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NEOPLASIA
Objectives
   1. Definition of Neoplasia
   Nomenclature.
   Examples

Neoplasia – Latin, „new growth‟
Cancer – „crab‟
Rupert Willis, 1950s
Definition


   A neoplasm is : abnormal mass
    of tissue which grows in an
    uncoordinated manner even
    after ces...
   Tumor = neoplasm
   Benign tumor = innocent-acting tumor
   Malignant tumor = evil-acting tumor
Nomenclature
         Neoplasm



Benign                 Malignant



           Carcinoma          Sarcoma
Neoplastic Proliferation:
   Benign
       Localized, non-invasive.
   Malignant (Cancer)
       Spreading, Invasive.
Nomenclature Cont.
   Benign tumors are named using -oma as
    a suffix with the organ name as the root.
    eg a benign...
Examples
               of Nomenclature


   Benign tumor of
    the thyroid is
    called(adenoma)
   Note the normal-...
Nomenclature


    Benign Tumors

•Encapsulated
• Well defined
Nomenclature Cont.

   Cancers are classified by the type of
    cell that the tumor resembles and is
    therefore presu...
   Malignant neoplasm of epithelial cell
    origin derived from any of the three
    germ layers called carcinomas – e.g...
Carcinomas
   – Malignant tumor arise from epithelial
    tissue
    • Adenocarcinoma – malignant tumor
       of glandul...
Sarcoma
   Malignant tumor arising from
    connective tissue
    (i.e. bone, cartilage, fat, nerve)
    develop from cel...
   Sarcomas –
    • Chondrosarcoma –
      malignant tumor of
      chondrocytes .
    • Angiosarcoma – malignant
      t...
   Malignant tumor
    (adenocarcinoma) of the
    colon. The cancerous
    glands are irregular in
    shape and size an...
Adenocarcinoma: malignant glands surrounded by fibrous stroma
Squamous cell carcinoma demonstrates enough differentiation. The
cells are pink and polygonal in shape with intercellular ...
This sarcoma has many mitoses. A very large abnormal mitotic figure
is seen at the right.
    Lymphoma and leukemia: These two
    classes of cancer arise from
    hematopoietic (blood-forming) cells
    that le...
Seminoma. A, Low magnification shows clear
seminoma cells divided into poorly demarcated
lobules by delicate septa. B, Mic...
SPECIALISED TUMOURS

    Adenosquamous carcinoma
    Adenoacanthoma
    Collision tumour – Two different
    cancers in...
Adenosquamous      carcinoma     demonstrates     blended
adenocarcinoma and squamous cell carcinoma within a single
tumor...
   This mixed tumor
    of the parotid
    gland contains
    epithelial cells
    forming ducts and
    myxoid stroma th...
   Teratoma –These tumours are made up
    of a mixture of tissue types arising from
    totipotent cells derived from th...
A, Gross appearance of an opened cystic teratoma of the ovary.
Note the presence of hair, sebaceous material, and tooth. B...
   Teratoma may be
    benign or mature ( mostly
    ovarian ) or malignant or
    immature ( mostly testicular
    terat...
   Blastoma      –    Blastoma     or
    embryomas are a group of
    malignant tumours which arise
    from     embryon...
   Tumours occur more frequently in
    infants and childrens under 5 yrs
    of age eg.
    Neuroblastoma ,
    Hepato...
   Hamartoma – Benign tumour which is
    made up of mature but disorganised
    cells of tissues indigenous to the
    p...
DIFFERENCE IN BENIGN AND
  MALIGNANT TUMOURS
CHARECTERISTI    BENIGN           MALIGNANT
CS
Surface          Smooth           Irregular


Rate of growth   Slow and    ...
Microscopic            BENIGN            MALIGNANT
features

Differentiation   Well               Lack of
                ...
Fibroadenoma of the breast. The tan-
colored, encapsulated small tumor is
sharply demarcated from the whiter
breast tissue.
Multiple leiomyomas of the
uterus.   The    neoplasm   is
composed     of    monomorphic
spindle shaped cells.
Liomyosarcoma of the uterus: soft fleshy tumor arising from
myometrium.
The tumor shows bundles of malignant smooth muscle...
   Differentiation   Extent to which
                      parenchymal cells
                      resembles to normal ce...
EXAMPLES OF
      DIFFERENTIION


   Benign tumours are well differentiated
    eg Leiomyoma .
   Malignant neoplasms ra...
FEATURES OF Lack
      OF
      DIFFERENTIATION


   • 1. Pleomorphism refers
    variation in size and shape of cell
  ...
      2. Abnormal nuclear morphology.
    Characteristically the nuclei contain
    abundant chromatin and are dark
    s...
   3. Nuclear-to-cytoplasm ratio
    may approach 1 : 1 instead of
    normal 1 : 4 or 1 : 6. The nuclear
    shape is of...
Signs of malignant process..




         Malignant cell showing Pleomorphism
         ,
   4 . Mitoses –

   Increased mitosis reflect the
    higher proliferative activity of
    the parenchymal cells.
   M...
The presence of mitoses, however,
  does not necessarily indicate that a
  tumor is malignant or that the tissue
  is neop...
Other conditions of increased mitosis

   Many normal tissues exhibiting
    rapid turnover eg.
    Bone marrow, have nu...
Malignant cell showing abnormal quadripolar mitotic
figure
   5. Loss of polarity refers to –


   Sheets or large masses of
    tumor cells grow in an anarchic,
    disorganized ...
   6 . Other changes --


   Formation of tumor giant cells,
    some possessing only a single
    huge polymorphic nuc...
Example of
       tumour gaint cell


   M/E-
    Anaplastic tumor of
    the skeletal muscle
    (rhabdomyosarcoma)
    ...
   7. Necrosis - Often the vascular
    stroma is scant, and in many
    anaplastic tumors, large central
    areas under...
WHAT IS
       DYSPLASIA


   Dysplasia is a term that literally
    means disordered growth.
   Characterized by    los...
Features of dysplasia
   Pleomorphism ,
   Hyperchromatic nuclei with a
   High nuclear-cytoplasmic ratio.
   The arch...
NOTE


      In dysplastic stratified squamous
    epithelium,    mitoses     are  not
    confined to the basal layers b...
GRADING OF DYSPLASIA


Graded as mild, moderate or severe.
  Mild , Moderate: usually
  reversible
  Severe: usually pro...
Normal gland   Mild dysplasia
Moderate dysplasia   Severe dysplasia
WHAT IS Ca Insitu

   When dysplastic changes are
    marked and involve the entire
    thickness of the epithelium but
 ...
   Once the tumor cells breach
    the basement membrane ,
    the tumor is said to be
    invasive .
Carcinoma in situ. This low – power view shows that the entire
thickness of the epithelium is replaced by atypical dysplas...
Classification of
Cervical intraepithelial neoplasia
  (CIN) and       dysplasia
CIN I               MILD            INVOLVE
                    DYSPLASIA       LOWER 3rd OF
                             ...
CLASSIFICATION
   OF TUMORS
TISSUE OF       BENIGN       MALIGNANT
ORIGIN

