Berek and Novak's Gynecology 15th Ed.

36 Cervical and Vaginal Cancer

Caela Miller

John C. Elkas

• Human papillomavirus (HPV) infection is the causal agent of cervical cancer.

• Screening programs are effective at decreasing the incidence of cervical cancer. Vaccines also help decrease the incidence of cervical cancer.

• The most common histologic type of cervical cancer is squamous, and the relative and absolute incidence of adenocarcinoma is increasing; both histologies are caused by HPV infection.

• Cervical cancer is clinically staged, although modern radiographic modalities such as computed tomography, magnetic resonance imaging, ultrasound, or positron emission tomography may be beneficial for individual treatment planning.

• Treatment of cervical cancer is based on stage of disease. Early stage disease (stages I to IIA) can be treated with either radical surgery or radiation therapy. Advanced stage disease (stages IIB to IV) is best treated with chemoradiation.

• Vaginal cancer is a rare disease with many similarities to cervical cancer. Radiation therapy is the mainstay of treatment for most patients; however, select patients may be treated with radical surgery.

Cervical cancer ranks as the third most common gynecologic neoplasm in the United States, behind cancer of the corpus and ovary, mainly as a result of the effectiveness of screening programs. Worldwide, cervical carcinoma continues to be a significant health care problem. In developing countries, where health care resources are limited, cervical carcinoma is the second most frequent cause of cancer death in women. Because cervical cancer is preventable, it is imperative that gynecologists and other primary health care providers to women be familiar with vaccination programs, screening techniques, diagnostic procedures, and risk factors for cervical cancer and management of preinvasive disease. Vaginal cancer is a rare tumor that shares an epidemiology and risk factor profile that is similar to cervical cancer.

Cervical Cancer

Epidemiology and Risk Factors

Invasive cancer of the cervix is considered a preventable disease because it has a long preinvasive state, cervical cytology screening programs are currently available, and the treatment of preinvasive lesions is effective.In spite of the preventable nature of this disease, 12,710 new cases of invasive cervical cancer resulting in 4290 deaths were anticipated in the United States in 2011 (1). Nationally, the lifetime probability of developing cervical cancer is 1:128. Although screening programs in the United States are well established, it is estimated that 30% of cervical cancer cases will occur in women who have never had a Papanicolaou (Pap) test. In developing countries, this percentage approaches 60% (2). Nevertheless, the worldwide incidence of invasive disease is decreasing, and cervical cancer is being diagnosed earlier, leading to better survival rates (1,3). The mean age for cervical cancer in the United States is 47 years, and the distribution of cases is bimodal, with peaks at 35 to 39 years and 60 to 64 years of age (1).

There are numerous risk factors for cervical cancer: young age at first intercourse (younger than 16 years), multiple sexual partners, cigarette smoking, race, high parity, low socioeconomic status, and chronic immune suppression. The relationship to oral contraceptive use was debated. Some investigators proposed that use of oral contraceptives might increase the incidence of cervical glandular abnormalities; however, this hypothesis was not consistently supported (4,5). Many of these risk factors are linked to sexual activity and exposure to sexually transmitted diseases. Infection with the herpes virus was thought to be the initiating event in cervical cancer; however, infection with human papillomavirus (HPV) was determined to be the causal agent in the development of cervical cancer, with herpes virus and Chlamydia trachomatis likely acting as cofactors. The role of human immunodeficiency virus (HIV) in cervical cancer is mediated through immune suppression (4). The Centers for Disease Control and Prevention described cervical cancer as an acquired immune deficiency syndrome (AIDS)–defining illness in patients infected with HIV (6).

The initiating event in cervical dysplasia and carcinogenesis is infection with HPV. HPV infection was detected in up to 99% of women with squamous cervical carcinoma. HPV is the causative agent in both squamous and adenocarcinoma of the cervix, but the respective tumors may have different carcinogenic pathways (7). There are more than 100 different types of HPV, more than 30 of which can affect the lower genital tract. There are 14 high-risk HPV subtypes; two of the high-risk subtypes, 16 and 18, are found in up to 62% of cervical carcinomas. The mechanism by which HPV affects cellular growth and differentiation is through the interaction of viral E6 and E7 proteins with tumor suppressor genes p53 and Rb, respectively. Inhibition of p53 prevents cell cycle arrest and cellular apoptosis, which normally occurs when damaged DNA is present, whereas inhibition of Rb disrupts transcription factor E2F, resulting in unregulated cellular proliferation (8). Both steps are essential for the malignant transformation of cervical epithelial cells. Two HPV vaccines, the quadrivalent Gardasil and the bivalent Cervarix, are approved by the U.S. Food and Drug Administration (FDA) and protect against subtypes 16 and 18. After 3 years, the efficacy of Gardasil was 99% for preventing cervical intraepithelial neoplasia grades 2 and 3 caused by HPV 16 or 18 in females who were not previously infected with either HPV 16 or 18 before vaccination; however, efficacy was only 44% in those who were infected prior to vaccination (9). Because the quadrivalent and bivalent HPV vaccines both protect only against certain types of HPV, vaccinated women need to continue to receive Pap test screening according to guidelines.

Evaluation

Vaginal bleeding is the most common symptom occurring in patients with cancer of the cervix. Most often, this is postcoital bleeding, but it may occur as irregular or postmenopausal bleeding. Patients with advanced disease may present with a malodorous vaginal discharge, weight loss, or obstructive uropathy. In asymptomatic women, cervical cancer is most commonly identified through evaluation of abnormal cytologic screening tests. The false-negative rate for Pap tests in the presence of invasive cancer is up to 50%, so a negative Pap test should never be relied on in a symptomatic patient (10).

Initially, all women suspected of having cervical cancer should have a general physical examination performed to include evaluation of the supraclavicular, axillary, and inguinofemoral lymph nodes to exclude the presence of metastatic disease. On pelvic examination, a speculum is inserted into the vagina, and the cervix is inspected for suspicious areas (Fig. 36.1). The vaginal fornices also should be closely inspected. With invasive cancer, the cervix is usually firm and expanded, and these features should be confirmed by digital examination. Rectal examination is important to help establish cervical consistency and size, particularly in patients with endocervical carcinomas. Rectal examination is the only way to determine cervical size if the vaginal fornices have been obliterated by menopausal changes or by the extension of disease. Parametrial extension of disease is best determined by the finding of nodularity beyond the cervix on rectal examination.

Figure 36.1 Gross appearance of cervical cancer on examination.

When obvious tumor growth is present, a cervical biopsy is usually sufficient for diagnosis. If gross disease is not present, a colposcopic examination with cervical biopsies and endocervical curettage is warranted. If the diagnosis cannot be established conclusively with colposcopy and directed biopsies, which may be the case with adenocarcinoma, cervical conization may be necessary.

Colposcopic Findings of Invasion

Colposcopic examination is mandatory for patients with suspected early invasive cancer based on cervical cytology and a grossly normal-appearing cervix. Colposcopic findings that suggest invasion are (i) abnormal blood vessels, (ii) irregular surface contour with loss of surface epithelium, and (iii) color tone change. Colposcopically directed biopsies may permit the diagnosis of frank invasion and thus avoid the need for diagnostic cone biopsy, allowing treatment to be administered without delay. If there is debate about the depth of invasion based on the cervical biopsies, and if the clinical stage may be upstaged to stage IA2 or IB1, the patient should undergo a conization. In the presence of a large cervical biopsy specimen showing invasion greater than 3 mm, or two biopsy specimens separated by 7 mm showing invasive cervical carcinoma, therapy should proceed without delay, and the patient could undergo radical surgery or radiation therapy.

Abnormal Blood Vessels

Abnormal vessels may be looped, branched, or reticular. Abnormal looped vessels are the most common colposcopic finding and arise from the punctated and mosaic vessels present in cervical intraepithelial neoplasia (CIN). As the neoplastic growth process proceeds and the need for oxygen and nutrition increases, angiogenesis occurs as a result of tumor and local tissue production of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and other cytokines, resulting in the proliferation of blood vessels and neovascularization. Punctate vessels push out over the surface of the epithelium in an erratic fashion, producing the looped, corkscrew, or J-shaped pattern of abnormal vessels characteristic of invasive disease. Abnormal blood vessels arise from the cervical stroma and are pushed to the surface as the underlying cancer invades. The normally branching cervical stromal vessels are best observed over nabothian cysts. In this area, the branches are generally at acute angles, with the caliber of vessels becoming smaller after branching, much like the arborization of a tree. The abnormal branching blood vessels seen with cancer tend to form obtuse or right angles, with the caliber sometimes enlarging after branching. Sharp turns, dilations, and luminal narrowing also characterize these vessels. The surface epithelium may be lost in these areas, leading to irregular surface contour and friability.

Abnormal reticular vessels represent the terminal capillaries of the cervical epithelium. Normal capillaries are best seen in postmenopausal women with atrophic epithelium. When cancer involves this epithelium, the surface is eroded, and the capillary network is exposed. These vessels are very fine and short and appear as small comma-shaped vessels without an organized pattern. They are not specific to invasive cancer; atrophic cervicitis may also have this appearance.

Irregular Surface Contour

Abnormal surface patterns are observed as tumor growth proceeds. The surface epithelium ulcerates as the cells lose intercellular cohesiveness secondary to loss of desmosomes. Irregular contour may occur as a result of papillary characteristics of the lesion. This finding can be confused with a benign HPV papillary growth on the cervix. For that reason, biopsies should be performed on all papillary cervical growths to avoid missing invasive disease.

Color Tone

Color tone may change as a result of increasing vascularity, surface epithelial necrosis, and in some cases, production of keratin. The color tone is yellow-orange rather than the expected pink of intact squamous epithelium or the red of the endocervical epithelium.

Adenocarcinoma

Adenocarcinoma of the cervix does not have a specific colposcopic appearance. All of the aforementioned blood vessels may be seen in these lesions. Because adenocarcinomas tend to develop within the endocervix, endocervical curettage is required as part of the colposcopic examination, and traditional screening methods are less reliable (10).

Histologic Appearance of Invasion

Cervical conization is required to assess correctly the depth and the linear extent of involvement when microinvasion is suspected. Early invasion is characterized by a protrusion of malignant cells from the stromal–epithelial junction. This focus consists of cells that appear better differentiated than the adjacent noninvasive cells and have abundant pink-staining cytoplasm, hyperchromatic nuclei, and small- to medium-sized nucleoli (11). These early invasive lesions form tonguelike processes without measurable volume and are classified as International Federation of Gynecology and Obstetrics (FIGO) stage IA1. With further progression, more tonguelike processes and isolated malignant cells appear in the stroma, followed by a proliferation of fibroblasts (desmoplasia) and a bandlike infiltration of chronic inflammatory cells (Fig. 36.2). With increasing depth of invasion, lesions occur at multiple sites, and the growth becomes measurable by depth and linear extent. Lesions that are less than 3 mm in depth are classified as FIGO stage IA1. Lesions that are 3 to 5 mm or more in depth and up to 7 mm in linear extent are classified as FIGO stage IA2 (12). As the depth of stromal invasion increases, so does the risk of capillary lymphatic space involvement. Dilated capillaries, lymphatic spaces, and foreign-body multinucleated giant cells containing keratin debris are often seen in the stroma.

Figure 36.2 Microinvasive squamous carcinoma. Multiple irregular tonguelike processes and isolated nests of malignant cells are seen, some surrounded by clear spaces, simulating capillary lymphatic invasion. This is an artifact caused by tissue shrinkage. The depth of stromal invasion is measured from the basement membrane of the overlying cervical intraepithelial neoplasia (CIN). In this case, it is 1.2 mm.

The depth of invasion should be measured with a micrometer from the base of the epithelium to the deepest point of invasion. Depth of invasion is a significant predictor for the development of pelvic lymph node metastasis and tumor recurrence. Although lesions that have invaded 3 mm or less rarely metastasize, patients in whom lesions invade between 3 to 5 mm have positive pelvic lymph nodes in 3% to 8% of cases (13). The significance of the cutoff at 3 mm is not identified completely; it was postulated that small capillary–lymphatic spaces at this level are incapable of facilitating the transport of malignant cells. Uneven shrinkage of tissue by fixative often creates space between the tumor nests and the surrounding fibrous stroma, simulating vascular lymphatic invasion (Fig. 36.2). Therefore, suspected vascular–lymphatic involvement with invasion of less than 3 mm should be interpreted with care. A lack of endothelial lining indicates that the space is a fixation artifact rather than true vascular invasion.

Staging

Cervical cancer is a clinically staged disease. The FIGO staging system is the standard and is applicable to all histologic types of cervical cancer. The FIGO staging system is presented in Table 36.1 and Figure 36.3. The staging procedures allowed by FIGO are listed in Table 36.2. When there is doubt concerning the stage to which a cancer should be allocated, the earlier stage should be selected. After a clinical stage is assigned and treatment is initiated, the stage must not be changed because of subsequent findings by either extended clinical staging or surgical staging. The upstaging of patients during treatment will produce an erroneous perception of improvement in the results of treatment of low-stage disease. Following is a breakdown of the incidence of cervical cancer by stage at diagnosis: 38%, stage I; 32%, stage II; 26%, stage III; and 4%, stage IV (3,13,14).

Additional Staging Modalities

Various investigators used lymphangiography, computed tomography (CT), ultrasonography, magnetic resonance imaging (MRI), and positron emission tomography (PET) in an attempt to improve the accuracy of clinical staging (15–25). These modalities suffer from poor sensitivity and high false-negative rates. Evaluation of the para-aortic lymph nodes with lymphangiography is associated with a false-positive rate of 20% to 40% and a false-negative rate of 10% to 20% (15–17). Overall, lymphangiography has a sensitivity of 79% and specificity of 73% (20). CT has poor sensitivity (34%) but excellent specificity (97%) (21). The accuracy of CT scanning is 80% to 85%; the false-negative rate is 10% to 15%, and the false-positive rate is 20% to 25% (16–18). Ultrasound has a high false-negative rate (30%), low sensitivity (19%), but high specificity (99%) (19). Early data showed that MRI results were comparable to those of CT scanning, a finding confirmed on meta-analysis (21,22). However, a systematic review comparing CT scan with MRI showed that MRI is significantly more sensitive with equivalent specificity. Additionally, MRI has excellent sensitivity on T2-weighted images for the detection of parametrial disease (23). As a result, MRI is the preferred study to evaluate tumor size, lymph node metastasis, and local tumor extension.

Table 36.1 FIGO Staging of Carcinoma of the Cervix Uteri (2008)

Stage I	The carcinoma is strictly confined to the cervix (extension to the corpus would be disregarded)
IA	Invasive carcinoma which can be diagnosed only by microscopy, with deepest invasion ≤5 mm and largest extension ≤7 mm
IA1	Measured stromal invasion of ≤3.0 mm in depth and extension of ≤7.0 mm
IA2	Measured stromal invasion of >3.0 mm and not >5.0 mm with an extension of not >7.0 mm
IB	Clinically visible lesions limited to the cervix uteri or pre-clinical cancers greater than stage IAa
IB1	Clinically visible lesion ≤4.0 cm in greatest dimension
IB2	Clinically visible lesion >4.0 cm in greatest dimension
Stage II	Cervical carcinoma invades beyond the uterus, but not to the pelvic wall or to the lower third of the vagina
IIA	Without parametrial invasion
IIA1	Clinically visible lesion ≤4.0 cm in greatest dimension
IIA2	Clinically visible lesion >4 cm in greatest dimension
IIB	With obvious parametrial invasion
Stage III	The tumor extends to the pelvic wall and/or involves lower third of the vagina and/or causes hydronephrosis or non-functioning kidneyb
IIIA	Tumor involves lower third of the vagina, with no extension to the pelvic wall
IIIB	Extension to the pelvic wall and/or hydronephrosis or non-functioning kidney
Stage IV	The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. A bullous edema, as such, does not permit a case to be allotted to Stage IV
IVA	Spread of the growth to adjacent organs
IVB	Spread to distant organs
FIGO Committee on Gynecologic Oncology. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int Cynecol Obst 2009;105:103–104. aAll macroscopically visible lesions, even those with superficial invasion, are allotted to stage IB carcinomas. Invasion is limited to a measured stroma invasion with a maximal depth of 5.0 mm and a horizontal extension greater than 7.0 mm. Dept of invasion should not be greater than 5 mm taken from the base of the epithelium of the original tissue squamous or glandular. The depth of invasion should always be reported in millimeters, even those cases with “early minimal stromal invasion” (∼1 mm). The involvement of vascular/lymphatic spaces should not change stage allotment. bOn rectal examination, there is no cancer-free space between the tumor and the pelvic wall. All cases with hydronephrosis or non-functioning kidney are included, unless they are known to be due to another cause.

