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Cervix uteri cancer, or cervical cancer, is the fourth most common cancer in women worldwide, and it has the fourth highest mortality rate among cancers in women, with those in developing countries disproportionately affected.[1] In the United States, however, this malignancy is relatively rare, ranking 21st among common cancers.[2]
Most cases of cervical carcinoma are preventable by routine screening and by treatment of precancerous lesions.[3]
The image shows a post–total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAH-BSO) specimen. The cervical tumor is a nonkeratinizing squamous carcinoma. In addition, a Brenner tumor has replaced the right ovary, and a mucinous cystadenoma has replaced the left ovary.
Image courtesy of Flickr/Ed Uthman, MD.
Cervical cancer originates at the squamous-columnar junction (SCJ)[3,4]; it can involve the outer squamous cells, the inner glandular cells, or both.[3] The precursor lesion is dysplasia—cervical intraepithelial neoplasia (CIN) or carcinoma in-situ—which can develop into invasive cancer.[3,4]
Squamous cell carcinoma comprises approximately 80%-90% of cervical cancers, and adenocarcinoma comprises the majority of the remaining cervical cancers.[4,5] Adenosquamous (or mixed) and small cell carcinomas are relatively rare, but they generally have a poor prognosis. Primary sarcomas of the cervix as well as primary and secondary malignant lymphomas of the cervix have also been reported.[6]
Top left image: Evaluation of the SCJ with saline solution. Lower left image: Panoramic view of the SCJ with blue dye. Top right image: Microcolposcopy contact view with normal superficial cells. Note the regular and picnotic nuclei, and the regular nucleocytoplasmic proportion. Lower right image: Microcolposcopy view with high-grade nuclear abnormalities. Note the significant numbers of inhomogeneous nuclei with altered nucleocytoplasmic proportions.
Image courtesy of Valli E, Fabbri G, Centonze C, et al. Int J Biomed Sci. 2013 Sep;9(3):148-52. [Open access.] PMID: 24170989, PMCID: PMC3809345.
In the United States, the incidence of and mortality from cervical cancer has declined steadily over the past few decades.[2,4] The trend in decreasing deaths has largely been attributed to mass screening with Papanicolaou (“Pap”) tests, which can detect precancerous lesions with high sensitivity and allow for potential preventive treatments.[4,5]
In 2015, the National Cancer Institute (NCI) and American Cancer Society (ACS) estimate there will be 12,900 new US cases of cervical cancer—representing approximately 0.8% of all new US cancer cases—with about 4,100 deaths (0.7% of all cancer deaths) from this disease.[2] Data from 2010 to 2012 indicate about 0.6% of women will be diagnosed with cervical cancer in their lifetime.[2]
Adapted image courtesy of the NCI/Surveillance, Epidemiology, and End Results Program (SEER) Program.[2]
Human papilloma virus
The major risk factor for development of preinvasive or invasive carcinoma of the cervix appears to be infection with human papilloma virus (HPV).[3-7] The role of HPV as the primary etiologic infectious agent far outweighs other known risk factors; it causes nearly all cases of cervical cancer.[4,7] However, although transient HPV infection is common, particularly in young women, cervical cancer is rare; chronic HPV infection increases the risk of developing precursor lesions and malignant disease.[3,4]
HPV subtypes 16 and 18 have a strong association with, and are highly predictive of, the development of high-grade dysplasia and cancer.[3,4] Evidence exists to show that acute infection with HPV 16 increases the risk of developing high-grade CIN by 11 fold; HPV 18, by nearly 17 fold.[3]
HPV 16 has been found more frequently in younger women than in older ones.[8] HPV 16 alone accounts for up to half of invasive cervical cancers, whereas HPV 18 accounts for about a quarter of such malignancies.[6]
The main image shown is a ThinPrep liquid-based Pap smear: Normal squamous cells are on the left side of the image, whereas HPV-infected cells with mild dysplasia (low-grade squamous intraepithelial lesions [LSILs]) are on the right side. The inset image depicts an electron micrograph of a negatively stained HPV.
Pap smear courtesy of Flickr/Ed Uthman, MD; HPV micrograph courtesy of the NCI/Laboratory of Tumor Virus Biology.
Other risk factors
Other risk factors for cervical cancer include the following[3-5]:
A genetic component may exist for cervical cancer. Women who have an affected first-degree relative have a two- to three-fold increased risk of developing a cervical malignancy.[4]
Immunosuppression via human immunodeficiency virus (HIV) infection may contribute to a greater risk of persistent HPV infection and neoplastic pathogenesis.[4,9] Women infected with HIV have a five-fold increased risk of developing cervical cancer.[10]
Historically, in-utero diethylstilbestrol (DES) exposure has been associated with the development of clear cell adenocarcinoma of the cervix and the vagina.[4]
The left image shows erosion of the cervix that was later demonstrated to be low-grade cervical carcinoma. The right image demonstrates a mosaic pattern (metaplastic squamous epithelium under microscopy) on the cervix of a woman who was exposed to DES in utero. The delicate vascular latticework outlines irregular areas of white epithelium.
