Cervical cancer COPY Flashcards
What percentage of women will be infected with HPV in their lifetime?
% of cervical ca due to HPV?
70%
- 99.7%
Which strains of HPV cause:
- Cervical cancer and high grade abnormalities
- Genital warts and low grade abnormalities
- HPV 16 & 18 (70% cervical ca and 50% high grade change)
2. HPV 6 & 11 (>90% warts, 10% low grade change)
Other cancers associated with HPV
Vulval, vaginal
Oropharyngeal
Penile cancer
Anal cancer
HPV virology
Double stranded DNA
Genome enclosed in protein capsule
Major capsid protein from L1 gene is on the outer surface- vaccine creates immune response to this
- early (E) genes and late (L) genes
- E genes conduct its replication and life cycle
- L genes used later in the piece to complete new virus particles
- E genes are in the lower layers and L genes in more superficial layers
- Low risk serotypes 6 and 11 cause genital warts
- Serotypes 16 and 18 cause neoplasia (+ 45 and 31)
Transmission
- penetrative intercourse
- oral and digital also possible
- congenital possible
LLETZ
Indication: excision of CIN
Need to orientate specimen
Cone biopsy
Indication: Glandular lesions, can’t see all of CIN, discrepancy between smear and colp findings, unreliable pt, incomplete LLETZ
Investigations for cervical ca
Colposcopy and biopsy
Cone biopsy
EUA +/- cystoscopy + PR +/- sigmoidoscopy
CXR- for distant spread to lungs
CT/MRI/PET scan - not part of formal FIGO staging but can help with surgical planning (FIGO now changed slightly so this is now integrated into staging for HIC)
Minimal resources but advanced disease: CXR and USS to look for hydronephrosis
Investigations for cervical ca
Colposcopy and biopsy Cone biopsy EUA +/- cystoscopy + PR +/- sigmoidoscopy CXR- for distant spread to lungs Intravenous pyelogram
CT/MRI/PET scan - not part of formal FIGO staging but can help with surgical planning.
FIGO staging cervical ca - Stage 2
The carcinoma invades beyond the uterus, but has not extended onto the lower third of the vagina or to the pelvic wall
IIA Involvement limited to the upper two‐thirds of the vagina without parametrial involvement
○IIA1 Invasive carcinoma <4 cm in greatest dimension
○IIA2 Invasive carcinoma ≥4 cm in greatest dimension
IIB With parametrial involvement but not up to the pelvic wall
FIGO staging cervical ca - Stage 3
The carcinoma involves the lower third of the vagina and/or extends to the pelvic wall and/or causes hydronephrosis or non‐functioning kidney and/or involves pelvic and/or paraaortic lymph nodesc
IIIA Carcinoma involves the lower third of the vagina, with no extension to the pelvic wall
IIIB Extension to the pelvic wall and/or hydronephrosis or non‐functioning kidney (unless known to be due to another cause)
IIIC Involvement of pelvic and/or paraaortic lymph nodes, irrespective of tumor size and extent (with r and p notations)c
○IIIC1 Pelvic lymph node metastasis only
○IIIC2 Paraaortic lymph node metastasis
FIGO staging cervical ca - Stage 4
The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. A bullous edema, as such, does not permit a case to be allotted to stage IV
IVA Spread of the growth to adjacent organs
IVB Spread to distant organs
Summary of treatment for cervical ca:
1A1 and 1A2= microinvasive disease. Either hysterectomy or cone/trachelectomy for fertility sparing. 1A2= lymphadenectomy or SNL
1B1, 1B2, 2A1: Invasive cervical carcinoma. Radical hysterectomy and lymphadenectomy
1B3 and >2A2: Bigger tumours or more invasive therefore risk higher. Chemoradiation instead of surgery as otherwise 80% need radiation after surgery - which has higher morbidity than going straight to chemoradiation. Addition of chemotherapy has a survival benefit at 5 years.
- 4: individualised
CIN1
Low grade abnormality - conservative follow up with repeat smear in 12 months
High grade abnormality- CIN2 or 3
High-grade pre-invasive changes (CIN2 to 3) are treated via diathermy (wire loop excision), laser or cryotherapy. Single treatment is usually extremely effective. A cone biopsy involves a larger excision of cervical tissue and is generally reserved for adenocarcinoma in situ (the glandular ‘equivalent’ of CIN3), disease going up the cervical canal that cannot be fully visualised at colposcopy, or if invasive disease is suspected.
Patients treated for adenocarcinoma in situ, despite clear margins on cone biopsy, are at ongoing risk for developing further pre-invasive or invasive disease long term, and are therefore advised to have a completion hysterectomy (with ovarian conservation) once childbearing is completed.
Risk factors for cervical cancer
smoking, early coitus, multiple partners, multiple pregnancies, poor general health, poor nutrition a genetic predisposition to cervical cancer. ?COC makes HPV more virulent
Lifestyle factors include: prolonged stress, eating disorders, poor diet, excessive exercise and inadequate rest.
