Vulvar Carcinoma Robert L. Coleman, MD Joseph T. Santoso, MD*

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1 Vulvar Carcinoma Robert L. Coleman, MD Joseph T. Santoso, MD* Address University of Texas, Southwestern Medical Center, Division of Gynecologic Oncology, 5323 Harry Hines Blvd., J7.124, Dallas, TX , USA. *University of Texas, Medical Branch, Galveston, Division of Gynecologic Oncology, 301 University Blvd., Galveston, TX 77551, USA. Current Treatment Options in Oncology 2000, 1: Current Science Inc. ISSN Copyright 2000 by Current Science Inc. Opinion statement Carcinoma of the vulva is an uncommon gynecologic malignancy primarily affecting postmenopausal women. The lesion is most commonly associated with HPV DNA, although, for many, a defined preinvasive to invasive connection is not readily apparent. Most patients experience symptoms of pruritus, irritation, and even pain for weeks or months before the diagnostic biopsy is performed. Patient embarrassment and unfamiliarity and reluctance on the part of the physician to fully evaluate these symptoms add to the delay. Vulvar carcinoma is staged surgically following resection. A concerted effort to conserve as much normal tissue as possible has been the focus of recent investigation. Separate incision resection of the vulvar mass and groin has improved wound healing and quality of life for many patients. The effect these conservative procedures have on long-term survival is currently being evaluated. Increased use of radiation therapy or chemoradiation has allowed organ preservation in many otherwise exenterative cases. In some instances, this neoadjuvant therapy has provided an opportunity to surgically clear otherwise unresectable lesions. Current radiotherapy techniques might also be as effective as groin dissection in certain low-risk patients. Adjuvant radiation and chemoradiation improve local control and reduce groin recurrence risk. In addition, patients with histologically positive groins enjoy longer survival when the pelvis is also treated. Selected use of multimodality therapy will likely extend the lives of women with vulvar cancer. Introduction Carcinoma of the vulva is an uncommon neoplasm, accounting for 4% to 5% of all gynecologic primary tumors [1 ]. It primarily affects older women (median 61 years) with an incidence peak in the seventh decade of life. However, it has been diagnosed with some increasing frequency among younger, premenopausal women [2]. Approximately 15% of patients diagnosed are under age 40 [3]. The predominant histologic type is squamous (85% to 90%); however, pathologic variants, such as verrucous carcinoma, adenocarcinoma, melanoma, Bartholin s gland cancer, Paget s disease, and sarcoma, are well described [4]. Etiological events/ agents are controversial, but most vulvar cancers are preceded by condyloma or squamous dysplasia and are associated with human papilloma virus (HPV) infection [5,6]. Preinvasive lesions (vulvar intraepithelial neoplasia [VIN]) are commonly diagnosed in younger patients and tend to coexist with other preinvasive lesions of the genital tract (vagina and cervix) and perianal region. HPV DNA is isolated in approximately 10% to 50% of vulvar carcinomas. Other genetic events are being described in HPV-negative vulva carcinoma [7]. Detection of disease and diagnosis is straightforward but requires awareness of the disease by both the patient and physician. Characteristic presentation is a long-standing pruritic vulva for which no formal evaluation has been made yet has been treated with an armamentaria of topical and oral therapeutics. The pruritus may precede a lump or mass. Pain, burning, irritation, odor, and bleeding generally occur later. Inspection and biopsy, especially of new or changing pigmented lesions, are confirmatory in nearly all cases.

2 178 Gynecologic Tumors Symptomatic patients without visible lesions should undergo vulvoscopic examination with acetic acid (5% solution). Because of the keratin layer, characteristic acetowhite changes may require up to 5 minutes to manifest. Directed biopsy can then be performed. Approximately 60% to 85% of all patients present with early (stage I or II) disease, and the 5-year survival rate is 65% to 90% in this cohort. Patients with more advanced local disease or metastatic nodal disease fair less well. To facilitate communication and comparison of patients, staging schema have been developed. The International Federation of Gynecology and Obstetrics (FIGO) uses surgical information to assign tumor, nodes, and metastasis (TNM) classification of the American Joint Commission on Cancer (AJCC) [8,9] (Tables 1 and 2). Tumor stage generally reflects the clinical extent of disease and allows some insight into prognostic factors, which may aid in decision making following primary therapy. Table 1. International Federation of Gynecology and Obstetrics Tumor, Nodes, and Metastasis (TNM) classification Stage 0 TIS Stage I T1 N0 M0 IA IB Stage II T2 N0 M0 Stage III T3N0M0 T1N1M0 T2N1M0 T3N1M0 Stage IV A T1N2M0 T2N2M0 T3N2M0 T4, any N M0 Stage IV B Any T, Any N, M1 Carcinoma in situ, intraepithelial carcinoma. Tumor 2 cm and confined to vulva. No nodal metastases stromal invasion 1 mm* stromal invasion >1 mm* Tumor >2 cm and confined to vulva or perineum. No nodal metastases. Tumor of any size that extends to vagina, perineum, lower urethra, anus, or unilateral node metastasis Tumor extends to bladder mucosa, rectal mucosa, upper urethra, pubic bone, or bilateral regional nodal metastasis Any distant metastases, including pelvic lymph nodes * 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. Table 2. Tumor, Nodes, and Metastasis (TNM) classification of carcinoma of the vulva Primary tumor (T) TIS Preinvasive carcinoma (carcinoma in-situ) T1 Tumor confined to the vulva and/or perineum 2 cm in greatest dimension T2 Tumor confined to the vulva and/or perineum >2 cm in greatest dimension T3 Tumor of any size with adjacent spread to the urethra, vagina, or anus T4 Tumor of any size infiltrating the bladder mucosa or the rectal mucosa, including the upper parts of the urethral mucosa, or fixed to the bone Regional lymph nodes (N) N0 No lymph node metastasis N1 Unilateral regional lymph node metastasis N2 Bilateral regional lymph node metastasis Distant metastasis (M) M0 No clinical metastasis M1 Distant metastasis (including pelvic lymph node metastasis)

