Abstract

Context: Vulval cancer surgery has become more conservative and it is important to understand whether resection margins alone influence recurrence rates or whether other prognostic factors should be considered when planning treatment. Aims: The aim of this study is to define factors that predict vulval cancer recurrence, enabling development of a recurrence prediction model. Settings and Design: This was a Aretrospective descriptive analysis of new vulval squamous cell carcinoma cases in a gynecological oncology center (January 1, 2007 to December 31, 2013). Subjects and Methods: Analysis of tumor characteristics and treatments. Patient outcomes were recorded, identifying recurrences, and subsequent interventions. Statistical Analysis Used: Univariable and multivariable logistic regression tools applied to determine recurrence risk factors. Results: Seventy patients underwent primary vulval surgery. Bilateral groin node dissection was performed in 26/70 (37.1%) cases and unilateral groin node dissection in 9/70 (12.9%) cases. 57/70 (82%) cases had a negative vulval resection margin, with 67% <8 class="b" xss=removed>Conclusions: We reported a reduction in the size of tumor-free margins at primary excision. The recurrence rate of 30% is within the previously reported range, suggesting that factors aside from resection margin (LVSI, stage, and groin node involvement) are also important in predicting recurrence. These factors should be incorporated into a prediction model when planning adjuvant treatment.

Introduction

In 2014, 1289 new cases of vulval cancer were reported in the UK, with a crude mortality rate of 1.5/100,000 women.[1] Recurrence rates range from 15% to 33%, mostly in the vulva and groin.[2] Several prognostic variables can influence recurrence and overall survival: disease-free margin, depth of invasion, lymphovascular space invasion (LVSI), the size of the primary tumor, and stage of the disease.[3],[4]

Surgical management of vulval cancer has previously been defined by large vulval excisions that achieve the required margins and depth to reduce recurrence, usually at the expense of significant patient morbidity. Sacrificing continence mechanisms to achieve margin status impacts on the quality of life, so there has been a shift toward suboptimal margins.

Heaps et al. recommend that a minimum of 8 mm is an acceptable tumor-free margin.[5] De Hullu et al. reported a small but significant increase in the overall recurrence rate with more conservative surgery.[6] The study also highlighted that surgical margins were prone to shrinkage and excision margins of 2 cm should be considered to ensure a tumor-free margin of at least 8 mm. Our evidence to define a “good margin” is in these two studies. These conclusions were reinforced in Van der Velden's Cochrane review, although also acknowledged that the main observational studies are over 10 years old.[6],[7],[8],[9] The recent AGOCaRE-1 multicenter study concluded that tumor-free margin distance may not be as significant as first thought, but this did not include UK centers.[10]

Depth of tumor invasion also influences the risk of recurrence. Hacker et al. reported a depth of invasion above 1 mm as significant in predicting nodal metastasis, with risk increases proportionally to depth.[11] Subsequently, inguinofemoral lymphadenectomy is now recommended for tumor depth >1 mm.

Following excision, adjuvant treatment is recommended if margins are involved, but other factors have been less influential in guiding treatment decisions. Currently, no prediction model exists to identify recurrences irrespective of margin status. The aim of this study was to further define these factors, aiding the development of a recurrence prediction model.

Subjects and Methods

All new cases of squamous cell carcinoma of the vulva treated in our center from January 1, 2007 to December 31, 2013 were reviewed to determine factors that influence recurrence in vulval cancer. In 2007, expansion of the minimum dataset for histopathological reporting of vulval neoplasms was introduced by the Royal College of Pathologists and to maintain consistency, all cases were reviewed from 2007.

Cases were identified through patient coding and electronic patient records. Data were collected from electronic patient records, patient notes, and pathology database to ensure full details of demographics, pathological features, and recurrences were available for analysis.

Patients had their definitive surgery performed by a designated gynecological oncologist. Tumors were excised with a 2-cm healthy skin and tissue excision margin wherever possible. If this was not achieved, the decision-making and reasoning were recorded carefully; for example, to preserve continence. If the depth of invasion on biopsy was ≥1 mm, ipsilateral or bilateral groin node dissection was performed either as a combined procedure or as a subsequent procedure. Bilateral groin node dissection was required in tumors of the labia minora, central tumors within 1 cm of the midline, or large lateral lesions of >2 cm, while ipsilateral dissection was performed in the remaining cases. In some cases, full groin node dissection was not performed despite being clinically indicated due to significant patient comorbidities.

