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Y1 - Pathology > 10_Neoplasia II > Flashcards

10_Neoplasia II Flashcards

1
Q

neoplasm:

define

A
  • abnormal mass of tissue which exceeds and is uncoordinated w/ that of the normal tissues;
  • persists in the same excessive manner after the cessation of the stimuli which evoked the change
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2
Q

what are the 3 basic principles of neoplasia?

A
  1. New tissue growth
  2. Unregulated, irreversible, and monoclonal
  3. Differs from hyperplasia and tissue repair
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3
Q

what are the 6 different types of abnormal cell growth?

A
  1. atrophy
  2. hyperplasia
  3. dysplasia
  4. metaplasia
  5. hypertrophy
  6. hypertrophy AND hyperplasia
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4
Q

hypertrophy:

define

A
  • an increase in cell size; can be physiologic or pathologic
  • e.g.
    • Increase in skeletal muscle fiber size is a physiologic response to exercise, but
    • cardiac hypertrophy shown above is a pathologic response to abnormally elevated blood pressure.
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5
Q

hyperplasia:

define

A
  • an increase in the number of cells.
  • e.g.
    • Postpartum breast lobules undergo hyperplasia for lactation, but
    • endometrial hyperplasia in a postmenopausal woman is abnormal

The large fronds of endometrium seen in this uterus opened to reveal the endometrial cavity are a result of hyperplasia. This resulted from increased estrogen. With hyperplasia, there is an increase in cell numbers to produce an increase in tissue size. However, the cells are normal in appearance. Sometimes hyperplasias can be “atypical” and the cells not completely normal. Such conditions can be premalignant.

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6
Q

metaplasia:

define

A
  • an initial change from normal cells to a different cell type
  • e.g. (such as chronic irritation of cigarette smoke causing ciliated pseudostratified epithelium to be replaced by squamous epithelium more able to withstand the insult)
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7
Q

dysplasia:

define

A
  • an increasing degree of disordered growth or maturation of the tissue (often thought to precede neoplasia)
  • e.g.
    • such as cervical dysplasia as a result of human papillomavirus infection. Dysplasia is still a reversible process.
    • However, once the transformation to neoplasia has been made, the process is not reversible.
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8
Q

relationship of neoplasia, dysplasia, and metaplasia?

A

there is a natural history from metaplasia to dysplasia to neoplasia.

e.g.This is best evidenced in development of uterine cervix and respiratory tract neoplasms

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9
Q

neoplasia:

define, and examples

A
  • “New growth” ; Unregulated cell proliferation as a result of genetic changes.
  • ex:
    • In adenocarcinoma of the lung, autonomous growth of glandular cells occurs as a result of oncogene expression (KRAS) and loss of tumour suppressor genes (p53).
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10
Q

anaplasia:

define, and examples

A
  • “To form backward” ; Lack of cell differentiation; a hallmark of malignancy
  • e.g. In colorectal cancer, there is progressive dedifferentiation of colon epithelial cell. High grade anaplastic cells are hyperchromatic, pleomorphic, and disorganized.
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11
Q

what is the mechanism and cancer risk for:

hypertrophy

A
  • Mech: Increase in protein production in response to mechanical stress and growth factors
  • Cancer risk: negative
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12
Q

what is the mechanism and cancer risk for:

hyperplasia

A
  • mech: Growth factors stimulate cell proliferation from existing mature cells or stem cells.
  • cancer risk: +
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13
Q

what is the mechanism and cancer risk for:

metaplasia

A
  • mech:
    1. External stimuli triggers altered gene transcription,
    2. leading to differentiation of stem cells to a different cell type;
    3. not a conversion from one differentiated cell type to another.
  • cancer risk: ++
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14
Q

what is the mechanism and cancer risk:

dysplasia

A
  • mech: Dysregulation of cell maturation and growth as a result of altered gene expression or genetic mutations.
  • cancer risk: +++
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15
Q

what is the mechanism and cancer risk of:

anaplasia

A
  • mech: New theories suggest that anaplasia results from lack of differentiation of cancer stem cells instead of dedifferentiation of mature cells.
  • cancer risk: cancer formed
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16
Q

what is the mechanism and cancer risk of:

neoplasia

A
  • mech: Genetic and epigenetic changes
  • cancer risk: cancer formed
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17
Q

describe the neoplastic growth, and which layers are affected?

