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Vulvar Cancer: The Evolution of Current Management Strategies
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GYNAECOLOGY
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VULVAR CANCER: THE EVOLUTION OF CURRENT MANAGEMENT STRATEGIES R.]. Osborne, MBA, MD, FRCSC, 1 Gillian M. Thomas, BSc., MD, FRCPC, 2 1
Assistant Professor, Division of Gynaecologic Oncology, Department of Obstetrics and Gynaecology, 2 Associate Professor, Departments of Radiation Oncology and Obstetrics and Gyaecology, Head, Division of Radiation Oncology, 1 .2University of Toronto, Toronto-Sunny brook Regional Cancer Centre, Toronto, Ontario ABSTRACT The treatment of wlvar cancer is evolving [ram the single incision "en bloc" highly marbid resection of the entire wlva, groin, and pelvic nodes for all stages of this disease. Currently, micro-invasive disease is treated conservatively by wide local excision, and stage 1 and 2 disease by wide local excision and superficial groin dissection. Vulvar tumours of all stages which by locatioTt or size preclude both a one em surgical margin and the sparing of critical mklline anatomy; clitoris, urethra or anal sphincter, can now be considered for primary irradiation rather than surgery. This approach may preserve the function and anatomic integrity of these important structures. Surgico-pathologic factors can greatly assist in identifying those post-surgical patients at higher than normal risk of relapse, so that they can receive targeted, adjunctive therapy. The extent of the psychological sequelae of the diagnosis and treatment of wlvar cancer is becoming known. Further information about these non-physical marbidities may help us to choose between the available treatment options, based on additional outcome measures including cost of treatment and patient preference. At this time, our clinical goal is to maintain cure and local control rates and to minimize marbidity in early disease, while we attempt to improve local control and curability for patients with advanced disease. This wiU be achieved by 1) limiting the amount of tissue treateJ/excised for patients with early stage/good prognosis disease and, 2) by minimizing the physical and psychologic marbidity, without sacrificing curability, for patients with advanced disease or with adverse risk factors.
RESUME La resection «en bloc»' amarbidite extremement elevee, de Ia wive, de l'aine et des gang/ions pelviens, qui etait systematique dans taus les cas de cancer de Ia wive, que! qu' en soit I.e stade, n'a plus cours desormais. La maladie micro-invasive est maintenant traitee de maniere conservatrice par une large excision locale, tandis que les stades 1 et 2 font l' objet d' une
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' ' ' large excision locale et d' une dissection superficieUe de !'aine. On preconise mainterulnt l' irradiation primaire pluwt que l' intervention chirurgicale, lorsque Ia tumeur vulvaire, quel que soit san stade, ne perrnet pas de laisser une marge chirurgicale de I em et d' epargner les structures rnedianes critiques, le clitaris, !'uretre ou le sphincter anal, du fait de sa position ou de sa grosseur. Cette rnetlwde perrnet de mieux preserver Ia fonctian et l' integrite anatomique de ces structures importantes. Des facteurs chirurgico-pathologiques peuvent faciliter grandement !'identification des patientes qui' apres chirurgie' presen tent un risque de recidive superieur aIa normale' de maniere apouvoir leur prescrire un traitement d'appoint cible. On commence arecannaitre l' ampleur des sequeUes psychologiques du diagnostic et du traitement du cancer de Ia vulve. Une cannaissance plus approfandie de ces morbidites nan physiques pourraient nous aider achoisir entre differentes options de traitement, en nous basant sur des facteurs supplementaires tels que le cot1t du traitement et les preferences de Ia patiente. A l'heure actueUe, notre objectif clinique est de maintenir les taux de gu&isan et de cantrole local et de minimiser Ia morbidite en debut de ma1adie, tout en tentant d'arneliorer le cantrole local et les possibilites de gu&isan dans les cas de ma1adie avancee. Cet objectif sera atteint I) en limitant Ia quantite de tissus traites ou excises pour les maladies a leur debut/presentant un ban pronostic et 2) en minimisant Ia morbidite physique et psychologique, sans sacrifier cependant les possibilites de guerisan, en cas de ma1adie avancee ou de facteurs de risque defavorables.
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KEY WORDS
Vulva, cancer, treatment.
In addition, we have begun to identify risk or prognostic factors which permit the clinician to estimate the likelihood of loco-regional control with standard management and to plan additional, targeted, adjuvant treatment for women with vulvar cancer at increased risk of recurrence. Better anaesthetic technique, better medical management, and new surgical options have also recently been developed both to limit the resection of early lesions and to provide more aesthetic, more functional tissue coverage for patients with advanced disease who still require large area resection to achieve loco-regional clearance. This disease remains confined to the vulva and the inguinal lymph nodes for a considerable period of time. When the groin nodes are histologically negative, the few cases of recurrent disease are localized to the vulva. 4 Distant disease is an uncommon occJrrence at presentation, is generally not observed until very late in the disease process and usually occurs in association with extensive nodal diseaseY Numerous studies of the regional lymph nodes and the lymphatic drainage of the vulva have suggested a sequential pattern of lymph node involvement in the approximately 30 percent of patients (all stages) who develop lymph node metastasesY Vulvar cancer is relatively curable with average reported five-year survival rates between 46 to 75 percent. 45 ·8 More importantly, disease-specific survival, although not generally reported, is conservatively another 10 percent higher, given the older patient age at the time of diagnosis and the significant, attendant medical co-morbidities often observed in these women.
INTRODUCTION
Carcinoma of the vulva is a lesion not often seen by the practising gynaecologist. Vulvar cancer constitutes approximately four percent of genital neoplasia and is a rare cause of death in women. There is evidence that many vulvar cancers, particularly those found in younger women, are the result of sexually transmitted infection of the lower genital tract by the Human Papillomavirus (HPV), specifically its oncogenic sub-types, the so-called "16-18 group." 1•2 We might reasonably expect to see the incidence of (pre)invasive vulvar cancer rise in the next decade as a delayed consequence of the changes in sexual mores which followed the introduction of oral contraception in the 1960s. The attempts to cure vulvar cancer in the 1940s were characterized by very wide or radical vulvar surgery which often included resection of the rectum, urethra, and pubis. Within the last 10 years, the management of this cancer has begun to evolve for several reasons. Vulvar cancer is now being observed in younger women, probably due to the putative association of this disease with HPV, a sexually transmitted virus. It has been reported that 15 percent of women with vulvar cancer will have a concomitant (pre)invasive lesion on the cervix which is also likely related to the HPV virus. 3 Vulvar cancer is also being identified at an earlier stage than was the case several decades ago, as older women in particular become more aware of themselves and much less likely to neglect an ulcer or sore on the external genitalia.
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' ' ' The clinical management of vulvar cancer has changed considerably over the last 10 years. Operability rates have risen substantially,9 and better technical and radiobiological knowledge have decreased the likelihood of longterm morbidity from radiation therapy. Treatment is directed nowadays towards minimizing morbidity for all patients, particularly those with socalled low risk disease who are unlikely to fail primary treatment, and to the exploration of new treatment options and combinations of therapies for patients at high risk of loco-regional relapse.
