NEOPLASIA

Neoplasia
- new growth - It is defined as abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissue and persists in the same manner after cessation of stimuli which evoked the change

- Cancer- common term to all malignancies - All neoplasms utimately depends on the host for their nutrition and vascular supply. - Two basic components of Neoplasia : 1. proliferating neoplastic cell-parenchyma 2. supportive stroma- connective tissue and blood vessels.

Nomenclature

Parenchyma
Proliferating neoplastic cells

Stroma
Connective tissue and blood vessels

Classification of Neoplasms
A. Site B. Biologic Behavior benign, borderline, malignant C. Cell ( tissue of origin ) D. Embryologic derivation E. Differentiation potential of cell of origin totipotent cell F. Etiology

 Tumors

are classified to 2 broad categories: benign and malignant.

Benign vs. Malignant

Slow growing Encapsulated Expansile growth No Metastasis Well Differentiated

Rapidly growing Non encapsulated Infiltrative growth Metastasis Well-Poorly differentiated

NOMENCLATURE

Benign Tumors suffix oma Malignant Tumors 2 broad categories: Carcinomas - epithelial cells sarcomas - mesenchymal tissues Some tumors with more than one parenchymal cell type: mixed tumors & teratomas Two non-neoplastic lesions bear the names that are deceptively similar to tumors: choristomas &

hamartomas

Choristoma: ectopic rest of normal tissue

Hamartoma: mass of disorganized but mature specialized cells or tissue native to the particular site

Cell of origin + OMA Fibroma, chondroma, osteoma Adenoma: derived from glands/ glandular pattern Tubular adenoma, colon

Benign Tumors

Papillomas: architecture finger like projections

Polyp: macroscopic projection of mucosal surface

CHARACTERISTICS OF MALIGNANT NEOPLASMS

Malignant tumors: differentiation and anaplasia dysplasia Rapid rate of growth Widespread invasion metastases

1. Anaplasia
Lack of differentiation Hallmark of malignant transformation Numerous morphologic changes

Pleomorphism: variation in size and shape

Abnormal nuclear morphology: hyperchormatic (abundant DNA), increased N:C ratio (normal 1:4- 1:6)

Mitoses: increased, bizarre

Loss of polarity

Tumor giant cells

Dysplasia: disordered growth

Loss of uniformity Loss of architecture Pleomorphism Hyperchromasia Abnormal located mitosis

Cell (tissue) of Origin:

I. Composed of One Parenchymal Cell type: A. Epithelial B. Mesenchymal II. More than one Neoplastic Cell Typederived from one germ layer: A. Salivary Gland B. Breast C. Renal Anlage III. More than one Neopalstic Cell Type derived from more than one germ layer: Teratoma

Tissue of origin Mesenchymal/ connective tissue Fibroma Lipoma Chondroma Osteoma

Benign

Malignant Fibrosarcoma Liposarcoma Chondrosarcoma Osteogenic sarcoma Angiosarcoma Lymphangiosarcoma Synovial sarcoma Mesothelioma Invasive meningioma Leukemias Lymphomas

Endothelial and related tissues

Hemangioma Lymphangioma

Meningioma Hematopoietic Muscle Epithelial Leiomyoma Rhabdomyoma Squamous papilloma Adenoma Papilloma Cystadenoma Bronchial adenoma Renal tubular adenoma Liver cell adenoma Transititonal cell papilloma Hydatiform mole

Leiomyosarcoma Rhabdomyosarcoma SCC or epidermoid CA BCC Adenocarcinoma Papillary carcinoma Cystadenocarcinoma Bronchogenic carcinoma Renal cell carcinoma Transitional cell carcinoma Choriocarcinoma Seminoma Embryonal CA

More than one neoplastic cell- MIXED Salivary gland Renal Teratogenous ( from more than one germ cell layer Totipotential cells Mature teratoma/ dermoid cyst Immature teratoma, teratocarcinoma Pleomorphic adenoma Malignant mixed tumor of salivary gland origin Wilms tumor

Pre-malignant (pre-cancerous) Lesions:

A. Hyperplasia -Endometrial Hyperplasia -Lobular and Ductal Hyperplasia -Cirrhosis of the liver B. Dysplasia C. Metaplasia -Barrets Esopahgus D. Inflammatory Lesions -Ulcerative Colitis, Atorphic Gastritis -Autoimmune(Hashimotos) Thyroiditis E. Benign neoplasms - Colonic Adenoma

Mechanisms and Causes of Neoplasia

-

At MOLECULAR LEVEL , neoplasia is defined as disorder of growth regulatory genes ( proto-oncogenes and tumor suppressor genes ). Origin of Neoplasia: 1. Monoclonal Origin 2. Field Origin

MOLECULAR BASIS OF CANCER

Oncogenes and Cancer

Oncogenes Protooncogenes

Protein products of Oncogenes Activation of Oncogenes

Point mutations Chromosomal rearrangements Gene amplifications

Proto-oncogenes(Cellular Oncogenes ) - code for a variety of of growth

factors, receptors, and signal-relay or transcription factors which act in concert to control entry into the cell cycle.

Tumor suppressor Genes (anti-oncogenes) which serve to down-regulate the cell cycle. note: a net increase in the production of stimulatory (promoter) factors, a decrease in inhibitory (suppressor) growth factors may lead to uncontrolled cell growth.

