Exam #2: Neoplasia IV Flashcards
What is dysplasia? What are the characteristics of dysplasia?
Dysplasia refers to disordered growth in epithelial cells that includes:
1) Loss of uniformity of individual cells
2) Loss of architectural orientation
*****This is a precursor to cancer, but does NOT invariably progress to cancer
Describe the spectrum of neoplasia in the cervix.
CIN1 CIN2 CIN3 CIS Invasive carcinoma
CIN is defined by the epithelium occupied by immature cells i.e. undifferentiated
What is CIN1?
- 1/3 of the full-thickness of the cervical epithelium from the basement membrane contains immature cells
- This is also called mild dysplasia
What is the definition of CIN2?
- 1/3 - 2/3 of the full-thickness of the cervical epithelium from the basement membrane contains immature cells
- This is also called moderate dysplasia
What is the definition of CIN3?
- > 2/3 of the full-thickness of the cervical epithelium from the basement membrane contains immature cells
- This is also called severe dysplasia
What is the definition of CIS?
Carcinoma in situ refers to full thickness of the cervical epithelium containing immature cells
What is the difference between carcinoma in situ and invasive carcinoma?
CIS= full-thickness WITHOUT breach of the basement membrane
Invasive carcinoma= invasion of the basement membrane
What can oral hairy leukoplakia transform into?
Squamous cell carcinoma
What can Barett’s esophagus transform into?
Adenocarcinoma of the esophagus
Describe the different stages of GERD, Barrett’s Esophagus, and Adenocarcinoma?
1) Esophagitis i.e. inflammation of the esophagus
2) Barrett’s Esophagus (metaplasia–columnar epithelium)
3) Dysplasia
4) Carcinoma
What can chronic atrophic gastritis lead to? What about chronic ulcerative colitis?
- Gastric adenocarcinoma
- Adenocarcinoma of the colon
*Note that only ulcerative colitis transforms to cancer, Chron’s Disease DOES NOT
What cancerous progression can occur following Hepatitis B or C infection?
1) Hepatitis B or C
2) Macronodular cirrhosis
3) Hepatocellular carcinoma
What can be the result of simple/complex hyperplasia of the endometrium?
Endometrial adenocarcinoma
What can solar keratosis of skin lead to?
Skin cancer (usually squamous cell carcinoma)
What is the definition of a tumor?
Monoclonal expansion of a mutated cell
*****Teratomar still follows this rules; originally from one cell that immediately goes to three different lineages.
What is carcinogenesis? What does carcinogenesis lead to?
Carcinogenesis is non-lethal genetic damage that leads to:
1) Inherited germline mutations
2) Acquired mutations
What are the three outcomes of genetic mutations that are carcinogenic?
1) Activation of growth promoting genes i.e. “proto-oncogenes”
2) Inactivation of tumor suppressor genes i.e. “anti-oncogenes”
3) Alteration in genes that regulate apoptosis
What is heterogeneity?
Heterogeneity is the process by which new subclones arise from the descendants of the original transformed cell by multiple mutations
- Remember, a tumor cell comes from one cell i.e. “monoclonal”
- This cell divides and leads to diverging cellular lineages with different adaptations and characteristics
Thus, in a tumor, there are a number of different cells with different characteristics i.e. the tumor is “heterogenous”
What are the seven essential alterations for malignant transformation?
1) Self-sufficiency in growth signals
2) Insensitivity to growth-inhibitory signals
3) Evasion of apoptosis
4) Limitless replicative potential
5) Sustained angiogenesis
6) Ability to invade and metastasize
7) Defects in DNA repair
**Note that not ALL of these are needed for malignant transformation
What are the four classes of normal regulatory genes?
1) Growth promoting proto-oncogenes
2) Growth inhibiting tumor suppressor genes
3) Genes regulating apoptosis
4) Genes regulating DNA repair
**MircoRNA is a new class of regulatory molecules
What is the difference between a proto-oncogene & an oncogene?
