NEOPLASIA

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NEOPLASIA
Core Pathology
Spencer B. Gilbert, M.D.
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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
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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.

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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

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GENERAL ASPECTS Definitions (continued)

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

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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.

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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

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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 )

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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 )

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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)

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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

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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)

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Benign tumorPapilloma of the colon
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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)

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Benign tumorColonic polyp Adenoma. Gross
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Benign tumorColonic polyp Adenoma. Micro
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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.

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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

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Malignant tumors

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

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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.

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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)

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Malignant Tumors (continued)

• Malignant Micro
• Pleomorphism - variation in size and shape of the
  cells and nuclei.
• Formation of tumor giant cells

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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)

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Benign tumorMixed tumor, parotid gland
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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)

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Benign tumorCystic teratoma (dermoid cyst),
ovary. Gross
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Benign tumorCystic teratoma (dermoid cyst),
ovary. Micro
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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.

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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.

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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.

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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.

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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.

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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

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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

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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

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Benign tumorLeimyoma (fibroid), uterus.
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Benign tumorAdenoma, thyroid
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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)

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Carcinoma-in-situ TumorCervix
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Carcinoma-in-situ TumorCervix
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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

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Malignant TumorAdenocarcinoma, colon, micro
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Malignant TumorWell-differentiated squamous cell
carcinoma, skin
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Malignant TumorRhabdomyosarcoma, skeletal muscle
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Malignant TumorAnaplastic tumor, site unknown
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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.

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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)

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Benign tumorFibroadenoma, breast. Gross
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Benign tumorFibroadenoma, breast. Micro
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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)

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Malignant TumorInfiltrating duct carcinoma,
breast. Gross
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Malignant TumorInfiltrating duct carcinoma,
breast. Micro
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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.

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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)

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Malignant Tumor. MetastaticLymph node, breast
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Malignant Tumor. MetastaticAdenocarcinoma,
liver. Gross
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Malignant Tumor. MetastaticAdenocarcinoma,
liver. Micro
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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

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Age

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

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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...

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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).

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Protein Products of Oncogenes

• Growth factors
• Growth factor receptors
• Proteins involved in Signal Transduction
• Nuclear regulatory proteins
• Cell cycle regulators

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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

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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

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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.

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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.

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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.

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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.

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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)

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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

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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

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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

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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.

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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.

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Biology of Tumor Growth

• Kinetics of tumor cell growth
• Tumor angiogenesis
• Tumor progression and heterogeneity

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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

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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

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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.

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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.

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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.

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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.

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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.

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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

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Carcinogenic ChemicalsInitiators

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

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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

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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)