Pre-invasive disease of the lower genital tract

Question 1

Regarding cervical intraepithelial neoplasia (CIN):

The epithelial cell nuclear abnormality found in CIN1 is only seen in the lower-third of the epithelium

Choose one
True
False

Answer 1

True

The answer is true. The cells next to the basement epithelium of the cervix are termed basal cells and are undergoing active mitosis. They begin to mature and migrate towards to the surface (superficial zone) via the mid zone. Cells with nuclear abnormalities (dyskaryosis; for example, pleomorphisim), increased nuclear cytoplasmic ratio, and nuclear enlargement, that are found predominantly in the lower third are termed CIN1. If these cells are found in the upper thirds and are more dyskaryotic then the epithelium is termed CIN2 and 3.

Question 2

Regarding cervical intraepithelial neoplasia (CIN):

Approximately 5% of women with untreated CIN3 are expected to develop invasive cancer over 20 years.

Choose one
True
False

Answer 2

The answer is false. It is unclear exactly what proportion of women will develop invasive malignancy.

As part of an unethical clinical study in New Zealand, women with CIN3 were left untreated. Analysis of the long-term follow-up of these women provides the most valid direct estimates yet available of the rate of progression from CIN3 to invasive cancer. In 143 women managed only by punch or wedge biopsy (i.e. inappropriate treatment), cumulative incidence of invasive cancer of the cervix or vaginal vault was 31.3% at 30 years, and 50.3% in the subset of 92 such women who had persistent disease within 24 months of initial diagnosis. However, cancer risk at 30 years was only 0.7% in 593 women whose initial treatment was deemed adequate or probably adequate, and whose treatment for recurrent disease was conventional.

Question 3

Regarding cervical intraepithelial neoplasia (CIN):

With the development of cervical screening, the incidence of cervical cancer in the UK is falling

Choose one
True
False

Answer 3

True

The answer is true. The mortality from cervical cancer in the UK was falling prior to the introduction of the national screening programme by 1.5% per year. Following the introduction of an organised programme the rate of decline was 7%. The incidence of cervical cancer fell by 26% between 1992 and 1997.

Question 4

Regarding cervical intraepithelial neoplasia (CIN):

Vulval intraepithelial neoplasia (VIN) in young women is ideally treated by vulvectomy

Choose one
True
False

Answer 4

False

The answer is false. The majority of VIN in young women is of a high grade type associated with HPV infection and is classically basalo-warty VIN. In comparison, the older population generally has a low-grade VIN associated with chronic dermatoses, such as lichen sclerosis, lichen simplex and dermatitis. The chance of malignancy in this older population is much smaller than the younger population.

Although there is a significant but undermined risk of malignancy in the younger population, a vulvectomy is not normally performed due to the disfiguring nature and long-term physical and psychological consequences of the procedure. Local and less radical excisional techniques are used. It is imperative that long-term follow-up of these women occurs as there is still a significant risk of invasive disease in the remainder of the vulva.

Question 5

Regarding cervical intraepithelial neoplasia (CIN):

The mean age at diagnosis of VIN has fallen over recent years

Choose one
True

Answer 5

True

The answer is true. This is probably related to HPV infection but may also be as a result of increased awareness of the disease in terms of patient presentation and diagnosis.

Question 6

Regarding human papillomavirus (HPV) infection:

All HPV infections of the genital tract cause preinvasive disease, which can progress to invasive cancer

Choose one
True
False

Answer 6

False

The answer is false. HPV types 6 and 11 are associated with genital warts that are not usually associated with preinvasive and invasive disease.

Question 7

Regarding human papillomavirus (HPV) infection:

HPV 16 is a causative factor in more than 50% of cervical cancers

Choose one
True
False

Answer 7

True

The answer is true. HPV 16 accounts for about 65% of cervical cancers with HPV 18, 33 and 31 being the next most important (6, 5 and 4%, respectively).