Connective Tissue and masenchymal origin

              Fibroma      Fibros...
EPITHELIAL           BENIGN          MALIGNANT
TUMOURS

Stratified           Squamous cell   Squamous cell
squamous       ...
Neuroectoderm      NEVUS               Malignant
                                       Melanoma

Renal Epithelium   Renal...
Fibroma




Bindles   of   spindle   cells
separated by collagen bundles
Lipoma; composed   of   adult
adipocytes.
Osteoma
formed
bundles of
compact
bone




         Chondroma formed of
         chondrocytes in a hyaline
         matrix
A small hepatic adenoma,
                    an   uncommon     benign
                    neoplasm,   with    well-
      ...
A small hepatic adenoma,
                    an   uncommon     benign
                    neoplasm,   with    well-
      ...
Multiple adenomatous polyps (tubulovillous adenomas) of the cecum
are seen here in a case of familial adenomatous polyposi...
Tubular adenoma, colon




Colonic adenoma: adenomatous polyp (Polypoid adenoma)
Squamous cell papilloma




Transitional cell papilloma
Transitional cell carcinoma; papillary type.
A




    B




    A: Neurofibroma
    B: Schwannoma:
    Both     show  bundles  of
    schwann cells separated by
    n...
Squamous cell carcinoma:
                          malignant ulcer of the scalp




Bronchogenic carcinoma,
lung
         ...
Cervical squamous cell carcinoma. Note the disorderly growth
of the malignant squamous epithelial cells forming large nest...
Squamous cell carcinoma demonstrates enough differentiation.
The cells are pink and polygonal In shape . However, the
neop...
Adenocarcinoma: malignant glands surrounded by fibrous stroma
Signet ring carcinoma: malignant cells with clear vacuolated cytoplasm
due to accumulation of mucin. Mucin can be seen by ...
Papillary carcinoma: a variant of adenocarcinoma forming
papillae
BASAL CELL CARCINOMA
BCC: Groups of neoplastic
 basaloid cells infiltrating the
 dermis. The cells at periphery
 show palisade. The groups of
 ...
Malignant melanoma of the skin is much larger and more irregular
than a benign nevus.
Melanoma (melanocarcinoma): there are
aggregates of malignant melanocytes
infiltrating the dermis
This sarcoma has many mitoses. A very large abnormal mitotic figure
is seen at the right.
Here is an osteosarcoma
of bone. The large, bulky
mass arises in the
cortex of the bone and
extends outward




    The os...
This large mass lesion is a
liposarcoma. Common sites are
the retroperitoneum and thigh,
and they occur in middle aged
to ...
Chondrosarcoma: malignant chondrocytes in a hyaline matrix
Meningioma




             Meningioma: is formed of bundles of
             meningiothelial cells arranged in
           ...
DISEASES ASSOCIATED WITH
   INCREASED INCIDENCE
       OF CANCER
PRENEOPLASTIC          NEOPLASM


   Down Syndrome        Acute Myeloid Leukemia

   Xeroderma            Squamous Carci...
Epidemiology of
       MALIGNANCY


      Epidemiologic studies established
    the relation of -
    Smoking and lung ca...
   High dietary fat and low fiber in the
    development of colon cancer.
   Alcohol with carcinomas of the
    orophary...
OTHER FACTORS

   Obesity is associated with
    approximately 14% of cancer
    deaths in men and 20% in
    women.
   ...
   The risk of cervical cancer is
    linked to age at first intercourse
    and the number of sex partners,
    and it i...
AGE

   Age has an important influence on the
    likelihood of being afflicted with cancer.
   Most carcinomas occur in...
   Carcinomas, the most common
    general category of tumor in
    adults, are rare among children.
    Acute leukemia ...
   The common neoplasms of
    infancy and childhood include
    the so-called small round blue
    cell tumors such as
...
CHILDHOOD NEOPLASMS                SITE
 Acute Lymphocytic        Blood and marrow
Leukemia
 Lymphoblastic leukemia   Lymp...
What is metastasis




The term metastasis denotes the
development of secondary implants
discontinuous with the primary
tu...
MODE OF METASTASIS


   Lymphatic
   Haematogenous
   Retrograde
   Transcoelomic
    Lymphatic Spread.
Transport through lymphatics is the
 most common pathway for the
 initial dissemination of carcinom...
   Retrograde metastasis –


   Due to obstruction of the
    lymphatics by the tumour cells
    the lymph flow is distu...
Examples of
retrograde metastasis

   Ca. of prostate to the
    supraclavicular lymph nodes ,
   Metasatic deposits fro...
   What is Virchows lymph nodes ?
     Nodal metastasis preferentially
    to supraclavicular lymph nodes
    from cancer...
The pattern of lymph node
     involvement follows the natural routes
     of lymphatic drainage.

   carcinomas in the u...
    Regional lymph nodes draining the
    tumour are invariably involved
    producing regional nodal metastasis
    eg.
...
Skip metastasis”
Local lymph nodes,      may be
bypassed          called  “skip
metastasis” because of venous
-lymphatic  ...
   Hematogenous Spread.

   Hematogenous spread is typical of
    sarcomas but is also seen with
    carcinomas. Arterie...
METASTATIC
CASCADE:
Steps involved
in the
hematogenous
spread of a
tumor


    The liver and lungs are most
    frequently       involved        in
    hematogenous         dissemination
    be...
   Common site of blood borne metastasis –
    Liver , Lungs , Brain , Bone , Kidney
    ,Adrenals.
   Few organs eg Spl...
   Certain cancers have a propensity for
    invasion of veins.
   Renal cell carcinoma often invades the
    branches o...
   Transcoelomic spread –
   a. Carcinoma of stomach seeding both
    the ovaries ( Krukenberg tumour)
   b. Carcinoma ...
Small tan tumor nodules seen over the peritoneal surface of the
mesentery (peritoneal spread of carcinoma)
   d. Ca. of bronchus and breast seeding
    to the pleura and pericardium.
       Spread along epithelial lined surfaces...
A liver studded with
metastatic cancer
Microscopically, metastatic adenocarcinoma is seen in a lymph node
here. It is common for carcinomas to metastasize to lym...
A breast carcinoma has spread to a lymphatic within the lung.
Branches of peripheral nerve are invaded by nests of malignant
cells. This is termed perineural invasion. This is often th...
Colon carcinoma invading
pericolonic adipose tissue
Axillary lymph node with metastatic breast carcinoma. The
subcapsular sinus (top) is distended with tumor cells. Nests of ...
EFFECTS OF TUMOURS

I.Local effects: local destruction of
tissues causes loss of function,
ulceration, hemorrhage, obstruc...
II. Cancer cachexia: i.e. wasting
  and weakness. May be due to
  loss of appetite, and production
  of TNF-alpha (cachect...
III –PARANEOPLASTIC SYNDROMES
     Symptoms caused by elaboration of
    active substances or hormones not
    indigenous...
ENDOCRINOPATHIES

