Carcinoma of the
Cervix

Cancer of the cervix is a malignant tumor of the epithelial linings of the cervix.

The Cervix is the lowermost part of the uterus, a cylindrical-shaped structure composed of stroma and epithelium.

The intravaginal part, the ectocervix, projects into the vagina and is lined by squamous epithelium.

The endocervical canal extends from the internal os at the junction with the uterus to the external os which opens into the vagina and is lined by columnar epithelium.

Almost all cases of cervical carcinoma originate in the transformation zone from the ecto-or endocervical mucosa.

The transformation zone is the area of the cervix between the old and new squamocolumnar junction.

The fact that the cervix can be easily visualized and sampled, and can be treated by freezing and burning with little or no anesthesia, has contributed to the understanding of the natural history of this cancer along with the development of simple outpatient techniques of screening and prevention

Blood supply— internal iliac arteries →uterine arteries →vaginal and cervical branches at 3 & 9 o’clock positions.

Veins drain to hypogastric venous plexus

Lymphatic drainage to common, internal & external iliac, obturator & parametrial nodes

Nerve supply -from hypogastric plexus

The epithelium

Lined by stratified squamous epithelium on the ectocervix and columnar epithelium on the endocervix.

The Squamo-Colomnar junction (SCJ) appears as a sharp line with a step due to difference in height of the stratified squamous & the mucin-secreting columnar epithelium

Location in relation to external os is variable

Original SCJ – junction between columnar epithelium and squamous epithelium laid down during embryo development, not seen at birth.

Original SCJ is up at or very close to internal os during childhood and perimenarche.

It thus becomes located in the cervical canal, far away from the external os.

After puberty & during reproductive period – oestrogen – growth of genital organs – cervix swells & enlarges – endocervical canal elongates.

The new SCJ now moves down and is located on the ectocervix.

Again, this is reversed with, age & shrinking of the genital organs, the new SCJ withdraws moving backwards towards the internal os.

At menopause, it lies completely within the endocervical canal and is often invisible on visual examination.

Human Papilloma Virus (HPV) is central to the development of cervical neoplasia. (HPV 16 and 18). Persistent high risk HPV (hrHPV) infection is a necessary but not sufficient cause. HPV leads to progressive changes in the cervical epithelium that can be detected before frank malignancy.

Persistence HPV infection occurs in only 4 – 12%.

Almost all African women are infected by HPV at some point in their lives

In most populations, prevalence peaks soon after sexual debut, then falls

In Africa, the fall in prevalence is shallower and high prevalence continues well into adult life

Prevalence of HPV infection and multiple infection is high

Sexual behavior -Multiple sexual partners, Early onset of sexual activity, History of sexually transmitted diseases (Herpes virus and Chlamydia trachomatis especially)

Multiparity

Cigarette smoking

Immunosuppression- Human immunodeficiency virus (HIV) infection, Acquired immune deficiency syndrome (AIDS), other forms of immunosuppression.

In HIV immuno-Incompetent women the development of cervical cancer precursors occurs at a younger age and the progression to cancer may be quicker. They are more likely to have persistent HPV infection

Generally, cancer of the cervix is a slowly developing process that could last 10 to 15 years.

Most probably begin as a high-grade intraepithelial lesion or carcinoma in situ with gradual progression over a period of several years

At least 90% of squamous cell carcinomas of the cervix develop from the intraepithelial layers

Cervical cancers are usually precesded by a long phase of preinvasive disease. There are low grade and high grade lesions before progression to invasive cancer.

The process is initiated by infection with a virus – the Human Papilloma Virus (HPV).

Almost always within 1cm of the squamo-columnar junction of the cervix either on the portio vaginalis of the cervix or slightly higher in the endocervical canal.

Early stromal invasion (stage1A1) is a localized process, provided there is no pathologic evidence of lymphovascular space involvement.

When lymphatics are involved, tumor cells are carried to the regional pelvic lymph nodes (parametrial, hypogastric, obturator, external iliac and sacral)

The more extensive the local disease, the greater the likelihood of lymph node involvement.

As the tumor grows, it also spreads by direct extension to the parametria.

The more advanced the local disease, the greater the likelihood of distant metastases

Ovarian involvement is rare. The liver and the lungs are the most common sites of blood borne metastases, but the tumor may involve the brain, bones, bowels, adrenal glands, spleen or pancreas.

Where cancer of the cervix is untreated or fails to respond to treatment, death occurs in 95% of patients within 2 years after the onset of symptoms.

Death can occur from uremia, pulmonary embolism, or hemorrhage from direct extension into blood vessels. Life threatening sepsis from complications of pyelonephritis or vesico-vaginal and rectovaginal fistulas is possible.

Large bowel obstuction from direct extension of tumour into the rectosigmoid colon can be the terminal event.

Pain from perineural extension is a significant management problem of advanced disease.

The progressive development of cellular changes from HPV infection to cervical cancer is shown visually below. It starts with infection of the basal cell layers of the epithelium by HPV. The whole process generally takes about 10–20 years although, in a very few cases, it may only take 1–2 years. CIN I changes can arise within 3 months of infection, CIN II within 6 months and CIN III within 1–2 years.

