Cancers of the Cervix, Vulva, and Vagina

Epidemiology

For 2016, the American Cancer Society estimated that 12,990 cases of invasive cervical carcinoma and approximately 4120 cervical cancer deaths would occur in the United States. Since 2004, rates have decreased by 2.1% per year in women younger than 50 years and by 3.1% per year in women aged 50 years and older. A much larger population of American women (approximately fourfold) will be diagnosed with cervical dysplasia that will never develop into invasive neoplasia.

Although cervical cancer is the third most common gynecologic malignancy in the United States, it ranks as the most common gynecologic malignancy worldwide and is the fourth most common cancer in women in the world, with 569,547 cases and 311,365 deaths in 2018. Marked disparity in incidence exists between countries where routine gynecologic care and Pap smear screening are available, and countries in Latin America, the Caribbean, and Africa, where cervical cancer is the most common cause of cancer-related death in women.

It has long been appreciated that the incidence of invasive cervical carcinoma is related to sexual activity. Early age at first intercourse, multiple sexual partners, a history of venereal infection, and other parameters of sexual activity have long been recognized as factors associated with the development of invasive cervical cancer. Women from lower socioeconomic strata and African American and Hispanic populations have an increased frequency of disease. Incidence rates in the United States are estimated at 7.5 new cases per 100,000 white women each year as compared with 9.7 per 100,000 in African American women and 10 per 100,000 in Hispanics. The mortality rate from cervical cancer has consistently declined in the United States over the past 6 years; however, despite the decline, mortality persists, and women in deprived socioeconomic strata have a 76% higher cervical cancer mortality rate than their more advantaged counterparts in society.

Molecular epidemiologic studies have demonstrated that correlation of sexual activity with cervical carcinoma is related to transmission of the epithelial trophic and oncogenic HPV. Most HPV infections are transient, resulting in no changes or low-grade intraepithelial lesions (cervical intraepithelial neoplasia [CIN] 1) that will be spontaneously cleared in most young women. Development of high-grade intraepithelial lesions will occur in a small minority of women, usually within 24 months. High-grade lesions (CIN 2 and 3) may progress to invasive cervical cancer if not treated.

Cases of CIN 2 or 3 that progress to invasive cancer will do so over a period of 8 to 12 years, which has been referred to as the detectable preclinical phase. Accordingly, the opportunities for early detection and intervention are abundant. However, an estimated one-half of the invasive cervical cancers diagnosed in the United States are found in women who have never been screened, and an additional 10% are diagnosed in women who have not been screened within the preceding 5 years.

Based on a comprehensive review of available evidence, the American Cancer Society released new screening recommendations for the prevention and early detection of cervical cancer on March 12, 2012. Table 84.1 is a synopsis of these recommendations. The biggest change from the past is that Pap tests are no longer recommended every year and there are two types of tests that are used for cervical cancer screening. The Pap test can find early cell changes and treat them before they become cancer. The HPV test finds certain infections that can lead to cell changes and cancer. The HPV test may be used along with a Pap test or to help doctors decide how to treat women who have an abnormal Pap test result.

Human Papillomavirus Biology

HPV is a double-stranded DNA virus in the Papovaviridae family ( Fig. 84.1 ). This virus, made up of approximately 8000 nucleotides, encodes seven early genes and two late genes and has a small, untranslated region. Approximately 100 different serotypes with limited DNA homology have been identified. Although the identification of high-risk subtypes of HPV has been important in defining potential therapeutic targets for the prevention of cervical carcinoma, HPV infection has not adequately explained all of the biologic features of preinvasive disease and progression to invasive disease. Studies in sexually active college women demonstrated that infection with HPV is extremely common, occurring in up to 50% of women who become sexually active between the ages of 16 and 21 years, with the first abnormal Pap smear appearing in only a subset of women 1 year after infection. These infections typically are associated with low-grade dysplastic lesions and usually are transient. Persistent infection with associated high-grade dysplastic lesions is seen in only a small proportion of infected women (perhaps 1% or 2%). Biologic and/or immunologic cofactors that allow the persistence of HPV infection in a small subset of women remain unclear. Epidemiologic studies suggest that coinfection with herpes simplex virus type II, long-term oral contraceptive use, cigarette smoking, and high parity may increase the risk of persistent infection, carcinoma in situ (CIS), and invasive disease. Although long-term epidemiologic studies undertaken since appreciation of the role of HPV remain incomplete, it is known that in the large majority of women, the period between HPV infection, dysplasia, and then invasive carcinoma typically is years to decades, offering the potential for screening and early intervention to change the natural history and morbidity associated with this disease.

