Cervix Cancer

Cancer of the uterine cervix is largely a preventable disease that is characterized by a long lead time; precancerous lesions gradually progress through recognizable stages before developing into invasive disease.1,2,3,4,5,6,7 The disease process is almost certainly curable if it is identified before its progression to invasive cancer. However, invasive cervical cancer remains a disease of significant morbidity, and it is a major cause of cancer deaths in women worldwide, although the incidence and mortality rates of invasive cervical cancer have declined substantially (particularly in countries that have well-developed screening programs).8,9 Cancer of the cervix in its early stages is readily managed with surgery. Radiation or chemoradiation therapies are reserved for high-risk early stages or advanced disease.10


Computed tomography scan of a large, lobulated mass that is replacing the cervix and showing nonuniform hypoattenuation. The air and fluid in the center of the mass are consistent with tumor necrosis and a complicating infection (the patient had purulent discharge). The central hypoattenuation in the uterine corpus is suggestive of minimal fluid in the cavity.


Human papillomavirus (HPV) is now recognized as the most important causative agent in cervical carcinogenesis at the molecular level, although HPV may not induce many of the identified molecular alterations.11,12 As many as 5% of cervical cancers may not be associated with HPV.13,14 First intercourse at an early age, sexual promiscuity, high parity, race, and low socioeconomic status are presently thought to increase the risk for cervical cancer because these factors are linked to sexual behavior that increases the likelihood of exposure to HPV and/or because they are cofactors that modify the risk in women who are infected with HPV. Tobacco smoking is also a significant independent risk factor.

For excellent patient education resources, visit eMedicine's Cancer and Tumors Center, Procedures Center, Women's Health Center, and Sexually Transmitted Diseases Center. Also, see eMedicine's patient education articles Cervical Cancer and Pap Smear.

Pathophysiology

Origins and growth patterns

Cancer of the cervix typically originates from a dysplastic or premalignant lesion previously present at the active squamocolumnar junction. The transformation from mild dysplastic to invasive carcinoma generally occurs slowly within several years, although the rate of this process varies widely.

Carcinoma in situ is particularly known to precede invasive cervical cancer in most cases. In different reported series of patients with untreated carcinoma in situ who were followed up for many years, invasive carcinoma developed in about 30% of patients at 10 years and in about 80% of patients at 30 years. However, the carcinoma-in-situ lesion may regress after the initial diagnosis; such an occurrence was reported in 17 (25%) of 67 patients who were followed up for at least 3 years. Progression to invasive carcinoma becomes established and is considered irreversible once the malignant process extends through the basement membrane and invasion of the cervical stroma occurs.

Multiple local growth patterns of invasive cervical cancer have been described, with combination growth patterns being common. The patterns include the following: exophytic, nodular, infiltrative, and ulcerative.

The exophytic variety is the most common growth pattern. It usually arises from the exocervix and is often polypoid or papillary in form. Exophytic cervical cancer may result in a large, friable, bulky mass that involves only the superficial aspect of the cervix and has the tendency for excessive bleeding.

The nodular variety typically arises in the endocervix and grows through the cervical stroma into confluent, firm masses that cause the cervix and isthmus to expand. Large, nodular-type tumors that circumferentially involve the endocervical region and large, exophytic-type tumors that originate from the endocervix and extend into the endocervical canal result in what has been referred to as a barrel-shaped cervix.

The infiltrative growth pattern leads to a stone-hard cervix that may be predicated to have minimal visible ulcerations or an exophytic mass. Infiltrative exocervical lesions tend to invade the vaginal fornices and the upper part of the vagina. On the other hand, infiltrative endocervical lesions tend to extend into the corpus and the lateral parametrium.

The ulcerative growth pattern is associated with tumor necrosis and sloughing, with the formation of a cavity that is marginated by the invasive tumor. This process is usually complicated by infection that causes seropurulent discharge.