3 Vulvar Carcinoma Coleman and Santoso 179 Treatment Therapy of vulvar preinvasive and invasive disease depends on diagnosis, histology, location and size of the primary lesion, and performance status of the patient. This therapy is largely surgical, although recent studies incorporating radiation or chemoradiation suggest a role for multimodality therapy in certain patients. The trend in recent years has been to individualize therapy and perform more conservative resections. However, the impact of these strategies on local control and ultimate treatment failure is not completely known and must be considered. Vulvar intraepithelial neoplasia/carcinoma in-situ Treatment of vulvar dysplasia depends to some extent on the symptoms of the patient and the associated pathology. Outside of patients in the immunocompromised state, heavy smokers, and the elderly, progression of early dysplastic lesions to carcinoma in-situ or cancer is slow, and in some patients never occurs [2,6,10]. Persistent or spontaneous regression is a feature often observed among young patients with multifocal lesions and active HPV infection. However, the possibility of an occult underlying invasive lesion must not be overlooked. The frequency of this event varies by population studied and degree of dysplasia, but up to 22% of vulvar carcinoma in-situ lesions undergoing excision have an underlying carcinoma [11,12,13 ]. This is most common in large, solitary lesions in elderly patients. Treatment planning of vulvar dysplasia involves a clear delineation of the affected vulvar skin and its pathology. Options include pharmacologic ablation, mechanical ablation, and excision. In some cases, a combination of these options is required because of the extent of disease or condition of the patient. However, if a surgical approach is made, gross clearance (0.5 mm to 1 mm) of the lesion or lesions is recommended. Surgical treatment Local excision Standard procedure An inked margin around the lesion is made providing gross clearance (0.5 mm to 1 mm) at resection. The depth of resection is to the subcutaneous fat but no deeper. Closure depends on the size of resection but is often by primary approximation. Smaller resections may not require closure, and larger lesions may require local advancement skin flaps. Contraindications Inability to tolerate anesthesia; known or gross invasive disease. Complications Infection (especially anogenital location); wound breakdown. Special points Vulvar skin thickness varies considerably by location. Particular care must be taken in the clitoral, urethral, anal, and labia minora locations because the squamous epithelium is very thin. Resections in this area do not require deep dissection, and every effort should be made to minimize trauma. Cost effectiveness Can be done in the office under local anesthesia. Superficial vulvectomy or partial vulvectomy Standard procedure This procedure employs the same techniques as a local excision, although it encompasses a larger area of the vulva and is tailored to the lesion. Closure of the resultant defect frequently requires local advancement skin flap, primary closure, or, occasionally, a skin graft. Contraindications Inability to tolerate anesthesia; known or gross invasive disease.

4 180 Gynecologic Tumors Skinning vulvectomy with skin graft Complications Infection (especially anogenital location), wound breakdown, bleeding. The larger area of resection requires attention to tension along the lines of skin approximation. Special points As with all larger vulvar excisions, strict attention to a vulvar postoperative routine enhances healing. This involves keeping the surgical site clean and dry with reduced shearing trauma. Cost effectiveness These procedures are usually done in the operating room but do not always require hospitalization. Standard procedure This procedure involves removal of the entire vulvar skin. It is rarely performed unless the patient has widespread involvement or an unusual histology such as Paget s disease. It is no longer advocated simply for prophylactic purposes. The most effective closure of the surgical site is a skin graft, most commonly split thickness (0.018 in), although smaller resections may be closed primarily. Strict attention to intraoperative hemostasis and postoperative care is necessary for a successful outcome [14]. Contraindications Inability to tolerate anesthesia; known or gross invasive disease; active infection. Complications Infection, wound breakdown, bleeding, graft failure, donor site infection. Special points Bolsters (suture or staple) to the site are generally left for 2 to 4 days. Inspection of the site should be made to evaluate take of the graft. Cost effectiveness This procedure requires hospitalization frequently for several days. Ablation (laser or Cavitron ultrasonic aspirator) Standard procedure Ablation of the vulva requires an understanding of the anatomic variations of the vulva, the differences of hair-bearing and non hair-bearing skin (regarding both skin thickness and location of possible dysplasia), and a working knowledge of the surgical tools [15,16]. Laser energy and wavelengths are very important to successful application and are presented elsewhere [17]. The extent of ablation depends on the factors mentioned and should employ some degree of gross margin ablation. The Cavitron ultrasonic surgical aspirator (CUSA) is an alternative to laser, which is quite successful for large condylomatous lesions and early dysplasia. Its use in severe dysplasia may be associated with a higher recurrence risk compared with laser [18]. Surgical principles for ablation apply similarly to CUSA. Contraindications Inability to tolerate anesthesia; known or gross invasive disease. Complications Superinfection of the site; overly aggressive ablation; pain; recurrence of disease (25%). Special points Laser ablation procedures do not retrieve a surgical specimen. Confidence that no invasive disease exists is important to patient selection. The CUSA collects cells from the aspirate, although information about invasion is difficult to get. Healing of the surgical site comes from re-epithelialization from basal cells in the hair shafts and peripheral migration. Exudate from the site is expected, and care of the site should proceed as mentioned previously. Pain is experienced for a longer duration than with excisional techniques. Application of silver sulfadiazine cream three times a day may reduce bacterial count and pain. Because healing occurs by neighboring epithelia, recurrence from similarly affected cells not yet phenotypically altered may occur. Margin status appears to be an important predictor of this recurrence as well. Modesitt et al. [11] demonstrated recurrence in 18 of 39 (46%) of patients with positive margins compared with 3 of 18 (17%) patients with negative histologic margins. Cost effectiveness Smaller lesions may be treated in the office under local anesthesia; larger lesions generally require more regional anesthesia. Hospitalization is usually not necessary.

