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Neoplasia Part 2: Biologic and Clinical Aspects

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Title: Neoplasia Part 2: Biologic and Clinical Aspects


1
Neoplasia Part 2 Biologic and Clinical Aspects
  • I Biologic Features of Malignant Neoplasia
  • II Tumor - Host Interactions
  • III Epidemiology of Cancer
  • IV Carcinogenic Agents and Effects
  • V Laboratory Diagnosis of Cancer

Paul G. Koles, MD Associate Professor
of Pathology and Surgery Boonshoft School of
Medicine at Wright State University
paul.koles_at_wright.edu
2
Natural History of a Malignant Neoplasm
local invasion
transformation
growth
metastasis
  • 1) Transformation of target cell the genetic
    damage and associated molecular changes that
    transform a single normal cell into a neoplastic
    cell.
  • 2) Growth of transformed cells a single
    transformed cell, by mitotic division, becomes a
    clone of neoplastic cells, while overcoming host
    defenses.
  • 3) Local invasion penetration of neoplastic
    cells through basement membranes into the stroma
    of the organ in which it arose (a reliable marker
    of malignant behavior, but local invasion may be
    challenging to identify microscopically)
  • 4) Metastasis spread of neoplastic cells
    outside the organ in which the neoplasm arose
    (definitive biologic proof that a neoplasm is
    malignant benign tumors do not metastasize)

3
Requirements for Growth, Invasion, and Metastasis
  • ? Capacity for sustained replication
  • Capacity to develop adequate vascularity
  • Mechanisms to accomplish local invasion
  • Mechanisms to promote metastasis

4
Potential for Sustained Replication
Fig. 7-35, PBD 8th ed
5
Angiogenesis
  • Angiogenesis development of new blood vessels
    (neovascularization)
  • If blood supply inadequate hypoxia and
    apoptosis of tumor cells via activation p53 gene
  • ? Necessary for both growth and metastasis solid
    tumors cannot grow larger than 2 mm diameter
    unless angiogenesis occurs
  • Effects of neovascularization
  • ? provides nutrients oxygen for growing cells
  • ? endothelial cells secrete growth factors for
    tumor cells (insulin-like growth factor, PDGF,
    GM-CSF)
  • ? promotes metastasis via new lymphatics blood
    vessels

6
Tumor Angiogenesis (2)
  • Microvessel density in a neoplasm correlates with
    probability of metastasis (more vessel density,
    more likely metastasis)
  • Angiogenic switch change from inhibition of
    new vessel formation toward angiogenesis,
    occurring as tumor cells acquire capacity for
    local invasion
  • angiogenic promoters vascular endothelial
    growth factor (VEGF) basic fibroblast growth
    factor (bFGF) synthesis upregulated by hypoxia
    of tumor cells and mutations in RAS, MYC
  • angiogenesis inhibitors produced by proteolysis
    of physiologic proteins
  • plasminogen ?angiostatin
  • collagens ? endostatin
  • transthyretin ? vasculostatin

Pharmacologic Application bevacizumab, MoAb
against VEGF, approved for therapy of multiple
cancers
7
Mechanisms of Metastasis
  • Local invasion into extracellular matrix
  • Vascular dissemination and homing of tumor
    cells to distant sites
  • Extravasation and growth (colonization) of
    cells in sites of metastasis

