Obstetrics and Gynecology

Vulvar Cancer

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Vulvar Cancer

1. What every clinician should know Are you sure your patient has disease? What should you expect to find?

Vulvar cancer is a relatively rare cancer that affects approximately 3,500 women annually in the United States. It is usually a relatively indolent cancer that presents with pruritis and a visible lesion. The majority of women will have symptoms for 6-12 months before diagnosis. The most common symptoms are pruritis (major symptom), a raised and/or pigmented lesion, and symptoms associated with locally advanced tumors, such as difficulties with urination, sexual function, or defecation.

Vulvar cancer has a typically bimodal age distribution, however most women with this cancer type are postmenopausal. Risk factors include human papillomavirus (HPV), chronic vulvar inflammatory lesions, smoking, and any prior history of genital neoplasia. HPV is found in 40% of vulvar cancers and 80% of VIN III.

2. Diagnosis and differential diagnosis

The differential diagnosis for any vulvar lesion includes vulvar cancer, infection, Paget's, genital warts, vulvar intraepithelial neoplasia (VIN), or other vulvar dystrophies. The final determination is based on a tissue biopsy. When vulvar cancer is in the differential, it is important to perform an extensive initial evaluation of disease extent and stage. A thorough history and physical with evaluation of adjacent organs (especially vagina, cervix, and anus) for field effect and possible involvement must be performed. The gold standard for definitive diagnosis is biopsy of the lesion and obtaining multiple representative samples and underlying stroma. This is easily done with local anesthesia and a punch biopsy.

Additionally, evaluation for potential inguinal lymphadenopathy should be performed as well as a chest x-ray. For larger lesions, CT scan (or PET) could be utilized to evaluate for nodal involvement, and cystoscopy and/or proctoscopy are performed if bladder or rectal involvement is suspected. Lastly, biopsy of any suspected metastatic lesion should be performed.

Vulvar cancer spreads by several mechanisms, including direct extension, lymphatics (usually to ipsalateral nodes if a lateralized lesion, but it can be both), or via the hematogenous route. For larger lesions, these potential metastatic sites must be evaluated as previously delineated. Vulvar cancer is most commonly of squamous cell histology (80-90%), followed by melanoma (5-10%, almost exclusively in white women), basal cell (<2%), and other very rare types, including adenocystic, adenocarcinoma of Bartholin's gland, and sarcoma.

Vulvar cancer is surgically staged and the treatment recommended will be determined largely on the stage, which will impact the extent of resection, size of margins, extent of lymphadenctomy, and adjuvant radiation/chemotherapy. See Table I for more information.

Table I.

FIGO Staging
Stage Description
Stage 0 No stromal invasion (VIN)
Stage 1 A: Limited to vulva, < 2 cm and < 1 mm invasionB: Limited to vulva, but exceeding above qualifications
Stage 2 Involving adjacent perineal structures (lower third of urethra, vagina, anus) but negative nodes
Stage 3 A: One positive node, or two < 5mmB: Two nodes > 5 mm, or three or more nodesC: Positive node with extracapsular involvement
Stage 4 A: Rectal or bladder mucosal involvementB: Distant metastatic disease (including pelvic nodes)

3. Management

A. What therapies should you initiate immediately?

This type of tumor is generally slow growing and locally invasive. In the absence of adjacent organ compromise (e.g., urethral obstruction) or distant metastatic disease, treatment can be held until a full evaluation is complete.

B. What should the initial definitive therapy for the cancer be?

Vulvar carcinoma is a rare gynecologic cancer whose treatment has evolved over time from a radical dissection (radical vulvectomy with en bloc bilateral inguinofemoral lymphadenectomy) with its concomitant morbidity to tailored levels of excision based on risk factors. Early stage disease is now treated by a radical local excision with or without inguinofemoral lymphadenectomy based on the stage of disease. For advanced disease, radical vulvectomy is often still necessary, but the morbidity has been limited by the use of the triple incision technique. Currently, multimodality therapy using chemoradiation is often offered as a way to further limit morbidity.

This section will review the treatment of the most common types of vulvar carcinoma, which include squamous cell, melanoma, and basal cell cancers. Most treatment decisions are based on histology and the stage of vulvar cancer.