Figure 36.3 Carcinoma of the cervix uteri: staging cervical cancer (primary tumor and metastases). (From Benedet JL, Odicino F, Maisonneuve P, et al. Carcinoma of the cervix. J Epidemiol Biostat 2001;6:5–44, with permission.)

Table 36.2 Staging Procedures

Physical examinationa	Palpate lymph nodes
	Examine vagina
	Bimanual rectovaginal examination (under anesthesia
	recommended)
Radiologic studiesa	Intravenous pyelogram
	Barium enema
	Chest x-ray
	Skeletal x-ray
Proceduresa	Biopsy
	Conization
	Hysteroscopy
	Colposcopy
	Endocervical curettage
	Cystoscopy
	Proctoscopy
Optional studiesb	Computerized axial tomography
	Lymphangiography
	Ultrasonography
	Magnetic resonance imaging
	Positron emission tomography
	Radionucleotide scanning
	Laparoscopy
aAllowed by the International Federation of Gynecology and Obstetrics (FIGO). bInformation that is not allowed by FIGO to change the clinical stage.

PET scans are increasingly being utilized either alone or in conjunction with CT or MRI to detect metastatic disease; however, large prospective data series are limited. Early studies suggest that PET may be more useful than other techniques for the detection of abdominal and extrapelvic disease, with comparable or better sensitivity (76% to 100%) and specificity (94%) (24,25). In addition, PET scans may be better predictors of treatment outcome. Although early studies show promise for the use of PET scans in evaluating cervical cancer, the sensitivity for detecting metastatic disease less than 1 cm in size appears to be limited (26).

When abnormalities are noted on CT, MRI, or PET, radiographic-guided fine-needle aspirations (FNA) can be performed to confirm metastatic disease and individualize treatment planning. Because these tests are not available equally throughout the world and the interpretation of results can be variable, these studies are not used for staging. They may be useful in individual treatment planning.

The clinical staging system developed by FIGO is based on the belief that cervical cancer is a local disease until rather late in its course. The accuracy of clinical staging is limited, and surgical evaluation, although not practical or feasible in all patients, can more accurately identify metastatic disease. Surgical staging is advocated by providers who believe that surgical information details the extent of disease, allowing the treatment to be tailored to the individual (27). However, other providers believe that surgical staging should be limited to patients who are enrolled in clinical trials. These beliefs are based on the lack of randomized controlled studies demonstrating a survival benefit in patients who had surgical staging.

Pathology

Squamous Cell Carcinoma

Invasive squamous cell carcinoma is the most common variety of invasive cancer in the cervix. Histologically, variants of squamous cell carcinoma include large cell keratinizing, large cell nonkeratinizing, and small cell types (28). Large cell keratinizing tumors consist of tumor cells forming irregular infiltrative nests with laminated keratin pearls in the center. Large cell nonkeratinizing carcinomas reveal individual cell keratinization but do not form keratin pearls (Fig. 36.4). The category of small cell carcinoma includes poorly differentiated squamous cell carcinoma and small cell anaplastic carcinoma. If possible, these two tumors should be differentiated. The former contains cells that have small- to medium-sized nuclei and more abundant cytoplasm than those of the latter. The designation of small cell anaplastic carcinoma should be reserved for lesions resembling oat cell carcinoma of the lung. Small cell anaplastic carcinoma infiltrates diffusely and consists of tumor cells that have scanty cytoplasm, round to oval small nuclei, coarsely granular chromatin, and high mitotic activity. The nucleoli are absent or small. Immunohistochemistry or electron microscopy can differentiate the small cell neuroendocrine tumors. Patients with the large cell type of carcinoma, with or without keratinization, have a better prognosis than those with the small cell variant. Small cell anaplastic carcinomas behave more aggressively than poorly differentiated squamous carcinomas that contain small cells. Infiltration of parametrial tissue and pelvic lymph node metastasis affect the prognosis.

Figure 36.4 Invasive squamous cell carcinoma, large cell nonkeratinizing type. Tumor cells form irregular nests and have abundant eosinophilic cytoplasm and distinct cell borders indicative of squamous differentiation.

Other less common variants of squamous carcinoma include verrucous carcinoma and papillary (transitional) carcinoma. Verrucous carcinomas may resemble giant condyloma acuminatum, are locally invasive, and rarely metastasize. Papillary carcinomas histologically resemble transitional cells of the bladder and may have more typical squamous cell invasion at the base of the lesion. Papillary carcinomas behave and are treated in a manner similar to traditional squamous cell cancers, except that late recurrences were noted.

Adenocarcinoma

There is an increasing number of cervical adenocarcinomas reported in women in their 20s and 30s. Although the total number of cases of adenocarcinoma is relatively stable, this disease is appearing more frequently in young women, especially as the number of cases of invasive squamous cell carcinoma decreases. Older reports indicated that 5% of all cervical cancers were adenocarcinomas, whereas newer reports show a proportion as high as 18.5% to 27% (29–31). Much of this proportional increase is related to a decreasing incidence of squamous carcinoma secondary to screening programs (which are less accurate at identifying preinvasion adenocarcinoma), greater exposure to oral contraceptives, and a greater exposure to HPV (4,5).

Adenocarcinoma in situ (AIS) is believed to be the precursor of invasive adenocarcinoma, and it is not surprising that the two often coexist (32). In addition to AIS, intraepithelial or invasive squamous neoplasia occurs in 30% to 50% of cervical adenocarcinomas (33). A squamous intraepithelial lesion may be observed colposcopically on the ectocervix, and the coexistent adenocarcinoma often is higher in the cervical canal.

Patients with AIS who are treated with conization should undergo close clinical follow-up. Endocervical curettage, often used in surveillance, may miss residual or invasive disease, and false-negative rates as high as 50% were reported (34). In addition, skip lesions not resected at the time of conization may be present. For these reasons, hysterectomy should be considered the standard therapy for patients who have completed their childbearing. In two reports, patients with negative cone biopsy margins were followed conservatively, with few requiring repeat surgical procedures (35,36). Because cervical AIS tends to affect women during their reproductive years, a thorough discussion of risks and benefits should take place, and treatment should be individualized.

Adenocarcinoma of the cervix is managed in the same manner used for squamous cell carcinoma. Adenocarcinoma was believed to be associated with a worse prognosis and outcome when compared with squamous cell carcinoma. A study of 203 women with adenocarcinoma and 756 women with squamous carcinoma supported this assertion (30). This study showed 5-year survival rates of 90% versus 60%, 62% versus 47%, and 36% versus 8% for stages I, II, and III, respectively. Although some attributed these rates to a relative resistance to radiation, they are more likely a reflection of the tendency of adenocarcinomas to grow endophytically and to be undetected until a large volume of tumor is present. When adjusted for tumor size, it appears that there is no difference in prognosis between the two histologic subtypes. Adenocarcinoma may be detected by cervical sampling, but less reliably so than squamous carcinomas. A definitive diagnosis may require cervical conization.

The clinical features of stage I adenocarcinomas are well studied (30,37–39). These studies identified size of tumor, depth of invasion, grade of tumor, and age of the patient as significant correlates of lymph node metastasis and survival. When matched with squamous carcinomas for lesion size, age, and depth of invasion, the incidence of lymph node metastases and the survival rate appear to be the same (38,39). Patients with stage I adenocarcinomas can be selected for treatment according to the same criteria as for those with squamous cancers (39).

The choice of treatment for bulky stage I and II tumors is controversial. Some advocated treatment with radiation alone, whereas others support radiation plus extrafascial hysterectomy (40–42). In 1975, Rutledge et al. reported an 85.2% 5-year survival rate for all patients with stage I disease treated with radiation alone and an 83.8% survival rate for those who had radiation plus surgery (41). The central persistent disease rate was 8.3%, compared with 4% for those who had radiation plus surgery. In stage II disease, the 5-year survival rate was 41.9% for radiation alone and 53.7% for radiation plus surgery. A subsequent report revealed no significant difference in survival among patients treated with radiation alone or radiation plus extrafascial hysterectomy (43).

Invasive adenocarcinoma may be pure (Fig. 36.5A, B) or mixed with squamous cell carcinoma. Within the category of pure adenocarcinoma, the tumors are quite heterogeneous, with a wide range of cell types, growth patterns, and differentiation (30). About 80% of cervical adenocarcinomas consist predominantly of the endocervical type cells with mucin production. The remaining tumors are populated by endometrioid cells, clear cells, intestinal cells, or a mixture of more than one cell type. By histologic examination alone, some of these tumors are indistinguishable from those arising elsewhere in the endometrium or ovary. Within each cell type, the growth patterns and nuclear abnormalities vary according to the degree of differentiation. In well-differentiated tumors, tall columnar cells line the well-formed branching glands and papillary structures, whereas pleomorphic cells tend to form irregular nests and solid sheets in poorly differentiated neoplasms. The latter may require mucicarmine and periodic acid–Schiff (PAS) staining to confirm their glandular differentiation.

Figure 36.5 Invasive adenocarcinoma of the cervix, well-differentiated. A. Irregular glands are lined with tall columnar cells with vacuolated mucinous cytoplasm resembling endocervical cells. B. Nuclear stratification, mild nuclear atypism, and mitotic figures are evident in higher power.

There are several special variants of adenocarcinoma. Minimal deviation adenocarcinoma (adenoma malignum) is an extremely well-differentiated form of adenocarcinoma in which the branching glandular pattern strongly simulates that of the normal endocervical glands. The lining cells have abundant mucinous cytoplasm and uniform nuclei (44,45). Because of this, the tumor may not be recognized as malignant in small biopsy specimens, thereby causing considerable delay in diagnosis. Special immunohistochemical staining may be required to establish the diagnosis. Earlier studies reported a dismal outcome for women with this tumor, but more recent studies found a favorable prognosis if the disease is detected early (46). Although rare, similar tumors were reported in association with endometrioid, clear, and mesonephric cell types (47).

An entity described as villoglandular papillary adenocarcinoma deserves special attention (48). It primarily affects young women, some of whom are pregnant or users of oral contraceptives. Histologically, the tumors have smooth, well-defined borders, are well differentiated, and are either in situ or superficially invasive. Follow-up information is encouraging. None of these tumors recurred after cervical conization or hysterectomy, and no metastasis was detected among women undergoing pelvic lymphadenectomy. This tumor appears to have limited risk for spread beyond the uterus.

Adenosquamous Carcinoma

Carcinomas with a mixture of malignant glandular and squamous components are known as adenosquamous carcinomas. Patients with adenosquamous carcinoma of the cervix were reported to have a poorer prognosis than those with pure adenocarcinoma or squamous carcinoma (49). Whether this is true when corrected for size of lesion is controversial (38,39).

In mature adenosquamous carcinomas, the glandular and squamous carcinomas are readily identified on routine histologic evaluation and do not cause diagnostic problems. In poorly differentiated or immature adenosquamous carcinomas, however, glandular differentiation can be appreciated only with special stains, such as mucicarmine and PAS. In one study, 30% of squamous cell carcinomas demonstrated mucin secretion when stained with mucicarmine (47). These squamous cell carcinomas with mucin secretion have a higher incidence of pelvic lymph node metastases than do squamous cell carcinomas without mucin secretion, and they are similar to the signet-ring variant of adenosquamous carcinoma (47,50).

Glassy cell carcinoma is recognized as a poorly differentiated form of adenosquamous carcinoma (51). Individual cells have abundant eosinophilic, granular, ground-glass cytoplasm, large round to oval nuclei, and prominent nucleoli. The stroma is infiltrated by numerous lymphocytes, plasma cells, and eosinophils. Approximately half of these tumors contain glandular structures or stain positive for mucin. The poor diagnosis of this tumor is linked to understaging and resistance to radiotherapy.

Other variants of adenosquamous carcinoma include adenoid basal carcinoma and adenoid cystic carcinoma. Adenoid basal carcinoma simulates the basal cell carcinoma of the skin (51). Nests of basaloid cells extend from the surface epithelium deep into the underlying tissue. Cells at the periphery of tumor nests form a distinct parallel nuclear arrangement, so-called peripheral palisading. An “adenoid” pattern occasionally develops, with “hollowed-out” nests of cells. Mitoses are rare, and the tumor often extends deep into the cervical stroma.

Adenoid cystic carcinoma of the cervix behaves much like such lesions elsewhere in the body. The tumors tend to invade into the adjacent tissues and metastasize late, often 8 to 10 years after the primary tumor was removed. Like other adenoid cystic tumors, they may metastasize directly to the lung. The pattern simulates that of the adenoid basal tumor, but there is a cystic component, and the glands of the cervix are involved (51). Mitoses may be seen but are not numerous.

Sarcoma

The most important sarcoma of the cervix is embryonal rhabdomyosarcoma, which occurs in children and young adults. The tumor has grapelike polypoid nodules, known as botryoid sarcoma, and the diagnosis depends on the recognition of rhabdomyoblasts. Leiomyosarcomas and mixed mesodermal tumors involving the cervix may be primary but are more likely to be secondary to uterine tumors. Cervical adenosarcoma is described as a low-grade tumor with a good prognosis (52). If recurrence develops, it is generally a central recurrence that may be treated with resection and hormonal therapy.

Malignant Melanoma

On rare occasions, melanosis is seen in the cervix. Malignant melanoma may arise de novo in this area. Histopathologically, it simulates melanoma elsewhere, and the prognosis depends on the depth of invasion into the cervical stroma.

Neuroendocrine Carcinoma

The classification of neuroendocrine cervical carcinoma includes four histologic subtypes: (i) small cell, (ii) large cell, (iii) classical carcinoid, and (iv) atypical carcinoid (53). Neuroendocrine tumors of the cervix are rare, and treatment regimens are based on small case series of patients.

Small cell (neuroendocrine type) carcinoma of the cervix is aggressive in nature and is similar to cancer arising from the bronchus (54). The hallmark of neuroendocrine tumors is their aggressive malignant behavior with the propensity to metastasize. At the time of diagnosis, it is usually disseminated, with bone, brain, liver, and bone marrow being the most common sites of metastases. In one study of 11 patients with disease apparently confined to the cervix, a high rate of lymph node metastasis was noted (55). Pathologically, the diagnosis is aided by the finding of neuroendocrine granules on electron microscopy and by immunoperoxidase studies that are positive for a variety of neuroendocrine proteins such as calcitonin, insulin, glucagon, somatostatin, gastrin, and adrenocorticotropic hormone (ACTH). In addition to the traditional staging for cancer of the cervix, these patients should undergo bone, liver and brain scanning and bone marrow aspiration and biopsy to evaluate the possibility of metastatic disease. Therapyconsists of surgery, chemotherapy, and radiation. Because patients with early-stage disease have distant metastases, multimodal therapy is recommended. The main active chemotherapeutic agent is etoposide.

Local therapy alone gives almost no chance of cure of small cell carcinoma. Regimens of combination chemotherapy improved the median survival rates in small cell bronchogenic carcinoma, and these regimens are used for treatment of small cell carcinoma of the cervix. Combination chemotherapy may consist of vincristine, doxorubicin, and cyclophosphamide (VAC) or VP-16 (etoposide) and cisplatin (EP) (56). Patients must be monitored carefully because they are at high risk for developing recurrent metastatic disease (57).

