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Flashcards in Pathology Deck (107):
1

Apoptosis findings

- Cell shrinkage
- Chromatin condensation
- Membrane blebbing
- Formation of apoptotic bodies (which are then phagocytosed)
- Eosinophilic cytoplasm
- Basophilic nucleus

2

Sensitive indicator of apoptosis

DNA laddering (fragments in multiples of 180 bp)

3

Occurs when a regulating factor is withdrawn from a proliferating cell population

Intrinsic (mitochondrial) apoptotic pathway

4

BAK

Pro-apoptotic

5

What makes bcl-2 anti-apoptotic

Bcl-2 prevent cytochrome c release by binding to and inhibiting APAF-1. APAF-1 normally binds to cytochrome c and induces activation of caspase 9, inhibiting caspase cascade.

6

Extrinsic (death receptor) apoptotic pathway

2 pathways:
- Ligand receptor interactions (FasL binding to Fas [CD95] or TNF-α binding to TNF)
- Immune cell (cytotoxic T-cell release of perforin and granzyme B)

Fas-FasL interaction is necessary in thymic medullary negative selection. Mutations in Fas ↑ numbers of circulating self reacting lymphocytes due to failure of clonal deletion.

Defective Fas-FasL interactions cause AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME

7

Autoimmune lymphoproliferative syndrome caused by

Defective Fas-FasL interactions (form of extrinsic apoptotic pathway)

8

Compare coagulative and liquefactive necrosis

Coagulative → proteins denature then enzymatic degradation

Liquefactive → enzymatic degradation first then proteins denature

9

Compare wet and dry gangrenous necrosis

Dry → ischemia; coagulative necrosis

Wet → superinfection; liquefactive superimposed on coagulative

10

Ischemia of kidney

- Straight segment of proximal tubule (medulla)
- Thick ascending limb (medulla)

11

Cellular injury reversible with O2

- Cellular/ mitochondrial swelling (↓ ATP → ↓ activity of Na+/K+ pumps)
- Nuclear chromatin clumping
- Membrane blebbing
- ↓ glycogen
- Fatty change
- Ribosomal/ polysomal detachment (↓ protein synthesis)

12

Irreversible cellular injury

- Mitochondrial permeability/ vacuolization; phospholipid-containing amorphous densities within mitochondria (swelling alone is reversible)
- Nuclear pyknosis (condensation), karyorrhexia (fragmentation), karyolysis (fading)
- Plasma membrane damage (degradation of membrane phospholipid)
- Lysosomal rupture

13

Contains multiple blood supplies

- Liver
- Lung
- Intestine
- Testes

14

Solid organs with single (end-arterial) blood supply

- Heart
- Kidney
- Spleen

15

Functio laesa

- Loss on function
- Characterization of inflammation

16

Chronic inflammation

- Mononuclear (monocyte/macrophage, lymphocytes, plasma cells) and fibroblast mediated
- Characterized by persistent destruction and repair
- Associated with blood vessel proliferation, fibrosis
- Granuloma: nodular collections of epithelioid macrophages and giant cells
- Outcomes include scarring and amyloidosis

17

Chromatolysis

Reaction of neuronal cell body to axonal injury. Changes reflect ↑ protein synthesis in effort to repair damaged axon. Characterized by:
- Round cellular swelling
- Displacement of the nucleus to the periphery
- Dispersion of Nissl substance through cytoplasm

Concurrent with Wallerian degeneration → degeneration of axon distal to site of injury; macrophages remove debris and myelin

18

Dystrophic calcification

- Ca2+ deposition in abnormal tissues secondary to injury or necrosis
- Seen in TB (lungs and pericardium), liquefactive necrosis of chronic abscesses, fat necrosis, infarcts, thrombi, schistosomiasis, Monckeberg arteriolosclerosis, congenital CMV + toxoplasmosis, psammoma bodies
- Normocalcemic

19

Metastatic calcification

- Widespread (ie diffuse, metastatic) deposition of Ca2+ in normal tissue secondary to hypercalcemia or high calcium-phosphate product levels
- Ca2+ deposits predominantly in interstitial tissues of kidney, lung, and gastric mucosa (these tissues lose acid quickly; ↑ pH favors deposition)
- NOT normocalcemic

20

Step 1 Extravasation: Margination and rolling

- Defective in leukocyte adhesion deficiency type 2 (↓ Sialyl-Lewis-x)

