Cervix is lined with 2 types of epithelial cells: squamous epithelial cells (that cover the surface the interior part of the cervix near to uterus) and glandular epithelial cells (that cover the exterior part of the cervix, near the vagina). The junction of 2 types of cells is known as transformation zone, which is the most common site of cervical cancer.
Types of Cervical Cancer
- Squamous cell carcinomas are the most commonly encountered (about 90% of all cases) cervical cancers.
- Adenocarcinoma is the less common type of cervical cancer.
Most cervical cancers develop from precancerous lesions, for example, cervical intraepithelial neoplasia (CIN) or adenocarcinoma in situ. These pre-cancerous changes can develop into invasive cervical cancer by a slow process. However, in some cases, the process can be faster.
Causes of Cervical Cancer
Human Papilloma Virus Infection
We are well aware that HPV infection is the single most important risk factor which is found associated with almost all the cases of cervical cancer. Although the incidence of HPV infection is very common (about 50%) in women who become sexually active between the ages of 16 and 21 years but very few women with HPV infection ultimately develop pre-cancerous cervical lesions or invasive cervical cancer.
HPV is a group of about 150 DNA viruses with high-risk subtypes including HPV-16 and HPV-18 that are found in about 70% of all the cases of cervical cancer. Researchers believe that HPV consists of two proteins known as E6 and E7 which inactivate some tumor suppressor genes and lead to cervical cancer.
Chronic tobacco chewing or cigarette smoking exposes the body to various carcinogens that suppress the immune system to fight against HPV infection and increase the risk of cervical cancer.
Out if the 4 categories of tobacco related cancers (convincing, probable, possible, unlikely), cervical cancer lies in “probable” category.
Women who become sexually active at a younger age and had HPV infection are considered at high risk of developing cervical cancer.
Women who had a full-term pregnancy at an age younger than 17 years are more likely to develop cervical cancer than those who become pregnant after the age of 25 years.
Multiple sexual partners
Women who have multiple sexual partners or have partners with multiple partners are considered to be at higher risk of developing cervical cancer due to higher chances of sexually transmitted HPV infection.
Prolonged use of oral contraceptives
Women who are using or who have used oral contraceptives for many years are generally at higher risk of developing cervical cancer.
Weak immune system
Women with a weak immune system that may be due to any cause, for example, infection with human immunodeficiency virus (HIV), use of medicines that suppress the immune system, an autoimmune disorder, and others. A weak immune system renders women more prone to HPV infection and thus to the development of cervical cancer.
Risk of developing cervical cancer increases in females with a history of cervical cancer in first-degree relatives (mother, daughter, or sister). The risk further increases with the increase in the number of affected relatives.
An increased body mass index or waist circumference has also been linked to increased incidence of cervical cancer, based on observations in many epidemiological studies.
Low Socioeconomic status
Cervical cancer generally occurs in women of lower socioeconomic status or who belong to lower income group due to less access to healthcare services and cervical cancer screening.
Consumption of diet low in fruits and vegetables, in utero exposure to diethylstilbestrol (DES), history of a sexually transmitted disease, and chlamydial infection are other reported risk factors for cervical cancer.
Symptoms and Signs of Cervical Cancer
What are Early Signs of Cervical Cancer?
Abnormal Vaginal Bleeding
Cervical cancer usually presents with abnormal vaginal bleeding. It usually presents as irregular bleeding or spotting in the postmenopausal women. So, after attaining menopause, if you notice bleeding or spotting per vaginum, it may be a sign of cervical cancer.
In premenopausal women, it may present as irregular menstrual bleeding (metrorrhagia) or excessive bleeding during menstrual cycles (menorrhagia). It may also be associated with excessive pain in the lower abdomen or pelvis during the menstrual cycles (dysmenorrhea).
Unusual Vaginal Discharge
Sometimes an abnormal vaginal discharge may be present that may be odourless, or have a foul smell. Although, many other conditions and infections may cause such complaint.
Bleeding and Pain during Coitus
Cervical cancer may present with painful sexual intercourse (dyspareunia) with may/may not be associated with bleeding after intercourse. Other causes of dyspareunia must be rule out.
Pain in Abdomen or Pelvis
Pain or discomfort in lower abdomen or pelvis may be due to many causes, benign or malignant. But cervical cancer should be kept as a possible differential diagnosis, especially when one or more of the other signs are present, as described above.
It may occur due to locoregional extension of cervical cancer in nearby structures. Also, constipation due to intestinal obstruction may cause such complaints.
Problems in urination like painful urination, difficulty in passing urine or passage of blood in urine may be a sign of cervical cancer.
Swelling of Legs
Swelling of one or both the legs may be sign of locally advanced cervical cancer. It usually occurs due to the blockage of venous flow from lower limbs, when the cervical mass compresses the vessels.