Molecular epidemiologic studies have divided HPV serotypes into high-, intermediate-, and low-risk subtypes for the development of cervical neoplasia. Low-risk subtypes are associated with venereal warts (condylomata acuminata), whereas intermediate- and high-risk subtypes are associated with cervical dysplasia and invasive carcinoma. A worldwide review of HPV typing demonstrated that 87% of squamous cell carcinomas had an identifiable HPV genome associated with the tumor as compared with 76.4% of adenocarcinomas. HPV-16 was the predominant type, associated with 46% to 63% of the squamous carcinomas, whereas HPV-18 was associated with 10% to 14% of squamous cell carcinomas. Sixteen other HPV types were associated with the remaining 25% of cases, including HPV-45, HPV-31, and HPV-33. Most epidemiologic studies have demonstrated a higher incidence of HPV-18 (37%–41%), followed by HPV-16 (26%–36%) in women with adenocarcinoma of the cervix. Several authors have shown a positive association between the presence of certain HPV subtypes and prognosis. Barnes and colleagues showed that, among invasive carcinomas, HPV-18 is associated with poorly differentiated histology and higher incidence of nodal metastases. Similarly, Walker reported that HPV-18–associated cancers were more likely to recur than were HPV-16–associated cancers. By contrast, HPV-16 was associated with large cell keratinizing tumors, and these tumors were less likely to recur. Lombard and colleagues demonstrated HPV-18–associated tumors to have a relative risk of death 2.4 times greater than that observed for patients with HPV-16–associated tumors and 4.4 times greater than that for patients with a tumor associated with another HPV type.

The mechanism by which these epithelial trophic viruses cause neoplasia has been defined through an elaborate collection of experiments that have focused on the role of the E6 and E7 early genes. Virally encoded E6 binds to the p53 protein, leading to targeting of this cellular checkpoint protein for proteosomal destruction. The E6 protein product also enters the nucleus and interacts with other important nuclear proteins. The second virally encoded protein, E7, sequesters the retinoblastoma gene product (Rb), releasing the Rb-associated E2F transcription factor, which results in the initiation of a number of nuclear events important in driving the cell through the cell cycle. Recent studies also have suggested that p21 is sequestered and inactivated by the E7 protein. Elimination of the p53 and Rb checkpoint results in dysregulated cell growth and dysplasia. In addition, the E7 and E6 proteins both independently lead to mitotic instability, with abnormality in chromosomal segregation during mitosis and increased chromosome instability. This may explain, in part, the long latency period between HPV infection and carcinoma. Loss-of-heterozygosity studies and other molecular events have defined chromosomal changes and changes in other oncogenic proteins that are neither primary nor secondary effects of HPV infection, but are instead caused by coinfection or other non-HPV factors. Although data suggest that HPV infection may be critical in initiating the neoplastic transformation, it is not clear that therapy that targets the HPV genome or HPV-related protein products will be useful in reversing the fully transformed phenotype.

The observation that in a large portion of HPV-infected women invasive carcinoma never develops suggests that the preinvasive neoplastic cells can be cleared by the immune system. Studies have identified T cells that specifically identify peptide epitopes of the E6 and E7 proteins. Certain human leukocyte antigen DR2 and TAP genes have been associated with invasive cervical carcinoma. Understanding the biology of cervical cancer initiation and propagation requires an understanding of HPV biology and its interaction with its epithelial cell target, and an understanding of cervical immunity.

The HPV virus is epithelial trophic. Unlike other oncogenic viruses (such as the hepatitis viruses), systemic exposure to the virus is not required for infection of the target organ. Analysis has demonstrated that E6-specific T cells in the majority of healthy women are responsible (at least in part) for eradication of infection. Tetramer analysis in patients with cervical CIS or invasive cervical cancer has in general demonstrated few HPV-16 E7-reactive T cells, typically representing less than 0.1% of the CD8+ T cells in the systemic circulation. Attempts to generate productive and/or long-term HPV-16 infection have been accomplished by using an HPV-16 virus–like particle vaccine.

In a randomized, placebo-controlled study, the delivery of three vaccinations at day 0, month 2, and month 6 reduced the risk of persistent new HPV-16 infection from 3.8 cases per 100 woman-years at risk to 0 per 100 woman-years in the group that was vaccinated, for a 100% efficacy rate. In this study, involving 2392 young women between the ages of 16 and 23 years, nine cases of HPV-16–related CIN were noted, all in the placebo recipients. Two vaccines are presently commercial available, and the American Cancer Society, the Advisory Committee for Immunization Practices, and the Centers for Disease Control and Prevention recommend three doses for routine HPV vaccination for girls and boys age 11 or 12 years, and catch-up vaccines for males through age 21 and for females through age 26. In 2014, the World Health Organization updated its recommendation and cited a vaccine schedule of two doses of the HPV vaccine for girls between 9 and 13 years of age. The use of the vaccine worldwide should help eliminate cervical and head and neck cancers caused by HPV-16; however, the adoption of the vaccine has been inconsistent, with only 2% uptake in females between the ages of 9 and 24 years throughout the world, and nonexistent in those countries where the incidence rate of cervical cancer is the highest, as a result of multiple barriers including cost, fear of the vaccine, religious objections, and many other barriers.