Cancer-Suppressor Genes

Genes That Regulate Apoptosis

Protein Products of Tumor Suppressor Genes Gene amplifications p53 BRCA-1 and BRCA-2 APC gene NF-1 gene cell surface receptors WT-1

Genes That Regulate DNA Repair

bcl-2

Molecular Basis of Multistep Carcinogenesis

hMSH2 and hMLH1

gatekeeper genes - APC, NF-1, and Rb caretaker genes - DNA repair genes

Selected oncogenes, their mode of activation, and associated human tumors

Category
Growth Factors
PDGF- chain sis overexpression Astrocytoma

Protooncogenes

Mechanism

Associated Tumor

Growth Factor Receptors

EGF-receptor family erb-B1 overexpression Squamous cell CA of the lungs

Proteins involved in Signal Transduction pathway

GTP-binding ras Point mutations CA ofLung, colon, pancreas; many leukemias

Nuclear Regulatory proteins

Transcriptional activators myc Translocation Burkitt lymphoma

Cell Cycle Regulators

Cyclins cyclin D Translocation Mantle cell lymphoma

Activation is the functional concept whereby the normal action of growth regulation is diverted into oncogenesis. Mechanisms of Occurrence : 1. Mutation 2. Translocation 3. Insertion

KARYOTYPIC CHANGES IN TUMOR CELLS

Three types of nonrandom chromosomal abnormalities have been described: (1) translocation (2) deletions (3) amplification

Neoplasia Associated with Constant Genetic Abnormality: a. Philadelphia Chromosome- CML b. Retinoblastoma-Rb gene c. Wilms Tumor-WT-1 d. Familial Polyposis Coli-APC

BIOLOGY OF TUMOR GROWTH

Kinetics of Tumor Cell Growth

variables influence tumor cell growth:

doubling time of tumor cells growth fraction cell production and loss

Tumor Angiogenesis

2 most important tumor angiogenic factors are:

vascular endothelial growth factor (VEGF) basic fibroblast growth factor (bFGF).

BIOLOGY OF TUMOR GROWTH

Tumor Progression and Heterogeneity Mechanisms of Invasion and Metastasis

Invasion of Extracellular Matrix

Detachment of tumor cells attachment to matrix components degradation of extracellular matrix Migration of tumor cells

Vascular Dissemination and Homing of Tumor Cells

CARCINOGENIC SITES

Chemical Carcinogenesis

Initiation Promotion
DNA
alkylating agents, aromatic hydrocarbons, azo dyes etc

Molecular Targets of Chemical Carcinogens

Carcinogenic Chemicals

CARCINOGENIC SITES

Radiation Carcinogenesis

UV rays and ionizing radiations

Viral and Microbiological Carcinogenesis

DNA Viruses

(1) HPV, Epstein-Barr virus (EBV) and Hepatitis B virus (HBV) (HTLV-1)

RNA Oncogenic Viruses

HOST DEFENSE AGAINST TUMORS

Immunosurveillance
Increased frequency of cancers in patients with congenital or acquired immunodeficiency increased susceptibility to EBV infections and EBVassociated lymphoma in boys with X-linked immunodeficiency

Tumors may escape immunosurveillance

selective outgrowths of antigen-negative variants loss or reduced expression of histocompatibility antigens tumor-induced immunosuppression failure of sensitization apoptosis of cytotoxic T cells

CLINICAL FEATURES OF TUMORS

Local and Hormonal Effects

related to location hormone production

Cancer Cachexia Paraneoplastic Syndromes

endocrinopathies Hypercalcemia Acanthosis nigricans clubbing of fingers and hypertrophic osteoarthopy thromboembolic diatheses

Paraneoplastic syndromes

Approach to Cancer Diagnosis:

I. Clinical Suspicion II. Screening Tests III. Tumor Markers IV .Definitive Diagnosis - tissue biopsy ( most accurate ) 1.Ordinary H and E stain 2. Immunohistochemistry 3. Electron Microscopy

LABORATORY DIAGNOSTICS OF CANCER

Histologic and Cytologic Methods Fine-Needle Aspiration Cytologic (Papinacolaou Smears) Immunohistochemistry DNA Probe Analysis Flow Cytometry Tumor Markers

GRADING AND STAGING OF TUMORS

Grading
grades I to IV with increasing anaplasia imperfect because

(1) the differentiated parts of the same tumor may display different degrees of differentiation (2) the grade of tumor may change as the tumor grows

Staging
anatomic extent of the tumor TNM

Information Provided by Pathologic Diagnosis: 1. Type of Neoplasm - name of the neoplasm 2. Biologic Behavior- benign or malignant 3. Histologic Grade degree of differentiation 4. Degree of Invasion- depth 5. Staging - size of the mass/depth of involvement - involvement of nodes - +/- metastasis

Treatment of Neoplasms:
A. Benign surgical removal B. Malignant - surgery ( radical, wide excision, palliative surgery ) - Lymph node removal - Palliative : a. Chemotherapy b. Radiotherapy c. Immunotherapy

What Are The Final Complications Of Malignancy (Causes Of Death)

PNEUMONIA CACHEXIA RENAL FAILURE BLEEDING SEVERE ANEMIA, THROBOCYTOPEINA INFECTIONS HYPERCOAGULABILITY DIC PAIN MORE OF DEVASTATING SYMPTOM THAN A
COMPLICATIONHAS TO BE CONTROLED

MULTIPLE ORGAN FAILURE