Surgical Treatment of Vulvar Cancer Treatment & Management

Neoadjuvant therapy for vulvar cancer may be considered for tumors that manifest with bowel or bladder involvement that would require extensive or exenterative surgery. The Gynecologic Oncology Group (GOG) reported its experience with a combination of cisplatin and 5-fluorouracil with hyperfractionated radiation for patients with unresectable stage III or stage IV squamous cell carcinoma of the vulva. After chemotherapy and radiation, 71 of 73 women were candidates for surgery and almost half had no visible disease. Urinary and fecal continence was preserved in all but 3 of these women. ^[8]

Except in the neoadjuvant setting, chemotherapy for vulvar carcinoma is palliative and often ineffective. Only bleomycin has been reported to produce a complete clinical response. In a series of 11 patients, Trope and colleagues administered bleomycin at a dose of 15 mg twice weekly and noted two complete responses (19%) and three partial responses (27%), for a total response rate of 46%. ^[18]

The only other agent that has been reported to be effective in recurrent vulvar cancer is doxorubicin. Deppe et al reported a partial response in 3 of 4 patients treated at a dose of 45 mg/m². ^[19]

In women with locally advanced vulvar cancer, no significant differences in survival or adverse events were found when primary chemoradiation or neoadjuvant chemoradiation were compared with primary surgery. However, these findings were based on small numbers and few studies in this Cochrane review. ^[20] Good, quality studies that compare primary treatments in locally advanced vulvar cancer are needed.

Cisplatin and 5-fluorouracil (5-FU) have been used in the neoadjuvant setting but have not been studied extensively in recurrent vulvar cancer. However, due to a lack of effective chemotherapy agents, these drugs are often used in recurrent vulvar cancer.

Great effort has been devoted to decreasing the morbidity of surgery for vulvar carcinoma. Traditional surgery has been a large en bloc resection of the vulva with the superficial and deep inguinal nodes through a single incision with at least 2-cm margins around the tumor and deep resection to the genitourinary diaphragm (see images below). This procedure resulted in significant surgical morbidity and distressing change in body image for the patient.

Specimen after removal with at least 1 cm margins around the tumor. (Photograph courtesy of Tom Wilson)

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The surgical defect after a radical vulvectomy specimen is removed. (Photograph courtesy of Tom Wilson)

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The surgical defect is closed after a radical vulvectomy. (Photograph courtesy of Tom Wilson)

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Refinements to surgery include (1) a definition for microinvasive carcinoma that does not require radical vulvar dissection or inguinal node dissection, (2) unilateral inguinal node dissection for small ipsilateral tumors, (3) using a triple-incision technique instead of an en bloc approach, (4) using radical local resection with 1-cm margins instead of complete vulvectomy, and (5) sparing the saphenous vein in an attempt to reduce the incidence of lymphedema. ^{[21, 22]} Few high quality studies are available on the surgical treatment of early stage vulva cancer. An analysis in 2008 indicated that there was no difference in local recurrence rates between radical local excision and radical vulvectomy. Recurrence of tumor in the groin are similar between ipsilateral groin node dissection and bilateral groin node dissection in women with a well-lateralized lesion. ^[23]

Many gynecologic oncologists omit dissection of the deep inguinal lymph nodes, although this surgical approach is controversial. In an attempt to decrease the morbidity from inguinal node dissection, radiation alone has been used to treat the groin lymph nodes but was shown to be inferior to groin node dissection. ^[24] A 2009 review comparing primary groin irradiation and primary groin surgery for early stage vulvar cancer concluded there was insufficient evidence to state that radiotherapy is equivalent to surgery for vulvar cancer. ^[25]

Sentinel lymph node (SLN) dissection has become part of the standard of care for women with early stage vulvar cancer.{ref24, 81, 87) This idea assumes metastasis occurs first to the SLNs, followed by metastasis to the other inguinal lymph nodes. This orderly metastasis has been validated in breast cancer and cutaneous melanoma. 