Spread

The main pathways for the spread of invasive cervical cancer consist of the following: (1) microscopic spread into the vaginal mucosa beyond a visible or palpable tumor; (2) extension into the endometrium or myometrium of the corpus; (3) direct extension into the parametrium and, in advanced stages, into the adjacent structures; and (4) spread into the regional pelvic lymph nodes and, potentially, into the retroperitoneal, inguinal, or thoracic lymph nodes.

The extrauterine spread of cervical cancer occurs primarily by means of direct extension and lymphatic invasion that initially affects the contiguous tissues in the region of the laterally positioned cardinal ligament. Later, the tumor may involve the anterior or posterior parametrium, which are separated from the cervix by the pubovesicocervical fascia. The lateral paracervical and parametrial regions are more vulnerable to tumor invasion than the anterior and posterior parametrium because of the lack of a protective fascial covering at the lateral regions and because of the natural lymphatic drainage through the lateral paracervical tissues into the cardinal ligaments.

The local spread of cervical cancer may progress through the parametrium to involve the ureters and, eventually, the pelvic sidewalls. In some patients, the sciatic plexus is involved. Hydronephrosis, pyelonephritis, and renal failure are common complications of progressive disease. Involvement of the urinary bladder and rectum can occur in advanced cases because of direct tumor extension or subsequent to invasion of the vesicouterine or uterosacral ligaments, respectively. A vesicovaginal fistula or rectovaginal fistula may or may not develop. A tumor that extends through the posterior aspect of the cervix or corpus infrequently leads to intraperitoneal spread. Adnexal metastases are uncommon intheearlystages of the disease.

Lymphatic tumor spread usually occurs in a fairly orderly pattern or sequence that first involves the regional paracervical and parametrial lymph nodes and then the internal and external iliac lymph nodes. This may then be followed by spread to the common iliac nodes, the para-aortic nodes, and eventually the supraclavicular nodes via the thoracic duct. Metastasis to the para-aortic lymph nodes without involvement of pelvic lymph nodes is unusual.

Hematogenous tumor spread may be a result of a lymphatic venous anastomosis or direct venous invasion. The most common sites of hematogenous metastases are the lungs, bones, and liver.

Histopathologic types

Squamous cell carcinoma (SCC) accounted for 80-90% of all cervical malignancies in a large case series.15 Most of the information regarding the etiology and epidemiology of cervical cancer is derived from experience and research that are related to the most common SCC lesion. The major histopathologic SCC subtypes include: (1) well-differentiated, keratinizing, large-cell SCC (25% of cases); (2) moderately differentiated, nonkeratinizing, large-cell SCC (70% of cases); and (3) small-cell undifferentiated carcinoma (about 5% of cases), which is associated with a distinctly poor prognosis.

Pure adenocarcinomas arise from endocervical-type cells and constitute 5-20% of all cervical malignancies. A trend toward an absolute increase in the incidence of adenocarcinoma has been observed during the past 20-30 years.13,14 In particular, among women younger than 35 years, the incidence more than doubled between 1970 and the mid-1980s.13,14 The histologic patterns include well-differentiated mucinous adenocarcinoma, papillary adenocarcinoma, and a clear-cell pattern that contains glycogen but no mucin. Many of these lesions may simulate endometrial adenocarcinoma. There is a relatively higher incidence of poorly differentiated and more aggressive histologic subtypes of cervical adenocarcinoma that are associated with a poorer prognosis than SCC.

Miscellaneous uncommon or rare cancers of the cervix include variants of SCC and adenocarcinomas, mixed carcinomas, small-cell carcinoma that are similar to neuroendocrine tumors occurring elsewhere, sarcoma, lymphoma, melanoma, and metastatic tumors. Most metastases are from the endometrium, and in some patients with extensive or bulky cervical involvement, determining the true origin of the lesion may be difficult. Other common sources of metastases include the ovary, colon, and breast. Metastasis to the cervix is typically found in the setting of a patient whose site of origin of the primary malignancy is already known clinically.