5 Vulvar Carcinoma Coleman and Santoso 181 Pharmacologic therapy Specific drugs 5-fluorouracil (5% topical cream) Standard dosage Twice daily of an amount to sufficiently cover the lesion for approximately 5 to 10 weeks. Contraindications Vulvar irritation, known sensitivity to fluoropyrimidine. Main drug interactions None, topical. Main side effects Irritation, necrosis, sloughing of the skin. Special points This therapy is neither well tolerated nor particularly effective. The vulva skin is sensitive and is subjected to frequent shearing forces. Care to avoid overtreatment of affected areas is required. A mirror is necessary to visualize the treatment field [19 21]. Cost effectiveness Inexpensive compared with other modalities. Microinvasive vulvar carcinoma Wide local excision Solitary lesions measuring 2 cm or less (T1), which also have a depth of invasion 1-mm or less, are termed microinvasive and designated as FIGO stage 1A. This distinction is made because these lesions have a very low incidence of lymphatic metastasis (0% to 2.6%) and are controlled surgically with wide local excision alone [22]. Although the distinction does not account for lymphatic vascular space invasion, this additional characteristic is considered by some to be necessary to preclude lymphatic dissection [1 ]. Standard procedure This procedure requires a tumor-free surgical margin in all dimensions and therefore is distinguished from local excision as outlined previously. The principal difference is resection into the subcutaneous tissue. Margin of resection is a minimum of 10 mm. Closure of the surgical site is generally made primarily or with local advancement flaps. Contraindications Higher stage, medically inoperable. Complications Bleeding, infection, wound breakdown. Special points Knowledge of the vascular supply to the vulva and, in particular, to the subcutaneous structures is necessary for resection and reconstruction. Cost effectiveness This procedure generally requires the operating suite and may require hospitalization. T1 or T2 lateral vulvar carcinoma Consideration of the lateralized lesion is important because the principal lymphatic drainage is to the ipsilateral groin and because contralateral lymphatic spread is uncommon (2.8%) [23]. In this scenario, some investigators believe that if the contralateral groin is clinically uninvolved and the lesion does not come within 2 cm of the midline, a bilateral groin dissection may be excluded [24]. The surgical procedure of choice is radical excision of the primary tumor with ipsilateral superficial and deep node resection (inguinal femoral lymphadenectomy). The resection should employ a 2-cm margin around the primary lesion, and the depth of resection should go to the muscular fascia of the urogenital diaphragm. The options for resection include separate vulvar and groin incisions or en bloc resection of the primary tumor and groin, including the intervening skin and lymphatics. Some investigators alternately advocate unilateral inguinal-femoral lymphadenectomy for T1 lesions only [25].

6 182 Gynecologic Tumors Prognostic factors for local failure relate principally to the size of the surgical margin. In a Gynecologic Oncology Group (GOG) study, all local recurrences were observed in patients with surgical-free margins of less than 8 mm [26]. In this study, recurrence was observed in 21 of 44 (48%) patients with margins less than 8 mm. Technique of excision (separate versus en bloc) has also been suspected to influence local failure. However, local recurrence in selected series demonstrate that this event occurs with nearly the same frequency for separate incision (7.2%) resection as en bloc (6.3%) resection [27]. Clitoral sparing procedures can be performed for posterior lesions. The extent of the groin dissection is somewhat controversial and may be additionally difficult to interpret because of procedure nomenclature variation [28]. The standard operation involves removal of the superficial and deep lymphatic tissues overlying and including fossa ovalis to the medial margin of the adductor longus fascia. A more limited, superficial dissection (preserving the cribriform fascia) appears to lead to a higher rate of groin recurrence [29]. The ominous finding of this occurrence has lead most surgeons to abandon the procedure except in the most selected circumstances. In addition, the GOG has studied whether groin control could occur with radiation alone. In a randomized trial comparing groin radiation to inguinal femoral lymphadenectomy, the former was found to be statistically inferior, and the trial was closed early [30]. Significant criticism of the trial has been detailed, and it has been estimated that the technique used in treatment for radiation therapy may have undertreated 50% of the cohort. Subsequent trials have shown that alternate radiotherapy techniques can effectively control disease in the unoperated groin [31]. Clinical data continue to evolve regarding the safety of these alternatives. Lymphatic mapping New information about the natural variation in lymphatic drainage from the primary site is being gathered from lymphatic mapping procedures [35 ]. The purpose of lymphatic mapping is to identify a sentinel node or nodal group that serves as a basin for the primary tumor. These nodes are the a highest risk for metastasis and should represent the nodal pathology of the entire groin. Microstaging may be possible as these lymphatic undergo sharper pathologic scrutiny, either visually or through molecular markers. The procedure is currently being performed with vital blue dye or lymphoscintigraphy, or both. Feasibility of this procedure has been described [35 ]. If the technique is validated, a negative sentinel node could obviate further groin exploration. Surgical procedure Standard procedures Radical wide excision with ipsilateral superficial inguinal lymphadenectomy; radical wide excision with ipsilateral inguinal femoral lymphadenectomy; radical hemivulvectomy with en bloc ipsilateral inguinal-femoral lymphadenectomy; radical vulvectomy with bilateral inguinal-femoral lymphadenectomy. Contraindications Medically inoperable. Complications Locally: wound breakdown and infection. En bloc vulvar groin resections and radical vulvectomy are more often associated with wound breakdown and seroma. Groin complications are much more common following complete lymphadenectomy and include lymphocele, chronic leg edema, paresthesia, breakdown, and vascular injury. Mortality from the procedure is under 5%. Special points Creative use of local advancement flaps or myocutaneous flaps (gracilis, rectus, and gluteal) is occasionally required for closure.

