3.1 Premalignant gynaecological conditions

Question 1

What is the criteria for screening to be good and useful?

Answer 1

Health problem: Must be an important and relevant problem

Natural history: Adequately understood and recognisable latent/early stage

Diagnosis: Availability of suitable test and acceptability to general population

Treatment: Availability of facilities and agreed policy on whom to treat

Case finding: Economically balanced (in relation to possible expenditure on medical care as a whole) and continuing process (not ad-hoc)

Question 2

Cervical cancer may result mainly from __________ or __________ → both treated the same way:
• Other types of cervical cancer include adenosquamous carcinoma (5 – 6%), small cell cancer (~3%), and other rarer types (e.g. lymphomas, sarcomas)

Answer 2

squamous lesions (squamous cell carcinoma) or glandular lesions (adenocarcinoma)

Question 3

what is a CIN 1 squamous cell cervical carcinoma?

Answer 3

mildly atypical cells confined to the lower 1/3 of the epithelium

Question 4

what is a CIN 2 squamous cell cervical carcinoma?

Answer 4

atypical cellular changes affecting the basal 2/3 of the epithelium

Question 5

what is a CIN 3 squamous cell cervical carcinoma?

Answer 5

cellular changes affecting more than 2/3 of the epithelium (including full-thickness lesions) → slow transformation into cancer

Question 6

what does CGIN stand for?

Answer 6

cervical glandular intraepithelial neoplasia

Question 7

what does AIS stand for?

Answer 7

adenocarcinoma in situ

Question 8

What are the high risk HPV types?

Answer 8

HPV type 16, 18 (most prevalent; causing 70% of cervical cancers):
• Type 16: closely related to types 31 & 33 (high risk types)
• Type 18: closely related to types 45 & 51

Question 9

What are the low risk HPV types?

Answer 9

HPV type 6, 11, 42, 43

Question 10

Cervical cancer/CIN only develops with the necessary precursor of an HPV infection.

1) Acute HPV infection Virus exclusively infects the __________________
• Disrupts cell cycle control → promotes uncontrolled cell division and accumulates genetic damage

2) Viral persistence: Virus is not cleared from the infected cells
3) Clonal progression ________________ results from cellular changes and proliferation of the infected cells
4) Invasive cervical cancer Integration of the HPV genome into the host genome → viral DNA affects normal epithelial cells and transforms them into ___________________

Answer 10

metaplastic squamous epithelium of the transformation zone (TZ);

Pre-cancer (CIN lesions) ;

dyskaryotic cells (dyskaryosis)

Question 11

The transformation zone (TZ) of the cervix is the area between the __________________ and ______________→ site of squamous metaplasia:
• Vaginal environment is acidic during the reproductive year/pregnancy → _________________ is involved in squamous metaplasia
• ________________ in the area of ectropion (where columnar cells form on the ectocervix) are exposed to acidic environment → repeated destruction → eventually replaced by newly formed metaplastic epithelium
• Metaplastic regions may become cancerous under certain exposures

Answer 11

original squamocolumnar junction and the new squamocolumnar junction;

oestrogen-induced acidity;

Columnar epithelial cells

Question 12

Squamous metaplasia in cervical cancer is cellular adaptation occurring in 3 stages
1) Reserve cell hyperplasia: Reserve cells in the _________________ start to divide

2) Immature squamous metaplasia: Proliferation to form multilayer of undifferentiated cells → surface layer of _______________
• Most susceptible to carcinogens (most cervical cancers arise here)

3) Mature squamous metaplasia: Undifferentiated cells differentiate into __________________ (almost indistinguishable from the original squamous epithelium)

Answer 12

endocervical epithelium (basal layer);

mucinous columnar cells;

mature squamous epithelium

Question 13

How is a conventional pap smear done?

Answer 13

Vaginal speculum used to hold the vaginal walls apart → sample of cells collected from the cervix using a small cone-shaped brush or tiny wooden spatula → smeared onto slide

Question 14

Why is liquid based cytology > pap smear?

Answer 14

Replaces conventional Pap smears (overcomes specimen quality issues):
• Allows ancillary testing of HPV, gonorrhoea or chlamydia from the same medium

Question 15

How does thin prep (liquid based cytology) work?

Answer 15

collection device agitated to dislodge cervical cells into the medium

Question 16

How does sure path (liquid based cytology) work?

Answer 16

collection device deposited into vial and both are sent to the lab for processing (less expensive)

Question 17

What are the categories of British Society for Colposcopy and Cervical Pathology under the results of pap smear?

Answer 17

• Normal cells: represents 90% of obtained results
• Borderline changes (< 5%): cells show some abnormality (too mild to be classified as dyskeratosis) → most resolve spontaneously
• Mild dyskaryosis (< 5%): most resolve spontaneously
• Moderate dyskaryosis (0.5%) and severe dyskaryosis (0.5%)

Question 18

What are the categories of Bethesda under the results of pap smear?

Answer 18

• Low-grade squamous intraepithelial lesion (LSIL): incorporates borderline changes and mild dyskaryosis
• High-grade squamous intraepithelial lesion (HSIL): incorporates moderate and severe dyskaryosis

Question 19

High risk HPV (HR-HPV) testing is defined by a ________________________:
• 15 – 20% of women with borderline/mild abnormalities on Pap smear have significant abnormalities which require treatment
• If they test negative for HR-HPV, they can safely return to normal Pap smear screening

Answer 19

triage of borderline/low grade abnormalities in cervical smears to identify high-risk HPV infections

Question 20

What are the uses of HR- HPV testing?

