Angela J. Ziebarth, Kenneth H. Kim, and Warner K. Huh
Cervical cancer is one of the most common cancers in women worldwide. Nearly all invasive squamous cell carcinomas are preceded by persistent human papillomavirus (HPV) infection and cervical intraepithelial neoplasia (CIN), and vast improvements in screening over the last 60 years have dramatically lowered the incidence of invasive disease in the developed world. Localized and some advanced cervical cancers in the United States have excellent prognoses, yet in developing countries, this disease remains the most lethal malignancy in women.
EPIDEMIOLOGY
Key Points
1. Minority and low-socioeconomic status patients are still at risk for developing cervical cancer in the United States due to lack of screening and early treatment.
2. The largest risk factor for cervical cancer is persistent HPV infection. Other risk factors include history of sexually transmitted diseases, multiple sexual partners, high parity, immunosuppression, and smoking.
3. The HPV oncoproteins E6 and E7 bind and inactivate the tumor suppressor genes p53 and pRB, respectively, which contributes to cervical carcinogenesis.
Incidence
Cervical cancer is the third most common cancer in women worldwide, with more than 450,000 cases diagnosed annually. Developed countries have demonstrated a decreasing incidence and mortality from squamous cervical cancers over the last 50 years. This is likely due to improved access to screening, decreasing parity, and lower baseline prevalence of HPV. Adenocarcinomas of the cervix account for approximately 15% of cervical cancers in the United States and have risen slightly over the last 20 to 30 years. The recent availability of an HPV vaccine has been shown to decrease the incidence of high-grade CIN and may further reduce the incidence of cervical cancer in years to come.1
In 2010, the American Cancer Society estimates 12,200 new cases of cervical cancer in the United States, with 4210 women predicted to die from this disease. The peak incidence for this disease is 45 years. Although the overall incidence of cervical cancer is low in the United States, the incidence in African Americans is nearly 50% higher than in Caucasians, and the incidence in the Hispanic population is more than double that of Caucasians. Furthermore, in comparison with Caucasians. African Americans are more frequently diagnosed with advanced-stage tumors and are less likely to receive treatment.2
Risk Factors
Several established risk factors are known to contribute to cervical carcinogenesis. More than 99% of cervical cancers are associated with infection with HPV; risk factors associated with HPV infection are the same for CIN and cervical cancer. These include multiple sexual partners, history of other sexually transmitted infections, high parity, immunosuppression, and cigarette smoking.3 Obesity has been associated with a slightly increased risk of adenocarcinoma of the cervix.4 However, neither parity nor smoking has been associated with increased risk of adenocarcinoma of the cervix.5 Interestingly, although cervical cancer is not a typical genetically inherited disease, it does tend to aggregate in families.6
Women who smoke have a dose-dependent increased risk of having persistent HPV. Cigarette smoking may contribute to the development of high-grade cervical dysplasia in women with underlying HPV infection.7 This may be due to genotoxicity secondary to the presence of tobacco-derived carcinogens in cervical secretions. Cigarette smoking has also been found to have immunosuppressive effects and may predispose patients to persistent HPV infection.
High parity has been associated with increased rates of cervical cancer and dysplasia, although the mechanism is not clear.8 Oral contraceptives are a difficult variable to study in regard to HPV infection, because of the difficulty in separating sexual habits and contraceptive use. However, one large multicenter case-control study and several meta-analyses revealed that women taking oral contraceptives may have an elevated risk of invasive cervical cancers.3,9,10Parity has also been found to be an independent risk factor, potentially secondary to cervical trauma.11 Additionally, coinfection with Chlamydia trachomatis has also been associated with HPV persistence, cervical neoplasia, and cervical cancer.12
Several protective behaviors have been identified as well. Consistent condom use has been associated with a partial protective effect against HPV infection and cervical dysplasia.13 Additionally, circumcision has been associated with reduced HPV detection in males, and wives of men with multiple sexual partners have been found to have higher rates of cervical cancer.14
Patients infected with human immunodeficiency virus (HIV) commonly have concurrent HPV infections. In patients HIV-associated immunosuppression, abnormal cervical cytology rates may be as high as 78%.15 Increased incidence of abnormal cervical cytology has been correlated with low CD4+ lymphocyte counts, but not with duration of HIV infection, antiretroviral therapy, or viral load.16
Pathogenesis
The malignant transformation of cervical cells is intimately related to HPV infection. HPV is an extremely common, double-stranded DNA virus acquired by sexual contact. HPV infects basal keratinocytes and replicates during keratinocyte differentiation. More than 100 types of HPV have been sequenced, and many more have been partially characterized. Of these, approximately 40 infect the genital tract, and these are responsible for condylomata, some hyperproliferative lesions, and dysplastic lesions of the cervix, vulva, vagina, and anus. In the United States, HPV16 is the most carcinogenic type, and genotypes 16 and 18 have been associated with nearly 70% of cervical cancers worldwide.17 In particular, HPV18 accounts for approximately 50% of adenocarcinomas, as compared with only 15% of squamous cell carcinoma.18
All papillomaviruses have regulatory, early (E), and late (L) genomic regions. Early proteins are required for replication and/or cellular transformation. These include proteins E6 and E7, the major HPV oncoproteins. The E6 protein binds specifically to E6-AP, which associates with the tumor-suppressor protein p53, causing rapid degradation. Loss of p53 results in failure of growth arrest and loss of appropriate apoptotic signaling in response to cell damage. E7 interacts with the retinoblastoma tumor suppressor gene (pRb), which normally complexes with E2F transcription factors. Formation of E7-pRb complexes disrupts the pRB-E2F complex, which initiates cell growth. E7 is able to immortalize keratinocytes independently, but the combination of E6 and E7 in transgenic mice have been found to result in aggressive invasive cancers.19
HPV genomes initially infect the cell in circular extrachromosomal copies. Over time, however, the HPV viral genome can become inserted into host cell DNA in a process called integration. Integrated HPV has been found to be present in 83% of invasive cervical cancers, as compared with 8% of low-grade squamous epithelial lesions, suggesting that integration may be associated with the transition of low-grade to high-grade lesions.20 Once integration has occurred, E6 and E7 transcription is not downregulated by the viral regulatory protein E2, and intracellular E6 and E7 oncoprotein levels increase. Keratinocytes that express E6 and E7 are immortalized and may ultimately become tumorigenic.
