Path: Neoplasia 1 & 2 Flashcards Preview

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Flashcards in Path: Neoplasia 1 & 2 Deck (78):
1

What is a neoplasia?

Automomous, irreversible, clonal, benign or malignant cell proliferation outside of normal control by growth factors, contact inhibition, etc.

2

Define a malignant neoplasm.

One that invades and/or metastasizes. Commonly with destruction of surrounding tissue.

3

List the 5 systematic descriptors of a gross pathological lesion.

1) size
2) shape
3) color
4) consistency (cannot be assessed in a picture)
5) relationships

4

Describe the growth of a benign tumor.

Cohesive, expansile, local growth. Commonly with fibrous capsule.

5

If you see a tumor that is round, with visible margins, is it likely benign or malignant?

Benign

6

If you see a tumor that displays infiltrative, invasive local growth, invading surrounding tissue, making it difficult to see the margins of the tumor, is this likely a benign or malignant tumor?

Malignant.

7

What is a carcinoma?

Malignant neoplasm of epithelial cells

8

What is a sarcoma?

Malignant neoplasm of mesenchyme-derived tissue.

9

What is an adenoma?

Benign epithelial neoplasm forming glands or derived from glands.

10

What is an adenocarcinoma?

Malignant epithelial neoplasm forming glands or derived from glands.

11

What is desmoplasia?

From Nichols:
Formation of abundant fibrous stroma by some carcinomas (reactive)
From Wiki:
The growth of fibrous or connective tissue. It is also called desmoplastic reaction to emphasize that it is secondary to an insult. Desmoplasia may occur around a neoplasm, causing dense fibrosis around the tumor, or scar tissue (adhesions) within the abdomen after abdominal surgery.

Desmoplasia is usually only associated with malignant neoplasms, which can evoke a fibrosis response by invading healthy tissue.

12

What is a hamartoma?

A mass of mature but disorganized tissue indigenous to its site (developmental anomaly)

13

What is a choristoma?

It is an ectopic rest, aka a mass of normal tissue present outside its normal site. (developmental anomaly)

14

What is a teratoma aka mixed germ cell tumor?

Benign or malignant neoplasm with components of more than one germ cell layer, usually all three (ectoderm, mesoderm, endoderm)

15

What is a polyp?

A macroscopic projection above a mucosal surface. A bump or a nodule on a stalk.
Pedunculated = on a stalk
Sessile= flat, like a plateau

16

What is anaplasia?

The lack of visible differentiation of malignant tumor cells giving them the appearance of primitive unspecialized cells.

17

What are some features of anaplastic cells?

Larger than differentiated cells.
Higher nuclear/cytoplasmic ratio (bigger nucleus, less cytoplasm)
Pleomorphic (varying in size/shape)
Nuclear abnormalities (angulated shape, hyperchromatism, clumped chromatin, mitoses, nucleoli)

18

Describe the 2 forms of dysplasia.

1) congenital embryonically abnormal organization of cells
2) acquired cellular atypia, usually premalignant, +/- reversible

19

What is carcinoma in situ?

Tissue with all the cytologic (individual cell) features of malignancy without the visible invasion

20

Describe a carcinoma microscopically.

Cells throughout with basal layer features and loss of the orderly progression to flattened cells on the surface.

21

Benign and malignant tumors can be distinguished from one another based on these 3 things:

degree of differentiation
rate of growth
local invasiveness
distant spread

22

Are benign or malignant tumors more differentiated?

benign. Malignant tumors are less well differentiated or completely undifferentiated (anaplastic)

23

Are benign or malignant tumors more likely to have acquired unexpected functions due to derangements in differentiation?

malignant

24

Which grow faster, benign or malignant tumors?

Malignant

25

A fibrous capsule is more characteristic of a benign or malignant tumor?

Benign

26

(Benign or malignant ?) tumors grow autonomously, but tend to grow slowly, gradually compressing surrounding tissue, causing pressure atrophy and slowly progressive necrosis with fibrous tissue replacement creating a capsule.

Benign

27

(Benign or malignant) tumors tend to form spheres given monoclonal cell proliferation in soft yielding tissue, creating a spherical mass.

Benign

28

Why don't malignant tumors grow all round-like?

Subclones of a malignant tumor are more likely to have additional mutations making them grow faster, disrupting the spherical growth pattern.
Subclones can also invade surrounding tissue.
Parts of a rapidly growing malignant tumor can outgrow their blood supply, undergo necrosis and shrink, disrupting spherical growth.