1. Endocrinopathies: Ectopic

hormone production by non-
endocrine neoplasms
(inappropriate hormone
secr...
EXAMPLES OF
      ENDOCRINOPATHY


   Cushing‟s syndrome – caused by
    small cell (oat cell) bronchogenic
    carcinoma...
   2. Acanthosis nigricans: a verrucous
    pigmented lesion of the skin .
   3. Clubbing of the fingers and
    hypertr...
Grading of Malignant
Neoplasms




 Grade                 Definition
   I       Well differentiated
    II     Moderately ...
Staging of Malignant Neoplasms

Stage                           Definition
Tis     In situ, non-invasive (confined to epit...
TNM Staging
system of the
tumor:
T: Tumor size
N: L.N. metastasis
M: Distant
metastasis
GRADING OF TUMOURS

    .Grading is based on the degree
    of differentiation and the
    number of mitotic figures in th...
    Tumors are classified as Grades I
    to IV with increasing anaplasia.
    High grade tumors are generally
    more a...
STAGING OF CANCER

   Staging is based on the size of the
    primary tumor and the extent of
    local and distant sprea...
    Two methods of staging are
    currently used:
   1.The TNM (Tumor, Node,
    Metastases) system.
   2.The AJC (Ame...
METHODS OF DIAGNOSIS OF CANCER


. 1 . Histologic examination (paraffin-
embedded fixed sections, stained by
H&E) .
. 2 . ...
4 . IMMUNOCYTOCHEMISTRY
   . Detection of surface markers or
    cell   products    by   monoclonal
    antibodies.
    ...
Gastric adenocarcinoma is positive for cytokeratin,
with brown-red reaction product in the neoplastic cell
cytoplasm . Thi...
This sarcoma is      positive for     vimentin   by
immunohistochemical staining.    This is a typical
immunohistochemical...
A: Normal smear
of   the    uterine
cervix
B:        Abnormal
smear containing
sheet            of
malignant      cells
sh...
DNA ANALYSIS (MOLECULAR DIAGNOSIS)
1.DNA Probe Analysis: used for detection of
oncogenes; such as N-myc, bcr-c-abl gene pr...
EXAMPLES OF TUMOUR MARKERS

   HORMONES
    HCG (trophoblastic tumors and non-
    seminomatous testicular tumors)
    ...
ONCOFETAL ANTIGENS

-Alpha-fetoprotein (liver cancer & non-
seminomatous testicular tumors)

- CEA (carcinoma of colon, pa...
ISOENZYMES
  PSA (prostate cancer)
  NSE (small cell carcinoma of lung,
  neuroblastoma)
SPECIFIC PROTEINS
  Immunoglob...
CARCINOGENESIS
Molecular Basis of Cancer
CARCINOGENESIS
   MOLECULAR BASIS OF CANCER

 Cancer is a genetic disease.
The genetic injury may be inherited
in the germ...
Carcinogenesis or oncogenesis
Carcinogenesis or oncogenesis
means mechanism of induction of
tumors .
The literature on the...
What is carcinogen and role
of carcinogen in CANCER.
   Carcinogens – substances known to
    cause cancer or produces an increase in
    incidence of cancer in animals or
  ...
NOTE

   Carcinogenesis is caused by mutation
    of the genetic material of normal
    cells .
   More than one mutatio...
    Mutations of genes play vital
    roles in cell division,
   Mutation of gene regulating
    apoptosis (cell death),...
Large-scale mutations involve the
 Deletion or gain of a portion of a

  chromosome.
 Genomic amplification
  occurs whe...
Genomic amplification

   Chromosomal alterations that result
    in increased number of copies of a
    gene is found in...
    Translocation eg -
    Philadelphia chromosome -
    translocation of chromosomes
    9 and 22, which occurs in chro...
   The Philadelphia chromosome,
    characteristic of CML provides the
    prototypic example of an oncogene
    formed b...
   Small-scale mutations include
   Point mutations,
   Deletions, and
   Insertions
   Point mutation of RAS family genes is
    the single most common abnormality
    of proto-oncogenes in human tumors.
 ...
Carcinogenesis is a multi-step process.
   Characteristic features of malignant
    tumors
     Excessive rate of growth,...
    Four classes of regulatory genes.
    1. Promotors – Proto-oncogenes

    2. Inhibitors – Cancer-suppressor

       g...
    Genetic alterations may involve:
     1. Growth-promoting proto-
    oncogenes (activation of growth-
    promoting ...
Molecular Basis of Multistep
      Carcinogenesis
   MULTISTEP CARCINOGENESIS INCLUDES
   INITIATION
   PROMOTION
   PROGRESSION
MULTISTEP CARCINOGENESIS
                   1) Initiation.
Chemical carcinogen reacts with DNA to
produce a mutation.
In...
MULTISTEP CARCINOGENESIS
                  2) Promotion
Tumor promotors contribute to
carcinogenesis by nongenotoxic mech...
Stages of Carcinogenesis




Initiation       Promotion      Progression
MULTISTEP CARCINOGENESIS
               3)Tumor Progression
Tumors acquire ability to invade and establish
 distant metas...
ETIOLOGICAL AGENTS
OF CARCINOGENESIS
Chemical Carcinogenesis:

   Direct Acting Carcinogens:
       Alkylating Agents: Cyclophosphamide


   Procarcinogenes...
Metabolic activation
Procarcinogen              Ultimate carcinogen   DNA
  [stable]                 [Reactive            ...
   A virus that can cause cancer is
    called an oncovirus. These include

    Human papillomavirus (cervical
    carci...
   Kaposi's sarcoma herpesvirus
    (Kaposi's Sarcoma and primary
    effusion lymphomas),
   hepatitis B and hepatitis ...
   Bacterial infection may also increase
    the risk of cancer eg.
    Helicobacter pylori-induced gastric
    carcinom...
   RADIATION CARCINOGENESIS
   Radiant energy, whether in the form of the
    UV rays of sunlight or as ionizing
    ele...
   Sources of ionizing radiation include
    medical imaging, and radon gas. non-
    ionizing radiation from ultraviolet...
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Neoplasia

