Clinical Expert Series

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Carcinoma of the Vulva

Frederick B. Stehman,
MD,

and Katherine Y. Look,

MD

The objective of this review is to summarize the published data about squamous carcinoma of the vulva and to identify promising areas for future investigation. Rather than the routine use of complete radical vulvectomy, a radical wide excision of the vulvar lesion to achieve at least a 1-cm gross margin appears sufficient to treat the primary lesion. A surgical assessment of the groin is required for all patients who have invasion greater than 1 mm. Ipsilateral groin node dissection can be performed through a separate incision. All the nodal tissue medial to the vessels and above the fascia should be removed. Sentinel node evaluation may be a significant step forward, but the false-negative rate is not well enough defined to consider this a standard. Patients with positive inguinal nodes at groin dissection should receive radiation therapy to the ipsilateral groin and hemipelvis. For those patients who have unresectable primary disease or if nodes are palpably suspicious, fixed, and/or ulcerated preoperatively, chemoradiation is the preferred option. Exenterative procedures may rarely be required. Chemotherapy for recurrent or metastatic disease has not been proven to be of value. Although survival rates are high for those with negative nodes, the morbidity associated with standard radical techniques has prompted innovation. Adequately powered trials aimed at further reducing morbidity without compromising survival are underway.
(Obstet Gynecol 2006;107:71933)

here are approximately 4,000 new cases of vulvar cancer each year in the United States, which represents between 5% and 8% of all gynecologic cancers. Annually, approximately 1,000 patients will succumb to the disease. Radical surgery has been shown to be effective but is associated with considerable morbidity. Recent research has been aimed at better understanding the natural history of the disease, prevention, earlier detection, and less morbid treatments. This review summarizes the extant literature on squamous cell carciFrom the Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana. Corresponding author: Frederick B. Stehman, MD, Indiana University School of Medicine, 550 North University Boulevard, UH 2440, Indianapolis, IN 46202; e-mail: fstehman@iupui.edu. Financial Disclosure Drs. Stehman and Look are funded investigators of the Gynecologic Oncology Group. 2006 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/06

noma of the vulva and highlights opportunities for future investigation. We conducted a MEDLINE search using Ovid with the search term vulvar neoplasms and the sub-headings complications, diagnosis, imaging, radiation therapy, epidemiology, mortality, and surgery. We searched reference lists of articles and files of the authors, selecting those which we judged relevant. Only articles in English with complete manuscripts were used. Three randomized clinical trials were identified,13 two of which were closed after interim analyses. There were 3 case control studies.4 6 The majority of studies were observational-descriptive, level II-3 or level III evidence. Meta-analytic techniques were not employed.

EPIDEMIOLOGY
Approximately 90% of patients with cancer of the vulva will have squamous cell carcinoma. The most common other histologies are melanoma and basal cell carcinoma, but these are not addressed in this

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review. The disease is most commonly observed in or after the seventh decade of life,79 but invasive carcinoma has been reported in younger women. The number of younger women with invasive disease appears to be increasing.10 12 This apparent increase could not be correlated with a change in referral patterns, smoking habits, or screening bias.11 Invasive disease is often seen in association with preinvasive disease13,14 in younger women, whereas in elderly patients without any evidence of preinvasive disease, invasive cancer may arise in a field of lichen sclerosis.15,16 It has been suggested that there are different subtypes of squamous vulvar cancer, one associated with human papilloma virus and one which is not.1720 Jones et al21 reported 2 cohorts separated by 2 decades. Of note in the earlier cohort, only 2% of patients were under 50 years of age, whereas in the most recent cohort, 21% were under 50.21 Studies in Europe and North America have shown an increase in the rate of preinvasive disease without an increase in invasive carcinoma. It is not yet clear whether this discordance relates to a period of inherent latency in the disease or a disconnect between preinvasive disease and invasive disease.8,2224 It is known that sexual practices associated with the acquisition of human papilloma virus and a prior history of genital warts increase ones risk.7,10,11,2527 In an adequately powered case-control study, Brinton et al4 identified that an increasing number of sexual partners, venereal warts, cigarette smoking, and a history of abnormal cervical cytology were associated with increased risk. Sherman et al6 conducted a case-control study and found that both carcinoma in situ and invasive carcinoma were more common among those with a history of condylomata, gonorrhea, and herpes simplex virus. Human papilloma virus nucleic acid has been found in both preinvasive and invasive specimens.27 Patients who are immuno-

compromised because of disease or a suppressed immune system secondary to corticosteroid use may be at risk of acquiring preinvasive disease or progressing to invasive cancer after papilloma virus exposure because of their inability to eradicate the virus from their lower genital tract epithelium.10,28,29