Maiman investigated the disease characteristics, recurrence risks, and survival rates of human immunodeficiency virus (HIV)–seropositive patients with CIN and invasive cervical cancer. HIV-infected women had significantly higher rates of recurrence of CIN after standard therapies than did seronegative women. HIV-infected women with cervical cancer had significantly more advanced disease than did those who were not infected. Only 3 (19%) of 16 HIV-seropositive patients were first seen with an early-stage disease (defined as stage IA or nonbulky IB) compared with 35 (51%) of 68 in the HIV-seronegative group. When cancer was upstaged based on surgicopathologic findings, only one (6%) HIV-infected patient had early-stage disease compared with 40% of uninfected patients. The response to therapy and prognosis were poorer among HIV-seropositive women, with higher recurrence and death rates. The majority of seropositive women had lymph node metastases and high-grade tumors. They generally were asymptomatic with respect to their HIV disease, but died of cervical cancer. The significant impact of immune status on disease progression was made evident by prolonged disease-free follow-up in seropositive patients with CD4 counts greater than 500/mm ³ , in contrast to those with CD4 counts less than 500/mm ³ . The observed marked increased risk of invasive cervical carcinoma in women infected with the HIV virus and the demonstration that highly effective antiretroviral therapy is capable of doubling the CIN regression rates in women infected with HIV, as compared with those women not receiving highly effective antiretroviral therapy, provide suggestive, indirect clinical evidence supporting the critical importance of the intact immune system in limiting the progression of HPV infection to invasive cancer in healthier populations.

Pathology

The epithelium of the cervix is composed of squamous epithelium that covers the exocervix and glands and columnar epithelial cells that line the endocervix. The border between the squamous and columnar epithelium is called the squamocolumnar junction, the site of ongoing squamous metaplasia believed to be most vulnerable to viral neoplastic transformation. With increasing age, the squamocolumnar junction migrates from the exocervix into the distal endocervical canal ( Fig. 84.2 ), with the region between the original and subsequent locations termed the transformation zone. The transformation zone is the most common location for detection of early cervical cancers ( Fig. 84.3 ). Tumors arising on the ectocervix typically are squamous cell carcinomas, whereas adenocarcinomas are more likely to have their epicenter in the endocervix.

A continuum appears to exist from CIN to frankly invasive squamous cell carcinoma ( Fig. 84.4 ). The mean age of women with CIN is 15.6 years younger than that of women with invasive cancer, suggesting slow progression of CIN to invasive carcinoma. The natural history of HPV infection and CIN in part reflects the host immune system response to the virus. Seventy-five percent of CIN 1 lesions will spontaneously regress or persist as CIN 1, without progression to invasive carcinoma.

Miller reported that, in a 13-year observational study, only 14% of CIN 3 lesions had progressed, whereas 61% persisted, and the remainder disappeared. Patients taking corticosteroids or other immunosuppressive drugs and patients with HIV infection are at higher risk of progressing to invasive cancer and may have a shorter transit time for this progression.

Squamous Cell Carcinomas of the Cervix

Approximately 75% of invasive cervical carcinomas are squamous cell carcinomas. Tumor histologic features differ among well, moderately, or poorly differentiated tumors. Squamous carcinomas ( Fig. 84.5 ) may be keratinizing (sometimes containing characteristic keratin pearls) or nonkeratinizing. Large cell and small cell variants exist. True verrucous cancers of the cervix are rare.

Cervical Adenocarcinomas

Adenocarcinomas account for 15% to 25% of invasive cervical carcinomas. Typically arising in the endocervix, adenocarcinomas can be more difficult to detect during visual inspection of the cervix. These tumors may infiltrate deeply into the stroma of the cervix, sometimes with parametrial extension and nodal metastases without gross destruction of the exocervix. In addition to the classic endocervical type, histologic variants of adenocarcinoma include endometrioid carcinoma, villoglandular, mesonephric, serous, intestinal-type, and signet ring morphologic types.

