Introduction

Cancers of the cervix, vulva, and vagina represent the major malignancies of the lower female genital tract. With the exception of the endocervix, this portion of the genital tract is available for physical examination, including direct visual inspection and palpation. Currently, cytologic screening and surveillance by Papanicolaou (Pap) smear, testing for the presence of oncogenic strains of the human papillomavirus (HPV), colposcopy, and a variety of confirmatory biopsy techniques are capable of diagnosing preinvasive disease or very early stage invasive disease that can be treated with a high probability of cure.

Improvements in diagnostic imaging and assessment of disease extent before therapeutic intervention and more routine use of integrated, multimodality therapy together offer the opportunity for better outcomes for women with invasive local or regional disease.

Squamous cell carcinomas are the dominant histologic type in all three sites, with many tumors associated with oncogenic strains of HPV. In the last decade, improved understanding of HPV biology, the epidemiology and natural history of HPV infection, and early studies on HPV-directed vaccines offer hope that the incidence of invasive disease could decrease in the decades ahead. In the future, anticipated use of HPV-targeted vaccines worldwide in the pediatric population offers the potential to dramatically reduce worldwide morbidity and mortality associated with this group of diseases.

Epidemiology

For 2012, the American Cancer Society estimated that 12,170 cases of invasive cervical carcinoma and approximately 4220 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 of age and by 3.1% per year in women 50 years of age 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 third most common cancer in women in the world, with an estimated 530,000 cases in 2008. 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.¹

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 8.1 new cases per 100,000 white women each year as compared with 11 per 100,000 in African American women and 14.4 per 100,000 in Hispanics.

Molecular epidemiological studies have demonstrated that correlation of sexual activity with cervical carcinoma is related to transmission of the epithelial trophic and oncogenic HPV.4–4 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.^5,6 Development of high-grade intraepithelial lesions will occur in a small minority of women, usually within 24 months.⁷ High-grade lesions (CIN 2/3) may progress to invasive cervical cancer if not treated.^8,9

Cases of CIN 2/3 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.10–13 Thus 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.¹⁴

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 87-1 is a synopsis of their recommendations.¹⁵ The biggest change from the past is that Pap tests are no longer recommended every year and there are two types of test 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.

Human Papillomavirus Biology

HPV is a double-stranded DNA virus in the Papovaviridae family (Fig. 87-1). This virus, made up of approximately 8000 nucleotides, encodes seven early genes and two late genes, as well as having 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 biological 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%). Biological and/or immunologic cofactors that allow the persistence of HPV infection in a small subset of women remain unclear. Epidemiological 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.^16,17 Although long-term epidemiological 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.^18–22

Molecular epidemiological studies have divided HPV serotypes into high-, intermediate-, and low-risk subtypes for the development of cervical neoplasia.²³ Low-risk subtypes are associated with venereal warts (condylomata acuminata), whereas intermediate- and high-risk subtypes are associated with cervical dysplasia and invasive carcinoma. Recent 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 between 46% and 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, -31, and -33. Most epidemiological studies have demonstrated a higher incidence of HPV-18 (37% to 41%), followed by HPV-16 (26% to 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 colleagues²⁴ showed that, among invasive carcinomas, HPV-18 is associated with poorly differentiated histology and higher incidence of nodal metastases. Similarly, Walker²⁵ 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.²⁶ Lombard²⁷ 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 proteasomal destruction. The E6 protein product also enters the nucleus and interacts with the 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/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. Recent studies 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, as well as 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. Recent 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 recent 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 women-years at risk to 0 per 100 woman-years in the group that were 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.²⁸ The HPV vaccine with just HPV-16 and another double-variant vaccine are now commercially available and are recommended for both girls and boys from the ages of 9 through 31 years. The use of the vaccine worldwide should help eliminate cervical and head and neck cancers caused by HPV-16.

Maiman, Fruchter, and associates29–32 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 (52%) of 68 in the HIV-seronegative group. When upstaged based on surgicopathological findings, only one (6%) HIV-infected patient had early-stage disease compared with 40% of uninfected patients. The response to therapy and prognosis was 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/mm³, in contrast to those with CD4 counts less than 500/mm³. 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, provides 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. 87-2), 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. 87-3). 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. 87-4). 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.¹⁸ 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.^18–21

Miller²² reported, in a 13-year observational study, that 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 histology differs between well, moderately, or poorly differentiated tumors. Squamous carcinomas (Fig. 87-5) 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 on 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 morphologies.

