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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 112Neoplasms of the Cervix

, MD and , MD, PhD.

Cervical cancer is the third most common cancer among women worldwide, preceded only by breast and colorectal cancer. Approximately 371,200 new cases of cervical cancer occur every year, accounting for approximately 10% of all cancers in women.1 In the United States, cervical cancer is the third most common neoplasm of the female genital tract. In 1999, 12,800 cases of invasive cervical cancer were expected to be diagnosed among U.S. women, and approximately 4,800 women were expected to die from this neoplasm.2

Epidemiology

Incidence and Mortality

Incidence and mortality rates reported worldwide for cervical cancer show a wide geographic variation, including a 21-fold difference between the highest and the lowest age-standardized incidence rate. Higher incidence and mortality rates are reported in developing countries, where approximately 80% of all cervical cancer cases occur. Higher rates are reported in Latin America and the Caribbean, whereas lower rates are reported in Israel, Kuwait, Finland, Spain, China, and Canada (British Columbia) and in Caucasians in the United States.3

In the last 40 years, primarily because of the introduction of screening with the Pap smear, incidence and mortality rates for cervical cancer have declined in most developed countries.4 In the United States, incidence rates have declined by approximately 70% during this period. A larger decline has been observed among women aged 50 and older (50.5%) than among younger women (36.4%) and among African-American (60.2%) than Caucasian women (44.5%).5 In developing countries, however, cervical cancer continues to be a significant health problem in women because of the lack of effective screening programs and treatment for precancerous conditions. Furthermore, the decline in incidence and mortality observed in the United States and other developed countries since the mid-1980s seems to be leveling off or reversing.6

There are no reliable data on the prevalence and incidence of precancerous cervical lesions. The American Cancer Society estimated in 1995 that 65,000 new cases of carcinoma in situ (CIS) of the cervix are diagnosed annually among U.S. women; the American College of Obstetricians and Gynecologists estimates that 250,000 to 1 million new cases of cervical intraepithelial neoplasia (CIN) are diagnosed in the United States annually.7,8 The National Breast and Cervical Cancer Early Detection Program has reported that between 1991 and 1997 more than 26,000 (3.05%) cases of precancerous conditions were detected in 851,818 Pap smears of underserved women.9

In the United States, the annual age-adjusted (1970 U.S. standard population) incidence rate for invasive cervical cancer for 1992 to 1996 was 7.9 per 100,000 women.5 Incidence rates are three times higher among women age 50 years and older (15.8 per 100,000) than among younger women (5.3 per 100,000).5 A large racial-ethnic variation in incidence rates is observed in the U.S. population. The highest age-adjusted incidence rates are reported among Vietnamese women (43 per 100,000), followed by Hispanic (16.2 per 100,000), native Alaskan (15.8 per 100,000), Korean (15.2 per 100,000), and African-American (13.2 per 100,000) women. Intermediate rates are observed among American-Indian, Filipino, and Hawaiian women (9.9, 9.6, and 9.3 per 100,000, respectively). The lowest rates have been reported in Japanese and non-Hispanic Caucasian women (5.8 and 7.5 per 100,000, respectively).10 This racial/ethnic variation is poorly understood, but such barriers as cultural characteristics, a primary language other than English, and inadequate access to screening and medical care may explain these differences in part.

The age-adjusted (1970 U.S. standard population) mortality from cervical cancer in the United States from 1992 to 1996 was 2.8 per 100,000 women.5 Mortality rates were more than six-fold higher among women age 50 years and older (7.6 per 100,000) than among younger women (1.2 per 100,000).5 Mortality is about 2.5-fold higher in African-American women (5.9 per 1000,000), intermediate among American-Indian (3.6 per 100,000) and Hispanic (3.5 per 100,000) women (2.4 per 100,000), and lowest among Caucasian women.

The overall 5-year relative survival rate has remained constant in the last 20 years (1974–1995).5 The overall 5-year relative survival rate for 1989–1995 in the United States was approximately 70%. Survival rates are higher for Caucasian and younger women (80.5% among Caucasian women under 50 years of age compared with 53.1% among African-American women age 50 years and older). Similarly, a higher survival rate is observed among women with an early diagnosis (91.3%) than among women with advanced disease at diagnosis (12.6%).5

Risk Factors for Cervical Neoplasia

Human Papillomavirus and Other Sexually Transmitted Agents

Epidemiologic evidence has long suggested a sexually transmitted etiology for cervical neoplasia. Supporting this hypothesis, several measures of sexual behavior (such as multiple sexual partners, early age at first sexual intercourse, and sexual habits of male partners) have been consistently associated with an increased risk for cervical neoplasia.11 Over the years, several sexually transmitted infectious agents have been the focus of research, including herpes simplex virus type 2 (HSV-2), Chlamydia trachomatis, Trichomonas vaginalis, cytomegalovirus, Neisseria gonorrhoeae, and Treponema pallidum.11,12 In the mid-1970s, the hypothesis of a causal relationship between human papillomavirus (HPV) and cervical neoplasia was first proposed.13 Since then, a large body of experimental, clinical, and epidemiologic research has accumulated supporting an etiologic role for some types of HPV.14

Of more than 78 types of HPV that have been described, more than 35 are associated with anogenital disease, and 30 or more are associated with cancer.15 In an international study, HPV DNA was detected in 93% (range, 75%–100%) of cancer specimens collected in 22 countries and analyzed by the polymerase chain reaction (PCR) technique.16 Similarly, HPV DNA has been detected by PCR in up to 94% of women with preinvasive lesions (CIN) and in up to 46% of women with cytologically normal tissue.14,17

HPV types classified as intermediate- and high-risk types have been identified in about 77% of high-grade squamous intraepithelial lesions (HGSILs) (CIN 2 and 3) and in 84% of invasive lesions.18 In the series studied by Bosch and colleagues, HPV types 16, 18, 31, and 45 were detected in approximately 80% of the cases.16 HPV 16 is by far the most prevalent HPV type, present in up to 50% of HGSILs and invasive lesions,14,16 and it is the most common HPV type identified in cytologically normal women.18

The association between cervical neoplasia and HPV is independent of study population, study design, and HPV detection method.14,17,19 Higher risk has been associated with specific HPV types (16, 18, 31, 33, 35, and 45), increasing viral load, and concurrent infection with multiple HPV types.20–24 An increased risk for high-grade CIN ranging from 16- to 122-fold has been reported among women whose test results were positive for HPV of any type. The number of cases of these lesions attributed to HPV has been estimated to range from 60 to 92%.17 In addition, adjustment for HPV status appears to account for most of the associations between cervical neoplasia and number of sexual partners and other characteristics of sexual behavior.17,23,25

Although a strong and consistent association between HPV and cervical neoplasia has been clearly established, the discrepancy between HPV prevalence and the incidence of cervical neoplasia suggests that other cofactors are necessary for the development and progression of the disease. The role of sexual and reproductive history, smoking habits, and hormonal and dietary factors, as well as their interaction with HPV, has been assessed in recent studies. Future research will need to assess the effect of recent trends on these factors and their impact on the occurrence of cervical neoplasia.11

Numerous studies have addressed the association between human immunodeficiency virus (HIV) and cervical neoplasia.12 The Centers for Disease Control added invasive cervical cancer to the list of acquired immunodeficiency syndrome (AIDS)-related conditions in 1993.26 HIV-positive women have been reported to have higher rates of cervical abnormalities, larger lesions, higher grades of lesions, and higher recurrence rates than HIV-negative women do. In addition, HIV-positive women have been reported to have higher HPV prevalence and HPV persistence rates than HIV-negative women do. A meta-analysis by Mandelblatt and colleagues27 concluded that HIV is a cofactor in the association between HPV and cervical neoplasia, and this association seems to vary with the level of immune function. Results from Ruche and colleagues28 in Africa support the theory of interaction between HIV-1 and HPV. Although the biologic mechanism for this interaction is not as well understood, it could be explained by the effect of HIV infection on the immune system or by the existence of a molecular interaction between HIV and HPV. Studies are needed to confirm these observations and to assess the role of viral factors for both HPV and HIV.

HSV was the focus of intensive study during the 1960s and 1970s. Serologic studies showed a higher prevalence of HSV-2 antibodies among women with cervical neoplasia than among controls. Two potential mechanisms of action have been suggested: a “hit-and-run” effect and a synergistic effect between HSV-2 and HPV.29 A statistically significant interaction between HSV-2 and HPV 16/18 was detected by Hildesheim and colleagues30 and Baldauf and colleagues31; however, several recent studies continue to provide conflicting evidence.19,27,32–37

An association between the presence of antibodies for Chlamydia trachomatis and cervical neoplasia persisting after controlling for HPV status and other potential factors has been reported.19,32,34,35 However, others have failed to show an association with Chlamydia trachomatis using antibody determinations33,37 or other measures of exposure such as a self-reported history of Chlamydia trachomatis infection,36 culture for Chlamydia trachomatis,19,34,38 and PCR detection of Chlamydia trachomatis.39

Cytomegalovirus has been suspected as a risk factor for cervical neoplasia in previous studies. Higher levels of antibodies to cytomegalovirus have been reported among women with cervical neoplasia than among controls; however, some other studies have failed to identify an increased risk for cervical neoplasia.11 The evidence remains conflicting and the role of cytomegalovirus as an etiologic factor or cofactor is unclear.19,34,35,37,40,41 Inconclusive evidence for other genital infectious agents, including Trichomonas vaginalis, Epstein-Barr virus, hepatitis B and C virus, Neisseria gonorrhoeae, Gardnerella vaginalis, and Treponema pallidum have been reported.12

Sexual Behavior

Although previous studies report a strong and consistent association between cervical neoplasia and some characteristics of sexual behavior of women and their male sexual partners,11 other studies, in which HPV infection has been accounted for, have found an association of less strength.23,42 The decrease in the magnitude of these associations after controlling for HPV status support the notion that characteristics of sexual behavior may be only a proxy measurement of HPV infection and/or other sexually transmitted infectious agents causally related to cervical neoplasia.

After controlling for HPV infection and other risk factors, the association with number of sexual partners has been of lower magnitude for preinvasive lesions than for invasive lesions. In most studies of preinvasive disease, the effect of the number of sexual partners is substantially reduced after adjustment for HPV.19,22,23,43,44 But in studies of invasive lesions, the association with the number of sexual partners remained statistically significant45,46 or on the borderline.47 Furthermore, no association is observed between number of sexual partners and cervical neoplasia among HPV-positive women, whereas a positive association remains among HPV-negative women.19,23,43,4648 Misclassification of HPV status, the effect of unmeasured cofactors, or a different etiology for the disease among HPV-negative women could explain the latter finding.

The role of age at first sexual intercourse has been less consistent. After controlling for HPV and other risk factors, a statistically significant association between age at first sexual intercourse and cervical neoplasia has remained in some studies,46,48 but in others, no association has been observed.19,20,23,25,36,43-45 The association between cervical neoplasia and early age at sexual intercourse may indicate a period of higher susceptibility of the cervical tissue, a higher likelihood of exposure, or a longer period of exposure to carcinogenic factors. Whatever the association, establishing age at first sexual intercourse as an independent effect is difficult because of its high correlation with number of sexual partners.

Considering male sexual partners, a reservoir of sexually transmitted factors causally related to cervical neoplasia has also been suggested.49 Males’ large number of sexual partners and frequent contact with prostitutes could explain high rates of cervical cancer in developing countries in which women are traditionally monogamous or have few sexual partners. Penile HPV DNA prevalence is higher in husbands of women with cervical neoplasia than in husbands of women without cervical neoplasia.17 Among men, the prevalence of HPV has been associated with number of sexual partners and use of prostitutes.50 In addition, higher HPV prevalence has been reported among males in geographic areas with higher rates of cervical cancer incidence than in geographic areas with lower rates, which supports the role of male partners in cervical carcinogenesis in their female sex partners.50

Reproductive Factors

No consistent relationships have been established between cervical neoplasia and menstrual and reproductive characteristics, including age at menarche or menopause; parity; number of spontaneous or induced abortions; age at first pregnancy, first live birth, or last birth; and number of vaginal deliveries or cesarean sections. An association between parity or number of live births and cervical neoplasia has been reported in six case-control studies after controlling for HPV status.23,25,43,45,47,48 However, no association was found for preinvasive lesions by Becker and colleagues44 and Olsen and colleagues47 or for invasive cancer by Bosch and colleagues.22 In Denmark, women who had had two or more pregnancies were found to have approximately 80% higher risk of CIS compared with nulliparous women. Schiffman and colleagues43 observed a three-fold increased risk of CIN among women with four or more live births than among nulliparous women. Muñoz and colleagues48 found a two-fold increased risk for CIN 3 associated with high parity (six or more pregnancies) in Colombian women but not in Spanish women. Eluf-Neto and colleagues42 in Brazil and Herrero and colleagues45 observed five-fold (among women with ≥10 pregnancies) and two-fold (among women with ≥12 live births) increased risks for invasive cancer.

Interesting is the finding of a strong association between invasive cervical cancer and early age at first birth, reported by Bosch and colleagues,22 coupled with the absence of an association with parity. The parity association appears to be independent of early age at sexual intercourse, HPV status, additional childbearing after age 22 years, and other potential confounding factors. Similarly interesting is the 70% increased risk of high-grade dysplasia (CIN 2 and 3) among women with one or more vaginal deliveries reported by Becker and colleagues,44 an association that also persisted after adjustment for HPV status, ethnicity, and other sexual and reproductive characteristics. Although there is no clear biologic mechanism to support this association, repeated trauma to the cervix during childbirth has been suggested.

Smoking Habits

Several epidemiologic studies have provided evidence supporting an association between cigarette smoking and cervical neoplasia. Most studies have shown a two-fold increased risk among smokers and a dose-response relationship with duration and intensity of smoking.51 In most early studies, confounding was controlled by adjusting for sexual behavior characteristics, particularly lifetime number of sexual partners, as a proxy measure of the sexually transmitted pathogen causally linked with the disease.

Therefore, it is suggested that residual confounding, particularly in populations in which cigarette smoking and sexual behavior are highly correlated, was responsible for the observed association.52 Results from most recent studies controlling for HPV status have been inconsistent. Some support an independent effect,48,53–59 whereas others do not.19,20,23,2536,43,45,46,60 Although a possible interaction between HPV and smoking has been proposed,29 few studies have examined this joint effect. Results from these studies have also been inconsistent.43,45,47,5356,58,61

In addition to the epidemiologic research, several studies have provided biologic plausibility to this association. Reports have been published of high levels of nicotine and cotinine and tobacco-specific N-nitrosamines in the cervical mucus of active and passive smokers, DNA damage in cervical tissue and exfoliated cells of women smokers, and impairment of the local cell-mediated immune response in smokers. Furthermore, reduction of lesion size has been documented among women participating in a smoking cessation intervention.63 In summary, although the mechanism of carcinogenesis of smoking in cervical tissue is not fully understood, current biologic, epidemiologic, and clinical studies suggest that cigarette smoking may be a risk factor for cervical neoplasia.

Oral Contraceptives

The role of oral contraceptives in cervical neoplasia development remains unclear, despite evidence in support of a biologic mechanism. Early studies showed a weak but statistically significant association, particularly for long-term users.64 Interpretation of the results, however, is confounded by the correlation between oral contraceptive use, sexual behavior, and patterns of screening for cervical neoplasia; potential surveillance bias; selection of comparison groups; and lack of control for HPV in earlier studies.64

Results from epidemiologic studies in which control for HPV status has been attained are conflicting.19,20,23,2536,43,44,46-48 Most of these studies failed to show an association between cervical neoplasia and different measures of oral contraceptive exposure.19,20,23,2543,46,48,64 An interaction between oral contraceptive use and HPV infection has been suggested; however, epidemiologic evidence of interaction is also conflicting.43,46,47,64,65 The analysis of an interaction effect is based on a very small number of cases, and results need to be interpreted with caution.

Dietary Factors

Several lines of evidence suggest that some nutrients may have a protective effect against cervical neoplasia, particularly vitamin A, carotenoids, vitamin C, vitamin E, and folic acid. The association between vitamin A intake and cervical neoplasia is hypothesized, based on the relationship of vitamin A and other epithelial tumors, mainly squamous cell carcinomas. Vitamin A is capable of reversing metaplastic changes in bronchial epithelium, providing a biologic basis for the association with cervical neoplasia.66 Vitamin C plays a role in the maintenance and protection of the normal epithelium against carcinogens. Folic acid functions as a coenzyme in the metabolism of single-carbon compounds, such as nucleic acid synthesis and amino acid metabolism. 66 It has been hypothesized that a subclinical folate deficiency may act as a cofactor in the integration of the HPV genome into host DNA.67

Despite these findings, epidemiologic studies on the association of vitamin A, carotenoids, vitamin C, and folic acid with cervical neoplasia have provided conflicting results.11,68 Different methods of nutrient measurement, variation in selection of case and comparison groups, and differences in control of confounding factors make the comparison of these studies difficult. In addition, the correlation between nutrients makes the interpretation of the results a difficult task. In some studies, in which control of confounding factors has been better, findings of the association between dietary or serum/plasma levels of nutrients and cervical neoplasia remain inconclusive.69–77 An interaction between red blood cell folate levels with HPV 16-positive status, cigarette smoking, and parity has been suggested.67 This interaction is consistent with current knowledge on the role of folate in carcinogenesis.

Summary

Cervical neoplasia continues to be a major health problem worldwide. Higher incidence and mortality rates are observed in developing countries. Among more developed countries, a significant decline in incidence and mortality has been observed in the last 40 years, which has been attributed to the introduction of screening programs. Current epidemiologic data support a strong role for HPV infection in the etiology of cervical neoplasia. This association satisfies all criteria for causality in epidemiologic research: strength, consistency, and specificity of the association, dose-response and temporal relationship, and biologic plausibility.17 HPV infection appears to explain many of the established risk factors for cervical neoplasia, including sexual behavior and cigarette smoking. Nonetheless, the high prevalence of HPV infection in young healthy women compared with the low incidence of cervical neoplasia and the low progression rate of untreated CIN lesions supports the existence of other cofactors in cervical carcinogenesis.78 Future epidemiologic studies will need to further assess the role of these cofactors and their interaction with HPV. In addition, the role of viral factors such as HPV persistence and HPV variants in the progression of cervical neoplasia as well as of the determinant factors of HPV persistence will require further evaluation.79 Similarly, the impact of recent trends in such environmental factors as smoking, exogenous hormones, and dietary factors deserves further attention.11

Histologic Classification of Epithelial Tumors

The histologic classification of epithelial tumors of the uterine cervix by the World Health Organization (WHO) separates them into three main groups: squamous cell carcinomas, adenocarcinomas, and other epithelial tumors (Table 112.1).80,81 The majority of cervical carcinomas are squamous cell carcinomas that are classified as either large cell nonkeratinizing or large cell keratinizing. The nonkeratinizing carcinoma is characterized by squamous cells with somewhat hyperchromatic nuclei and a moderate amount of cytoplasm growing in discrete nests separated by stroma (Fig. 112.1). In the center of some of the nests, the squamous cells appear to differentiate and degenerate. The second type, the keratinizing carcinoma, cells with very hyperchromatic nuclei and densely eosinophilic cytoplasm, grow in irregular invasive nests, and many of these nests have central “pearls” that contain abundant keratin. The average age of patients with squamous cell carcinoma is 51.4 years.

Table 112.1. Modification of the World Health Organization’s Histologic Classification of Epithelial Tumors of the Uterine Cervix.

Table 112.1

Modification of the World Health Organization’s Histologic Classification of Epithelial Tumors of the Uterine Cervix.