DIAGNOSIS AND STAGING

Historically, this disease has been characterized by delay in diagnosis by both the patient and the physician.30 The diagnosis of invasive squamous carcinoma of the vulva is generally not difficult. Most patients present with burning, itching, bleeding, or pain in the vulva, and there will be a visible lesion accessible to biopsy (Figs. 1A and 1B). These lesions may be raised, flat, ulcerated, exophytic, or plaque-like. Standard biopsy techniques are readily available and definitive. The lymphatic drainage of the vulva has been extensively described.31,32 Lateralized lesions generally drain to the ipsilateral groin. Nodes that are superficial and medial are most commonly involved. Pelvic lymph nodes are rarely involved unless the ipsilateral inguinal nodes are involved.33 Midline lesions or lesions within 1 cm of the midline can drain to either side.34,35 Although there are anatomical pathways of lymphatic drainage from the clitoris directly to the pelvis, it is unusual for clitoral lesions to involve the pelvic nodes unless the groin nodes are involved.33,34 The International Federation of Gynecology and Obstetrics, the American Joint Committee on Cancer, and the International Union Against Cancer have agreed on a standard surgical staging for vulvar carcinoma based on primary tumor characteristics, regional lymph nodes, and distant metastases (Table 1). The current staging system assigns all patients with unilateral positive groin nodes to stage III and those with bilateral groin nodes to stage IV. Staging based

Fig. 1. Visible lesions on the vulva, with A showing a small well-lateralized tumor and B showing a large tumor encroaching on other structures. Illustration: John Yanson.
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Table 1. Staging for Vulvar Carcinoma: Stage Grouping

Stage Stage Stage Stage 0 I II III Tis T1 T2 T1 T2 T3 T3 T1 T2 T3 T4 Any T N0 N0 N0 N1 N1 N0 N1 N2 N2 N2 Any N Any N M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

Stage IVA

Stage IVB

Tis, carcinoma in situ; T1, tumor of vulva or perineum, 2 cm in greatest dimension; T2, tumor of vulva or perineum, 2 cm in greatest dimension; T3, tumor involving lower urethra, vagina, or anus; T4, tumor involving bladder/rectal mucosa, upper urethra, or bone; N0, no lymph node metastases; N1, unilateral regional lymph node metastases; N2, bilateral regional lymph node metastases; M0, no distant metastases; M1, distant metastases.

on surgical findings was adopted in 1995 because of the approximately 25% discrepancy that was recognized between surgical and clinical evaluation of lymph node status.36 38 Even large nodes that are completely replaced by cancer can escape notice on palpation alone.3,39 Approximately one fourth of patients who are thought to have nonsuspicious nodes (N0/N1) on clinical palpation will be found at histopathologic examination to harbor metastasis. Similarly, approximately one fourth of patients whose lymph nodes are considered clinically suspicious (N2/ N3) will have negative lymph nodes when dissected. The clinical staging system, although not accurate for any single patient, did discriminate patient risk groups well.36 If nodes are palpably suspicious, fixed, and/or ulcerated preoperatively, fine needle aspiration can be used to help determine if they are involved.40 Chemoradiation (with or without surgery at a later date) is an option for those patients who, on clinical staging, have unresectable, ulcerated, or fixed nodes in the groin and/or primary disease that would require an exenteration to achieve negative margins.41

ative nodes.56,57 Nodal metastases are significantly correlated with clinical node status, depth of invasion, and primary lesion size as well as capillary space involvement (Table 2). Bilateral lymph node involvement has a more ominous prognosis than unilateral node involvement.36,58,59 Homesley et al36 noted that patients with one node involved have substantially less risk of recurrence than patients with 2 or more nodes. Curry et al58 reported that patients with unilateral groin node metastases had better survival than those with 3 or more nodes or bilateral metastases (57% versus 23%) (Table 3). Local relapse is associated with positive or close margins,60,61 positive capillary space involvement (capillary-like space invasion),36 greater depth of invasion,36 and large primary lesion size (Table 4).36,59,61 Heaps and colleagues60 analyzed a series of specimens and found that there were no local recurrences among 91 patients when the fresh specimen margin was 1 cm and the formalin-fixed margin was greater than 8 mm. Patients who have vulvar intraepithelial neoplasia (VIN) III at the margin have a higher risk of relapse.14 The marginal involvement with undifferentiated VIN appeared to be a less ominous prognostic find than marginal involvement with squamous cell hyperplasia or lichen sclerosis.62

TREATMENT
For many years the standard treatment for invasive squamous cell carcinoma of the vulva was radical surgery. The Bassett-Way operation commenced with a curvilinear incision from one anterior superior iliac Table 2. Tumor Thickness and Size as Predictors of Positive Nodes
Positive Nodes (%)
Depth of invasion (mm) 1 2 3 4 5 5 Tumor diameter (cm) 1 2 3 4 5 5 3 9 19 31 33 48 18 19 31 54 39 52

