Introduction

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

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

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

Epidemiology

For 2012, the American Cancer Society estimated that 12,170 cases of invasive cervical carcinoma and approximately 4220 cervical cancer deaths would occur in the United States. Since 2004, rates have decreased by 2.1% per year in women younger than 50 years of age and by 3.1% per year in women 50 years of age and older. A much larger population of American women (approximately fourfold) will be diagnosed with cervical dysplasia that will never develop into invasive neoplasia.

Although cervical cancer is the third most common gynecologic malignancy in the United States, it ranks as the most common gynecologic malignancy worldwide and is the third most common cancer in women in the world, with an estimated 530,000 cases in 2008. Marked disparity in incidence exists between countries where routine gynecologic care and Pap smear screening are available, and countries in Latin America, the Caribbean, and Africa, where cervical cancer is the most common cause of cancer-related death in women.¹

It has long been appreciated that the incidence of invasive cervical carcinoma is related to sexual activity. Early age at first intercourse, multiple sexual partners, a history of venereal infection, and other parameters of sexual activity have long been recognized as factors associated with the development of invasive cervical cancer. Women from lower socioeconomic strata, and African American and Hispanic populations have an increased frequency of disease. Incidence rates in the United States are estimated at 8.1 new cases per 100,000 white women each year as compared with 11 per 100,000 in African American women and 14.4 per 100,000 in Hispanics.

Molecular epidemiological studies have demonstrated that correlation of sexual activity with cervical carcinoma is related to transmission of the epithelial trophic and oncogenic HPV.4–4 Most HPV infections are transient, resulting in no changes or low-grade intraepithelial lesions (cervical intraepithelial neoplasia [CIN] 1) that will be spontaneously cleared in most young women.^5,6 Development of high-grade intraepithelial lesions will occur in a small minority of women, usually within 24 months.⁷ High-grade lesions (CIN 2/3) may progress to invasive cervical cancer if not treated.^8,9

Cases of CIN 2/3 that progress to invasive cancer will do so over a period of 8 to 12 years, which has been referred to as the detectable preclinical phase.10–13 Thus the opportunities for early detection and intervention are abundant. However, an estimated one half of the invasive cervical cancers diagnosed in the United States are found in women who have never been screened, and an additional 10% are diagnosed in women who have not been screened within the preceding 5 years.¹⁴

Based on a comprehensive review of available evidence, the American Cancer Society released new screening recommendations for the prevention and early detection of cervical cancer on March 12, 2012. Table 87-1 is a synopsis of their recommendations.¹⁵ The biggest change from the past is that Pap tests are no longer recommended every year and there are two types of test that are used for cervical cancer screening. The Pap test can find early cell changes and treat them before they become cancer. The HPV test finds certain infections that can lead to cell changes and cancer. The HPV test may be used along with a Pap test or to help doctors decide how to treat women who have an abnormal Pap test.

Squamous Cell Carcinomas of the Cervix

Approximately 75% of invasive cervical carcinomas are squamous cell carcinomas. Tumor histology differs between well, moderately, or poorly differentiated tumors. Squamous carcinomas (Fig. 87-5) may be keratinizing (sometimes containing characteristic keratin pearls) or nonkeratinizing. Large cell and small cell variants exist. True verrucous cancers of the cervix are rare.

Cervical Adenocarcinomas

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

Clinically important subtypes also include clear cell adenocarcinomas of the cervix associated with in utero diethylstilbestrol (DES) exposure, which tend to be diagnosed at a younger age than most other adenocarcinomas, and so-called adenomalignum or minimal deviation adenocarcinoma (Fig. 87-6), an entity associated with deceptively bland or benign-appearing cells, which may be cause for undertreatment of a true malignancy, with a significant likelihood of recurrence even when diagnosed at an early stage.^33,34

Adenosquamous Carcinomas

Adenosquamous carcinomas consist of a malignant glandular component and a malignant squamous component and make up approximately one-third of cervical carcinomas with glandular differentiation. Opinions vary regarding the prognosis of adenosquamous carcinoma compared with pure adenocarcinoma or pure squamous carcinoma when prognosis is adjusted for clinical stage at diagnosis. A clinically important variant of adenosquamous carcinoma is the so-called glassy cell carcinoma, thought to represent a very poorly differentiated adenosquamous carcinoma, the name of which derives from the ground-glass or granular appearance of the cytoplasm seen in many cases. Additional features may include an intense stromal inflammatory infiltrate composed predominantly of eosinophils and plasma cells. Some patients may have accompanying eosinophilia in their circulating blood, with elevated absolute eosinophil counts. This histologic type is associated with a rapid clinical rate of growth, proclivity for early regional dissemination, and increased risk of recurrence after surgical therapy or radiation therapy, even in the absence of other recognized adverse prognostic factors.35–38

Clinical Presentation

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

Screening

Screening for cervical cancer and its precursors with the Pap smear and pelvic examination has resulted in dramatic reductions in cervical cancer mortality in every country where this has been widely used, and is arguably the most effective screening program in effect for any neoplastic disease, in either gender. Table 87-1 outlines the current screening guidelines of the American Cancer Society. The false-negative rate of the Pap smear is approximately 10% to 15% in women with invasive cancer, but the sensitivity, as defined by the detection of biopsy-proven CIN, is 51%.^45–45 The sensitivity of the test may be improved by ensuring adequate sampling of the squamocolumnar junction and the endocervical canal. Smears without endocervical or metaplastic cells may be inadequate and possibly should be repeated.⁴⁶

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

In the 1980s, cytology laboratories began reporting an increasing number of smears with changes of “squamous atypia” in response to concerns from clinicians over an unacceptably high false-negative cytology rate and increased recognition by cytopathologists of the cytologic changes associated with HPV infection. The use of multiple classification systems with inconsistently defined numeric grading conventions added further imprecision. In an attempt to eliminate confusion among clinicians and cytopathologists, a uniform system for reporting epithelial cell abnormalities was established in 1988 at a National Cancer Institute (NCI) workshop for reporting cervical and vaginal cytologic diagnoses.⁴⁷

The Bethesda System has since been revised, in 1991 and again in 2001 (Table 87-2),⁴⁸ to reflect laboratory and clinical experience gained since the original implementation, as well as the increased use of new technologies and results from interval research studies. An important contribution of the Bethesda System was the creation of a standardized format and nomenclature for cytology laboratory reports that includes both a descriptive diagnosis and an evaluation of specimen adequacy.

Colposcopy

Patients with a gross lesion of the cervix should undergo cervical biopsy. For patients with an abnormal cytologic evaluation, without a gross lesion, a colposcopic examination with directed punch biopsies is required. Colposcopy allows the clinician to identify areas suggestive of dysplasia. A 3% acetic acid solution is applied to the cervix for 30 to 90 seconds, which causes a transient reaction with the envelope proteins of the papillomavirus, in addition to producing an osmotic dehydration of the dysplastic cells, thereby accentuating the optically dense chromatin to produce a whitish area. The skilled colposcopist can further distinguish between grades of dysplasia based on acetowhitening and types of vascular patterns (Fig. 87-7). An additional technique to help visualize abnormal areas is the application of quarter-strength Lugol iodine after the initial inspection for acetowhitening. High-grade lesions turn mustard yellow.

Endocervical Curettage or Endocervical Brush

Study of the endocervical canal is required when no abnormalities are found on colposcopic examination, when the entire squamocolumnar junction cannot be visualized, or when atypical endocervical cells are present on Pap smear. Some experts advocate the use of endocervical curettage (ECC) as part of every colposcopic examination to safeguard against missing occult cancer within the endocervical canal. Others reserve ECC for patients with recurrent cytologic atypia after therapy. A sleeved endocervical brush is an alternative to ECC that is less uncomfortable for many patients. A recent, prospective comparison of ECC specimens with sleeved endocervical brush specimens (both obtained from the same patient sequentially after randomization with respect to the order of obtaining specimens) before cervical conization or hysterectomy revealed a higher rate of inadequate specimens from ECC, comparability of the two techniques with respect to sensitivity and specificity in unmatched analysis, and superior sensitivity of the sleeved endocervical brush in matched analysis. As the sleeved endocervical brush is at least isoeffective and possibly better than ECC but more comfortable for the patient, many clinicians prefer this maneuver, which may serve to increase patient compliance with subsequent surveillance follow-up and repeated assessment.⁵⁹

Excisional Biopsy

Diagnostic cervical conization (cone biopsy) leads to an accurate diagnosis and decreases the incidence of inappropriate therapy in the following situations: (a) the squamocolumnar junction is not visualized on colposcopy; (b) dysplastic epithelium extends into the endocervical canal; (c) cytology is suggestive of high-grade dysplasia or worse; (d) microinvasive carcinoma is found on directed biopsy; (e) sampling of the endocervical canal shows high-grade intraepithelial neoplasia; and (f) cytology is suggestive of adenocarcinoma in situ.

Loop Electrodiathermy Excision Procedure

LEEP uses wire-loop electrodes in conjunction with a radiofrequency alternating current to excise the entire transformation zone and distal canal under local anesthesia (Fig. 87-8). Compared with ablative procedures, LEEP has the major advantage of obtaining tissue for histologic evaluation. At many centers, LEEP has become the preferred treatment for CIN that can be assessed adequately with colposcopy.^60–72

Complications include bleeding, with a reported incidence of 1% to 8%,73,74 cervical stenosis (1%), and, rarely, pelvic cellulitis or adnexal abscess. In some cases, LEEP may not be an adequate alternative to formal excisional conization, such as in those patients in whom microinvasive or invasive cancer is suspected, or in those with adenocarcinoma in situ, because it may treat disease within the cervical canal inadequately and complicate pathological interpretation of the specimen. Appropriate application of this technique will yield tissue suitable for pathological study and reliable diagnosis. Excess heat may result in thermal artifact that can compromise interpretation of margins and the therapeutic adequacy of the LEEP procedure.

Diagnostic or Therapeutic Excisional Conization (Cone Biopsy)

Diagnostic or therapeutic excisional conization (cone biopsy) must be performed under general or regional anesthesia. Complications, which include hemorrhage, sepsis, infertility, stenosis, and cervical incompetence, occur in 2% to 12% of patients, depending on depth and geometry of excision.75–75 Width and depth of the cone should be tailored to the topography of the lesion, to produce the least amount of injury while providing clear surgical margins. Conization may be performed with a cold knife or with the carbon dioxide laser.

Patient Evaluation in Patients with Invasive Disease

A thorough history should be obtained before diagnostic assessments are initiated, because skilled questioning will elicit information that will serve to guide subsequent evaluation. A sexual history should be obtained from all patients, which may alert the physician to screen for HIV and other sexually transmitted diseases. This also will serve to establish a baseline for sexual function and expectations that may be helpful in the posttreatment counseling and sexual rehabilitation of patients after completion of therapy. A complete history and systems review also should assess comorbid conditions (e.g., neurologic, cardiovascular, pulmonary, gastrointestinal, endocrine) that may affect the selection and implementation of treatment strategy.