DIAGNOSIS
Key Points
1. Early-stage cervical cancers are frequently asymptomatic; advanced-stage disease may present with malodorous or bloody vaginal discharge, back pain, hematuria, or rectal bleeding.
2. Cervical cancer staging according to the International Federation of Gynecology and Obstetrics (FIGO) system is performed clinically and may only include such radiographic studies as chest radiograph, intravenous pyelogram, or barium enema.
Clinical Features
The majority of women with early-stage cervical cancers are asymptomatic and are typically diagnosed after evaluation of an abnormal screening Pap smear. For patients with large tumors or advanced-stage disease, the most common presentation is abnormal vaginal bleeding, particularly after intercourse. With tumor growth and necrosis, patients may have additional complaints of malodorous vaginal discharge. In advanced cases, cervical cancer can also cause pelvic pressure and pain or bleeding with urination or defecation. Meta-static disease may cause difficulties with radiating or neuropathic pain, or lower-extremity edema.
On physical examination, the most common finding is a cervical lesion, which should be biopsied. Cervical cancer is clinically staged, and the examination is critical for treatment planning. For this reason, examination should include a detailed description of the size (depth and width) of the primary cervical lesion, as well as documentation of a rectovaginal examination to evaluate for potential parametrial and pelvic sidewall extension. Additionally, regional and distant lymph nodes should be examined for potential metastases; these include the superficial groin and femoral nodes, as well as supraclavicular nodes.
Diagnostic Testing
Diagnostic tests may be included in the clinical staging of cervical cancer; these are limited to standard chest radiography, intravenous pyelogram, and barium enema. Chest radiography may identify metastatic lesions to the lungs, whereas intravenous pyelogram can determine hydronephrosis, suggesting metastatic disease to the pelvic sidewall. Barium enema is useful when patients report rectal bleeding; it can identify metastases to the recto-sigmoid colon.
Although findings from additional imaging tools such as computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET) are not formally included in the staging system, they may supplement clinical suspicion of parametrial and sidewall disease and influence treatment planning. Of these techniques, MRI is the most sensitive for detecting locally advanced disease. A prospective collaborative trial sponsored by the American College of Radiology Imaging Network and the Gynecologic Oncology Group (GOG) demonstrated a sensitivity of 53% with MRI compared with 29% for clinical staging and 42% for CT.21 Furthermore, the negative predictive value of MRI in detecting parametrial invasion is 95%.22 It is more difficult to determine parametrial invasion based on MRI, and positive predictive value remains significantly lower; this is due to the similarity of the radiographic appearance of parametrial tissue and cervical tumor.23 In addition, PET imaging may identify lymph nodes suggestive of metastatic disease. PET imaging rapidly evaluates metabolic activity, therefore using physiologic processes rather than the anatomic changes detected by conventional radiography. Fusion of CT and PET images has high sensitivity and specificity in detecting lymph node metastases.24,25
Diagnostic Procedures
Several diagnostic procedures are pertinent in the diagnosis of cervical cancer. Small cancers may be identified after cervical conization or loop electrosurgical excision for dysplasia. Because this disease is not staged surgically, operative findings such as lymph node metastases do not influence the staging system. However, examination under anesthesia with cystoscopy and proctoscopy should be considered when office examination is limited due to anatomic distortion from tumor or patient discomfort or when suspicion for bladder or rectal involvement is high.
Role of the General Gynecologist
Primary care providers, including family medicine physicians, internists, obstetrician/gynecologists, as well as physician assistants and nurse practitioners, play a critical role in cervical cancer screening, cervical dysplasia management, and establishing the diagnosis of cervical cancer. The American Cancer Society, American Society for Colposcopy and Cervical Pathology, United States Preventative Services Task force, and the American Congress of Obstetricians and Gynecologists provide regularly updated screening guidelines and recommendations for the general practitioner, which are detailed in Chapter 4. Procedures commonly used by the general obstetrician/gynecologist include colposcopy, cervical biopsy, and cervical conization procedures in the management of cervical dysplasia; once a formal diagnosis of cervical cancer is made, referral should be made to a gynecologic oncologist for definitive treatment planning.
PATHOLOGY
Key Points
1. The majority of cervical cancers are of squamous histology and spread via direct extension.
2. Adenocarcinomas constitute a smaller percentage of cervical cancers, but both the overall incidence and proportion of adenocarcinomas of the cervix appear to be rising.
3. Stage IA1, or microinvasive carcinoma, is defined by a depth of invasion less than 3 mm and a lesion width no greater than 7 mm.
Histopathology
Squamous Cell Carcinoma
The majority of cervical cancers are of squamous cell histology (Table 5-1). Squamous cell cancers develop after an interval of preinvasive disease, as discussed in Chapter 4. Dysplastic cells are characterized by an increased nuclear-to-cytoplasmic ratio and have prominent mitotic figures. CIN can progress to carcinoma in situ, with subsequent invasive disease identified after penetration of dysplastic cells through the basement membrane (Figure 5-1).
FIGURE 5-1. Demonstration of the progression of cytologic atypia. (A) Normal cervical epithelium; (B) cervical intraepithelial neoplasia (CIN) 1; (C) CIN2; (D) CIN3; (E) adenocarcinoma in situ.
Table 5-1 Histologic Subtypes of Cervical Cancer
|
Squamous cell carcinoma |
|
Adenocarcinoma |
|
Adenosquamous carcinoma |
|
Glassy cell carcinoma |
|
Adenoid cystic carcinoma |
|
Adenoid basal tumors of the cervix |
|
Large-cell neuroendocrine carcinoma |
|
Small-cell carcinoma |
Grossly, squamous cell cervical cancers can exhibit a heterogeneous appearance, ranging from small nodular lesions to large, bloody friable tumors with malodorous exudate. Microscopically, cervical cancers demonstrate infiltrative nests of cells with eosinophilic cytoplasm and large, hyperchromatic nuclei. There is frequently a desmoplastic stromal response surrounding the nests of carcinoma. Mitoses are frequently numerous. Lesions may be further characterized as keratinizing or nonkeratinizing, depending on the presence of keratin pearls (Figure 5-2). They are also graded; grade 1 tumors are well differentiated and uncommon. They have mild atypia, large numbers of keratinized cells, and scant mitotic figures. Grade 2 tumors are more common and are largely nonkeratinizing with numerous mitoses, pleomorphic nuclei, and an infiltrative pattern. Grade 3 tumors are poorly differentiated and are pleomorphic with anaplastic nuclei and a tendency to form spindle cells and may be difficult to distinguish from sarcomas without cytokeratin staining.