Question 8

Regarding human papillomavirus (HPV) infection:

As HPV infection is more common in younger women (20–24 years), HPV testing is most useful in this group

Choose one
True
False

Answer 8

False

The answer is false. Although the rate of infection in young people is much higher than the older population, after exposure to HPV, a cell-mediated immune response is mediated, which is effective in the majority of people over a period of 6–12 months. Thus, testing young women as part of a screening programme is unhelpful as the rate of HPV-positive women is high and the majority of these women will not develop high-grade or persistent CIN. There is some evidence that there may be a role for HPV testing as part of a screening programme in the triage of women with low-grade smears and in the follow-up of women after treatment of CIN.

Question 9

Regarding human papillomavirus (HPV) infection:

HPV virus-like particle (VLP) vaccine trials have demonstrated a reduction in HPV infection for vaccinated individuals

Choose one
True
False

Answer 9

rue

The answer is true. This forms the basis of the vaccines currently available for the prevention of CIN.

Question 10

Regarding human papillomavirus (HPV) infection:

The HPV E7 protein binds to p53

Choose one
True
False

Answer 10

False

The answer is false. Cells of the cervix normally exit the cell cycle to undergo differentiation. The HPV virus uses the cell cycle to replicate and the rationale of the virus is to force the cell into a synthetic state resembling the synthesis (S) phase of the cell cycle. The virus does this with E6 and E7 proteins, which interact with the cellular proteins of p53 and pRB, respectively. This interruption of the cell cycle results in the abnormal proliferation of cells and causes dyskaryosis.

Question 11

Are the following risk factors for the development of cervical/vulval intraepithelial neoplasia?

A - HPV infection
B - A high-fat diet
C - Early age of first intercourse
D - Multiple sexual partners
E - Excessive alcohol consumption
F - Smoking

Answer 11

A - TRUE
B - FALSE 
C - TRUE
D - TRUE 
E - FALSE
F - TRUE

Question 12

Are the following are risk factors for the development of CIN/VIN?

A - BRCA mutation positive
B - Sun exposure
C - Immunocompromise
D - Tampon use
E - Low socioecomonic status
F - Lack of physical exercise

Answer 12

A - FALSE
B - FALSE 
C - TRUE
D - FALSE
E - TRUE 
F - FALSE

Question 13

Original squamocolumnar junction

• Is it visible with naked eye
• Inner or outer margin of TZ

Answer 13

Original squamocolumnar junction

• not visible with naked eye
• Outer margin of TZ

Question 14

Are the following colposcopic findings associated with CIN?

A - Acetowhite change
B - Iodine negative
C - Thickened epithelium
D - Punctation
E - Mosaicism
F - Atypical vessels

Answer 14

A - TRUE
B - TRUE 
C - FALSE
D - TRUE 
E - TRUE 
F - TRUE

Application of acetic acid to atypical epithelium results in temporary coagulation of cytokeratins within the surface epithelium. This is seen as whitening. Dysplastic cells have a higher nuclear cytoplasmic ratio and the acetic acid causes dehydration of the cells. Cells with less cytoplasm, i.e dysplastic cells, will dehydrate more easily and will reflect more light than those that are not dysplastic; further enabling the differentiation of dyplastic cells from normal cells. The finding of acetowhite epithelium is not in itself diagnostic of intraepithelial neoplasia as it can occur for other reasons, such as HPV infection, in the presence of healing tissue and also invasive disease.

Iodine stains normal tissue brown due to its glycogen content and fails to stain abnormal squamous epithelium as a consequence of poor glycogenation (Schiller’s test).

Question 15

Following cover:
Gardasil® –
Cervarix® –

Answer 15

Gardasil® – quadrivalent (6, 11, 16 and 18)

Cervarix® – bivalent (16 and 18); used in the UK.

