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Flashcards in Pathology 2 Deck (411):
0

What does innate immunity consist of?

Barrier
Phagocytes - neutrophils and macrophages
NK cells
Plasma proteins - compliment, CRP, mannose-binding lectin

1

What is the job of NK cells, how are they regulated, and what do they secrete?

Killers of virus infected and tumor cells.
Activating receptors: activated by viral and stress-induced proteins
Inhibiting receptors: engaged by normal levels of MHC I
Secrete: IFN-y and TNF

2

What occurs with Tcell activation?

Release of cytokines, proliferation, differentiation into effector or memory cells.

3

What is the difference between TH1 and TH2 cells?

TH1: Release IL-2 and IFN-gamma. Tcell proliferation, macrophage activation, Ab production

TH2: Release IL-4, 5, 13. eosinophil activation and IgE synthesis

4

What are 2 subclasses of T regulatory cells?

Treg: Express CD4, CD25, and FoxP3. Suppress Tcell activity, APCs. Suppress autoreactive Tcells

adaptive regulatory Tcells: Express CD4 and upregulate CD25 in the periphery (MALT). induced by inflammation

Release IL-10 and TGF-B

5

CD8 cell function

Interact with MHC I (expressed on most cells). Activated by foreign peptide, self-restricted. Important in response to virus infection.

6

What effect does CD 21 have on Bcell activation?

amplifies. Binds complement component (Cdg) that is attached to pathogen surface. Amplifies BCR signal and Bcell response

7

What is the function of Dendritic cells? What is a follicular dendritic cell?

Dendritic cells: in epithelium and interstitium. major APC for CD4+ Tcells. Can migrate to lymph organs

Follicular dendritic cells: found in germinal centers of lymph follicles. Present to B cells -> activation

8

What chromosome houses MHC / HLA genes?

Chromosome 6

9

What genetec loci encode MHC I variable regions?

HLA A, B, C

10

What genetic loci encode MHC II variable regions?

Subregions of HLA D:
HLA DP, DQ, DR

11

What types of proteins are presented by MHC I and II?

MHC I: cytoplasmic antigens

MHC II: exogenous antigens

12

Type I hypersensitivity

Anaphylactic type
IgE mediated, TH2 dependent
Antigen -> dendritic cell -> presentation to Tcell -> TH2 activation, secretion of IL-4 -> Bcell activation -> IgE plasma cell -> IgE attaches to mast cells (first exposure)
Second exposure: allergen cross-links IgE on mast cell -> degranulation

13

What is released with degranulation of mast cells / basophils in the setting of allergic reaction?

1. Primary response - preformed mediators in granules: biogenic amines (histamine, adenosine), chemotactic factor (eosinophil), enzymes, proteoglycans

2. Secondary response - newly synthesized (later): PLP A2 activation -> leukotrienes (LTB4, C4, D4) and prostaglandins (PGD2), PAF
cytokine / chemokine secretion: Interleukins, TNFa, GM-CSF

14

What histopathologic findings are associated with Type I hypersensitivity?

Vascular: vasodilation, increased permeability, edema
-histamine, PAF, LTC4 and D4
Bronchial sm. muscle contractoin: biogenic amines, LTC4 and D4, PAF, PGD2
Increased secretion - mucinous metaplasia: histamine, PGD2
Infiltration - eosinophil, chron. inflamm. cels: eosinophil chemotactic factor, LTB4, PAF, TNFa

15

What is type II hypersensitivity?

Involves antibody binding to cell surfaces or tissue antigens.
May or may not involve complement
Results in cell destruction or cell/ tissue dysfunction

16

Examples of Type II hypersensitivity, w/ and w/o compliment.

Compliment dependent:
Autoimmune rxn to blood cells
Transfusion rxns, hemolytic disease of the newborn
Autoimmune skin-bistering (pemphigous vulgaris)
Goodpasture (Ab to glomerular and pulmonary basement membrane)

Antibody-dependent cell-mediated cytotoxicity (ADCC):
Response to parasite / malignant cells


Antibody mediated tissue dysfunction: no cell death
Myasthenia gravis, Graves

17

What are type III hypersensitivity reactions?

Immune complex mediated
Excess antigen -> immune complex formation and deposition in tissue -> complement activation -> acute inflammation / coagulation, tissue injury

Results in vasodilation, edema, necrosis

18

What is an Arthus Reaction?

Local immune complex disease
tissue necrosis resulting from acute immune complex vasculitis, usually elicited in the skin.

Immune complexes precipitate in vessel walls -> fibrinoid necrosis

19

What are 3 phases of Type III hypersensitivity?

1) immune complex formation (exogenous or endogenous antigen)
2) immune complex depisition (local or systemic)
3) tissue injury (complement activation (not at native site), acute inflammation, coagulation)

20

Examples of Type III hypersensitivity

Acute post-streptococcal glomerulonephritis
SLE
Polyarteritis Nodosa
Rheumatoid Arthritis

21

What type of necrosis is associated with Type III hypersensitivity?

fibrinous

Due to compliment activation and MAC -> coagulation -> fibrin deposition

22

What is the key pathologic finding in Type III hypersensitivity?

Acute necrotizing vasculitis of small to medium sized blood vessels

23

What is Type IV hypersensitivity?

Cell mediated: delayed or cytotoxic
Delayed: TH1 mediated
Cytotoxic: CD8 mediated

24

Examples of Type IV hypersensitivity

Delayed: TB and TB skin test, contact dermatitis (poison ivy), fungal infections

Cytotoxic: viral infection, tumor immunity, acute graft rejection

25

IL-12

Produced by macrophages
Results in differentiation and activation of TH1 cells

26

Describe the Direct and Indirect pathways of transplant rejection

Direct: recipient Tcells recognize MHC on donor APCs. (Acute rejection)
--Paradoxical Mimicry
a) MHC-1 -> CD8+ Tcell proliferation and cytotoxic hypersensitivity. Results in apoptotic death of graft cells
b) MHC-II -> CD4+ Tcell proliferation (TH1) -> delayed type hypersensitivity. IL-2, TNF-a, and IFN-y ->Inflammatory response and tissue destruction by mobilized macrophages

Indirect: Usual mode of rejection (Chronic Rejection)
Host APCs present graft antigen on self-MHC II
CD4+ Tcell activation -> delayed type hypersensitivity and transplant rejection

27

What is rejection vasculitis?

Antibody mediated transplant rejection
a) hyperacute: preformed Ab
b) acute: induced Ab

28

What is hyperacute rejection?

Due to preformed antibody -> rejection vasculitis
w/in minutes - hours of transplant

immune complex formation and vascular deposition -> complement activation -> vasodilation, vascular permeability -> inflammatory infiltrate -> necrosis, hemorrhage, thrombosis -> infarction

29

How long after transplantation does acute rejection take place? What usually causes it?

days to weeks after transplant or later due to reduction in immunosuppression

30

What drugs are frequently used to prevent transplant rejection?

Cyclosporine: calcineurin inhibitor - decreases IL-2 expression
Tacrolimus: binds FKPB to inhibit calcineurin (less nephrotoxic)
Corticosteroids: anti-inflammatory and decreases lymphocytes, monoycytes, eosinophils and basophils
Azothioprine: inhibits denovo purine synth. converted to 6-MP
Anti-Tcell receptor Ab

31

GVH disease and tissues affected

Graft vs. Host disease: donor's CD4 and CD8 cells react against host tissue
Skin: maculopapular rash, desquamation
Mucosal surfaces: GI: NVD ; eyes and mouth: dryness and irritation
Liver: jaundice (bile duct injury)
Lymph organs: coumpound recipients immunodeficiency may -> autoimmune disease

32

What are 4 mechanisms of peripheral immunotolerance?

1. Anergy - recognition of self antigen w/o co-stimulatory signal -> negative signal -> eventual inactivation / inability to propogate stimulatory signal.
2. Suppression - regulatory Tcells suppress self-reactive Tcells
3. Deletion - repeated activation of self-recognizing Tcells -> expression of Fas and Fas ligand -> apoptosis
4. Antigen sequestration - antigens "hidden" in tissues not directly exposed to blood and lymph. Ex: brain, testes, eye

33

how can infection lead to autoimmunity?

1) infection -> increased expression of co-stimulatory molecules on APCs -> activation of self-recognizing Tcells
2) tissue damage 2ndary to infection -> release / alteration of self antigens and exposure of previously "hidden" antigen -> reactivity of self-specific lyphocytes.

34

What is the genetic link in SLE?

Disease is multifactorial
Increased frequency in family members of pts. w/ SLE, especially monozygotic twins.
-assoc. between certain HLA alleles and certain SLE antibodies (anti-dsDNA, anti-Smith Ag)
-inherited deficiencies in complement in minority of SLE patients - impaired immune complex clearance

35

What environmental factors are associated w/ SLE?

UV radiation - pyrimidine dimerization -> cell death -> exposure to nuclear Ag
Elevated sex hormones - estrogen - women more affected
Certain meds - hydralazine (HTN)

36

What are the major antibodies seen in SLE (3 groups)?