FIGURE 5-2. Invasive squamous cell carcinoma of the cervix. (A) Nonkeratinizing invasive carcinoma; (B) keratin pearls.
There are several rare histologic variants of squamous cell carcinomas of the cervix that include verrucous, papillary squamotransitional, warty, and lymphoepithelioma-like carcinomas. Verrucous carcinomas appear grossly as a large, sessile tumor that may be confused for condyloma acuminatum. Clinically, verrucous carcinoma behaves in a slow-growing, locally invasive fashion; however, it rarely involves regional lymph nodes or distant metastases. Histologically, verrucous carcinoma of the cervix is characterized by frond-like papillae, which may be keratinized, without a connective tissue core. In order to make the correct diagnosis, the base of the tumor must be evaluated, as superficial layers frequently lack atypia or frequent mitosis. The basal layer is composed of well-circumscribed invasive nests of epithelium that invade the cervical stroma in a pushing fashion and have a characteristically inflammatory appearance at the base of the epithelium.
Papillary squamotransitional carcinoma may present with a variety of histologic appearances, but often demonstrate superficial papillary architecture with a connective tissue core. They may also have extensive mitoses, nuclear atypia, and keratinization. They may also display the multiple layers and oval-shaped, hyperchromatic nuclei typical of transitional cell carcinomas. Papillary squamotransitional carcinomas typically have immunohisto-chemistry markers of squamous differentiation. HPV16 has also been found in transitional cell carcinomas.26
Warty carcinoma is another rare variant of squamous cell carcinomas with marked condylomatous changes. They are associated with coinfection by several strains of HPV and have deep margins that demonstrate features typical of invasive squamous cell carcinoma.27 Many warty cell tumors also demonstrate notable cytoplasmic vacuolization. For this reason, they may be confused on cytology as low-grade koilocytosis.
Lymphoepithelioma-like carcinoma of the cervix is more common in Asian women and has been reported to have better prognosis than typical squamous cell carcinomas of the cervix. It has been associated with Epstein-Barr virus.28 Lymphoepithelioma-like carcinoma of the cervix is histologically similar to nasopharyngeal lymphoepitheliomas: The cells are poorly differentiated, with abundant cytoplasm and enlarged vesicular nuclei. Inflammatory cells including large numbers of T cells are prominent, and therefore, lymphoepithelioma-like carcinomas can be confused for glassy cell carcinoma (Figure 5-3). However, the cells tend to have indistinct cell borders that contrast with the distinctively bordered cells in glassy cell carcinomas.
FIGURE 5-3. Lymphoepithelioma-like carcinoma. Note abundant cytoplasm, enlarged vesicular nuclei, and infiltration of inflammatory cells. A. Low-power view shows prominent inflammatory cells. B.High-power view shows poorly differentiated cells with abundant cytoplasm and enlarged vesicular nuclei.
Adenocarcinoma
Adenocarcinomas are the second most common histo-logic type of cervical cancer. In contrast to squamous cell cancers, adenocarcinomas arise from the endocervical mucus-producing glandular cells. Grossly, the ectocervix may appear benign, but the cervix may be expanded or “barrel-shaped” given the disease in the endocervix. In contrast to squamous cell carcinomas, adenocarcinomas of the cervix may not be confluent and can exhibit so-called skip lesions. Histologically, foci of adenocarcinoma in situ or minimally invasive adenocarcinoma may be interspersed with areas of benign glands.
Endocervical-type mucinous adenocarcinomas are the most common subtype of cervical adenocarcinomas. Their cells resemble columnar cells found in normal endocervical mucosa. They are largely moderately to well-differentiated. The glandular elements may be arranged in a racemose, glandular pattern, appearing similar to the configuration of normal endocervical mucosa. Nuclei are basally located, but appear stratified with mitotic figures present. Endocervical mucinous adenocarcinomas may have uniform nuclei with minimal stratification. Well differentiated (grade 1) neoplasms demonstrate less than 10% solid components. Moderately differentiated (grade 2) disease displays increased mitotic figures, with solid components comprising up to half of the neoplasm. Poorly differentiated (grade 3) adenocarcinomas have more pleomorphic nuclei, mitoses, and may have a larger solid component, areas of marked desmoplasia, and necrosis (Figure 5-4).
FIGURE 5-4. Invasive adenocarcinoma of the cervix. (A) Well differentiated; (B) poorly differentiated.
There are also several histologic variants of cervical adenocarcinomas. Mucinous adenocarcinoma may contain goblet cells with intestinal differentiation. They may form glands with papillae or may demonstrate architecture similar to colonic adenocarcinoma. Glands may be lined by pseudostratified, malignant-appearing cells with intracytoplasmic mucinous vacuoles, goblet cells, or occasionally Paneth cells. Intestinal subtypes are extremely rare, and care must be taken to rule out metastatic disease from the gastrointestinal tract.
Minimal deviation adenocarcinoma is an uncommon, very well-differentiated form of cervical adenocarcinoma, previously referred to as adenoma malignum. Cells do not demonstrate features typical of malignancy. These tumors comprise approximately 1% to 3% of all cervical adenocarcinomas. They may be associated with mucinous adenocarcinomas and sex cord tumors of the ovary.29 They may occur as a sporadic neoplasm; however, they have also been associated with Peutz-Jeghers syndrome.30 However, they have not been associated with HPV infection. Clinically, minimal deviation adenocarcinomas may be associated with watery mucinous vaginal discharge or abnormal endocervical cells on cervical cytology. On physical examination, advanced tumors may appear as polypoid lesions and firm yellow neoplasms. Microscopically, glands are more infiltrative in appearance. Nuclei are bland and located at the base of the epithelium. In the endometrioid type, cells lining the glands resemble benign proliferative endometrium. Glands may appear similar to normal endocervical glands; however, they may vary in size or have atypical angular outpouchings surrounded by desmoplasia. Mitotic figures in benign endocervical glands are very rare; however, on high-power magnification, minimal deviation carcinoma can be noted to have mitoses. Therefore, one of the most reliable criteria is the depth of involvement of the cervical stroma. Whereas normal endocervical crypts are rarely deeper than 7 mm, minimal deviation carcinoma may extend through up to two-thirds of the cervical stroma29 (Figure 5-5). Immunochemistry has revealed that minimal deviation carcinoma may stain focally for carcinoembryonic antigen, and estrogen and progesterone receptors have been found to be uniformly negative in this disease.