For patients who have invasive vulvar cancer ( > 1 mm invasion), historical practice has been a so-called radical vulvectomy and bilateral en bloc inguinofemoral node dissection as described by Way, Taussig and others.17·18 This operation variously removed the entire vulva including one or more critical anterior midline structures; clitoris or lower third of urethra. For locally advanced lesions and some early tumours located close to the anus, posterior exenteration and colostomy had been used to clear the cancer, but this was invariably associated with significant short and longterm morbidity. 19 Typically, all of the groin nodes, both the superficial and deep inguinal and the superficial and deep femoral nodes, were removed with the vulva en bloc through a single "butterfly" shaped or "Texas longhorn" vulva-inguinal incision. Historically, if the groin nodes were clinically involved or if the vulvar lesion was large, the external iliac lymph chain was also excised by transecting the inguinal ligament its midpoint and continuing the dissection retroperitoneally along each pelvic sidewall to the bifurcation of the common iliac vessels. 17 More recently, the groin node dissections have been performed through separate infra-oblique groin incisions, the so-called "three incision" technique, with no loss of loco-regional control and no higher incidence of recurrence in the groin or in the skin "bridge" between the vulva and groin. 4·20 In 1979, in one of the first attempts to limit the extent (and morbidity) of invasive vulvar surgery, DiSaia suggested that, when the vulvar tumour was < 1 em in size, a "superficial" dissection of the groin node tissue above the cribriform fascia be performed first. If, when frozen sections were examined, these nodes were negative, the vulvar lesion could be treated by wide local excision. 21 DiSaia realized the critical importance of determining the status of the groin nodes before completing treatment to the vulva, as the metachronous development of positive groin nodes after primary treatment has been shown, in one review of the literature, to result in the death of 89 percent of such patients. 16 A corroborative study of DiSaia's hypothesis for patients with tumours characterized by < 5 mm invasion, no lymphovascular space involvement, and negative groin nodes, suggested a significantly higher incidence of treatable vulvar recurrences but not death when these patients were treated by wide local excision and ipsilateral groin dissection. 21 There are now several reported series which
THE VULVA SURGERY
In the early 1970s, Wharton among others defined the entity of micro-invasive vulvar cancer which, it was surmised, was very unlikely to have metastasized to the regional nodes at the time of presentation. This lesion could, therefore, be treated by a surgical intervention which was confined to the vulva and tailored to the dimensions of the lesion, leaving most of the "normal" vulva intact. 10 Micro-invasion was originally described in a manner analogous to micro-invasive carcinoma of the cervix ( <5 mm invasion) and was limited to visible lesions of< 2 em in greatest dimension.U It was soon realized that a more rigorous definition of micro-invasion was required when subsequent studies documented a small but consistent proportion of patients who met the existing criteria for micro-invasion but who had inguinal lymph node metastases. 12 ·13 The definition was subsequently revised to include only unifocallesions of <2 em size without capillary space involvement and with <1 mm invasion. 14 For such patients, (radical) wide local excision of the vulvar lesion, including at least a 1 em surgical margin without groin node dissection, has become standard practice. The risk of vulvar recurrence in the first two years following treatment for micro-invasion is about seven percent. 15 Often, these patients will also have extensive vulvar intra-epithelial neoplasia (YIN) which also must be encompassed in the treatment field. Such patients require meticulous colposcopic follow-up, particularly if they continue to smoke, a known cofactor in the evolution of this disease which can substantially diminish longterm control ofHPV and VINY
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' ' ' several recent reports demonstrated that, even in patients with advanced disease, it was possible to cure vulvar cancer. 30 ·31 •32 In 1982, Boronow reported 3 7 patients with locally advanced (stage 3/4) disease and achieved 86 percent surgically confirmed local control, effectively reopening the question of the use of radiation in the primary management of this disease. 31 There is good evidence that radiation can control and cure local vulvar disease if a dose is given that is appropriate for the particular tumour volume. Although there are no specific detailed or case controlled data about vulvar cancer, there are excellent data on the radiation control of squamous cell cancers from the head and neck literature to show that 45 Gy in five weeks will sterilize in excess of 90 percent of subclinical nodal disease and that 65 Gy can effectively sterilize a tumour volume of 3 em. 15 A report by Backstrom has also suggested a radiation dose/response effect in vulvar cancer. 36 Frequently, for the vulvar primary, a small perineal port using electrons whose energy is tailored to the size and depth of the lesion may be used in preference to anterior and posterior pelvic portals, in order to limit the depth of penetration and to minimize damage to surrounding tissues. The groins and pelvic nodes are treated using parallel opposed pelvic fields, usually with a central block to exclude the vulva if vulvar irradiation is not indicated. The pelvic nodes are treated up to the level of the mid-sacroiliac joint. 37 The concurrent use of a radiation sensitizing drug such as 5-Auorouracil (5FU) may enhance tumour regression in vulvar cancer38 •39·40 as has been observed with several other epidermoid carcinomas, specifically those of the, cervix, oesophagus, and anal canal. 41 .42 Platinum and its analogues may also be effective radio-sensitizers. Although they have been successfully tested in vitro using the new 96 well-plate clonogenic assay, 43 there are as yet no clinical trials of the utility of Platinum compounds in vulvar cancer. Several phase two trials have looked at the value of pre-operative vulvar irradiation for advanced vulvar cancer to limit the extent of primary surgery. 30•31 •12 Radiation has also been advocated as primary treatment when the cancer involves one or more critical midline structures including clitoris, urethra, anal sphincter or anal margin. 28 •40 .44 Specifically, if a 1 em surgical margin cannot be obtained around any one of these structures, primary radiation may be used in preference to surgery, in order to preserve anatomic integrity.
confirm that, in the absence of a multi-focal cancer, (radical) wide local excision does not compromise ultimate local control of the vulva for stage 1 and 2 disease. 22- 26 A report from Italy also suggests that this is a safe approach for more locally advanced vulvar tumours (stage 3 ). 27 A recent report has emphasized the need to obtain at least a 10 mm surgical margin (8 mm pathologic margin given the average 20% shrinkage artifact with standard histologic fixation). 26 RADIATION
Generally, an inguinal groin node dissection should be performed in all patients before the vulva is treated so that 1) the status of the nodes can be clarified at the outset of treatment and 2) as definitive therapy for most. An ipsilateral node dissection and a wide local excision of the vulvar cancer will suffice for most patients. Lesions which cross or come within 1 em of the anatomic midline should have a bilateral groin node dissection. For lesions which cannot be cleared from the critical midline structures by at least 1 em, as good a therapeutic result and a substantially better cosmetic and possibly functional result may be achieved with primary vulvar irradiation following the groin dissection. In addition, for patients treated with primary surgery, the identification of surgicopathologic factors in the vulvar specimen may suggest that some individuals are at higher than normal risk of vulvar recurrence. For such patients, a course of postoperative, adjuvant irradiation may decrease their risk of vulvar relapse. 28 There is evidence from the psychosocial literature that the extent of surgical resection correlates positively with patient anxiety, depression, and changes in postoperative sexual function. 29 Primary radiation may permit a less extensive resection and/or may obviate the need for any surgical intervention in some patients.30•31 •32 Until recently, radiation was used to treat those vulvar cancers considered inoperable either on medical grounds or which involved bladder, proximal urethra, anus or pubis; lesions which would otherwise have required an exenterative procedure and/or resection of the pubis for surgical clearance. The first attempts at vulvar irradiation were characterized by low survival and excess morbidity, in large part the result of patient selection, inadequate dosing, and severe acute radiation complications which precluded completion of treatment. As a result, primary radiation fell into disrepute, 33 •34 until
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' ' ' There is evidence that the risk of groin failure and pelvic node involvement after surgery increases with the nodal burden of disease. 7•52 •53 There is not yet, however, agreement as to where the best discrimination point lies with respect to the number of involved nodes. Studies have shown variously that two or more, or three or more involved lymph nodes each are predictive of deep pelvic node involvement. 6•16•52 •54 There is additional information that capsular penetration and complete replacement of a single node are both independently predictive of groin failure. 55 The groin nodes are good predictors of pelvic node involvement. The pelvic nodes are found to contain tumours in 20 percent of patients with positive groin nodes or six percent overall. If the groins are histologically considered to be "high risk" following surgery (which variously may include one or more of the following factors; > 1 microscopically positive nodes, capsular penetration or complete replacement of a single node,) then adjuvant, postoperative groin irradiation which also encompasses the next higher lymph node group will control disease more effectively than a pelvic node dissection. 54
The dose prescriptions suggested by Thomas for the management of vulvar cancer are; 45 to 50 Gy to the vulva as postoperative, adjuvant (consolidation) therapy for microscopic residuum or in patients with high risk surgicopathologic factors, 55 Gy plus concurrent 5FU as pre-operative treatment for macroscopic disease when the intent is curative and minimal tissue resection is contemplated, and up to 65 Gy for tyrimary, curative treatment when no therapeutic surgical intervention is planned. 28•40 The morbidity observed with these treatment strategies is minimized if the fraction size is kept below 160 to 170 cGy. 28 FACTORS PREDICTIVE OF VULVAR FAILURE
We are now aware of several surgico-pathologic predictors of vulvar failure following conventional surgery. Although the reports are not entirely consistent, it appears that depth, tumour size, and possibly grade and lymphovascular space involvement may each be independently predictive oflocal (vulvar) failure. 7•8•10.4HB A report by Heaps has suggested that the adequacy of the surgical margin may also be an excellent predictor of vulvar recurrence. 46 In a large longitudinal review of vulvar cancer from the Norwegian Radium Hospital, Kaern reported that node involvement (p<0.0001) and aneuploidy (p
SURGERY