A social assessment should be routinely obtained and will assist in determining supportive interventions that may be necessary to facilitate patient compliance with complex diagnostic programs and multimodality treatment programs. In the United States, patients with advanced cervical cancer may be uninsured or underinsured, often will have cultural or language barriers to obtaining and complying with care, may have limited educational attainment and medical sophistication, and will have variable degrees of familial or other social support.

A general physical examination should be carried out, with attention to accessible lymph node groups, including the supraclavicular nodes and the inguinal nodes. Physical examination also should assess the heart, lungs, and large vasculature (i.e., the carotid, dorsalis pedis, posterior tibial, and femoral arteries; the aorta; and the veins of the lower extremities). Pelvic examination must include meticulous inspection of all potentially visible sites and palpation of the perineum, the vulva, the full length of the vagina, and the anorectum. Some patients will manifest areas of preinvasive disease at multiple separate sites along the lower reproductive tract or synchronous invasive primary cancers of the lower reproductive tract and the anus, representing “field cancerization” consequent to exposure to a common etiologic agent. Typically, tumors arising from the ectocervix or transformation zone are easily visualized and sampled with biopsy. Occasionally tumors arising in the uterine corpus or lower uterine segment can invade the uterine cervix or protrude through the cervical os, causing confusion in the diagnosis. Often this can be sorted out by histopathology and by diagnostic imaging, with magnetic resonance imaging (MRI) being most useful in this context. Once the diagnosis of cervical carcinoma is established, staging includes careful clinical evaluation of the vagina, cervix, uterus, and parametria. The adnexal areas should be palpated as well, because some patients will harbor adnexal pathology (tuboovarian abscesses or, less commonly, adnexal metastases) that optimally are diagnosed and addressed before initiation of cancer treatment.

Conventionally, pelvic examinations in the setting of invasive cancer were performed under general or regional anesthesia to assist in the most accurate possible physical evaluation of disease extent. Relaxation of the muscles of the pelvic floor and the opportunity to conduct vigorous and prolonged examination without inflicting discomfort or pain may identify disease extension that may be missed in an outpatient clinic examination. For example, examination under anesthesia may be critical in very anxious, young, nulliparous women, as well as in elderly patients who may not be regularly sexually active and in whom the vagina may be stenotic. Examination under anesthesia also affords the opportunity to perform cystoscopy and proctosigmoidoscopy when indicated. However, in an era of cost containment and constrained health care resources, examination under anesthesia may be omitted when a cooperative patient is amenable to satisfactory examination in the clinic or, in rare circumstances, in patients with locally extensive disease requiring rapid initiation of treatment.

Staging

The revised 2009 staging criteria (Table 87-3)⁷⁶ of the International Federation of Obstetrics and Gynecology (FIGO) are a mixture of histopathological, clinical, and radiographic assessments that reflect the fact that invasive cervical cancer is most prevalent in less-developed portions of the globe where sophisticated and expensive imaging modalities may not be widely available. Cervical cancer is clinically staged, and staging is based primarily on inspection and palpation of the cervix, vagina, parametrium, and pelvic sidewalls. Only the subclassification of stage I (Ia1, Ia2) requires pathological assessment. The FIGO staging system permits assessment through biopsy, physical examination, cystoscopy, proctoscopy, excretory urography (intravenous pyelography), and plain film radiography of the chest and skeletal system. Results of lymphangiography, computed tomography (CT), MRI, and positron emission tomography (PET) may be of great value in planning treatment, but do not influence assignment of clinical stage in the FIGO formalism. When findings are equivocal, by convention, a patient is assigned to a lower stage. Once clinical stage has been assigned, it cannot be altered by subsequent events or findings. Findings from surgical evaluation (by laparoscopy or by surgical assessment of retroperitoneal lymph nodes via extraperitoneal or transperitoneal node dissection) will not alter assignment of clinical stage. However, these findings may profoundly influence subsequent treatment. Similarly, evidence of nodal or other spread discerned at the time of hysterectomy does not alter clinical stage.

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

Diagnostic Imaging Evaluation of Cervical Cancer

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

The FIGO staging system is based predominantly on clinical examination under anesthesia, ultrasonography, intravenous urography, cystoscopy, proctoscopy, and chest radiography. Significant inaccuracies occur in this staging because of possible errors in gynecologic examination (24% to 39%).⁷⁷ The various imaging modalities have a complementary role in the accurate staging and complete evaluation of the cancer that have important therapeutic implications.

Today, clinicians most often obtain a contrast-enhanced CT scan of the abdomen and pelvis for patients with disease of stage Ib2 or greater (Fig. 87-9).⁷⁸ Lymph nodes larger than 1.0 to 1.5 cm in diameter are suspicious for tumor involvement and should be biopsied. Unfortunately, microscopic metastases are not readily detected with CT, and the inflammation commonly associated with advanced disease may cause enlargement of nodes that do not contain metastases. The sensitivity of MRI in the detection of regional metastases is similar to that of CT. However, MRI provides better anatomic delineation and accurate estimation of the tumor size, volume, and local extent within the pelvis, which can influence the choice of therapy (Fig. 87-10). Involvement of the vagina, parametrium, pelvic wall muscles, ureter, bladder, and rectum can be better assessed with MRI for accurate staging (Fig. 87-11).⁷⁷ MRI before and after vaginal opacification with contrast medium can be used if imaging evaluation of the vaginal wall or fornices is required.⁷⁹ T₂-weighted images obtained by using phased-array coil, fast spin-echo or conventional spin-echo techniques are accurate in local staging and lymph nodal assessment; the former technique is faster with increased resolution.⁸⁰ Dynamic contrast-enhanced T₁-weighted images are helpful in identifying smaller tumors, fistulous tracts, and invasion into bladder and rectum.⁷⁷ Dynamic contrast-enhanced imaging is useful in differentiating areas composed predominantly of tumor cells (well-enhanced areas) from those of fibrous tissue with scattered cancer cells (poorly enhanced areas). This information can be helpful, as radiation therapy is more effective in well-enhanced tumors.⁸¹

MRI is very useful in the evaluation of tumor volume and enlarged lymph nodes, inherently important prognostic factors as well as determinants of the design of radiation treatment ports and selection of radiation dose. However, MRI cannot identify micrometastases to lymph nodes and differentiate malignant from nonmalignant enlargement. MRI with newer contrast agents like ultrasmall superparamagnetic iron oxide has been useful in distinguishing benign from malignant nodes.⁸² The shape, volume, and direction of the growth of the tumor can be well assessed, and these are crucial for planning brachytherapy and external beam radiotherapy.⁷⁷ MRI also is useful in the follow-up evaluation of the tumor, its response to treatment, and identification of recurrences. However, benign conditions, like edema or inflammation, sometimes cannot be differentiated from tumors. Dynamic contrast-enhanced MRI is useful in differentiating malignant lesions that usually have shorter and stronger enhancement than benign conditions in patients who have abnormalities after treatment for cervical cancer.⁸³

Recent studies have suggested that ¹⁸F-fluorodeoxyglucose PET (FDG-PET) is more sensitive and specific than more standard radiographic studies in the detection of lymph node involvement by cervical cancer.^86–86 Grigsby and colleagues⁸⁷ have reported a strong correlation between abnormal posttherapy FDG uptake and tumor recurrence. PET scans are now Medicare approved and considered standard of care for staging purposes for all newly diagnosed cervical carcinomas.

Laboratory Evaluation

Routine laboratory assessment should include complete blood counts with differential counts and red cell indices. Many patients with advanced disease will be anemic at the time of diagnosis, often reflecting chronic blood loss and iron deficiency. Anemic patients treated with radiation or chemoradiation have poorer outcomes than do patients with near-normal hemoglobin levels.88–91 Anemia at diagnosis (before treatment) correlates significantly with reduced pelvic control and survival with univariate analysis, but not always when data are subjected to multivariate analysis. In contrast, multivariate analysis reveals that hemoglobin level during the course of radiation therapy or chemoradiation is a robust predictor of local outcome and survival.^88–91 Transfusion for anemic patients with maintenance of average weekly nadir hemoglobin levels at or above 11 to 12 g/dL through radiation therapy is associated with improvement in prognosis to that associated with patients with near-normal or normal hemoglobin levels at diagnosis.^88,90 This effect may be partially mediated through better tumor oxygenation and oxygen-enhanced radiation lethality to clonogenic cells, as well as reduced angiogenesis in better-oxygenated tumors. With pelvic or extended-field radiation that will encompass a substantial percentage of adult bone marrow, hemoglobin may decline slowly, even when adequate iron stores are present and patients are supported with hematinics. Concurrent administration of cisplatin further aggravates this problem, and can result in clinically significant reduction in hemoglobin levels over the course of a 6- to 8-week program of chemoradiation, even in patients with normal hemoglobin levels at the time of diagnosis. Frequent monitoring of hemoglobin levels as well as white cell counts and platelets should be performed throughout a course of chemoradiation, and hemoglobin level should be supported, either by transfusion or through the use of recombinant erythropoietin. The minimal hemoglobin level required is uncertain, but it seems prudent to target a minimum of 10 g/dL.

Neutropenia may indicate supportive treatment with granulocyte colony-stimulating factor to avoid prolonged treatment interruptions that are known to adversely affect local tumor control in patients treated with radiation.92,93 Absolute neutrophil counts should be monitored at least weekly in patients undergoing chemoradiation.

An elevated platelet count has been associated with advanced malignancy and is considered a consequence of increased platelet production.⁹⁴ Hernandez and associates⁹⁵ identified this effect in advanced cervical cancer, and Rodriguez and coworkers⁹⁶ identified the preoperative platelet count as an adverse prognostic factor, even for patients with stage Ib cervical carcinoma. The cumulative 5-year survival of women with a platelet count greater than 300,000 (85 women) was 65%, compared with 84% for the group with a normal value (134 women). At issue was the question of whether the value could have been elevated simply because of bleeding from the primary tumor, but no association was found with the preoperative hematocrit. This study of surgically treated patients with early disease also demonstrated that the effect was not a consequence of metastatic disease and did correlate with tumor volume, with nearly half of the patients with platelet counts in excess of 300,000 having “large” lesion size, in contrast to only 28% (32 of 114) patients with normal counts.⁹⁷ In a multivariate analysis, adjusting for age, race, tumor size, and presence of lymph node metastases, high platelet count was still associated with an adverse prognosis.