The surgical technique and approach was in keeping with a previous review of vulval cancer management in this region by Falconer et al. [12] Analysis of adherence to these standards [Table 1] in this cohort allows for comparison of management with the 1997–2002 cohort and can further differentiate trends in surgical management. A small group of patients (n = 3) were eligible for participation in the GROINSS-VI trial, assessing the role of sentinel lymph node dissection in the management of vulval cancer. However, two of these cases were still within the “learning curve” component of the trial, so a full groin node dissection was performed in addition to the sentinel node detection and biopsy. Histological samples were examined by the pathology team, led by an experienced gynecological histopathologist (JP). Information was recorded according to the Royal College of Pathologists' minimum dataset [Table 2].[3]

| Figure 1  Overall survival in patients treated for vulval cancer

| Figure 2  Disease-free interval in patients treated for vulval cancer

Discussion and Conclusions

Falconer et al. carried out a prospective audit between 1997 and 2002 and found that the proportion of cases with a tumor-free margin >8 mm reduced from 54% to 35% during the study period. This pattern appears to have continued within our cohort, with 18/70 (26%) cases having tumor-free margins >8 mm [Figure 3]. The reasons for the reduction in adequate histological margin are multifactorial: seemingly adequate skin margins at surgery but clinically occult involvement of apparently healthy skin, reduced skin margins for the preservation of urethral and anal function, and more conservative surgery on older patients who are less likely to tolerate extensive morbidity-inducing surgery.

Logistic regression analysis was performed to predict recurrence. The most significant factors in predicting recurrence were found to be LVSI, positive groin histology, and stage of disease. Cox-regression analysis was also used to predict recurrence, using the disease-free interval as the outcome measure, but none of the factors were found to be statistically significant.

| Figure 3  Tumor-free skin margins

Within our cohort, 68% (49/72) patients were aged 70 or over at diagnosis, which is much higher than the overall UK average. The Cancer Research UK Statistics report that 55% of vulval cancer cases in the UK each year are diagnosed in females aged 70 and over (2012–2014).[1]

Counseling patients for groin dissection surgery, more extensive vulval excision and radiotherapy will undoubtedly include discussion of the impact of treatment on survival, prognosis, and risk of recurrence. It could be argued that patients at the upper end of the age range are less likely to opt for more aggressive treatments that will impact significantly on their quality of life at a time when other comorbidities are likely to be more influential in their life expectancy.

In this study, there were several cases where groin dissection was not performed due to patient comorbidities, despite being clinically indicated. It is possible that with the introduction of more sentinel lymph node surgery in vulval cancer, those patients who would have previously been deemed unfit for full groin node dissection or were not willing to pursue such surgery could opt for this less invasive and less complicated procedure. This in turn would enable more effective triage of patients who are likely to benefit from more justified adjuvant treatment or a full lymphadenectomy.

The recurrence rate in this study was 30% of cases, which is within the range of reported recurrence rates in the literature (15%–33%).[14] The mean time for recurrence was at 24 months, and 14/21 (67%) recurrences occurred locally at the vulva. One of the statistically significant factors for recurrence was found to be the involvement of the lateral skin margin, so more conservative surgery may account for a recurrence rate which is at the higher end of reported rates. However, LVSI, stage, and positive groin histology were also statistically significant in predicting recurrence, so these factors also need to be considered carefully in decision-making about adjuvant treatment and repeat surgery.

There were seven cases of groin recurrence, which accounted for one-third of all recurrences. However, only two of these cases were true recurrences since the remainder did not have any prior groin surgery at the site of recurrence: One case had previously negative groin histology and so did not have adjuvant radiotherapy, while the other case had positive groin histology and received external beam radiotherapy. It is difficult to draw conclusions about these two cases, but one consideration is whether initial groin dissection was extensive enough to remove all of the inguinofemoral lymph nodes. Previous research has debated over the extent of inguinofemoral lymphadenectomy and whether the saphenous vein should be preserved to reduce complications such as wound breakdown, cellulitis, and lymphedema, although this could leave residual lymph node tissue with microscopic disease. Thomas et al. reported a similar incidence of recurrent disease with and without saphenous vein sparing in their study.[15]

The question of this study was whether surgical techniques have become too conservative and are adversely affecting recurrence rates. The main factors that contribute to recurrence were identified as LVSI, lateral margin involvement, positive groin histology, and increasing stage of tumor. It appears that margin involvement is a significant contributor, and in fact, the proportion of margins <8>

In terms of influencing factors regarding disease-free interval, there was not a clear significant factor identified within this study. It, therefore, seems that our current surveillance program is acceptable and there is no indication to tailor the follow-up interval according to the particular patient or tumor factors.

