Cervical cancer

Question 1

What percentage of women will be infected with HPV in their lifetime?

% of cervical ca due to HPV?

Answer 1

70%

• 99.7%

Question 2

Which strains of HPV cause:

1. Cervical cancer and high grade abnormalities
2. Genital warts and low grade abnormalities

Answer 2

1. HPV 16 & 18 (70% cervical ca and 50% high grade change)

2. HPV 6 & 11 (>90% warts, 10% low grade change)

Question 3

Other cancers associated with HPV

Answer 3

Vulval, vaginal
Oropharyngeal
Penile cancer
Anal cancer

Question 4

HPV virology

Answer 4

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

Question 5

LLETZ

Answer 5

Indication: excision of CIN

Need to orientate specimen

Question 6

Cone biopsy

Answer 6

Indication: Glandular lesions, can’t see all of CIN, discrepancy between smear and colp findings, unreliable pt, incomplete LLETZ

Question 7

Investigations for cervical ca

Answer 7

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

Question 8

Investigations for cervical ca

Answer 8

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.

Question 9

FIGO staging cervical ca - Stage 2

Answer 9

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

Question 10

FIGO staging cervical ca - Stage 3

Answer 10

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

Question 11

FIGO staging cervical ca - Stage 4

Answer 11

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

Question 12

Summary of treatment for cervical ca:

Answer 12

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

Question 13

CIN1

Answer 13

Low grade abnormality - conservative follow up with repeat smear in 12 months

Question 14

High grade abnormality- CIN2 or 3

Answer 14

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.

Question 15

Risk factors for cervical cancer

Answer 15

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.

Question 16

Presenting symptoms

Answer 16

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

Question 17

Radical hysterectomy

Answer 17

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.

Question 18

Radical trachelectomy

Answer 18

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.

Question 19

Chemoradiation

Answer 19

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

Question 20

HPV vaccine

Answer 20

• 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

Question 21

3 types of cancers of the cervix?

Answer 21

Squamous cell carcinoma (70-80%)

• keratising
• non keratising
• small cell squamous

Adenocarcinoma (10-15%)

• mucinous
• adenoasquamous
• clear cell

Epithelial- eg neuroendocrine, undifferentiated..

Question 22

How does squamous cell carcinoma develop?

Answer 22

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

Question 23

How can cervical cancer spread?

Answer 23

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)

Question 24

Bad prognostic signs for cervical ca

Answer 24

• 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

Question 25

Adenocarcinoma

Answer 25

(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

Question 26

Follow up after treatment

Answer 26

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

Question 27

Complications of surgery

Answer 27

- ureteral stricture - bladder dysfunction - constipation - wound breakdown - lymphocyst - lymphoedema - (radiotherapy after will increase risk of these complications)

Question 28

Radiotherapy complications

Answer 28

- 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

Question 29

Incidence cervical cancer in Australia?

Answer 29

6.9 per 100,000

Question 30

Survival rates for cervical cancer in Australia?

Answer 30

74% 5 year Indigenous women 2.5times more likely to have cervical ca and 3.5 times more likely to die from it

Question 31

HrHPV testing vs conventional smear - summary

Answer 31

- 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.

Question 32

Development of cervical cancer

Answer 32

- 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

Question 33

What happens in the cervix when exposed to HPV?

Answer 33

- 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

Question 34

``` 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? ```

Answer 34

1. >100 2. 40 affect anogenital tract 3. 15 are oncogenic 4. Most common are 16 and 18, account for 70-80% of cervical ca 5. 50-80% of sexually active women will have HPV at some stage

Question 35

What are the oncogenic HPV strains?

Answer 35

16, 18 = 70% of cervical ca ``` Other oncogenic strains (most common, still more): 31 33 45 52 58 ```

Question 36

Cervical screening Australia- new recommendations?

Answer 36

- 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

Question 37

In Australia- who is suitable for self swab for HPV?

Answer 37

- under screened or never screened women aged >30 | - Should still be guided by a medical professional or nurse

Question 38

Justification for increasing cervical smear screening age to 25?

Answer 38

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

Question 39

Question 40

Self collection for HPV- issues

Answer 40

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

Question 41

Epithelial lining of the ectocervix?

Answer 41

Squamous epithelium

Question 42

Epithelial lining of the endocervix?

Answer 42

Columnar epithelium

Question 43

What is the average rate of HPV infection in women <25?

Answer 43

25%

Question 44

FIGO staging cervical cancer- stage 1

Answer 44

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

Question 45

Complication of lymph node sampling

Answer 45

infection bleeding lymphocele lymphocyst

Question 46

Fertility sparing treatment options for cervical cancer?

Answer 46

- 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.

Question 47

Criteria for postoperative radiotherapy? (PORT)

Answer 47

- 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

Question 48

Follow up for treatment of women with 1A1-1A2 disease?

Answer 48

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