Squamous cell vulvar carcinoma

Early stage vulvar carcinoma (stage I/II)

Surgical management

Primary tumor resection

Most stage I and stage II tumors are treated with primary resection. Similar outcomes and survival rates with decreased morbidity have been observed with radical excision compared to traditional en bloc vulvectomy. It is important to attempt to attain a minimum 1-2 cm gross tumor free margin during the resection, when surgically feasible, in order to limit local recurrence. However, depending on the size and location of the lesion, a radical vulvectomy and possibly a partial removal of vital structures (e.g., urethra) may be necessary to achieve adequate surgical margins.

Nodal resection

Research has consistently found that lymph node involvement was the most important prognostic factor with regard to survival. Accurate evaluation of the nodal status is therefore imperative to making treatment decisions. Nodal involvement also positively correlates with depth of invasion of the primary tumor (see Table II ).

Table II.

Depth of Invasion Correlated with Inguinofemoral Lymph Node Status
Depth of Invasion Percent Positive Nodes
< 1 mm 0.0%
1.1-2 mm 10.5%
2.1-3 mm 11.8%
3-5 mm 14.3%
> 5 mm 42.9%

Positive nodes require adjuvant treatment, and groin recurrence is almost universally fatal. The standard procedure is a bilateral inguinofemoral lymphadenectomy, which includes both the superficial inguinal nodes and the deep femoral nodes. However, lymph node dissection is associated with wound complications and lymphedema, and there have been efforts to decrease morbidity by carefully tailoring who receives a full dissection and evaluating sentinel nodes.

There are two clinical scenarios that obviate the need for bilateral lymph node dissection:

  1. Stage IA: When the depth of stromal invasion is ≤1 mm, there is a negligible rate of lymph node involvement (< 1%). In this case, the inguinofemoral lymph node dissection may be omitted entirely.

  2. Lateralized Stage IB tumors: When the depth of invasion is ≥1 mm, the risk of nodal metastasis rises to > 8% and a lymph node dissection should be performed. Depending on the type of lesion, this dissection is either unilateral or bilateral. Studies of vulvar lymphatic drainage demonstrate that the direction of flow is primarily ipsilateral. When the lesion is > 1 cm from the midline and there are no positive ipsilateral nodes, a unilateral lymphadenectomy is acceptable, since the rate of node metastasis is <1%. GOG 36 supported this finding, noting only 2.5% of lateral lesions with negative ipsilateral nodes had a positive contralateral node. If the lesion does not meet these criteria, a bilateral dissection is recommended.

Radiation

Adjuvant vulvar radiation

There are no prospective data available. However, retrospective data shows possible benefit. High risk patients are defined as those with positive or close ( ≤ 8 mm) surgical margins. These high risk patients were found to have significantly decreased local recurrence if given adjuvant radiation when compared to those followed with observation alone (recurrence rate: 16 % vs. 58% in radiated vs. observed patients, respectively). Busch et al. showed that 45Gy as adjuvant treatment increased the five year survival from 55% to 88% in early stage disease. Without further study, it is unclear if the optimal treatment for close surgical margins is simply close observation, repeat resection, or adjuvant radiation therapy.

Primary groin radiation versus inguinofemoral lymphadenectomy

The Cochrane 2011 analysis of primary groin irradiation versus primary groin surgery for early vulvar cancer identified, 12 studies but only one study, GOG 88, met the inclusion criteria. GOG 88 was a prospective randomized controlled trial that was closed early (N=52) due to an interim analysis that showed a significantly better progression free (p= 0.03) and overall survival (p= 0.04) in the groin dissection arm. This study has been criticized for likely delivering an inadequate dose of radiation to the inguinal nodes.

Although some retrospective studies have shown success with radiation, the Cochrane analysis points out that all of these studies used non-standard surgeries or early stage disease that was not reported separately from all other stages, which makes cross trial comparison impossible. Based on GOG 88, the Cochrane review recommends surgery over radiation as the first line treatment. In the case of patients who are unable to stand the stress of surgery, primary radiation does remain an alternative.

Advanced stage vulvar carcinoma (stage III/IV)

Surgical management

Traditionally, a radical vulvectomy with en bloc bilateral inguinofemoral lymphadectomy was the procedure of choice for advanced stage disease. The triple incision technique, which utilizes a separate incision for each groin node dissection, has gained almost universal acceptance now as the standard surgical procedure due to decreased morbidity (lower wound break down and lymphedema rates) associated with leaving bilateral skin bridges intact.

