Samenvatting/Summary of Pathology exam 1+2

EXAM1
Lecture: introduction
Disease  an abnormality that causes loss of health, a set of features (signs, symptoms,
morphological and functional manifestations)
Systematic description:
- Epidemiology
- Cause (etiology)
- Pathogenesis (disease mechanisms)
- Symptoms, manifestations
- Complications & sequelae
- Prognosis
- Mortality
Biopsy process  registration of the material that arrives at the department => cutting room =>
cutting => cassettes => tissue processing (=> fixation => dehydration => embedding => paraffin blocks
=> cutting => slides => H&E stain) => evaluation by residents and pathology specialists
Relevant information:
- Diagnosis
o Benign vs malignant
o Type of tumour
- Prognosis
o TNM classification
o Radicality
- Prediction
o Response to treatment

Lecture: Ch1 cell injury, cell death and adaptations
Etiology  why a disease occurs.
Pathology  essential in understanding disease, but is also the basis for developing rational
treatments.
Describing the organs microscopically
Iosin (C) stains tissue, HE
Lung carcinoma have a EGF mutation and are targetable
Necrosis or apoptosis are two ways for a cell to die.
Causes of cell injury:
- Etiology  causes of disease.
o Hypoxia and ischemia
o Toxins
o Infections
o Abnormal immune reactions
o Genetic abnormalities
o Missense mutation

, - Pathogenesis  mechanisms of disease, sequence of cellular, biochemical and molecular
events
o Biochemical changes
- Abnormalities in cells and tissues (genes)
o Missense mutation
- Clinical manifestations  signs and symptoms of disease
Sequence of events in cell injury and cell death:
- Reversible cell injury:
o Morphologic correlates:
 Cell will swell and increase in size when there occurs hypoxia or ischemia.
 Fatty cells
 ATPase failure leads to disbalance of osmose.
- Irreversible cell injury
o 3 phenomena:
o Inability to restore mitochondrial function.
o Altered structure and loss function of the plasma and intracellular membranes.
o Loss of structural integrity of DNA and chromatin
o => necrosis
Necrosis:
- Fall apart of cell membranes => leakage of enzymes => inflammatory reaction
- Always a pathologic phenomenon
- Morphologic patters
o Some severe injuries result in the death of many or all cells in a tissue or organ due to
ischemia, infection, inflammatory reactions.
 Coagulative necrosis
o Usually secondary to ischemia
o Injury of structural proteins, but also of enzymes
o Wedge shape yellow discoloration, firm texture
o Tissue architecture is preserved for at least days after the injury.
o Over time: recruited leukocytes digest dead cells.
o Characteristic of infarcts in all solid organs except the brain
 Liquefactive necrosis
o At sites of bacterial infections and sometimes fungal infections
 Death tissue is visible as pus or an abscess.
o Ischemic necrosis in CNS
o Finally removed by phagocytes
 Caseous necrosis
o Tuberculous infection
o Granulomatous inflammation
 Obliteration of tissue architecture, cellular outlines
 Granular, amorphous, pink cellular debris
 Fat necrosis (saponification)
o Acute pancreatitis
 Lipases eat the pancreas.
o Abdominal trauma
o Histology: fat cell necrosis, granular basophilic calcium deposits
 Fibrinoid necrosis
o Immune-mediated diseases
o Deposition of immune complexes

,  Antigen for example




Necrosis vs apoptosis
- Pro-inflammatory anti-inflammatory
- Pathologic part of normal physiology
- Cellular catastrophe, no regulation cellular suicide, under strict regulation
- Cell contents are released extracellularly cells contents are not released.
- Occurs now and then occurs continuously.
- Induces repair and defence no induction of repair.


Apoptosis  programmed cell death, usually part of normal physiology.
- Cells activate enzymes that degrade their own nuclear DNA.
- Phagocytosis removes the apoptotic cell.
- Causes of apoptosis
o Physiologic conditions:
 B cells in lymph node => Antibody formation
 During embryogenesis
o Pathologic conditions:
 DNA damage
 Accumulation of misfolded proteins
 infections
 2 pathways:
o Regulated by biochemical pathways that control the balance of death- and survival-
inducing signals and ultimately the activation of enzymes called caspases.
 Mitochondrial (intrinsic) pathway
o Responsible for apoptosis in most physiologic and pathologic situations
o Cytochrome c
 Electron transport
 Induction of apoptosis
 Activates caspases 9.
o BCL2 (anti-apoptotic protein)
 Important regulator
 Keeps BAX or BAK in check.
 Sensor proteins become activated.
 Opening of BAX/BAK channel will release cytochrome c in cell.
 B-cell (follicular) lymphoma  loss of apoptosis response by overexpression
of BCL2 gene because BCL2 gene is brought under control of the promotor of
the heavy chain of immunoglobulin.
 Death receptor (extrinsic) pathway
o Many cells express surface molecules, called death receptors, which trigger
apoptosis.
o Type 1 TNF receptor or FasL receptor
o Cytotoxic T cells are able to induce apoptosis.
o Leads to induction of caspase 8.
 Caspase causes the breakdown of proteins and cytoskeleton and activation of enzymes
including endonuclease.

,  Eventually both pathways stimulate the activation of enzymes called caspases.
- Execution phase and clearance
o


Mechanisms of cell injury and cell death: general principles
- The cellular response to injurious stimuli depends on the type of injury and its duration and
severity.
- The consequences of an injurious stimulus also depend on the type of cell and tis metabolic
state, adaptability and genetic makeup.
- Cell injury usually results from functional and biochemical abnormalities in one or more
essential cellular components
 Mitochondrial dysfunction and damage
- Failure of oxidative phosphorylation, leading to: decreased ATP generation and ATP depletion
o Reduced activity of plasma membrane ATP-dependent sodium pumps
o Increase in anaerobic glycolysis
o Structural disruption and of the protein synthetic apparatus
- Abnormal oxidative phosphorylation leads to the formation of reactive oxygen species (ROS)
o Free radicals
o Many circumstances involve damage by free radicals:
 Chemical/radiation injury, hypoxia, cellular aging, injury by inflammatory
cells, ischemia-reperfusion injury
o The accumulation of ROS is determined by their rates of production and removal
 DNA damage
- Mutations and DNA breaks
- Indirect: ROS generation
- Direct effects of radiation or chemotherapeutic agents
- Lead to p53 accumulation => cell cycle arrest or triggers apoptosis
 ER stress
- The accumulation of misfolded proteins in a cell can stress compensatory pathways in the Er
and lead to cell death by apoptosis
- Causes:
o Infections, changes in intracellular pH and redox state, aging (decreased capacity to
correct misfolding), deprivation of glucose and oxygen


Cellular adaptations to stress
 Adaptations are reversible changes in size, number, phenotype, metabolic activity or function
of cells in response to changes in their environment: physiologic or pathologic
 Hypertrophy  increase in the size of cells, no increase in number of cells
- In tissues with limited capacity for replication (heart)
- May occur in concurrence with hyperplasia
- In pathological conditions:
o In heart hypertrophy can be problematic
 Hyperplasia  increase in the number of cells, not increase in the size
- Physiologic: e.g. tanner stages
- Pathologic:
o Benign prostate hypertrophy
o Abnormal menstrual bleeding
 Atrophy  Decrease of tissue due to cell size of cell number