8
Local Invasion Squamous Cell Carcinoma of Cervix
Full-thickness dysplasia of squamous mucosa
(carcinoma-in-situ)
Intact basement membrane
Local Invasion neoplastic cells breaking
through the epithelial basement membrane into the
stroma. Stromal connective tissue proliferates
in response to invasive tumor
Carcinoma-in-situ (an intraepithelial neoplasm)
becomes invasive carcinoma when tumor cells cross
the basement membrane into connective tissue
stroma
Fig. 13F.17, Diagnostic Histopathology of Tumors,
Churchill Livingstone, 2000
9
Mechanisms of local invasion 4 steps
A. Loosening IC junctions Downregulation
E-cadherin expression (decreasing cell adhesion
and connectivity) Mutations in catenin, a
subplasmalemmal protein that binds to E-cadherin
and links it to other cytoskeletal proteins
B. Degradation basement membrane Tumor cells
secrete proteases or induce stromal cells to do
same, allowing invading edge of tumor to degrade
membrane proteins Matrix metalloproteinase 9
degrades type IV collagen in epithelial and
vascular basement membranes releases growth
factors
Fig. 7-37, Robbins Cotran PBD, 8th ed
10
Mechanisms local invasion (2)
C. Augmented Attachment Neoplastic cells
attach to basement membrane proteins via
receptors for laminin fibronectin, using
enhanced or abnormal expression of integrins
Neoplastic cells may express such receptors for
b.m. proteins diffusely on cell membrane (vs.
basal surface expression only in normal cells)
D. Migration into stroma ? Mediated through
contraction of actin cytoskeleton in tumor cell
Cleavage products of collagen and laminin have
chemotactic effects Tumor cells develop
receptors for ECM matrix proteins and secrete
growth factors with autocrine effects, enhancing
motility and migration
Fig. 7-37, Robbins Cotran PBD, 8th ed.
11
Mechanisms of hematogenous metastasis (1)
? Intravasation through b.m. of capillary or
venule by mechanism similar to invasion through
epithelial b.m. Circulating cytotoxic T or NK
cells destroy tumor cells in circulation (most
circulating tumor cells never extravasate to form
metastatic tumor) Adhesion/aggregation of
tumor cells with platelets enhances survival and
implantability on vascular endothelium (platelet
adhesion)
Fig. 7-36, Robbins Cotran PBD, 8th ed, 2010
12
Mechanisms of hematogenous metastasis (2)
How is extravasation accomplished? --organ-speci
fic endothelial ligands for tumor cell adhesion
molecules --receptors for chemokines allow homing
to organs expressing chemokines (e.g., breast
carcinoma cells have CXCR4 and CCR7 receptors
these chemokines are strongly expressed in common
sites of metastatic breast CA) --some tissues
unreceptive to extravasation spleen, skel.
muscle ?Colonization growth of tumor cells
after extravasation --Example breast cancer in
bone secrete PTH-RP ? activate osteoblasts to
make RANK ligand ? RANKL activates osteoclasts ?
matrix degraded, growth factors released ? cancer
cells proliferate
Fig. 7-36, Robbins Cotran PBD, 8th ed, 2010
13
Proof of malignancy Multiple metastatic tumors
in liver, originating from primary pancreatic
adenocarcinoma
Which 2 kinds of vessels did malignant pancreatic
cells enter by intravasation ?
1) 2)
Which other sites probably contain metastases?
____________near pancreas
Fig. 7-20, Robbins and Cotran Pathologic Basis of
Disease, 7th ed, 2005
14
Multistep molecular basis of carcinogenesis
Observations 1)Cancers result from multiple
mutations acquired over years 2) Many benign
neoplasms with mutations never become
malignant 3) Analysis breast colon cancers
avg. 90 mutant genes (many unknown effects)
Fig. 7-40, Pathologic Basis of Disease, 8th
edition, Elsevier 2010 (based on research by
Fearon and Vogelstein, 1990, for which Nobel
Prize in Medicine was awarded)
15
Biology of Tumor Growth
When a lung neoplasm is diagnosed at its smallest
clinically detectable size (5-10 mm
diameter), what percentage of its potential
biologic lifespan has it completed? _____________
Clinical Application 30-40 of persons with
newly diagnosed malignant neoplasms (non-skin)
already have metastases at the time of diagnosis.
Fig 7-12, Robbins and Cotran Pathologic Basis of
Disease, 7th ed, Elsevier 2005
16
II. Tumor Host Interactions
17
T-H Interactions Host Defense Against Tumors
  • Recognition of Tumor Antigens
  • Host Immune Effector Mechanisms
  • Cell-mediated
  • Humoral
  • Immune Surveillance and Escape from Immune
    Defenses

18
Tumor Antigens recognized by cytotoxic T cells
(CD8)
Fig. 7-45, Robbins and Cotran PBD, 8th ed
19
Tumor antigens overexpression
  • ? Overexpressed antigens proteins encoded by
    genes that are overexpressed in tumors
  • c-erbB2 (her-2/neu) is overexpressed in 30
    breast carcinomas
  • Overexpression implies a worse prognosis cancer,
    but does allow therapy with trastuzumab, a MoAb
    which binds to the extracellular domain of human
    epidermal growth factor receptor 2 (her-2) protein

Amplification c-erbB2 gene by flourescent in-situ
hybridization
Overexpression c-erbB2 protein by IHC
Fig. 16-68, Diagnostic Histopathology of Tumors,
2nd ed., 2000
20
More tumor antigens
  • Oncofetal antigens expressed in embryonic
    tissues and cancers, normally suppressed in adult
  • Alpha-fetoprotein (AFP), associated with
    hepatocellular carcinomas and some gonadal germ
    cell neoplasms
  • Carcinoembryonic antigen (CEA), expressed by many
    carcinomas, used to monitor therapy of colon
    carcinoma by measuring level of CEA in patients
    serum
  • Altered surface glycoproteins and glycolipids
  • MUC-1 breast ductal carcinomas Tcell response,
    ? vaccine
  • GM2 glycolipids melanomas therapeutic Abs, ?
    vaccine
  • Differentiation antigens expressed by normal and
    neoplastic cells
  • CD20 in B-cell lymphoma use anti-CD20 MoAb
    therapy
  • Prostate-specific antigen (PSA) in prostate
    carcinoma