The results of lymphoscintigraphy and blue dye used in 59 patients with vulvar cancer was reported by de Hullu. All 37 SLNs interpreted as positive on frozen section were confirmed on final pathologic examination, resulting in a positive predictive value of 100%. ^[26] A more recent study examined the use of identification of the SLN in patients with squamous cell carcinoma. Patients were divided into two groups. Twenty-eight women had a vulvectomy and lymphadenectomy with identification of the SLN using lymphoscintigraphy with technetium-99 colloid albumin and 27 women had a vulvectomy and lymphadenectomy with no attempt to identify the SLN. SLN identification failed in one case. There was 1 false-negative SLN. The average number of SLNs identified was 2.2. Recurrent disease was similar in both groups. The authors did not report which patients developed recurrent disease in the inguinal area. ^[27]

In 2008, Ate and colleagues reported results of a multicenter observational study on sentinel node detection using radioactive tracer and blue dye in 403 patients with vulvar cancer. The results indicated that in patients with negative sentinel node(s), the groin recurrence rate is low, survival excellent, and morbidity minimal. ^[28]

In 2012, the Gynecologic Oncology Group published the results of lymphatic mapping and sentinel lymph node biopsy (SLNB) in 452 women with squamous cell carcinoma of the vulva. ^[29] Eligibility for this study included a primary tumor size of at least 2 cm but smaller than 6 cm and no clinically suspicious groin lymph nodes. All women underwent intraoperative lymphatic mapping and SLNB with isosulfan blue dye. The protocol was amended two years after study activation, requiring perioperative lymphoscintigraphy and intraoperative radiolocalization. There were 132 node-positive women, including 11 women (8.3%) with false-negative nodes. The authors believe SLNB should be offered to well-selected patients, preferably to those patients with primary tumors smaller than 4 cm, and surgery should be performed by well-trained gynecologic oncologists. If the SLNB is negative in this group of patients, the risk of groin relapse due to a false-negative SLNB is less than 3%.

A meta-analysis in 2013 examined the role of lymphatic mapping and SNLB in patients with squamous cell carcinoma. The authors reviewed 47 studies. Their conclusion was sentinel lymph node mapping for inguinal node staging using radiotracer and blue dye methods in patients without palpable inguinal nodes yielded the highest detection rate and sensitivity. False-negative results were highest in patients with midline vulvar lesions. ^[30]

The initial definition for microinvasive lesions was a depth of 5 mm below the basement membrane for tumors smaller than 2 cm. However, the risk of groin node metastasis in lesions with 3-5 mm of invasion was noted to possibly be as high as 20%. It was later determined that women with 1-mm invasion or less had a negligible chance of node metastasis and could be treated with wide local excision with a 1-cm clinical margin around the tumor. A GOG study suggested that women with well-differentiated tumors up to 2 mm in depth had a very low risk of lymph node metastasis.

A study by Yoder and colleagues identified three features most important in predicting tumor recurrence: depth of invasion, presence of squamous cell carcinoma at the surgical margins, and the histologic grade. ^[31] Omitting the groin node dissection in women with 1-2 mm of invasion can be considered if the tumor is well differentiated and the patient is elderly, debilitated, or at significant risk of lymphedema.

• The risk of lymph node metastasis based on the depth of invasion

  • Invasion to less than or equal to 1 mm - 0% (n = 34)

  • Invasion to 1.1-2 mm - 10% (n = 19)

  • Invasion to 2.1-3 mm - 12% (n = 17)

  • Invasion to 3.1-5 mm - 14% (n = 7)

  • Invasion to deeper than 5 mm - 43% (n = 7)

In stage I lesions, 0 of 177 patients had positive findings from contralateral groin nodes when the ipsilateral node findings were negative and the lesion was not located in the midline. Therefore, contralateral groin node dissection has been omitted when patients present with a primary lesion smaller than 2 cm and have negative ipsilateral lymph node findings.