  1. 1. NEOPLASIA
  2. 2. Objectives  1. Definition of Neoplasia  Nomenclature.  Examples 
  3. 3. Neoplasia – Latin, „new growth‟ Cancer – „crab‟ Rupert Willis, 1950s
  4. 4. Definition  A neoplasm is : abnormal mass of tissue which grows in an uncoordinated manner even after cessation of the stimuli which evoked the change.
  5. 5.  Tumor = neoplasm  Benign tumor = innocent-acting tumor  Malignant tumor = evil-acting tumor
  6. 6. Nomenclature Neoplasm Benign Malignant Carcinoma Sarcoma
  7. 7. Neoplastic Proliferation:  Benign  Localized, non-invasive.  Malignant (Cancer)  Spreading, Invasive.
  8. 8. Nomenclature Cont.  Benign tumors are named using -oma as a suffix with the organ name as the root. eg a benign tumor of smooth muscle cells is called a leiomyoma . Note Confusingly, some types of  malignant also use the - oma suffix, e.g. • Melanoma • Seminoma.
  9. 9. Examples of Nomenclature   Benign tumor of the thyroid is called(adenoma)  Note the normal- looking (well- differentiated), colloid-filled thyroid follicles
  10. 10. Nomenclature Benign Tumors •Encapsulated • Well defined
  11. 11. Nomenclature Cont.  Cancers are classified by the type of cell that the tumor resembles and is therefore presumed to be the origin of the tumor. These types include:  Carcinoma: Cancers derived from epithelial cells. the breast, prostate, lung, pancreas, and colon.
  12. 12.  Malignant neoplasm of epithelial cell origin derived from any of the three germ layers called carcinomas – e.g. .  Arising from epidermis of ectodermal origin,  Carcinoma arising from cells of renal tubules are of mesodermal origin .  Ca derived from cells lyning the gastrointestinal tract are of endodermal origin .
  13. 13. Carcinomas  – Malignant tumor arise from epithelial tissue • Adenocarcinoma – malignant tumor of glandular cells . • Squamous cell carcinoma – malignant tumor of squamous cells .
  14. 14. Sarcoma  Malignant tumor arising from connective tissue (i.e. bone, cartilage, fat, nerve) develop from cells originating in mesenchymal cells outside the bone marrow.
  15. 15.  Sarcomas – • Chondrosarcoma – malignant tumor of chondrocytes . • Angiosarcoma – malignant tumor of blood vessels . • Rhabdomyosarcoma – malignant tumor of skeletal muscle cells .
  16. 16.  Malignant tumor (adenocarcinoma) of the colon. The cancerous glands are irregular in shape and size and do not resemble the normal colonic glands. The malignant glands have invaded the muscular layer of the colon
  17. 17. Adenocarcinoma: malignant glands surrounded by fibrous stroma
  18. 18. Squamous cell carcinoma demonstrates enough differentiation. The cells are pink and polygonal in shape with intercellular bridges . However, the neoplastic cells show pleomorphism, with hyperchromatic nuclei. A mitotic figure is present near the center.
  19. 19. This sarcoma has many mitoses. A very large abnormal mitotic figure is seen at the right.
  20. 20.  Lymphoma and leukemia: These two classes of cancer arise from hematopoietic (blood-forming) cells that leave the marrow and tend to mature in the lymph nodes and blood, respectively.  Germ cell tumor: Cancers derived from pluripotent cells, most often presenting in the testicle or the ovary (seminoma and dysgerminoma, respectively.
  21. 21. Seminoma. A, Low magnification shows clear seminoma cells divided into poorly demarcated lobules by delicate septa. B, Microscopic examination reveals large cells with distinct cell borders, pale nuclei, prominent nucleoli and a sparse lymphocytic infiltrate.
  22. 22. SPECIALISED TUMOURS  Adenosquamous carcinoma  Adenoacanthoma  Collision tumour – Two different cancers in the same organ which donot mix with each other .  Mixed tumour of the salivary gland or pleomorphic adenoma is the term used to benign tumours having both epithelial and mesenchymal elements
  23. 23. Adenosquamous carcinoma demonstrates blended adenocarcinoma and squamous cell carcinoma within a single tumor.Small glandlike structures are seen blending with sheets of squamous epithelium.
  24. 24.  This mixed tumor of the parotid gland contains epithelial cells forming ducts and myxoid stroma that resembles cartilage
  25. 25.  Teratoma –These tumours are made up of a mixture of tissue types arising from totipotent cells derived from the germ layers –ectoderm , mesoderm , endoderm .  Most common sites are ovaries and testis Extragonadal sites mainly in the midline of the body eg . Head and neck region , mediastinum , retroperitonium, Sacrococcygeal region.
  26. 26. A, Gross appearance of an opened cystic teratoma of the ovary. Note the presence of hair, sebaceous material, and tooth. B, A microscopic view of a similar tumor shows skin,sebaceous glands, fat cells, and a tract of neural tissue (arrow).
  27. 27.  Teratoma may be benign or mature ( mostly ovarian ) or malignant or immature ( mostly testicular teratoma )
  28. 28.  Blastoma – Blastoma or embryomas are a group of malignant tumours which arise from embryonal or partially differntiated cells which would form blastoma of the organs and tissue during embryogenesis.
  29. 29.  Tumours occur more frequently in infants and childrens under 5 yrs of age eg.  Neuroblastoma ,  Hepatoblastoma ,  Retinoblastoma ,  Meduloblastoma and  Primary blastoma.
  30. 30.  Hamartoma – Benign tumour which is made up of mature but disorganised cells of tissues indigenous to the particular organ eg Hamartoma of lung consist of mature cartilage , mature smooth muscles and epithelium.  Choristoma – Ectopic islands of normal tissues . This is hetrotopia not a true tumour.
  31. 31. DIFFERENCE IN BENIGN AND MALIGNANT TUMOURS
  32. 32. CHARECTERISTI BENIGN MALIGNANT CS Surface Smooth Irregular Rate of growth Slow and Erratic Expensile Capsule Well Invasive capsulated Size Small or Large Small to large sometimes very Large. Course Rarelly fatal Usually fatal if untreated
  33. 33. Microscopic BENIGN MALIGNANT features Differentiation Well Lack of differentiated differentiation Cytological Cells similar to Marked variation features normal in shape and size of cells Mitosis Normal Increased abnormal Necrosis unusual Necrosis and haemorrhage common Metastasis Absent Present
  34. 34. Fibroadenoma of the breast. The tan- colored, encapsulated small tumor is sharply demarcated from the whiter breast tissue.
  35. 35. Multiple leiomyomas of the uterus. The neoplasm is composed of monomorphic spindle shaped cells.
  36. 36. Liomyosarcoma of the uterus: soft fleshy tumor arising from myometrium. The tumor shows bundles of malignant smooth muscle fibres.
  37. 37.  Differentiation Extent to which parenchymal cells resembles to normal cells . Neoplastic Cells resembling the mature  Well differentiated normal cells of the tissues of origin .  Poorly differentiated undifferentiated tumours Primitive appearing unspecialised cells .
