Cervical cancers

Question 1

What is a radical hysterectomy (type C)
What is removed
This is done with a pelvic lymphadenopathy
- what nodes must be removed?

Answer 1

Removal of
Uterus
parametrium
upper vagina
part of the paracolpium 
Adjacent connective tissues involve
anterior vesicouterine ligament anterior and posterior leaf
lateral cardinal ligaments 
posterior sacrouterine and rectovaginal ligaments 

Lymphadenectomy includes
parametrial
obturatory
external and internal and common iliac

Question 2

Other then +ve nodes that factors increase the risk of recurrence

Answer 2

+ LVSI - lymphovascular space invasion
Invasion outer 1/3 cervical stroma
Tumor over 4 cm

Question 3

Who gets adjuvant Tx after OT

Answer 3

RT and Chemo
\+ nodes
Parametrial infiltration
\+ margins
Deep stromal involvement

2/3 of recurrence risk factors
Tumor over 4 cm
LVSI
invasion into the outer 1/3 cervical stroma

Question 4

What viral strains are n gardasil 9

Answer 4

HPV 6,11,16,18,31,33,45,52 and 58

Question 5

What viral strains are bad for what?

Answer 5

Of the oncogenic HPVs, types 16 and 18 account for about 70% of cervical cancers
Non-oncogenic HPV types 6 and 11 cause genital warts.

Cervical cancer in NZ
50% HPV 16
21% HPV 18
31,45,52 (few % each)

Question 6

Prevelence of HPV

Answer 6

HPV infection is common with an estimated 70-80% of sexually active women
worldwide becoming infected at some stage in their life

Question 7

What type of virus is HPV

What is the mechanism for carcinogenesis

Answer 7

HPV double-stranded DNA, non-enveloped capsid virus

• Mechanism of carcinogenesis involves the up-regulation of E6 and E7 HPV gene products.
• They prevent damaged cells from apoptosis

The two most important HPV genes in the development of cancer are E6 and E7. Both of these genes need to be on all the time in order for cancer to develop.

E6 and E7 Can Let Damaged Cells Live On

Question 8

What % of people with HPV develop cancer?

Answer 8

1%
70% of woman have HPV

70% of cervical cancers are HPV

90 % of other cancer sites are HPV
Vulval and vaginal 
anal 
Penis  
Head and neck cancers

Question 9

What HPV is related to anogenital warts?

Answer 9

6 and 1 accounts for 90% of anogenital warts

Question 10

what is the nz HPV programme

Answer 10

school based immunisation in year 8
funded 9 -26 year olds male or female
non residence under 18 funded
3 doses 0,2,6 months

Question 11

HPV vaccine

What type of vaccine is it? How does it work ?

Answer 11

VLP – virus like proteins that are NOT live, attenuated or killed viruses
IM injection the VLP induces an antibody response
DO not treat existing lesions
Currently using Gardasil 9 (9 HPV types)
6,11,16,18,31,33,45,52,58 which prevents 90% of cervical cancers
95-100% efficacy against HPV types
2 doses at 0 and 5-13 months if 15 or less
If immunocompromised or older then 15 3 doses is recommended at 0,2,6 months

Question 12

Can she have HPV vaccine in pregnancy?
In breastfeeding?

any risks?

Answer 12

Safe in breast feeding
Not safe in pregnancy
monitoring of woman who have inadvertently received Gardasil has not identified any risk to mother of fetus

Anaphylaxis after HPV vaccine 1-3 X / million
No other serious reactions identified (some local side effects, fever, headache)

Can be given with other vaccines but different needle and injection sites should be used

Efficacy in clinical trials has been shown (14000 people 97% efficacy)

Best if given under 15 and before sexual intercourse

IN Australia and Denmark there is a profound reduction in the number of genital warts

Reduction In high grade cervical abnormalities - in young woman by 75%

Question 13

Cervical cancer in NZ
how many annual
deaths annual
have they been screened?

Does screening change cervical cancer rate?

