Ch7 Neoplasm

7/28/2019 Ch7 Neoplasm

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Neoplasia


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NEOPLASIA (TUMORS)

Definitions

Nomenclature

Biology of Tumor Growth

Epidemiology

Molecular Basis of Cancer

Molecular Basis of Carcinogenesis

Agents (The Usual Suspects)

Host Defense (Tumor Immunity)

Clinical Features of Tumors


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Defnition of Neoplasia

A neoplasm is an abnormal mass of tissue, the

growth of which exceeds and is

uncoordinated with that of the normal tissues

and persists in the same excessive manner

after cessation of the stimuli which evoked

the change-Willis

Genetic changes

Autonomous

Clonal


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Nomenclature Benign Tumors

-oma = benign neoplasm (NOT carcin-, sarc-, lymph-,

or melan-)

Mesenchymal tumors (mesodermal derived)

chrondroma: cartilaginous tumor

fibroma: fibrous tumor osteoma: bone tumor

Epithelial tumor (ecto- or endo- derived)

adenoma: tumor forming glands

papilloma: tumor with finger like projections

papillary cystadenoma: papillary and cystic tumor forming

glands

polyp: a tumor that projects above a mucosal surface


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Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 28 July 2005 03:41 PM)

2005 Elsevier


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Colonic Polyp: Tubular Adenoma

Stalk

Tumor


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Tumors with mixed differentiation mixed tumors: e.g. pleomorphic adenoma of salivary gland

carcinosarcoma

Teratoma tumor comprised of cells from more than one germ layer

arise from totipotent cells (usually gonads)

benign cystic teratoma of ovary is the most common teratoma

Aberrant differentiation (not true neoplasms) Hamartoma: disorganized mass of tissue whose cell types are

indiginous to the site of the lesion, e.g., lung

Choriostoma: ectopic focus of normal tissue (heterotopia),e.g., pancreas, perhaps endometriosis too

Misnomers hepatoma: malignant liver tumor

melanoma: malignant skin tumor

seminoma: malignant testicular tumor

lymphoma: malignant tumor of lymphocytes


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Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 28 July 2005 03:41 PM)

2005 Elsevier


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Natural History Of Mal ignan t Tumors

1. Malignant change in the target

cell, referred to as

transformation

2. Growth of the transformed cells

3.Local invasion

4. Distant metastases.


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Differentiation

Well differentiated neoplasm Resembles mature cells of tissue of origin

Poorly differentiated neoplasm

Composed of primitive cells with littledifferentiation

Undifferentiated or anaplastic tumor

Correlation with biologic behavior Benign tumors are well differentiated

Poorly differentiated malignant tumors usually

have worse prognosis than well differentiated

malignant tumors.


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If cells LOOK BAD, they are probably going to BEHAVE BADLooking bad means NOT looking like the cells they supposedly

arose from!


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If cells LOOK GOOD, they are probably going to BEHAVE GOODLooking good means looking like the cells they supposedly arose from!


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ANAP ASIA CANCER


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***Pleomorphism

Size shape

Abnormal nuclear morphology

***Hyperchromasia High nuclear cytoplasmic ratio Chromatin clumping

Prominent nucleoli

Mitoses Mitotic rate

Location of mitoses

Loss of polarity

ANAPLASIA = CANCER


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Dysplasia

Literally means abnormal growth Malignant transformation is a multistep process

In dysplasia some but not all of the features of

malignancy are present, microscopically

Dysplasia may develop into malignancy Uterine cervix

Colon polyps

Graded as low-grade or high-grade, often prompting

different clinical decisions

Dysplasia may NOT develop into malignancy

HIGH grade dysplasia often classified with CIS


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Tumor Growth Rate Doubling time of tumor cells

Lengthens as tumor grows

30 doublings (109 cells) = 1 g (months to years)

10 more doublings (1 kg) = lethal burden ()

Fraction of tumor cells in replicative pool May be only 20% even in rapidly growing tumors