Anti Nuclear Ab: Type III hypersensitivity rxns
Anti-phospholipid: bind proteins assoc. w/ phospholipids
-in vivo: hypocoagulability (lupus anticoagulant)
-in vitro: hypercoagulability (secondary antiphospholipid antibody syndrome)
-anti B2-glycoprotein Ab binds cardiolipin -> false (+) syphilis
Anti-formed element: type II hypersensitivity (anemia, thrombocytopenia, leukopenia)

37

What are the 5 classes or lupus glomerular nephritis?

I: minimal mesangial: appears normal under LM, but EM reveal mesangial immune complex deposition
II: Mesangial lupus nephritis: visible increase in mesangial cell number and matrix volume
III: Focal proliferative glomerulonephritis: 1/2 of all glomeruli are affected. ***Most severe, most common***
same as III, but more widespread, maybe more necrosis/thrombosis
V: Membranous glomerulonephtiris: Thickening of glom. capillary walls. "wire loop" lesions (may be present in III and IV as well)

38

How can Lupus effect the heart?

1. pericarditis most common - fibrinous inflammation of serous membrane -> chronica inflamm, fibrosis
2. Libman Sacks endocarditis - vegetations present on any surface of any valve
3. Myocarditis

39

How does SLE effect joints?

Results in synovial inflammation w/o articular erosion

40

What pattern of immunoflorescent Anti-Nuclear-Antibody (ANA) testing is most specific for SLE?

Rim pattern - "rim" of flourescence around exposed nuclei is indicative of the presence of Anti-dsDNA Ab in patient's serum.

Other patterns are non-specific or suggest other diagnoses.

41

What are nucleolar and centromere patterns of ANA immunofluorescence suggestive of?

Nucleolar: systemic sclerosis
Centromere: limited systemic sclerosis (CREST)

42

What antibodies are most common in SLE?

Anti-dsDNA and Smith Ag

43

What is a Lupus Erythmatosus (LE) cell or hematoxylin body?

Neutrophil or macrophage that has phagocytosed the nuclei of injured cells.

Seen in SLE

44

What is chronic discoid lupus erythematosis?

Causes scarring skin plaques
Usually only involves the skin

45

What is subacute cutaneous lupus erythematosis?

Mild form of SLE that typically manifests as a non-scarring photosensitive cutaneous rash. Mild systemic effects.

ANAs are present, especially anti-Ro (SS-A) Ab.

46

What medications can cause lupus like symptoms?

hydralazine, procainamide
Symptoms usually resolve with removal of med.
ANAs (esp. antihistone) may be present w/o symptoms

47

What is Sjorgen Syndrome?

Chronic autoimmune disorder primarily affecting lacrimal and salivary glands.
Mostly women 50-60 y/o
Primary - sicca syndrome
Secondary - associated w/ other disorder (usually RA)

48

What antibodies are most often seen in Sjorgen's?

Anti-ribonucleoproteins
Anti-Ro (SS-A), Anti-La (SS-B)

49

What serious condition does Sjogren syndrome increase risk for?

B-cell lymphoma - high rate of replication -> increased chance for errors

50

Systemic sclerosis and variants. What causes?

chronic excessive fibrosis. Mostly women 40-50.
1) diffuse: rapidly progressing. start with all skin, progress to visceral organs
2) limited: slowly progressing. limited to skin of face and distal upper extremities - includes CREST

Caused by inappropriate activation of CD4+ Tcells -> secretion of cytokines, growth factors -> fibroblast activation -> excessive collagen production

51

What is CREST?

subset of limited systemic sclerosis
Calcinosis
Reynaud's
Esophogeal dysmotility
Sclerodactyly
Telangiectasia

52

What antibodies have been found in systemic sclerosis?

Anti-nuclear Ab:
1) anti-Scl 70: against DNA Topoisomerase I. specific for diffuse Systemic sclerosis
2) anti-centromere Ab. mostly CREST

53

What is mixed connective tissue disease?

Has overlapping features of SLE, polymyositis, RA, and systemic sclerosis.
Patients have high titers of anti-U1 RNP
Patients present with minimal renal disease.
Excellent response to corticosteroids

54

What is SCID?

Severe Combined Immunodeficiency Diseases
T and B cell dysfunction
Heterogenous group of diseases

55

What is the most common form of SCID? What causes it?

X-linked recessive SCID
50-60% of all cases
Abnormal IL receptor protein

56

What is the most common cause of autosomal recessive SCID? Others?

Adenosine Deaminase (ADA) deficiency ~50% of AR cases
abnormal metabolism of adenosine / deoxyadenosine -> accumulation of alt. metabolites -> decreased DNA synth and cell toxicity
-especially affects Tcells
-has been treated w/ gene therapy (retrovirus w/ normal ADA gene)
Also:
-MHC II deficiency (bare lymphocyte)
- abnormal receptor or signaling
-PNP deficiency (purine metabolism

57

What are the clinical findings in a patient w/ SCID?

Minimal lymph tissue
Small, non-descended thymus
Severe lymphopenia - decreased mature T and B cells
Deficient cell-mediated immunity: in vitro - no lymphoproliferative response to mitogen or allogeneic substance
in vivo - no delayed-type hypersensitivity or allograft rejection
Deficient humoral immunity: scant IgG, absent M and A

58

What infections are SCID patients susceptible to?

Pyogenic bacteria (PSA, Strep, Staph, H.influenzae
Fungi and protozoa
Viruses
Viable attenuated vaccines -> illness

59

How is SCID treated?

Early allogenic stem cell transplant
Good chance for take, but high risk for GVH. Donor sample must be depleted of mature Tcells

60

What causes DiGeorge Syndrome?

Defective development of 3rd and 4th pharyngeal pouch.
Usually due to 22q11deletion

61

What are clinical features of DiGeorge?

Hypoplastic or absent thymus
Low-normal lymphocyte count (Bcells are normal)
Paracortical areas of lymph nodes and PALS in spleen are depleted
Deficient cell-mediated immunity (no delayed hypersensitivity or graft rejection)
**Absent or rudimentary parathyroid glands** hypocalcemia -> tetany in first days of life
congenital defects of heart and great vessels, facial deformity

62

What infections are DiGeorge patients susceptible to?

Viral, Fungal, Mycobacterial

**most bacterial infections are Tcell independent, so immunity is not compromised**

63

How is DiGeorge treated?

Ca++ supplimentation for life
Cardiac surgery
Fetal thymus transplant - often unnecessary. Body has other Tcell maturation zones - often outgrow Tcell deficiency

64

What is the pathogenesis of Bruton's X-linked agammaglobulinemia?

Bruton's Tyrosine Kinase mutation -> inability for Bcells to mature

**X-linked recessive**

65

What infections are XLAG patients particular susceptible to?

pyogenic bacteria (Strep, Staph, PSA, Hib)
certain viruses (entero and hepatitis)
Giardia Lamblia (watery diarrhea)

66

How is XLAG treated?

periodic gamma-globulin injections

67

What is the most common primary immunodeficiency ?

Isolated IgA deficiency

68

What causes isolated IgA deficiency?

Block in differentiation of IgA Bcells
Other classes are usually normal

May be congenital (variable inh. pattern) or acquired (toxoplasmosis, virus, drugs)

69

What infections are selective IgA deficient patients susceptible to?

Respiratory and GI (sinopulmonary infections and diarrhea: loss of mucosal defense)

Patients may be asymptomatic

70

What is a concern with blood transfusion in selective IgA deficient patients?

~40% of pts. have anti-IgA Ab.

If given blood containing IgA, may have anaphylactic reaction

71

What is common variable immunodeficiency?

Heterogenous group of disorders diagnosed in teens and young adults
Hypogammaglobulinemia (usually all, sometimes only G)
Congenital (variable) or acquired

Bcell deficit - failure to mature to plasma cells
May be defective Tcell regulation: either deficient Thelper or excessive Treg

72

What are features of Common Variable Immunodeficiency?

Normal number of Bcells, but plasma cells lacking
Hyperplastic Bcell areas of lymph tissue in nodes, spleen, GI
Recurrent infections: pyogenic bacteria, intestinal - giardia and C.diff
Non-caseating granulomas (not sure why)
ex. duodenal nodular lymphoid hyperplasia

73

What is Wiscott Aldrich?

Diagnostic triad: 1) cellular and humoral immunodeficiency 2) eczema 3) thrombocytopenia

Recurrent infections, bleeding complications or malignancy -> death around 6-8 yrs

X-linked recessive : defective WASp protein - cytoskeletal actin rearrangement

susceptibility to encapsulated pyogenic bacteria

74

How is Wiscott Aldrich treated?

Stem cell transplant

75

What is the immunoglobin profile seen in Wiscott-Aldrich?

low IgM, normal IgG, elevaged IgA and E

76

What pathogens are Wiscott-Aldrich patients particularly susceptible to?

polysaccharide antigens

77

What is Ataxia-Telangiectasia?

Defect in Ataxia-Telangiectasia Mutant (ATM) gene -> chromosomal instability (compromised DNA repair)

Patients have progressive neurologic dysfunction, cerebellar ataxia, oculocutaneous telangiectasia, X-ray sensitivity, impaired organ development (elevated a-fetoprotein)
Variable immunodeficiency, malignancies

78

What is desmoplasia?

Dense collagenous stroma often induced by malignant neoplasm, especially carcinoma.

Responsible for "hardness" of tumor.

