Prof. Yusuf Yıldırım

CAUSES & RISK FACTORS

Cervical cancer occurs with abnormal and uncontrolled proliferation of epithelial cells covering the cervix. The most common types of cervical cancer are squamous cell carcinoma (85%) and adenocarcinoma. Cervical cells that undergo cancerous change are mostly cells in the transformation zone. Normal cervical cells do not suddenly turn into cancer. Initially, "pre-cancerous" abnormal changes (called CIN, SIL or dysplasia) develop gradually. For most women, the precancerous cells will disappear without any treatment. In some women, transforms into real (invasive) cancers over the years. Proper treatment of precancerous cervical condition can prevent almost all cervical cancers. This type of cancer is the third most common gynecological cancer in developed countries with a lifetime development risk of approximately 0.6%. However, it is in the first rank among gynecological cancers in frequency and cancer-related mortality in developing countries where cervical cancer screening as well as vaccination programs are not carried out widely and effectively. Cervical cancer is most commonly diagnosed in women between the ages of 35 and 44, with the average age of diagnosis being 50. It is rarely seen after the age of 65 in women who have previously had regular cervical cancer screening.

Human papillomaviruses (HPV) have a main role in the development of cervical neoplasia and are positive in 99.7% of cases. HPV16 and 18 are responsible for over 70% of HPV cases. HPV has two proteins known as E6 and E7 that inhibit certain tumor suppressor genes such as p53 and Rb. This inhibition can allow cells lining the cervix to grow excessively and develop additional gene changes that can lead to cancer in some cases. However, HPV is not the only cause of cervical cancer. Most women with HPV do not develop cervical cancer and other risk factors, such as smoking and HIV infection, affect the likelihood of women exposed to HPV developing cervical cancer. Known risk factors for cervical cancer include:

• HPV (Human papillomavirus) infection – Infection with human papillomavirus (HPV) is major risk factor for cervical cancer. There are more than 150 subtypes of HPV and nearly half of them can infect genital area. Some types (types 6, 11, 30, 40, 42, 43, 44, 54, 55, 62, 61, 72, 81, 84, 87, 90, 91), cause formations called papilloma (wart) in different parts of the body, more commonly in the genital and anal areas. Which are low-risk HPV types as they are rarely linked to cancer. A group of HPV types are called high (or possibly high*) risk types (types 16, 18, 26*, 31, 33, 34, 35, 39, 45, 51, 52, 53*, 56, 58, 59, 66*, 68, 70*, 73*, 82); as they are strongly linked to several cancer types, including  cervical, vulvar and vaginal cancer in women, penial cancer in men and anal mouth and throat in both genders.
• Sexual history – Beginning sexual activity at an early age (especially before the age of 18), having multiple sexual partners, and having a high-risk partner (who has HPV infection or has had many sexual partners) increase the risk.
• Chlamydia and HSV-2 infections 
• Vulvar and vaginal precancerous disease (VIN, VAIN) or history of cancer 
• Smoking 
• Oral contraceptives (birth control pills) 
• Weakened immune system (chronic immunosuppression) 
• Being multiparous 
• First pregnancy at a young age
• Low socio-economic status
• Nutritional deficiencies and a diet low in fruits and vegetables
• Being obese or overweight
• Diethylstilbestrol (DES) exposure
• Family history

SYMPTOMS, DIAGNOSIS & STAGES

Women with early cervical cancer or cervical precancerous disease often have no symptoms. An average of 20% of women with cervical cancer may have no symptoms. Symptoms usually do not begin until the cancer has grown and spread to nearby tissue(s). The most common symptoms in those with a certain level of advanced disease are:

• Abnormal vaginal bleeding – such as bleeding after vaginal intercourse, bleeding after menopause, bleeding and spotting between menstrual periods, or menstrual periods that are longer or heavier than usual.
• An unusual vaginal discharge (a watery and bloody vaginal discharge).
• Pain and discomfort during sex
• Pelvic/abdominal pain (advanced disease)
• Swollen legs (advanced disease)
• Urinary or defecation problems (advanced disease): painful defecation, bleeding during defecation, blood in urine, difficult and painful urination, etc.
• Fatigue, weight loss, loss of appetite (advanced disease)

Diagnostic methods for cervical cancer are:

• Medical history and physical examination 
• Colposcopy 
• Cervical biopsy – Various types of biopsies can be used to diagnose cervical precancerous lesions and cancers. These are punch biopsy, endocervical curettage and cone biopsy (conization). Commonly used methods for cone biopsies are loop electrosurgical excision procedure (LEEP), also known as large wide loop excision of the transformation zone (LLETZ) and cold conization. Initially, electrically heated ring-shaped wires are used, and the procedure can be performed in the doctor's office under local anesthesia. In cold conization, a scalpel or laser is used instead of a hot wire to remove the tissue, and the procedure is performed in a hospital (under general or epidural anesthesia). Possible complications of cone biopsies include bleeding, infection, and cervical stenosis. Having a cone biopsy does not prevent most women from becoming pregnant, but there may be a higher risk of premature birth if a large amount of tissue has been removed.
• Pelvic exam, cystoscopy and proctoscopy under anesthesia 
• Imaging studies 

In cervical cancer cases, generally the “clinical staging” is used which is based on the results of a doctor's physical examination, biopsies, imaging tests and in some cases, it is also based on other tests such as cystoscopy and proctoscopy. If surgery is performed, the "pathological (surgical) stage" can also be determined from the findings of the surgery, however, this does not change the clinical stage, and the treatment plan is made based on the clinical stage. FIGO (International Federation of Gynecology and Obstetrics) stages of cervical cancer are as follows:

• Stage I (including IA1, IA2, IB1, IB2 and IB3 substages)- Cancer cells are limited to the cervix. It has not spread to nearby lymph nodes or distant areas.
• Stage II (with IIA1, IIA2, IIB substages )- Cancer has grown beyond the cervix and uterus (into the upper vagina or parametrium) but has not spread to the pelvic walls or lower part of the vagina.
• Stage III (includes IIIA, IIIB, IIIC1 and IIIC2 substages)- Cancer has spread to the lower part of the vagina or pelvis side walls. Cancer may be blocking the ureters (tubes that carry urine from the kidneys to the bladder).
• Stage IV (IVA and IVB substages)- Cancer has reached the bladder or rectum or has metastasized to distant organs/sites such as lungs, bones, or distant lymph nodes.

TREATMENT & PROGNOSIS

The stage of cervical cancer is major factor in determining treatment options. Nevertheless, other factors, such as the exact cancer location within the cervix, type of cancer (squamous cell or adenocarcinoma), patient's age and general health and whether you want to have children in the future may also affect treatment options.

Treatment of Stage IA1, IA2 Cervical Cancer

Treatment for these stages depends on whether you want to have children (maintain fertility) and whether the cancer has invaded blood or lymph vessels (lymphovascular invasion-LVSI). For all women with stage IA1 (including those who do not want to preserve fertility), “conization (cone biopsy)” or “simple trachelectomy” is sufficient treatment. If the cone edges do not contain cancer cells (negative surgical margins), the patient can be closely monitored without further treatment, unless the cancer recurs. If there are cancer cells around the edges of the cone biopsy (positive margins), cancer might be left behind. Which can be treated by repeat cone biopsy or radical trachelectomy. In stage IA1 disease, lymph node evaluation is not required for those with negative LVSI while SLNB may be considered for those with positive LVSI. In stage IA2, conization, simple trachelectomy, radical trachelectomy or simple hysterectomy (for women who do not want to maintain their fertility) can be performed. Pathological evaluation of lymph nodes should also be performed especially in those with positive LVSI.

Treatment of Stage IB1, IB2 and IIA1 Cervical Cancer

The treatment of choice for Stage IB1 women and all other (Stages IB2 and IIA1) women who do not want to maintain their fertility is radical hysterectomy with removal of pelvic and in some cases para-aortic lymph nodes. If the tumor is large or invades the connective tissue (stroma) that supports the uterus, bladder, and vagina, definitive “chemoradiotherapy (CTRT)” may still be considered as an option. Furthermore, if a patient is not healthy enough for surgery or decides does not want to have surgery, CTRT can be administered.

In the pathological evaluation after radical hysterectomy, if cancer has spread to tissues next to the uterus known as the parametrium or to any lymph nodes or if there are positive margins in the removed tissue (high risk group), external radiation therapy (CTRT) is usually recommended along with chemotherapy. In some cases, brachytherapy can additionally be recommended after the completion of chemoradiation. Patients in the intermediate risk group (with at least two of the following: tumor diameter >4 cm, LVSI and deep stromal invasion findings) are given only adjuvant radiotherapy (without chemotherapy). Other (low risk) patients are not given adjuvant treatment.

