Cervical Pathology & The Pap Smear Flashcards
What type of epithelium lines the endocervix, ectocervix & tranformation zone?
- endocervix
- mucus, secreting columnar cells
- ectocervix
- mature squamous cell continuous with vaginal lining
- transformation zone
- squamous-columnar junction
- location varies with age & hormonal influence
What is squamous metaplasia & how is it related to cervical cancer?
replacement of columnar epithelium with squamous cells
immature squamous cells of transformation zone are most susceptible to HPV, so this area is most susceptible to lesions/cancer
What part of the cervix is most susceptible to squamous dysplasia & cancer?
transformation zone
What is the significance of lactobacilli in the vagina?
produce lactic acid & keep pH < 4.5, which suppresses the growth of pathogenic organisms
Overgrowth of bacteria can cause what issues in the female reproductive tract?
vaginitis / cervicitis
What condition is likely based on the histological slides from a PAP smear?
Cervicitis
What condition is shown on the provided image?
Endocervical Polyp
small, sessile “bumps” to large polyploid masses protruding through external os
it can appear pink b/c it is very vascular
smalls
The provided slide is a microscopic sample of what condition?
Endocervical Polyp
- prominent vascularity
- loose, fibromyxoid stroma covered with muco-secreting endocervical glands
- stroma may show edema
What are the High Risk HPV strains?
16 (60% cervical cancers)
18 (10% cervical cancers)
What are the low risk HPV strains?
6
11
90% of HPV infections clear within what time frame?
2 years
HPV infects what type of cells?
immature basal cells of squamous epithelium in areas of epithelial breaks or squamo/columnar junctions (transformation zone)
What are the two most important HPV proteins in the pathogenesis of cervical neoplasia?
E6
E7
What do E6 and E7 do?
inactivate crucial cell cycle proteins
- genetic instability
- mutations
- malignant progression
Describe the interaction between E6 and p53 inside infected cells? This has what impact on the cell?
E6 binds to p53 & causes it degradation
- unchecked cellular cycling - uncontrolled proliferation
- anti-apoptotic effect - chromosomal instability
- stimulate mitotic activity via regulating Src tyrosine kinases
- upregulate telomerase expression
proliferation of genetically unstable infected cells
What is the role of p53 in a healthy cell?
inhibitor of cell growth - controlling transition from G0G1 to S phase
tumor suppressor - preventing cell growth after chromosomal damage
How are HPV infected cell immortalized?
E6 upregulates telomerase expression
Describe the interaction between E7 and p53.
sensitizes wild-type p53 cells to undergo apoptosis & exerts an anti-apoptotic effect in cells with mutated p53
How does E7 interact with Rb? This has what impact on infected cells?
E7 binds to activated retinoblastoma (Rb) protein & promotes its degradation, removing its antiproliferative effect
What is the role of Rb in an uninfected cell?
Retinoblastoma (Rb) protein, when active, binds and inhibits E2F transcription factors that regulate genes required for cells to pass through the G1/S cell cycle checkpoint
Rb has an antiproliferative effect on the cell cycle
How does E7 interact with p21 and p27? This has what impact on infected cells?
E7 binds & inhibits p21 and p27 (cyclin-dependent kinase inhibitors)
- enhances cell cycle progression
- impairs the ability of the cells to repair DNA damage
What are the similarities & differences between Dysplasia and Carcinoma in situ in the cervix?
Similarities
- occur at transformation zone
- associated with HPV 16 & 18
Differences
- Dysplasia
- disordered growth & maturation beginning at basal layer & extending upward
- nuclei hyperchromatic w/ irregular outlines
- Carcinoma in situ
- full-thickness dysplasia with no maturation & no invasion
Which Cervical Intraepithelial Neoplasia levels are considered high grade & which are considered low grade?
- Low grade (LSIL)
- CIN I
- High grade (HSIL)
- CIN II
- CIN III
LSIL is associated with what variable?
productive HPV infection with a high level of viral replication (usually high risk HPV)
Is LSIL treated as a pre-malignant condition?
no, it is not becauseSCC does not directly arise from it, only from HSIL
- 60% LSIL regress
- 30% persist
- 10% progress to HSIL
HSIL is associated with what variable?
progressive deregulation of the cell cycle
lower rate of viral replication than LSIL
100% are associated with high risk HPV (usually type 16)
Is HSIL treated as a pre-malignant condition?
yes, all are treated as high risk for progression to carcinoma
- 30% regress
- 60% persist
- 10% progress to carcinoma
What condition is depicted by the special stain on the provided slide?
HSIL
p16 stain
strong & fairly confluent positive brown staining of both cytoplasm and nuclei
What is the function of p16?
a tumor suppressor protein that inhibits cyclin D-dependent protein kinases CDK4 and CDK6, which helps to maintain Rb in its active state
Why do HPV cells express high levels of p16?
