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Flashcards in CH3 - Principles of Neoplasia Deck (169):
1

Neoplasia is

new tissue growth that is unregulated, irreversible, and monoclonal

2

What features distinguish neoplasia from hyperplasia and repair?

unregulated, irreversible, and monoclonal

3

Monoclonal means

that the neoplastic cells are derived from a single mother cell

4

Clonality can be determined by?

glucose-6-phosphate dehydrogenase (G6PD) enzyme isoforms.

5

Multiple isoforms

G6PDA, G6PDb, and G6PDc exist; only one isoform is inherited from each parent.

6

lyonization

In females, one isoform is randomly inactivated in each cell by lyonization

7

G6PD is present on what chromosome

X

8

Normal ratio of active isoforms in cells of any tissue is

1:1 (e.g 50% of cells have G6PDa , and 50% ofcells have G6PDG)

9

In hyperplasia what happens to the ratio?

1:1 ratio is maintained in hyperplasia, which is polyclonal (cells are derived from multiple cells).

10

In neoplasia what can be said about the isoform?

Only one isoform is present in neoplasia, which is monoclonal

11

Clonality can also be determined by

androgen receptor isoforms, which are also present on the X chromosome.

12

Clonality of B lymphocytes is determined by

immunoglobulin (Ig) light chain phenotype.

13

Ig is comprised of

heavy and light chains.

14

Each B cell expresses

light chain that is either kappa or lambda.

15

Normal kappa to lambda light chain ratio is

3:01

16

Kappa to lambda ratio in hyperplasia

This ratio is maintained in hyperplasia, which is polyclonal

17

kappa to lambda ratio in lymphoma?

Ratio increases to > 6:1 or is inverted (kappa to lambda ratio = 1:3) in lymphoma, which is monoclonal

18

Neoplastic tumors are

benign or malignant

19

Benign tumors

remain localized and do not metastasize

20

Malignant tumors

(cancer) invade locally and have the potential to metastasize.

21

Tumor nomenclature is based on

lineage of differentiation (type of tissue produced) and whether the tumor is benign or malignant

22

What benign growths result from the epithelium?

Adenoma, papilloma

23

What malignant growths result from the epithelium?

Adenocarcinoma and papillary carcinoma

24

What benign growths result from the mesenchyme?

Lipoma

25

What malignant growths result from the mesenchyme?

Liposarcoma

26

What benign growths result from the lymphocyte?

Does not exist

27

What malignant growths result from the lymphocyte?

Lymphoma/Leukemia

28

What benign growths result from the melanocyte?

Nevus (mole)

29

What malignant growths result from the melanocyte?

Melanoma

30

What is the 2nd leading cause of death in both adults and children?

cancer

31

What are the leading causes of death in adults?

(1) cardiovascular disease (2) cancer (3) cerebrovascular disease

32

What are the leading causes of death in children?

(1) accidents (2) cancer (3) congenital defects

33

What are the most common cancers by incidence in adults?

(1) breast/prostate (2) lung (3) colorectal.

34

What are the most common causes of cancer mortality in adults?

(1) lung (2) breast/prostate (3) colorectal

35

Cancer begins as a

single mutated cell.

36

Approximately how many divisions occur before the earliest clinical symptoms arise?

30

37

Cancers that do not produce symptoms until late in disease

will have undergone additional divisions and, hence, additional mutations.

38

Cancers that are detected late

tend to have a poor prognosis.

39

Goal of screening is

to catch dysplasia (precancerous change) before it becomes carcinoma or carcinoma before clinical symptoms arise.

40

Common screening methods include

1. Pap smear 2. Mammography 3. PSA and DRE 4. Hemoccult test and colonoscopy

41

Pap smear

detects cervical dysplasia (CIN) before it becomes carcinoma

42

Mammography

detects in situ breast cancer (e.g DCIS) before it invades or invasive carcinoma before it becomes clinically palpable

43

PSA and DRE

Prostate specific antigen (PSA) and digital rectal exam detects prostate carcinoma before it spreads

44

Hemoccult test

for occult blood in stool

45

colonoscopy

detect colonic adenoma before it becomes colonic carcinoma or carcinoma before it spreads

46

Cancer formation is initiated by

damage to DNA of stem cells. The damage overcomes DNA repair mechanisms, but is not lethal.

47

Carcinogens are

agents that damage DNA, increasing the risk for cancer.