PROGNOSTIC FACTORS
Prognostic factors in vulvar cancer have been assessed primarily with retrospective descriptive series. International Federation of Gynecology and Obstetrics (FIGO) stage, tumor size, depth of invasion, capillary lymphatic space invasion, and nodal metastases are each highly predictive of survival.9,37,38,4255 There is considerable consistency among the findings. Patients with positive nodes have also been noted to experience recurrence earlier than patients with neg-

Adapted from Homesley HD, Bundy BN, Sedlis A, Yordan E, Berek JS, Jahshan A, et al. Prognostic factors for groin node metastasis in squamous cell carcinoma of the vulva (a Gynecologic Oncology Group study). Gynecol Oncol 1993;49:279 83.37 Copyright 1993, with permission from Elsevier.

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Table 3. Tumor Size and Positive Nodes as Predictors of Survival

Relative 5-Year Survival (%) Tumor Diameter (cm)
01 12 23 34 4 2 2.13 3.14 4.1

5-Year Survival (%)*

90 89 83 63 44

Nodes

Nodes

97.9 90.5 75.5 81.5

78.6 59.1 56.8 44.8

* Data from Podratz KC, Symmonds RE, Taylor WF, Williams TJ. Carcinoma of the vulva: analysis of treatment and survival. Obstet Gynecol 1983, 61:6374.38 Modified from Homesley HD, Bundy BN, Sedlis A, Yordan E, Berek JS, Jahshan 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: 9971003. Copyright 1991, with permission from Elsevier.36

Table 4. Local Failure Rates

Absent (%)
Size 5 cm Depth 11 mm CLSI Margin 8 mm 8 10 11 0

Present (%)
18 18 18 48

Fig. 2. The Bassett-Way operation (A), which has since been replaced by a less radical operation, with a unilateral incision in the groin and an elliptical excision of the small lesion (B). Illustration: John Yanson.
Stehman. Vulvar Cancer. Obstet Gynecol 2006.

CLSI, capillary-like space invasion.

spine to the other, then down the bilateral groins and labiocrural folds, bringing the incisions together with a transverse incision across the perineal body. All skin, subcutaneous tissue, fat, lymph nodes, and superficial veins were removed (Fig. 2A).63 65 The operation produced a substantial improvement in outcomes compared with what had previously been a lethal disease. Morley reported a 73.9% corrected 5-year survival for all patients.52 This success led to acceptance of this operation for all patients, irrespective of tumor size or risk factors. The wound defect left after the Basset-Way incision was difficult to close and wound disruptions were nearly universal. Longterm lymphedema was common. Early stage III disease: As early as 1940, Taussig66 suggested using separate incisions for the groins and the vulvar excision as one approach to reducing the operative morbidity. This recommendation did not take hold until some 35 years later.67 Hacker and colleagues,68 reported on 100 patients treated with separate incisions and noted corrected actuarial

5-year survival rates of 97.4% for clinical stage I, 86% for stage II, and 49.2% for stage III disease. Only 14% of patients had major groin wound breakdown, and no patients experienced isolated metastasis in the groin or the inguinal skin bridge. This approach was a step forward in reducing both acute and chronic morbidity.68 Siller et al5 carried out a small casecontrol study of triple incision operation and en bloc operation and observed no difference in recurrence rate, local recurrence, or 5-year survival rate between the 2 groups. The study, however, was underpowered, with only 27 patients having the triple incision and 20 having en bloc operation. This reviews authors believe that the triple incision technique has lessened morbidity and shortened length-of-stay for patients with this disease. This has been the standard surgical approach at our institution for early stage disease for more than a decade.69 Considerable study has been undertaken in an attempt to identify a cohort of patients who would be suitable for less radical dissection of the groin. This