Images courtesy of the CDC (left) and the NCI (right).
Women with precancerous lesions or early stage disease may be asymptomatic.[3-5] As the lesions progress, signs/symptoms of cervical cancer may include the following[3-5]:
The tumor grows by extending along the squamous and glandular epithelial surfaces and then upward to the endometrial cavity, throughout the vaginal epithelium, and laterally to the pelvic wall.[11] In advanced disease, direct invasion of the bladder and rectum can occur, resulting in constipation, hematuria, fistula formation, and ureteral obstruction.[11] Distant metastasis most commonly affects the lung, abdominal cavity, liver, and gastrointestinal tract.[3]
Image courtesy of Dreamstime/Designua.
CIN grading
CIN most often occurs among young women, but cervical cancer rates are higher among older women.[3,12] Precursor lesions are graded by the amount of dysplasia present and range from CIN 1 (least dysplastic) to CIN 3 (highly dysplastic).
Image courtesy of Blausen Medical Communications, Inc, via Wikimedia Commons.
Staging evaluates the extent of the disease and is made on the basis of clinical rather than surgical findings.[4] The two major systems for staging cervical cancer are the American Joint Committee on Cancer (AJCC) tumor, node, and metastasis (TNM) classification system and the International Federation of Gynecology and Obstetrics (FIGO) system.[4]
The stages of cervical cancer include the following[4,13]:
Substages provide greater detail regarding the size, location, and extent of the disease.
Adapted table courtesy of the National Comprehensive Cancer Network (NCCN).[5]
Complete evaluation starts with Pap testing and a detailed history and physical examination, including a thorough pelvic examination.
Current screening recommendations for specific age groups are based on guidelines from the ACS, the American Society for Colposcopy and Cervical Pathology (ASCCP), and the American Society for Clinical Pathology (ASCP)[14]; the US Preventive Services Task Force (USPSTF)[15]; and the American Congress of Obstetricians and Gynecologists (ACOG).[16] The age-specific screening guidelines are as follows[14-17]:
Image of a normal Pap smear courtesy of Department of Pathology, Calicut Medical College via Wikimedia Commons/Government Medical College, Kozhikode.
Abnormal Pap test results should prompt colposcopy and biopsies (colposcopic, endocervical curettage, cone) with further workup of CIN, including excisional procedures.[4,11] Refer patients to a gynecologic oncologist if pathologic evaluation after cone biopsy (cold knife conization [CKC], loop electrosurgical excision procedure [LEEP], or large loop excision of the transformation zone [LLETZ]) suggests invasive cancer with positive margins.[4,11] Any patients with suspicious or grossly abnormal cervical lesions on physical examination should undergo biopsy regardless of the cytologic findings.[11]
Laboratory studies include complete blood cell (CBC) count with platelets and renal and hepatic function tests.[5] Findings from these tests may show abnormalities and indicate potential metastatic disease.[11]
The cytologic specimen shows squamous cell carcinoma of the cervix (Pap staining; 200× magnification).
Image courtesy of the NCI.
Staging procedures
In the FIGO guidelines for staging, procedures are limited to the following[5]:
The left images show high-grade squamous intraepithelial neoplasia (HSIL) on Pap smear (100× magnification). The right image demonstrates CIN 2 from a biopsy specimen.
Images courtesy of Chivukula M, Austin RM, Shidham VB. Cytojournal. 2007 Jan 22;4:2. [Open access.] PMID: 17241469, PMCID: PMC1794257.
Imaging studies
Obtain a routine chest radiograph to help rule out pulmonary metastasis.[4] This imaging modality may be optional for disease that is stage IB1 or lower.[5]
In the United States, more complex radiologic imaging studies such as computed tomography (CT) scanning, magnetic resonance imaging (MRI), and positron-emission tomography (PET) scanning are often used to guide management decision making. Surgical staging may also be a part of this process.[5]
Abdominal and pelvic CT scanning aids in the evaluation for metastasis in the liver, lymph nodes, or other organs, as well as helps to rule out hydronephrosis or hydroureter.[4,11]
The CT scans shown are from a patient who had fatal invasive disease owing to untreated cervical dysplasia. Image a: Local tumor progression in the pelvis with vesical invasion and hemorrhage. Image b: Left ureter obstruction is evident. Image c: Ileus is observed through the descending colon, and rectosigmoid obstruction is present. Image d: Malignant pleural effusion is seen. Images e and f, respectively: Spleen and liver metastases have occurred.