Tumor stem cells

Rate at which tumor cells are shed or lost Apoptosis

Maturation

Implications for therapy


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clonal


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Features of Malignant Tumors

Cellular features

Local invasion Capsule Basement membrane

Metastasis

Unequivocal sign of malignancy Seeding of body cavities

Lymphatic

Hematogenous


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Significance of Nodal Mets

Example of breast cancer

Halsted radical mastectomy Sentinel node biopsy

Prognostic

Number of involved nodes is an importantcomponent of TNM staging system

Therapeutic

Overall risk of recurrence Extent of nodal involvement

Histologic grade and other considerations

Adjuvant chemotherapy


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Change In Incidence Of Various Cancers With

Migration From Japan To The United States

Predisposing Factors for Cancer


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Predisposing Factors for Cancer Age

Most cancers occur in persons 55 years

Childhood cancers Leukemias & CNS neoplasms

Bone tumors

Genetic predispostion Familial cancer syndromes

Early age at onset Two or more primary relatives with the cancer (soil theory)

Multiple or bilateral tumors

Polymorphisms that metabolize procarcinogens, e.g., nitrites

Nonhereditary predisposing conditions Chronic inflammation?

Precancerous conditions Chronic ulcerative colitis

Atrophic gastritis of pernicious anemia

Leukoplakia of mucous membranes

Immune collapse?


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Defnition of Neoplasia

A neoplasm is an abnormal mass of tissue, the growthof which exceeds and is uncoordinated with that of

the normal tissues and persists in the same excessive

manner after cessation of the stimuli which evoked

the change - Willis

Genetic changes

Autonomous Clonal


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TRANSFORMATION &


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TRANSFORMATION &

PROGRESSION Self-sufficiency in growth signals

Insensitivity to growth-inhibiting signals

Evasion of apoptosis Defects in DNA repair: Spell checker

Limitless replicative potential: Telomerase

Angiogenesis

Invasive ability

Metastatic ability


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PROTO- Mode of Associated Human


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Category

PROTO

Oncogene

Mode of

Activation

Associated Human

Tumor

Signal

TransductionProteins

GTP-binding K-RAS Point mutation Colon, lung, and pancreatic

tumors

H-RAS Point mutation Bladder and kidney tumors

N-RAS Point mutation Melanomas, hematologic

malignancies

Nonreceptor

tyrosine kinase

ABL Translocation Chronic myeloid leukemia

Acute lymphoblastic leukemia

RAS signal

transduction

BRAF Point mutation Melanomas

WNT signal

transduction

-catenin Point mutation Hepatoblastomas,

hepatocellular carcinoma

Mode of


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Category

PROTO-

Oncogene

Mode of

Activation Associated Human

Tumor

NuclearRegulatory

Proteins

Transcrip.

activators

C-MYC Translocation Burkitt lymphoma

N-MYC Amplification Neuroblastoma,

small cell

carcinoma of lungL-MYC Amplification Small cell

carcinoma of lung

C


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MYCEncodes for transcription factors

Also involved with apoptosis


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P53 and RASp53

Activates DNA repair

proteins

Sentinel of G1/Stransition

Initiates apoptosis

Mutated in more than50% of all human

cancers

RAS H, N, K, etc., varieties

Single most common

abnormality ofdominant oncogenes in

human tumors

Present in about 1/3 ofall human cancers


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Tumor (really GROWTH)


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Tumor (really GROWTH )suppressor genes

TGF- COLON E-cadherin STOMACH NF-1,2 NEURAL TUMORS APC/-cadherin GI, MELANOMA SMADs GI RB RETINOBLASTOMA P53 EVERYTHING!! WT-1WILMS TUMOR p16 (INK4a) GI, BREAST (MM if inherited) BRCA-1,2 BREAST KLF6 PROSTATE


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Evasion of APOPTOSIS

BCL-2

p53

MYC


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DNA REPAIR GENE DEFECTS

DNA repair is like a spell checker

HNPCC (Hereditary Non-Polyposis Colon

Cancer [Lynch]): TGF-, -catenin, BAX Xeroderma Pigmentosum: UV fixing gene

Ataxia Telangiectasia: ATM gene

Bloom Syndrome: defective helicase

Fanconi anemia


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METASTATIC GENES?

