PAJ 5101 Clinical Pathophysiology

Abnormal Cell Growth and Differentiation (act or process of becoming a mature cell)

Lecture prepared and presented by:Hugh G Rappa, MD

ProfessorAcademic Director

Associate Dept. Chair 1

Learning ObjectivesAt the conclusion of the lecture, in conjunction with

required readings, lecture notes and any recommended internet web pages, the student should be able to:

1. Compare and contrast the various etiologies and risk factors for coronary heart disease2. Compare and contrast nonneoplastic abnormalities of cell growth3. Compare and contrast neoplastic abnormalities of cell growth4. Compare and contrast the routes of tumor spread5. Compare and contrast the different types of benign tumors according to origin6. Compare and contrast the different types of malignant tumors according to origin7. Compare and contrast the categories of gene alterations in carcinogenesis8. Describe the steps of chemical carcinogenesis2

Learning Objectives

9. Describe microorganisms’ role in carcinogenesis

10.Compare and contrast the theories of heredity and carcinogenesis

11.Define cancer staging12.Describe the TNM staging system

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Nonneoplastic Abnormalities in Cell Growth

Agenesis/aplasia (without creation / growth)a. Failure of an organ to develop at all

Hypoplasiaa. partial development of an organb. results in functional deficiency

Atrophya. shrinkage of a tissue or organ that has formed or matured normally (not loss of cell, cells become smaller)

Hypertrophy (more nourishment)• a. enlargement of a tissue or organ due to

enlargement of individual cells• tissue consists of permanent, non-dividing cells 4

Nonneoplastic Abnormalities in Cell GrowthMetaplasia

a. change of 1 cell type to another cell type in response to a chronically irritating or injurious stimulus; involves change in differentiation

Dysplasia (cervical dysplasia – looking for different cells)

a. disordered growth (difficult) typically occurring in epithelial cells which results in variation of cellular size and shape,b. There is a loss of architectural orientation; c. cell nuclei may be darker and larger than normal; d. may progress to cancer: precancerous

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Neoplastic Cell Growth and Differentiation

Neoplasm (no insight if benign or malignant)a. abnormal mass of tissue growing autonomously

thus is self-perpetuating without physiologic growth stimulib. The entire cell population which is proliferating is

derived from 1 cell that underwent genetic alterationc. Components of a neoplasm

1. parenchyma: proliferating neoplastic cells2. stroma: connective tissue and blood vessels

d. Interchangeable with the term tumor6

Neoplastic Cell Growth and Differentiation

Cancer (no contact inhibition, keeps growing even after it touches surrounding cells)a. malignant neoplasm (goes into surrounding tissue)b. features of malignancy ( e.g. invasive growth)c. derived from Latin term for crab because it “adheres to any

tissue that it seizes upon” ; it reaches out with “ claws” like a crab, and invades surrounding tissue

Metastasisa. portion of a cancer that has migrated from the primary site

to other sites (EX. Colon cancer liver: from portal system)

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Neoplastic DifferentiationThe degree that neoplasm is similar to comparable

normal cells in appearance and function (the more it is further from the parent cell the more aggressive it is: cancer)

a.Well differentiated (I) - close resemblance (to parent cell)

b.Moderately differentiated (II) - intermediate resemblance (to parent cell)

c.Poorly differentiated (III) - poor resemblance (to parent cell)

d. Anaplasia – (IV) lack of differentiation. (doesn’t function or look like parent cell)

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Benign vs. Malignant Tumors

Benign Tumors1. Well circumscribed border2. Compresses surrounding

tissue3. Often has a fibrous capsule4. Usually well differentiated5. Does not metastasize

(migrate)6. Slow growing

Malignant tumor1. Ragged border, not easily

discernable2. Infiltrates and invades

surrounding tissue3. Various degrees of

differentiation4. May metastasize (migrate)5. Grow rapidly

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Routes of Tumor MetastasisSpread through Blood Vessels (HEMATOgenous spread )

a. spread is typically through VEINS ( especially the portal vein and inferior vena cava so cancers often spread to liver or lungs respectively)

b. mechanism: 1. tumor cells SEPARATE from each other and

degrade intercellular tissue with enzymes2. cells invade vessel and multiple tumor fragments travel to other

organs3. an organ may have multiple metastatic tumor nodules

Spread through Lymphatic Systema. mechanism: cancer spreads into lymphatic vessels located at the tumor

margin and follows the natural route of lymphatic drainage

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Routes of Tumor Metastasis

Seeding Body Cavities and Surfacesa. Pericardial, pleural, peritoneal cavities: defined by membrane covering organs in cavity ( heart; lungs; abdominal organs respectively ) and membrane covering body cavity wall; joint cavitiesb. subarachnoid spacec. mechanism

1. invasion of tumor through organ surface into cavity

2. most commonly occurs in peritoneal cavity

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Classification of Benign Tumors

Mesenchymal tumors a. tumors derived from supportive tissueb. e.g.: connective tissue; adipose tissue; cartilage; smooth and striated muscle; bone

Epithelial tumors:a. Adenoma- benign epithelial tumorb. forming a glandular pattern histologically or derived from a glandc. sometimes secrete hormone (s) produced by gland of origin

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Classification of Benign Tumors

papilloma: tumor producing microscopically or macroscopically visible “finger-like” or warty projections from an epithelial surface

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Classification of Malignant Tumors

Mesenchymal origin a. originate from supportive tissue b. called sarcomas

epithelial origin: (how they name it)a. called carcinomas (carcinomata – plural?)

1.carcinoma with glandular growth pattern: adenocarcinoma

2. carcinoma with squamous cell differentiation: squamous cell carcinoma

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Normal Tumor

•Abnormal regulation of cell growth

•Abnormal cell-cell interactions

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Normal Tumor

Normal stem cell Cancer “stem cell”

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Characteristics of Stem Cells• Unlimited capacity for self-renewal

– Cellular “immortality”– But relatively low rate of proliferation

• Capable of differentiation into the mature cells that constitute organ function – Proliferation can be dramatic once a cell has committed to

differentiation– But differentiated cells have limited life-span

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Etc., Etc., Etc.

Maturation

Compartment

Etc.

Maturation Compartment

Stem cellCompartment

Proliferative

Compartment

Normal Cancer

Cell loss (apoptosis)

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Lessons From Stem Cell Kinetics

• Abnormal differentiation of cancer cells results in a greater percentage of cells in the proliferative pool (at the expense of the maturation pool)

• Tumor (mass) growth exceeds normal growth due to a higher proliferative fraction and a lower rate of cell loss (death)

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Benign Malignant

pleomorphism abnormal nuclei mitoses abnormal differentiation

(far from parent cell)

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Abnormal cell-substratum interaction (can go through surrounding tissuesIn either direction)

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Invasion into adjacent structures

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Penetration of vasculature Survival in circulationSurvival in a new organ 23

metastatic spread is not random but determined by:-pattern of venous blood flow-specific receptors on tumor and endothelial cells-metastatic “fitness” is genetically determined

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MECHANISMS OF CARCINOGENESIS

1. Multistep process resulting in the formation of cancer secondary to the damage to multiple normal regulatory genes

2. damaged genes:a. may be inherited and/or b. develop from the effects of

1. chemical carcinogens, 2. ultraviolet and ionizing radiation,3. microbial organisms ( viruses and a bacterium )

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Categories of Gene Alterations in Carcinogenesis

1. protooncogenes: a. promote regulated cell growth-b. are growth factors, growth factor receptors, nuclear

regulatory proteins, and proteins involved with signal transduction

c. mutations convert these genes to oncogenes which encode

d. oncoproteins: oncoproteins promote continued growth in an uncontrolled manner

2. tumor suppressor genes: a. inhibit cell growth b. important examples: NF-1; NF-2; RB; APC2.

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Categories of Gene Alterations in Carcinogenesis

3. genes promoting repair of damaged DNAa. important examples: BRCA-1 and BRCA-2

4. genes promoting self destruction of cells with damaged DNA ( apoptosis ):a. necessary to prevent damage from becoming continued in dividing cells and permanent

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Chemical Carcinogenesis

Initiation (caused by initiators):a. chemicals cause permanent damage to DNAb. Examples:

1. polycyclic aromatic hydrocarbons ( produced by combustion of tobacco ) bladder and lung cancer (some of most powerful carcinogens known )

Promotion (caused by promoters): a. cause sustained or enhanced proliferation of cells damaged by initiating agents resulting in increased risk of successive mutations leading to cancer

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 Microbes and Cancer

VIRUSES1. human papilloma virus ( HPV): cervical cancera. many genetic subtypes; types 16 and 18 most commonly cause cervical cancerb. HPV incorporates its viral DNA into the host cell genome in a location resulting in excessive production of the viral proteins, E6 and E7: c. E6 blocks p53 ( is needed to promote self destruction of mutated cells ) and d. E7 blocks RB ( is needed to inhibit cell growth , tumor suppressor gene)

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Microbes and Cancer

Epstein Barr virus: (family of Herpes)a. certain B cell lymphomas and nasopharyngeal

carcinomab. infects B lymphocytes and “immortalizes them” c. also infects epithelial cells of oropharynxd. patients with normal immune function do not

have “immortalization of their B lymphocytes” resulting in cancer, but are instead asymptomatic, or have self limited infectious mononucleosis

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Microbes and Cancer

Hepatitis B virus (HBV): a. hepatocellular carcinomab. by infecting the liver chronically and causing chronic liver cell injury, it stimulates continuous regenerative attempts and proliferation of liver cells; these cells are at RISK for genetic mutations c. encodes a protein which binds to p53 and interferes with its function

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Radiation and Cancer

Ultraviolet radiationa. UVB

Ionizing radiation

Can cause abnormal DNA

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Heredity and Cancer1. alterations of tumor suppressor proteins

a. normally suppress cell growthb. Rb protein: associated with development of retinoblastoma ( a rare childhood tumor of eye) as well as osteosarcoma ( bone cancer) c. NF 1 and 2: neurofibromatosis which is associated with a variety of tumors of both central and peripheral nervous system ( NF-1 = neurofibromatosis type 1; NF-2 = neurofibromatosis type 2 )d. p16 ( INK4a ): malignant melanoma e. APC: familial adenomatosis polyposis syndrome: patients develop 500- 2500 premalignant colon tumors (adenomatous polyps ) in their teens and twenties; they develop colon cancer by age 50

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Heredity and Cancer2. Inherited alterations of genes that allow repair of damaged

DNAa. a minority of breast cancer patients have an inherited mutation of

the DNA repair genes BRCA- 1 and BRCA- 2 b. xeroderma pigmentosum: patients inherit defective

DNA repair genes and cannot repair mutations caused by UVB radiation increased risk of developing skin cancer in sun exposed skin areas

3. Inherited alterations of genes necessary for preventing propagation of DNA mutations by causing mutated cells to self destruct ( undergo apoptosis )

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Cancer Staging

1. Purposes of cancer staging:a. indicates extent of spread of a cancer within the

patient b. determines prognosisc.guides management

2.Staging is based on:a. size of primary lesionb. extent of spread to regional lymph nodesc. presence or absence of blood-borne

metastases35

TMN Cancer StagingT = Primary Lesion

a. Tis: lesion has not invaded through tissue basement membrane ( is refers to “in situ” )

b. T1- T3 ( or higher ): increasing size of primary lesion; increasing depth of invasion (through substratum)

N = Regional Lymph Nodesa. Nx: regional lymph nodes cannot be assessed

b. N0: no regional lymph node metastasis

c. N1 N2 ( or higher ): involvement of increasing # and range of lymph nodes

M = Metastasisa. Mx: distant metastasis cannot be assessed

b. M0: (NO) distant metastasis

c. M1: (YES) distant metastasis36