21
Detection of tumor antigens assists diagnosis of
a neoplasm of unknown origin by
surgical pathologist
Tumor in pelvic lymph node of 70 yo male, solid
sheets of cells with no glands ? origin
Tumor cells stain positively with antibody
against PSA, supporting origin from prostate
gland
Figs. 14A.53 14A.54, Diagnostic Histopathology
of Tumors, 2nd ed, 2000
22
Immune mechanisms antitumor response
System Effector Cell Anti-tumor function
Innate Monocyte, macrophage Phagocytosis, processing, and presentation of tumor Ags to T cells some tumor cell cytotoxicity
Natural Killer (NK) Direct tumor cell lysis particularly effective against cells with reduced MHC expression. No prior sensitization to tumor cell required.
Acquired CD8 T cells MOST IMPORTANT EFFECTOR CELL in TUMOR IMMUNITY direct tumor cell lysis by recognition of abnormal antigens presented by MHC class I molecules. Tumor-specific CD8 cells can be harvested, expanded in vitro, and reinfused into host (adoptive immunotherapy)
CD4 T cells Regulate and stimulate other immune effector cells
B lymphocyte Anti-tumor antibodies made, but not typically protective against tumor development or growth. However, MoAbs in therapeuitic doses may be effective induce apoptosis, complement-mediated lysis, enable NK cells to bind to Fc portion of Mo Ab.
23
Host immune response to malignant melanoma
Malignant melanocytes within epidermis and
invading dermis (black circle)
Brisk dermal lymphocytic host response to
invasive malignant cells (blue circle--many
small oval nuclei are lymphocytes)
Fig. 27-8, Robbins Pathologic Basis of Disease,
6th ed., 1999.
24
Theory of Immunosurveillance
  • Burnet coined term immunosurveillance (1970) to
    describe continuous monitoring and destruction of
    transformed neoplastic cells by T-lymphocytes
  • Evidence neoplasms more frequent in
    immunodeficient
  • Congenital immunodeficiency 5 develop
    lymphomas
  • AIDS, organ transplants higher incidence of many
    neoplasms, especially B-cell lymphomas
  • Why do tumors develop in immunocompetent persons?
  • Selective outgrowth of Ag-negative variants that
    escape immunity
  • Reduced expression HLA class I molecules in tumor
    cells (CD8 T cells need HLA
    class I for recognition of foreign peptide)
  • Tumor cells may not express costimulatory
    molecules (eg, B7) needed to sensitize T cells.
  • Immunosuppression by tumor cells (e.g., secretion
    of TGF-beta)
  • Apoptosis of host cytotoxic T-cells by tumor
    cells expressing Fas ligand, activating the
    death-receptor initiated pathway in T cells.
  • Tumors outwit host defenses in evil, sneaky ways

25
How do tumors evade immune destruction?
selective outgrowth
Which other immune cell could still kill tumor?
Fig. 7-46, Robbins and Cotran PBD, 8th edition
26
T-H Interactions CLINICAL EFFECTS of NEOPLASIA
ON HOST
  • Local effects
  • Hormonal effects
  • Cachexia
  • Paraneoplastic syndromes

27
Local Effects of Tumor
  • Ulceration of mucosal surfaces secondary
    inflammation and hemorrhage
  • Obstruction of lumen by tumor secondary
    dysfunction or diminished outflow (colon, common
    bile duct, urethra)
  • Destruction of critical structures

28
Ulceration of mucosal surfaces
Ulcerated adenocarcinoma of esophagus at E-G
junction
29
Ulceration mucosal surfaces, continued
Esophageal-aortic fistula created by ulcerated
cancer, resulting in
Massive hematemesis and death by hypovolemic shock
30
Obstruction of lumen by neoplasm
Complete obstruction of lumen by circumferential
colon carcinoma
Fig. 8-51, Slide Atlas of GI Pathology, Gower
Medical Publishing, 1989
31
Destruction of critical structures

Large midline neoplasm of which endocrine gland?
(compressing destroying optic chiasm
superiorly, causing loss of visual fields )
32
Hormonal Effects of Tumors
  • Pituitary adenomas make prolactin, GH, ACTH ?
    symptoms and signs
  • Islet cell neoplasms of pancreas most common
    one secretes insulin ? severe, persistent
    hypoglycemia ? altered cognition/seizures
  • Gastrinomas gastrin-producing tumors arising
    from G-cells in duodenum or pancreas
    (Zollinger-Ellison syndrome) ? bad ulcers
  • Carcinoid tumors neuroendocrine cell tumors
    which secrete serotonin (5-hydroxytryptamine),
    histamine, bradykinin, kallikrein,
    prostaglandins. Metastatic GI tract carcinoid
    tumor may produce distinctive carcinoid syndrome
    in patients with liver metastases
  • Vasomotor disturbances (flushing or cyanosis)
  • Intestinal hypermotility (diarrhea, cramps,
    vomiting)
  • Bronchoconstrictive attacks (acting on bronchial
    smooth muscle)
  • Systemic fibrosis, especially of tricuspid
    cardiac valve

Which metabolite of serotonin can be measured in
a 24-hour urine sample, and is secreted in
increased amount in carcinoid syndrome ?
33
CACHEXIA SYNDROME ( the dwindles )
  • Cachexia syndrome is often the first sign of
    clinically occult cancer
    (before the tumor is detected by patient or
    physician)
  • M malaise
  • A anorexia (suppressed appetite)
  • W weakness
  • W wasting (both subcutaneous fat muscle)
  • Postulated factors (not well understood)
    TNF-alpha, from macrophages or tumor cells,
    burns fat and induces anorexia in experimental
    animal models. Increased glucose utilization by
    tumor, increased metabolic rate (despite reduced
    food intake), overproduction of cytokines that
    induce protein (muscle) catabolism