Presence of one or more of above symptoms may warrant further investigations to diagnose and stage the disease.
Symptoms of Stage 4 Advanced or Metastatic Cervical Cancer
Metastatic or stage 4 cervical cancer has spread to involve one or more distant organs. The signs will depend on the organ involved.
Abdominal Distention or Bloating
Collection of ascitic fluid in peritoneal cavity may occur due to microscopic or macroscopic spread of cervical cancer cells to the peritoneum and omentum. When the amount of fluid collection is significant, it causes distention of abdomen and bloating sensation. It may also be accompanied by nausea and/or vomiting.
Breathlessness, Cough or Chest Pain
Spread of cervical cancer to lungs or pleura (leading to pleural effusion) or mediastinal lymph nodes may cause respiratory symptoms like difficulty in breathing or painful breathing, cough, chest pain or discomfort.
Jaundice or yellowish discoloration of eyes and/or urine may be a sign of metastatic cervical cancer, when it has spread to liver, or causes obstruction of bile duct. Also, it may be associated with pruritus, or excessive itching on the skin.
Other signs of metastatic disease include pain at one or more bony sites due to bone metastasis from the tumor. Rarely, spread to brain may cause unconsciousness, seizures, weakness in arms or legs.
Cervical Cancer Diagnosis
Here we discuss investigations required to confirm the diagnosis of cervical cancer and stage the disease.
George Papanicolaou in 1920 discovered that tumor cells could be found in vaginal fluid of women with cervical cancer. There has been 75% reduction in the incidence and a 70% reduction in the mortality from invasive cervical cancer due to the Pap test. IARC data suggests that even screening women just once in their lives, at age 35 could reduce cervical cancer incidence by 40% and mortality by 26%.
Procedure of PAP Smear
- The patient should not be actively menstruating. (8-12th day )
- It is preferable that the patients refrain from sexual activity or use of vaginal medications or spermicides for the 48 hours prior to the test.
- Appropriately sized bivalve speculum should be used. Instead of lubricant jelly, water should be used for easier passage of speculum.
- If mucus or small amounts of blood are on the cervix, gently remove with a large cotton swab (to avoid removing cells from the transformation zone).
- Scrape cervix with the Ayre’s spatula by inserting the larger irregularly shaped side of the spatula into the endocervix and turning 360 degrees, making sure to cover the entire transformation zone.
- Spread the cells from the spatula onto a numbered slide, evenly, avoiding clumping. Immediately fix the smear in a coplin jar containing 95% alcohol.
Liquid Based Cytology
It is a technique which provides a uniform thin layer of cells for examination in smear without any debris / cell contamination. The cervix brush is used to collect the sample. Central bristles inserted into cervical canal and lateral bristles fully bend against Ectocervix and then rotated for 5 to 9 times. No smear needs to be prepared and the entire sample collected by the brush is transported to the laboratory in the fixative vial after proper labeling.
Visual Inspection Methods
Their advantages are that they are simple, safe and well accepted, require very low infrastructure, can be performed by a wide range of personnel with a short training (1-3 weeks) and provide immediate results. But these also have some disadvantages like lesions may not be readily visible in women over 50 years of age as squamocolumnar junction recedes towards the endocervix. Moreover, underlying infections may increase inflammation and render the inspection difficult. Also, the specificiity of these tests may be lower.
Visual inspection using acetic acid (VIA)
In this test, clinical inspection of cervix is done using only a speculum and light source. Patient is positioned in a modified lithotomy position on a couch and a sterile vaginal speculum is gently introduced. 5% acetic acid is applied using a cotton swab soaked in acetic acid and cervix carefully look at to see whether any white lesions appear, particularly in the transformation zone close to the squamocolumnar junction, or dense, non-removable acetowhite areas in the columnar epithelium. The results one minute after application of acetic acid should be reported. Acetic acid causes reversible coagulation of intracellular proteins called as ‘Acetowhitening’.
Visual inspection using Lugol’s Iodine (VILI)
Lugol’s Iodine stains glycogen stored in the cervical epithelial cells. The mature squamous epithelium is stained black or dark brown, whereas, the cancerous epithelium stains saffron yellow.
