Neoplasia Flashcards
1
Q
Neoplasia
A
‘Any new autonomous growth (independent of growth)
New growth’
2
Q
Classification of neoplasms
A
A. Benign (oma): 1. Epithelial Papilloma, adenoma 2. Mesenchymal B. Malignant: 1. Epithelial Carcinoma 2. Mesenchymal Sarcoma
3
Q
Papilloma
A
- Finger like projections with fibrovascular core
2. Adenoma : tumour of a gland
4
Q
Exceptions of nomenclature of neoplasms
A
Malignancies like:
Seminoma, lymphoma, chordoma, chloroma, melanoma
5
Q
Mixed tumours
A
1. Single germ layer Pleomorphic adenoma 2. More than one germ layer Teratoma: A. Cystic/ dermoid cyst B. Mature teratoma: benign C. Immature teratoma: malignant
6
Q
Choriostoma
A
Normal tissue in abnormal location (Ectopic crest of normal tissue)
Not a neoplasm or cancer
7
Q
Hamartoma
A
Abnormal tissue in normal location
The abnormal tissue is disorganised/ haphazard
Eg., pulmonary hamartoma
Recently, it is discovered that they show clonal chromosomal rearrangements and therefore can be considered as tumours
8
Q
Anaplasia
Hallmark of malignancy
A
Lack of differentiation 1. Pleomorphism is seen (variation in shape and size of cells) 2. High N/C ratio of 1:1 (instead of (1:4-1:6) 3. Hyperchromatic nuclei 4. Prominent nucleoli 5. Loss of polarity 6. Abnormal mitosis Seen in malignant tumour, not in benign
9
Q
Molecular basis of cancer, or Hallmarks of cancer
A
- Self sufficiency in growth signals (oncogenes)
- Insensitivity to growth inhibitory signals (tumour suppressor genes)
- Evasion of apoptosis
- Limitless replicative potential
- Sustained angiogenesis
- Invasion and metastasis
- Altered cellular metabolism
- Escape of immune recognition
10
Q
Protooncogenes
A
- Growth factors
- Growth factor receptor
- Signal transduction proteins
- Nuclear transcription factors
- Cyclins and CDKs
11
Q
Examples of growth factors leading to cancers
A
- sis (PDGF-β) ➡️ astrocytoma
- Hepatocyte GF ➡️ Hepatocellular carcinoma HCC
- HST-1 ➡️ osteosarcoma
Their overexpression leads to these cancers
12
Q
Examples of growth factor receptor that leads to cancer
A
- C-kit (CD-117) ➡️ GIST via point mutation
Via overexpression of EGFR: - EGFR-1 (ERB-1) ➡️ adenocarcinoma
- EGFR-2 (ERB-2) ➡️ breast and ovarian cancer
- RET ➡️ Medullary carcinoma of thyroid and MEN-2 syndrome via point mutation
- ALK➡️ various cancers
13
Q
Loss of function mutation in RET leads to
A
Hirshsprung’s disease
14
Q
ALK gene and cancer
A
Anaplastic lymphoma kinase gene of chromosome 2 Gene for a growth factor receptor Mutation leads to: 1. ALCL (anaplastic large cell lymphoma) 2. Inflammatory myofibroblastic tumours 3. Adenocarcinoma of lung
15
Q
Signal transduction proteins leading to cancer
A
- ABL ➡️ CML, ALL
- RAS (most common oncogene mutated in human malignancy)
- BRAF V600
- NOTCH ➡️ ALL
16
Q
ABL as protooncogene
A
ABL (9th chromosome) undergoes translocation with BCR t(9:22) ➡️ bcr:abl fusion transcript ➡️constitutive activation of tyrosine kinase ➡️ leukaemia :
- P210 kDa➡️ CML or
- P190 kDa ➡️ ALL (poor prognosis)
17
Q
RSA as protooncogenes
A
Point mutation of RSA➡️
GAPs (GTPase activation proteins become ineffective ➡️
GTP RAS not inactivated to GDP RAS ➡️
cancer
18
Q
Cancers caused by RAS gene mutation
A
Most common oncogene mutated in human malignancy
K. K-RAS ➡️ colon, pancreas, lung cancer
H. H-RAS ➡️ bladder/ kidney tumours
N. N-RAS ➡️ melanoma
19
Q
Cancers caused by BRAF V600 mutation
A
P. Papillary carcinoma of thyroid L. Langhan’s cell histiocytosis A. Astrocytoma C. Colon cancer H. Hairy cell leukaemia
20
Q
Nuclear transcriptions factors leading to cancers
A
myc oncogene
3 types:
L. L-myc➡️ small cell carcinoma of lung (via amplification)