There is some concern that patients treated with the triple technique are at increased risk of local recurrence due to remaining disease in the tissue left behind. No prospective studies have looked at this problem, but a Cochrane review of the data supported the use of the triple incision technique as long as a pathologic tumor free margin of > 8 mm was maintained. The consensus remains that the decreased morbidity of the triple incision technique outweighs a small increase in skin bridge recurrence.

In the case of deeply involved vital structures (urethra, anus, or pelvic bone), radical vulvetomy may not provide an adequate resection. Procedures such as pelvic exenteration with subsequent urinary diversion and/or colostomy may be indicated. All these procedures come with significant physical and psychological morbidity. For example, exenteration has a mortality rate of 0-20%, with a mean of 4%. Given these problems, neoadjuvant radiation, chemotherapy, and combined chemoradiation are currently being investigated.

Radiation

Adjuvant radiation

There are certain high risk clinical features that should prompt consideration of adjuvant therapy in advanced stage vulvar cancer. For example, in women with positive surgical margins, radiation has demonstrated a survival benefit. Some authors also recommend adjuvant radiation for patients with a high risk of local recurrence, which includes those with stage IVA disease, LVSI, and deep invasion.

In patients with positive groin nodes, adjuvant therapy has not been shown to improve outcomes with a single microscopically positive node. Benefit from adjuvant radiation has been shown in those with clinically appreciable nodes, ≥2 positive nodes, or evidence of extracapsular spread (GOG 37). Improvement in two year survival for radiation therapy versus lymph node dissection was most evident in those with clinically positive nodal disease (59% vs. 37%) and ≥2 positive nodes (63% vs. 37%).

Summary:

  • Close or positive margins may benefit from local adjuvant radiation.

  • A single microscopic node does not require adjuvant radiation therapy.

  • Patients with > 2 positive nodes, macroscopic nodal disease, extra-capsular spread, or stage IVA disease should get groin and pelvic radiation therapy.

Chemotherapy

Neoadjuvant

There is limited data available on chemotherapy alone for locally advanced disease, and response rates vary from 50-100%. Table III summarizes several small studies that have looked at neoadjuvant therapy in locally advanced disease. Further studies are needed to confirm these findings and determine the optimal chemotherapeutic regimen.

Table III.

Research Regarding Neoadjuvant Therapy in Locally Advanced Disease
Study Patients Chemotherapy Regimen Response Rate
Shimizu et al. 1 Bleo 5U IV days 1-6, Vin 1mg IV day 6, Mito 10mg IV day 6, CDDP 100mg day 6 monthly 100%
Durrant et al. 28 Bleo 5mg IM days 1-5, MTX 15mg orally days 1 & 4, lomustine 40mg orally days 5-7 67%
Wagenaar et al.* 25 Bleo 5mg IM days 1-5, MTX 15mg orally days 1 & 4, lomustine 40mg orally days 5-7 during the first week. Weeks 2-6: Bleo 5mg IM days 1 & 4, MTX 15mg orally day 1 56%
Geisler et al. 10 CDDP 50mg/m 2 day 1, 5-FU 1000mg/m 2 continuous infusion days 1-4 100%
Benedetti-Panici et al. 21 CDDP 100mg/m2 day 1, Bleo 15mg days 1 and 8, MTX 300mg/m2 day 8 67%

Adjuvant chemotherapy

Lymphadenectomy and adjuvant radiation remain the standard adjuvant therapy. There is very limited data on chemotherapy as an adjuvant treatment modality. One study by Bellati et al. treated patients with multiple positive groin nodes with four cycles of adjuvant cisplatin 100mg/m 2 every three weeks. There were four recurrences in 14 patients. The three-year overall survival and progression free survival were 89% and 71%, respectively, and the authors concluded this was a safe and reasonable adjuvant therapy. Further study comparing chemotherapy to radiation and chemoradiation is needed.

