cell cycle by phosphorylating critical
    target proteins that are required for progression
    of the cells to the next phase of the cell cycle.
  • translocation
  • amplification
  • point mutation

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Activation of Oncogenes
  • Changes in the structure of the gene
  • Changes in regulation of gene expression
  • Point mutations
  • Chromosomal rearrangements
  • Gene amplification

83
Activation of Oncogenes
  • Point mutations
  • Distinct mutations reduce the GTPase activity of
    the ras proteins.
  • The mutant ras protein is permanently activated
    leading to continuous stimulation of cells
    without any external trigger.

84
Activation of Oncogenes
  • Chromosomal rearrangements
  • Translocations - results in overexpression of
    protooncogenes (fig. 8-28, p. 285). The
    Philadelphia chromosome is characteristic of
    chronic myeloid leukemia.
  • Inversions

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Activation of Oncogenes
  • Gene amplification - overexpression may result
    from reduplication and manifold amplification of
    their DNA sequences. This may produce several
    hundred copies of the protooncogene in the tumor
    cell.
  • N-myc in neuroblastoma
  • c-erb B2 in breast cancer

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Cancer-Suppressor Genes
  • The function of these genes is to regulate cell
    growth, not to prevent tumor formation. If the
    genes mutate, the cell will grow deregulated.
  • The mutations required to produce retinoblastoma
    involve the Rb gene (recessive cancer gene).
  • Table 8-9, p. 287 ( to be learned some day)

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Protein Products of Tumor-Suppressor Genes
  • Growth inhibitory signals originate outside the
    cell and use receptors, signal transducers, and
    cell cycle and nuclear transcription regulators.
    (fig 8-31, p. 289)
  • Molecules that regulate nuclear transcription and
    cell cycle
  • Rb Gene
  • p53 Gene
  • BRCA-1 BRCA-2 Genes

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Rb Gene
  • Rb is a nuclear phosphoprotein
  • When cells are stimulated by growth factors, the
    Rb protein is inactivated by phosphorylation, the
    brake is released, and the cells transverse the
    G1 -- S checkpoint. (fig 8-31, p. 289)
  • The state of pRb phosphorylation is a critical
    determinant of the cell cycle progression.

94
Rb Gene (continued)
  • Loss of normal cell cycle control is central to
    malignant transformation and that at least one of
    the four key regulators of cell cycle (p16,
    cyclin D, CDK4, Rb) is mutated in the vast
    majority of human cancers.

95
p53 Gene (fig. 8-32, p. 291)
  • Over 50 of human tumors contain mutations in
    this gene.
  • Functions primarily by controlling transcription
    of several other genes.
  • p53 applies the emergency brakes when DNA is
    damaged by irradiation, UV light, or mutagenic
    chemicals.
  • p53 assists in DNA repair or directs the cell to
    undergo apoptosis.

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BRCA-1, BRCA-2 Genes
  • Breast, ovarian and other cancers.
  • Approximately 5-10 of breast cancers are
    familial mutations in BRCA-1 BRCA-2 account
    for 80 of the familial cases.
  • Mutations are rarely found in sporadic breast
    cancer.
  • Involved in transcriptional regulation DNA
    repair.

98
Molecules that Regulate Signal Transduction
  • APC (adenomatous polyposis coli) loss is one of
    the first steps in the evolution of colorectal
    cancers.
  • Inactivation of APC gene up-regulates cellular
    proliferation.
  • NF-1 gene (neurofibromatosis type I)

99
Cell Surface Receptors
  • TGF-B (growth-inhibitory factor) up-regulates
    transcription of growth-inhibitory genes.
  • Cadherins - glue its loss favors local invasion
    or metastases.
  • DCC (deleted in colon carcinoma)
  • Others

100
Genes that Regulate Apoptosis (fig. 8-33, p. 295)
  • Genes that inhibit cell death
  • bcl-2
  • bcl-xL
  • Genes that favor programmed cell death
  • bax
  • bad
  • bcl-xS

101
bcl-2
  • Overexpression of bcl-2 protects lymphocytes from
    apoptosis and allows them to survive for long
    periods of time thus, there is a steady
    accumulation of B lymphocytes in the blood, lymph
    nodes , bone marrow and other organs.
  • Up-regulation of bax suppresses tumor growth by
    promoting apoptosis (fig. 8-33)