NM23

KAI-1KiSS

CHROMOSOME CHANGES


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CHROMOSOME CHANGES

in CANCER

TRANSLOCATIONS and INVERSIONS

Occur in MOST Lymphomas/Leukemias

Occur in MANY (and growing numbers) ofNON-hematologic malignancies also

Malignancy Translocation Affected Genes

Chronic myeloid leukemia (9;22)(q34;q11) Ab1 9q34


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Chronic myeloid leukemia (9;22)(q34;q11) Ab1 9q34

bcr22q11

Acute leukemias (AML and ALL) (4;11)(q21;q23) AF4 4q21

MLL 11q23(6;11)(q27;q23) AF6 6q27

MLL 11q23

Burkitt lymphoma (8;14)(q24;q32) c-myc8q24

IgH 14q32

Mantle cell lymphoma (11;14)(q13;q32) Cyclin D 11q13

IgH 14q32

Follicular lymphoma (14;18)(q32;q21) IgH 14q32

bc l-2 18q21

T-cell acute lymphoblastic leukemia (8;14)(q24;q11) c-myc8q24

TCR- 14q11

(10;14)(q24;q11) Hox11 10q24

TCR- 14q11

Ewing sarcoma

(11;22)(q24;q12)

Fl-1 11q24

Carcinogenesis is MULTISTEP


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Carcinogenesis is MULTISTEP NO single oncogene causes cancer

BOTH several oncogenes AND severaltumor suppressor genes must be involved

Gatekeeper/Caretaker concept

Gatekeepers: ONCOGENES and TUMORSUPPRESSOR GENES

Caretakers: DNA REPAIR GENES Tumor PROGRESSION

ANGIOGENESIS

HETEROGENEITY from original single cell

Carcinogenesis:


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Carcinogenesis:

The USUAL (3) Suspects

Initiation/Promotion concept: BOTH initiators AND promotors are needed

NEITHER can cause cancer by itself

INITIATORS (carcinogens) causeMUTATIONS

PROMOTORS are NOT carcinogenic by

themselves, and MUST take effect AFTER

initiation, NOT before

PROMOTORS enhance the proliferation ofinitiated cells


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Q: WHO are the usual suspects?

Inflammation? Teratogenesis?

Immune

Suppression?

Neoplasia?

Mutations?

A: The SAME 3 that are


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A: The SAME 3 that are

ALWAYS blamed!

1) Chemicals

2) Radiation

3) InfectiousPathogens

CHEMICAL CARCINOGENS:


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INITIATORS

DIRECT

-Propiolactone

Dimeth. sulfate

Diepoxybutane

Anticancer drugs

(cyclophosphamide,

chlorambucil,

nitrosoureas, and others) Acylating Agents

1-Acetyl-imidazole

Dimethylcarbamyl chloride

PROCARCINOGENS

Polycyclic and Heterocyclic

Aromatic Hydrocarbons

Aromatic Amines, Amides,

Azo Dyes Natural Plant and Microbial

Products

Aflatoxin B1 Hepatomas

Griseofulvin Antifungal

Cycasin from cycads

Safrole from sassafras

Betel nuts Oral SCC



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INITIATORS

OTHERS Nitrosamine and amides (tar, nitrites)

Vinyl chloride angiosarcoma in Kentucky Nickel

Chromium

Insecticides

Fungicides

PolyChlorinated Biphenyls (PCBs)



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PROMOTORS

HORMONES

PHORBOL ESTERS (TPA), activate kinase C

PHENOLS

DRUGS, many

Initiated cells respond and proliferateFASTER to promotors than normal cells

RADIATION CARCINOGENS


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RADIATION CARCINOGENS

UV: BCC, SCC, MM (i.e., all 3)