Clinically important subtypes also include clear cell adenocarcinomas of the cervix associated with in utero diethylstilbestrol (DES) exposure, which tend to be diagnosed at a younger age than most other adenocarcinomas, and so-called adenoma malignum or minimal deviation adenocarcinoma ( Fig. 84.6 ), an entity associated with deceptively bland or benign-appearing cells, which may be cause for undertreatment of a true malignancy, with a significant likelihood of recurrence even when diagnosed at an early stage.

Clinical Presentation

Preinvasive neoplastic disorders of the cervix usually are asymptomatic, hence the need for regular screening by cytologic evaluation of cells collected from the exocervix and endocervix. Early invasive cancers also may be asymptomatic, although some women will notice postcoital, intermenstrual, or postmenopausal spotting. Other symptoms may include malodorous vaginal discharge, dyspareunia, or cramping pelvic pain from uterine contractions caused by the accumulation of blood and uterine deciduas in menstruating patients with occlusion of the endocervical canal. Chronic blood loss may result in symptomatic anemia in some patients. Major hemorrhage is unusual except in locally advanced disease. Pelvic pain, lower extremity swelling (from occlusion of pelvic lymphatics or thrombosis of the external iliac vein), or problems with micturition or defecation indicate advanced regional disease and portend an ominous prognosis. Metastatic disease involving supraclavicular nodes, bones, or lungs can be the cause of presenting symptoms, but rarely in the absence of pelvic symptoms. Constitutional symptoms, including anorexia, dysgeusia, and weight loss, are seen most often in patients with very advanced disease.

Screening

Screening for cervical cancer and its precursors with the Pap smear and pelvic examination has resulted in dramatic reductions in cervical cancer mortality in every country where this has been widely used, and is arguably the most effective screening program in effect for any neoplastic disease, in either sex. Table 84.1 outlines the current screening guidelines of the American Cancer Society. The false-negative rate of the Pap smear is approximately 10% to 15% in women with invasive cancer, but the sensitivity, as defined by the detection of biopsy-proven CIN, is 51%. The sensitivity of the test may be improved by ensuring adequate sampling of the squamocolumnar junction and the endocervical canal. Smears without endocervical or metaplastic cells may be inadequate and possibly should be repeated.

Factors contributing to abnormal cytologic smears include the presence of hemorrhage, necrosis, and intense inflammation. Therefore gross symptomatic lesions should be sampled with biopsy rather than assessed with exfoliative cytology.

In the 1980s, cytology laboratories began reporting an increasing number of smears with changes of “squamous atypia” in response to concerns from clinicians over an unacceptably high false-negative cytology rate and increased recognition by cytopathologists of the cytologic changes associated with HPV infection. The use of multiple classification systems with inconsistently defined numeric grading conventions added further imprecision. In an attempt to eliminate confusion among clinicians and cytopathologists, a uniform system for reporting epithelial cell abnormalities was established in 1988 at a National Cancer Institute (NCI) workshop for reporting cervical and vaginal cytologic diagnoses.

The Bethesda system has since been revised, in 1991 and again in 2001, to reflect laboratory and clinical experience gained since the original implementation, and the increased use of new technologies and results from interval research studies. An important contribution of the Bethesda system was the creation of a standardized format and nomenclature for cytology laboratory reports that includes both a descriptive diagnosis and an evaluation of specimen adequacy.

With the formulation of Bethesda 2001, a specimen is designated “satisfactory for evaluation” or “unsatisfactory for evaluation.” The category “satisfactory but limited by …” has been eliminated as confusing. Minimal cellularity requirements for a specimen to qualify as satisfactory depend on specimen type, with an estimated 8000 to 12,000 well-visualized squamous cells for conventional smears and 5000 squamous cells for liquid-based preparations. Comments on partially obscuring inflammation or blood may be added to the “satisfactory” designation, with a specimen considered “partially obscured” when 50% to 75% of the epithelial cells cannot be visualized. When more than 75% of epithelial cells are obscured, a specimen is designated “unsatisfactory.” A notation is made regarding the presence or absence of an endocervical or transformation zone component for specimens with adequate squamous cellularity, with the numeric criterion being at least 10 well-preserved endocervical or squamous metaplastic cells. Cell clusters are not required.