79

-oma suffix

refers to benign tumor

80

-carcinoma suffix

epithelial cell malignancy

81

-sarcoma malignancy

mesenchymal cell malignancy - bone, fat, cartilage, epithelial

82

adeno- prefix

glandular epithelium

83

leiomyo- prefix

smooth muscle

84

rhabdomyo- prefix

skeletal muscle

85

what is papillary growth pattern?

multiple finger like projections growing into a cystic space.

86

Polypoid tumor growth

neoplastic cell mass projecting above a mucosal surface.

87

Seminoma

Malignancy of testicular germ cell line

-oma exception

88

Teratoma

Germ cell neoplasm that shows differentiation toward more than one germ cell layer (ecto, meso, or endo - often all 3)

May be benign or malignant

89

Choristoma

Benign tumor - nodules of normal tissue in abnormal places
"ectopic rest of normal tissue"

90

Hamartoma

Benign mass of normal, mature tissue - disorganized.
Often found in lung - cartilage, bronchi, vessels

91

what is anaplasia?

Morphologic alterations seen with loss of differentiation.
Anaplasia is a hallmark of malignancy. Reversal of differentiation to a more primitive level.
Associated with pleomorphism, hyperchromatic nuclei, mitoses, loss of polarity, giant tumor cells

92

What atypical functions can be taken on by neoplastic cells?

Aberrant hormone synth: PTH by squamous cell carcinoma of lung; Gastrin by pancreatic islet cell tumor of pancreas
Fetal protein synth: a-fetoprotein by hepatocellular carcinoma; carcinoembryonic antigen produced by colon carcinoma

93

What is dysplasia?

Abnormal growth.
Potentially pre-malignant. Confined to epithelial surface. Does not penetrate basement membrane
-Failure of normal maturation
-Loss of polarity
-Cytologic features of anaplasia

Full thickness = carcinoma in situ

94

What tends to grow faster: poorly, moderately, or well differentiated malignancy?

Well differentiated tends to grow fastest

95

How do carcinoma and sarcoma spread?

Carcinoma: lymph -> venous -> lung -> arterial circ. and systemic metastasis

Sarcoma: hematogenous spread before lymph

96

What tissues are common sites of venous metastatic spread

Liver - hepatic portal system
Lungs
Vertebral bodies - paravertebral plexus (prostate carcinoma)

97

What are clinical features of metastasis by seeding of body cavities?

Fluid collection (ascites, plural effusion, hydrocephalus)- angiogenesis -> exudative edema

Accumulation of mucinous material: ex. mucus secreting ovarian carcinoma

98

What is malignancy "grade?"

Based on extent of differentiation
Scale: I-IV (well - poorly differentiated)

99

What is meant by malignancy Stage?

Based on TNM system: Tumor size, lymph Node involvement, hematogenous Metastasis
Scale: 0-IV (T: 0-4, N: 0-3, M: 0-1)

**more valuable than stage for determining prognosis and treatment**

100

What underlies cachexia due to malignancy?

Cytokines produced by macrophages or tumor cells
TNF, IL-1 -> decreased appetite + increased fat / muscle catabolism -> wasting

101

What tumor type is associated with Cushing's?

Bronchogenic small cell carcinoma
Ectopic production of ACTH or ACTH-like product -> increased release of corticosteroids

102

What tumor type is associated with SIADH?

Syndrome of inappropriate ADH secretion
Bronchogenic small cell carcinoma
Ectopic ADH production

103

What tumor type is associated with hypercalcemia?

Bronchogenic squamous cell carcinoma
Ectopic production of PTH

104

What is carcinoid syndrome and what tumor activity causes it?

Characterized by flushing, sweating, bronchospasm, colicky abdominal pain, diarrhea, right sided CV fibrosis.

Caused by ectopic serotonin produced by tumors (ileal)

105

What is polycythemia and what tumor type is it associated with?

Increased RBC mass
Renal cell carcinoma
Ectopic production of erythropoietin

106

What is the name and cause of neuromyopathies seen in association with neoplasm?

Myasthenia Syndrome
Cross-reactive antibodies

107

What is acanthosis nigricans?

Darkening of the skin, usually in fold areas - axilla, back of neck
Associated with neoplasm

108

What is hypertrophic osteoarthropathy and what tumor type is it associated with?

Periosteal new bone formation of distal long bones and accompanying arthritis and fingertip clubbing

Associated with bronchogenic carcinoma (usually non-small cell)

109

What is Trousseau's Syndrome and what tumor type is it associated with?

Migratory Thrombophlebitis associated with pancreatic adenocarcinoma.

Hypercoagulability -> clot formation, vasculitis and pain in the affected area.

110

What tumors are associated with nonbacterial thrombotic endocarditis?

Mucinic adenocarcinomas
Mucin reacts with platelet selectin -> platelet aggregation and deposition on valve leaflets.
vegetations consist of fibrin and platelets

111

3 hypercoagulation disorders associated with malignancies

Migratory Thrombophlebitis (Trousseau's)
Nonbacterial thrombotic endocarditis
Disseminated Intravascular Coagulation

Most assoc. w/ mucinous adenocarcinomas (pancreatic)

112

4 most common cancers in men and women

Men: 1) prostate 2) lung 3) colon 4) urinary tract
Women: 1) breast 2) lung 3) colon 4) uterus (endometrium)

*note that all are carcinomas

113

Overall cancer mortality rate and 3 leading cancer mortalities in men and women

Overall mortality 20-25%
Men: lung, prostate, colon
Women: lung, breast, colon

114

What is the key factor underlying the proliferative potential of cancer cells?

Increased telomerase activity

115

What is N/C ratio and what does it say about a cell?

Nucleus / Cytoplasm ratio
Higher ratio = less differentiated cell
Cancer cells tend to have high N/C ratio

116

What is the cause of follicular lymphoma?

Loss of apoptotic capability -> increased survival of lymphocytes
Tumor arises from germinal center Bcells
BCL-2 often hyperactivated
Common translocation: t(14;18)(q32;q21)

117

What kind of receptors are GFR?

Tyrosine Kinase

118

What cancers are HER-1 associated with?

Squamous Cell Carcinoma
Non Small Cell Lung Cancer (NSCLC)
Colon Cancer

119

What cancers are associated with HER-2?

Breast
Adenocarcinoma (ovary, lung, stomach, salivary

120

What are HER-1 and HER-1?

Both are Human Epidermal Growth Factor Receptors
HER-1 also ERBB1
HER-2 also ERBB2 and NEU

HER family consists of 1-4

121

What is the result of EGFR activation?

Dimerization, auto (cross) phosphorylation, activation of RAS

122

How can an increase in number affect cell proliferation?

More receptors available for ligand -> more likely response or amplified response
More recpetors -> constitutive activity (due to numbers/ proximity -> autophosphorylation)

123

What happens to HER-2 activity that leads to breast cancer?

Ligand independent activation
Gene amplification -> HER-2 overexpression
-> reduced survival

124

What is GIST and what mutation is it associated with?

Gastro Intestinal Stromal Tumor - most common stromal neoplasm
Mutated EGFR c-Kit (TK domain mutation -> constitutive activity) is almost always present.

125

What mutation is associated with lung adenocarcinoma and what group is most at risk?

TK domain mutation of EGFR
Female, Oriental, Non-smokers

126

What mutation is seen in many glioblastomas?

Deletion of EC domain of EGFR

127

What drugs target EGFRs?

Anti EGFR Ab: Cetuximab
Anti HER-2 Ab: Trastuzumab (Herceptin)

Tyrosine Kinase Inhibitors - target catalytic site
-Iressa (Gefitinib), Erlotinib (Tarceva), Imatinib (Gleevac)

128

What molecule facilitates Ras return to inactive state?

Neurofibromin

129

What is the effect of KRAS mutation and what tumors are associated?

KRAS mutation -> constitutively active RAS signaling
*Tumors are not responsive to anti-EGFR therapy*

Tumors: Pancreas, Colon, Lung, Endometrium, Liver

130

What causes Neurofibromatosis 1?

Autosomal Dominant disorder -> inactivation of Neurofibromin 1
-> increased Ras activity
-proliferation of nerve sheath cells, cafe au lait spots, nodules in iris
-propensity for malignant transformation (neurofibrosarcoma)

131

What colon cancer mutations are associated with ineffectiveness of anti-EGFR therapy?

Ras mutation or downstream Ser/Thr kinase (BRaf) mutation

132

What is an oncogene? Dominant or recessive?

Has cancer promoting ability in heterozygous state
dominant

EGFR, HER-2, Ras

133

What are tumor suppressor genes? Dominant or Recessive?

Genes that inhibit cancer promoting activity (growth / proliferation)
Recessive - homozygous inactivation is needed for cancer formation

Neurofibromin, Rb

134

Steps that follow Ras activation

Ser-Thr kinase activation -> increase of transcription factors -> Cyclin D -> low levels of Rb phosphorylation -> Cyclin E -> hyperphosphorylation of Rb -> S phase

135

How are cyclins degraded?

Ubiquitylation
ubiquitin added to phosphorylated cyclin, targed for proteosome destruction

136

What is responsible for negative control of cyclin / CDK complexes?

CDKI (CDK inhibitor) - induced by growth inhibitors (TGF-B, p53)

137

What is the result if CDKI inhibition?

malignancy w/ homozygous inactivation of CDKI gene

138

What cyclin facilitates passage through the G1 restriction point?