In general terms, patients whose inguinal nodes are surgically negative have a 90 percent chance of longterm cure, groin node positive patients have a substantially reduced five-year survival rate (25 to 40%), and patients who develop metachronous groin nodes die of their disease. Surgery remains the mainstay of treatment for groin nodes, as it is both diagnostic and therapeutic in the majority of patients. With lateralized lesions, the recent trend has been towards a more limited ipsilateral groin dissection with conservation of the intervening "bridge" of skin. Pelvic node dissection has largely been discarded as atherapeutic intervention following a Gynecologic Oncology Group (GOG) study which clearly demonstrated the therapeutic superiority of pelvic nodal irradiation.54 These variations of the classical surgical treatment of the lymph nodes for vulvar carcinoma have substantially reduced groin morbidity without a demonstrable decrease in survival or any increase in loco-regional recurrence.49•50 There is compelling evidence that the inguinal nodes do not need to be removed en bloc with the vulvar specimen. Resection of these node groups through separate infra-inguinal incisions, the "three incision" technique which leaves a skin bridge intact between the
REGIONAL LYMPH NODES FACTORS PREDICTIVE OF NODAL INVOLVEMENT
Ten percent of patients with stage 1 disease and 30 percent of all patients irrespective of stage can be expected to have positive groin nodes. 14•23 We have information on surgicopathologic factors from the vulvar specimen which predict for groin node metastases. 5•50 •51 In one study, the combination of lymphovascular invasion, tumour thickness >2 mm, and the amount of keratin correctly classified 97 percent of the lymph node negative group and 63 percent of the lymph node positive group (overall accuracy of 87%). 50 In a report by Shimm, groin node involvement was significantly correlated with tumour size and gradeY A Norwegian study failed to find that the ploidy status of metastatically involved inguinal lymph nodes was of prognostic value.49
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' ' ' vulva and groin dissection, does not appear to alter survival or loco-regional control, but does substantially reduce postoperative morbidity. 53·55·56 DiSaia first advocated a superficial inguinal node dissection in the primary management of some patients FIGO stage 1 disease (lesion< 1 cm).Zl The deep femoral nodes which lie medial to the femoral vein in the femoral canal are not removed, but the accessory saphenous, external pudendal, superficial epigastric, and superficial lateral circumflex veins are ligated. The operation leaves intact the saphenous vein, cribriform fascia, and the femoral canal. The rationale for this procedure is that the lymphatic drainage from the leg is less likely to be disrupted if the femoral canal is not dissected and the long saphenous vein is not ligated. Therefore, chronic lymphoedema, lymphocyst formation, and wound breakdown should be reduced. Despite these theoretical considerations, there is evidence that conservation of the long saphenous vein does not alter morbidity. Of note, however, is the concern expressed by some that superficial groin dissection may lead to a five percent incidence of failure in the groin, probably the result of aberrant lymph drainage. 16·24 If a vulvar cancer is "lateralized," suggesting that the lesion does not extend to within one em of the midline, 28 then an ipsilateral groin node dissection may be performed safely. With a lateralized stage 1lesion, the likelihood of contralateral groin involvement, if the ipsilateral groin is positive, is 10 percent of the 10 percent risk to the ipsilateral groin. This would translate into a one percent risk of nodal disease in the contralateral groin. There is a negligible risk to the contralateral groin if the ipsilateral groin is surgically negative. 57 The pelvic nodes are positive in about six percent of all patients with vulvar cancer. Direct involvement of the pelvic nodes without spread to the groin nodes, even with midline or mucosal lesions, is thought to be extremely rare. 8 If the groin dissection is negative, the chance of positive iliac/pelvic nodes is negligible, but if the groin nodes are positive, the iliacs contain metastatic disease in about 20 percent of patients.8'19 A Gynecologic Oncology Group study demonstrated that the addition of pelvic node dissection may be curative in 20 percent of patients with positive pelvic nodes. The study also demonstrated that postoperative radiation to the pelvic nodes, when more than one groin node was involved, resulted in significantly higher survival rates
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than surgical resection alone, due to better inguinal node control. The addition of radiation to the node dissection resulted in no additional morbidity. 54 RADIATION
There is evidence to suggest that the groin nodes are as sensitive to radiation as the vulva. 5859 However, the conclusions from a randomized study of groin dissection versus primary groin irradiation suggest that the methodology of groin irradiation may need to be revisited. In this study, which was closed prematurely, an excess of groin failures was found in patients treated with standard groin radiation.55·60 A subsequent study by Koh suggested that the radiation prescription in the earlier study (45 Gy at 3 em from the skin surface) was likely inadequate for many of the patients treated. 61 In the Koh study, the average depth of the femoral vessels from the skin surface, based on scanning, ranged from two to 18.5 em (mean 6.1 em). As usual practice has been to assume that the nodes are three to four em deep to the skin, this recent finding suggests that both the depth prescription and the dose for primary groin radiation need to be individualized. 61 Currently, the indications for postoperative, adjuvant radiation to the groins, pelvic and/or para-aortic lymph nodes are based on surgico-pathologic factors from the groin node dissection. Fixed or ulcerated groin nodes (U .I.C.C. N3) are usually treated by primary groin irradiation without resection.
cr
MORBIDITY SURGERY
The incidence of morbidity following vulvar or groin resection is related to the amount of tissue excised. The most frequently observed postoperative physical morbidities are wound breakdown, cellulitis, venous thrombosis, genital prolapse, lymphocoele formation, and chronic lymphoedema. It is very difficult to define with accuracy the incidence of these surgical complications given the lack of uniform reporting definitions. 22 •24·26 Hacker et al. reported a 15 percent reoperation rate for complications related to surgery4 but that was not supported by other series where re-operation was unusual. The recent trend to wide local excision of the vulva and more limited groin dissection using separate incisions for stage 1 and 2 lesions has resulted in substantially fewer major complications and markedly shorter hospital stays. 62·61
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' ' ' Several surgical manoeuvres have been proposed to limit postoperative groin morbidity. These include removal of an ellipse of skin over the infra-inguinal incision to improve the vascularity of the skin edges, aggressive groin drainage using a variety of drains and continuous or intermittent suction. Transposition of the sartorius muscle over the femoral vessels has long been used to minimize the risk of rupture of the femoral vessels in the event of wound breakdown. Honey dressings have been used to reduce groin breakdown and cellulitis to a minimum because of its properties as an (occlusive) bacteriostatic dressing. Hyperbaric oxygen has also been used postoperatively to decrease wound breakdown.64 Prophylactic antibiotics can diminish major postoperative infection in other gynaecologic procedures, but their value in major vulvar surgery has not been independently verified. A recent autopsy series from Borgno et al. suggests that all of the deep femoral lymph nodes lie beneath the cribriform fascia but within the fossa ovalis, and that there are no nodes lateral to the medial border of the femoral vein. 65 This strongly argues that the femoral canal and cribriform fascia do not need to be excised in order to remove all of the femoral nodes. In addition, a recent review of lymphangiography of the groin argues that there are no inguinal nodes over the lateral 20 percent of the inguinal ligament and, therefore, this tissue also does not need to be excised. Based on this study, there appear to be lymph channels in this same region which flow directly from the leg to the axilla. 66 If these were left intact, the surgeon might reasonably expect that lymph drainage from the leg would improve and that the likelihood of chronic lymphoedema would diminish. In the last few years, a great deal of innovation has occurred in the management of large operative perineal or vaginal defects. A remote myocutaneous flap using rectus abdominus muscle, gracilis, the epigastric portion of internal oblique plus transversalis and the underlying parietal peritoneum or one of several other regional muscles, can be safely and reliably mobilized to fill and cover these defects. Local fasciocutaneous flaps or rhomboid skin flaps can also be used to repair smaller defects. 67 •68 ·69 The psychological morbidity following major vulvar excision may be profound. In one paper, patients who had undergone radical vulvectomy were compared to a control group who had not undergone surgery. 29
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The surgical group were found to be in the eighth percentile in terms of sexual arousal and in the fourth percentile for perceived body image, a truly significant and potentially far reaching observation. In a paper by Corney et al., the prevalence of psychosexual dysfunction after radical vulvar surgery was found to be common and to remain chronic. 70 The loss of fertility, anatomical disfigurement, and the depression and anxiety about desirability as a sexual partner were strongly felt. Fifteen percent never resumed sexual intercourse after surgery and two-thirds of the women who were sexually active prior to surgery indicated ongoing sexual problems. 70 However, Weijmar Schultz et al. argue that postoperative sexual satisfaction is more dependent on the patient's pre-existing psychological and social characteristics than on any change in the patient's physical variables related to the operation. 71 Virtually all patients treated for cure with primary vulvar radiation will experience moist desquamation.29,7 2 The most commonly observed chronic/late complications of vulvar radiation are vulvar fibrosis, telangiectasia, and tissue necrosis which may be decreased if the daily fraction size is kept below 160 to 170 cGy per day. 40 These problems may be more pronounced for patients with diseases such as diabetes which alter the microvascular circulation. It is not known how functional the clitoris is following curative vulvar radiation but it is probably related to the amount of radiation fibrosis produced by the treatment, which can in turn be correlated to the radiation dosage and fractionation schedule. With respect to chronic leg oedema, Holmsley et al. reported that there was no additional morbidity when groin radiation followed groin node dissection. 54 Psychosexual problems following treatment for vulvar cancer were not confined to surgical patients. Corney et al. reported that eighty-two percent of a cohort of women < 50 years old who had had primary radiotherapy for vulvar cancer suffered from sexual dysfunction, usually due to lack of desire rather than pain. This effect was more likely related to clitoral dysfunction after radiation. The presence of a stable pre-existing relationship before the diagnosis aided in coping. Single, young women were found to be a particularly vulnerable group. In general, patients wanted more information than they were given about both treatment and prognosis, and the provision of sexual counselling appeared to improve their psychosexual outcomes. 73
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' ' ' SUMMARY
many of these issues, including the role of adjuvant radiation for "high risk" patients following wide local excision, and the possible additive benefit of sensitizing chemotherapy and radiation in node-positive patients. This trial will also address the issues of anatomical integrity and body image and will include measurement of patient quality of life.