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Genes that Regulate DNA Repair
  • DNA repair genes are not oncogenic, but they
    allow mutations in other genes during the process
    of normal cell division.
  • replication error
  • microsatellite instability
  • HNPCC - Hereditary nonpolyposis colon cancer
    syndrome
  • Xeroderma pigmentosum
  • Ataxia telangietasia

104
Telomeres and Cancer
  • With each cell division, telomeres shorten. Once
    the telomeres are shortened beyond a certain
    point, the loss of telomere function leads to
    end-to-end chromosome fusion and cell death.
    Telomerase causes considerable extension of cell
    life.

105
Molecular Basis of Multistep Carcinogenesis
  • Multiple steps in initiation and promotion.
  • Activation of several oncogenes and loss of 2 or
    more cancer-suppressor genes. (fig. 8-34, p.297)
  • Gatekeeper genes directly regulate the growth
    of tumors.
  • Caretaker genes affect genomic stability (fig.
    8-35, p.298)
  • Summary - Fig.8-36, p. 299

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Karyotypic changes in Tumors
  • Balanced translocations
  • Deletions
  • Gene amplification
  • Whole chromosomes may be gained or lost.

110
Biology of Tumor Growth
  • Kinetics of tumor cell growth
  • Tumor angiogenesis
  • Tumor progression and heterogeneity

111
Kinetics of tumor cell growth
  • Clinically detectable tumor mass and doubling
    time (fig. 8-37, p. 300)
  • The rate of tumor growth depends on the growth
    fraction and the degree of imbalance between cell
    production and cell loss (fig. 8-38, p.301)

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Tumor Angiogenesis
  • Tumors cant grow over 2mm without their own
    blood supply.
  • Hypoxia induces apoptosis by activation of p53
  • Perfusion supplies nutrients and oxygen. Newly
    formed endothelial cells stimulate the growth of
    adjacent tumor cells by secreting polypeptides
    such as insulin-like growth factors, PDGF,
    GM-CSF, IL-1.

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Tumor Angiogenesis
  • Tumor-associated angiogenic factors
  • VEGF - vascular endothelial growth factor
  • bFGF - basic fibroblast growth factor

117
Tumor Progression Heterogeneity
  • Most malignant tumors are monoclonal in origin
    but their cells are extremely heterogeneous.
    Subpopulations of cells develop that differ with
    respect to
  • invasiveness
  • rate of growth
  • metastatic ability
  • karyotype
  • hormonal responsiveness
  • susceptibility to antineoplastic drugs

118
Mechanisms of Invasion and Metastasis
  • Invasion of the Extracellular Matrix
  • Vascular dissemination and homing of tumor cells
  • Fig. 8-39, p. 303

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Invasion of the Extracellular Matrix
  • Detachment (loosening up) of the tumor cells
    from each other
  • Attachment to matrix components
  • Degradation of the extracellular matrix
  • Migration of the tumor cells
  • Fig. 8-40, p. 304

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Vascular Dissemination and Homing of Tumor Cells
  • Once in the circulation, tumor cells are
    particularly vulnerable to destruction by natural
    and adaptive immune defenses.
  • Formation of platelet-tumor aggregates seems to
    enhance tumor cell survival and implantability.
  • Some target organs may liberate chemoattratants
    that tend to recruit tumor cells to the site.

126
Molecular Genetics of Metastases
  • Certain oncogenes or tumor-suppressor genes may
    elicit metastases.
  • In breast cancer, nm23 levels were highest in
    tumors that had 3 or 4 positive nodes.
  • In prostate cancer, the KAI-I gene suppresses
    metastases.
  • In melanoma, the KiSS-1 gene suppresses
    metastases.

127
Carcinogenic Agents Their Cellular Interactions
  • Chemical carcinogens
  • Radiant energy
  • Oncogenic microbes, mainly viruses
  • Several of the above agents may act in concert or
    synergize the effects of others.

128
Chemical Carcinogenesis
  • Sir Percival Pott showed an increased incidence
    of scrotal skin cancer in chimney sweeps due to
    chronic exposure to soot.
  • Dupont - 1919
  • Incomplete combustion of fossil fuels.
  • Plants, microorganisms, medical drugs.

