Neoplasia

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Neoplasia
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Neoplasia

• Neoplasia means new growth
• A neoplasm is an abnormal mass of tissue, the
  growth of which exceeds and is uncoordinated with
  that of normal tissues and persists in the same
  excessive manner after cessation of the stimuli
  which evoked the change.
• This 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
  although tumors remain dependent on their host
  for their nutrition and blood supply.

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Nomenclature

• Tumors (benign malignant) have 2 basic
  components
• parenchymal proliferating cells
• supportive stromal tissues
• Malignant tumors
• Sarcoma arise from mesenchymal tissue
• Carcinoma epithelial tissue tumors, can be
  associated with desmoplasia (induced
  non-neoplastic proliferation of fibrous tissue
• Squamous cell- stratified epithelium or areas of
  squamous metaplasia (bronchi), produce keratin
• Transitional cell- urinary tract
• Adenocarcinoma- glandular epithelium, may or may
  not produce something,
• .

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• Benign tumors designated by the suffix oma
• Adenoma - glandular epithelium tumor usually
  producing a substance (mucin) which froms cystic
  structures
• Papilloma epithelial tumor forming finger like
  projections with a connective tissue core
• Polyp a tumor projecting from the mucosal
  surface of a hollow organ
• Mesenchymal- like malignant types but with out
  the sarc-
• Choristomas- normal tissue just in the wrong
  place
• Hamartomas- non-neoplastic disorganized rests of
  cells, may produce symptoms due to location.
• Some tumors appear to have more than one
  parenchymal cell type
• Mixed tumors derived from a single germ cell
  layer that differentiates into more than one cell
  type.
• Teratomas made of a variety of parenchymal cell
  types that derive from more than one germ cell
  layer formed by totipotent cells that are able to
  from ectoderm, endoderm mesoderm (teratomas).
• Exceptions
• Melanoma, lymphoma, mesothelioma, hepetoma,
  retinoblastoma
• Eponymously named tumors Wilms tumor, Burkitts
  lymphoma, Hogdkins disease, etc.

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Teratomas
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Biology of Tumor Growth Benign vs. Malignant

• The distinction between benign and malignant
  tumors is based on morphology and clinical
  behavior using 4 criteria
• Malignant change (transformation ) of the target
  cell
• Rate of growth
• Local invasion
• Metastases

Morphological characteristics are associated with
a particular clinical behavior however it is
ultimately clinical behavior which determines the
malignant state of a neoplasm.
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Differentiation Anaplasia

• Differentiation is the extent to which tumor
  cells resemble normal tissue. Benign tumor cells
  closely mimic normal cells, frequently
  microscopic examination is identical. Malignant
  neoplasms are less like their normal
  counterparts, although they may range
  histologically from well differentiated to poorly
  differentiated.
• Lack of differentiation is called anaplasia this
  is a hallmark of malignancy.
• Anaplasia is based on a number of
  characteristics
• Nuclear cellular pleomorphism variation in the
  shape size of cells nuclei.
• Hyperchromasia darkly stained nuclei that
  frequently contain prominent nucleoli.
• Nuclear-cytoplasmic ratio Approaches 11,
  normally this ratio is 14 16 (this reflects
  nuclear enlargement).
• Abundant mitoses reflects prominent
  proliferative activity, especially if mitotic
  figures are abnormal.
• Loss of polarity anaplasia is associated with a
  disturbed orientation of normally developing
  tissue cells resulting in disorganized masses.
• Tumor giant cells contain a single large or
  multiple abnormally shaped nuclei.

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Tumor giant cells
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Numerous mitoses
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Nuclear pleomorphism Multiple mitoses
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• Well differentiated tumors, either benign or
  malignant tend to retain the functional
  characteristic of normal tissue poorly
  differentiated tumor display architectural
  functional disarray.
• Differentiated tumors may produce their normal
  product and this may be used to monitor the state
  of disease.
• Poorly differentiated tumors may elaborate normal
  cell products abnormally or abnormal cell
  products.

Prolactin secreting pitutary tumor
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Dysplasia

• Dysplasia refers to disorderly but not neoplastic
  growth usually encountered in epithelial tissue.
  
