Approach Considerations
Complete evaluation starts with Papanicolaou testing, with positive findings prompting colposcopy and biopsies with further workup of cervical intraepithelial neoplasia (CIN), including ablative or explicative procedures. If, however, the pathological evaluation is suggestive of invasive cancer with positive margins on loop electrosurgical excision procedure, the patient should be referred to a gynecologic oncologist.
Once the diagnosis is established, imaging studies are performed for staging purposes. In the International Federation of Gynecology and Obstetrics (Federation Internationale de Gynecologie et d’Obstetrique [FIGO]) guidelines for staging, procedures are limited to colposcopy, biopsy, conization of cervix, cystoscopy, and proctosigmoidoscopy.[11] In the United States, more complex radiologic imaging, such as CT, MRI, and PET scans, as well as surgical staging, are often done to guide therapeutic options.
Also see Cervical Cancer Imaging.
Screening Recommendations
The American Cancer Society (ACS) and the US Preventive Services Task Force (USPSTF) recommend that all women should begin screening for cervical cancer at 21 years, regardless of sexual history (see Table).[12, 13]
Table. Summary of 2012 Screening Guidelines from the American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology (Open Table in a new window)
| Parameters | ACS Recommendations | |
| Age to start screening | Begin screening with cytology at 21 years old, regardless of sexual history | |
| Screening interval age 21–29 | Screen with cytology alone every 3 years.* HPV testing should not be used in this age group. | |
| Screening interval age 30-65 | Screen with a combination of cytology and HPV testing every 5 years (preferred) or cytology alone every 3 years. Screening by HPV testing alone is generally not recommended.* | |
| Age to stop screening | Age 65, if the woman has adequate negative prior screening and is not otherwise at high risk for cervical cancer | |
| Screening after hysterectomy | Not indicated for women without a cervix and without a history of a high-grade precancerous lesion (eg, CIN2 or CIN3) in the past 20 years or cervical cancer ever | |
| HPV-vaccinated women | Screen according to the same recommendations as for unvaccinated women | |
| These guidelines do not address special populations (eg, women with a history of cervical cancer, women who were exposed in utero to diethylstilbestrol, women who are immunocompromised) who may require more intensive or alternative screening. *If abnormal test results are present, further testing and management should be performed according to the ASCCP Guidelines as noted below under Management of Abnormal Cytology. | ||
The ACS and USPSTF 2012 guidelines do not address special populations (eg, women with a history of cervical cancer, women who were exposed in utero to diethylstilbestrol (DES), women who are immunocompromised) who may require more intensive or alternative screening. ACOG recommends annual screenings for immunocompromised patients; women with history of CIN2, CIN3, or cancer; and women who were exposed to DES in utero. HIV-positive women should be screened twice in the first year following diagnosis and yearly thereafter. Screening should continue for at least 20 years after treatment of CIN2 or worse.[14]
Screening for Cervical Cancer
If cervical cancer is the suggested diagnosis, a Papanicolaou test should be performed. Patients with positive results should be referred to a gynecologist for colposcopy, direct biopsies, and endocervical curettage.
Papanicolaou test
For many years, the standard method for cervical cancer screening has been the Papanicolaou test. The false-negative rate of a Papanicolaou test is 20%, which mostly results from sampling error. Physicians can reduce sampling error by ensuring adequate material is taken from both the endocervical canal and the ectocervix. Smears without endocervical or metaplastic cells must be repeated. Upon physical examination, suspicious or grossly abnormal cervical lesions should undergo biopsy regardless of cytologic findings.
The limitations of the conventional Papanicolaou test include limited sensitivity and a significant proportion of inadequate specimens. In addition, accurate interpretation of conventional Papanicolaou tests are often compromised by the presence of artifacts (eg, blood, mucus, obscuring inflammation, scant cellular material, air-drying artifact).
ThinPrep Papanicolaou test
The ThinPrep Papanicolaou test samples are collected the same way as the conventional Papanicolaou test. However, the specimen is placed in a preservative solution rather than on a slide. An automated processor prepares the sample and makes a uniform slide for review. Mucus and blood are removed in the process. The ThinPrep Papanicolaou test was approved in 1996 by the US Food and Drug Administration (FDA) as an alternative to the traditional conventional smear.