129
Steps Involved in Chemical Carcinogenesis
  • Initiation results from exposure of cells to an
    appropriate dose of a carcinogenic agent (
    initiator ).
  • Initiation causes permanent DNA damage
    (mutations)
  • Promoters can induce tumors in initiated cells,
    but are nontumorigenic by themselves
  • Fig. 8-41, p. 306

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Initiation of Carcinogenesis
  • Direct and indirect acting (Table 8-10)
  • Most of the known carcinogens are metabolized by
    cytochrome P-450-dependent mono-oxygenases.
  • Age, sex,and nutritional status also determine
    the internal dose of toxicants.
  • Ames test - The ability of a chemical to induce
    mutations in Salmonella typhi.

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Initiation of Carcinogenesis
  • Almost all chemicals that are mutagenic in vitro
    are carcinogenic in vivo.
  • DNA is the primary target for chemical
    carcinogens.
  • In initiated cells, the damaged DNA template must
    be replicated so that the change in DNA becomes
    fixed within 72-96 hrs.

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Promotion of Carcinogenesis
  • After initiation, promoters lead to proliferation
    and clonal expansion of the initiated cell.
  • The process of tumor promotion includes multiple
    steps proliferation of preneoplastic cells,
    malignant conversion, and eventually tumor
    progression.

136
Carcinogenic ChemicalsInitiators
  • Direct-acting Alkylating agents
  • chemotherapeutic agents
  • immunosuppressive agents
  • Polycyclic aromatic hydrocarbons
  • produced by burning tobacco
  • Aromatic amines azo dyes
  • B-naphthylamine
  • butter yellow
  • scarlet red

137
Carcinogenic ChemicalsInitiators
  • Naturally occurring carcinogens
  • aflatoxin B1
  • hepatitis B virus
  • Nitrosamines amides
  • nitrate preservatives
  • Others
  • asbestos
  • vinyl chloride
  • chromium, nickel, and other metals

138
Carcinogenic ChemicalsPromoters
  • Cigarette usage
  • Viral infections
  • Hormones such as estrogens
  • Bile salts
  • Diethylstilbestrol
  • Intake of high levels of dietary fat

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Radiation Carcinogenesis
  • Ultraviolet rays - the carcinogenicity of UVB
    light is attributed to its formation of
    pyrimidine dimers in DNA.
  • DNA damage is repaired by nucleotide excision
    repair (NER) 5 steps, 20 genes.
  • Xeroderma pigmentosum, autosomal recessive
    disease, caused by a mutation in one of several
    genes involved in NER.
  • Mutations in oncogenes and tumor -suppressor genes

140
Radiation Carcinogenesis
  • Ionizing radiation - electromagnetic (x-rays,
    gamma-rays) and particulate radiations (alpha and
    beta particles, protons, neutrons) are all
    carcinogenic.
  • Radiologists
  • Miners of radioactive elements
  • Survivors of the atomic bombs
  • Therapeutic irradiation

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Viral CarcinogenesisDNA Oncogenic Viruses
  • Transforming DNA viruses form stable associations
    with the host cell genome.
  • The integrated virus is unable to complete its
    replicative cycle.
  • Those viral genes that are transcribed early in
    the viral life cycle are important for
    transformation.

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Viral CarcinogenesisDNA Oncogenic Viruses
  • Human Papillomavirus- cervical cancer
  • Epstein-Barr virus - Burkitts lymphoma, B-cell
    lymphomas, and others.
  • Hepatitis B virus - liver cancer

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Viral CarcinogenesisRNA Oncogenic Viruses
  • Hepatitis C virus - liver cancer
  • Human T-cell Leukemia virus Type I - T-cell
    leukemia/lymphoma (fig. 8-44, p.
    314)

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Microbial Carcinogenesis
  • Helicobacter Pylori - bacterium associated with
    ulcers also gastric lymphomas.
  • Treatment of the infection with antibiotics
    results in regression of the lymphoma in most
    cases.

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TUMOR IMMUNITY
  • Immune surveillance - recognition and destruction
    of nonself tumor cells.
  • Tumor-specific antigens (TSAs) are present only
    on tumor cells and not on any normal cells.
  • Tumor-associated antigens (TAAs) are present on
    tumor cells and also on some normal cells.