Frequency
United States

Invasive cancer of the cervix is the third most common genital malignancy in women, after cancers of the endometrium and the ovary.13 The American Cancer Society estimated approximately 11,150 cases of invasive cervical cancer were diagnosed in 2007.8 The incidence of carcinoma in situ is estimated to be about 4 times that of invasive cancer.8
International

Worldwide, invasive cervical cancer is the most common genital female malignancy and the second most common malignancy in women, after breast cancer.14 The estimated total number of new cases is 371,200 per year worldwide or 9.8% of all cancers in women.

Invasive cervical cancer is more common in economically disadvantaged developing countries, in which 78% of worldwide cervical cancers occur.14 These account for 15% of all cancers in women. The associated lifetime risk of invasive cervical cancer in such countries is about 3%. In developed countries, the disease accounts for 4.4% of all new cancers in women, and it is associated with a lifetime risk of about 1.1%. This disparity is attributed to the lack of effective screening programs in developing countries that have a high incidence of cervical cancer.

Reported global cancer statistics show that the incidence is highest in Latin America, the Caribbean, southern Asia, Southeast Asia, and sub-Saharan Africa.14
Mortality/Morbidity

The prognosis of cervical cancer is relatively good in low-risk countries, with a reported 5-year survival rate of 72% for all stages combined.8 The 5-year survival rate is reportedly about 48% in developing countries, where patients are likely to seek medical attention when the cancer is more advanced.14 The 5-year survival rate for early invasive cancer is about 92%, and that for preinvasive cervical cancer is nearly 100%.8

However, invasive cervical cancer is second only to breast cancer as a leading cause of worldwide cancer-related mortality in women. Approximately 190,000 deaths per year occur worldwide as a result of cervical cancer; these account for 8.5% of all cancer deaths in women. In the United States, an estimated 3670 women died from cervical cancer in 2007.8

The presence of metastatic adenopathy is an important factor in the prognosis of cervical cancer.
Race

Compared with non-Hispanic white women, the incidence in black women is 50% higher, and the 5-year survival rate is lower.8 The rate in Hispanic women is over twice that of non-Hispanic white women.8
Age

Cervical carcinoma in situ is most commonly detected in women aged 25-34 years. Invasive cervical cancer is most frequently diagnosed in women older than 50 years, and it is uncommon in women younger than 25 years.
Anatomy

The uterus is a pear-shaped muscular organ with thick walls and a flattened hollow cavity. It consists of the corpus, or body, and the cervix, or neck. The cervix is in the most caudal position and is a relatively narrow, cylindrical segment of the uterus that measures approximately 2-4 cm in length. The uterine corpus and cervix are externally demarcated from each other by a subtle constriction called the isthmus, and they are internally demarcated by a slight narrowing of the endocervical canal called the internal os.

The cervix enters the vagina through the anterior vaginal wall, forming an oblique attachment line that separates it into a supravaginal segment and a lower intravaginal segment (portio vaginalis and exocervix). The supravaginal segment is posteriorly covered by the peritoneum in the region of the posterior cul-de-sac (pouch of Douglas or rectovaginal pouch). Anteriorly, it is separated from the urinary bladder by fatty tissue without being covered by the uterovesical pouch of the peritoneum. Laterally, it is connected to the broad ligament and the parametrium, the extraperitoneal connective tissue through which the vasculature reaches the cervix.

The vaginal segment projects into the vaginal vault and consists of about one third of the anterior aspect and one half of the posterior aspect of the cervix. At the vaginal surface of the cervix is the external os, which is generally a small, circular aperture. However, the external os may be oval or almost linear. The usually spindle-shaped endocervical canal extends from the external os to the internal os, where it joins the endometrial cavity. The transition from endocervical to endometrial glands is the histologic landmark for the internal os.

The cervix has a preponderance of fibrous tissue, as compared with the predominantly muscular uterine corpus. The cervical stroma is primarily composed of collagenous connective tissue with a small amount of interspersed stratified muscle fibers (about 10% of the stromal tissues) and a small amount of elastic tissue.

The exocervix (portio vaginalis) is covered by stratified squamous epithelium that is essentially identical to the vaginal epithelium. A single layer of columnar epithelium, supported by a basement membrane, lines the endocervical surface. The squamocolumnar junction is located at the exocervix in young individuals and gradually migrates into the endocervical region with age as the exocervical lips atrophy. Approximately 90% of SCCs arise from the squamocolumnar junction. The mucosa of the endocervical canal forms branching intramucosal folds called the plicae palmatae.