34
Paraneoplastic Syndromes
  • Definition Symptom complexes in cancer-bearing
    patients that cannot readily be explained, either
    by the local or distant spread of the tumor, or
    by hormones produced normally by the tumor cell
    type (paraphrase, PBD 8th ed, p 321).
  • Simplification strange, unexpected side effects
  • Why is it important for physicians to recognize
    paraneoplastic syndromes?
  • MAY BE EARLIEST SIGN OF CLINICALLY OCCULT
    NEOPLASM (EARLIER TREATMENT MAY LEAD TO CURE)
  • Occur in 10 of patients with malignant disease
  • Potentially lethal problems needing treatment
  • Syndromes may mimic metastatic disease (even
    though no metastases are present ! )

35
Types of Paraneoplastic Syndromes
  • Endocrine (most common type)
  • Neuromuscular
  • Skin
  • Bone, Joint, Soft Tissue
  • Vascular
  • Hematologic

Exhaustive List Table 7-11, Robbins Cotran
Pathologic Basis of Disease, 8th ed, Elsevier
2010.
36
ACTH from lung carcinoma stimulates adrenal
cortex to produce excessive cortisol (Cushing
syndrome) weight gain, central obesity, moon
facies, excess soft tissue on posterior
neck/upper back
Small cell undifferentiated carcinoma of lung
(malignant neuroendocrine neoplasm) produces ACTH
Fig. 5-13A, Diagnostic Histopathology of Tumors,
2nd ed, 2000 Fig. 26-23, Pathologic Basis of
Disease, 6th ed, 1999
37
Paraneoplastic syndrome acanthosis nigricans
Left axilla, patient with gastric cancer
Right oral mucosal involvement Fig. 188-2,
Cecil Textbook of Medicine, 22nd ed, Saunders,
2004
Importance in adults gtage 40, presence of
acanthosis nigricans is associated with internal
malignancy in about 50 of cases, probably
related to secretion of epidermal growth factors
by the neoplasm
38
III. EPIDEMIOLOGY OF CANCER

39
Notes (CDC 2008) 1) marked decrease in death
rates from heart disease and stroke since 1950,
but heart disease still 1 2) Cancer death rate
has decreased 12 during 1990-2005, mainly
reflecting decreasing rate of death from lung
cancer 3) expectation cancer death rate may
exceed heart disease death rate by 2010
CDC data, pub. 2009
40
Overview American Cancer Society Estimates for
U.S. population, 2008
  • Incidence new cases of disease in a population
    of persons at risk
  • Mortality death due to disease in a population
    of persons at risk

1,437,000 cases 566,000 deaths (23 U.S.
deaths)
Jemal A et al. Cancer Statistics, 2008. CA
Cancer J Clin 5871, 2008.
41
Both Sexes, Incidence Mortality
Male Incidence and total cases Rank Male Mortality and total cases
Prostate 25 1 Lung 31
Lung 15 2 Prostate 10
Colorectal 10 3 Colorectal 8
Bladder 7 4 Pancreas 6
Melanoma 5 Lymphoma 5 5 Leukemia 4 Esophagus 4 Liver 4
Female Incidence and total cases Rank Female Mortality and total cases
Breast 26 1 Lung 26
Lung 14 2 Breast 15
Colorectal 10 3 Colorectal 9
Uterus 6 4 Pancreas 6
Melanoma 4 Lymphoma 4 Thyroid 4 5 Ovary 6
Adapted from Jemal, et.al. Cancer Statistics,
2008 (American Cancer Society)
42
Significant Trends Cancer
  • Women overall death rate has decreased 10
    since 1991
  • Better detection / Rx breast colorectal CA
  • Decreased cervical cancer
  • Increased lung cancer (more smokers)
  • Men overall death rate decreased 18 since
    1990
  • Marked decrease in lung cancer (fewer smokers)
  • Better detection / Rx prostate and colorectal CA
  • Both sexes deaths from liver cancer doubled
    1978-2008, primarily due to hepatocellular
    carcinomas arising in patients with chronic
    hepatitis C

43
Trends in Cancer Death Rates, Males, 1930-2000
1 Lung
2 Prostate
3 Colon rectum
4 Pancreas
5 Leukemia
44
Trends in Cancer Death Rates, Females, 1930-2000
3 Colorectal
1 Lung
2 Breast
4 Pancreas
5 Ovary
45
Cancer in Children
  • 10 deaths in children ages 1-15 due to cancer
    (accidents 1 cause)
  • 60 of childhood cancer deaths are due to acute
    leukemias (1 cause) and CNS malignancies (2)
  • Improved therapies (biologic, chemotherapy,
    surgical, and radiation) have significantly
    improved likelihood of survival in children with
    malignant neoplasms.