Patterns of Spread

Cancer of the cervix spreads by (i) direct invasion into the cervical stroma, corpus, vagina, and parametrium; (ii) lymphatic metastasis; (iii) blood-borne metastasis; and (iv) intraperitoneal implantation. The incidence of pelvic and para-aortic nodal metastasis is shown in Table 36.3.

Table 36.3 Incidence of Pelvic and Para-aortic Lymph Node Metastasis by Stage

The cervix is commonly involved in cancer of the endometrium and vagina. The latter is rare, and most lesions that involve the cervix and vagina are designated cervical primaries. Consequently, the clinical classification is that of cervical neoplasia extending to the vagina, rather than vice versa. Endometrial cancer may extend into the cervix by three modes: direct extension from the endometrium, submucosal involvement by lymph vascular extension, and multifocal disease. The latter is most unusual, but occasionally a focus of adenocarcinoma may be seen in the cervix, separate from the endometrium. This lesion should not be diagnosed as metastasis but rather as multifocal disease. Malignancies involving the peritoneal cavity (e.g., ovarian cancer) may be found in the cul-de-sac and extend directly into the vagina and cervix. Carcinomas of the urinary bladder and colon occasionally extend into the cervix. Cervical involvement by lymphoma, leukemia, and carcinoma of the breast, stomach, and kidney is usually part of the systemic pattern of spread for these malignancies. Isolated metastasis to the cervix in such cases may be the first sign of a primary tumor elsewhere in the body.

Treatment Options

The treatment of cervical cancer is similar to the treatment of any other type of malignancy in that both the primary lesion and potential sites of spread should be evaluated and treated. The therapeutic modalities for achieving this goal include primary treatment with surgery, radiotherapy, chemotherapy, or chemoradiation. Whereas radiation therapy can be used in all stages of disease, surgery is limited to patients with stage I to IIa disease. The 5-year survival rate for stage I cancer of the cervix is approximately 85% with either radiation therapy or radical hysterectomy. A study using the National Cancer Institute’s Surveillance Epidemiology and End Results data by an intent-to-treat analysis showed that patients in the surgery arm had an improved survival when compared with patients in the radiation arm (58). Optimal therapy consists of radiation, or surgery alone, to limit the increased morbidity that occurs when the two treatment modalities are combined. Recent improvements in the treatment of cervical carcinoma include adjuvant chemoradiation in patients discovered to have high-risk cervical carcinoma after radical hysterectomy and in patients with locally advanced cervical carcinoma.

Surgery

There are advantages to the use of surgery instead of radiotherapy, particularly in younger women for whom conservation of the ovaries is important. Chronic bladder and bowel problems that require medical or surgical intervention occur in up to 8% of patients undergoing radiation therapy (59). Such problems are difficult to treat because they result from fibrosis and decreased vascularity. This is in contrast to surgical injuries, which usually can be repaired without long-term complications. Sexual dysfunction is less likely to occur after surgical therapy than radiation, because of vaginal shortening, fibrosis, and atrophy of the epithelium associated with radiation. Surgical therapy shortens the vagina, but gradual lengthening can be brought about by sexual activity. The epithelium does not become atrophic because it responds either to endogenous estrogen or to exogenous estrogens if the patient is postmenopausal.

Radical hysterectomy is reserved for women who are in good physical condition. Advanced chronologic age should not be a deterrent. With improvements in anesthesia, elderly patients withstand radical surgery almost as well as their younger counterparts (60). It is prudent not to operate on lesions that are larger than 4 cm in diameter because these patients will require postoperative radiation therapy. When selected in this manner, the urinary fistula rate is less than 2%, and the operative mortality rate is less than 1% (61,62). A summary of the management of cervical cancer is presented in Table 36.4.

Table 36.4 Management of Invasive Cancer of the Cervix

Stage IA1	≤3 mm invasion, no LVSI	Conization or type I hysterectomy
	≤3 mm invasion, w/LVSI	Radical trachelectomy or type II radical hysterectomy with pelvic lymphadenectomy
IA2	>3–5 mm invasion	Radical trachelectomy or type II radical hysterectomy with pelvic lymphadenectomy
IB1	>5 mm invasion, <2 cm	Radical trachelectomy or type III radical hysterectomy with pelvic lymphadenectomy
	>5 mm invasion, >2 cm	Type III radical hysterectomy with pelvic lymphadenectomy
IB2		Type III radical hysterectomy with pelvic and para-aortic lymphadenectomy or primary chemoradiation
Stage IIA1, IIA2		Type III radical hysterectomy with pelvic and para-aortic lymphadenectomy or primary chemoradiation
IIB, IIIA, IIIB		Primary chemoradiation
Stage IVA		Primary chemoradiation or primary exenteration
IVB		Primary chemotherapy ± radiation
LVSI, lymphovascular space invasion.

If radiation therapy is needed, transposing the ovaries out of the planned radiation field may preserve ovarian function. Although transposition provides some protection, studies suggest that normal ovarian function is preserved in fewer than 50% of patients (63,64). Metastasis to the ovaries occurs in 0.9% of cases of early stage cervical cancer, so preservation of the ovaries, particularly with adenocarcinoma, may confer a small recurrence risk (65).

Cone Biopsy of the Cervix

Cone biopsy of the cervix serves both a diagnostic and therapeutic role in cervical cancer. The procedure is indicated to confirm the diagnosis of cancer, and to definitively treat stage Ia1 disease when preservation of fertility is desired. For effective treatment, there must be no evidence of lymph–vascular space invasion, and both endocervical margins and curettage findings must be negative for cancer or dysplasia. Because stage Ia1 cancers have less than a 1% risk of lymph node metastasis, lymphadenectomy is not necessary. If the endocervical margin or curettage is positive for dysplasia or malignancy, further treatment is necessary because these findings are strong predictors of residual disease. For squamous cell carcinoma, the risk of residual disease is 4% if both the endocervical margin and curettage are negative for dysplasia or malignancy, 22% if the endocervical margin alone is positive, and 33% if both are positive (66). In cases of AIS, the status of the cone margins is particularly important, with residual preinvasive and invasive disease noted in up to 25% and 3%, respectively, of cases with negative margins, and up to 80% and 7%, respectively, in cases with positive margins (67,68).

Figure 36.6 Abdominal radical trachelectomy.

Simple (Extrafascial) Hysterectomy

Type I hysterectomy is an appropriate therapy for patients with stage Ia1 tumors without lymph–vascular space invasion who are not desirous of future fertility. In such cases, lymphadenectomy is not recommended. If lymph–vascular space invasion is found, a modified radical hysterectomy with pelvic lymphadenectomy is appropriate and effective therapy.

Radical Trachelectomy

Radical trachelectomy is a procedure that is gaining popularity as a surgical management option for women with stage 1A2 and IB1 disease who desire uterine preservation and fertility. This procedure may be performed vaginally, abdominally, laparoscopically, or robotically (Fig. 36.6), and it usually is accompanied by pelvic lymphadenectomy and cervical cerclage placement. The risk of positive pelvic lymph nodes with stage Ia2 cancer may be as high as 8%, indicating the need for lymphadenectomy. Lymphadenectomy may be performed laparoscopically, robotically, or by the open laparotomy technique. Experience with this therapeutic modality is limited, although early results are promising, and it is uncertain whether the long-term outcome is similar to that of traditional therapy. Patients who are ideal candidates for this procedure have tumors less than 2 cm in diameter and have negative lymph nodes. Lymphadenectomy can be performed at the beginning of the procedure, and depending on those results, the procedure can be continued or abandoned. A retrospective trial comparing patients who had tumors with these attributes and were treated with either laparoscopic radical hysterectomy or laparoscopic radical trachelectomy showed similar outcomes and recurrence (69). There are limited data on subsequent pregnancy outcomes after radical trachelectomy; however, successful outcomes were reported. A study found that for women attempting to conceive after radical trachelectomy, the 5-year cumulative pregnancy rate was 52.8%, with an increased risk of miscarriage (70). Although radical trachelectomy and lymphadenectomy are performed with curative intent, it should be remembered that if a recurrence develops, definitive therapy with surgery or radiation is necessary.

Radical Hysterectomy

The radical hysterectomy (Fig. 36.7A, B) performed most often in the United States is that described by Meigs in 1944 (71). The operation includes pelvic lymphadenectomy along with removal of most of the uterosacral and cardinal ligaments and the upper one-third of the vagina. This operation is referred to as the type III radical hysterectomy (72).

The hysterectomy described by Wertheim is less extensive than a radical hysterectomy and removes the medial half of the cardinal and uterosacral ligaments (62). This procedure is often referred to as the modified radical or type II hysterectomy. Wertheim’s original operation did not include pelvic lymphadenectomy but instead included selective removal of enlarged lymph nodes. The modified radical hysterectomy (type II) differs from the radical hysterectomy (type III) in the following ways:

Figure 36.7 A: Radical hysterectomy. An intraoperative photograph showing the lateral dissection during a radical hysterectomy. Note the ureter running beneath the uterine artery (tissue in the clamp). B: Radical hysterectomy specimen.

1. The uterine artery is transected at the level of the ureter, thus preserving the ureteral branch to the ureter.

2. The cardinal ligament is not divided near the sidewall but instead is divided close to its midportion near the ureteral dissection.

3. The anterior vesicouterine ligament is divided, but the posterior vesicouterine ligament is conserved.

4. A smaller margin of vagina is removed.

Radical hysterectomies can be further classified as extended radical hysterectomy (type IV and type V). In the type IV operation, the periureteral tissue, superior vesicle artery, and as much as three-fourths of the vagina are removed. In the type V operation, portions of the distal ureter and bladder are resected. This procedure is rarely performed because radiotherapy should be used when such extensive disease is encountered (72).

The abdomen is opened through either a midline incision or a low transverse incision after the methods of Maylard or Cherney. The low transverse incision requires division of the rectus muscles and provides excellent exposure of the lateral pelvis. It allows adequate pelvic lymphadenectomy and wide resection of the primary tumor. After the abdomen is entered, the peritoneal cavity is explored to exclude metastatic disease. The stomach is palpated to ensure that it has been decompressed to facilitate packing of the intestines. The liver is palpated, and the omentum is inspected for metastases. Both kidneys are palpated to ensure their proper placement and lack of congenital and other abnormalities. The para-aortic nodes are palpated transperitoneally.

During exploration of the pelvis, the fallopian tubes and ovaries are inspected for any abnormalities. In premenopausal patients, the ovaries can be conserved. The peritoneum of the vesicouterine fold and the rectouterine pouch should be inspected for signs of tumor extension or implantation. The cervix is palpated between the thumb anteriorly and the fingers posteriorly to determine its extent, and the cardinal ligaments are palpated for evidence of lateral tumor extension or nodularity.

Lymphadenectomy

After inspection of the abdomen and pelvis, the pelvic and para-aortic lymph nodes should be inspected and palpated. Lymph nodes suspicious for gross disease should be excised and evaluated by frozen section. If metastatic disease is identified, consideration should be given to abandoning radical surgery in favor of primary chemoradiation therapy. If the patient has no gross evidence of metastatic disease, the pelvic lymphadenectomy is begun.

Pelvic Lymphadenectomy

The pelvic lymphadenectomy is begun by opening the round ligaments at the pelvic sidewall and developing the paravesical and pararectal spaces. The ureter is elevated on the medial flap by a Deaver retractor to expose the common iliac artery. The common iliac and external iliac nodes are dissected, with care taken to avoid injuring the genitofemoral nerve, which lies laterally on the psoas muscle. At the bifurcation of the common iliac artery, the external iliac node chain is divided into lateral and medial portions.

The lateral chain is stripped free from the artery to the circumflex iliac vein distally. A hemoclip is placed across the distal portion of the lymph node chain to reduce the incidence of lymphocyst formation. The medial chain is dissected. The obturator lymph nodes are dissected; for this procedure, the lymph nodes are grasped just under the external iliac vein, and traction is applied medially. In most patients the obturator artery and vein are dorsal to the obturator nerve; however, 10% have an aberrant vein arising from the external iliac vein. The node chain is separated from the nerve and vessels and clipped caudally. Dissection continues cephalad to the hypogastric artery. The cephalad portion of the obturator space should be entered lateral to the external iliac artery and medial to the psoas muscle, where the remainder of the obturator node tissue can be dissected as far cephalad as the common iliac artery. Drainage of the pelvic and para-aortic lymph node beds is not performed because of the increase in complications in patients in whom drains were used (73).

Figure 36.8 The pelvic ligaments and spaces. (From Berek JS, Hacker NF. Berek & Hacker’s Gynecologic Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:360, with permission.)

Patients who have bulky cervical tumors or grossly positive pelvic nodes, or for whom frozen section evaluation will be performed, should undergo para-aortic lymph node evaluation to determine the full extent of disease and to guide adjuvant therapy.

Para-aortic Lymph Node Evaluation

The bowel is packed to expose the peritoneum overlying the bifurcation of the aorta. The peritoneum is incised medial to the ureter and over the right common iliac artery. A retractor is placed retroperitoneally to expose the aorta and the vena cava. Any enlarged para-aortic lymph nodes are removed, hemoclips are applied for hemostasis, and specimens are sent for analysis by frozen section. If the lymph nodes are positive for metastatic cancer, an option is to discontinue the operation and treat the patient with radiation therapy (71). If the lymph nodes are negative for disease, the left side of the aorta is palpated through the peritoneal incision with a finger passed under the inferior mesenteric artery. The lymph nodes on this side of the aorta are more lateral and nearly behind the aorta and the common iliac artery. If the left para-aortic lymph nodes appear healthy and the cervical tumor is small with no suspicious pelvic lymph nodes, these additional lymph nodes are not submitted for frozen-section analysis. If they are removed, they may be dissected through the incision made for the right para-aortic nodes, or they may be dissected after reflection of the sigmoid colon medially.

Development of Pelvic Spaces

The pelvic spaces are developed by sharp and blunt dissection (Fig. 36.8).

The paravesical space is bordered by the following structures:

1. The obliterated umbilical artery running along the bladder medially.

2. The obturator internus muscle along the pelvic sidewall laterally.

3. The cardinal ligament posteriorly.

4. The pubic symphysis anteriorly.

The attachments of the vagina to the tendinous arch form the floor of the paravesical space.

The pararectal space is bordered by the following structures:

1. Rectum medially

2. Cardinal ligament anteriorly

3. Hypogastric artery laterally

4. Sacrum posteriorly

The coccygeus (levator ani) muscle forms the floor of the pararectal space.

The development of these spaces before pelvic lymphadenectomy will aid in identification and dissection of the pelvic lymph nodes and dissection of the ureter as it passes into the vesicouterine ligament tunnel.

Dissection of the Bladder

The dissection of the bladder from the anterior part of the cervix and vagina is a critical step. Occasionally, tumor extension into the base of the bladder (which cannot be detected with cystoscopy) precludes adequate mobilization of the bladder flap, leading to the abandonment of the operation. Therefore, this portion of the operation should be undertaken early in the procedure. The bladder should be mobilized off of the upper third of the vagina to remove the tumor safely and with adequate margins.

Dissection of the Uterine Artery

The superior vesicle artery is dissected away from the cardinal ligament at a point near the uterine artery. The uterine artery, which usually arises from the superior vesicle artery, is thus isolated and divided, preserving the superior vesicle arteries. The uterine vessels are brought over the ureter by application of gentle traction. Occasionally, the uterine vein passes under the ureter.