The cervix has a rich network of lymphatics that drain principally into the paracervical lymph nodes and subsequently to the hypogastric and external iliac nodes (of which the obturator nodes are the innermost component). The pelvic lymphatics drain into the common iliac and the para-aortic lymph nodes.
Presentation

Early cervical cancer is usually asymptomatic, and as many as 20% of patients who have invasive cervical cancer are asymptomatic when the disease is diagnosed by means of a Papanicolaou (Pap) smear/test or routine clinical examination.16

Approximately 80-90% of patients with cervical cancer experience a form of abnormal vaginal bleeding such as postmenopausal bleeding, irregular menses, heavy menstrual flow, painless metrorrhagia, or postcoital bleeding. In some case series and in geographic regions where endometrial cancer is not common, postmenopausal bleeding is the most common presenting symptom of cervical cancer. Abnormal vaginal discharge is a presenting symptom in about 10% of patients; the discharge may be watery, purulent, or mucoid. Pelvic or abdominal pain and urinary or rectal symptoms occur in advanced cases.

Preferred Examination

Medical procedures

The American Cancer Society guidelines for the early detection of cervical cancer recommend screening with an annual conventional Pap smear (or every 2 y with the newer liquid-based Pap test) and a pelvic examination in all women approximately 3 years after they begin having vaginal intercourse but no later than age 21 years.17 In women aged 30 years and older, the Pap test may be performed less frequently (usually every 2-3 y), at the discretion of the physician, after 3 consecutive normal results.

An alternative is for women older than age 30 years to be screened every 3 years with either the conventional or liquid-based Pap test, in addition to the HPV deoxyribonucleic acid (DNA) test.17 Women with certain risk factors (eg, prenatal diethylstilbestrol [DES] exposure, human immunodeficiency virus [HIV] infection, etc) should be screened annually. The National Comprehensive Cancer Network (NCCN) and American Society for Colposcopy and Cervical Pathology have similar guidelines.18,19

Screening for cervical intraepithelial neoplasia (CIN) with the Pap smear allows the early detection of preinvasive disease, and the test is generally accepted to be effective in reducing the incidence and mortality rate of cervical cancer. Nonetheless, the Pap smear is only a screening tool, as opposed to a definitive diagnostic procedure, and it has a 15-25% false-negative rate in the detection of cervical dysplasia.

No gross cervical abnormality may be visualized during the speculum pelvic examination if the tumor is small or if it is located in the endocervix. As many as one third of the cancers are endocervical. In this location, some fairly large tumors may escape inspection, or they might be appreciated only with bimanual rectovaginal examination. However, in most patients, a visible lesion is detected, and it may be ulcerative, plaquelike, or exophytic.

Except in pregnant patients, colposcopy-directed biopsy and endocervical curettage are advised when a cervical lesion is suspected on the basis of the clinical findings or if the Pap smear reveals a precancerous lesion or malignant cells. Punch biopsy of any gross cervical lesion should be performed, and samples of any suspicious areas in all 4 quadrants of the cervix or vagina should be obtained. Curettage of the endometrium may also be performed if tumor extension in a superior direction is suspected.

Colposcopy is usually adequate for the evaluation of the exocervix and of a segment of the endocervix near the transition of the squamous and columnar epithelium. Conization biopsy is used to evaluate a subclinical tumor when the colposcopic results are insufficient or inadequate, when the colposcopic biopsy findings suggest microinvasive cancer, when the endocervical curettage samples show dysplastic fragments, or when no gross cervical lesion is visualized and endocervical disease is suspected. Conization is usually contraindicated in patients with overt cancer because of the increased risk of hemorrhage and treatment complications. Dysplasia and carcinoma in situ may be managed with cold-knife conization or with other excision or ablation methods such as laser conization, loop electrosurgical excision procedures (LEEP), laser vaporization, and cryotherapy. Cervical conization may eventually prove tobetherapeutic in many patients.

