Week 6 - B - Pathology of the Cervix, Vulva&Vagina - Cervical ectropian, Nabothian follicles, Cervical Neplasia, Vulva&Vagina Neoplasia

Question 1

The outermost layer of human skin (keratin layer of the epidermis) is composed of dead stratified squamous, keratinized epithelial cells.

What is the difference between the epithelium of the ectocervix and the skin?

Answer 1

The epithelium of the ectocervix is composed of stratified squamous non-keratinizing epithelium

Question 2

What are the cells that are taken from the ectocervix for the cervical smear?

Answer 2

It is the exfoliating cells of the ectocervix which are taken during a cervical smear

Question 3

What does the word stratified when describing epithelium signify? What does the word sqaumous signify about the cells?

Answer 3

Stratified signifies two or more layers of epithelial cells Squamous signifies flattened cells

Question 4

As we move up the cervical canal we reach the transformation zone and then the endocervix What is the cell type in the endocervix? What is the transformation zone?

Answer 4

* Endocervix - cell type is columnar epithelium

* Ectocervix - cell type squamous (stratified) epithelium

Transformation zone (TZ) – Squamo-columnar junction between ectocervical (squamous) and endocervical (columnar) epithelia

Question 5

The position of the transformation zone alters during life as a physiological response to what?

Answer 5

• Menarche
• Pregnancy
• Menopause

Question 6

Which area of the cervix is the area which is predisposed to malignant change?

Answer 6

It is the transformation zone of the cervix that is predisposed to malignant change

Question 7

What is cervical ectropion? What is it also known as?

Answer 7

Cervical ectropion is a normal phenomenon where the glandular (columnar) epithelium (of the endocervix) are present on the ectocervix (where stratified squamous cells are) It is also known as cervical eversion

Question 8

What causes cervical ectropion?

Answer 8

Some woman are born with the condition cervical ectropion whereas it can be caused by: Hormonal changes - meaning it can be common in young women Pregnancy Taking the combined pill to protect from pregnnacy

Question 9

How does pregnancy, taking the combined pill to protect from pregnancy and hormone changes in young women lead to cervical ectropion?

Answer 9

This is because there is an increase in oestrogen during these times - this causes the cervical os to open exposing the endocervical cells to the ectocervix

Question 10

Why is that the cervix looks red raw in a cervical ectropion?

Answer 10

The area that the columnar cells move onto in the ectropion is red because columnar cells are red - giving the raw appearance

Question 11

As columnar epithelium is soft and glandular, it is prone to bleeding, excess mucus production and infection If these complications of the cervical ectropion are a nuisance, what can be used as treatmnet? Usually no treatment is required in this condition

Answer 11

The cervical ectropion can be treated by:

• * Discontinuing the oral contraceptive pill (therefore the oestrogen production is not there to allow the cervix to increase mucus producton)
• Or * Cryocautery - a procedure that uses very cold temperatures to treat abnormalities of the female genital tract in addition to other areas of the body such as the skin. Very cold temperatures cause tissue destruction just as very hot temperatures

Question 12

The squamocolumnar junction, where the columnar secretory epithelium of the endocervical canal meets the stratified squamous covering of the ectocervix, is located at the external os before puberty. As estrogen levels rise during puberty, the cervical os opens, exposing the endocervical columnar epithelium onto the ectocervix. This area of columnar cells on the ectocervix forms an area that is red and raw in appearance called an ectropion How does the cervical ectropion become normal squamous cells?

Answer 12

The cervical ectropion changes from the columnar cells due to the exposure of the delicate endocervical epithelium to the acidic environment of the acid leading to squamous metaplasia

Question 13

Cervical ectropion - normal due to increase in oestrogen (hormones entering puberty, contraceptive for pregnancy, pregnancy itself) - red raw appearance of cervix due to red glandular tissue - the glandular tissue goes through squamous metaplasia due to the vaginal acid environment What are the symptoms of cervical ectropion? Symptoms can be treated by discontinuation of the pill or by cryocautery

Answer 13

Symtpoms Can be associated with excessive but non-purulent vaginal discharge due to the increased area of columnar epithelium containing mucus secreting glands (glandular epithelium) Can also have post-coital bleeding - the columnar epithelium is very delicate Prone to infection due to being delicate

Question 14

What is squamous metaplasia? State an example of columnar metaplsia?

