1. Cellular Pathology Outline
1. Necrosis
2. Apoptosis
3. Pathologic calcification
4. Cellular aging
Reading Assignment: Robbins pp ;

2. Necrosis Mechanism
Robbins Fig. 1-3

3. Necrosis Cellular Morphology
1. Nuclear changes
- Pyknosis (shrinking)
- Karyorrhexis (fragmentation)
- Karyolysis (dissolution)
2. Mitochondrial changes
- Dense bodies
3. Cytoplasmic changes
- Increased eosinophilia

4. Necrosis Pyknosis & Karyolysis - Micro
Pyknosis is the condensation or darkening of nuclei, and is reversible.

5. Necrosis Pyknosis - EM
EM appearance.

6. Necrosis Karyorrhexis - EM
Karyorhexis is the dissolution of the nucleus by DNAse and RNAse. It is irreversible.

7. Necrosis Karyolysis - EM
Karyolysis is the further degradation of DNA and RNA, as the nucleus disappears under the light microscope. It is irreversible.

8. Necrosis Mitochondrial Dense Bodies - EM
Dense (calcium) deposits in the mitochondria are characteristic of cell death at the EM level.

9. Cytoplasmic Eosinophilia - Micro
Necrosis
Cytoplasmic Eosinophilia - Micro
Robbins Fig. 1-12

10. Necrosis Histologic Types
1. Coagulative
2. Liquefactive
3. Fat
4. Caseous
5. Fibrinoid

11. Coagulative Necrosis Characteristics
1. Organs
- Heart and kidney
2. Histology
- Preservation of cell outlines
- Loss of nuclei

12. Coagulative Necrosis Heart - Gross
Hemorrhage – the earliest gross sign of acute myocardial infarction.

13. Coagulative Necrosis
Heart - Micro
Robbins Fig. 1-12

14. Coagulative Necrosis Coronary Artery - Gross
Thrombus in a coronary artery.

15. Atheroma Coronary Artery - Micro
Coronary artery 50% occluded by a “soft” atherosclerotic plaque. These are the most dangerous kind.

16. Thrombotic Atheroma Coronary Artery - Micro
Thrombosis of a coronary artery.

17. Coagulative Necrosis Kidney - Gross
Note wedge-shaped “pale” infarct. The underlying microscopic structure is preserved, at least for a short time, until repair (scarring) takes place.

18. Coagulative Necrosis Kidney - Micro
Note preservation of structure.

19. Coagulative Necrosis Foot - Gross
Gangrene of the foot – amputation specimen from surgical pathology.

20. Liquefactive Necrosis Characteristics
1. Organs
- Brain (ischemic injury)
- Pyogenic (pus forming) infection
of any organ
2. Histology
- Loss of cell outlines
- Loss of nuclei
- Neutrophil infiltration (if pyogenic)

21. Liquefactive Necrosis Lung - Gross
Note the expansion of the upper lobe, due to lobar pneumnonia (Polymorphonuclear cells within the alveolar spaces. Note also that a portion of the lung has dissolved (liquifactive necrosis), forming an abscess. (A space formed within an organ, due to a collection of pus – liquifactive necrosis).

22. Liquefactive necrosis Lung - Gross
Numerous microabscesses are seen in this lung. These are usually seen with virulent organisms, like Staphylococcus aureus.

23. Liquefactive necrosis Lung - Micro
Lung, abscess with collection of pus and bacteria (blue material at upper left).

24. Fat Necrosis Characteristics
1. Organs
- Adipose tissue
(Pancreas, mesentery, breast)
2. Histology
- Shadowy outlines of fat cells
- Loss of nuclei
- Basophilic calcium deposits
(dystrophic calcification)

25. Fat Necrosis Pancreas - Gross
Calcium soaps in the pancreas, gross.

26. Fat Necrosis Pancreas - Micro
The outline of the dead fat cells can often be seen (top of picture). The calcium soaps stain blue with standard H&E stains (bottom of picture).