Treatment of Stage IB3-IVA (Locally Advanced) Cervical Cancer

Although fundamental; treatment at these stages is primary chemoradiation (CTRT), radical hysterectomy with pelvic lymph node dissection and para-aortic lymph node sampling is also an option for IB3 and IIA cases. In cases of positive surgical margins or if there are cancer cells in the removed lymph nodes, (adjuvant) radiation therapy is administered after surgery, which is usually given along with chemo (chemoradiation-CTRT).

In this group of patients, PET/CT should be performed prior to treatment, in order to evaluate the exact extent of disease and rule out pelvic/para-aortic lymph node involvement.

If adequate response has not been achieved in cases where primary CTRT is applied (if there is residual disease in the cervix after treatment), simple hysterectomy can be implemented. Moreover, some centers routinely perform post-treatment hysterectomy in patients with large baseline tumor diameter at (>7 cm) and lower uterine segment involvement.

Chemo can be cisplatin, carboplatin, or cisplatin + 5 fluorouracil (5FU), though mostly a single agent (cisplatin or carboplatin) is chosen. Radiation therapy includes external beam radiation (EBRT) and brachytherapy.

Patients treated for locally advanced disease, usually a PET/CT is done for follow-up purposes 3-4 months after the end of treatment. Some experts recommend lymphadenectomy or CT-guided biopsy for pathological confirmation in cases with evidence of para-aortic involvement. Some do not perform further evaluation if PET/CT is positive. Radiotherapy to patients with suspected or pathologically confirmed para-aortic node involvement is administered as extended-field radiotherapy.

Treatment in Metastatic (Stage IVB) or Recurrent Disease

In stage IVB (metastatic) cervical cancer, the cancer has spread from pelvis to other parts of the body which is usually considered uncurable. Treatment often includes one of the following systemic treatment options, with or without radiotherapy, trying to slowdown cancer growth or relieve symptoms:

• Chemotherapy: Most standard chemo regimens include a platinum drug (Cisplatin or Carboplatin) along with another drug such as Paclitaxel (Taxol®), Gemcitabine (Gemzar®), or Topotecan (Hycamtin®).
• Chemotherapy + targeted drug Bevacizumab (Altuzan® or Avastin®)
• Targeted drug Tisotumab vedotin-tftv (Tivdak®)
• Immunotherapy with Pembrolizumab (Keytruda®)
• Pembrolizumab + Chemotherapy (±Bevacizumab).

Cancer that appears again following a treatment is known as recurrent cancer. It may recur locally (at or near where it first started, such as near the cervix, uterus or pelvic organs) or at distant sites (such as in the lungs or bone). If the cancer has recurred only in the centre of the pelvis (central recurrence), extensive surgery called pelvic exenteration can be an option for certain patients with a chance of recovery. Radiotherapy (sometimes combined with chemotherapy) may also be an option for local and regional recurrences in patients who have not previously received radiation therapy. If surgery or radiotherapy is not possible, chemotherapy, immunotherapy or targeted drug therapy may be used to slow caner growth or relieve symptoms, even though not expected to cure the cancer completely. Patients with distant site recurrence are treated similarly to patients with Stage IVB (metastatic) disease. Comprehensive genomic profiling (CGP) is recommended to test whether patients are suitable for targeted drug treatments and/or immunotherapy.

Treatment Success and Prognosis (outlook)

The 5-year overall survival for cervical cancer is around 65%. However, depending on many factors the rate may vary. Prognostic and predictive factors for cervical cancer include:

• Tumor size and volume 
• Depth of stromal invasion 
• Local extent 
• Surgical margins 
• Number of lymph nodes removed 
• Status of lymph nodes 
• Stage – Disease stage is a very important prognostic factor in cervical cancer. Earl stage cancer has a better prognosis than advanced stage cancer. Tumors that grow into the sides of the pelvis, the connective tissue around the uterus (parametrium), or other parts of the body have worse outcomes than cancer that occurs only in the cervix. 5-year survival is around 92% in localized disease (e.g., 95% in Stage IA, 90% in IB1), 60% in regional disease, and 18% in metastatic (Stage IVB) disease.
• Lymphovascular invasion (LVSI) status 
• Surgical method (open vs laparoscopic) – studies conducted in recent years have found worst prognosis in patients who had laparoscopic (closed) surgery thus, currently open surgery is mostly recommended for cervical cancer.
• Tumor type (Histological type) 
• Whether surgery should be included in the treatment or not 
• Age and general health 
• Marital status 
• Anemia 
• Smoking – Some studies have reported that women who smoke have a poor prognosis.
• HIV status – HIV-positive patients have very poor prognosis.

You can visit our current website “oncosurgery.com.tr” for further information about cervical cancer and its surgery.