P1253296801MpcEo

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What is pathology?

• Study of disease/suffering
• Pathophysiology what goes wrong and why?
• Diagnostic medicine, based on examination and
  interpretation of changes in tissues, organs (and
  now molecules)

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What causes disease?

• Injury due to environmental forces
• Defect in gene-regulated biologic functions
• Both

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Examples of environmental threats

• Biological bacteria, viruses, fungi
• Physical radiation, mechanical trauma
• Chemical nicotine, mercury, medications

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Tissue reactions

• Usual tissue reactions are an appropriate
  gene-regulated response to the usual
  environmental forces the appearance or pattern
  of these reactions is considered normal
• Defensive tissue reactions are appropriate
  gene-regulated responses to threatening forces
  the pattern of these reactions is called
  inflammation.

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Are defensive tissue reactions disease?

• What is the outcome?
• The threat is resolved subclinically
• The patient feels sick for a brief time and then
  fully recovers
• The process persists the patient develops a
  chronic disease.
• The process overwhelms the patient vital
  functions are compromised beyond a certain level
  the patient dies.

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What is the process of inflammation?

• To start
• Cells under threat release signal molecules to
  alert nearby cells
• Recruited inflammatory cells release more signal
  molecules and organize coordinated response

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Defendokines

• Inflammation-associated molecules are
  innumerable, chemically diverse, and interactive,
  making it almost impossible to isolate their
  individual functions in vivo. E.g. IL-1, IL-8,
  interferons, tumor necrosis factors, etc
• Their role as a group is to activate and regulate
  defense cells, circulatory cells, epithelial
  cells, stromal cells, etc to eliminate threat and
  repair damage.

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Specific defendokine activities

• Activate epithelial cells to increase barrier
  permeability and increase normal functions, i.e.
  secreting mucus, ciliary beating, myoepithelial
  contractions

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• Activate microvasculature to bring about three
  classic signs of inflammation
• -rubor
• -calor
• -tumor

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Microvascular changes

• Precapillary cells dilate to increase local blood
  flow calor and rubor.
• Postcapillary cells increase vessel permeability
  higher pressure/flow plus increased leakiness
  tumor (edema).
• Fibrinogen, RBCs, platelets extravasate and form
  temporary scaffolding and plug holes clots.

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• Defendokines activate local nerves to create
  fourth classic sign of inflammation
• -dolor

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• Defendokines activate local immune cells,
  histiocytes, to mount specific cellular responses
  aimed at eliminating specific kinds of threats,
  e.g. neutrophilic (suppurative) or lymphocytic
  responses.

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• Circulating defendokines lead to non-localized
  clinical symptoms fever, chills, sweats, aches,
  malaise, weight loss, etc.
• Ideally, the defendokines and the entire
  inflammatory response restore order, but with
  loss of regulatory controls, inflammatory
  mediators contribute to the pathological
  state/disease.

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Resolving Inflammation

• Inflammatory resolution depends on eliminating
  threat and repairing damage
• Repair process is simple or complicated depending
  on the extent of damage
• Repair can result in restoration of original
  structure and function
• Or, permanently altered structure with loss of
  functional capacity

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Repair process

• Repair involves accelerated cellular renewal and
  new cellular-extracellular matrix interactions
• Cell proliferation is stimulated by group of
  defendokines called growth factors
• If cellular regeneration mechanisms are
  compromised, healing is impaired

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Repair process contd

• Coordinated by histiocytes
• Break down and clear debris
• Stimulate epithelial cells to regenerate
• Stimulate circulatory cells to form new network
  of capillaries
• Stimulate stromal cells to lay down new collagen
  framework

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Fibrosis

• If cell renewal mechanisms and extracellular
  framework are intact, results are close to
  original state
• If cells cant regenerate sufficiently or fibrous
  framework has been destroyed, fibrosis results
• Damaged elements broken down, and new,
  re-inforced fibrous structure is laid down

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Scar

• When normal tissue is replaced by fibrous
  elements (mostly collagen), the result is a
  fibrous scar, which is often stronger that
  original tissue, but less functional.

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Persistence of Inflammation

• If defensive response cannot eliminate threat,
  then there is on-going inflammatory activity and
  on-going repair efforts, with fibrosis.
• Sometimes, destruction and maintenance can be
  balanced and function maintained.
• Often, the destruction outpaces the protective
  measures and worsening fibrosis and loss of
  function ensue

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Classification of disease states

• Clinical and pathological classification of acute
  and chronic inflammatory diseases is extremely
  inconsistent.
• Multiple etiologies can result in the same
  clinical or histological appearance.
• The same process taking place in different
  locations receives different names.
• Historical names arent updated with new
  understanding.

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Treatment contributes additional complications

• Ideally, medications act as supplemental defenses
  or help regulate inflammatory response.
• Commonly, medications also act as additional
  adverse forces, either by direct damage to
  cells/tissues, by interfering with normal
  functions, or by interfering with
  defensive/compensatory functions.