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clinical scenario is analogous to microinvasion in the cervix, ie, patients with invasion but the risk of nodal involvement is so low that the lymphatic drainage could be ignored.70 77 Most investigators agree that if invasion depth is greater than 1 mm, the risk of lymph node involvement merits a surgical assessment of the groin.72 Thickness and depth of invasion from the basement membrane represent 2 different measurements. The pattern of invasion should be noted as well, and infiltrating/spray margins are of greater concern than pushing margins.73,78,79 It is important that the gynecologist understand what technique of measurement is used by the pathologist at his or her institution. In 1979, DiSaia et al80 reported a small series of 20 patients with primary lesions less than 1 cm in size and invasion less than 5 mm in depth, who underwent a wide local excision and removal of the superficial inguinal nodes through an 8-cm incision. This manuscript described removal of all nodal tissue, medial to the vessels, and above the fascia. Approximately 8 10 nodes were removed from each groin. In a follow-up study from the same institution,81 the sample size was increased to 50 patients, and no isolated groin recurrences were observed in this selected population. The authors did not describe plucking 1 or 2 nodes from the groin but rather a complete removal of the intact fat pad. Conservative surgical modifications were adopted by many centers9,82,83 and were commonly recommended for patients with early disease. Hacker et al47,84 urged caution that a portion of the lymph node dissection not be omitted, recognizing that groin recurrence is often fatal. Based on the surgical principles recommended by DiSaia et al80 and the prognostic factor data generated by its own surgical pathologic studies,36,37,78 the Gynecologic Oncology Group undertook a cohort trial for patients with primary lesions less than 2 cm in size and less than 5 mm in depth, no lymph-vascular space involvement in the primary lesions, and clinically negative nodes.85 There were 121 evaluable patients, each of whom underwent a modified radical excision of the primary lesion and a superficial, ipsilateral, inguinal lymph node dissection. Incising the fascia and skeletonizing the femoral vessels were not required. There were 19 patients who experienced recurrence. Ten recurrences were on the vulva, and 8 of these patients were salvaged by subsequent operation. Nine recurrences (7.4%) were in the groin, and 5 of these patients died. Even though the morbidity was reduced and the length of the stay was shortened, these data suggested that superficial lymph

node dissection as carried out in a multicenter setting led to an unacceptable number of groin recurrences.85 Gordinier and colleagues86 reviewed their experience with superficial inguinal lymphadenectomy. They found 9 groin recurrences among 104 patients. These patients were all thought to have negative nodes at the time of the initial diagnosis. There was a median of only 7 nodes per groin. Six of the 9 patients whose disease recurred are dead. Additional slides cut from the resected nodes did not reveal any unrecognized microscopic metastasis. Their conclusion was that these 9 patients had positive nodes, which were not resected. These 2 series85,86 are discordant with the observations of DiSaia et al.80 Burke and colleagues87 previously reported radical wide local excision and selected inguinal lymph node dissection in 76 patients between 1978 and 1994. Twelve percent of patients experienced recurrence in the vulva; all local recurrences were controlled with repeat operation. Four patients (5.2%) experienced recurrence in a previously negative groin, 3 of whom died of disease. The rate of acute complications was low (8% in the vulva and 11% in the groin), although 29% had delayed complications in the groin. All patients with positive nodes at initial operation received additional treatment. It would appear that there is some overlap in the patient populations reported in these 2 series.86,87 Careful anatomic, embryologic, and cadaveric dissections88 90 have shown that, although there are lymph nodes found in the fenestrations of the cribriform fascia, there are no lymph nodes below the deep fascia, and no nodes distal to the lower margin of the fossa ovalis. It is not necessary to remove the deep fascia to perform a complete removal of the inguinal and femoral nodes. If the superficial fat pad is placed on tension and removed in its entirety, all the inguinal and femoral lymph nodes would be removed in one packet. Levenback et al91 reported on a survey conducted on the membership of the Society of Gynecologic Oncologists demonstrating a wide variety in how groin operations are performed among and between gynecologic oncologists and what terminology is used to describe those procedures. If the complete lymph fat pad is removed from the groin, removing 8 12 lymph nodes, the risk of groin relapse and subsequent mortality associated with lesser operation is no higher than with the complete radical procedure.33,9295 (Table 5). These studies have had a significant impact in changing the standard of practice across North America,69,96 98 such that a radical wide local excision of the vulvar lesion to achieve a 1-cm gross margin is considered sufficient to address the primary lesion

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Table 5. Groin Failure After Superficial Inguinal Node Dissection

Author, Year
Berman, 1989 Stehman, 199285 Burke, 199587 Gordinier, 200386 Kirby, 200595
81

