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Lectures > Etiology and Pathogenesis of Neoplasia > Flashcards

Etiology and Pathogenesis of Neoplasia Flashcards

1
Q

Carcinogenesis

A

Non-lethal genetic damage
All tumors are monoclonal –> tumor is formed by clonal expansion of a single precursor cell that has incurred genetic damage
Tumor progression: most malignant tumors are monoclonal in origin - by the time they become clinically evident their constituents are extremely heterogeneous
Carcinogenesis is a multistep process at both the phenotypic and genetic levels resulting from the accumulation of multiple mutations –> with progression, the tumor mass becomes enriched for variants that are more adept at evading host defenses and are likely to be more aggressive

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2
Q

Alterations essential for malignant transformation

A
  • self sufficiency in growth signals
  • insensitivity to growth inhibiting signals
  • evasion of apoptosis
  • limitless replicative potential avoiding cellular senscence and mitotic catastrophe
  • sustained angiogenesis
  • ability to invade and metastesize
  • defects in DNA repair –> DNA instability and mutations in protooncogenes and tumor suppressor genes
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3
Q

Regulatory genes damaged in carcinogenesis

A
  • protooncogenes
  • tumor suppressor genes
  • genes that regulate apoptosis
  • genes involved in DNA repair
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4
Q

Oncogenes
Protooncogenes
Oncoproteins

A

Oncogenes: Genes that promote autonomous growth in cancer cells

Protooncogenes: Normal cellular counterparts

Oncoproteins: Products of oncogenes –> often devoid of important internal regulatory elements - cell becomes autonomous

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5
Q

Types of oncogenes

A
  1. Growth factors
  2. Growth factor receptors
  3. Signal transducing agents
  4. Non-receptor tyrosine kinases
  5. Transcription factors
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6
Q

Oncogenes - growth factors

A
  • PDGF - overexpressed in many tumors due to overexpression of S/S protooncogene
  • TFGalpha
  • hepatocyte growth factor
  • fibroblast growth factor family
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7
Q

Oncogenes - growth factor receptors

A
  • EGFR (ERB B1)
  • ERB B2 (HER2/Neu)
  • Receptors for stem cell factor = c-KIT gene –> amenable to specific inhibition by tyrosine kinase inhibitor = imatinib mesylate
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8
Q

Oncogenes - signal transducing proteins

A

Typically GTP binding proteins

  • Ras oncogene - mutated in many tumors
  • -> kras - mutated in carcinomas (colon + pancreas)
  • downstream members of the Ras signaling cascade = raf, mapkinase –> may also be altered
  • -> mutations in braf in >60% of melanomas + >80% of benign nevi
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9
Q

Oncogenes - non-receptor TKs

A
  • c-ABL gene on chromosome 9 translocated to 22 in CML –> fuses with BCR gene = philadelphia chromosome
  • -> fusion gene has potent TK activity = inhibited by by drug imatinib
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10
Q

Oncogenes - transcription factors

A
  • myc protooncogene - translocated in Burkitt’s lymphoma –> comes under influence of Ig heavy chain = 8,14 translocation
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11
Q

Tumor suppressor genes

A

Products negatively regulate cell proliferation

Knudson’s 2 hit hypothesis: Both copies must be absent for neoplasm to develop
- germ line mutations in one gene often present in inherited cancer syndromes

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12
Q

RB gene

A

Chromosome 13q14
Regulates E2F transcription factors
- 2 mutations at the RB locus leads to neoplastic proliferation of retinal cells
- familial form –> all somatic cells inherit one mutant Rb gene from a carrier parent

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13
Q

P53

A

Most common target for genetic alteration in human tumors
Chromosome 17p13.1
Thwarts neoplastic transformation by 3 interlocking mechanisms:
1. activation of temporary cell cycle arrest –> quiscence
2. induction of permanent cell cycle arrest –> senescence
3. triggering of programmed cell death –> apoptosis