Proto-oncogenes are NORMAL
Oncogenes are proto-oncogenes that have undergone mutations to promote “autonomous” cell growth that is devoid of regulatory elements
How many alleles are there of tumor suppressor genes? What is the clinical implication of heterzygous vs. homozygous mutations?
2x
- Heterozygous mutations do NOT result in cancer (increased risk)
- Homozygous mutations result in cancer
What are the different classes of oncogenes?
1) Growth factors synthesis
2) Growth factor receptor synthesis
3) Signal transduction
4) Nuclear transcription
5) Cell cycle regulators
What are the mechanisms that can activation of an oncogene?
1) Point mutation
2) Translocation
3) Amplification
What are the two potential results of the activation of oncogenes?
- Normal protein is overproduced
- Mutant protein is produced and has an aberrant function
What are ERBB2 (HER-2/NEU) mutations associated with?
- ERBB2 is the receptor for EGF
- Mutation results in amplification
- Implicated in breast & ovarian cancer
What are RET mutations associated with?
- RET= Receptor for Neurotrophic Factors
- Point mutation
- Multiple endocrine neoplasia types 2a & 2b (MEN 2A & MEN 2B
What are KRAS mutations associated with?
- KRAS= GTP-binding protein
- Point mutation
- Pancreatic, colon, and lung cancer
What are ABL mutations associated with?
- ABL= Non-receptor tyrosine kinase
- Translocation
- CML & ALL i.e. Chronic myeloid leukemia & Acute lymphoblastic leukemia
What are BRAF mutations associated with?
- Ras signal transduction pathway
- Point mutation
- Melanoma
What are B-Catenin mutations associated with?
- WNT signal transduciton
Liver cancer:
- Hepatoblastomas & -hepatocellular carcinoma
What are C-myc mutations associated with?
- Transcriptional activator
- Translocation
- Burkitt’s Lymphoma
What are N-myc mutations associated with?
- Transcriptional activator
- Amplification
- Neuroblastoma & small cell cancer of the lung
What are Cyclin D mutations associated with?
- Cell cycle regulator
- Translocation= Mantle cell lymphoma
- Amplification= Breast & esophageal cancer
What is MEN-2a or MEN-2b?
- Multiple endocrine neoplasia types 2a & 2b
- Caused by RET mutations
- Symptoms include the familial occurrence of a combination of:
1) Medullary thyroid carcinoma
2) Bilateral pheochromocytoma
3) Hyperparathyroidism due to hyperplasia or tumor
Outline the chromosomal translocation that occurs in CML.
- “Philadephila chromosome”
- c-abl proto-oncogene on chromosome 9 is translocated to bcr, and oncogene on chromosome 22 i.e. 9x22
- Resulting fusion gene encodes for a protein with increased tyrosine kinase activity
What is the treatment for CML? What is the mechanism of action of the drug?
Imatinib mesylate (Gleevec) inhibits tyrosine kinase
Outline the translocation that occurs in Burkitt Lymphoma
- Translocation of c-myc proto-oncogene from chromosome 8 to a site adjacent to the Ig heavy chain locus on chromosome 14 i.e. 8x14
What is the difference between endemc, sporadic, and HIV-associated Burkitt’s Lymphoma?
Endemic/ African= patients present with a jaw mass
Sporadic= patients present with an abdominal mass
HIV-associated
What is the mechanism of B-cell follicular lymphoma?
Translocation of 14x18 leads to overexpression of BCL-2
- BCL-2 produces a gene product that prevents the leakage of cytochrome c
- This prevents the apoptosis of B-lymphocytes
What cancer is caused exclusively by the evasion of apoptosis?
B-cell follicular lymphoma
What is neuroblastoma?
Aggressive childhood tumor with marked N-MYC amplicfication
Outline the pathogenesis of neuroblastoma.
Amplification of N-myc, which is a transcriptional activator
How does neuroblastoma commonly present in children?
Abdominal masses