48

Important carcinogens include

chemicals, oncogenic viruses, and radical ions

49

DNA mutations eventually disrupt

key regulatory systems, allowing for tumor promotion (growth) and progression (spread)

50

Disrupted key regulatory systems include

proto-oncogenes, tumor suppressor genes, and regulators of apoptosis

51

Proto-oncogenes are essential to?

cell growth and differentiation;

52

mutations of proto-oncogenes form

oncogenes that lead to unregulated cellular growth.

53

Categories of oncogenes include

growth factors, growth factor receptors, signal transducers, nuclear regulators, and cell cycle regulators

54

Growth factors induce

cellular growth (e.g PDGFB in astrocytoma),

55

Growth factor receptors

mediate signals from growth factors (e.g. ERBB2 HER2/neu in breast cancer).

56

What do signal tranducers do?

Relay receptor activation to the nucleus (eg. ras)

57

Ras is associated with

growth factor receptors in an inactive GDP-bound state.

58

Aflatoxins

Hepatocellular carcinoma Derived from Aspergillus, which can contaminate stored grains

59

Alkylating agents

leukemia/lymphoma side effect of chemotherapy

60

Alcohol

Squamous cell carcinoma of oropharynx and upper esophagus, pancreatic carcinoma, and hepatocellular carcinoma

61

Arsenic

Squamous cell carcinoma of skin, lung cancer, and angiosarcoma of liver. Arsenic is present in cigarette smoke.

62

Asbestos

Lung carcinoma and mesothelioma. Exposure to asbestos is more likely to lead to lung cancer than mesothelioma.

63

Cigarette smoke

Carcinoma of oropharynx, esophagus, lung, kidney, and bladder. Most common carcinogen worldwide; polycyclic hydrocarbons are particularly carcinogenic.

64

Nitrosamines

Stomach carcinoma, Found in smoked foods, responsible for high rate of stomach carcinoma in japan

65

Naplithylamine

Urothelial carcinoma of bladder. Derived from cigarette smoke

66

Vinyl chloride

Angiosarcoma of liver, occupational exposure; used to make polyvinyl chlurkle (PVC) for use in pipes

67

Nickel, chromium, beryllium, or silica

Lung carcinoma Occupational exposure

68

Oncogenic viruses

EBV, HHV-8, HBV and HCV, HTLV-1, High-risk HPV

69

EBV

Nasopharyngeal carcinoma, Burkitt lymphoma and CNS lymphoma in AIDS

70

HHV-8

Kaposi sarcoma

71

HBV and HCV

Hepatocellular carcinoma

72

HTLV-1

Adult T-cell leukemia/lymphoma

73

High-risk HPV (e.g. subtypes 16, 18, 31, 33)

Squamous cell carcinoma of vulva, vagina, anus, and cervix; adenocarcinoma of cervix

74

Ionizing radiation

(nuclear reactor accidents and radiotherapy) AML, CML and papillary carcinoma of the thyroid. Generates hydroxyl free radicals.

75

Non Ionizing (UVB sunlight is most common source)

Basal cell carcinoma, squamous cell carcinoma, and melanoma of skin

76

Non Ionizing radiation results in?

formation of pyrimidine dimers in DNA, which are normally excised by restriction endonuclease

77

Ras Receptor binding causes

GDP to be replaced with GTP, activating ras.

78

What does activated ras do?

sends growth signals to the nucleus

79

How is Ras deactivated?

inactivates itself by cleaving GTP to GDP; this is augmented by GTPase activating protein

80

Mutated ras

inhibits the activity of GTPase activating protein. This prolongs the activated state of ras, resulting in increased growth signals.

81

Cell cycle regulators mediate what?

progression through the cell cycle (e.g. cyclin and cyclin-dependent kinase).

82

Cyclins and cyclin-dependent kinases (CDKs) do what?

form a complex which phosphorylates proteins that drive the cell through the cell cycle.

83

The cyclin D / CDK4 complex does what?

phosphorylates the retinoblastoma protein, which promotes progression through the G-S checkpoint

84

What do tumor supressor genes do?

Regulate cell growth decreasing (suppress) the risk of tumor formation;

85

What are some classic examples of tumor supressor genes?

p53 and Rb (retinoblastoma)

86

What does p53 regulate?

progression of the cell cycle from G to S phase

87

In response to DNA damage, what does p53 do?

slows the cell cycle and upregulales DNA repair enzymes.