Fail/Total
0/50 6/121 4/76 9/104 3/65

%
0 5.0 5.2 8.6 4.6

(Fig. 2B). Ipsilateral groin node dissection can be performed through a separate incision. Bilateral dissection should be performed if there is a midline lesion or if the ipsilateral nodes are positive. No longer is a single en bloc radical operation applied for all patients at all stages. There are 2 other operative modifications that have been studied and deserve mention. Preservation of the saphenous vein during the groin dissection has been found to lessen lower extremity edema.99,100 The sartorius muscle was historically transferred from its origin to the inguinal ligament to cover the femoral vessels exposed by node dissection.101 Judson et al102 reported in a randomized clinical trial that sartorius transposition was not beneficial but was associated with an increase in lymphocyst formation. The authors of this review offer their opinion that the innovations in groin dissection technique described above, with preservation of the skin and its attendant blood supply above the femoral vessels and universal application of suction drains, has substantially lessened morbidity. However, morbidity is still high enough103 to warrant further investigation. One of the most interesting new developments in the evaluation of the inguinal nodes has been sentinel node evaluation and mapping. Initially introduced for penile cancer,105 the technique has been widely adopted for cutaneous melanoma.106 Sentinel node evaluation involves injection of a blue dye and/or a radioactive colloid into the primary, with subsequent identification and removal of the blue or hot node to determine if metastases are present. If the sentinel node contains metastases, then a complete dissection is undertaken. If the sentinel node is negative, then the rest of the basin is left intact. The procedure is based on the assumption of orderly metastases. For cutaneous melanoma and breast cancer, the technique has been validated, limiting morbidity. The earliest trials in vulvar cancer were performed by Levenback et al.107109 Nine patients had 12 groins injected with isosulfan blue, and a sentinel node was identified in 7 of 12 groin basins. There were no false negatives.107 The authors expanded their series to 21

patients and were able to locate a sentinel node in 86% of patients and 66% of groins by using a blue dye only.108 Additional studies used either isosulfan blue dye or technetium-99 and lymphoscintigraphy.110 112 de Hullu and colleagues113 published their experience with sentinel node identification using a combined technique of blue dye and lymphoscintigraphy in 59 patients and 107 groins. Ninety-five groins underwent complete dissection, with a median yield of 12 nodes per groin. The 95 groins contained 139 sentinel nodes. Twenty-seven groins from 20 patients were node-positive, and 68 were node-negative. All 37 sentinel nodes found to be positive were confirmed positive on routine histology assessment, yielding a positive predictive value of 100%. Of the 102 nodes negative by routine sectioning, 4 were positive on subsequent step sectioning with immunohistochemistry. These authors believed that the combined technique was superior to the blue dye alone. Other authors have confirmed the value of blue dye in combination with lymphoscintigraphy.114,115 A collective review of the published literature in 2002 by Plante et al116 found 12 series with 353 patients with vulvar cancer. Ninety-two percent had a sentinel node detected, and the positive predictive value was 99%. The blue dye was an inexpensive and quick approach. Lymphoscintigraphy is a more expensive and cumbersome technology. The technique is limited by the fact that a sentinel node is not always identifiable, midline lesions may drain bilaterally, and step sectioning may show metastases in nodes considered negative on frozen section. Complications from using either isosulfan blue or technetium colloid are rare but include pulmonary compromise. A substantial body of information is being amassed suggesting that sentinel node evaluation is a significant step forward.117119 Anecdotal reports of false-negative sentinel nodes have been published.39,120,121 In at least one of these cases, it appears that a node was falsely negative because it was completely replaced by tumor and lymphatic channels were clogged. The Gynecologic Oncology Group is currently conducting a prospective clinical trial (C. Levenback, personal communication, January 12, 2006). This large trial will be able to identify an increase in the relative risk of a false-negative sentinel node even though the absolute risk is low. In their staging study of complete inguinal-femoral lymph node dissection,36,37 one patient in 387 (0.3%) suffered a groin recurrence despite having had a negative groin node dissection (Table 6). If sentinel node mapping has a 3% false-negative rate, this would represent a 10-fold

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Table 6. Failure Rates After Radical Vulvectomy and Groins (n 588)

Site
Vulva Groin Pelvis Distant

Nodes (%)
10.1 0.3 1.0 1.3

Nodes (%)
16.3 11.8* 3.9 9.9

Total (%)
12.2 4.3 2.0 4.3

* With postoperative surgery (22.0%); with postoperative RT (5.1%). Information from Homesley HD, Bundy BN, Sedlis A, Adcock L, Radiation therapy versus pelvic node resection for carcinoma of the vulva with positive groin nodes. Obstet Gynecol 1986;68: 733401; Homesley HD, Bundy BN, Sedlis A, Yordan E, Berek JS, Jahshan 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;164:997 100336; Homesley HD, Bundy BN, Sedlis A, Yordan E, Berek JS, Jahshan A, et al. Prognostic factors for groin node metastasis in squamous cell carcinoma of the vulva (a Gynecologic Oncology Group study). Gynecol Oncol 1993;49:27983.37

increase in risk. The current trial is powered to determine how many more recurrences would be expected after a negative sentinel node dissection. Another concept for reducing the morbidity of groin surgery is the use of a vapor-heated fibrin sealant to reduce the length of time suction drains are required and to reduce lymphocyst formation. The Gynecologic Oncology Group is conducting a study of this product (J. W. Carlson, personal communication, January 12, 2006). It is too early to make any assessment of its efficacy.