Answer 14

Squamous metaplasia is the bengin change of a type of epithelium to squamous morphology Baret’s oesopahgus - the columnar cells of the stomach invade the lower 1/3rd of the oesophagus lead the oeosphageal lining being replaced by the intestine like columnar cells

Question 15

A nabothian cyst (or nabothian follicle) is a mucus-filled cyst on the surface of the cervix. What is the usual cause of the nabothian cyst (follicle)?

Answer 15

It is usually caused when stratified squamous epithelium grows over the columnar epithelium of the endocervix - this tissue can block the cervical crypts resulting in trapped cervical mucus - leading to the endocervical glands swelling up and becoming cysts

Question 16

Nabothian cysts are considered harmless and usually disappear on their own, although some will persist indefinitely What is the usual treatment for the nabothian cyst?

Answer 16

As the cysts are harmless they are usually not treated If the cysts are discharging, cryocautery may be used

Question 17

Cervical pathology is usually inflammatory or neoplasia Two inflammatory conditions are cervicitis or cervical polyps What is cervicitis?

Answer 17

This is inflammation of the cervix possibly resulting in vaginal discharge

Question 18

WHat is the usual causative agents of cervicitis?

Answer 18

Cerviciits is most commonly caused by Chlamydia trachomatis (up to 50% of cases) but can be cause by neisseria gonorrhea (and other organisms less commonly)

Question 19

Describe the symptoms of cervicits? What can cervicitis lead to?

Answer 19

Cervicitis is often asymptomatic - can however present with a discharge - be it follicular or mucopurulent Also pain during sex or a foul smell and abnormal vaginal bleeding Cervicits can lead to pelvic inflammatory disease (PID) if not diagnosed and treated - can cause infertility due to damage to the fallopian tubes

Question 20

What is the definitive test for diagnosing chlamydia and gonorrhea in patients with cervicits?

Answer 20

Definitive test would be to carry out NAAT - nucleic acid amplification testing to determine whether the patient had cervicitis or not

Question 21

What is the treatment of cervicitis if there is chlamydia or gonorrhea diagnosed?

Answer 21

Chlamydia diagnoses - would treat with azithromycin 1g stat (can use doxyclince but required week long treatment) Gonoccoal infection - Ceftriaxone IM and azithromycin orally

Question 22

Cervical polyp is a localised inflammatory growth What can the presenting symptoms of a cervical polyp be? Are cervcal polyps usually found in the endo or ectocervix?

Answer 22

A cervical polyp is a common benign polyp or tumour on the surface of the cervical canal - usually doesn’t show symptoms Cervical polyp is usually found in the endocervix Symptoms - can present with a mucus discharge or post-coital bleeding

Question 23

99% of cervical polyps will remain benign and 1% will at some point show neoplastic change. Cervical polyps are unlikely to regrow. What can be done to confirm the nature of the growth in the cervix? Ie to confirm that it is a polyp

Answer 23

Dilation and curettage (dilate the cervix and then curettage) - A D&C may help diagnose or treat growths such as fibroids, polyps, hormonal imbalances, or uterine cancer. A sample of uterine tissue is viewed under a microscope to check for abnormal cells.

Question 24

When is the dilation and curettage usually carried out for a cervical polyp?

Answer 24

IN younger woman - the cervical polyp can simply be avulsed Dilatation and curettage is usually done in older woman to exclude intrauterine pathology

Question 25

Cervical pathology

• .Neoplastic
  
  • * Cervical Intraepithelial Neoplasia (CIN)
  • * Cervical Cancer
    
    • * Squamous carcinoma
    • * Adenocarcinoma

What is the most common type of cervical carcinoma?

Answer 25

Squamous type carcinoma account for 75-95% of malignant cervical tumours Adenocarcinoma account for 5-25% of malignant cervical tumours

Question 26

Many different types of cervical cancer but squamous and adenocarcinoma are commonest What is the pre-invasive type of cervical carcinoma known as?

Answer 26

The pre-invasive type of cervical cancer is known as Cervical Intrapeithelial Neoplasia

Question 27

The human papilloma virus has a circular, double stranded DNA, protected by capsid proteins What is a capsid?

