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Pathoma > Principles of Neoplasia > Flashcards

Principles of Neoplasia Flashcards

1
Q

Basic principles of neoplasia

A

Neoplasia: new tissue growth that is unregulated, irreversible, and monoclonal –> these features distinguish it from hyperplasia and repair

  • monoclonal = neoplastic cells are derived from a single mother cell
  • clonality was historically determined by G6PD enzyme isoforms –> only 1 isoform is present in neoplasia, which is monoclonal
  • clonality of B lymphocytes is determined by Ig light chain phenotype
  • -> normal kapp to lambda light chain ration is 3:1 - this ratio is maintained in hyperplasia which is polyclonal but increases to >6:1 or is inverted (1:3) in lymphoma, which is monoclonal
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2
Q

Tumor nomenclature

A

Epithlium

  • benign = adenoma/papilloma
  • malignant = adenocarcinoma/papillocarcinoma

Mesenchyme

  • benign = lipoma
  • malignant = liposarcoma

Lymphocyte = lymphoma/leukemia

Melanocyte

  • benign = nevus/mole
  • malignant = melanoma
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3
Q

Cancer epidemiology

A

Cancer is the second leading cause of death in both adults and children

  • leading causes of death in adults = 1) cardiovascular disease 2) cancer 3) chronic respiratory disease
  • leading causes of death in children = 1) accidents 2) cancer 3) congenital defects

Most common cancers by incidence in adults:

1) breast/prostrate
2) lung
3) colorectal

Most common causes of cancer mortality in adults:

1) lung
2) breast/prostate
3) colorectal

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4
Q

Role of screening

A
  • cancer begins as a single mutated cell - approximately 30 divisions occur before the earliest clinical symptoms arise
  • each division/doubling time results in increased mutations
  • cancers that do not produce symptoms until late in disease will have undergone additional divisions and mutations
  • cancers that are detected late have a poor prognosis
  • goal of screening is to catch dysplasia before it becomes carcinoma, or carcinoma before clinical symptoms arise
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5
Q

Basic principles of carcinogenesis

A
  • cancer formation is initiated by damage to DNA of stem cells - the damage overcomes DNA repair mechanisms but is not lethal
  • carcinogens are agents that damage DNA, increasing the risk for cancer
  • DNA mutations eventually disrupt key regulatory systems, allowing for tumor promotion (growth) and progression (spread)
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6
Q

Aflatoxins

A

Hepatocellular carcinoma

- derived from aspergillus, which can contaminate stored rice and grains

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7
Q

Alkylating agents

A

Leukemia/lymphoma

- side effect of chemotherapy

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8
Q

Alcohol

A

Squamous cell carcinoma of oropharynx and upper esophagus + hepatocellular carcinoma

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9
Q

Arsenic

A

Squamous cell carcinoma of skin, lung cancer + angiosarcoma of liver
- present in cigarette smoke

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10
Q

Asbestos

A

Lung carcinoma + mesothelioma

- exposure to asbestos is more likely to lead to lung cancer than mesothelioma

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11
Q

Cigarette smoke

A

Carcinoma of oropharynx, esophagus, lung, kidney, bladder + pancreas

  • most common carcinogen worldwide
  • polycyclic hydrocarbons are particularly carcinogenic
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12
Q

Nitrosamines

A

Stomach carcinoma

  • found in smoked foods
  • responsible for high rate of stomach carcinoma in Japan
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13
Q

Naphthylamine

A

Urothelial carcinoma of bladder

- derived from cigarette smoke

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14
Q

Vinyl chloride

A

Angiosarcoma of liver

  • occupational exposure
  • usesd to make polyvinyl chloride for use in pipes
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15
Q

Nickel, chromium, beryllium, or silica

A

Lung carcinoma

- occupational exposure

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16
Q

EBV

A
  • nasopharyngeal carcinoma
  • burkitt lymphoma
  • CNS lymphoma in AIDS
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17
Q

HHV-8

A

Kaposi sarcoma

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18
Q

HBV + HCV

A

Hepatocellular carcinoma

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19
Q

HTLV-1

A

Adults T-cell leukemia/lymphoma

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20
Q

HPV

A

Squamous cell carcinoma of vulva, vagina, anus and cervix

Adenocarcinoma of the cervix

21
Q

Ionizing radiation

A

Generates hydroxyl free radicals

  • AML
  • CML
  • papillary carcinoma of the thyroid
22
Q

Non-ionizing radiation (UVB sunlight)