• Dysplasia is associated with the loss of cellular
  uniformity and architectural orientation there
  may be an increased number of mitotic cells
  occurring in abnormal locations.
• When dysplasia involves the entire thickness of
  the epithelium but does not breech the basement
  membrane it is described as carcinoma-in-situ,
  this is considered a potentially pre-cancerous
  state.
• Once the basement membrane is violated the
  process becomes invasive.

CIS of the cervix
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Normal to Abnormal Cervical Epithelium
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Rates of growth

• Tumors are clonal expansions of a single
  transformed cell, it requires 30 doubling times
  for a single cell to yield a cell mass of 1gram
  (10 ? 9 cells) this is the smallest size tumor
  that can be detected.
• Most malignant tumors grow more rapidly than
  benign tumors or normal tissue. The rate of
  growth of tumor is determined by 3 main factors
• The doubling time of tumor cells
• The fraction of tumor cell that are in the
  replicative pool
• The rate at which cells die and/or leave the
  replicative pool

Unless it produces an active product
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• Fig 7.12

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• The proportion of cells in a tumor that are
  actively growing is the growth fraction. early in
  tumor growth the growth fraction is very high.
• As tumor size increase the portion of cells in
  the replicative pool decreases, cells leave the
  replicative pool due to shedding, lack of
  nutrients or apoptosis.
• As tumors enlarge and the growth fraction
  decreases, tumors reaching a clinically
  detectable size have a large portion of
  non-dividing cells.
• While a lower growth fraction delays tumor growth
  it also impairs the ability of anti-cancer
  treatments from reaching full effectiveness.
• Cancer therapies are directed to kill growing
  cells (the faster growing the more susceptible
  they are).
• A strategy in cancer treatment is to manipulate
  the tumor to enhance the growth fraction
  debulking surgery and radiation therapy have role
  in decreasing tumor cell numbers evoking an
  enhanced proliferative response in the remaining
  cell, this increases their susceptibility to
  therapies.

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• Fig 7.13

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• In general, the growth rate of tumors correlates
  with their level of differentiation with more
  malignant tumors growing more rapidly than
  benign rates can be influenced by hormonal
  milieu, blood supply, nutrition, etc

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Cancer Stem Cells Cancer Cell Lineages

• A clinically detectable tumor (109 cells) is a
  heterogeneous cell population originating form
  the clonal expansion of a single transformed
  cell.
• These tumor stem cells have the capacity to
  initiate sustain tumor growth.
• Tumor stem cells constitute a small fraction of
  the tumor cells present and may have a low rate
  of replication.
• Therapies that kill rapidly growing cells may
  select for the survival of these cancer stem
  cells.

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Local Invasion

• A distinguishing characteristic of malignant
  tumors is the ability to invade and violate
  anatomical structures.
• Benign tumors tend to grow as a cohesive mass
  pushing and/or encircling normal structures,
  benign tumors are not associated with distant
  spread.
• Malignant tumors are associated with invasion
  infiltration of local and distant tissue.
  Malignancies are able to breech almost all
  anatomic boundaries, this along with the ability
  to spread distantly are hallmarks of malignancy.

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Metastasis

• The process of metastasis involves invasion of
  lymphatics, blood vessels or body cavities by
  tumor followed by transport growth of secondary
  tumor masses that are independent of the primary
  tumor. The ability to metastasize is the most
  important distinguishing feature of a malignant
  neoplasm.

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Pathways of Spread

• There are 3 basic pathways
• 1. Spread into body cavities This occurs by
  seeding surfaces of the peritoneal, pleural,
  pericardial or subarachnoid spaces. The location
  of the primary frequently determines the cavity
  involved (liver?peritoneal, ling?pleural, etc)
• 2. Lymphatic invasion Invasion of lymphatic
  vessels allows tumor cells to be transported to
  regional lymph nodes which drain to more
  centrally located nodes allowing the cancer to
  spread. Staging of tumors to accurately assess
  appropriate treatment prognosis always
  involves evaluation of local regional lymph
  nodes

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• 3. Hematogenous spread This is a common
  mechanism fro metastasis, because of their thin
  wall veins are more often the initial pathway for
  spread. Organs with a large amount of venous
  blood flow (liver lung) are common sites for
  hematogenous spread. Once tumor cells reach the
  heart they are disseminated via the arterial
  system, brain mets are common due to the large
  amount of CO directed at this organ.
• Although not true metastasis direct extension of
  malignant tumors is a common complication of
  neoplasia.