Chemoradiation

Chemoradiation has been used as primary therapy and as neoadjuvant therapy to shrink tumors that are either inoperable or would require surgery with subsequent colostomy and urostomy to achieve adequate surgical margins. In most cases, this would involve locally advanced tumors. The use of chemoradiation in vulvar cancer is based on the experience gained in the treatment of cervical and anal cancer. Most trials have focused on 5-fluorouracil with ciplatin and mitomycin C with a variety of radiation regimens.

The Gynecologic Oncology Group prospectively investigated chemoradiation in locally advanced vulvar cancer in GOG 101. Pre-operative chemoradiation consisted of two cycles of Cisplatin (50mg/m 2) and 5-fluorouracil (1000mg/m 2/day) and a delivered dose of 47.6 Gy. Two populations were investigated using this protocol:

  1. Unresectable with radical vulvectomy T3/T4 tumors: 48% (34/71 patients) had a complete clinical response, with 70% of those being negative on pathological examination. Only 3% of patients were unresectable after neoadjuvant chemoradiation, and 16% had recurrent local disease at a mean follow up of 50 months.

  2. Unresectable N2/N3 tumors: 95% (38/40) patients were deemed resectable after chemoradiation, 37 of those specimens were evaluable, and 41% had negative pathology.

These studies were further supported by a 2006 Cochrane analysis which determined that patients with an inoperable primary tumors or nodes benefited from neoadjuvant chemoradiation, but if adequate treatment can be obtained with a radical vulvectomy and bilateral groin lymph node dissection, the chemoradiation is not indicated given the associated morbidity.

Cochrane released a new review of chemoradiation of the vulva in 2011. There was no difference in overall survival and adverse outcomes between primary chemoradiation, neoadjuvant chemoradiation, and primary surgery, which implies they are all equally effective and morbid. This review excluded studies used in the previous review, as they were non-comparative, which may explain the difference in outcome. Further complicating a comparison of chemoradiation studies is the variety of regimens used among the available studies.

New data from the publication of GOG 205 may help provide clarity. This is a prospective phase II trial currently available only in abstract that looked at the efficacy of chemoradiation in locally advanced squamous vulvar carcinoma. Locally advanced tumors that were not amenable to resection were treated with radiation (5760cGy in 180cGy fractions for 32 days) along with concurrent weekly cisplatin (40 mg/m 2). This was followed by surgical resection or biopsy to confirm response to treatment.

A complete clinical response rate of 64% (37/58 patients) was achieved. Of the women with a response, 34 had a surgical biopsy, which confirmed a complete pathologic response in 78%. The authors concluded that radiation plus weekly cisplatin has a higher response rate than radiation plus combination cisplatin and 5-fluorouracil. Although full toxicity data is not available, the authors concluded that toxicity was acceptable, with the most common reaction being leukopenia, pain, radiation dermatitis, and metabolic effects.

Chemoradiation offers the possibility of another treatment modality for women with advanced disease that would allow improved tailoring of the risk benefit profile to individual patients, as none of the available therapeutic options is clearly superior.

Importance of surgical margins

Surgical margin is the most important predictor of local recurrence. Heaps et al. showed that a surgical margin of 0.8 cm resulted in no local recurrences, while a margin of 4.8-8.0 mm had an 8% chance of recurrence, and < 4.8 mm had a 54% recurrence rate. De Hullu et al. expanded on this work and confirmed that a tumor free margin of > 8 mm was associated with no local recurrences.

A margin of ≤8mm had a 22% rate of local recurrence. Additionally, 50% of the patients in the study were found to have histologically measured tumor free margins of ≤8mm, despite the intent of achieving a 1 cm margin at the time of surgery. One possible explanation for this discordance is the reduction of surgical margin seen between the time of surgery and pathological examination. A 15% reduction of surgical margins has been observed due to the fixation process. Based on these findings, a 2 cm gross surgical margin is recommended.

Vulvar melanoma

Vulvar melanoma is the second most common type of vulvar cancer (8-10%) and appears unrelated to ultraviolet radiation exposure. Common symptoms include a pigmented lesion, pruritis, bleeding, and less often, ulceration. Tissue biopsy is crucial in making the diagnosis. Immunohistochemical staining with S100 and melanoma specific antigen can also be helpful in differentiating melanomas from other pathologic vulvar lesions.

Melanoma has three histologic types:

  • Superficial spreading: most common type, with primarily radial growth and later vertical spread.