Micro-invasive vulvar cancer ( < 1 mm invasion without capillary space involvement) can be treated with wide local excision of the lesion without node groin dissection. Stage 1 and 2 (and possibly stage 3) diseases may be treated by (radical) wide local excision (to include at least a 1 em surgical margin both laterally and deeply). No "head to head" comparison of this approach versus radical vulvectomy has been reported. Vulvar tumours involving critical midline structures (clitoris, urethra, anal sphincter, or anal mucosa) may be treated with primary radiation in order to preserve anatomic integrity. Persistent vulvar disease after primary radiation or localized vulvar recurrence can usually be controlled with a "tailored" excision of the lesion. The groin(s) is treated best by superficial groin node dissection which spares the femoral canal and long saphenous vein. If the lesion is > 1 em from the anatomic midline (lateralized), only the ipsilateral groin needs to be resected. If the groin nodes are clinically positive, the deep femoral nodes are dissected but a pelvic node dissection is not performed. Adjuvant, postoperative irradiation to the groin is recommended if there is replacement of, or capsular penetration in one node, or if more than one node is microscopically involved. Radiation to the contralateral groin and the pelvic nodes is individualized and based on surgico-pathologic factors from the vulvar and groin dissections. Today, exenteration has little place in the primary management of vulvar cancer, but may occasionally be required for vulvar recurrence following radiation. Patients treated with less than a radical vulvectomy have residual "normal" vulvar epithelium remaining which should be considered to be at increased risk for a second primary and/or recurrence of the initial lesion. Women treated for carcinoma of the vulva should have longterm colposcopic followup. Many of the present treatment innovations for this disease are based on assumptions from non-randomized case series, and remain untested. As vulvar cancer is such an uncommon lesion, it is important that questions regarding treatment be asked within the setting of a prospective and randomized clinical trial, and that quality oflife issues and patient preference for the various treatment interventions be quantified. In the near future, the GOG will begin a clinical trial (#145) to examine
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Kiviat N, Koutsky L. Specific Human Papillomavirus types as the causal agents of cervical intraepithelial neoplasia: implications for current views and treatment. J Nat Cane lnst 1993;85:934-5. Trimble C, Shah K, Kurman R. Squamous carcinoma of the vulva: two distinct entities with corresponding histologies. Gynecol Oncol1993;49:126. Shiffman M, Bauer H, Hoover R, Glass A et al. Epidemiologic evidence showing that Human Papillomavirus infection causes most cervical intraepithelial neoplasia. J Nat Cane lnst 1993;85:958-64. Hacker N, Leuchter R, Berek J, Castaldo T, Lagasse L. Radical vulvectomy and bilateral inguinal lymphadenectomy through separate groin incisions. Obstet Gynecol 1981;58:574-9. Podratz K, Symmonds R, Taylor W. Carcinoma of the vulva: analysis of treatment failures. Amer J Obstet Gynecol 1982;143:340-2. Hacker N, Berek J, Lagasse L, Leuchter R, Moore J. Management of regional lymph nodes and their prognostic influence on vulvar cancer. Obstet Gynecol1983;61: 408-12. Holmesley H, Bundy B, Sedlis A et al. Assessment of current International Federation of Gynecology and Obstetrics staging of vulvar carcinoma relative to prognostic factors for survival (A GOG study). Amer J Obstet Gynecol 1991; 164:997-1004. Franklin E, Routledge F. Prognostic factors in epidermoid cancer of the vulva. Obstet Gynecol 1971 ;37:892-901. Kirschner C, DeSerto T, Isaacs J. Surgical treatment of the elderly patient with gynecologic cancer. Surg Gynecol Obstet 1990; 170:379-84. Wharton T, Gallager S, Rutledge F. Micro-invasive carcinoma of the vulva. Amer J Obstet Gynecol 197 4; 118:159-62. Parker R, Duncan I, Rampone J, Creasman W. Operative management of early invasive epidermoid cancer of the vulva. Amer J Obstet Gynecol1975;123:349-54. Iverson T, Abeler V, Aalders J. Individualized treatment of stage 1 carcinoma of the vulva. Obstet Gynecol 1981 ;57:85-9. Hacker N, Nieberg R, Berek J, Leuchter Ret al. Superficially invasive vulvar cancer with nodal metastases. Gynecol Oncol1983;15:65-77.
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' ' ' 14. Wilkinson E, Kreate B, Lynch P. Report of the I.S.S.V.D. Tumorology Committee. J Reprod Med 1986;31:973-4. 15. Kelly J, BurkeT, Tornes C et al. Minimally invasive vulvar cancer: an indication for conservative surgical therapy. Gynecol Oncol1992;44:240-4. 16. Hacker N, van der Velden J. Conservative management of early vulvar cancer. Cancer 1993;71 :1673-7. 17. Taussig F. Cancer of the vulva: an analysis of 155 cases. Amer J Obstet Gynecol 1940;40: 764-79. 18. WayS, Henninger M. The late results of extended radical vulvectomy for carcinoma of the vulva. J Obstet Gynaecol Brit Commonw 1966;73:594-8. 19. Hopkins M, Morley G. Pelvic exenteration for the treatment of vulvar cancer. Cancer 1992;70:2835-8. 20. Christopherson W, Buchsbaum H, Voet R, Lifschitz S. Radical vulvectomy and bilateral groin lymphadenectomy utilizing separate groin incisions: report of a case with recurrence in the intervening skin bridge. Gynecol Oncol 1985;21 :247-51. 21. DiSaia P, Creasman W, Rich W. An alternate approach to early cancer of the vulva. Amer J Obstet Gynecol 1979; 133:825-32. 22. Stehman F, Bundy B, Dvoretsky P, Creasman W. Early stage 1 carcinoma of the vulva treated with ipsilateral superficial inguinal lymphadenectomy and modified radical hemivulvectomy: a prospective study of the Gynecologic Oncology Group. Obstet Gynecol1992;79:490-7. 23. van der Velden J, Hacker N. Update on vulvar carcinoma. Cane Treat Res 1994;70:101-19. 24. BurkeT, Stringer C, Gershenson D et al. Radical wide local excision and selective inguinal node dissection for squamous cell carcinoma of the vulva. Gynecol Oncol 1990;38:328-32. 25. BurkeT. Changing surgical approaches to vulvar cancer. Curr Opinion Obstet Gynecol 1992;4:86-90. 26. Farias-Eisner R, Cirisano F, Grouse D, Leuchter Ret al. Conservative and individualized surgery for early squamous carcinoma of the vulva: the treatment of choice for stage 1 and 2 (T1-2 N0-1 MO) disease. Gynecol Oncol1994;53:55-8. 27. Micheletti L, Borgno G, Barbero M et al. Deep femoral lymphadenectomy with preservation of the fascia lata: preliminary report on 42 invasive vulvar carcinomas. J Reprod Med 1990;35:1130-3. 28. Thomas GM, Dembo AJ, Bryson SC, Osborne RJ, DePetrillo AD. Changing concepts in the management of vulvar cancer. Gynecol Oncol 1991 ;42:9-21. 29. Anderson B, Hacker N. Psychosexual adjustment after vulvar surgery. Obstet Gynecol 1983;62:457 -62. 30. Hacker N, Berek J, Juillard G, Lagasse L. Preoperative radiation therapy for locally advanced vulvar cancer. Cancer 1984;54:2056-61. 31. Boronow R. Combined therapy as an alternative to exenteration for locally advanced vulvovaginal cancer. Cancer 1982;49: 1085-91.
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32. Rotmensch J, Rubin S, Sutton H et al. Preoperative radiotherapy followed by radical vulvectomy with inguinal lymphadenectomy for advanced vulvar carcinomas. Gynecol On col 1990;36: 181-4. 33. Tod M. Radium implantation in treatment of carcinoma of the vulva. Brit J Radio 1949;22:508-12. 34. Fischbier H, Thomsen K. Treatment of carcinoma of the vulva with high energy electrons. Amer J Obstet Gynecol 1971 ;111 :431-5. 35 Cummings C, Fredrickson J, Harker Let al. Radiation therapy and treatment of cervical lymph nodes. In: Otolaryngology - head and neck surgery, Mosby, St. Louis, 1986;2:1671-91. 36. Backstrom A, Edsmyr F, Wicklland A. Radiotherapeutic treatment of cancer of the vulva. Acta Obstet Gynaecol Scand 1972;51:109-15. 37. Snijders-Keilholz T, Trimbos J, Hermans J, Leer J. Management of vulvar carcinoma radiation toxicity, results and failure analysis in 44 patients (1980-1989). Acta Obstet Gynaecol Scand 1993;72:668-73. 38. Russell A, Mesic J, Scudder Setal. Synchronous radiation and cytotoxic chemotherapy for locally advanced or recurrent squamous cancer of the vulva. Gynecol Oncol 1992;47:14-20. 39. Koh W, Wallace H, Greer B, Cain Jet al. Combined radiotherapy and chemotherapy in the management of localregionally advanced vulvar cancer. lnt J Rad Oncol Bio Phys 1993;26:809-16. 40. Thomas G, Dembo A, DePetrillo A, Pringle J, Ackerman I, Bryson S, Balogh J, Osborne R. Concurrent radiation and chemotherapy in vulvar cancer. Gynecol Oncol 1989; 34:263-7. 41. Cummings B, Keane T, Thomas G, Harwood A, Ryder W. Results and toxicity of the treatment of anal canal carcinoma by radiation therapy or radiation and chemotherapy. Cancer 1984;54:2062-8. 42. Pekkola-Heino K. Radiation response of squamous carcinoma: in vitro studies with cell lines in a 96well plate clonogenic assay. Diss Abstr lnt 1993; 54:488. 43. Pekkloa-Heino K, Kulmala J, Grenman R. Carboplatinradiation interaction in squamous cell carcinoma lines. Arch Oto 1992;118:1312-5. 44. Perez C, Grigsby P, Galakatos A et al. Radiation therapy in the management of carcinoma of the vulva with emphasis on conservation therapy. Cancer 1993; 71:3707-16. 45. Malmstrom H, Janson H, Simonsen E et al. Prognostic factors in invasive squamous cell carcinoma of the vulva treated with surgery and irradiation. Acta Oncol 1990; 29:915-9. 46. Heaps J, Fu Y, Montz F, Hacker N, Berek J. Surgicalpathologic variables predictive of local recurrence in squamous carcinoma of the vulva. Gynecol Oncol 1990; 38:309-14.
