Surgical Margins

Surgical margin status is a powerful predictor of local recurrence, with most oncologists agreeing that patients with positive margins experience increased local recurrence and decreased overall survival. The classic study by Heaps et al of surgical-pathologic factors in 135 women with vulvar cancer treated surgically without adjuvant therapy showed that the strongest predictor of local recurrence was pathological margin <8 mm measured from formalin-fixed tissue (<10 mm clinically in fresh tissue).2 All 21 vulvar recurrences in the Heaps study had a margin <8 mm; the local recurrence rate was 62% for patients whose margin was <4.8 mm.2 The prognostic significance and threshold for pathologically close margins, however, has been debated, with some authors arguing that any close margin is associated with an increased risk of local recurrence and others suggesting that only microscopically positive margins are relevant.2 6–8 Multiple studies have reported that for patients with pathologic margins <8 mm, the local recurrence rate is approximately 50%, whereas those with greater margins experience no local recurrences.2 9–12 In a large retrospective review of 205 patients with stage I–IVA vulvar cancer, for example, compared with patients with negative margins (>10 mm clinically), both those with close and positive margins had significantly increased risk of local recurrence (hazard ratios 3.03 and 7.02, respectively).7 Conversely, a retrospective study of 130 patients with vulvar cancer reported a significantly higher local recurrence risk for patients with pathologic margins of 2 mm or less,13 and the AGO-CaRE-1 multicenter retrospective study suggested that only microscopically positive margins are relevant.14 In the AGO-CaRE-1 study, local recurrence rates were 12.6% in patients with a margin <8 mm and 10.2% in patients with a margin ≥8 mm, with no significant association between margin distance and local recurrence on multivariate analysis.14 Another retrospective Dutch study (where all pathology slides were independently reviewed by two expert pathologists) reported that pathologic margin distance was not associated with local recurrence irrespective of cut-off point used (8 mm, 5 mm, or 3 mm).15 On multivariable analysis, differentiated vulvar intraepithelial neoplasia in the margin, differentiated vulvar intraepithelial neoplasia and lichen sclerosis in the margin, and FIGO stage II or higher disease were independently associated with a higher local recurrence rate.15 The systematic review by Grootenhuis et al showed that the prognostic relevance of a pathological free margin of <8 mm remains questionable.3

The extent of margin size is clinically important as more extensive and more radical surgery is disfiguring, disabling, and associated with significant morbidity; the use of smaller margins with appropriate adjuvant therapy might save women from treatment-related distress.16 A 2019 retrospective study reviewed the outcomes of patients with FIGO stage IA and IB vulvar squamous cell carcinoma with close or positive margins (defined as <8 mm), to determine whether further therapy with re-excision or adjuvant radiotherapy would improve local recurrence-free survival compared with no further therapy.17 Of the 47 patients included in the final analysis, 21 received additional treatment with either re-excision (n=17) or radiotherapy (n=4).17 There was no difference in recurrence or death after adjusting for age and margin status (HR 0.29, p=0.2), although there was a trend towards improved local control with additional therapy.17

Additional Risk Factors for Local Recurrence

Additional risk factors for local recurrence include lymphovascular space invasion, depth of invasion, and tumor size. The Heaps study showed that in addition to pathological margin <8 mm, positive lymphovascular space invasion and depth of invasion >5 mm also correlated with local recurrence.2 An analysis of prognostic factors in 194 patients with vulvar cancer identified depth of invasion >1 mm as a significant prognostic factor and found the highest risk of local failure in patients with tumor size ≥6 cm and depth of invasion >4 mm or tumor size >8 cm irrespective of depth of invasion.18 Other authors have similarly described increased risk of recurrence in tumors ≥4 cm.19–22

Role of Post-operative Radiotherapy to the Vulva

Local recurrence is associated with decreased disease-specific survival and overall survival as recurrences are often unsalvageable.5 23 Post-operative radiotherapy has been used to optimise local control in patients with high-risk features, including positive or close margins (where further re-excision is not feasible), tumor size >4 cm, lymphovascular space invasion, and depth of invasion ≥5 mm.2 7 9 22 23 In a retrospective cohort of patients who underwent surgical resection for stage I–IV vulvar squamous cell carcinoma, the addition of post-operative radiotherapy decreased the risk of local recurrence for patients with positive or close (<8 mm) margins and improved overall survival for patients with positive margins.23 A larger multicenter retrospective study of 257 patients showed that among patients with positive/close margins (defined as <10 mm), 5-year overall survival was significantly longer for those who received adjuvant radiotherapy (67.6% vs 29%, p<0.001).24 Another study with 205 patients found that adjuvant radiotherapy decreased local recurrence for women with positive margins only but not close margins.7 A dose–response relationship was observed in this cohort—for the 39 women who received vulvar radiotherapy, the crude rate of local recurrence was 21% for women receiving ≥56 Gy and 34% for those receiving ≤50.4 Gy (p=0.046).7