A
  • the basal cells penetrate through the squamous cells, and protrude out to the surface
18
Q

which biological mechanisms allow cancer to override normal control of tissue growth?

A
  • Unregulated cell cycle progression
  • Abnormal secretion of growth factors
  • Evasion of apoptosis
  • Unlimited cell division
19
Q

cell cycle:

define

A
  • a series of highly regulated steps that governs cell proliferation. There are 4 phases:
    • M phase
    • G1 phase
    • S phase
    • G2 phase
    • M
20
Q

M phase:

define

A

•(mitotic segregation): the cell undergoes mitosis and divides.

21
Q

G1 phase:

define

A
  • the first gap phase can be divided into an early and a late stage, which is separated by the restriction (R) point.
  • Cyclin and cyclin-dependent kinases (CDKs) control progression by phosphorylation of regulatory proteins.
    • An example is the RB (retinoblastoma tumour suppressor) protein. Unphosphorylated RB binds to and inhibits E2F, the activation of which will drive gene transcription and cause progression to the late stage of G1 and forward. CDK4 binds with cyclin D to phosphorylate RB, which allows progression through the R point.
22
Q

G1 phase:

checkpoints

A
  • Early G1 stage (mitogen-dependent): requires extrinsic growth factors (mitogens) which provide the stimulatory signal to proceed forward
  • G0 phase (quiescence): cells can exit the cell cycle to the G0 phase if no mitogens are present. The cells are typically smaller and have reduced metabolic activity.
  • R point: the “point of no return” where the cell is committed to progression to the next phase. Hyperphosphorylation of RB by CDK4/cyclin D is important in passing through the R point.
  • Late G1 stage (mitogen-independent): no longer requires mitogen signal to proceed.
  • G1/S checkpoint: controlled by CDK2, this important checkpoint requires no damage to the DNA structure before DNA replication proceeds. DNA damage may lead to DNA repair pathways or apoptosis.
23
Q

S phase:

define

A

•(synthesis): DNA replication occurs.

24
Q

G2 phase:

define

A

•the second gap phase allows replicated DNA to be checked before mitosis at the G2/M checkpoint.

25
Q

how can growth factors play into neoplasia and possivle malignant formation?

A
  • Neoplastic cells can alter growth factor signaling to increase proliferation.
  • Although it does not directly lead to malignant transformation, it can help increase the risk of mutation by reducing time for DNA repair during rapid progression of the cell cycle.
26
Q

describe the changes that neoplastic cells can make to growth factors:

  • autocrine stimulation
  • constitutive activation
  • overexpression
A
  • Autocrine stimulation: tumor cells may secrete growth factors to stimulate self-growth in an autocrine fashion
  • Constitutive activation: tumor cells may also harbor growth factor receptor mutations that make the receptor constitutively active; i.e., active without having a growth factor bound to it. This allows continuous stimulatory signal to proliferate.
  • Overexpression: more commonly, tumor cells may overexpress growth factor receptors, leading to increased signaling. For example, a type of epidermal growth factor (EGF) receptor, called HER2, is overexpressed in a special group of breast tumors (HER-positive). Trastuzumab (Herceptin) is a monoclonal antibody directed against the HER2 receptor that is used to treat HER2-positive breast cancers.
27
Q

which type of neoplasm grows faster?

(well-differentiated or less-differentiated)

A
  • the less differentiated a neoplasm, the faster it grows (more malignant).
    • The cell cycle of neoplastic cells is not shortened, rather the growth fraction of cells proliferating is increased. This is offset by neoplastic cell death.
28
Q

how is tumor growth expressed?

A
  • “doubling time” or the time to increase twice in volume (e.g., from 1 to 1.3 cm diameter).
    • this is exponential growth; you can calculate the constant experimentally –> to determine rate of growth of the tumor
  • An aggressive malignant neoplasm doubles in 1 to 3 months, while benign neoplasms double in years.
29
Q

how do host factors and blood supply affect tumor growth?