Dissection of the Ureter

The ureter is dissected free from the medial peritoneal flap at the level of the uterosacral ligament. As the ureter passes near the uterine artery, there is a consistent arterial branch from the uterine artery to the ureter. This branch is sacrificed in the standard radical (type III) hysterectomy but preserved in the modified radical (type II) hysterectomy. Dissection of the ureter from the vesicouterine ligament (ureteral tunnel) may now be accomplished. If the patient has a deep pelvis, ligation of the uterosacral and cardinal ligaments may be undertaken first to bring the ureteral tunnel dissection closer to the operator. The roof of the ureteral tunnel is the anterior vesicouterine ligament. It should be ligated and divided to expose the posterior ligament. The posterior ligament is divided in the radical (type III) hysterectomy but conserved in the modified radical (type II) hysterectomy.

Posterior Dissection

The peritoneum across the cul-de-sac is incised, exposing the uterosacral ligaments. The rectum is rolled free from the uterosacral ligaments, which are divided midway to the sacrum in a radical (type III) hysterectomy and near the rectum in the modified radical (type II) operation. This allows the operator to isolate and separate the cardinal ligament from the rectum. A surgical clamp is placed on the cardinal ligament at the lateral pelvic sidewall in a radical hysterectomy and at the level of the ureteral bed in the modified radical procedure. A clamp is placed on the specimen side to maintain traction and to ensure that the full cardinal ligament is excised with the specimen. A right-angled clamp is placed caudad to this clamp across the paravaginal tissues. A second paravaginal clamp is usually needed to reach the vagina.

The vagina is entered anteriorly, and a suitable margin of proximal vagina is removed with the specimen. More vaginal epithelium can be excised if necessary, depending on the previous colposcopic findings. The vaginal edge may be sutured in a hemostatic fashion and left open with a drain from the pelvic space or closed with a suction drain placed percutaneously. The ureteral fistula and pelvic lymphocyst rates from these two techniques are similar.

Complications of Radical Hysterectomy

Acute Complications

The acute complications of radical hysterectomy include (74):

• Blood loss (average, 0.8 L)

• Ureterovaginal fistula (1% to 2%)

• Vesicovaginal fistula (1%)

• Pulmonary embolus (1% to 2%)

• Small bowel obstruction (1%)

• Febrile morbidity (25% to 50%)

Febrile morbidity is most often caused by pulmonary infection (10%) and is seen frequently with pelvic cellulitis (7%) and urinary tract infection (6%). Wound infection, pelvic abscess, and phlebitis all occur in fewer than 5% of patients (75).

Subacute Complications

The subacute effects of radical hysterectomy are postoperative bladder dysfunction and lymphocyst formation. For the first few days after radical hysterectomy, bladder volume is decreased, and filling pressure is increased. The sensitivity to filling is diminished, and the patient is unable to initiate voiding. The cause of this dysfunction is unclear. It is important to maintain adequate bladder drainage during this time to prevent overdistention. Bladder drainage is usually accomplished with a suprapubic catheter. It is more comfortable for the patient and allows the physician to perform cystometrography and determine residual urine volume without the need for frequent catheterization. In addition, the patient is able to accomplish voiding trials at home by clamping the catheter, voiding, and releasing to check the residual urine level. Cystometrography may be performed 3 to 4 weeks after surgery. For the catheter to be discontinued, the patient must be able to sense the fullness of the bladder, initiate voiding, and void with a residual urine level of less than 75 to 100 mL. Otherwise, voiding trials should continue at home until these criteria can be fulfilled.

Lymphocyst formation occurs in fewer than 5% of patients, and the cause is uncertain (75). Adequate drainage of the pelvis after radical hysterectomy may be an important step in prevention. However, routine placement of retroperitoneal drains did not reduce this morbidity (73). Ureteral obstruction, partial venous obstruction, and thrombosis may occur from lymphocyst formation. Simple aspiration of the lymphocyst is generally not curative, but percutaneous catheters with chronic drainage may allow healing. If this treatment is unsuccessful, operative intervention with excision of a portion of the lymphocyst wall and placement of either large bowel or omentum into the lymphocyst should be performed.

Chronic Complications

The most common chronic effect of radical hysterectomy is bladder hypotonia or, in extreme instances, atony. This condition occurs in about 3% of patients, regardless of the method of bladder drainage used (76,77). It may be a result of bladder denervation and not simply a problem associated with bladder overdistention (78). Voiding every 4 to 6 hours, increasing intra-abdominal pressure with Credé’s maneuver, and intermittent self-catheterization may be used to manage bladder hypotonia.

Ureteral strictures are uncommon in the absence of postoperative radiation therapy, recurrent cancer, or lymphocyst formation (78). If the stricture is associated with lymphocyst formation, treatment of the lymphocyst usually alleviates the problem. Strictures that occur after radiation therapy should be managed with ureteral stenting. If a ureteral stricture is noted in the absence of radiotherapy or lymphocyst formation, recurrent carcinoma is the most common cause. A CT scan of the area of obstruction should be obtained and cytologic assessment by FNA should be performed if there is a target lesion to exclude carcinoma. If the results of these tests are negative, a ureteral stent may be placed to relieve the stricture. Close observation for recurrent carcinoma is necessary, and the diagnosis of recurrence may ultimately require laparotomy.

Nerve-Sparing Radical Hysterectomy

Nerve-sparing radical hysterectomies were described in recent years in an attempt to diminish the bladder dysfunction, sexual dysfunction, and colorectal motility disorders commonly encountered after traditional radical hysterectomy. Multiple techniques were described involving the identification of the pelvic autonomic nerves at the sacral promontory followed by various surgical methods of nerve preservation as the nerves transit the cardinal ligaments. These techniques are promising and in small series did reduce postoperative bladder dysfunction (79,80).

Laparoscopic Radical Hysterectomy

Laparoscopic-assisted radical vaginal hysterectomy is being performed with increasing frequency in highly selected patients. In one large series of 200 women with stages IA1 to IIB cervical cancer treated with laparoscopic lymphadenectomy followed by radical vaginal hysterectomy, the authors found a 5-year survival rate comparable to patients treated with a similar abdominal approach and a comparable rate of intraoperative complications (81).

The use of laparoscopy in cervical cancer patients is appealing because it may lead to less blood loss, improved cosmetic results, shorter duration of hospitalization, and faster recovery.

Robotic Laparoscopic Radical Hysterectomy

Robotic laparoscopic radial hysterectomy is a relatively new technique. Proponents argue that in highly selected patients it can decrease hospital admission time and decrease the surgical morbidity in obese patients. One study reports comparable body mass index, operative times, parametrial margin, and number of lymph nodes collected when compared to open cases. Robotic cases had significantly shorter hospital stays and blood loss, while having significantly larger incidence of postoperative bladder dysfunction. The technique is still too new to tabulate cancer outcome data (82,83).

Sentinel Lymph Node Evaluation

Sentinel lymph node detection has become an integral part of the management strategy for breast cancer and melanoma and is being investigated as a diagnostic tool in multiple human malignancies, including carcinoma of the cervix. The sentinel node is a specific lymph node (or nodes) that is the first to receive drainage from a malignancy and is a primary site of nodal metastasis. In theory, the presence or absence of metastatic disease in the sentinel node should reflect the status of the nodal basin as a whole. Thus, a negative sentinel lymph node would allow omission of lymphadenectomy of the involved nodal basin. Sentinel lymph nodes are detected through perilesional injection of radiolabeled technicium-99 or blue dye followed by intraoperative identification of the sentinel lymph nodes utilizing handheld gamma probes or visual identification of blue-stained nodes. These techniques are primarily applicable in patients with early-stage disease and clinically negative lymph nodes, in whom lymph node status may influence the extent of the procedure or the use of adjuvant treatment.

Although data utilizing sentinel lymph node detection techniques in cervical cancer are limited, several interesting conclusions can be drawn from completed studies. Sentinel nodes can be detected in 80% to 100% of cervical cancer patients, and these rates were confirmed by both laparotomy and laparoscopy. A combination of dye and radiolabeled techniques appears to be superior for the detection of sentinel lymph nodes over either technique used alone. Test sensitivity of 65% to 87% can be expected with a 90% to 97% negative predictive value. The likelihood of detecting sentinel nodes may depend on the tumor volume, the time from injection to retrieval of the sentinel nodes, and the volume of dye or radiolabeled tracer injected. Sentinel node detection rates do not appear to be influenced by prior cold knife cone biopsy. False-negative results were reported. The role of sentinel node detection in cervix cancer is investigational; although the technique is promising, complete lymphadenectomy, when indicated, remains the standard of care (84).

Postoperative Management

Prognostic Variables for Early-Stage Cervical Cancer (Ia2–IIa)

The survival of patients with early-stage cervical cancer after radical hysterectomy and pelvic lymphadenectomy depends on the presence or absence of several intermediate and high-risk pathologic factors (76,85–99).

Intermediate risk factors for recurrent disease are:

1. Large tumor size

2. Cervical stromal invasion to the middle or deep one-third

3. Lymph–vascular space invasion

High risk factors for recurrent disease are:

1. Positive or close margins

2. Positive lymph nodes

3. Microscopic parametrial involvement

Patients treated with radical hysterectomy who have intermediate or high risk factors have a 30% and 40% risk, respectively, of recurrence within 3 years (100–102).

Lesion Size

Lesion size is an independent predictor of survival. Patients with lesions smaller than 2 cm have a survival rate of approximately 90%, and patients with lesions larger than 2 cm have a 60% survival rate (89). When the primary tumor is larger than 4 cm, the survival rate drops to 40% (87,97). An analysis of a Gynecologic Oncology Group (GOG) prospective study of 645 patients showed a 94.6% 3-year disease-free survival rate for patients with occult lesions, 85.5% for those with tumors smaller than 3 cm, and 68.4% for patients with tumors larger than 3 cm (98).

Depth of Invasion

Patients in whom depth of invasion is less than 1 cm have a 5-year survival rate of approximately 90%, but the survival rate falls to 63% to 78% if the depth of invasion is more than 1 cm(76,98,102–105).

Parametrial Spread

Patients with spread to the parametrium have a 5-year survival rate of 69%, compared with 95% when the parametrium is negative. When the parametrium is involved and pelvic lymph nodes are positive, the 5-year survival rate falls to 39% to 42% (90,106).

Lymph–Vascular Space Involvement

The significance of finding lymph–vascular space involvement is somewhat controversial. Several reports show a 50% to 70% 5-year survival rate when lymph–vascular space invasion is present and a 90% 5-year survival rate when invasion is absent (76,89,93,107,108). Others found no significant difference in survival if the study is controlled for other risk factors (98,99,109–112). Lymph–vascular space involvement may be a predictor of lymph node metastasis and not an independent predictor of survival.

Lymph Nodes

The variable that is most independently predictive of survival is the status of the lymph nodes. Patients with negative nodes have an 85% to 90% 5-year survival rate, whereas the survival rate for those with positive nodes ranges from 20% to 74%, depending on the number of nodes involved and the location and size of the metastases (94–96,99,102,105,111–113).

Data on lymph node status is summarized as follows:

1. When the common iliac lymph nodes are positive, the 5-year survival rate is about 25%, compared with about 65% when only the pelvic lymph nodes are involved (106,114,115).

2. Bilateral positive pelvic lymph nodes portend a less favorable prognosis (22% to 40% survival rate) than unilateral positive pelvic nodes (59% to 70%) (114,115).

3. The presence of more than three positive pelvic lymph nodes is accompanied by a 68% recurrence rate, compared with 30% to 50% when three or fewer lymph nodes are positive (94,112).

4. Patients in whom tumor emboli are the only findings in the pelvic lymph node have an 82.5% 5-year survival rate, whereas the survival rate is 62.1% and 54% with microscopic invasion and macroscopic disease, respectively (84).

Given the high risk of recurrent disease in surgically treated patients with early-stage cervical cancer who exhibit intermediate- or high-risk pathologic factors, adjuvant radiation or chemoradiation therapy should be considered.

Primary Radiation Therapy

Radiotherapy can be used to treat all stages of cervical cancer, with cure rates of about 70% for stage I, 60% for stage II, 45% for stage III, and 18% for stage IV (3). A comparison of surgery and radiation for treatment of low-stage disease is shown in Table 36.5. Primary radiation treatment plans consist of a combination of external teletherapy to treat the regional lymph nodes and to decrease the tumor volume, and brachytherapy delivered by intracavitary applicators or interstitial implants to provide a treatment boost to the central tumor. Intracavitary therapy alone may be used in patients with early disease when the incidence of lymph node metastasis is negligible.

Table 36.5 Comparison of Surgery versus Radiation for Stage IB/IIA Cancer of the Cervix

	Surgery	Radiation
Survival	85%	85%
Serious complications	Urologic fistulas 1%–2%	Intestinal and urinary strictures and fistulas 1.4%–5.3%
Vagina	Initially shortened, but may lengthen with regular intercourse	Fibrosis and possible stenosis, particularly in postmenopausal patients
Ovaries	Can be conserved	Destroyed
Chronic effects	Bladder atony in 3%	Radiation fibrosis of bowel and bladder in 6%–8%
Applicability	Best candidates are younger than 65 years of age, <200 lb, and in good health	All patients are potential candidates
Surgical mortality	1%	1% (from pulmonary embolism during intracavitary therapy)

The treatment sequence depends on tumor volume. Stage IB lesions smaller than 2 cm may be treated first with an intracavitary source to treat the primary lesion, followed by external therapy to treat the pelvic lymph nodes. Larger lesions require external radiotherapy first to shrink the tumor and to reduce the anatomic distortion caused by the cancer. Such a treatment strategy enables the therapist to achieve intracavitary dosimetry. The usual doses delivered are 7,000 to 8,000 cGy to point A (defined as 2 cm superior to the external cervical os and 2 cm lateral to the internal uterine canal) and 6,000 cGy to point B (defined as 3 cm lateral to point A), limiting the bladder and rectal dosage to less than 6,000 cGy. To achieve this level, it is necessary to adequately pack the bladder and bowel away from the intracavitary source. Localization films and careful calculation of dosimetry are mandatory to optimize the dose of radiation and to reduce the incidence of bowel and bladder complications. Local control depends on delivering an adequate dose to the tumor from the intracavitary source.

Although brachytherapy was traditionally prescribed using a low-dose rate technique, high-dose rate techniques are becoming more popular, and controversy exists over which technique is superior. Low-dose rates use caesium-137 as the source, whereas high-dose rates use iridium-192. Proponents of high-dose rate techniques argue that the exposure of radiation to medical personnel is less, ambulatory therapy is possible, and total treatment time is less. Advocates of low-dose rate techniques cite literature suggesting that complication rates are higher with higher-dose rate therapy. Several published trials show that there may be slight stage-related differences in survival between patients treated with low- and high-dose rate regimens, but the techniques have comparable survival and complication rates (116–118).

As noted, clinical staging is imprecise and fails to accurately predict disease extension to the para-aortic nodes in 7% of patients with stage IB, 18% with stage IIB, and 28% with stage III disease(119). Such patients will have “geographic” treatment failures if standard pelvic radiotherapy ports are used. As a result, treatment plans for these patients are individualized based on CT scans, PET scans, and biopsies of the para-aortic lymph nodes for consideration of extended-field radiotherapy. The routine use of extended-field radiation for prophylactic para-aortic radiation without documentation of distant metastasis to the para-aortic nodes was evaluated and is not practiced because of the increased enteric morbidity associated with this treatment modality.

Intensity Modulated Radiation Therapy

A method of providing external beam therapy, known as intensity modulated radiation therapy (IMRT), may be a significant therapeutic development. This technique uses computer-generated algorithms that accurately distinguish between target treatment volumes and normal tissue. The radiation beam intensity is modulated to optimize the delivery of radiation to the specified treatment volume while sparing adjacent normal tissue. The result appears to be much more accurate treatment of the tumor with minimal toxicity. Emphasizing this point is a study in 40 gynecologic cancer patients in which IMRT was used. Excellent coverage of the planned treatment volume was obtained, with no patient suffering grade 3 toxicity, and only 60% of patients suffering grade 2 toxicity, compared with a historical rate of 90% toxicity with conventional techniques (120). This technique is especially promising for treating cervical cancer because it allows higher doses to be delivered much more precisely, allowing patients who are unable to undergo brachytherapy because of pelvic anatomy and tumor geometry a chance for curative therapy. Studies utilizing IMRT in treating patients with cervical cancer are limited, but experience with this technique is increasing. Initial papers comparing the two techniques report decreased toxicity with comparable locoregional control, but they do not have long-term data on 5-year survival rates, so this technique is yet to be validated (121).