  38. 38. EXAMPLES OF DIFFERENTIION  Benign tumours are well differentiated eg Leiomyoma .  Malignant neoplasms range from well differentiated to undifferentiated .  Lack of differentiation or anaplasia is considered a hallmark of malignant transformation .
  39. 39. FEATURES OF Lack OF DIFFERENTIATION   • 1. Pleomorphism refers variation in size and shape of cell and nuclei . Thus, cells within the same tumor are not uniform, but range from large cells, many times larger than their neighbors, to extremely small and primitive appearing.
  40. 40.  2. Abnormal nuclear morphology. Characteristically the nuclei contain abundant chromatin and are dark staining (hyperchromatic).  The nuclei are disproportionately large for the cell, and the nuclear cytoplasmic ratio os increased .
  41. 41.  3. Nuclear-to-cytoplasm ratio may approach 1 : 1 instead of normal 1 : 4 or 1 : 6. The nuclear shape is often irregular, and the chromatin is coarsely clumped and distributed along the nuclear membrane. Large nucleoli are usually present in these nuclei .
  42. 42. Signs of malignant process.. Malignant cell showing Pleomorphism ,
  43. 43.  4 . Mitoses –  Increased mitosis reflect the higher proliferative activity of the parenchymal cells.  Malignant and undifferentiated tumors usually possess large numbers of mitoses .
  44. 44. The presence of mitoses, however, does not necessarily indicate that a tumor is malignant or that the tissue is neoplastic. More important feature of malignancy are atypical, bizarre mitotic figures, sometimes producing tripolar, quadripolar, or multipolar forms of mitosis .
  45. 45. Other conditions of increased mitosis  Many normal tissues exhibiting rapid turnover eg.  Bone marrow, have numerous mitoses, and  Non-neoplastic proliferations such as hyperplasias contain many mitotic figures .
  46. 46. Malignant cell showing abnormal quadripolar mitotic figure
  47. 47.  5. Loss of polarity refers to –  Sheets or large masses of tumor cells grow in an anarchic, disorganized fashion.
  48. 48.  6 . Other changes --   Formation of tumor giant cells, some possessing only a single huge polymorphic nucleus and others having two or more large, hyperchromatic nuclei .
  49. 49. Example of tumour gaint cell  M/E- Anaplastic tumor of the skeletal muscle (rhabdomyosarcoma) with marked cellular and nuclear pleomorphism, hyperchromatic nuclei, and tumor giant cells
  50. 50.  7. Necrosis - Often the vascular stroma is scant, and in many anaplastic tumors, large central areas undergo ischemic necrosis.
  51. 51. WHAT IS DYSPLASIA  Dysplasia is a term that literally means disordered growth.  Characterized by loss in the uniformity of the individual cells as well as a loss in their architectural orientation .
  52. 52. Features of dysplasia  Pleomorphism ,  Hyperchromatic nuclei with a  High nuclear-cytoplasmic ratio.  The architecture of the tissue disordered.  Mitotic figures are more abundant than usual .
  53. 53. NOTE  In dysplastic stratified squamous epithelium, mitoses are not confined to the basal layers but instead may appear at all levels, including cell surface .
  54. 54. GRADING OF DYSPLASIA Graded as mild, moderate or severe.  Mild , Moderate: usually reversible  Severe: usually progresses to carcinoma in situ (CIS). • Next step after CIS invasive carcinoma
  55. 55. Normal gland Mild dysplasia
  56. 56. Moderate dysplasia Severe dysplasia
  57. 57. WHAT IS Ca Insitu  When dysplastic changes are marked and involve the entire thickness of the epithelium but remains confined by the basement membrane, it is considered a preinvasive neoplasm or carcinoma in situ
  58. 58.  Once the tumor cells breach the basement membrane , the tumor is said to be invasive .
  59. 59. Carcinoma in situ. This low – power view shows that the entire thickness of the epithelium is replaced by atypical dysplastic cells. The basement membrane is intact. B, A high-power view of another region shows marked nuclear and cellular pleomorphism, and numerous mitotic figures extending toward the surface.
  60. 60. Classification of Cervical intraepithelial neoplasia (CIN) and dysplasia
  61. 61. CIN I MILD INVOLVE DYSPLASIA LOWER 3rd OF EPITHELIUM  CIN I Mild dysplasia CIN II MODERATE INVOLVE UP TO DYSPLASIA MIDDLE 3rd OF EPITHELIUM CIN III SEVERE INVOVEMENT DYSPLASIA UP TO UPPER 3rd OF EPITHELIUM
  62. 62. CLASSIFICATION OF TUMORS
  63. 63. TISSUE OF BENIGN MALIGNANT ORIGIN Connective Tissue and masenchymal origin Fibroma Fibrosarcoma Lipoma Liposarcoma Chondroma Chondrosarcoma Osteoma Osteosarcoma
  64. 64. EPITHELIAL BENIGN MALIGNANT TUMOURS Stratified Squamous cell Squamous cell squamous papilloma carcinoma Basal cell of skin Basal cell ca. Glands and ducts Adenoma Adenocarcinoma Papilloma Papillary ca. Cystadenoma Cystadeno ca. Respiratory Bronchogenic ca. passage
  65. 65. Neuroectoderm NEVUS Malignant Melanoma Renal Epithelium Renal Tubular RCC Adenoma Liver Cell Liver Cell HCC Adenoma Urinary Tract Transitional Cell TCC epithelium Papilloma Placental Hydatidiform Mole Choriocarcinoma Epithelium Testicular Seminoma Epithelium Embryonal Ca
  66. 66. Fibroma Bindles of spindle cells separated by collagen bundles
  67. 67. Lipoma; composed of adult adipocytes.
  68. 68. Osteoma formed bundles of compact bone Chondroma formed of chondrocytes in a hyaline matrix
  69. 69. A small hepatic adenoma, an uncommon benign neoplasm, with well- demarcated border (solid adenoma). Mucinous cystadenoma of the ovary
  70. 70. A small hepatic adenoma, an uncommon benign neoplasm, with well- demarcated border (solid adenoma). Mucinous cystadenoma of the ovary
  71. 71. Multiple adenomatous polyps (tubulovillous adenomas) of the cecum are seen here in a case of familial adenomatous polyposis, a genetic syndrome in which an abnormal genetic mutation leads to development of multiple neoplasms in the colon. The genetic abnormalities present in neoplasms can be inherited or acquired.
  72. 72. Tubular adenoma, colon Colonic adenoma: adenomatous polyp (Polypoid adenoma)
  73. 73. Squamous cell papilloma Transitional cell papilloma
  74. 74. Transitional cell carcinoma; papillary type.
  75. 75. A B A: Neurofibroma B: Schwannoma: Both show bundles of schwann cells separated by nerve fibres.
  76. 76. Squamous cell carcinoma: malignant ulcer of the scalp Bronchogenic carcinoma, lung Squamous cell carcinoma arising on top of squamous metaplasia of bronchial epithelium
  77. 77. Cervical squamous cell carcinoma. Note the disorderly growth of the malignant squamous epithelial cells forming large nests with pink keratin in the centers.
  78. 78. Squamous cell carcinoma demonstrates enough differentiation. The cells are pink and polygonal In shape . However, the neoplastic cells show pleomorphism, with hyperchromatic nuclei. A mitotic figure is present near the center.
  79. 79. Adenocarcinoma: malignant glands surrounded by fibrous stroma
