NEOPLASIA

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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 Malignant
• Usually Harmless 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
  finger-like or warty projections from epithelial
  surfaces are referred to as papillomas.

• Adenoma of the thyroid

Papilloma of the colon with finger-like
projections into the lumen
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• 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.
  Egovarian cystic
• teratoma.

• 
  
• Pleomorphic adenoma
• Cystic teratoma of ovary

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HISTORY OF MALIGNANT TUMOURS

• Normal cell
• Transformed cell
• Growth of transformed cells
• Local invasion
• Distant metastases

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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
• - 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 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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METASTASIS

• 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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PATHWAYS OF SPREAD

• Direct seeding of body cavities or surfaces Eg
  pseudomyxoma peritonei

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• 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.
• Liver and lungs are most frequently involved.

Numerous metastases from a renal cell carcinoma
Metastasis of colon cancer into the liver
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Metastatic cascade
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CARCINOGENESIS ??
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MOLECULAR BASIS
OF CANCER

• Acquired DNAdamaging agents
• Chemicals
• Viruses
• radiation

Normal cell
Successful DNA repair
DNA damage

• Inherited mutations in
• Genes affecting DNA
• Repair
• Genes affecting cell
• Growth or apoptosis

Failure of DNA repair
Mutation in the genome Of somatic cells
Activation of growth Promoting oncogenes
Alterations in genes That regulate apoptosis
Inactivation of tumor Suppressor genes
Decreased apoptosis
Unregulated cell proliferation
TRANSFORMED 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 ß-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
• ß-naphthylamine
• - Natural plant and microbial products eg
• aflatoxin B1
• - others Nitrosamine and amides
• vinyl chloride, nickel,
  chromium etc.

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Chemical carcinogenesis
scheme 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 restrains to cell
  proliferation

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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
  (a particles, ß 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
• confound treatment

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Paraneoplastic syndromes
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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

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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
• UICC(union Internationale Contre Cancer)
• 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 Definition
• Tis - In situ, non-invasive
• T1 Small, minimally invasive within
  primary
• organ site
• T2 Larger, more invasive within the
• primary organ site
• T3 Larger and/or invasive beyond margins
• of primary organ site
• T4 Very large and/or very invasive, spread
• to adjacent organs
• N0 No lymph node involvement
• N1 Regional lymph node involvement
• N2 Extensive regional lymph node
• involvement
• N3 More distant lymph node involvement
• M0 No distant metastases

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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.
• 2) cytological
• smears

Numerous malignant cells that have pleomorphic,
hyperchromatic nuclei interspersed are some
normal polymorphonuclear leukocytes
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• 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
• therapeuticsignificance

Anticytokeratin immunoperoxidase stain of 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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Tumour markers

• 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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Selected tumour markers
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THANK YOU