FIGURE 5-5. Minimal deviation adenocarcinoma. A. Mitotic figures in benign endocervical glands are very rare; however, on high-power magnification, minimal deviation carcinoma can be noted to have mitoses. B. Deep invasive minimal deviation adenocarcinoma. Therefore, one of the most reliable criteria is the depth of involvement of the cervical stroma.
Villoglandular adenocarcinomas of the cervix are low-grade carcinomas that may appear similar to intestinal villous adenomas. Villoglandular adenocarcinoma of the cervix is characterized by low-grade atypia and rare mitotic figures. Histologically, these neoplasms have a long, filamentous, often inflammatory-appearing connective tissue core with an overlying layer of well-differentiated cells. They are frequently associated with high-risk HPV. Because these tumors may be associated with more aggressive carcinomas, the formal diagnosis should be made on cone biopsy. Villous adenocarcinomas tend to occur in young women, and unless associated with an underlying adenocarcinoma of poorer prognosis, these tumors have very good prognosis.31
Additional cervical adenocarcinomas include clear cell, papillary serous, and mesonephric tumors. Clear cell cancers are associated with intrauterine diethylstilbestrol exposure. Clear cell adenocarcinomas appear histologically as sheets of cells with atypical nuclei, mitotic figures, and abundant clear cytoplasm (Figure 5-6). Papillary serous carcinomas are morphologically similar to the more common papillary serous tumors of the ovary and endometrium and are not associated with HPV infection.32 Mesonephric neoplasms are a rare glandular subtype derived from wolffian duct remnants. Remnants of the mesonephric ducts are present in the lateral aspects of up to 20% of cervical specimen. They appear as small glandular structures with intraluminal Periodic acid-Schiff (PAS) stain–positive material. They are lined with cuboidal cells. Reti-form, tubular, and sex cord patterns have also been described. Patients may develop benign mesonephric hyperplasia of the cervix, and in 2 series of 49 and 14 cases, no consequences of disease were noted.33,34
FIGURE 5-6. Glassy cell carcinoma. A. Cells are large and polygonal, with eosinophilic, ground glass–type cytoplasm. B. Glassy cell carcinomas have abundant mitotic features, well-defined cell borders, and prominent infiltrate of eosinophils and plasma cells. C. High-power view.
However, mesonephric hyperplasia may be responsible for cervical cytology revealing atypical glandular cells. Histologically, it may be difficult to differentiate between benign mesonephric hyperplasia in the cervix and mesonephric adenocarcinoma, particularly because mesonephric carcinomas are likely to develop within areas of mesonephric hyperplasia.33
Other Epithelial Tumors
In addition to squamous cell and adenocarcinomas, there are several less common types of cervical cancer. For example, adenosquamous carcinomas contain both malignant squamous and glandular cells. Between 5% and 25% of cervical neoplasias are of adenosquamous histology. These tumors tend to behave in a more aggressive fashion. They are more likely to have higher tumor grade, higher incidence of vascular invasion,35 and higher incidence of lymph node metastasis.36 Glassy cell carcinomas are a rare, poorly differentiated subtype of adenosquamous carcinoma of the uterine cervix. These behave particularly aggressively and respond poorly to both surgical management and radiotherapy. The mean age of patients affected by glassy cell carcinoma of the cervix is approximately 10 years younger than that of patients with squamous cell and adenocarcinomas of the cervix.37 Clinically, these may appear on gross examination as a barrel-shaped cervix. Histologically, cells are large, polygonal, with eosinophilic, ground glass–type cytoplasm. Glassy cell carcinomas have abundant mitotic features, well-defined cell borders, and prominent infiltrate of eosinophils and plasma cells (Figure 5-7).
FIGURE 5-7. Clear cell carcinoma, characterized by atypical nuclei, mitotic figures, and abundant clear cytoplasm.
Adenoid cystic carcinoma is a rare neoplasm, comprising 10% to 15% of all salivary neoplasms and 1% to 2% of all head and neck malignancies. Adenoid cystic carcinoma of the cervix is particularly rare and accounts for less than 1% of cervical adenocarcinomas. The tumor is most common in postmenopausal females and is more common in African American patients. It has been associated with high-risk HPV. Clinically, these tumors generally present with a large, palpable lesion that can be ulcerated or friable. Histologically, adenoid cystic carcinoma is characterized by basaloid tumor cells with high nuclear-to-cytoplasmic ratios, numerous mitoses peripheral palisading, and a cribriform appearance, often with areas of necrosis. Lymphatic involvement is common. The cells are cytokeratin positive and also stain positively for MNF-116. This tumor behaves aggressively, with frequent recurrence despite radical surgical management.
Adenoid basal tumors of the cervix may be confused with adenoid cystic carcinoma, but differentiation is important, as adenoid basal tumors rarely exhibit malignant behavior. These tumors may be composed of nests of cells with basaloid, squamous, or glandular differentiation. However, the tumors are typically associated with high-grade squamous intraepithelial lesions and high-risk HPV.38 Clinically, because these patients may be asymptomatic without grossly visible lesions, these tumors are most commonly detected incidentally. Tumors may be locally aggressive, but rarely metasta-size. When the primary tumor is bland in appearance and does not have more atypical features present, it behaves in a benign fashion, and some authors have proposed renaming typical adenoid basal tumors of the cervix adenoid basal epithelioma to describe their benign course. However, adenoid basal carcinomas are frequently associated with more aggressive histo-logic subtypes of cervical cancers, which behave more aggressively.
Large-cell neuroendocrine carcinomas are aggressive, rare tumors with a histologic appearance that includes insular, trabecular, glandular, and solid growth patterns. All tumors stain positively for chromogranin, and the majority of the tumors are noted to be argyrophilic, have eosinophilic cytoplasmic granules, and have areas of necrosis (Figure 5-8). Small-cell carcinoma is another rare tumor and is associated with poor outcome, with 5-year survival rates less than 30%. The tumor is composed of sheets and cords of small, anaplastic cells with scant cytoplasm. Lymphatic involvement is common. Immunohistochemistry may be helpful for diagnosing difficult cases, and these tumors may express chromogranin, synaptophysin, and p53 protein. Approximately 60% of small-cell carcinomas of the cervix are associated with HPV18.