Vascular/stroma: Leukocyte
- E-selectin: Sialyl-Lewis-x
- P-selectin: Sialyl-Lewis-x
- GlyCAM-1, CD34: L-selectin

21

Step 2 Extravasation: Tight-binding

- Defective in leukocyte adhesion deficiency type 1 (↓ CD18 integrin subunit)

Vascular/stroma: Leukocyte
- ICAM-1 (CD54): CD11/18 integrins (LFA-1, Mac-1)
- VCAM-1 (CD106): VLA-4 integrin

22

Step 3 Extravasation: Diapedesis

- WBC travels between endothelial cells and exits blood vessel

Vascular/stroma: Leukocyte
- PECAM-1 (CD31): PECAM-1 (CD31)

23

Step 4 Extravasation: Migration

Chemotactic products released in response to bacteria:
- C5a
- IL-8
- LTB4
- Kallikrein
- Platelet-activating factor

24

Inhalation injury and sequelae

- Pulmonary complication associated with smoke and fire
- Caused by heat, particulates (

25

Tensile strength after scar formation

70-80% of tensile strength regained at 3 months, little additional tensile strength will be regained afterward

26

Compare collagen organization of hypertrophic and keloid scars

Hypertrophic → parallel organization
Keloid → disorganized

27

PDGF

- Secreted by activated platelets and macrophages
- Induces vascular remodeling and smooth muscle migration
- Stimulates fibroblast growth for collagen synthesis

28

FGF

Stimulates angiogenesis

29

EGF

Stimulates cell growth via tyrosine kinases (eg EGFR, ErbB1)

30

TGF-β

- Angiogenesis
- Fibrosis
- Cell cycle arrest

31

Metalloproteinases

Tissue remodeling

32

VEGF

Stimulates angiogenesis

33

Inflammatory stage of wound healing

- Up to 3 days after wound
- Effector cells → platelets, neutrophils, macrophages
- Clot formation
- ↑ vessel permeability and neutrophil migration into tissue
- Macrophages clear debris 2 days later

34

Proliferative stage of wound healing

- Day 3 - weeks after wound
- Effector cells → fibroblasts, myofibroblasts, endothelial cells, keratinocytes, macrophages
- Deposition of granulation tissue and type III collagen
- Angiogenesis
- Epithelial cell proliferation
- Dissolution of clot
- Wound contraction (mediated by myofibroblasts)

35

Remodeling stage of wound healing

- 1 week - 6+ months after wound
- Effector cells → fibroblasts
- Type III collagen replaced by type I collagen
- ↑ tensile strength of tissue

36

Bacterial infections that cause granuloma formation

- Mycoplasma
- Bartonella henselae
- Listeria monocytogenes
- Treponema pallidum

37

Parasitic infections that cause granuloma formation

Schistosomiasis

38

Fungal infections that cause granuloma formation

Endemic mycoses

39

Granuloma formation

- TH1 cells secrete IFN-gamma, activating macrophages
- TNF-alpha from macrophages induces and maintains granuloma formation

40

Compare causes of exudate and transudate accumulation

Exudate → lymphatic obstruction (chylous), inflammation/infection, malignancy

Transudate → ↑ hydrostatic pressure (eg HF, Na+ retention), ↓ oncotic pressure (eg cirrhosis, nephrotic syndrome)

41

How does ESR work

Products of inflammation (eg fibrinogen) coat RBCs and cause aggregation. The denser RBCs aggregate and fall at a faster rate within a pipetic tube. Often co-tested with CRP levles.

42

↑ ESR

- Most anemias
- Infections
- Inflammation (eg giant cell arteritis, polymyalgia rheumatica)
- Cancer (eg metastases, multiple myeloma)
- Renal disease (end-stage or nephrotic syndrome)
- Pregnancy

43

↓ ESR

- Sickle cell anemia (altered shape)
- Polycythemia (↑ RBCs "dilute" aggregation factors)
- HF
- Microcytosis
- Hypofibrinogenemia

44

AL (primary) amyloidosis

- Due to deposition of proteins from Ig Light chains
- Can occur as a plasma cell disorder or associated with multiple myeloma
- Often affects multiple organ systems, including renal (nephrotic syndrome), cardiac (restrictive cardiomyopathy, arrhythmia), hematologic (easy bruising, splenomegaly), GI (hepatomegaly) and neurologic (neuropathy)