Vulvar Reconstructive Procedures

Considerable attention has been paid to efforts to restore the appearance and function of the vulva after radical local excision, which leaves significant defects. One of the most versatile approaches uses local transfer flaps, such as the rhomboid flap, as described by Barnhill and colleagues.122 A variety of flaps from the thigh and the buttock can be rotated to cover skin and subcutaneous tissue defects.123,124 More extensive defects can be covered with myocutaneous flaps such as the gracilis flap125,126 and the transverse rectus abdominis flap.127

TREATMENT OF ADVANCED STAGE IIIIV DISEASE

For some patients, exenterative procedures have been used when lesions encroached upon the urethra, bladder, rectum, or anal sphincter.128 130 Still, virtually all patients with positive nodes succumbed to their disease.129 Innovative techniques to avoid permanent fecal diversion have been reported.131 The consider-

able morbidity, mortality, and psychosexual sequelae have prompted investigation into alternative approaches for advanced disease. We feel that exenteration has a limited role in the treatment of this disease. The intact vulva is made up of loose areolar tissue, which frequently becomes edematous after local trauma. Radiation therapy was considered to have had virtually no role in the treatment of carcinoma of the vulva until the mid-1980s because of the moist desquamative vulvitis associated with tangential beams and the vulvas moist overlapping skin folds. The Gynecologic Oncology Group conducted a randomized trial for patients with positive inguinal nodes after groin dissection in which pelvic lymph node dissection was compared with radiation to the groin and pelvis.1 The study was stopped after an interim of analysis of the first 114 patients because of significant advantages in survival for the radiation group (68% versus 54%, P .03). This study set a new standard for the treatment of patients with positive nodes. Pelvic lymph node dissection through the groin has largely passed into disuse. The advantage was particularly noted in patients with more than 2 positive nodes or patients with fixed or ulcerated nodes. This study opened the door for a reexamination of the use of radiation therapy in carcinoma of the vulva.98,132 Before that trial, several authors133,134 had recommended the use of radiation to the intact, undissected groin to avoid the morbidity of lymph node dissection. After these promising uncontrolled trials and the study of Homesley et al,1 the Gynecologic Oncology Group undertook a trial for patients with N0 or N1 nodes and randomized them to inguinal femoral lymph node dissection or external radiation to the groin. This study was closed after interim analysis revealed that 5 patients in the operative group had positive nodes without any groin failures and 5 of 27 patients (18.5%) in the radiation group suffered a groin failure. There was a significant difference in progression-free interval and survival.3 Others have studied the issue of irradiation of the intact groin and found a similar increased groin failure rate.135 In this study it was noted again that clinical assessment of the groin nodes is not reliable. Several patients who underwent dissection were found to have nodes that were 3 cm in size and completely replaced by tumor. A number of the patients had body mass index greater than 30, making clinical assessment difficult. Prior experience with lymphoma and vulvar cancer suggested a radiation dose prescribed to a depth of 3 cm was appropriate.133,134 A radiation prescription for 50 Gy at 3 cm cannot be expected to control gross disease. Koh et al136 carefully studied a series of

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patients computed tomographic scans and determined that the average depth of the femoral vessels is 6 cm below the skin of the intact groin. However, attempts to increase the dose at depth could result in damage to the femoral neck.137 When carefully prescribing dose, depth, and particles, it may be possible to gain complete control in an undissected groin.138 The Cochrane Database review of the existent data, which includes one randomized trial, one case-control study, and observational studies, provides no evidence for comparable or superior control in the groin with radiation therapy compared with surgery.139 The authors of this review conclude that, at the present time, until the completion of the Gynecologic Oncology Group study of node mapping, operative assessment of the complete inguinal-femoral fat pat should be standard. The most extensive evaluations of radiation therapy in vulvar cancer have been for those patients who have extensive T3 or T4 disease, wherein achievement of negative surgical margins would require an exenteration. Boronow140,141 was one of the first to propose the use of radiation as an alternative to exenteration, but local tissue injury with available techniques inhibited widespread adoption.142 Others used radiation alone or preoperative radiation to shrink the tumor before undertaking a less radical resection.143145 Recognizing the success of concurrent chemoradiation in other sites such as the cervix, a series of small studies of concurrent chemoradiation for patients with advanced vulvar cancer were conducted. Russell et al146 studied 25 patients, 18 of whom had had no prior therapy. Twenty of 25 patients had complete response with radiation and concurrent 5-fluorouracil, with or without cisplatin, and with or without mitomycin-C. Koh and his fellow investigators147 treated 20 poorrisk patients and observed 10 complete responses. Other investigators with small series have found similar encouraging results.148 152 In a prospective phase II cohort trial, the Gynecologic Oncology Group studied patients with T3, T4 cancers that would have required exenteration to achieve negative surgical margins.41 Seventy-three patients with advanced disease received 47.60 Gy of radiation with 5-fluorouracil and cisplatin and splitcourse radiotherapy. There was a 46.5% complete response rate, but 53.5% still had visible cancer at the time of operation. In only 3 patients was it necessary to resort to interruption of gastrointestinal or genitalurinary continuity to clear disease.41 In a companion study to evaluate patients with unresectable lymph nodes,153 52 patients with clinical N2 or N3 nodes had a similar course of radiation with concurrent chemo-