Figure 112.1. Squamous cell carcinoma, nonkeratinizing.

Figure 112.1

Squamous cell carcinoma, nonkeratinizing.

Adenocarcinomas represent 20 to 25% of cervical carcinomas today, whereas from 1950 to 1960 they represented 5%.82 This change in prevalence is a worldwide phenomenon.83 The mean age for patients with invasive adenocarcinoma is between 47 and 53 years. Mucinous adenocarcinoma is the most common type of cervical adenocarcinoma.84,85 In the classification, the first type is composed of cells that resemble the columnar cells of the normal endocervical mucosa and is referred to as the endocervical type (Fig. 112.2). The second type is termed the intestinal type because it is composed of cells similar to those present in adenocarcinomas of the large intestine. A third type is composed of signet-ring cells and designated as the signet-ring type (Fig. 112.3). Frequently, the mucinous adenocarcinoma is a mixture of these cell types.

Figure 112.2. Mucinous adenocarcinoma, endocervical type.

Figure 112.2

Mucinous adenocarcinoma, endocervical type.

Figure 112.3. Mucinous adenocarcinoma, signet-ring type.

Figure 112.3

Mucinous adenocarcinoma, signet-ring type.

Endometrioid adenocarcinoma is the second most common type of endocervical primary tumor, accounting for 30% of all endocervical primary tumors. These endocervical tumors resemble typical endometrioid adenocarcinoma arising from the endometrial cavity (Fig. 112.4). Identification of the site of origin (i.e., whether the primary tumor is in the endocervix or endometrium) may be difficult, but proper identification significantly influences therapy.

Figure 112.4. Endometrioid adenocarcinoma.

Figure 112.4

Endometrioid adenocarcinoma.

Clear cell adenocarcinomas account for 4 to 11% of endocervical primary tumors.85,86 This cancer is composed of clear or hobnail cells arranged in solid, papillary, or tubulocystic patterns or a combination of these patterns (Fig. 112.5). Young women who develop these carcinomas may have a history of prenatal exposure to diethylstilbestrol. Carcinomas of this type occurring in older women with no history of exposure to diethylstilbestrol are histologically identical to the cancers that occur in younger women. The disease follows a clinical course similar to that of other cervical adenocarcinomas.

Figure 112.5. Clear cell adenocarcinoma.

Figure 112.5

Clear cell adenocarcinoma.

The category designated other epithelial tumors includes mixed squamous cell carcinomas and adenocarcinomas. Adenosquamous carcinomas are defined as tumors that contain an admixture of histologically malignant squamous and glandular cells.87 Adenosquamous carcinomas account for 5 to 25% of the carcinomas in some series.88–90 These carcinomas are similar in their clinical presentation, epidemiology, and pattern of spread to squamous cell carcinomas and adenocarcinomas.91,92 The poorly differentiated form of adenosquamous carcinoma has been referred to as glassy cell carcinoma. These carcinomas are made up of large uniform polygonal cells with a finely granular cytoplasm of the ground-glass type—hence the term glassy cell (Fig. 112.6). Similar to other undifferentiated tumors, glassy cell carcinomas spread early and are aggressive.93,94 The mucoepidermoid carcinoma, also placed in this category, contains large-cell nonkeratinizing or focally keratinizing squamous carcinoma, which stains positive for mucin but lacks recognizable glands. The mucinous component includes goblet or signet-ring–type cells localized in a nest of squamous cells. These carcinomas represent 20% of the carcinomas in some series if mucin is sought.

Figure 112.6. Glassy cell carcinoma.

Figure 112.6

Glassy cell carcinoma.

Selected Variants of Squamous Cell Carcinomas

The histologic variants of both squamous cell carcinoma and adenocarcinoma are described separately below. Some require less intense therapy than the standard types.

Verrucous Carcinoma

Verrucous carcinomas are exophytic with frondlike papillae and macroscopically resemble condylomas. They invade locally and rarely metastasize, but local invasion can be extensive. Death usually occurs because of ureteral obstruction, infection, or hemorrhage.

Histologically, the epithelium lacks cytologic atypia and mitotic activity, and the epithelial papillae lack a central fibroconnective tissue core. Mitotic activity may be evident in cells at the base of the tumor, and invasive nests of epithelium are observed along with well-circumscribed nests with a clearly visible or defined tumor-stroma interface. The inflammatory reaction at the epithelial stromal junction is marked. The treatment is a type II modified radical hysterectomy if the lesion is confined to the cervix. There is no evidence that a pelvic lymphadenectomy is beneficial. Lesions extending beyond the cervix require a more radical procedure depending on the extent of the tumor. Because lymph node metastasis is not an issue, the surgeon’s goal is complete excision of the carcinoma with an adequate surgical margin. Radiation therapy is appropriate for advanced cancers; however, dose intensity must be maintained. There is evidence in the literature that less than full-intensity radiation therapy can modify the growth characteristics of these carcinomas and result subsequently in a more aggressive clinical course. Pelvic exenteration is reserved for patients whose disease is unsuited for irradiation therapy or for patients whose radiotherapy fails to be effective.

Warty Carcinoma

The surface of warty (condylomatous) carcinoma closely resembles that of a condyloma acuminatum. The appearance may prove deceptive inasmuch as these are invasive cancers and not large condylomata. When these carcinomas are confused with verrucous carcinomas, it compromises therapy’s success, since the nodes are at risk in these patients. The deep margins of the warty carcinoma show the typical invasive features of squamous cell carcinomas, and they should be treated like any other squamous cell carcinoma. Similar lesions appear on the vulva.

Papillary Squamous Cell Carcinoma

Papillary squamous cell carcinomas of the uterine cervix with transitional or squamous differentiation often resemble transitional cell carcinomas of the urinary tract (Fig. 112.7). Tumors with transitional cell features (differentiation) have been described in every site in the female genital tract. Koenig and colleagues studied 32 cases of papillary cervical carcinomas from Armed Forces Institute of Pathology files over a 50-year period.95 By definition, all 32 cases showed focal papillary areas characterized by narrow fibrovascular cores covered by multilayered epithelium displaying cytologic atypia and mitotic activity. These 32 cases were predominantly squamous cell, transitional cell, or mixed squamous cell and transitional carcinomas. Patients’ ages ranged from 22 to 93 years (average, 50 years). Case specimens available for study ranged from 0.7 cm to 6.0 cm in diameter. Treatment and follow-up data were available for 12 patients, of whom 5 had undergone hysterectomy and 3 had died of disease. Two patients with advanced disease underwent irradiation and died of disease.

Figure 112.7. Papillary squamous cell (transitional) carcinoma.

Figure 112.7

Papillary squamous cell (transitional) carcinoma.

Immunochemical tests identifying cytokeratin (CK) polypeptides CK 7 and CK 20 are useful in differentiating primary genital tract transitional cell carcinoma from urinary tract transitional tumors.96 Urinary tract transitional cell carcinomas have a CK profile strongly positive for CK 20.

Invasive papillary transitional cell carcinomas of the uterine cervix are potentially aggressive carcinomas. It is important to distinguish these carcinomas from benign squamous papillomas and condyloma acuminata.97 Biopsy material must include the underlying stroma in order to identify invasion. Invasive carcinomas should be treated like other primary carcinomas of the cervix, which are determined by tumor size and spread.

Lymphoepithelioma-Like Carcinoma

Lymphoepithelioma-like carcinomas are histologically similar to lymphoepitheliomas arising in the nasopharynx and salivary glands (Fig. 112.8). These carcinomas are usually well circumscribed and composed of undifferentiated cells. The cells are surrounded by inflammatory infiltrates composed of lymphocytes, plasma cells, and eosinophils.98 Hasumi and colleagues99 reported 39 cases from the Cancer Institute Hospital in Tokyo. Their patients, 72% of whom were younger than 50 years old, were treated with a radical hysterectomy and pelvic lymphadenectomy. Two patients had positive lymph nodes. At the time of the report, 38 of the 39 were alive. The single death occurred 5 months after the surgery and was due to serum hepatitis.

Figure 112.8. Lymphoepithelioma-like carcinoma.

Figure 112.8

Lymphoepithelioma-like carcinoma.

Selected Variants of Adenocarcinoma

Minimal Deviation Adenocarcinoma

It is difficult to differentiate cytologically the carcinomas of the endocervical type (adenoma malignum) from normal endocervical glands (Fig. 112.9). A distinguishing feature is a bizarre and irregular glandular branching pattern. These irregular glands invade deeply into the stroma, and diagnosis requires a large tissue specimen (i.e., a cone biopsy). Diagnosis is frequently made from the hysterectomy specimen. These lesions are malignant and should be treated as intensely as other primary adenocarcinomas of the endocervix. The survival rate is poor if the well-differentiated pattern leads to undertreatment. These carcinomas have been reported in association with mucinous neoplasms of the ovary.100

Figure 112.9. Mucinous adenocarcinoma, endocervical type (adenoma malignum).

Figure 112.9

Mucinous adenocarcinoma, endocervical type (adenoma malignum).

Adenocarcinomas in this category may also contain a predominately endometrioid, or clear cell, pattern.100,101 Young and Scully102 describe five of these cases in women 34 to 42 years old. Tumors were incidental findings at hysterectomy in three cases. Two cases had abnormal Pap smears, and diagnosis was made at cervical cone biopsy. Both patients had hysterectomies, one extrafascial and one radical, and both had pelvic lymphadenectomies. The nodes were negative. The follow-up examinations at 1, 2, 2.5, and 7 years suggest a favorable prognosis for these tumors. Young and Scully102 thought the tumors were unique because the epithelium lining the abnormal glands was of the endometrioid type and the diagnosis of carcinoma could be missed.

Mesonephric Carcinoma

Mesonephric carcinomas develop deep in the lateral wall of the cervix and lateral vagina near mesonephric duct remnants. Residual mesonephric ducts are usually noted in the histologic sections, and florid hyperplasia of these glandular remnants can be difficult to distiguish from carcinoma. The supporting stroma may have a malignant spindle cell component. Such findings of a sarcoma pattern do not seem to have an impact on prognosis. The carcinomas consist of tubular glands that infiltrate the stroma (Fig. 112.10). Various patterns, such as endometrioid, sex-cord-like, solid, and retiform have been described.

Figure 112.10. Mesonephric adenocarcinoma.

Figure 112.10

Mesonephric adenocarcinoma.

Clement and colleagues103 report eight cases, bringing the number of cervical mesonephric carcinomas reported in the literature to 14. Follow-up was available on six of the eight cases: three of the patients were alive without evidence of recurrence at 3 years, one was alive after chemotherapy at 2 years, another had liver and intra-abdominal metastases at 9 and 11 years but was alive with disease at 13 years, and another had died of an independent primary. These carcinomas are best treated with full-intensity therapy based on tumor size and extent. Obtaining the largest biospy possible helps better define the carcinoma.

The literature suggests an indolent course. In such situations, therapy decisions are best based on tumor characteristics. If the carcinoma is confined to the cervix, a radical hysterectomy and pelvic lymph node dissection is suitable. Because these carcinomas are infiltrative and deep in the wall of the cervix, the paracervical portion of the radical hysterectomy should be as wide as possible. Bulky carcinomas or disease spread beyond the cervix may be treated with full-intensity radiation therapy with or without concomitant chemotherapy.

Well-differentiated Villoglandular Adenocarcinoma

Well-differentiated villoglandular adenocarcinoma is composed of papillae lined by epithelium whose cells may have endocervical, endometrioid, or intestinal features with very little cytologic atypia (Fig. 112.11). The carcinoma usually has an exophytic growth pattern. The infiltrative portion of the carcinoma is composed of irregular branching glands. Jones and colleagues104 reviewed the clinical and pathologic features of 24 cases of patients between 27 and 54 years old. All tumors were polypoid, and exophytic lesions were confined to the cervix. Five patients were treated with cone biopsy, four by extrafascial hysterectomy, and 15 with radical hysterectomy. All patients were alive and well during follow-up (7–77 months). Reed and colleagues105 described five cases of clinical stages IB and IIA. Four were treated with radical hysterectomy and one with simple hysterectomy, and all received postoperative chemotherapy. The patients were alive and well after a follow-up of 18 to 28 months. Reed and colleagues, thinking such aggressive treatment is unnecessary, recommend conization or hysterectomy. A review of the literature since 1989 confirms that an excellent prognosis may be achieved without a radical hysterectomy when the tumor is superficial and has no vascular or lymphatic invasion.106

Figure 112.11. Well-differentiated villoglandular adenocarcinoma.

Figure 112.11

Well-differentiated villoglandular adenocarcinoma.

Adenoid Cystic Carcinoma

Adenoid cystic carcinoma occurs in postmenopausal women who are symptomatic. It consists of solid areas of basaloid tumor cells, where cylindrical hyaline bodies lie (Fig. 112.12).107,108 Mitosis is frequent, and this aggressive carcinoma spreads readily to lymph nodes. Treatment should be based on tumor size and extent.108–110

Figure 112.12. Adenoid cystic carcinoma.

Figure 112.12

Adenoid cystic carcinoma.

Adenoid Basal Carcinoma

Adenoid basal carcinoma consists of small uniform cells that resemble basal cell carcinoma (Fig. 112.13). This uncommon neoplasm is usually a coincidental finding at hysterectomy in cases of HGSIL. Adenoid basal carcinomas are insignificant, and patients with an aggressive neoplasm who are diagnosed as having an adenoid basal carcinoma are generally misdiagnosed.

Figure 112.13. Adenoid basal carcinoma.

Figure 112.13

Adenoid basal carcinoma.

Papillary Serous Adenocarcinoma

Papillary serous adenocarcinoma of the cervix is histologically identical to serous adenocarcinomas arising in the endometrium, ovary, and peritoneum. The tumors are composed of papillary tufts and complex papillae lined by cells with high-grade nuclei (Fig. 112.14). The presenting symptoms are similar to those of other carcinomas of the cervix. Zhou and colleagues111 studied 17 patients who ranged in age from 26 to 70 years. Two patients had stage IA disease, 12 had stage IB, two had stage II, and one had stage III. Tissue blocks were available for immunohistochemical staining in 12 patients. Tissue from 6 of the 12 stained positive for carcinoembryonic antigen (CEA), and tissue from nine stained positive for CA 125. An elevated serum CA 125 level was associated with a bad prognosis; however, the serum levels decreased when there was a therapeutic response to therapy. Of the two patients with stage 1A tumors, one was treated with a radical hysterectomy, but no information regarding therapy is available for the second. Eight of 12 patients with stage 1B tumors were treated by radical hysterectomy: five of these received postoperative radiotherapy, one received postoperative radiotherapy and chemotherapy, and one had a vaginal hysterectomy followed by pelvic radiotherapy. The remaining three patients were treated with radiotherapy with the addition of adjuvant chemotherapy in one case. The three patients with more advanced disease were treated with primary radiotherapy. Fifteen patients were followed from 6 months to 11 years (mean, 56 months), and six died within 5 years of diagnosis because of disease. Patients whose therapy failed had extensive disease, which encompassed the lymph nodes, peritoneal surfaces, liver, and lungs.

Figure 112.14. Papillary serous adenocarcinoma.

Figure 112.14

Papillary serous adenocarcinoma.

These tumors are very uncommon and little information is available on therapy. Stage I carcinomas in this series behaved like other cervical adenocarcinomas. Combined chemotherapy and radiation therapy seems appropriate in treating large stage 1B or more advanced carcinomas.

Selected Variants of Neuroendocrine Carcinomas

Carcinoid-like Tumors

Carcinoid-like tumors are well-differentiated small cell carcinomas that contain neurosecretory granules and are histologically similar to intestinal carcinoid tumors (Fig. 112.15). The granules stain positive for a wide variety of endocrine substances, such as adrenocorticotropic hormones, calcitonin, histamine, and antidiuretic hormone.112 These tumors are very rare. Albores-Saaverda and colleagues reported 12 cases in 1976.113 The clinical and gross features were identical to those of invasive squamous cell carcinoma. Six of the patients were diagnosed as having well-differentiated lesions and two died. Six of the patients were diagnosed as having poorly differentiated carcinomas and four died of disease. None of the 12 patients presented the carcinoid syndrome nor could a multiple endocrine neoplasia syndrome be identified.

Figure 112.15. Carcinoid tumor.

Figure 112.15

Carcinoid tumor.

The series was recently updated and expanded.114 It includes 16 cases of well-differentiated carcinoid tumors of the cervix and reports a 50% mortality rate. The “poorly differentiated” carcinoid tumors have been acknowledged by authors today as being neuorendocrine small cell tumors. The cervical carcinoid-like tumors behave more aggresively than carcinoid tumors at other sites. Radical hysterectomy with pelvic lymphadenectomy or radiation therapy seems appropriate should one encounter this rare carcinoma.

Small Cell Neuroendocrine Carcinomas

Small cell carcinomas, well defined in the WHO’s classification of cervical tumors, contain small anaplastic cells with scant cytoplasm (Fig. 112.16). These highly aggressive cancers diffusely infiltrate the cervical stroma.115 By immunohistochemistry, neuroendocrine markers are present in most cases. Women with small cell carcinoma are likely to be 10 years younger than those with squamous cell carcinoma. These carcinomas are different and more aggressive than nonkeratinizing squamous carcinoma with small cells. Both may stain positive for neuroendocrine markers. Usually, there will be some areas showing squamous or glandular differentiation in the nonkeratinizing squamous cell carcinoma with small cells.

Figure 112.16. Small cell carcinoma.

Figure 112.16

Small cell carcinoma.

These carcinomas respond to radiation therapy; however, local control is not the primary issue with small cell neuroendocrine carcinoma. The cancer is so aggressive that distant metastases are usually present at the time of diagnosis. Systemic chemotherapy in a neoadjuvant or adjuvant setting is being administered with regimens resembling those used to treat small cell carcinoma of the lung. Because the neoplasm histologically resembles oat cell carcinoma of the lung, numerous chemotherapy regimens active against lung cancers have been used. Small cell carcinoma of the cervix is not as sensitive to chemotherapy as is small cell lung cancer.

Morris and colleagues reported experience with 10 patients with small cell carcinoma of the cervix treated with cisplatin (50 mg/m2 day 1), doxorubicin (50 mg/m2 day 1), and etoposide (75 mg/m2 days 1–3) every 28 days for six cycles.116 Seven patients had stage IB cancers on entry into the study, and three had stage II cancers. Three patients received chemotherapy after radical hysterectomy (three patients with stage IB lesions), and one patient received chemotherapy after radiation therapy. The remaining six patients received chemotherapy prior to radiotherapy. Seven patients had measurable disease prior to receiving chemotherapy. Four of these patients had measurable responses (three complete and one partial). Four patients were alive and disease free at the time of publication with a median survival of 28 months.116

Currently, at The University of Texas M.D. Anderson Cancer Center in Houston, patients with stage IB carcinomas less than 4 cm in diameter are treated with an initial radical hysterectomy and pelvic lymphadenectomy or primary radiation therapy. Surgery or radiation is followed with adjuvant chemotherapy with cisplatin, etoposide with or without Adriamycin or cisplatin and taxol for six cycles. In the author’s experience (JTW), these carcinomas respond to external-beam radiation therapy (EBRT) and intracavitary brachytherapy, as do other undifferentiated cervical carcinomas, and the addition of concurrent cisplatin (40 mg/m2 weekly) for patients with stage IIB and larger tumors deserves clinical testing. Following control of the primary tumor and local spread, there is still an option for adjuvant systemic chemotherapy. Recurrent or metastatic small-cell carcinoma should be treated with a regimen similar to the most current and effective regimen used to treat recurrent or metastatic small cell carcinoma of the lung.