Answer 13

160 Dx annual, 60 die annually
Half of the woman dx has never been screened
1/3 irregular and infrequent screening
Screening dropped the incidence of invasive cervical cancer by 50%
Narrowing inequity between Maori and non Maori (still significant disparity)

Question 14

What is the rate of screening in NZ?

Answer 14

Coverage 70-75% for total population (hystetectomy adjusted)

50-60% Maori and Pacific or Asian woman

Coverage is better with an opt off register

Question 15

NZ cervical screening
When to start
When to stop
What was the change

Answer 15

Changes from starting at 20 to now 25
(this is the same as australia, England, scotland, the netherlands, and lots of the EU)

stop when turn 70

3 yearly screening

In addition to the planned age range change, the Ministry is working towards implementing human papillomavirus (HPV) primary screening for its National Cervical Screening Programme (NCSP) from 2021.

Question 16

How to manage unsatisfactory smears

Answer 16

Need a number of well visualized, well preserved, squamous cells
The presence or absence of transformation zone cells does not effect the adequacy of the smear

Types of unsatisfactory sample
Inadequate sampling of cells

Clinical factors –bleeding, inflammation, cytolysis

Lab technical factors

3 consecutive unsatisfactory samples recommend a colp to exclude a high grade lesion

After an unsatisfactory result smear takes should consider LBC technique
Better if excessive cervical mucus, discharge or blood, recurrent inflammatory smears, recurrent unsatisfactory smears

Repeat in 3 months

Question 17

What is AS CUS

what is the risk of progression

Answer 17

ASC US - atypical squamous cells of undetermined significance
considered in risk the same as LSIL

Manifestation of viral infection that will resolve in most woman under 30
Median time for HPV clearance is 6-18 months
FU for woman under 30 is 12 months
If any abnormality on the next smear – refer to colp

Woman over 30 with HrHPV + are at an increased risk of developing a high grade lesion (infections are more persistent)
If negative then repeat in 12 months
If abnormal refer to colp

If neg, repeat in 12 months
If + refer to colp

If sx or abnormal appearing cx must have colp
If she is very anxious or wants a specialist review this may help her

Any woman with an abnormal smear in the last 5 years – referral to colp

Question 18

Why do smear results fluctuate?

Answer 18

Transition from active HPV to resolution followed by reinfection

Underlying persistent abnormality that is not constantly sampled

Question 19

What are high grade abnormalities

Answer 19

ASC-H

HSIL

Refer for colp for any high grade changes

CIN 2/3 - moderate dysplasia, severe dysplasia / carcinoma in situ

CIN 2/3 difference is subjective and not reliable enough to permit a stratification of risk

Threshold for Tx is CIN2 in most cases except if under 20 or pregnancy as chance of regression is high

Question 20

Treatment options - threshold CIN 2/3

What are the risks of treatment

when is the risk of persistence / recurrence?

What is the risk of treatment failure ?

Answer 20

No difference in efficacy for tx options

Increased risk PTL, LBW, PPROM
Increased risk of excision more then 10mm
treatment
(must be at least 7 mm)
Persistence and recurrence greatest after the initial 2 years but risk persists for at least 10 years

Recurrence could be incomplete excision

Tx failures 10%

Involved margins increases the risk of Tx failure

Risk of recurrence increases with age
New lesion
Persistent disease

Question 21

What are the treatment options for CIN 2/3

Answer 21

Ablative therapy 
Entire lesion can be visualized 
Satisfactory colp 
Targeted biopsy has confirmed dx  
No invasive cancer or glandular lesion 

Cryotherapy
Not recommended

LLETZ or LEEP
Take care to reduce excess diathermy artefact in order to assess margins

Cone biopsy
Indicated for
Unsatisfactory colp (unable to see upper limit of transformation zone)
Suspicion of early invasive cancer
Suspected presence of additional glandular abnormality (adenocarcinoma insitu) (mixed lesion)

Hysterectomy 
 Not generally indicated for CIN 2/3 alone, if concurrent abnormalities the following must be met 
Colp assessment if satisfactory 
Target biopsy confirmed Dx 
No evidence of invasive cancer 
Entire lesion visualised

Question 22

Cervical glandular abnormalities

What are of invasive cancers are glandular?
Is it HPV related?