7 Vulvar Carcinoma Coleman and Santoso 183 T1 or T2 midline vulvar carcinoma or bilateral vulvar carcinoma Surgical procedure Because lymphatic drainage from the midline will go to either groin, bilateral resection is indicated. Arguments to the completeness of this dissection are outlined above. Choices from local resection include radical wide excision or radical vulvectomy. The triple incision technique is associated with a lower frequency of wound breakdown than is the en bloc (Taussig) procedure [24,27,32]. Experience with lymphatic mapping procedures has suggested that the first order lymphatics (sentinel nodes) in clitoral and anterior midline primaries are very medial and more amenable to en bloc resection [33]. If a triple incision technique is chosen, care must be taken to remove these nodes. Posterior midline lesions may undergo radical resection, sparing the clitoris and urethra. Standard procedure Radical vulvectomy with bilateral inguinal-femoral lymphadenectomy; radical wide excision with bilateral inguinal femoral lymphadenectomy. Contraindications Medically inoperable. Complications Similar to lateral lesions. Special points Although in vivo studies have documented direct clitoral node pathways to the pelvic nodes, clinically these are seldom encountered at the time of the surgery. T3 vulvar carcinoma By definition, T3 vulvar carcinoma involves the mucosa of the vagina, urethra, or anus. In certain patients, the involvement is minor, and organ preservation may ensue with judicious use of adjuvant radiation or chemoradiation. For others, the involvement is more extensive, and triage should include consideration of preoperative radiation or chemoradiation with limited surgical resection or brachytherapy to attempt organ preservation. Lesions involving the vagina may involve the lower tract and may be amenable to extended radical vulvectomy. However, extension to the upper vagina may preclude local resection without exenterative consideration. Surgical consideration of the upper half of the vagina also must include an evaluation of the pelvic lymphatics (eg, computed tomography scan, magnetic resonance imaging) to address this alternate lymphatic drainage [34]. Lower urethral or anal involvement requires some mucosal resection. In the case of the urethra, approximately one-third can be removed with maintenance of continence. More extensive involvement should indicate preoperative radiotherapy consideration with re-evaluation after 45 to 55 Gy. Resection following radiotherapy generally requires flap (local or myocutaneous) reconstruction. In selected cases, radical tailored resection or exenteration must be performed. Surgical procedure Standard procedure Extended radical vulvectomy (to encompass known disease) with bilateral inguinalfemoral lymphadenectomy; modified exenterative excision (anovulvectomy) with bilateral inguinal-femoral lymphadenectomy; preoperative pelvic and groin radiation or chemoradiation with or without brachytherapy followed by limited surgical resection. Complications Related to the extent of primary extirpative surgery. Radiation, and in particular, chemoradiation is associated with desquamation and superinfection (viral, bacterial, and fungal). In most series, up to one-third of patients require some treatment interruption because of these effects. Exquisite care of the perineum, occasionally requiring hospitalization, is necessary for completion of therapy. Other complications observed with radiation/chemoradiation in the neoadjuvant setting are venous

8 184 Gynecologic Tumors thrombosis, bowel obstruction, and diarrhea. Monitoring of hematologic indices is indicated, although this toxicity uncommonly interrupts therapy. Several regimens of concomitant chemotherapy have been described [35,36 39]. Most employ cisplatin, 5-fluorouracil, or mitomycin-c, either alone or in combination. Fractionation size (under 180 cgy/d) helps reduce acute effects and has been associated with a lower incidence of late effects (vulvar fibrosis, necrosis, and atrophy). T4 vulvar carcinoma T4 vulvar carcinoma is generally not amenable to organ preservation and in many situations is not primarily resectable. If primary clearance is ventured, exenterative resection is usually necessary [40,41]. Unfortunately, patients with nodal metastases are rarely cured. Preoperative evaluation of the at-risk nodal basins is part of the operative evaluation. For most other patients, successful outcome generally requires neoadjuvant radiation or chemoradiation. Evaluation for subsequent surgery, brachytherapy, or both follows external irradiation. In a recently completed phase II chemoradiation neoadjuvant trial of patients with T3 and T4 carcinomas not amenable to radical vulvectomy, Moore et al. reported complete response of the primary lesion among in 47% of patients [39]. Only 3 of 67 patients undergoing subsequent, postirradiation resection could not have urinary or gastrointestinal continence, and only 2 patients remained unresectable. Surgical procedure Standard procedure Modified exenterative excision (anovulvectomy) with bilateral inguinal-femoral lymphadenectomy; anterior or posterior or total exenteration; preoperative pelvic and groin radiation or chemoradiation with or without brachytherapy followed by surgical resection. Vulvar carcinoma with clinically positive nodes A distinction is made here between those patients with clinically positive nodes and those with fixed or ulcerative nodes. In the former case, the lymphatic group is generally resectable. In the latter, resection is usually incomplete either microscopically or grossly (debulking) because of close approximation or invasive involvement of the femoral vessels. Although