Non–Small Cell Neuroendocrine Carcinomas

Non–small cell neuroendocrine carcinomas of the cervix have been reported,117,118 but they are not listed in the current WHO classification of cervical tumors. The tumors contain intermediate to large cells, high-grade nuclei, and eosinophilic cytoplasmic granules of the type seen in neuroendocrine cells. A trabecular pattern is frequently evident with or without glandular differentiation (Figs. 112.17, 112.18). Tumors are usually immunoreactive for chromogranin (Fig. 112.19). Reported survival rates for these aggressive carcinomas are similar to those associated with small cell carcinoma. Optimal therapy for non–small cell neuroendocrine tumors of the cervix has not been established.

Figure 112.17. Non-small cell neuroendocrine carcinoma.

Figure 112.17

Non-small cell neuroendocrine carcinoma.

Figure 112.18. Non–small-cell neuroendocrine carcinoma.

Figure 112.18

Non–small-cell neuroendocrine carcinoma.

Figure 112.19. Immunoreaction of non–small-cell neuroendocrine carcinoma cells to chromogranin.

Figure 112.19

Immunoreaction of non–small-cell neuroendocrine carcinoma cells to chromogranin.

Terminology for cervical neuroendocrine tumors is confusing, and many pathologists are recommending application of the classification system used for the more common pulmonary neuroendocrine tumors (i.e, typical carcinoid tumor, atypical carcinoid tumor, large cell neuroendocrine carcinoma, and small [oat] cell carcinoma).119

Natural History of Epithelial Carcinomas of the Uterine Cervix

Premalignant Lesions

CIS, a precursor lesion for invasive carcinoma, was described by Cullen at the turn of the century. The term was reintroduced by Broder in the 1930s, and a relationship between CIS and invasive carcinoma was described by a number of investigators. During the 1930s, cancer detection programs, based on cytologic screening to detect precursor lesions, were being created. The identification of a spectrum of precursor lesions followed, and terminology was defined in the 1940s and 1950s. Reagan and Hamonic120 introduced the term dysplasia to refer to the spectrum of cervical abnormalities that featured cells whose abnormalities were fewer or less severe than those found in CIS. Dysplastic cells resembled cells of the basal layer but had nuclear atypia and other cytoplasmic and nuclear abnormalities. The degree of dysplasia was classified on the basis of the relative thickness of the process in relationship to the thickness of the epithelium. By definition, in dysplasia, atypical cells did not occupy the full thickness of the epithelium, nor did they penetrate the basement membrane.121 Mild or moderate dysplasia was thought to have a lower potential for progressing to invasive carcinoma than did severe dysplasia. The term carcinoma in situ was reserved for atypical cells involving the full thickness of the epithelium. This division of noninvasive cervical lesions into two groups, dysplasia and CIS, was confusing. Clinicians considered dysplasia to be a potentially reversible lesion, whereas they thought of CIS as potentially dangerous and treated it with hysterectomy. Among pathologists, variability in distinguishing severe dysplasia from CIS was common, making a precise definition that had clinical application a necessity.

DNA ploidy studies had demonstrated a similarity between severe dysplasia and CIS. Both entities were found to consist of monoclonal proliferations of abnormal squamous epithelial cells with an aneuploid nuclear DNA content. These findings suggested that the progression from dysplasia to invasive carcinoma actually represented a disease spectrum. Richart introduced the term cervical intraepithelial neoplasia in the late 1960s.122 The CIN terminology assumed that all types of lesions—from precursor lesions to invasive squamous cell carcinoma—represented a single disease process. Furthermore, because the CIN terminology represented a spectrum of histologic changes that shared a common etiology, its use fit nicely into a clinical treatment plan. When these lesions were diagnosed and adequately treated or destroyed, invasive carcinoma could be prevented.

The introduction of new diagnostic terms with the 1988 Bethesda System for Reporting Cervical/Vaginal Cytological Diagnoses was somewhat problematic. The system classifies precursor lesions as squamous intraepithelial lesions (SILs).121 Generally, low-grade SILs (LGSILs) have cellular changes that are associated with a heterogeneous group of HPV types and are equivalent to mild dysplasia (CIN I). These lesions are usually diploid or polyploid. HGSILs are usually associated with intermediate- (31, 33, 35, 51, 58) or high-risk (16, 18, 56) HPV types. This category includes moderate dysplasia (CIN II), severe dysplasia (CIN III), and CIS. The high-grade lesions are typically aneuploid and are more likely to progress to invasive carcinoma, which makes the HGSILs the most important clinically. A significant percentage of these lesions will progress to invasive cancer if followed long term.124,125 LGSILs usually behave in the opposite manner. One half will regress spontaneously, and only 16% will progress to HGSILs.126 Pathologists use a variety of terms for these lesions. The written report may use the new Bethesda system for both histologic and cytologic diagnoses, or it may just use the new terminology for the cytologic diagnosis. The older terminology for the histologic diagnosis remains popular. Mild dysplasia is CIN I, moderate dysplasia is CIN II, and severe dysplasia is CIN III or CIS.

The precursors of invasive adenocarcinoma of the cervix were recognized in the 1950s.127 The best defined precursor, if one exists, is adenocarcinoma in situ, which occurs infrequently in comparison with HGSILs. A large fraction of adenocarcinoma in situ occurs in conjunction with SILs.128–130 Adenocarcinoma in situ is associated with HPV DNA, mostly HPV 18, as opposed to HPV 16 in SILs. Adenocarcinoma in situ is less likely to be detected by Pap smear than are SILs.130 In the majority of cases, adenocarcinoma in situ involves the transformation zone and is unifocal.128 The transition between normal glands and adenocarcinoma in situ is sharp. The cell type is usually endocervical and consists of atypical columnar glands.131 Other types of adenocarcinoma in situ may contain colonic-type epithelium and endometrioid or clear cells.132 The diagnosis of adenocarcinoma in situ is sometimes difficult and may pose a challenge to the experienced pathologist. Tissue specimens that are intact and properly oriented on arrival to the laboratory, of adequate size, and accompanied by the appropriate clinical history are extremely helpful in obtaining the correct diagnosis.

Diagnosis and Treatment

Precancerous Lesions

Cervical intraepithelial neoplasia is an increasingly common finding among sexually active young women. Since the introduction of the Bethesda system, Pap smears identified as having low-grade cytologic abnormalities, smears with minimal or ambiguous cytologic changes classified as atypical squamous cells of undetermined significance (ASCUS), or smears identified as having LGSILs have increased.133 Approximately 50 million Pap smears are taken yearly in the United States, and 5 to 10% of these smears are reported as having low-grade cytologic abnormalities, involving an estimated 2.5 million women.

Although near consensus exists regarding the evaluation and management of HGSILs and carcinoma detected on Pap smear, controversy continues regarding appropriate management of atypical and low-grade abnormalities.134 Issues include the risk of progression of the disease, the anxiety caused to the patient, the risk of overtreating patients with minor disease, and, more recently, the financial implications of prompt intervention and treatment.135

Management of Low-grade Cytologic Abnormalities

Previously low-grade cytologic abnormalities were usually considered benign and attributed to an underlying infection.136 The common practice was to disregard the cytologic findings and repeat the Pap smear the following year.136,137 In the 1970s, it was suggested that a more aggressive approach to a mildly atypical Pap smear might be warranted. Staffl and Mattingly138 reported that approximately 25% of women with a colposcopic diagnosis of HGSILs (CIN 2 and 3) had been referred with an initial diagnosis of a mildly atypical Pap smear. Similarly, Figge and colleagues139 reported that 15% of women with invasive cervical cancer had been initially referred because of a mildly atypical Pap smear. Most clinicians started treating any underlying vulvovaginal infection with antibiotics and repeating the smear several months later. If the smear result regressed to normal, the patient was scheduled for an annual Pap smear screening, whereas patients whose smears remained abnormal were referred for colposcopic evaluation.

As more studies of women with mildly atypical Pap smears were published, data showed that 5 to 20% of women presenting with a single mildly atypical Pap smear were at risk of HGSILs or other more severe lesions.140–143 In addition, it has been recently estimated that more than one-third of the HGSIL cases in a routine screening population are signaled by a cytologic diagnosis of ASCUS.144 This has led some clinicians to suggest that it is safer and more expeditious to perform colposcopy in such cases.142,145 However, given the relatively high frequency of low-grade cytologic abnormalities in the absence of significant disease and the high financial and emotional cost of colposcopy, some have argued that these women should be evaluated by repeat cytology rather than colposcopy. The American College of Obstetricians and Gynecologists and a National Cancer Institute Consensus Panel have acknowledged that managing a single mildly atypical Pap smear by repeating the test is an acceptable practice.134,146

The main goal in managing these lesions is identifying those women at higher risk for HGSILs, primarily women more than 25 years old, who are unreliable for long-term follow-up, who are suspected of having or known to have a history of abnormal cytology or treatment for cervical neoplasia, who may be promiscuous, and who have no history of adequate screening.147 Currently, two strategies are recommended for managing these lesions: the physician may repeat the Pap smear and perform a colposcopic evaluation,134,147 or, for patients with an ASCUS cytologic diagnosis or LGSILs without clinical evidence of cervical disease and without risk factors, the physician may repeat the Pap smear without performing colposcopy (Fig. 112.20). Patients should be monitored by Pap test every 4 to 6 months for 2 years. After three consecutive negative smears in the 2-year follow-up period, patients can be monitored by a routine cervical cancer screening protocol. For patients with clinical suspicion of cancer or persistent abnormal Pap smears during the 2-year follow-up, colposcopic evaluation is recommended. Depending on reliability for follow-up and the risk factor profile, women with persistent LGSILs can be treated by such ablative therapies as cryotherapy or loop electrosurgical excision procedure (LEEP). Patients undergoing treatment for LGSILs will be monitored every 4 to 6 months for up to 2 years by cytologic examination and colposcopic and histologic examination if required.

Figure 112.20. Algorithm for management and treatment after abnormal findings on cervical cytology.

Figure 112.20

Algorithm for management and treatment after abnormal findings on cervical cytology.

Because of the costs, both emotional and economic, associated with evaluating women with low-grade abnormal cytologic abnormalities, considerable interest has risen in developing novel, cost-effective triage strategies for these patients. HPV DNA testing, automated cytology screening, and cervicography are being evaluated as adjunct methods in the assessment and triage of patients with low-grade abnormal cytologic abnormalities. Most research has focused on the assessment of HPV testing in the triage of low-grade lesions. In 1995, The National Cancer Institute began a large randomized trial to assess the value of HPV testing for the triage of cases of ASCUS or LGSILs. Results from this trial are expected in the year 2001.

Several researchers have assessed the value of HPV DNA testing as a specific and economical alternative for triage of low-grade cytologic abnormalities and as an adjunct to cervical cytology in primary screening (Fig. 112.21).148–151 On the basis of HPV DNA test results, women can be divided into a group with high oncogenic risk (women with HPV types that would be at greater risk for having serious cervical disease) and a group lacking these HPV types (women at little or no risk).152–154 Studies have reported a range of sensitivity values from 58% to 93%.155 Early studies using first-generation HPV DNA such as Southern blotting and in situ hybridization testing reported that the technique was neither specific enough nor sensitive enough to be used as intermediate triage.156–158 With second-generation HPV DNA detection methods, including PCR-based methods and the hybrid capture HPV DNA assay manufactured by Digene Diagnostics, both of which have a higher sensitivity and detect a broader range of HPV types with high oncogenic risk than earlier methods, results have been more consistent, supporting the role of HPV typing in the triage of patients with low-grade cytologic abnormalities and as an adjunct to cytology in primary screening.148–151 Wright and colleagues reported that the hybrid capture HPV DNA assay had a sensitivity of 59 and 80% for detecting CIN among women with a referral diagnosis of ASCUS and LGSILs.150 Cox and colleagues reported that HPV testing had a sensitivity of 86% for the detection of CIN (any grade) and of 93% for detection of HGSILs. Repeating the Pap smear alone had a sensitivity of only 60% for the detection of any grade of CIN.148 In addition, they estimated that HPV testing could reduce the colposcopy rate by 58% if only women with a cytologic diagnosis of ASCUS and HPV-positive tests were referred and reduce the cost of detection of each case of CIN by 38%, despite the added cost of HPV testing.155 Similarly, Manos and colleagues observed that among women referred with a diagnosis of ASCUS, the HPV test had a sensitivity of 89% in detecting HGSIL, whereas the sensitivity of the repeat Pap smear was 76%.151

Figure 112.21. Algorithm for including HPV testing as an integral part of triage and management of low-grade cervical abnormalities.

Figure 112.21

Algorithm for including HPV testing as an integral part of triage and management of low-grade cervical abnormalities.

Management of High-grade Cytologic Abnormalities

No dispute exists regarding the optimal management of HGSILs. These cases require colposcopic evaluation and biopsy. The consensus is that HGSILs should be treated once diagnosed.159 For biopsy-proven SILs with negative findings on endocervical curettage (ECC), a satisfactory colposcopy examination, and congruent Pap smear and biopsy results, ablation of the transformation zone has been the standard of care for several decades. Three outpatient therapies are used in the United States for treating these lesions: cryotherapy, laser ablation, and LEEP. For patients with unsatisfactory colposcopic examination findings, a Pap smear result more severe than the biopsy findings, presence of an adenomatous component, suspicion of invasive cancer, or a positive ECC, a cone biopsy is indicated. Cone biopsies remove tissue between 20 and 30 mm in depth and up to 30 mm in diameter, including the transformation zone.

The three outpatient therapies, including cryotherapy, laser vaporization, and LEEP, have been the focus of controversy. Safety, efficacy, and cost issues have dominated the debate. Cryotherapy, introduced in 1972, was the first outpatient treatment for CIN and remains a dependable treatment because of its reliability, low complication rate, ease of use, and low cost.160 Another advantage of cryotherapy is that leaving a large dead viral HPV load within disrupted cells may improve the immune response to the causative agent of CIN. Major disadvantages include lack of ability to tailor treatment to the size of the lesion, lack of a tissue specimen, and the risk of treatment of undetected invasive lesions. Eligible for cryotherapy are those cases with satisfactory colposcopic examination, with negative ECC, and with small lesions (2.5–3.0 cm in diameter) that allow the entire lesion and transformation zone to be covered by the cryotherapy probe.

Laser vaporization was introduced in 1977. It has the advantage of being easily tailored to lesion size, but the cost of equipment and the lack of a tissue specimen are major disadvantages.160 In addition, it requires more training and skills than the other two procedures and has more serious safety issues (eye injuries and inadvertent burns). Candidates for this procedure are patients with large CIN lesions, young women with suspicious or invasive lesions or adenocarcinoma in situ in whom preservation of fertility is desired, and patients unwilling to undergo LEEP under local anesthesia. LEEP was introduced in 1989, and it is currently the technique of choice for the treatment of HGSILs. LEEP is reliable and easy to use. It can be tailored to lesion size and provides a tissue specimen.160 The advantage of this last characteristic is underscored by the finding of unsuspected adenocarcinoma in situ and microinvasive squamous cell carcinoma in 2 to 4% of LEEP specimens.147,160 LEEP, however, has the potential for unintentional removal of excessive cervical stroma and removal of disease-free tissue (more frequent when LGSILs are treated). Other disadvantages include its high cost and the increased risk of bleeding and infection. Bleeding after LEEP treatment has been reported in 2 to 7% of cases.160 The high rates of overtreatment observed with LEEP have been related to misdiagnosis of abnormality and multiple punch biopsies of small lesions prior to treatment.147 The use of LEEP in see-and-treat protocols has been shown advantageous to improving patient compliance with treatment when patient selection is adequate. This strategy has been suggested as having the greatest potential benefit for populations with poor treatment compliance.147 No statistically significant differences in success rates (based on recurrence and persistence) between cryotherapy and laser vaporization have been reported, but variability in these rates from study to study is striking. In nonrandomized clinical studies, these treatment modalities have shown success rates of 86 to 91% for cryotherapy and of 89 to 97% for laser vaporization.161 Similar success rates have been reported for LEEP therapy (range, 84–95%). All these studies have shown an association between persistent or recurrent disease and high histologic grade, disease affecting endocervical gland crypts, and size of lesion. The only randomized controlled trial comparing the efficacy of all three treatment options reported no statistically significant difference in varying success rates: cryotherapy 24%, laser vaporization 17%, and LEEP 16%.160 Similarly, no statistically significant differences in complication rates were observed between groups. Only lesion size was statistically associated with persistent disease, but risk of recurrence was associated with age more than 30 years, positivity for HPV 16 or 18, and previous treatment for CIN. The effect on fertility of the three therapies, as well as of conization and electrocoagulation diathermy, showed that only cold cone biopsy increased the risk of second-trimester abortions, preterm labor, and having infants of low birth weight. The amount of tissue removed by laser, cryotherapy, and LEEP is small, so these techniques have no adverse effect on pregnancy.

The preferences of clinician and patient and cost considerations should dictate the choice of treatment of CIN; however, proper management of LGSILs is expected to remain a fiercely debated question. Although management guidelines have increasingly included nontreatment of LGSILs as an option for patients who may be reliable for long-term follow-up, concerns over legal responsibility for progressive lesions continue to drive intensive follow-up protocols, particularly in the United States, that may not be cost-efficient.161

New Therapy

Chemotherapy and vaccines are at the forefront of new therapies in cervical cancer.

Chemopreventative management

  One of the more exciting research areas in the therapy for CIN is the use of chemopreventative agents. These therapies involve ingestion of an agent that reverses precancerous changes, returning the tissue to normal. Studies performed in other organ sites using retinoids have demonstrated that this reversal can be successfully accomplished. Trials are under way in the cervix.

Vaccine development

Another possible approach to eliminating cervical neoplasia is to develop vaccines. To understand how these work, we must review the molecular biology of HPV, which is widely regarded as an etiologic agent in cervical cancer development. The HPV genome is circular and composed of approximately 8,000 base pairs, which are functionally divided into the open reading frame (ORF) region and the long control region (LCR). The ORF contains seven regulatory gene-encoding sequences, referred to as “early” sequences because they are believed to be expressed early in the virus life cycle. Two of the early gene products, E6 and E7, have been the focus of recent research. The ORF also contains two late genes, which encode for capsid structure. The LCR contains the promoter and enhancer components of the ORF gene sequence. Based on the association of HPV genotypes with high-grade dysplasias and carcinomas, certain genotypes are considered high risk, or oncogenic, types. These include HPV 16, 18, 31, 33, and 35. During infection, DNA of high risk HPV types can integrate into the host genome.162 Integration leads to increased expression of E6 and E7, and this increased expression is necessary for maintenance of the transformed state.

The role of HPV in carcinogenesis is explained by the ability of E6 and E7 to disrupt critical cell regulatory mechanisms. Two gene proteins, p53 tumor-suppressor protein and retinoblastoma tumor-suppressor gene product (pRB), which act to restrict cell-cycle progression and proliferation, are inactivated. E6 targets p53 in a variety of ways.163 In addition to inducing proteolytic degradation of p53, E6 also interferes with the transcriptional activation and repressor functions of p53. The loss of p53 function decreases the cancer cells’ susceptibility to apoptosis and promotes cellular survival after DNA damage. The accumulation of damaged DNA further disrupts the cell regulatory process.164 E7 binds to and destabilizes pRB, which abrogates critical cell-cycle regulatory pathways. The HPV E7 protein also disrupts cellular growth regulatory pathways by overcoming the activity of cyclin-dependent kinase inhibitors.165

The combined actions of E6 and E7 are so significant that these two virus-encoded proteins may serve as targets for inactivation. Inactivation may prove seminal in preventing cervical neoplasia by inhibiting the development of precursor lesions and also prove important in therapeutic applications for patients with invasive cancers.