E7 oncoprotein inactivates Rb and leads to overexpression of p16
Doe LISL stain positive or negative on a p16 stain?
negative
What is the most common cervical carcinoma?
squamous cell carcinoma (80%)
What is the biggest risk factor for developing cervical carcinoma?
HPV infection
What is the typical age of presentation of cervical carcinoma?
45yr
What pathology is shown in the provided gross sample?
Invasive Squamous Cell Carcinoma of the Cervix
(superficially invasive tumors are not grossly visible, except via colonoscopy or application of acetic acid)
The histological samples are examples of what pathology?
Squamous Cell Carcinoma of the Cervix
- Left
- small nest of invasive cells breaking through the basement membrane
- Right
- nests & tongues of malignant squamous epithelium
- may or may not produce keratin
What pathology is shown in the provided histological sample?
Adenocarcinoma
- Left: In situ
- pseudostratified, hyperchromatic nuclei
- Right: invasive
- proliferation of glands
- large, hyperchromatic nuclei, nuclear stratification & decreased cytoplasmic mucin
How does cervical SCC spread?
direct extension to contiguous tissues & via lymphatic/vascular invasion
What is the most successful cancer screening test ever developed?
Pap smear
How does the Pap smear help detect cancer?
most cervical cancers arise from precursor lesions and take years to develop
these lesions shed cells that may be detected on cytological examination
What are the two types of Pap smear processing?
- Traditional
- cells are immediately smeared on glass slide & sprayed with fixative
- Liquid
- cells placed into vial of liquid fixative that is spun down onto a slide
How is the physical collection of the pap smear performed?
transformation zone is circumferentially sampled with a “broom”, spatula or brush
What is the the specificity of the Pap smear? What variable contributes to this specificity?
70%
reactive conditions may mimic dysplasia
What is the the sensitivity of the Pap smear? What variable contributes to this specificity?
80%
- dysplastic cells may be missed or not present
- Issues with pap smear
- poor sampling
- obscuring blood or inflammation
- air-dry artifact with traditional smears
- thick or poorly prepared traditional smears
What are the three major advantages of the liquid-based processing method of a Pap smear?
What is the disadvantage
- Advantages
- morphology is better - easier to read (higher sensitivity)
- sample can also be used for molecular methods of testing
- residual material in vial can be used to prepare cell blocks & special stains
- Disadvantages
- expensive
The provided microscopic slide of a pap smear is an example of normal, LISIL or HSIL? How do you know?
Normal
- abundant cytoplasm & small, round/oval nuclei
- basal epithelial cells are smaller with relatively larger nuclei
The provided microscopic slide of a pap smear is an example of normal, LISIL or HSIL? How do you know?
HSIL
- cells are smaller than LSIL, have less cytoplasm but bigger nuclei
- higher nuclear: cytoplasm ratio
The provided microscopic slide of a pap smear is an example of normal, LISIL or HSIL? How do you know?
LSIL
- with koilocytes
- cell may be multinucleated & nuclei are hyperchromatic with irregular nuclear membranes
- higher nuclear:cytoplasm ratio than normal
What pathology is characteristic of the cells shown on the provided slides?
Squamous Cell Carcinoma
- Left
- keratinizing SCC in inflammatory background
- cells are large, pleomorphic, have large, hyperchromatic nuclei & red cytoplasm
- Right
- non-keratinizing SCC in bloody background
- cells smaller than keratinizing SCC
- higher N:C ratio
What pathology is characteristic of the cells shown on the provided slides?
Adenocarcinoma
- Left: in situ
- Right: invasive
clusters of crowded, atypical glandular cells with high N:C ratio, nuclear hyperchromasia & prominent nucleoli
When should someone get their first pap smear?
at 21 yrs or within 3 years of onset of sexual activity
At what intervals should someone get Pap smears?
every 3 years until 30 yrs
After 30
- If (-) high risk HPV
- sceened every 3-5 yrs
- If (+) high risk HPV
- screen every 6-12 months
After 65, no more screening indicated if adequate prior screening
What are the next steps after an abnormal cytology is noted on a pap smear?
perform colposcopic examination of the cervix and vagina to identify & biopsy the lesion
What is the treatment for HSIL?
- Superficial excision
- cold knife cone
- Loop electrosurgical excision (LEEP)
- Lasar ablation
- cryotherapy
What is the treatment for LSIL?
usually treated conservatively but doctors may perform local ablation
What are the steps to the colposcopic procedure?
- acetic acid is applied to the cervix & vagina
- mucosa is examine with a strong light & magnifying glass
- abnormal epithelium appears as white spots
- any aceto-white areas are biopsied
What demographic is recommended to receive the HPV shot?
all girls & boys age 11-12
young men & women up to 45 yrs
All 3 HPV vaccines protect against what two types? What additional types are covered by ⅔ vaccines?
- All 3
- 16 & 18
- ⅔
- 6 & 11
