National Cancer Society National Cancer Institute World Health OrganizationIARC
BMJclinical Evidence AP John Institute
Cervical cancer is the second most common cancer in women worldwide. Cervical cancer accounted for an estimated 11.070 new cases and 3870 deaths in the USA for 2008. Nearly 1/3 of patients who present with invasive cervical cancer will die of their disease. Cervical Cancer is named for the part of the body in which it begins. Cancers of the cervix also are named for the type of cell in which they begin. Most cervical cancers are squamous cell carcionmas. Squamous cells are thin, flat cells that form the surface of the cervix. In many developing countires, hwere mass screening programs are not widely available, the clinical problem is more serious. Woldwide, the number of new cases is estimated to be 471,000 with a four year survival rate of only 40%. A large body of epidermioloigcal and molecular biological evidence has established human papillomavirus (HPV) infection as a causative factor in cervical cancer. HPV is found in 85% or more of squamous cell invasive lesions, which represent the most common histoloigcal type seen in cervical carcinoma. Additional cofactors have also been identified, including oncogenes that have been activated by point mutations and chromosomal translocations or deletions. In light of this, cervical cancer remains a highly preventable form of cancer when pre-invasive lesions are detected early. Tytological examination of Papanicolaou-stained cervical smears (also referred to as Pap smears) is currently the principle method for detecting cervical cancer. The effectiveness of Pap smear screening varies depending not only upon the quality of the sampel being used, but also upon subjective parameters that are inherent to the analysis.
The recurrence rate of cervical cancer is between 10% and 20% for FIGO stages Ib-IIa and 50-70% in locally adevanced cases (stages IIb-IVa). Patients with recurrent disease or pelvic metastases have a poor prognosis with a 1 year survival rate between 15% and 20%. (see Chemotherapy for recurrent cervical cancer, Pectasides et al. Cancer Treatment Reviews (2008)).
Causes/Etiology:
Infection with high risk types of human papillomavirus is the main cause of cervical cancer. HPV DNA is double-stranded, containing 7,900 base pairs, which are arranged in a circle. The genome consists of 8 open reading frames, 6 early genes (E1, E2, E4, E5, E6 and E7) encoding the early protein and 2 late genes (L1 and L2) encoding the late protein. E1 protein aids in viral replication utilizing the host replication machinery. E5, E6 and E7 proteins are considered to be associated with virus immune evasion.
HPV infection starts with the contact of the virus with the basement membrane, which is often exposed by micro-abrasions on the cervical surface. Suitable receptors increase the probability of hrHPV infection. Studies have found several receptors involved in this process. Interaction between the virus’ capsid protein and the cell receptors promotes virus capsid conformational changes, thus aiding the cell entry process.
HrHPV infection promotes immune cell migration to the dermis. In the squamous epidermis, macrophages, Langerhans cells (LC), KCs, T lymphocytes, dendritic cells (DC), natural killer cells (NK) and B lymphocytes play important roles during the immune response to infection. HrHPV infection could cause the immune system to become more tolerant to the infection, thus creating a microenvironment susceptible to further infection and facilitating CIN progression. The mechanisms that have been proposed and proved are as follows: Firstly, HPV remains silent for a long time; its duplication and assembly do not cause cytolysis or the cytopathic death of the host cells. Secondly, hrHPV inhibits interferon (IFN) synthesis through E6 and E7 oncoproteins interfering with IFN signaling pathways. Thirdly, HPV infection induces regulatory T cell (Treg) infiltration and interleukin (IL)-10 or transforming growth factor β (TGF-β) production. Fourthly, the infected cells express low levels of MHC class I, resulting in impaired CTL function. Fifthly, they could induce an accumulation of ineffective CD4 and CD8 T lymphocytes in stage II/III CINs. See Song
Prevention:
Vaccination as well as screening are the primary ways to prevent cervical cancer. The preventive vaccination against HPV16 and 18 has now become widely used. Antigen-specific immunotherapy is one of the effective methods to elicit immune responses to hrHPV. Listeria monocytogenes (LM) has been used to eliminate palpable, vascularized tumors in several mouse models due to its ability to generate CD8+ tumor-infiltrating lymphocytes. Two vaccines, LM-LLO-E7 and LM-ActA-E7, have been created by a truncated listeriolysin O (LLO) fused to E7 and a fragment of the ActA protein fused to E7, respectively. These vaccines overcome central tolerance by expanding low avidity CD8+ T cells specific for E7. See Sounders
symptoms:
certical cancer usually originates in the transformation zone of the cervix, and spreads to regional lymph nodes. Clinical presentation depends mainly on the location and extent of disease.
Precancerous changes or very early stage disease are usually asymptomatic and are detected on a cervical smear.
Symptoms usually appear when the tumour causes spontaneous or contact bleeding, or pain if lymph nodes are involved. Other symptoms include serosanguineous foul smelling vaginal discharge or backache.
Diagnosis:
When a lesion is visible with the naked yee, conisation is contraindicated, and a cervical biopsy will usually provide the diagnosis. Conisation is indicated when frank invasion cannot be ruled out by a colposcopically directed biopsy, or when colposcopy is unsatisfactory and the results of a smear test show a high grade lesion.
Pathology:Squamous (thin, falt cells that form the surface of the cervix) cell carcinoma accounts for about two thirds of all cervical cancers. Adenocarcinoma has many histological variations and is found in 15-25% of cases. Unusual histological variants include clear cell carcinoma, neuroendocrine carcinoma, and adeno-squamous carcinoma.
Tumour grade (wee differentiated, moderately differentiated, and prooly differentiated), depth and width of invasion, and presence (or absence) of invasion of lymphovascular space are prognostic factors that should be adequately assessed.
Recurrent disease:
Recurrent cervical cancer is almost always incurable and less than 5% of patients who develop recurrence are alive at 5 years.
pateints who develop pelvic recurrence after radical hysterectomy may be salvaged with chemoradiotheraphy if they have not previously been irradiated.
Central pelvic recurrences after radiation or chemoradiotherpahy may udnergo curative surgery with pelvic exenteration in the absence of metastatic disease.
Most recurrences occur in the first two years after primary treatment. The recurrence rate is between 10% and 20% for FIGO stages Ib-IIa and 50-70% in locally advanced cases (stages IIb-IVa). Both persistent and locally recurrent pelvic tumors are characterized by an advanced malignant progression and often exhibit an anatomically complex topography rendering curative treatmetn very difficult and rarely successful. The role of chemotherpahy in patients with recurrent or metastatic disease is merely palliative. There is no standard but when chemotheraphy is indicated, cisplatin administered in dosage of 50-100 mg/m every 3 weeks seems to be a reasonable option.
Physical examination includes rectovaginal examination, nodal assessment (especially supraclavicular) and cervical smears. Examination should be performed every six months and after 5 years annually. Pain, vaginal bleeding, and gastrointestinal or genitourinary dysfunction must be investigated.
Treatment: see ouline