Squamous atypia is a mild cellular abnormality characterized by slight nuclear enlargement and minimal changes of the nuclear chromatin. Cellular changes that show morphologic features of papillomavirus infection or mild CIN (grade 1) are termed low-grade squamous intraepithelial lesions (LSILs). Cellular changes consistent with moderate (CIN 2) or severe (CIN 3) dysplasia are termed high-grade squamous intraepithelial lesions (HSILs). The division of squamous intraepithelial lesions into high- and low-grade strata reflects accumulating evidence that LSIL generally is indicative of transient infection with HPV, particularly in young women, and does not routinely require colposcopy or treatment, whereas HSIL cytology detects precursor lesions that require further evaluation and treatment. Important refinements in the 2001 Bethesda system relate to the reporting of equivocal results. Atypical squamous cells (ASCs) are now further qualified as “of undetermined significance” (ASC-US) or “cannot exclude HSIL” (ASC-H). The qualifier “undetermined significance” was retained, because some cases of ASC-US are associated with underlying CIN 2 or CIN 3. All ASCs are considered to be suggestive of squamous intraepithelial lesions, and thus the category “ASC-US favor reactive” has been eliminated, with a portion of cases previously so designated being downgraded to “negative for intraepithelial lesion or malignancy.” The new term ASC-H includes true HSIL and its mimics and is thought to have a positive predictive value for CIN 2 or CIN 3 intermediate between ASC-US and HSIL. The term atypical glandular cells of undetermined significance ( AGUS ) has been eliminated to avoid confusion with ASC-US. Glandular cell abnormalities now are classified as atypical endocervical, endometrial, or glandular cells. The term atypical epithelial cells may be used when a squamous versus glandular origin cannot be ascertained.

Diagnosis

Management of the patient with an abnormal Pap smear with respect to further diagnostic assessments, therapeutic intervention, and subsequent surveillance follow-up is a complex arena in which guidelines continue to evolve. The American Society for Colposcopy and Cervical Pathology (ASCCP) has developed contemporary guidelines for management of cervical cytologic abnormalities and CIN based on current reporting terminology (Bethesda 2001). Techniques for further evaluation can include colposcopy, endocervical curettage (ECC) or brushing, and cervical conization by cold knife or loop electrodiathermy excision procedure (LEEP).

Testing for high-risk, oncogenic HPV DNA synchronously, or subsequent to cytologic screening, is proving to be a useful complementary tool in triage of patients with ASC-US smears, and in determining the need for colposcopy and the intervals for repeated screening. It may be helpful in the follow-up of younger patients with LSIL smears, and a useful tool in identifying older women who can safely be screened at 3-year intervals instead of annually.

HPV triage of patients with an ASC-US smear is at least as sensitive as immediate colposcopy for ultimately detecting CIN 3 and results in referral of about half as many women to colposcopy. A follow-up strategy that uses repeated cytologic assessment is sensitive at an ASC-US referral threshold but requires two follow-up visits and, ultimately, more colposcopic examinations than does HPV triage.

Cytologic and HPV screening in women older than 30 years (after which most sexually active women have been exposed to HPV and have, or have not, spontaneously cleared the infection) may be a mechanism through which low-risk HPV-negative and cytologically negative patients can be identified for whom screening at 3-year intervals is prudent and appropriate.

Colposcopy

Patients with a gross lesion of the cervix should undergo cervical biopsy. For patients with abnormal cytologic evaluation findings, without a gross lesion, a colposcopic examination with directed punch biopsies is required. Colposcopy allows the clinician to identify areas suggestive of dysplasia. A 3% acetic acid solution is applied to the cervix for 30 to 90 seconds, which causes a transient reaction with the envelope proteins of the papillomavirus, in addition to producing an osmotic dehydration of the dysplastic cells, thereby accentuating the optically dense chromatin to produce a whitish area. The skilled colposcopist can further distinguish between grades of dysplasia based on acetowhitening and types of vascular patterns ( Fig. 84.7 ). An additional technique to help visualize abnormal areas is the application of quarter-strength Lugol iodine after the initial inspection for acetowhitening. High-grade lesions turn mustard yellow.

Loop Electrodiathermy Excision Procedure

LEEP uses wire-loop electrodes in conjunction with a radiofrequency alternating current to excise the entire transformation zone and distal canal under local anesthesia ( Fig. 84.8 ). Compared with ablative procedures, LEEP has the major advantage of obtaining tissue for histologic evaluation. At many centers, LEEP has become the preferred treatment for CIN that can be assessed adequately with colposcopy.

Complications include bleeding, with a reported incidence of 1% to 8%, cervical stenosis (1%), and, rarely, pelvic cellulitis or adnexal abscess. In some cases, LEEP may not be an adequate alternative to formal excisional conization, such as in those patients in whom microinvasive or invasive cancer is suspected, or in those with adenocarcinoma in situ, because it may treat disease within the cervical canal inadequately and complicate pathologic interpretation of the specimen. Appropriate application of this technique will yield tissue suitable for pathologic study and reliable diagnosis. Excess heat may result in thermal artifact that can compromise interpretation of margins and the therapeutic adequacy of the LEEP procedure.