  80. 80. Signet ring carcinoma: malignant cells with clear vacuolated cytoplasm due to accumulation of mucin. Mucin can be seen by special stain “mucinocarmine”
  81. 81. Papillary carcinoma: a variant of adenocarcinoma forming papillae
  82. 82. BASAL CELL CARCINOMA
  83. 83. BCC: Groups of neoplastic basaloid cells infiltrating the dermis. The cells at periphery show palisade. The groups of cells are surrounded by clear zone due to fixation artifact ( characteristic for BCC). BCC: peripheral cells are arranged in a palisade with artificial artifact in the stroma
  84. 84. Malignant melanoma of the skin is much larger and more irregular than a benign nevus.
  85. 85. Melanoma (melanocarcinoma): there are aggregates of malignant melanocytes infiltrating the dermis
  86. 86. This sarcoma has many mitoses. A very large abnormal mitotic figure is seen at the right.
  87. 87. Here is an osteosarcoma of bone. The large, bulky mass arises in the cortex of the bone and extends outward The osteosarcoma is composed of spindle cells. The pink osteoid formation seen here is consistent with differentiation that suggests osteosarcoma.
  88. 88. This large mass lesion is a liposarcoma. Common sites are the retroperitoneum and thigh, and they occur in middle aged to older adults. yellowish, like adipose tissue, and is well- differentiated. Large bizarre lipoblasts . .
  89. 89. Chondrosarcoma: malignant chondrocytes in a hyaline matrix
  90. 90. Meningioma Meningioma: is formed of bundles of meningiothelial cells arranged in whorls. Some whorls show central calcification (psammoma bodies).
  91. 91. DISEASES ASSOCIATED WITH INCREASED INCIDENCE OF CANCER
  92. 92. PRENEOPLASTIC NEOPLASM  Down Syndrome Acute Myeloid Leukemia  Xeroderma Squamous Carcinoma of pigmentosum skin.  Gastric Atrophy Gastric Cancer  Actinic dermatitis Squamous carcinoma skin  Cirrhosis HCC  Ulcerative colitis Colon carcinoma  Pagets ds bone Osteosarcoma
  93. 93. Epidemiology of MALIGNANCY Epidemiologic studies established the relation of -  Smoking and lung cancer .  Implicated in cancer of the mouth, pharynx, larynx, esophagus, pancreas, bladder, and most significantly about 90% of lung cancer deaths .
  94. 94.  High dietary fat and low fiber in the development of colon cancer.  Alcohol with carcinomas of the oropharynx , larynx, esophagus and hepatocellular carcinoma.  Alcohol and tobacco together increases the danger of incurring cancers in the upper aerodigestive tract.
  95. 95. OTHER FACTORS  Obesity is associated with approximately 14% of cancer deaths in men and 20% in women.  Environmental,  Racial (possibly hereditary),  Cultural influences to the occurrence of specific neoplasms.
  96. 96.  The risk of cervical cancer is linked to age at first intercourse and the number of sex partners, and it is now known that infection by venereally transmitted human papillomavirus (HPV) contributes to cervical dysplasia and cancer.
  97. 97. AGE  Age has an important influence on the likelihood of being afflicted with cancer.  Most carcinomas occur in the later years of life (>55 years).  Cancer is the main cause of death among women aged 40 to 79 and among men aged 60 to 79;  the decline in deaths after age 80 is due to the lower number of individuals who reach this age.
  98. 98.  Carcinomas, the most common general category of tumor in adults, are rare among children.  Acute leukemia and primitive neoplasms of the central nervous system are responsible for approximately 60% of childhood cancer deaths.
  99. 99.  The common neoplasms of infancy and childhood include the so-called small round blue cell tumors such as  Neuroblastoma,  Wilms tumor,  Retinoblastoma,  Acute leukemias, and  Rhabdomyosarcomas.
  100. 100. CHILDHOOD NEOPLASMS SITE Acute Lymphocytic Blood and marrow Leukemia Lymphoblastic leukemia Lymph node and lymphoid tissue Burkitts lymphoma Lymph node and lymphoid tissue Meduloblastoma Cerebellum Retinoblastoma Retina Neuroblastoma Adrenal medulla Nephroblastoma Kidney Hepatoblastoma Liver Osteosarcoma Bone
  101. 101. What is metastasis The term metastasis denotes the development of secondary implants discontinuous with the primary tumour .
  102. 102. MODE OF METASTASIS  Lymphatic  Haematogenous  Retrograde  Transcoelomic
  103. 103.  Lymphatic Spread. Transport through lymphatics is the most common pathway for the initial dissemination of carcinomas and sarcomas may also use this route.
  104. 104.  Retrograde metastasis –  Due to obstruction of the lymphatics by the tumour cells the lymph flow is disturbed and tumour cells spread against the flow of lymph causing retrograde metastasis .
  105. 105. Examples of retrograde metastasis  Ca. of prostate to the supraclavicular lymph nodes ,  Metasatic deposits from bronchogenic ca to axillary lymph nodes
  106. 106.  What is Virchows lymph nodes ? Nodal metastasis preferentially to supraclavicular lymph nodes from cancers of abdominal organs eg cancer stomach , colon and gallbladder.
  107. 107. The pattern of lymph node involvement follows the natural routes of lymphatic drainage.  carcinomas in the upper outer the breast quadrants, disseminate first to the axillary lymph nodes.  Cancers of the inner quadrants drain to the nodes along the internal mammary arteries thereafter infraclavicular and supraclavicular nodes
  108. 108.  Regional lymph nodes draining the tumour are invariably involved producing regional nodal metastasis eg.  Ca of breast to axillary lymph nodes  Ca thyroid to lateral cervical LN.  Bronchogenic ca. to hilar and paratracheal lymph nodes .
  109. 109. Skip metastasis” Local lymph nodes, may be bypassed called “skip metastasis” because of venous -lymphatic anastomoses or inflammation or radiation has obliterated lymphatic .
  110. 110.  Hematogenous Spread.  Hematogenous spread is typical of sarcomas but is also seen with carcinomas. Arteries, with their thicker walls, are less readily penetrated than are veins.  Arterial spread may occur, however, when tumor cells pass through the pulmonary capillary beds .
  111. 111. METASTATIC CASCADE: Steps involved in the hematogenous spread of a tumor
  112. 112.   The liver and lungs are most frequently involved in hematogenous dissemination because all portal area drainage flows to the liver and all caval blood flows to the lungs.
  113. 113.  Common site of blood borne metastasis – Liver , Lungs , Brain , Bone , Kidney ,Adrenals.  Few organs eg Spleen , Heart , Skelatal muscles donot allow tumour metastasis to grow .  Spleen is unfavourable site due to open sinusoidal pattern which doesnot allow tumour cells to metastasise .  Limbs ,head , neck and pelvis drain blood via vena cava so cancers from these sites metastasise to lungs.