Adjuvant Radiation

In an effort to improve survival rates, postoperative radiotherapy was recommended for patients with high and intermediate risk factors such as metastasis to pelvic lymph nodes, invasion of paracervical tissue, deep cervical invasion, or positive surgical margins (76,86,89,90,106,111,112,122). Although most authors agree that postoperative radiotherapy is necessary in the presence of positive surgical margins, the use of radiation in patients with other high risk factors is controversial. Increasing evidence supports the use of adjuvant radiation. Particularly controversial, but best studied, is the use of radiation in the presence of positive pelvic lymph nodes. The rationale for treatment is the knowledge that pelvic lymphadenectomy does not remove all of the nodal and lymphatic tissue and subsequent radiotherapy can eradicate microscopic disease. The hesitancy to recommend postoperative radiotherapy derives from the significant rate of postradiation bowel and urinary tract complications (123). Most of the available data are retrospective. However, a randomized study by the GOG comparing radiation with no further treatment for patients at high risk for recurrence with negative pelvic nodes revealed a 30% serious complication rate, 16% reoperation rate, and a 2% mortality rate as a result of treatment-related complications (124).

Based on retrospective studies, it appears that postoperative radiation therapy for positive pelvic nodes can decrease pelvic recurrence but does not improve 5-year actuarial survival rates. One multi-institutional study showed no difference in survival in patients with three or fewer positive pelvic nodes (59% versus 60%) (112). However, there seemed to be a benefit when radiotherapy was given to those with more than three positive nodes.

In a study of 60 pairs of irradiated and nonirradiated women matched for age, lesion size, number, and location of positive nodes after radical hysterectomy, no significant difference was found in projected 5-year survival rates (72% for surgery alone, 64% for surgery plus radiation) (125). The proportion of recurrences confined to the pelvis was 67% in patients treated with surgery only and 27% in patients treated with postoperative radiation (p = 0.03). In a Cox regression analysis of 320 women who underwent radical hysterectomy, for the 72 who received postoperative radiation, there was a significant decrease in pelvic recurrence but no survival benefit (95). A multi-institutional retrospective study was performed on 185 women with positive pelvic nodes after radical hysterectomy, including 103 who received postoperative radiotherapy (97). Multivariate analysis disclosed that radiotherapy was not an independent predictor of survival, whereas age, lesion diameter, and number of positive nodes did influence survival. These authors concluded that additional treatment is needed to improve survival rates. Because survival is limited by distant recurrence, the addition of chemotherapy to postoperative radiotherapy was proposed. A 75% disease-free survival rate was reported at 3 years in 40 high-risk patients given cisplatin, vinblastine, and bleomycin after radical hysterectomy, and a 46% disease-free survival rate was found in 79 comparable patients who refused treatment (126). Only 4 (11.8%) of 34 patients with positive pelvic nodes had recurrences, whereas disease recurred in 8 (33%) of 24 untreated patients with positive nodes. An 82% rate of disease-free survival was reported at 2 years among 32 patients who were treated postoperatively with radiation therapy plus cisplatin and bleomycin (127).

The location of lymph node metastases apparently is relevant to postirradiation recurrence rates. When common iliac lymph nodes are involved, the survival rate drops to 20%. As the number of positive pelvic nodes increases, the percentage of positive common iliac and low para-aortic nodes increases (i.e., 0.6% when pelvic lymph nodes are negative, 6.3% with one positive pelvic node, 21.4% with two or three positive nodes, and 73.3% with four or more positive nodes). This information was used to recommend extended-field radiotherapy to patients with positive pelvic lymph nodes in an attempt to treat undetected extrapelvic nodal disease (107). A 3-year disease-free survival rate of 85% occurred in patients with positive pelvic nodes, and a survival rate of 51% occurred in patients with positive common iliac nodes; these rates are better than the survival rates of 50% and 23%, respectively, for historical control groups receiving radiotherapy to the pelvis alone.

The GOG reported the results of a randomized controlled trial on patients with cervical cancer treated by radical hysterectomy and found to have at least two of the following risk factors: capillary lymphatic space invasion, more than one-third stromal invasion, and large tumor burden (101). A total of 277 patients were entered into the study, with 140 patients randomized to no further therapy and 137 patients randomized to adjuvant pelvic radiotherapy. Patients with these risk factors who were treated postoperatively with radiation therapy had a statistically significant (47%) decrease in recurrent disease. After extensive follow-up, there is no statistically significant difference in mortality rates (128). The morbidity with combination therapy was acceptable, with a low rate of enteric and urinary complications. A second GOG study of patients with high-risk cervical cancer randomized patients to concurrent chemoradiation therapy or radiation therapy alone, as discussed below (100).

Concurrent Chemoradiation

Radiation therapy fails to achieve tumor control in 20% to 65% of patients with advanced cervical cancer. Chemotherapy, despite its relative lack of success in treating patients with cervical cancer, was evaluated as neoadjuvant treatment in combination with surgery. Concomitant use of chemotherapy and radiation was studied extensively by the GOG and results of five randomized studies were reported. The concept of chemoradiation encompasses the benefits of systemic chemotherapy with the benefits of regional radiation therapy. The use of chemotherapy to sensitize cells to radiation therapy improved local–regional control. These new results changed the way cervical cancer is treated in many medical centers.

An Intergroup trial involving the GOG, the Southwestern Oncology Group, and the Radiation Therapy Oncology Group evaluated postoperative chemoradiation therapy in patients with stage IA2, IB, or IIA cervical cancer who had positive pelvic lymph nodes, positive parametrial extension, or positive vaginal margins at the completion of radical hysterectomy (127). A total of 243 patients were assessed in this trial, with 127 receiving chemoradiation (cisplatin, 5-fluorouracil [5-FU], radiation therapy) and 116 receiving radiation. The results of this trial showed a statistically significant improvement in progression-free survival and overall survival at 43 months for the patients receiving concurrent chemoradiation. The 4-year survival rates for the patients receiving chemoradiation versus radiation alone were 81% and 71%, respectively. The toxicity levels in the two groups were acceptable, with a higher rate of hematologic toxicity in the concurrent chemoradiation arm. This study showed that in patients with these high-risk factors after radical hysterectomy for stage IA2, IB, and IIA disease, chemoradiation is the postoperative treatment of choice.

Concurrent chemoradiation was evaluated in patients with advanced cervical carcinoma. GOG protocol 85 was a prospective study that enrolled patients with stage IIb to IVA cervical cancer and compared concurrent chemoradiation (129). There were 177 patients treated with cisplatin, 5-FU, and radiation. These patients were compared with 191 patients treated with hydroxyurea and radiation. The median follow-up of patients who were alive at the time of the analysis was 8.7 years. Patients who received concurrent chemoradiation and were treated with cisplatin and 5-FU had a statistically significant improvement in progression-free interval and overall survival (129). Hematologic toxicity levels in the two groups were similar. This study showed that cisplatin-based concurrent chemoradiation was a superior treatment when compared with hydroxyurea and concurrent radiation.

GOG Protocol 120 was initiated to evaluate patients with negative para-aortic nodes and cervical carcinoma stage IIB to IVA treated with concurrent chemoradiation. The treatment arms in this study consisted of radiation plus weekly cisplatin; or cisplatin, 5-FU, and hydroxyurea; or hydroxyurea. There were 176 patients in the weekly cisplatin arm; 173 patients in the cisplatin, 5-FU, and hydroxyurea arm; and 177 patients in the hydroxyurea arm (130). The two treatment arms with cisplatin-based chemotherapy and radiation showed an improvement in progression-free interval and overall survival at a median follow-up of 35 months. The relative risks for progression of disease or death were 0.55 and 0.57, respectively, for patients treated with cisplatin-based chemotherapy and radiation, compared with the patients treated with hydroxyurea and radiation (130). This study confirmed the findings of GOG Protocol 85 and reaffirmed the finding that cisplatin-based concurrent chemoradiation is the treatment of choice for patients with advanced-stage cervical cancer.

A third GOG trial evaluated patients with stage IB to IVA cervical cancer. Of the patients enrolled in this study, 70% had stage IB or IIA disease (131). A total of 403 patients were enrolled and evaluated. The 5-year survival rates were 73% in patients treated with chemoradiation and 58% in patients treated with radiation therapy alone. The cumulative rates of disease-free survival at 5 years were 67% in patients treated with concurrent chemoradiation and 40% in patients treated with radiation therapy alone. Survival and progression-free intervals for patients receiving concurrent chemoradiation were significantly improved (131). The results of this study suggested that chemoradiation is the treatment of choice for stage IIB to IVA disease and that those patients with stage IB2 and IIA disease may benefit from chemoradiation.

A GOG study of chemoradiation comparing concurrent cisplatin and radiation with radiation alone in patients with bulky IB cervical cancer included adjuvant hysterectomy after completion of the radiation (132). There were 183 patients assigned to the concurrent chemotherapy and radiation arm and 186 patients treated with radiation alone. The median duration of follow-up was 36 months, with disease recurrence detected in 37% of the patients treated with radiation alone, compared with 21% who were treated with concurrent chemoradiation (132). The 3-year survival rates were 83% in the group who received concurrent chemoradiation and 74% in the group who received radiation alone (132). The study also included adjuvant hysterectomy after completion of radiation treatment. Because the results did not show an improvement in survival by using adjuvant hysterectomy, the authors concluded that adjuvant hysterectomy would not be part of their recommendations. This study supports the results of previous studies and shows that patients with bulky stage IB and IIA cervical cancer treated with concurrent chemoradiation have survival rates superior to those treated with radiation alone. These two studies indicate that patients with bulky stage IB and IIA disease should have primary treatment consisting of chemoradiation, with the chemotherapy agent being weekly cisplatin.

Surgical Staging before Radiation

Surgical staging procedures designed to discover positive lymph nodes may be forgone with use of PET/CT imaging studies. The use of transperitoneal exploration was associated with a 16% to 33% mortality rate from radiotherapy-induced bowel complications and a 5-year survival rate of only 9% to 12% (133,134). To avoid these complications, extraperitoneal dissection of the para-aortic nodes is recommended, and the radiation dose should be reduced to 5,000 cGy or less (135,136). When this approach is used, postradiotherapy bowel complications occur in fewer than 5% of patients, and the 5-year survival rate is 15% to 26% in patients with positive para-aortic nodes (19,137,138). Survival appears to be related to the amount of disease in the para-aortic nodes and to the size of the primary tumor. In patients whose metastases to the para-aortic lymph nodes are microscopic and whose central tumor has not extended to the pelvic sidewall, the 5-year survival rate improves to 20% to 50% (139,140). Surgical staging techniques have improved to include laparoscopic assessment of the para-aortic and pelvic lymph nodes. Studies demonstrated benefit from surgical staging with improved survival and changes in treatment plans in 40% of patients (136,137). When PET/CT is compared with surgicopathological staging of para-aortic lymph nodes, some patients with histologically positive para-aortic lymph nodes are missed with surgicopathological staging (141).

Management of Grossly Positive Para-aortic Lymph Nodes

The management of patients with macroscopic or grossly positive para-aortic lymph nodes discovered at the time of surgery or by imaging studies is controversial. It is likely that grossly positive nodes are beyond the ability of radiation therapy alone to sterilize. Therefore, to improve survival, additional therapy is required. In a representative study of the multiple reports in the literature, lymph node metastases were noted in 133 of 266 patients. Pelvic and para-aortic nodes were positive in 44 patients and positive para-aortic nodes were noted in only 2 patients. Five- and 10-year survival rates were similar for patients with macroscopically positive resectable nodes and microscopically positive nodes. Patients with unresectable nodal disease had a worse survival rate than those with resectable disease. All patients underwent extraperitoneal lymph node resections and subsequent radiotherapy. There was a 10% incidence of severe morbidity related to radiation use. Consistent with other reports in the literature, this study showed that extraperitoneal debulking lymphadenectomy confers a survival advantage similar to that enjoyed by patients with micrometastatic disease without additional morbidity (27).

Prophylactic Para-aortic Radiation Therapy

Prophylactic extended-field radiation therapy is an alternative to surgical staging of the para-aortic lymph node chain in women with advanced cervical cancer judged to be at high risk but without radiological or clinical evidence of para-aortic lymph node involvement. This treatment strategy was evaluated in 441 patients with stages I to III disease (142). High rates of gastrointestinal toxicity were noted in the treatment group. There was no difference in disease-free survival or overall survival between the control and treated groups, although treated patients had fewer para-aortic failures. A lack of difference in survival rates in this study may be related to high local and regional failure rates, suggesting that ideal patients for prophylactic radiotherapy would be those in whom there is a high likelihood of achieving pelvic control. A survival benefit was noted in a study by the Radiation Therapy Oncology Group, in which 367 patients with stages IB to IIB disease were randomized to pelvic radiotherapy versus pelvic and extended field radiotherapy (143). The extended field treatment arm suffered more grade 4 and 5 toxicity, confirming previous studies. Complicating the issue is another study from the Radiation Therapy Oncology Group that revealed that in locally advanced cervical cancer, pelvic radiation therapy with concurrent cisplatinchemotherapy was superior to extended-field radiation therapy (131). The appropriate role of prophylactic para-aortic radiation therapy is still under investigation.

Supraclavicular Lymph Node Biopsy

Although not standard practice, the performance of a supraclavicular lymph node biopsy was advocated in patients with positive para-aortic lymph nodes before the initiation of extended-field irradiation and in patients with a central recurrence before exploration for possible exenteration. The incidence of metastatic disease in the supraclavicular lymph nodes in patients with positive para-aortic lymph nodes is 5% to 30% (144). Node enlargement and increased metabolic activity can be assessed with chest PET/CT scanning. Cytologic assessment by FNA can obviate the need for an excisional biopsy and should be performed if any enlarged nodes are present. If the scalene lymph nodes are positive, chemotherapy should be considered.

Complications of Radiation Therapy

Perforation of the uterus may occur with the insertion of the uterine tandem. This is particularly a problem for elderly patients and those who had a previous diagnostic conization procedure. When perforation is recognized, the tandem should be removed, and the patient should be observed for bleeding or signs of peritonitis. Survival may be decreased in patients who have uterine perforation, possibly because these patients have more extensive uterine disease (145). Fever may occur after insertion of the uterine tandem and ovoids. Fever most often results from infection of the necrotic tumor and occurs 2 to 6 hours after insertion of the intracavitary system. If uterine perforation was excluded by ultrasonography, intravenous broad-spectrum antibiotic coverage, usually with a cephalosporin, should be administered. If the fever does not decrease promptly or if the temperature is higher than 38.5°C, an aminoglycoside and a bacteroides species–specific antibiotic should administered. If fever persists or if the patient shows signs of septic shock or peritonitis, the intracavitary system must be removed. Antibiotics are continued until the patient recovers, and the intracavitary application is delayed for 1 to 2 weeks.

Acute Morbidity

The acute effects of radiotherapy are caused by ionizing radiation on the epithelium of the intestine and bladder and occur after administration of 2,000 to 3,000 cGy. Symptoms include diarrhea, abdominal cramps, nausea, frequent urination, and occasionally bleeding from the bladder or bowel mucosa. Bowel symptoms can be treated with a low-gluten, low-lactose, and low-protein diet. Antidiarrheal and antispasmodic agents may help. Bladder symptoms may be treated with antispasmodic medication. Severe symptoms may require a week of rest from radiotherapy.