Answer 27

A capsid is the protein shell of a virus Capsid is the green Remember HPV is a double stranded DNA

Question 28

Infection by HPV infects epithelial cells in the cervical mucosa. HPV then integrates into the cellular genome to cause cervical cancer. What are the two main types of HPV causing cervical cancers? Account for approx 70% of HPV cancers

Answer 28

The two main types are HPV 16 and 18

Question 29

What is the vaccine that protects against cervical cancers? Who is it given to?

Answer 29

The vaccine is known as gardasil - protects against HPV strains 6,11,16 and 18 Given to females aged 12-13 years - 2 injections 6 months apart

Question 30

Infection by HPV affects the epithelial cells – HPV can undergo vral replication causing changes in the nucleus – the virus moves t the surface and therefore is present in the surface exfoliating cells 90% of women heal within two years A small percentage (0.8) go on to develop cancer - we can treat the people What cells do HPV infect to start the spread of their replication?

Answer 30

HPV infects the basal cells of the tissue The basal cells are where the mitoses of cells is in normal epithelium before the new cells then spread to the top of the epithelium

Question 31

What is seen as risk factors for cervical cancer?

Answer 31

Early age at first intercourse Smoking increases the risk High parity And Long term use of combined oral contraceptive - 5 years use - should return to baseline after 10 years without use

Question 32

Which HPV viruses cause warts? Which cause anogenital warts? State again risk factors for cervical cancer?

Answer 32

HPV types 1-4 - causes palmar and plantar warts HPV types 6 & 11 - anogenital warts * Smoking * Long term (>5 years) use of combined oral contraceptive * High parity * Early first intercourse

Question 33

What is koilocytosis?

Answer 33

Koilocytosis is the process through which a squamous epithelial cell undergoes a number of structural changes, occurring as a result of infection by the human papilloma virus The squamous epithelial cell is now known as a koilocyte

Question 34

Describe again what koilocytosis is?

Answer 34

Koilocytosis is the process via which a squamous epithelial cell undergoes structural changes as a result of infection by human papilloma virus

Question 35

Describe the cell changes in a koilocyte? (can be 4) ThinPrep pap smear with group of normal cervical cells on left and HPV-infected cells showing features typical of koilocytes:

Answer 35

Nuclear enlargement - two to three normal size There is an irregularity of the nuclear membrane colour The nucleus stains dark (hyperchromasia) There is clear area around the nucleus (perinuclear halo)

Question 36

How long does it take for a HPV infetion to cause a high grade CIN infection? How long does it take for the high grade CIN infection to become Invasive cancer?

Answer 36

HPV infection - high grade CIN infection - 6 months to 3 years High grade CIN infection - INvasive Cancer - 5 years to 20 years Hence the estimation of 10-30years from infection time until cancer begins

Question 37

80% cumulative prevalence in a lifetime Most develop immunity Persistence increases risk of disease This would be called mild dyskaryosis – CIN 1 in the biopsy – biopsy taken via colposcopy What does dyskaryosis mean?

Answer 37

Dyskaryosis means abnormal nucleus and refers to the abnormal epithelial cell which may be found in cervical sample. It is graded from low to high grade based on degree of abnormality.

Question 38

Describe the features of cervical intraepithelial neoplasia Where does it occur? Can you see it? Symptoms? How is it detected?

Answer 38

* Pre invasive stage of cervical cancer * Occurs at the transformation zone * Can involve a large area * Dysplasia of squamous cell * Not visible to the naked eye * Asymptomatic * Detected by cervical screening Women who present with post coital bleeding should be worrying as CIN is asymptomatic and therefore cervical cancers need to be considered

Question 39

This slide is a diagram of cervical epithelium showing progressive degrees of dysplasia and neoplasia, and the correlating terminology. Describe each of the stages of CIN?

Answer 39

CIN 1 - basal 1/3rd of the epithelium occupied by abnormal cells

• * Raised number of mitotic figures in lower 1/3rd

CIN 2 - abnormal cells extend to the middle 1/3rd

• * Mitoses in middles 1/3rd
• * Abnormal mitotic figures

CIN 3 - abnormal cells occupy full thickness of epithelium

• * Mitoses and abnormal cells often in upper 1/3rd Often koilocytes present in each CIN stage

Question 40

When describing the histological features of CIN - usually there is immature basal cells occupying more of the epithelium - hence why mitotic figures are present Describe the changes to the nuclus?