A process as complex as cervical neoplasia is probably owed to multiple factors. Mutations, immunologic deficit, or other tumor promotion events, such as oncogene expression, may act independently of the virus-host relationship.166 Researchers are now developing therapeutic vaccines meant to induce an immune response against tumor cells that express HPV E6 and/or E7 protein. Candidate vaccines are being designed and produced that theoretically would be capable of prompting both cell-mediated and antibody responses against HPV.167 Cell-mediated immune responses against HPV, in the form of specific cytotoxic T lymphocytes (CTLs)168,169 and delayed-type hypersensitivity mediated by CD4+ T helper cells, are being studied.170,171

Recombinant viral vectors are nonpathogenic viruses that act as hosts for foreign genes. A gene encoding the antigen to which immunity is desired is inserted in the live virus, creating a recombinant construct. Vaccinia, a well-understood recombinant viral vector, has been used for many different recombinants, one of which is known as TA-HPV. Developed for human studies, it is currently in use in a multicenter trial of adjuvant immunotherapy.172

An additional product uses HPV peptides, which are capable of inducing CTLs. HPV 16 peptides bind to human leukocyte antigen (HLA) molecules and induce CTLs capable of lysing cervical cancer cells in vitro.173 The major disadvantage of peptide vaccination is the restriction of peptide binding by the patient’s HLA genotype; therefore, vaccines may need to consist of different peptides with binding affinities for a range of HLA alleles.174

Many obstacles continue to bar development of a successful vaccine against cervical neoplasia. A variant of HPV 16 E6 epitope has been identified, which may impair CTL recognition.175 In many tumors, HLA class I molecules are frequently lost from the cell surface.176 Since HLA molecules are necessary for viral antigen presentation to T lymphocytes, their loss will impair the immune response. Despite the barriers, research and successful development of an HPV vaccine potentially could eliminate the need for cervical screening and ultimately prevent most cases of invasive epithelial cancer of the cervix.

Invasive Lesions: Patterns of Spread

During the transition from in situ to invasive carcinoma, tumor cells penetrate the epithelial basement membrane and enter the underlying cervical stroma. Once the cervical stroma is invaded, the lymphatics and blood vessels are accessible, and dissemination beyond the cervix is possible.

The lymphatic network of the cervix has been described in the classic textbook by Plentl and Friedman.177 The cervical, vaginal, and uterine lymphatic channels coalesce to form major drainage pathways. The major lymphatic trunks are the utero-ovarian (infundibulopelvic), parametrial, and presacral, which drain into the paracervical, obturator, hypogastric, external iliac, common iliac, inferior gluteal, presacral, and lower aortic lymph nodes. A series studying the incidence and distribution pattern of retroperitoneal lymph node metastatis in 208 patients with stages 1B, IIA, and IIB cervical carcinomas who underwent radical hysterectomy and systemic pelvic node dissection reported that 53 patients (25.5%) had node metastasis.178 The obturator lymph nodes were the most frequently involved, with a rate of 18.8% (39/208) and the authors proposed them as sentinel nodes for cervical cancers. In fact, finding negative obturator nodes may be an indication that the pelvic lymph node dissection can be limited.

The most important prognostic factors in patients with cervical cancers is lymph node status and size and extent of the primary. In patients with early disease, 5-year survival rate drops to 60% with three or more positive nodes and to 25 to 30% with positive para-aortic nodes. Cervical cancers of comparable size may have a very different metastatic potential, depending on their intrinsic aggressiveness and histologic cell type. Cervical carcinomas also invade directly. Disease may extend to the lateral pelvic walls, into the bladder and/or rectum, or into the vagina as the cancer grows.

The incidence of lymph node metastases as related to squamous cell carcinoma stages designated by the International Federation of Gynecology and Obstetrics (FIGO) is well defined by surgical series.179–185 Pelvic node involvement as related to FIGO stage occurs in 10 to 25% of stage I carcinomas, 25 to 30% of stage II carcinomas, and 30 to 45% of stage III and IV carcinomas. Stage I carcinomas are more likely to metastasize to nodes when they reach 3 cm.186

Carcinoma of the cervix spreads in an orderly manner. Nodes adjacent to the cervix are usually the first to be involved, and “skip” metastases are uncommon. Patients with positive para-aortic nodes usually have positive pelvic nodes. The incidence of positive para-aortic nodes in 978 patients with stages IB and IIA carcinoma whose aortic nodes were sampled prior to radical hysterectomy was 4.7 and 8.4%, respectively. The incidence of positive nodes in patients with adenocarcinomas is probably equal to that of squamous cell carcinomas when cancer size, histologic differentiation, and extent of tumor or FIGO stage are comparable. Many large series report survival rates for patients with adenocarcinomas that are poorer than those for patients with squamous cell carcinomas, especially for those who have bulky lesions.187,188 Because most patients with large bulky adenocarcinomas are treated with radiation therapy, the incidence of positive nodes as related to tumor size is not as well defined as that for squamous cell carcinomas. The incidence of positive nodes for poorly differentiated squamous cell carcinomas, as well as for poorly differentiated adenocarcinomas, is higher than that for the better differentiated carcinomas. Small cell carcinoma and some of the carcinomas classified as other epithelial tumors are particularly aggressive. Carcinomas of the cervix, regardless of histology and size of the primary tumor, may contain highly malignant clones of cells that can prove unpredictable and spread extensively.

The prognostic factors for invasive squamous cell carcinoma and adenocarcinoma are related to the following: size and extent of the primary carcinoma, depth of stromal invasion, degree of cellular differentiation, presence of vascular space invasion, and status of the pelvic and para-aortic lymph nodes.181,189

Invasive Cancer

Diagnosis

Presentation

The clinical symptoms of carcinoma of the cervix are vaginal bleeding, discharge, and pain. The growth pattern of the carcinoma plays a role in the development of symptoms. Exophytic carcinomas bleed earlier in a sexually active patient because of contact than do lesions that expand the cervix. Lesions that expand the endocervix in a barrel-shaped configuration may leave the squamous epithelium of the exocervix intact until the lesions exceed 5 or 6 cm in transverse diameter; therefore, carcinomas with this growth pattern may be silent and grow large before the patient bleeds. Cytology may be negative unless the endocervix is sampled with a brush device. Ulcerative lesions that destroy the exocervix bleed early and necrosis and infection induced by the cancer’s outgrowing its blood supply result in a foul-smelling vaginal discharge.

Severe pelvic pain experienced during the pelvic examination may indicate salpingitis. Tubal infections require management before radiation therapy. Patients with an adnexal mass need surgical treatment before starting radiation therapy.

Paracervical extension of a carcinoma may remain silent until fixation to the pelvic wall occurs. Fixation with or without nodal involvement may obstruct a ureter. Ureteral encroachment is usually a silent process. Patients may present with bilateral ureteral obstruction with impending renal failure and report no history of urinary system complaints. Direct invasion of branches of the sciatic nerve roots causes back pain, and encroachment on the pelvic wall veins and lymphatics causes edema of a lower extremity. The triad of back pain, edema of an extremity, and a nonfunctioning kidney is evidence of an advanced carcinoma.

The anatomic position of the bladder, being so closely adjacent to the cervix, favors contiguous spread from the cervix to the bladder. Urinary frequency and urgency are early manifestations, whereas bleeding indicates mucosal infiltration with ulceration. The cause of hematuria should be confirmed by cystoscopy and biopsy. In contrast, posterior extension to the rectum and disruption of the rectal mucosa is an unusual pattern of disease spread in untreated patients. The deep cul-de-sac provides anatomic separation of the rectum and cervix. In the patient who presents with rectal mucosal involvement, there is usually extensive involvement of the posterior vaginal wall with direct extension to the rectum. For staging and treatment planning, cystoscopy and sigmoidoscopy are essential. Metastatic carcinoma in para-aortic nodes may extend through the node capsule and directly invade the vertebrae and adjacent nerve roots. Back pain owing to involvement of the lumbar vertebrae and psoas muscles may be a manifestation of massive nodal disease; however, hematogenous spread to the lumbar vertebrae and involvement of the psoas muscle without significant nodal disease may occur.

Diagnosis

The diagnosis of carcinoma is made by pathologic examination of a tissue specimen. A biopsy taken from the periphery of a tumor is more likely to contain morphologically intact neoplastic cells that are best able to represent the tumor pathologically. A biopsy specimen taken from the center of a tumor mass may include necrotic tumor debris, the result of hypoxia induced by the tumor’s outgrowing its blood supply. Therefore, to rely on these dead and distorted cells is to compromise the accuracy of the histologic profile.

The endocervix should be curetted if no lesion is visible or if the cervix is enlarged, nodular, or hard. Older patients with adenocarcinoma require an endometrial biopsy. It may be difficult to distinguish an endocervical primary tumor from an endometrial primary tumor involving the lower uterine segment.

Patients with an abnormal Pap smear and no visible lesion require colposcopy and biopsy. See Fig. 112.20 for a simplified generic algorithm to use for finding the source of an abnormal Pap smear. (Fig. 112.21 outlines management of low-grade cervical abnormalities using HPV testing.) The tissue specimen may be a simple colposcopy-directed biopsy, an endocervical specimen obtained with a curette, or a conization specimen.

FIGO’s current recommendation is to classify as stage IA any invasive cancer that can only be identified with a microscope. All gross lesions, even with superficial invasion, are stage IB cancers. Stage IA1 is invasion of the stroma to 3 mm in depth and no greater than 7 mm in width. Stage IA2 is invasion of stroma greater than 3 mm and no greater than 5 mm in depth and no wider than 7 mm. The depth of invasion should not be more than 5 mm, measured from the base of the epithelium, either squamous or glandular, from which it originates. Vascular space involvement, either venous or lymphatic, should not alter staging.

Many clinicians prefer to use the term microinvasion and use criteria recommended by the Society of Gynecologic Oncologists. Microinvasion is invasion limited to 3 mm in depth, is measured from the base of the squamous or glandular epithelium of origin, and does not encompass lymphatic or vascular space involvement. A simple punch biopsy is inadequate for making the diagnosis of microinvasion: a conization specimen, containing the entire neoplastic process, is necessary. Additional tissue is required from patients with positive cone margins because an occult, frankly invasive carcinoma may lie adjacent to a positive margin.

Evaluation and Staging

Successful therapy planning requires detailed evaluation of the patient’s general medical condition and the size and extent of the carcinoma. Medical illness is stabilized and anemia is corrected. Patients with anemia, which has been extensively studied,190,191 have a higher local relapse rate than patients with a normal hemoglobin count (Table 112.2). The patient’s surgical history is important, and operative notes may describe the status of the abdominal organs as well as report abdominal and/or pelvic operations. Diagnoses of importance to therapy planning include ulcerative bowel disease, diverticulitis, and pelvic inflammatory disease. Such inflammatory conditions induce adhesions and fix loops of the intestines to each other, adjacent organs, and peritoneal surfaces. Patients with small stage I carcinomas should have a chest x-ray, intravenous pyelogram, complete blood count, urinalysis, and blood chemistry analysis before treatment. Patients with advanced carcinomas require cystoscopy and proctoscopy. It is important to apply the FIGO rules for clinical staging (Table 112.3).192 FIGO guidelines clearly state that for staging purposes, the following examinations are permitted: cystoscopy, inspection, colposcopy, endocervical curettage, hysteroscopy, proctoscopy, intravenous pyelography, chest x-ray, and skeletal x-rays.193 Findings from such examinations as lymphangiography, laparotomy, laparoscopy, computed tomography (CT) scanning, magnetic resonance imaging (MRI), and other examinations unnamed by FIGO should not be the basis for changing the clinical stage, despite the fact that such examinations or procedures can provide valuable information for planning therapy. The tumor, node, metastasis (TNM) staging categories have also been accepted by FIGO.194 Lymph node status is not addressed in the FIGO staging system for carcinoma of the cervix, but three radiologic imaging techniques are available to evaluate lymph node status: CT, MRI, and lymphangiography.

Table 112.2. Relapse Rates for Patients with Stage IIB or III Cancer of the Cervix According to Average Hemoglobin Level during Radiation Therapy.

Table 112.2

Relapse Rates for Patients with Stage IIB or III Cancer of the Cervix According to Average Hemoglobin Level during Radiation Therapy.

Table 112.3. Modified FIGO Staging.

Table 112.3

Modified FIGO Staging.

The best radiologic imaging technique for detecting lymph node metastases is unclear. No prospective randomized studies in the same patient population compare CT, MRI, and lymphangiography. Lymphangiography well defines nodal size and architecture, but technical problems are common, it is difficult to perform, and it is not universally available. A large node completely filled with cancer may not fill with any contrast material. In addition, the hypogastric, obturator, and presacral nodes usually do not fill with contrast dye, so these drainage pathways are not studied.195 Nonetheless, when lymphangiography performed by a skilled radiologist produces evidence of the classic filling defect in the lymph nodes, it supplies very powerful evidence of metastatic cancer.

CT or MRI can detect enlarged nodes, but MRI is also useful in determining the size of the cervical tumor, the absence or presence of parametrial extension, and the regression of the size of the cervical primary following neoadjuvant chemotherapy or primary radiation therapy.196–198 One large study compares lymphangiography and CT. Heller and colleagues reported for lymphangiography a sensitivity of 79% and a specificity of 73%, and for CT a sensitivity of 34% and a specificity of 96%.199 Three other studies compare CT and MRI.200–202 All three studies support MRI as the cross-sectional imaging technique of choice in carcinoma of the cervix. Although such findings support MRI, they lack statistical power to detect significance. Both CT and MRI have a place in detecting the spread of cervical cancer, but CT and MRI findings must be verified by obtaining a tissue specimen at surgery by fine-needle aspiration. Lymphangiography can also provide excellent results, especially in those institutions that have a specific interest in it. The skill of the interpreting radiologist, the quality of films, and the experience of the technicians performing lymphangiography account for differences in the results of the studies. The author (JTW) is in agreement with the consensus statement issued by the National Institute of Health in the 1996 meeting on cervical cancer concerning the effectiveness of lymphangiography in detecting lymph node metastases in cervical cancer.203 For a comprehensive view, see Scheidler and colleagues, who present a meta-analysis of radiologic studies evaluating lymph node metastases in patients with cervical cancer.204

When lymph node metastases are sought surgically, the extraperitoneal approach is currently the preferred technique (Figs. 112.22 to 112.25).205,206 It is preferred because high complication rates resulted from using a transperitoneal approach followed by radiation therapy.207 During surgery, selected pelvic and para-aortic nodes are removed. These include a representative node from the obturator group, external iliac, common iliac, precaval, and para-aortic nodes. In addition, any suspicious nodes are removed, whether identified clinically or by presurgical imaging studies. All methods of detecting nodal disease have the potential for false-negative findings.

Figure 112.23. A right lower quadrant J-shaped incision was used in the “extraperitoneal” lymph node dissection.

Figure 112.23

A right lower quadrant J-shaped incision was used in the “extraperitoneal” lymph node dissection.

Figure 112.22. Shown here and in Figures 112.

Figure 112.22

Shown here and in Figures 112.23 to 112.25 are films of a case with nodal enlargement. This lymphangiogram indicates enlargement in the right external and common iliac group.

Figure 112.25. This photograph of the vessels was taken after complete removal of the involved node.

Figure 112.25

This photograph of the vessels was taken after complete removal of the involved node.

Figure 112.24. The enlarged node is identified and is 5 × 6 cm.

Figure 112.24

The enlarged node is identified and is 5 × 6 cm.

As for pelvic washings for cytology, their need is questionable. Peritoneal cytology was obtained in 242 patients with stages 1B–IIB squamous cell carcinoma of the cervix treated surgically, and results were positive in 4 (1.7%) patients. The authors concluded that peritoneal cytology in these patients was of little value in treatment planning.208

In patients treated with surgery, surgeons rely on the pathologist’s findings as extremely accurate statements on the extent of disease. Although these findings are not allowed to change the FIGO clinical stage, the American Joint Commission on Cancer encourages the use of the TNM pathologic classification nomenclature for surgically treated patients.194

Treatment

Radiotherapeutic Management

The management of invasive carcinoma of the cervix with primary radiation therapy involves a combination EBRT plus a contribution of either low-dose-rate or high-dose-rate intracavitary irradiation.

Types of radiotherapy
External beam radiation therapy

Many different types of equipment are available for delivering EBRT. The high-energy era began in 1954 with the development of the cobalt-60 machines. Today, however, linear accelerators provide a wide range of high-energy photons that have advantages over cobalt 60 (Fig. 112.26).209 These high-beam energies (15–25 MV) are preferred for patients with cervical carcinoma. The build-up of these energies is 3 to 4 cm beneath the skin, whereas the maximum build-up for the cobalt 60 and 4 MV is less than 1 cm beneath the skin. There is no tissue at risk for disease in the build-up area for the 15- to 25-MV teletherapy machines, and the skin-sparing effect is desirable.

Figure 112.26. These three figures compare dose distributions from external-beam radiation in a patient with an anterior-posterior diameter of 22 cm.

Figure 112.26

These three figures compare dose distributions from external-beam radiation in a patient with an anterior-posterior diameter of 22 cm. A.Numbers indicate dose distribution (measured in cGy units) using anterior and posterior opposed beams of cobalt 60. (more...)

EBRT is used initially in patients with bulky tumors. The usual plan is to give 40 to 45 Gy to the whole pelvis. This gives a homogeneous distribution to the central mass plus the regional lymph nodes. Such treatment reduces the primary tumor and any regional lymph nodes harboring disease, and it destroys microscopic foci in lymph-vascular spaces adjacent to the tumor. The shrinkage of the primary tumor allows better dose distribution from intracavitary irradiation.

A standard course of 40 to 45 Gy whole-pelvis EBRT plus two 48-hour or equivalent intracavitary irradiation systems usually delivers at least 85 Gy to point A (a reference location 2 cm lateral and 2 cm superior to the cervical os) and 50 to 56 Gy to the lateral pelvic wall structures. Patients treated with cobalt 60 or 4- to 6-MV photons to 40 to 45 Gy can obtain some skin-sparing effect with the four-field technique using parallel opposed anterior/posterior-posterior/anterior fields and lateral fields. The four-field technique may also be used with 15- to 25-MV machines. There are no standard-size pelvic or lateral portals in contemporary radiation therapy planning for patients with carcinoma of the cervix. Patients are heterogeneous in reference to size and bony landmarks and require individual study for the proper selection of field size. Greer and colleagues210 studied the anatomy of the common iliac, external iliac, and presacral lymph nodes and attachments of the uterosacral and cardinal ligaments at the time of pretreatment retroperitoneal node removal in patients with advanced carcinomas of the cervix. Their observations have helped define the field sizes necessary to cover various node groups.

Simulation films, as well as CT, MRI, and lymphangiography, guide the radiation oncologist in selecting boundaries for the portals. The lower boundary of the anterior/posterior-posterior/anterior field is midpubis or 4 cm below the lowest extent of vaginal or cervical disease. The upper border is the L4-L5 interspace. This interspace includes the external iliac nodes and a portion of the common iliac nodes in most patients (Fig. 112.27).211 The lateral margins extend 1.5 to 2 cm lateral to the pelvic margins. The lateral margins of anterior/posterior–posterior/anterior fields will not consistently cover the obturator-hypogastric nodes unless a crescent of the femoral head is included. If a four-field technique is used, selection of the lateral margins usually encompasses S3 posteriorly.