Question 16

Regarding preinvasive diseases of the cervix:

Colposcopy can only be performed by gynaecologists

Answer 16

False

The answer is false. Other healthcare professionals can perform colposcopy, including GPs and nurses. It is imperative, however, that they have been appropriately trained under the auspices of the British Society of Colposcopy and Cervical Pathology (BSCP) and continue their registration with this society, which involves audit of their own practice and attendance at recognised educational meetings. A colposcopist should work in an accredited colposcopy department

Question 17

Regarding preinvasive diseases of the cervix:

In the UK, all women are referred for colposcopic examination of the cervix if they are found to have an abnormal smear

Answer 17

False

The answer is false. Not all women with abnormal smears are referred for colposcopic assessment. Those women with a borderline nuclear result will have repeat testing, and if three smears results show borderline abnormalities, a referral for colposcopy is made. The chance of high-grade lesions in this group is low and there is a high chance that the smear will be normal on repeat assessment.

Question 18

Regarding preinvasive diseases of the cervix:

A total of 30% of smears taken using conventional techniques are unsatisfactory and are unable to be interpreted by cytologists

Answer 18

False

The answer is false. Approximately 10% of conventional smears are deemed unsatisfactory. They may be too heavily blood stained or there may be drying of the cells before fixation, which makes it difficult for the cytologist to read the smear. The use of liquid-based cytology reduces the incidence of unsatisfactory smears.

Question 19

Regarding preinvasive diseases of the cervix:

HPV 16 is the high-risk HPV type most commonly found in high-grade cervical lesions and also in cervical cancer

Answer 19

True

The answer is true. HPV 16 accounts for about 65% of cervical cancers with HPV 18, 33, and 31 being the next most important (6% 5% and 4%, respectively).

Question 20

Regarding preinvasive diseases of the cervix:

Five HPV types cause 50% of cervical cancers worldwide

Answer 20

False

The answer is false. HPV 16 accounts for about 65% of cervical cancers with HPV 18, 33, and 31 being the next most important (6% 5% and 4%, respectively)

Question 21

Regarding preinvasive diseases of the lower genital tract:

There is an incidence of occult microinvasive disease in biopsy specimens of VIN (10–20%) and so biopsy should be undertaken prior to ablative treatment

Answer 21

True

The answer is true. Biopsy is essential in such circumstances to rule-out occult malignancy. The depth of invasion could affect the choice of treatment modalities.

Question 22

Regarding preinvasive diseases of the lower genital tract:

Colposcopy should not be performed during pregnancy

Answer 22

False

The answer is false. Colposcopy can safely be performed in pregnancy. A woman who meets the criteria for colposcopy still needs colposcopy if she is pregnant. The primary aim of colposcopy for pregnant women is to exclude invasive disease and to defer biopsy/treatment until the woman has delivered. Colposcopy in pregnancy is difficult and should be performed by an experienced colposcopist. If a pregnant woman with previous normal smears has gone beyond 3 years without having a smear, then the smear may be taken up to 20 weeks of gestation. If a previous smear was abnormal and in the interim the woman becomes pregnant the smear should not be delayed.

Question 23

Regarding preinvasive diseases of the lower genital tract:

HPV testing is known to have a high negative predictive value (96–99%), as women who are negative for high-risk HPV can be considered free of cervical cancer or CIN

Answer 23

True

The answer is true. The negative predictive value of HPV testing (the proportion of patients with negative test results who are correctly diagnosed, i.e. those without HPV on who do not have CIN, is very high, which could make the test very useful for the follow up of patients with CIN. Those who are negative for HPV could be discharged. Primary HPV screening in isolation is unhelpful due to the high prevalence of the virus in the population; however, it may be useful in the older population whose HPV rate is lower. Combing the results of HPV testing and with low-grade smears could be useful in reducing the number of patients to the colposcopy clinic. Patients who are negative for HPV and who have a low-grade smear have a very low risk of CIN.