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' ' ' 47. Shimm D, Fuller A, Orlow E, Dosoretz D, Aristizabal S. Prognostic variables in the treatment of squamous cell carcinoma of the vulva. Gynecol Oneal 1986;24:343-58. 48. Preto M, Micheletti L, Barbero M et al. Histologic parameters of vulvar invasive carcinoma and lymph node metastases. J Reprod Med 1993;38:28-32. 49. Kaern J, Iverson T, Trope C et al. Flow cytometric DNA measurements in squamous cell carcinoma of the vulva: an important prognostic method. lnt J Gynecol Cancer 1992;2:169-74. 50. Binder SW, Huang I, Fu YS, Hacker NF, Berek JS. Risk factors for the development of lymph node metastasis in vulvar squamous cell carcinoma. Gynecol Oncol1990; 37:9-16. 51. Malfetano J. Current management and treatment of squamous cell carcinoma of the vulva. Sem Surg Oneal 1990;6:354-8. 52. Curry S, Wharton J, Ruddy F. Positive lymph nodes in vulvar squamous carcinoma. Gynecol Oncol1980;9:63-7. 53. Sutton G, Miser M, Stehman F, Look K, Ehrlich C. Trends in the operative management of invasive squamous carcinoma of the vulva at Indiana University, 197 4 to 1988. Amer J Obstet Gynecol1991 ;164:1472-8. 54. Holmesley H, Bundy B, Sedis A, Adcock L. Radiation therapy versus pelvic node resection for carcinoma of the vulva with positive groin nodes. Obstet Gynecol 1986; 68:733-40. 55. Keys H. Gynecologic Oncology Group randomized trials of combined technique therapy for vulvar cancer. Cancer 1993;71:1691-6. 56. Helm C, Hatch K, Austin J et al. A matched comparison of single and triple incision techniques for the surgical treatment of carcinoma of the vulva. Gynecol Oneal 1992;46: 150-6. 57. Berek J, Hacker N. In: Practical Gynecologic Oncology. Williams and Wilkins 1989;1 :391-423. 58. Petereit D, Mehta M, Buchler D, Kinsella T. lnguinofemoral radiation of NO, N1 vulvar cancer may be equivilent to lymphadenectomy if proper radiation technique is used. lnt J Rad Oneal Bio Phys 1993;27:963-7. 59. Petereit D, Mehta M, Buchler D, Kinsella T. A retrospective review of nodal treatment for vulvar cancer. Amer J Clin Oncol1993;16:38-42. 60. Stehman F, Bundy B, Thomas G, Varia M et al. Groin dissection versus groin radiation in carcinoma of the vulva: a Gynecologic Oncology Group study. lnt J Oneal Bioi Phys 1992;24:389-96. 61. Koh W, Chiu M, Stelzer K, Greer B et al. Femoral vessel depth and the implications for groin node radiation. lnt J Rad Oneal Bioi Phys 1993;27:969-74. 62. Hoffman M, Roberts W, Finan M et al. A comparative study of radical vulvectomy and modified radical vulvectomy for the treatment of invasive squamou.; cell carcinoma of the vulva. Abstract 23; Eur Soc Gynecol Oneal, 1993. Barcelona, Spain.
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63. Lin J, DuBeshter B, Angel C, Dvoretsky P. Morbidity and recurrence with modifications of radical vulvectomy and groin dissection. Gynecol Oncol1992;47:80-6. 64. Reedy M, Capen C, Baker D, Peterson W, Kuehl T. Hyperbaric oxygen therapy following radical vulvectomy: an adjunctive therapy to improve wound healing. Gynecol Oncol1994;53:13-6. 65. Borgno G, Micheletti L, Barbero Metal. Topographic distribution of groin nodes. A study of 50 female cadavers. J Reprod Med 1990;35:1127-9. 66. Nicklin JL, Hacker N. Personal communication. 67. Shepard J, Van DamP, Jobling T, Breach N. The use of myocutaneous flaps following excision of vulvar cancer. Brit J Obstet Gynaecol1990;97:1020-5. 68. Mayer A, Rodriguez R. Vulvar reconstruction using a pedicle flap based on the superficial external pudendal artery. Obstet Gynecol1991;78:964-8. 69. Helm C, Hatch K, Partridge E, Shingleton H. The rhomboid transposition flap for repair of the perineal defect after radical vulvar surgery. Gynecol Oncol1993; 50:164-7. 70. Corney R, Everett H, Howells A, Crowther M. Psychosocial adjustment following major gynaecological surgery for carcinoma of the cervix and vulva. J Psych Res 1992; 36:561-8. 71. Weijmar Schultz W, van der Wiel H, Bouma J et al. Psychosexual functioning after the treatment of cancer of the vulva: a longitudinal study. Cancer 1990;66:402-7. 72. Roberts W, LaPolla J, Greenberg H et al. Management of radionecrosis of the vulva and distal vagina. Abstract 46; Proc Amer Rad Soc 1990 San Francisco. 73. Corney R, Crowther M, Everett H, Howells A, Shepherd J. Psychosexual dysfunction in women with gynaecological cancer following radical pelvic surgery. Br J Obstet Gynaecol1993;1 00:73-8.
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GYNAECOLOGY
' ' ' ' ' '
VULVAR CANCER: THE EVOLUTION OF CURRENT MANAGEMENT STRATEGIES R.]. Osborne, MBA, MD, FRCSC, 1 Gillian M. Thomas, BSc., MD, FRCPC, 2 1
Assistant Professor, Division of Gynaecologic Oncology, Department of Obstetrics and Gynaecology, 2 Associate Professor, Departments of Radiation Oncology and Obstetrics and Gyaecology, Head, Division of Radiation Oncology, 1 .2University of Toronto, Toronto-Sunny brook Regional Cancer Centre, Toronto, Ontario ABSTRACT The treatment of wlvar cancer is evolving [ram the single incision "en bloc" highly marbid resection of the entire wlva, groin, and pelvic nodes for all stages of this disease. Currently, micro-invasive disease is treated conservatively by wide local excision, and stage 1 and 2 disease by wide local excision and superficial groin dissection. Vulvar tumours of all stages which by locatioTt or size preclude both a one em surgical margin and the sparing of critical mklline anatomy; clitoris, urethra or anal sphincter, can now be considered for primary irradiation rather than surgery. This approach may preserve the function and anatomic integrity of these important structures. Surgico-pathologic factors can greatly assist in identifying those post-surgical patients at higher than normal risk of relapse, so that they can receive targeted, adjunctive therapy. The extent of the psychological sequelae of the diagnosis and treatment of wlvar cancer is becoming known. Further information about these non-physical marbidities may help us to choose between the available treatment options, based on additional outcome measures including cost of treatment and patient preference. At this time, our clinical goal is to maintain cure and local control rates and to minimize marbidity in early disease, while we attempt to improve local control and curability for patients with advanced disease. This wiU be achieved by 1) limiting the amount of tissue treateJ/excised for patients with early stage/good prognosis disease and, 2) by minimizing the physical and psychologic marbidity, without sacrificing curability, for patients with advanced disease or with adverse risk factors.
RESUME La resection «en bloc»' amarbidite extremement elevee, de Ia wive, de l'aine et des gang/ions pelviens, qui etait systematique dans taus les cas de cancer de Ia wive, que! qu' en soit I.e stade, n'a plus cours desormais. La maladie micro-invasive est maintenant traitee de maniere conservatrice par une large excision locale, tandis que les stades 1 et 2 font l' objet d' une
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' ' ' large excision locale et d' une dissection superficieUe de !'aine. On preconise mainterulnt l' irradiation primaire pluwt que l' intervention chirurgicale, lorsque Ia tumeur vulvaire, quel que soit san stade, ne perrnet pas de laisser une marge chirurgicale de I em et d' epargner les structures rnedianes critiques, le clitaris, !'uretre ou le sphincter anal, du fait de sa position ou de sa grosseur. Cette rnetlwde perrnet de mieux preserver Ia fonctian et l' integrite anatomique de ces structures importantes. Des facteurs chirurgico-pathologiques peuvent faciliter grandement !'identification des patientes qui' apres chirurgie' presen tent un risque de recidive superieur aIa normale' de maniere apouvoir leur prescrire un traitement d'appoint cible. On commence arecannaitre l' ampleur des sequeUes psychologiques du diagnostic et du traitement du cancer de Ia vulve. Une cannaissance plus approfandie de ces morbidites nan physiques pourraient nous aider achoisir entre differentes options de traitement, en nous basant sur des facteurs supplementaires tels que le cot1t du traitement et les preferences de Ia patiente. A l'heure actueUe, notre objectif clinique est de maintenir les taux de gu&isan et de cantrole local et de minimiser Ia morbidite en debut de ma1adie, tout en tentant d'arneliorer le cantrole local et les possibilites de gu&isan dans les cas de ma1adie avancee. Cet objectif sera atteint I) en limitant Ia quantite de tissus traites ou excises pour les maladies a leur debut/presentant un ban pronostic et 2) en minimisant Ia morbidite physique et psychologique, sans sacrifier cependant les possibilites de guerisan, en cas de ma1adie avancee ou de facteurs de risque defavorables.