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 adenomalignum or minimal deviation adenocarcinoma (Fig. 87-6), 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.^33,34

Neuroendocrine Tumors of the Cervix

Neuroendocrine tumors in the cervix include typical and atypical carcinoid tumors, and large cell, small cell neuroendocrine carcinomas, and undifferentiated small cell carcinoma. Both large cell and small cell neuroendocrine tumors resemble similar carcinomas arising in the lung and other aerodigestive sites.39,40 Undifferentiated small cell carcinoma is a very poorly differentiated carcinoma with neuroendocrine features, histologically similar to anaplastic small cell carcinoma of the lung.⁴¹ Neuroendocrine carcinomas tend to behave very aggressively, with frequent widespread metastasis to multiple sites, including bone, liver, and skin. Brain metastases may occur when disease is advanced but usually are preceded by lung metastases.⁴³ Efforts to treat these tumors by using approaches typically used for small cell carcinomas of the lung have had mixed results.⁴²

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).49,50 Techniques for further evaluation can include colposcopy, endocervical curettage or brushing, and cervical conization by cold knife or loop electrodiathermy excision procedure (LEEP).

Testing for high-risk, oncogenic HPV DNA51–57 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 cytology is sensitive at an ASC-US referral threshold, but requires two follow-up visits and, ultimately, more colposcopic examinations than does HPV triage.⁵⁸

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 an abnormal cytologic evaluation, 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. 87-7). 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. 87-8). 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.^60–72

Complications include bleeding, with a reported incidence of 1% to 8%,73,74 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 pathological interpretation of the specimen. Appropriate application of this technique will yield tissue suitable for pathological 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.

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 in this staging because of possible errors in gynecologic examination (24% to 39%).⁷⁷ The various imaging modalities have a complementary role in the accurate staging and complete evaluation of the cancer that have 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. 87-9).⁷⁸ Lymph nodes larger than 1.0 to 1.5 cm in diameter are suspicious for tumor involvement and should be biopsied. 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. 87-10). Involvement of the vagina, parametrium, pelvic wall muscles, ureter, bladder, and rectum can be better assessed with MRI for accurate staging (Fig. 87-11).⁷⁷ MRI before and after vaginal opacification with contrast medium can be used if imaging evaluation of the vaginal wall or fornices is required.⁷⁹ 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.⁸⁰ Dynamic contrast-enhanced T₁-weighted images are helpful in identifying smaller tumors, fistulous tracts, and invasion into bladder and rectum.⁷⁷ 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, as radiation therapy is more effective in well-enhanced tumors.⁸¹

MRI is very useful in the evaluation of tumor volume and enlarged lymph nodes, inherently important prognostic factors as well as determinants of the design of radiation treatment ports and selection of radiation dose. However, MRI cannot identify micrometastases to lymph nodes and differentiate malignant from nonmalignant enlargement. MRI with newer contrast agents like ultrasmall superparamagnetic iron oxide has been useful in distinguishing benign from malignant nodes.⁸² 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.⁷⁷ MRI also is useful in the follow-up evaluation of the tumor, its response to treatment, and identification of recurrences. However, benign conditions, like 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.⁸³

Recent studies have suggested that ¹⁸F-fluorodeoxyglucose PET (FDG-PET) is more sensitive and specific than more standard radiographic studies in the detection of lymph node involvement by cervical cancer.^86–86 Grigsby and colleagues⁸⁷ have 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.

Prognostic Factors

Prognostic factors fall into two groups: tumor-related factors and patient-related factors. Probably the most important tumor-related factor is tumor size, and this is true both for patients treated with hysterectomy97,98 and for patients treated with radiation therapy.^101–101 In fact, FIGO, in 1995, divided stage Ib into two groups according to size; other stage categories act, in part, as surrogates for tumor size. For patients treated with surgery, histologic evidence of extracervical spread is associated with a poorer prognosis. Parametrial extension is associated with a higher rate of lymph node involvement, local recurrence and death from cancer.^102,103 Uterine body involvement is associated with an increased rate of distant metastases in patients treated with radiation therapy or surgery.^104,105