Multiple international consensus guidelines recommend that post-operative radiotherapy should be considered for all women with positive margins (where re-excision is not feasible) and close margins.25–28 Notably, adequate margin size remains debated and there is no consensus for the threshold below which post-operative radiotherapy is recommended.27 Radiotherapy may also be considered for women with other factors that have been shown to be predictive of local recurrence, such as tumor size >4 cm, positive lymphovascular space invasion, and a depth of invasion >5 mm.28

Nodal Evaluation

Inguinofemoral nodal status is the important prognostic factor in vulvar cancer and inguinofemoral nodal recurrences are almost universally fatal.12 29 Nodal management has historically involved either a unilateral or bilateral inguinofemoral lymphadenectomy, which is associated with significant morbidity, including wound dehiscence, infection, seroma formation, thrombosis, chronic lymphedema, and psychosexual impairment.30 31 Given these problems, alternative treatments such as sentinel lymph node biopsy have been evaluated as morbidity-reducing alternatives to inguinofemoral lymphadenectomy32; this is based on the premise that there is a first lymph node in a chain of lymph nodes draining a particular area of the body. If the sentinel lymph node is negative for metastasis, then the remainder of the lymph nodes in the region should also be free of tumor cells, and therefore, a full inguinofemoral lymphadenectomy can be avoided. A multicenter observational study (GROINSS-V I) showed that when full inguinofemoral lymphadenectomy was omitted in 259 patients with unifocal disease <4 cm and negative sentinel nodes, actuarial rate for groin recurrence after 2 years was 2.3%, with a 3-year overall survival rate of 97%.33 For patients with positive sentinel nodes, completion inguinofemoral lymphadenectomy was performed and the proportion of patients with additional non-sentinel nodal metastases increased with the size of sentinel-node metastasis: from 4.2% with isolated tumor cells to 62.5% with sentinel nodal metastasis >10 mm.34 GOG 173 showed that sentinel lymph node biopsy had a sensitivity of 91 .% and false-negative predictive value of 3.7% in patients with vulvar cancer 2–6 cm. The false-negative predictive value was 2% in patients with tumor <4 cm.32

Prognostic Significance of Positive Lymph Nodes

It is well established that patients with two or more positive lymph nodes have an increased risk of recurrence and death.18 35 The role of radiotherapy in mitigating this poor prognostic factor has been explored. GOG 37 randomized patients with positive inguinal nodes to pelvic lymphadenectomy versus post-operative radiotherapy (45–50 Gy to pelvis midplane halfway between the superior border of the obturator foramina and L5/S1) covering the pelvic and inguinal lymph nodes (but not the vulvar bed).35 Post-operative radiotherapy was shown to decrease groin recurrence (24% vs 5%) and improve 2-year overall survival (68% vs 54%) and 6-year overall survival rates (36% vs 13%).35 36 On subgroup analysis, this benefit was retained in patients with clinically positive or fixed ulcerated nodes and in patients with two or more positive lymph nodes. There was no significant benefit for patients with only one positive node.36 Similar results were described by Aragona et al, who reported that compared with patients with negative nodes or one positive node, those with two or more positive nodes have an increased risk of recurrence.18 GOG 37, however, was underpowered to evaluate the effect of radiotherapy for a single positive node.36 A Surveillance, Epidemiology and End Results analysis of women with vulvar cancer with positive inguinal nodes demonstrated a survival benefit to adjuvant radiotherapy versus no adjuvant treatment (54 vs 24 months; p<0.01).37 The benefit of radiotherapy persisted in women with just one positive node (median survival not reached versus 39 months; p<0.01).37 Similar results were seen in a National Cancer Database study where post-operative radiotherapy yielded a survival advantage for women with one positive node (HR 0.81 p=0.027) and women with two or more positive nodes (HR 0.59, p<0.001).38 The authors argue that all patients with node-positive vulvar cancer should receive adjuvant radiotherapy.37 38

Lymph node ratio, defined as the number of positive lymph nodes divided by the total number of lymph nodes excised, also remains an important prognostic factor—patients with a lymph node ratio >20% have been shown to have an increased risk of recurrence (58% vs 36%) and cancer-related death (58% vs 33%) than patients with lymph node ratio ≤20%.36 39 Post-operative radiotherapy has been shown to improve overall survival in patients with high lymph node ratios.36 39

Lastly, extranodal extension has been shown to be an additional poor prognostic factor, regardless of the number of positive lymph nodes. A retrospective review of 71 patients identified the presence of extranodal extension as the most significant prognostic factor for survival.40 Similarly, in a 2016 meta-analysis, patients with extranodal extension had significantly higher rates of all-cause mortality, cancer-specific mortality, and recurrence.41