Additional laboratory tests should include a complete chemistry panel with serum electrolytes and measurements of renal and hepatic function. Electrolytes and renal function should be monitored repeatedly through a course of chemoradiation. Creatinine may be elevated secondary to hydroureter/hydronephrosis that may require ureteral stent placement or nephrostomies before radiation therapy, particularly if cisplatin chemotherapy is anticipated. Serum sodium and potassium may become abnormal during the course of chemoradiation, particularly in elderly patients, consequent to diarrhea with potassium loss, inadequate oral replenishment, and inadequate or inappropriate fluid intake.

Superficial Ablative Therapy

A major deficiency of all ablative therapies is the absence of full histopathological assessment of the lesion treated, and the hazard of undertreatment of an occult invasive lesion. For this reason, use of ablative techniques is declining. Three superficial ablative techniques used historically are electrocoagulation diathermy, cryosurgery, and CO₂ laser therapy.

Hysterectomy

Hysterectomy involves the removal of the uterus and varying amounts of surrounding tissue (Fig. 87-12). Because the risk of ovarian metastases is low (0.5%), ovarian preservation usually is recommended in premenopausal women, obviating the need for hormone replacement therapy.¹⁴³ An important exception is when nodal metastases from a primary cervical adenocarcinoma are detected intraoperatively, when the risk of ovarian metastasis escalates steeply, perhaps to as high as 25%.¹⁴⁴ Five types of hysterectomy have been described.¹⁴⁵

Extrafascial or Simple Hysterectomy (Type I)

Extrafascial or simple hysterectomy involves the removal of the cervix, adjacent tissues, and a small cuff of the upper vagina in a plane outside the pubocervical fascia; it is appropriate treatment for stage Ia1 disease. Minimal disturbance occurs to the bladder and ureters, which decreases the risk of urinary complications.

Modified Radical Hysterectomy (Type II)

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

Radical Hysterectomy (Type III)

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

Extended Radical Hysterectomy (Type IV)

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

Partial Exenteration (Type V)

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

Surgical Alternatives to Conventional Radical Abdominal Hysterectomy

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

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

Laparoscopy/robot have been coordinated with vaginal hysterectomy, with varying amounts of surgery being carried out via the laparoscopic or robotic approach, ranging from pelvic and paraaortic lymphadenectomy to lymphadenectomy plus important components of the radical hysterectomy.148–148

Radical trachelectomy is an operation suitable for selected patients with small, generally exophytic squamous tumors (usually <2 cm, although some patients with larger tumors have been treated in this fashion) involving primarily the cervix who desire conservation of reproductive capacity. In this surgery, the main trunk of the uterine artery is preserved, although branches to the cervix and vaginal fornices are sacrificed before amputation of the cervix at a point approximately 5 mm caudal to the uterine isthmus. The uterus is suspended from the lateral stumps of the transected paracervical ligaments. Isthmic cerclage is performed in a fashion similar to that used as prophylaxis against miscarriage, and an anastomosis between the vaginal mucosa and the isthmic mucosa is performed. Variations on this surgery can be performed vaginally with laparoscopy, or abdominally. The margin between the superior extent of the tumor and the uterine isthmus must be a minimum of 1.5 cm, but 2 cm is preferable. MRI can be used preoperatively to assist in patient selection for this procedure. Intraoperative assessment by inspection of the trachelectomy specimen and frozen-section pathological study are done to ensure an adequate surgical margin, and patients must be prepared for hysterectomy in the eventuality that a satisfactory margin cannot be obtained. Numerous successful pregnancies have been reported after such surgery, although the risk of miscarriage is increased. In carefully selected patients, the risk of cancer recurrence is very small.151–151

Damage to the pelvic autonomic nerves during radical hysterectomy is responsible for much of the late morbidity after surgical treatment of FIGO stages Ia2 to IIa cervical cancer, including problems with bladder function, defecation, and sexual dysfunction. Nerve-sparing radical abdominal hysterectomy¹⁵² endeavors to spare important components of the autonomic innervation of the true pelvis by identification and preservation of the hypogastric nerves, which carry sympathetic fibers; the inferior hypogastric plexus formed from the fusion of the hypogastric nerves with fibers of the pelvic splanchnic nerves derived from sacral roots S2 to S4, which carry parasympathetic fibers; and the most distal part of the hypogastric plexus, which extends to the lateral vaginal wall and the base of the bladder. In aggregate, these structures are important in controlling bladder compliance, urinary continence, vaginal lubrication and genital engorgement during sexual arousal, small muscle contractions with orgasm, and some rectal functions. This recent surgical innovation is intended not to compromise the efficacy of the cancer surgery, while preserving important components of quality of life in cancer survivors. Precise criteria for patient selection have not been defined.

Radiation Therapy

Radiation therapy for cervical cancer usually consists of a combination of external radiation (teletherapy) and intracavitary or interstitial radioisotope therapy (brachytherapy).

Patients with very-small-volume cervical tumors of stages Ia1 to Ib1 (Ib1, <1 cm in diameter) can be treated successfully with intracavitary brachytherapy alone, with results that parallel the efficacy of surgery.¹⁵³ Brachytherapy alone, particularly if conducted on an outpatient basis with high-dose-rate (HDR) technology, may serve as suitable alternative therapy for medically compromised patients for whom operative intervention implies more than minimal risk of intraoperative or perioperative morbidity. At the other end of the spectrum of invasive disease, patients with very extensive stage III or IVa cervical cancer may not have geometry compatible with brachytherapy, and cure sometimes may be accomplished with teletherapy administered alone (or, more commonly, in combination with chemotherapy) by using progressively smaller teletherapy treatment volumes carried to progressively higher cumulative radiation dose (“shrinking fields technique”). However, radiation-based therapy with curative intent is accomplished for most patients with a combination of external beam (teletherapy) and intracavitary or interstitial isotope therapy (brachytherapy).

Conventional teletherapy is given in a fractionated course by using daily doses of 1.8 to 2 Gy per fraction, 5 fractions weekly. Altered fractionation may serve to keep the overall duration of treatment as short as possible, which has been correlated with improved local control and survival. It should be emphasized that target volumes and teletherapy dose distributions are not standardized and should be based on pretreatment imaging studies that define disease extent rather than on FIGO stage. Depending on the presence or absence of nodal metastases and the anatomic level of nodal disease, teletherapy ports may encompass only nodes caudal to the bifurcations of the common iliac arteries (approximately at the interspace between the fifth lumbar vertebra and the first sacral segment), nodes to the level of the aortic bifurcation (approximately at the level of the third lumbar vertebra), or to a volume extending to encompass paraaortic nodes to the level of the cisterna chyli (approximately at the level of the twelfth thoracic vertebra). Treatment of such widely differing volumes, particularly when done with synchronous chemotherapy, implies substantial variability in acute symptomatic tolerance, hematologic tolerance, and potential delayed sequelae of treatment. Routine treatment of standard volumes is not a substitute for appropriate diagnostic assessment of disease extent and treatment tailored in consideration of both tumor and patient factors.

The brachytherapy dose conventionally has been calculated and prescribed at points A and B (Fig. 87-13). Doses to the bladder neck and anterior rectal wall (dose-limiting normal structures) usually are specified as well (Fig. 87-14).¹⁵⁴ Brachytherapy usually is accomplished by using one or two intracavitary or interstitial inpatient applications of low-dose-rate (LDR) (40 to 60 cGy/h) technologies. Most applicators for intracavitary brachytherapy resemble the apparatus in Figure 87-15, and consist of intrauterine tandem and paired colpostats or ovoids, which are placed in the lateral vaginal fornices, resulting in a classic pear-shaped isodose distribution. The customary strategy is intracavitary brachytherapy supplemented by tailored teletherapy treatment to boost volumes, generally lateral and posterior to the cervix and medial parametria. In patients whose vaginal anatomy does not accommodate tandem and colpostat devices (a so-called conical vagina with flush or ablated fornices and a narrowed upper vagina) or patients with extensive, lateral parametrial invasion, interstitial implantation may provide more satisfactory dose distribution when gross tumor extends beyond the traditional pear-shaped dose envelope provided by intracavitary brachytherapy (Fig. 87-16). Interstitial templates have been used to treat cervical cancer for many years; however, reported series have been small, and patient follow-up rarely has been sufficient to permit calculation of long-term survival rates.^157–157 One of the largest series is from University of California–Irvine, where they described 5-year survival rates of 21% and 29%, respectively, for patients with stage IIB and IIIB disease with high complication rates.¹⁵⁸ At present, there is no definite evidence to indicate that interstitial therapy improves the outcome of patients with advanced intact cervical lesions.

LDR brachytherapy procedures require insertion under anesthesia and hospitalization for radiation safety and patient immobilization. Alternatively, multiple outpatient intracavitary insertions may be performed by using HDR (100 cGy/min) remote afterloading technology. Most commonly, five intracavitary insertions are performed when HDR technology is used. Because of miniaturization of the high-activity source and the hardware used for treatment, these insertions may be accomplished under conscious sedation when cooperative patients with favorable vaginal anatomy are selected. More tailored dose distributions often can be designed with the inherently more flexible HDR systems than with historically used LDR equipment using multiple sources with fixed physical dimensions and a limited spectrum of source strengths. The comparative data that exist suggest that HDR and LDR technologies are approximately isoeffective for tumor control and roughly equivalent with respect to complications when appropriate dose-rate corrections have been applied.159,160

It seems increasingly clear that either approach (LDR or HDR brachytherapy) in the hands of physicians with substantial brachytherapy experience is likely to be superior to the other approach in the hands of the clinician who treats only a limited number of patients. Brachytherapy often has been described as an art and not a science. The American Brachytherapy Society is attempting to place brachytherapy on a more rational, scientific basis by developing guidelines grounded in established practice and data driven to replace what has often been based on subjective criteria and intuition coupled with the hard lessons of experience.161,162 Improvements in diagnostic imaging (MRI, CT, PET, and combination, hybrid, or fusion studies) are anticipated to facilitate these efforts by providing improved understanding of the spatial relations of brachytherapy sources and both cancer and dose-limiting normal tissues. This effort, however, remains a work in progress.

The side effects of radiation therapy are both immediate and late. Acute reactions are seen in tissues with the most rapid cell turnover rates such as skin, intestinal mucosa, urothelium, vaginal mucosa, and bone marrow. Acute side effects of pelvic irradiation include diarrhea, abdominal cramps, tenesmus, urinary frequency, urgency, and dysuria. Some women experience vaginal bacterial overgrowth consequent to alterations in the integrity of the vaginal mucosa, causing discharge and pruritus. Occasionally, small-volume bleeding from the bladder or rectum may occur. Aggravation of hemorrhoidal disease is common. Older patients with extensive diverticular disease are vulnerable to the development of diverticulitis, which may result in pain, bleeding, perforation, and significant delay in completion of treatment. Rare patients experience bacterial overgrowth with Clostridium difficile, even in the absence of antecedent antibiotic exposure. Severe, prolonged diarrhea poorly responsive to standard medications and dietary modification should arouse the clinician’s suspicion. Not uncommonly, pelvic radiation will provoke a recrudescence of herpes simplex virus type II, usually manifest as focal, discrete, well-marginated ulcerations on the labia caudal to the irradiated volume, although lesions may affect the urethra, bladder, and vagina. It is important for the radiation oncologist to recognize the labial lesions, the pattern of which tends to be discrete ulcerations, usually quite different from the more confluent, irregularly bordered, moist desquamative reaction seen with acute radiation dermatitis, because treatment for these conditions is quite different.