What is the significance of atypical glandular cells on a smear?

Answer 22

15-20% of invasive cancers are glandular

Cervical screening less effective at preventing adenocarcinoma then SCC

90% of cervical adenocarcinoma or AIS (adenocarcinoma insitu) is HrHPV related

Atypical glandular cells (AGC) are associated with underlying neoplastic process
Adenocarcinoma of the Cx
endometrium
Ovary or tube

Therefore all woman with AGS should be referred to colp / gynae onc

Glandular and squamous cells can co exist

Low threshold for diagnostic excisional procedures as high index of suspicion and low quality of Dx tests

Question 23

If a smear shows a glandular abnormality

What to do?

How to manage

Answer 23

Colp assessment of glandular abnormality is Mandatory
If colp satisfactory and normal

MDT review – if AGC or AIS then for cone and D+C
If not seen on MDT review then plan individualized

If abnormal colp ? Cancer then punch biopsy and gynae onc
If abnormal ? Neoplastic process then cone and D+C

If unsatisfactory - cytology ? Neoplasm then cone and D+C

If not confirmed MDT decision

Cone is the gold standard of Tx for glandular abnormalities

A cone before a hysterectomy is necessary to rule out invasive cancer

Question 24

What is the significance of endometrial cells on a smear?

Answer 24

‘normal endometrial cells’
Benign endometrial cells on a premenopausal womans smear is rarely associated with pathology and no further Ix is necessary
If post menopausal OR 40 and older
Rarely pathological
If no other abnormalities it is driven by the smear taker / clinician who should factor in other parts of hx / PMB / HRT

Atypical endometrial cells
High correlation with endometrial pathology – URGENT referral is recommended

Question 25

How is screening recommendations different for immunocompromised people?

Answer 25

This includes
HIV/AIDS
In America they do first 2 smears 6 months apart then annually
SLE, UC
Immunosuppressive tx re cancer or organ transplants

Guidelines for care
Annual screening
Refer to colp even if low grade changes
Entire genital tract should be assessed (cervical, vaginal, anal and vulva)
Excisional methods should be used and FU with colp and cytology
FU infinite and annual

Question 26

What colp should be arranged for DES exposure in utero

Answer 26

Increased risk of clear cell adenocarcinoma of the vagina and cx
Increased risk HSIL and cervical cancer

These woman should be given annual cytological screening and colposcopic exam of the cx and vagina screening should begin anytime and continue indefinitely

Question 27

If a woman has had a hysterectomy does she need vault smears?

Answer 27

Post TAH Vault screening

Aim of taking a smear of the vault is for the prevention of vaginal cancer
If TAH for benign reasons, normal smear hx, and cx shows no malignant or premalignant change, then they do not require further screening

If prev low grade smear that had reverted to normal before the hysterectomy and normal cx on histological exam then does not require further screening

Woman with a hysterectomy for CIN 2/3 may be an increased risk of vaginal cancer and should have annual vault smears

If previously Tx VAIN are at risk of developing VAIN and should have vault smears every 1-2 years

If immunocompromised and have had a hysterectomy for benign disease she should have vault smears every 3 years

Question 28

What makes colp in pregnancy hard?