Li-Fraumeni syndrome: germ line mutation

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14
Q

APC/Beta-catenin pathway

A

APC gene - chromosome 5q21 –> APC downregulates beta catenin = a protein involved in regulation of several transcription factors and cell cycle genes
- germ line mutation = familial adenomatous polyposis

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15
Q

Genes involved in evasion of apoptosis

A

Bcl-2 gene = anti-apoptotic –> expression = decreased cell death
- translocated to Ig heavy chain locus on chromosome 14q32 in follicular B cell lymphomas (14:18 translocation)

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16
Q

Defects in DNA repair genes

A
  1. Defects in mismatch repair: microsatellite instability –> hereditary polyposis cancer syndrome = germline mutation in MSH2 + MLH1
  2. Defects in DNA repair by homologous recombination: increased susceptibility to DNA damage caused by ionizing radiation, O2 free radicals and DNA crosslinking agents
    - ataxia-telangiectasia
    - bloom syndrome
    - fanconi anemia
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17
Q

Chromosome mutations

A

Enable tumor progression

  • rearrangements = translocations + inversions –> most in hematopoeitic tumors and sarcomas (bcr-abl)
  • deletions = more common in solid tumors (Rb)
  • gene amplification = N-myc –> neuroblastoma; ERBB2 –> breast cancers

Epigenetic changes: reversible changes in gene expression that occur without mutations
- involve post translational modifications of histones and DNA methylation

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18
Q

miRNAs + cancer

A

Enable increased expression of oncogenes and/or decreased expression of tumor suppressor genes
- miRNAs regulate normal cellular differentiation –> patterns of miRNA expression can provide clues to the cell of origin in classification of tumors = miRNA profiling

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19
Q

Tumor immunity/immune surveillance

A

Evasion of host immunity enables cancer progression
- Immune surveillance: Protective role of immune system against cancer development

Mechanisms of tumor escape from immune surveillance:

  • selective outgrowth of antigen-negative variants
  • decreased expression of MHC molecules –> escapes cytotoxic T cells, may trigger NK cells
  • antigen masking –> tumor cells often express more glycocalyx than normal cells
  • immunosuppression –> TGFbeta = potent immunosuppressant - secreted in large quantities by tumor cells
  • apoptosis of cytotoxic t cells
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20
Q

Tumor antigens

A

REgocnized by circulating CD4 and CD8 T cells –> recognize tumor proteins as different from self

  • normal proteins are overexpressed
  • oncofetal antigens = expressed at high levels on cancer and fetal cells but not adult tissue
  • proteins by latent DNA viruses = HPV + EBV
  • surface glycoprotieins + glycolipids = diagnostic markers and targets for therapy
  • differentiation antigens = specific for particular lineage or differentiation of various cell types –> targets for immunotherapy and diagnosis
  • -> ex: CD20 on B cells
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21
Q

Carcinogenic agents - chemical agents

A
  • direct acting carcinogens –> alkylating agents (eg. anticancer drugs)
  • procarcinogens that require metabolic activation –> polycyclic + heterocyclic aromatic hydrocarbons
  • aromatic amines, amides + azo dyes
  • natural plant + microbial products –> aflatoxin
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22
Q

Radiation carcinogenesis

A
  • UV: causes pyrimidine dimers in DNA –> repaired by nucleotide excision repair pathway
  • ionizing radiation:
  • -> acute/chronic myeloid leukemia
  • -> cancer of thyroid in children
  • -> breast, lung + salivary gland cancers
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23
Q

Microbial carcinogenesis

A
  • oncogenic RNA viruses = HTLV1
  • oncogenic DNA viruses = HPV, EBV, HepB
  • HepC + H. Pylori = not directly but through increased inflammation
24
Q

Autosomal dominant inherited cancer syndromes

A
  • inheritance of a single autosomal dominant mutant gene –> usually a point mutation occurring in a signel allele of a tumor suppressor gene
  • silencing of the second allele occurs in somatic cells –> usually a deletion or recombination
  • tumors tend to arise in certain sites/tissues –> may involve more than one site
  • no increase in predisposition to cancers in general
  • tumors exhibit a marker phenotype
  • both incomplete penetrance and variable expression occur
  • ex: retinoblastoma + BRCA
25
Q