primary surgical approach can be extended to both, the latter case is generally the best approach following radiation therapy. If the groin is considered resectable, an evaluation of the pelvic lymph nodes is generally performed radiographically. Bulky pelvic nodes are an ominous finding, and a decision is made as to whether debulking through pelvic lymphadenectomy can be performed. This procedure is easily done at the time of groin exploration through a supra-inguinal ligament incision. For patients without enlarged pelvic nodes, a bilateral groin dissection should be performed. Clinicopathologic evaluation studies have demonstrated that patients with histologically positive groin metastases are at risk for contralateral groin involvement even if the primary vulvar lesion is lateralized. The number of metastatic nodes and their preoperative clinical suspicion influences this risk (11% to 24%) [42]. Postoperative radiotherapy is administered to at least the ipsilateral pelvis with standard fields and doses. Homesley et al. [42] demonstrated that among patients with clinically suspicious or positive groin nodes, 45% also had pelvic node metastases. This randomized trial demonstrated that patients had a longer overall survival if they underwent pelvic irradiation without pelvic node dissection compared with pelvic node dissection alone. Radiation

9 Vulvar Carcinoma Coleman and Santoso 185 administered in this trial was directed to the whole pelvis. Vulvar irradiation was not administered in this trial but has been advocated by others to reduce the local recurrence rate (approximately 9%) in this cohort. If the groin nodes are fixed or ulcerative and the pelvic nodes are involved, a similar triage decision is made. Debulking procedures in the groin commonly leave gross disease or risk vascular injury; preoperative radiotherapy or chemoradiotherapy is therefore given. The techniques for groin irradiation are described elsewhere [43,44]. Postirradiation resection may require muscle flap reconstruction such as a sartorius muscle or tensor fascia lata flap [45,46]. If this resection is incomplete, electron beam boosting can be performed. Vascular clip identification of these sites aids with postsurgical re-irradiation. Postoperative radiation therapy The three sites for consideration of irradiation are the vulva, the groin (ipsilateral, contralateral, or both), and the pelvis (ipsilateral or both). Many clinical scenarios for adjuvant irradiation have been outlined above. Two additional considerations are patients with complete local resection and negative histologic nodes and patients with clinically negative but histologically positive nodes identified either intraoperatively or postoperatively. Surgical pathologic studies demonstrate that certain features may increase the risk of recurrence and may indicate adjuvant irradiation in the presence of clear surgical margins and negative nodal histology [38,47]. Bulky primary size, poor histologic differentiation, lymphatic-vascular space invasion, tumor confluence, and less than 8 mm surgical margins have been implicated. Although opinions vary as to the strength of association among these factors under some instances, adjuvant irradiation is warranted, particularly with close surgical margins. Depending on the size and location of the primary tumor, up to 49% of clinically negative or normal groins contain metastases at the time of dissection [42,48]. Patients with gross unilateral metastases found intraoperatively may undergo contralateral dissection or receive adjuvant radiation. Opinions are divided as to whether further therapy (surgical or radiation) is necessary for a solitary positive node [21,49]. However, certain pathologic features, such as extranodal extension, poor differentiation, and nodal replacement with tumor have been suggested as high-risk features for recurrence and may be more appropriate for adjuvant therapy [50]. As discussed previously, the GOG and others have demonstrated longer survival in this cohort with pelvic radiation compared with pelvic lymphadenectomy. Follow-up Protocols for patient follow-up after primary and adjuvant therapy vary from institution to institution, but nearly all recommend close evaluation for the first 2 to 3 years. In this setting, more than 75% of the recurrences are discovered. The authors routine is clinical examination every 3 months for the first 2 years, then every 6 months to 5 years. Thereafter, visits are annual. Costoutcome analyses of this type of routine for vulvar cancer are not currently available; however, this traditional follow-up schedule among other sites suggests that the routine may not be very cost effective. Certainly, most health care utilization requirement occurs proximal to the time of surgery and/or radiation or chemoradiation. Patients are generally given compression stockings postoperatively and instructed to reduce trauma of the lower extremity associated with the groin dissection. Some authors advocate use