Pretherapeutic evaluation of the extent of disease20,21,22,23,24,25

The pretreatment evaluation of patients with cervical cancer includes physical examination, chest radiography, and intravenous urography (IVU) or cross-sectional imaging (computed tomography [CT] scanning or magnetic resonance imaging [MRI]). In early-stage disease with a small tumor confined to the cervix, IVU and cross-sectional imaging are not routinely performed because of their relatively low yield.26,27 IVU is not needed when cross-sectional imaging is performed because both modalities are similarly accurate in depicting urinary obstruction and because cross-sectional imaging has the additional ability to depict a gross tumor that involves the urinary tract. Barium enema examination, radioisotope bone scanning, cystoscopy, and proctosigmoidoscopy have a low yield, particularly in early disease, and these procedures are performed for only specific indications that are based on the symptoms or clinical findings.28,29

MRI has excellent soft-tissue contrast resolution, which exceeds that of CT scanning and ultrasonography (US).30,31,32,33,34,35,36,37 Consequently, MRI is significantly more valuable than CT and US in the assessment of the size of the tumor, the depth of the cervical invasion, and the locoregional extent of the disease (direct invasion of the parametrium, pelvic sidewall, bladder, or rectum).33,38,39,40,41,42,43 CT scanning and MRI are approximately equivalent, and both are significantly superior to US, in the detection of enlarged lymph nodes.44,45,46,47,48,49,50 Overall, CT scanning and MRI are more accurate staging modalities than US. Furthermore, US is not suited for staging of the full extent of the tumor spread because of the inability of this technique to adequately depict all the potential sites of metastasis or the anatomic regions that contain lymph nodes.

Despite the advantages of MRI, the gynecology literature mostly recommends the use of CT scanning for the pretreatment evaluation of cervical cancer.26,51,52,53 Reportedly, the additional information provided with the excellent soft-tissue contrast resolution of MRI often has no significant effect on clinical decision making or on the choice of therapy.54 In general, CT scanning and MRI are not warranted in patients with small-volume early disease (stage Ib disease and a cervical tumor diameter

The International Federation of Gynecology and Obstetrics (FIGO) believes that any staging system should be universally feasible and applicable, as well as provide a worldwide standardized classification that allows various medical centers to compare results.

According to FIGO, only clinical staging fulfills these criteria, and therefore, the staging classification of cervical cancer should be entirely based on findings from the pretreatment clinical evaluation. Costly CT scanning and MRI examinations are generally not readily available worldwide, the technology and imaging techniques are variable, and the quality of the imaging interpretation is not uniform or ensured. Surgicopathologic staging is not available or feasible in patients with early disease who are receiving radiation therapy, is not indicated for patients with advanced disease, and may not be an option in countries where the economic resources and surgical expertise are limited.

The examinations permitted by FIGO for consideration in the clinicodiagnostic staging include palpation, inspection, colposcopy, biopsy, endocervical curettage, hysteroscopy, cystoscopy, proctoscopy, IVU, and radiographic evaluation of the lungs and skeleton.55 The physical examination is one of the most valuable components of the clinical staging process. A meticulous, bimanual rectovaginal examination of the pelvis should be performed (preferably with the patient under anesthesia) to evaluate potential sites of locoregional tumor spread such as the parametrium, uterosacral ligaments, pelvic sidewalls, rectum, and bladder. Any suspected tumor invasion of the rectum or bladder should be confirmed by means of endoscopically guided biopsy.