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KEY WORDS
Vulva, cancer, treatment.
In addition, we have begun to identify risk or prognostic factors which permit the clinician to estimate the likelihood of loco-regional control with standard management and to plan additional, targeted, adjuvant treatment for women with vulvar cancer at increased risk of recurrence. Better anaesthetic technique, better medical management, and new surgical options have also recently been developed both to limit the resection of early lesions and to provide more aesthetic, more functional tissue coverage for patients with advanced disease who still require large area resection to achieve loco-regional clearance. This disease remains confined to the vulva and the inguinal lymph nodes for a considerable period of time. When the groin nodes are histologically negative, the few cases of recurrent disease are localized to the vulva. 4 Distant disease is an uncommon occJrrence at presentation, is generally not observed until very late in the disease process and usually occurs in association with extensive nodal diseaseY Numerous studies of the regional lymph nodes and the lymphatic drainage of the vulva have suggested a sequential pattern of lymph node involvement in the approximately 30 percent of patients (all stages) who develop lymph node metastasesY Vulvar cancer is relatively curable with average reported five-year survival rates between 46 to 75 percent. 45 ·8 More importantly, disease-specific survival, although not generally reported, is conservatively another 10 percent higher, given the older patient age at the time of diagnosis and the significant, attendant medical co-morbidities often observed in these women.
INTRODUCTION
Carcinoma of the vulva is a lesion not often seen by the practising gynaecologist. Vulvar cancer constitutes approximately four percent of genital neoplasia and is a rare cause of death in women. There is evidence that many vulvar cancers, particularly those found in younger women, are the result of sexually transmitted infection of the lower genital tract by the Human Papillomavirus (HPV), specifically its oncogenic sub-types, the so-called "16-18 group." 1•2 We might reasonably expect to see the incidence of (pre)invasive vulvar cancer rise in the next decade as a delayed consequence of the changes in sexual mores which followed the introduction of oral contraception in the 1960s. The attempts to cure vulvar cancer in the 1940s were characterized by very wide or radical vulvar surgery which often included resection of the rectum, urethra, and pubis. Within the last 10 years, the management of this cancer has begun to evolve for several reasons. Vulvar cancer is now being observed in younger women, probably due to the putative association of this disease with HPV, a sexually transmitted virus. It has been reported that 15 percent of women with vulvar cancer will have a concomitant (pre)invasive lesion on the cervix which is also likely related to the HPV virus. 3 Vulvar cancer is also being identified at an earlier stage than was the case several decades ago, as older women in particular become more aware of themselves and much less likely to neglect an ulcer or sore on the external genitalia.
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' ' ' The clinical management of vulvar cancer has changed considerably over the last 10 years. Operability rates have risen substantially,9 and better technical and radiobiological knowledge have decreased the likelihood of longterm morbidity from radiation therapy. Treatment is directed nowadays towards minimizing morbidity for all patients, particularly those with socalled low risk disease who are unlikely to fail primary treatment, and to the exploration of new treatment options and combinations of therapies for patients at high risk of loco-regional relapse.
For patients who have invasive vulvar cancer ( > 1 mm invasion), historical practice has been a so-called radical vulvectomy and bilateral en bloc inguinofemoral node dissection as described by Way, Taussig and others.17·18 This operation variously removed the entire vulva including one or more critical anterior midline structures; clitoris or lower third of urethra. For locally advanced lesions and some early tumours located close to the anus, posterior exenteration and colostomy had been used to clear the cancer, but this was invariably associated with significant short and longterm morbidity. 19 Typically, all of the groin nodes, both the superficial and deep inguinal and the superficial and deep femoral nodes, were removed with the vulva en bloc through a single "butterfly" shaped or "Texas longhorn" vulva-inguinal incision. Historically, if the groin nodes were clinically involved or if the vulvar lesion was large, the external iliac lymph chain was also excised by transecting the inguinal ligament its midpoint and continuing the dissection retroperitoneally along each pelvic sidewall to the bifurcation of the common iliac vessels. 17 More recently, the groin node dissections have been performed through separate infra-oblique groin incisions, the so-called "three incision" technique, with no loss of loco-regional control and no higher incidence of recurrence in the groin or in the skin "bridge" between the vulva and groin. 4·20 In 1979, in one of the first attempts to limit the extent (and morbidity) of invasive vulvar surgery, DiSaia suggested that, when the vulvar tumour was < 1 em in size, a "superficial" dissection of the groin node tissue above the cribriform fascia be performed first. If, when frozen sections were examined, these nodes were negative, the vulvar lesion could be treated by wide local excision. 21 DiSaia realized the critical importance of determining the status of the groin nodes before completing treatment to the vulva, as the metachronous development of positive groin nodes after primary treatment has been shown, in one review of the literature, to result in the death of 89 percent of such patients. 16 A corroborative study of DiSaia's hypothesis for patients with tumours characterized by < 5 mm invasion, no lymphovascular space involvement, and negative groin nodes, suggested a significantly higher incidence of treatable vulvar recurrences but not death when these patients were treated by wide local excision and ipsilateral groin dissection. 21 There are now several reported series which
THE VULVA SURGERY
In the early 1970s, Wharton among others defined the entity of micro-invasive vulvar cancer which, it was surmised, was very unlikely to have metastasized to the regional nodes at the time of presentation. This lesion could, therefore, be treated by a surgical intervention which was confined to the vulva and tailored to the dimensions of the lesion, leaving most of the "normal" vulva intact. 10 Micro-invasion was originally described in a manner analogous to micro-invasive carcinoma of the cervix ( <5 mm invasion) and was limited to visible lesions of< 2 em in greatest dimension.U It was soon realized that a more rigorous definition of micro-invasion was required when subsequent studies documented a small but consistent proportion of patients who met the existing criteria for micro-invasion but who had inguinal lymph node metastases. 12 ·13 The definition was subsequently revised to include only unifocallesions of <2 em size without capillary space involvement and with <1 mm invasion. 14 For such patients, (radical) wide local excision of the vulvar lesion, including at least a 1 em surgical margin without groin node dissection, has become standard practice. The risk of vulvar recurrence in the first two years following treatment for micro-invasion is about seven percent. 15 Often, these patients will also have extensive vulvar intra-epithelial neoplasia (YIN) which also must be encompassed in the treatment field. Such patients require meticulous colposcopic follow-up, particularly if they continue to smoke, a known cofactor in the evolution of this disease which can substantially diminish longterm control ofHPV and VINY
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' ' ' several recent reports demonstrated that, even in patients with advanced disease, it was possible to cure vulvar cancer. 30 ·31 •32 In 1982, Boronow reported 3 7 patients with locally advanced (stage 3/4) disease and achieved 86 percent surgically confirmed local control, effectively reopening the question of the use of radiation in the primary management of this disease. 31 There is good evidence that radiation can control and cure local vulvar disease if a dose is given that is appropriate for the particular tumour volume. Although there are no specific detailed or case controlled data about vulvar cancer, there are excellent data on the radiation control of squamous cell cancers from the head and neck literature to show that 45 Gy in five weeks will sterilize in excess of 90 percent of subclinical nodal disease and that 65 Gy can effectively sterilize a tumour volume of 3 em. 15 A report by Backstrom has also suggested a radiation dose/response effect in vulvar cancer. 36 Frequently, for the vulvar primary, a small perineal port using electrons whose energy is tailored to the size and depth of the lesion may be used in preference to anterior and posterior pelvic portals, in order to limit the depth of penetration and to minimize damage to surrounding tissues. The groins and pelvic nodes are treated using parallel opposed pelvic fields, usually with a central block to exclude the vulva if vulvar irradiation is not indicated. The pelvic nodes are treated up to the level of the mid-sacroiliac joint. 37 The concurrent use of a radiation sensitizing drug such as 5-Auorouracil (5FU) may enhance tumour regression in vulvar cancer38 •39·40 as has been observed with several other epidermoid carcinomas, specifically those of the, cervix, oesophagus, and anal canal. 41 .42 Platinum and its analogues may also be effective radio-sensitizers. Although they have been successfully tested in vitro using the new 96 well-plate clonogenic assay, 43 there are as yet no clinical trials of the utility of Platinum compounds in vulvar cancer. Several phase two trials have looked at the value of pre-operative vulvar irradiation for advanced vulvar cancer to limit the extent of primary surgery. 30•31 •12 Radiation has also been advocated as primary treatment when the cancer involves one or more critical midline structures including clitoris, urethra, anal sphincter or anal margin. 28 •40 .44 Specifically, if a 1 em surgical margin cannot be obtained around any one of these structures, primary radiation may be used in preference to surgery, in order to preserve anatomic integrity.