therapy. Forty-two patients completed treatment, and 38 of 40 had resectable lymph nodes. Fifteen of 37 lymph node dissections were negative. Some of these patients had T3/T4 primary lesions as well. Nineteen patients developed recurrent disease, 9 on the vulva, 1 in the groin, 8 with distant disease only, and 1 on the vulva and distant. Thirty-six of 37 patients had local nodal control; 29 of 38 had control of the primary disease with this regimen.153 Chemoradiation appears to be the treatment of choice for these patients with extensive disease at diagnosis. The Gynecologic Oncology Group initiated a phase II study in 2005 of concurrent weekly cisplatin for patients with T3, T4 lesions. This regimen obviates the need for two 4-day infusions of 5-fluorouracil (D. H. Moore, personal communication, January 12, 2006). Some of these patients who require extensive groin dissection after chemoradiotherapy may benefit from groin coverage with procedures such as a tensor fascia lata flap.154

TREATMENT COMPLICATIONS
As treatment has evolved into less extensive procedures, the associated morbidity and complications have become less problematic. Most patients wounds can be closed primarily without tension; urinary and fecal continence and continuity can be maintained. Minor wound breakdowns managed by delayed secondary closure, still occur in approximately one fourth of patients. When resection comes close to or involves the distal urethra, patients can suffer urinary incontinence.155 The most limiting morbidities continue to be associated with the node dissection. Sedlis et al78 noted that, because node positivity is the exception rather than the rule, three fourths of patients experience the morbidity of node dissection without benefit. In the Netherlands, 80% of patients, particularly those over the age of 74, did not have a groin node dissection performed.24 Less radical dissections in the groin have lesser, but still significant morbidity. Lin et al156 noted a 22% groin breakdown for patients with separate incisions and a 15% incidence of postoperative lymphocyst and/or lymphedema. Gould et al157 observed a series of 67 patients with 112 groin dissections and noted a 22.6% incidence of wound breakdown, 29.5% incidence of lymphedema, and 18.1% incidence of lymphocyst. Rouzier et al103 noted that the extended lymph node dissection, sartorius transfer, and radiation therapy all increased the risk of edema and complications. In a large series from Europe using modern techniques, Gaarenstroom et al104 studied 172 patients with 187 groin dissections between 1993 and 2000 in a single hospital using the

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triple incision technique. Both superficial and deep nodes were removed, and a mean of 10 nodes per groin were retrieved. Overall 66% of patients and 52% of groins had some complication of the groin dissection. Wound breakdown occurred in 17%, wound infection in 39%, lymphocyst formation in 40%, and lymphedema in 28%. Patients with positive nodes, patients who had postoperative radiation therapy, patients over the age of 65 years, and patients who had the saphenous vein removed were at greater risk of having complications in the groin.

whether site of recurrence was prognostic. Outcome after local recurrence was 73% survival at 1 year and 50% survival at 5 years. Those patients with nodal status, large tumors, close margins, and depth invasion were at higher risk of death. Those patients who had recurrence on the skin bridge had an increased risk of death due to vulvar cancer, but this was not the case in those patients who had recurrence at a different site on the vulva and away from the skin bridge.61

Groin Recurrence
Six to thirty percent of recurrences will occur in the groins, depending in part on the frequency of groin node involvement at the time of initial diagnosis.36,37,47,50,54,159,164 Recurrence in the groin occurs primarily if the groin is neglected or if the groin nodes are defined to be involved at the outset of therapy. Recurrence in the groin has an ominous prognosis, with the vast majority of patients succumbing to disease. In the Gynecologic Oncology Group series, of 37 recurrences after conservative therapy, the median time to recurrence in the groin was 7.0 months and the median time of survival after groin recurrence was only 9.4 months, with 91% of those with groin recurrences succumbing to disease.57 Others have also noted that groin recurrences tend to happen sooner than local relapses and that survival after a groin recurrence is much less likely than after a local recurrence.50,165 Radical excision of groin recurrence appears to be of some benefit if the femoral vessels are not involved.162 Excision can be followed by chemoradiation.

RECURRENCE
Adequate operation on the vulva results in 8590% local control of disease, even among patients with positive lymph nodes. The predominant site of recurrence is on the vulva, even when radical operations are performed.158 Recurrences at the local site are 3 times as common as recurrences in the groin, pelvis, or distant sites.