  • Nodular: second most common type, with only a vertical growth phase.

  • Acral Lentiginous: least common type, with radial and vertical growth.

Lesions typically originate on the labia minora, labia majora, or clitoris. Multiple studies have shown that central lesions have a significantly worse prognosis compared to lateral lesions. A central primary lesion is associated with a higher rate of recurrence. Other important risk factors include positive lymph nodes, tumor depth of invasion, stage of disease, histologic type (nodular has worse prognosis), and LVSI. Risk factors that only apply to local disease are ulceration and clinical amelanosis.

Staging of vulvar melanomas is complicated by multiple systems which include the FIGO staging for vulvar carcinomas and the AJCC (American Joint Commission for Cancer) system, as well as three microstaging systems (Clark, Chung, and Breslow). Phillips et al. concluded in a prospective GOG that vulvar melanomas have similar behaviors to cutaneous melanomas and that the AJCC stage was the best predictor of recurrence free survival.

This study concluded that AJCC staging was the preferred system for vulvar melanomas and, if unavailable, use of the Breslow microstaging system was the next most prognostic. With the introduction of the latest AJCC staging guidelines in 2002, repeat studies confirmed that the staging criteria were predictive of overall survival. See Table IV for the most recent AJCC staging system.

Table IV.

2002 AJCC Staging System
Stage Primary Tumor (T) Lymph node (N) Metastasis (M)
0 In situ (Tis) No nodes None
IA < 1.00 mm no ulceration or Clark's II/III (T1a) No nodes None
IB < 1.00 mm plus ulceration or Clark's IV/V (T1b)1.01-2.00 mm no ulceration (T2a) No nodes None
IIA 1.01-2.00 mm plus ulceration (T2b)2.01- 4.00 mm no ulceration (T3a) No nodes None
IIB 2.01-4.00 mm plus ulceration (T3b) >4.00 mm no ulceration (T4a) No nodes None
IIC >4.00 mm plus ulceration (T4b) No nodes None
IIIA Any thickness, no ulceration 1 node micrometastases (n1a) None
IIIB Any thickness, with ulceration Any thickness, no ulcerationAny thickness, with or without ulceration 1 node micrometastases (n1a) Up to 3 nodes micrometastasis (n2a)In-transit met(s)/satellites without metastatic lymph nodes None
IIIC Any thickness, with ulceration Any thickness with or without ulceration Up to 3 nodes macrometastasis (n2b) ≥ Metastatic nodes/matted nodes/ in-transit with nodes (n3) None
IV Any thickness Any nodes Present

Treatment

Vulvar melanoma has historically been treated with radical vulvectomy with bilateral inguinofemoral lymphadenectomy. Several studies have found no difference in survival rates between those who underwent radical vulvectomy and those receiving a radical local excision. Treatment is now individualized to radical local excision with surgical margins of 2 cm (some authors have suggested 1 cm for depth of invasion <1 mm) to limit risk of recurrence.

The indications for lymphadenectomy also remain unclear as it gives prognostic information but may not be able to impact survival. Much of the available data is from the cutaneous melanoma literature. These studies have shown that superficial lesions rarely have nodal involvement. Slingluff et al. found no positive nodes when the depth of invasion was <0.76 mm, leading to the recommendation by some authors that that lyphmadenectomy be omitted in this population.

In melanomas with intermediate invasion (0.76-4mm), lymphadenectomy may be performed, however this is felt to be more prognostic in nature than therapeutic, as multiple trials have shown no survival difference. Another option under investigation is sentinel lymph node biopsy, which has a low false negative rate with minimal morbidity. Although there is limited data in vulvar disease, many authors suggest performing a sentinel node biopsy in intermediate invasion melanomas and saving a full lymphadenectomy only for those with a positive biopsy.

Adjuvant therapy in vulvar melanomas remains unclear, as there are limited studies available.

Recurrence and survival

Vulvar melanoma has a poor prognosis, with a five-year survival rate of 30%-54% (see Table V ). Local recurrence varies from 30%-50%. The most common site of recurrence is the groin, followed by the perineum, rectum, vagina, urethra, and cervix. Time to recurrence is reported as one month to 14 years, with an average of one year. After recurrence, survival is extremely limited.

Table V.