Cyclin D1

139

2 CDKIs, their activators and inhibitors

P21 - activated by TGF-B (weakly) and DNA damage via p53
- targets CDKs A,B,E

p15 - activated by TGF-B
- targets CDK D

140

What malignancies are increased levels of CDK 4 associated with?

CDK4: liposarcoma

141

What malignancies are increased levels of Cyclin E associated with?

Breast cancer
- significantly higher mortality with higher levels of cyclin E

142

Decreased p27 is associated with a worse outcome in what kind of cancer?

breast

143

Rb inactivation is seen in what malignancies?

Small cell carcinoma of the lung
breast ca
glioblastoma

144

Inherited mutations of Rb cause what malignancy?

malignant retinal tumor

145

Leukocoria

Most common presentation of Retinoblastoma
Eye appears whitish (vs. normal red-eye) under special lighting

146

2 forms of Retinoblastoma

Sporadic: usually unilateral. Age of diagnosis ~24 mos
Familial: Autosomal Dominant. Bilateral disease. Age of diagnosis ~8mos

147

Rosettes

Seen microscopically in Retinoblastoma
Rings of undifferentiated cells

148

What is Loss of Heterogenosity?

In setting of inherited mutation - one gene affected, other is normal. Normal gene is shut down, usually by methylation.
EX: Rb - dominant pattern of inheritance, but molecularly is recessive - both genes must be deactivated for disease to manifest. Penetrance is near 100% due to high rate of LOH

149

What cancer associated gene type is frequently inactivated by methylation?

Tumor Supressor genes (Rb)

150

What risk is presented by treating familial Rb with radiation treatment?

500x increased risk of 2ndary tumor

151

How does low penetrance Rb differ from usual familial Rb?

Low penetrance mutations result in either decreased expression or expression of a partially functional product vs. deletion as seen in the usual familial mutation.

152

At what rate do mutations occur in normal cells?

1 per 10^-9 or 10^-10 cell divisions

153

What is the effect of inactivation of house keeping genes?

Mutations in other genes

154

What is the key ability of a carcinogen?

Ability to oxidize DNA

155

4 examples of chemical carcinogens and associated turmors.

Aromatic Hydrocarbons:lung, bladder, pancreas, sq. of uper aero digestive (cig. smoke)
Asbestos: Malignant Mesothelioma
Chemo drugs: Hematologic Malignancies
-aklylating agents (Busulfan, Melphalan)
Nitrosamines: Gastric

156

2 naturally occurring carcinogens and associated tumors

Aflatoxin B1: Hepatocellular carcinoma
Bile acids: colon cancer

157

What malignancies are ionizing and UV radiations associated with?

Ionizing: hematologic, thyroid
UV: skin

158

3 outcomes of DNA adduct formation

Repair
Cell death
Permanent lesion

159

What is Benzopyrene?

Procarcinogen found in cigarette smoke. Must be metabolized to BPDE for carcinogenic effect.

160

What is BPDE?

benzo(a)pyreinediolepoxide.
Carcinogenic product of benzopyrene. Inserts into DNA double helix, distorting and facilitating mutation

161

3 substances that ROS react with

Fatty acids
Proteins
DNA

162

Barret's Esophagus

normal squamous epithelium -> goblet cells due to reflux
May precede dysplasia and invasive esophageal adenocarcinoma

163

Anti-inflamatories and cancer

May reduce risk.
NSAID: adenoma and colorectal in FAP and sporadic settings
-gastric ca. in pts w/ gastritis
Aspirin: post diagnosis of colorectal ca. lowers risk of recurrence, morbidity and mortality (esp. COX2 tumors)

164

What does glutathione reductase do?

Reduces ROS -> OH groups (electron donation)

165

What is GST loss associated with?

GST: glutathione S-transferase (reductase)
Lost in 90% of all prostate cancers
Variants w/ decreased activity -> increased risk

166

What is HNPCC and what mutation is it associated with?

Hereditary Non-Polyposis Colorectal Cancer
Associated with DNA mismatch repair enzyme abnormality
Autosomal Dominant, molecularly recessive

167

What is a loss of MLH-1 associated with?

Sporadic endometrial carcinoma

168

How does carcinogenic inactivation of DNA mismatch repair enzymes occur in HNPCC?

Via mutation of TGF-B receptor -> truncated, inactivated protein

169

Truncation of TGF-B recpetor has what effect?

Inactivation of DNA mismatch repair enzymes -> HNPCC

170

BRCA1 and BRCA 2

BRCA1: 65% LT risk of breast cancer (women only)
40-60% risk of 2nd occurrence
39% LT risk of ovarian

BRCA2: 45% LT risk of breast cancer (women)
6% LT risk of breast cancer (men)
11% LT risk of ovarian cancer

1:40 carrier rate in Ashkenazi Jews

171

What is the function of BRCA genes?

Sensing and responding to DNA damage, sim. to p53

172

Xeroderma Pigmentosum

Caused by defect in Nucleotide Excision Repair Ezymes (any one)
High risk of basal cell ca, squamous cell ca, melanoma

Inability to repair UV damage to DNA

173

NER enzyme

Nucleotide Excision Repair
repairs DNA damage caused by UV
Often involved in Xeroderma Pigmentosum

Polymorphic Variants - involved in esophogeal ca., breast ca., and acute lymphoid leukemia

174

2 things that induce p53

Hypoxia and Mutagens

175

Li Fraumeni Syndrome

Caused by p53 mutation
Increased risk of many cancers

176

In addition to mutation, what can negatively affect the function of p53?

Interaction w/ other molecules such as HPV protein can -> functional inactivation

177

3 molecules that p53 acts through and what is the effect?

p21 -> G1 arrest
GADD45 -> DNA repair
Bax -> apoptosis

178

What is the most commonly altered tumor suppressor gene?

p53

179

What inheritance pattern does Li Fraumeni follow and what is the penetration?

Autosomal Dominant

Penetration:
Males: 75%
Females: 100%

180

Atypical hyperplasia

Form of dysplasia seen in uterus and breast

181

Compex hyperplasia

Pre-malignancy seen in uterus

182

Barret's esophagus

Metaplasia of esophagus due to reflex
Squamous -> columnar
May preceed dysplasia and invasive columnar adenocarcinoma

183

What is intraepithelial neoplasia?

Term for Dysplasia

184

Pleomorphism

In dysplasia: cells show variation in shape and size

185

How is dysplasia graded?

extent of epithelial occupation by dysplastic cells
4 teir model: mild, moderate, severe, cancer in situ
2 teir model: low and high grade

186

What change takes place in progression from dysplasia to cancer in squamous epithelium?

Breech of basement membrane (epithelium)
Other barriers in other tissues
breast: myoepithelial cells
colon: muscularis mucosae

187

What is Comedo type DCIS?

Type of Ductal Carcinoma in Situ seen in breast
Most likely form to become invasive carcinoma
Has necrotic pus-like center (eosinophilic)
Assoc. w/ HER-2 overexpression

188

What is the relative risk of developing invasive carcinoma for the following conditions:
Nonproliferative fibrocyscic disease
Atypical Ductal Hyperplasia
Ductal Carcinoma in Situ

Nonproliferative fibrocystic disease: RR = 1.0
Atypical Ductal Hyperplasia: RR = 4.0-5.0 (both breasts)
Ductal Carcinoma in Situ: RR = 8.0-10.0 (ipsilateral breast)

189

What is "field effect?"

Cancer often arises from a background of multifocal precursor lesions in an organ or system.

Implies need for systemic rather than local (surgical) treatment.

190

Tamoxifen and use in cancer prevention

Selective Estrogen Receptor Modifier (SERM)
Antagonist in Breast: inhibits cellular prolif
Agonist in Bone (antiresorptive) and Uterus (pro-proliferative)

Reduces risk of contralateral breast cancer in pre-menopausal women.

191

How long does it normally take normal tissue to progress to malignant?

Decades
20-40 years

192

What factors are the most important influences in progression of cervical premalignant lesions (cervical intraepithelial neoplasia- CIN)?

Early detection / eradication: PAP, vaccine
Viral serotype: high vs. low risk
p53 polymorphism
Immunocompetence

193

What strains of HPV are high risk?

16,18, 31, 45

194

What is the defining feature of 'high-risk' HPV groups?

Ability to tightly bind p53 and Rb
viral transforming proteins induce cel immortality:
E6: binds p53
E7: binds p53, p21, Rb

195

3 AIDS defining malignancies

Non-Hodgkin's Lymphoma
Kaposi's Sarcoma
Cervical Carcinoma

196

How does pathological stage differ from clinical stage?

Pathological based on complete tissue exam (TNM)
Clinical stage based on imaging and clinical exam

197

At what cell populations are tumors visible via x-ray, palpable, and likely to cause death?

Visible on x-ray: 10^8 cells
Palpable: 10^9 cells
Likely to cause death: 10^12 cells

198

What is the utility of TNM staging?

Indicate tumor burden, extent of spread.
Best indicator of prognosis

199

T staging in TNM model

T1-2: contained w/in organ boundaries
ex. kidney: w/in renal capsule
ex. colon: w/in serosa.(T1 penetrates M.mucosa, T2 penetrates M.propria, but not serosa)

T3: escapes boundaries.
ex. kidney: outside renal capsule, still w/in Gerota's fascia
ex. colon: wide infiltration of bowel wall

T4: invasion of neighboring tissue, skin (ex. pectoral muscle or skin ulceration

200

In T staging how does breast tumor size reflect stage?