FIGURE 5-8. Large-cell neuroendocrine tumor of the cervix. Such tumors are argyrophilic, have eosinophilic cytoplasmic granules, and have areas of necrosis.
Metastatic Spread Patterns
The most common method of spread of cervical carcinoma is via direct extension to adjacent tissues, including the parametria, the vagina, the pelvic sidewall, and the bladder and rectum. Although less common, cervical cancer may also metastasize to the ovaries. In addition, cervical cancer may spread lymphatically to the parametrial, obturator, and iliac lymph nodes. Hematogenous spread is less common, but may include sites in the lung, bone, liver, and mediastinum and, even less commonly, the spleen, adrenal, and brain.
FIGO Staging
Cervical cancer is clinically staged using a system developed by FIGO and involves bimanual examination with or without anesthesia and limited imaging studies such as chest radiography, intravenous pyelo-gram, and barium enema. CT, MRI, and PET imaging may be used to assist in case of clinical suspicion of parametrial or sidewall disease; however, identification of lymph nodes suggestive of metastatic disease does not influence the clinically assigned stage.
The FIGO staging system is presented in Table 5-2. Early-stage disease typically refers to FIGO stages I through IIA, and advanced-stage disease describes stages IIB and higher. Identification of hydronephrosis on intravenous pyelogram or CT permits assignation of stage IIIB.
Table 5-2 Updated FIGO 2009 Staging of Cervical Carcinoma
Stage I disease reflects disease limited to the cervix. It is important to note the specific guidelines for stage IA1, or microinvasive squamous cell carcinoma, as this disease may be managed more conservatively. Microinvasive disease is defined by a limited depth of invasion, where only small tongues of malignant cells have penetrated the basement membrane less than 3 mm; the overall width of the lesion can be no larger than 7 mm. This may affect either surface or glandular cervical epithelium. In order for a formal diagnosis of microinvasive squamous carcinoma, the cone or LEEP biopsy must encompass the entire cervical lesion and have negative margins. Microinvasive cells may be larger, with more prominently enlarged, pleomorphic nuclei, more pronounced eosinophilic cytoplasm, and surrounding desmoplastic stromal reaction. Two separate definitions for microinvasive carcinoma have been developed. FIGO has defined microinvasive squamous carcinoma to be stage IA1 lesions. More stringently, the SGO (Society of Gynecologic Oncology) Committee on Nomenclature further defined microinvasive squamous carcinoma as disease that must not exceed a depth of 3 mm and has no lymphovascular space involvement. The application of a microinvasive subtype to adenocarcinomas of the cervix remain controversial, in part due to the presence of skip lesions with this histology.
TREATMENT
Key Points
1. Stage IA1 microinvasive squamous cell carcinoma may be managed conservatively with a cone biopsy or extrafascial hysterectomy.
2. Early-stage disease may be primarily managed surgically with radical hysterectomy and pelvic lymphadenectomy.
3. Chemoradiation is the most effective treatment for advanced-stage disease and may also be employed with great efficacy in patients with early-stage disease who are poor surgical candidates.
Primary Treatment Modalities
Cervical cancer may be treated with several modalities. Early-stage disease is typically managed with surgery, whereas advanced-stage disease is best treated with primary radiation and concurrent low-dose chemotherapy. Treatment options are summarized by stage in Table 5-3.
Table 5-3 Treatment Summary for Cervical Cancer by Stage
|
Stage I |
|
Stage II |
|
Stage III |
|
Stage IV |
Early-Stage Disease
Stage IA1, or microinvasive carcinoma, may be managed with either simple hysterectomy or cervical conization, depending on the patient’s desires for future fertility. These guidelines are supported by several studies that have demonstrated that there is minimal risk of nodal involvement in patients with disease less than 3 mm in depth and less than 7 mm in breadth. Takeshima and colleagues analyzed 402 patients with invasive squamous cell carcinoma of the cervix with less than 5 mm of invasion. Only 1 of 82 patients (1.2%) with lesions less than 3 mm in depth demonstrated lymph node metastasis, compared with 5 of 73 (6.8%) in patients with 3 to 5 mm depth of invasion.39 More recently, Bisseling and colleagues40 performed a review of the literature reporting on 1565 patients with stage IA1 disease. Eight hundred fourteen patients underwent pelvic lymphadenectomy, of whom 12 had positive nodes. Lymphvascular space invasion (LVSI) was present in 25 patients, none of whom had lymph node metastasis. Because of this low incidence of extracervical disease, stage IA1 squamous cell carcinoma of the cervix may thus be managed conservatively with a near-perfect rate of control.41
Several tumor characteristics may predict prognosis and recurrence with conservative management of IA1 disease. Roman and colleagues42 determined that patients with LVSI were more likely to have occult lymph node metastasis, and this finding has been confirmed by others.43,44 Additionally, Raspagliesi and colleagues42 showed that patients with LVSI or lateral negative margins less than 8 mm or apical negative margins less than 10 mm were both associated with recurrence. When fertility is no longer desired, patients with close margins or positive LVSI may be offered completion hysterectomy.
Radical hysterectomy with pelvic lymphadenectomy remains the standard of care for patients with stage IA2, IB, and IIA disease (Figure 5-9). Although some data suggest that patients with stage IA2 disease may be managed with cervical conization or extrafascial hysterectomy without lymphadenectomy, the safety of such a conservative approach has yet to be proven. For example, the risk of lymph node metastases with stage IA2 disease has been shown to be 7.4% in one retrospective review, whereas another study observed a 48% incidence of residual disease in the radical hysterectomy specimen after conization for this stage.44,45 Radical hysterectomy with pelvic lymphadenectomy should thus be recommended; for patients who are poor surgical candidates, intracavitary brachy-therapy may be used with excellent results.
FIGURE 5-9. Standard specimen from type III radical hysterectomy, including parametria, uterosacral ligaments, and upper 2 to 3 cm of the proximal vagina.