Cytological screening works by detecting cells scraped from the surface of these lesions, which are then classified as LSIL or HSIL by cytology. In addition, there are cytology categories of ASC-US (atypical squamous cells of uncertain significance) for abnormal cell changes thought to show possible minor, low-grade changes and ASC-H for abnormal cells that might show high-grade abnormality. There is also a pathway to glandular (adeno) carcinoma that includes adenocarcinoma in situ (AIS) and atypical glandular cells of undetermined significance (AGUS).

Ostor (1993) reviewed the literature on the natural regression, persistence and progression of pre-cancerous cervical lesions.

He calculated the approximate likelihood of regression of CIN I was 57%, persistence 32%, progression to CIN III 11% and progression to invasion 1%. The corresponding approximations for CIN II were 43%, 35%, 22% and 5% respectively. And the likelihood of CIN 3 regressing was 32% and progressing to invasion greater than 12%. There are other studies estimating different percentages of regression, progression and persistence, but the overall message is that the more advanced the pre-cancerous lesions are, the more likely they will be to progress to invasive cervical cancer.

• Squamous cell carcinomas– 70-75%
• Adenocarcinomas– 20-25%
• Adenosquamous carcinoma– 3-5%
• Undifferentiated carcinoma

Metastatic tumors to the cervix

• Direct extension- endometrium, rectum and bladder.
• Lymphatic and vascular metastases occur less often

Cervical cytology was designed to screen for cellular changes

Only a minority of precancerous lesions will progress to cervical cancer

It takes time for pre - cancerous lesions to progress into malignancy or invasive disease

Aim is to protect women at risk from developing cancer and to avoid over treatment

Prognosis

LSIL and persistent HPV will regress without treatment within 2-5 years, in 60-80% of all cases

CIN 3 (HSIL) is proven to be a true pre cursor for cervical cancer.

20% of women with HSIL will progress to invasive cancer without treatment

Nigeria epidemiology

It is the second most common cancer among women in this environment

370,000 new cases diagnosed every year

Average age of diagnosis is 51yrs, however, disease can occur in the 2nd decade of life and during pregnancy.

Although, considered preventable, with the limited health resources in our environment, it remains a significant cause of mortality.

All the studies showed the women to be multiparous with average parity varying from 5.6 (Ekanem) to 6.5 (Banjo).

While studies from Zaria showed most women to have had multiple marriages, studies from Benin did not reveal that the patients had multiple partners.

The age range for cervical cancer varied from 23-85 years in Ilorin, 27-80 years in Lagos. Recent studies and observation have shown cases to occur in women as young as 17 years.

Majority of the patients were in the age range 40-55 and the average age incidence was found to be 51.8 years in Ilorin, 52.4 years in Lagos. The lowest average age incidence of 17yrs was recorded in Ibadan. Similar age presentation was also recently recorded in Lagos.

Cervical Cancer Profile

Crude cervical cancer incidence per 100 000 women (2020): 11.9

Age-standardized cervical cancer incidence per 100 000 women (2020): 18.4

Cumulative risk of cervical cancer, ages 0-74 (2020): 1.9%

Cervical cancer deaths (2019): 10,600

Cervical cancer mortality-to-incidence ratio (2020): 0.66

Abnormal vaginal bleeding- serosanguinous discharge, spotting, frank bleeding or postcoital bleeding

Pelvic pain, often unilateral and radiating to the hip or thigh

Involuntary loss of urine or feces through the vagina

Weakness, weight loss, and anemia.

Enlargement, irregularity and a firm consistency of the cervix and the parametria.

Growth pattern can be endophytic, leading to a barrel-shaped enlargement of the cervix, or exophytic where the lesion appears as a friable, bleeding, cauliflowerlike lesion of the portio vaginalis

Ulceration of the cervix may be primary manifestation- initially superficial, with further progression of the disease, the ulcer becomes deeper and necrotic, with indurated edges and a friable, bleeding surface.

Adjacent vaginal fornices may become involved next

Nodular thickening of the uterosacral and cardinal ligaments with resultant loss of mobility and fixation of the cervix

Full blood count, VDRL, HIV

Electrolyte, urea & Creatinine, LFT

Grouping and crossmatching

Chest x-ray, MRI/CT Scan

Intravenous Urography

Examination Under Anesthesia (EUA) for clinical Staging, this usually involves cystoscopy, sigmoidoscopy, and biopsy of the cervix.

Radiological Tests

Chest radiograph:

• A chest x-ray should be obtained in all patients.
• Its purpose is primarily as a preoperative test
• Rather than as a screening examination to detect lung metastasis.
• Lung metastasis is said to occur in less than 5% of patients with otherwise known clinical stages 3 and 4 disease.

Intravenous Urogram:

• Pretreatment evaluation of the urinary tract is also mandatory for all stages of disease.
• It will rule out duplicated collecting system or a pelvic kidney.
• The likelihood of patients having hydronephrosis from tumor is about 6% for stage 1 disease, 15% for stage 2, and 35% for stage 3.