45

AA (secondary) amyloidosis

- Seen with chronic inflammatory conditions such as rheumatoid arthritis, IBD, spondyloarthropathy, familial Mediterranean fever, protracted infection
- Fibrils composed of serum Amyloid A
- Often multisystem like AL amyloidosis

46

Dialysis-related amyloidosis

- Fibrils composed of β2-microglobulin in patients with ESRD and/or on long-term dialysis
- MAY PRESENT AS CARPAL TUNNEL SYNDROME

47

Heritable amyloidosis

Heterogeneous group of disorders, including familial amyloid polyneuropathies due to transthyretin gene mutation

48

Age-related (senile) amyloidosis

- Due to deposition of normal (wild-type) transthyretin (TTR) predominantly in cardiac ventricles
- Slower progression of cardiac dysfunction relative to AL amyloidosis

49

Organ specific amyoidosis

- Amyoid deposition localized to a single organ
- Most important form is amyloidosis in Alzhemier disease due to deposition of beta-amyloid protein cleaved from APP
- TIIDM → islet amyloid polypeptide (IAPP) → amylin in pancreatic islets
- Normal aging → atrial amyloidosis → atrial natriuretic peptide

50

Lipofuscin

- A yellow-brown "wear and tear" pigment associated with normal aging
- Formed by oxidation and polymerization of autophagocytosed organellar membranes
- Autopsy of elderly person will reveal deposits in heart, colon, liver, kidney, eye and other organs

51

Compare grade and stage

Grade → degree of cellular differentiation and mitotic activity on histology

Stage → degree of localization/spread based on site and size of primary lesion, spread to regional lymph nodes, presence of metastases; TNM, where M is often most important

52

Compare hamartoma and choristoma

Hamartoma → disorganized overgrowth of tissues in their native location)

Choristoma → normal tissue in a foreign location

53

Paraneoplastic hypercalcemia

PTHrP → squamous cell carcinomas of lung, head and neck; renal, bladder, breast and ovarian carcinomas

↑ 1,25-(OH)2 vitamin D3 (calcitriol) → lymphoma

54

Paraneoplastic polycythemia

↑ EPO → renal cell carcinoma, hepatocellular carcinoma, hemangioblastoma, pheochromocytoma, leiomyoma

55

Paraneoplastic pure red cell aplasia

Anemia with LOW reticulocytes → thymoma

56

Good syndrome

Paraneoplastic hypogammaglobulinemia → thymoma

57

Trosseau syndrome

Migratory superficial thrombophlebitis → adenocarcinomas, especially pancreatic

58

Paraneoplastic nonbacterial thrombotic (marantic) endocarditis

Deposition of sterile platelet thrombi on heart valves → adenocarcinomas, especially pancreatic

59

Anti-NMDA receptor encephalitits

Psychiatric disturbance, memory deficits, seizures, dyskinesias, autonomic instability, language dysfunction → ovarian teratoma

60

Opsoclonus-myoclonus ataxia syndrome

"Dancing eyes, dancing feet" → neuroblastoma (children), small cell lung cancer (adults)

61

Paraneoplastic cerebellar degeneration

Antibodies against Hu, Yo, Tr antigens in Purkinje cells → Small cell lung cancer, gynecologic and breast cancers, and Hodgkin lymphoma

62

Paraneoplasic encephalitis

Antibodies against Hu antigens in neurons → small cell lung cancer

63

ALK

- Oncogene
- Receptor tyrosine kinase
- Lung adenocarcinoma

64

BCR-ABL

- Oncogene
- Tyrosine kinase
- CML, ALL

65

BCL-2

- Oncogene
- Anti-apoptotic molecule
- Follicular and diffuse large B cell lymphoma

66

BRAF

- Oncogene
- Serine/threonine kinase
- Melanoma, non-Hodgkin lymphoma

67

c-KIT

- Oncogene
- Cytokine receptor
- Gastrointestinal stromal tumor (GIST)

68

c-MYC

- Oncogene
- Transcription factor
- Burkitt lymphoma

69

HER2/neu (c-erbB2)