88

PDGFB

Platelet-derived growth factor, overexpression, autocrine loop, astrocytoma

89

FRBB2 [HER2f neu]

Epidermal growth factor receptor, Amplification mechanism, Subset of breast carcinomas

90

RET

Neural growth factor receptor, Point mutation MEN 2A, MEN 2B and sporadic medullary carcinoma of thyroid

91

KIT

Stem cell growth factor receptor, Point mutation, Gastrointestinal stromal tumor

92

RAS gene family

GTP-binding protein, Point mutation, Carcinomas, melanoma, and lymphoma

93

ABL

Tyrosine kinase T(9;22) with BCR CML and some types of ALL

94

What are the nuclear regulators?

C-MYC, N-MYC, L-MYC

95

c-MYC

Transcription factor, t(8;I4) involving IgH, Burkitt lymphoma

96

N-MYC

Transcription factor, Amplification, Neuroblastoma

97

L-MYC

Transcription factor, Amplification, Lung carcinoma (small cell)

98

CCND1 (cyclin D1)

Cyclin t(8;14) involving IgH, Mantle cell lymphoma

99

If DNA repair is not possible, what does p53 do?

induces apoptosis.

100

How does p53 induce apoptosis?

upregulates BAX, which disrupts Bcl2 leading to cytochrome c leaks from the mitochondria activating apoptosis

101

Knudson two-hit hypothesis

both copies of the p53 gene must be knocked out for tumor formation, Both copies of Rb gene must be knocked out for tumor formation

102

Loss of p53 is seen in what percentage of cancers?

>50% of cancers.

103

p53 Germline mutation results in

Li-Fraumeni syndrome (2nd hit is somatic),

104

Li-Fraumeni syndrome is characterized by?

the propensity to develop multiple types of carcinomas and sarcomas,

105

Rb

regulates progression from G0 to S phase.

106

How does Rb regulate the progression to S phase?

holds the E2F transcription factor, which is necessary for transition to the S phase

107

E2F is released when?

RB is phosphorylated by the cyclinD/cyclin-dependent kinase 4 (CDK4) complex

108

Rb mutation results in

constitutively free E2F, allowing progression through the cell cycle and uncontrolled growth of cells.

109

Sporadic mutation

(both hits are somatic) and it is characterized by unilateral retinoblastoma

110

Rb Germline mutation results in

familial retinoblastoma (2nd hit is somatic) and is characterized by bilateral retinoblastoma and osteosarcoma.

111

What is the function of regulators of apoptosis?

Prevent apoptosis in normal cells, but promote apoptosis in mutated cells whose DNA cannot be repaired (e.g Bcl2)

112

Bcl2

normally stabilizes the mitochondrial membrane, blocking release of cytochrome c

113

Disruption of Bcl2 allows what to happen?

Cytochrome c to leave the mitochondria and activate apoptosis

114

Bcl2 in follicular lymphoma?

it is overexpressed in follicular lymphoma,

115

Why is Bcl2 overexpressed in follicular lymphoma?

t(14;18) moves Bcl2 (chromosome 18) to the Ig heavy chain locus (chromosome 14), resulting in increased Bcl2.

116

How is apoptosis inhibited in follicular lymphoma?

Mitochondrial membrane is further stabilized by overexpressed Bcl2, prohibiting apoptosis.

117

In follicular lymphoma, how does the inhibition of apoptosis lead to lymphoma?

B cells that would normally undergo apoptosis during somatic hypermutation in the lymph node germinal center accumulate, leading to lymphoma.

118

What is necessary for cell immortality?

Telomerase

119

Normally telomeres do what?

shorten with serial cell divisions, eventually resulting in cellular senescence

120

What is the relationship between cancers and telomerase?

cancers often have up regulated telomerase, which preserves telomeres

121

Angiogenesis and tumors

(production of new blood vessels) is necessary for tumor survival and growth.

122

FGF and VEGF

(angiogenic factors) are commonly produced by tumor cells.

123

Tumor survival and the immune system?

Avoiding immune surveillance is necessary for tumor survival

124

Immune surveillance and tumor survival?

Mutations often result in production of abnormal proteins, which are expressed on MHC class 1, CD8+ T cells detect and destroy such mutated cells, Tumor cells can evade immune surveillance by downregulating expression of MHC class 1.

125

How do tumor cells evade immune surveillance?

by downregulating MHC class 1

126

Immunodeficiency and cancer

(both primary and secondary) increases risk for cancer

127

Accumulation of mutations eventually result in what?

tumor invasion and spread

128

Epithelial tumor cells are normally attached to one another by what?

cellular adhesion molecules (e.g., E-cadherin).

