Cervix Flashcards
What does the cervix consist of?
- External vaginal portion (ectocervix) and the endocervical canal
What is visible on vaginal examination?
- Ectocervix
What covers the ectocervix?
- Mature squamous epithelium that is continuous with the vaginal wall
What covers the endocervix?
- Columnar, mucus secreting epithelium
What is the squamocolumnar junction?
- The point where the squamous and columnar epithelium meet
- Position is variable and changes with age and hormonal influence (in general, the junction moves up the canal with age)
What is squamous metaplasia?
- The replacement of the glandular epithelium
What is the transformation zone?
- The area of the cervix where the columnar epithelium coexists with the squamous epithelium
What happens to the SCJ during reproductive years?
- SCJ moves out onto the ectocervix (calle ectropion)
What happens to the SCJ as a women ages beyond reproductive years?
- Retreats up into the endocervical canal
What happens during menarche in response to estrogen production?
- Maturation of the cervical and vaginal squamous mucosa
- Formation of intracellular glycogen vacuoles in the squamous cells
- As the squamous cells shed, they glycogen provides a substrate for various bacteria,like lactobacilli, which is the dominant bacteria in a normal vagina
What does lactobacillus do in the vagina?
- Produces lactic acid to keep the vaginal pH under 4.5 in order to suppress growth of other organisms like Candida
- At low pH, lactobacilli produces H2O2 which is bacterial toxic
What happens if the vagina becomes alkaline?
- Hydrogen peroxide production decreases
What can cause the vagina to become alkaline?
- Bleeding
- Sexual intercourse
- Vaginal douching
What is an exogenous source that causes the pH to rise in the vagina?
- Antibiotics that suppress lactobacilli
What are endocervical polyps?
- ## Common benign exophytic growths that arise within the endocervical canal
What do endocervical polyps look like?
- Vary from small, sessile bumps to large polypoid masses that may protrude through the cervical os
What is the main significance of endocervical polyps?
- May be the source of irregular vaginal spotting or bleeding that arouses suspicion of some more ominous lesion
What is the treatment for endocervical polyps?
- Simple curette or surgical excision
What viruses are considered oncogenic viruses?
- HTLV-1
- Epstein Barr virus
- Hep B and C
- Merkel cell carcinoma
- Kaposi sarcoma associated herpesvirus
- HPV
What does HPV affect?
- Any squamous cell component (Vulva, Vagina, and Cervix)
What are the highest risk types of HPV?
- 16, 18, 31, and 45
What are the primary low risk types of HPV?
- 11 and 6
What is HPV?
- Non-enveloped, double stranded, circular DNA virus with an icosahedral capsid
What proteins compose HPV?
- E1-E7
- L1 and L2
What does the E5 protein do in HPV?
- Stimulates cell proliferation and prevents differentiation
- Downregulates surface MHC class I expression
What does the E6 protein do in HPV?
- Downregulates cell cycle control through p53 inactivation/degradation
- Induces malignant transformation together with E7
What does the E7 protein do in HPV?
- Keeps cells active in the cell cycle through Rb inactivation
- Induces malignant transformation together with E6
What cells does HPV infect?
- Immature basal cells of the squamous epithelium in areas of epithelium breaks or immature metaplastic squamous cells
What cells are most susceptible to HPV infection?
- Immature squamous cells in the transformation zone
- As a result, this is where the majority of cervical precursor lesions and cervical cancers develop
What cell type is safe from HPV infection?
- Mature superficial squamous cells that cover the cervix, vagina, or vulva
How is HPV integrated into the host genome in the low risk types of HPV?
- In types 6 and 11, the HPV genome is maintained in a nonintegrated episomal form
How is HPV integrated into the host genome in the high risk types of HPV?
- In types 16 and 18, the HPV genome is integrated into the host genome
What happens to the cells once HPV in integrated into the genome?
- Viral genome starts expressing the early proteins that maintain the keratinocytes in a rapidly dividing state
- Productive replication is established such that the viral genome is amplified to more than 1000 copies and expression of capsid proteins is induced
- Once the expression of capsid proteins is induced, infectious virions are synthesized and released
Why is it theorized that there is a delayed immune response in HPV?
- Could be due to the fact that the complete cycle takes place above the basal layer and does so without directly triggering cell lysis
What does HPV protein E6 do to cause cell immortalization?