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TUMOR IMMUNITY
  • Tumor-Specific shared antigens
  • Tissue-Specific antigens
  • Antigens resulting from mutations
  • Overexpressed antigens
  • Viral antigens
  • Others

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Antitumor Effector Mechanisms
  • Cytotoxic T lymphocytes
  • Natural killer cells
  • Macrophages
  • Humoral mechanisms
  • (fig. 8-46, p. 318)

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Escaping Immunosurveillance
  • Selective outgrowth of antigen-negative variants
  • Loss or reduced expression of HLA antigens
  • Lack of co-stimulation
  • Immunosuppression
  • Apoptosis of cytotoxic T cells

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Clinical Features of Tumors
  • Effects of Tumor on the Host
  • Grading Staging of Tumors
  • Laboratory Diagnosis of Cancer

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Effects of Tumor on the Host
  • Local Hormonal Effects
  • Cachexia - wasting syndrome
  • Paraneoplastic syndromes (Table 8-11)
  • endocrinopathies
  • nerve muscle syndromes
  • dermatologic disorders osseous, articular, and
    soft tissue changes
  • vascular hematologic changes
  • others

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Grading of Tumors
  • Grading of a cancer is based on the degree of
    differentiation of the tumor cells and the number
    of mitoses within the tumor as presumed
    correlates with the tumors aggressiveness.
  • Tumors are classified as grades I thru IV with
    increasing anaplasia.

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Histologic Grading of Malignant Tumors General
Principles
  • Grade I (Well differentiated)
  • Tumor tissue closely resembles tissue of origin
  • (e.g., gland formation in adenocarcinoma,
    keratinization and epithelial pearls in squamous
    cell carcinoma)
  • Few mitoses
  • Little variation in size and shape of tumor cells

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Malignant TumorAdenocarcinoma, colon, micro
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Malignant TumorWell-differentiated squamous cell
carcinoma, skin
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Histologic Grading of Malignant Tumors General
Principles
  • Grade II (Moderately differentiated)
  • Tumor tissue resembles tissue of origin less well
  • Increased mitoses
  • Increased variation in size and shape of tumor
    cells

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Histologic Grading of Malignant Tumors General
Principles
  • Grades III, IV (Poorly differentiated)
  • Tumor tissue does not closely resemble tissue of
    origin
  • Many mitoses
  • Large variation in size and shape of tumor cells

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Malignant TumorRhabdomyosarcoma, skeletal muscle
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Malignant TumorAnaplastic tumor, site unknown
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Staging of Tumors
  • The staging of cancers is based on the size of
    the primary lesion, its extent of spread to
    regional lymph nodes, and the presence or absence
    of distant (blood-borne) metastases.

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TX
  • Primary tumor cannot be assessed, or tumor proven
    by presence of malignant cells in sputum or
    bronchial washings but not visualized by imaging
    or bronchoscopy
  • TO
  • No evidence of primary tumor

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Tis
  • Carcinoma in situ
  • T1
  • Tumor 3 cm or less in greatest dimension,
    surrounded by lung or visceral pleura, without
    bronchoscopic evidence of invasion more proximal
    than the lobar bronchus (i.e., not in the main
    bronchus)

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T2
  • Tumor with any of the following features of size
    or extent more than 3 cm in greatest dimension
    involves main bronchus, 2 cm or more distal to
    the carina invades the visceral pleura or
    associated with atelectasis or obstructive
    pneumonitis which extends to the hilar region but
    does not involve the entire lung

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T3
  • Tumor of any size that directly invades any of
    the following chest wall (including superior
    sulcus tumors), diaphragm, mediastinal pleura,
    parietal pericardium or tumor in the main
    bronchus less than 2 cm distal to the carina,
    but without involvement of the carina or
    associated atelectasis or obstructive pneumonitis
    of the entire lung

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T4
  • Tumor of any size that invades any of the
    following mediastinum, heart, great vessels,
    trachea, esophagus, vertebral body, carina or
    tumor with a malignant pleural effusion

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Note
  • The uncommon superficial tumor of any size with
    its invasive component limited to the bronchial
    wall, which may extend proximal to the main
    bronchus is also classified T1.