A

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

  • basal cell carcinoma
  • squamous cell carcinoma
  • melanoma of skin
23
Q

Oncogenes

A

Proto-oncogenes are essential for cell growth and differentiation; mutations form oncogenes that lead to unregulated cellular growth
Categories of oncogenes:
- growth factors - induce cell growth
- growth factor receptors - mediate signals from growth factors
- signal transducers - relay receptor activation to the nucleus
- nuclear regulators
- cell cycle regulators - mediate progression through the cell cycle
–> ex: cyclin + cyclin dependant kinases = form a complex which phosphorylates proteins that drive the cell through the cell cycle
–> cyclinD/CDK4 complex phosphorylates the rb protein, which promotes progression through the G1/S checkpoint

24
Q

Ras

A
  • ras is associated with growth factor receptors in an inactive GDP-bound state
  • receptor binding causes GDP to be replaced with GTP –> activates ras
  • activated ras sends growth signals to the nucleus
  • ras inactivates itself by cleaving GTP to GDP –> augmented by GTPase activating protein (GAP)
  • mutated ras inhibits the activity of GAP –> prolongs the activated state of ras = increased growth signals
25
Q

p53

A

Regulates the progression of the cell cycle from G1 - S phase

  • in response to DNA damage, p53 slows the cell cycle and upregulates DNA repair enzymes
  • If DNA repair is not possible, p53 induces apoptosis –> upregulates BAX = disrupts bcl2 –> causes cyt c to leak from the mitochondria = activates apoptosis

Both copies of p53 gene must be knocked out for tumor formation = knudson two-hit hypothesis

  • loss is seen in >50% of cancers
  • germline mutation results in Li-Fraumeni syndrome –> characterized by propensity to develop multiple types of carcinomas and sarcomas
26
Q

Rb

A

Regulates progression from G1 - S phase

  • Rb holds the E2F transcription factor, which is necessary for transition to the S phase
  • E2F is released when Rb is phosphorylated by the cyclinD/CDK4 complex
  • Rb mutation results in constitutively free E2F –> allows progression through cell cycle and uncontrolled cell growth

Both copies of Rb gene must be knocked out for tumor formation

  • sporadic mutation when both hits are somatic is characterized by unilateral retinoblastoma
  • germline mutation results in familial retinoblastoma where second his is somatic –> characterized by bilateral retinoblastoma and osteosarcoma
27
Q

Regulators of apoptosis

A

Prevent apoptosis in normal cells, but promote apoptosis in mutated cells whose DNA cannot be repaired - eg. Bcl2

  • Bcl2 normally stabilizes the mitochondrial membrane, blocking release of cyt c
  • disruption of Bcl2 allows cyt c to leave the mitochondria and activate apoptosis

Bcl2 is overexpressed in follicular lymphoma

  • 14:18 translocation moves Bcl2 from chromosome 18 to the Ig heavy chain locus on chromosome 14 = increased Bcl2 expression –> mitochondrial membrane is further stabilized, prohibiting apoptosis
  • B cells that would normally undergo apoptosis during somatic hypermutation in the lymph node germinal center accumulate –> lymphoma
28
Q

Other important features of tumor development

A

Telomerase is necessary for cell immortality

  • normally telomeres shorted with serial cell divisions –> eventually results in cellular senescence
  • cancers often have upregulated telomerase –> preserves telomeres

Angiogenesis is necessary for tumor survival and growth
- GFG and VEGF = angiogenic factors –> commonly produced by tumor cells

Avoiding immune surveillance is necessary for tumor survival

  • mutations often result in production of abnormal proteins –> expressed on MHC I
  • cd8 t cells detect and destroy such mutated cells
  • tumor cells can evade immune surveillance by downregulating expression of MHC I
  • immudeficiency increases risk for cancer
29
Q

Tumor invasion and spread

A

Accumulation of mutations eventually results in tumor invasion and spread

  • epithelial tuomr cells are normally attached to one another by cellular adhesion molecules = E cadherin
  • downregulation of E- cadherin leads to dissociation of attached cells
  • cells attach to laminin and destroy basement membrane (collagen type 4) via collagenase
  • cells attach to fibronectin in the ECM and spread locally
  • entrance into vascular or lymphatic spaces allows for metastasis
30
Q

Routes of metastasis

A

Lymphatic spread is characteristic of carcinomas –> initially spready to regional draining lymph nodes

Hematogenous spready is characteristic of sarcomas and some carcinomas

  • renal cell carcinoma –> often invadesrenal vein
  • hepatocellular carcinoma –> often invades hepatic vein
  • follicular carcinoma of the thyroid
  • choriocarcinoma

Seeding of body cavities is characteristic of ovarian carcinoma –> often involves the peritoneum = omental caking