Resection margins will contribute to recurrence rates, but decision-making regarding primary treatment and adjuvant treatment should also incorporate other significant factors such as presence of LVSI, tumor stage, and groin node status. These factors can be incorporated into a recurrence prediction model, and this will be the next stage of our research.

In addition, it is very clear from this study that many patients who were eligible for adjuvant treatment or groin node dissection did not always opt for these interventions. There can often be a multidisciplinary team decision that such treatments are not suitable for older patients with significant comorbidities, particularly if a recurrence is not likely to occur within their life expectancy. However, with increased tumor stage and groin involvement being predictive of recurrence, we should aim to deliver either sentinel or full groin node dissection and adjuvant radiotherapy for the majority of our patients if it is indicated. Patients may choose to decline these interventions, but this should be following a detailed discussion of the risks and benefits and should then be fully documented. The role of groin ultrasound scanning in disease surveillance should be considered for patients who decline groin surgery and adjuvant treatment despite clinical indications.

1.  Cancer Research. Information Originally Obtained from Office National Statistics. http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/vulval-cancer#heading-Two Available from: [Last accessed on 2017 Jul 16]
2.  Royal College of Obstetricians and Gynaecologists/British Gynaecological Cancer Society. Guidelines for the Diagnosis and Management of Vulval Carcinoma. London, UK: Royal College of Obstetricians and Gynaecologists/British Gynaecological Cancer Society; 2014
3.  Royal College of Pathologists. Datasets for the Histopathological Reporting of Vulval Neoplasms. 3rd ed. London, UK: Royal College of Pathologists; 2010
4.  Yap J, O'Neill D, Nagenthiran S, Dawson CW, Luesley DM. Current insights into the aetiology, pathobiology, and management of local disease recurrence in squamous cell carcinoma of the vulva. BJOG 2017; 124: 946-54
5.  Heaps JM, Fu YS, Montz FJ, Hacker NF, Berek JS. Surgical-pathologic variables predictive of local recurrence in squamous cell carcinoma of the vulva. Gynecol Oncol 1990; 38: 309-14
6.  De Hullu JA, Hollema H, Lolkema S, Boezen M, Boonstra H, Burger MP. et al. Vulvar carcinoma. The price of less radical surgery. Cancer 2002; 95: 2331-8
7.  Van der Velden J. Surgical interventions for early squamous cell carcinoma of the vulva. Cochrane Database of Systematic Reviews 2000; 2 Art. No.: CD002036. DOI: 10.1002/14651858.CD002036.
8.  Burke TW, Levenback C, Coleman RL, Morris M, Silva EG, Gershenson DM. et al. Surgical therapy of T1 and T2 vulvar carcinoma: Further experience with radical wide excision and selective inguinal lymphadenectomy. Gynecol Oncol 1995; 57: 215-20
9.  DiSaia PJ, Creasman WT, Rich WM. An alternate approach to early cancer of the vulva. Am J Obstet Gynecol 1979; 133: 825-32
10.  Woelber L, Griebel LF, Eulenburg C, Sehouli J, Jueckstock J, Hilpert F. et al. Role of tumour-free margin distance for loco-regional control in vulvar cancer-a subset analysis of the Arbeitsgemeinschaft Gynäkologische Onkologie CaRE-1 multicenter study. Eur J Cancer 2016; 69: 180-8
11.  Hacker NF, Van der Velden J. Conservative management of early vulvar cancer. Cancer 1993; 71: 1673-7
12.  Falconer AD, Hirschowitz L, Weeks J, Murdoch J. South West Gynaecology Tumour Panel. The impact of improving outcomes guidance on surgical management of vulval squamous cell cancer in Southwest England (1997-2002). BJOG 2007; 114: 391-7
13.  Moskovic EC, Shepherd JH, Barton DP, Trott PA, Nasiri N, Thomas JM. et al. The role of high resolution ultrasound with guided cytology of groin lymph nodes in the management of squamous cell carcinoma of the vulva: A pilot study. Br J Obstet Gynaecol 1999; 106: 863-7
14.  Piura B, Masotina A, Murdoch J, Lopes A, Morgan P, Monaghan J. et al. Recurrent squamous cell carcinoma of the vulva: A study of 73 cases. Gynecol Oncol 1993; 48: 189-95
15.  Dardarian TS, Gray HJ, Morgan MA, Rubin SC, Randall TC. Saphenous vein sparing during inguinal lymphadenectomy to reduce morbidity in patients with vulvar carcinoma. Gynecol Oncol 2006; 101: 140-2