  114. 114.  Certain cancers have a propensity for invasion of veins.  Renal cell carcinoma often invades the branches of the renal vein and then the renal vein itself to grow in a snakelike fashion up the inferior vena cava, sometimes reaching the right side of the heart.  Hepatocellular carcinomas often penetrate portal and hepatic radicles to grow within them into the main venous channels.
  115. 115.  Transcoelomic spread –  a. Carcinoma of stomach seeding both the ovaries ( Krukenberg tumour)  b. Carcinoma of the ovary spreading to entire peritoneal cavity without infiltrating the underlying structures.  c. Pseudomyxoma peritonei is the gelatenous coating of the peritoneum from mucin secreting ca. of ovary or appendix .
  116. 116. Small tan tumor nodules seen over the peritoneal surface of the mesentery (peritoneal spread of carcinoma)
  117. 117.  d. Ca. of bronchus and breast seeding to the pleura and pericardium. Spread along epithelial lined surfaces  a. Through fallopian tube from endometrium to ovaries vice versa.  b . Through bronchus to alveoli.  c. Through ureters from kidney into lower urinary tract.  Spread via ceribrospinal fluid.  Implantation.
  118. 118. A liver studded with metastatic cancer
  119. 119. Microscopically, metastatic adenocarcinoma is seen in a lymph node here. It is common for carcinomas to metastasize to lymph nodes.
  120. 120. A breast carcinoma has spread to a lymphatic within the lung.
  121. 121. Branches of peripheral nerve are invaded by nests of malignant cells. This is termed perineural invasion. This is often the reason why pain associated with cancers is unrelenting.
  122. 122. Colon carcinoma invading pericolonic adipose tissue
  123. 123. Axillary lymph node with metastatic breast carcinoma. The subcapsular sinus (top) is distended with tumor cells. Nests of tumor cells have also invaded the subcapsular cortex
  124. 124. EFFECTS OF TUMOURS I.Local effects: local destruction of tissues causes loss of function, ulceration, hemorrhage, obstruction, … Hormone production: well differentiated (benign) tumors of endocrine glands may secrete hormones, and cause hyperfunction.
  125. 125. II. Cancer cachexia: i.e. wasting and weakness. May be due to loss of appetite, and production of TNF-alpha (cachectin) and possibly other factors by tumor cells and by reactive macrophages.
  126. 126. III –PARANEOPLASTIC SYNDROMES  Symptoms caused by elaboration of active substances or hormones not indigenous to the tissue of the origin of neoplasm. Most common are:  1. Endocrinopathies  2. Acanthosis nigricans  3. Hypertrophic osteoarthropathy  4. Thrombotic diatheses  5. Others.
  127. 127. ENDOCRINOPATHIES 1. Endocrinopathies: Ectopic hormone production by non- endocrine neoplasms (inappropriate hormone secretion by tumors).
  128. 128. EXAMPLES OF ENDOCRINOPATHY  Cushing‟s syndrome – caused by small cell (oat cell) bronchogenic carcinoma --> ACTH.  Hypercalcemia - Caused due to parathyroid hormone secretion by bronchogenic squamous cell carcinoma, (and by T-cell leukemia/lymphoma) .
  129. 129.  2. Acanthosis nigricans: a verrucous pigmented lesion of the skin .  3. Clubbing of the fingers and hypertrophic osteoarthropathy; associated with lung cancer, and regress after resection of the neoplasm.  4.Haematological - Thromombo- plastic substances by tumor cells can cause DIC or nonbacterial thrombotic endocarditis (NBTE)
  130. 130. Grading of Malignant Neoplasms Grade Definition I Well differentiated II Moderately differentiated III Poorly differentiated IV Nearly anaplastic
  131. 131. Staging of Malignant Neoplasms Stage Definition Tis In situ, non-invasive (confined to epithelium) 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 M1 Distant metastases present
  132. 132. TNM Staging system of the tumor: T: Tumor size N: L.N. metastasis M: Distant metastasis
  133. 133. GRADING OF TUMOURS .Grading is based on the degree of differentiation and the number of mitotic figures in the . tumor.
  134. 134.  Tumors are classified as Grades I to IV with increasing anaplasia. High grade tumors are generally more aggressive than low grade ones.  The grade of tumor may change as the tumor grows (with tumor progression), and different parts of the same tumor may show different degrees of differentiation
  135. 135. STAGING OF CANCER  Staging is based on the size of the primary tumor and the extent of local and distant spread. Staging proved to be of more clinical value than grading.
  136. 136.  Two methods of staging are currently used:  1.The TNM (Tumor, Node, Metastases) system.  2.The AJC (American Joint Committee) system.  Both systems assign to higher stages those tumors that are larger, locally invasive and metastatic.
  137. 137. METHODS OF DIAGNOSIS OF CANCER . 1 . Histologic examination (paraffin- embedded fixed sections, stained by H&E) . . 2 . Cytologic smears (Papanicolaou): examination of already shed cancer cells in body secretions. 3 . Fine-needle aspiration: cytologic examination of aspirated tumor cells from palpable masses .
  138. 138. 4 . IMMUNOCYTOCHEMISTRY  . Detection of surface markers or cell products by monoclonal antibodies.  It can be used for detection of cytokeratin, vimentin, desmin, calcitonin, neuron-specific enolase, prostate specific antigen, products of tumor suppressor genes (p53), and oncogenes (c-erb B2), etc ...
  139. 139. Gastric adenocarcinoma is positive for cytokeratin, with brown-red reaction product in the neoplastic cell cytoplasm . This is a typical staining reaction for carcinomas and helps to distinguish carcinomas from sarcomas and lymphomas.
  140. 140. This sarcoma is positive for vimentin by immunohistochemical staining. This is a typical immunohistochemical staining reaction for sarcomas.
  141. 141. A: Normal smear of the uterine cervix B: Abnormal smear containing sheet of malignant cells showing large hyperchromatic and pleomorphic nuclei with the presence of mitosis in one cell
  142. 142. DNA ANALYSIS (MOLECULAR DIAGNOSIS) 1.DNA Probe Analysis: used for detection of oncogenes; such as N-myc, bcr-c-abl gene products. 2.Flow Cytometry: a measurement of DNA content of tumor cells (degree of ploidy). TUMOR MARKERS They are of value to support the diagnosis, To determine the response to therapy and  To indicate relapse during follow- up.
  143. 143. EXAMPLES OF TUMOUR MARKERS  HORMONES  HCG (trophoblastic tumors and non- seminomatous testicular tumors)  Calcitonin (medullary carcinoma of thyroid)  Catecholamin & metabolites (pheochromocytoma & related tumours)  Ectopic hormones (paraneoplastic syndromes)
  144. 144. ONCOFETAL ANTIGENS -Alpha-fetoprotein (liver cancer & non- seminomatous testicular tumors) - CEA (carcinoma of colon, pancreas, lung , stomach & breast)
  145. 145. ISOENZYMES  PSA (prostate cancer)  NSE (small cell carcinoma of lung, neuroblastoma) SPECIFIC PROTEINS  Immunoglobulins (multiple myeloma & other gammopathies) MUCINS & OTHER GLYCOPROTEINS  CA-125 (ovarian cancer)  CA-19-9 (colon & pancreatic cancer)