Staging

The revised 2009 staging criteria ( Table 84.2 ) of the International Federation of Gynecology and Obstetrics (FIGO) are a mixture of histopathologic, clinical, and radiographic assessments that reflect the fact that invasive cervical cancer is most prevalent in less-developed portions of the globe where sophisticated and expensive imaging modalities may not be widely available. Cervical cancer is clinically staged, and staging is based primarily on inspection and palpation of the cervix, vagina, parametrium, and pelvic sidewalls. Only the subclassifications of stage I (IA1, IA2) require pathologic assessment. The FIGO staging system permits assessment through biopsy, physical examination, cystoscopy, proctoscopy, excretory urography (intravenous pyelography), and plain film radiography of the chest and skeletal system. Results of lymphangiography, computed tomography (CT), MRI, and positron emission tomography (PET) may be of great value in planning treatment, but do not influence assignment of clinical stage in the FIGO formalism. When findings are equivocal, by convention, a patient is assigned to a lower stage. Once clinical stage has been assigned, it cannot be altered by subsequent events or findings. Findings from surgical evaluation (by laparoscopy or by surgical assessment of retroperitoneal lymph nodes via extraperitoneal or transperitoneal node dissection) will not alter assignment of clinical stage. However, these findings may profoundly influence subsequent treatment. Similarly, evidence of nodal or other spread discerned at the time of hysterectomy does not alter clinical stage.

A staging system based largely on findings from clinical pelvic examination is inherently imprecise and somewhat subjective, with overstaging and understaging of the parametria being the most problematic issue and the one most likely to alter management. However, FIGO stage does correlate with prognosis and does permit cautious interinstitutional and intrainstitutional comparisons of treatment outcomes.

Diagnostic Imaging Evaluation of Cervical Cancer

The goals of clinical staging in patients with invasive disease include determining the appropriateness and extent of initial surgical treatment, as opposed to initial treatment with combined radiation therapy and synchronous chemotherapy. Although not formally part of clinical staging, modern sophisticated diagnostic imaging can enhance clinical assessment of disease volume and extent in women with cervical carcinoma, thus refining both selection of treatment and technical implementation of treatment modalities.

The FIGO staging system is based predominantly on clinical examination under anesthesia, ultrasonography, intravenous urography, cystoscopy, proctoscopy, and chest radiography. Significant inaccuracies occur with use of this staging system because of possible errors in gynecologic examination (24%–39%). The various imaging modalities have a complementary role in the accurate staging and complete evaluation of the cancer, with important therapeutic implications.

Today, clinicians most often obtain a contrast-enhanced CT scan of the abdomen and pelvis for patients with disease of stage IB2 or greater ( Fig. 84.9 ). Lymph nodes larger than 1.0 to 1.5 cm in diameter are suspicious for tumor involvement and should undergo biopsy. Unfortunately, microscopic metastases are not readily detected with CT, and the inflammation commonly associated with advanced disease may cause enlargement of nodes that do not contain metastases. The sensitivity of MRI in the detection of regional metastases is similar to that of CT. However, MRI provides better anatomic delineation and accurate estimation of the tumor size, volume, and local extent within the pelvis, which can influence the choice of therapy ( Fig. 84.10 ). Involvement of the vagina, parametrium, pelvic wall muscles, ureter, bladder, and rectum can be better assessed with MRI for accurate staging ( Fig. 84.11 ). MRI before and after vaginal opacification with contrast medium can be used if imaging evaluation of the vaginal wall or fornices is required. T2-weighted images obtained by using phased-array coil, fast spin-echo or conventional spin-echo techniques are accurate in local staging and lymph nodal assessment; the former technique is faster with increased resolution. Dynamic contrast-enhanced T1-weighted images are helpful in identifying smaller tumors, fistulous tracts, and invasion into bladder and rectum. Dynamic contrast-enhanced imaging is useful in differentiating areas composed predominantly of tumor cells (well-enhanced areas) from those of fibrous tissue with scattered cancer cells (poorly enhanced areas). This information can be helpful, because radiation therapy is more effective in well-enhanced tumors.

MRI is very useful in the evaluation of tumor volume and enlarged lymph nodes, inherently important prognostic factors and determinants of the design of radiation treatment ports and selection of radiation dose. However, MRI cannot depict micrometastases to lymph nodes or differentiate malignant from nonmalignant enlargement. MRI with newer contrast agents such as ultrasmall superparamagnetic iron oxide has been useful in distinguishing benign from malignant nodes. The shape, volume, and direction of the growth of the tumor can be well assessed, and these are crucial for planning brachytherapy and external beam radiotherapy. MRI also is useful in the follow-up evaluation of the tumor, its response to treatment, and identification of recurrences. However, benign conditions, such as edema or inflammation, sometimes cannot be differentiated from tumors. Dynamic contrast-enhanced MRI is useful in differentiating malignant lesions that usually have shorter and stronger enhancement than benign conditions in patients who have abnormalities after treatment for cervical cancer.

