Management of Cancer Cervix

Review Article

Austin J Cancer Clin Res 2015; 2(7): 1064.

Management of Cancer Cervix

Sahu L, M.D, FICOG*

Maulana Azad Medical College and Lok Nayak Hospital, India

*Corresponding author: Latika Sahu, Maulana Azad Medical College and Lok Nayak Hospital, Flat No: B-47, Manu Apartments, Mayur Vihar Phase-1, New Delhi- 91, India

Received: August 10, 2015; Accepted: October 25, 2015; Published: October 27, 2015

Abstract

Cancer cervix is the most common gynaecologic malignancy. About 86% of cervical cancer cases and 13% of female cancer occur in developing countries. As the causative agent is Human Papilloma Virus (HPV), this cancer is preventable by regular screening and HPV vaccination. HPVDNA vaccines are promising approach for antigen-specific T cell mediated immunotherapy against HPV infection and they have significant therapeutic potential for clinical application in the treatment of HPV related cervical cancer, reducing morbidity, mortality, and improving quality of life. Trials show that vaccination against HPV- 16 and 18 reduces newer and persistent infections with 92% and 100% efficacy respectively. Eighty five percent of cervical cancers are of squamous cell type and others of adenocarcinoma type and very few other rare tumors. FIGO stages I-IIA are referred as early stage disease and stages IIB and higher are advanced disease. For early stage invasive cancer surgery is the choice and for advanced stage radiotherapy (RT) with or without chemotherapy is the choice. Treatment of cancer cervix requires multidisciplinary approach. Prognosis depends on- FIGO stage, tumor size, and surgical staging. Lymph node involvement in early stage cervical cancer, Stage I to IIA-single lymph node vs. multiple lymph nodes metastasis, stage IIB to IV, no lymph node involvement vs. one positive lymph node vs. multiple involved nodes, Microscopic vs. macroscopic nodal involvement will affect the prognosis. Clinical stage at diagnosis is the single most important prognostic factor for cervical cancer during pregnancy.This review article focused on recent trends of management protocols and newer trials on cervical cancer.

Keywords: Cervical cancer; HPV virus infection and related cancer; Management of cancer

Introduction

Cervical cancer is the third most common cancer in woman following breast and colorectal cancer in all age group and second most common in woman of reproductive age group [1,2]. As per WHO estimation in 2008 worldwide there were 529,409 new cases of cancer cervix and 274,288 deaths. The ratio of mortality to incidence is 52% [2]. The low incidence of cervical cancer in developed countries proves the success in regular screening. The majority (85%) of cases are squamous cell carcinoma and rest are adenocarcinoma [2,3].

Risk factors and etiopathogenesis

Other than demographic risk, HPV a sexually transmitted infection, early coitarche, multiple sexual partners, multi-parity, smoking, and lack of regular Pap smear screening are the associated risk factors for cervical cancer [3].

Human papilloma virus (HPV), infection

(HPV 16 and 18) is the etiologic agent of cervical cancer is now proved by clinical, epidemiological and molecular data [3,4]. The HPV viral oncogenes integrate into the cellular genome during cell divisions and differentiation of basal epithelium to stratified epithelium and high risk HPV DNA enhances replication of E6 and E7 genes. When viral DNA is in episomal conformation (inside nucleus but not bound to host DNA), form low-grade squamous intraepithelial lesions. When HPV DNA is in integrate conformation (binds to host cellular DNA), high-grade squamous intraepithelial lesions and invasive carcinomas develop [5]. They affect cell cycle control, independent cell growth regulation, resistance to apoptosis, immune response escape, and angiogenesis, and progression to malignancy [6].

Lower socioeconomic and educational status, older age are independently related to lesser rate of cervical cancer screening due to limited access or responsibility. Active and passive cigarette smoking increases the risk of HSIL and invasive cervical cancer by two to three folds. Current smoking alters the immunity system leads to reduced clearance of High risk HPV and increases chances of developing squamous cell carcinoma more than adenocarcinoma [7]. Woman with prior seven full term pregnancies have fourfold increase risk and those with one or two have twofold increase risk as compared with nulliparous for developing cervical cancer [3].

Long term combined oral contraceptive (COC) Pill use increase the risk up to four fold of developing cervical cancer as studies shows positive correlation between a low serum estradiol: progesterone ratio and shorter overall cervical cancer survival in premenopausal women [8] Estrogen acts as an anti-apoptotic agent permitting proliferation of cells infected with oncogenic HPV. Current and within 9 years of COC users have significantly higher risk of developing both squamous cells and adenocarcinoma of cervix. Multiple sexual partners (>6 lifetime partner), and coitarche before 20 years of age increases the risk of developing cervical cancer. Abstinence from sexual activity and use of barrier contraception during sexual intercourse decreases the cervical cancer risk [9].