Since the early part of the 20th century, the traditional surgery has been a radical dissection of the primary lesion with a bilateral groin node dissection performed through a single incision. Although this technique was later modified to remove less skin, the primary wound breakdown rate exceeded 50%. Taussig eventually adopted a triple-incision technique in response to the high wound breakdown rate. Concern was raised over the triple-incision technique because of the possibility of residual disease in the "skin bridges" due to cancer cells in the lymphatics between the primary tumor and the lymph nodes. Hacker et al reported a series of 100 patients who had undergone surgery with a triple-incision technique and reported a 56% primary healing rate. Although 2 patients had metastasis in the skin bridge, neither of these instances were isolated metastasis. ^[6]

Helm et al reported findings when comparing the cases of 32 women treated with a single incision with 32 similar patients treated with a triple incision. Patients with a triple incision had a significantly shorter operative time, less blood loss, and a shorter hospital stay. No difference was observed in the overall survival or recurrence rate between the 2 groups, and none of the women in the triple-incision group developed skin bridge metastasis. The biggest difference in the 2 groups was that the single-incision group had a 19% complete wound-breakdown rate, compared to only 3% for the triple-incision group. Similar results have been noted for women with larger lesions. ^[32]

A less-radical approach was adopted following the discovery that the local recurrence risk was low when the pathologic margin around the primary lesion was 8 mm. When taking into account the shrinkage during tissue fixation, this translates to a 1-cm clinical margin. Deep dissection to the urogenital diaphragm is performed, but most of the vulva can be spared if the primary lesion is small.

The traditional description of a groin node dissection includes ligation of the saphenous vein during removal of the superficial groin lymphatics. A review of 139 cases of groin node dissection demonstrated that when the saphenous vein was preserved, the incidence of wound cellulitis and acute and chronic lymphedema was significantly lower. Only one patient in this series with saphenous vein preservation developed chronic lymphedema. This occurred in a patient who received postoperative radiation therapy. No evidence indicated that an attempt to save the saphenous vein significantly increased blood loss or operative time. ^[21]

The idea to implement radiation therapy to treat the groin lymphatics without surgery has been studied by the GOG. The GOG performed a study on the efficacy of groin irradiation compared to surgery. Women with clinically negative findings from groin nodes were randomized to radiation alone or lymphadenectomy with radiation when the groin nodes were pathologically positive. The study was discontinued prematurely as an interim analysis demonstrated a significant decrease in survival in women receiving only groin irradiation. ^[24]

This study has been criticized due to the radiation dosage. The prescribed dose of radiation was at 3 cm, regardless of body habitus or the actual groin node location.

Studies of CT scan data have demonstrated that this technique delivers 100% of the prescribed dose to only 18% of women, and fewer than half the women would have received more than 60% of the prescribed dose to the entire groin lymphatic area.

Many physicians now omit deep groin node dissection. Opening the femoral sheath and removing the deep nodes is not without morbidity. Deep lymph node dissection may increase the incidence of lymphedema. In addition, infection of the groin over the femoral vessels after deep groin dissection can result in catastrophic bleeding. The sartorius muscle historically was transferred to the inguinal ligament to cover the exposed femoral vessels. Judson reported this technique is not beneficial based on a randomized control trial and increased the risk of lymphocyst formation. ^[33]

Several authors have examined the incidence of unexpected groin failure in the presence of pathologically negative superficial lymph node findings. The incidence rate of unanticipated failure is approximately 0-5%. ^{[34, 35, 36]} These percentages match those of an older series by Stanley Way, in which he examined both nodal groups separately and found that the deep nodes (deep femoral and pelvic) were involved in only approximately 3% of cases when the superficial lymph node findings were negative. He later adopted a technique of using the deep inguinal nodes to predict the need for pelvic lymph node dissection but continued to remove both the superficial and deep inguinal nodes. A survey of a group of gynecologic oncologists found that less than 25% of respondents still perform deep inguinal node dissection. ^[37]

Surgery for vulvar carcinoma is often performed with the woman's legs in adjustable stirrups to facilitate both the groin node dissection and the perineal phase of the operation. A surgical team can greatly reduce operative time. After the patient is prepared and draped, make an incision approximately 2 cm below the inguinal ligament. The tissue is undermined below the Scarpa fascia. Proceed with the dissection down to the tensor fasciae latae. Next, dissect the superficial inguinal nodal group off the cribriform fascia, taking care to not injure the great saphenous vein.

If the deep nodes are to be dissected, open the cribriform fascia laterally and take this tissue as part of the specimen. Then, dissect the femoral vein free and remove the nodes from the medial portion of the femoral vein. After a deep groin node dissection, the sartorius muscle can be divided at its insertion on the anterior iliac spine and sutured to the inguinal ligament to cover the femoral vessels. Bring closed suction drains in through a separate incision and suture to the skin. Close Scarpa fascia with 3-0 absorbable sutures, and close the skin with mattress sutures or with staples.