Defective DNA repair syndromes

A
  • autosomal recessive:
  • -> xeroderma pigmentosum
  • -> ataxia-telangiectasia
  • -> bloom syndrome
  • autosomal dominant:
  • -> HNPCC = inactivation of a DNA MMR gene - most common cancer predisposing syndrome = increased susceptibility for cancer of colon, small intestine, ovary and endometrium
26
Q

Familial cancers

A
  • occur at increased frequencies within families without a clear pattern of transmission
  • virtually all common sporadic cancers also occur in familial form
  • earlier age of onset, tumors in 2 or more close relatives of index case, and multiple/bilateral tumors
  • 2-3x risk in siblings
27
Q

Interaction between genetic and non-genetic factors

A

Tumor development depends on action of multiple contributory genes

  • risk of developing tumor can be greatly influenced by non-genetic factors
  • genotype can significantly influence likelihood of developing environmentally induced cancers –> polymorphisms of enzymes that metabolize carcinogens to their active forms
28
Q

Geographic and environmental factors

A

Most significant cause of sporadic cancer

  • UV radiation
  • drugs
  • occupational hazards –> asbestos, vinyl chloride, 2-napthylamine
  • obesity, alcohol, smoking
29
Q

Age and cancer

A
  • most cancers occur > 55 y.o.
  • cancer is the main cause of death in women age 40-79 and men age 60-79
  • accumulation of somatic mutations and decline in immunocompetence occurs with aging
  • childhood cancers = 10% of deaths in kids almost never epithelial
  • -> leukemia, CNS tumors, “small round blue cell tumors”
30
Q

Non-hereditary predisposing states

A

Chronic inflammatory states

  • activated immune cells produce growth factors, cytokines + chemokines –> promote cell survival, tissue remodeling and angiogenesis
  • causes genomic stress and mutations
  • reactive O2 species are directly genotoxic
  • ulcerative colitis, crohns, chronic pancreatitis, hepatitis, H. pylori, gastritis
31
Q

Pre-malignant conditions

A
  • non-neoplastic disorders: solar keratosis of the skin + ulcerative colitis –> increase risk of cancer at those sites
  • metaplasia: bronchial squamous metaplasia in smokers, barrets esophagus
  • dysplasia: bronchial epithelium in smokers and barrets esophagus
32
Q

Angiogenesis in carcinogenesis

A

Neovascularization is necessary for tumor growth and metastasis

  • tumors produce VEGF or lose inhibitors of angiogenesis
  • new vessels produce IGF, PDGF + granulocyte-macrophage colony stimulating factor = stimulates growth of tumor cells
  • antibodies to VEGF + angiogenesis inhibitors are being investigated as anti-cancer agents
33
Q

Invasion + metastasis

A
  • cells must detach from each other –> loss of E cadherin
  • penetration of basement membrane
  • creation of passage way for migration –> MMPs
  • penetration of vascular basement membrane
  • locomotion
34
Q

Pathways of metastatic spread

A
  • direct seeding: invasion of metastatic tumor into a natrual open space
  • lymphatic metastasis: to lymph nodes –> follow natural patterns of lymph draining (epithelial malignancies)
  • hematogenous metastasis: mesnchymal + epithelial malignancies
  • hematogenous dissemination + homing: tumor adhesion molecules whose ligands are expressed preferentially on endothelial cells of target organ
  • -> prostate carcinoma = bone
  • -> lung carcinoma = adrenals + brain
  • -> colon cancer = liver
  • -> sarcoma = lungs
35
Q