46
2010 ACS Recommendations Early Cancer
Detection
Organ Recommendation (average risk persons)
Breast Mammogram and clinical exam at age 40 and annually for as long as a woman is in in good health (normal mammogram does not rule out cancer, especially if palpable breast mass present). Earlier screening and use of MRI if positive family history or proven genetic mutations.
Prostate Make informed decision with physician about risks/benefits of screening. If screening is elected, do serum PSA and digital rectal exam at age 50 (if African-American or family history, age 45).
Colon Colonoscopy every 5-10 years beginning age 50 (earlier if high risk) additionally, annual fecal occult blood test or fecal immunochemical test are useful. Earlier screening if positive family history or proven genetic mutation.
Cervix Liquid-based Pap test every 2 years after beginning vaginal intercourse or age 21 (whichever is sooner). Age 30 decrease screening to q. 3 years after 3 consecutive normal Pap tests. HPV test and HPV vaccine may alter these recommendations in the future.
Specific recommendations are missing for which
organ with high cancer incidence and mortality?
__________________
47
Inherited Predisposition to Cancer
  • Most cancers are influenced by a combination of
    environmental genetic risk factors
  • Only 10 of human cancers occur in patients with
    documented inherited mutations predisposing them
    to development of cancer.
  • Three categories of inherited predisposition
  • 1) inherited cancer syndromes (autosomal
    dominant) a single mutant gene increases risk
    for cancer of specific type in specific organ(s)
  • 2) familial cancers complex mode of inheritance
  • 3) Defective DNA repair syndromes most autosomal
    recessive and rare HNPCC autsomal dominant,
    common

48
Autosomal Dominant Cancer Syndromes
  • Inherited mutation gametes carry mutation,
    usually a point mutation in single allele of a
    tumor suppressor gene. A somatic cell mutation
    involving the second allele is acquired later in
    life to produce cancer.
  • familial retinoblastoma inherited defective Rb
    gene on chromosome 13 imparts 10,000 fold
    increased risk for retinal neoplasm
  • familial adenomatous polyposis inherited defect
    in APC gene, chromosome 5q21 gt100 colonic
    adenomas by age 20, colon cancer inevitable by
    age 50 therefore, prophylactic total colectomy
    is treatment of choice (coming in GI course)
  • multiple endocrine neoplasia syndromes several
    endocrine organs involved by neoplasms (endocrine
    course)

49
Retinoblastoma inherited vs. sporadic
Chr. 13
Fig.7-35, Pathologic Basis of Disease, 7th
edition, Elsevier 2000
50
Familial Cancers
  • Clustering of common cancers in families,
    particularly when those cancers appear at early
    age
  • Transmission pattern usually unclear (not single
    gene) likely that multiple alleles contribute
  • Risk for siblings of affected 2-3x higher than
    population
  • Examples common carcinomas in breast, colon,
    ovary gliomas of brain melanomas, lymphomas
  • Some familial cancers due to specific mutations
    in tumor suppressor genes
  • BRCA-1 (female breast and ovary)
  • BRCA-2 (female and male breast, ovary)
  • p16 INK4a (20 familial malignant melanoma)

51
Syndromes of Defective DNA Repair
  • DNA instability ? increased rate of mutations
  • Most have autosomal recessive inheritance pattern
    (rare)
  • Examples
  • xeroderma pigmentosum skin cancers after UV
    light exposure
  • ataxia-telangiectasia syndrome mutation ATM
    gene, causing loss of p53-induced delay in cell
    cycle. Acute sensitivity to ionizing radiation
    and defective lymphocyte maturation, leading to
    increased lymphomas
  • hereditary nonpolyposis colon cancer syndrome
    (HNPCC)
  • autosomal dominant inheritance pattern
  • Inactivation DNA mismatch repair gene
  • HNPCC is the most common cancer predisposition
    syndrome which has been well described.

52
Acquired (non-hereditary) Preneoplastic Disorders
very common !
  • Disorders of altered cell replication (fertile
    soil for mutations leading to malignant
    neoplasm)
  • endometrial hyperplasia ? endometrial carcinoma
  • cervical dysplasia ? cervical carcinoma
  • bronchial squamous metaplasia ? dysplasia ? lung
    carcinoma
  • chronic inflammatory diseases ? chronic demand
    for regeneration of injured cells ? more likely
    mutations
  • chronic atrophic gastritis ? dysplasia ? gastric
    carcinoma
  • chronic ulcerative colitis ? dysplasia? colonic
    adenoma or carcinoma
  • chronic reflux esophagitis ? Barretts glandular
    metaplasia? glandular dysplasia ? adenocarcinoma

53
Pathogenesis of carcinoma via altered cell
replication laryngeal carcinoma
many years of tobacco smoke / ethanol
Biopsy of larynx in chronic cigarette smoker
squamous hyperplasia with mild dysplasia
Carcinoma-in-situ (severe dysplasia with marked
nuclear disorder and pleomorphism)
54
Pathogenesis laryngeal carcinoma 2
Carcinoma-in-situ, but basement membrane still
intact
Laryngectomy invasive squamous carcinoma
Invasive squamous carcinoma
55
IV. CARCINOGENIC AGENTS AND ASSOCIATED
NEOPLASMS
56
Definitions C and C
  • Carcinogenesis a progressive process involving
    multiple steps (hits) in which carcinogens
    affect those portions of the genome involved in
    regulation of cell growth, resulting in
    uncontrolled growth of cells (neoplasm).
  • Carcinogen (dual definitions)
  • EXPERIMENTAL agent capable of inducing
    neoplastic transformation of cells in vitro or
    capable of inducing neoplasms in animal
    experiments
  • EPIDEMIOLOGIC agent linked by clinical evidence
    to development of neoplasms (e.g., cigarette
    smoking)