In situ: small
T1: up to 2 cm
T2: 2.1-5 cm
T3: >5cm

201

N staging in breast and lung cancer

extent of lymph node involvement: more = greater mortality
breast: N0: no nodes involved
N1: 1-3 nodes
N2: 4+
Lung: N0: none
N1: ipsi peribronchial or hilar
N2: mediastinal or subcarinal
N3: contralateral involvement

202

TNM staging I-IV generalizations

I: small, superficial - limited to organ
II: large, deep or regional nodes positive
III: contiguous extension to adjacent structure and/or high Nstage
IV: Hematogenous metastasis

203

How are benign / malignant tumors differentiated in a lab?

Pattern recognition
H&E stain

204

How are tumors classified morphologically?

How much does the tumor resemble a specific tissue type
-Type of differentiation
Light micro, special stains, immunohistochemistry, genetics are used

205

What 2 features are characteristic of squamous cell carcinoma?

Keratinization
IC bridges

206

Key identifying histological characteristic of lymphoma

No stroma - patternless proliferation of monotonous neoplastic cells

207

Histological characteristic of sarcoma

Spindle shaped cells

208

Histological characteristic of carcinoma

Dense stromal response - heavy collagen deposition - hard tumor

209

How is genetic testing used in cancer treatment (carcinoma vs. sarcoma)

Sarcoma: diagnostic. Translocations are characteristic of certain sarcomas

Carcinoma: guide therapy. treatments targeted tumor specific mutations. ex: EGFR sensitivity to TKi

210

Tumor grades I-IV

I: Low grade: well differentiated
II: Intermediate grade: moderately differentiated
III: High grade: poorly differentiated
IV: Anaplastic: undifferentiated

211

What is quantitative tumor grade useful for?

stratifying prognosis in patients with the same stage cancers

212

How is squamous cell carcinoma graded?

How much keratinization is present
More keratin: well differentiated - lower grade
Less keratin: less differentiated - higher grade

213

What morphological criteria are used in quantitative tumor grading?

Organization (prostate and breast)
Pleomorphism (breast)
Number of mitoses (breast)

214

What is Gleason Grade?

Prostate cancer grading scale
Major and minor growth patterns are scored on 1-5 scale (doubled if only one pattern)

Good predicter of survival / recurrance for organ-confined disease
Predicts survival of prostate cancers

215

What are the criteria used in the Nottingham scale for breast cancer grade?

Tubule formation
Mitotic count
Nuclear pleomorphism

scale 0-9

216

3 consequences of an absent or defective enzyme

1. substrate accumulation
2. diversion of substrate into minor pathways -> alternate end product
3. decreased end product

217

Are most enzyme defects dominant or recessive traits?

Recessive
Only need a small amt. of enzyme for normal function - single allele is usually sufficient.

218

How are lysosomal storage diseases classified and what are 3 classifications?

Classified by accumulated substrate
-mucopolysaccharide
-sphingolipid
-glycoprotein

219

What is the general synthesis pathway of lysosomal enzymes?

Synth in ER
Transport to Golgi
Post-translational modification (addition of Mannose-6-phosphate)
Segregation and release in vessicles
Fusion with lysosome

220

Are most lysosomal storage diseases dominant or recessive? Exceptions?

Recessive

Exceptions: Fabry and Hunter are X-linked

221

6 mucopolysaccharides

Dermatin Sulfate
Heparan Sulfate
Keratan Sulfate
Chondroitin Sulfate
Hyaluronic Acid
Heparin

222

Enzyme defect in muccopolycaccharidosis has what effect?

Tissue accumulation
Urine excretion

of relavent mucopolysaccharide

223

Clinical features of mucopolysaccharaidosis?

Chronic, progressive course
Multisystem involvement
Organomegaly
Dysostosis multiplex
Abnormal Facies

224

3 methods of diagnosing mucopolysaccharidosis

1. GAGs in urine: age dependent (normal up to 1 yr). small amt. of chondroitin, heparan and dermatin sulfate normal
2. GAGs in amniotic fluid
3. Enzyme assay
-prenatal: cultured cells from amniotic fluid (chorionic villi sampling less desireable - less enzyme activity)
-postnatal: measure enzyme activity in plasma or leukocyte
measure enzyme activity from skin fibroblast

225

Hurler Disease

MPS I
Most common mucopolysaccharidosis
a-L-iduronindase deficiency -> lysosomal accumulation of heparan and dermatan sulfate

Onset: infancy: 6-8 mos, death befor 10 yrs

226

Features of Hurler Disease (MPS I)

Respiratory disease
-restrictive: small ribcage, oar shaped ribs, hepatomegaly
Upper airway obstruction (due to storage)
-enlarged tongue, lymph tissue, airway epithelium, pharyngeal tissue
Joint and Skeletal Disease: joint pain, stiffness and contracture, short stature, deformity
Cardiovascular disease: valvular disease, CAD, CHF
Hepatosplenomegaly
Opthalmic Disease: corneal clouding, retinal disease, glaucoma, blindness
CNS disease: mtard, hydroceph, headache, SC compression, thickened leptomeninges

227

What is the usual cause of death in Hurler Syndrome?

Cardiovascular complication

228

What is Alder-Reilley anomaly?

Dense granulation seen in all leukocytes / PMNs in mucopolysaccharidosis - accumulation of mucopolysaccharides

229

Hunter Disease

MPS II
Deficiency of iduronate sulfatase
X-linked

phenotypically similar to Hurler, but milder. Appears in late infancy, early childhood. No corneal clouding. Slower progression

230

What are sphigolipids and examples

class of membrane lipids
-Sphingomyelin
-Glycosphingolipids
-Cerebrosides
-Sulfatides
-Globosides
-Gangliosides

231

Neimann-Pick Disease

Sphingomyelinase deficiency -> sphingomyelin accumulation
Type I A: severe infantile
-missense mutation -> near complete lack of enzyme
-first weeks of life: hypotonia, failure to thrive
-death by 3 yrs
-Severe neurodegeneration and visceral accumulation
-50% have macular cherry-red spot
Type I B: Chronic Visceral
-splenomegaly and eventually general visceral involvement

232

Neimann-Pick Type C

Most Common Neimann-Pick
Defect in NPC-1 (95%) and NPC-2
Cholesterol accumulation in spleen, liver, bone marrow, and neurons

233

Neimann Pick Type C presentation

Appears in early childhood
variable hepatosplenomegaly
*vertical supranuclear opthalmoplegia* (supranuclear palsy)
progressive ataxia and psychomotor regression

Hydrops fetalis and stillbirth
Fatal neonatal liver disease: giant cell hepatitis
Adult presentation: psychosis and dementia

234

What is Type D Neimann Pick?

Similar to type III, but less severe.
Mostly limited to Nova Scotia population

235

What disease is associated with neonatal giant cell hepatitis?

Neimann-Pick type III

236

GM1 Gangliosidosis Type I and presentation

Deficiency in B-galactosidase A,B,and C -> ganglioside accumulation in neurons
mucopolysaccharides accumulate in other locations (pseudo-Hurler)
Infantile - 6 mos
Neurodegeneration, ganglioside accumulation in neurons, liver, spleen, renal tubular epithelium, cherry red spot on macula
skeletal deformities

237

GM1 Gangliosidosis Type II and presentation

Juvenile
Absence of A and B isotypes of B-galactosidase
later onset than type I: 1-2 years
slower progression of psychomotor retardation, less visceromegaly
Death 3-10 yrs

238

In a peripheral smear what is a lymphocyte with many small bubbles indcative of?

Gangliosidosis (not unique to this disorder, but may support diagnosis)

239

What are GM2 gangliosidoses?

Tay-Sachs (Hexoseaminidase a subunit)
Sandhoff (Hexoseaminidase B subunit)
GM2 activator deficiency (activator unit of

All result in accumulation of GM2 so similar phenotype

240

features of GM2 gangliosidoses

Accumulation of GM2 in many tiss, esp. CNS and retina
-loss of motor skills at 3-6 mos
-prominent macular cherry red spot
-progressive neurodegeneration w/ death by 2-4 years
-Ashkenazi jews: 1/30 carrier rate

241

Metachromatic Leukodystrophy

Deficiency of Arylsulfatase A -> accumulation of non-degradable cerebroside sulfate in:
-white matter of brain
-peripheral nerves
-liver and kidney

-> demyelination and gliosis (neurodegenerative)

242

3 forms of metachromatic leukodystrophy

Late Infantile: most common- regression of motor skills, mental deterioration, rigidity, convulsions, loss of white matter of CNS on imaging. death by 5 yrs
Juvenile: change in gait, cognitive skills, general regression. death by 6-8 yrs.
Adult onset: psychiatric / cognitive symptoms and later motor symptoms

243

How are sulfatidoses diagnosed?

Urine spot test (acidified cresyl violet) or quantitative analysis
Imaging: loss of white matter
Sural nerve biopsy: demyelination and metachromatic granules
Arylsulfatase A activity levels
**Genetic testing: 22q

244

Gaucher Disease Type I

Glucocerebrosidase deficiency -> glucocerebroside accumulation
Type1: Most common (99%). Chronic non-neuropathic. Children and adults, ashkenazi jews.
-Accumulation limited to mononuclear phagocytes throughout body. No brain involvement.
-Hepatosplenomegaly
-Bone: avascular necrosis (esp. hip), osteopenia w/ fx
Bone crisis: collections of gaucher cells interfere w/ vascularization causing severe pain
Erlenmeyer flask deformity: new bone formation w/ flat ends of femur.

