Lecture 34 - Cervical and vulval pathology Flashcards
VIN
Vulval intraepithelial neoplasia
CIN
Cervical intraepithelial neoplasia
CGIN
Cervical glandular intraepithelial neoplasia
VaIN
Vaginal intraepithelial neoplasia
AIN
Anal Intraepithelial neoplasia
Dysplasia
Earliest morphological manifestation of multistage process of neoplasia
In-situ disease ; non-invasive
Shows cytological features of malignancy, but no invasion
No invasion = no metastasis = curable
If left, significant chance of developing invasive malignancy
Human Papillomaviruses (HPVs)
- Double standard DNA viruses
- 7.9kb circular genome, 7 ‘early genes’, 2 ‘late’ genes
- > 100 subtypes, based on DNA sequence
- Different types affect different tissues
- Lifecycle linked to epithelial differentiation
- Genital HPVs grouped into low and high oncogenic rislk
HPV risk groups - Low risk
Associated with genital warts and other low-grade cytological abnormalities: 6, 11, 40, 42, 43, 44, 53, 54, 61, 72, 73 and 81
6, 11 - linked with genital warts - most common
High risk HPV groups
High-risk subtypes associated with high-grade pre-invasive and invasive disease are 16, 18, 31, 33, 35, 39, 45, 51, 52
99,7% of cervical cancers contain HPV DNA
Types 16, 18 associated with - 70% OF CERVICAL CANCERS
Low risk HPV
6, 11 - lower genital tract warts (condylomas= benign squamous neoplasms), low grade ‘IN’s’
Very rare in malignant lesions
High risk HPV
16, 18, 31, 33
High grade Intraepithelial Neoplasia’s and Invasive carcinomas
Human Papilloma Virus vaccinations
2 vaccines
Gardasil (Merck) HPV - 6,11,16,18
cervarix (MSK) HPV - 16,18
uk vaccinations started in sep 2008 - cervarix
Age 12 -13 with catch-up to 18
Switch to Gardasil Sep 2012
Mode of action of High risk HPV
early genes expressed at onset of infection which
control viral replication
oncogenic viruses - involved in cell transformation
Late genes code capsid proteins
High risk HPV’s integrate into host chromosomes
Upregulates E6, E7 expression
E6 binds to and inactivates p53
E7 binds to RB1 gene product
p53 mediates apoptosis in response to DNA damage - accumulation of genetic damage
RB1 is tumour suppressor gene
Controls G1/S checkpoint in cell cycle - dysregulation of cell proliferation
What does E6 expression do
E6 binds to and inactivates p53
What does E7 binds to RB1 gene product
E7 binds to RB1 gene product
What does p53 do and what does inactivation do?
Mediates apoptosis in response to DNA damage - accumulation of genetic damage
What does RB1 do and what does inactivation do?
is a tumour suppressor gene
controls G1/S checkpoint in cell cycle - dysregulation of cell proliferation
Classical/ warty/ baseloid VIN
graded VIN 1-3
Related to HPV
Younger people
Differentiated VPN
not graded
not HPV related
Occurs in chronic dermatoses esp. lichen sclerosis
Older people
Behaviour of VIN
35-50% recur
Positive margins predict recurrence
Progression to invasive carcinoma in 4-7% treated women and up to 87% of those untreated
When is invasion more likely to occur in VIN?