Answer 40

The nucleus stains darker (hyperchromasia) Nucleocytoplasmic ratio is increased - still have the clear border around the nucleus of cytoplasm (perinuclear halo) Irregularity of the nucleu membrane

Question 41

Describe which stage of cervical intraepithelial neoplasia this would be?

Answer 41

This would be CIN 3 - this means there is full epithelial thickness of abnormal cells as seen Mitoses and abnormal mitotic figures may also be present in the upper 1/3rd

Question 42

Describe which stage of cervical intraepithelial neoplasia this would be?

Answer 42

This would be CIN 1 Can see the abnormal cells ar eonly affecting the basal 1/3rd of the epithelium

Question 43

Describe which stage of cervical intraepithelial neoplasia this would be?

Answer 43

This would be CIN 2 The abnormal mitotic cells are affecting up to the middle 1/3rd of the epithelium (can see the top of the epithelium has unaffected cells)

Question 44

Most cases of CIN 1 will regress (most is cleared) – not common for low grade CIN will progress to high grade How does CIN 3 grade invade the stroma? (layers beneath the epitheium - smooth muscle, fibrous and elastic tissue)

Answer 44

CIN 3 - invades the endocervical crypts/glands as it expands until the cells break through the basement and into the stroma - now known as invasive cancer

Question 45

If you’ve had an abnormal cervical screening test result, or your symptoms suggest that you may have cervical cancer, what will your gynaecologist usually carry out?

Answer 45

If you’ve had an abnormal cervical screening test result, or your symptoms suggest that you may have cervical cancer, your gynaecologist will usually carry out a colposcopy. This examination looks for abnormalities in your cervix. During a colposcopy, a small microscope with a light source at the end (colposcope) is used. As well as examining your cervix, your gynaecologist may remove a small tissue sample (biopsy) so that it can be checked under a microscope for cancerous cells.

Question 46

How is cervical screening carried out?

Answer 46

Cervical screening is carreied using something known as a PAP smear The Papanicolaou test is a method of cervical screening used to detect potentially pre-cancerous and cancerous processes in the cervix

Question 47

Invasive squamous carcinoma accounts for 75-95% of malignant cervical tumours How common is invasive squamous cancer worldwide in females? Develops from pre-existing CIN, therefore most cases should be preventable by screening What is the cervical screening programme?

Answer 47

Invasive squamous cancer is the 2nd most common female cancer in worldwide The screening programme in Scotland Those aged 25-49 screening every 3 years Those aged 50-64 screened every 5 years Over 64 - only women who havent been screened since 50 or abnormal tests in the last 3 tests

Question 48

Whilst 2nd commonest female cancer worldwisde, 12th commonest female malignancy in Scotland – due to the successful screening programme If after PAP smear and colposcopy, the patient is found to have cancer WHat is the type of biopsy taken to confirm diagnosis histologically and identify subtype? What is the other option and why isnt it carried out as regularly?

Answer 48

Type of biopsy taken is usually a LLETZ biopsy (Large Loop Excision of the Transformation Zone) - this can be performed under local anaesthetic and allows tissue to be examiend LLETZ uses a small wire loop with an electrical current running through it to cut away the affected area of tissue and seal the wound at the same time. Other option is a cone biopsy – not carried out as much as it requires general anaesthetic

Question 49

Invasive squamous carcinoma has stage 1 to stage 4 Describe stage 1 of invasive squamous carcinoma? (Stage 1A1, 1A2 and 1B)

Answer 49

Stage 1A1 - cancer up to depth 3mm and , depth up to 7mm Stage 1A2 - depth up to 5mm, width up to 7mm Stage 1B - cancer confined to the cervix (anything width over 5mm or depth 7mm that is confined to the cervix)

Question 50

Describe stage 2 of grading invasive cervical carcinoma Can try Stage 2 A1 and Stage 2 A2 and Stage 2B if feeling ambitious (to do with extension into the vagina)

Answer 50

Invades beyond the cervix but not to the lateral side wall or to the distal 1/3rd of the vagina Stage 2 A1 - beyond the cervix and only involves 4cm of the vagina Stage 2B involves the parametrium

Question 51

What is the parametrium?