N. N-myc ➡️ neuroblastoma (via amplification)
C. C-myc ➡️ Burkit’s lymphoma (via t(8:14)
21
Q
Cyclins and CDKs leading to cancers
A
Mantle cell lymphoma
t(11:14) ➡️ leads to overexpression of cyclin D ➡️ cell proliferation continues
11 chromosome ➡️ cyclin D
14 chromosome ➡️ IgH
22
Q
Rb gene
A
Gene on chromosome 13q14 Governor of cell cycle Regulated G1-S transition Rb two forms: 1. hypophosphorylated ➡️ active 2. hyperphosphorylated ➡️ inactive Mutation of Rb leads to: 1. Retinoblastoma 2. Osteosarcoma
23
Q
Knudson’s two hit hypothesis
Loss of heterozygosity
A
Both alleles of Rb must be mutated for retinoblastoma Rb to develop
In familial Rb, 1 copy of mutated allele by birth, 2nd by mutation after birth
Thus ‘Loss of heterozygosity’ occurs
24
Q
p53
Properties
A
Gene in chromosome 17p
Mutation of p53 ➡️ Difraumeni syndrome (autosomal dominant)
Guardian of genome/ molecular policeman of cell
Mutation in >50% of malignancy
25
Functions of p53
1. Induces p21 ➡️ CDK inhibitor ➡️ cell cycle arrest
2. GAF 45 ➡️ repair cells ➡️ re enter cell cycle, if this fails ➡️
3. Activates pro apoptotic factor BAX, BAK ➡️ apoptosis
26
Examples of chemical carcinogens
```
Polycyclic aromatic hydrocarbons (PAH)
Aflatoxin
Arsenic
Asbestos
PVC
Diethyl stilbestrol
Benzene
β-Naphthylamine/azo dyes
```
27
Polycyclic hydrocarbons cause
| Aflatoxin causes
Bronchogenic cancers
Hepato Cellular Carcinoma
28
Arsenic causes
Asbestos causes
Skin cancer, lung cancer
Lung cancer (adenocarcinoma), malignant mesothelioma
29
Polyvinyl chloride PVC causes
Diethyl stilbesterol causes
Cadmium causes
Hepatic angiosarcoma
Vaginal cancer
Prostate cancer
30
Benzene causes
β-Naphthylamines/azo dyes of dry cleaning causes
Leukaemia
Bladder cancer
31
Ionising radiation causes cancers like
1. All leukaemias except CLL
2. Papillary carcinoma, thyroid,
breast cancer, lung cancer,
saliva gland cancer (mucoepidermoid cancer)
32
Microbial carcinogens
1. H pylori: gastric adenocarcinoma, maltoma
2. HPV
3. HBV, HCV
4. HTLV-1
5. HHV-8
6. EBV
33
Diseases caused by HPV
```
1. Low risk:
HPV-6,11
Condyloma acuminatum
2. High risk:
HPV-16,18
Cervical, Anogenital and Laryngeal cancer
3. Intermediate risk:
HPV-31,33
```
34
Pathogenesis of human papilloma virus
| Microscopy
E6+p53 ➡️ inactivated
E7+Rb ➡️ inactivated
```
Microscopy:
Koilocytic changes:
Cell with thick membrane
Resin like nucleus
Perinuclear halo/hoff
```
35
Cancers caused by
| HBV, HCV and HTLV-1
HBV and HCV ➡️ Hepatocellular carcinoma
HTLV-1 (Human T cell Leukaemia Virus) ➡️ T cell leukaemia
36
Diseases caused by HHV-8
Human Herpes Virus-8 causes:
1. Kaposi’s sarcoma
2. 1° effusion lymphoma
3. Multicentric Castleman disease
37
Ebstein Barr virus (EBV) causes:
1. Hodgkin’s lymphoma and non Hodgkin’s lymphoma like
2. Extra nodal T cell lymphoma
3. Nasopharyngeal carcinoma
4. Burkitt’s lymphoma
5. Post transplant lymphoproliferative disorders (PTLD)
Non neoplastic lesion: infectious mononucleosis
38
EBV properties
Affects B-lymphocytes
Binds to CD-21
Pathogenesis:
1. LMP-1 (Latent membrane protein) ➡️ activates NF-kβ (growth signaling pathway) ➡️ cell proliferation
2. EBNA-2 ➡️ activates cyclin D ➡️ cell proliferation
39
Two malignancies which do not metastasise
Glioma
| Basal cell carcinoma (rodent ulcer)
40
Desmoplasia
Abundant collagenous tissue producing tumour is called desmoplasia
41
Dysplasia
Disordered proliferation
Contains features of anaplasia
Limited by a basal membrane so also called ‘carcinoma in situ’
Reversible in early stages, whereas metaplasia is reversible
42
Routes of metastasis
```
1. Lymphatics:
most carcinomas
2. Hematogenous:
most sarcomas
to lung, liver,...