10 186 Gynecologic Tumors of prophylactic antibiotics for 3 to 6 months to reduce the possible occurrence of gram-positive infection [51]. Lymphocele formation after surgery is relatively common but infrequently requires surgical intervention. Symptomatic lymphoceles may be drained or sclerosed if chronic [52]. Recurrent vulvar cancer Recurrent vulvar cancer in all sites except an unirradiated vulva is an ominous finding, from which few patients survive. Several factors relating to local or groin recurrence have been presented. In many cases, site recurrence represents a failure of initial treatment strategy, either surgically or adjuvantly (radiation or chemoradiation). Locally recurrent vulvar cancer can occasionally be excised. If there has been vulvar radiation, such resections are at high risk for breakdown even with local flap reconstruction. Occasionally the local recurrence necessitates radical excision of the lower genital tract through exenteration or modified exenterative procedures. Limited data on this approach have suggested a 38% 5-year survival in recurrent patients [42,43]. Alternately, vulvar brachytherapy has been used with some success [53]. Complications such as necrosis and fistula are associated risks with this technique. Recurrent vulvar carcinoma in the groin is more difficult to eradicate completely and presents other logistic problems. Uncontrolled groin metastatic growth risks vascular invasion and rupture. In addition, patients complain of pain, limitation in range of movement, edematous extremities, and, when skin eruption occurs, necrosis, odor, and infection. A surgical approach may be indicated if the groin mass is not fixed or ulcerative. If the groin is not previously irradiated, a combined surgical and radiation or chemoradiation approach may offer some local control. Patients previously irradiated may undergo secondary resection in limited circumstances. Closure of the wound site generally requires myocutaneous (eg, tenor fascia lata) flap reconstruction. For others not amenable to these approaches, chemotherapy (most commonly platinum-based) has been advocated. Response rates with single or combination chemotherapy range from 20% to 40%, and median survival is approximately 7 months. Other malignancies Treatment of melanoma The second most common neoplasm of the vulva is melanoma and accounts for approximately 10% of new cases [4]. It generally occurs among white women between the ages of 50 and 80. These neoplasms are frequently located on the labia minora or clitoris and appear to arise both de novo or from a preexisting lesion. Diagnosis follows biopsy of suspicious pigmented or changing lesions. Patients generally report pruritic symptoms or relate the presence of a lump or mass on the vulva. Later stages are associated with pain, bleeding, or discharge. Staging of vulvar melanoma (Table 3) follows cutaneous melanoma rather than FIGO because the latter schema does not address adequately the natural history of spread or reflect its prognostic factors. In general, the Clark s levels are less precise for vulvar lesions because the reticular dermis level is not well developed. The traditional surgical approach to vulvar melanoma has been wide radical excision (2 cm or greater) or radical vulvectomy with groin dissection. Recent data have supported that a more modest surgical margin

11 Vulvar Carcinoma Coleman and Santoso 187 Table 3. Staging vulvar melanoma Level Clark s Breslow s Chung s I Intraepithelial <0.75 mm Intraepithelial II Extension to papillary dermis mm <1 mm invasion into dermis or lamina propria III Filling dermal papillae mm mm invasion into sub-epithelial tissue IV Invasion of collagen in reticular dermis mm >2 mm invasion to fibrous tissue V Subcutaneous fat >3.0 mm Subcutaneous fat (1 to 2 cm) is equally effective as radical vulvectomy [54]. Occasionally, exenterative procedures are required to surgically clear large, midline, or vulvovaginal primary lesions. Routine groin dissection appears to be unwarranted, especially in lesions with less than 1 mm invasion [55]. Groin pathology, however, is prognostic, and in cases with thicker, larger lesions or those cases exhibiting lymph-vascular space invasion, a groin dissection may be appropriate. Radiotherapy has been used infrequently. Radiobiologic data suggest sensitivity of this neoplasm [56]. However, the fractionation schema traditionally used on cutaneous lesions is not well tolerated in the vulva or groin. Late recurrences have been observed. Further study is warranted in these lesions, and patients are encouraged to participate in clinical trials of adjuvant treatment protocols. Treatment and staging of Bartholin s gland carcinoma Primary carcinoma of the Bartholin s gland accounts for about 5% of vulvar malignancies. They can be represented by squamous cell carcinoma, adenocarcinoma, or transitional cell carcinoma depending on which part of the gland or duct the carcinoma arises. Adenoid cystic and adenosquamous lesions have also been reported. Enlargement of the gland among postmenopausal women requires histologic diagnosis because these cancers are often mistaken as benign cysts or abscesses [57]. Although these lesions arise from the subcutaneous tissues and generally do not have a surface component until the lesion is large, the FIGO staging system is most commonly applied to these lesions as outlined above for squamous cell carcinoma. Prognostic factors are similar. Local resection of these lesions is performed by radical vulvectomy or radical wide excision as outlined above. If the lesion extends deeply into the vulva, exploration of the ischial-rectal fossa may be necessary. In addition, because the deep lymphatics in this area may alternately drain into tributaries of the rectal lymphatics, pelvic or para-rectal nodal disease may be discovered. Because of these conditions, some have advocated either pelvic node exploration or pelvic radiotherapy in selected cases. Occasionally, the lesion cannot be surgically cleared without organ excision, particularly the anus/rectum. In these cases, a neoadjuvant or exenterative approach as outlined for T3/T4 vulvar cancer is appropriate. Treatment of Paget s disease Paget s disease of the vulva is an intraepithelial neoplasm, arising as an aberrant differentiation of apocrine glandular cells. The disease presents with extreme pruritus and soreness and is characterized by red or bright pink desquamated eczematoid areas admixed with raised areas of white hyperkeratosis. The diagnosis is made by biopsy and can represent a significant challenge to the clinician because large areas of affected skin