Images courtesy of Braun S, Reimer D, Strobl I, et al. J Med Case Rep. 2011 Jul 18;5:316. [Open access.] PMID: 21767367, PMCID: PMC3156764.
MRI and PET scanning are alternative imaging modalities to CT scanning. MRI is used to determine soft-tissue and parametrial involvement in advanced disease,[5] and it may detect metastatic spread to the central nervous system.[4] In addition, magnetic resonance whole-body diffusion-weighted (MR-DWI) MRI appears to be able to differentiate not only cervical cancer from normal cervix but also metastatic nodes from benign nodes.[18]
Combined 18F-fluorodeoxyglucose (FDG) PET-CT scanning may be used to assess the disease extent in the entire body.[4] PET scanning can also aid in the evaluation of the nodal volume of coverage for external beam radiotherapy (EBRT).[5]
The left image shows an initial radiotherapy field in a woman with FIGO IIB cervical cancer; the common iliac nodes are not included in the field. The right image is a maximum-intensity-projection (MIP) from the same patient 2 years later. The arrow points to an isolated left iliac recurrence near the border of the original irradiation field.
Images courtesy of Herrera FG, Prior JO. Front Oncol. 2013 Feb 26;3:34. [Open access.] PMID: 23549376, PMCID: PMC3581867.
A multidisciplinary team is involved in management decision making and includes a gynecologist as well as gynecologic, radiation, and medical oncologists.[4] Treatment options for cervical cancer are made on the basis of the disease stage at diagnosis and may consist of monotherapy or a combination of therapies, such as the following[3,4]:
The images shown are from the same patient as in the previous slide. The left image is an FDG PET-CT scan. Note the focus of intense FDG uptake in the left iliac region. The right image depicts re-irradiation of the patient with helical tomotherapy.
Images courtesy of Herrera FG, Prior JO. Front Oncol. 2013 Feb 26;3:34. [Open access.] PMID: 23549376, PMCID: PMC3581867.
Standard treatment options for cervical cancer vary with the stage of the disease and whether or not fertility sparing is desired, such as the following[3-5]:
Both images depict squamous cell carcinoma (arrows). In the right image, a round uterine leiomyoma is also present.
Images courtesy of Flickr/Ed Uthman, MD.
Surgery and radiotherapy
Surgery and radiation therapy are equally effective for early-stage, small-volume disease.[3] In younger patients, surgery may be used to preserve fertility and avoid vaginal atrophy and stenosis. Cancer of the cervical stump may be effectively treated with radiation therapy, with outcomes that are comparable to those seen in women with an intact uterus.[3]
The left image shows clear cell adenocarcinoma of the posterior lip of the cervix with a collar overlying the anterior lip. The right image illustrates the area removed with a posterior exenteration for cancer of the cervix.
Images courtesy of the NCI (left) and Cancer Research UK via Wikimedia Commons (right).
Chemotherapy
Chemotherapy is typically administered in conjunction with radiation therapy for most patients with stage IB (high-risk) to stage IVA cervical cancer.[3-5] Cisplatin is the most commonly used agent, although 5-fluorouracil (5-FU) is also frequently used.
For patients with metastatic disease, cisplatin remains the most active agent. Topotecan, carboplatin, and paclitaxel may also be used in this setting. The combination of topotecan and cisplatin improves overall survival but also increases acute toxicities.[5]
In August 2014, the US Food and Drug Administration (FDA) approved bevacizumab (Avastin) for the management of persistent, recurrent, or late-stage (metastatic) carcinoma of the cervix.[19] This agent is also approved for combination chemotherapy with paclitaxel and cisplatin or with paclitaxel and topotecan.[5]
Image of an older woman receiving chemotherapy courtesy of the NCI/Rhoda Baer.
Immunization
Evidence suggests that HPV vaccines prevent infection with HPV 16 and HPV 18.[5,7] There are currently three HPV vaccines approved by the US Food and Drug Administration: bivalent (HPV2) (Cervarix), quadrivalent (HPV4) (Gardasil), and nonavalent (HPV9) (Gardasil 9) vaccines.[20-23] These are all administered in a three-dose schedule, in which the second dose is given at least 1-2 months after the first dose and with a minimum 6-month interval between the first and third dose.[20-22]
The Advisory Committee on Immunization Practices (ACIP) recommendations for HPV vaccination are as follows[20,22]:
Image courtesy of the CDC/Judy Schmidt.
The prognosis in patients with cervical cancer is also dependent on the stage at diagnosis. Other prognostic factors include patient age, tumor size, periaortic/pelvic lymph node status, performance status, and bilateral disease.[3]
About 68% of all women diagnosed with cervical cancer survive for 5 years or longer.[2] In general, the 5-year survival rates by stage at diagnosis are as follows[2,4]:
Adapted image courtesy of the NCI/SEER Program.[2]
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