NEOPLASIA

BY DR. DAYANANDA.S.BILIGI PROFESSOR, DEPT OF PATHOLOGY B.M.C.R.I

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 Tumor was originally applied to the swelling caused by inflammation. Tumor- Neoplasia -"new growth, Oncology (Greek oncos = tumor) is the study of tumors or neoplasms. Cancer is the common term for all malignant tumors Crab.
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The eminent British oncologist Sir Rupert Willis has given the definition : "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."
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 The persistence of tumors, even after the inciting stimulus is gone Results from heritable genetic alterations that are passed down to the progeny of the tumor cells.

These genetic changes allow excessive and unregulated proliferation that becomes autonomous.
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CLASSIFICATION
TUMOURS

Benign Usually Harmless

Malignant Aggressive Kills if not treated

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 All tumors, benign and malignant, have two basic components: (1) proliferating neoplastic cells that constitute their parenchyma (2) supportive stroma made up of connective tissue and blood vessels. Sometimes the parenchymal cells stimulate the formation of an abundant collagenous stroma, referred to as desmoplasia.
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NOMENCLATURE
In general, benign tumors are designated by attaching the suffix -oma to the cell of origin. Tumors of mesenchymal cells generally follow this rule. For example, a benign tumor arising from fibroblastic cells is called a fibroma, a cartilaginous tumor is a chondroma, and a tumor of osteoblasts is an osteoma.
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 Adenoma is the term applied to a benign epithelial neoplasm that forms glandular patterns as well as to tumors derived from glands . Those that form large cystic masses, as in the ovary, are referred to as cystadenoma. Benign epithelial neoplasms producing microscopically or macroscopically visible fingerlike or warty projections from epithelial surfaces are referred to as papillomas.

Adenoma of the thyroid

www.similima.com 9 Papilloma of the colon with finger-like projections into the lumen

 When a neoplasm, benign or malignant, produces a macroscopically visible projection above a mucosal surface is termed a Polyp. The term polyp is restricted to benign tumours.Malignant polyps are called polypoid cancers.
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MALIGNANT TUMOURS
Malignant tumours arising in mesenchymal tissue are usually called sarcomas (Greek sar = fleshy).Eg: fibrosarcoma, liposarcoma... Malignant neoplasms of epithelial origin,derived from any of the three germ layers, are called carcinomas. Adenocarcinoma Squamous cell carcinoma etc.
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 Divergent differentiation of parenchymal cells into other tissue creates mixed tumours.Eg : pleomorphic adenoma

Teratomas, are made up of a variety of parenchymal cell types representative of more than one germ layer, usually all three. Eg:ovarian cystic teratoma.

Pleomorphic adenoma

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HISTORY OF MALIGNANT TUMOURS

Normal cell Transformed cell Growth of transformed cells Local invasion
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Characteristics Benign
Differentiation Rate ofgrowth Growth pattern Metastasis Well slow Pushing absent

Malignant
Poor fast infiltrative If present typical

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DIFFERENTIATION AND ANAPLASIA

Differentiation refers to the extent to which neoplastic cells resemble comparable normal cells,both morphologically and functionally.

LIPOMA
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 Anaplasia is lack of differentiation which is a hallmark of malignant transformation.

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Morphological changes
Pleomorphism / monomorphism Abnormal nuclear morphology : - hyperchromatic / euchromatic - Nucleomegaly / normal sized nucleus - Irregular nuclear membrane/ regular nuclear membrane - clumped chromatin / normal chromatin - prominent nucleoli / inconspicuous nucleoli Mitoses : - Increased www.similima.com 18 - Typical / atypical

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 Loss of polarity : the orientation of anaplastic cells is markedly disturbed (i.e., they lose normal polarity). Sheets or large masses of tumor cells grow in an anarchic, disorganized fashion. Other changes : Tumour giant cells Ischemic necrosis

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RATE OF GROWTH

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INVASION
Nearly all benign tumours grow as cohesive expansile masses that remain localized to their site of origin. They develop a rim of compressed connective tissue, sometimes called a fibrous capsule which separates them from host tissue. Where as the growth of cancers is accompanied by progressive infiltration, invasion and destruction of surrounding tissue. Next to metastases, invasiveness is the most reliable feature that differentiates malignant from benign tumours.
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BASAL CELL CARCINOMA

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METAPLASIA

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DYSPLASIA

Dysplasia literally means disordered growth. It is characterized by a constellation of changes that include a loss in the uniformity of the individual cells as well as in their architectural orientation. Dysplastic cells exhibit pleomorphism, hyperchromatic nuclei, abundant mitotic figures, mitoses in abnormal locations www.similima.com within the epithelium.

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CARCINOMA IN SITU
When dysplastic changes are marked and involve the entire thickness of epithelium, but the lesion remains confined to the normal tissue & the basement membrane is intact, it is called carcinoma in situ, a preinvasive neoplasm.