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Note
  • Most pleural effusions associated with lung
    cancer are due to tumor. However, there are a
    few patients in whom multiple cytopathologic
    examinations of pleural fluid are negative for
    tumor. In these cases, fluid is non-bloody and
    is not an exudate. When these elements and
    clinical judgment dictate that the effusion is
    not related to the tumor, the effusion should be
    excluded as a staging element and the patient
    should be staged T1, T2, or T3.

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REGIONAL LYMPH NODES (N)
  • The regional lymph nodes are the intrathoracic,
    scalene, and supraclavicular nodes.

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NX
  • Regional lymph nodes cannot be assessed
  • NO
  • No regional lymph node metastasis

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N1
  • Metastasis in ipsilateral peribronchial and/or
    ipsilateral hilar lymph nodes, including direct
    extension
  • N2
  • Metastasis in ipsilateral mediastinal and/or
    subcranial lymph node (s)

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N3
  • Metastasis in contralateral mediastinal,
    contralateral hilar, ipsilateral, or
    contralateral scalene or supraclavicular lymph
    node(s)

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DISTANT METASTASIS (M)
  • MX
    Presence of distant metastasis cannot be assessed
  • MO
    No distant metastasis
  • M1
    Distant metastasis

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AJCC/UICC STAGE GROUPING
  • OCCULT CARCINOMA TX NO MO
  • Stage 0 Tis NO MO
  • Stage 1 T1 NO MO T2 NO MO
  • Stage II T1 N1 MO T2 N1 MO

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AJCC/UICC STAGE GROUPING
  • Stage IIIA T1 N2 MO T2 N2 MO T3 NO
    MO T3 N1 MO T3 N2 M0
  • Stage IIIB Any T N3 MO T4
    Any N MO
  • Stage IV Any T Any N
    M1

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Laboratory Diagnosis of Cancer
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Cytologic Diagnosis
  • Exfoliated cells (sputum, urine, CSF, body cavity
    fluids)
  • Brushings or scrapings of epithelium
  • Fine needle aspiration (FNA)

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Histologic Diagnosis
  • The definitive method for establishing diagnosis
    of a neoplasm.

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Techniques
  • Frozen section method
  • Paraffin section method
  • Immunoperoxidase techniques - ( labeled
    antibodies are used to identify marker antigens
    in tumors and tissue by producing a colored
    product )
  • Electron microscopy

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Information provided by Pathological Diagnosis
  • Type of neoplasm
  • Biological behavior
  • Histologic grade
  • Degree of invasion or spread
  • Pathologic stage

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Serologic Diagnosis
  • Detects cancer cell products in the serum.
    Products are
  • Secreted by cancer cells
  • Antigens released by death of some cancer cells

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Serologic Assays for Cancer Diagnosis or Follow-up
  • Substance in Serum
  • Carcinoembryonic antigen (CEA)
  • Cancer Type
  • Gastrointestinal tract cancer (especially colon),
    breast, and lung cancer, elevated levels in some
    non-cancerous states

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Serologic Assays for Cancer Diagnosis or Follow-up
  • Substance in Serum
  • a-Fetoprotein (AFP)
  • Cancer Type
  • Hepatoma, yolk sac tumors

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Serologic Assays for Cancer Diagnosis or Follow-up
  • Substance in Serum
  • Human chorionic gonadotropin (HCG)
  • Cancer Type
  • Greatly elevated in choriocarcinoma rarely
    elevated in other neoplasms

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Serologic Assays for Cancer Diagnosis or Follow-up
  • Substance in Serum
  • Prostatic acid phosphatase prostate-specific
    epithelial antigen
  • Cancer Type
  • Two separate molecules levels of both are
    elevated in metastatic prostatic cancer

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Serologic Assays for Cancer Diagnosis or Follow-up
  • Substance in Serum
  • Monoclonal immunoglobulin
  • Cancer Type
  • Myeloma, some B cell lymphomas

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Serologic Assays for Cancer Diagnosis or Follow-up
  • Substance in Serum
  • Specific hormones
  • Cancer Type
  • Endocrine neoplasms and "ectopic"
    hormone-producing tumors

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Serologic Assays for Cancer Diagnosis or Follow-up
  • Substance in Serum
  • CA 125
  • Cancer Type
  • Ovarian carcinoma other neoplasms

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Radiological Diagnosis
  • X-ray
  • CT scans (Computed Tomography)
  • MRI scans (Magnetic Resonance Imaging)
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