Neoplasia

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					Neoplasia

   Pathophysiology of tumors and
   cancer


                                   1
Cells normally differentiate, grow,
mature and divide.
These are regulated processes,
balanced in a healthy system such that
cell birth is nearly equal to cell death




                                           2
Regulation of cell division includes:
1. Signaling by biochemicals released from
one cell that interact with other cells growth
factors or cytokines
2. Other external factors , such as contact
inhibition




                                                 3
3. Genes and internal factors that
promote and regulate cell division
genes and chromosomal factors -
telomeres




                                     4
A tumor cell’s growth is autonomous –
independent of controls


Neoplasm – a type of tumor – group of
neoplasic cells
Study of tumors is oncology from Greek for
tumor



                                             5
Two major types: Benign and Malignant
Benign: grow slowly
         low mitotic rate
         well differentiated
         not invasive; well-defined borders
          remain localized; do not
                   metastasize

                                              6
Any increase in tissue size is not
necessarily neoplasia.

left ventricular cardiac hypertrophy due
to hypertension.




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   Hypertrophy: an increase in cell size.
    Increase in skeletal muscle fiber size is a
    physiologic response to exercise

   Hyperplasia: an increase in the number of
    cells. Postpartum breast lobules undergo
    hyperplasia for lactation, but endometrial
    hyperplasia in a postmenopausal woman is
    abnormal.
The endometrium seen in this uterus opened to reveal the
endometrial cavity are a result of hyperplasia.


However, the cells are normal in appearance. Sometimes
hyperplasias can be "atypical" and the cells not completely
normal. Such conditions can be premalignant.
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The first step toward neoplasia is cellular transformation.

Metaplasia: the exchange of normal epithelium for another type of
epithelium.

Metaplasia is reversible when the stimulus for it is taken away. Like
normal respiratory laryngeal epithelium on the right to squamous
epithelium on the left in response to chronic irritation of smoking. The
two forms of cellular transformation that are potentially reversible,
but may be steps toward a neoplasm

Dysplasia: a disordered growth and maturation of an epithelium,
which is still reversible if the factors driving it are eliminated.




                                                                           12
This is the next step toward neoplasia. Here, there is normal cervical
squamous epithelium at the left, but dysplastic squamous epithelium at
the right. Dysplasia is a disorderly growth of epithelium, but still
confined to the epithelium. Dysplasia is still reversible.               13
Of course, neoplasms can be benign as well as malignant, though it is not
always easy to tell how a neoplasm will act. Here is a benign lipoma on the
serosal surface of the small intestine. It has the characteristics of a benign
neoplasm: it is well circumscribed, slow growing, and resembles the tissue of
origin (fat).                                                                    14
At low power magnification, a lipoma of the small intestine is seen to be well
demarcated from the mucosa at the lower center-right. This neoplasm is so
well-differentiated that, except for its appearance as a localized mass, it is
                                                                                 15
impossible to tell from normal adipose tissue.
Remember that the most common neoplasm is a benign nevus (pigmented mole)
of the skin, and most people have several, as seen here over the skin of the chest.
As a general rule, benign neoplasms do not give rise to malignant neoplasms. 16
Malignant – cancer
Grow rapidly ; high mitotic index, poorly
differentiated; do not have a capsule; invade
surrounding structures; can metastasize from
the primary to a secondary site (metastasis).




                                           17
Some epithelia are accessible enough, such as the cervix, that cancer
screening can be done by sampling some of the cells and sending
them to the laboratory. Here is a cervical Pap smear in which
dysplastic cells are present that have much larger and darker nuclei
than the normal squamous cells with small nuclei and large amounts of
                                                                        18
cytoplasm.
When the entire epithelium is dysplastic and no normal epithelial cells are
left, then the process is beyond dysplasia and is now neoplasia. If the
basement membrane is still intact, as shown here, then the process is
called "carcinoma in situ" because the carcinoma is still confined to the
epithelium.
                                                                              19
This is a neoplasm. Neoplasia is uncontrolled new growth. Note the mass of
abnormal tissue on the surface of the cervix. The term "tumor" is often used
synonymously with neoplasm, but a "tumor" can mean any mass effect,
whether it is inflammatory, hemodynamic, or neoplastic in origin. Once a
neoplasm has started, it is not reversible.
                                                                               20
This is the microscopic appearance of neoplasia, or uncontrolled new growth.
Here, the neoplasm is infiltrating into the underlying cervical stroma.
                                                                               21
This gastric adenocarcinoma is positive for cytokeratin by
immunoperoxidase. This is a typical staining reaction for carcinomas
and helps to distinguish carcinomas from sarcomas and lymphomas.
Immunoperoxidase staining is helpful to determine the cell type of a
neoplasm when the degree of differentiation, or morphology alone, does
not allow an exact classification.                                       22
Here is a small hepatic adenoma, an uncommon benign
neoplasm, but one that shows how well-demarcated an benign
neoplasm is. It also illustrates how function of the normal tissue
is maintained, because the adenoma is making bile pigment,
giving it a green color.                                             23
In contrast, this hepatocellular carcinoma is not as well circumscribed (note the
infiltration of tumor off to the lower right) nor as uniform in consistency. It is also
arising in a cirrhotic (nodular) liver.                                               24
Malignant neoplasms are
also characterized by the
tendency to invade
surrounding tissues. Here, a
lung cancer is seen to be
spreading along the bronchi
into the surrounding lung.




