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
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
3
Q
Regulatory genes damaged in carcinogenesis
A
- protooncogenes
- tumor suppressor genes
- genes that regulate apoptosis
- genes involved in DNA repair
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
5
Q
Types of oncogenes
A
- Growth factors
- Growth factor receptors
- Signal transducing agents
- Non-receptor tyrosine kinases
- Transcription factors
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
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
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
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
10
Q
Oncogenes - transcription factors
A
- myc protooncogene - translocated in Burkitt’s lymphoma –> comes under influence of Ig heavy chain = 8,14 translocation
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
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
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
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
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)
16
Q
Defects in DNA repair genes
A
- Defects in mismatch repair: microsatellite instability –> hereditary polyposis cancer syndrome = germline mutation in MSH2 + MLH1
- 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
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
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
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
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
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
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
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
Defective DNA repair syndromes
- 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
Familial cancers
- 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
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Interaction between genetic and non-genetic factors
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
Geographic and environmental factors
Most significant cause of sporadic cancer
- UV radiation
- drugs
- occupational hazards --> asbestos, vinyl chloride, 2-napthylamine
- obesity, alcohol, smoking
29
Age and cancer
- 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
Non-hereditary predisposing states
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
Pre-malignant conditions
- 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
Angiogenesis in carcinogenesis
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
Invasion + metastasis
- 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
Pathways of metastatic spread
- 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
Local effects of tumor on the host
- 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
Hormonal effects of tumor on the host
Hormone production --> eg. insulin/glucagon production by pancreatic islet cell tumors
37
Cachexia
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
Paraneoplastic syndromes
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
Hypercalcemia
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
Carcinoid syndrome
Bronchial carcinoid
- GI carcinoids metastatic to liver
- serotoninc, bradykinin, histamine, kallikrein and prostaglandins
41
Hypertrophic osteoarthropathy
- 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
Syndrome of innappropiate ADH secretion
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
Neuromyopathic paraneoplastic syndromes
- 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
Coagulopathies
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
Tumor diagnosis
- history and physical
- radiology
- pathologic diagnosis
- lab analysis
46
Pathologic tumor diagnosis
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
Pathologic tumor diagnosis - surgery
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
Limitations of diagnosis
- 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
Important questions in pathologic tumor diagnosis
- 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
Histologic grading of tumors
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
Tumor staging
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
Ancillary methods, immunohistochemistry
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
Serum tumor markers
- 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
Serum tumor marker: CEA
- 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
Serum tumor marker: AFP
- 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
Other serological tumor markers
- PSA = prostate cancer
- CA-125 = ovarian tumors --> turned out to not be specific and not used
- HCG = testicular cancers
- CA19-9