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Neoplasia, a disorder of cell proliferation
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Normal cell proliferation

• Gene-regulated process that provides proper
  number of terminally differentiated, functionally
  specific cells types, then shuts down
• Necessary component of tissue maintenance and
  repair
• Cell populations vary in normal rate of cell
  proliferation

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Abnormal cell proliferation

• Can occur in any cell line
• Gene-altered, monoclonal process that is not
  under the normal regulatory controls
• Tends to produce too many cells does not have
  normal limits or shut-down mode

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Neoplasia new growth

• Each neoplastic growth begins as a genetically
  altered stem cell
• Its gene alterations (mutations) are responsible
  for the disordered proliferative activity that
  produces too many cells.
• This abnormal population of mutated cells often
  have some similarities to original cell line, but
  can become unrecognizable

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Mutational transformation

• Mutational transformation of stem cell into
  potentially neoplastic cell is complex
• Environmental forces and/or inherited gene
  mutations play a role
• Again, environmental forces include physical,
  chemical and microbiological agents

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Mutations affect cell proliferation activities

• Hyperactivate proliferation genes
• Inactivate proliferation inhibition genes
• Inactivate programmed cell death genes

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Will a transformed cell become a clinically
evident neoplasm?

• Original transformed cell might remain dormant
• Original cell or its early progeny might be
  eliminated by bodys defense system
• Might multiply and grow to be clinically evident

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Tumors, masses and polyps

• Patients and clinicians frequently confronted
  with newly discovered lump
• Is it neoplastic?
• If so, what kind of neoplasia, i.e. where is it,
  what does it look like and how bad is its
  behavior likely to be?

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Reactive vs Neoplastic growth

• In response to irritation/inflammation, cells
  regenerate and form hyperplastic growths with
  lots of mitotic figures and enlarged cells, but
  process is regulated
• Neoplastic cells also dividing actively, cells
  enlarged (and nucleus-cytoplasm ratio increased),
  but mutational changes lead to unregulated
  process
• Can be clinically and histologically difficult to
  differentiate

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Diagnostic terminology for neoplasms

• Grossly evident organ location, e.g. lung
• Histologically evident tissue or cell population
  of origin, e.g. respiratory epithelium
• Histologically or immunocytochemically apparent
  cell type differentiation, e.g. pulmonary
  surfactant secretory type
• Gross or histologic growth pattern

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Terms for types of neoplasms

• Sarcoma
• Lymphoma, leukemia
• Melanoma
• Carcinoma
• Adenoma vs. adenocarcinoma

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Benign vs. Malignant

• A spectrum of behavior, rather than black or
  white dichotomy

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Benign features

• -Respond to local tissue constraints
  well-circumscribed, symmetric growth pattern
• -Cells are larger than normal cells but have
  orderly architecture, related normally with each
  other and the surrounding stroma
• -Slow growth (percentage dividing cells is low)
• -diploid genome

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Malignant features

• Not restrained by tissue boundaries asymetric,
  poorly-circumscribed borders
• Cells often much larger than normal
• Cells differ wildly from each other
  pleomorphic
• Often aneuploid
• May not resemble normal cells structurally or
  functionally

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• Malignancy is established by invasive and
  metastatic behavior
• But there are entities that metastasize but are
  not lethal, and non-metastatisizing, deadly
  neoplasms
• Some neoplasms are considered malignant, but
  often dont kill the patient

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Diagnostic assessment

• Stage size and spread of tumor
• -non-invasive, locally invasive, regionally
  invasive, metastatic
• Grade Cytologic appearance and histologic growth
  pattern
• -how different from normal cells in size, shape,
  architectural arrangement, growth rate
• Different staging and grading schemes for each
  body part/type of neoplasm.

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Invasion

• Growth beyond tissue compartment delineated by
  basement membrane
• Can be microscopic
• Can invade neighboring structures/organs

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Metastasis

• Spread to new location, either in same tissue
  (satellite lesions), local lymph nodes, or
  distant tissue (e.g. lung, liver, bone) via blood
  or lymphatic vessels.

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Malignant potential

• Some lesions are self-limited and will never
  invade and metastasize
• Some lesions are easily removed and cured, but if
  left alone might eventually progress
• Some invasive lesions can be removed, but it is
  unclear whether they have already metastasized
  subclinically

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Non-invasive neoplasms (in-situ)

• Generally considered benign
• Concern over potential progression sometimes
  leads to aggressive labeling and treatment

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Prognosis and treatment

• Appearance/behavior of neoplasm at time of
  discovery (i.e. stage and grade)
• Historical statistics gathered on similar
  neoplasms (same type, stage, and grade)

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Neoplastic progression

• Many neoplasms seems to undergo continued
  karyotypic instability and become increasingly
  genetically abnormal, with corresponding
  worsening behavior
• Radiation and chemotherapy often accelerate this
  process

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