Illnesses that increase a woman’s risk include diabetes and immune disorders. Immunosuppressent agents also increase a woman’s risk.
Presenting symptoms
Abnormal bleeding e.g. persistant post coital bleeding
Advanced disease: Pain (particularly sciatic type pain), pressure symptoms and sometimes vaginal passage of urine or faeces
Radical hysterectomy
compared to a simple hysterectomy to achieve adequate clearance from the tumour, a vaginal and paracervical cuff of tissue is excised in continuity with the cervix.
Much of the morbidity of this procedure comes from the additional dissection required to attain lateral clearance (bladder and bowel dysfunction) but this is usually temporary.
Radical trachelectomy
in patients with no lymph vascular invasion (LVSI) and tumours <2cm who want ongoing fertility, this procedure involves radical excision of the cervix with a vaginal and paracervical cuff, with reanastamosis of the vagina to the isthmus of the uterus with or without cerclage.
This procedure enables the patient to undergo future childbearing, can be performed vaginally, laparoscopically or abdominally, and is combined with a pelvic lymphadenectomy.
Chemoradiation
definitive radiation with concomitant chemotherapy (weekly cisplatin 40mg/m2). Chemoradiation compared to radiation alone for the treatment of cervical cancer has been shown to provide a 30–50 per cent reduction in the risk of death, and is now the preferred option for the treatment of cervical cancer
HPV vaccine
- humoral antibodies that neutralise HPV before it can affect cells.
- Prevent establishment of persistent infection
- Gardasil protects against 6, 11, 16 and 18 (90-100% protection)
o Genital warts
o CIN - (Cervarix is only 16 and 18)
- 3x intramuscular doses during 6 months.
- Prior to intercourse
- Routine is to immunise 11-12yr olds.
Vaccine free to girls born after January 1st 1990 or 1991, starting Dec 2011
Now year 8 offered vaccine
Can vaccinate sexually active girls
Can vaccinate girls with known HPV infection
Can vaccinate girls with previous warts or CIN
Need for ongoing smears should be recommended
Pregnancy category B2 however recommended to differ until after pregnancy (even if mid regime)
Can offer to women over 26yrs however is not endorsed as peak HPV infection is 5yrs after intercourse
Is approved for males 9-15yrs
3 types of cancers of the cervix?
Squamous cell carcinoma (70-80%)
- keratising
- non keratising
- small cell squamous
Adenocarcinoma (10-15%)
- mucinous
- adenoasquamous
- clear cell
Epithelial- eg neuroendocrine, undifferentiated..
How does squamous cell carcinoma develop?
Squamous cell carcinoma - arises at squamocolomnar junction - after infection with HPV (oncogenic serotype 16 and 18) - most women clear the virus - preinvasive dysplasia develops - molecular alterations complex and not well understood - cancer arises from an interaction of o environment o host immunity o genomic variations
The oncogenic serotypes are able to integrate into human genome.
- amplification
- replication
- E7 oncoprotein binds to tumour suppressor gene- retinoblastoma, E6 oncoprotein binds to p53.
- This leads to unregulated cell
- They are then “immortalised” or hard to kill
How can cervical cancer spread?
Local spread: parametrium, vagina, uterus and adjacent organs, i.e., bladder and rectum
Lymphatic spread: First to: parametrial/paracervical lymph nodes -> obturator, external iliac and internal iliac and then to common iliac and para-aortic
Haematogenous spread: growth tracks through uterine arteries for haematogenous spread to liver, lungs and skeleton
Note: posterior cervix can drain through rectal lymph nodes
(remove with uterosacral ligaments during hysterectomy)
Bad prognostic signs for cervical ca
- Advanced FIGO stage
- Depth of tumour
- Tumour dimensions
- Vaginal or parametrial involvement
- lymphovascular space invasion
- nodal metastases (ie one vs multiple) (microscopic vs macroscopic)
- extension to pelvic side wall, ureteral blockage
- bladder invasion
Adenocarcinoma
(15%)
- may be more advanced before becoming clinically evident
- mucinous endocervical adenocarcinomas are the most common
- (can get neuroendocrine tumours of cervix too)
Gynaecology Oncology Group have shown Stage 1B squamous and adenocarcinoma are similar.
FIGO has also shown no difference in the survival of stage 1
However for more advanced stage disease adenocarcinoma looks to be worse
Follow up after treatment
Follow up
- MRI at 3 months
- Offer HRT to all premenopausal, prior to treatment
- Smears are performed but difficult to interpret
- Clinical exam
- 3 monthly for two years, 6 monthly to complete 5 years
Complications of surgery
- ureteral stricture
- bladder dysfunction
- constipation
- wound breakdown
- lymphocyst
- lymphoedema
- (radiotherapy after will increase risk of these complications)
Radiotherapy complications
- altered sexual function (shortened vagina)
- dysparaeunia
- psychological factors
- vaginal stenosis
- bowel and urinary fistulas
- enteritis/ proctitis
- bowel obstruction
Think of an organ and add ‘itis’ - applies to acute complications and then long term
Incidence cervical cancer in Australia?