245

Gaucher Disease Type II

Acute Neuropathic, no Ashkenazi assoc.
Complete lack of glucocerebrosidase
Progressive CNS involvement, death before 2 yrs.
Hepatosplenomegaly, cytopenia secondary to hypersplenism

246

Gaucher Type III

Subacute, intermediate, juvenile form
Reduced glucocerebrosidase
Progressive CNS involvement beginning in teens / twenties
Hepatomegaly, splenomegaly, cytopenias, bone involvement

247

Classic Galactosemia

Galactose-1-phosphate uridyltransferase deficiency
Galactose-1-phosphate accumulation -> minor pathways

Symptoms in infancy a few days after first milk consumption
-vomiting, failure to thrive, diarrhea, liver dysfunction
-renal failure, hepatomegaly, cirrhosis, cataracts, brain damage, increased frequency of E.coli septicemia

Newborn screening
Diet for life

248

Glycogen storage disease

Hepatomegaly, hypoglycemia, growth failure, excessive fat in face and buttocks, mild serum transaminase elevation

Hepatic form type I (Von Gierke)
G6P defect
Hepatomegaly, renomegaly, short stature, xanthomas, hypoglycemia
Distended hepatocytes, uniform distribution of glycogen.
Normal muscle cells

249

McArdle disease

Glycogen Storage type V: Myopathic Form
Deficiency of muscle phosphorylase
Muscle weakness, cramps after exercise (no increase lactate)
Prolonged excercise -> muscle necrosis, myoglobinuria, acute renal failure - potentially fatal
Glycogen accumulation in skeletal muscle

250

Pompe Disease

Type II glycogen storage disease
a-1,6-glucosidase (acid maltase) deficiency
Infantile presentation, but very rare
Muscle weakness - profound hypotonia
Heart involvement (progressive HF)
Hepatomegaly
Enlarged tongue
Death in 1-2 years
Glycogen deposits in myocardium, muscle, liver, etc.

251

5 glycogen storage disease

VPCAM
I. Von Gierke
II. Pompe
III. Cori
IV. Anderson
V. MacArdle

252

Anderson disease

Type IV glycogen storage disorder
Brancher enzyme disorder (amylo-1,4,6-transglucosidase)
Generalized
Hepatomegaly, failure to thrive in1st year
Progressive portal fibrosis -> cirrhosis -> death
Cardiomyopathy, muscle atrophy

253

What is deficient in phenylketonuria?

Phenylalanine hydroxylase (PAH) - 98%
BH4 synth / recycling abnormality - 2%

254

Clinical features of amino acid metabolism disorders

Mtard
fair hair, blue eyes
musty odor
eczema

255

What lab testing is done for PKU?

Urine: minor Phenylalanine metabolism pathway products
phenylpyruvic acid, phenyllactic acid, phenylacetic acid

Serum: phenylalanine levels

256

Describe CFTR function in airway and sweat duct

Airway: Cl- exported from cell to mucus secretion. Keeps Na+ in secretion, thereby keeping water in secretion. In CF, Na+ re-enters cell with water -> very thick secretion

Sweat duct: Cl- pumped into cell -> Na+ re-enters cell. Excessively salty sweat

257

What is the most common mutation seen in cystic fibrosis?

F508 deletion
loss of phenylalanine at position 508
Chromosome 7Q31.2

258

What organs are most affected by CF?

Lungs
Intestines
Pancreas
Vas Deferens

259

What defect is seen in Marfan's syndrome?

Fibrillin defect - microfibrils in ECM
FBN1 gene on chromosome 15q21

260

What pattern of inheritance does Marfan follow?

Autosomal Dominant

261

What are the clinical features of Marfan?

CV: aortic dilation (ascending), aneurism, dissection (cystic medionecrosis)
Skeletal: tall, abnormal joint flexibility, scoliosis, arachnodactyly
Ocular: ectopia lentis, myopia

262

What gene is affected in Neurofibromatosis and where is it located?

NF-1
17q11.2

263

What inheritance pattern does NF-1 follow?

Autosomal Dominant

264

Diagnostic criteria for NF1

CANNOT FAIL 2 B 1ST

2 or more of:
CA: 6 cafe au lait spots
NN: 2 neurofibromas or 1 plexiform neurofibroma
OT: OpTic gliomas
FAI: Freckling - Axial or Inguinal
L2: 2 Lisch nodules
B: Bone abnormalities
1st: first degree relative w/ NF-1

265

What is the genetic defect seen in Neurofibromatosis II?

NF-2 gene defect - codes for protein merlin
chromosome 22

266

What are the features of NF-2?

Bilateral acoustic neuroma
multiple meningiomas
ependymomas of spinal cord

267

Most common cause of Trisomy 21

Meiotic non-disjunction
95% are 47, XX, +21

268

What cancer are Trisomy 21 patients predisposed to?

Leukemia

269

What is Edward's Syndrome?

Trisomy 18

270

What is seen in Trisomy 18 (Edward's)?

Severe Mtard
Congenital heart defects
Renal problems
Apnea
Overlapping fingers / clenched fists
Rocker bottom feet
Micrognathia

271

What is trisomy 13?

Patau

272

What are the features of trisomy 13 (Patau)?

Midline defects: cleft lip / palate, proboscis, cyclopism, micropthalmia
Mtard
polydactyly
rocker bottom feet
congenital heart defects
renal defects (cysts)
umbilical hernia

273

How is 22q11 deletion diagnosed?

FISH

274

What is Kleinfelter Syndrome?

2 or > X + a Y chromosome
one of most common causes of male hypogonadism

275

What is Turner Syndrome?

one X chromosome

276

What causes fragile X?

Triplet repeat of FMR 1 gene at Xq27.3
Codes for FXMR

277

What are the two most common causes of mental retardation?

1. Trisomy 21
2. Fragile X

278

How many copies of FMR 1 does it take to cause disease?

10-55 = normal
55-200 = transmitting male / carrier female
>200 = full mutation
>230 -> gene methylation and suppression of the gene

279

What is Fragile X Related Tremor / Ataxia?

Occurs in males w/ premutation
late onset cerebellar ataxia and intention tremor.
MRI -> white matter lesions in middle cerebellar peduncles and/ or brain stem

280

What disorder is seen in women w/ FMR 1 premutation?

FMR-1 related premature ovarian failure
20% of women w/ premutation
menopause before 40 yrs

281

What is genomic imprinting and where does it occur?

Selective inactivation of a paternal or maternal gene due to functional difference between maternal / paternal genes.

Occurs in sperm / ovum -> passed to all somatic cells of offspring.

282

Cause of Prader-Willi syndrome

Maternal imprinting of genes at 15q11-13 results in functional allele being provided by father
Deletion of paternal allele -> P-W
Uniparental disomy: both alleles being from mother (thus inactivated) -> P-W

283

Phenotype of Prader-Willi

hypotonia at birth
Mtard
Short w/ small hands and feet
Hypogonadism
Obesity
Face: narrow bifrontal diameter, almond eyes, full cheeks

284

What is the cause of Angleman's syndrome?

Genes on 15q are imprinted (silenced), functional allele comes from mother.
If maternal allele is missing-> Angelman

285

What are the characteristics of Angelman's Syndrome?

Mtard
Large mouth, prominent chin
Ataxic gait, seizures
Inappropriate laughter (happy puppets)

286

What is the explanation for a phenotypically "normal" parent having 2+ children with an autosomal dominant defect?

Genetic mosaicism
Mutation occurs during early embryonic development and involves cells destined for gonads.
-> set of cells w/ defect that can be transmitted to offspring.

287

2 mitochondrial disorders

MERRF: myoclonal epilepsy and ragged red fiber disease
MELAS: mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes

288

What cancer is bcl-2 [t(14:18)] associated with?

Follicular lymphoma

289

Leading causes of death by age group 0 - 25 yrs.

<1yr: congenital abnormality, prematurity, low birth weight, SIDS
1-4 yrs: accident, congenital abnormality, malignancy
5-14 yrs: accident, malignancy, homicide
15-24 yrs: accident, homicide, suicide

290

What periods is the fetal period divided into?

Fetal previable: 9-20 weeks
Fetal viable: 20-38 weeks
Fetal full-term: 38-42 weeks

291

What is the approximate weight of a fetus at term?

3300 grams

Remember: quadruple numbers in last trimester

292

What are the percentile ranges for AGA, SGA, and LGA?

AGA: 10-90%
SGA: 90%

293

What is intrauterine growth retardation?

Child is SGA in weight, height and head circumference (<10%)

294

What is a very low birth weight infant?

birth weight <1500g
Usually extreme prematurity. Accounts for 1/2 of all neonatal deaths

295

Type I growth retardation and causes

Symmetric growth retardaion
Fetal in origin, early onset, proportional body and organs
Causes:
chromosomal abnormality
congenital anomoly / malformation syndromes
early intrauterine infections (TORCH)

296

Type II growth retardation and causes

Asymmetric growth retardation
uteroplacental in origin, later onset, disproportional body / organs
*brain relatively spared*
Causes:
maternal: vascular insufficiency, nutrition, toxin/drug, infection

297

What are causes for pathologically large infants?