- Block p53 which is the guardian of the genome
- Increase telomerase expression
What does HPV protein E7 do to cause cell immortalization?
- Inhibit p21 which causes increased CDK4/cyclin D which blocks RB-E2F
- Inhibits RB-E2F causing cell cycle to continue
What are some qualities of HPV infections?
- Extremely common and mostly asymptomatic
What is the peak age of onset for HPV positivity?
- Age 20-24
Does the immune system clear most HPV infections?
- Yes, 50% are cleared in 8 months and 90% are cleared in 24 months
What about HPV causes an increased risk for cervical cancer?
- Persistent infection
- Infection with HPV alone is not sufficient for carcinogenesis
What else is needed with HPV for carcinogenesis?
- Cotransfection with a mutated RAS gene results in full malignant transformation
What are some environmental factors that act in concert with HPV to increase the risk of cervical cancer?
- Cigarette smoking
- Coexisting microbial infections
- Dietary deficiencies
- Hormonal changes
Why has cervical cancer decreased in mortality?
- We did not have a screening test for it
What is the screening test for cervical cancer?
- Pap smear
- It detects cervical precursor lesions, some of which would have progressed to cancer if not treated
- Can also detect low-stage, highly curable cancers
What is the best system when regarding patient management?
- The two tiered system
What is the two tiered system?
- A system that classifies growth as either low grade or high grade
- This is done to determine treatment options (observation vs surgical treatment)
What does the low grade squamous intraepithelial lesion designation cover?
- HPV (HPV)
- CIN I (mild dysplasia)
What does the high grade squamous intraepithelial lesion designation cover?
- CIN II (moderate dysplasia)
- CIN III (severe dysplasia and carcinoma in situ)
What is LSIL associated with?
- High level of viral replication but only mild alteration in growth of infected cells
- 80% of cases are associated with high-risk HPV serotypes
How are most cases of LSIL treated?
- No like premalignant lesion
- Observation/HPV testing/biopsy
Which SIL is more common?
- LSIL (10x more)
Does LSIL progress directly to invasive carcinoma?
- No
What is seen in HSIL?
- Dysregulation of the cell cycle by HPV leads to increased cellular proliferation, decreased or arrested epithelial maturation, and lower rate of viral replication
- Derangements may be irreversible
What does HSIL develop from?
- Most develop from LSIL
What is HSIL associated with?
- 100% are associated with high risk serotypes (HPV 16)
- Considered high risk for progression to squamous cell carcinoma (takes place over several decades)
What is a punitive marker for HPV infections?
- Overexpression of p16
What is the average age of a patient with cervical carcinoma?
- 45-50
What are the histological types of cervical carcinoma?
- Squamous cell carcinoma (80%)
- Adenocarcinoma (15%)
- Mixed adenosquamous or neuroendocrine (5%)
Who are most cervical cancers seen in?
- Women who were not in regular screening program
What is done when a pap smear is abnormal?
- Colposcopic examination of the cervix and vagina is performed to identify the lesion
- Mucosa is examined with a magnifying glass following application of acetic acid which will highlight abnormal epithelium as white spots
- Cone biopsy
What are the different stages of cervical cancer?
- Stage 0: carcinoma in situ
- Stage 1: confined to cervix
- Stage 2: carcinoma extend beyond cervix but not to the pelvic wall (involves vagina)
- Stage 3: carcinoma has extended to the pelvic wall
- Stage 4: carcinoma has extended beyond true pelvis or has involved the mucosa of bladder or rectum
Where does cervical cancer metastasize to?
- Primary pelvic nodes first then para-aortic nodes
- Distant mets to lung, other nodes, liver, and bone (can be the initial presentation)
What is death mainly due to in cervical cancer?
- Complications related to local tumor invasion rather than distant mets
What are some of the vaccines for HPV?
- Gardasil (gardasil 9)
- Cervarix
Who is vaccinated for HPV?
- All girls and boys who are 11 or 12
- Could be started at 9
- Recommended for young women through age 26 and young men through age 21
What are some special cases of people who are recommended to get the HPV vaccine?
- Young men who have sex with men
- Young men who identify as bisexual or gay or who intend to have sex with men through age 26
- Young adults who are transgender through age 26
- Young adults with certain immunocompromised conditions through age 26