- Oncogene
- Tyrosine kinase
- Breast and gastric carcinomas

70

JAK2

- Oncogene
- Tyrosine kinase
- Chronic myeloproliferative disorders

71

KRAS

- Oncogene
- GTPase
- Colon cancer, lung cancer, pancreatic cancer

72

MYCL1

- Oncogene
- Transcription factor
- Lung tumor

73

MYCN

- Oncogene
- Transcription factor
- Neuroblastoma

74

RET

- Oncogene
- Tyrosine kinase
- MEN 2A and 2B, medullary thyroid cancer

75

APC

- Tumor suppressor gene
- Colorectal cancer (associated with FAP)

76

BRCA1/BRCA2

- Tumor suppressor gene
- Breast and ovarian cancer
- DNA repair protein

77

CDKN2A

- Tumor suppressor gene
- Melanoma, pancreatic cancer
- p16, blocks G1 → S phase

78

DCC

- Tumor suppressor gene
- Colon cancer
- DCC → deleted in colon cancer

79

DPC4/SMAD4

- Tumor suppressor gene
- Pancreatic cancer
- DPC → deleted in pancreatic cancer

80

MEN1

- Tumor suppressor gene
- MEN1
- Menin

81

NF1

- Tumor suppressor gene
- NF1
- Ras GTPase activating protein (neurofibromin)

82

NF2

- Tumor suppressor gene
- NF2
- Merlin (schwannomin) protein

83

PTEN

- Tumor suppressor gene
- Breast cancer, prostate cancer, endometrial cancer

84

Rb

- Tumor suppressor gene
- Retinoblastoma, osteosarcoma

85

TP53

- Tumor suppressor gene
- Most human cancers, Li-Fraumeni syndrome
- p53, activates p21, blocks G1 → S phase

86

TSC1

- Tumor suppressor gene
- Tuberous sclerosis
- Hamartin protein

87

TSC2

- Tumor suppressor gene
- Tuberous sclerosis
- Tuberin protein

88

VHL

- Tumor suppressor gene
- von Hippel-Lindau disease, renal cell carcinoma
- Inhibits hypoxia inducible factor 1a

89

WT1/WT2

- Tumor suppressor gene
- Wilms tumor (nephroblastoma)

90

2nd leading cause of lung cancer after cigarette smoke

Radon

91

Alkaline phosphatase

- Metastases to bone or liver
- Paget disease of bone
- Seminoma (placental ALP)

92

AFP

- Hepatocellular caricnoma
- Hepatoblastoma
- Yolk sac (endodermal sinus) tumor
- Mixed germ cell tumor

Normally made by fetus. Transiently elevated in pregnancy. High levels associated with neural tube and abdominal wall defects, low levels associated with Down syndrome.

93

hCG

- Hydatiform mole
- Choriocarcinoma
- Testicular cancer
- Mixed germ cell tumor

Produced by synciotrophoblasts of the plascenta

94

CA 15-3/ CA 27-29

Breast cancer

95

CA 19-9

Pancreatic adenocarcinoma

96

CA 125

Ovarian cancer

97

Calcitonin

Medullary thyroid carcinoma

98

CEA

CarcinoEmbryonic Antigen

Very nonspecific but produced by around 70% of colorectal and pancreatic cancers. Also produced by gastric, breast and medullary thyroid carcinomas.

99

PSA

- Prostate specific antigen
- Prostate cancer

Can also be elevated in BPH and prostatitis. Questionable risk/benefit for screening.

100

P-glycoprotein

- Multidrug resistance protein 1 (MDR1)
- Classically seen in adrenal cell carcinoma but also expressed by other cancer cells (eg colon, liver)
- Used to pump out toxins, including chemotherapeutic agents (one mechanism of ↓ responsiveness or resistance to chemotherapy over time)

101

Cachexia

Weight loss, muscle atrophy, and fatigue that occur in chronic disease (eg cancer, AIDS, heart failure, COPD)

Mediated by TNF, INF-gamma, IL-1, IL-6

102

Sarcomas generally spread

Hematogenously

103

Carcinomas generally spread

Lymphatically

104

Carcinomas that spread hematogenously

- Renal cell carcinoma
- Choriocarcinoma
- Hepatocellular carcinoma
- Follicular thyroid carcinoma

105

Site of metastases → brain

Lung > breast > prostate > melanoma > GI

106

Site of metastases → liver

Colon >> stomach > pancreas

107

Site of metastases → bone

Prostate, breast > lung, thyroid, kidney

Breast → mixed
Lung → mixed
Thyroid → lytic
Kidney → lytic
Prostate → blastic

Predilection for axial skeleton