Chronic Morbidity

The chronic effects of radiotherapy result from radiation-induced vasculitis and fibrosis and are more serious than the acute effects. These complications occur several months to years after radiotherapy is completed. The bowel and bladder fistula rate after pelvic radiation therapy for cervical cancer is 1.4% to 5.3%, respectively (59,61). Other serious toxicity (e.g., bowel bleeding, stricture, stenosis, or obstruction) occurs in 6.4% to 8.1% of patients (59,61).

Proctosigmoiditis

Bleeding from proctosigmoiditis should be treated with a low-residue diet, antidiarrheal medications, and steroid enemas. In extreme cases, a colostomy may be required to rest the bowel completely. Occasionally resection of the rectosigmoid must be performed.

Rectovaginal Fistula

Rectovaginal fistulas or rectal strictures occur in fewer than 2% of patients. The successful closure of fistulas with bulbocavernosus flaps or sigmoid colon transposition was reported (146,147). Occasionally, resection with anastomosis is feasible. Diversion resulting in colostomy may be the optimal therapy in patients who have poor vascular supply to the pelvis and a history of an anastomotic leak or breakdown from prior repairs.

Small Bowel Complications

Patients with previous abdominal surgery are more likely to have pelvic adhesions and thus sustain more radiotherapy complications in the small bowel. The terminal ileum may be particularly susceptible to chronic damage because of its relatively fixed position at the cecum. Patients with small bowel complications have a long history of crampy abdominal pain, intestinal rushes, and distention characteristic of partial small bowel obstruction. Often, low-grade fever and anemia accompany the symptoms. Patients who have no evidence of disease should be treated aggressively with total parenteral nutrition, nasogastric suction, and early surgical intervention after the anemia resolves and good nutritional status is attained. The type of procedure performed depends on individual circumstances (148). Small bowel fistulas that occur after radiotherapy rarely close spontaneously while total parenteral nutrition is maintained. Recurrent cancer should be excluded; aggressive fluid replacement, nasogastric suction, and wound care should be instituted. Fistulography and a barium enema should be performed to exclude a combined large and small bowel fistula. The fistula-containing loop of bowel may be either resected or isolated and left in situ. In the latter case, the fistula will act as its own mucous fistula.

Urinary Tract

Chronic urinary tract complications occur in 1% to 5% of patients and depend on the dose of radiation to the base of the bladder. Vesicovaginal fistulas are the most common complication and usually require supravesicular urinary diversion. Occasionally, a small fistula can be repaired with either a bulbocavernosus flap or an omental pedicle. Ureteral strictures are usually a sign of recurrent cancer, and a cytologic sample should be obtained at the site of the obstruction using FNA guided by a CT scan. If the findings are negative, the patient should undergo exploratory surgery to evaluate the presence of recurrent disease. If radiation fibrosis is the cause, ureterolysis may be possible or indwelling ureteral stents may be passed through the open urinary bladder to relieve obstruction.

Chemotherapy

Neoadjuvant Chemotherapy

Randomized trials were initiated by the GOG and other large centers to determine the efficacy of neoadjuvant chemotherapy. In the era of effective chemoradiation therapy, there is no evidence that neoadjuvant chemotherapy offers superior results or a survival advantage over standard therapy.

Chemotherapy for Advanced Disease

Chemotherapy was studied in advanced cervical cancer with mixed results. Single-agent chemotherapy was the standard for advanced or recurrent disease. Active agents include cisplatin, carboplatin, paclitaxel, and ifosfamide, but response rates are only 10% to 20% with a median duration of only 4 to 6 months. A number of trials were performed to determine whether multiagent chemotherapy is superior. The GOG Protocol 149 studied patients with histologically confirmed, advanced stage (IVb), recurrent or persistent squamous cell cancer of the cervix and randomized these patients to one of two combination chemotherapy treatment arms. Of the 287 patients, 146 patients were randomized to the cisplatin and ifosfamide arm, and 141 patients received cisplatin, ifosfamide, and bleomycin. There were no differences in overall survival, progression-free survival, response rates, or overall toxicity between the two combination chemotherapy regimens (149). In another trial sponsored by the GOG, single-agent cisplatin was compared to cisplatin plus either dibromodulcitol or ifosfamide plus mesna. In this trial, the combination of cisplatin plus ifosfamide had a better response rate (31% vs. 18%) and median time to progression (4.6 months vs. 3.2 months) compared with single agent cisplatin. Toxicity was notably higher in the combination regimen, and there was no overall survival advantage demonstrated (150). The GOG published the results of a study comparing single-agent cisplatin to cisplatin plus paclitaxel in women with stage IVb squamous cell cancer of the cervix. Although the response rate (36% vs. 19%) and progression-free survival (4.8 months vs. 2.8 months) were greater for the combination regimen, there was only a 1-month increase in overall survival (151). Finally, the regimen of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), which received considerable attention because of preliminary studies suggesting high response rates, was evaluated in POG Protocol 179. In this study, MVAC was compared to cisplatin alone, and cisplatin combined with topotecan. The MVAC arm was prematurely closed because of excessive toxicity, and the remaining cisplatin arms were compared. Although the combination of cisplatin and topotecanwas superior to cisplatin alone, the improvement in overall survival was only 3 months. The combination arm had a higher complete response rate, overall response rate, progression-free survival, and overall survival (152). Doublet therapy with cisplatin and paclitaxel is considered standard therapy based on GOG 204, which analyzed four cisplatin-containing doublets (topotecan, paclitaxel, vinorelbine, and gemcitabine) for the best efficacy; although no major differences existed in overall survival for the four doublets, the cisplatin and paclitaxel doublet trended toward the best results (153). Overall, it appears that multiagent regimens offer an improved response rate and slightly higher overall survival but with increased toxicity. Other studies showed comparable survival and less toxicity with carboplatin and paclitaxel (154).

Treatment of Cervical Cancer by Stage

Stage IA

Until 1985, no FIGO recommendation existed concerning the size of lesion or the depth of invasion that should be considered microinvasive (stage Ia). This led to considerable confusion and controversy in the literature. Over the years, as many as 18 different definitions were used to describe microinvasion. In 1974, the Society of Gynecologic Oncologists recommended a definition that is accepted by FIGO: A microinvasive lesion is one in which neoplastic epithelium invades the stroma to a depth of less than 3 mm beneath the basement membrane and in which lymphatic or blood vascular involvement is not demonstrated. The purpose of defining microinvasion is to identify a group of patients who are not at risk for lymph node metastases or recurrence and who therefore may be treated with less than radical therapy.

Diagnosis must be determined on the basis of a cone biopsy of the cervix. The treatment decision rests with the gynecologist and should based on a review of the conization specimen with the pathologist. It is important that the pathologic condition be described in terms of (i) depth of invasion, (ii) width and breadth of the invasive area, (iii) presence or absence of lymph–vascular space invasion, and (iv) margin status. These variables are used to determine the degree of radicality of the operation and whether the regional lymph nodes should be treated (12).

Stage IA1 ≤3 mm Invasion

Lesions with invasion less than or equal to 3 mm have less than 1% incidence of pelvic node metastases. Within this group, it appears that the patients most at risk for nodal metastases or central pelvic recurrence are those with definitive evidence of tumor emboli in lymph vascular spaces (74,155). Therefore, patients with less than 3 mm invasion and no lymph–vascular space invasion may be treated with extrafascial hysterectomy without lymphadenectomy. Therapeutic conization appears to be adequate therapy for these patients if preservation of childbearing capability is desired. Surgical margins and postconization endocervical curettage must be free of disease. If there is lymph–vascular space invasion, a type I (extrafascial) or II (modified radical) hysterectomy with pelvic lymphadenectomy should be considered.

Treatment of microinvasive cervical adenocarcinoma is complicated by a lack of agreement on approaches. Recent reports show that patients with stage Ia1 cervical adenocarcinoma may be treated in a fashion similar to patients with this stage and a squamous lesion (103–105). Some experts disagree with this interpretation because of the difficulty in establishing a pathologic diagnosis of microinvasion from a frankly invasive adenocarcinoma. Patients diagnosed with microinvasive cervical adenocarcinoma should have expert pathologic assessment before considering treatment with extrafascial hysterectomy or conization.

Stage IA2 >3–5 mm Invasion

Lesions with invasion of greater than 3 to 5 mm have a 3% to 8% incidence of pelvic node metastases; thus, pelvic lymphadenectomy is necessary for these lesions (155,156). The primary tumor may be treated with a modified radical hysterectomy (type II) or a radical trachelectomy if preservation of fertility is desired. If intermediate- or high-risk pathologic factors are identified in the surgical specimen, adjuvant radiation or chemoradiation therapy is recommended.

Stages IB1, IB2, and IIA1 Invasive Cancer

Stage Ib lesions are subdivided into stage IB1, which denotes lesions that are 4 cm or smaller in maximum diameter, and stage IB2, which denotes lesions that are greater than 4 cm. Stage IIA1 disease involves the upper two-thirds of the vagina, but total lesion size is 4 cm or less. These patients may be managed with either radical trachelectomy or a type III radical hysterectomy, with pelvic lymphadenectomy. Radical trachelectomy should be restricted to candidates with low-risk disease and a tumor size less than 2 cm. The para-aortic lymph node chain must be evaluated, especially if pelvic nodal disease is encountered. Adjuvant radiation therapy is recommended if intermediate risk factors are identified postoperatively. Adjuvant chemoradiation is indicated if high risk features are found.

Alternatively, primary chemoradiation therapy with curative intent is appropriate. A comparison of radical hysterectomy with radiation resulted in similar survival rates for the two treatment modalities. Several studies comparing patients treated by either radical hysterectomy or radiation therapy showed similar survival rates and outcomes for both groups (85,157). However, patients treated with type III radical hysterectomy who subsequently received postoperative radiation had a higher rate of intestinal and urinary morbidity compared with patients treated with either modality alone. Therefore, some clinicians advocate using radiation and avoiding surgery in these patients because many will require adjuvant postoperative radiation.

Bulky Stages IB2 and IIA2 Invasive Cancer

Patients with bulky IB2 and IIA2 disease may be treated with either primary chemoradiation or radical surgery. Because many of these patients will have intermediate or high risk factors postoperatively, strong consideration should be given to primary chemoradiation. If surgical therapy is desired, a type III radical hysterectomy with pelvic and para-aortic lymphadenectomy, followed by adjuvant chemoradiation if intermediate or high risk factors are present, is appropriate therapy. This option has benefits of complete surgical staging and ovarian preservation, if desired. Disadvantages of primary surgery include increased morbidity if multimodality therapy is utilized (157).

Stages IIB to IIIB Invasive Cancer

Therapy for patients with stage IIB or greater cervical cancer traditionally was radiation therapy. Primary pelvic radiotherapy fails to control disease progression in 30% to 82% of patients with advanced cervical carcinoma (3). Two-thirds of these failures occur in the pelvis (158). A variety of agents were used in an attempt to increase the effectiveness of radiation therapy in patients with large primary tumors. Because chemoradiation was superior to radiation therapy alone, chemoradiation is the preferred treatment strategy for these patients, with cisplatin the chemotherapy agent of choice. Nodal involvement, particularly the para-aortic lymph nodes, is the most important factor related to survival (see section above on Concurrent Chemoradiation).

Stages IVA and IVB Cancer

Primary exenteration may be considered for patients with direct extension to the rectum or bladder, but it is rarely performed. For patients with extension to the bladder, the survival rate with radiation therapy is as high as 30%, with a urinary fistula rate of only 3.8% (159). The presence of tumor in the bladder may prohibit cure with radiation therapy alone; thus, consideration must be given to removal of the bladder on completion of external beam radiation treatment. This is particularly true if the disease persists at that time and the geometry is not conducive to brachytherapy. Rectal extension is less commonly observed but may require diversion of the fecal stream before chemoradiation to avoid septic episodes from fecal contamination. In certain clinical situations, such as with patients who have stage IVA disease and present with vesicovaginal or rectovaginal fistula, urinary or rectal diversion may be performed, followed by chemoradiation.

Patients with stage IVB cervical carcinoma are candidates for chemotherapy and palliative pelvic radiation therapy. Control of symptoms with the least morbidity is of primary concern in this patient population.

Patient Evaluation and Follow-up after Therapy

Patients who receive radiotherapy should be monitored closely to assess treatment response. Tumors may be expected to regress for up to 3 months after radiotherapy. During the pelvic examination, progressive shrinkage of the cervix and possible stenosis of the cervical os and surrounding upper vagina is expected and should be noted. During rectovaginal examination, careful palpation of the uterosacral and cardinal ligaments for nodularity is important. Cytologic assessment by FNA of suspicious areas should be performed to allow early diagnosis of persistent disease. In addition to the pelvic examination, the supraclavicular and inguinal lymph nodes should be carefully examined, and cervical or vaginal assessment should be performed every 3 months for 2 years and then every 6 months for the next 3 years. Endocervical curettage may be performed in patients with large central tumors.

Radiography of the chest may be performed yearly in patients who have advanced disease. Metastasis to the lung was reported in 1.5% of cases. Solitary nodules are present in 25% of cases with metastasis. Resection of a solitary nodule in the absence of other persistent disease may yield some long-term survivors (160). Although intravenous pyelography (IVP) is not a part of routine postradiotherapy surveillance, it should be performed if a pelvic mass is detected or if urinary symptoms warrant evaluation. The finding of ureteral obstruction after radiotherapy in the absence of a palpable mass may indicate unresectable pelvic sidewall disease, but this finding should be confirmed, usually by FNA cytologic assessment (161).

Patients who had radical hysterectomy and who are at high risk for recurrence may benefit from early recognition of recurrence because they might be saved with radiation therapy. In these patients, a routine CT urogram 6 to 12 months after surgery may be beneficial. After radical hysterectomy, about 80% of recurrences are detected within 2 years (162). The larger the primary lesion, the shorter the median time is to recurrence (163).

Special Considerations

Cervical Cancer during Pregnancy

The incidence of invasive cervical cancer associated with pregnancy is 1.2 in 10,000 (164). A Pap test should be performed on all pregnant patients at the initial prenatal visit, and any grossly suspicious lesions should be biopsied. Diagnosis is often delayed during pregnancy because bleeding is attributed to pregnancy-related complications. If the result of the Pap test is positive for malignant cells, and invasive cancer cannot be diagnosed using colposcopy and biopsy, a diagnostic conization procedure may be necessary. Conization in the first trimester of pregnancy is associated with hemorrhagic and infectious complications, and an abortion rate as high as 33% (165,166). Because conization subjects the mother and fetus to complications, it should not be performed before the second trimester and only in patients with colposcopy findings consistent with cancer, biopsy-proven microinvasive cervical cancer, or strong cytologic evidence of invasive cancer. Inadequate colposcopic examination may be encountered during pregnancy in patients who had prior ablative therapy. Close follow-up throughout pregnancy may allow the cervix to evert and develop an ectropion, allowing satisfactory colposcopy in the second or third trimester. Patients with obvious cervical carcinoma may undergo cervical biopsy and clinical staging similar to that of nonpregnant patients.

After conization, there appears to be no harm in delaying definitive treatment until fetal maturity is achieved in patients with stage Ia cervical cancer (165,167,168). Patients with less than 3 mm of invasion and no lymphatic or vascular space involvement may be followed to term. Historically, these patients were allowed to deliver vaginally, and a hysterectomy was performed 6 weeks postpartum if further childbearing was not desired. However, in a multivariate analysis of 56 women with cervical cancer diagnosed during pregnancy and 27 women with cervical cancer diagnosed within 6 months of delivery, vaginal delivery was the most significant predictor of recurrence. In addition, most recurrences after vaginal delivery involved distant sites. The ideal delivery method for these patients is not known definitively; however, strong consideration should be given to performing a cesarean birth in women with cervical cancer of any stage (169). If vaginal delivery is chosen, close inspection of the episiotomy site is required during follow-up because of rare reports of metastatic cervical cancer at these locations (170).