HPV tests
The Hybrid Capture II assay for human papillomavirus (HPV) was approved by the FDA in 2003 as a new approach for cervical cancer. This test is indicated for women aged 30 years and older, in conjunction with the Papanicolaou test. If both tests are negative, then the next Papanicolaou test can be delayed for 5 years.[12]
The HPV test is also useful for interpreting equivocal results from a Papanicolaou test. If a woman has a Papanicolaou test result showing atypical squamous cells of undetermined significance (ASCUS) and a positive HPV test, then additional workup with a colposcopy is indicated. Marks et al suggest that the use of combined oral contraceptives for longer than 6 years may negatively impact early upstream events in the natural history of HPV infection.[15]
Complete Blood Cell Count and Serum Chemistry
After the diagnosis is established, a complete blood cell count and serum chemistry for renal and hepatic functions should be ordered. These studies are intended to look for abnormalities from possible metastatic disease.
Imaging Tests
A routine chest radiograph is obtained to help rule out pulmonary metastasis. Chest radiography may be considered optional for disease that is stage IB1 or lower.[16]
A CT scan of the abdomen and pelvis is performed to look for metastasis in the liver, lymph nodes, or other organs and to help rule out hydronephrosis/hydroureter. MRI or positron-emission tomography (PET) scanning is an alternative to CT scanning; in fact, PET scanning is now recommended for patients with stage IB2 disease or higher.[16]
Magnetic resonance whole-body diffusion-weighted imaging scanning has been used to distinguish uterine cervical carcinoma from normal uterine cervix and can separate metastatic nodes from benign nodes.[17]
Also see Cervical Cancer Imaging.
Studies for Patients with Bulky Primary Tumor
In patients with bulky primary tumor, cystoscopy and proctoscopy should be performed in these patients to help rule out local invasion of the bladder and the colon. Barium enema studies can be used to evaluate extrinsic rectal compression from the cervical mass.
Surgical Staging
Clinical staging protocols can fail to demonstrate pelvic and aortic lymph node involvement in 20-50% and 6-30% of patients, respectively. For that reason, surgical staging sometimes is recommended.
Pretreatment surgical staging is the most accurate method to determine the extent of disease. However, little evidence suggests an improvement in overall survival with routine surgical staging. Therefore, pretreatment surgical staging should be individualized after a thorough nonsurgical workup, including fine-needle aspiration of lymph nodes, has failed to demonstrate metastatic disease.
Histologic Findings
Precancerous lesions of the cervix usually are detected via Papanicolaou test. The Papanicolaou test classification system has evolved over the years. Standardized Papanicolaou test reporting emerged from a 1988 workshop sponsored by the National Cancer Institute. Currently, cervical cytology results are reported according to the 2001 Bethesda System.[18]
The 2001 Bethesda System for Reporting Cervical Cytologic Diagnoses
Specimen adequacy may be the single most important quality assurance component of the system. Specimen classifications are as follows:
- Satisfactory for evaluation (note presence/absence of endocervical/transformation zone component)
- Unsatisfactory for evaluation (specify reason)
- Specimen rejected/not processed (specify reason)
- Specimen processed and examined, but unsatisfactory for evaluation of epithelial abnormality because of (specify reason)
General categorization (optional) is as follows:
- Negative for intraepithelial lesion or malignancy
- Epithelial cell abnormality
- Other
Possible interpretations/results are as follows:
- Negative for intraepithelial lesion or malignancy
- Observed organisms (eg, Trichomonas, Candida, bacteria) and cellular changes consistent with herpes simplex virus are reported.