Maternal Diabetes mellitus
Postmaturity syndrome

298

What is the most common cause of SGA infants?

Maternal : usually low placental blood flow
-CV, renal, coagulopathy, infection, narcotics, ETOH, smoking

299

Abortion vs. stillbirth

Abortion: termination of pregnancy prior to fetal viability (~22wk)
-may be spontaneous or induced

Stillbirth: death prior to delivery of a potentially viable fetus (>22-23 wk)
-intrauterine: >24 hrs prior to delivery -> macerated stillborn
-intrapartum: fresh stillborn

300

When are most spontaneously aborted fetuses lost?

>60% are lost prior to 12 weeks
Most are unrecognized pregnancies

301

Progression of maceration - determining time of death

12-24 hours: skin autolysis
color: 1-2 weeks - change from normal -> purple -> yellow/brown -> gray
fluid in body cavities, tissue changes (fibrin deposition, dessication, fibrosis and calcification): after 1 week

302

What trisomy is particularly associated with Intrauterine Growth Retardation (IUGR)?

Trisomy 16
Frequently -> spontaneous abortion
Only mosaic is viable

303

What is hydrops fetalis?

Generalized edema of the fetus

304

What are causes of hydrops fetalis?

Immune:
Rh incompatibility: 90% due to D antigen
ABO incompatibility: principal cause of immune hydrops, usually type A infants - significant disease uncommon

Non-immune:
congenital heart disease, chromosomal abn, twin-twin transfusion, infection, lung / urinary tract malformation, tumor, metabolic disorder

305

What are the possible outcomes of maternal immune reaction against fetal Rh?

ex Rh- mother previously sensitized to Rh+ infant:
Removal and destruction of Rh+ erythrocytes -> anemia: 1) extramedullary hematopoiesis 2) cardiac decompensation and hydrops
Hemoglobin degradation -> increased billirubin -> 1) jaundice 2) kernicterus

306

What is the pathogenesis of non-immune hydrops?

High venous / capillary pressure caused by high output state, vascular obstruction, cardiac failure

Decreased oncotic pressure caused by low albumin production (liver) increased albumin excretion (kidney)

Damaged capillary integrity due to sepsis, drugs, toxins, hypoxia

307

What is the incidence of intrapartum injury?

0.2-0.7/1000 births

308

What is Caput Succedaneum?

Blood or fluid in soft tissues of scalp - common intrapartum injury, but not clinically significant

309

What is cephalhematoma?

Hemorrhage into scalp. Common intrapartum injury - not clinically significant

310

What causes intracranial hemorrhage in an intrapartum setting?

Related to excess molding of the head and sudden sudden pressure changes
Most common important birth injury

311

What is occipital osteodiastasis?

Uncommon intrapartum injury - separation of skull sutures and overlap of bones

312

What is APGAR scoring used for?

Evaluating infants cardiopulmonary and neurologic function at sit intervals (1,5,10 mins) after birth.

Low score -> delivery room intervention, resuscitation, poorer outcomes

313

APGAR scoring

Heart Rate: 0: absent, 1: 100
Respiratory Effort: 0: absent, 1: slow / irreg., 2: good / crying
Muscle Tone: 0: limp, 1: some flexion, 2: active motion
Response to Nasal Cath: 0: non, 1: grimace, 2: cough / sneeze
Color: 0: blue/ pale, 1: pink body, blue extremities, 2: all pink

Score: good is 9 or 10
most are >7
low is 0-3

314

definition of premature birth

spontaneous or induced birth prior to 37 wks GA

315

Birth weight relationship to viability

<500g usually do not survive
500-1000g may survive w/ ICU care, but high risk for morbidity / mortality
1000-2500g usually survive, but elevated morbidity / mortality

316

When do type II pneumocytes begin developing?

appear at ~22 wks gestation, but inadequate surfactant before 36 wks.

317

What test of amniotic fluid is used to estimate fetal lung maturity?

L/S ratio: lecithin/sphingomyelin
>2:1 indicates ability to produce adequate surfactant
--low risk of neonatal respiratory distress syndrome

318

What is the leading cause of neonatal morbidity / mortality?

Neonatal respiratory distress syndrome
progressive inability to oxygenate blood

319

What happens to alveoli in RDS?

Endothelial / epithelial damage to alvoli -> plasma infiltration and coagulatin -> inflammation, fibrin and necrotic cells -> increased diffusion gradient

320

What is bronchopulmonary dysplasia?

Caused by continued lung development and growth following injury and scarring.

clinical def: seen in neonates under 32 weeks requiring oxygen for >28 days with persistent respiratory difficulty

pathology: fibrous scarring w/ distortion and obliteration of air spaces. Squamous metaplasia, impaired growth.

321

What is the germinal matrix?

Embryonic structure persisting until ~30wks GA.
Highly cellular / vascular area of brain. Cells migrate out. Around ventricles.
Point of spontaneous hemorrhage.

322

Grading of germinal matrix hemorrhages

I: confined to germinal matrix
II: bleed into ventricle
III: blood fills and expands ventricle
IV: grade III + rupture back to brain parenchyma

323

What causes Neonatal Necrotizing Enterocolitis?

Occurs in premature infants recovering from RDS
Usually follows introduction to oral feeding.
Hypoperfusion to intestinal mucosa to provide O2 to vital organs

Ischemic injury -> migration of gut bacteria -> inflammation and necrosis -> perforation, peritonitis, sepsis, shock

324

What complications may occur in survivors of necrotizing enterocolitis?

Short gut syndrome, malabsorption, stricture

325

Legal definition of SIDS

Sudden death, <1 yr. of age, unexplained after complete post-mortem investigation.

326

Medical definition of SIDS

Sudden death, 3wk-8mo age, during sleep and not preceeded by symptoms or signs of lethal disease.

327

Peak age for occurrance of SIDS

2-4 mos.
90% of deaths before 6 mos.

328

What are typical findings at SIDS autopsy?

congested lungs
petechiae - pleura, thymus, epicardium
involution of thymus
evidence of URI, but insufficient to account for death
mild gliosis of brainstem and cerebellum
-cardio-respiratory control center
Alteration in serotonin activity in medulla

329

At what point does fetal immune gain function? At what point does it reach adult efficiency?

Cellular elements: monocytes / macrophages 4-5wk GA; T, B, and granulocytes 7-8wk GA
Function begins at about 12wk GA
Adult function at >1yr postnatal

330

4 routes of fetal infection

Transplacental - hematogenous, mom's bloodstream - viral (HIV, HepB, TORCH, listeria
Transcervical - cervical insufficiency
Fetal instrumentation - amniocentesis
Intrapartum

331

TORCH

Microbes pass from mother to fetus, transplacental.
-> hepatosplenomegaly, jaundice, thrombocytopenia, growth retardation

Toxoplasma, Other - syphilis, etc., Rubella, CMV, HSV2

332

What is erythema infectiosum?

Fifth disease - caused by parvovirus B19
-> abortion, stillbirth, hydrops, congenital anemia
Intracellular viral inclusions in infant bone marrow cells

333

What is chorioamnionitis and funisitis?

chorioamnionitis: inflammation of placental membranes
funisitis: inflammation of fetal umbilical cord

334

What is a pathogenic sequence?

Cascade of events secondary to single primary malformation or disruption

335

What is Potter sequence?

Oligohydraminos sequence
Due to oligohydraminos secondary to renal agenesis.

-> pulmonary hypoplasia
-> fetal compression -> altered facies, positioning defects of hands, feet, etc.; breech presentation

336

What are the most common causes of developmental abnormality / malformation ?

40-60% unknown
20-25% multifactorial
6-8% maternal disease (DM, endocrinopathy)
2-3% infection (TORCH etc)
10-15% karyotype
2-10% single gene mutation

337

4 most common chromosomal syndromes

1. Downs (21)
2. Kleinfelter's (XXY)
3. Turner (X0)
4. Patau (13)

338

What fetal malformations can CMV cause (CMV syndrome)?

Periventricular calcification
Mtard, Microcephaly, Deafness, Hepatosplenomegaly

339

What is the most dangerous time of fetal development for CMV infection?

2nd trimester

340

What is Rubella syndrome?

Triad: cataracts, congenital heart disease, deafness
Risk from before conception - 16wks, esp. first 8 wks

341

What period of development is most susceptible to terratogens?

Embryonic period: 3-9 weeks.

0-3 weeks: usually SAB
After 9 weeks: less susceptible. more susceptible to IUGR and injury to formed organs.

342

Cruetzfeldt-Jakob

Prion disease
Abnormal PrP (alpha changed to B sheet) -> rapidly deteriorating dementia (4-6 mos)

343

What are the underlying causes of Cretuzfeldt-Jakob?

1. spontaneous misfolding - most common -> sporadic cases
2. mutation of PRNP gene
3. direct infection

344

What is the the characteristic inflammatory response seen w/ viral infection?

Perivascular and interstitial lymphocytic infiltrate

345

What kind of virus is mumps virus?

paramyxovirus: enveloped, neg sense ssRNA

346

What is the incubation period for mumps?

2-3 weeks

347

What organs are affected by mumps?