Patients with 3 to 5 mm of invasion and those with lymph–vascular space invasion may be followed to term or delivered early after establishment of fetal pulmonary maturity (165,168). They may have cesarean delivery, immediately followed by modified radical hysterectomy and pelvic lymphadenectomy. Patients with more than 5 mm invasion should be treated as having frankly invasive carcinoma of the cervix. Treatment depends on the gestational age of the pregnancy and the wishes of the patient. Modern neonatal care affords a 75% survival rate for infants delivered at 28 weeks of gestation and 90% for those delivered at 32 weeks of gestation. Fetal pulmonary maturity can be determined by amniocentesis, and prompt treatment can be instituted when pulmonary maturity is documented. Although timing is controversial, it is probably unwise to delay therapy for longer than 4 weeks (167,168). The recommended treatment is classic cesarean delivery followed by radical hysterectomy with pelvic lymphadenectomy. There should be a thorough discussion of the risks and options with both parents before any treatment is undertaken.

Patients with stages II to IV cervical cancer should be treated with radiotherapy. If the fetus is viable, it is delivered by classic cesarean birth, and therapy is begun postoperatively. If the pregnancy is in the first trimester, external radiation therapy can be started with the expectation that spontaneous abortion will occur before the delivery of 4,000 cGy. In the second trimester, a delay of therapy may be entertained to improve the chances of fetal survival. If the patient wishes to delay therapy, it is important to ensure fetal pulmonary maturity before delivery is undertaken. Neoadjuvant chemotherapy has been administered to women during pregnancy with cervical cancer after 13 weeks gestation, without clear short-term harm to the fetus, although longer clinical follow-up is necessary (171).

The clinical stage is the most important prognostic factor for cervical cancer during pregnancy. Overall survival for these patients is slightly better because an increased proportion of these patients have stage I disease. For patients with advanced disease, there is evidence that pregnancy impairs the prognosis (165,168). The diagnosis of cancer in the postpartum period is associated with a more advanced clinical stage and a corresponding decrease in survival (169).

Cancer of the Cervical Stump

Cancer of the cervical stump was more common many decades ago when supracervical hysterectomy was popular; because this operation is being performed more frequently, this situation may become increasingly familiar. Early-stage disease is treated surgically, with very little change in technique from that used when the uterus is intact (172). Radical parametrectomy with upper vaginectomy and pelvic lymphadenectomy is the standard procedure.Advanced-stage disease may present a therapeutic problem for the radiotherapist if the length of the cervical canal is less than 2 cm. This length is necessary to allow satisfactory placement of the uterine tandem. If the uterine tandem cannot be placed, radiation therapy can be completed with vaginal ovoids or with an external treatment plan in which lateral ports are used to augment the standard anterior and posterior ports. Such a technique will reduce the dosage to the bowel and bladder and thus reduce the incidence of complications.

Pelvic Mass

The origin of a pelvic mass must be clarified before treatment is initiated. A CT urogram can exclude a pelvic kidney, and a barium enema helps to identify diverticular disease or carcinoma of the colon. An abdominal x-ray film may show calcifications typically associated with benign ovarian teratomas or uterine leiomyomas. Pelvic ultrasonography differentiates between solid and cystic masses and indicates uterine or adnexal origin. Solid masses of uterine origin are most often leiomyomas and do not need further investigation.

Pyometra and Hematometra

An enlarged fluid-filled uterine cavity may be a pyometra or a hematometra. The hematometra can be drained by dilation of the cervical canal and will not interfere with treatment. The pyometra also should be drained, and the patient should be given antibiotics to cover bacteroides species, anaerobic staphylococcus and streptococcus species, and aerobic coliform bacterial infection.Placement of a large mushroom catheter through the cervix was advocated, but the catheter itself may become obstructed, leading to further occlusion of the drainage. Repeated dilation of the cervix with aspiration of pus every 2 to 3 days is more effective.

If the disease is stage I, a radical hysterectomy and pelvic lymphadenectomy may be performed. However, a pyometra is usually found in patients with advanced disease, and thus radiotherapy is required. External-beam therapy can begin after the pyometra is healed. Patients often have a significant amount of pus in the uterus or a tubo-ovarian abscess without signs of infection; therefore, a normal temperature and a normal white blood cell count do not necessarily exclude infection. Repeat physical examination or pelvic ultrasonography is necessary to ensure adequate drainage.

Cervical Carcinoma after Extrafascial Hysterectomy

When invasive cervical cancer is found after simple hysterectomy, further treatment is predicated on the extent of disease. Microinvasive disease in patients at low risk for lymph node metastasis does not require further treatment. Invasive disease may be treated with radiotherapy or reoperation involving a pelvic lymphadenectomy and radical excision of parametrial tissue, cardinal ligaments, and the vaginal stump (173).

Reoperation

Reoperation is indicated for a young patient who has a small lesion and in whom preservation of ovarian function is desirable. It is not indicated for patients who have positive margins or obvious residual disease (173). Survival rates after radical reoperation are similar to those after radical hysterectomy for stage I disease.

Concurrent cisplatin-based chemoradiation is recommended for gross residual disease, positive imaging, disease in the lymph nodes or parametrium, or a positive surgical margin; individualized brachytherapy is clearly indicated for a positive vaginal margin (174).

Radiation Therapy

Survival after radiotherapy depends on the volume of disease, the status of the surgical margins, and the length of delay from surgery to radiotherapy. Patients with microscopic disease have a 95% to 100% 5-year survival rate; the 5-year survival rate is 82% to 84% in those with macroscopic disease and free margins, 38% to 87% in those with microscopically positive margins, and 20% to 47% in those with obvious residual cancer (175–177). A delay in treatment of more than 6 months is associated with a 20% survival rate (177).

Acute Hemorrhage

Occasionally, a large lesion can produce life-threatening hemorrhage. A biopsy of the lesion should be performed to verify neoplasia, and a vaginal pack soaked in Monsel’s solution (ferric subsulfate) should be packed tightly against the cervix. After proper evaluation, external radiation therapy can be started with the expectation that control of bleeding may require 8 to 10 daily treatments at 180 to 200 cGy per day. Broad-spectrum antibiotics should be used to reduce the incidence of infection. If the patient becomes febrile, the pack should be removed. Rapid replacement of the pack may be necessary, and a fresh pack should be immediately available. This approach to management of hemorrhage in patients previously untreated is preferable to exploration and vascular ligation. Vascular embolization under fluoroscopic control may be required in severe cases, and this procedure may obviate a laparotomy. However, vascular occlusion ultimately may lead to decreased blood flow and oxygenation of the tumor, compromising the effectiveness of subsequent radiotherapy.

Ureteral Obstruction

Treatment of bilateral ureteral obstruction and uremia in previously untreated patients should be determined on an individual basis. Transvesical or percutaneous ureteral catheters should be placed in patients with no evidence of distant disease, and radiotherapy with curative intent should be instituted. Patients with metastatic disease beyond curative treatment fields should be presented with the options of ureteral stenting, palliative radiotherapy, and chemotherapy. With aggressive management, a median survival rate of 17 months may be achieved for these patients (178).

Barrel-Shaped Cervix

The expansion of the upper endocervix and lower uterine segment by tumor is referred to as a barrel-shaped cervix. Patients with tumors larger than 6 cm in diameter have a 17.5% central failure rate when treated with radiotherapy alone because the tumor at the periphery of the lower uterine segment is too far from the standard intracavitary source to receive an adequate tumoricidal dose(179). Attempts were made to overcome this problem radiotherapeutically by means of interstitial implants into the tumor with a perineal template, but high central failure rates were reported with this technique (180).

One approach is to use a combination of radiotherapy and surgery for treatment of patients with a barrel-shaped cervix. An extrafascial hysterectomy is performed 2 to 3 months after the completion of radiation therapy in an effort to resect a small, centrally persistent tumor. The dose of external radiotherapy is reduced to 4,000 cGy, and a single intracavitary treatment is given, which is followed by an extrafascial hysterectomy (181,182). This method appears to result in a lower rate of central failure (2%), although it is not clear that the overall survival rate is improved. There is disagreement concerning the need for extrafascial hysterectomy, and the GOG is undertaking a randomized study to compare adjuvant hysterectomy with radiotherapy alone in patients who have no evidence of occult metastases in the para-aortic nodes (see stages IB and IIA discussion).

The narrow upper vagina of older patients may preclude the use of an intracavitary source of radiation. These patients must receive their entire course of therapy from external sources, leading to a higher central failure rate and more significant bowel and bladder morbidity. If stage I disease is present in such a patient, a radical hysterectomy with pelvic lymphadenectomy is preferable, if the patient’s medical condition allows this approach. There may be a role for IMRT in the management of such tumors.

Recurrent Cervical Cancer

Treatment of recurrent cervical cancer depends on the mode of primary therapy and the site of recurrence. Patients who were treated initially with surgery should be considered for radiation therapy, and those who had radiation therapy should be considered for surgical treatment. Chemotherapy is palliative only and is reserved for patients who are not considered curable by either surgery or radiation therapy.

Radiotherapy for recurrence after surgery consists primarily of external treatment. Vaginal ovoids may be placed in patients with isolated vaginal cuff recurrences. Patients with a regional recurrence may require interstitial implantation with a Syed type of template in addition to external therapy. A 25% survival rate can be expected in patients treated with radiation for a postsurgical recurrence (162).

Radiation Retreatment

Retreatment of recurrent pelvic disease by means of radiotherapy with curative intent is confined to patients who had suboptimal or incomplete primary therapy. This may allow the radiotherapist to deliver curative doses of radiation to the tumor. The proximity of the bladder and rectum to the cancer and the relative sensitivity of these organs to radiation injury are the major deterrents to retreatment with radiation. The insertion of multiple interstitial radiation sources into locally recurrent cancer through a perineal template may help overcome these dosimetric considerations (173,183). The fistula rates are high, and those consequences must be considered before interstitial therapy is initiated. For patients considered curable with interstitial implant therapy, pelvic exenteration is a better treatment choice. Palliative radiotherapy can be given to patients with localized metastatic lesions that are deemed incurable. Painful bony metastases, central nervous system lesions, and severe urologic or vena caval obstructions are specific indications.

Surgical Therapy

Surgical therapy for postirradiation recurrence is limited to patients with central pelvic disease. A few carefully selected patients with small-volume disease limited to the cervix may be treated with an extrafascial or radical hysterectomy. However, the difficulty of assessing tumor volume and the 30% to 50% rate of serious urinary complications in these previously irradiated patients have led most gynecologic oncologists to recommend pelvic exenteration as a last chance for cure (184,185).

Exenteration

There are three types of exenterative procedures: (i) an anterior exenteration (removal of the bladder, vagina, cervix, and uterus), (ii) a posterior exenteration (removal of the rectum, vagina, cervix, and uterus), and (iii) a total exenteration (removal of both bladder and rectum with the vagina, cervix, and uterus (Fig. 36.9). A total exenteration that includes a large perineal phase includes the entire rectum and leaves the patient with a permanent colostomy and a urinary conduit (infralevator). In selected patients, a total exenteration may take place above the levator muscle (supralevator), leaving a rectal stump that may be anastomosed to the sigmoid, thus avoiding a permanent colostomy.

Preoperative Evaluation and Patient Selection

It is imperative to search for metastatic disease before undergoing an exenteration. The presence of metastatic disease in this setting is considered a contraindication to exenterative procedures.Physical examination includes careful palpation of the peripheral lymph nodes with FNA cytologic sampling of any nodes that appear suspicious. A random biopsy of nonsuspicious supraclavicular lymph nodes is advocated by some clinicians but is not routinely practiced (145,186). A PET/CT scan of the chest and abdomen and pelvis CT helps in the detection of liver metastases and enlarged nodes. Cytologic study of any abnormality should be undertaken with CT-guided FNA. If a positive cytologic diagnosis is obtained, it will obviate the need for exploratory laparotomy.

Extension of the tumor to the pelvic sidewall is a contraindication to exenteration; however, this may be difficult for even the most experienced examiner to determine because of radiation fibrosis.If any question of resectability arises, exploratory laparotomy and parametrial biopsies should be offered (187–190). The clinical triad of unilateral leg edema, sciatic pain, and ureteral obstruction is nearly always pathognomonic of unresectable disease on the pelvic sidewall. Preoperatively, the patient should be prepared for a major operation. Total parenteral nutrition may be necessary to place the patient in an anabolic state for optimal healing. A bowel preparation, preoperative antibiotic administration, and prophylaxis for deep venous thrombosis with low-dose heparin or pneumatic calf compression should be undertaken (191). Surgical mortality increases with age, and the operation should rarely be considered in a patient who is older than 70 years. Other medical illnesses should be taken into account. When life expectancy is limited, exenterative surgery is unwise.

Anterior Exenteration

Candidates for anterior exenteration are those in whom the disease is limited to the cervix and anterior portion of the upper vagina. Proctoscopic examination should be performed because a positive finding would mandate a total exenteration. However, a negative proctoscopic examination finding does not exclude disease in the rectal muscularis, and findings at laparotomy still must be considered. The presence of disease in the posterior vaginal mucosa directly over the rectum mandates removal of the underlying rectum.

Posterior Exenteration

A posterior exenteration is rarely performed for recurrent cervical cancer. It is indicated, however, for the patient with an isolated posterior vaginal recurrence in which dissection of the ureters through the cardinal ligaments will not be necessary.

Figure 36.9 Pelvic exenteration specimen.

Total Exenteration

Total exenteration with a large perineal phase is indicated when the disease extends to the lower part of the vagina (Fig. 36.9). Because distal vaginal lymphatics may empty into the nodal basins of the inguinal region, these nodes should be carefully evaluated preoperatively. A supralevator total exenteration with low rectal anastomosis is indicated in the patient whose disease is confined to the upper vagina and cervix (192,193). Samples from margins of the rectal edge should be obtained for frozen-section evaluation because occult metastases to the muscularis may occur.

The development of techniques to establish continent urinary diversion help improve a woman’s physical appearance after exenteration (194–196). When both a rectal anastomosis and a continent diversion are performed, the patient will not have a permanent external appliance. Associated psychological trauma in such cases may be avoided. Every effort should be made to create a neovagina simultaneously with the exenteration (197). This procedure helps in the reconstruction of the pelvic floor after extirpation of the pelvic viscera. Regardless of whether a neovagina is constructed, it is desirable to mobilize the omentum on the left gastroepiploic artery to create a new pelvic floor.

Surgical mortality from exenterative procedures has steadily decreased to less than 10%. Common causes of postoperative death are sepsis, pulmonary thromboembolism, and hemorrhage. Fistulas of the gastrointestinal and genitourinary tract are serious surgical complications, with a 30% to 40% mortality rate despite attempts at surgical repair. The risk for fistula formation is decreased if nonirradiated segments of bowel are used for formation of the urinary conduit (191). The 5-year survival rate is 33% to 60% for patients undergoing anterior exenteration and 20% to 46% for those undergoing total exenteration (187–197). Survival rates are worse for patients with recurrent disease (larger than 3 cm), invasion into the bladder, positive pelvic lymph nodes, and recurrence diagnosed within 1 year after radiotherapy (190). The 5-year survival rate of patients with positive pelvic lymph nodes is less than 5%; thus, the performance of an extensive lymphadenectomy in the irradiated field is not warranted. Discontinuation of the procedure is advisable if any nodes are positive for metastatic cancer. Patients who have any disease in the peritoneal cavity have no chance of survival.

Laterally Extended Endopelvic Resection

Locally recurrent cervical cancer in a previously irradiated field is associated with a dismal prognosis. Exenterative therapy traditionally was reserved for the highly select patient with centrally recurrent disease, a selection criteria that excludes most patients with recurrence. A technique called the laterally extended endopelvic resection (LEER) procedure was described, which offers a surgical treatment option for patients with recurrent disease involving the pelvic sidewall. The LEER procedure involves extending the lateral resection plane of the traditional pelvic exenteration to include resection of the internal iliac vessels; the endopelvic portion of the obturator internus muscle; and the coccygeus, iliococcygeus, and pubococcygeus muscles. Extension of the surgical plane allows for resection of lateral tumors with a negative margin. Experience with it is limited to one center, which reports as high as a 62% recurrence-free survival, but as high as 70% moderate to severe morbidity (198).