Late complications (onset months to years after radiation therapy) can be a result of intimal proliferation in small arteries/arterioles with decreased blood supply and subsequent fibrosis or focal infarction. The larger the dose per treatment fraction, the greater the risk of late complications in normal tissues unavoidably included within the treatment volume. Most late complications of radiation therapy involve the rectum, bladder, or small bowel. Although most serious gastrointestinal complications occur within the first 3 years, serious side effects may occur several decades after treatment. The average time to onset of major urinary tract complications tends to be longer than that of intestinal complications. Late effects of pelvic irradiation may include chronic radiation cystitis with urothelial atrophy, irritative symptoms, and bleeding. In rare patients, vesicovaginal fistulae may develop, usually at the level of the bladder neck where the brachytherapy dose often is highest. Vaginal stenosis with dyspareunia and compromised ability to perform surveillance follow-up is a somewhat avoidable consequence of radiation therapy if informed and compliant patients are provided with vaginal dilators and instructed in their use, as well as provided with vaginal estrogen cream.

Chronic radiation proctitis or sigmoiditis with pain and small-volume bleeding can occur in some patients, with focal injury to the anterior rectal wall consequent to brachytherapy being the most common site. Bleeding often can be controlled through conservative, judicious laser ablation of bleeding telangiectatic vessels. Symptomatic large bowel stricture is uncommon, but may require fecal diversion in severe instances. Rectovaginal fistulae may be the consequence of severe injury to the rectovaginal septum and anterior rectal wall. This complication usually requires permanent fecal diversion, but occasional patients can have segmental resection with reestablishment of intestinal continuity. Most intestinal injury is to small intestine, commonly manifested by obstructive symptoms. The usual site is in the terminal ileum, but focal jejunal injury may be seen, particularly in patients undergoing extended-field treatment to encompass paraaortic lymph nodes.

If the ovaries are in the treatment field, ablation of both endocrine and reproductive function will be the inevitable consequence of pelvic radiation therapy administered to a high dose to premenopausal women. Symptoms of estrogen deprivation may take several months to develop after pelvic radiation, depending on the age of the patient and endogenous body stores of estrogen. Usually the endometrium is ablated consequent to high mucosal dose from intracavitary brachytherapy. Occasional patients will have remnants of functioning endometrium. With the almost inevitable occlusion of the endocervical canal after brachytherapy, painful hematometra may develop in such patients if unopposed estrogen replacement therapy or cyclical hormone replacement is instituted. Generally, combined hormone replacement therapy will avoid this complication, which may necessitate hysterectomy in severe cases.

Chemoradiation

Synchronous administration of radiation and cytotoxic chemotherapy will enhance acute radiation reactions within all tissues included in the treatment volume, resulting in more severe acute symptoms. Impact on chronic radiation injuries is less predictable. Anxiety regarding normal tissue tolerance, both immediate and late, has delayed extrapolation of successful chemoradiation strategies for anal cancer to the larger volumes of vulnerable tissues routinely irradiated in the treatment of cervical cancer.

Multiple clinical trials have investigated the sequential use of neoadjuvant chemotherapy followed up by conventional radical radiation therapy for patients.163–166 In several of these studies, patients treated with neoadjuvant chemotherapy followed up by radiation had worse survival probability than did patients treated with radiation alone. This has been attributed to selection of cross-resistant tumor clonogens, as well as delay in initiation of the potentially curative therapy.

In dramatic contrast to the manifest failure of sequential chemotherapy and radiation, the large majority of prospective, randomized controlled trials investigating radiation and synchronous chemotherapy have demonstrated improvements in both local control and survival. Data from five phase III randomized clinical trials sponsored by the NCI have shown that the addition of concurrent cisplatin-containing chemotherapy to radiation results in a reduction in risk of recurrence by 21%.108,167–170 Four of these trials pertained to women with locally advanced cervical cancer, stages Ib2 to IVa. The fifth studied high-risk postoperative patients stages Ib to IIa with cancer extension to parametrium, surgical margins, or regional lymph nodes.

The optimal drug regimen is uncertain. Four of these trials had an experimental arm containing 5-fluorouracil (5-FU); however, the Gynecologic Oncology Group (GOG) prospectively compared weekly cisplatin with continuous-infusion 5-FU at 225 mg/m² for 5 days weekly (a lower daily dose than the 1000 mg/m² per 24 hours for 96 hours used in the previous positive studies) and terminated the study (GOG protocol 165) when it became clear that no possibility existed that the 5-FU arm might ultimately prove superior. Weekly cisplatin at a dose of 40 mg/m² for 6 doses has become the most commonly used regimen for concurrent chemotherapy with radiation for advanced cervical cancer. The National Cancer Institute of Canada prospectively compared radiation alone with radiation plus weekly cisplatin in 259 patients with squamous cancers with bulky (≥5 cm) stage Ib2 to IIa, or smaller tumors with positive nodes, and patients with stages IIb to IVa cancers.¹⁷¹ The study was designed to have an 80% probability of detecting a 15% survival difference at 5 years. Although patients receiving the cisplatin regimen did marginally better, the study failed to find a statistically significant difference.¹⁷¹ The NCI made a clinical announcement in 1999, after the 5 trials from the United States, that “strong consideration should be given to the incorporation of concurrent chemotherapy with radiation therapy for patients who require radiation therapy for the management of cervical cancer.”¹⁷²

The NCI announcement was further confirmed by three additional prospective, randomized studies that found relapse-free survival benefit from the synchronous administration of epirubicin with radiation,¹⁷³ mitomycin-C with radiation,¹⁷⁴ and 5-FU plus mitomycin-C with radiation¹⁷⁵ (Table 87-4). A meta-analysis was done to assess the effect of chemoradiotherapy on outcome in patients with local advanced cervical cancer.¹⁷⁶ In the meta-analysis, based on 13 randomized trials, they found a 6% improvement in 5-year survival with chemoradiotherapy. A larger advantage was seen in stages I and II disease compared with stage III disease. They found a significant survival benefit in both groups of trials that used platinum-based (P = 0.017) and non–platinum-based (P = 0.009). Interestingly, there was a larger survival benefit seen in the two trials that used adjuvant chemotherapy in addition to concurrent chemoradiation therapy and the conclusion of the meta-analysis was that the results endorsed the recommendation of the NCI. However, both platinum-based and non–platinum-based chemoradiotherapy could be used.¹⁷⁶

The most recent study evaluating concurrent chemotherapy and radiation therapy, published in 2010, was conducted in eight developing world countries and was completed in less than 2 years.¹⁷⁷ This was a phase III randomized study evaluating standard concurrent weekly cisplatin and pelvic irradiation compared to weekly cisplatin and gemcitabine and pelvic radiation therapy followed by two additional courses of adjuvant gemcitabine+cisplatin. The authors reported a 9% improvement in progression-free survival associated with the experimental arm of gemcitabine+cisplatin+radiation compared to the standard arm of cisplatin+radiation at 3 years follow-up, with increased but clinically manageable toxicity.¹⁷⁷ These results are very promising, especially because the study was done in developing countries and so quickly; however, the study does raise a lot of questions, including whether the observed benefit was related to the concurrent use of chemotherapy, the adjuvant use chemotherapy, or both. It does not answer the question of whether this regimen was equally effective in stage IIB patients as well as stage III patients (see Table 87-4). Most studies have demonstrated that the use of combined chemotherapy and radiation therapy is associated with a statistically significant increase in gastrointestinal and hematologic toxicity that, although significant, has been tolerable. Data suggest that synchronous administration of chemotherapy potentiates radiation effect in cycling, immediately responding cell systems, in both cancer and normal tissue. Thus both immediate normal tissue reactions and side effects are potentiated. Importantly, an increase in catastrophic late complications such as bowel obstruction, fistula formation, or second malignancies, has not been seen. Given the preponderance of evidence, which suggests that synchronous radiation with radiopotentiating chemotherapy favorably affects the probability of cancer-free survival, clinical research into the optimal drugs and schedule of administration is likely to play a central role in clinical investigation for the foreseeable future.

Stages Ib1, Ib2, and IIa

Stage Ib is defined as a clinically evident lesion confined to the cervix or preclinical lesions greater than those of Ia2. Patients with IIa disease have extension to the upper vagina without parametrial involvement. The incidence of pelvic nodal metastases is approximately 15% to 25% for patients with stage Ib disease.¹⁸² Treatment must be directed toward the lymph nodes, cervix, parametrial tissue, paravaginal tissue, and upper vagina; therefore, a radical (type III) hysterectomy with bilateral pelvic lymphadenectomy and paraaortic lymph node evaluation has historically been the treatment of choice. Radiation therapy is as effective as surgery based on a prospective, randomized comparison conducted in Italy.¹⁸³ In that study, 337 analyzed patients (FIGO stages Ib1, Ib2, and IIa) were randomly assigned to treatment with initial type III hysterectomy or with radiation therapy using a radiation dose (cumulative teletherapy and brachytherapy dose of 76 Gy at point A) that is substantially lower than the 85 to 90 Gy used in leading centers in the United States. Postoperative pelvic radiation therapy was administered to patients with positive nodes, positive margins, positive parametria, or less than a 3-mm surgical margin. Forty-six of 55 patients (84%) with tumors larger than 4 cm in diameter received postoperative radiation therapy. Chemotherapy was not used. Five-year survival and disease-free survival rates were identical in both groups (83% and 74%, respectively). Serious complications occurred in 28% of the group treated initially with surgery, and 12% of the radiation therapy group. Theoretically, results with chemoradiation might well be superior to those with surgery, but the benefit for synchronous administration of chemotherapy has been documented only in patients with tumors larger than 4 cm (Ib2) or more advanced stages of disease.

Given that surgery and radiation therapy are approximately isoeffective with respect to cancer control, treatment generally is selected on the basis of physician and patient preference and differences in treatment-related morbidity. Surgery provides important prognostic information and offers premenopausal women the option of ovarian conservation, because the risk of ovarian metastases is only 0.5%.¹⁴³ Considerable debate concerns whether sexual function is more feasible or better after surgical treatment or radiation therapy. Both forms of treatment carry some risk of urologic or bowel injury. However, the nature of those complications, the ability to remedy those complications, and the impact of chronic complications on quality of life are both challenging to quantitate and vulnerable to subjective interpretation. Radiation carries a small but not trivial risk of late induction of second malignancies.