Patients with stage IB to IIA disease may also be managed successfully with either radical hysterectomy and pelvic lymphadenectomy or primary radiotherapy. Landoni and colleagues addressed this issue in a prospective trial of 469 patients with such disease, randomizing their treatment to either surgery or radiation. In this study, the patients undergoing radical hysterectomy were prescribed subsequent adjuvant radiation in the event of close or positive margins or positive lymph node metastases. They observed a statistically equivalent 5-year overall and disease-specific survival.46 In this trial, 42 patients (25%) undergoing surgery experienced recurrence, as compared with 44 (26%) in the radiotherapy group. Of note, the surgical patients did demonstrate greater severe morbidity as compared with those who received radiation.
The morbidity of surgery may be minimized with application of a modified approach to the radical hysterectomy. Patients undergoing a type II radical hysterectomy have a less extensive dissection of the parametria and vagina, without impact on survival. This was confirmed in a prospective trial of 243 patients with stage IB and IIA cervical cancer who were randomized to either type II or type III radical hysterectomy. Patients undergoing type II radical hysterectomy had a significantly shorter operative time and late urologic morbidity. Blood loss, need for transfusion, immediate postoperative complications, and postoperative stay were not significantly different. Recurrence and death secondary to disease were not significantly different between the 2 groups of treatment. The authors concluded that both type II and III radical hysterectomies are effective treatment for stage IB and IIA cervical cancer, but that type II hysterectomy was associated with fewer late complications.47
The decision to treat with either surgery or radiation depends on several factors, including menopausal status, age, medical comorbidities, tumor histology, and primary tumor diameter. In general, younger and thinner patients without concurrent medical illnesses who desire preservation of ovarian function are better candidates for a surgical approach, although age and obesity are not necessarily contraindications to surgery. Given the radiosensitive nature of the ovaries, women who undergo primary radiotherapy will likely lose ovarian function and can also develop fibrosis of the vagina. A surgical approach allows for preservation of the ovaries and fallopian tubes. The safety of omitting oophorectomy was first established by a prospective GOG trial of 990 patients with stage IB disease; 0.5% of women with squamous cell histologies and 1.7% with adenocarcinomas had ovarian metastases. This was further confirmed in a review of 3471 Japanese patients with early-stage cervical cancers; for women with stage IB to IIA disease, ovarian metastases were observed in less than 1% for patients with squamous cell cancers and less than 5% for those with adenocarcinomas.48
Tumor diameter may also influence the decision to treat with surgery or radiation. In general, patients with stage IB2 disease are at higher risk for nodal disease, distant metastasis, and local and distant recurrences. Patients who undergo radical hysterectomy typically will require postoperative radiotherapy, and the rationale for a primary radiotherapy approach primarily reflects the perceived minimization of morbidity with a single, compared with a multiple, treatment modality. However, several single-institution reviews have reported on the primary management of patients with bulky IB disease with radical hysterectomy, to be followed with adjuvant radiotherapy in patients with particularly high-risk features. Five-year survivals range from 62% to 72%.49,50 The National Comprehensive Cancer Network (NCCN) panel on cervical cancer’s most recent recommendations states that surgery followed by chemoradiation is an acceptable treatment option (category 2); however, they also include pelvic radiotherapy with brachytherapy as a category 1 recommendation.51
Occasionally, patients selected for radical hysterectomy are found to have metastatic nodal disease at the time of operation. Options for management intraoperatively remain controversial and include resection of existent adenopathy and performing adjuvant radiation, resection of adenopathy and proceeding with radical hysterectomy and adjuvant radiation, or aborting the procedure entirely and proceeding with curative intent radiation therapy. There are no randomized controlled studies regarding subsequent therapy in this population, and retrospective reviews may be biased because of intraoperative selection. However, Cosin and colleagues52 identified that patients with macroscopic metastatic lymph nodes who underwent resection had a 50% 5-year survival rate, compared with a 0% 5-year survival rate for those who had bulky adenopathy that was not resected. Although these data are retrospective, they suggest a therapeutic role in resecting grossly metastatic lymph nodes at the time of surgery.
Advanced-Stage Disease
Stage IIIA cervical carcinomas are quite rare and represent a unique therapeutic challenge, owing to the lymphatic drainage of the distal third of the vagina to the inguinal nodes. Although radiotherapy remains primary treatment, there is difficulty in sterilizing inguinal fields without providing inappropriate radiation to the femoral heads. Kavadi and colleagues53 reviewed cases of stage III disease at the MD Anderson cancer center and found the 5-year survival rate to be 37% and 10-year actuarial survival rate to be 34%. The 5-year survival rate was significantly lower in those patients with parametrial disease (25% vs. 56% [P = .05]) and in patients with discontinuous lesions in the lower third of the vagina (15% vs. 48% in patients with contiguous lesions 
).53 Dittmer et al proposed a unique technique using a posterior field for the pelvis and anterior field for the inguinal nodes; however, as intensity-modulated techniques improve, this may become a preferred modality for groin irradiation.54
For patients with stages IIB, IIIB, and IVA disease, primary radiotherapy, with external beam and intracavitary radiation, is recommended. Several randomized controlled studies examining chemosensitization as an adjunct to radiation confirmed the superior survival when chemotherapy is administered concurrently, and this is now considered the standard of care.55-57 These findings were recently confirmed by a large-scale population-based study in Ontario.58 Quantitative meta-analysis by the Cochrane collaborative reveals that there is a 6% improvement in 5-year survival with chemoradiotherapy (hazard ratio 
; 
). Radiation with chemosensitization also improved disease-free survival while reducing recurrence and progression. Acute toxicities were increased with chemoradiotherapy; however, there were a limited number of trials with long-term follow-up to comment on long-term toxicity and complications.59 Weekly single-agent cisplatin is most often administered in this setting, but the NCCN also states that carboplatin or non-platinum chemotherapies may be considered for those patients who may have difficulties with cisplatin-containing options.60
Special Situations
Radical Trachelectomy
Radical trachelectomy entails removal of the cervix, the parametrium, and vaginal cuff while leaving the corpus and adnexa intact. This surgery may be approached vaginally, abdominally, or in a laparoscopically assisted manner. This procedure, in combination with a laparoscopic pelvic lymphadenectomy, provides an acceptable fertility-sparing option for patients with early cervical cancer. At case completion, a permanent isthmic cerclage is placed to assist with preventing preterm delivery. Primary cesarean is indicated for patients who have undergone trachelectomy. As of 2008, more than 900 cases had been performed and reported, with nearly 200 subsequent live births. The overall incidence of prematurity before 32 weeks is acceptable (10%), and overall success in curing disease has been high, with 31 recurrences (4%) and 16 deaths (2%).61 Alternatively, for patients with early-stage operable disease who desire preservation of fertility, radical trachelectomy is a viable option. Multiple studies have shown comparable oncologic outcomes in well-selected patients.62,63
Ovarian Transposition
Ovarian transposition or oophoropexy is not in itself a therapeutic procedure; however, in patients who are to undergo primary radiation for cervical disease, ovarian transposition may serve as a way to prevent radiation-induced menopause. In this procedure, the utero-ovarian attachments are ligated, and the infundibulopelvic ligament and ovarian vasculature are mobilized to allow transposition of the ovaries above the pelvic brim. This procedure may be successfully performed abdominally or via laparoscopic approach.64 Despite transposition, however, up to 50% of patients who subsequently receive postoperative radiotherapy will still develop ovarian failure.