57
Types of Carcinogens
  • CHEMICAL
  • RADIATION
  • VIRAL
  • Others awaiting discovery by class 2012

58
Definitions chemical carcinogenesis
  • Initiation irreversible alteration of cells
    DNA after exposure to a carcinogenic agent
    (initiator)
  • Promotion reversible process of cellular
    proliferation after exposure to a promoter
    (promoter does not damage DNA directly, but
    induces replication of cells with mutated DNA)
  • Chemical carcinogens
  • Complete -- agents which induce both initiation
    and promotion
  • Incomplete -- agents inducing initiation only

59
Experimental chemical carcinogenesis in skin
of mouse
Initiation alone not enough to cause tumor
Initiation permanent DNA damage
Promoter alone no DNA damage to cause tumor
Promoters effects reversible
Fig. 7-41, Robbins and Cotran Pathologic Basis of
Disease, 8th ed., 2010
60
Multistep Theory of Chemical Carcinogenesis
Keys ?indirect carcinogens (e.g., benzopyrene in
cigarette smoke) must be metabolically activated
cytochrome P-450 system ?Protective
1) detoxification active
carcinogens 2) DNA repair 3) apoptosis
Emergence of malignant neoplasm requires more
mutations after proliferation produces a
preneoplastic clone of altered cells
Fig.7-42, Robbins and Cotran Pathologic Basis
of Disease, 8th ed., 2010
61
Occupation-related chemical carcinogens
AGENT OBSERVED CANCER
Arsenic Skin/lung carcinomas
Aromatic hydrocarbons (soot, tars) Skin/lung carcinomas
Aromatic amines (benzidine, naphthylamine) Bladder carcinoma
Aflatoxin B1 (produced by Aspergillus on moldy grains/nuts) Liver cell carcinoma
Asbestos fibers (amphibole type more pathogenic than serpentine type) Mesothelioma (pleura and peritoneum) and lung carcinoma
Polyvinyl chloride (PVC) Angiosarcoma of liver
Chromium and nickel Lung carcinoma
62
Carcinogenic Therapeutic Agents
Drug (s) Increased Risk for These Cancers
Azathioprine cyclosporine (immunosuppressants) Lymphoma
Chlorambucil, melphalan (direct carcinogens, alkylating agents) Lymphoma, Leukemia
Cyclophosphamide (direct, alkylating agent) Bladder
Conjugated estrogens (higher doses) Endometrium
Diethylstilbestrol (synthetic estrogen) Vagina, Cervix
Methoxsalen with ultraviolet A Skin
Phenacetin-containing analgesics Renal Pelvis Ureter
Modified from table 186-3, Cecil Textbook of
Medicine, 22nd ed, Saunders, 2004
63
Radiation Carcinogenesis
  • Forms of radiant energy
  • Ultraviolet light (sun)
  • Electromagnetic (x-rays, gamma rays)
  • Particulate radiation (a and ß particles,
    protons, neutrons)
  • Effects of radiant energy cumulative and latent
  • Particulate radiation higher linear energy than
    x-rays and gamma rays (greater damage to cells)
  • Hierarchy of vulnerability to radiation-induced
    cancers
  • Highest Risk hematopoietic cells
    (leukemias/lymphomas)
  • Still high risk thyroid epithelial cells in
    children/adolescents
  • Intermediate risk breast, lungs, salivary glands

64
Radiation effects long latent period
Stimulus atomic bomb on Hiroshima

Excess first detected observed increase in
myelogenous leukemias Max. excess of
leukemias 7 years post-bomb (avg. latent
period) Epithelial tumors (thyroid, breast)
20-40 year latent periods
65
Skin cancers most common
radiation-associated cancer
  • Ultraviolet rays from sunlight esp. UVB
    (280-320 nm)
  • At risk fair skin (less protective melanin),
    lifelong total exposure, sunburns
  • Mechanisms
  • UVB forms pyrimidine dimers in DNA
  • Dimers normally repaired by nucleotide excision
    pathway
  • Excessive UVB repair pathways capacity
    exceeded some cells with mutations survive and
    are replicated

66
Microbial Carcinogenesis
  • Helicobacter pylori and gastric neoplasms
  • Two classes of carcinogenic viruses
  • DNA human papilloma virus (HPV), Epstein-Barr
    virus (EBV), hepatitis B and C viruses
  • RNA human T-cell leukemia virus-1 (HTLV-1)

67
H. pylori gastric adenocarcinoma and
B-cell lymphomas
  • Gastric adenocarcinoma
  • setting epithelial regeneration in chronic
    inflammation (more opportunity for mutations)
  • only 3 of persons with chronic infections
  • Hp strains with increased risk
    cytotoxin-associated A gene product enters
    epithelial cells ? simulates unregulated growth
    factor stimulation
  • B-cell lymphoma (MALTomas)
  • In inflammation, reactive T-cell produce
    polyclonal B cells
  • One B-cell may undergo further mutation to start
    monoclonal tumor
  • B-cells depend on T-cells for activation of
    transcription factors
  • Treatment eradicate Hp ? removes Ag stimulating
    T cells ? B cell proliferation
    inhibited