In postmenopausal/immunocompromised
Spontaneous regression may occur particularly in young postpartum women (after childbirth)
Squamous cell carcinoma
most common vulval cancer - 90%
What can squamous cell carcinoma be associated with
Associated with VIN AND INFLAMMATORY DERMATOSES
Squamous cell carcinoma associated with VIN
Age less than 60
Assoc lower genital tract neoplasia - CIN
HPV +ve
Squamous cell carcinoma associated with inflammatory dermatoses
age more than 70
licen sclerosis
Lichen planus
what is the risk of malignancy for symptomatic lichen sclerosus
15% risk of malignancy
Vulval squamous cell carcinoma
Associated with VIN
associated with inflammatory dermatoses
eroded plaque or ulcer
how does Vulval squamous cell carcinoma spread
locally to involve vagina and distal urethra
to ipsilateral inguinal LNs
to contralateral inguinal LNs,
deep iliofemoral LNs (25% if inguinal nodes +ve)
Risk of lymph node mets for vulval squamous cell carcinoma
Depth of invasion LN Mets
< 1 mm Very rare
1 - 3 mm 10% - wide local excision
> 4 mm 40 % - Lymph node sampling groin node dissection or sentinel node biopsy
Prognosis of Vulval squamous cell carcinoma
stage 1 - 95% stage 2- 90% stage 3 - 70% stage 4a - 20% stage 4b - <10%
overall prognosis 70%
FIGO staging system
vulval tumours - malignant melanomas
5% of vulval cancers
Mean age 50 - 60
Local recurrence in 1/3, spread to urethra frequent
Lymph node/ haematogenous spread common
Depth of invasion correlates with LN involvement
Paget’s disease
Extramammary
- 5% Vulval cancers, mean age 80
- pruritic/burning/eczematous patch
- In-situ adenocarcinoma of squamous mucosa
- Tend to recur following excision
- Can develop invasive adenocarcinoma
Paget’s disease location
bladder
cervix
exclude primary rectal ca
wherever there is a prominent perianal component
what is a transformation zone
Physiological area of squamous metaplasia
TZ is vulnerable to oncogenic effects of HPV - site of development of CIN
Cervical intraepithelial neoplasia (CIN)
pre-invasive stage of cervical SCC
Detection is aim of cervical screening programme
graded according to increasing abnormality
CIN 1
Regression 60%
Persistence 30 %
Progression to CIN III 10%
Progression to invasion 1%
CIN 2
Regression 40%
Persistence 40 %
Progression to CIN III 20%
Progression to invasion 5%
CIN 3
Regression 33%
Persistence ~56%
Progression to invasion 20% - 70%
Cervical screening programme
Available test has high sensitivity and specificity Test is not harmful Defined pre-invasive stage Long enough to allow intervention Simple, successful treatment
Is not a test for cancer
Cervical screening programme schedule
Agegroup(years) Frequency of screening
25 First invitation
25 – 49 3 yearly
50 – 64 5 yearly
65+ Only screen those who have not
been screened since age 50 or
have had recent abnormal tests
Uses liquid based cytology and focused high risk HPV testing
Why there is no screening under 25
Evidence does not support its use
High HPV carriage rate, incl high risk types – 70-80% will be eliminated
Reactive changes produce confusing cytology
Unnecessary LLETZ procedures can have obstetric consequences
What is dyskaryosis?
Abnormal cytologic changes of squamous epithelial cells characterized by hyperchromatic nuclei and/or irregular nuclear chromatin
what do you do we with a borderline nuclear change/ low grade dyskaryosis
HPV testing
if +ve - refer for colposcopy + Rx
if -ve = normal recall
What do you do with high grade dyskaryosis or similar ?
Refer for a colposcopy + Rx
Colposcopy and treatment of CIN
Large Loop Excision of the Transformation Zone (LLETZ)
Cervical squamous cell carcinoma causes
High risk HPV is most important causative factor Multiple sexual partners Male partner with multiple partners Young age at first intercourse High parity Low socioeconomic group SMOKING Immunosuppression
Cervical adenocarcinoma
Presentation/spread same as SCC
Related to high risk HPV
Precursor is Cervical Glandular Intraepithelial Neoplasia (CGIN)
Treated same as CIN/SCC
Stage for stage worse prognosis that SCC ?due to radioresistance
what is a precursor of cervical adenocarcinoma
Cervical Glandular Intraepithelial Neoplasia
Spread and prognosis of cervical carcinoma - FIGO staging
Simplified FIGO staging
I Confined to cervix
II Invades beyond uterus, not to pelvic side wall
III Extends to pelvic wall, lower 1/3 vagina, hydronephrosis
IV Invades bladder or rectum or outside pelvis
Metastasis
Predictably to pelvic and para-aortic lymph nodes
Via blood to lungs, bone etc