12 188 Gynecologic Tumors References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: Of interest Of outstanding interest 1. Practice guidelines: vulvar cancer. Society of Gynecologic Oncologists Clinical Practice Guidelines. Oncology (Huntingt) 1998, 12: This article outlines the clinical practice guidelines set forth by the SGO. It is comprehensive and references the classic articles defining vulvar cancer management. 2. Basta A, Adamek K, Pitynski K: Intraepithelial neoplasia and early stage vulvar cancer. Epidemiological, clinical and virological observations. Eur J Gynaecol Oncol 1999, 20: Creasman WT, Phillips JL, Menck HR: The National Cancer Data Base report on early stage invasive vulvar carcinoma. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 1997, 80: Wilkinson E: Premalignant and malignant tumors of the vulva. In Blaustein's Pathology of the Female Genital Tract. Edited by Kurman R. New York: Springer-Verlag; Hildesheim A, Han CL, Brinton LA, et al.: Human papillomavirus type 16 and risk of preinvasive and invasive vulvar cancer: results from a seroepidemiological case-control study [see comments]. Obstet Gynecol 1997, 90: Madeleine MM, Daling JR, Carter JJ, et al.: Cofactors with human papillomavirus in a population-based study of vulvar cancer [published erratum appears in J Natl Cancer Inst 1997 Dec 17;89(24):1896]. J Natl Cancer Inst 1997, 89: may exist. Compared with Paget s disease of the breast, vulvar Paget s disease is much less often associated with underlying or concomitant adenocarcinoma. Paget s disease may be invasive or may be associated with an underlying adenocarcinoma, most commonly arising from the skin adnexa. Underlying invasive disease occurs in approximately 10% to 20% of cases [58]. Treatment of Paget s disease is through wide excision. Subcutaneous tissue should be removed along with the overlying skin to assess whether invasive disease coexists. Although the intraepithelial lesion generally has demarcated borders, pagetoid cells can often be found several centimeters from an apparently clear margin. In general, 2-cm margins are attempted. Reconstruction of the vulvar defect may require skin grafting. However, this does not preclude recurrence because several cases of post graft involvement have been reported [59]. Traditionally, circumferential intraoperative frozen section evaluation of the surgical margins has been performed. This procedure is time-consuming and taxes the surgical pathology department extensively. A decision should be made as to whether chasing a surgical margin is more appropriate than treating potentially recurrent disease. In either case, confidence in not overlooking a potentially invasive focus is paramount to long-term success. If invasive disease is detected, radical vulvectomy and groin dissection as outlined above should ensue. Staging follows the FIGO system. 7. Flowers LC, Wistuba II, Scurry J, et al.: Genetic changes during the multistage pathogenesis of human papillomavirus positive and negative vulvar carcinomas. J Soc Gynecol Investig 1999, 6: American Joint Committee on Cancer: AJCC Cancer Staging Manual. Philadelphia, PA: Lippincott-Raven Publishers; Shepherd JH: Cervical and vulva cancer: changes in FIGO definitions of staging [see comments]. Br J Obstet Gynaecol 1996, 103: Chiasson MA, Ellerbrock TV, Bush TJ, et al.: Increased prevalence of vulvovaginal condyloma and vulvar intraepithelial neoplasia in women infected with the human immunodeficiency virus. Obstet Gynecol 1997, 89: Modesitt SC, Waters AB, Walton L, et al.: Vulvar intraepithelial neoplasia III: occult cancer and the impact of margin status on recurrence [see comments]. Obstet Gynecol 1998, 92: Rettenmaier MA: Vulvar intraepithelial neoplasia III: occult cancer and the impact of margin status on recurrence [letter; comment]. Obstet Gynecol 1999, 93: Husseinzadeh N, Recinto C: Frequency of invasive cancer in surgically excised vulvar lesions with intraepithelial neoplasia (VIN 3). Gynecol Oncol 1999, 73: This important paper demonstrates the common finding of unexpected invasive cancer among patients undergoing excision of high-grade dysplasia.

13 Vulvar Carcinoma Coleman and Santoso Rettenmaier MA, Berman ML, DiSaia PJ: Skinning vulvectomy for the treatment of multifocal vulvar intraepithelial neoplasia. Obstet Gynecol 1987, 69: Reid R, Greenberg MD, Lorincz AT, et al.: Superficial laser vulvectomy. IV. Extended laser vaporization and adjunctive 5-fluorouracil therapy of human papillomavirus-associated vulvar disease. Obstet Gynecol 1990, 76: Baggish MS, Dorsey JH: CO 2 laser for the treatment of vulvar carcinoma in situ. Obstet Gynecol 1981, 57: Reid R: Superficial laser vulvectomy. III. A new surgical technique for appendage-conserving ablation of refractory condylomas and vulvar intraepithelial neoplasia. Am J Obstet Gynecol 1985, 152: Miller B, Katasanis W: Treatment of vulvar intraepithelial neoplasia with ultrasonic surgical aspiration. Proc Am Soc Clin Oncol 1999, 18:380a. 19. Reid R, Greenberg MD, Pizzuti DJ, et al.: Superficial laser vulvectomy. V. Surgical debulking is enhanced by adjuvant systemic interferon. Am J Obstet Gynecol 1992, 166: Krebs HB: Prophylactic topical 5-fluorouracil following treatment of human papillomavirus-associated lesions of the vulva and vagina. Obstet Gynecol 1986, 68: Lifshitz S, Roberts JA: Treatment of carcinoma in situ of the vulva with topical 5-fluorouracil. Obstet Gynecol 1980, 56: Kelley JLD, Burke TW, Tornos C, et al.: Minimally invasive vulvar