Question 24

A 27-year-old nulliparous woman is seen in colposcopy following a smear report of severe dyskaryosis. Colposcopy reveals a transformation zone with large areas of dense acetowhite epithelium consistent with CIN3. 
What is the most appropriate management for this patient?

HPV testing of the smear
Loop excision of the cervical transformation zone
Repeat colposcopy in 12 months
Repeat smear in 6 months
Single punch biopsy from the transformation zone

Answer 24

Loop excision of the cervical transformation zone
The correct answer is loop excision of the cervical transformation zone. A severely dyskaryotic smear is associated with the colposcopic finding of high-grade CIN (CIN2/3) in 80–90% of cases. This risk increases with the size of the lesion. Punch biopsy may underestimate the degree of CIN in up to 57% of cases and a single biopsy is likely to underrepresent a large lesion.

Question 25

A 34-year-old woman is referred for colposcopy by her GP with a cervical smear that shows ‘mild dyskaryosis’. Her BMI is 35 and she has smoked 20 cigarettes a day since the age of 14. She has had four children, all normal vaginal deliveries, and has been using the combined oral contraceptive pill for the past 3 years. At colposcopy you note thin, smooth acetowhite lesions with well-demarcated margins. She is keen to discuss management with you.

Which of the following options is most suitable for her?

Hysterectomy
Knife cone biopsy
Large loop excision of the transformation zone
Laser cone biopsy
Punch biopsy

Answer 25

Punch biopsy
The correct answer is punch biopsy. Firstly, although it is ideal to refer to colposcopy, it is acceptable to repeat the smear within primary care prior to referral. Low-grade CIN is often seen as thin, smooth acetowhite lesions with well-demarcated, but irregular, feathery or digitating or angular margins. A punch biopsy will identify whether this is likely CIN 1 or something more sinister. In order to prevent progression to invasive disease, there is a general consensus that CIN 2 and CIN 3 should be treated. CIN 1 probably does not require immediate treatment, as it has a much lower malignant potential than the higher grades, and in many cases will resolve spontaneously. Approximately 50% of women with low-grade cytological abnormality who are not treated at the first visit will eventually revert to normal cytology and colposcopy. With CIN 1, which has a low malignant potential and will usually resolve spontaneously, it is important to encourage the woman to quit smoking and if persistent may be treated (excision/ablation).

Question 26

A 29-year-old woman is referred to colposcopy by her GP. Her cervical smear shows ‘moderate dyskaryosis’. Her BMI is 29. She has had two children, all normal vaginal deliveries, and has been using the combined oral contraceptive pill for the past 2 years. At colposcopy you note coarse vascular patterns with punctation and mosaicism and large dense acetowhite lesions with irregular margins. She is keen to discuss management with you.

Which of the following options is most suitable for her?

Follow up in colposcopy clinic
Hysterectomy
Knife cone biopsy
Large loop excision of the transformation zone
Punch biopsy

Answer 26

Large loop excision of the transformation zone
The correct answer is large loop excision of the transformation zone. The findings of the colposcopic examination suggest high grade CIN, possibly CIN 3. With moderate and severe dyskaryosis, if the colposcopic appearance is of high grade disease, then it is important to offer the patient LLETZ. This can be followed up with a test of cure high risk HPV testing and cytology in 6 months. Treatment of CIN 2/3 may be undertaken at the time of initial colposcopic assessment and, in this case, it is referred to as ‘see and treat’. In this situation, the treatment must be excisional in order for an histopathological assessment to be made.

Question 27

Pre-invasive disease of the cervix occurs within the transformation zone. The cervical transformation zone is defined by two colposcopic or anatomical landmarks.
What best describes the boundaries of the cervical transformation zone?

External cervical os and new squamo-columnor junction
External cervical os and original squamo-columnor junction
Internal cervical os and new squamo-columnor junction
Internal cervical os and original squamo-columnor junction
Original squamo-columnor junction and new squamo-columnor junction

Answer 27

Original squamo-columnor junction and new squamo-columnor junction