| Figure 1  Overall survival in patients treated for vulval cancer

| Figure 2  Disease-free interval in patients treated for vulval cancer

| Figure 3  Tumor-free skin margins

1.  Cancer Research. Information Originally Obtained from Office National Statistics. http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/vulval-cancer#heading-Two Available from: [Last accessed on 2017 Jul 16]
2.  Royal College of Obstetricians and Gynaecologists/British Gynaecological Cancer Society. Guidelines for the Diagnosis and Management of Vulval Carcinoma. London, UK: Royal College of Obstetricians and Gynaecologists/British Gynaecological Cancer Society; 2014
3.  Royal College of Pathologists. Datasets for the Histopathological Reporting of Vulval Neoplasms. 3rd ed. London, UK: Royal College of Pathologists; 2010
4.  Yap J, O'Neill D, Nagenthiran S, Dawson CW, Luesley DM. Current insights into the aetiology, pathobiology, and management of local disease recurrence in squamous cell carcinoma of the vulva. BJOG 2017; 124: 946-54
5.  Heaps JM, Fu YS, Montz FJ, Hacker NF, Berek JS. Surgical-pathologic variables predictive of local recurrence in squamous cell carcinoma of the vulva. Gynecol Oncol 1990; 38: 309-14
6.  De Hullu JA, Hollema H, Lolkema S, Boezen M, Boonstra H, Burger MP. et al. Vulvar carcinoma. The price of less radical surgery. Cancer 2002; 95: 2331-8
7.  Van der Velden J. Surgical interventions for early squamous cell carcinoma of the vulva. Cochrane Database of Systematic Reviews 2000; 2 Art. No.: CD002036. DOI: 10.1002/14651858.CD002036.
8.  Burke TW, Levenback C, Coleman RL, Morris M, Silva EG, Gershenson DM. et al. Surgical therapy of T1 and T2 vulvar carcinoma: Further experience with radical wide excision and selective inguinal lymphadenectomy. Gynecol Oncol 1995; 57: 215-20
9.  DiSaia PJ, Creasman WT, Rich WM. An alternate approach to early cancer of the vulva. Am J Obstet Gynecol 1979; 133: 825-32
10.  Woelber L, Griebel LF, Eulenburg C, Sehouli J, Jueckstock J, Hilpert F. et al. Role of tumour-free margin distance for loco-regional control in vulvar cancer-a subset analysis of the Arbeitsgemeinschaft Gynäkologische Onkologie CaRE-1 multicenter study. Eur J Cancer 2016; 69: 180-8
11.  Hacker NF, Van der Velden J. Conservative management of early vulvar cancer. Cancer 1993; 71: 1673-7
12.  Falconer AD, Hirschowitz L, Weeks J, Murdoch J. South West Gynaecology Tumour Panel. The impact of improving outcomes guidance on surgical management of vulval squamous cell cancer in Southwest England (1997-2002). BJOG 2007; 114: 391-7
13.  Moskovic EC, Shepherd JH, Barton DP, Trott PA, Nasiri N, Thomas JM. et al. The role of high resolution ultrasound with guided cytology of groin lymph nodes in the management of squamous cell carcinoma of the vulva: A pilot study. Br J Obstet Gynaecol 1999; 106: 863-7
14.  Piura B, Masotina A, Murdoch J, Lopes A, Morgan P, Monaghan J. et al. Recurrent squamous cell carcinoma of the vulva: A study of 73 cases. Gynecol Oncol 1993; 48: 189-95
15.  Dardarian TS, Gray HJ, Morgan MA, Rubin SC, Randall TC. Saphenous vein sparing during inguinal lymphadenectomy to reduce morbidity in patients with vulvar carcinoma. Gynecol Oncol 2006; 101: 140-2