- Reporting other non-neoplastic findings is optional (ie, inflammation, atrophy)
- Epithelial cell abnormalities
- Squamous cell
- Atypical squamous cells (ASC)
- ASC of undetermined significance (ASCUS)
- ASC, cannot exclude high-grade squamous intraepithelial lesion (ASC-H)
- Low-grade squamous intraepithelial lesion (LSIL)
- Encompassing: human papillomavirus/mild dysplasia/cervical intraepithelial neoplasia (CIN) 1
- High-grade squamous intraepithelial lesion (HSIL)
- Encompassing: moderate and severe dysplasia, carcinoma in situ, CIN 2, and CIN 3
- Squamous cell carcinoma (see the image below)
Squamous cell cervical carcinoma. - Glandular cell
- Atypical glandular cells (AGC) (specify endocervical, endometrial, or not otherwise specified)
- AGC, favor neoplastic (specify endocervical or not otherwise specified)
- Endocervical adenocarcinoma in situ (AIS)
- Adenocarcinoma
- Other (List not comprehensive)
- Endometrial cells in a woman aged 40 years or older
Automated review and ancillary testing are included as appropriate. Educational notes and suggestions are optional.
The histology of cervical malignancy is predominantly of epithelial origin, with squamous cell carcinoma representing approximately 80% and adenocarcinomas representing almost 20%. Less common histologies include small cell carcinoma, melanoma, and lymphoma.
FIGO and TNM Staging
Two staging systems are frequently used in cervical cancer: FIGO, in collaboration with the World Health Organization (WHO), and TNM system of the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC).[11, 19] (See the tables below.)
Table 1. Cervical Cancer Staging (primary tumor [T]) (Open Table in a new window)
| TNM Stage | FIGO Stage | |
| Tx | - | Primary tumor cannot be assessed |
| T0 | - | No evidence of primary tumor |
| Tis | 0 | Carcinoma in situ |
| T1 | I | Cervical carcinoma confined to uterus (extension to corpus should be disregarded) |
| T1a | IA | Invasive carcinoma diagnosed only by microscopy. All macroscopically visible lesions--even with superficial invasion--are T1b/1B. Stromal invasion with a maximal depth of 5.0 mm measured from the base of the epithelium and a horizontal spread of 7.0 mm or less. Vascular space involvement, venous or lymphatic, does not affect classification. |
| T1a1 | IA1 | Measured stromal invasion 3 mm or less in depth and 7 mm or less in lateral spread |
| T1a2 | IA2 | Measured stromal invasion more than 3 mm but not more than 5 mm with a horizontal spread 7 mm or less |
| T1b | IB | Clinically visible lesion confined to the cervix or microscopic lesion greater than IA2 |
| T1b1 | IB1 | Clinically visible lesion 4 cm or less in greatest dimension |
| IB2 | Clinically visible lesion more than 4 cm | |
| T2 | II | Cervical carcinoma invades beyond uterus but not to pelvic wall or to the lower third of vagina |
| T2a | IIA | Tumor without parametrial invasion |
| T2b | IIB | Tumor with parametrial invasion |
| T3 | III | Tumor extends to the pelvic wall and/or involves the lower third of the vagina and/or causes hydronephrosis or nonfunctioning kidney |
| T3a | IIIA | Tumor involves lower third of vagina; no extension to pelvic wall |
| T3b | IIIB | Tumor extends to pelvic wall and/or causes hydronephrosis or nonfunctioning kidney |
| - | IV | Cervical carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the bladder mucosa or rectal mucosa. Bullous edema does not qualify as a criteria for stage IV disease. |
| T4 | IVA | Spread to adjacent organs (bladder, rectum, or both) |
| M1 | IVB | Distant metastasis |
Regional lymph nodes (N), AJCC staging only, include paracervical, parametrial, hypogastric (obturator), common, internal and external iliac, presacral and sacral.
- NX: Regional lymph nodes cannot be assessed.
- N0: No regional lymph nodes metastasis.
- N1: Regional lymph nodes metastasis.