The major categories of the FIGO classification are as follows:

* Stage 0 – Carcinoma in situ
* Stage I – Invasive carcinoma that is strictly confined to the cervix
* Stage II – Locoregional spread of the cancer beyond the uterus but not to the pelvic sidewall or the lower third of the vagina
* Stage III – Cancerous spread to the pelvic sidewall or the lower third of the vagina, and/or hydronephrosis or a nonfunctioning kidney that is incident to invasion of the ureter
* Stage IV – Cancerous spread beyond the true pelvis or into the mucosa of the bladder or rectum

The FIGO stages are further categorized as follows:

* Stage Ia cervical carcinoma – Preclinical invasive carcinoma that can be diagnosed only by means of microscopy
* Stage Ib cervical carcinoma – A clinically visible lesion that is confined to the cervix uteri
o Stage Ib1 – The primary tumor is not greater than 4.0 cm in diameter.
o Stage Ib2 – The primary tumor is greater than 4.0 cm in diameter.
* Stage IIa cervical carcinoma – Spread into the upper two thirds of the vagina without parametrial invasion
* Stage IIb cervical carcinoma – Extension into the parametrium but not into the pelvic sidewall
* Stage IIIa cervical carcinoma – Extension into lower one third of the vagina, without spread to the pelvic sidewall
* Stage IIIb cervical carcinoma – Extension into the pelvic sidewall and/or causes a nonfunctioning kidney or hydronephrosis due to invasion of the ureter
* Stage IVa cervical carcinoma – Extension of the tumor into the mucosa of the bladder or rectum
* Stage IVb cervical carcinoma – Spread of the tumor beyond the true pelvis and/or by metastasis into distant organs

The strict FIGO clinical staging guidelines do not include the status of the lymph nodes, although the presence of metastatic adenopathy is an important factor in treatment planning and in the prognosis. Extended clinical staging with cross-sectional imaging (CT scanning and/or MRI) includes the status of the lymph nodes in the assessment of the extent of the disease. The detection of enlarged pelvic lymph nodes is considered equivalent to pelvic sidewall tumor extension (stage III), and the detection of enlarged lymph nodes in the para-aortic, paracaval, or inguinal regions is considered extrapelvic tumor spread (stage IV).

The major limitations of the FIGO clinical staging system are encountered in the estimation of the size of the primary tumor, particularly when the tumor is endocervical. The size of the tumor is significant because, in each stage, the incidence of lymph node metastases increases and the prognosis deteriorates with increased volume of the primary tumor. Other limitations occur in the evaluation of tumor extension into the parametrium and pelvic sidewalls and in the detection of metastatic lymphadenopathy or distant metastasis.

Extended clinical staging with cross-sectional imaging (CT scanning and/or MRI) and surgicopathologic staging, including pelvic and abdominal retroperitoneal lymphadenectomy, provide additional diagnostic value. Each has been proven to be superior to the conventional FIGO clinical staging system in determining the full extent of the tumor spread. However, once the clinical stage is assigned on the basis of the clinical pretreatment workup results (in compliance with the FIGO guidelines), the stage should not be altered as a result of subsequent findings. Instead, any additional information that is revealed by cross-sectional imaging or surgery is primarily used for planning treatment regimens, and they should not be used to revise the assigned clinical stage.
Limitations of Techniques

CT scanning uses ionizing radiation and the CT image quality is degraded by metallic prostheses, an extremely large body habitus, and patient or respiratory motion. The use of intravenous iodinated contrast material for CT imaging is associated with a risk of significant allergic reactions (including fatal anaphylaxis), nephrotoxicity, and complications due to its extravasation into the soft tissues at the injection site.

MRI is contraindicated in patients who have vital metallic biomedical devices or metallic objects in strategic anatomic regions. MRI is more costly and less readily available than CT scanning and requires long image acquisition times. The image quality is degraded by artifacts that are related to respiratory motion and bowel peristalsis, which are likely to occur during the long image acquisition time. No effective gastrointestinal (GI) contrast material is currently available for MRI. Claustrophobia deters some patients from undergoing MRI.

US is operator dependent. The image quality is degraded by a large body habitus, and visualization of portions of the pelvis and abdomen is precluded by bowel gas and bony structures. The transabdominal approach is also influenced by the degree of bladder filling and is impeded by the presence of surgical incisions, dressings, drains, or skin lesions. Transvaginal US and transrectal US (TRUS) probes have inherent limitations, including a small field of view, a short range of target penetration with high-frequency transducers, and occasional patient intolerance of the transvaginal or transrectal approach.

source:http://emedicine.medscape.com/article/402329-overview