confirm that, in the absence of a multi-focal cancer, (radical) wide local excision does not compromise ultimate local control of the vulva for stage 1 and 2 disease. 22- 26 A report from Italy also suggests that this is a safe approach for more locally advanced vulvar tumours (stage 3 ). 27 A recent report has emphasized the need to obtain at least a 10 mm surgical margin (8 mm pathologic margin given the average 20% shrinkage artifact with standard histologic fixation). 26 RADIATION
Generally, an inguinal groin node dissection should be performed in all patients before the vulva is treated so that 1) the status of the nodes can be clarified at the outset of treatment and 2) as definitive therapy for most. An ipsilateral node dissection and a wide local excision of the vulvar cancer will suffice for most patients. Lesions which cross or come within 1 em of the anatomic midline should have a bilateral groin node dissection. For lesions which cannot be cleared from the critical midline structures by at least 1 em, as good a therapeutic result and a substantially better cosmetic and possibly functional result may be achieved with primary vulvar irradiation following the groin dissection. In addition, for patients treated with primary surgery, the identification of surgicopathologic factors in the vulvar specimen may suggest that some individuals are at higher than normal risk of vulvar recurrence. For such patients, a course of postoperative, adjuvant irradiation may decrease their risk of vulvar relapse. 28 There is evidence from the psychosocial literature that the extent of surgical resection correlates positively with patient anxiety, depression, and changes in postoperative sexual function. 29 Primary radiation may permit a less extensive resection and/or may obviate the need for any surgical intervention in some patients.30•31 •32 Until recently, radiation was used to treat those vulvar cancers considered inoperable either on medical grounds or which involved bladder, proximal urethra, anus or pubis; lesions which would otherwise have required an exenterative procedure and/or resection of the pubis for surgical clearance. The first attempts at vulvar irradiation were characterized by low survival and excess morbidity, in large part the result of patient selection, inadequate dosing, and severe acute radiation complications which precluded completion of treatment. As a result, primary radiation fell into disrepute, 33 •34 until
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' ' ' There is evidence that the risk of groin failure and pelvic node involvement after surgery increases with the nodal burden of disease. 7•52 •53 There is not yet, however, agreement as to where the best discrimination point lies with respect to the number of involved nodes. Studies have shown variously that two or more, or three or more involved lymph nodes each are predictive of deep pelvic node involvement. 6•16•52 •54 There is additional information that capsular penetration and complete replacement of a single node are both independently predictive of groin failure. 55 The groin nodes are good predictors of pelvic node involvement. The pelvic nodes are found to contain tumours in 20 percent of patients with positive groin nodes or six percent overall. If the groins are histologically considered to be "high risk" following surgery (which variously may include one or more of the following factors; > 1 microscopically positive nodes, capsular penetration or complete replacement of a single node,) then adjuvant, postoperative groin irradiation which also encompasses the next higher lymph node group will control disease more effectively than a pelvic node dissection. 54
The dose prescriptions suggested by Thomas for the management of vulvar cancer are; 45 to 50 Gy to the vulva as postoperative, adjuvant (consolidation) therapy for microscopic residuum or in patients with high risk surgicopathologic factors, 55 Gy plus concurrent 5FU as pre-operative treatment for macroscopic disease when the intent is curative and minimal tissue resection is contemplated, and up to 65 Gy for tyrimary, curative treatment when no therapeutic surgical intervention is planned. 28•40 The morbidity observed with these treatment strategies is minimized if the fraction size is kept below 160 to 170 cGy. 28 FACTORS PREDICTIVE OF VULVAR FAILURE
We are now aware of several surgico-pathologic predictors of vulvar failure following conventional surgery. Although the reports are not entirely consistent, it appears that depth, tumour size, and possibly grade and lymphovascular space involvement may each be independently predictive oflocal (vulvar) failure. 7•8•10.4HB A report by Heaps has suggested that the adequacy of the surgical margin may also be an excellent predictor of vulvar recurrence. 46 In a large longitudinal review of vulvar cancer from the Norwegian Radium Hospital, Kaern reported that node involvement (p<0.0001) and aneuploidy (p
SURGERY
In general terms, patients whose inguinal nodes are surgically negative have a 90 percent chance of longterm cure, groin node positive patients have a substantially reduced five-year survival rate (25 to 40%), and patients who develop metachronous groin nodes die of their disease. Surgery remains the mainstay of treatment for groin nodes, as it is both diagnostic and therapeutic in the majority of patients. With lateralized lesions, the recent trend has been towards a more limited ipsilateral groin dissection with conservation of the intervening "bridge" of skin. Pelvic node dissection has largely been discarded as atherapeutic intervention following a Gynecologic Oncology Group (GOG) study which clearly demonstrated the therapeutic superiority of pelvic nodal irradiation.54 These variations of the classical surgical treatment of the lymph nodes for vulvar carcinoma have substantially reduced groin morbidity without a demonstrable decrease in survival or any increase in loco-regional recurrence.49•50 There is compelling evidence that the inguinal nodes do not need to be removed en bloc with the vulvar specimen. Resection of these node groups through separate infra-inguinal incisions, the "three incision" technique which leaves a skin bridge intact between the
REGIONAL LYMPH NODES FACTORS PREDICTIVE OF NODAL INVOLVEMENT
Ten percent of patients with stage 1 disease and 30 percent of all patients irrespective of stage can be expected to have positive groin nodes. 14•23 We have information on surgicopathologic factors from the vulvar specimen which predict for groin node metastases. 5•50 •51 In one study, the combination of lymphovascular invasion, tumour thickness >2 mm, and the amount of keratin correctly classified 97 percent of the lymph node negative group and 63 percent of the lymph node positive group (overall accuracy of 87%). 50 In a report by Shimm, groin node involvement was significantly correlated with tumour size and gradeY A Norwegian study failed to find that the ploidy status of metastatically involved inguinal lymph nodes was of prognostic value.49
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' ' ' vulva and groin dissection, does not appear to alter survival or loco-regional control, but does substantially reduce postoperative morbidity. 53·55·56 DiSaia first advocated a superficial inguinal node dissection in the primary management of some patients FIGO stage 1 disease (lesion< 1 cm).Zl The deep femoral nodes which lie medial to the femoral vein in the femoral canal are not removed, but the accessory saphenous, external pudendal, superficial epigastric, and superficial lateral circumflex veins are ligated. The operation leaves intact the saphenous vein, cribriform fascia, and the femoral canal. The rationale for this procedure is that the lymphatic drainage from the leg is less likely to be disrupted if the femoral canal is not dissected and the long saphenous vein is not ligated. Therefore, chronic lymphoedema, lymphocyst formation, and wound breakdown should be reduced. Despite these theoretical considerations, there is evidence that conservation of the long saphenous vein does not alter morbidity. Of note, however, is the concern expressed by some that superficial groin dissection may lead to a five percent incidence of failure in the groin, probably the result of aberrant lymph drainage. 16·24 If a vulvar cancer is "lateralized," suggesting that the lesion does not extend to within one em of the midline, 28 then an ipsilateral groin node dissection may be performed safely. With a lateralized stage 1lesion, the likelihood of contralateral groin involvement, if the ipsilateral groin is positive, is 10 percent of the 10 percent risk to the ipsilateral groin. This would translate into a one percent risk of nodal disease in the contralateral groin. There is a negligible risk to the contralateral groin if the ipsilateral groin is surgically negative. 57 The pelvic nodes are positive in about six percent of all patients with vulvar cancer. Direct involvement of the pelvic nodes without spread to the groin nodes, even with midline or mucosal lesions, is thought to be extremely rare. 8 If the groin dissection is negative, the chance of positive iliac/pelvic nodes is negligible, but if the groin nodes are positive, the iliacs contain metastatic disease in about 20 percent of patients.8'19 A Gynecologic Oncology Group study demonstrated that the addition of pelvic node dissection may be curative in 20 percent of patients with positive pelvic nodes. The study also demonstrated that postoperative radiation to the pelvic nodes, when more than one groin node was involved, resulted in significantly higher survival rates
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than surgical resection alone, due to better inguinal node control. The addition of radiation to the node dissection resulted in no additional morbidity. 54 RADIATION
There is evidence to suggest that the groin nodes are as sensitive to radiation as the vulva. 5859 However, the conclusions from a randomized study of groin dissection versus primary groin irradiation suggest that the methodology of groin irradiation may need to be revisited. In this study, which was closed prematurely, an excess of groin failures was found in patients treated with standard groin radiation.55·60 A subsequent study by Koh suggested that the radiation prescription in the earlier study (45 Gy at 3 em from the skin surface) was likely inadequate for many of the patients treated. 61 In the Koh study, the average depth of the femoral vessels from the skin surface, based on scanning, ranged from two to 18.5 em (mean 6.1 em). As usual practice has been to assume that the nodes are three to four em deep to the skin, this recent finding suggests that both the depth prescription and the dose for primary groin radiation need to be individualized. 61 Currently, the indications for postoperative, adjuvant radiation to the groins, pelvic and/or para-aortic lymph nodes are based on surgico-pathologic factors from the groin node dissection. Fixed or ulcerated groin nodes (U .I.C.C. N3) are usually treated by primary groin irradiation without resection.