Answer 51

The parametrium is the fibrous tissue that separates the supravaginal portion of the cervix from the bladder

Question 52

Describe stage 3 of the staging of cervical carcinoma? (Stage IIIA and IIIB)

Answer 52

Stage IIIA: involves lower third of the vagina Stage IIIB: extension to the pelvic sidewall, non-functioning kidney, or hydronephrosisl

Question 53

Describe stage 4 of the cervical carcinoma staging? (Stage 4A and B)

Answer 53

Stage IV A - cancer has local metastases to bladder or rectum Stage IV B - cancer has extensive metastases to distant organs

Question 54

Now describe all the stages of invasive cervical carcinoma * Stage IA1, IA2 and IB * Stage IIA1, IIA2 and IIB * Stage IIIA and IIIB * Stage IVA and IVB

Answer 54

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Question 55

After confirming abnormal smear on PAP test, then using colposcopy to give CIN grade or diagnose cancer, then biopsy to diagnose cancer histologically and identify subtype, what is used to stage the cancer?

Answer 55

USually use CT/MRI scan for cancer staging

Question 56

What are the symptoms of invasive carcinoma of the cervix? At which stage does ureteric obstruction cause hydronephrosis?

Answer 56

Symptoms * Abnormal bleeding * Post-coital * Post-menopasual (not as common) * Pelvic pain * Ureteric obstruction/renal failure - this is stage IIIb

Question 57

Friability - the condition of being friable, describes the tendency of a solid substance to break into smaller pieces under duress or contact, especially by rubbing. The opposite of friable is indurate. Why is it that the cervical tumour is said be friable?

Answer 57

This is because the tumour bleeds on contact - often provoked by sexual intercourse

Question 58

There are usually no symptoms at the microinvasive lesions When is the tumour said to be macroscopic?

Answer 58

Macrscopic is Stage 1b

Question 59

Cervical cancer when bigger – post coital bleeding or post menopausal bleeding – can have discharge Women with advanced cancer can also present with pelvic pain What are the ways in which cervical cancer can spread?

Answer 59

Local - uterine body, vagina, bladder, rectum Lymphatic - pelvic / paraaortic nodes Haemategenous - liver, lungs, bone

Question 60

As well as staging the invasive cervical squamous carcinoma, the cancers are also graded Well differentiated Moderately differentiated Poorly differentiated Undifferentiated / anaplastic What does a well differentiated cancer mean?

Answer 60

This means to say that the cancer looks squamous A poorly differentiated cancer means to say it is difficult to diagnose whether it is squamous or adenocarcinoma

Question 61

In well differentiated squamous carcinomas – can see the keratin produced Where is the kertin in this picture?

Answer 61

Can see the big pink swirl that is the keratin

Question 62

What is often carried out for treatment of CIN 1-3?

Answer 62

CIN1 - often regresses itself If CIN2or3- LLETZ biopsy may be recommended to remove cancerous cells

Question 63

What is the advised treatment for the different stages of invasive cervical squamous cancer? Stage 1A1 - conservative? Stage 1AII-IIA - surgery vs chemoradiation? (tumour being 4cm or less) Stage IIB onwards WHat is the chemotherapy drug of choice?

Answer 63

Stage IA1 - Manage conservatively with cone biopsy (total hysterecotmy if the cone margins have tumour cells)

• * Stage IAII - IIA - radical hysterectomy with lymphadenectomy
• * (For tumours 4 cm or less (Stage IB1 and IIA1 ), radical hysterectomy with lymphadenectomy is preferred to chemoradiation. For tumours larger than 4 cm (Stage IB2 and IIA2), chemoradiation is preferred. )
• * Stage IIB onwards - chemoradiation is the main therapy used - cisplatin

Chemoradiation from stage Ib is a safe bet for a question https://www.cancer.org/cancer/cervical-cancer/treating/by-stage.html https://cks.nice.org.uk/cervical-cancer-and-hpv#!scenario:1

Question 64

Stage IA1 - Manage conservatively with cone biopsy (radical trachelectomy if the cone margins have tumour cells - removes cervix and upper vagina) Stage IIB onwards - chemoradiation is the main therapy used - cisplatin Describe again hwo radical hysterecomty/chemotherapy is decided for tumours FIGO staged IA2 to IIA1?