129

Downregulalion of E-cadherin leads to what?

dissociation of attached cells

130

How do the tumor cells spread locally?

Cells attach to laminin and destroy basement membrane (collagen type IV) via collagenase. Cells attach to fibronectin in the extracellular matrix and spread locally

131

Metastasis of tumor cells.

Entrance into vascular or lymphatic spaces allows for metastasis (distant spread)

132

What are the routes of metastasis?

Lymphatic, hematogenous, seeding of body cavities

133

Lymphatic spread is characteristic of what?

carcinomas

134

Where does the initial lymphatic spread occur?

In the regional draining lymph nodes

135

Hematogenous spread is characteristic of what?

sarcomas and some carcinomas

136

What are some examples of hematogenous spread?

renal cell carcinoma, hepatocellular carcinoma, follicular carcimoma of the thyroid, choriocarcinoma

137

Seeding of body cavities is characteristic of?

ovarian carcinoma, often involves the peritoneum 'omental caking'

138

What is omental caking?

where the peritoneum is often involved in ovarian carcinoma

139

Describe benign tumors.

tend to be slow growing, well circumscribed, distinct, and mobile

140

Malignant tumors are usually

rapid growing, poorly circumscribed, infiltrative, and fixed to surrounding tissues and local structures.

141

What is generally required before a tumor can be classified as benign or malignant with certainty?

Biopsy or excision

142

Why is biopsy necessary?

Some benign tumors can grow in a malignant-like fashion, and some malignant tumors can grow in a benign-like fashion.

143

Benign tumors are usually

well differentiated

144

What are some characteristics of benign tumors?

1. Organized growth 2. Uniform nuclei 3. Low nuclear to cytoplasmic ratio 4. Minimal mitotic activity 5. Lack of invasion (of basement membrane or local tissue) 6. No metastatic potential

145

Malignant tumors are classically

poorly differentiated (anaplastic)

146

Characteristics of malignant tumors include

1. Disorganized growth (loss of polarity) 2. Nuclear pleomorphism and hyperchromasia 3. High nuclear to cytoplasmic ratio 4. High mitotic activity with atypical mitosis 5. Invasion (through basement membrane or into local tissue)

147

What is the hallmark of malignancy?

Metastatic potential - benign tumors never metastasize

148

What is the target cell type for the immunohistochemical stain of Keratin?

Epithelium

149

What is the target cell type for the immunohistochemical stain of Vimentin

Mesenchyme

150

What is the target cell type for the immunohistochemical stain of desmin

Muscle

151

What is the target cell type for the immunohistochemical stain of Neurofilament

Neurons

152

What is the target cell type for the immunohistochemical stain of PSA

Prostatic epil helium

153

What is the target cell type for the immunohistochemical stain of ER

Breast epithelium

154

What is the target cell type for the immunohistochemical stain of Thyroglobulin

thyroid follicular cells

155

What is the target cell type for the immunohistochemical stain of chromogranin?

neuroendocrine cells (small cell carcinoma of lung and carcinoid tumors)

156

What is the target cell type for the immunohistochemical stain of S-100?

Melanoma

157

What is used to characterize tumors that are difficult to classify on histology?

Immunohistochemistry

158

What are serum tumor markers?

Proteins released by tumor into serum (e.g PSA)

159

Serum tumor markers are useful for what?

screening, monitoring response to treatment, and monitoring recurrence

160

Elevated levels of serum tissue markers require what?

it requires tissue biopsy for diagnosis of carcinoma (e.g., biopsy of prostate with elevated PSA),

161

What is involved in the grading of cancer?

Microscopic assessment of differentiation (how much a cancer resembles the tissue in which it grows); takes into account architectural and nuclear features

162

What is low grade?

Well differentiated?resembles normal parent tissue

163

What is high grade?

poorly differentiated?does not resemble parent tissue

164

Cancer grading is important for what?

determining prognosis; well-differentiated cancers have better prognosis than poorly-differentiated cancers.

165

What is staging of cancer?

its an assessment of size and spread of a cancer,

166

How does the staging of cancer compare to the grading of cancer?

Key prognostic factor; more important than grading

167

When is the staging of cancer determined?

after final surgical resection of the tumor

168

What is the TNM staging system?

T?tumor (size and/or depth of invasion), N?spread to regional lymph nodes; second most important prognostic factor, M?metastasis; single most important prognostic factor

169

In the TNM staging system what is the most important prognostic factor?

Metastasis