Adjuvant Hysterectomy After Radiation Therapy
In general, adjuvant hysterectomy after primary radiation therapy with chemosensitization should not be offered to patients with bulky cervical cancer. Keys and colleagues65 examined 256 patients with tumors measuring more than 4 cm who were randomized to either external and intracavitary irradiation or attenuated irradiation with subsequent extrafascial hysterectomy. Hysterectomy was not found to increase grade 3 or 4 toxicity. Although there was a lower incidence of relapse in the hysterectomy cohort at 5 years (27% vs. 14%), there was no impact on overall survival.
Adjuvant Postoperative Pelvic RT
After radical hysterectomy, adjuvant therapy is recommended for patients with intermediate or high risk for recurrence. Intermediate risk is assigned to those patients following an algorithm including large tumor size, deep stromal invasion, and lymphvascular space involvement of tumor. In a randomized study of 277 patients with stage IB disease meeting these criteria, adjuvant radiation was found to significantly improve recurrence-free survival, with a decrease in recurrence from 28% to 15%.66 Patients at high risk include those with metastatic lymph nodes or obvious extrauterine spread of disease, such as to the adnexae or parametria. Patients with high-risk features should undergo adjuvant radiation with chemosensitization.
Carcinoma of the Cervical Stump
Although the American Congress of Obstetrics and Gynecology states that there is no specific benefit to supracervical hysterectomy, it is not an uncommon procedure in the United States and accounts for a significant portion of hysterectomies performed for benign indications. These patients remain at risk for cervical carcinoma, and their surgical history makes primary treatment more difficult. Radical trachelectomy may be considered in patients with carcinoma of the cervical stump. One large retrospective review of 213 patients with carcinoma of the cervical stump found that although there were no stage-for-stage survival benefits associated with surgical management, there was a significantly higher number of patients receiving brachytherapy who had improved locoregional control as compared with those undergoing external radiation alone. Complication rates of those patients undergoing primary radiation for cancer of the cervical stump were similar to those of patients undergoing primary radiation for cervical cancer in the intact uterus.67
SURVIVAL AND PROGNOSIS
Key Points
1. Early-stage cervical cancer carries an excellent prognosis after appropriate treatment.
2. Lymph node metastasis is the most important prognostic factor in women with cervical cancer.
3. Localized recurrent disease may be successfully treated with pelvic exenteration; extrapelvic recurrence is typically managed with palliative chemotherapy.
Survival Outcomes
With the introduction of chemosensitization to radiotherapy, both in the adjuvant and primary setting, the survival for women with cervical cancer has improved dramatically. In general, patients with stage IA1 and IA2 disease have an overall disease-specific survival of 100%; those with stage IB and IIA disease have long-term survival ranging from 80% to 88%; those with stage IIB to IVA disease have survival of 45% to 65%.54-56,68
Prognostic Factors
In addition to the correlation between clinical stage and prognosis, several other elements have been found to affect outcome of patients with cervical cancer; these include primary tumor diameter, lymph node metastasis, lymphatic vascular space invasion, microscopic evidence of parametrial extension, and histology. Although it is not formally part of the FIGO clinical staging for cervical cancer, lymph node involvement is the most important prognostic factor for patients with cervical cancer. Patient 5-year overall survival is dramatically lower in patients with positive lymph node metastasis (50% vs. 85%).69,70 In addition, tumor size correlates consistently with decreased progression-free and overall survival. The GOG has explored the prognostic factors involved in 1125 patients with stage I squamous cell carcinoma of the cervix who were treated with radical surgery with and without adjuvant radiotherapy. The disease-free interval at 3 years was 94.6% in patients with occult tumors, 85.5% for patients with tumors ~ 3 cm, and 68.4% in patients with tumors 3 cm or greater.68 This same study defined several further significant independent prognostic factors. These include capillary or lymphatic involvement of tumor, depth of tumor invasion, and presence of disease at the parametrial margins. All of these factors were associated with decreased disease-free survival and have been confirmed by other investigators.70,71
In addition to these surgical-pathologic factors, both anemia and tumor hypoxemia are associated with poorer survival in patients with cervical cancer.72 The relationship between anemia, tumor oxygen saturation, and prognosis is complex. Although anemia has been associated with poorer outcomes in patients with cervical cancer, it is somewhat unclear whether this is a result of more advanced tumors or whether it is a variable that could influence prognosis if corrected.73 This complex relationship was observed in a multi-institution retrospective review of 605 Canadian patients that revealed that anemic patients whose hemoglobin levels were corrected to greater than 12 g/dL had similar survival rates as those who had normal hemoglobin without transfusion, noting that correction beyond 13 g/dL was not associated with additional survival improvement.74 However, other data have suggested that transfusion is associated with increased levels of interleukin-10, diminishing host immunity. In one study designed to study optimal methods of determining intratumoral oxygen tension, only half of patients undergoing transfusion for cervical cancer treatment had increased tumor oxygenation.75
Another method that has been proposed to improve tumor oxygenation and hemoglobin is the use of erythropoietins. The Southwest Oncology Group performed a phase 2 trial of women receiving chemoradiation for stage IIB to IVA cervical cancer. They were administered erythropoietin and iron to achieve a hemoglobin level greater than 12.5 g/dL. Although treatment was successful at increasing hemoglobin, there was a 13% incidence of venous thromboembolism during and immediately after treatment. The survival for patients enrolled in this trial was poor when compared with that of prior studies, and although this may have been secondary to baseline patient characteristics, an adverse effect of erythropoietin and iron on survival could not be excluded.76
MANAGEMENT OF RECURRENT DISEASE
Key Points
1. A small number of patients with recurrent central cervical cancer may be cured by surgery or radiotherapy.
2. Before proceeding with curative intent salvage, examination and imaging should be used to exclude the possibility of distant metastases.