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 Metastases are tumour implants discontinuous with the primary tumour. Major exceptions are gliomas and BCC. Both are locally invasive, rarely metastasize. More aggressive, the more rapidly growing, and the larger the primary neoplasm, the greater the likelihood that it will metastasize.
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METASTASIS

PATHWAYS OF SPREAD
1) Direct seeding of body cavities or surfaces Eg : pseudomyxoma peritonei

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1) Lymphatic spread
most common for carcinomas, follows the natural routes of drainage. Sentinel lymph node is the first node in a regional lymphatic basin that receives lymph from primary tumour. (breast-axillary- sentinel lymph node).

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3) Hematogenous spread Typical for sarcomas but also seen with carcinomas.

Numerous metastases from a renal cell carcinoma

Liver and lungs are most frequently involved.

Metastasis of colon cancer www.similima.com into the liver 31

Metastatic cascade

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CARCINOGENESIS ??

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MOLECULAR BASIS OF CANCER

Acquired DNAdamaging agents Chemicals Viruses radiation

Normal cell DNA damage Failure of DNA repair Mutation in the genome Of somatic cells Successful DNA repair
Inherited mutations in Genes affecting DNA Repair Genes affecting cell Growth or apoptosis

Activation of growth Promoting oncogenes

Inactivation of tumor Suppressor genes

Alterations in genes That regulate apoptosis Decreased apoptosis

Unregulated cell proliferation

TRANSFORMED www.similima.com

CELL

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 Chemical carcinogens Biological carcinogens Physical carcinogens

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Chemical Carcinogenesis
First described by Sir Percival Pott in 1775
Chimney sweeps and scrotal cancer Relationship between occupational exposure to chimney soot and scrotal carcinoma was established

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Major Chemical Carcinogens

Direct-Acting Carcinogens : - Alkylating agents eg: -propiolactone - Acylating agents eg: 1-Acetyl-imidazole Procarcinogens that require metabolic activation : - Polycyclic and Heterocyclic Aromatic Hydrocarbons eg: Benz(a)anthracene - Aromatic amines, amides, azo dyes eg: -naphthylamine - Natural plant and microbial products eg : aflatoxin B1 - others Nitrosamine and amides www.similima.com 38 vinyl chloride, nickel, chromium etc.

Chemical carcinogenesis

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of events

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Microbial carcinogenesis
Oncogenic DNA viruses - Human Papillomavirus - Epstein- Barr virus - Hepatitis B virus Oncogenic RNA viruses - Human T- cell Leukemia virus Type1 - Helicobacter Pylori
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Human Papilloma virus

Effect of HPV proteins E6 and E7 on the cell cycle. E6 and E7 enhance p53 degradation, causing a block in apoptosis and decreased activity of the p21 cell cycle inhibitor. E7 associates with p21 and prevents its inhibition of the Cyclin/CDK4 complex; E7 can bind to RB, removing cell cycle restriction. The net effect of HPV E6 and E7 proteins is to block apoptosis and remove the 42 www.similima.com restrains to cell proliferation

Epstein -Barr virus

It is a member of herpes family. Implicated in the pathogenesis of 1) African form of Burkitt lymphoma 2) B-cell lymphomas in immunosuppressed 3) Hodgkin lymphoma 4) Nasopharyngeal carcinoma
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Scheme depicting the possible evolution of Epstein-Barr virus (EBV)-induced Burkitt lymphoma.

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RADIATION CARCINOGENESIS

Radiant energy, whether in the form of the UV rays of sunlight or as ionizing electromagnetic and particulate radiation, can transform virtually all cell types and induce neoplasms. Ultraviolet Rays UV rays derived from the sun induce an increased incidence of squamous cell carcinoma, basal cell carcinoma, and possibly malignant melanoma of the skin. UV rays have a number of effects on cells 1) inhibition of cell division 2)inactivation of enzymes 3)induction of mutations 4)in sufficient dosage, death of cells
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 The carcinogenicity of UVB light is attributed to its formation of pyrimidine dimers in DNA. This type of DNA damage is repaired by the nucleotide excision repair (NER) pathway. With excessive sun exposure, the capacity of the NER pathway is overwhelmed; hence, some DNA damage remains unrepaired. This leads to large transcriptional errors and, in some instances, cancer. The importance of the NER pathway of DNA repair is illustrated by a study of patients with the hereditary disorder xeroderma pigmentosum.