HPV DNA Testing
Persistent infection with an oncogenic type of HPV is the necessary cause of developing cervical carcinoma. HPV DNA is found in 99.8% of all cervical cancer cases. The table below compares the sensitivity and specificity of Pap test and HPV DNA testing. As we can clearly see, the sensitivity of HPV DNA test is much better as compared to that of Pap test. Specificity of this test is lower than conventional pap. But when used together with Pap test, sensitivity of both tests used together is 100%, and the specificity is 92.5%. The risk of CIN 3 or cancer is approximately 1% among women with a negative test for HPV.
|Pap||55.4 %||96.8 %|
|HPV DNA testing||94.6 %||94.1 %|
Colposcopy is a diagnostic technique which uses a colposcope – a device equipped with magnifying lenses, a light source, and some special instruments for biopsy or surgery. This device enable doctors to closely examine the cervix surface to determine the presence of abnormal cells. Cervical surface is first treated with a 3% acetic acid solution that reacts with the HPV proteins, dehydrate the dysplastic cells (if any), and allow easy identification of any abnormal cells in the cervix. Some other reagents like Lugol iodine may also be used to distinguish between low and high-grade lesions. Doctor can also collect biopsy samples with the help of a biopsy forceps if an abnormal area is observed during the procedure.
Biopsy sample(s) from the cervix is generally collected in case an abnormal area(s) is observed during the colposcopy procedure. Endocervical curettage/scraping: This technique is used when the entire transformation zone could not be visualized via colposcope. A biopsy sample from the endocervical canal is obtained with the help of a curette scraping or sleeved endocervical brush. The biopsy sample is then tested in a laboratory for the presence of any abnormal/cancerous cells.
Cone biopsy: This is a type of excisional biopsy also known as conization as a cone-shaped biopsy sample is removed from the affected area (mostly from the transformation zone) in the cervix. This technique can also be used as a treatment option for certain very early-stage cervical cancers that are limited to superficial cervical layer. This technique is employed for the diagnosis of cervical cancer, when:
- abnormal area extends up to the endocervical canal;
- high-grade cancerous lesion is suspected; or
- invasive carcinoma or adenocarcinoma in situ is suspected.
Following are procedures generally employed for cone biopsy:
Loop Electrosurgical Excision Procedure (LEEP): In this procedure, a thin wire loop that can be heated with electricity is used to obtain cone biopsy from the transformation zone.
Cold Knife technique: In this procedure, a surgical scalpel or a laser is used to excise the cervix tissue.
These help in detemining the extent of locoregional and distant spread of the disease and determine the stage.
- Computed tomography (CT) scan
- Positron emission tomography (PET) scan
- Magnetic resonance imaging (MRI) scan
- Intravenous pyelogram (IVP)
- Chest X-ray
Staging of Cervical Cancer
The primary tumor has invaded into deeper cervical layer but is present only in the Uterus. It might or might not have spread to nearby lymph nodes without any spread to distant body parts.
Stage Ia1 – The cancer cells are visible only under a microscope. Cervical stromal invasion </=3.0 mm in depth and horizontal epithelium invasion </=7.0 mm. It might or might not have spread to nearby lymph nodes without any spread to distant body parts.
Stage Ia2 – The cancer cells are visible only under a microscope. Cervical stromal invasion >3.0 mm but </=5.0 mm in depth and horizontal epithelium invasion </=7.0 mm. It might or might not have spread to nearby lymph nodes without any spread to distant body parts.
Stage Ib1 – The cancer cells are visible without a microscope and tumor size </=4.0 cm. It might or might not have spread to nearby lymph nodes without any spread to distant body parts.
Stage Ib2 – The cancer cells are visible without a microscope and tumor size >4.0 cm. It might or might not have spread to nearby lymph nodes without any spread to distant body parts.
Stage II Cervical Cancer
The cancer cells have invaded beyond the cervix and the uterus but haven’t spread to the pelvic wall or to the lower part of the vagina. It might or might not have spread to nearby lymph nodes without any spread to distant body parts.
Stage IIa1 – The cancer cells have invaded beyond the cervix and the uterus but haven’t spread to the parametria and tumor size </=4.0 cm. It might or might not have spread to nearby lymph nodes without any spread to distant body parts.
Stage IIa2 – The cancer cells have invaded beyond the cervix and the uterus but haven’t spread to the parametria and tumor size >4.0 cm. It might or might not have spread to nearby lymph nodes without any spread to distant body parts.
Stage IIb – The cancer cells have spread to the parametria. It might or might not have spread to nearby lymph nodes without any spread to distant body parts.
Stage III Cervical Cancer
The cancer cells have spread to the pelvic wall or to the lower part of the vagina. It may block the ureter causing hydronephrosis. It might or might not have spread to nearby lymph nodes without any spread to distant body parts.
Stage IIIa – The cancer cells have spread to the lower part of the vagina. It might or might not have spread to nearby lymph nodes without any spread to distant body parts.
Stage IIIb – The cancer cells have spread to the pelvic wall. It may have blockage the ureter causing hydronephrosis. It might or might not have spread to nearby lymph nodes without any spread to distant body parts.
Stage IV Cervical Cancer
STAGE IVA – The cancer cells have invaded beyond the pelvis wall into the bladder or the rectum. It might or might not have spread to nearby lymph nodes without any spread to distant body parts.