68
H. Pylori and gastric neoplasia
  • Antibiotics for H. pylori usually induce
    regression of low-grade lymphomas
  • If MALToma (Mucosa-Associated Lymphoid Tumor)
    acquires additional mutations (e.g., t (1118)
    that activate transcription independent of T-cell
    stimulation, the neoplasm may spread despite
    eradication of H. pylori
  • Morphologic development of gastric
    adenocarcinoma prolonged H. pylori infection
    induces morphologic sequence of changes
  • Chronic inflammation ? epithelial regeneration ?
    intestinal-type metaplasia ? dysplasia ? carcinoma

MALToma of stomach (low-grade B-cell
lymphoma)
69
DNA virus Human papilloma virus (HPV)
  • Cuiffo (1907) showed human warts were caused by a
    cell-free transmissible agent
  • 70 genetically distinct types HPV, most causing
    benign papillomas of skin and mucosa
  • Cancer-associated subtypes of HPV
  • 5, 8,14 skin carcinoma
  • 16,18 risky for high-grade squamous dysplasia
    squamous carcinoma of uterine cervix and
    anogenital region. HPV-16 and 18 account for 70
    of cervical carcinomas
  • 30,40 squamous carcinoma of larynx

70
HPV proteins and cell cycle
Fig. 7-43, PBD 8th ed, 2010
HPV integrates in host cell DNA, and
overexpresses viral proteins E6 E7 (early gene
products in types 16 and 18). These disable two
important tumor suppressor proteins (p53, RB)
which normally regulate the cell cycle E6 and
E7 bind to p53, degrades p53 and BAX ? inhibits
apoptosis E7 inactivates p21 (CDK inhibitor) ?
promotes progression cell cycle E7 binds to
RB-E2F complex, displaces E2F transcription
factors ? promotes progression cell cycle
71
DNA virus Epstein-Barr virus
Burkitt lymphoma B cell lymphoma Most common
childhood tumor in Central Africa and New Guinea
gt90 African Burkitt lymphomas have EBV genome
in tumor cells
  • Pathogenesis African Burkitt lymphoma
  • B cell infection latent no viral replication
  • Infected B-cell pool expanded by gene product
    latent membrane protein-1 (LMP-1)
  • Acts like CD40 receptor (T-helper signal)
  • Activates proliferation autonomously of T
  • Inhibits activation BCL2 ? no apoptosis
  • NET subpopulation evades T cell killing and is
    available for additional mutation (MYC
    translocation) to develop a monoclonal neoplasm
    of B-cells

t(814) puts c-MYC oncogene next to Ig gene locus
Fig. 7-44, Robbins and Cotran Pathologic Basis of
Disease, 8th ed., 2010
72
DNA viruses Hepatitis B and C
  • 80 of hepatocellular carcinomas worldwide arise
    in persons with chronic hepatitis B or C
  • HBV endemic in Africa, China high incidence
  • Recent U.S. increase in liver carcinoma due
    mainly to rise in chronic hepatitis C
  • Molecular pathogenesis unclear some inhibition
    of apoptosis in hepatocytes
  • Persistent hepatocellular damage and
    regeneration opportunities for mutations

73
RNA Virus Human T-Cell Leukemia Virus Type 1
(HTLV-1)
  • Associated with adult T-cell leukemia / lymphoma
    in endemic areas of Japan, Pacific Islands, West
    Indies
  • Tropic for CD4 T lymphocytes
  • Infected T cells transmitted by sexual
    intercourse, blood products, and breast feeding
    long latent period of 40-60 years before leukemia
    develops
  • Viral tax gene product polyclonal proliferation
    T cells, inactivates cell cycle inhibitor
    p16/INK4a, activates NF-?b (anti-apoptosis
    transcription factor)
  • Additional mutations of proliferating T cells
    required AFTER HTLV-1 infection, since only 3-5
    of those with infection ever develop T-cell
    leukemia

74
ALCOHOL-RELATED CANCERS
  • Oropharynx (tobacco abuse synergistic)
  • Larynx (tobacco abuse synergistic)
  • Esophagus (tobacco abuse synergistic)
  • Liver (alcohol-induced cirrhosis increases risk
    for hepatocellular carcinoma)

75
COFFIN NAILS
  • Cigarette smoking has been called the single
    most important environmental factor contributing
    to premature death in the United States
  • --S.R. Robbins, Pathologic Basis of Disease,
    2nd edition, 1979.
  • Stanley R. Robbins, 1915-2003, author and first
    editor of Robbins Pathologic Basis of Disease,
    first published in 1974

76
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77
Death Rates in Cigarette Smokers
78
Cancer deaths in smokers
LUNG cancer
79
Dose effect cigarette smoking lung cancer
80
Laboratory Diagnosis of Cancer

81
TISSUE IS THE ISSUE
  • The anatomic pathologist serves as an essential
    consultant to clinicians by establishing a
    definitive tissue diagnosis for all neoplastic
    diseases.
  • Accurate diagnosis, based on study of neoplastic
    tissue, determines prognosis treatment options
    for patients with neoplasms.
  • All other means of investigation (history,
    physical exam, imaging studies, lab tests) may
    provide supportive evidence for neoplasm, but
    diagnosis of cancer must be proven by tissue or
    cytologic examination. TISSUE IS THE ISSUE.
  • Treatment of cancer without a proven pathologic
    diagnosis is malpractice.