Genetic susceptibility

Genetic susceptibility is found to be the cause for less than 1% of cervical cancers. Women with history of a first degree biologic relative affected with a cervical tumor have a twofold relative risk of developing a cervical tumor [10]. Tumor necrosis factor (TNF) initiate the cell apoptosis, Polymorphism with Tp53 involved in apoptosis and gene repair and some HLA gene anomalies are found to be associated with an increased risk of HPV infection progressing to cervical cancer [11-13]. The chemokine receptor-2(CCR2) gene on chromosome 3p21 may disrupt the immune response to HPV and also influence the genetic susceptibility of an individual to cervical cancer [14]. The CASP8 gene has a polymorphism in the promoter region and is associated with a reduced risk of cervical cancer. Aberrant DNA methylation pattern may also be involved in development of cervical cancer [15].

Tumor extension

The pattern of local growth may be exophytic if cancer arises from the ectocervix or endophytic if it arises from the endocervical canal. Growth may be infiltrative or ulcerative lesion if necrosis accompanies the growth. Lymphatic drainage is into the paracervical and parametrial lymph nodes then through the cardinal ligament empty into ureteric nodes then flows into obturator and internal, external and common iliac lymph nodes and lyphatics from posterior cervix course through the rectal pillars and the uterosacral ligaments to the rectal lymph nodes. Presence of lymphovascular space invasion (LVSI) during deeper tumor invasion into the stroma, blood capillaries and lymphatic channels is regarded as poor prognostic indicator in early stage cancers. Local tumor extension can cause ureteral blockage (commonly), bladder invasion through vesicouterine ligaments, rectum involve late as it is separated from cervix by posterior cul de sac. Distance metastasis may occur through haematological spread to lungs, ovaries, liver and bone. There are some rare cervical cancers like-adenosquamous, adenoid cystic, adenoid basal epithelioma, glassy cell carcinoma, large cell and small cell neuroendocrine tumor of cervix, sarcomas and malignant lymphomas.

Diagnosis

Most of the patients are asymptomatic and diagnosed with abnormal Pap smear. Early stage cervical cancer will have watery discharge per vaginum usually blood tinged and intermittent vaginal bleeding following coitus or douching. Later there can be vaginal discomfort, malodorous discharge and dysuria. As malignancy advances may cause uncontrolled bleeding from tumor bed, pressure symptoms like lower extremity and low back pain, ureteral obstruction, hydronephrosis, uremia, hematuria and symptoms of vesicovaginal or rectovaginal fistula.

In early stage cervical cancer the physical findings may be normal. When the disease advances there may be enlarged supraclavicular or inguinal lymphadenopathy, lower extremity edema, ascites or decreased breath sound. Speculum examination and thorough vaginal and rectal examination will give the proper clinical staging. Lesions may appear as exophytic or endophytic growth; as a polypoid mass, papillary tissue, or barrel shaped cervix; as a cervical ulceration or granular mass; or as necrotic tissue with purulent or bloody discharge.

Differential diagnosis

Cervical leiomyoma, cervical polyp, prolapsing uterine sarcoma, vaginitis, cervical eversion, cervicitis, threatened abortion, placenta previa, cervical pregnancy, condyloma acuminata, herpetic ulcer and chancre. Primary melanoma, Paget’s disease and vaginal cancer can also be differential diagnosis.

Clinical Approach

Screening with Papanicolaou (Pap) testing is the basic evaluation. If pap positive colposcopy and biopsies with further workup of cervical intraepithelial neoplasia (CIN), including excisional procedures should be done. If pathologic evaluation after loop electrosurgical excision or conisation suggests invasive cancer with positive margins then radical treatment should be done. Patients with suspicious or grossly abnormal cervical lesions on physical examination should undergo biopsy regardless of the cytologic findings. Once the diagnosis is made serum biochemical test for renal and liver function tests, complete blood count (CBC) including platelets, and imaging studies (optional for stages ≤ IB1) should be done for staging and surgical staging in early stage. Cystoscopy and proctoscopy should be performed in patients with bulky (≥ stage I B2) tumor to rule out local invasion of the bladder and the colon respectively. Barium enema studies can be used to evaluate extrinsic rectal compression from the cervical mass [3].

American society for colposcopy and cervical pathology (ASCCP) and American society for clinical pathology (ASCP) recommend screening guidelines as follows [16].

After 65 years of age women who have positive HPV test may require continued screening. Women who had undergone a total hysterectomy may not require cervical cancer screening except after supracervical hysterectomy, hysterectomy for CIN 2/3 lesion treated in past 20 years or cervical cancer.

Women in whom HPV test is positive but Pap smear is negative should have follow-up every 12 month interval. Women with Pap smear report of atypical squamous cells of undetermined significance(ASCUS) but HPV test is negative then she can be rescreened in 5 years or with cytology alone screening in 3 years. Colposcopy is indicated if a women show positive HPV test.

MRI or PET scanning is better over CT scan for patients with stage 1B2 disease or higher to know metastasis in the body. Magnetic resonance whole-body diffusion weighted imaging can differentiate metastatic nodes from benign nodes [17].

Staging of cervical cancer usually done clinically and preferably confirmed with a bimanual pelvic examination under anaesthesia. FIGO staging in collaboration with who and the international Union against cancer (UICC) is followed worldwide [18,19] (Table 1).

Citation: Sahu L. Management of Cancer Cervix. Austin J Cancer Clin Res 2015; 2(7): 1064.