Local Recurrence
Of all recurrences, between 43% and 54% will occur on the vulva.37,47,50,54,159 The risk of local recurrence increases as a function of depth of invasion and primary lesion size.36,37 de Hullu et al94 reported a series of 253 patients with T1 or T2 disease treated with either en bloc or radical vulvectomy and groins or wide local excision and triple incisions. The recurrence rate in the triple incision group was 33.3%, compared with 19.9% in the en bloc group (P .03). This higher recurrence rate was not associated with a significant difference in survival (5/79 versus 2/179). With so few deaths, the question of whether their study was underpowered to show a small difference or whether there was an impact of salvage therapy remains unanswered. A margin of 8 mm or less has been associated with local failure.60,61,94,160 In a series of 37 patients with recurrences after conservative therapy, the Gynecologic Oncology Group reported that the median time to recurrence on the vulva was 35.9 months, and the median survival after local recurrence was 52.4 months.57 These data support the hypothesis of Rowley and coworkers161 that recurrences on the vulva, particularly those remote from the initial site, may well represent re-occurrences rather than recurrences in the classic sense. Many recurrences in the vulva are amenable to consideration for re-excision.54,162,163 Rarely, an exenteration may be the appropriate procedure. Two hundred fifteen patients with relapse were followed carefully by Rouzier et al61 to determine

Distant Recurrence
Pelvic recurrences are rare, approximately 5% of all recurrences.50,164 Of all recurrences, 8 23% are distant and are associated with a dismal prognosis.54,164 Chemotherapy for recurrent or metastatic disease has not been extensively studied nor proven to be of great value.166 Patient age, performance status, and toxicity have limited the delivery of therapy. Cisplatin, which is used in many gynecologic malignancies, has been disappointing. Responses have been unacceptably infrequent in phase II trials. The authors prefer to recommend local palliative measures for symptomatic recurrent lesions

QUALITY OF LIFE
There has been little objective quality of life and outcomes research published. Vulvectomy has been shown to contribute to disruption of sexual activity, decline in body image, and significant levels of dis-

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tress and depression compared with healthy patients.167 Recently, a reliable and validated instrument,168 sensitive to vulvar cancerspecific issues, has been published and made available for investigators. This instrument, the Functional Assessment of Cancer TherapyVulvar (FACT-V), correlated lower quality of life scores with lower performance status, higher stage, and recurrence of disease.

FOLLOW UP
Most authors recommend regular follow-up for patients after treatment. Most schedules include visits every 3 4 months for the first 12 years, with less frequent visits through 5 years. These recommended schedules are more empiric than based on the time frame of relapse. Oonk and coworkers159 identified 65 patients with recurrent disease; 42 of these recurrences were found at a routinely scheduled screening examination. Symptoms were present in 21 of these 42 patients, however. At least half of these lesions would have been found in the same time frame with unscheduled appointments. The risk of second primaries other than vulva, such as cervix, is also noted to be a reason for routine follow-up.29,12 Other issues related to the patients treatment, such as urinary incontinence, may also justify close monitoring.155

Over the last several decades progress has been made in the treatment of this uncommon disease. Surgical innovation with the triple incision technique has made it possible to maintain local control rates with less morbidity. Sentinel node sampling is being studied to determine whether complete groin dissection can be foregone in those without positive groin nodes. Adoption of chemoradiation approaches to advanced disease has maintained survival rates and spared many patients exenterative-type surgery. Multidisciplinary collaboration through cooperative trials must continue if further progress is to be achieved. REFERENCES
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SUMMARY
After assessment of the available evidence, the authors make the following recommendations: 1. A radical wide local excision of the vulvar lesion, sufficient to achieve at least a 1-cm gross margin, will address the primary lesion. 2. If invasion depth is greater than 1 mm, the risk of lymph node involvement merits a surgical assessment of the groin. 3. Ipsilateral (or sometimes bilateral) groin node dissection can be performed through a separate incision. All the nodal tissue medial to the vessels and above the fascia should be removed. 4. A substantial body of information suggests that sentinel node evaluation is a step forward, but the false-negative rate is not well defined. 5. Patients with positive inguinal nodes at groin dissection should receive radiation therapy to the ipsilateral groin and hemipelvis. 7. For those patients who have unresectable primary disease, which would require an exenteration or if nodes are palpably suspicious, fixed, and/or ulcerated, chemoradiation is the preferred option. 8. Exenterative procedures may rarely be required, particularly for recurrence. No treatment has been consistently shown to be effective for patients with groin recurrence, 9. Chemotherapy for recurrent or metastatic disease has not been proven to be of value.

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