Lymph node involvement is another important tumor-related factor. After radical hysterectomy, reported-year survival rates usually are about 35% to 40% lower when the pelvic lymph nodes are involved.106,107 However, studies suggest that postoperative chemoradiation improves these results.¹⁰⁸ Several reports suggest that survival decreases with increasing size of the largest involved nodes,^109,110 increasing number of nodes involved,^106,110,111 and the increasing level of regional involvement and with extent of central disease in the cervix. Overall, the survival rates for patients with positive paraaortic nodes are about half those of patients who have similar stages of disease without paraaortic lymph node involvment.^114–114 Lymphovascular space invasion (LVSI) also is correlated with an increased risk of recurrence. This reflects, in part, the strong correlation between LVSI and lymph node involvement; however, in a large number of postoperative studies, LVSI is an independent predictor of prognosis.^{107,115–117}

Investigators have compared the outcome of patients with adenocarcinomas with squamous carcinomas and have reached varying conclusions about the relative prognoses of the two histologic types of cervical cancer.120–120 In a review of 1767 patients with stage Ib disease (229 with adenocarcinoma), Eifel and colleagues¹²¹ found that patients with adenocarcinoma had a significantly higher risk of recurrence and death from disease, independent of age, tumor size, or tumor morphology. The rate of distant metastasis for patients with bulky (>4 cm) adenocarcinomas was almost twice that for patients with squamous carcinoma (37% vs. 21%, P < 0.01). Several investigators have reported high recurrence rates after radical hysterectomy for adenocarcinomas. In a subset analysis of a randomized Gynecologic Oncology Group study, Rotman and associates¹²² reported a high recurrence rate (11 of 25 patients [44%]) after treatment with radical hysterectomy alone for adeno-adenosquamous carcinomas of the cervix; in contrast, only 3 of 31 patients (10%) who received postoperative radiation therapy had recurrences. However, all of these comparisons had a relatively small number of patients treated with cervical adenocarcinomas.

Other tumor factors include correlation between the serum concentration of squamous cell carcinoma antigen and the extent of squamous carcinoma of the cervix.125–125 Increased tumor vascularity has been associated with a relatively poor prognosis,^126,127 and a strong inflammatory response in the cervical stroma tends to predict a good outcome.¹²⁶ Some authors have reported a correlation between HPV subtype and prognosis.²⁷ Several investigators have reported a higher recurrence rate in patients with histologically negative lymph nodes when a polymerase chain reaction assay of the lymph nodes was strongly positive for HPV DNA.^128,129 Other authors have correlated poor prognosis with the presence of HPV messenger RNA¹²⁸ or HPV-related proteins¹³⁰ in the peripheral blood of cervical cancer patients.

Patient-related factors have been discussed elsewhere in this chapter and include age, hemoglobin, platelet counts, race, and smoking.¹³¹ Several studies have demonstrated that in the United States, women of color with invasive cervical cancer present with higher-stage disease^134–134 and lower hemoglobin levels^135,136 than do white women. Differences in socioeconomic status may influence minority patients’ access to care and ability to comply with treatment recommendations.¹³⁶ In a study of 1304 women treated with radiation for cervical cancer, Kucera and colleagues¹³¹ reported that smokers with cervical cancer had a poorer 5-year survival rate than nonsmokers. This difference was statistically significant for patients with stage III disease (5-year survival rate 20.3% vs. 33.9%, P < 0.01). However, the authors did not analyze the possible influence of smoking-related deaths from causes other than cervical cancer.

Treatment Overview

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/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 modified radical hysterectomy. Stages Ib1 and small-volume IIa may be managed with either radical surgery (generally, 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, chemotherapy in a variety of possible sequences).

After initial radical surgical therapy, patients with adverse histopathological 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, lymphovascular space invasion, 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.139–139 Intraoperative radiation therapy may be part of salvage surgery when lateral or posterior surgical margins will be predictably inadequate.^140,141 Recurrent disease after initial radical surgery historically has been treated with salvage radiation, but currently should be treated with chemoradiation.¹⁴²

Hysterectomy

Hysterectomy involves the removal of the uterus and varying amounts of surrounding tissue (Fig. 87-12). 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.¹⁴³ 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%.¹⁴⁴ Five types of hysterectomy have been described.¹⁴⁵

Partial Exenteration (Type V)

Partial exenteration

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