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Ionizing Radiation
Electromagnetic (x-rays, -rays) and particulate ( particles, particles, protons, neutrons) radiations are all carcinogenic. Most telling is the follow-up of survivors of the atomic bombs dropped on Hiroshima and Nagasaki. There was a marked increase in the incidence of leukemiasprincipally acute and chronic myelocytic leukemiaafter an average latent period of about 7 years. Subsequently the incidence of many solid tumors with longer latent periods (e.g., breast, colon, thyroid, and lung) increased.
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Paraneoplastic syndromes

DEFINITION : Symptom complexes in cancer- bearing patients that cannot readily be explained, either by the local or distant spread of the tumour or by the elaboration of hormones indigenous to the tissue from which the tumour arose. - May represent the earliest manifestation of an occult neoplasm - May represent significant clinical problems & may even be lethal - May mimic metastatic disease & www.similima.com 48 confound treatment

Paraneoplastic syndromes
clinical syndrome underlying cancer mechanism

Endocrinopathies
cushing syndrome hypercalcemia small cell ca of lung ACTH or ACTH like substance SCC of lung Breast carcinoma renal carcinoma parathyroid hormone related protein

Nerve and muscle syndromes

Myasthenia Bronchogenic ca immunologic

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Dermatologic disorders
Acanthosis nigricans gastric ca lung ca immunologic

osseous,Articular and soft tissue changes

hypertrophic osteoarthropathy bronchogenic ca unknown

vascular changes
venous thrombosis (trousseau phenomenon) pacncreatic ca Tumour products (mucin)
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Grading and Staging of tumours

Grade level of differentiation Stage extent of spread of cancer with in the patient Grading It is based on the degree of differentiation of the tumour cells and the number of mitoses within the tumour. Cancers are classified with increasing anaplasia.
Well differentiated: Grade 1 Moderately differentiated: Grade 2 Poorly differentiated: Grade 3 www.similima.com

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grade1

grade2 grade3

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Staging Staging is based on the size of the primary lesion, its extent of spread to regional lymph nodes and the presence or absence of blood- borne metastases. Two major staging systems 1) UICC(union Internationale Contre Cancer) 2) AJC ( American Joint Committee)
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 UICC employs TNM system T primary tumour ( T0,Tis,T1,T2,T3,T4) N regional lymph node ( N0,N1,N2, N3) M metastases( M0,M1) AJC divides all cancers into stages 0 IV ( incorporating size of the lesion, nodal spread and distant metastasis). Staging has proved to be of greater clinical value than grading.

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Staging of Malignant Neoplasms

Stage Tis T1
T2 T3 T4 N0 N1 N2 N3 M0 M1 -

Definition In situ, non-invasive Small, minimally invasive within primary organ site Larger, more invasive within the primary organ site Larger and/or invasive beyond margins of primary organ site Very large and/or very invasive, spread to adjacent organs
No lymph node involvement Regional lymph node involvement Extensive regional lymph node involvement More distant lymph node involvement No distant metastases Distant metastases present

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Laboratory Diagnosis of Cancer

Cytology 1) Fine needle aspiration- involves aspirating cells with a small-bore needle, followed by cytologic examination of the stained smears. Used most commonly for the lesions in sites such as breast, thyroid, and lymph nodes. Numerous malignant cells that have pleomorphic, 2) cytological hyperchromatic nuclei; interspersed are some normal polymorphonuclear leukocytes www.similima.com 56 smears

 Histopathology

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 Immunohistochemistry
- uses specific monoclonal antibodies to identify cell products or surface markers. - useful in Categorization of undifferentiated malignant tumours Categorization of leukemias and lymphomas Determination of site of origin of metastatic tumours Detection of molecules that have prognostic or Anticytokeratin immunoperoxidase stain of therapeuticsignificance a tumor of epithelial origin (carcinoma).
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 Molecular diagnosis Molecular techniques like cytogenetics, FISH and PCR are useful in - Diagnosis of malignant neoplasms - Prognosis - Detection of minimal residue disease - Diagnosis of hereditary predisposition to cancer

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 They are biochemical indicators of the presence of a tumour. They include 1) cell surface antigens 2) cytoplasmic proteins 3) enzymes 4) hormones Their main utility is in 1) supporting the diagnosis 2) determining response to therapy 3) Indicating relapse
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Tumour markers

Selected tumour markers

Markers
HORMONES Human chorionic gonadotropin calcitonin ONCOFETAL ANTIGENS -fetoprotein carcinoembryonic antigen HCC, germ cell tumours of testis Ca colon, pancreas, lung,stomach
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Associated cancers

Trophoblastic tumours Nonseminomatous testicular tumors medullary carcinoma of thyroid

ISOENZYMES Prostatic acid phosphatase Neuron specific enolase SPECIFIC PROTEINS Immunoglobulins PSA and PSMA MUCINS CA-125 CA- 19-9 NEW MOLECULAR MARKERS Ovarian cancer ca colon, pancreatic cancer multiple myeloma prostate cancer Prostate cancer Neuroblastoma

P53,APC,RASmutation colon cancer

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