For patients with stage Ib1 who are young and free of major comorbid conditions, surgery tends to be the preferred option. In patients who are poor surgical risks or elderly, radiation therapy is more sensible. Radiation therapy usually is a combination of teletherapy intended to encompass the primary, microscopic regional extensions, and regional lymph nodes, supplemented by intracavitary brachytherapy intended selectively to take the gross disease in the uterus and cervix to a much higher dose while sparing normal tissues including bladder and rectum. When disease is very small (<1 cm in diameter), the risk of nodal metastases is low, and the treatment approach may be modified to intracavitary brachytherapy therapy alone with excellent results.¹⁵³

The treatment of patients with stage Ib2 disease remains a source of continued controversy. With either surgery or radiation therapy, progressive decrements in survival probability are found as tumor size increases. In some centers, patients with stage Ib2 disease continue to undergo initial surgery, recognizing that most will have indications for postoperative radiation therapy, but that surgery will clear gross central disease, which is the most likely site of pelvic failure in patients treated with radiation. Because the morbidity of combined therapy is greater, some surgeons limit the radicality of surgical extirpation in anticipation of postoperative radiation therapy in a sensible effort to limit morbidity.¹⁸⁴ Neoadjuvant chemotherapy with cisplatin, vincristine, and bleomycin for 3 cycles at 10-day intervals before attempted radical hysterectomy has been used with encouraging results in Ib2 cancers as reported by Sardi and colleagues in Argentina.¹⁸⁵ Pathological downstaging was observed in patients operated on after neoadjuvant chemotherapy compared with patients undergoing initial surgery. These results have not been reproduced in the context of a multiinstitutional trial, when tested by the GOG.

Alternatively, radiation has been used as initial therapy supplemented by type I adjuvant hysterectomy to clear central disease. The GOG compared radical radiation therapy with attenuated preoperative radiation therapy supplemented by extrafascial hysterectomy.¹⁶⁷ A lower cumulative incidence of local relapse was noted in the radiation therapy plus hysterectomy group (at 5 years: 27% vs. 14%). No statistical differences were observed in outcomes between regimens, except for the adjusted comparison of progression-free survival, although all indicated a slightly lower risk in the adjuvant hysterectomy regimen (unadjusted relative risk of progression, 0.77; P = 0.07; unadjusted relative risk of death, P = 0.26; both one-tailed). Because preliminary analysis of this trial suggested benefit from surgery in improved local control, the GOG carried out a successor trial in which all patients had attenuated preoperative radiation therapy, followed by extrafascial hysterectomy. Half of the patients were randomized to receive weekly cisplatin at 40 mg/m² during teletherapy. The rates of both progression-free survival (P < 0.001) and overall survival (P = 0.008) were significantly higher in the combined therapy (chemoradiation) group at 4 years.¹⁶⁷

Although interpretations of the outcomes of these studies vary, it has become less common to carry out adjunctive hysterectomy routinely in patients undergoing chemoradiation for Ib2 or bulky IIa disease. However, selected patients may benefit who have poor response to teletherapy and chemotherapy assessed at the time of intracavitary insertion, or who have poor vaginal anatomy, limiting the dose of brachytherapy that can be prudently prescribed.

Patients undergoing primary surgery for stages Ib and IIa cancer who are found to have adverse clinicopathological prognostic factors may be advised to undergo adjuvant postoperative pelvic radiation therapy or adjuvant chemoradiation. Much effort has been expended in attempting to define clinicopathological factors that reliably identify patients at high-risk for failure after initial surgical therapy. Primary tumor size, depth of cervical invasion, and LVSI are thought to be independent prognostic factors in node-negative patients with surgically treated stage Ib squamous carcinoma of the cervix.¹⁰⁷ Parametrial extension¹⁸⁶ and parametrial node metastasis,¹⁸⁷ independent of retroperitoneal lymph node status,¹⁰³ predict an increased risk of recurrence in surgically treated patients. Positive or insecure margins including vaginal margins,¹⁸⁸ extension of cancer to the lower uterine segment,^189,190 and adverse histopathology³⁷ are additional parameters that may correlate with a more ominous outlook. Controversies persist concerning the relative importance of some of these factors in multivariant analysis. However, with consensus approaching unanimity, metastasis to pelvic lymph nodes is recognized as a dominant prognostic indicator.¹⁹¹

Two cooperative NCI-sponsored intergroup studies have been carried out prospectively evaluating adjuvant therapy for patients with adverse histopathological features after radical hysterectomy. Sedlis¹⁹² reported on 277 “intermediate-risk” node-negative patients who were identified based on combinations of tumor size, depth of cervical stromal invasion, and lymphatic space invasion. Based on historic outcomes, these patients were estimated to have an approximate 25% probability of recurrence after surgery, with the pelvis being the most probable site of relapse. Patients were randomly assigned to observation versus adjuvant pelvic teletherapy. In an update of this series by Rotman,¹²² there was a 46% reduction in the risk of recurrence (P = 0.007) and a significant improvement in recurrence or death (hazard ratio = 0.58) when postoperative pelvic irradiation was given. Although there was a 30% reduction in the risk of death for patients who received radiation therapy, this difference was not statistically significant (P = 0.07).

Peters¹⁰⁸ reported on 243 analyzable “high-risk” patients who had positive nodes, parametrial extension, or positive surgical margins. After radical hysterectomy, these patients were randomly assigned to receive adjuvant pelvic radiation therapy, or the same adjuvant radiation regimen with 2 cycles of synchronous 5-FU and cisplatin followed by 2 further cycles of sequential 5-FU and cisplatin. Cisplatin was administered at 70 mg/m², and 5-FU was administered at 1000 mg/m² per 24 hours for 96 hours with each cycle. The projected progression-free survival at 4 years was 80% for the patients in the radiation-plus-chemotherapy arm compared with 63% in patients receiving adjuvant radiation alone. Analysis of patterns of treatment failure at the time of initial recurrence revealed that 11 of 127 patients receiving chemoradiation had a component of pelvic recurrence compared with 25 of 116 patients receiving radiation, suggesting that the addition of chemotherapy resulted in a 60% reduction in the rate of pelvic failure. A component of distant metastatic spread was seen in 13 of 127 patients in the chemoradiation group and 18 of 116 patients in the radiation group, suggesting that the addition of chemotherapy resulted in a 34% reduction in distant spread. Paradoxically, the effect of the chemotherapy appears to have been greater on local disease than on distant dissemination, suggesting that the primary benefit may have been as a potentiator of local radiation effect.

In a small, randomized trial, Tattersall¹⁹³ reported that the addition of 3 cycles of cisplatin, vinblastine, and bleomycin before adjuvant pelvic radiation produced no benefit compared with immediate postoperative radiation therapy in patients with stages Ib to IIa disease with pelvic node metastases. In a complementary, randomized trial in which all patients received adjuvant postoperative chemotherapy, Curtin¹⁹⁴ reported that the addition of delayed adjuvant radiation produced no benefit in either pelvic control or survival.

Stages IIb and III

In the United States, patients with advanced disease are treated with chemoradiation. Teletherapy with synchronous chemotherapy is supplemented with intracavitary brachytherapy whenever feasible. The Syed-Neblett or Martinez interstitial templates are alternative brachytherapy approaches that have the theoretic advantage of extending the brachytherapy isodoses laterally to treat pelvic side walls and parametrium.195,196 However, it is unclear that this provides any advantage compared with conventional intracavitary brachytherapy supplemented by teletherapy boost treatments to limited volumes.

It is important to remember that even patients with very large tumors (even tumors measuring 7 cm or more in diameter) have a chance of being cured with radiation therapy alone, particularly if the patient is not found to have extensive regional metastases. Before the use of concurrent chemoradiation, 5-year survival rates for patients with stage IIb disease usually were reported to be between 50% and 75%.101,197,198 The broad range probably reflects differences in staging, patient selection, and treatment technique between reporting institutions. For patients with stage IIIb disease, reported survival rates after treatment with radiation therapy alone ranged between 30% and 50%.^99,198–200 However, in recent years, prospective trials with concurrent chemotherapy and radiation have improved survival even more,^{108,167–170} and have become the standard of care in this group of patients. The data and studies have been discussed earlier in this chapter; however, two major studies and their updates are discussed below.

Although the preliminary finding of Radiation Therapy Oncology Group (RTOG) 90–01, first published in 1999, demonstrated a highly significant overall survival benefit from chemotherapy among patients with stage Ib to IIb (79% vs. 55% at 5 years, P < 0.0001), no significant difference was found in survival among patients with stages III to IVa disease; at the time, follow-up was incomplete and the total number of patients with the more advanced stage was small, contributing to large confidence intervals on the results.¹⁶⁹ However, an update in 2004²⁰¹ showed a significant difference in disease free-survival (54% vs. 37%, P = 0.05) and a trend toward improved overall survival (59% vs. 45%, P = 0.07). An update of GOG 120, in which a greater percentage of patients enrolled had stages III to IV disease, found a significant improvement in progression-free survival and overall survival in patients receiving concurrent cisplatin-based chemotherapy with radiation therapy compared with patients receiving hydroxyurea and radiation, and the results were analogous in patients with stages IIb and III (each P < 0.025) (see Table 87-4).²⁰²

Stage IVa

Fewer than 5% of cases of invasive cervical cancer are truly stage IVa. Most of these are classified as IVa because of bladder involvement; rectal involvement very rarely is seen at initial diagnosis. The management of stage IVa disease is challenging because the tumors usually are large, often fixed to pelvic structures, and usually regionally metastatic. Brachytherapy often is compromised or impossible to perform because vesicovaginal fistulae develop before diagnosis or during treatment. However, at least 10% to 20% of stage IVa tumors are curable with radiation therapy alone.

Regional Disease

Most patients treated with radical hysterectomy who are found to have lymph node metastases require postoperative radiation therapy. On the basis of the findings of Peters and colleagues,¹⁰⁷ concurrent chemotherapy is recommended if no medical contraindications are present.

Patients with paraaortic node involvement can be treated effectively with extended-field irradiation. Five-year survival rates range between 25% and 50%. Some investigators have advocated prophylactic irradiation of the aortic nodes for patients with an increased risk of metastases to this region. The value of prophylactic extended-field irradiation was tested in two randomized trials. In RTOG 79–20,²⁰³ patients with stage Ib2 to IIb disease were randomly assigned to receive brachytherapy plus external beam radiation therapy to the pelvis or to the pelvis and paraaortic nodes. The absolute 5-year survival rate was significantly better for those who had paraaortic treatment, but no difference was found in disease-free survival. A European trial²⁰⁴ done at the same time had a similar randomization, but included patients with more advanced disease (e.g., with pelvic lymph node metastases or bulky stages IIb or IIIb disease). No significant difference was found in the 4-year disease-free survival rates between the two arms, but the rate of paraaortic node recurrence was significantly higher for patients in whom that area was not treated.