Figure 112.27. Anterior-posterior and cross-table lateral drawings of a patient whose lower extremity lymphangiogram was normal.

Figure 112.27

Anterior-posterior and cross-table lateral drawings of a patient whose lower extremity lymphangiogram was normal. The obturator and hypogastric nodes are not visible. The drawings illustrate and name the regional lymphatics of the pelvis and lower lumbar (more...)

Custom blocks may be used to shield the small bowel, soft tissue, and, in some cases, the lower rectum for the lateral fields. Techniques for shielding vary greatly among radiation therapists. Perez and colleagues employ numerous shielding techniques in both anterior/posterior-posterior/anterior prescriptions and for lateral fields.212

Para-aortic node involvement requires extended fields. We prefer a single anterior/posterior-posterior/anterior field that encompasses the pelvic and para-aortic nodes. The width of the extended or para-aortic field is 6 to 8 cm. The radiation dose to the entire field is 1.8 Gy daily (the typical daily fraction for pelvic radiation therapy) for a total dose of 45 Gy.

Patients with grossly positive pelvic nodes within the 40- to 45-Gy field require a boost with a small field (Figs. 112.28, 112.29).213 The dose to the boost area is 8 to 10 Gy. The total dose to the positive nodes, including a 1- to 2-cm margin, is 60 to 62 Gy, which includes the contributions from two brachytherapy intracavitary systems.

Figure 112.28. Shown here and in 112.

Figure 112.28

Shown here and in 112.29 are the films of a 46-year-old woman who was referred with a diagnosis of squamous cell carcinoma of the cervix identified by cone biopsy. Pelvic examination revealed a bulky lesion, 4.5 cm in diameter, that involved the cervix. (more...)

Figure 112.29. The patient received an additional 10 Gy in 1 week to the positive node through 7 × 6-cm fields using 25 MV photons.

Figure 112.29

The patient received an additional 10 Gy in 1 week to the positive node through 7 × 6-cm fields using 25 MV photons. Reprinted with permission from Fletcher.

An occasional patient will have disease so extensive that only EBRT can be used. Field reductions usually start after 45 Gy and total doses range from 60 to 65 Gy. The use of EBRT alone is undesirable because local control of the primary cervical carcinoma is highly dependent on the intense central dose delivered by intracavitary irradiation therapy.

Intracavitary radiation therapy

Radium was used early in this century to treat cervical malignancies, and the uterus and vagina provided ideal receptacles for radium sources. Radium sources placed in an intrauterine tandem, which passes through the endocervical canal, irradiates the tumor circumferentially, and two vaginal ovoids placed lateral to the exocervix contribute to the dose from the sources in the tandem. The high dose delivered by the radioactive sources in the tandem and ovoids rapidly diminishes when measured at a point 1 to 2 cm away from the radioactive sources. This dose reduction explains how organs adjacent to the cervix are spared the high doses received by the cervix. The physics of intracavitary radiation therapy in which the dose rapidly falls off (intensity is calculated by the inverse square law) makes radium and cesium ideal sources for delivering a high dose to the cervix and much lower doses to the surrounding normal tissue, sparing the bladder and rectum.

The radiation dose to a reference point in the pelvis depends on the amount of radium or cesium in each ovoid and in the intrauterine tandem, the distance from each source to the reference point, and the length of time the radioactive source remains in place (Fig. 112.30). The radioisotopes used for low-dose intracavitary irradiation systems are radium 226 and cesium 137. Because radon gas is a product of radium decay and can pose radiation problems, radium is being replaced with cesium 137, which is safer but has the same therapeutic value. These sources usually deliver at least 85 Gy to point A (a reference location 2 cm lateral and 2 cm superior to the cervical os) and 50 to 56 Gy to the lateral pelvic wall structures. Optimal placement of the Fletcher-Suit-Delclos uterine tandem and ovoids (which are shielded anteriorly and posteriorly and hold the radioactive source perpendicular to the axis of the vagina) produces a pear-shaped distribution laterally and a very high dose centrally. This rapid fall-off in dose offers an excellent therapeutic advantage.

Figure 112.30. Intracavitary applicators for treating carcinoma of the cervix take advantage of the inverse square law.

Figure 112.30

Intracavitary applicators for treating carcinoma of the cervix take advantage of the inverse square law. The dose delivered by a radioactive source varies inversely as the square of the distance from the source to that point. A.The drawing shows the influence (more...)

Numerous designs for intracavitary applicators are currently in use. Each applicator system commercially available has recommended loading prescriptions. Since the physical characteristics of these applicators are quite different, the loading recommendations between systems are not interchangeable.

The Fletcher-Suit-Delclos applicator used at The University of Texas M.D. Anderson Cancer Center in Houston consists of a rigid metal tandem with an adjustable flange, which can be set to correspond to the length of the uterine canal, and two cylindrical colpostats that are positioned in the vaginal fornices (Fig. 112.31). X-rays are taken in the operating room to check the position of the tandem and ovoids in reference to silver seeds that mark the anterior and posterior lips of the cervix. If the position is not optimal, the applicator is removed and reinserted and the process is repeated until the tandem and ovoids are in the desired relationship to the cervix. Variables are repositioned, if necessary, and rechecked. The cycle is repeated until the desired relationship is obtained. The system is loaded manually or by remote control after the patient returns to her room. Radiation exposure to personnel is minimal. Intracavitary radiation therapy is initiated within 1 to 2 weeks of completion of pelvic radiotherapy, and two equal applications are given approximately 2 weeks apart. At the M.D. Anderson Cancer Center, intracavitary irradiation therapy is specified by the descriptions of the volume encompassed by the 63-Gy isodose contour, and calculated doses to the bladder, rectal, and vaginal reference points are made.

Figure 112.31. Left to right; Afterloading colpostats (2 cm in diameter) and plastic jackets used to increase the diameters to medium (2.

Figure 112.31

Left to right; Afterloading colpostats (2 cm in diameter) and plastic jackets used to increase the diameters to medium (2.5 cm) and large (3 cm); half cylinders (radius, 0.8 cm) for narrow vaults (maximum diameter with the afterloading tandem in between (more...)

The dose distribution from various tandems and ovoids is markedly variable. Some of the variations can be attributed to the patient’s anatomy (influenced by age and obstetrical history) and tumor growth characteristics. The dose to a specific point in the pelvis in one patient may bear minimal resemblance to the dose received at that exact point in another patient. In 1985, the International Commission of Radiation Units and Measurements recommended that such reference points as point A not be used because they are located in a region where the dose gradient is high and any inaccuracy in the determination of distance results in large uncertainties in the absorbed doses evaluated at these points.214 (Point A is located 2 cm lateral to and 2 cm superior to the external os.) Despite these well-known objections, many clinicians persist in using the point A method to describe intracavitary implants in the treatment of cervical cancer.

Practice patterns also vary widely among radiation oncologists.215 High-dose rate (HDR) is slowly replacing conventional low-dose rate (LDR) primarily because of radiation safety. HDR also is credited with a lower risk of late complications.216 The optimal fractionation schedule for treating cervical cancer using HDR brachytherapy is unknown, leaving only single institutions with significant experience to serve as models for dose fractionation.217

Complications of radiation therapy

Women with gynecologic cancers are at risk of experiencing some of the most serious complications of radiation therapy. Radiation injury from EBRT to the pelvic structures is a function of the daily dose, total dose, and the size of the portals or fields treated.218 Injury to the bladder, vagina, and rectum is a summation of radiation from EBRT and from brachytherapy applicators.

Radiobiologically, the therapeutic ratio in patients with cervical cancer is generally favorable, that is, the curve for tumor control is displaced to the left of the curve for normal-tissue injury (Fig. 112.32).218 This therapeutic ratio confers a high level of cancer cell death. Normal tissues usually incur only sublethal injury from the dose given, and cells retain the ability to repair; however, it is impossible to predict both radiocurability and the potential for radiation injury in individual patients. Equal doses of ionizing radiation have different biologic effects in individual patients; therefore, curability and normal-tissue tolerance is unpredictable. Occasionally, patients with small lesions treated with conventional doses of radiation suffer normal-tissue injury. Fortunately, severe injury is infrequent when patients receive 40 Gy in 4 weeks or 45 Gy in 5 weeks of whole-pelvis radiation and undergo two well-planned and executed intracavitary brachytherapy insertions. Patients may be treated with EBRT in excess of 40 Gy in 4 weeks; however, reductions are usually made in the size of the external beam portals and the dose from brachytherapy. Patients with advanced cancers that require large fields and high total doses are expected to have some problems with normal-tissue healing. Cancers with large diameters require larger doses of radiotherapy than those with small ones to ensure a reasonable chance of cure.

Figure 112.32. Tumor control probability (TCP) and the probability of normal tissue injury as a function of radiation dose in a hypothetical case in which the therapeutic ratio is “favorable” (i.

Figure 112.32

Tumor control probability (TCP) and the probability of normal tissue injury as a function of radiation dose in a hypothetical case in which the therapeutic ratio is “favorable” (i.e., the curve for tumor control is displaced to the left (more...)

Because certain patients are at an increased risk for injury to the gastrointestinal tract, bladder, and vagina, models have been devised to predict their risk of injury.219 Patients who have previously had abdominal operations, pelvic inflammatory disease, peritonitis, or any process that causes loops of bowel to become fixed because of scar tissue are more likely to experience injury. Similarly, the vascular occlusive effects of collagen diseases, diabetes, or arteriosclerosis are accelerated by radiation-induced endarteritis.

Normal tissue’s sensitivity to ionizing radiation is dependent on cell type. Rapidly proliferating mucosal cells are very sensitive, and those of the intestines and bladder are killed during treatment. The acute clinical manifestation may be diarrhea. Because radiation’s effects are cumulative, the clinical effects of chronic injury appear near the termination or after completion of treatment. Ionizing radiation has a progressive occlusive effect on blood vessels and induces scarring in connective tissue.220 Initially, damage to the intima of the small arteries leads to hyalinization of the intima and media, and the arterial wall becomes hypertrophic. The lumen of the artery is irreversibly occluded and the final process is termed endarteritis, which is specific for radiation-induced vascular changes. The submucosal and serosal venules and lymphatics become telangiectatic, and the bowel wall is thickened as increased collagenization and hyalinization occur (Fig. 112.33). The thickened serosa is covered by an inflammatory exudate that promotes adherence to adjacent bowel segments. Poorly vascularized segments become edematous as veins thrombose and arteries occlude. Ischemia induces focal necrosis, which produces mucosal ulceration. The end point of the process depends on the severity of the ischemia and ulceration and the degree of fibrosis accompanying the healing process. The spectrum of events extends from minor fibrosis of no consequence to fibrous strictures that cause obstruction or to full-thickness necrosis (Fig. 112.34) of the bowel wall with perforation.

Figure 112.33. Note the agglutination by adhesions and scar tissue, inducing an obstructed distal ileum.

Figure 112.33

Note the agglutination by adhesions and scar tissue, inducing an obstructed distal ileum. Note the proximal small bowel, which is normal, at the top of the incision.

Figure 112.34. Chronic injury to the small bowel resulted in the development of a necrotic loop.

Figure 112.34

Chronic injury to the small bowel resulted in the development of a necrotic loop.

Problems during therapy

Consequences of pelvic irradiation include symptoms related to the bowel, bladder, rectum, and vagina. Minor small-bowel motility disturbances with diarrhea as the main complaint are relieved with antiparasympathetic drugs. Patients who undergo extended-field irradiation are more susceptible to acute symptoms than are patients who receive pelvic treatment. Concomitant use of chemotherapy with EBRT will intensify these acute but usually reversible events. The duodenum and the terminal ileum are fixed by their mesentery and prone to receive higher doses than bowel segments that have a longer mesentery and are mobile. Acute reactions are clinically evident when the mucosa becomes thin, flat, and atrophic. The actively proliferating intestinal crypt cells are the primary targets. Stem cells are responsible for the maintenance of epithelial cells in the crypts and for villus height and function. Insufficient stem cell activity causes flattening of the villi. The loss of surface area as a result of flattening and denudation of the epithelium causes a decrease in the absorption of bowel contents, such as bile salts, which results in diarrhea and abdominal cramps. Nausea and vomiting may occur when the upper small bowel is included in the treatment field. Disturbances in fluid and electrolyte balance can occur with excessive vomiting or diarrhea. If the irradiation is continued when acute reactions are clinically evident, superficial mucosal ulcerations develop, and absorption or transudation of bacteria and other toxic products may result in local serosal irritation. In extreme cases, the clinical picture will mimic acute abdominal distress with rebound tenderness followed by an adynamic ileus. Surgical intervention is not indicated unless there is clear evidence of perforation. Treatment is cessation of radiation therapy and medical management. In severe cases, the patient receives nothing orally, and intravenous fluids are required for 7 to 10 days. Cessation of irradiation and bowel rest result in healing. Therapy interruptions are discouraged; however, when necessary they should be limited to 7 to 10 days. The diarrhea and abdominal pain may continue after completion of external beam irradiation, but they represent a limited process and disappear within 2 to 3 weeks.

Pelvic irradiation may cause acute proctosigmoiditis. Two to 3 weeks after starting therapy, patients may experience diarrhea, pass bloody mucus, and have rectal tenesmus. The latter is more of a problem in patients who have the full length of the vagina irradiated. This is a limited process that heals when therapy is complete. Patients who have diarrhea and anemia after therapy usually have a late or chronic injury, and sigmoidoscopy may show an ulcer.

During radiation therapy, dysuria may also develop, making patients need to urinate frequently. If no bacteria are identified, the symptoms are attributed to the acute effects of radiation on the cells of the bladder mucosa. These symptoms can be alleviated with bladder antispasmodics. If hematuria is severe, causes of hematuria other than radiation injury must be ruled out.

Vaginal mucositis may also develop during therapy. When the entire vagina is covered in the external-beam field, physicians should expect mucositis of the vagina and labia minora by the end of the third week of therapy. Brachytherapy may cause mucositis involving the upper half of the vagina. Pain and discharge are frequent but generally self-limiting, and healing is complete in 4 to 6 weeks. On inspection, a gray, very superficial mucositis, appearing inflammatory, may be found. Healing may be assisted by using an estrogen-containing vaginal cream and an antibacterial vaginal suppository or cream. Prompt attention and follow-up are necessary because some injuries progress to necrosis, which has much more serious consequences.

Problems after therapy
Rectal Injury

 The rectum is fixed in close proximity to the cervix and receives, in addition to EBRT, a high dose from brachytherapy sources. Injuries are usually self-limiting, and healing is uneventful. Strictures with significant narrowing of the lumen are more likely to involve the sigmoid colon, and the intrauterine tandem contributes to this injury (Figs. 112.35, 112.36). Management with diet modifications and stool softeners may be successful. Significant narrowing causing symptoms, with or without ulceration and bleeding, requires surgical intervention. Narrowing with obstruction may lead to necrosis of the bowel wall and abscess formation. This abscess is not static and may drain along the path of least resistance, inducing a fistula, or the abscess may rupture into the peritoneal cavity and induce peritonitis. Prompt diagnosis and fecal stream diversion are the first phase in surgical management. Resection of the injured area and reanastomosis of the bowel is a matter of timing and the severity of the injury. If the tissue is unfit for reanastomosis, the perforated segment must be exteriorized or resected, leaving a Hartmann’s pouch and performing an end colostomy. Obstruction without perforation is treated with a diverting ileostomy or right or hepatic flexure colostomy if later resection and anastomosis are the treatment plan. Resection and reanastomosis require a properly prepared bowel. The blood supply to the descending colon may be disrupted if a descending colostomy is performed when there is the possibility for resection and reanastomosis at a later date.

Figure 112.35. Here and in Figure 112.

Figure 112.35

Here and in Figure 112.36 is a case in which stricture of the sigmoid colon occurred. Left;An anterior-posterior drawing shows the injury and a long intrauterine tandem. Right;This lateral view indicates two locations for a posterior-positioned tandem (more...)

Figure 112.36. This barium enema film was taken 18 months after radiotherapy and shows a strictured segment of injured sigmoid colon.

Figure 112.36

This barium enema film was taken 18 months after radiotherapy and shows a strictured segment of injured sigmoid colon.

Small-Bowel Injury

The treatment of choice for an obstructed and damaged segment of small bowel is resection and reanastomosis. This approach is preferred if enough bowel remains to prevent a short-bowel syndrome. The author’s preference is to anastomose the small bowel to the transverse colon, inasmuch as the middle colic artery is a dependable blood supply. Chances for a successful anastomosis are increased if one of the segments of bowel used in the anastomosis has not been irradiated.

Some patients have dense adhesions with multiple loops of bowel adherent to each other and firmly fixed deep in the cul-de-sac. In this case, the best surgical option may be intestinal bypass instead of resection. The aim is to free enough bowel to sustain the patient and anastomose the proximal small bowel to the transverse colon. Such an anastomosis may be performed using a side-by-side anastomosis or an end-to-side anastomosis with the creation of a mucus fistula. The risk of postoperative complications is high for patients having a bypass operation, since the bypassed small bowel or injured segments remain. A loop of dead or severely compromised bowel may be present and hidden from view. Longer term, the patient may have blind loop syndrome, with all of the clinical and metabolic complications that accompany it.

Injury may be less obvious when the obstruction is very low grade and intermittent or when malabsorption or bleeding is the patient’s problem. Such events are chronic in nature, and the patients usually have had gastrointestinal complaints for months before diagnosis. Patients with a partial low-grade small-bowel obstruction present a complex diagnostic challenge. Symptoms may be limited to intermittent episodes of postprandial cramps and distention. Weight loss is common. Patients with chronic nonspecific gastrointestinal complaints are frequently diagnosed as having a neurosis related to their previous cancer. Physical examinations are usually negative, and such diagnostic imaging techniques as barium studies of the small bowel are not distinctly abnormal. Patients may have multiple areas of narrowing that do not cause diagnostic changes on imaging studies. Chronic injuries of this nature are slowly progressive. The patient will eventually present with clinical findings of a small-bowel obstruction. Some obstructions are hard to identify at the time of surgery (Figs. 112.37, 112.38). During hospitalization, as efforts are made to correct the underlying nutritional and metabolic imbalance, nasogastric suction decompresses the bowel and alleviates abdominal pain. After a few days, a subset of patients will feel better, and a level of bowel function will return as abdominal distention resolves. The return of bowel function is not an indication that the problem has been solved by medical management. These patients may leave the hospital temporarily relieved; however, they frequently return, and the previous delay in surgical management increases the chances for the occurrence of such a catastrophic event as necrosis with perforation (Figs. 112.39, 112.40).

Figure 112.37. Note the subtle stricture indicated by the arrow.

Figure 112.37

Note the subtle stricture indicated by the arrow.

Figure 112.38. Note the thickened lamina propria, scarred bowel wall, and disrupted mucosa.

Figure 112.38

Note the thickened lamina propria, scarred bowel wall, and disrupted mucosa. Such events lead to symptomatic subacute obstructions. The partial obstruction induces stasis, which favors malabsorption and anemia.

Figure 112.39. Note the free air beneath the diaphragm on the chest x-ray.

Figure 112.39

Note the free air beneath the diaphragm on the chest x-ray.

Figure 112.40. The arrows point to a necrotic loop of distal ileum that was perforated because of radiation therapy-induced endarteritis.

Figure 112.40

The arrows point to a necrotic loop of distal ileum that was perforated because of radiation therapy-induced endarteritis. The patient had had two prior admissions, and her incomplete small-bowel obstruction was managed medically.