To initiate the radical vulvectomy, outline the lesion with a marking pen and make an incision to encompass 1-cm margins around the tumor. In contrast to a simple vulvectomy, the dissection is taken down deep to the perineal membrane. Care must be taken at the posterior aspects of the incision where the pudendal vessels enter the vulva. The lower portion of the bulbocavernosus muscle should be clamped and ligated to prevent bleeding. Once the lesion is removed, the vagina and vulvar skin can be mobilized to reduce the tension on the incision. The defect is closed in layers with 2-0 polyglycolic absorbable suture, and the skin is closed with horizontal or vertical mattress sutures. The authors' preference is to use 3-0 polyglycolic acid for the mattress sutures and to reinforce the incision with a running 4-0 polyglycolic acid suture.

The surgical defect is closed after a radical vulvectomy. (Photograph courtesy of Tom Wilson)

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Closure of a large single-incision radical vulvectomy. The complete wound breakdown rate from this procedure is often greater than 50%. (Photograph courtesy of James B. Hall, MD)

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Frequent sitz baths are recommended by many surgeons after surgery. Patients should dry the vulva completely after each sitz bath. A Foley catheter may be needed for a prolonged period after surgery around the urethra. Low molecular weight heparin or pneumatic compression stockings should be used in all women to prevent postoperative venous thrombosis. A Jackson-Pratt or similar type of drain should be placed in the inguinal space at the time of lymphadenectomy. Leave this drain in place until drainage is approximately 25 mL or less per day. Drainage may persist in many cases for more than 2 weeks.

A limited number of studies have been published on the impact of surgical treatment for vulvar cancer on sexual function, partner relationship, and overall quality of life. ^[38] Studies indicate these women,  after surgery , are at high risk for sexual dysfunction, even in the absence of a functional problem after surgery. Sexual dysfunction seems to be related to a disturbance in body image, leading to hypoactive sexual disorder and aversion disorder. Depression and increasing age are risk factors for sexually active women to discontinue intercourse after surgery. Interestingly, few studies have been able to correlate sexual dysfunction with extent of surgery if the clitoris was preserved.

Women who have tumor involvement with two or more inguinal lymph nodes are likely to benefit from adjuvant radiation therapy to the inguinal and pelvic nodes. The GOG studied the use of pelvic node resection compared with radiation of the groin and pelvis. The cancer-related death rate at 6 years for women having a pelvic lymph node resection was 51% compared with 29% in women who underwent radiation. The authors concluded that radiation after vulvectomy and inguinal lymphadenectomy significantly reduces local relapses and decreases cancer-related deaths for patients with node-positive vulvar cancer. ^[39]  More recently, Mahner and colleagues emphasize radiotherapy is the most important adjuvant treatment for women with vulvar cancer. ^[40] A clear benefit for radiation has not been proven in women with positive microscopic tumor in one lymph node, but, as groin recurrence is almost universally fatal, adjuvant radiation is often recommended.

Monitor patients closely after treatment for vulvar carcinoma. The most common site of recurrence is the vulva. An examination every 3-6 months for the first 2 years is recommended as more than two thirds of recurrences are in this time period. Detection of local recurrence of vulvar carcinoma is important because it can be treated by radical surgical excision. National Comprehensive Cancer Network guidelines recommend surveillance exams every 6-12 months after 2 years from diagnosis. ^[41]

The long-term survival rate after radical excision of a vulvar recurrence has been reported as 50-60%. Survival is better in women who originally presented with early-stage disease. Other factors that diminish the cure rate after local recurrence include disease at sites other than the vulva and a short interval from initial treatment to recurrence. For a large recurrence, an exenterative procedure can be attempted. A long-term survival rate of 38% has been reported after exenterative surgery for vulvar carcinoma.

Resection of a groin recurrence is not usually recommended. Previous radiation therapy to the inguinal area significantly impairs healing. Generally, the procedure should not be considered curative. The only situation in which resection of a groin node recurrence should be attempted is if the groin node is an isolated recurrence and the patient has not been previously irradiated.