3. Chemotherapy may assist with improved progression-free survival and palliation of symptoms in the recurrent setting, though it only modestly improves overall survival.
Surveillance
After primary therapy for cervical cancer, women should be followed closely for evidence of recurrence. Typically, women with cervical cancer are followed with office visits, to include directed history and pelvic/rectal examination, with performance of a screening Pap test. Although the utility and cost-effectiveness of Pap testing as a surveillance technique has recently been challenged, abnormal results may indicate early recurrence at the vaginal cuff (after radical hysterectomy) or at the remaining cervix (after primary radiotherapy). In addition, women with cervical cancer are at increased risk for vaginal dysplasia, and Pap testing may be useful to identify such lesions.
Recommended Treatment Options
Despite advances in the management of both early-and advanced-stage cervical cancer, women who develop recurrence of this disease have limited treatment options. The decision to proceed with surgery or chemotherapy depends primarily on the site of recurrence. For those women with small, mobile recurrent tumors limited to the vaginal cuff or cervix, pelvic exenteration is a possibility. This procedure includes radical resection of the pelvic organs, with colostomy and creation of a neo-bladder. Despite the attendant surgical morbidity and mortality, exenteration remains the only modality for long-term survival, as cytotoxic therapy is only palliative.
Pelvic exenteration was first described by Brunschwig as a radical treatment for advanced or recurrent cervical cancer in 1948. This procedure involves complete or partial colpectomy (with hysterectomy if the uterus was not removed at primary therapy) and removal of the bladder and/or rectum with reconstruction of these organs. Exenteration is appropriate to consider in patients with small and central recurrences in the pelvis; furthermore, candidates should not have severe medical comorbidities and must accept the changes in anatomy and self-image inherent with such a radical procedure. When carefully selected, those patients who undergo pelvic exenteration for recurrent cervical cancer previously treated by definitive radiotherapy may have up to a 50% 5-year survival.77 Despite advances in perioperative management, thromboprophylaxis, antibiotic therapy and surgical technique, exenteration remains a morbid operation, with perioperative mortality that can range from 2% to 14%.
Given the morbidity of this procedure, appropriate patient selection is imperative. Patients with positive nodes at the time of the planned exenteration have a survival of less than 20%. Patients who have positive margins at the time of exenteration have only a 10% 5-year survival rate, with a median overall survival of 4 months. This is in contrast to those with negative margins after exenteration, in whom there is a 55% 5-year survival rate and median overall survival of 22 months.78 Careful attention must be given to ensuring that the recurrent disease is fully resectable, and preoperative and intraoperative exploration must ensure that there are no sites of metastatic disease outside the pelvis. Preoperative PET is appropriate to help identify metastatic disease and can accurately identify sites of metastasis before planned pelvic exenteration. PET/CT may have improved specificity; however, it may be underutilized as a result of cost considerations. Others propose diagnostic laparoscopy for pre-exenterative evaluation.
In regards to morbidity, Berek and colleagues77 reported on the University of California, Los Angeles’s experience with pelvic exenteration in 75 patients with a median age of 52.5 years. They found that 70.2% of patients had at least 1 major complication, including ileus, ureteral anastomotic insufficiency, abscess, and cardiothrombotic events. Thirty percent developed intestinal fistulae. Goldberg and colleagues reported similar morbidity in 1003 patients undergoing exenteration at Albert Einstein, with complications including ureteral anastomotic leaks (14%) and wound complications (17%).79 Patients with small central recurrences may be candidates for radical hysterectomy instead of pelvic exenteration. Coleman and colleagues80 reviewed 50 patients who underwent radical hysterectomy for recurrent or persistent isolated central disease after radiotherapy. One subgroup of 10 patients had normal lesions limited to the cervix less than 2 cm. This subgroup had a 5-year survival rate of 90%. More recently, Maneo et al81 reported on 34 patients who underwent radical hysterectomy for recurrence after radiotherapy. They confirmed that patients with small tumors had improved outcomes. Both of these studies reported high rates of toxicity, with up to 44% of patients experiencing grade 3 to 4 toxicity and 14% to 28% of patients with fistula.
Alternatively, chemotherapy may be offered to patients with recurrent cervical cancer, especially in patients with extrapelvic sites of disease or who are poor candidates for exenteration. Cisplatin in doses of 50 to 100 mg/m2 offer response for 4 to 6 months, with overall survival of approximately 7 months. A randomized controlled trial conducted by the GOG compared several regimens of platinum-based chemotherapy for the treatment of recurrent cervical cancer. They found that higher doses of cisplatin (100 mg/m2 vs. 50 mg/m2) induced a higher response rate and had greater toxicity, but offered no differences in terms of progression-free or overall survival.82
Combination chemotherapies have also been evaluated for recurrent cervical cancer; only until recently, however, has such a regimen been shown to improve survival. In 2005, Long and colleagues83 reported on a GOG trial designed to determine whether survival is improved with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) compared with cisplatin alone, or cisplatin with topotecan. The MVAC arm was closed secondary to treatment-related death. They observed that cisplatin with topotecan offered an improvement in both progression-free survival and overall survival (9.4 vs. 6.5 months) in patients with recurrent cervical cancer. However, this was associated with increased hematologic toxicity,83 although an ancillary study revealed that overall quality of life was not affected.84
FUTURE DIRECTIONS
The treatment of cervical cancer is ever changing, and the standard of care for managing this disease will continue to evolve as new treatment paradigms are explored. There are a vast number of studies currently being conducted regarding cervical cancer therapy. These trials include addition of chemotherapy to chemosensitizing radiotherapy in intermediate-risk patients; the evaluation of preoperative PET and CT imaging to detect lymph node metastases; the use of simple hysterectomy, versus radical, in very early-stage disease; and efficacy of targeted agents such as bevacizumab in addition to cytotoxic chemotherapy in recurrent disease. As surgical management, chemotherapy, and radiotherapy in this disease continue to progress, the survival and morbidities of women undergoing treatment for cervical cancer should continue to improve.
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