Studies have suggested that fluorine-18 ( ¹⁸ F) fluorodeoxyglucose–positron emission tomography (FDG-PET) is more sensitive and specific than more standard radiographic studies in the detection of lymph node involvement by cervical cancer. Grigsby and colleagues reported a strong correlation between abnormal posttherapy FDG uptake and tumor recurrence. PET scans are now Medicare approved and considered standard of care for staging purposes for all newly diagnosed cervical carcinomas.

Treatment

The treatment of patients with cervical cancer is determined primarily by the stage and extent of disease. As a general rule, CIS and microinvasive cervical cancer with no more than 3 mm of stromal invasion and no more than 7 mm breadth (FIGO stage IA1) are managed with conservative surgery (excisional conization or extrafascial or simple hysterectomy). Microinvasive cervical cancer with 3 to 5 mm of stromal invasion and no more than 7 mm breadth (FIGO stage IA2) may be managed with trachelectomy, simple hysterectomy, or modified radical hysterectomy. Stage IB1 and small-volume stage IIA disease may be managed with either surgery (in general, radical hysterectomy or modified radical hysterectomy), fertility-sparing surgery if less than 2 cm, radiation alone, or chemoradiation. Controversies surround the optimal management of patients with bulky stage IB2 (>4 cm) cancer, who may be treated with triple-modality therapy in selected instances (surgery, radiation, and chemotherapy in a variety of possible sequences).

After initial radical surgical therapy, patients with adverse histopathologic factors may be advised to undergo adjuvant pelvic radiation or adjuvant chemoradiation. Risk factors for recurrence include metastatic disease in regional nodes, positive surgical margins, parametrial extension, deep cervical stromal invasion, LVSI, and large tumor size.

Patients with large FIGO stage IIA or with stages IIB through IVA disease usually are managed with chemoradiation. Some patients with an incomplete response to chemoradiation may benefit from a combined approach using adjunctive hysterectomy to clear persistent central disease after chemoradiation. Patients with bulky IB2 or IIA disease and rare patients with bulky central stage IIB lesions with minimal, medial parametrial invasion may be considered for this approach. For patients in whom disease recurs centrally in the pelvis after maximal chemoradiation, radical exenterative surgery can be performed, provided that no distant disease is present. Optimal candidates have mobile central disease without lymph node involvement. Intraoperative radiation therapy may be part of salvage surgery when lateral or posterior surgical margins will be predictably inadequate. Recurrent disease after initial radical surgery historically has been treated with salvage radiation, but currently should be treated with chemoradiation.

Hysterectomy

Hysterectomy involves the removal of the uterus and varying amounts of surrounding tissue ( Fig. 84.12 ). Because the risk of ovarian metastases is low (0.5%), ovarian preservation usually is recommended in premenopausal women, obviating the need for hormone replacement therapy. An important exception is when nodal metastases from a primary cervical adenocarcinoma are detected intraoperatively, when the risk of ovarian metastasis escalates steeply, perhaps to as high as 25%. Five types of hysterectomy have been described.

Extrafascial or simple hysterectomy (type I)

Extrafascial or simple hysterectomy involves the removal of the cervix, adjacent tissues, and a small cuff of the upper vagina in a plane outside the pubocervical fascia; it is appropriate treatment for stage IA1 disease. Minimal disturbance occurs to the bladder and ureters, which decreases the risk of urinary complications.

Modified radical hysterectomy (type II)

Modified radical or Wertheim hysterectomy , less extensive than radical hysterectomy, involves removal of the cervix and proximal 1 to 2 cm of vagina, including the paracervical and parametrial tissues. The ureters are dissected to the point of entry to the bladder to allow safe removal of parametrial and paracervical tissue. The medial half of the cardinal ligaments and the uterosacral ligaments also are removed.

Radical hysterectomy (type III)

A radical ( Meigs ) hysterectomy includes removal of the uterus, cervix, and paracervical, parametrial, and paravaginal tissues to the pelvic sidewalls bilaterally in continuity, with as much of the uterosacral ligaments as possible. The uterine vessels are ligated at their origin, and the proximal one-fourth to one-third of the vagina and paracolpos is resected. This operation usually is performed in conjunction with bilateral therapeutic pelvic lymphadenectomies. Acute complications include blood loss (average, 800 mL), ureterovaginal fistula (1%–2%), vesicovaginal fistula (<1%), pulmonary embolus (1%–2%), small bowel obstruction (1%), and febrile morbidity (25%–50%). Subacute complications include transient bladder dysfunction lasting 1 to 7 weeks (30%) and lymphocyst formation (<5%). Chronic complications include bladder hypotonia and atonia in approximately 3% of patients and, uncommonly, ureteral strictures. Rare patients may have transient or permanent lower extremity lymphedema.