Vaginal Necrosis

Vaginal necrosis may develop after completion of intracavitary radiation therapy. The process is usually diagnosed shortly after treatment. This injury is painful and associated with a foul-smelling discharge. On speculum examination, the apex of the vagina is replaced by an ulcer with a necrotic center. The important aspect of patient care is prompt recognition. The treatment requires hospitalization. Then, three or four times a day, the patient should be placed on the gynecologic examination table, and, with the aid of a speculum and a good light source, the area of necrosis should be carefully cleansed with dilute hydrogen peroxide and water. Some clinicians apply estrogen cream and antibacterial cream at the conclusion of each cleansing. Persistence with this treatment will clear the necrosis. Failure to recognize and start prompt therapy may allow the necrosis to progress, resulting in further tissue destruction and in the formation of vesicovaginal or rectovaginal fistulae. Vesicovaginal and rectovaginal fistulae, occurring in the first few months following completion of radiation therapy, are usually preceded by progressive vaginal necrosis.

Urologic Complications

Severe late complications include ureteral stenosis, urinary fistula bladder ulcers, hemorrhagic cystitis, and bladder contraction. A retrospective analysis of 10,709 patients with gynecologic malignancies treated over 22 years with radiotherapy was reviewed for severe late urologic complications. The study identified 133 cases (1.24%) with severe late urologic complications. The most common was bladder dysfunction (65 patients), which included 38 patients with hematuria and/or dysuria, followed by urinary fistula (35 patients) and ureteral stenosis (33 patients). One hundred and eighteen patients underwent surgery to correct the complications, and there were five (4.24%) postoperative deaths. Although this complication rate is low, late effects of therapy can be very serious, requiring careful monitoring in follow-up evaluations.221

Radiation-induced hematuria may progress to severe hemorrhage. Clots form in the bladder and may block the urethra or extend in retrograde fashion up the ureters. Endoscopy is necessary to evacuate blood clots and to identify the source of the bleeding. Malignancy is ruled out with cytology or biopsy. Discrete areas or points of bleeding may be controlled with laser therapy. Medical management with continuous irrigation of the bladder is the recommended initial treatment. Bleeding is usually diffuse, and continuous saline solution irrigation is the simplest solution. The irrigation flow rate is fast enough to prevent clot formation. Persistent irrigation and transfusions to keep the hemoglobin count above 10 gm/dL with replacement of clotting factors induces hemostasis in most cases. Other choices for bladder irrigation agents are a 1% alum solution for 5 days or prostaglandin E1 (400 μg/dL in normal saline) instilled intravesically and retained for 30 minutes three times a day for 5 days.222

Formalin instillation is quite effective for intractable hemorrhage unresponsive to other agents, but significant morbidity is associated with formalin use, even in experienced hands. Complications include detrusor muscle fibrosis with loss of capacity, ureteral obstruction due to fibrosis induced by reflux, and papillary necrosis. In extreme cases, formalin may enter the circulation during instillation, and fatal liver failure may occur. In order to use the effectiveness of formalin yet overcome the morbidity, physicians have used topical formalin in patients with severe bladder and rectal bleeding. Ribbon gauze is soaked with 4% dilute formalin solution, and the rectum is packed.223 Endoscopic topical placement of formalin-soaked pledgets have been successful in controlling hemorrhage due to radiation cystitis.224

Severe hemorrhage resistant to conventional therapies may be controlled by interventional radiography techniques. Arteriography followed by the injection of an occlusive material may suffice. As a last resort, urinary diversion with or without cystectomy is effective. Postoperative complication rates are high, and all other methods should be tried before surgical intervention.

Guidelines for managing complications
General Guidelines

In summary, the following guidelines are helpful in managing late or chronic gastrointestinal or urinary complications: (a) injuries are expected to involve multiple sites, and studies should include evaluation of the bladder, rectum, sigmoid colon, and small bowel; (b) fistula tracts as well as ulcerated sites should undergo biopsy to rule out recurrent cancer; (c) fistulagrams are helpful in defining the extent and complexity of fistulae; and (d) preoperative review of the radiation therapy record defines the size of the external-beam portals, treatment time, and total dose from external-beam irradiation and brachytherapy, and assists the surgeon in pretherapy patient preparation; (e) bowel rest, total parenteral hyperalimentation, and aggressive local care of necrotic areas improve chances for successful operative intervention.

Following high-dose radiation therapy, especially in older patients, the vaginal apex agglutinates and scars, and the vagina shortens. These changes are not unexpected and are of no consequence unless they interfere with sexual function, which may change in any patient treated for carcinoma of the cervix, irrespective of treatment modality. Regular intercourse helps a couple adjust to the change. Vaginal dilators are routinely issued but rarely routinely used. An estrogen-containing vaginal cream and use of the dilator are beneficial if used nightly for the first 6 months after therapy.

The M.D. Anderson Cancer Center Experience

A report by Eifel and colleagues225 describes the long-term complications encountered in 1,784 patients with stage IB carcinoma of the uterine cervix treated at The University of Texas M.D. Anderson Cancer Center between 1969 and 1989. This retrospective review studied the complication rate associated with treatment with the Fletcher-Suit-Delclos afterloading intracavitary system. Fifteen hundred and fifty patients were treated by irradiation alone. The majority received external-beam irradiation to the pelvis for a total dose of 40 Gy delivered at 2 Gy per fraction 5 days per week. When a midline block was used during EBRT, it was usually 4 cm in diameter and covered the intracavitary placements. For 64 patients with suspected pelvic nodal disease, a small anterior and posterior field was used to boost exposure to the node(s) for a minimal dose of 60 Gy (a combination of external-beam and intracavitary system radiation). Two hundred thirty-four patients had an adjuvant extrafascial hysterectomy, and 111 patients had a transperitoneal pretreatment laparotomy. Table 112.4 includes the grading system used for judging the severity of complications. Overall, patients who survived 3 years after treatment had a 7.7% probability of having a major complication from radiation therapy. At 5 years, the risk increased to 9.3%. Table 112.5 gives the complications by site and severity. The actuarial method was used to calculate complication rates.226 The most severe urinary tract complications were hematuria, ureteral stricture, and vesicovaginal fistula. Of 25 patients hospitalized for hematuria, 65% had no other bleeding episodes (median follow-up, 54 months). Twenty-nine patients had ureteral strictures, and 21 patients experienced bladder fistulae. Three fistulae healed and one was surgically repaired. Eight patients had urinary diversions with a conduit, and four died, three with complex bowel and bladder fistulae and one of a myocardial infarction during an episode of hematuria. Forty-five patients had complications involving the rectum, usually causing symptoms within the first 24 months following therapy. Twenty patients had rectal stricture, and 16 had a rectovaginal fistula. Nine patients had sigmoid complications, seven experienced perforation, and three died. Forty patients developed fistulae of a grade ≥3. The overall risk of fistula formation was 3.0% at 20 years. The risk of fistula formation was higher in the 234 patients who underwent adjuvant hysterectomy (5.3 vs. 2.6% at 20 years; p = .004) and in the 111 who underwent pretreatment laparotomy (5.2 vs. 2.9%; p = .007). The risk of small-bowel obstruction was 5.3% at 20 years. The rate of small-bowel obstruction was greater in patients having pretreatment laparotomy (14.5 vs. 3.7% at 10 years; p < .0001). The risk of small-bowel obstruction was also increased in 299 patients who weighed less than 120 pounds at the time of treatment (8.2 vs. 3.6%; p = .004). These complication rates compare favorably with those of others.212,227

Table 112.4. Grading of Complications.

Table 112.4

Grading of Complications.

Table 112.5. Complications of Radiation Therapy in 1,784 Patients with Stage IB Carcinoma of the Uterine Cervix.

Table 112.5

Complications of Radiation Therapy in 1,784 Patients with Stage IB Carcinoma of the Uterine Cervix.

Surgical Management
Cervical conization

 Cervical conization is a procedure that can be diagnostic, therapeutic, or both. A conization specimen is conical, as the name implies, and its size varies according to the area in question. The cone is shallow when removing an exocervical lesion. A deeper cone is taken when the endocervix is being investigated. Patients requiring conization usually have one of the following: normal colposcopy findings and an abnormal Pap smear or positive endocervical curettage specimens; abnormal colposcopy findings because of failure to visualize the entire squamocolumnar junction or to define the extent of the lesion; microinvasive carcinoma on a biopsy specimen, adenocarcinoma in situ on biopsy or endocervical curettage specimen, or a lack of correlation between cytologic (Pap smear), colposcopic, and histologic interpretations. Conizations may be done with a scalpel, laser, or with a LEEP device.

Performing conization well is not easy. Good surgical judgment and experience are essential to obtaining a proper specimen for diagnosis and/or treatment, retaining a competent cervical os, and avoiding injury or laceration to the lateral cervical wall and accompanying hemorrhage. Complications can occur with any of the described techniques.

Hysterectomy: History and classification

The use of hysterectomy to treat carcinoma of the cervix deserves some discussion. In 1898, Wertheim of Vienna developed a surgical procedure for removal of some of the pelvic lymph nodes as well as the parametrium during hysterectomy in the treatment of invasive carcinoma of the cervix. Wertheim reported a series of 270 patients in 1905 and a series of 500 patients in 1911.228 The complication rate was high. Therapy for cervical cancer was changing because radium was being used during this same time interval, and deep x-ray therapy was added in the early 1920s.

Meigs in Boston, who was concerned with cases in which disease recurred in nodes after radiation therapy, started doing complete pelvic lymphadenectomies. Meigs also extended the parametrial dissection and obtained a wide vaginal cuff. He described a technique for freeing the ureter from its tunnel, which allowed wide excision of the uterosacral and cardinal ligaments. He deserves credit for the type III, or radical, hysterectomy as practiced today.229 Although Meigs removed all of the pelvic nodes, Wertheim performed a selective lymphadenectomy. Meigs’ initial report gave a 5-year survival rate of 75% for selected patients with stage I carcinomas of the cervix; however, there was a 9% ureteral fistula rate. Reports by experienced gynecologists over the years have shown better survival rates and a decreasing fistula rate. In 1976, Morley and Seski reported a series of 208 unselected patients with stage IB carcinomas with an 87% 5-year cure rate and a 4.8% incidence of ureteral fistula.184 In 1993, Averette and colleagues reported the largest single series in the United States.179 In 978 patients treated with the traditional Wertheim-Meigs radical hysterectomy and pelvic lymphadenectomy between 1965 and 1990, the combined urinary fistula rate was 1.4% (0.8% ureteral and 0.6% bladder). The corrected 5-year survival rate for patients with stage IB carcinoma was 90.1%, and the overall 5-year survival rate was 87.9%. Comparable survival rates have been published since 1970 and attest to the effectiveness of the operation (Table 112.6230–234

Table 112.6. 5-Year Survival Rates for Patients with Stage IB–IIA Cervical Cancer Treated with Radical Hysterectomy and Bilateral Pelvic Lymphadenectomy.

Table 112.6

5-Year Survival Rates for Patients with Stage IB–IIA Cervical Cancer Treated with Radical Hysterectomy and Bilateral Pelvic Lymphadenectomy.

A variety of operations have been adopted for primary treatment of preinvasive and invasive carcinoma of the cervix, and these extrafascial hysterectomies have been described by Rutledge.235 The intrafascial hysterectomy was first described in 1929 by Richardson.236 This operation was initially for patients with benign fibroids, and the indications were expanded to include other benign diseases. The technique offered a safe way to remove large fibroids, to prevent blood loss by double clamping and ligating the vessels, and to protect the distal ureter.

The modified radical hysterectomy (type II) was originally meant to allow protection of a lateral segment of the pubovesicocervical fascia attached to the lower ureter. Further observations and studies of the spread pattern of stage IB carcinomas of the cervix had also shown that the cardinal ligaments rarely contained microscopic disease, providing a biologic basis for preservation of part of this tissue. The need to modify the type III radical hysterectomy and to decrease ureteral and bladder injury became apparent as the use of preoperative intracavitary irradiation significantly decreased central recurrences. Modifications of the radical hysterectomy were used by Stallworthy237 and others in conjunction with intracavitary irradiation and pelvic lymphadenectomy. Rutledge235 also used a modification (type II) of the more extensive Meigs operation. The modified radical hysterectomy as described by Te Linde (type I) did not include a pelvic lymphadenectomy and was a treatment for preinvasive cervical neoplasia.238 The technique was initially recommended as treatment for CIS and microinvasive carcinoma of the cervix. As the diagnosis of CIS became more precise, there was no longer a need to consider the proximal parametrium medial to the ureter as a risk area. The procedure became obsolete.

Intrafascial hysterectomy

Intrafascial hysterectomy, most frequently used for benign disease, is essentially performed today as described by Richardson in 1929.236 The operation is described for historical purposes so that differences in technique as applied for benign compared with malignant disease can be appreciated. The transection of the round ligament, allowing opening of the broad ligament, is basic to all hysterectomies. The opened broad ligament exposes the ureters and the common iliac, external iliac, and internal iliac vessels. An opened broad ligament provides an approach to the origin of the uterine vessels and exposes the ureter and external iliac artery. The single or double ligation of the infundibulopelvic vessels is performed when the fallopian tubes and ovaries are to be removed. Triple clamping and double ligation of the vascular pedicles were described in the original paper.236 Blood replacement technology was in its infancy. The bladder mobilization may be done with blunt dissection. The uterine vessels are not skeletonized but simply clamped, with the tip of the clamp sliding off the lateral wall of the cervix. The vessels are clamped in this manner, allowing the doubly ligated pedicle to stay as evenly medial to the ureters as possible. As the bladder is separated from the cervix, the pubovesicocervical fascia comes into view and is incised transversely and vertically. The blunt end of the scalpel is useful in dissecting the pubovesicocervical fascia from the cervix. The fascia is rich in small blood vessels and is saved. The clamping of the vaginal angles is done with the closed technique, and the tip of the clamp slides inside the pubovesicocervical–cervical fascial plane. Precise placement of the tip of the clamp inside the fascial plane virtually eliminates ureteral or bladder injury. The vagina is amputated as close to the cervix as possible to prevent any shortening of the vagina and then is closed with interrupted sutures. No effort is made to obtain a vaginal cuff. This intrafascial hysterectomy, by virtue of staying as close to the cervix as possible in securing the uterine vessels and moving inside the pubovesicocervical fascia to protect the bladder and the blood supply to the distal ureters, has a low incidence of urinary tract injuries. This technique is used for patients with benign disease.

Extrafascial hysterectomy

The extrafascial hysterectomy is described for comparison with the intrafascial hysterectomy. Characterizing the extrafascial hysterectomy are the following: (a) the uterine vessels are skeletonized (to lessen the need to slide the tip of the clamp off the cervix) and are clamped and cut to allow the ligated vessels to fall away from the cervix; (b) the pubovesicocervical fascia is not separated from the cervix and is excised with the specimen; (c) the plane for bladder separation from the cervix is created with sharp dissection because blunt dissection is more often associated with accidental entry into the bladder; and (d) the uterosacral ligaments are transected separately near their insertion into the cervix. This frees the uterus and cervix posteriorly and gains mobility for the specimen. This facilitates amputation of the vagina in front of the cervix, securing at least a 1-cm vaginal cuff. The extrafascial hysterectomy as described is frequently used following EBRT and intracavitary irradiation therapy for bulky endocervical carcinomas.

This operation is very similar to a type I modified radical hysterectomy. Both operations require protection of the lateral walls of the cervix, removal of the pubovesicocervical fascia, and establishment of an identifiable vaginal cuff that ensures complete removal of the cervix.

Radical hysterectomies
Type I Radical Hysterectomy

The type I radical hysterectomy is an extrafascial hysterectomy that is essentially the modified radical hysterectomy described by Te Linde.238 Its purpose is to excise the cervix totally with a margin of vagina as well as to avoid incision into the cervix. The initial dissection separates the anterior and posterior sheaths of the broad ligament. The technique uses dissection or skeletonization of the fibroconnective tissue in the broad ligament to expose the uterine artery and vein. The uterine artery and vein are ligated away from the cervix. The ureters, in their tunnels, are undisturbed. The uterosacral ligaments are individually clamped. With the supporting tissues and vessels deflected outward, the vagina becomes mobile, and a 1- to 2-cm cuff can be obtained. This operation can be applied to patients who have high-grade intraepithelial lesions, adenocarcinoma in situ, and microinvasive squamous cell lesions.

Type II Radical Hysterectomy

The type II radical hysterectomy is a less radical version of the type III radical hysterectomy. The mesial half of the parametrium and upper one-third of the vagina are included in the surgical specimen. This is accomplished by exposing the ureters and taking the medial half of the cardinal and uterosacral ligaments instead of taking these ligaments where they attach to the pelvic wall and pelvic floor. The key to success is exposure. The posterior approach is the author’s choice. The posterior peritoneum is incised and the cul-de-sac entered. The uterosacral ligaments are defined by entering the pararectal space. The uterosacral ligament is divided lateral to the rectum, sparing the base of the ligament. This releases the cervix and vagina posteriorly and allows better exposure of the ureters. The bladder is freed from the vagina with sharp dissection, proceeding to the area of the ureterovesical junction. If the ureters are identifiable, they are freed in a retrograde fashion by dividing the tissue medially and superior to the ureters. This allows lateral deflection without removing the ureters from their tunnel, and the distal ureter retains its lateral attachment to the remnants of the pubovesicocervical ligament. The ureteral blood supply from the superior vesicle and uterine arteries is undisturbed. If the exact location of the ureters is not obvious at the ureterovesical junction, the ureters can be freed by entering the web or ureteral tunnel in the broad ligament. The roof of the tunnel is opened medially and superior to the ureter. The uterine vessels are ligated medial to the ureter. This allows the ureters to be rolled laterally, exposing the parametrial and paravaginal tissue. Clamps are placed at a position halfway between the cervix and pelvic wall. The paravaginal tissue is clamped and divided, and the vagina is amputated. The primary indication for the hysterectomy is early invasive carcinoma. The type II operation is applicable when invasion is present, yet the tissue orientation or preparation is not optimal for precise interpretation by the pathologist. The type II operation ensures an adequate paracervical specimen and a vaginal cuff of 2 to 3 cm.

The type II hysterectomy can be performed with a modified or complete pelvic lymphadenectomy. The modified lymphadenectomy includes removal of the following node groups: the obturator, the medial chain of the external iliac node group, and the node at the bifurcation of the common iliac artery. The nodes and lymphatic channels superior and lateral to the external iliac artery and vein are retained and lessen the risk of lymphocyst and edema of the lower extremities.

The type II operation is useful because bladder and ureteral complications are lower with it than those encountered with a type III procedure.

Type III Radical Hysterectomy

The type III radical hysterectomy is the classic Wertheim-Meigs radical hysterectomy. This operation is reserved for patients with stage IB and selected stage IIA carcinomas. The vaginal extension for stage IIA patients should be limited to no more than 1 cm. The parametrium, cardinal, and uterosacral ligaments are severed at the pelvic wall, and half of the vagina is removed. The uterine vessels are taken at their origin from the internal iliac vessels. The ureters are taken out of their tunnel and reflected laterally. This dissection of the distal ureters sacrifices the blood supply from the uterine and superior vesicle arteries. Reflection of the ureters clears the way for applying instruments across the parametrium along the pelvic wall. Complete removal of the cardinal ligaments and the rectal pillars and uterosacral ligaments at their base results in a greater risk of bladder atony, and loss of the distal ureter blood supply results in a greater risk of fistulae.