IONIZING: photons and particulate

Hematopoetic and Thyroid (90%/15yrs) tumorsin fallout victims

Solid tumors either less susceptible or require a

longer latency period than LEUK/LYMPH

BCCs in Therapeutic Radiation

VIRAL


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VIRAL CARCINOGENESIS

HPV SCC EBV Burkitt Lymphoma HBV HepatoCellular Carcinoma (Hepatoma) HTLV1 T-Cell Malignancies KSHV Kaposi Sarcoma

H l i C C OG S S


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H. pylori CARCINOGENESIS

100% of gastric lymphomas (i.e., M.A.L.T.-omas)

Gastric CARCINOMAS also!

HOST DEFENSES


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HOST DEFENSES

IMMUNE SURVEILLENCECONCEPT

CD8+ T-Cells NK cells

MACROPHAGES

ANTIBODIES


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CYTOTOXIC CD8+ T-CELLS are the main eliminators of tumor cells

How do tumor cellsi ill ?


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escape immune surveillance?

Mutation, like microbes

MHC molecules on tumor cell surface

Lack of CO-stimulation molecules, e.g.,(CD28, ICOS), not just Ag-Ab recognition

Immunosuppressive agents

Antigen masking

Apoptosis of cytotoxic T-Cells (CD8), i.e.,

the damn tumor cell KILLS the T-cell!

Eff t f TUMOR th HOST


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Effects of TUMOR on the HOST

Location anatomic ENCROACHMENT HORMONE production

Bleeding, Infection

ACUTE symptoms, e.g., rupture, infarction

METASTASES

CACHEXIA


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CACHEXIA Reduced diet: Fat loss>Muscle loss

Cachexia: Fat loss AND Muscle loss

TNF ( by default) IL-(6)

PIF (Proteolysis Inducing Factor)


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ENDOCRINE


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Cushing syndrome Small cell carcinoma of lung ACTH or ACTH-like substance

Pancreatic carcinoma

Neural tumors

Syndrome of inappropriateantidiuretic hormonesecretion

Small cell carcinoma of lung;intracranial neoplasms

Antidiuretic hormone or atrialnatriuretic hormones

Hypercalcemia Squamous cell carcinoma of lungParathyroid hormone-related protein

(PTHRP), TGF-, TNF, IL-1

Breast carcinoma

Renal carcinoma

Adult T-cell leukemia/lymphoma

Ovarian carcinoma

Hypoglycemia Fibrosarcoma Insulin or insulin-like substance

Other mesenchymal sarcomas

Hepatocellular carcinomaCarcinoid syndrome Bronchial adenoma (carcinoid) Serotonin, bradykinin

Pancreatic carcinoma

Gastric carcinoma

Polycythemia Renal carcinoma Erythropoietin

Cerebellar hemangioma

Hepatocellular carcinoma

GRADING/STAGING


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GRADING/STAGING

GRADING: HOWDIFFERENTIATED ARE THE

CELLS?STAGING: HOW MUCH

ANATOMIC EXTENSION? TNM

Which one of the above do youthink is more important?


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ADENOCARCINOMA GRADINGLets have some FUN!


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Lets have some FUN!


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TUMOR MARKERS


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TUMOR MARKERS

HORMONES: (Paraneoplastic Syndromes) ONCOFETAL: AFP, CEA

ISOENZYMES: PAP, NSE

PROTEINS: PSA, PSMA (M = membrane) GLYCOPROTEINS: CA-125, CA-195, CA-153

MOLECULAR: p53, RAS

NOTE: These SAME substances which can

be measured in the blood, also can be stained

by immunochemical methods in tissue

MICRO-ARRAYS


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MICRO ARRAYS

THOUSANDS of genes identified fromtumors give the cells their own identity

and FINGERPRINT and may give

important prognostic information as well

as guidelines for therapy. Some say this

may replace standard histopathologicidentifications of tumors.

What do you think?

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Ch7 Neoplasm