Stage I

Cervical carcinoma is confined to the cervix (extension to the corpus would be disregarded)

• Stage 1A — cancer diagnosed by microscopy only
• Stage1B— clinically visible lesion (macroscopic) confined to the cervix or microscopic disease greater than stage 1A
• Stage1B1— lesion not greater than 4 cm
• Stage1B2— lesion greater than 4 cm

Stage II

Cancer extends beyond the cervix but not to the pelvic side walls or lower third of the vagina

• Stage IIA — vaginal involvement without parametrial involvement
• StagaIIB — parametrial involvement

Stage III

Tumor extends to pelvic sidewall and/or causes hydronephrosis and/or extends to lower third of vagina

• Stage IIIA — involvement of lower third of vagina with no extension to sidewall
• Stage IIIB — extension to pelvic sidewall and/or hydronephrosis

Stage IV

Extension beyond the true pelvis or into mucosa of rectum or bladder

• Stage IVA — extension into adjacent organs
• Stage IVB — distant metastases

Prognosis

Most important prognostic factors are, staging and lymph node status.

• Stage I – 98% - 86%
• Stage II-68% - 64%
• Stage III - 43% -40%
• Stage IV - 19% - 15%

• Treat primary lesion and potential first sites of spread
• Aim to cure disease
• Reduce progression
• Reduce recurrence
• Prolong life
• Improve the quality of remaining life

Available treatment options

Surgery

• Radical hysterectomy and lymphadenectomy
• Stages I and IIa only

Radiotherapy

• External Beam Radiation Therapy (EBRT)
• Brachytherapy
• All stages

Chemotherapy

• Platinum based chemotherapy
• All stages

Treatment is based on the stage of the disease.

In general, early stage disease (I-IIa) can be treated with either radical surgery or radiation therapy. Advanced stage (IIb-IV) disease is best treated with chemoradiation.

Stages IIa2, IIb and III: Locally advanced disease

Best treated with primary radiation (external beam plus brachytherapy) with concomitant chemotherapy.

Radical chemoradiotherapy indicated

• External beam radiation followed by brachytherapy
• Platinum based chemotherapy

Radiotherapy

• Uses an external radiation source in teletherapy while in contrast;
• It uses an internal radiation source that is placed adjacent to or within the tumor itself in brachytherapy.

Types of Radiotherapy

Teletherapy

Sources used

• Gamma rays from Cobalt-60 machines
• X-rays from Linear Accelerators

Brachytherapy

Sources used; placed intracavitary

• Iridium-192, Cobalt-60
• Ceasium-137, Iodine-125

Tandem goes into the uterine cavity, and Ovoids stay at the lateral fornices

Cylinders are used in the patient who previously had hysterectomy

Brachytherapy delivers 7,000- 8,000cGy to point A infractions over 3 – 5days. Point A is defined as 2cm superior to the external cervical os and 2cm lateral to the internal cervical canal.

External beam (Teletherapy) delivers 6,000 cGy to point B in fractions over 5 – 6weeks. Point B is defined as 3cm lateral to point A.

Chemoradiation - Concomitant use of weekly chemotherapy (with platinum based agents acting as radiosensitizer) and daily fractions of radiation, has been shown to increase survival.

Acute hemorrhage:

• Pack the vagina tightly – replace after 24-48 hrs
• Emegency pelvic radiotherapy
• Antibiotic cover

Pyometria/hematometria/mucometria:

• Dilatation and drainage
• Antibiotics

Recurrence:

• Radiotherapy or Surgery
• Retrospective studies have shown that recurrence could occur within the first 2 years. As a result, most guidelines suggest routine follow-up every 3 to 4 months for the first 2 years, followed by evaluations every 6 months.

Challenges in implementing preventive measures, such as the development and use of preventive drugs and therapies

Challenges of early detection and diagnosis

• Accurate and timely histologic diagnosis and staging
• Availability of good diagnostic equipment
• Adequate training for practitioners

Challenges of treatment

• Cost of care of cancer patients is extremely high – Availability, Access, Affordability.

Disease heterogeneity (no universal treatment for all cancers)

Numerous environmental and genetic risk factors

Complexity of cellular interactions and cell signaling within the tumor microenvironment

Difficulty in getting model organisms to simulate human disease and response

90% of girls fully vaccinated with the HPV vaccine by the age of 15 (among 9-14-year-old girls)

70% of women are screened with a high-performance test by 35 years of age and again by 45 years of age

90% of women identified with cervical disease receive treatment

Cervical Cancer is the 2nd commonest cancer among women, and it is recognized as a major cause of morbidity and mortality all over the world. Prognosis for patients is markedly affected by the extent of disease at diagnosis.

Challenges to optimal care are from – challenges of implementing preventive measures, timing of diagnosis of cancer and available treatment options.

Significant reduction in the incidence, morbidity and mortality associated with this cancer can be achieved through effective preventive and treatment programs.

To recapitulate -

Primary prevention:

• Avoiding exposure to risk factors
• Vaccination

Secondary prevention:

• Detecting the precancerous lesions through screening
• Providing treatment.

Tertiary prevention:

• Measures to reduce recurrence
• Reduce progression of an invasive disease
• Palliative measures
• Multi-disciplinary team approach