27. Fat Necrosis Saponification Reaction
Triglyceride – (fat)
R-C-O-CH2 O
R-C-O-CH + lipase + Ca++ = (3) RCOO-Ca++ (soap) O
R-C-O-CH2 O

28. Caseous Necrosis Characteristics
1. Organs
- Mycobacterial or fungal infection
(any organ)
2. Histology
- Large granuloma (histiocytes)
- Central region amorphous granular debris
- Loss of cell outlines
- Loss of nuclei

29. Caseous Necrosis Lung - Gross

30. Caseous Necrosis Lung - Micro

31. Fibrinoid Necrosis Characteristics
1. Organs
- Blood vessels
(acute vasculitis, malignant hypertension)
2. Histology
- Increased eosinophilia of vessel wall
- Caused by infiltration of plasma proteins
- A misnomer (not true necrosis)

32. Fibrinoid Necrosis Arteriole - Micro
Renal glomerulus – influx of fibrin into the afferent arteriole, due, in this case, to malignant hypertension.

33. Reperfusion Necrosis Characteristics
1. Definition
- Cell death occurring after
reperfusion of ischemic organs
2. Organs
- Heart and brain
3. Mechanism
- Acute inflammation
- Oxygen free radicals

34. Reperfusion Necrosis Heart - Micro
Infiltration by polymorphs occurs from hours post MI.

35. Apoptosis
Robbins Fig. 1-16

36. Apoptosis Mechanism
Robbins Fig. 1-20

37. Apoptosis Physiologic Processes
1. Embryogenesis
2. Menstruation
3. Menopause
4. Intestinal homeostasis
5. Immune tolerance

38. Apoptosis Pathologic Processes
1. Acute inflammation
2. Organ atrophy
3. Neoplasia
4. Graft rejection
5. Viral hepatitis

39. Apoptosis Morphology 1. Cell shrinkage 2. Chromatin peripheralization
3. Isolated cell involvement
4. Absence of inflammation

40. Apoptosis Chromatin Peripheralization
Robbins Fig. 1-17

41. Apoptosis Light Microscopy
Skin
Liver
Robbins Fig. 1-18

42. Pathologic Calcification Types
1. Dystrophic calcification
- Occurs in nonviable tissue
2. Metastatic calcification
- Occurs in viable tissue
- Caused by hypercalcemia
or hyperphosphatemia

43. Dystrophic Calcification Examples
1. Necrotic tissue
- fat, coagulative, liquefactive, caseous
2. Atherosclerosis
- Central necrotic core
3. Damaged or aging heart valves

44. Dystrophic Calcification Aortic Valve - Gross
Robbins Fig. 2-13

45. Dystrophic Calcification Mechanism
Pathologic Microvesicles
Robbins Fig. 2-14

46. Metastatic Calcification Mechanisms
1. Increased PTH secretion
- parathyroid tumor
- ectopic PTH secretion
2. Bone destruction
- tumors
- Paget’s disease
- immobilization
3. Vitamin D disorders
- vitamin D toxicity
- sarcoidosis
4. Renal failure
- hyperphosphatemia

47. Metastatic Calcification Anatomic Sites
1. Lungs
- respiratory failure
2. Kidneys
- nephrocalcinosis, kidney failure
3. Stomach
4. Arteries
5. Pulmonary veins

48. Metastatic Calcification Lung - Micro
Von Kossa Stain

49. Cellular Aging Mitotic Activity is Limited
Robbins Fig. 2-15
Dice JF: Physiol Rev 73: 150, 1993

50. Cellular Aging Mechanisms
1. Telomere shortening
- telomerase
2. Clock gene activation
- clk-1 gene in C. elegans
3. Oxygen free radical damage
4. Nonenzymatic protein glycation

51. Cellular Aging Telomere Elongation
TTAGGG Repeat
Robbins Fig. 2-16

52. Cellular Aging Telomere - Telomerase Hypothesis
Robbins Fig. 2-17

53. Cellular Aging Biochemical Changes
1. Increased lipid oxidation
2. Increased glycation end products
- protein cross-linking
3. Abnormally folded proteins

54. Cellular Aging Functional Changes
1. Reduced mitochondrial function
- oxidative phosphorylation
2. Reduced protein synthesis
3. Reduced nutrient uptake
4. Reduced DNA repair

55. Cellular Aging Morphologic Changes
1. Vacuolated mitochondria
2. Decreased endoplasmic reticulum
3. Distorted Golgi apparatus
4. Increased lipofuscin pigment

56. Cellular Aging Lipofuscin Pigment
Cardiac Myocyte
- Electron dense
granules in
lysosomes
- Perinuclear
location
Robbins Fig. 2-11

57. Cellular Pathology Summary
1. Necrosis
- one type of cell death
- many histologic subtypes
2. Apoptosis
- second type of cell death
- physiologic and pathologic causes
3. Pathologic calcification
- dystrophic and metastatic
4. Cellular aging
- mechanisms and morphology