31
Q

PDGFB

A

Platelet derived growth factor

Oncogene mechanism: Overexpression, autocrine loop

Associated tumor: Astrocytoma

32
Q

ERBB2 (HER2/Neu)

A

Epidermal growth factor receptor

Oncogene mechanism: Amplification

Associated tumor: Subset of breat carcinomas

33
Q

RET

A

Neural growth factor receptor

Oncogene mechanism: Point mutation

Associated tumors:

  • MEN2A
  • MEN 2B
  • sporadic medullary carcinoma of thyroid
34
Q

KIT

A

Stem cell growth factor receptor

Oncogene mechanism: Point mutation

Associated tumor: GI stromal tumor

35
Q

RAS gene family

A

GTP binding protein

Oncogene mechanism: Point mutation

Associated tumors:

  • carcinomas
  • melanoma
  • lymphoma
36
Q

ABL

A

Tyrosine kinase

Oncogene mechanism: 9:22 translocation with BCR

Associated tumors:

  • CML
  • some types of ALL
37
Q

c-MYC

A

Transcription factor

Oncogene mechanism: 8:14 translocation involving IgH

Associated tumor: Burkitt lymphoma

38
Q

N-MYC

A

Transcription factor

Oncogene mechanism: Amplification

Associated tumor: Neuroblastoma

39
Q

L-MYC

A

Transcription factor

Oncogene mechanism: Amplification

Associated tumor: Lung carcinoma (small cell)

40
Q

CCND1 (cyclin D1)

A

Cyclin (cell cycle regulator)

Oncogene mechanism: 11:14 translocation involving IgH

Associated tumor: Mantle cell lymphoma

41
Q

CDK4

A

Cyclin dependent kinase

Oncogene mechanism: Amplification

Associated tumor: Melanoma

42
Q

General clinical features of neoplasia

A
  • benign tumors tend to be slow growing, well circumscribed, distinct and mobile
  • malignant tumors are usually rapid growing, poorly circumscribed, infiltrative and fixed to surrounding tissues and local structures
  • biopsy or excision is generally required before a tumor can be classified as benign or malignant with certainty
  • some benign tumors can grow in a malignant like fashion, and some malignant tumors can grow in a benign like fashion
43
Q

Histologic features of benign tumors

A
  • usually well differentiated
  • organized growht
  • uniform nuclei
  • low nuclear to cytoplasmic ration
  • minimal mitotic activity
  • lack of invasion of basement membrane or local tissue
  • no metastatic potential
44
Q

Histologic features of malignant tumors

A
  • classically poorly differentiated = anaplastic
  • disorganized growth/loss of polarity
  • nuclear pleomorphism and hyperchromasia
  • high nuclear to cytoplasmic ratio
  • high mitotic activity with atypical mitosis
  • invasion through basement membrane or into local tissue
  • metastatic potential is the hallmark of malignancy - benign tumors never metastasize
45
Q

Immunohistochemical stains for intermediates:

  • epithelium
  • mesenchyme
  • muscle
  • neuroglia
  • neurons
A
  • epithelium = keratin
  • mesenchyme = vimentin
  • muscle = desmin
  • neuroglia = GFAP
  • neurons = neurofilaments
46
Q

Immunohistochemical stains for:

  • prostatic epithelium
  • breast epithelium
  • thyroid follicular cells
  • neuroendocrine cells
  • melanoma, schwannoma and langerhans cell histiocytosis
A
  • prostatic epithelium = PSA
  • breast epithelium = ER
  • thyroid follicular cells = thyroglobulin
  • neuroendocrine cells = chromogranin (eg small cell carcinoma of lung and carcinoid tumors)
  • melanoma, schwannoma and langerhans cell histiocytosis = S-100
47
Q

Serum tumor markers

A
  • proteins released by tumor into serum (eg PSA)
  • useful for screening, monitoring response to tx and monitoring recurrence
  • elevated levels require tissue biopsy for dx of carcinoma
48
Q

Grading of cancer

A

Microscopic assessment of differentiation - how much a cancer resembles the tissue in which it grows –> takes into account architectural and nuclear features

  • well differentiated = low grade –> resembles normal parent tissue
  • poorly differentiated = high grade –> does not resemble parent tissue

Important for determining prognosis –> well differentiated cancers have better prognosis

49
Q

Staging of cancer

A

Assessment of size and spread of a cancer –> key prognostic factor, more important than grade
- determined after final surgical resection of the tumor

Utilizes TNM staging

  • T = tumor size/depth of invasion
  • N = spread to regional lymph nodes, second most important prognostic factor
  • M = metastasis, single most important prognostic factor

Pathoma (16 decks)

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