29

What is the pathway that appears to be the most frequently mutated oncogenic pathway in human neoplasms?

The receptor tyrosine kinase pathway

30

Which tumor type is most associated with the BCR-ABL fusion gene abnormality?

Chronic myelogenous leukemia

31

Which tumor type is most associated with the EML4-ALK fusion gene abnormality?

Lung primary adenocarcinoma

32

Which tumor type is most associated with the Fli-EWS fusion gene abnormality?

Ewing Sarcoma

33

Which tumor type is most associated with the overexpression of the BCL2 gene?

Follicular lymphoma

34

Which tumor type is most associated with the overexpression of HMGA2 gene?

Parotid pleomorphic adenoma

35

Which tumor type is most associated with overexpression of MYC gene?

Burkitt lymphoma

36

Which tumor type is most associated with the TMPRSS-ETS fusion gene abnormality?

Prostate adenocarcinoma

37

What is oncogene addiction?

Where tumor cells are highly dependent on the activity of one or more oncogenes.

38

How can chemotherapy capitalize on oncogene addiction in treating cancer?

It can inhibit the signalling through a gene-oncogene pathway (of variable kinases), thus inhibiting their proliferation and survival.

39

Why does treatment of oncogene addiction with inhibitors of their signalling pathways NOT lead to a cure?

Even though the proliferating component of the tumor is suppressed by gene-oncogene inhibitors and the pt seems completely well, rare "stem cells" harboring the gene-oncogene fusion gene persist, apparently because these cells do not require the gene-oncogene signals for their survival. As a result, the inhibition therapy must be continued indefinitely.

40

What is the targeted therapy for chronic myelogenous leukemia and how does it work?

Imatinib (tyrosine kinase inhibitor)- inhibits BCR-ABL signaling

41

What is the targeted therapy for lung primary adenocarcinoma and how does it work?

Crizotinib- inhibits EML4-ALK fusion gene signaling (only present in <4% of lung cancers)

42

What is the targeted therapy for chronic myelogenous leukemia and how does it work?

Imatinib (tyrosine kinase inhibitor)- inhibits BCR-ABL signaling

43

What is the targeted therapy for lung primary adenocarcinoma and how does it work?

Crizotinib- inhibits EML4-ALK fusion gene signaling (only present in <4% of lung cancers)

44

Most, possibly all, cancers have molecular defects that affect these 3 pathways of cellular signaling:

1) signal transducer RAS- operates immediately downstream of RTK
2) Mitogen-activated protein kinase (MAPK) pathway- one of two signaling "arms" downstream of RAS
3) Phosphoinositidyl-3-kinase (PI3K)/AKT pathway- the other of the two signaling "arms" downstream of RAS

45

T/F: some cancer cells acquire the ability to synthesize the growth factors to which they are responsive, creating an autocrine loop.

True

46

Receptor tyrosine kinases can be constituatively activated in tumors by multiple mechanisms, including:

point mutations, gene rearrangements, and gene amplifications

47

What is the targeted therapy for chronic myelogenous leukemia and how does it work?

Imatinib (tyrosine kinase inhibitor)- inhibits BCR-ABL signaling

48

What is the targeted therapy for lung primary adenocarcinoma and how does it work?

Crizotinib- inhibits EML4-ALK fusion gene signaling (only present in <4% of lung cancers)

49

Most, possibly all, cancers have molecular defects that affect these 3 pathways of cellular signaling:

1) signal transducer RAS- operates immediately downstream of RTK
2) Mitogen-activated protein kinase (MAPK) pathway- one of two signaling "arms" downstream of RAS
3) Phosphoinositidyl-3-kinase (PI3K)/AKT pathway- the other of the two signaling "arms" downstream of RAS

50

T/F: some cancer cells acquire the ability to synthesize the growth factors to which they are responsive, creating an autocrine loop.

True

51

Receptor tyrosine kinases can be constituatively activated in tumors by multiple mechanisms, including:

point mutations, gene rearrangements, and gene amplifications

52

Mutations in ______, a member of the RAF family, have been detected in close to 100% of hairy cell leukemias, more than 60% of melanomas, 80% of benign nevi, and a smaller percentage of a wide variety of other neoplasms, including colon carcinomas and dendritic cell tumors.

BRAF

53

Using tyrosine kinase inhibitors to block HER2 activity not only cause the cessation of tumor growth but also induce ________ and ________ _______, reflecting the ability of receptor tyrosine kinase signaling to augment cell survival as well as proliferation.

apoptosis; tumor regression

54

How can cancers being treated for mutations with one gene-oncogene relationship side-step the treatment and continue to proliferate?