venous > arteriolar
3. Direct seeding of body cavities:
Pseudomyxoma peritonii
4. Trans-coelomic spread:
Krukenberg’s tumour
```
43
Carcinomas which do not metastasise via lymphatic route
1. Choriocarcinoma
2. Hepatocellular carcinoma
3. Renal cell carcinoma
These metastasise via hematogenous route
44
Sarcoma which do not metastasise via hematogenous route
1. Alveolar Rhabdomyo sarcoma
2. Synovial sarcoma
Metastasise via lymphatic route
45
Tumours that spread via CSF
1. Medulloblastoma:
Drop metastasis to cauda equina
2. Ependymoma
46
Tumours that undergo spontaneous regression
1. Retinoblastoma, Neuroblastoma
2. Renal cell carcinoma
3. Malignant melanoma
4. Chriocarcinoma
47
Small round blue cell tumours of childhood
1. Retinoblastoma: Flexner Wintersteiner rosette
2. Neuroblastoma: Holmer Wright rosette
3. Nephroblastoma (Wilm’s tumour)
4. Hepatoblastoma and Medulloblastoma
5. Ewing’s sarcoma
6. PNET
7. Rhabdomyosarcoma
8. Few lymphoma
Rossetes are seen
48
Most radiosensitive phase of cell cycle
Most radioresistant phase
G2M (M)
S phase
49
Longest phase of cell cycle
Interphase
50
Cyclin-CDK pairs
D4,6
E2
A2
B1
Eg., cyclin D ➡️ CDK 4 and CDK 6
51
Earliest cyclin to increase in cell cycle is
Cyclin D
Which combines with CDK-4,6 during G2➡️S
Last is cyclin B + CDK1
52
Cyclins involved during G1S transition
Cyclin D + CDK4 (more important)
| Cyclin E + CDK2
53
Cyclins involved in G2M transition
Cyclin A + CDK2
| Cyclin B+ CDK1 (more important)
54
CDK inhibitors
```
1. Cip/Kip family
P21- induced by p53
P27- induced by TGF β
P57
2. INK 4A/ARF
P14,15,16,18
P16 is most important among these
```
55
Role of Rb in cell cycle
```
2 forms:
Hypophosphorylated-active
Hyperphosphorylated-inactive
E2F transcription factor in its pocket in active state
When Cyclin D + CDK4 increases ➡️
Rb is inactivated ➡️
release of E2F, which is required for S phase
G1-S transition regulation
```
56
Important tumour suppressor genes and the chromosomes they are located in
1. p53: 17p
2. Rb: 13q14
3. NF-1: 17
4. NF-2: 22
5. BRCA-1: 17
6. BRCA-2: 13
7. WT-1: 11
8. WT-2: 11
9. PTEN: 10
10. VHL: 3
11. APC: 5
57
Tumour suppressor genes and the cancers related to them
1. p53
2. Rb
3. NF-1: Neurofibromas, meningeomas
4. NF-2: Schwannoma
5. BRCA-1: breast, ovarian cancer
6. BRCA-2: male breast cancer, prostate cancer
7. WT-1 and WT-2: Wilm’s tumour
8. PTEN: Endometrial cancer, prostate cancer
9. VHL: clear cell renal carcinoma, cerebellar hemangioblastoma
10. APC: FAP, adenocarcinoma colon
58
Example of evasion of cell death causing cancer
Follicular lymphoma
| t(14:18) i.e, IgH+BCL2 ➡️ increased expression of BCL-2 (anti-apoptotic)➡️ evasion of cell death
59
Examples of pro angiogenic factors
1. VEGF-vascular endothelium
2. PDGF-platelet derived
3. FGF-fibroblast derived
60
Examples of anti angiogenic factors
1. Vasculostatin
2. Endostatin
3. Angiostatin
4. Thrombospondin-1
61
Warburg effect
Cancer cell in presence of normal O2 concentration produces ATP via glycolysis only
This is utilised in PET scan
62
Steps in invasion and metastasis by tumour cells
1. Detach from each other by decreased expression of E-cadherin
2. Attach to ECM by integrins which combines with laminin,fibronectin
3. ECM degradation and breakdown of basement membrane by MMPs and type 4 collagenase
4. Cells enter blood vessels
5. Cells +platelets➡️ tumour emboli to organs and ,via venules, the lymph nodes
63
MMPs
Matrix metalloproteinases for ECM degradation and breakdown of basement membrane along with toe 4 collagenase