In several phase II studies, concurrent chemotherapy has been given with extended field irradiation.205,206 Although side effects are more significant when treatment fields are enlarged, combined therapy may be tolerable if careful consideration is given to the chemotherapy regimen, the volume of tissue irradiated, and other factors that might increase the risk of serious toxicity. However, new imaging techniques such as PET and safer methods of surgical evaluation of lymph nodes (e.g., retroperitoneal or laparoscopic lymphadenectomy), may increase the precision with which the extent of regional disease can be estimated, decreasing the margin for improvement to be gained by treating large volumes prophylactically. However, it is important to remember that there is no evidence that chemotherapy given concurrently with radiation can prevent recurrence in nonirradiated nodal sites (the rate of aortic recurrence in patients treated on RTOG 90–01 with pelvic chemoradiation was 9%).²⁰¹

Some bulky nodal metastases can be difficult to control with external beam radiation therapy alone. Some investigators have suggested resections of nodes larger than 2 cm before radiation therapy. Several investigators have reported high local control rates in patients treated with excision of bulky nodes and radiation; however, the numbers of patients in these series are small.207,208 With standard radiation therapy, it is difficult to deliver a high enough dose to the node without exceeding normal tissue tolerance limits; however, with modern conformal or intensity-modulated radiation therapy (IMRT) techniques, this may be possible.

Epidemiology

Vulvar cancer is predominantly a disease of postmenopausal women, most commonly observed in the seventh and eighth decades of life, and with a mean age at diagnosis of 65 years. Age-specific incidence rates in the United States increase steeply at age 70 years and continue to increase beyond age 80 years.²²⁸ The coexistence of vulvar intraepithelial neoplasia (VIN) or invasive squamous carcinoma of the vulva with in situ or invasive epidermoid carcinoma of the cervix has long been known, and synchronous or sequential (usually antecedent) cervical lesions may be present in as many as 20% of women with primary vulvar lesions. This observation suggests a common etiology in at least some patients.^229–235

VIN, a precursor lesion, often is multifocal. After conservative local excision of invasive vulvar cancer with preservation of clinically normal vulva, cancer may develop at anatomically distinct structures within conserved vulvar tissues. Rather than recurrence, this phenomenon may be a manifestation of the so-called field change model of oncogenesis, representing metachronous appearance of independent primaries.²³⁶

Etiology

Risk factors for the development of invasive vulvar cancer include a history of condyloma acuminatum, VIN, smoking, and chronic vulvar dystrophies including lichen sclerosus and squamous hyperplasia (hyperplastic dystrophy).237–240

Vulvar carcinoma often coexists with vulvar dystrophy, particularly in older women, with dystrophic changes in adjacent skin in up to 50% of patients with invasive vulvar cancer.241,242

However, it is unknown whether lesions such as lichen sclerosus or squamous hyperplasia are true precursor lesions. Detection of HPV in VIN or invasive disease is most common in young patients and less frequent in older patients.243,244 These observations have led to the hypothesis that patients with vulvar cancer may be segregated into two broad groups: an older population with cancer arising in association with vulvar dystrophy and unassociated with HPV, and a younger population with HPV-associated tumors often adjacent to areas of VIN.^240,245

An increasing incidence of VIN and reports of invasive vulvar cancer in young patients may be consequences of the sexual revolution and transmission of HPV. Invasive vulvar cancer has been reported in young patients with both naturally occurring and iatrogenic immune compromise.245–251 Patients infected with HIV-1 are much more likely to have HPV infection than women who are not infected with HIV, and they may be more vulnerable to development of VIN than HIV-negative controls. VIN may be more difficult to clear in HIV-infected women and may progress to invasive disease with greater rapidity.^252,253

Detection of HIV in very young patients with vulvar cancer raises the specter of increasing rates of vulvar as well as cervical cancer as the acquired immunodeficiency syndrome (AIDS) epidemic unfolds.²⁵⁴

A patient with any degree of cellular atypia associated with vulvar dystrophy is at risk of invasive vulvar cancer. Patients with cellular atypia compose approximately 10% of those patients with histopathology-proven vulvar dystrophy, and vulvar cancer will develop in fewer than 5% of these patients.²⁵⁵ The International Society for the Study of Vulvar Disease (ISSVD) established a classification for vulvar dystrophies and atypias based on histopathology (Table 87-6).²⁵⁶ The ISSVD now advises that “dystrophy” is no longer an acceptable term and recommends use of specific terminology (e.g., lichen sclerosus, lichen planus, lichen simplex chronicus, psoriasis), although these recommendations have not been adopted uniformly.^259–259

Paget Disease

Vulvar Paget disease was first reported in 1901 by Dubreuilh.²⁶⁰ The disease is seen predominantly in postmenopausal women, with common presenting symptoms of vulvar pruritus and soreness, sometimes accompanied by persistent oozing. Grossly, Paget disease may have an eczematoid appearance. With extensive disease, it may appear raised and velvety. Under the light microscope, the presence of large, pale Paget cells that are rich in mucopolysaccharide and that are periodic acid-Schiff–positive and diastase resistant is pathognomonic of this disorder (Fig. 87-17). Paget cells stain for carcinoembryonic antigen (CEA), cytokeratin-7, and gross-cystic-disease fluid protein.^261,262 Paget cells rarely express CA-125, and testing for estrogen receptors usually is negative.^263,264 Many cases express c-erB2 (HER-2/neu), which is not thought to influence the risk of metastatic spread.^265,266 Nondiploid tumors are more likely to recur. Electron microscopic studies have demonstrated that Paget cells are derived from the stratum germinativum of the epidermis.²⁶⁷ Squamous keratinocytes, sweat gland cells, and hair follicles also are derived from this epidermal layer, possibly explaining the characteristic finding of more Paget cells in juxtaposition to the basal layer of cells in the epidermis, as opposed to within higher strata.

In approximately one-sixth of cases, Paget disease involving the vulva is associated with an underlying adenocarcinoma of the vulva, often arising in apocrine glands or within Bartholin glands. Paget disease is also associated with a synchronous primary invasive cancer in another female genital tract site in approximately one-fourth of patients.270–270

Wide local excision is recommended as treatment, with verification of surgical margins by frozen section.271,272 Repeated excision sometimes is required for marginal recurrence.²⁷³

Intraepithelial Squamous Cell Neoplasia of the Vulva

The term VIN now replaces such terms as Bowen disease, erythroplasia of Queyrat, carcinoma simplex, bowenoid papulosis, bowenoid dysplasia, hyperplastic dystrophy with atypia, and condylomatous dysplasia. The ISSVD recognizes squamous cell CIS. VIN is appearing with increasing frequency in women younger than age 40 years, and seems to be associated with high-risk strands of the HPV virus. Histopathologically, these lesions are characterized by varying degrees of cytoplasmic and nuclear maturation, giant cells with abnormal nuclei, and disruption of the normal epithelial architecture (Fig. 87-18). On rare occasions, pearl formation at the base of the rete pegs can be seen, without significant abnormality in the overlying epithelium. Buscema and colleagues²⁷⁴ reported that invasive vulvar cancer developed in approximately 4% of patients with VIN. Fu and colleagues²⁷⁵ observed that all intraepithelial lesions analyzed had an aneuploid DNA pattern when associated with HPV. The term bowenoid papulosis historically has been used as a synonym for multifocal intraepithelial neoplasia of the vulva. This lesion also is associated with HPV infection. The invasive potential of this entity appears to be very low. Therapy for VIN usually consists of surgical excision. Laser vaporization may be useful as an alternative when large areas would require excision or functionally important areas are involved, but carries a small risk of failure to detect areas of true invasion. The risk of occult invasion may be as high as 20% in patients with VIN 3.²⁷⁶ Cavitational ultrasonic surgical aspiration provides another conservative surgical modality to treat VIN with minimal loss of functionally important tissue and provision of tissue for histologic study.²⁷⁷ Laser excision, by providing tissue for histologic evaluation, is less likely to miss a clinically occult area of invasion.²⁷⁸

Invasive Squamous Cell Carcinoma of the Vulva

Clinical Features

Histologically, squamous cell carcinoma accounts for more than 90% of cases of malignancy involving the vulva. Common presenting symptoms include chronic vulvar pruritus; a mass, lump, or sore; and small-volume bleeding. About two-thirds of the lesions involve the labia majora, whereas lesions originating on the labia minora and the clitoris occur less commonly. Lesions arising in the vestibular (Bartholin) glands are first seen as a swelling or mass, sometimes without invasion of overlying skin. Tumors arising in the Bartholin glands tend to be adenocarcinomas. In 10% of cases, the lesion will be too extensive to determine the site of origin, and in 5% of cases, the lesions are multifocal.²⁷⁹ From the site of origin, carcinomas of the vulva can extend to invade the vagina, urethra, or anus; advanced vulvar carcinoma can invade adjacent pelvic bones, particularly the pubis.

Routes of Spread

Direct extension occurs to adjacent structures including the vagina, perineum, clitoris, and anus. The vulva is richly supplied with lymphatic vessels that often cross the midline. As a result, the risk of regional spread is significant for any vulvar carcinoma that has invaded to a depth of more than 1 mm. The lymphatics of the vulva consist of a network that covers the entire labia minora, fourchette, prepuce, and distal vagina below the hymenal membrane. These coalesce anteriorly, forming larger trunks that run laterally to the clitoris to the mons veneris, acquiring tributaries from the lymphatics of the labia majora, which run in a parallel fashion anteriorly from the perineal body. The vulvar lymphatics run through the vulva and do not cross the labiocrural fold. The lymphatics of the perineum, however, course lateral to the labiocrural fold through the superficial tissues of the upper medial thigh. In the treatment of patients with advanced vulvar cancer that extends beyond the vulva to the perineal skin, these more lateral channels must be taken into consideration. Similarly, direct proximal extension of an advanced vulvovaginal cancer along the vaginal cylinder may spread through vaginal lymphatics directly to pelvic nodes. At the mons veneris, the vulvar lymphatic trunks diverge laterally to the primary regional nodes, the ipsilateral or contralateral inguinal nodes. Study of the localization of dye or radiolabeled tracer in regional lymph nodes after focal injection of discrete sites in the vulva and on the perineum reveals that the lymphatic drainage of the perineum, clitoris, and anterior labia minora is bilateral, whereas the lymph flow from well-lateralized sites in the vulva is, predominantly, to the ipsilateral groin.280,281 Discrete (≤2 cm diameter), well-lateralized primary cancers limited to the vulva and not approaching midline structures rarely manifest spread to contralateral groin nodes in the absence of spread to ipsilateral nodes.^282–287

From the superficial inguinal nodes, secondary lymphatic drainage is through the cribriform fascia to the femoral nodes (Fig. 87-19), with subsequent tertiary flow under the inguinal ligaments to the external iliac nodes. However, metastases have been reported to the femoral lymph nodes without involvement of the superficial inguinal lymph nodes, especially from carcinomas of the clitoris and Bartholin gland.^288,289 A GOG study also found an unexpectedly high incidence of ipsilateral groin recurrences secondary to presumed involvement of lymph nodes deep to the cribriform fascia, despite having negative superficial nodes.²⁹⁰ Levenback and colleagues²⁹¹ further supported these data by lymphatic mapping studies.