Answer 28

Hypertrophied cx

hyperaemic

Increased vaginal laxity

Deciduosis in pregnancy can have an appearance suggestive of malignancy and the features of squamous metaplasia may be exaggerated

Exaggerated vascular changes and patterns

Question 29

What is the purpose of colp in pregnancy

Answer 29

Exclude invasive malignancy
same guidelines for referral

Low grade changes often resolve

CIN 2/3 doesn’t need treatment in pregnancy but less likely to resolve

Biopsy safe but not necessarily needed

Question 30

How to manage invasive cervical cancer in pregnancy
What is the rate
How to stage
What are the treatment options

Answer 30

1/10 000
MRI for staging (not as good as CT for lymph nodes but this is contraindicated)
Chemo may be possible

MDT input
can do a LND before 22 weeks and use that information to decide on further treatment

<2cm
+ nodes - TOP
- ve nodes - cone, trachelectomy or delay until maturity

> 2cm
+ nodes TOP
-ve nodes Chemo and post partum OT

After 22-25 weeks cant do LND
Options are
Chemo - stabilises tumor and prevents dissemination
Await maturity and radical caesarean hysterectomy

Question 31

Lancet March 2018 Oncological management and obstetric and neonatal outcomes for woman with cancer in pregnancy – 1170 pts 20 year cohort study

Findings ?

Answer 31

67% antenatal Tx

37% chemotherapy

86% had live births

52% term deliveries

Of the preterm 42% iatrogenic

Risk of congential abnormalities was similar for the general population

No difference in cognitive function

Over time as increases treatment in pregnancy, less terminations, more cancer Tx, less prematurity bur more SGA and NICU admissions

Question 32

What are the most common cancers in woman

1,2,3,4

Answer 32

Breast
colorectal
lung
cervical

In low and middle income countries cervical is second most common

Question 33

Types of cervical cancer

Answer 33

Squamous
70-80%
Keratinizing and non keratinising

Glandular
10-15%
Papillary tumors more likely adenocarcinoma

Epithelial
neuroendocrine
Undifferentiated

Question 34

How to stage cervical cancer

Answer 34

It can be clinically, radiologically or pathologically staged
FIGO has no recommendations for routine investigations

MRI is best for parametrial involvement
If in doubt - use the lower stage

If frank invasive cancer then at least CXR and assessment for ureteric obstruction should be done

Cystoscopy:
Symptoms
if tumor in anterior vaginal wall
Barrel shaped endocervical growth

Question 35

Cervical cancer what is stage 1

Answer 35

The carcinoma is strictly confined to the cervix uteri (extension to the corpus should be disregarded)

IA Invasive carcinoma that can be diagnosed only by microscopy, with maximum depth of invasion <5 mma
○IA1 Measured stromal invasion <3 mm in depth
○IA2 Measured stromal invasion ≥3 mm and <5 mm in depth

IB Invasive carcinoma with measured deepest invasion ≥5 mm (greater than stage IA), lesion limited to the cervix uteri

○IB1 Invasive carcinoma ≥5 mm depth of stromal invasion and <2 cm in greatest dimension
○IB2 Invasive carcinoma ≥2 cm and <4 cm in greatest dimension
○IB3 Invasive carcinoma ≥4 cm in greatest dimension

Question 36

Cervical cancer what is stage 2

Answer 36

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 37

Cervical cancer what is stage 3

Answer 37

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 38

Cervical cancer what is stage 4

Answer 38

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 39

Who is at higher risks for radiation complications?

Answer 39

●Active collagen vascular disease, which is a well-known relative contraindication to radiotherapy [4].

●Inflammatory bowel disease (IBD) – Patients with IBD may be at an increased risk of acute and late bowel complications [5], although the data appear to be conflicting, especially when trying to tease out the effects related to RT from those that might be related to the natural history of IBD [6,7].

●Vascular disorders – Retrospective data suggest that diabetes and hypertension may increase the risk for late toxicity, presumably related to microvascular disease. This includes reports of a greater preponderance of significant bowel complications following definitive radiation for cervix cancer [8,9], although the presence of these conditions was not associated with a greater risk for acute toxicity in at least one report that included women with endometrial cancer

Question 40

Whats types of RT are options for cervical cancer?

Answer 40

The two types of radiation therapy most often used to treat cervical cancer include:

External beam radiation

Brachytherapy

There are two types of brachytherapy:

Low-dose rate (LDR) brachytherapy is completed over a few days. During this time, the patient stays in bed in a private room in the hospital with instruments holding the radioactive material in place. While the radiation therapy is being given, the hospital staff will care for you, but also take precautions to lessen their own radiation exposure.

