Cervical cancer

Cervical cancer is (broadly speaking) a cancer that derives from the human papilloma virus (HPV). It, unlike most cancers, is a cancer that commonly affects young women.

🦴 Anatomy

The cervix is a canal found at the inferior portion of the uterus and superior portion of the vagina. It can be referred to as the neck of the uterus but it is both anatomically and histologically distinct from the uterus. It is approximately 1 inch wide and 1 inch long.

The function of the cervix is to:

• Facilitate sperm passage into the uterine cavity.
• Sterilise the superior portion of the reproductive tract by protecting it from non-sterile components that lie inferior to it. This is done with the external os, cervical mucus and endometrial shedding that occurs too.

The cervix itself is made up of 2 regions:

1. Ectocervix - the portion of the cervix that enters the vagina. It is made up of stratified squamous epithelium. It transitions into the endocervix with the external os.
2. Endocervix - the endocervix is the inner canal of the cervix, and it is made up of simple columnar epithelium that are mucus-secreting. The endocervix transitions into the uterus via the internal os.

The region where the glandular (columnar) and squamous cells meet is known as the transformation zone. This is also the origin site of most cervical cancers.

Pathophysiology

As there are 2 cell types within the cervix, there are 2 types of cancers that can form:

1. Squamous cell carcinoma (80-90%) - this is the cancer affecting the squamous cells of the ectocervix.
2. Adenocarcinoma (10-20%) - this is the cancer affecting the columnar cells of the endocervix.

About 3-10% of the cancers may be mixed adenosquamous carcinomas (however, these are managed as if they were squamous cell carcinomas). An even smaller subset of cancers of the cervix may be neuroendocrine tumours and undifferentiated carcinomas.

The most important factor behind the aetiology of cervical cancer is HPV infection. Almost 99.7% of cervical cancer tumours involve HPV. The most common serotypes of HPV involved are serotypes 16 and 18 which make up around 70% of the cases. Other serotypes to note are 31, 33, 45 and 52. However, there are many many more subtypes which considered high-risk. HPV is spread by skin-to-skin sexual contact. It most commonly affects women in their late teens and early 20s, however, the majority clear the infection 6 months after the infection is acquired.

Let’s discuss the pathophysiology of HPV:

HPV has 2 oncoproteins in its genome, E6 and E7. Normally HPV has its genome in an episome - non-integrated round DNA which can replicate independently. This is the case in benign warts, for example. However, with high-risk strains of HPV, what we see is linearisation (straightening) of the round DNA into a format that is able to integrate itself into the human genome. Once this occurs, there is increased translation of the E6 and E7 genes which results in malignancy.

So what exactly do E6 and E7 do?

• E6 - it binds to p53, a tumour suppressor gene and “guardian of the genome”. It ultimately forms a complex with p53 that results in degradation of p53. P53 normally responds to damaged or abnormal DNA with either reparation of the DNA or apoptosis. If p53 is degraded by E6 then this means that apoptosis is blocked and we lose control of the cell cycle → increasing the likelihood of mutations and cancers.
• E7 - it binds to pRB, another tumour suppressor gene that binds to E2F. pRB normally inhibits E2F. E2F acts to allow cells through the R checkpoint (the checkpoint between G1 and S-phase of mitosis). Therefore if pRB is bound to E7 instead of E2F, then E2F is uninhibited. This is basically a green light for the cells to pass through the checkpoint uninhibited and once again increases the likelihood of mutations to occur.

⚠️ Risk factors

😷 Presentation

💡 As we have a screening programme, the majority of cases are picked up when they are asymptomatic.

Symptoms that may present (especially in more advanced disease) are:

🔢 Grading and staging

Cervical intraepithelial neoplasia (CIN)

Cervical intraepithelial neoplasia (CIN) is the terminology that is used to refer to the pre-invasive disease. At the stage of CIN the cells are dysplastic but are not malignant. CIN is important as approximately 1/3rd of the women with CIN II or III will develop cervical cancer within 10 years.

CIN grading	Histological findings
CIN I	Mild dysplasia involving 1/3rd of the epithelium.
CIN II	Moderate dysplasia involving 2/3rds of the epithelium.
CIN III/carcinoma in-situ (CIS)	Severe dysplasia involving full thickness of the epithelium but not invading the basement membrane. It is essentially “stage 0” cervical cancer.

Sometimes we may refer to CIN I as low-grade squamous intraepithelial lesion (LSIL) and CIN II and III may be referred to as high-grade squamous intraepithelial lesion (HSIL).

Staging cervical cancer

Staging of the cancer is vital as it does impact management of the disease. The staging system used is the FIGO (Fédération Internationale de Gynécologie et d’Obstétrique) staging system. It can be divided into 4 stages:

FIGO staging is also the most important prognostic factor to determine survival rates:

🔍 Investigations

🔍

Investigating cervical cancer:

• A good initial assessment would be to perform a thorough clinical examination. This could include:
1. Speculum and bimanual pelvic examination
2. Abdominal examination
3. Lymphadenopathy assessment - especially inguinal and supraclavicular lymph nodes.

⚠️ A cervical smear should not be done if there are clinical features that are suspicious of cervical cancer.

• 🏆 Often there are no detectable signs, especially if early on in the disease stage. Therefore, the most important thing to do would be to arrange a 2-week wait urgent referral for colposcopy and biopsy + gynaecology assessment.
• 🦠 In pre-menopausal women, a vulvovaginal or endocervical swab to test for chlamydia trachomatis would also be useful.

Once a diagnosis is confirmed, then it would be important to perform an MRI, chest X-ray, PET/CT scan to look for metastases, lymph node involvement, hydronephrosis assessment etc.

We will discuss what things are seen on smear in the page on cervical screening.

🧰 Management

The management of the disease is dependent on the FIGO staging as well as the desire for fertility. Let’s look at the options:

🧰

Management of stage IA1 cervical cancer:

💡 Stage IA1 is an invasive carcinoma with <3mm stromal invasion.

• 🥇 Cone biopsy (conisation) is the first-line option in women who wish to preserve fertility. It can be done in multiple:
• Loop electrosurgical excision procedure (LEEP) - an electric current is driven through wire loop to heat it and this wire loop is used to remove a small cone shaped bit of the cervix.
• Cold knife conisation (CKC) - a scalpel is used to remove the cone shaped wedge of dysplastic cervical cells.
• Simple hysterectomy - can be offered if the woman does not wish to preserve fertility.

🧰

Management of IB3 - IVA cervical cancer:

💡 Stage IVA is an invasive carcinoma with metastasis to pelvic organs (bladder and rectum). Essentially, it is locally advanced disease.

Surgery is unlikely to be curative and carries a high risk of morbidity when combined with chemoradiotherapy. Therefore, chemoradiotherapy is the preferred option in these patients, with aims to prolong duration of life, reduce risk of recurrence and increase chance of cure.

There are 3 components to our first-line chemoradiotherapy regimen:

• 🥇 Cisplatin
• 🥇 External beam radiotherapy (EBRT)
• 🥇 Intracavity brachytherapy - this is when there is radiotherapy provided with a radiotherapy source internally placed within the uterus and vagina.

Other important management considerations, especially for advanced disease, are:

• Pain management
• Renal complications (due to ureteric obstruction)
• Haemorrhage
• Bladder and bowel symptoms
• Lymphoedema

🚨 Complications