5-Year Survival Stratified by Depth of Invasion
Clark Staging Chung Staging Breslow Staging
Level 1: 100% Level 1: 100% < 1.5 mm: 60-90%
Level 2: 100% Level 2: 81% > 1.5mm: 16-50%
Level 3: 83% Level 3: 87%
Level 4: 65% Level 4: 11%
Level 5: 23% Level 5: 33%

Basal cell vulvar carcinoma

Basal cell vulvar carcinoma is very rare, comprising 2-3% of vulvar cancer. Typically basal cell carcinoma is caused by ultraviolet light, but the lack of sun exposure to the vulva makes this explanation unlikely. Other proposed etiologic agents include ionizing radiation, syphilis, chronic inflammation, and inherited skin conditions (e.g., nevoid basal cell carcinoma syndrome). At this time, the etiology of vulvar basal cell carcinoma remains unclear.

The most commonly affected population is elderly white women, who commonly present with symptoms like irritation, pain, itching, and a palpable lesion. Basal cell carcinoma tends to spread along the path of least resistance. Although metastasis is possible, it is extremely rare. Risk factors associated with an increased risk of metastasis are large size (>2 cm) and aggressive histology. The most common site of metastasis was found to be the inguinal lymph nodes in the limited number of cases reported in the literature.

Treatment

Wide local excision alone is adequate therapy, and given the extreme rarity of nodal involvement, lymph node dissection may be omitted except in exceeding large lesions or suspected lymph node involvement. Care should be taken to obtain adequate margins, as inadequate resection has been associated with an increased risk of recurrence. Currently, the role of radiation and chemotherapy has not been well studied and is not part of standard treatment.

Prognosis

Outcomes are generally excellent, but local recurrence has been noted in some studies at a rate of up to 20%. Survival data is unavailable for metastatic disease, but metastatic basal cell cancer is associated with a poor prognosis.

4. Complications

A. What complications could arise as a consequence of condition? Are there strategies to lower risk of complications?

Complications from vulvar carcinoma are rare. If the disease progresses, complications include lymphedema, cellulitis, bone metastasis, and urethral obstruction.

B. What complications could arise as a consequence of the management – chemotherapy, radiation, and surgical?

The morbidity associated with radical vulvectomy and bilateral inguinfermoral lymphadenectomy is a significant factor that should be considered during treatment planning.

Surgical complications

The traditional "en bloc" technique is particularly morbid, with a wound complication rate of greater than 50% in some reports. The triple incision technique has been widely adopted as it has similar treatment efficacy and decreased surgical morbidity. A recent review of the literature regarding the complication rate from the triple incision technique by de Hullu et al. reported a "wound breakdown" rate of 13%-38%, lymphocele rate of 12%-40%, and lymphedema rate of 13%-53%. Currently, it is unclear if acute complications predispose to chronic complications, as the literature has varying results.

Complications are broken up into acute and chronic categories. Some of the commonly associated problems from radical vulvar surgery include acute issues, such as wound complications (separation, infection, etc), thombosis, UTI, incontinence, seroma, hematoma, phlebitis, and osteitis, and chronic complications such as lymphedema, lymphocele, vaginal stenosis, dyspareunia, pelvic relaxation, abnormal micturation, and incontinence.

Management of treatment-related complications has met with varied success. Many authors recommend tension free closures, wound drainage, vigilant post-op care, and prophylactic antibiotics. Common complaints such as lymphocysts are treated conservatively with drainage and compression dressings if symptomatic. Lymphedema may take months to develop, but can be persistent and particularly distressing to patients. Additionally, patients who receive radiation treatment are at a higher risk of developing lymphedema than those treated with surgery alone. Treatment consists of compression hose, massage, exercise with periodic rest and elevation to help with drainage, and avoidance of irritation to the involved area to limit additional inflammation.

Psychosexual problems can arise due to cosmetic changes as well as physiological barriers such as lymphedema, dyspareunia, or loss of the clitoris. These problems can be particularly distressing in younger patients. Pre-treatment discussions and frequent post-op follow up are important in identifying those patients needing further support.

Radiation complications

Radiation therapy increases the risk of treatment morbidity. Acute complications are related to inflammation, and include radiation dermatitis, cystitis, and colitis. Topical treatments include estrogen cream, good hygiene, antiseptics, and, in some cases, delay of treatment.