Positive groin nodes at the time of initial surgery increase the risk of recurrence in the groin in the first 2 years. After the first 2 years, the risk of groin recurrence is low, regardless of the status of the nodes at the time of the initial surgery. There remains a long-term risk of local failure on the vulva after the surgery. A report from the Mayo clinic indicates that up to 10% of patients treated for vulvar cancer had a local recurrence more than 5 years after the original diagnosis.

Lymphocyst formation is noted in 7-19% of patients after groin lymphadenectomy. Although cellulitis after vulvectomy has been associated with an increase in the incidence of lymphedema, it has not been associated with an increase in lymphocyst formation. Do not remove drains after inguinal node dissection until the daily output of the drain is less than 25 mL.

Lymphocysts usually manifest as an asymptomatic mass in the groin. To exclude a groin recurrence, aspirate fluid from the cyst and send for cytologic evaluation. Multiple aspirations are often required and may not be curative. If the mass is symptomatic, the lymphocyst can be removed surgically. However, in one small series, lymphocysts were successfully treated by placing a drain in the groin until the output was less than 25 mL/d. The drain was then removed and a pressure dressing was placed to prevent reaccumulation of the fluid. Sclerosis of lymphocysts with Betadine solution has also been described.

Cellulitis and lymphangitis can occur after groin node dissection. The incidence rate of cellulitis requiring antibiotics ranges from 20-40%. Often, patients who develop lymphocysts are at increased risk of lymphangitis. The etiologic agent is most often a streptococcal species, and treatment with penicillin is adequate. If drains are still in place, first-generation cephalosporins may be more appropriate to treat Staphylococcus aureus.

Chronic lymphedema has been reported in 10-20% of women after groin node dissection. This can be a disabling problem and is more common if radiation is required after groin dissection. Limiting groin node dissection in women with early cancers and preserving the saphenous vein decreases the incidence of this problem. The use of graduated compression stockings after lymphadenectomy can help prevent lymphedema. If edema does develop, the use of compression stockings, massage therapy, and limb wraps can help control the accumulation of fluid. However, lymphedema can be chronic and disabling in severe cases. Many major centers offer lymphedema treatment programs.

A prophylactic quadrivalent vaccine was approved by the Food and Drug Administration (FDA) in 2006 for the prevention of anogenital lesions including genital warts, vulvar and vaginal intraepithelial neoplasia, and cervical lesions associated with HPV 6, 11, 16, and 18. The first study to demonstrate the efficacy with HPV type 16 vaccine was reported by Koutsky and colleagues in 2002. ^[42] This vaccine contained virus-like particles (VLPs) that do not contain viral DNA. Two studies were subsequently published examining the efficacy of the quadrivalent vaccine. These studies demonstrated significant vaccine efficacy in decreasing the incidence of anogenital lesions caused by HPV 6, 11, 16, and 18. ^{[43, 44]}

In the summer of 2008, the FDA approved marketing of the quadrivalent vaccine for the prevention of vulvar and vaginal cancer. ^[45]  The FDA in December 2014 approved HPV 9-valent vaccine to protect against precancerous vulvar lesions and vulvar cancer. ^[46]

Based on work in breast cancer and melanoma, a sentinel lymph node (SLN) can be identified and can be predictive of patients who will have other involved nodes. The technique of SLN dissection is attractive in vulvar carcinoma since most women will have negative lymph nodes. If the sentinel node dissection proves to be sufficiently sensitive, full groin node dissection could be limited only to women with positive lymph nodes. There are two studies that report the efficacy of this SLN biopsy. A sentinel node can be identified in approximately 85% of women with isosulfan blue dye and 100% with the injection of Tc-99 labeled albumin. ^[47] The GOG lymphatic mapping and SLNB study from 2012 in 452 women supports the use of SLNB for women with primary tumors smaller than 4 cm performed by well-trained gynecologic oncologists. ^[29]

The combination of chemotherapy with radiation in cervical cancer has produced marked improvement in survival for locally advanced disease. This concept appears to also be effective in locally advanced vulvar carcinoma. Chemotherapy combined with radiation also may improve the cure rate in women with positive groin node findings, but acceptance of routine chemoradiation in women with positive node findings will probably require prospective evaluation. ^{[48, 49]}