Extended radical hysterectomy (type IV)

In addition to the tissue removed in type III hysterectomy, extended radical hysterectomy involves removal of the periureteral tissue, the superior vesicle artery, and up to three-fourths of the vagina. This procedure is rarely done, because patients with the anatomic extent of disease that would warrant such treatment generally should be treated with chemoradiation.

Partial exenteration (type V)

Partial exenteration is rarely performed, because radiation therapy should be used for patients with the extent of disease that would require surgery of this extent for gross anatomic clearance. Parts of the distal ureters and bladder are resected in this procedure. This may be appropriate initial surgery for patients with FIGO stage IVA cancer with large vesicovaginal fistulas and incontinence. However, vesicovaginal fistulas may scar closed in some patients after high-dose radiation therapy if the upper vagina is permitted to fuse shut, thus restoring urinary continence.

Surgical alternatives to conventional radical abdominal hysterectomy

The late 1980s and the 1990s witnessed a proliferation of surgical techniques consequent to the availability of the sophisticated instruments and optical equipment required for laparoscopic surgery, a resurgence of interest in vaginal hysterectomy, and concerns about preserving reproductive potential in young women with early cervical cancer.

Radical vaginal hysterectomy carried out with the methods of Schauta-Stoeckel (less radical) or Schauta-Amreich (more radical) is a surgical alternative to radical or modified radical abdominal hysterectomy (types II and III) that may be associated with shorter hospital stays and more rapid recuperation. Laparoscopic or robotic-assisted radical hysterectomy is an operation comparable to a radical hysterectomy (type III hysterectomy) performed entirely through the laparoscope or robotic system, including the vaginal closure.

Laparoscopy and robotic-assisted techniques have been coordinated with vaginal hysterectomy, with varying amounts of surgery being carried out via the laparoscopic or robotic-assisted approach, ranging from pelvic and paraaortic lymphadenectomy to lymphadenectomy plus important components of the radical hysterectomy.

Radical trachelectomy is an operation suitable for selected patients with small, generally exophytic squamous tumors (usually <2 cm, although some patients with larger tumors have been treated in this fashion) involving primarily the cervix who desire conservation of reproductive capacity. In this operation, the main trunk of the uterine artery is preserved, although branches to the cervix and vaginal fornices are sacrificed before amputation of the cervix at a point approximately 5 mm caudal to the uterine isthmus. The uterus is suspended from the lateral stumps of the transected paracervical ligaments. Isthmic cerclage is performed in a fashion similar to that used as prophylaxis against miscarriage, and an anastomosis between the vaginal mucosa and the isthmic mucosa is performed. Variations on this procedure can be performed vaginally with laparoscopy, or abdominally. The margin between the superior extent of the tumor and the uterine isthmus must be a minimum of 1.5 cm, but 2 cm is preferable. MRI can be used preoperatively to assist in patient selection for this procedure. Intraoperative assessment by inspection of the trachelectomy specimen and frozen-section pathologic study are done to ensure an adequate surgical margin, and patients must be prepared for hysterectomy in the eventuality that a satisfactory margin cannot be obtained. Numerous successful pregnancies have been reported after such operations, although the risk of miscarriage is increased. In carefully selected patients, the risk of cancer recurrence is very small.

Damage to the pelvic autonomic nerves during radical hysterectomy is responsible for much of the late morbidity after surgical treatment of FIGO stages IA2 to IIA cervical cancer, including problems with bladder function, defecation, and sexual dysfunction. Nerve-sparing radical abdominal hysterectomy endeavors to spare important components of the autonomic innervation of the true pelvis by identification and preservation of the hypogastric nerves, which carry sympathetic fibers; the inferior hypogastric plexus formed from the fusion of the hypogastric nerves with fibers of the pelvic splanchnic nerves derived from sacral roots S2 to S4, which carry parasympathetic fibers; and the most distal part of the hypogastric plexus, which extends to the lateral vaginal wall and the base of the bladder. In aggregate, these structures are important in controlling bladder compliance, urinary continence, vaginal lubrication and genital engorgement during sexual arousal, small muscle contractions with orgasm, and some rectal functions. This recent surgical innovation is intended not to compromise the efficacy of the cancer surgery while preserving important components of quality of life in cancer survivors. Precise criteria for patient selection have not been defined.