This operation produces an excellent cure rate in properly selected patients. In the young patient, ovaries are spared. Today, bladder dysfunction is one of the more serious complications encountered. Patient education and the teaching of self-catheterization techniques have reduced this postoperative problem, but loss of the nerve supply to the bladder plagues the operation. A 25-year prospective series showed a combined ureteral and bladder fistula rate of 1 to 2% and also showed that successful repair could be anticipated when a fistula occurred.179

Therapy Guidelines and Decisions

There are some general therapy guidelines. All available information including diagnostic images, laboratory work-ups, endoscopy, or other special procedure reports, pathology reports, slides, or other findings are available for the multidisciplinary review group. A gynecologic oncologist, medical oncologist, pathologist, and radiation oncologist review the pathology slides and diagnostic images and discuss treatment options. The parameters are clearly stated and used in therapy planning (Table 112.7). Patients are examined by the gynecologic oncologist and the radiation oncologist before the therapy decision. Once the therapy plan is put into action, optimal treatment results require re-evaluation by the gynecologic oncologist and the radiation oncologist during therapy.

Table 112.7. Multidisciplinary Therapy Planning; Parameters To Be Considered in Patients with Carcinoma of the Cervix.

Table 112.7

Multidisciplinary Therapy Planning; Parameters To Be Considered in Patients with Carcinoma of the Cervix.

The size and extent of the cancer are the most important factors; therefore, histologic characteristics do not change the therapy plan. Therapy is the same whether the patient has a squamous cell carcinoma, adenocarcinoma, or mixed adenosquamous cell carcinoma. Lesions of equal size and extent are treated in a similar manner. Excellent survival rates have been reported internationally using the Fletcher-Suit-Delclos applicators as well as the Fletcher therapy principles and philosophy (Table 112.8).239 Standard radiation therapy plus cisplatin or cisplatin and fluorouracil is currently the recommended therapy for patients with advanced or bulky carcinomas. This combination therapy is much more labor intensive than radiotherapy alone, and additional paramedical support personnel are required to ensure compliance with the plan. Stage IB or IIA carcinomas may be treated with surgery.

Table 112.8. Pelvic Disease Control Rates and Survival Rates of 1,383 Patients with Carcinoma of the Intact Uterine Cervix Treated with Irradiation Alone According to the Fletcher Guidelines: A French Cooperative Study.

Table 112.8

Pelvic Disease Control Rates and Survival Rates of 1,383 Patients with Carcinoma of the Intact Uterine Cervix Treated with Irradiation Alone According to the Fletcher Guidelines: A French Cooperative Study.

Current Practice

Carcinoma in Situ and Microinvasion

Treatment of HGSILs is rapidly changing. LEEP, one of several new techniques, uses a thin wire loop electrode to excise the lesion, and it is effective therapy. Other techniques such as cryosurgery and laser ablation have also proven effective. Regardless of the technique used, HGSILs should be entirely visible by colposcopy, the entire transformation zone should be visualized, and the endocervical curettage specimen should be negative. Conization with a knife is preferred when the endocervical curettage specimen is positive. All margins must be clear of intraepithelial lesions.

Microinvasive squamous cell carcinomas that invade the stroma less than 3 mm and have no vascular space involvement are usually not visible to the unaided eye, and cytology is abnormal. The diagnosis requires conization. Cone biopsy not only provides a specimen adequate to evaluate and prove the diagnosis but also is a means of treating patients who wish to maintain their reproductive capacity. Conization alone is probably a low-risk therapy for patients who wish to retain fertility and who have invasion less than 3 mm in depth with no vascular space involvement. It is important to remember that the margins of a cone specimen must be negative. Cases in which the conization specimen has a positive margin require a second tissue specimen because foci of frankly invasive carcinoma may lie adjacent to the positive margin. Patients should be informed that the conservative approach carries a small risk.

Treatment of invasive carcinoma or carcinoma of FIGO stage IB or greater is best discussed in terms of tumor size and the presence or absence of lymph node metastases (Fig. 112.41).

Figure 112.41. This algorithm outlines treatment of invasive carcinoma of the cervix (FIGO = International Federation of Gynecology and Obstetrics; CT = computed tomography; MRI = magnetic resonance imaging; WP = whole pelvis; EBRT = external beam radiotherapy).

Figure 112.41

This algorithm outlines treatment of invasive carcinoma of the cervix (FIGO = International Federation of Gynecology and Obstetrics; CT = computed tomography; MRI = magnetic resonance imaging; WP = whole pelvis; EBRT = external beam radiotherapy).

Carcinomas 1 cm in Diameter

Squamous cell carcinomas invading 3 to 5 mm or those carcinomas with vascular space invasion are treated with radical hysterectomy and pelvic lymphadenectomy. This also applies to early invasive adenocarcinomas. A number of treatment options that allow excellent cure rates can be applied for patients with various medical diseases and other health disabilities. Many gynecologic oncologists will select the type II modified radical hysterectomy with a pelvic lymphadenectomy in healthy patients. Patients with more extensive lesions are treated with the Meigs-Wertheim or type III radical hysterectomy and pelvic lymphadenectomy. Medically compromised patients or any patient may elect to be treated with radiation therapy alone. A selected group of patients may be treated with intracavitary irradiation alone. Those patients at risk for node metastases undergo external beam plus intracavitary irradiation. The EBRT may be 40 Gy to the whole pelvis alone, 40 Gy to the parametrium alone, or a combination of the two. The dose contribution by intracavitary brachytherapy depends on the prescription for the external-beam therapy. Excellent results have been reported in selected patients treated with intracavitary irradiation alone.240

Carcinomas 1 to 4 cm in Diameter

Stage IB, IIA, or IIB lesions 1 to 4 cm in diameter collectively carry a 15 to 20% risk of lymph node metastases, and treatment is directed at the pelvic lymph nodes as well as the cervix. Three to 5% of these patients will have positive common iliac and para-aortic nodes. The surgical approach is a radical hysterectomy and pelvic lymphadenectomy. Para-aortic lymph nodes are removed and proved to be pathologically negative by frozen section before proceeding with radical surgery. Patients with positive pelvic nodes found on pathology review of the surgical specimen usually have postoperative whole-pelvis EBRT plus vaginal brachytherapy. Currently, convincing evidence argues for adding cisplatin and fluorouracil to postoperative radiation.241

The usual prescription for patients treated with primary radiation therapy is 40 to 45 Gy whole-pelvis EBRT plus two intracavitary brachytherapy insertions. The intracavitary systems are given 2 weeks apart, each delivering 3,000 mg-hours or remaining in place no more than 48 hours per insertion. This prescription is for the Fletcher-Suit-Delclos afterloading intracavitary system. Eifel and colleagues242 reported a retrospective study on the influence of size and morphology on outcome in patients with FIGO stage IB squamous cell carcinoma of the cervix. Patients were treated with EBRT plus the Fletcher-Suit-Delclos afterloading intracavitary system. For the 701 patients with cervical squamous carcinomas 4 cm in diameter, the overall 5-year disease-specified survival rate was 89.6%. The central tumor control rate at 5 years was an exceptional 98.9%, which establishes the Fletcher-Suit-Delclos afterloading system, as well as the principles and treatment philosophy, as the world’s standard. Excellent results have also been reported for patients with stage I adenocarcinoma of the uterine cervix who had tumors 4 cm in diameter.243 For this subset of patients, physicians and their patients may choose either primary radical hysterectomy with pelvic lymphadenectomy or radiation therapy alone. They are competitive and equally effective therapies.

Carcinomas Greater Than 4 cm in Diameter

Patients with tumors greater than 4 cm in diameter whose para-aortic lymph nodes are found free of disease have excellent survival rates when treated with whole-pelvis EBRT plus brachytherapy. The treatment plan consists of 40 to 45 Gy to the whole pelvis plus two Fletcher-Suit-Delclos tandem and ovoid insertions (3,000 mg-hours or 48 hours for each insertion) given 2 weeks apart. Although the rates of regional and distant metastases increase in a linear fashion as tumor size and invasiveness increase, central failures become a problem with primary radiation therapy when the carcinoma exceeds 6 cm.242

Recently, the Gynecologic Oncology Group completed a randomized study designed to determine whether weekly infusions of cisplatin during radiotherapy improved progression-free survival among patients with node-negative bulky 1B cervical cancer (tumors were ≥4 cm in diameter). Patients were randomly assigned to receive radiation alone (186 patients) or in combination with weekly cisplatin (184 patients). All underwent adjuvant hysterectomy. At 4 years, disease had recurred in 37% of patients receiving radiotherapy alone and 15% of patients receiving cisplatin plus radiation therapy. The group on combined therapy also had fewer whose disease recurred locally. The authors concluded that adding weekly infusions of 40 mg/m2 cisplatin (maximum weekly dose was limited to 70 mg) to pelvic radiotherapy followed by hysterectomy significantly reduced the risk of disease recurrence and death in this group of patients.244 The authors surmised, from published and unpublished data, that the adjunctive hysterectomy was probably not necessary.

The use of adjunctive hysterectomy following radiation therapy is one of the earlier applications of combined therapy. There is a relationship between tumor volume, positive nodes, and survival (Fig. 112.42). The larger the cervix, the lower the survival rate (Fig. 112.43). Cases characterized by large carcinomas have higher rates of local recurrence, nodal spread, and distant metastasis.

Figure 112.42. This graph indicates the relationship between the maximum clinical tumor diameter and the percentage of patients with positive lymphangiograms (LAG) in 758 patients who underwent lymphangiography as part of their initial evaluation.

Figure 112.42

This graph indicates the relationship between the maximum clinical tumor diameter and the percentage of patients with positive lymphangiograms (LAG) in 758 patients who underwent lymphangiography as part of their initial evaluation. The 7% incidence in (more...)

Figure 112.43. Disease-specific survival (DSS) is indicated for patients grouped according to size of cervix (NL = cervix of normal size; ENL = enlarged cervix, 4–4.

Figure 112.43

Disease-specific survival (DSS) is indicated for patients grouped according to size of cervix (NL = cervix of normal size; ENL = enlarged cervix, 4–4.9 cm). Reprinted with permission from Eifel et al.

The literature contains numerous reports on the use of an adjunctive hysterectomy for patients with bulky endocervical carcinomas.245–247 Definitions of bulky or barrel-shaped carcinoma differ in published reports. Traditionally, M.D. Anderson has considered lesions greater than 6 cm in diameter as bulky or barrel-shaped. Other groups have considered tumors with diameters of 4 or 5 cm as barrel-shaped or bulky carcinoma. Opinions are mixed concerning the value of combined radiation therapy and adjunctive hysterectomy.

In a recent retrospective review, researchers studied 371 patients for bulky endocervical carcinomas (> 6 cm diameter) at M.D. Anderson.248 Two hundred sixty-five patients were selected for comparison. One hundred eighty-three were treated with radiation therapy alone, and 82 were treated with radiation therapy followed by adjunctive hysterectomy. The survival rate for patients treated with radiation therapy plus surgery (59%) was better at 10 years than that for the group treated with radiation therapy alone (42%). However, selection biases were obvious: patients treated with radiation therapy alone were usually older, had a tumor greater than 8 cm in diameter, received less than 6,000 mg-hours of brachytherapy, and were more likely to have abnormal findings on lymphangiograms.249 The benefit of adjunctive hysterectomy is questionable in patients who have a favorable anatomy and receive full-intensity doses of brachytherapy.179,245 Today, at M.D. Anderson, adjunctive hysterectomy is reserved for patients with bulky carcinomas confined to the cervix who have a vaginal anatomy unfavorable for brachytherapy or who have other factors that preclude optimal brachytherapy. Multiple uterine fibroids are an example of a benign process that can distort the anatomy of the uterine cavity and lower the uterine segment.

A second study completed by members of the Radiation Therapy Oncology Group compared the effect of radiotherapy to the pelvis and para-aortic field with that of pelvic irradiation and concurrent chemotherapy with fluorouracil and cisplatin in women with advanced cervical cancer confined to the pelvis. Patients with stage IB or IIA carcinomas greater than 5 cm in diameter, patients with positive pelvic lymph nodes, and patients with stages IIB–IVA were eligible. Patients were ineligible for study inclusion if disease had spread outside the pelvis or to the para-aortic nodes.

Pelvic radiotherapy was delivered with anteroposterior and posterioanterior opposed beams. The field extended from the space between L4 and L5 to the mid-pubis or 4 cm below the most distal extension of disease. The four-field technique was allowed. In the patients who received radiotherapy alone, the superior-field border was the L1–L2 interspace. The dose delivered in each arm of the study was 45 Gy, given at a dose of 1.8 Gy per fraction. The isotopes used for low-dose intracavitary radiotherapy were cesium 137 or radium 226. The protocol specified that all patients receive a total cumulative dose to point A of 85 Gy.

Within 16 hours of the first radiation fraction, patients received intravenous infusion of cisplatin (75 mg/m2) over 4 hours followed by an intravenous infusion of fluorouracil (4,000 mg/m2) over 96 hours. Two additional cycles of chemotherapy were scheduled at 21-day intervals, and one was administered at the time of the second intracavitary insertion.

Of the 403 patients, 388 were eligible for analysis, 193 who received radiation alone and 195 who received radiation plus chemotherapy. Kaplan-Meier analysis revealed a survival rate of 76% for the group having radiation plus chemotherapy compared with 63% for the group having radiation alone (p = .004). Disease-free survival at 5 years for the group receiving radiation and chemotherapy was 67% compared with 40% for the group receiving radiation alone. Relapses owed to distant disease totaled 14% in the group undergoing combined therapy and 33% in the group undergoing radiation alone (p = .001). The late side effects of therapy were recorded, but the authors reported no differences between the two groups. The authors concluded that the addition of fluorouracil and cisplatin to radiation therapy significantly improved survival among women with locally advanced cervical cancer.250

Additional research, published by members of the Gynecologic Oncology Group, includes a three-arm randomized study of 526 patients with FIGO stages IIB, III, and IVA who had undergone extraperitoneal surgical sampling of the para-aortic nodes. Patients were eligible for enrollment if the para-aortic nodes were negative. All patients received radiotherapy. In addition, patients in regimen I received cisplatin (40 mg/m2) weekly for 6 weeks. Patients in regimen II received cisplatin (50 mg/m2) over 4 hours and fluorouracil (4,000 mg/m2) by continuous infusion over 96 hours for two courses plus oral hydroxyurea (2 gm/m2) twice a week for 6 weeks. Patients in regimen III received oral hydroxyurea at 3 gm/m2 twice a week for 6 weeks.

The rates of progression-free survival at 2 years were 67% for patients treated with radiation and cisplatin (regimen I) and 64% for patients treated with radiation, cisplatin, fluorouracil, and hydroxyurea (regimen II). Patients treated with radiotherapy and hydroxyurea (regimen III) had a progressions free survival at 2 years of 47%. Survival rates at 30 months show 59 deaths in patients treated in regimen I, 57 deaths in regimen II, and 89 deaths in regimen III. Survival rates were better in regimens I and II, and this improvement is credited to cisplatin. The authors conclude that regimens of radiotherapy and chemotherapy containing cisplatin improve the rates of survival and progression-free survival among women with locally advanced cervical cancer.251

Whitney and colleagues and members of the Gynecologic Oncology Group and Southwest Oncology Group (SWOG) report a randomized study involving 368 patients with FIGO stage IIB, III, or IVA carcinoma of the uterine cervix, and para-aortic nodes that were found free of disease. In this two-arm study, 191 patients were treated with radiation plus oral hydroxyurea (80 mg/kg twice weekly during ERBT), and 177 patients received radiation therapy and cisplatin (50 mg/m2 over 4 hours) followed by 4,000 mg/m2 fluorouracil by continuous infusion for 96 hours. The cycle, which included identical radiotherapy in both arms, was repeated 28 days after the initial cisplatin infusion. The authors concluded that progression-free survival and overall survival was better in the group receiving radiation therapy plus cisplatin and fluorouracil. This paper also gives extensive data on the adverse effects of both regimens.252

The standardization of radiotherapy concurrent with chemotherapy is based on sound medical data from appropriately designed prospective randomized studies. Longer follow-up will be necessary to accurately determine the rate of serious bowel or urinary tract injuries. In the author’s experience, the combination of surgical exploration to determine the extent of spread plus full-intensity radiation therapy is associated with an increase in life-threatening complications. This increase necessitates careful selection of patients for combination therapy.

Invasive Carcinomas with Metastasis

Metastatic cancer in the para-aortic lymph nodes may be confirmed with fine-needle aspiration, laparoscopy, or extraperitoneal laparotomy. Laparoscopy and laparotomy allow removal of positive nodes, which may enhance control with radiation therapy. Confirmation of suspected positive nodes helps in therapy planning. The fine-needle aspiration technique is excellent for such confirmation. The patient may have a laparoscopy or laparotomy using the extraperitoneal approach and have the nodes in question removed and other pelvic and para-aortic nodes sampled. The superior boundary of the extended EBRT portal provides a margin of 3 cm above the most cephalad of the positive nodes. The superior boundary limit is the T12 vertebra. Currently, patients with positive pelvic nodes or low common iliac nodes may have the field extended to the L1–L2 interspace.

Numerous articles in the literature report tumor control in patients who had positive para-aortic lymph nodes treated with extended-field radiation.253–258 Two randomized prospective trials have attempted to define the group of patients most likely to benefit from para-aortic treatment. The Radiation Therapy Oncology Group (RTOG) studied 367 patients with stages 1B and IIA cancers greater than 4 cm in diameter and patients with stage IIB disease in a randomized study. These patients received standard pelvic irradiation or extended-field radiation therapy prior to brachytherapy.259 Patients treated with extended-field radiation therapy (45 Gy up to L1–L2) had a better absolute survival rate than did those treated with standard pelvic irradiation (67% compared with 55% at 5 years). Para-aortic recurrences were not analyzed separately, and there was no standard method of assessing initial node status.120

Another trial from the European Organization for Research and Treatment of Cancer involved a similar randomization of patients between pelvic irradiation and extended-field irradiation (45 Gy up to L1–T12).260 Twelve centers entered 441 patients. Two hundred twenty-eight patients received radiation therapy to the pelvis, and 213 received radiation to the pelvis and para-aortic nodes. There was no statistically significant difference between the two treatment arms in terms of local control, overall distant metastases, and survival. The subset that received pelvic irradiation alone, which controlled the pelvic disease, had a higher incidence of subsequent para-aortic and distant disease. The enteric complications in this study were high, and the authors concluded that routine para-aortic irradiation for all high-risk patients with cervical carcinoma is of limited value.

A recent report suggests that combination chemotherapy plus extended-field radiation therapy for patients with biopsy-proven para-aortic node metastases can be given safely.261 Marhesh A. Varia and members of the Gynecologic Oncology Group have reported a multicenter trial of chemoradiation therapy to evaluate the feasibility of extended-field radiation therapy with fluorouracil and cisplatin. The end points were to determine progression-free survival, overall survival, and recurrence sites in patients with biopsy-confirmed paraaortic node metastases from cervical carcinoma. Patients entered by FIGO stage were stage 1, 14; stage II, 40; stage III, 27; and stage IVA, 5. The extended-field dose was 45 Gy with whole-pelvic doses determined by the size of the primary. The text has detailed descriptions of the dose of whole-pelvic radiation and dose contribution from brachytherapy. The chemotherapy doses were cisplatin 50 mg/m2 over 4 hours followed by fluorouracil 4,000 mg/m2 over 96 hours. The cycle was repeated in 28 days. Dose reductions were necessary in a few patients. Of 86 evaluable patients, 85 finished radiotherapy and 77 completed both courses of chemotherapy. The authors state that there were numerous protocol deviations. Toxicity was significant: 18.6% had grade 3 to 4 gastrointestinal toxicity and 15% had grade 3 to 4 hematologic toxicity. Seven patients had late rectal complications. Chronic radiation proctitis occurred in three patients, rectal stricture in two, perforation in one, and rectovaginal fistula in one. The 3-year survival rate was 39%. Recurrences were documented in 64% of the patients: pelvis only, 21%; distant metastases only, 31%; and pelvis plus distant metastasis, 10.5%. The authors show that patients with biopsy-proven para-aortic node metastases can tolerate and benefit from combination chemotherapy and extended-field radiation therapy.