                               25
This is an example of metastases to the liver. Note that the tan-white masses
are multiple and irregularly sized. A primary neoplasm is more likely to be a
solitary mass. Metastasis is the best indication that a neoplasm is malignant.   26
Here are three abnormal mitoses. Mitoses by themselves are not
indicators of malignancy. However, abnormal mitoses are highly
indicative of malignancy. The marked pleomorphism and
hyperchromatism of surrounding cells also favors malignancy.     27
Malignant tumors – use embryonic origin of
tissue
    Carcinomas come from ectoderm and
Endoderm - epithelial and glandular tissue
    Sarcomas arise from mesoderm
    connective tissue, muscle, nerve and
endothelial tissues


                                             28
Oncogenes
   in non-mutant state called
        proto-oncogenes
   stimulate cell growth and replication
   when turned “on” by mutation cause
       uncontrolled growth




                                           29
Tumor suppressor genes
    negatively regulate proliferation -
        antioncogenes
    want these to remain intact
    takes two “hits” to remove both genes




                                            30
Gene silencing
    regions of genes normally turned off
    can spread without mutation and turn
         off tumor suppressor genes
    drugs that demethylate DNA may turn
        genes back on




                                           31
Angiogenesis
     angiogenic factors or vascular
endothelial growth factor (VEGF) possible
source of new therapies




                                            32
Telomerase
Other factors:
     decreased cell-to-cell adhesion
     secretions of proteases
     ability to grow in new locations




                                        33
Genetics and cancer prone families
    to be passed down, mutations must
         occur in germ cells
    inherited mutations almost always in
    tumor suppressor genes
    these individuals are targets for cancer
         screening



                                           34
Viral causes of cancer:
    viruses assoc. with about 15 % of
cancers world wide – us. Cervix or liver
     hepatitis B or C in chronic form
     Human papilloma virus
          spread through sexual contact
          HPV integrates into DNA and
          uses viral oncogenes
                                           35
Epstein-Barr and Kaposi sarcoma
    both herpes viruses
Human T cell leukemia-lymphoma virus
    blood transfusions, needles, sex and
breast feeding
    infections may be asymptomatic
    may have high incidence, but low #’s of
             cancer
    cofactors increase the risk of cancer
                                            36
Bacterial causes of Cancer
    Helicobacter pylori infects >1/2 world’s
population
    assoc. with B cell lymphomas of the
stomach
     treatment with antibiotics can cause
regression of lymphoma



                                               37
Environmental factors
   Tobacco use
   Diet
   Alcohol use
   Sexual and reproductive behavior
   Air pollution
   Occupation hazards – asbestos
   UV radiation and other radiation
   hormones
                                       38
Gene-Environment Interactions:
    Exposure to environmental agents can
cause increased risk of cancer
    cancer in lab animals – carcinogens
    Comparisons of populations
         genetics vs. lifestyle



                                          39
“Genetics loads the gun; the
environment pulls the trigger.” director of
Nat’l Institute of Environmental Health &
Safety




                                              40
Diagnosis:
    screening procedures and blood tests:
    Tumor markers
         substances on plasma membranes
         in blood, spinal fluid or urine
         hormones, genes antigens or
             antibodies

                                            41
Markers can be used:
    to screen and identify individuals at
         high risk
    to help diagnose the specific type of
         tumor
    to follow the course of the cancer




