(46) Diseases of the reproductive system 1 Flashcards
What does VIN stand for?
Vulval intraepithelial neoplasia
What does CIN stand for?
Cervical intraepithelial neoplasia
What does CGIN stand for?
Cervical glandular intraepithelial neoplasia
What does VaIN stand for?
Vaginal intraepithelial neoplasia
What does AIN?
Anal intraepithelial neoplasia
What is dysplasia?
The earliest morphological manifestation of multistage process of neoplasia
What are the benefits of recognising dysplasia?
The cells show cytological features of malignancy but no invasion (in-situ disease)
no invasion = no metastasis = curable
Gives chance to treat potentially fatal tumour before it arises
What may happen if a dysplasia is left untreated?
Significant chance of developing invasive malignancy
Describe the main structural features of the human papilloma viruses (HPVs)
- double stranded DNA virus
- 7.9kb circular genome
- 7 ‘early genes’
- 2 ‘late’ genes
How many different types of HPV is there?
Over 100 subtypes, based on DNA sequence
Different types affect different tissues and cause different things
Is HPV common or rare?
Common - in most women, HPV will not cause long term harm and will be cleared by the immune system in most cases
How are HPVs divided/classified?
Into low and high oncogenic risk
What are low risk HPVs associated with?
Genital warts and other low-grade cytological abnormalities
What are the most common low risk HPVs?
HPV 6 and 11
What are high risk HPVs associated with?
High-grade pre-invasive and invasive disease
What are the most common high risk HPVs?
HPV 16 and 18
What proportion of cervical cancers contain HPV DNA?
99.7% of cervical cancers contain HPV DNA
Which types of HPV cause most cervical cancers?
Types 16 and 18 are associated with 70% of cervical cancers
What do low risk HPV 6 and 11 cause?
Lower genital tract warts (condylomas = benign squamous neoplasms), low grade INs (intraepithelial neoplasias)
- vary rarely in malignant lesions
What do high risk HPV 16, 18, 31 and 33 cause?
High grade intraepithelial neoplasia (IN) and invasive carcinomas
Why is the cervix painted with acetic acid in diagnostics?
Abnormal epithelium becomes ‘acetowhite’ (appears white when you put acetic acid on it) - colposcopist can recognise the pattern of acetowhite which has a high risk of being due to CIN
The Gardasil (Merck) vaccine protect against which HPV types?
6, 11, 16, 18
The Cervarix (MSK) vaccine protects against which HPV types?
16, 18
How has the UK HPV vaccination programme changed?
- began in sept 2008
- started with cervarix
- age 12-13 with catch up up to 18
- switch to gardasil in sept 2012
What are HPV early genes involved in?
- early genes are expressed at onset of infection
- they control viral replication
- in oncogenic viruses, they are involved in cell transformation
What do HPV late genes code for?
Capsid proteins
High risk HPVs integrate into host chromosomes and do what?
Upregulates E6 and E7 expression (E6 and E7 = early genes)
High risk HPVs cause up regulation of E6 and E7 (early genes). What does E6 do?
Binds to and inactivates p53 - this leads to accumulation of genetic damage
What is the role of p53?
‘guardian of the genome’ - p53 mediated apoptosis in response to DNA damage
Therefore, inactivation by E6 leads to accumulation of genetic damage
High risk HPVs cause up regulation of E6 and E7 (early genes). What does E7 do?
Binds to RB1 gene product - this leads to dysregulation of cell proliferation
What is the role of RB1?
It is a tumour suppress gene - it controls the G1/S checkpoint in the cell cycle
Therefore, binding of E7 to the RB1 gene product leads to dysregulation of the cell cycle/ cell proliferation
What are the 2 types of vulval intraepithelial neoplasia (VIN)?
- classical/warty/baseloid VIN
- differentiated VIN
Which type of VIN is related to HPV infection?
Classical/warty/baseloid is related to HPV infection
Differentiated VIN is not HPV-related
Who do the 2 different types of VIN affect?
Classical = younger people
Differentiated (non-HPV related) = older people
How is classical VIN graded?
Graded VIN 1-3
How is differentiated VIN graded?
Not graded
Which conditions does differentiated VIN tend to occur in?