By acquiring other mutations in other gene-oncogenes.

55

Point mutations of _____ family genes constitute the most common type of abnormality involving proto-oncogenes in human tumors.

RAS family (signal transducers)

56

List the 3 RAS genes.

HRAS, KRAS, NRAS

57

Which 4 types of tumor contain the highest rate of RAS gene mutation?

pancreatic adenocarcinomas (90%)
colon cancer (50%)
endometrial cancer (50%)
thyroid cancer (50%)

58

T/F: activated RAS can completely substitute for tyrosine kinase activity, driving malignant cell proliferation just as effectively, maybe even more than receptor tyrosine kinase activity.

True

59

Describe 2 mechanisms by which targeted therapy fails when mutations are placed upstream or downstream of the site of action.

1) Downstream mutations in signaling pathways to cell proliferation ruin the effectiveness of treatment targeted to upstream mutations earlier in the pathway.
2) Upstream alternative pathways in signaling cell proliferation ruin the effectiveness of treatment targeted to downstream mutations later in the pathway.

60

Because of its protean effects of metabolism, MYC can be considered a master _________ regulator of cell growth.

transcriptional

61

What happens if you have an activating mutation of BRAF?

Like activating RAS mutations, activating BRAF mutations stimulate each of these downstream kinases and ultimately activate transcription factors.

62

All signal transduction pathways converge on the _______, where deregulated mitotic signaling pathways cause inappropriate and continuous stimulation of nuclear transcription factors driving growth-promoting genes.

nucleus

63

Of the genes encoding transcription factors involved in human tumors, which is most commonly involved?

MYC

64

Describe the 4 ways MYC can be deregulated in cancer.

1) genetic alterations to MYC itself
2) translocations in Burkitt lymphoma and other B and T cell tumors
3) amplifications in neuroblastomas, small cell cancers of lung, some breast, colon, and many other carcinomas.
4) oncogenic mutations in upstream signaling pathways, elevating MYC protein levels by increasing MYC transcription, enhancing MYC mRNA translation, and/or stabilizing MYC protein:
a) constitutive RAS/MAPK signaling
b) Notch signaling
c) Wnt signaling
d) Hedgehog signaling

65

Virtually all pathways that regulate growth impinge on _______, and under normal circumstances, _____ protein concentrations are tightly controlled at the level of transcription, translation, and protein stability.

MYC; MYC

66

Describe how mutations can alter MYC expression, leading to cancer.

Several SNPs that are strongly linked to an elevated risk of cancers, fall within a large region devoid of recognizable genes that lies next to MYC, suggesting that these genetic variants alter the function of enhancer elements that regulate MYC expression.

67

Why is MYC so important, anyway?

MYC activates the expression of many genes that are involved in cell growth. Like D cycins (cell cycle progression)
MYC also upregulates the expression of rRNA genes and rRNA processing, thereby enhancing the assembly of ribosomes needed for protein synthesis.
MYC upregulates a program of gene expression that leads to metabolic reprogramming and the Warburg effect.

68

The fastest growing human tumors virtually always have a chromosomal translocation involving ______ and have the highest levels of this same protein.

MYC

69

In some contexts, MYC upregulates the expression of ________, on of several factors enabling endless replicative capacity of cancer cells.

telomerase

70

Which Cyclin:CDK pair bears the most important gain-of-function mutation resulting in uncontrolled cell growth and proliferation?

Cyclin D:CDK4

71

What is the protein present at the G1-S "checkpoint" that must be phosphorylated? Who is responsible for phosphorylating it?

Rb protein; Cyclin D:CDK4, Cyclin D:CDK6, Cyclin E:CDK2

72

What is the other protein active at the G1-S checkpoint?

p53 (tumor suppressor gene)

73

Which of the two checkpoints (G1-S and G2-M) is more important in cancer?

G1-S

74

What are cyclins? Why are they called "cyclins"?

Nuclear proteins that regulate the cell cycle. Called so because they are cyclically produced and degraded. Not present at constant concentrations.

75

Whut are CDKs?

Cyclin dependent kinases

76

Which Cyclin:CDK pair bears the most important gain-of-function mutation resulting in uncontrolled cell growth and proliferation?

Cyclin D:CDK4

77

The two most important tumor suppressor genes, _____ and ______ encode proteins that inhibit G1/S progression.

RB and P53

78

What is the targeted therapy for BRAF mutant kinase? What cancer type is it effective in treating?

Vemurafenib; melanoma