82
Role of Anatomic Pathologist
  • Study tissue/cells to classify tumor as to its
    cell type (cell of origin) and decide benign,
    malignant, uncertain biologic potential name
    of neoplasm
  • If malignant neoplasm, two determinations
  • GRADE how differentiated the neoplastic cells
    appear under microscope, compared to normal cell
    of origin
  • grade 1 well differentiated grades 3-4
    poorly differentiated
  • STAGE how far have neoplastic cells spread from
    the site where tumor started? (use data from
    tissues AND imaging)
  • stage 1 in organ of origin stage 4
    widespread metastases
  • Intermediate stages vary by organ and tumor
    type
  • STAGE MOST VALUABLE SINGLE PREDICTOR of
    PROGNOSIS

83
DIAGNOSTIC MODALITIES (interpreted by an
anatomic pathologist)
  • Cytology
  • Small Biopsy
  • Surgical Excision of Tumor

84
Cytology, cervical -vaginal smear high grade
squamous intraepithelial lesion ( severe
squamous dysplasia)
Normal superficial squamous cell
Dysplastic squamous cells enlarged nuclei of
variable size and shape, abnormal chromatin,
irregularities in nuclear membrane
85
Cytology, fine needle aspiration of breast mass
Diagnosis fibroadenoma (benign neoplasm)
86
Small biopsy bone marrow core biopsy
Biopsy is hypercellular hematopoietic cells and
fat are replaced by sheets of dysplastic plasma
cells
Diagnosis plasma cell myeloma (neoplasm of
mature B-cells)
87
SURGICAL EXCISION
  • Curative attempt to completely remove the
    neoplasm surgically (with margin of normal tissue
    around the neoplasm)
  • Palliative to relieve obstruction or pain,
    knowing that all neoplastic tissue cannot be
    removed
  • Debulking removing most of the neoplasm to
    decrease total tumor burden, in preparation for
    additional modes of therapy
  • For Diagnosis e.g. excision of enlarged lymph
    node to determine nature of process

88
Surgical excision nasal polyp
History 55 yo male with intermittent epistaxis
soft 1.5 cm polyp identified on nasal mucosa and
surgically excised
Diagnosis metastatic renal cell carcinoma
(this
patients primary tumor was subsequently found in
kidney)
89
THERAPY OF NEOPLASIA
  • Surgery
  • Radiation
  • Chemotherapy
  • Biologic Response Modifiers

90
Therapy SURGERY
  • Often curative in Stage I tumors
    (tumors confined to the organ in which they
    originate)
  • Palliative debulking of primary tumor and/or its
    metastases can enhance the effectiveness of
    subsequent therapies
  • Ineffective for systemic malignancies
    (e.g., leukemias, lymphomas)

91
Therapy RADIATION
  • Potentially curative for localized tumors
  • Often used post-surgery to treat residual
    unresected/microscopic tumor (tumor cells induced
    to enter cell cycle)
  • Useful for palliation or to alleviate painful
    symptoms (e.g., bone metastases)

92
Therapy CHEMOTHERAPY
  • Expanding role, often adjuvant treatment with
    surgery or radiation (adjuvant given in
    combination with another therapy)
  • Curative for some malignant neoplasms
  • Many neoplasms respond with decreased tumor
    burden and lengthening of symptom-free period
  • Treatment of choice for systemic malignancies
    (leukemias, lymphomas)

93
Therapy Biologic Response Modifiers
  • Also known as biologic therapy
  • Currently an intense area of research
  • Includes vaccines, hormones, cytokines, growth
    factors, and monoclonal antibodies
  • Often designed to supplement or enhance the
    immune response and its mediators
  • May be directed against a single tumor
    characteristic e.g., anti-VEGF drug bevacizumab
  • Wide open opportunities for class of 2012!

94
Bevacizumab, MoAb against VEGF
813 patients with previously untreated metastatic
colon carcinoma randomized to receive standard
IFL chemotherapy with placebo (411 patients) vs.
IFL plus bevacizumab (402 patients)
Hurwitz et.al. Bevacizumab plus Irinotecan,
Fluorouracil, and Leucovorin for Metastatic Colon
Cancer NEJM 3502335-2342, June 3, 2004
95
References (textbooks only)
  • Kumar, Abbas, Fausto, Aster Robbins and Cotran
    Pathologic Basis of Disease, 8th edition,
    Elsevier Saunders, 2010.
  • McGee, Isaacson, Wright Oxford Textbook of
    Pathology, Oxford University Press, 1992.
  • DeVita, Hellman, Rosenberg Cancer, Principles
    and Practice of Oncology, 5th edition,
    Lippincott-Raven, 1997.
  • Fletcher, DM Diagnostic Histopathology of
    Tumors, 2nd edition, Churchill Livingstone, 2000.
  • Goldman, Ausiello Cecil Textbook of Medicine,
    22nd edition, WB Saunders, 2004.
  • Mittros, FA Slide Atlas of Gastrointestinal
    Pathology, Gower Medical Publishing, 1989.
  • Townsend, Beauchamp, Evers, Mattox Sabiston
    Textbook of Surgery, 17th edition, Elsevier
    Saunders, 2004.
  • Vogelstein, Kinzler The Genetic Basis of Human
    Cancer, McGraw-Hill, 1998.
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