The figure below shows tumor infiltration posteriorly into rectum.
And here the tumor infiltrates anteriorly into bladder. STAGE IVB – The cancer cells have spread to distant body parts such as distant lymph nodes, lungs, bones, or liver.
Survival Rate/Life Expectancy according to Stage
It is calculated based on whether the disease is Localised, Regional or Distant.
- Cancer is limited to the cervix.
- 5 year survival 92%
- Cancer has spread to nearby structures or lymph nodes
- 5 year survival 56%
- Cancer has spread to distant body parts.
- 5 year survival 17%
Cervical Cancer Treatment by Stage
Cervical cancer treatment depends on various factors including the type of cervical cancer, stage of the disease, age and performance status of the patient, and on the patient’s preference (to retain fertility or not). But the final decision is taken by oncologist after assessing the patient.
Stage 0 cervical cancer can be treated by removal of the pre-cancerous lesion with the help of LEEP or cold knife technique as the preferred treatment option. Total hysterectomy (surgical removal of the uterus) is the standard treatment for women with cervical adenocarcinoma in situ and post-reproductive.
Cryosurgery/Laser surgery/Conization may be used for the treatment of certain very early-stage cervical cancers that are limited to superficial cervical layer. This is most suitable for patients with Stage IA disease. Cells in the affected are killed with the help of supercooled metal probe (cryosurgery), focused laser beam (laser surgery), or a cone-shaped tissue is removed with the help of a biopsy device (conization).
However, in stage IA1 with lymphovascular invasion, and in stage IA2 disease, pelvic lymph node dissection is also required. For women who wish to retain fertility, a trachelectomy procedure can be performed, where only the cervix along with the upper part of the vagina is removed keeping the uterus in place. This surgery allows a woman to have a child in future.
In case of Stage IB cervical cancer, hysterectomy is generally preferred in most of the cases. In a radical hysterectomy, the uterus along with associated tissues like parametria, uterus ligaments, part of the vagina, pelvic lymph nodes, and fallopian tubes and ovaries are removed.
Radiotherapy with/without chemotherapy may be used in some cases, when the patient is not a candidate for surgery or is not willing for the same. Also, in some cases of advanced disease, when the size of the lesion is more than 4 cm (Stage IB3), concurrent chemoradiation is the preferred therapy.
The treatment for stage II depends on whether it is atge IIA or IIB and for IIA disease, it depends on whether it is IIA1 or IIA2, ie, whether is is lesser than or greater than 4 cm in size.
For IIA1 disease, radical hysterectomy with pelvic lymph node dissection (as discussed above) is the preferred option, which may/may not be followed by chemoradiotherapy. Radiation therapy with/without chemotherapy is a less preferred option.
For advanced cases of stage II disease, including stage IIA2 and IIB disease, concurrent chemoradiotherapy is done in most of the cases. Radiation therapy (or radiotherapy) uses high-energy radiation directed to the affected area to kill cancerous cells. It can be employed either by using an external radiation source (external beam radiation therapy) and/or by directly placing the source of radiation near the cancer tissue (brachytherapy). When given in combination with chemotherapy, it is called as concurrent chemoradiation.
In case of Stage III cervical cancer, concurrent chemo radiotherapy is considered as the preferred treatment in most of the cases.
Chemotherapy with/without radiotherapy may be considered depending upon the extent of disease and other factors.
Chemotherapy means treatment with anti-cancer drugs that kill or decrease the growth of rapidly growing cancer cells. It is considered to be the mainstay of treatment for advanced stage disease that has spread to distant body parts.
Some chemotherapy agents that are a part of cervical cancer treatment regimens are-
- Carboplatin, Cisplatin
- Topotecan, Irinotecan
Targeted therapy is another option for treatment of stage 4 disease. Bevacizumab targets vascular endothelial growth factor (VEGF) that stimulates the formation of blood vessels in the cancerous tissue. Targeted drugs are generally used alone or in combination with chemotherapy for the treatment of advanced-stage disease. The side effects associated with targeted therapy vary according to the drug used.
Best Cervical Cancer Specialist in Delhi
Dr Sunny Garg is a renowned Medical Oncologist in New Delhi with an experience of around 10 years of treating cervical cancer patients. He has treated cervical cancer patients with Chemotherapy, Targeted Therapy, Immunotherapy and Personalized Cancer Treatment. He is currently practicing at Manipal Hospital, Dwarka.
Diagnostic modalities available at our hospital include Colposcopic Biopsy, CT Guided Biopsy, Whole Body PET CT, etc. Other treatment facilities for Cervix Cancer available are Hysterectomy, Trachelectomy, Cryosurgery, Laser Surgery, Conization, Radiation Therapy, etc.
Call +91 9686813020 for appointment.