Parotid glands : uni or bilateral - swelling (parotitis)
CNS: frequent, but usually no symptoms
orchitis: frequent - testicular atrophy, but no sterility
pancreatitis: uncommon. may -> hyperglycemia
oophoritis: uncommon

348

What kind of genome does herpesvirus have?

enveloped dsDNA

349

What is a Tzanck smear?

smear taken from the bottom of vessicle to test for herpesvirus (VZV)

Used for quick ID when clinically important. ex. woman in labor deciding to do C-section

350

Microscopic features of CMV

cytomegaly w/ large intranuclear basophilic inclusion surrounded by clear halo
smaller cytoplasmic inclusion

351

What are CMV symptoms? Who is at risk for life-threatening infection?

Usually asymptomatic in healthy adults. Otherwise mild, self-limiting mononucleosis type (fever, sore throat, lymphadenopathy, fatigue)

developing fetus and immunocompromized at risk for life threatening infection.

352

What is the most common TORCH pathogen?

CMV

353

How is fetal CMV acquired and what is the risk of infection?

Primary maternal infection can produce fetal infection
Risk of CNS abnormality
-periventricular calcification, sensorineural hearing loss, microcephaly, chorioretinitis
IUGR, hepatosplenomegaly, thrombocytopenia

354

Microscopic feature of Hep B infection?

Ground glass hepatocytes w/ high viral loads
-pink cytoplasm pushed to periphery due to high viral load

355

What constitutes HBV chronic carrier state?

Evidence of HBsAg +/- continuing liver disease for >6mos

-more common w/ HBV acquired early in life (esp. infancy) and immunocompromise

356

What kind of virus is HPV?

non-enveloped, ds circular DNA

357

How does HPV replicate?

basal epithelial cells - genome only
superficial mature keratinocytes - virus particle production

358

What are high-risk HPV strains?

16 and 18

359

What are koilocytes?

wrinkled raisinoid nuclei with perinuclear clearing
Hallmark of HPV

360

What is Verruca Vulgaris?

Common wart
caused by hpv

361

What is condyloma acuminatum?

Venereal wart (HPV)

362

What strains of HPV are most frequently associated with genital warts?

strains 6 and 11
low risk for cancer

363

Pathogenesis of HPV related cancers

infection w/ high-risk HPV -> integration of Viral DNA into genome -> viral E6 and E7 proteins -> inactivation of p53 and Rb, upregulation of telomerase -> increased replication + other factors (smoking, immune status)-> neoplasia

364

Major virulence factors of S.pneumo?

polysaccharide capsule and pneumolysin

365

What bacterial strain produces a double zone of hemolysis on blood agar?

C.perfringens

366

What are the major virulence factors of C.perfringens?

exotoxin, lecithinases (a-toxin), collagenase, hemolysin (B-hemolysis), hyaluronidase

367

What diseases does C.perfringens cause?

Food poisoning - undercooked meat - self limited 6-24 hours

Gas gangrene - usually post-surgical. inocculation into poorly oxygenated tussue

368

What is the microscopic hallmark of syphilis?

dense mononuclear inflammatory infiltrate with many plasma cells -> obliterative endarteritis

369

What is a gumma and what is it associated with?

destructive granulomatous lesion seen w/ tertiary syphilis.
Multiple tissues affected - skin, liver, bone

370

Lifecycle phases of Chlamydia trachomatis

Elementary body - infective
Reticulate body - replicative

371

Lymphogranuloma venereum

Chlamydia infectoin - more common in Africa and S. America. Starts as small painless genital ulcers and becomes painful inguinal lymphadenopathy

372

What is trachoma?

Occular infection caused by Chlamydia trachomatis
Scarring of conjunctiva and cornea -> blindness

Hygeine is a factor
Spread by flies that feed on human feces

373

Reiter syndrome

Reactive arthritis
may be seen in chlamydia infection - immune mediated
Polyarthritis, urethritis, conjunctivitis, often mucocutaneous lesions

374

Morphology of mycobacterium leprosae

gram pos, acid fast, rod-shaped, slow-growing bacillus

375

Hansen disease

Leprosy
Affects skin, peripheral nerves, URT, eyes.

376

What drugs are used to treat leprosy?

Dapsone, rifampin, clofazimine

377

Tuberculoid leprosy

Paucibacillary leprosy
Mildest infection - good cellular immune response
Granulomas form, walling off bacteria

378

What causes most disfigurement and loss of extremities in leprosy?

secondary infections
infection kills nerves, no pain w/ injury -> infection

379

What causes "valley fever"?

Coccioides immitis

380

Symptoms of coccidioides immitis infection

May be subclinical
Pulmonary symptoms, headache, arthralgia, skin manifestations
Similar to TB: cavitary progressive pulmonary and disseminated coccidioides

381

Fungus endemic to soil of Ohio, Missouri and Mississippi River valleys

Histoplasma capsulatum
especially prevalent in areas inhabited by bats and birds

382

What is a "coin lesion" on x-ray indicative of?

Histoplasma capsulatum - calcified granuloma. previous asymptomatic infection

383

What is a narrow based budding yeast w/ a prominent polysaccharide capusle?

Cryptococcus neoformans

384

What is aspergilloma?

"fungus ball"
localized collection of aspergillus growing in a previously existing cavitation
hemoptysis is common

385

2 zygomycetes

Mucor and Rhizopus sp

386

Who is particularly vulnerable to zygomycete infection?

immunosuppressed individuals w/ diabetes w/ ketoacidosis or neutropenia.

387

rhinocerebral disease

Infection of Zygomycetes (Mucor, Rhizopus)
Inhalation -> sinus infectoin -> orbital involvement -> necrotizing cellulitis, facial paralysis, CNS involvement

388

What is used to treat Giardia?

metronidazole

389

3 stages of Trypanosoma cruzi

1. epimastigote: replicative. found in insects
2. flagellate trypomastigote: infective
3. amastigote: replicative. found in mammals - intracellular. in cardiomyocytes and sm. muscle cells

390

What is Chagas disease?

caused by Trypanosoma cruzi (central and s. america, esp. brazil)
Results in myocarditis (trypanosomes w/in cardiomyocytes), GI involvement (megaespohagus and megacolon), nervous involvement (meningoencephalitis)

391

3 phases of Chagas disease

Caused by Trypanosoma cruzi

1. acute: often asymptomatic. localized swelling,
2. indeterminate phase: asymptomatic w/ few circulating parasites
3. chronic: occurs in 20-30% and occurs decades after infection

392

What is Lymphatic filariasis?

Elaphantiasis - caused by Wuchereria bancrofti (helminth) and to lesser extent Brugia sp.
Worms inhabit lymph nodes and vessels -> damage
Limb swelling and skin thickening

393

What is the physiological effect of nicotine?

Stimulates the release of catecholamines -> cardiovascular effect (increased BP, and pulse rate)

394

In what ways does tobacco smoking contribute to MI?

decreased O2 supply, increased O2 demand

395

What is the only known risk factor for pancreatic carcinoma

Smoking

396

3 paths of ETOH metabolism

Alcohol dehydrogenase in cytoplasm - main
Microsomal (CYP2E1) oxidation at high blood concentration
Catalase in peroxisomes

397

Where is acetaldehyde dehydrogenase found?

Mitochondria

398

3 ETOH related conditions that can -> upper GI bleed

peptic ulcer disease
gastritis
esophageal varices

399

Dry beri-beri is a result of what?

Thiamine deficiency
seen in chronic alcohol abuse

400

2 reasons that lead toxicity is more common in children than adults

increased intestinal absorption
less effective BBB

401

What effect does lead have in bone marrow and peripheral blood?

Inhibits d-aminolevulinic acid (ALA) dehydrogenase and ferrochelatase -> decreased iron incorporated in protoporphyrin -> increased level of protoporphyrin and decreased hemoglobin

Ringed sideroblasts in marrow

Microcytic hypochromic anemia w/ punctate basophilic stippling of erythrocytes

402

How does lead lead to reduced intelligence

Interference with Ca++ channels during nerve conduction

403

Saturine gout

Lead related gout
tubular injury with hyaline intranuclear lead inclusions -> decreased uric acid excretion

404

Acute As poisoning

Metallic taste, garlic odor, hypersalivation, vomiting, abd pain, bloody diarrhea, hemolytic anemia, hypovolemic shock, seizures, delerium, coma, death

405

Chronic low-level As poisoning

Pigmentation abnormalities (raindrop, Mees lines of nails), hyperkeratosis (palms and soles), sensorimotor peripheral neuropathy, CV, pulmonary, hepatic, renal, bone marrow disorders.

Malignancies (skin, lung, kidney, urinary bladder)

406

Main pathologic effect of Cd poisoning

Kidney dysfunction

glomerular damage and CKD

407

Vinyl chloride

Used in production of PVC
Hepatic angiosarcoma

408

2-Naphthylamine

Previously used in rubber and dye industries
Urothelial carcinoma

409

4 risks associated w/ estrogen replacement

1. thromboembolic events
2. breast carcinoma w/ continuous use (also increased breast density -> false pos. mammograms)
3. CV atherosclerotic disease (>60 yoa)
4. gallbladder disease

410

What is the most common cause of acute liver failure?

Acetaminophen toxicity
Toxic threshold is lowered by ETOH (induction of CYP2E1)
-> increase in NAPQ