The frequency of lymph node metastases to the inguinofemoral nodes is related to the lesion size and depth of stromal invasion.283,292 For lesions smaller than 1 cm in diameter, the incidence is approximately 5%. For lesions exceeding 4 cm, the rate of inguinofemoral lymph node metastases is 30% to 50%.^284,293 The overall incidence of metastases to the pelvic lymph nodes is 5% and is rare in the absence of three or more positive inguinofemoral lymph nodes. Hematogenous spread is rare in the absence of inguinofemoral lymph node involvement and usually occurs late in the course of the disease. However, in patients with three or more positive lymph nodes, the ultimate risk of hematogenous spread is 66%. By contrast, patients with fewer than three positive lymph nodes have only a 4% risk of hematogenous spread.^294,295 Sites of hematogenous spread include lung and bone.

Staging

Staging of invasive vulvar cancer is based on clinicopathologic measurement and assessment of anatomic extent of the primary lesion; the presence, laterality, and extent of regional lymph node metastases; and the presence or absence of distant metastases including pelvic lymph nodes. Historically, staging evaluation of the inguinal lymph nodes was based on palpation and clinical impression. Because the clinical assessment of inguinal lymph nodes is associated with false-positive and false-negative rates of approximately 20% (Table 87-7),^296–301 a surgical staging system for vulvar cancer initially was adopted by FIGO in 1988 and has been revised several times since, the last one in 2009 (Table 87-8).⁷⁶ However, many locally advanced vulvar lesions are treated with initial radiation or chemoradiation; consequently, the absence of a complete surgical specimen may interfere with accurate staging, particularly of the inguinal lymph nodes.

Table 87-7

Clinical Assessment of Inguinofemoral Nodes by Palpation

	Histologically (−)	Histologically (+)
Clinically (−) (N = 451 patients)	363 (80.5%)	88 (19.5%)
Clinically (+) (N = 243 patients)	53 (21.8%)	190 (78.2%)

Pooled data from six institutions.^296–301

Table 87-8

FIGO 2009 Stage Grouping

STAGE I

Tumor confined to the vulva • IA: Lesions ≤2 cm in size, confined to the vulva or perineum and with stromal invasion ≤1.0 mm*, no nodal metastasis • IB: Lesion >2 cm in size or with stromal invasion >1.0 mm*, confined to the vulva or perineum, with negative nodes

STAGE II

Tumor of any size with extension to adjacent perineal structures (one-third lower urethra, one-third lower vagina, anus) with negative nodes

STAGE III

Tumor of any size with or without extension to adjacent perineal structures (one-third lower urethra, one-third lower vagina, anus) with positive inguinofemoral lymph nodes • IIIA (i): With lymph node metastasis (≥5 mm), or • IIIA (ii): With 1 to 2 lymph node metastasis(es) (<5 mm) • IIIB (i): With 2 or more lymph node metastases (≥5 mm) or • IIIB (ii): With 3 or more lymph node metastases (<5 mm) • IIIC: With positive nodes with extracapsular spread

STAGE IV Tumor invades other regional (two-thirds upper urethra, two-thirds upper vagina), or distant structures

• IVA: Tumor invades any of the following:

• Upper urethral and/or vaginal mucosa, rectal mucosa, or fixed to pelvic bone or

• Fixed or ulcerated inguinofemoral lymph nodes

• IVB: Any distant metastasis, including pelvic lymph nodes

FIGO, Federation Internationale de Gynecologie et d’Obstetrique.

^*The depth of invasion is defined as the measurement of the tumor from the epithelial-stromal junction of the adjacent most superficial dermal papilla to the deepest point of invasion.

Surgical Treatment of Invasive Carcinoma

The operative approach to the treatment of vulvar carcinoma, consisting of a radical en bloc resection of the vulva, was developed at the beginning of the 20th century in response to the combination of patients first seen with regionally advanced disease and the poor results (approximately 20% to 25% 5-year survival) achieved with limited surgical excision.³⁰²

Basset³⁰³ first reported an en bloc operative removal of the vulva along with the regional lymph nodes, resulting in considerable improvement in 5-year survival rates (60% to 70%). Three decades later, Taussig³⁰⁴ of the United States, and Way^296,305 of the United Kingdom, popularized this radical en bloc dissection, which remained the standard of surgical care for vulvar cancer until the early 1980s. At that time, Hacker and others^306,307 introduced the concept of individualized and conservative surgery, proposing the use of separate groin incisions for women with stage I disease and demonstrating no difference in the incidence of recurrence between those women undergoing a radical vulvectomy compared with those undergoing a radical local excision (modified radical vulvectomy). The trend over the past 20 years has been toward less radical surgery for early-stage vulvar cancer in an attempt to decrease the significant physical and psychological morbidity associated with en bloc dissection (Fig. 87-20). Historically, exenterative procedures were undertaken to clear central disease in patients first seen with locally advanced disease.³⁰⁸ Increasingly, treatment has evolved to include combinations of preoperative radiation or preoperative chemoradiation to reduce tumor volume sufficiently to permit clearance of central disease without sacrifice of functionally important midline structures.^306–310

Surgical Techniques

Groin Lymph Node Dissection

The appropriate application of groin dissection is the single most important factor in decreasing the mortality of early vulvar cancer. The technique for groin dissection involves the removal of an ellipse of skin 1 cm below and parallel to the groin crease. The incision is carried down, with incising and dissecting, to the fascia lata and 2 cm above the inguinal ligament to remove the inguinal nodes. The saphenous vein is tied off, the fascia lata is then split, and the femoral nodes are dissected. Some surgeons conserve the saphenous vein in an effort to decrease both acute and chronic morbidity. A suction drain is placed, and the wound closed in two layers.

Surgical specimens from patients with primary tumors 2 cm or smaller in diameter (T1) clearly show escalating risk of node metastasis with progressive depth of invasion (Table 87-10).^{283,285,286,292,315,316} The probability of finding groin node metastasis is related to the size of the primary tumor (Table 87-11).^317,318 An infiltrative pattern of growth correlates with nodal spread,^319,320 and the presence of vascular or lymphatic space invasion substantially escalates the probability of finding metastases in dissected nodes.³⁰³ Metastatic spread to contralateral groin nodes in the absence of disease in ipsilateral nodes occurs in 15% or fewer of all patients with metastases to groin nodes,³²¹ generally in patients with larger lesions. The risk of contralateral nodal spread in the absence of ipsilateral metastasis is less than 1%,^{234,293,297,298,321–326} although it has been described in two patients with lateralized T1 lesions. When metastatic disease is present in multiple groin nodes, pelvic lymphadenectomy will detect disease in 15% to 25% of patients, but rarely when only one groin node is only microscopically contaminated.^327,328

A thoughtful appraisal of the risk of nodal spread and the anatomic level of potential contamination is an essential part of planning surgical therapy and determining target volume, dose, and technique for a course of radiation therapy. Diagnostic imaging may be helpful in the assessment of regional nodes in patients with vulvar cancer and tailoring the extent of surgery or radiation accordingly. MRI is highly specific for the detection of inguinal nodal involvement (97% to 100%). CT scanning also is useful in detecting nodal involvement (Fig. 87-21) that may be deeper in tissue than can be readily detected on physical examination. FDG-PET has a sensitivity of 67% to 80% in predicting lymph node metastasis. It also is more specific (90% to 95%) than CT alone and is useful in planning radiation therapy and as an adjunct to lymphatic mapping and sentinel lymph node dissection.³²⁹ Lymphoscintigraphy with technetium-99m sulfur colloid may be useful in the identification of sentinel nodes.³³⁰

Given the results of the GOG prospective randomized trial demonstrating better efficacy for adjuvant node radiation compared with pelvic node dissection, the indications for extending surgery proximal to the inguinal ligament are diminishing.³²⁴

Adjuvant Postoperative Radiation Therapy

Postoperative radiation therapy usually is indicated in the following situations: more than one positive inguinal node, one grossly positive inguinal node or extracapsular extension of nodal disease, small tumors in patients with medical problems that prohibit radical inguinofemoral lymph node dissection, and a vulvar resection margin of less than 8 to 10 mm.

The GOG conducted a randomized trial comparing pelvic lymphadenectomy with radiation therapy directed to the bilateral groins and pelvic nodes (but not the tumor bed or perineum) in patients who were found to have groin node metastasis. A total of 114 eligible patients were randomly assigned; 40 patients had only one positive groin node. In 15 (28.3%) patients of 53 undergoing pelvic lymphadenectomy, disease had spread to pelvic nodes; 9 (60%) of these patients died of cancer within 1 year of study entry. The overall survival advantage for radiation at 2 years (68% for radiation, 54% for pelvic node dissection) was limited to patients with two or more involved groin nodes (63% for radiation, 37% for pelvic node dissection) and was attributable to a decrease in recurrence in the groin among the irradiated patients (5.1%) compared with those patients treated with surgery alone (23.6%). Lymphedema was reported in 19% of irradiated patients compared with 11% of patients treated with surgery alone. Of the 44 patients who had recurrence, only 11 patients had recurrence with a component of “distant” disease (including three patients with relapse in the thigh, periaortic nodes, and abdominal skin), whereas 75% of relapsing patients relapsed with locoregional disease alone (vulvar area, groins, or pelvis). Eleven (25%) patients experienced recurrence in the unirradiated vulvar area; 10 of these had no other apparent sites of failure. As a consequence of this study, pelvic lymphadenectomy is less likely to be performed, and regional adjuvant radiation has become the standard of additional care for patients with metastasis to two or more regional nodes.³²⁴ Katz and coworkers³⁵⁵ recently found a higher rate of inguinal recurrence when patients started radiation therapy more than 50 days after their operation, and therefore concluded that postoperative radiation therapy should begin whenever possible within 4 to 6 weeks of surgery.