Late complications are secondary to radiation changes such as fibrosis, loss of skin sensation/elasticity, and vascular changes leading to ischemia. Possible complications include stenosis (urethral and vaginal), fistula, cutaneous changes, radiation proctitis, and radiation colitis. Treatment options are non-surgical, including topical estrogen and hyperbaric oxygen. Surgical intervention may be necessary but should be approached with caution given the ischemic and fibrotic changes in radiated tissues.

Chemoradiation complications

Toxicity is highly variable depending on the chemotherapy and radiation regimen used. Acute cutaneous reactions and wound complications are frequent. Other common reactions include lymphatic, hematological, gastrointestinal, urological, and cardiovascular complications. Treatment for complications is as noted above.

C. What other therapies are helpful for reducing complications?

Strategies for limiting lymphedema

Sentinel lymph nodes

The theory behind sentinel lymph nodes is that metastatic cells from a primary tumor lesion will collect in the first node, receiving lymphatic drainage before other nodes become involved. This opens up the possibility of limiting the nodal dissection to a single node or a small group of nodes and minimizing the morbidity associated with a full lymphadenectomy.

Two methods of detection for sentinel nodes are injection of isosulfan blue dye intra-operatively or pre-operative (intra-operative) injection of a radioactive tracer. Although these methods can be used individually, combining both methods allows improved identification of a sentinel lymph node in cutaneous melanoma (99.5% compared to an 84.0% detection rate with isosulfan blue alone). A review of feasibility studies looking at sentinel lymph nodes in vulvar cancer found a low false negative rate of 2%. This finding is of particular importance, as lymph node status is important prognostically and in determining the need for adjuvant radiation. Currently, the GOG is conducting a prospective trial (GOG 173) which compares standard inguinofemoral lymphadenectomy to sentinel lymph node biopsy.

The current recommendation is that if sentinel nodes are found to be positive, then full inguinofemoral lymphadenectomy is required. In terms of prognosis, the GROINNS-V study recently found that as the size of the sentinel node increased, the risk of further non-sentinel node involvement increased as well. Survival was also found to be significantly worse in those with > 2 mm sentinel nodes versus those ≤ 2 mm nodes (69.5% VS. 94.4%, p= 0.001).

Superficial inguinal node dissection

The rational of superficial inguinal node dissection is that the lymphatic spread seen in vulvar carcinomas typically involves the superficial inguinal nodes prior to the deep nodes below the cribiform fascia. Preliminary data showed that there were no groin recurrences in patients treated with superficial inguinal lymphadenectomy when the primary lesion was < 1cm and invasion was < 5 mm. The Gyncologic Oncology Group conducted a prospective trial of stage I disease with < 5 mm of invasion (GOG 74). Six groin recurrences were seen in 121 patients (~5%), which was a significantly increased risk of recurrence when compared to historical controls. At this time, the preferred method of groin lymphadenectomy includes both the superficial and deep nodes.

VH fibrin sealant (tisseel)

Fibrin sealant has significantly decreased total drainage and time until drain removal after axillary lymphadenectomy in breast cancer patients. Given these encouraging findings, a prospective randomized trial comparing fibrin sealant to suture closure was undertaken (GOG 195). There were 137 patients evaluated, and no difference was found in the incidence of lymphedema, overall complications, duration of drain use, drain output, inguinal infections, wound breakdown, or seromas. However, there was a significant increase in vulvar infections in those treated with fibrin sealant (23 of 69 patients) versus suture closure (10 of 70).

Saphenous vein sparing

Saphenous vein preservation has been shown to decrease the rate of lymphedema in small trials without increasing the risk of recurrence. Most surgeons elect to preserve this if surgically feasible.

Wound breakdown

As previously discussed, the use of less extensive primary surgical techniques (e.g., radical local excision and triple incision technique) has helped limit wound complications. Sartorious transposition is another technique that initially showed promise, but a prospective, randomized trial of 61 patients found no differences in the rates of wound breakdown, cellulitis, lymphedema, or readmission to the hospital. Use of this technique cannot be routinely advocated.