cr
MORBIDITY SURGERY
The incidence of morbidity following vulvar or groin resection is related to the amount of tissue excised. The most frequently observed postoperative physical morbidities are wound breakdown, cellulitis, venous thrombosis, genital prolapse, lymphocoele formation, and chronic lymphoedema. It is very difficult to define with accuracy the incidence of these surgical complications given the lack of uniform reporting definitions. 22 •24·26 Hacker et al. reported a 15 percent reoperation rate for complications related to surgery4 but that was not supported by other series where re-operation was unusual. The recent trend to wide local excision of the vulva and more limited groin dissection using separate incisions for stage 1 and 2 lesions has resulted in substantially fewer major complications and markedly shorter hospital stays. 62·61
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' ' ' Several surgical manoeuvres have been proposed to limit postoperative groin morbidity. These include removal of an ellipse of skin over the infra-inguinal incision to improve the vascularity of the skin edges, aggressive groin drainage using a variety of drains and continuous or intermittent suction. Transposition of the sartorius muscle over the femoral vessels has long been used to minimize the risk of rupture of the femoral vessels in the event of wound breakdown. Honey dressings have been used to reduce groin breakdown and cellulitis to a minimum because of its properties as an (occlusive) bacteriostatic dressing. Hyperbaric oxygen has also been used postoperatively to decrease wound breakdown.64 Prophylactic antibiotics can diminish major postoperative infection in other gynaecologic procedures, but their value in major vulvar surgery has not been independently verified. A recent autopsy series from Borgno et al. suggests that all of the deep femoral lymph nodes lie beneath the cribriform fascia but within the fossa ovalis, and that there are no nodes lateral to the medial border of the femoral vein. 65 This strongly argues that the femoral canal and cribriform fascia do not need to be excised in order to remove all of the femoral nodes. In addition, a recent review of lymphangiography of the groin argues that there are no inguinal nodes over the lateral 20 percent of the inguinal ligament and, therefore, this tissue also does not need to be excised. Based on this study, there appear to be lymph channels in this same region which flow directly from the leg to the axilla. 66 If these were left intact, the surgeon might reasonably expect that lymph drainage from the leg would improve and that the likelihood of chronic lymphoedema would diminish. In the last few years, a great deal of innovation has occurred in the management of large operative perineal or vaginal defects. A remote myocutaneous flap using rectus abdominus muscle, gracilis, the epigastric portion of internal oblique plus transversalis and the underlying parietal peritoneum or one of several other regional muscles, can be safely and reliably mobilized to fill and cover these defects. Local fasciocutaneous flaps or rhomboid skin flaps can also be used to repair smaller defects. 67 •68 ·69 The psychological morbidity following major vulvar excision may be profound. In one paper, patients who had undergone radical vulvectomy were compared to a control group who had not undergone surgery. 29
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The surgical group were found to be in the eighth percentile in terms of sexual arousal and in the fourth percentile for perceived body image, a truly significant and potentially far reaching observation. In a paper by Corney et al., the prevalence of psychosexual dysfunction after radical vulvar surgery was found to be common and to remain chronic. 70 The loss of fertility, anatomical disfigurement, and the depression and anxiety about desirability as a sexual partner were strongly felt. Fifteen percent never resumed sexual intercourse after surgery and two-thirds of the women who were sexually active prior to surgery indicated ongoing sexual problems. 70 However, Weijmar Schultz et al. argue that postoperative sexual satisfaction is more dependent on the patient's pre-existing psychological and social characteristics than on any change in the patient's physical variables related to the operation. 71 Virtually all patients treated for cure with primary vulvar radiation will experience moist desquamation.29,7 2 The most commonly observed chronic/late complications of vulvar radiation are vulvar fibrosis, telangiectasia, and tissue necrosis which may be decreased if the daily fraction size is kept below 160 to 170 cGy per day. 40 These problems may be more pronounced for patients with diseases such as diabetes which alter the microvascular circulation. It is not known how functional the clitoris is following curative vulvar radiation but it is probably related to the amount of radiation fibrosis produced by the treatment, which can in turn be correlated to the radiation dosage and fractionation schedule. With respect to chronic leg oedema, Holmsley et al. reported that there was no additional morbidity when groin radiation followed groin node dissection. 54 Psychosexual problems following treatment for vulvar cancer were not confined to surgical patients. Corney et al. reported that eighty-two percent of a cohort of women < 50 years old who had had primary radiotherapy for vulvar cancer suffered from sexual dysfunction, usually due to lack of desire rather than pain. This effect was more likely related to clitoral dysfunction after radiation. The presence of a stable pre-existing relationship before the diagnosis aided in coping. Single, young women were found to be a particularly vulnerable group. In general, patients wanted more information than they were given about both treatment and prognosis, and the provision of sexual counselling appeared to improve their psychosexual outcomes. 73
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' ' ' SUMMARY
many of these issues, including the role of adjuvant radiation for "high risk" patients following wide local excision, and the possible additive benefit of sensitizing chemotherapy and radiation in node-positive patients. This trial will also address the issues of anatomical integrity and body image and will include measurement of patient quality of life.
Micro-invasive vulvar cancer ( < 1 mm invasion without capillary space involvement) can be treated with wide local excision of the lesion without node groin dissection. Stage 1 and 2 (and possibly stage 3) diseases may be treated by (radical) wide local excision (to include at least a 1 em surgical margin both laterally and deeply). No "head to head" comparison of this approach versus radical vulvectomy has been reported. Vulvar tumours involving critical midline structures (clitoris, urethra, anal sphincter, or anal mucosa) may be treated with primary radiation in order to preserve anatomic integrity. Persistent vulvar disease after primary radiation or localized vulvar recurrence can usually be controlled with a "tailored" excision of the lesion. The groin(s) is treated best by superficial groin node dissection which spares the femoral canal and long saphenous vein. If the lesion is > 1 em from the anatomic midline (lateralized), only the ipsilateral groin needs to be resected. If the groin nodes are clinically positive, the deep femoral nodes are dissected but a pelvic node dissection is not performed. Adjuvant, postoperative irradiation to the groin is recommended if there is replacement of, or capsular penetration in one node, or if more than one node is microscopically involved. Radiation to the contralateral groin and the pelvic nodes is individualized and based on surgico-pathologic factors from the vulvar and groin dissections. Today, exenteration has little place in the primary management of vulvar cancer, but may occasionally be required for vulvar recurrence following radiation. Patients treated with less than a radical vulvectomy have residual "normal" vulvar epithelium remaining which should be considered to be at increased risk for a second primary and/or recurrence of the initial lesion. Women treated for carcinoma of the vulva should have longterm colposcopic followup. Many of the present treatment innovations for this disease are based on assumptions from non-randomized case series, and remain untested. As vulvar cancer is such an uncommon lesion, it is important that questions regarding treatment be asked within the setting of a prospective and randomized clinical trial, and that quality oflife issues and patient preference for the various treatment interventions be quantified. In the near future, the GOG will begin a clinical trial (#145) to examine
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63. Lin J, DuBeshter B, Angel C, Dvoretsky P. Morbidity and recurrence with modifications of radical vulvectomy and groin dissection. Gynecol Oncol1992;47:80-6. 64. Reedy M, Capen C, Baker D, Peterson W, Kuehl T. Hyperbaric oxygen therapy following radical vulvectomy: an adjunctive therapy to improve wound healing. Gynecol Oncol1994;53:13-6. 65. Borgno G, Micheletti L, Barbero Metal. Topographic distribution of groin nodes. A study of 50 female cadavers. J Reprod Med 1990;35:1127-9. 66. Nicklin JL, Hacker N. Personal communication. 67. Shepard J, Van DamP, Jobling T, Breach N. The use of myocutaneous flaps following excision of vulvar cancer. Brit J Obstet Gynaecol1990;97:1020-5. 68. Mayer A, Rodriguez R. Vulvar reconstruction using a pedicle flap based on the superficial external pudendal artery. Obstet Gynecol1991;78:964-8. 69. Helm C, Hatch K, Partridge E, Shingleton H. The rhomboid transposition flap for repair of the perineal defect after radical vulvar surgery. Gynecol Oncol1993; 50:164-7. 70. Corney R, Everett H, Howells A, Crowther M. Psychosocial adjustment following major gynaecological surgery for carcinoma of the cervix and vulva. J Psych Res 1992; 36:561-8. 71. Weijmar Schultz W, van der Wiel H, Bouma J et al. Psychosexual functioning after the treatment of cancer of the vulva: a longitudinal study. Cancer 1990;66:402-7. 72. Roberts W, LaPolla J, Greenberg H et al. Management of radionecrosis of the vulva and distal vagina. Abstract 46; Proc Amer Rad Soc 1990 San Francisco. 73. Corney R, Crowther M, Everett H, Howells A, Shepherd J. Psychosexual dysfunction in women with gynaecological cancer following radical pelvic surgery. Br J Obstet Gynaecol1993;1 00:73-8.
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