Extension Reaching the Pelvic Wall or Obstructing the Ureter

For patients with carcinomas that extend to one or both pelvic walls, the dose of EBRT is usually 50 Gy plus one 72-hour or two (one 24- and one 48-hour) brachytherapy insertions. The addition of cisplatin or cisplatin and fluorouracil may modify radiation dose; however, the dose to the lateral pelvic walls is important in pelvic wall control. The vaginal extent of the carcinoma is marked with a radiopaque seed, and a lower margin of 4 cm is included in the external beam portals. Skip metastases or bulky extensions from the cervix require interstitial radiation with iridium-192 wires.

Patients with nodes suspected of harboring disease must undergo fine-needle aspiration, laparoscopy, or laparotomy. The field should provide a 3-cm superior margin if positive nodes are identified. Patients require individualization of therapy depending on the size and extent of their carcinoma.

Extension Reaching Other Structures

Very advanced carcinomas that extend into the lower third of the vagina or into the bladder or rectum are difficult to treat. Bulky carcinomas that extend into the bladder or rectum may be treated entirely with external beam irradiation. The reducing-field technique is preferred, and doses as high as 65 Gy may be given. Chemotherapy is included with the EBRT, and the current chemotherapy of choice is cisplatin or cisplatin plus fluorouracil. Brachytherapy is always a desirable component of radiation therapy when anatomy or tumor spread permits optimal use.

Patients with carcinomas extending to the lower third of the vagina require individualized therapy. Delclos and colleagues describe the use of interstitial brachytherapy in Fletcher’s Textbook of Radiotherapy.262

Special Clinical Situations

The use of EBRT and brachytherapy with or without concurrent chemotherapy following surgical procedures is presented in Fig. 112.44.

Figure 112.44. Postoperative therapy, including radiotherapy and brachytherapy, may be with or without chemotherapy.

Figure 112.44

Postoperative therapy, including radiotherapy and brachytherapy, may be with or without chemotherapy.

Postoperative Radiotherapy Following Radical Hysterectomy

Gynecologic surgeons frequently request consultation with a radiation oncologist following a patient’s radical hysterectomy and pelvic lymphadenectomy when the surgical specimen was characterized by poor prognostic features. Patients with positive surgical margins need additional therapy and require a minimum of 45 Gy of EBRT plus ovoids or a vaginal cylinder to deliver an additional dose of 40 to 50 Gy to the surface of the apex of the vagina. An additional boost of 10 Gy of EBRT to a small field may be required if the patient has gross residual disease at a site following surgery. Similar treatment may be applicable to cases with lymph vascular space involvement. These patients are at an increased risk for therapy failure.189,263 The role of adjuvant chemotherapy after a radical hysterectomy and pelvic lymphadenectomy has been evaluated in a randomized study and disease-free survival and survival rates were not increased.264

The SWOG, in cooperation with three other oncology groups, completed a study of women with FIGO stage 1A2, 1B, and IIA carcinoma of the cervix. They had been treated with radical hysterectomy and pelvic lymphadenectomy and were eligible for additional therapy if poor prognostic factors were noted at pathologic review of the surgical specimen. Eligible patients had either metastatic disease in the pelvic lymph nodes, positive parametrial involvement, or positive surgical margins. Patients were ineligible if metastatic disease was present in the common iliac or para-aortic lymph nodes. Between 1992 and 1996, 268 patients were entered and, of these, 241 were evaluable. In one group of 126 patients, women received whole-pelvis EBRT (49.3 Gy) with cisplatin (70 mg/m2) followed by a 96-hour continuous infusion of fluorouracil every 3 weeks for four courses. In another group of 115 patients, women received the same dose of whole-pelvis EBRT but no chemotherapy. The median follow-up was 43 months. The 3-year survival rate for women who received chemotherapy was 87% compared with 77% for women who received radiotherapy alone, a statistically significant difference.242

This is convincing evidence that survival in patients with poor prognostic factors after radical hysterectomy and pelvic lymphadenectomy is better with radiotherapy plus cisplatin and fluorouracil than treatment with radiotherapy alone. A number of issues require further analysis. Late complications involving the urinary and gastrointestional tract need defining. It is well-known that patients who have had transperitoneal procedures, with or without retroperitoneal node dissection followed by EBRT, are at an increased risk for small-bowel injury. A second question concerns the selection of primary therapy. The 5-year survival rate for patients treated with primary radiation is 89% for stage I disease and 85% for stage IIB.239 The author (JTW) questions the use of a radical hysterectomy and pelvic lymphadenectomy for patients with lesions greater than 3 cm in diameter. Invariably, as shown in this study, individual patients are found to have poor prognostic factors on histologic analysis of the surgical specimen. Additional therapy is required for these patients, accompanied by such concerns as time, expense, quality-of-life issues, and morbidity. Regardless of our concerns or personal preferences, evidence is convincing that cisplatin alone or with fluorouracil plus radiation therapy is synergistic and improves survival.

The selection of patients to treat with combination EBRT plus chemotherapy would be enhanced by better technologies in contrast or cross-sectional imaging. Molecular profiling of tumors and identifying genetic abnormalities that influence virulence would be a significant step forward in identifying patients who should receive aggressive therapy. Below are described a number of other clinical situations in which radiation therapy plus chemotherapy is indicated.

Extrafascial Hysterectomy Following Treatment for Invasive Carcinoma

Patients who have a hysterectomy for what is presumed to be a benign pelvic condition have an unpleasant surprise after a pathologist studies the tissue specimen and detects unsuspected invasive cervical carcinoma. Many factors can lead to such an event.265 A false-negative Pap smear provides little opportunity for the gynecologist to avoid such events; however, the following oversights are avoidable: failure to evaluate an abnormal Pap smear, failure to perform a conization when indicated, and proceeding with a hysterectomy when there is a positive cone margin.

Postoperative treatment is determined after evaluation of the surgical specimen.266 The carcinoma is usually cut through at the level of the uterosacral and cardinal ligaments or at the lateral angles of the vaginal cuff when the surgeon attempts to enter the vagina. Suturing the cuff frequently incorporates disease at the lateral extent of the vaginal cuff. Some large endocervical lesions have a large central necrotic area, and traction and countertraction on the surgical specimen separate the fundus from the cervix. Removal of the distorted friable cervix is extremely difficult.

The therapy plan is based on the amount of residual disease. Patients with minimal invasion and no residual disease require at most brachytherapy to the vaginal apex; patients with gross disease at the specimen margin require full-intensity therapy. The author’s preference today for patients with residual disease would be EBRT supplemented with vaginal brachytherapy plus cisplatin with or without fluorouracil. Review of preoperative imaging studies, when available, can be very helpful. Patients with minimal or no known gross residual disease have excellent 5-year survival rates, whereas rates for patients with gross residual disease are poorer.266

Standard Therapies: Advanced or Recurrent Carcinomas

Surgical Therapy: Pelvic Exenterations

Pelvic exenteration is a potentially curative procedure for patients who, following radiation therapy, have a central pelvic recurrence or a new primary tumor in the irradiated field.267–273 Advances in surgical technique, anesthesia, and postoperative care have greatly reduced operative mortality because intraoperative and postoperative complications have decreased.265,270,273 Advances in ostomy appliances and care have given patients the opportunity to live a nearly normal life and to be able to meet their personal needs and responsibilities.

At M.D. Anderson, the most common indication for pelvic exenteration is recurrent cancer of the cervix or vagina. In many patients, the exact site of origin cannot be determined. Patient selection is one of the more difficult tasks. Pelvic examination and diagnostic imaging are inadequate for determining operability in many patients. The type of exenteration is determined by the anatomical site of the cancer.

Anterior exenteration

Anterior exenteration encompasses the removal of the uterus, adnexa, bladder, urethra, and vagina. Patients selected for this operation have cancers that are sufficiently anterior to allow clearance of the rectum and do not extend to involve the vaginal apex or the posterior vaginal wall. Vaginal reconstruction is performed as indicated.

Posterior exenteration

In posterior exenteration, the uterus, adnexa, anus, rectosigmoid colon, levator muscles, and vagina are removed. Many gynecologic oncologists leave a portion of the anterior vaginal wall to support the urethra, and this can lessen postoperative urinary incontinence. Patients are selected with lesions confined to the posterior vaginal wall and rectovaginal septum.

Total pelvic exenteration

The uterus, adnexa, bladder and urethra, vagina, rectosigmoid colon, levatores, and anus are all removed in total pelvic exenteration. Lesions are usually central or involve the upper half of the vagina. Contiguous extension to the base of the bladder and rectovaginal septum leave no opportunity to perform a less extensive operation. Vaginal reconstruction is performed for functional purposes and to aid in the reconstruction of the pelvic floor. An omental pedicle graft is required to aid in reconstruction of the pelvic floor, and this technique for bringing in a new blood supply has been a major factor in reducing postoperative complications.272 In both the anterior and total pelvic exenteration, a continent urinary conduit can be constructed.

Pelvic exenteration is widely used, and 5-year survival rates of 40 to 50% can be expected (Table 112.9). At M.D. Anderson, a total of 448 exenterations were done from 1955 to 1984 and reported by Rutledge.271 Four hundred and three were done, including 329 for carcinoma of the cervix, 55 for carcinoma of the vagina, and 19 for carcinoma of the vulva. Of the 403 patients, 45 had other diagnoses in addition to the ones named. The 5-year survival rates are shown in Fig. 112.45 for patients treated with exenteration.

Table 112.9. 5-Year Survival Rates after Pelvic Exenteration: A Review of the Literature.

Table 112.9

5-Year Survival Rates after Pelvic Exenteration: A Review of the Literature.

Figure 112.45. Survival curves are shown to compare the three types of exenterations performed in an M.

Figure 112.45

Survival curves are shown to compare the three types of exenterations performed in an M.D. Anderson series 1955–1984. Although the curves are similar, it should be noted that posterior exenteration is performed more frequently than the other procedures (more...)

Chemotherapy

Using chemotherapy to treat metastatic or recurrent carcinoma of the cervix is relatively ineffective. Median survival ranges between 4 and 8 months. Cisplatin is regarded as the most active agent in cancer of the cervix. The response rate is 17 to 21%. Doses used range from 50 mg/m2 to 100 mg/m2. Bonomi and colleagues compared 50 mg/m2 to 100 mg/m2 and noted an increase with the higher dose from 21 to 31% in the partial response rate and an increase from 10 to 13% in the complete response rate. Response duration, progression-free survival, and survival measures failed to improve.274 Carboplatin given at 340 to 400 mg/m2 every 28 days to 175 patients induced a complete response in 10 (5.7%).275 The total response rate for carboplatin from a number of studies is 19%.261

Nineteen single agents have activity, defined as the ability to induce a 15% response rate when used as a single agent.277,278 But survival rates have not been improved by adding other drugs to cisplatin.279–281 Numerous reports describe a higher response rate with combination therapies accompanied by an increase in toxicity. Receiving the most interest has been ifosfamide.282 Trials combining ifosfamide at 1.5 g/m2 daily for 5 days with mesna and cisplatin at 20 mg/m2 daily for 5 days or combining ifosfamide at 5 g/m2 on day 1 with mesna and carboplatin at 300 mg/m2 on day 1 in patients who had received no prior radiation therapy report high response rates.283,284

A recent Gynecology Oncology Group randomized trial reported that combining ifosfamide and cisplatin yielded a superior response rate to that with cisplatin alone (33% compared with 19%); however, there were no differences in progression–free survival or survival measures. The literature has numerous studies in which patients were treated with two-, three-, and four-drug combinations for metastatic or recurrent carcinoma of the cervix. Reproducibility of the improved response rates and some impact on the survival rate would be exciting steps forward.

A number of barriers have impeded drug evaluations in patients with cervical cancer. Most patients have had high-dose EBRT to the pelvis and lower vertebrae. The dose range of 40 to 55 Gy destroys the stem cell population of the bone marrow included within the treatment field. Because myelosuppression is the dose-limiting toxic effect of most drugs used for this disease, the reduced bone marrow reserve limits the amount of drug that can be given. Patients with advanced carcinoma frequently have renal impairment because of ureteral obstruction and loss of a kidney. Marginal renal function prompts dose reductions for drugs requiring renal clearance. Disease recurs in irradiated areas that are fibrotic and poorly vascularized. Drug deliverability is repressed by such hostile environments. Tumor regression is difficult to measure by both physical examinations and imaging techniques. Cellular mechanisms for chemotherapy and radiotherapy resistance need to be defined in patients with cervical cancer. Despite these obstacles, single-agent and combination chemotherapies have induced complete responses in patients with biopsy-proven carcinomas. New technologies that would identify these sensitive cancers are key future research opportunities.

Radiosensitizers

There is a definite relationship between tumor size and radiocurability. The larger the tumor, the more likey there will be necrotic areas that are anoxic and radioresistance. It has been appreciated since the early 1950s that the presence of molecular oxygen at the time of irradiation determines the cells’ radiosensitivity. Radiobiologists have experimentally shown that tumors only a few millimeters in size contain hypoxic cells.285 As the volume of the tumor increases, the populations of hypoxic cells expand. Theoretically, hypoxic cells are two and a half to three times more radioresistant than are fully oxygenated cells. The direct relationship between tumor volume and the dose of radiation required for control has clinical importance because the dose-limiting factor is normal tissue tolerance. Clinically, failure to control the cervical primary tumor and any metastatic disease in the nodes is more likely to occur in patients who have bulky primary tumors and large foci of metastatic carcinoma in pelvic nodes. Searching for substances that mimic the effect of oxygen in sensitizing hypoxic cells has been of significant clinical interest. The nitro imidazoles have been extensively studied.271 Besides sensitizing cells to radiation in animal models, these drugs are metabolized anaerobically to cytotoxic compounds that are concentrated maximally in the regions of the tumor. The nitro imidazoles metronidazole (Flagyl) and misonidazole have been used, but neurotoxicity has been significant.287 Grigsby and colleagues and members of the RTOG have published the final results of a study that was designed to evaluate tumor response, progression-free survival, local tumor control, and patterns of relapse and toxicity in patients with stages IIIB and IVA squamous carcinoma of the cervix. Patients were randomized to receive radiation alone (61 patients) or radiation plus 400 mg/m2 misonidazole daily 2 to 4 hours before irrradiation (59 patients). There were no statistically significant differences in any of the end points.288

High-linear energy-transfer radiation particles, such as neutrons that produce high-density ionization when coming to rest in tissues, have been extensively studied. Neutron-beam teletherapy has been used because these heavy particles are more efficient killers of hypoxic cells than are photons.289 The use of heavy particles has not been of value in patients with cervix cancer.

Patients have been pressurized and treated in hyperbaric oxygen chambers in an effort to increase available oxygen to anoxic tumors and to reduce radioresistance. Hyperbaric oxygen is a cumbersome process and has been abandoned. Unfortunately, hyperbaric oxygen, hypoxic cell sensitizers (misonidazole), and neutron-beam teletherapy have failed to improve tumor control to a degree that has clinical relevance.

The current focus is on the concomitant use of intravenous fluorouracil and cisplatin or cisplatin alone with radiation therapy. The synergism between chemotherapy and radiotherapy has a number of explanations. Chemotherapy may prevent the repair of sublethal damage induced by ionizing radiation and reduce the fraction of hypoxic cells that are resistant to radiation. Such mechanisms of cell killing may not be oxygen dependent. Cisplatin alone is less toxic than cisplatin plus fluorouracil and is standard treatment in many institutions for selected patients with carcinoma of the cervix. The contribution from fluorouracil may be synergistic, and this agent’s contribution requires additional study.

Neoadjuvant chemotherapy

Several strategies have been devised to test the effectiveness of chemotherapy before surgery or radiation therapy in an attempt to determine whether neoadjuvant chemotherapy is useful.290 Neoadjuvant chemotherapy is not burdened by bone marrow that has been compromised by prior EBRT. The same is true concerning the environment of the tumor, inasmuch as vascularization has not been disturbed by prior EBRT. Primary chemotherapy given before surgery has induced tumor regression in up to 50% of patients, resulting in increased local control rates with radiation and surgery in some series. Inoperable tumors have become operable, and the number of positive lymph nodes recovered on pelvic lymphadenectomy has been lower than expected in a purely surgical series. This outcome suggests that the initial chemotherapy eliminated metastatic deposits in regional lymph nodes.291–294 Pilot and phase II studies have proved that radical surgery following primary chemotherapy is not associated with unexpected increases in surgical bowel or urinary tract complications. Pelvic radiation therapy has also been given in standard fashion following primary chemotherapy and is no more toxic than pelvic irradiation alone.294 Some series report better survival rates; however, patient selection bias and many other factors may be responsible, and the answers are best sought in a randomized prospective trial.

The Cervical Cancer Study Group of the Asian Oceanian Clinical Oncology Association conducted a randomized trial to answer the question of whether primary chemotherapy given prior to radiation therapy improves local control and survival.295 Between October 1989 and February 1993, 260 patients with stages IIB to IVA cervical cancer received either standard pelvic radiation or primary chemotherapy with cisplatin (60 mg/m2) and epirubicin (110 mg/m2) every 3 weeks for three cycles followed by standard pelvic irradiation. The patient characteristics were well balanced. There were 129 patients in the chemotherapy-followed-by-radiotherapy arm and 131 patients in the radiotherapy-only arm. In 62 patients, the first site of progressive disease was the pelvis. Treatment failed in 33 patients in the chemotherapy-radiotherapy arm and in 21 patients in the radiotherapy-only arm. The higher failure rate in the primary chemotherapy group was statistically significant (p = .003). Seventy-six patients had died at the time of the report, and those patients who received primary chemotherapy had a significantly inferior survival rate compared with those who received radiotherapy alone. There is no evidence to support a conclusion that primary chemotherapy with cisplatin and epirubicin given before radiation therapy enhances pelvic control, nor is there any evidence that the chemotherapy has a favorable impact on the systemic spread of carcinoma.

Future Opportunities

New technologies that would define the aggressiveness of cervical cancers are an interesting future research opportunity. The value of combining such biologic therapeutic agents as the interleukins, specific monoclonal antibodies, vaccines, and interferons with chemotherapy has received little attention in patients with cervical cancer.

Adenocarcinomas of the cervix represent a heterogenous group of carcinomas. Their heterogeneity plus their lower frequency of occurrence (20%) in comparison to squamous cell carcinomas (80%) limits randomized trial opportunities. Primary papillary serous carcinomas of the cervix may have features in common with their look-alike tumors in the endometrium and ovary. Further research may tell us whether primary endometrioid carcinomas of the endocervix may have features and therapy responses similar to those of endometrioid carcinomas of the endometrium. Finally, neuroendocrine (small cell and non–small cell) carcinomas need standardization of terminology and definitions of histologic features that allow an opportunity for the pathologist and oncologist to diagnose and apply research-driven clinical therapies for these carcinomas. Large national groups have a unique opportunity to lead the way in finding active single agents and combination therapies for these very aggressive cancers.

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Bookshelf ID: NBK20787

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