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Epidemiology

• Geographical Environmental factors
• Environmental factors significantly influence the
  occurrence of specific forms of cancer in
  different parts of the world In Japan the death
  rate from gastric cancer is 6X greater than in
  the US, in the US colon cancer is much more
  common than in Japan. Immigrants from Japan
  have death rates from colon gastric cancers that
  are intermediate between Japan the US this is
  taken as evidence for the influence of
  environmental factors on carcinogenesis.
• Increased cancer risk has been well described for
  a number of environmental toxins asbestos, PCBs,
  vinyl chloride, benzene, and cigarette smoke
  (reportedly contains gt200 substances known to
  increase the risk of carcinogenesis).

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• Fig 7.25

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• Age
• Cancer incidence increase with age, particularly
  after the age of , it is the main causes of
  death in females aged 40-79 and in men aged
  60-79. Particular tumors are particularly common
  in thelt15 yo age group
• Hematopoietic neoplasias
• Neuroblastoma
• Wilms tumor
• Retinoblastoma
• Sarcomas

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Genetic Predisposition to Cancer

• Genetic predisposition to cancer can be divided
  into 3 categories
• 1. Autosomal dominant inherited cancer syndromes
  are characterized by inheritance of single mutant
  genes that greatly increase the risk of certain
  tumors. These are usually point mutations
  occurring in a single allele of a tumor
  suppressor gene subsequently the remaining
  allele is lost either by chromosome deletion,
  recombination or a second mutation. Examples of
  this type are retinoblastoma and familial
  adenomatous polyposis. Incomplete penetrance and
  variable expressivity are seen in these
  associations.
• Inherited cancer syndromes have some
  characteristic features
• 1. Tumor site is at specific sites or tissues
  retinoblastoma
• 2. Tumors usually have an associated marker
  phenotype (MEN associated with familial polyposis
  of the colon)

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• 2. Defective DNA repair syndromes are
  characterized by DNA instability that greatly
  increase the predisposition to environmental
  carcinogens (Xeroderma pigmentosa and UV
  exposure)
• 3. Familial cancers are characterized by familial
  clustering of specific cancers but the
  transmission pattern is not clear for individual
  cases breast, colon, brain and ovarian cancers
  can exhibit familial clustering. Familial
  cancers have some common features
• Early age of onset
• Increased incidence of bilateral or multiple
  tumors
• No marker phenotype (familial colon cancers do
  not arise in preexisting colon polyps)
• 4. The predisposition to familial tumors is
  usually autosomal dominant, but Multifactorial
  inheritance is possible as is increased risk due
  to a number of low penetrance alleles.

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• Table 7-6

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Nonhereditary Predisposing Conditions

• Certain clinical conditions are associated with
  an increased risk of developing cancer(e.g.,
  liver cirrhosis and hepatocellular carcinoma,
  ulcerative colitis and colon cancer).
• Chronic Inflammation
• Chronic inflammation is associated with increased
  carcinogenesis (Virchow 1863). There is an
  increased risk for GI cancers among patients with
  Crohns disease. , H. pylori gastritis, viral
  hepatitis and chronic pancreatitis all
  inflammatory states. This may be associated with
  chronic cytokine production, increased tissue
  stem cells due to on going inflammation
  attempted repair or the effects of chronic
  generation of ROS in the inflammatory process.
• Precancerous conditions
• Certain non-neoplastic disorders have such a well
  defined association with cancer that they are
  labeled precancerous conditions solar keratosis
  of the skin, leukoplakia, chronic ulcerative
  colitis, etc. Certain benign tumors are also
  associated with the subsequent development of
  cancer, villous adenomas of the colon often
  developed into cancer. The presence of these
  predisposing conditions warrants close monitoring
  for early diagnosis of cancer.

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• Table 7-2