                                            42
Tumor spread

   Local spread
    – Cellular multiplication
        Function of generation time

        Growth if cell reproduction > cell
         death




                                              43
Mechanical invasion
  along path of least resistance

  compresses blood vessels, leading to
  tissue death and increased space




                                     44
Lytic enzymes
  proteases, collagenases, plasminogen
  activators, lysosomal enzymes

  some involved in producing new blood
  vessels




                                         45
Decreased cell adhesion
  loss of anchoring molecules allows
  cancer to slip between normal cells




                                        46
Stages of cancer spread:
    Stage 1 – confined to site of origin
    Stage 2- cancer is locally invasive
    Stage 3 – cancer has spread to
    regional structures
    Stage 4- cancer has spread to
    distant sites



                                           47
TNM system:
    tumor spread
    node involvement
    presence of distant metastasis


Staging may influence choice of treatment



                                            48
Staging TNM system
1.Size of tumor – T0, T1, T2,T3
2.Degree of local invasion – lymph
  node involvement
3.Extent of spread – metastasis




                                     49
Patterns of spread:
Metastasis
   Direct or continuous extension
   By lymphatics or blood stream
    – As clumps or as single cells
    – Lymphatics most common




                                     50
Patterns of spread:
Metastasis
   Angiogenesis
    – Due to production of angiogenic factors
    – Due to drop in antiangiogenic factors




                                                51
A metastasis grows when:
    vascular network is developed
    host defenses are evaded
    a compatible environment is available




                                            52
Distribution and common sites of distant
metastases
•     often occurs in the first capillary
bed encountered
•Others show “organ tropism”
•Due to:
  •Local growth factors or hormones
  •Preferential adherence to the surface
  •Presence of chemotactic factors

                                            53
Clinical manifestations of
Cancer
   Pain
    – Usually not in early stages
    – 60 – 80 % of terminally ill
    – Psychogenic, cultural and physiologic
      components
    – Due to pressure, obstruction, stretching,
      tissue damage or inflammation


                                                  54
Branches of peripheral nerve are invaded by nests of malignant cells. This is
often why pain associated with cancers is unrelenting.

                                                                                55
 Clinical manifestations of
 Cancer
Fatigue
     sleep disturbances
     biochemical changes
     loss of muscle function




                               56
 Clinical manifestations of
 Cancer
Cachexia – wasting
    anorexia
    early satiety
    weight loss
    anemia
    marked weakness
    taste alterations
    altered metabolism

                              57
 Clinical manifestations of
 Cancer
Anemia
     chronic bleeding
     malnutrition
     medical therapies
     malignancy in blood forming organs
Administer erythropoietin
                                          58
   Clinical manifestations of
   Cancer
Leukopenia and thrombocytopenia
    tumor invasion of bone marrow
    chemotherapy or radiation




                                    59
Clinical manifestations of
Cancer
   Paraneoplastic Syndromes
    – Release of hormones by cancer cells
    – Hematological complications such as
      procoagulation factors
    – Causes weakness by attacking neuromuscular
      junction (similar to myasthenia gravis)




                                               60
Clinical manifestations of
Cancer
   Infection
      most significant cause of complications
       and death




                                                 61
Cancer Treatment
   Chemotherapy
    – Cytotoxic drugs + body defenses
        Single agent

        Combination chemotherapy

          –Avoids single agent resistance
          –Can use lower dose
          –Better remission and cure rate


                                            62
Cancer Treatment
Radiation
     targets DNA
     kill tumor without damage to
surrounding tissues
     tumor must be accessible




                                    63
Cancer Treatment
 Surgery
     method of choice
     can remove entire tumor
     debulking
     adjuvant chemotherapy or
           radiation
     palliation



                                64
  Cancer Treatment
Immunotherapy
    Nonspecific enhancement of the immune
    system – interferons or interleukins
    protect against recurrence
    eliminates cancer cells only
    T- cell based or antibody responses
    Conjugated antibodies
                                          65
Cancer Treatment

   Targeted Therapies
    – Drugs that target the processes of cancer
      cells specifically
         Thalidomide
    – Vaccines




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Side effects of treatment
   Gastrointestinal tract:
    – Oral ulcers
    – Malabsorption
    – Diarrhea
    – Vomiting – caused by effects on CNS




                                            67
    Side effects of treatment
Bone marrow:
    chemo and radiation suppress bone
    marrow

    decrease in red blood cells, white blood
    cells and platelets




                                               68
 Side effects of treatment
Hair and skin:
     alopecia
     skin breakdown and dryness




                                  69
   Side effects of treatment
Reproductive tract:
    affects gametes
    premature menopause
    also due to damage of hypothalamus
         and/or pituitary
    sperm or embryo bank




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posted:11/21/2011
language:English
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