Two types are used: 2 and 9
9 is more important
64
Repair pathway defects
1. Nucleotide exclusion repair:
xeroderma pigmentosa
2. DNA repair: ...
3. Mismatch repair: HNPCC/ MSI
65
Defect in DNA repair causes
Bloom’s syndrome
Fanconi anaemia
Ataxia telangiectasia
66
Mismatch repair defect causes
HNPCC (hereditary non polyposis colorectal carcinoma)
| Also called MSI (microsatellite instability defect)
67
Paraneoplastic syndrome
Symptom complexes in cancer patients which cannot be explained by the local or indigenous spread of the tumour
Most common: hypercalcemia
Small cell carcinoma produces the most paraneoplastic syndrome
68
List of paraneoplastic syndromes
| Part 1
1. SIADH: small cell carcinoma of lung (ADH)
2. Cushing’s syndrome: “” (ACTH)
3. Hypertrophic pulmonary osteoarthropathy: “”
4. Hypercalcemia: squamous cell carcinoma of lung, carcinoma breast (PTHrp)
5. Polycythemia: renal cell carcinoma (erythropoietin)
69
List of paraneoplastic syndrome
| Part 2
6. Hypoglycaemia: ovarian carcinoma, fibrosarcoma (insulin, IGFs)
7. Migratory thrombophlebitis: carcinoma pancreas, colon
8. Myasthenia gravis: thymoma, carcinoma lung
9. Acanthosis nigricans: carcinoma stomach, colon (EGF)
70
List of tumour markers, part 1
1. PSA and PAP (prostate acid phosphatase): prostate cancer
2. AFP: HCC hepatocellular carcinoma, NSGCT- yolk sac tumour
3. β-HCG: choriocarcinoma, gestational trophoblastic disease
4. CA-125: Ovarian cancer
71
List of tumour markers, part 2
5. CA 19-9: cancer colon, pancreas
6. Carcino embryonic antigen: “”
7. CA-15-3: breast cancer
8. Catecholamines: pheochromocytoma
9. Immunoglobulins: multiple myeloma
10. Calcitonin: medullary carcinoma thyroid
72
Immunohistochemical markers of tumour part 1
1. Carcinomas: cytokeratin
2. Sarcomas: vimentin
3. Glial: Glial Fibrillary Acidic Protein GFAP
4. Smooth muscle: Smooth Muscle Actin (SMA)
5. Skeletal muscle: Desmin, myogenin, Myo D-1
73
Immunohistochemical markers of tumour part 2
6. Vascular: vWF, CD-31, VEGF
7. Neuroendocrine: synaptophysin, chromogranin, neuron specific enolase
8. GIST: CD-117 (c-KIT), DOG-1, CD-34
9. Malignant melanoma: HMB-45, S-100
10. Malignant mesothelioma: Calretinin, CK-5/6
74
Immunohistochemical markers part 3
11. Ewing’s sarcoma: CD-99 (MIC-2)
12. Hepatocellular carcinoma: Hep par-1, arginase-3
13. Osteosarcoma: osteopontin, osteonectin, osteocalcin
14. Chrondrosarcoma: S-100
15. Liposarcoma: “”
75
Micro RNAs involved in cancer
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1. Oncogenic role:
Micro RNAs 155,200 ➡️ B-cell lymphoma
2. Tumour suppressor role:
Micro RNA 15,16
Affected in CLL
```
76
Chromothripsis
```
Chromosomes are shattered, then they join rapidly ➡️:
1. Oncogenic role increases
2. Tumour suppressor role decreases
Produces cancers like:
1. Osteosarcoma
2. Glioma
```