Chronic dermatoses especially lichen sclerosus
State the main features of classical/warty/baseloid VIN
- graded VIN 1-3
- related to HPV infection
- younger people
State the main features of differentiated VIN
- not graded
- not HPV related
- occurs in chronic dermatoses especially lichen sclerosus
- older people
How often does VIN recur?
35-50% recur
Positive margins predict recurrence
How often does VIN progress to invasive carcinoma?
Progression to invasive carcinoma in 4-7% of treated women and up to 87% of those untreated
Progression of VIN to become invasive is most likely to occur in whom?
Those who are post-menopausal or immunocompromised (as HPV is not contained by the immune system)
Spontaneous regression of VIN may occur, particular in whom?
Particularly in young, postpartum women
The most common vulval cancer (90%) is what type?
Squamous cell carcinoma
Describe the different oncogenic pathways leading to squamous cell carcinoma of the vulva
- associated with VIN
- associated with inflammatory dermatoses
Symptomatic lichen sclerosus carries what risk?
15% risk of malignancy
Vulval squamous cell carcinoma may be associated with what?
VIN or inflammatory dermatoses
Describe the typical predictable spread of vulval squamous cell carcinoma
- locally to involve vagina and distal urethra
- to ipsilateral inguinal lymph nodes
- to contralateral inguinal lymph nodes
- to deep iliofemoral lymph nodes (25% if inguinal lymph nodes +ve)
How does the depth of invasion of vulval squamous cell carcinoma relate to risk of lymph node metastasis?
less than 1mm depth of invasion = very rare lymph node mets
1-3mm = 10%
more than 4mm = 40%
What procedure would be done if after wide local excision, the depth of invasion of VSCC was found to be over 1mm?
Lymph node sampling (groin node dissection or sentinel node biopsy)
What staging system is used to stage gynaecological cancers including vulval squamous cell carcinoma?
FIGO staging system
What is the prognosis in vulval squamous cell carcinoma?
5 year survival stage I = 95% stage II = 90% stage III = 70% stage IVA = 20% stage IVB = less than 10%
Rather than vulval squamous cell carcinomas, 5% of vulval tumours are what?
Malignant melanomas (easy to recognise when pigmented, aggressive tumours)
What is the mean age of vulval malignant melanoma patients?
50-60
How common is local recurrence of vulval malignant melanoma?
1/3 of cases
Spread of vulval malignant melanoma to where is frequent?
Spread to the urethra is frequent
Lymph node/haematogenous spread is common
The depth of invasion (Breslow depth) of vulval malignant melanoma correlates with what?
Lymph node (LN) involvement
Rarely, a malignant melanoma has no pigment at all. What is this called?
Amelanotic melanoma
What makes up the other 5% of vulval tumours? (other than squamous cell carcinoma and malignant melanoma)
Paget’s disease (extra-mammary Paget’s disease)
What is the mean age of vulval Paget’s disease patients?
80
What sort of appearance do you get in vulval Paget’s disease?
Pruritis/burning/eczematous patch (may be eczema but Paget’s should be in differential diagnosis and biopsy should be considered)
What type of cancer is vulval Paget’s disease?
In-situ adenocarcinoma of squamous mucosa - tends to recur following excision
Can develop invasive adenocarcinoma
Paget’s disease of the vulval may be related to which carcinoma?
Low rectal carcinoma (where there is prominent perianal component)
Also bladder and cervix
Is there an underlying tumour in extramammary Paget’s disease?
Usually no underlying tumour
Whereas in Paget’s disease of the nipple, there is underlying ductal carcinoma in-situ spreading into the epidermis)
What is the transformation zone of the cervix?
A physiological area of squamous metaplasia in the cervix (where columnar cell lining becomes squamous cell lining)
When does the transformation zone develop?
After menarche
Why is the transformation zone an important area?
The TZ is vulnerable to the effects of HPV - it is the site of development of CIN
Is the squamous mucosa of the cervix ectocervical or endocervical?
squamous = ectocervical
columnar = endocervical (more inside)
Which type of mucosa of the cervix is more red in colour?
Columnar (endocervical) is more red in colour
Squamous/ectocervical is more pale
What happens to the location of the TZ post-menopause and what are the consequences?