Areas of controversy in the postoperative adjuvant therapy of resected, node-positive vulvar cancer include whether patients with only one node contaminated should receive adjuvant therapy, whether patients with only unilateral groin node metastasis should have radiation delivered to the contralateral groin and pelvis, and whether synchronous administration of chemotherapy might further improve outcomes. Retrospective outcomes analysis of node-positive patients undergoing adjuvant groin and pelvic radiation suggests the wisdom of including the operative bed of the primary lesion within the treatment volume.³⁴⁹

Preoperative Chemoradiation

Under circumstances in which the extent of the primary disease suggests that postoperative radiation therapy will be indicated, it is reasonable to consider preoperative irradiation if it has the potential to reduce the scope of surgery and to conserve normal tissue structure and function or to convert the patient’s status from unresectable to operable.310,331–335,343 An anticipated margin of 1 cm or less from structures that will not be surgically removed is a useful guide for selecting patients for preoperative irradiation.^313–313 Tumors that encroach on the anal sphincter, abut the pubic arch, or involve more than the distal urethra should be considered for preoperative radiation therapy. Patients with tumors that approach the clitoris or extend more than minimally past the vaginal introitus also should be considered for preoperative irradiation if conservation of sexual function is desired. Moderate-dose radiation (36 Gy to 54 Gy) has been given, followed by excision of residual palpable abnormalities that revealed no evidence of persistent cancer in 50% of cases (Table 87-12).

External beam radiation is used most commonly, but interstitial or intracavitary brachytherapy may apply a higher dose to a discrete tissue volume where a surgical margin is anticipated to be inadequate.³³¹

The GOG studied 73 patients with stages III to IV squamous cancers of the vulva who were judged not amenable to resection because of local disease extent beyond the conventional boundaries of radical vulvectomy. Preoperative chemoradiation, consisting of 47.6 Gy delivered in fractions of 1.7 Gy coordinated with 2 cycles of synchronous cisplatin and 5-fluorouracil (5-FU), converted 69 of 71 patients medically fit for surgery to having lesions considered amenable to resection. Ultimately, urinary and fecal continence was conserved in all but three patients. With the use of this approach, local tumor control has been excellent, with conservation of normal tissue integrity in many patients who otherwise would have required exenterative surgery for tumor clearance.³¹⁰ By using the identical regimen in 46 patients with extensive (matted, fixed, or ulcerated) and unresectable groin metastases, physicians of the GOG were ultimately able to resect groin nodes in 37 patients, of whom 15 had histologically negative groin specimens.³⁵⁶ The observation of complete histologic clearance of malignancy after moderate-dose preoperative radiation (alone or coordinated with synchronous chemotherapy) serves to encourage efforts to control vulvar cancer with radiation-based therapy under circumstances in which surgery is either technically unfeasible or medically contraindicated. The GOG just completed another phase II study evaluating radiation therapy and weekly cisplatin in locally advanced vulvar carcinoma and they found 37 patients (64%) with a complete clinical response.³⁵⁷ Among these women with a complete clinical response, 34 underwent a surgical biopsy and 29 (78%) were found to have a complete pathological response.³⁵⁷

Radical Radiation and Chemoradiation

Definitive radiation has been used to treat medically inoperable or technically unresectable patients. Historically, results have been poor, in terms of both tumor control and normal tissue sequelae, although the tumor-control probability for patients with disease of limited volume has approached that of surgery.335,358,359 Results with radiation alone in recent years have improved with better technique and dosimetry.³³⁶

The favorable experience with chemotherapy and reduced-dose radiation in the treatment of cancers of the anal canal has prompted increasing use of this approach in the treatment of advanced vulvar cancer. Most published experiences have used 5-FU, with or without cisplatin or mitomycin.339–341,345,347,356–363 Retrospective comparison³⁶³ suggests the superiority of chemoradiation compared with radiation alone, but prospective randomized data do not exist to validate the clinical impression of better results. Unquestionably, the administration of concurrent chemotherapy augments the acute reaction in normal tissues. Moist desquamation of the vulva necessitates treatment interruption in most patients. Hybrid dose/fractionation regimens have been developed to preserve dose intensity and to maximize potential synergistic effects. Twice-daily fractionation has become a popular strategy to exploit the radiation–drug interaction while minimizing the theoretical disadvantages of split-course radiation that is made mandatory by the enhanced effects in normal tissue.^310,346,347 Because of potential enhancement of late normal tissue effects, and because full radiation dose must be administered to some skin when treating what is fundamentally a skin cancer, it is advisable that the total dose not exceed approximately 54 Gy in 30 fractions, 59.5 Gy in 35 fractions, or 64 Gy in 40 fractions to gross disease when chemoradiation is used, and that the volume receiving the full dose be as small as possible, while including all areas of initial measurable clinical involvement.

Elective Groin Radiation

A contributing factor to perioperative complications and chronic morbidity is the dissection of the inguinofemoral nodes.³⁶⁴ In selected patients with limited primary tumors (T1a with ≤1 mm of invasion), omission of the node dissection is prudent. In others, limiting the groin dissection to superficial inguinal nodes (if histopathologically negative) has been an effective strategy for reducing acute and chronic morbidity. Preoperative identification of sentinel nodes may further enhance the safety of this approach. Elective irradiation of the clinically and radiographically negative groin nodes is an alternative strategy that has the theoretical advantage of treating all of the regional nodes rather than leaving some portion untreated. This approach also is applicable in patients with locally advanced primary tumors, in whom less than radical (superficial and deep) bilateral groin dissection would constitute less than adequate surgical treatment. Several series^365–368 have reported favorable results with elective or prophylactic groin irradiation (Table 87-13), but frequently in the setting in which groin nodes would be expected to be histologically uninvolved if treated surgically (T1 or T2 primary tumors of limited extent; see Table 87-12).³⁶⁹

The GOG conducted a randomized trial comparing groin irradiation with groin dissection in otherwise operable patients with resectable vulvar primaries.³⁷⁰ The study was terminated early because of an unacceptable rate of groin relapse (5 of 27 patients [18.5%]) and subsequent death from cancer (all five patients) in the group of women randomly assigned to radiation. Technical inadequacies in the radiation treatment that may have led to inadvertent underdosage of the nodes could have contributed to this outcome.³⁷¹

At the Radiation Oncology Centers of Sacramento³⁷² and at Loma Linda University,³⁷³ patients have undergone prophylactic chemoradiation to the groin nodes, generally as a component of preoperative or definitive chemoradiation for locally advanced primary cancers. Among 37 such patients treated, no groin relapses occurred (Table 87-14). It remains unclear whether the better results reflect better radiation technique or the radiopotentiating effect of synchronous chemotherapy.

Radiation Techniques, Volumes, and Doses

No standard approach is found to the treatment of vulvar cancer with radiation. The circumstance of radiation (postoperative, preoperative, or as definitive treatment) will influence the designation of target volume, fractionation, and dose. Clinical and histopathological characteristics of the primary and regional nodes may independently affect the selection of treatment parameters, which depends further on the scope of any coordinated surgery and whether chemotherapy is to be administered with radiation. Comorbidities in elderly patients may constrain the volume and intensity of treatment. Conservation of ovarian function and possible reproductive integrity in younger patients also may affect the technique of treatment.³⁷⁴ No substitute can be found for comprehensive assessment of disease extent followed by tailored, individualized therapy that takes into account the intent of treatment (i.e., preoperative, definitive, adjuvant postoperative), patient comorbidities, and patient preference. Table 87-15 is a guideline for radiation doses and fractionation.

Chemotherapy or Radiation Therapy for Recurrent, Persistent, or Metastatic Vulvar Carcinoma

Recurrent or persistent vulvar carcinoma after surgical therapy typically is treated with surgical resection or radiation-based therapy or both. Vulvar carcinoma that recurs in a local or regional area of prior radiation often is considered for surgical resection. Tumors that recur after surgery can be treated with radiation therapy.

Postsurgical, central, limited-volume, local recurrence in the residual vulva, at the introital margin, or on the perineum often are salvaged with secondary surgery, radiation, or combined-modality therapy.³⁵⁰ A disease-free interval of 2 or more years and lack of involvement of regional nodes portend a favorable outcome with salvage therapy, although most disease recurs within 2 years of initial surgery.^351,352 Under circumstances in which the anticipated surgical margin is less than that of the original surgery, when recurrence approaches or involves critical structures, or when the pattern of recurrence is multifocal, it is prudent to plan for delivery of radiation as at least a component of the salvage strategy. Regional relapse in the groin or in pelvic nodes is much less likely to be salvaged, regardless of the combination of modalities used.^{350,352–354} Salvage radiation alone, in doses ranging from 63 Gy to 72 Gy with progressive volume reductions or partial treatment with brachytherapy, often controls small-volume recurrence. Preoperative radiation ranging in dose from 45 Gy to 54 Gy followed by local excision may be less injurious in terms of delayed normal tissue effects than a high radiation dose to a large perineal volume in the absence of surgery.³⁵⁰

Tumors that are not controlled or amenable to surgical or radiotherapeutic approaches are difficult to manage because of a lack of active systemic agents; these tumors often are first seen in elderly patients with major comorbidities, and sometimes in individuals with altered immunity as a result of chronic immunosuppression. Because recurrent tumors are rare, no randomized phase III trials have evaluated systemic therapy. Very few phase II studies have been reported to guide clinicians in selecting treatment. The effectiveness of chemotherapy also is limited by the fact that many treatment failures are local, or locoregional,283,351–353,377–379 and typically within a prior radiation field (Table 87-17). These radiation-resistant tumors typically are also resistant to chemotherapy. Responses to treatment may be difficult to evaluate because of extensive anatomic abnormalities associated with prior surgery and radiation. Only six agents have been evaluated as single agents, with trials including only four to 22 patients, with most of these trials done in the early 1980s. Doxorubicin (Adriamycin) and bleomycin have demonstrated some single-agent activity.^382–382 An anecdotal response has been reported with liposomal doxorubicin.³⁸³ Unfortunately, the duration of response in most instances is disappointing and is measured in months.

Combination chemotherapy regimens that have been evaluated include bleomycin together with a variety of agents (Table 87-18).^384–388 The largest experience is with the regimen of bleomycin, methotrexate, and N-(2-chloroethyl)-N′-cyclohexyl-N-nitrosourea (CCNU).^384,385 Activity has been seen in two separate phase II studies that included 53 patients and demonstrated five complete responses and 27 partial responses, for an overall response rate of 60%, in a group of patients with locally advanced squamous cell carcinoma of the vulva.

In vitro studies with squamous cell cancer lines of the vulva demonstrate high expression of the EGFR and efficacy of ZD1839, either alone or in combination with chemotherapy.389,390 The role of this targeted agent in the clinic awaits formal testing.

Other Histologic Types