A
  • Some neoplastic growth is influenced by host factors. Estrogenic hormones aid growth of breast fibroadenomas or carcinomas and uterine leiomyomas because the tumor cells have hormone receptors.
  • Growth is also dependent upon the ability of the tumor to develop a blood supply. Factors secreted by neoplastic cells promote angiogenesis and fibroblast proliferation
30
Q

senescence:

theory, and what governs the process

A
  • theory: Healthy cells can only divide a limited number of times before becoming senescent
  • process: shortening of telomeres after each cycle of cell division.
    • Once the telomeres shorten to a certain threshold, DNA-repair mechanisms like p53 and pRB detect the abnormal telomere length and induce cell cycle arrest, thereby stopping further replication of this senescent cell.
31
Q

what happens to process of senescence if p53 is lost?

A
  • If p53 is lost, a special type of DNA “repair” occurs, called non-homologous end joining.
  • The ends of random chromosomes are joined together, forming a dicentric chromosome (with two centromeres).
  • Continuation of mitosis would lead to mitotic catastrophe with breakage of the chromosomes because of the pulling apart of aberrantly located centromeres.
  • This leads to cell death.
32
Q

what occurs to the process of senescence if a tumor cell has telomerase enzyme?

A
  1. In tumor cells, an enzyme called telomerase (typically only present in self-regenerating stem cells) –>
  2. allows lengthening of telomeres after each cell division.
  3. The tumor cell evades senescence
  4. can continue replicating despite accumulation of DNA damage.
33
Q

apoptosis vs. necrosis

A

differ by the pattern of cellular breakdown

  • apoptosis: regulated genetic process
  • necrosis: irreversible death of body tissue, from cellular injury (e.g. radiation, chemicals)
34
Q

apoptosis:

  • physiologic cause*
  • pathologic (cancer) cause (BCL2, p53)*
A
  • physiologically, apoptosis is induced when carcinogenesis causes an abnormal accumulation of DNA
  • pathologically, cell evades the protective mechanisms –> for neoplasia to form:
    • BCL2, an anti-apoptotic protein, is commonly upregulated in cancers to protect against apoptosis.
    • p53, a p_ro-apoptotic_ protein, is commonly downregulated in cancers to evade apoptosis, even in the face of irreparable DNA damage.
35
Q

which two steps of cellular transformation are potentially reversible, but are steps towards neoplasm?

A

Metaplasia and dysplasia are both reversible

  • Metaplasia: the exchange of normal epithelium for another type of epithelium. Metaplasia is reversible when the stimulus for it is taken away.
  • Dysplasia: a disordered growth and maturation of an epithelium, which is still reversible if the factors driving it are eliminated.
36
Q

when is cancer growth considered irreversible?

A

when it becomes invasive through the basement membrane

37
Q

when do symptoms of cancer start to arise?

what are the implications of this (re: prognosis)?

A
  • about 30 divisions occur –> then sxs arise (~230 cells)
  • **late detection –> poorer prognosis
38
Q

clonality:

define

genotypic vs. phenotypic

A
  • often defines the diseased state in hematology; clonal cells are genetically homogenous and derived from the same precursor; their detection is based on genotype or phenotype.
    • Genotypic clonality relies on somatic mutations to mark the clonal population.
    • Phenotypic clonality identifies the clonal population by the expression pattern of surrogate genes that track the clonal process.
      • (The most commonly used phenotypic clonality methods are based on the X-chromosome inactivation principle.
      • requires discrimination of the active from the inactive X chromosome and differentiation of each X chromosome’s parental origin. )
39
Q

how can clonality of B/T-cell neoplasms be determined?

A
  • by rearrangement of IHG/TCR
40
Q

why is clonality testing helpful?

A

Atypical B-cells represent clonal proliferation based on:

  • light chain phenotype
  • clonal rearrangements of the immunoglobulin heavy chain gene

Additional testing of bone marrow established the extent of the disease: identified lymphoid aggregate in BM is the same as in the lymph node

Y1 - Pathology (14 decks)

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