Local effects of tumor on the host

A
  • destruction of normal tissue by tumor
  • tumor erosion of mucosa/vessel/skin
  • -> melena
  • -> hematuria
  • -> coffee-ground emesis
  • -> hemoptysis
  • -> secondary infection
  • perineural invasion
  • -> pain
  • -> horner syndrome in pancoast tumor
  • space occupying effect
  • -> bowel obstruction
  • -> brain herniation
  • -> obstruction of a large vessel - superior vena cava syndrome
36
Q

Hormonal effects of tumor on the host

A

Hormone production –> eg. insulin/glucagon production by pancreatic islet cell tumors

37
Q

Cachexia

A

Progressive loss of body fat and lean body/muscle mass as a result of neoplasia

  • may be the presenting symptom
  • basal metabolic rate is increased
  • equal loss of fat and muscle
  • suspect catechexia if… involuntary weight loss of greater than 5% of premorbid weight within a 6 month period
38
Q

Paraneoplastic syndromes

A

A neoplasm producing a substance that results in an effect that is not directly related to growth, invasion or metastasis

  • most paraneoplastic syndromes result from production of hormone like substances
  • may be the presenting symptom
  • may be life threatening
  • ex: cushing syndrome: ectopic ACTH syndrome
39
Q

Hypercalcemia

A

Most common paraneoplastic syndrome

  • most life threatening metabolic disorder in cancer patients
  • symptomatic hypercalcemia is most often related to some form of cancer - most common cause is lung cancer
  • clinical presentation: weakness, confusion, lethargy, constipation
  • dx: hypercalcemia + low/normal serum PTH; elevated PTH related protein
  • hypercalcemia improves after tumor resection
40
Q

Carcinoid syndrome

A

Bronchial carcinoid

  • GI carcinoids metastatic to liver
  • serotoninc, bradykinin, histamine, kallikrein and prostaglandins
41
Q

Hypertrophic osteoarthropathy

A
  • 1-10% of patients with lung cancer
  • cause unknown
  • periosteal new bone formation, primarily at the distal ends of long bones, metatarsals, metacarpals and proximal phalanges
  • may be seen in benign conditions
  • its presence is significant, especially if its new
42
Q

Syndrome of innappropiate ADH secretion

A

Secretion of ectopic ADH or atrial natriuretic hormones

  • small cell carcinoma of lung + intracranial tumors
  • ADH excess causes resorption of excessive amounts of free water –> hyponatremia
  • cerebral edema and resultant neurologic dysfunction
43
Q

Neuromyopathic paraneoplastic syndromes

A
  • antibodies, presumably induced against tumor cells, cross-react with neuronal cells
  • peripheral neuropathies
  • cortical cerebella degeneration
  • polymyopathy resembling polymyositis, myasthenic syndrome similar to MG
  • Eaton-Lambert myasthenic syndrome
44
Q

Coagulopathies

A

DIC

  • acute promyelocytic leukemia
  • mucinous carcinomas of the lung, pancrease, colon, prostate and stomach
  • circulating mucin with procoagulant effect

Trousseau syndrome

  • aka migratory superficial thrombophlebitis, carcinogenic thrombophlebitis, trousseau sign
  • deep-seated cancers, most often carcinomas of the pancreas, colon or lung

Non-bacterial thrombotic endocarditis

  • small, non-bacterial fibrinous vegetations of the cardiac valve leaflets –> more often on left sided valves
  • potential sources of emboli
  • particularly in patients with advanced mucin-secreting adenocarcinomas
  • can be part of the Trousseau syndrome
45
Q

Tumor diagnosis

A
  • history and physical
  • radiology
  • pathologic diagnosis
  • lab analysis
46
Q

Pathologic tumor diagnosis

A

Cytology: for diagnosis

  • scrape/brush (pap smear)
  • body fluid cytology (pleural, peritoneal fluid, CSF)
  • fine needle aspiration biopsy

Biopsy: for diagnosis

  • tissue architecture –> can determine grade
  • tissue is fixed in formalin and embedded into paraffin blocks = formalin fixed paraffin embedded (FFPE)

Surgery:

  • for definitive pathologic staging
  • definitive treatment = radical resection
  • palliative treatment = debulking
  • rarely for diagnosis
47
Q

Pathologic tumor diagnosis - surgery

A

Frozen section diagnosis

  • resection margins
  • lymph node involvement by the tumor
  • involvement of other organs/sites
  • benign or malignant nature of a lesion

Permanent section

  • regular processing (overnight)
  • tissue is fixed in formalin and embedded into paraffin blocks = formalin fixed paraffin embedded
48
Q

Limitations of diagnosis

A
  • sampling error
  • improper handling - allowing the sample to dry, crushing the material, using the wrong fixative, delay in sending to lab
  • lack of correlation between histologic appearance and clinical presentation
49
Q

Important questions in pathologic tumor diagnosis

A
  • Benign, premalignant, or malignant?
  • If malignant…
  • -> what kind? from what cell or origin?
  • -> what grade? what stage?
  • -> has it been completely removed?
  • -> other important pertinent findings?
  • -> what is the prognosis?
  • -> most appropriate treatment?
50
Q

Histologic grading of tumors

A

Powerful prognostic factor for most tumors

  • most grading systems based on differentiation
  • well differentiated neoplasms are composed of cells that closely resemble the cell of origin
  • -> benign tumors
  • -> well-differentiated malignant tumors
  • poorly differentiated/undifferentiated/ anaplastic/dedifferentated –> highly malignant, difficult to classify, very aggressive

Different grading systems for various tumors - most systems based on:

  • architecture or resemblance to normal tissue of origin
  • mitotic activity
  • nuclear atypia
  • necrosis

Grading = I-IV

  • I = well differentiated
  • IV = nearly anaplastic
51
Q

Tumor staging

A

Most powerful prognostic indicator

  • T = for primary tumor
  • -> with increasing size the primary lesion is characterized as T1-T4
  • -> T0 = in situ lesion
  • N = regional lymph node involvement
  • -> N0 = no nodal involvement
  • -> N1-N3 = involvement of an increasing number and range of nodes
  • M = metastases
  • -> M0 = no distant metastases
  • -> M1/M2 = presence of metastases and some judgement as to their number
52
Q

Ancillary methods, immunohistochemistry

A

Used for poorly differentiated tumor metastasis, when primary tumor is unknown

  • work up with various panels of tissue specific antibodies to pinpoint the tissue of origin
  • identification of small metastases
  • prognostic/predictive marker assessment in tumors
  • -> proliferation rate measured by immunohistochemistry for Ki-67
  • -> potential treatment target assessment - ex: HER2/neu for herceptiv treatment (anti-Her2 antibody)
53
Q

Serum tumor markers

A
  • biochemical indicators of the presence of a tumor
  • a molecule that can be detected in plasma or other body fluids
  • main utility in clinical medicine - laboratory test to support the diagnosis and to follow the patient after treatment, not as a primary diagnosis
54
Q

Serum tumor marker: CEA

A
  • colorectal + pancreatic carcinomas
  • non-specific –> elevated in many benign disorders
  • preoperative CEA levels have prognostic importance –> the level is correlated with body burden of tumor, i.e. stage
  • elevated CEA levels 6 weeks after therapy indicates residual disease
  • rising CEA level indicates recurrence
  • lacks both specificity and sensitivity required for detection of early cancers
55
Q

Serum tumor marker: AFP

A
  • glycoprotein synthesized normally early in fetal life by the yolk sac, fetal liver and fetal GI tract
  • markedly elevated AFP in serum = cancer arising principally in the liver and germ cells of the testis
  • non-specific –> can be elevated in benign conditions
  • AFP levels decline rapidly after surgical resection of liver cell cancer or treatment of germ cell tumors
  • serial post-therapy measurements of AFP provide a senstive index of response to therapy and recurrence
56
Q

Other serological tumor markers

A
  • PSA = prostate cancer
  • CA-125 = ovarian tumors –> turned out to not be specific and not used
  • HCG = testicular cancers
  • CA19-9

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