6.9 per 100,000
Survival rates for cervical cancer in Australia?
74% 5 year
Indigenous women 2.5times more likely to have cervical ca and 3.5 times more likely to die from it
HrHPV testing vs conventional smear - summary
- Smear has low sensitivity (70%) but high specificity (>90%)
- HPV testing has high sensitivity but low specificity and is expensive (specificity improves in women>30)
- Several trials have found that HPV testing significantly reduces cervical cancer incidence and mortality, plus a negative HPV test allows screening to be stretched out to 5 years (Indian trial, ARTISTIC trial and Arbyn meta analysis)
Large US study followed college students over 10 years- those with HPV-ve had low rates of cervical ca, those with non 16/18 HrHPV had slightly higher rates but not very high. Those with 16/18 had up to 20% incidence of at least CIN 3 over 10 years- justification for screening for 16 and 18 specifically.
Development of cervical cancer
- Oncogenic HPV infection of metaplastic epithelium at TZ
- Persistence of HPV infection
- Progression of a clone of epithelial cells from persistent viral infection to intraepithelial neoplasia
- Invasion through the basement membrane to become carcinoma
What happens in the cervix when exposed to HPV?
- Exposure to HPV
- Expression of viral proteins: early proteins E1-7 and late proteins L1,2
- Leads to LSIL changes
- 98%- immune system clears and reverts to normal
In those where it doesn’t:
- 2% over 5 years- over expression of early proteins E6 and E7
- leads to HSIL changes
- Some will resolve, some will resort to cancer, typically 10-15 years
How many types of HPV are there? How many affect the anogenital tract? How many are oncogenic? Which are the 2 most common oncogenic? What % of women will be infected with HPV at some stage in their life?
- > 100
- 40 affect anogenital tract
- 15 are oncogenic
- Most common are 16 and 18, account for 70-80% of cervical ca
- 50-80% of sexually active women will have HPV at some stage
What are the oncogenic HPV strains?
16, 18 = 70% of cervical ca
Other oncogenic strains (most common, still more): 31 33 45 52 58
Cervical screening Australia- new recommendations?
- Screening age 25-69
- Start with HrHPV screen, if negative then HrHP every 5 years
- If positive then for reflex LBC (cytology) to triage further evaluation
- Exit test at 70-72 years
- National registry and linked to vaccination data
In Australia- who is suitable for self swab for HPV?
- under screened or never screened women aged >30
- Should still be guided by a medical professional or nurse
Justification for increasing cervical smear screening age to 25?
Cervical cancer very unlikely in women <25
No evidence that screening in women <25 advantageous
Screening in younger age group more likely to lead to unnecessary treatment and investigation
Vaccination rates mean cervical ca in young women even less likely to occur
Self collection for HPV- issues
Significant proportion of women don’t participate in screening programme
Of women diagnosed with cervical cancer, majority are those who are either under/never screened or late for their screening
Arbyrn meta-analysis originally showed suboptimal sensitivity and specificity from self screening when compared to HCP, hence strict criteria for self screen, However repeat meta analysis in 2018 looking at PCR only showed very similar rates
Epithelial lining of the ectocervix?
Squamous epithelium
Epithelial lining of the endocervix?
Columnar epithelium
What is the average rate of HPV infection in women <25?
25%
FIGO staging cervical cancer- stage 1
Disease confined to cervix and uterus
1A: microscopic (further subdivided). Depth of invasion <5mm
1B: Automatically at least 1B if lesion can be seen, depth of invasion >5mm
Complication of lymph node sampling
infection
bleeding
lymphocele
lymphocyst
Fertility sparing treatment options for cervical cancer?
- 1a1- cone biopsy only with close follow up
- 1a2: Cervical cone with lymphadenectomy or radical trachelectomy and pelvic lymphadenectomy.
- Ib1: tumors measuring less than or equal to 2 cm in largest diameter. Radical trachelectomy + lymphadenectomy.
Criteria for postoperative radiotherapy? (PORT)
- Tumour size >4cm (although FIGO moving to consider 2cm)
- LVSI +ve
- LN +ve
- Inadequate surgical margins
- Deep stromal invasion
Post op patients are divided into high risk/intermediate and low risk
High risk=PORT + chemo
Intermediate = PORT
Low = no radiation
PORT carries high morbidity
Follow up for treatment of women with 1A1-1A2 disease?
Follow-up with 3-monthly Pap smears for 2 years, then 6-monthly for the next 3 years is recommended after treatment of microinvasive carcinoma. With normal follow-up at 5 years, the patient can return to the routine screening schedule according to the national guidelines