High-dose rate (HDR) brachytherapy is done as an outpatient over several treatments (often at least a week apart). For each high-dose treatment, the radioactive material is inserted for a few minutes and then removed. The advantage of HDR treatment is that you do not have to stay in the hospital or stay still for long periods of time.

Question 41

What are short term RT complications?

Answer 41

Skin irritation

Skin changes: As the radiation passes through the skin to the cancer, it can damage the skin cells. This can cause irritation ranging from mild, short-term redness to peeling. The skin may release fluid, which can lead to infection, so the area exposed to radiation must be carefully cleaned and protected.

Irritation of Bowel,

The small bowel is very sensitive to the early effects of RT, and when it is contained within the RT field, radiation injury can present acutely as nausea and vomiting.

bladder – radiation cystitis

It can be associated with irritative voiding symptoms (dysuria, frequency, urgency, and nocturia) and bladder spasms. It is due to RT-induced bladder inflammation and edema, which can compromise urothelial integrity

vagina,
Radiation can make the vulva and vagina more sensitive and sore, and sometimes causes a discharge.

menopause, infertility

Fatigue

Question 42

What are long term RT complications?

Answer 42

Long term toxicity
Radiation fibrosis

urinary retention / urgency
Late GU toxicities generally arise as a result of RT-induced epithelial and microvascular changes, which can lead to changes in bladder physiology. These changes are often permanent and are largely mediated by fibrosis via collagen deposition within the epithelium and muscularis, resulting in diminished bladder capacity and loss of tissue compliance. Though the pathophysiology differs, late bladder effects can result in a similar spectrum of lower urinary tract symptoms to that seen in the acute phase, such as urgency and frequency. This is often attributed to bladder overactivity or contraction. With significant contraction, bladder dysfunction can result in urge incontinence.

GIT irritation
● Chronic diarrhea – When present symptoms may be best managed by a multidisciplinary team to include gastroenterology. Ongoing antidiarrheal medications are often necessary.
- Malabsorption – This can be related to RT involving the distal ileum. For example, vitamin B12 deficiency after irradiation for cervical cancer occurs in 12 to 20 percent. This usually develops over a period of several years and commonly requires replacement [40-42]. Cholestyramine may be helpful when bile salt malabsorption is present.

●Recurrent bouts of ileus or obstruction. This is best managed conservatively when possible, but commonly requires surgery with resection and anastomosis. Prolonged chronic radiation enteritis can lead to malnutrition, and as such, perioperative nutritional therapy may be an important intervention.

●Proliferative mucosal telangiectasias or ulcerations – The development of mucosal telangiectasias and/or ulcerations is related to vascular sclerosis and is most commonly observed in the rectosigmoid colon (radiation-induced proctopathy). The signs can include painless hematochezia, tenesmus, or pain. In addition, characteristic changes of mucosal pallor and proliferative telangiectasias often are seen on the anterior rectal wall on endoscopic evaluation in asymptomatic patients. When present, the median time to onset is 14 months and symptoms typically appear within three years

●For patients with rectal proctopathy, conservative management is often appropriate. Avoiding constipation may limit episodes of bleeding.

fistulas

vaginal stenosis
Both EBRT and brachytherapy can cause stenosis
Encourage frequent sex / dilator

pelvic fractures
Hip fractures are the most common, and might occur 2 to 4 years after radiation. Bone density tests are recommended to monitor the risk of fracture.

menopause
In premenopausal women <40 years old, laparoscopic ovarian transposition may be employed before a course of pelvic radiation - it is desirable for the transposed ovary to be at least 3 cm from the radiation field border. Often, clips are used to allow the radiation oncologist to identify the ovaries’ new location. High rates of preservation (80 to 88 percent) have been reported, with an improved likelihood of success when both ovaries are transposed

If pelvic lymph nodes are tx with radiotherapy - lymphodema