Chemotherapy for Recurrent Cervical Cancer

Recurrent cervical cancer is not considered curable with chemotherapy. The delivery of chemotherapy to recurrent tumor in a prior radiated field may be compromised because of altered blood supply caused by radiation. Topotecan and cisplatin had response rates of 15% to 20%, with a median duration of 6 to 9 months (199). Many other agents showed activity against cervical cancer and may be used in attempt to help control symptoms. Several clinical trials with various drugs (e.g., paclitaxel, topotecan, cisplatin, and carboplatin) showed response rates of up to 45%. Most responses are partial; complete responses are unusual and limited to patients with chest metastases in whom the dose of drug delivered to the disease is stronger than that delivered to the fibrotic postirradiated pelvis (200,201). Doublet therapy with cisplatin and paclitaxel is considered standard therapy based on GOG 204, which analyzed four cisplatin-containing doublets for the best efficacy; although no major differences existed in overall survival for the four doublets, the cisplatin and paclitaxel doublet trended toward the best results (153). Other studies showed comparable survival and less toxicity with carboplatin and paclitaxel (154).

Palliative Therapy

Palliative therapy for patients with incurable disease consists of radiation or chemotherapy or both. Palliative radiation therapy is intended to relieve symptoms of pain or bleeding associated with advanced disease and may be administered as either external beam therapy (teletherapy) or brachytherapy. Special care should be given to previously irradiated sites because additional radiation therapy may be associated with unacceptable morbidity. Single or multiagent palliative chemotherapy may be used with variable response rates. Symptomatic recurrent disease within previously irradiated fields may not respond well to palliative chemotherapy.

Vaginal Carcinoma

Primary vaginal cancer is a relatively uncommon tumor, representing only 2% to 3% of malignant neoplasms of the female genital tract. In the United States it is estimated that there were 2,160 new cases in 2009, and 770 deaths from the disease (1). Squamous histology accounts for 80% (202). Primary vaginal cancer should be differentiated from cancers metastatic to the vagina, which constitute the majority of cancers found in the vagina (84%) (203).

Staging

The FIGO staging of vaginal cancer dictates that a tumor extending to the vagina from the cervix be regarded as a cancer of the cervix, whereas a tumor involving both the vulva and the vagina should be classified as a cancer of the vulva.

The FIGO staging for vaginal carcinoma is shown in Table 36.6. Staging is performed by clinical examination and, if indicated, cystoscopy, proctoscopy, and chest and skeletal radiography. Information derived from lymphangiography, CT, MRI, or PET cannot be used to change the FIGO stage; however, it can be used for planning treatment. Less than 30% of vaginal cancers present at stage I (204–206).

Table 36.6 FIGO Staging of Vaginal Cancer

Stage I	The carcinoma is limited to the vaginal wall.
Stage II	The carcinoma has involved the subvaginal tissue but has not extended to the pelvic wall.
Stage III	The carcinoma has extended to the pelvic wall.
Stage IV	The carcinoma has extended beyond the true pelvis or has involved the mucosa of the bladder or rectum; bullous edema as such does not permit a case to be allotted to Stage IV
IVA	Tumor invades bladder and/or rectal mucosa and/or direct extension beyond the true pelvis
IVB	Spread to distant organs.
FIGO, International Federation of Gynecology and Obstetrics.From FIGO Annual Report. Int J Gynecol Obstet 2006;95:S29 and Int J Gynecol Obstet 2009;105:3–4.

Surgical staging and resection of enlarged lymph nodes may be indicated in selected patients. FIGO staging does not include a category for microinvasive disease. Because vaginal cancer is rare and treatment is by radiotherapy, there is very little information concerning the spread of disease in relation to depth of invasion, lymph–vascular space invasion, and size of the lesion.

Etiology

The association of cervical cancer with HPV suggests that vaginal cancer may have a similar association (207). A study of 341 cases revealed that in younger patients the disease seemed to be related to HPV infection, while in older patients there was no association (206). In addition, as many as 30% of women with vaginal cancer have a history of cervical cancer treated within the previous 5 years (208–210). As with cervical cancer, there appears to be a premalignant phase called vaginal intraepithelial neoplasia (VAIN) (see Chapter 19). The exact incidence of progression to invasive vaginal cancer from VAIN is not known; however, there are documented cases of invasive disease occurring despite adequate treatment of VAIN (211,212).

By convention, any new vaginal carcinoma developing at least 5 years after cervical cancer is considered a new primary lesion. There are three possible mechanisms for the occurrence of vaginal cancer after cervical neoplasia:

1. Residual disease in the vaginal epithelium after treatment of the cervical neoplasia

2. New primary disease arising in a patient with increased susceptibility to lower genital tract carcinogenesis (the role of HPV in this setting is suspected)

3. Increased susceptibility to carcinogenesis caused by radiation therapy

Screening

Routine screening of all patients for vaginal cancer is inappropriate. For women who had a cervical or vulvar neoplasm, the Pap test is an important part of routine follow-up with each physician visit, because these patients are at an increased lifetime risk for developing vaginal cancer. It is recommended that Pap test surveillance for vaginal cancer be performed yearly after the patient has completed surveillance for cancer of the cervix or vulva. For women who had a hysterectomy for benign disease and have no antecedent history of CIN 2–3, performance of Pap testing is unnecessary. If the patient has a history of cervical dysplasia or cervical cancer, yearly screening is recommended. When adjusted for age and prior cervical disease, the incidence of vaginal cancer is not increased in women who had hysterectomy for benign disease (213). Because primary vaginal tumors tend to be multicentric, the entire vaginal mucosa should be considered at risk. Therefore, in addition to screening cytology, careful bimanual examination of the entire vagina and vulva is recommended for women at high risk.

Symptoms

Painless vaginal bleeding and discharge are the most common symptoms of vaginal cancer. With more advanced tumors, urinary retention, bladder spasm, hematuria, and frequency of urination may occur. In a large series, 14% were asymptomatic and diagnosis was made by routine examination or abnormal cytology (206). Tumors developing on the posterior vaginal wall may produce rectal symptoms, such as tenesmus, constipation, or blood in the stool.

Diagnosis

The diagnostic workup includes a complete history and physical examination, careful speculum examination and palpation of the vagina, and bimanual pelvic and rectal examinations. It is important to rotate the speculum to obtain a careful view of the entire vagina because posterior wall lesions frequently occur and may be overlooked.

In early squamous cell lesions, the diagnosis is often suggested by an abnormal Pap test result; however, this is not true for clear cell adenocarcinomas, which are characterized by submucosal growth. In these cases, the diagnosis is suggested by cytologic findings in only 33% of cases. Visually suspicious areas in the vagina should be evaluated with a targeted biopsy using the same instruments as those used for cervical biopsies. Careful palpation of the vagina may be helpful in detecting submucosal irregularities. The most common site of vaginal cancer is in the upper one-third of the vagina on the posterior wall. The developing tumor may be missed during initial inspection because of obscured visualization caused by the blades of the speculum (214). Colposcopy is valuable in evaluating patients with abnormal Pap test results, unexplained vaginal bleeding, or ulcerated erythematous patches in the upper vagina. A colposcopically targeted biopsy may not allow a definitive diagnosis, and a partial vaginectomy may be necessary to determine invasion. Occult invasive carcinoma may be detected by such an excision, particularly in patients who have a history of prior hysterectomy in whom the vaginal vault closure may bury some of the vaginal epithelium at risk for cancer (215).

Pathology

Cancer of the vagina spreads most often by direct extension into the pelvic soft tissues and adjacent organs. Metastases to the pelvic and para-aortic lymph nodes may occur in advanced disease. Lesions in the lower one-third of the vagina may spread directly to the inguinal femoral lymph nodes and the pelvic nodes (216). Hematogenous dissemination to the lungs, liver, or bone may occur as a late phenomenon.

Squamous cell carcinomas are the most common form of vaginal cancer, occurring in 80% to 90% of cases. These tumors most commonly occur in the upper one-third, posterior wall of the vagina. The mean age of patients with squamous cell cancer is 60 years (217,218). Malignant melanoma is the second most common cancer of the vagina, accounting for 2.8% to 5% of all vaginal neoplasms (219–221). Other histologic subtypes include adenocarcinoma and sarcoma.

Primary adenocarcinoma of the vagina is rare, constituting 9% of primary tumors of the vagina. The most common adenocarcinoma of the vagina is metastatic, originating from the colon, endometrium, ovary, or, rarely, pancreas and stomach. In general, adenocarcinomas affect a younger population of women, regardless of whether they were exposed to diethylstilbestrol (DES) in utero(222). Adenocarcinomas may arise in wolffian rest elements, periurethral glands, and foci of endometriosis (223). In women exposed to DES in utero, adenocarcinoma may develop in vaginal adenosis.

Figure 36.10 Vaginal clear cell carcinoma. Note the formation of tubules with hobnail cells lining the lumen. These cells are characterized by nuclear protrusion into the apical cytoplasm.

DES was used in the United States from 1940 until 1971 to maintain high-risk pregnancies in women with a history of spontaneous abortions. In 1970, seven young women were reported with clear cell adenocarcinoma of the vagina (Fig. 36.10); later, an association between this cancer and maternal ingestion of DES during pregnancy was identified (224). Subsequently, more than 500 cases of clear cell cancer of the vagina and cervix were reported to the Registry for Research on Hormonal Transplacental Carcinogenesis.

The estimated risk for developing clear cell adenocarcinoma for an exposed offspring is 1 in 1,000 or less. The mean age of diagnosis is 19 years (225). Clear cell adenocarcinoma in women with a history of in utero exposure to DES typically presents in the exocervix or anterior, upper one-third of the vagina. These tumors vary greatly in size and are most frequently exophytic and superficially invasive. Stage is the most important prognostic factor. Other statistically significant factors include a tubulocystic growth pattern, size less than 3 cm², and less than 3 mm of stromal invasion. Because the use of DESin pregnant women was discontinued in 1971, most of these tumors probably have been discovered. It is uncertain, however, what will happen to this cohort of women as they move into their fifth, sixth, and seventh decades of life. Continued surveillance of these women is indicated.

Ninety-seven percent of cases of vaginal clear cell adenocarcinoma are associated with adenosis. Adenosis is characterized by the presence of persistent müllerian-type glandular epithelium. Although adenosis is the most common histologic abnormality in women exposed to DES in utero, adenosis can be found in women without a history of exposure. Adenosis typically appears as red, grapelike clusters in the vagina.

Malignant melanoma of the vagina is rare and lethal, occurring most often in white women. The average age of these patients is 58 years (226). Most lesions are deeply invasive, corresponding to a Clark level IV when compared with the staging for vulvar melanomas. The most common location of these tumors is in the lower one-third of the vagina (227). Melanomas have a wide variety of size, color, and growth patterns (225,228). Radical excision (vaginectomy, hysterectomy, and pelvic lymphadenectomy) is the mainstay of treatment. The goal of treatment is to avoid local (vaginal) recurrence, which is the most common site of recurrence (226,227). The need to dissect regional lymph nodes is uncertain. Because the disease is deeply invasive, hematogenous spread is the most common lethal recurrence. There is no difference in overall survival of patients with local as opposed to radical excision (226). The survival rate is approximately 10% at 5 years.

The most common benign and malignant mesenchymal tumors of the vagina in adult women are smooth muscle tumors (229). Vaginal sarcomas are usually fibrosarcomas or leiomyosarcomas and are extremely rare. Radical local excision, followed by adjuvant chemotherapy or radiation therapy, is the indicated treatment.

Figure 36.11 Embryonal rhabdomyosarcoma of the vagina (botryoid sarcoma). This lesion consists of primitive mesenchymal cells and rhabdomyoblasts, which have abundant eosinophilic cytoplasm. With further differentiation, cross striations may become evident.

The most common malignant mesenchymal tumor of the vagina in children and infants is botryoid rhabdomyosarcoma (Fig. 36.11). Botryoid sarcoma is usually found in the vagina during infancy and early childhood, in the cervix during the reproductive years, and in the corpus uteri during postmenopausal years. Preoperative chemotherapy with vincristine, actinomycin D, and cyclophosphamide, followed by conservative surgery or radiation, has improved survival.

Treatment

Treatment selection is based on the clinical examination, CT scan results, chest radiography results, age, and condition of the patient. PET scans may give more accurate information about disease spread than MRI or CT scan alone (230). Most tumors are treated by radiation therapy. Surgery is limited to selected cases. These are as follows:

1. Women with stage I disease involving the upper posterior vagina may be treated by radical vaginectomy and pelvic lymphadenectomy. If the uterus is in situ, it is removed as a radical hysterectomy specimen. When margins are clear and lymph nodes are negative, no additional therapy is necessary.

2. Patients with stage IV disease with either rectovaginal or vesicovaginal fistula may be candidates for primary pelvic exenteration with pelvic and para-aortic lymphadenectomy (225). Low rectal anastomosis, continent urinary diversion, and vaginal reconstruction are indicated and are more successful in these nonirradiated patients than in patients who received prior radiation therapy.

3. Women with central pelvic recurrence after radiation therapy are candidates for pelvic exenteration similar to that used for cervical cancer.

4. Surgical staging with resection of enlarged lymph nodes followed by radiation therapy may improve the control of pelvic disease.

Radiation therapy is the treatment of choice for all patients except those described previously. Small superficial lesions may be treated with intracavitary radiation alone (225). Larger, thicker lesions should be treated first with external teletherapy to decrease tumor volume and to treat the regional pelvic nodes, followed by intracavitary and interstitial therapy to deliver a high dose to the primary tumor (218,226). If the uterus is intact and the lesion involves the upper vagina, an intrauterine tandem and ovoids can be used. If the uterus was previously removed, a vaginal cylinder may be used for superficial irradiation. When brachytherapy is used, high- and low-dose rate techniques were described. If the lesion is more than 0.5 cm thick, interstitial radiation techniques can improve the dose distribution to the primary tumor. Surgical exploration or laparoscopy at the time of insertion of Syed interstitial implants defines more precisely the placement of the needles and ensures that needles do not pass into adherent loops of bowel. Extended-field radiation may be used for vaginal cancer in a manner similar to its use for cervical carcinoma, although there is no experience reported with the use of this technique in the treatment of vaginal cancer. Likewise, there is little reported experience with combination chemoradiation treatment (231). Although there will never be enough patients for a proper randomized control trial, concurrent use of 5-FU and cisplatin was highly successful in anal and cervical cancer and thus should be considered for treatment of vaginal cancer.

Sequelae

The proximity of the rectum, bladder, and urethra leads to a major complication rate of 10% to 15% for both surgery and radiation treatment. For large tumors, the risk of bladder or bowel fistula is significant. Radiation cystitis and proctitis are common, as are rectal strictures or ulcerations. Radiation necrosis of the vagina occasionally occurs, requiring debridement, and often leads to fistula formation. Vaginal fibrosis, stenosis, and stricture are common after radiation therapy. Use of vaginal dilators and resumption of regular sexual relations should be encouraged, along with the use of topical estrogen to maintain adequate vaginal function.

Survival

The overall 5-year survival rate for patients with vaginal cancer is 52% (Table 36.7). This reflects the difficulties of treatment and the fact the disease presents at late stage. For patients with stage I disease, the 5-year survival rate is 74%. Most recurrences are in the pelvis, either from enlarged regional nodes or from large central tumors. Radiation techniques, including interstitial implants with Syed applicator and combination chemoradiation, are the mainstay of therapy. Careful evaluation of patients who receive radiation therapy to detect central recurrence may allow some patients to be saved by pelvic exenteration. Because of the rarity of vaginal cancer, these patients should be treated in a center that is familiar with the complexity of treatment and modalities of therapy.

Table 36.7 Primary Vaginal Carcinoma: 5-Year Survival

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