Answer 20

• triaging: Helps to avoid unnecessary anxiety/investigations with effective use of available resources
• Primary screening for cervical cancer: Replacement of the traditional Pap smear with HR-HPV as a primary screening modality is being investigated:
  • Lower specificity than Pap smear
  • May not be useful in younger sexually active women (most likely positive anyway)
• Test of cure after CIN treatment HR-HPV status tested after treatment to streamline management:
  • 6 months post-initial treatment: repeat Pap smear, HR-HPV
  • If negative HR-HPV: safely return to normal screening

Question 21

What are the indications of colposcopy?

Answer 21

abnormal screening result (HR-HPV test positive + mild/moderate/severe dyskaryosis)

Question 22

Steps of colposcopy

1) Application of _____________ to the transformation zone:
• Mapping the site and grade of any area of abnormal cells → via reversible precipitation of nuclear proteins (white-staining)
• Abnormal dyskaryotic cells: possess greater amounts of _____________ (higher grades of abnormality) → stains more __________

2) Gentle application of after _________________:
• Identification of the complete area of abnormality → via reaction of iodine with ______________
• Normal squamous cervical cells stain _________; abnormal cells do not stain

3) Small biopsy from abnormal areas → for histological confirmation of CIN and further evaluation and treatment

Answer 22

mild acetic acid;

nuclear matter;

densely white ;

water based solution of iodine

intracellular glycogen ;

brown;

Question 23

What does one do if HR- HPV testing is positive?

Answer 23

colposcopy

Question 24

What does one do if HR- HPV testing is negative?

Answer 24

no action required

Question 25

PREVENTION OF CERVICAL CANCER
The HPV vaccine contains virus-like particles (VLPs) which are _____________, and are used for prevention of cervical cancer:
• Antibodies (humoral immunity) are generated against the ____________ on outer surface + local cell-mediated immunity
o Associated with lesion regression and protection against further infection with the same genotype of HPV
• 2 vaccines are currently approved under the National Immunisation Programme:

Answer 25

capsid proteins without viral DNA (non-infectious);

conformational epitopes on the major coat/capsid protein L1

Question 26

What strains of HPV does gardisil 4 target?

Answer 26

VLP L1 of HPV 6, 11, 16, 18

Question 27

what is the adjuvant for gardasil 4?

Answer 27

Aluminium (225μg amorphous aluminium hydroxyphosphate sulfate (AAHS))

Question 28

what is the usage for gardasil 4?

Answer 28

Females and males 9 – 26 years old

Question 29

what is the dosingt for gardasil 4?

Answer 29

• 3 doses via IM injection (0, 2, 6 months) for 9 – 26 years old
• 2 doses via IM injection (0, 6 months) for 9 – 13 years old

Question 30

What strains of HPV does cevarix target?

Answer 30

VLP L1 of HPV 16, 18

Question 31

what is the adjuvant for cevarix?

Answer 31

AS04 (500μg aluminium hydroxide + 50μg 3-deacylated monophosphoryl lipid A)

Question 32

what is the usage for cevarix?

Answer 32

Females 9 – 25 years old

Question 33

what is the dosingt for cevarix?

Answer 33

• 3 doses via IM injection (0, 1, 6 months) for 9 – 25 years old
• 2 doses via IM injection (0, 6 months) for 9 – 14 years old

Question 34

what are the common side effects of hpv vaccine?

Answer 34

Pain, swelling, itching, redness at site of infection, headache, fever, nausea

Question 35

What strains of HPV does gardisil 9 target?

Answer 35

The FDA approved the nonavalent HPV vaccine (Gardasil 9®) in 2014, which is active against HPV types 6, 11, 16, 18 + additional 5 high-risk HPV types 31, 33, 45, 52, 58:
• Adjuvant: 500μg AAHS

Question 36

when is treatment for CIN indicated?

Answer 36

High percentage of lower grade dysplasia lesions spontaneously resolve (especially in young patients) → treatment is only indicated in cases of persistent dysplasia or those associated with positive HR-HPV tests

Question 37

What is surgical treatment for CIN?

Answer 37

excision of transformation zone (LLETZ: large loop excision of transformation zone) or using ablative techniques (e.g. laser vaporisation, thermocoagulation, cryotherapy)

Question 38

Endometrial cancer: 6th most common cancer in women worldwide (primarily a cancer of the developed world → incidence is double):
• Mainly affects ________________
• Most patients are diagnosed at the early stage (due to ___________________) → high survival rates
• No screening: screening tools (e.g. cytology, USS) have limited accuracy in evaluating normal population and are unlikely to decrease cancer-associated mortality

Answer 38

postmenopausal women (~60 years at diagnosis);

early presentation like postmenopausal bleeding

Question 39

Ovarian cancer: Primarily occurs in developed countries:
• Most lethal of all gynaecological cancers (advanced stage by the time of presentation for >70% of women)
• No screening because _________________

Answer 39

no identifiable pre-cancer phase (no validated screening test for early stage)

Question 40

Vaginal/ vulval cancer: Often do not cause early symptoms, but may be found during ___________________:
• No screening: very rare cancers (vaginal cancer occurs more often in _______________; vulval cancer accounts for only 1% of all genital cancers)

Answer 40

routine pelvic examinations and Pap smears;

women > 50 years