It retracts up the canal, might not be seen colposcopically and might be difficult to sample cyologically. Might not be able to excise CIN easily with LLETZ - so diagnosing and treating CIN post-menopause is problematic
Where in the cervix is the squamocolumnar junction located?
At the external os
Which area is sampled in a cervical cytology sample?
The transformation zone
What is cervical intraepithelial neoplasia (CIN)?
The pre-inavsive stage of cervical squamous cell carcinoma (SCC)
What does the cervical screening programme aim to detect?
Cervical intraepithelial neoplasia (CIN)
What is CIN graded according to?
Increasing abnormality
How is CIN graded?
CIN I, II, and III
CIN I = low grade
CIN II and III = high grade
What is the chance of regression in the 3 grades of CIN?
I = 60%
II = 40%
III = 33%
What is the chance of persistence in the 3 grades of CIN?
I = 30%
II = 40%
III = 56%
What is the chance that CIN I will progress to CIN III?
10%
What is the chance that CIN I will progress to invasion?
1%
What is the chance that CIN II will progress to CIN III?
20%
What is the chance that CIN II will progress to invasion?
5%
What is the chance that CIN III will progress to invasion?
20-70%
What is the first management of CIN I?
Just watch and wait as there is a high chance of regression
High grade ones are treated as there is a significant risk of progression and invasion
What are the features that make the cervical screening programme a good test?
- high sensitivity and specificity
- test is not harmful
- there is a defined pre-invasive stage (CIN)
- natural history is long enough to allow intervention
- simple, successful treatment for pre-inasive stage
Is the cervical screening programme a test for cancer?
No! It is a test for the pre-invasive stage, not cancer (the test is not good at detecting invasive cancer)
How does the cervical screening programme affect rate of cervical cancers?
- regular attendance prevents 90% of cancers
- rate would be 50% higher without screening
At what ages is cervical screening done?
25 = first invitation
25-49 = 3 yearly
50-64 = 5 yearly
65+ = only screen those who have not been screening since age 50 or have had recent abnormal tests
What technique does the cervical screening programme use?
Uses liquid-based cytology (sample with brush, brush goes into liquid medium, liquid goes to cytology)
Focused high risk HPV testing
Why is there no cervical screening below the age of 25?
- evidence does not support its use
- reactive changes in young people produce confusing cytology
- unnecessary LLETZ procedures can have obstetric consequences
What is done if cervical screening shows borderline nuclear change/low grade dyskaryosis?
HPV testing (and then colposcopy +Rx is HPV comes back positive)
What is done if cervical screening shows high grade dyskaryosis/invasive malignancy?
Refer for colposcopy + Rx
In colposcopy, the cervix is often painted with what and why?
Acetic acid, to highlight potentially abnormal epithelium
What does LLETZ stand for?
Large loop excision of the transformation zone
What is the main surgical treatment for CIN?
LLETZ (as the transformation zone is where CIN happens)
What is the most important causative factor of cervical squamous cell carcinoma?
High risk HPV
Other than HPV, what are the other risk factors for cervical squamous cell carcinoma?
- multiple sexual partners
- male partner with multiple partners
- young age at first intercourse
- high parity
- low socioeconomic group
- SMOKING
- immunosuppression
What may be some clinical presentation features of an ulcerated cervical carcinoma?
- bleeding
- discharge
- signs of local spread eg. hydronephrosis, and urinary symptoms
At what age groups is cervical squamous cell carcinoma most common?
25-39
Name another type of cervical cancer (other than cervical SCC)
Cervical adenocarcinoma
What are the features of cervical adenocarcinoma?
- presentation/spread is the same as SCC
- related to high risk HPV
- precursor is cervical glandular intraepithelial neoplasia (CGIN)
- treated the same as CIN/CSCC
What is the precursor to cervical adenocarcinoma?
Cervical glandular intraepithelial neoplasia (CGIN)
Why is the stage for stage prognosis worse for cervical adenocarcinoma than for cervical squamous cell carcinoma?
Due to radioresistance
What is used to cure many cervical adenocarcinomas?
LLETZ
some require more radical surgery eg. lymph nodes dissection, and some chemotherapy and radiotherapy