carcinoma: an indication for conservative surgical therapy. Gynecol Oncol 1992, 44: Homesley HD, Bundy BN, Sedlis A, et al.: Assessment of current International Federation of Gynecology and Obstetrics staging of vulvar carcinoma relative to prognostic factors for survival (a Gynecologic Oncology Group study). Am J Obstet Gynecol 1991, 164: ; discussion Burke TW, Levenback C, Coleman RL, et al.: Surgical therapy of T1 and T2 vulvar carcinoma: further experience with radical wide excision and selective inguinal lymphadenectomy. Gynecol Oncol 1995, 57: Hacker NF: Current management of early vulvar cancer. Ann Acad Med Singapore 1998, 27: Heaps JM, Fu YS, Montz FJ, et al.: Surgical-pathologic variables predictive of local recurrence in squamous cell carcinoma of the vulva. Gynecol Oncol 1990, 38: Hacker NF, Van der Velden J: Conservative management of early vulvar cancer. Cancer 1993, 71: Levenback C, Morris M, Burke TW, et al.: Groin dissection practices among gynecologic oncologists treating early vulvar cancer [see comments]. Gynecol Oncol 1996, 62: Stehman FB, Bundy BN, Dvoretsky PM, Creasman WT: Early stage I carcinoma of the vulva treated with ipsilateral superficial inguinal lymphadenectomy and modified radical hemivulvectomy: a prospective study of the Gynecologic Oncology Group. Obstet Gynecol 1992, 79: Stehman FB, Bundy BN, Thomas G, et al.: Groin dissection versus groin radiation in carcinoma of the vulva: a Gynecologic Oncology Group study. Int J Radiat Oncol Biol Phys 1992, 24: Petereit DG, Mehta MP, Buchler DA, Kinsella TJ: Inguinofemoral radiation of N0,N1 vulvar cancer may be equivalent to lymphadenectomy if proper radiation technique is used [see comments]. Int J Radiat Oncol Biol Phys 1993, 27: Berman ML, Soper JT, Creasman WT, et al.: Conservative surgical management of superficially invasive stage I vulvar carcinoma. Gynecol Oncol 1989, 35: Levenback C, Burke TW, Morris M, et al.: Potential applications of intraoperative lymphatic mapping in vulvar cancer. Gynecol Oncol 1995, 59: Outwater E, Kressel HY: Evaluation of gynecologic malignancy by magnetic resonance imaging. Radiol Clin North Am 1992, 30: De Cicco C, Sideri M, Bartolomei M, et al.: Sentinel node biopsy in early vulvar cancer. Br J Cancer 2000, 82: Dr. De Cicco and colleagues present provocative data on the emerging role of intraoperative lymphatic mapping using lymphoscintigraphy. In the study, no patients had metastatic disease outside the designated sentinel node. If validated, this technique could replace lymphadenectomy offering a less morbid alternative to evaluation of the groin. 36. Cunningham MJ, Goyer RP, Gibbons SK, et al.: Primary radiation, cisplatin, and 5-fluorouracil for advanced squamous carcinoma of the vulva. Gynecol Oncol 1997, 66: Eifel PJ, Morris M, Burke TW, et al.: Prolonged continuous infusion cisplatin and 5-fluorouracil with radiation for locally advanced carcinoma of the vulva. Gynecol Oncol 1995, 59: Leiserowitz GS, Russell AH, Kinney WK, et al.: Prophylactic chemoradiation of inguinofemoral lymph nodes in patients with locally extensive vulvar cancer. Gynecol Oncol 1997, 66: Moore DH, Thomas GM, Montana GS, et al.: Preoperative chemoradiation for advanced vulvar cancer: a phase II study of the Gynecologic Oncology Group. 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14 190 Gynecologic Tumors 43. Perez CA, Grigsby PW, Chao C, et al.: Irradiation in carcinoma of the vulva: factors affecting outcome. Int J Radiat Oncol Biol Phys 1998, 42: Perez CA, Grigsby PW, Galakatos A, et al.: Radiation therapy in management of carcinoma of the vulva with emphasis on conservation therapy. Cancer 1993, 71: Paley PJ, Johnson PR, Adcock LL, et al.: The effect of sartorius transposition on wound morbidity following inguinal-femoral lymphadenectomy. Gynecol Oncol 1997, 64: Chafe W, Fowler WC, Walton LA, Currie JL: Radical vulvectomy with use of tensor fascia lata myocutaneous flap. Am J Obstet Gynecol 1983, 145: Faul CM, Mirmow D, Huang Q, et al.: Adjuvant radiation for vulvar carcinoma: improved local control. Int J Radiat Oncol Biol Phys 1997, 38: Homesley HD: Management of vulvar cancer. Cancer 1995, 76: Paladini D, Cross P, Lopes A, Monaghan JM: Prognostic significance of lymph node variables in squamous cell carcinoma of the vulva [see comments]. Cancer 1994, 74: van der Velden J, van Lindert AC, Lammes FB, et al.: Extracapsular growth of lymph node metastases in squamous cell carcinoma of the vulva. The impact on recurrence and survival. Cancer 1995, 75: Bouma J, Dankert J: Recurrent acute leg cellulitis in patients after radical vulvectomy. Gynecol Oncol 1988, 29: Hoffman MS, Mark JE, Cavanagh D: A management scheme for postoperative groin lymphocysts. Gynecol Oncol 1995, 56: Tewari K, Cappuccini F, Syed AM, et al.: Interstitial brachytherapy in the treatment of advanced and recurrent vulvar cancer. Am J Obstet Gynecol 1999, 181: Trimble EL, Lewis JL Jr, Williams LL, et al.: Management of vulvar melanoma. Gynecol Oncol 1992, 45: Trimble EL: Melanomas of the vulva and vagina. Oncology (Huntingt) 1996, 10: ; discussion Singhal RM, Narayana A: Malignant melanoma of the vulva: response to radiation. Br J Radiol 1991, 64: Copeland LJ, Sneige N, Gershenson DM, et al.: Bartholin gland carcinoma. Obstet Gynecol 1986, 67: Fanning J, Lambert HC, Hale TM, et al.: Paget's disease of the vulva: prevalence of associated vulvar adenocarcinoma, invasive Paget's disease, and recurrence after surgical excision. Am J Obstet Gynecol 1999, 180: DiSaia PJ, Dorion GE, Cappuccini F, Carpenter PM: A report of two cases of recurrent Paget's disease of the vulva in a split-thickness graft and its possible pathogenesis-labeled "retrodissemination". Gynecol Oncol 1995, 57: