NEoplasia Demonstration

NEOPLASIA

• Neoplasia means "new growth." A neoplasm, as defined by Willis, 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 the cessation of the stimuli which evoked the change.".

NOMENCLATURE

• A neoplasm is often referred to as a tumor, and the study of tumors is called oncology (from oncos, "tumor," and logos, "study of").

• Types: • Benign tumor

• Malignant tumor

• All tumors, benign and malignant, have two basic components: • (1) Parenchyma, made up of transformed or neoplastic cells.

• (2) Stroma, host-derived, non-neoplastic supporting tissue

• Parenchyma of the neoplasm largely determines its biologic behavior, and it is this component from which the tumor derives its name

• Benign Tumors: In general, benign tumors are designated by attaching the suffix -oma to the cell type from which the tumor arises.

Examples: • Fibrous tissue tumor is a Fibroma

• Cartilaginous tumor is a chondroma.

• Malignant Tumors:1.Mesenchymal tissue or its derivatives are called

sarcomas.eg Fibrosarcoma

2.Epithelial tissue origin are called carcinomas. Eg. Adenocarcinomas

• Degree of differentiation Benign tumors resemble the tissue of origin and are well differentiated;

• Rate of growth Benign tumors are slow growing,.

• Local invasiveness Benign tumors are well circumscribed and have a capsule;

• Distant spread Benign tumors remain localized to the site of origin,

• Degree of differentiation, malignant tumors are poorly or completely undifferentiated (anaplastic).

• Rate of growth, malignant tumors generally grow faster

• Local invasiveness, malignant tumors are poorly circumscribed and invade the surrounding normal tissues.

• Distant spread. malignant tumors are locally invasive and they metastasize to distant sites

MALIGNANT TUMORBENIGN TUMORS

Reference: Kristine Krafts, M.D. Tumor Characteristics

Neoplasia Outline

• Tumor nomenclature• Tumor characteristics

• Differentiation and anaplasia• Rate of growth• Local invasion• Metastasis

Differentiation and Anaplasia

• Differentiation = how much the tumor cells resemble their cells of origin• well-differentiated – closely resembles• moderately-differentiated – sort of resembles• poorly-differentiated – doesn’t resemble

• Benign tumors are usually well-differentiated

• Malignant tumors can show any level of differentiation

Differentiation and Anaplasia

• " It implies dedifferentiation, or loss of the structural and functional differentiation of normal cells

• Misnomer! Cells don’t de-differentiate.

• Just means cells are very poorly-differentiated

• Almost always indicates malignancy

Anaplasia = a state of complete un-differentiation

Differentiation and Anaplasia

• Pleomorphism (marked variation in size and shape)

• Hyperchromatic, large nuclei

• Bizarre nuclear shapes, distinct nucleoli

• Lots of mitoses, and atypical mitoses

• Architectural anarchy

Anaplastic cells show:

Abnormal mitoses

Rate of Growth

• Malignant tumors grow faster than benign ones.

• Poorly-differentiated tumors grow faster than well-differentiated ones.

• Growth is dependent on:• Blood supply• Hormonal factors• Emergence of aggressive sub-clones

Generalizations

Neoplasia Outline

• Tumor nomenclature• Tumor characteristics

• Differentiation and anaplasia• Rate of growth• Local invasion

Local Invasion

• Benign tumors• Stay where they are.• Can’t invade or metastasize.• Usually encapsulated.

• Malignant tumors• Infiltrate, invade, destroy surrounding tissue.• Then metastasize to other parts of body.• Not encapsulated.

Malignant tumor invading kidney

Neoplasia Outline

• Tumor nomenclature• Tumor characteristics

• Differentiation and anaplasia• Rate of growth• Local invasion• Metastasis

Metastasis

• Metastasis = development of secondary tumor implants in distant tissues

• Metastasis depends on:• Type of tumor • Size of tumor• Degree of differentiation of tumor

Carcinoma in situ

Invasive carcinoma

Invasive carcinoma

Metastasizing carcinoma

Liver with multiple metastases

• Seeding

• Lymphatic spread

• Hematogenous spread

Three ways tumors metastasize

Metastasis

• Seeding• Tumor invades body cavity • Bits break off and implant on peritoneal surfaces• Ovarian cancer

Three ways tumors metastasize

Metastasis

• Seeding

• Lymphatic spread• Tumor spreads to local lymph nodes • Moves through thoracic duct• Empties into subclavian vein

Three ways tumors metastasize

Metastasis

• Seeding

• Lymphatic spread

• Hematogenous spread• Veins are easier to invade than arteries• Liver and lungs are most common metastatic destinations