Answer 64

Basically If the tumour is less than or equal to 4cm with no parametrial invasion, then carry out radical hysterecotmy with lymphadenectomy If tumour is greater than 4cm -then chemoradiation * Stage IB1 - less than 4cm - radical * Stage IB2 - greater than 4cm so chemoradation * Stage IIA1 - less than 4cm so radical * Stage IIA2 - greater than 4cm so chemoradiation Safe bet - anything for IB2 and above is chemoradiation

Question 65

What is the preinvasive form of the endocervical adenocarcinoma? What proportion of cervical carcinomas do adenocarcinomas account for?

Answer 65

Cervical glandular intraepithelial neoplasia (CGIN) Adenoarcinomas account for 5-25% of cervical carcinomas

Question 66

CGIN is the preinvasive form of endocervical adenocarcinoma Where does it arise? Why is it more difficult to screen for? What are the different stages of CGIN?

Answer 66

Arises from the endocervix glandular tissue Difficult to screen for as the smear only reaches the transformation zone, cannot reach the endocervix Different stages - only have CGIN - if preinvasive then CGIN, if invasive then endocervical adenocarcinoma

Question 67

Endocervical adenocarcinoma 5-25% of cervical cancer ?Increasing incidence, particularly in young women Some are mixed (adenosquamous) ? arise from common cell of origin Do squamous or adenocarcinoma have a worse prognosis?

Answer 67

Adenocarcinomas have a worse prognosis as they are very aggressive tumours

Question 68

Adenocarcinomas of the cervix are also associated with HPV WHich HPV is found to be particularly causative?

Answer 68

HPV 18

Question 69

What is the advised treatment for endocervical adenocarcinoma?

Answer 69

The advised treatment is radical hysterectomy Radical hysterectomy – the womb and surrounding tissues are removed, including the fallopian tubes, part of the vagina, ovaries, lymph glands and fatty tissue Cone biopsy (a possible option for women who wish to have children). The cone specimen must have no cancer cells at the edges, and the woman must be closely watched after treatment. Once the woman has finished having children, a hysterectomy is recommended.

Question 70

All looked at in 1/3rds – ie upper (VIN III) , middle or lower (VIN I) 3rd affected WHat two types of women are usually affected by vulvar intraepithelial neoplasia? If it becomes invasive, what is the main type? WHo usually gets invasive?

Answer 70

Young women - often multifocal, recurrent or persistent causing treatment problems

Older women - greater risk of progression to invasiva squamous carcinoma of the vulva

Vulva carcinoma is very rare and usually only occurs in the elderly 90% are squamous Also have melanoma and others

Question 71

VIN is Often, but not always, HPV related. Differentiated VIN – higher risk of invasive maligannact and typically in older women If there is even 1mm of depth of invasion in vulvar invasive squamous carcinoma, what are you at risk of and what should be carried out?

Answer 71

If even 1mm depth invasion, at risk of lymphovascular spread to inguinal lymph nodes and therefore radical vulvectomy with inguinal lymphadenectomy is recommend

Question 72

WHat is vulvar pagets disease?

Answer 72

Vulvar Paget’s disease is very rare malignancy originating in vulvar apocrine-gland-bearing skin cells or as a manifestation of adjacent primary anal, rectal or bladder adenocarcinoma. It is also called extramammary Paget’s disease and affects both sexes, in the vulvar, perineal or scrotal areas. Usually a non-invasive andeoacarcinoma

Question 73

What are the symptoms of paget disease of the vulva? What do the tumour cells in the epidermis of paget disease of the vulva contain?

Answer 73

Crusting rash. Maybe an itching and buring and redness The tuomour cells contain mucin

Question 74

Vaginal Intraepithelial Neoplasia (VaIN) * .1. VaIN :Vaginal intraepithelial neoplasia. May also have cervical and vulval lesions. * 2.Squamous carcinoma: Less common than cervical and vulval counterparts. A disease of the elderly. * 3.Melanoma: Rare. May appear as a polyp. What is the most common vaginal tumour?

Answer 74

Most common is a squamous carcinoma of the vagina - vagina is lined by squamous epithelium and therefore after a VaIN 3 comes squamous carcinoma of the vagina

Question 75

What is clear cell adenocarcinoma of the vagina associated with?

Answer 75

This is associated with exposure to diethylstillbesterol during pregnancy - very rare