  146. 146. CARCINOGENESIS Molecular Basis of Cancer
  147. 147. CARCINOGENESIS MOLECULAR BASIS OF CANCER Cancer is a genetic disease. The genetic injury may be inherited in the germ-line, or it may be acquired in somatic cells. . Tumors are monoclonal (the progeny of a single genetically-altered progenitor cell).
  148. 148. Carcinogenesis or oncogenesis Carcinogenesis or oncogenesis means mechanism of induction of tumors . The literature on the molecular basis of cancer continues to proliferate at such a rapid pace that it is easy to get lost in the growing forest of information.
  149. 149. What is carcinogen and role of carcinogen in CANCER.
  150. 150.  Carcinogens – substances known to cause cancer or produces an increase in incidence of cancer in animals or humans  Cause of most cancers is unknown  Most cancers are probably multifactorial in origin  Known carcinogenic agents constitute a small percentage of cases  Unidentified „environmental‟ agents probably play a role in 95% of cancers
  151. 151. NOTE  Carcinogenesis is caused by mutation of the genetic material of normal cells .  More than one mutation is necessary for carcinogenesis.  This results in uncontrolled cell devision and the evolution of those cells by natural selection in the body.
  152. 152.  Mutations of genes play vital roles in cell division,  Mutation of gene regulating apoptosis (cell death), and DNA repair will cause a cell to lose control of its cell proliferation  Cancer is fundamentally a disease of disregulation of tissue growth.
  153. 153. Large-scale mutations involve the  Deletion or gain of a portion of a chromosome.  Genomic amplification occurs when a cell gains many copies (often 20 or more) .
  154. 154. Genomic amplification  Chromosomal alterations that result in increased number of copies of a gene is found in some solid tumors eg. Neuroblastoma with n-MYC HSR region , ERB – B in breast and ovarian carcinoma.
  155. 155.  Translocation eg -  Philadelphia chromosome - translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia, and results in production of the BCR – abl fusion protein, an oncogenic tyrosine kinase .
  156. 156.  The Philadelphia chromosome, characteristic of CML provides the prototypic example of an oncogene formed by fusion of two separate genes.  In Reciprocal translocation between chromosomes 9 and 22 relocates a truncated portion of the proto-oncogene c-ABL (from chromosome 9) to the BCR ( breakpoint cluster region ) on chromosome 22
  157. 157.  Small-scale mutations include  Point mutations,  Deletions, and  Insertions
  158. 158.  Point mutation of RAS family genes is the single most common abnormality of proto-oncogenes in human tumors. Approximately 15% to 20% of all human tumors contain mutated versions of RAS proteins. Eg. pancreatic adenoca , cholangioca , myeloid leukemia , lung ca, contain a RAS point mutation .
  159. 159. Carcinogenesis is a multi-step process.  Characteristic features of malignant tumors Excessive rate of growth, Invasiveness, and Escape from the host immune system, acquired in a stepwise series of genetic events, a process called “tumor progression”.
  160. 160.  Four classes of regulatory genes. 1. Promotors – Proto-oncogenes 2. Inhibitors – Cancer-suppressor genes – p53 3. Genes regulating Apoptosis. 4. DNA repair genes.
  161. 161.  Genetic alterations may involve:  1. Growth-promoting proto- oncogenes (activation of growth- promoting genes)  2. Growth-inhibiting tumor- suppressor genes (inactivation of genes that normally suppress cell proliferation, “tumor suppressor genes”)  3. Apoptosis-regulating genes (genes that prevent programmed cell death, “apoptosis”)
  162. 162. Molecular Basis of Multistep Carcinogenesis
  163. 163.  MULTISTEP CARCINOGENESIS INCLUDES  INITIATION  PROMOTION  PROGRESSION
  164. 164. MULTISTEP CARCINOGENESIS 1) Initiation. Chemical carcinogen reacts with DNA to produce a mutation. Involves carcinogen metabolism, DNA repair & cell proliferation. Initiation is irreversible but an initiated cell is not a cancer cell and does not necessarily become one.
  165. 165. MULTISTEP CARCINOGENESIS 2) Promotion Tumor promotors contribute to carcinogenesis by nongenotoxic mechanisms. Influence proliferation of initiated cells to form benign lesions which may regress or acquire additional mutations to become a malignant neoplasms.
  166. 166. Stages of Carcinogenesis Initiation Promotion Progression
  167. 167. MULTISTEP CARCINOGENESIS 3)Tumor Progression Tumors acquire ability to invade and establish distant metastases. Characterized by chromosome instability and mutations in oncogenes and tumor suppressor genes. Mutations may reflect selection of cells suited for neoplastic growth and may in turn increase chromosome instablity.
  168. 168. ETIOLOGICAL AGENTS OF CARCINOGENESIS
  169. 169. Chemical Carcinogenesis:  Direct Acting Carcinogens:  Alkylating Agents: Cyclophosphamide  Procarcinogenes (needs activation)  Polycyclinc hydrocarbons – Benzpyrene  Aromatic amines, dyes - Benzidine  Natural products - Aflotoxin  Others - Vinyl chloride, turpentine etc.
  170. 170. Metabolic activation Procarcinogen Ultimate carcinogen DNA [stable] [Reactive binding electrophile] detoxfication mutation Excretable metabolites [stable] Malignant transformation
  171. 171.  A virus that can cause cancer is called an oncovirus. These include  Human papillomavirus (cervical carcinoma),  Epstein-Barr virus (B-cell lymphoproliferative disease and nasopharyngeal carcinoma),
  172. 172.  Kaposi's sarcoma herpesvirus (Kaposi's Sarcoma and primary effusion lymphomas),  hepatitis B and hepatitis C viruses (hepatocellular carcinoma), and  Human T-cell leukemia virus-1 (T- cell leukemias).
  173. 173.  Bacterial infection may also increase the risk of cancer eg.  Helicobacter pylori-induced gastric carcinoma.  Parasitic infections strongly associated with cancer include -:  Schistosoma haematobium (squamous cell carcinoma of the bladder) and the liver flukes, Opisthorchis viverrini and Clonorchis sinensis (cholangiocarcinoma).
  174. 174.  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 in vitro and induce neoplasms .  UV light is clearly implicated in the causation of skin cancers .  Ionizing radiation exposure from medical or occupational exposure, nuclear plant accidents, and atomic bomb detonations have produced a variety of forms of malignant neoplasia
  175. 175.  Sources of ionizing radiation include medical imaging, and radon gas. non- ionizing radiation from ultraviolet radiation leukemias typically require 2–10 years to appear.  Some people, such as those with nevoid basal cell carcinoma syndrome or retinoblastoma, are more susceptible than average to developing cancer from radiation exposure.
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