Three ways tumors metastasize

• Cancer pathogenesis

Overview

• Basic underlying cause of cancer:

• Four kinds of normal genes are damaged:• Genes that promote growth (“proto-oncogenes”)• Genes that inhibit growth (“tumor-suppressor genes”)• Genes that regulate apoptosis• Genes involved in DNA repair

• Cancers develop in multiple steps

Genes

•Autonomous growth• Insensitivity to growth-inhibitory signals•Evasion of apoptosis•Limitless replication•Sustained angiogenesis• Invasion and metastasis

“Cancer genes” cause bad things in cells:

1. Autonomous Growth

•Proto-oncogene: a normal gene whose product promotes cell growth.

•Oncogene: mutated proto-oncogene! Causes cell to grow autonomously!

•Oncoprotein: the product of an oncogene.

Definitions

Autonomous Growth

• Growth factors may be made by cell itself!• Receptors may be over expressed or always on• Signal-transducing proteins may always be on• Nuclear transcription factors may always be expressed• Cyclins may be overactive

In cancer cells…

Cell divides on its own!!!

Autonomous Growth

•RAS is a signal transduction protein

•Mutated RAS is always on…

•…therefore, always transducing signals…

•…therefore, cell is always dividing.

Example: RAS gene

2. Insensitivity to Growth-Inhibitory Signals

•Tumor-suppressor genes: normal genes whose products act as “brakes” on the cell cycle.

•Mutation cause loss of these brakes!

Insensitivity to Growth-Inhibitory Signals

3. Evasion of Apoptosis

• Many proteins involved in apoptosis:• Fas (the “death receptor”)• Executioner caspases (cut DNA)• BCL2 protein family• p53 (the “guardian”)

• If genes for these proteins are mutated, the cell becomes immortal!

4. Limitless Replication

•Normal human cells: only 60-70 doublings

•Telomeres keep getting shorter…

•…leading to cell cycle arrest

•Stem cells and cancer cells use telomerase to maintain telomere length and keep replicating!

Molecular pathogenesis of cancer

p53 Gene: Guardian of the Genome

5. Sustained Angiogenesis

•Tumor cells need blood too!•Can’t grow >1-2 cm without new vessels•Tumor cells eventually learn how to stimulate

angiogenesis•Lots of cytokines involved•Tumor vessels are abnormal!

Definitions

6. Invasion and Metastasis

•To invade, tumor cells must:• Loosen contacts between cells• Degrade extracellular matrix• Migrate away from original site

•Some tumors lodge in nearest capillary bed•Some tumors show tropism

clonal growth

intravasation

metastatic subclone

tumor cell embolus

extravasation

Tumor cells now within vessel

Carcinogenic Agents

• Chemicals

• Radiation

• Viruses

Carcinogenic Agents

• Direct-acting agents• Carcinogenic as-is• Most are chemotherapy drugs• Cause secondary malignancies

Chemicals

Carcinogenic Agents

• Direct-acting agents

• Indirect-acting agents• Require conversion to become carcinogenic• Examples:

• Hydrocarbons (in tobacco)• Aflatoxin B (from Aspergillus-infected grains, nuts)• Nitrites (food preservative)

Chemicals

Carcinogenic Agents

• Direct-acting agents

• Indirect-acting agents

• Mechanism• Highly reactive groups bind to DNA• Important targets: RAS and p53

Chemicals

Carcinogenic Agents

• Ionizing radiation• Causes chromosome breakage, translocations• Examples:

• Unprotected miners: lung cancer• Atomic bomb survivors: leukemia, other cancers• Therapeutic head/neck radiation: thyroid cancer

Radiation

Carcinogenic Agents

• Ionizing radiation

• UV light• Causes formation of pyrimidine dimers • Examples: Melanoma

Radiation

Laboratory Diagnosis of Cancer

• Morphologic Methods » Frozen-section diagnosis » Fine-needle aspiration » Cytologic smears» Immunocytochemistry

• Biochemical assays

• Molecular Diagnosis

• PCR & FISH (flouresence in situ hybridization) are used for the detection of

» Melignancy by distinction between monoclonal (neoplastic) and polyclonal (reactive) proliferations .

» Prognosis and behavior: detect amplification of oncogenes such as HER-2/NEU and N-MYC

» Detection of minimal residual disease: detection of minimal residual disease after treatment.

» Diagnosis of hereditary predisposition to cancer

THANKS FOR PATIENCE AND HAVE A GOOD DAY