Table 2. AJCC Stage Grouping (Open Table in a new window)
| Stage | Tumor | Node | Metastasis |
| 0 | Tis | N0 | M0 |
| IA1 | T1a1 | N0 | M0 |
| IA2 | T1a2 | N0 | M0 |
| IB1 | T1b1 | N0 | M0 |
| IIA | T2a | N0 | M0 |
| IIB | T2b | N0 | M0 |
| IIIA | T3a | N0 | M0 |
| IIIB | T1 | N1 | M0 |
| - | T2 | N1 | M0 |
| - | T3a | N1 | M0 |
| - | T3b | Any N | M0 |
| IVA | T4 | Any N | M0 |
| IVB | Any T | Any N | M1 |
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| Parameters | ACS Recommendations | |
| Age to start screening | Begin screening with cytology at 21 years old, regardless of sexual history | |
| Screening interval age 21–29 | Screen with cytology alone every 3 years.* HPV testing should not be used in this age group. | |
| Screening interval age 30-65 | Screen with a combination of cytology and HPV testing every 5 years (preferred) or cytology alone every 3 years. Screening by HPV testing alone is generally not recommended.* | |
| Age to stop screening | Age 65, if the woman has adequate negative prior screening and is not otherwise at high risk for cervical cancer | |
| Screening after hysterectomy | Not indicated for women without a cervix and without a history of a high-grade precancerous lesion (eg, CIN2 or CIN3) in the past 20 years or cervical cancer ever | |
| HPV-vaccinated women | Screen according to the same recommendations as for unvaccinated women | |
| These guidelines do not address special populations (eg, women with a history of cervical cancer, women who were exposed in utero to diethylstilbestrol, women who are immunocompromised) who may require more intensive or alternative screening. *If abnormal test results are present, further testing and management should be performed according to the ASCCP Guidelines as noted below under Management of Abnormal Cytology. | ||
| TNM Stage | FIGO Stage | |
| Tx | - | Primary tumor cannot be assessed |
| T0 | - | No evidence of primary tumor |
| Tis | 0 | Carcinoma in situ |
| T1 | I | Cervical carcinoma confined to uterus (extension to corpus should be disregarded) |
| T1a | IA | Invasive carcinoma diagnosed only by microscopy. All macroscopically visible lesions--even with superficial invasion--are T1b/1B. Stromal invasion with a maximal depth of 5.0 mm measured from the base of the epithelium and a horizontal spread of 7.0 mm or less. Vascular space involvement, venous or lymphatic, does not affect classification. |
| T1a1 | IA1 | Measured stromal invasion 3 mm or less in depth and 7 mm or less in lateral spread |
| T1a2 | IA2 | Measured stromal invasion more than 3 mm but not more than 5 mm with a horizontal spread 7 mm or less |
| T1b | IB | Clinically visible lesion confined to the cervix or microscopic lesion greater than IA2 |
| T1b1 | IB1 | Clinically visible lesion 4 cm or less in greatest dimension |
| IB2 | Clinically visible lesion more than 4 cm | |
| T2 | II | Cervical carcinoma invades beyond uterus but not to pelvic wall or to the lower third of vagina |
| T2a | IIA | Tumor without parametrial invasion |
| T2b | IIB | Tumor with parametrial invasion |
| T3 | III | Tumor extends to the pelvic wall and/or involves the lower third of the vagina and/or causes hydronephrosis or nonfunctioning kidney |
| T3a | IIIA | Tumor involves lower third of vagina; no extension to pelvic wall |
| T3b | IIIB | Tumor extends to pelvic wall and/or causes hydronephrosis or nonfunctioning kidney |
| - | IV | Cervical carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the bladder mucosa or rectal mucosa. Bullous edema does not qualify as a criteria for stage IV disease. |
| T4 | IVA | Spread to adjacent organs (bladder, rectum, or both) |
| M1 | IVB | Distant metastasis |
| Stage | Tumor | Node | Metastasis |
| 0 | Tis | N0 | M0 |
| IA1 | T1a1 | N0 | M0 |
| IA2 | T1a2 | N0 | M0 |
| IB1 | T1b1 | N0 | M0 |
| IIA | T2a | N0 | M0 |
| IIB | T2b | N0 | M0 |
| IIIA | T3a | N0 | M0 |
| IIIB | T1 | N1 | M0 |
| - | T2 | N1 | M0 |
| - | T3a | N1 | M0 |
| - | T3b | Any N | M0 |
| IVA | T4 | Any N | M0 |
| IVB | Any T | Any N | M1 |
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