GROINSS-V II

The GROINSS-V II is a phase II single-arm treatment trial with stopping rules, investigating whether radiotherapy is a safe alternative to inguinofemoral lymphadenectomy in patients with unifocal vulvar squamous cell carcinoma <4 cm, no signs of lymph node involvement at imaging, and sentinel node metastases at surgery.42 Between 2005 and 2016, 322 (21%) of 1535 registered patients had sentinel node metastasis. In June 2020, the stopping rule was activated when 10 out of 91 sentinel node-positive patients developed isolated groin recurrence (exceeded the predefined threshold). Nine out of the 10 patients had sentinel node metastases >2 mm and/or extranodal extension. Therefore, the protocol was amended to allow only patients with micrometastasis ≤2 mm to receive radiotherapy; those with sentinel node macrometastasis >2 mm underwent inguinofemoral lymphadenectomy (with radiotherapy if ≥2 nodes positive, extranodal extension, or single nodal metastasis >2 mm). The protocol radiotherapy dose was 50 Gy in 25–28 fractions of 1.8–2 Gy. Final analysis showed 19 groin recurrences among the 162 patients with sentinel node metastases >2 mm (12.2% at 2 years). For these patients, the 2-year groin recurrence rate was 22% with radiotherapy versus 6.9% with a completion inguinofemoral lymphadenectomy ±post-operative radiotherapy (p=0.011). Of the 160 patients with sentinel node micrometastases (≤2 mm), 126 received radiotherapy, 16 underwent inguinofemoral lymphadenectomy, and 18 received no further treatment. Six isolated groin recurrences occurred (3.8% at 2 years). The 18 patients who did not receive any further treatment had a significantly higher ipsilateral isolated groin recurrence rate than those who were treated with radiotherapy according to protocol (2 year 11.8% vs 1.6%, p=0.006).42 Overall, GROINSS-V II showed that inguinofemoral radiotherapy with 50 Gy is a safe alternative to inguinofemoral lymphadenectomy in patients with sentinel node metastasis ≤2 mm, but not for patients with sentinel node metastasis >2 mm.42 In addition, lymphedema risk was 10.7% at 12 months with sentinel lymph node biopsy plus radiotherapy, and highest with sentinel lymph node biopsy plus inguinofemoral lymphadenectomy ±radiotherapy (22.9% at 12 months).

Indications for Post-operative Nodal Radiotherapy

Five-year overall survival rate decreased from 90% in vulvar cancer with uninvolved nodes to 65–75% with one or two positive nodes and decreased even further to 24–28% with four or more positive nodes.22 39 43 Data support the use of post-operative radiotherapy in patients following inguinofemoral lymphadenectomy, in the setting of two or more positive lymph nodes, any extranodal extension, and/or an lymph node ratio >20%, to improve overall survival for these patients. For patients with a single positive node >2 mm following inguinofemoral lymphadenectomy, post-operative radiotherapy should be strongly considered.37 44

Patients with sentinel node metastasis >2 mm following sentinel node biopsy should undergo completion inguinofemoral lymphadenectomy followed by post-operative radiotherapy—based on the GROINSS-V II study, the 2-year isolated groin recurrence rate remains unacceptably high (22%) with radiotherapy alone.42 Patients with sentinel node metastasis ≤2 mm can be safely treated with post-operative radiotherapy, which results in a low groin recurrence rate (2-year isolated groin recurrence rate 1.6%42; Figure 1).

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Figure 1

Treatment algorithm: nodal disease. *RT is indicated if ≥ 2 lymph nodes positive and/or extranodal extension, and should be strongly considered if single nodal metastasis > 2 mm. LND, lymph node dissection; RT, radiotherapy.

Radiotherapy Dose Prescription

There are limited data on the optimal dose of post-operative radiotherapy with most studies commonly using 45–50 Gy in 1.8–2 Gy fractions. Viswanathan et al reported that radiotherapy to a dose of 56 Gy could mitigate the significantly increased risk of local recurrence in patients with close or positive margins. Chapman et al49 reviewed the dose–response relationship in the setting of adjuvant radiotherapy in margin-positive vulvar squamous cell carcinoma and found that patients receiving ≥54 Gy experienced a reduction in mortality compared with those receiving 30–45 Gy.49 No benefit was found for higher radiotherapy doses beyond 60 Gy. Unfortunately, due to the nature of the study, data on the treated volumes and toxicity were not available.49 In a smaller retrospective review of 51 patients who underwent vulvectomy followed by inguinofemoral lymphadenectomy, patients receiving >54 Gy of post-operative radiotherapy had a lower risk of progression and death.50 Higher radiotherapy doses are required for grossly involved regions, and dose escalation is being evaluated in ongoing trials.51 52 In GOG 205, which included 58 patients with cT3 or T4 tumors who received pre-operative radiotherapy (with a planned surgical resection), the clinical complete response rate was 64% after a dose of 57.6 Gy.51

The National Cancer Comprehensive Network guidelines suggest 45–50 Gy to the primary surgical bed in the setting of negative margins, and 54–60 Gy for close or positive margins.47 For nodal bed, the suggested dose is 50–55 Gy if pathologically node positive with no extranodal extension or gross residual disease, 54–64 Gy if extranodal extension, and 60–67 Gy for gross residual nodal disease.47 Beyond investigating the addition of concurrent chemotherapy, the ongoing GROINSS-V III study is also evaluating the role of increasing the total dose in the involved groin from 50 to 56 Gy by applying a boost.42