5. Prognosis and outcome

A. What would you tell patient and family about the prognosis?

When squamous vulvar carcinoma is caught early, the prognosis is excellent (see the five year mortality data by stage in Table VI ). If adequate surgical margins are obtained and the depth of invasion is found to be less than 1 mm, there is a very small chance of nodal spread. Positive nodes have consistently been found to be the most important predictor of survival.

Table VI.

Five-Year Overall Survival by 2009 FIGO Staging (Beller et al.)
Stage Five-year Overall Survival
I 78.5%
II 58.8%
III 43.2%
IV 13.0%

Maggino et al. found the following five-year survival rates by site of recurrence:

  • Perineal: 60%

  • Inguinal/pelvic: 27%

  • Distant: 15%

  • Multiple recurrences: 14%

B. "What if" scenarios

Do all patients with early stage vulvar carcinoma and a positive sentinel node need full lymphadencetomy?

Currently, all patients with a positive sentinel node should have a complete inguinofemoral lymphadenectomy. The GROINSS-V trial looked for a possible cut off point and showed that patients with isolated tumor cells in sentinel nodes had a 97% five-year survival rate. The authors did not use this as a cut off point for omitting a full lymphadenectomy because the study did not account for the possible therapeutic effect of inguinofemoral lymphadectomy performed in all node positive disease.

Can radiation be substituted for lymphadenectomy in patients with early stage disease and positive sentinel nodes?

Currently lymphadectomy is performed by most surgeons, but this question is being addressed by the ongoing GROINNS-V-II study.

6. Follow up surveillance and therapy management of recurrences

Recurrence

The rate of recurrence has been reported to be between 24-37%. Of those recurrences, 40-60% will be in the first two years, with half of them being a localized recurrence. Risk factors of recurrence are positive lymph nodes, LVSI, and > stage II (by FIGO 1998). In terms of local recurrence, surgical margins are the most important prognostic indicator.

The pattern of recurrence is related to nodal status at the time of initial surgery. Positive nodes were predictive of distant and multiple recurrences and a low rate of isolated local recurrence (23% in node positive and 57% in node negative cases). Additionally, positive nodes predicted earlier recurrence and are the most important factor in determining survival.

Follow up

There is no set schedule for follow up of vulvar cancer. Suggested regimens range from every three to six months for two years, then bi-annually until year five, an annually thereafter. The exam includes inspection of the vulva, perineum, surgical sites, and inguinal nodes. Colposcopy can also be performed if indicated.

Treatment of recurrence

Treatment options for recurrent disease are based on location, but there is limited data for therapeutic recommendations.

Isolated recurrence

Local recurrences have a good prognosis, with one study showing a 51% five-year survival rate when treated with radical local excision. In those not previously radiated, some authors recommend radiation in addition to surgical resection. In those with previous groin node dissection, depending on the location of the recurrence, lymphadenectomy may be appropriate.

Advanced local recurrence

Most of these patients have already received radiation therapy, which limits therapeutic options. For central pelvic recurrences, exenteration had a five-year survival rate of 38% in one small study. However, the surgery is quite morbid, so patient screening for appropriate candidates is very important. Neoadjuvant radiation or chemoradiation along with radical local excision have been successful in avoiding exenteration and its associated morbidity.

Nodal or distant metastatic recurrence

The prognosis in both of these groups is poor. Treatment of inguinal recurrence is dictated by the presence or absence of prior radiation. In those without previous radiation, excision with radiation or chemoradiation is recommended. In patients who have had radiation to the inguinal area, surgery is contraindicated, given radiation predisposes to a high rate of complications. No standard therapy is available, but palliative brachytherapy or chemotherapy have been suggested.

Few studies have looked at treatment options for metastatic disease. Therapeutic strategies are generally individualized. Cisplatin, 5-fluorouracil, and bleomycin are the most commonly used chemotherapeutic agents. Topotecan has shown promise when used as a single agent and in combination, but its utility is limited by significant hematological toxicity.

Recently, biological agents which target EGFR (epidermal growth factor receptor) have shown promise. EGFR has been shown to inhibit apoptosis and increase metastatic potential. Monoclonal antibodies that block EGFR (e.g., Gefitinib and cetuximab) and theEGFR tyrosine kinase inhibitor erlotinib are currently being investigated. Case reports of erlotinib alone and cetuximab with radiation and ciplatin have shown promising results.

7. What is the evidence for specific management and treatment recommendations?

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