Best Practice & Research Clinical Obstetrics and Gynaecology

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1 YBEOG_proof April 0 / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (0) e Contents lists available at ScienceDirect Best Practice & Research Clinical Obstetrics and Gynaecology journal homepage: Q Sentinel node biopsy in vulvar cancer: Implications for staging Q M.H.M. Oonk, MD, PhD a, *, H. Hollema, MD, PhD, Professor b, A.G.J. van der Zee, MD, PhD, Professor a, QQ Q a Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Hanzeplein, 00RB Groningen, The Netherlands b Department of Pathology, University Medical Center Groningen, University of Groningen, Hanzeplein, 00RB Groningen, The Netherlands Keywords: vulvar cancer sentinel node procedure lymph node metastasis micrometastasis staging In 00, the first Groningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V) showed that omission of inguinofemoral lymphadenectomy is safe in patients with early-stage vulvar cancer and a negative sentinel node and it simultaneously decreases treatment-related morbidity. An important part of the sentinel node procedure is pathologic ultrastaging of the removed sentinel nodes. Subsequently, since the introduction of this procedure in the standard care of patients with early-stage vulvar cancer, more and smaller inguinofemoral lymph node metastases have been diagnosed. The clinical consequences of these micrometastases are not clear yet. With increasing size of the sentinel node metastasis, chances of non-sentinel node metastases increase and those of survival decrease. The size of lymph node metastases is included in the latest staging system for vulvar cancer, however at this moment without clinical implications. Furthermore, a separate category for micrometastases is not incorporated yet. More research is needed to determine the clinical consequences of the size of (sentinel) lymph node metastases. 0 Elsevier Ltd. All rights reserved. * Corresponding author. Tel.: þ 0 00; Fax: þ 0. addresses: m.h.m.oonk@umcg.nl (M.H.M. Oonk), h.hollema@umcg.nl (H. Hollema), a.g.j.van.der.zee@umcg.nl (A.G.J. van der Zee). Tel.: þ 0 ; Fax: þ / 0 Elsevier Ltd. All rights reserved. for staging, Best Practice & Research Clinical Obstetrics and Gynaecology (0),

2 YBEOG_proof April 0 / M.H.M. Oonk et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (0) e Vulvar cancer With an annual incidence of two to three per 0,000 women, vulvar cancer is the fourth most common gynecological malignancy. In the last decades, the incidence of vulvar cancer has been increasing [,]. The most common histological type is squamous cell cancer, comprising about 0% of all vulvar malignancies. Other types such as melanomas, adenocarcinomas, and basal cell cancers are much less common. In this review, we focus on the staging and treatment of vulvar cancers of squamous cell origin. The mean age at diagnosis is about 0 years, and recent studies show that the increase in incidence rate is most pronounced in the oldest patient group (>0 years) []. Other studies, however, showed that the increase in incidence was especially attributable to the younger patients, and that this might be caused by an increase in premalignant human papillomavirus (HPV)-associated vulvar disease []. Squamous cell cancer of the vulva spreads by three routes: the initial metastatic spread occurs usually to the inguinofemoral lymph nodes. The overall incidence of inguinofemoral lymph node metastases is approximately 0%. The presence and number of inguinofemoral lymph node metastases is the most important prognostic factor in patients with vulvar cancer [,]. Both hematogenous spread and spread by direct extension are infrequent. Staging Vulvar cancer has been clinically staged until. Considering that palpation of the groins is inaccurate in approximately % of the patients [,], the International Federation of Gynecology and Obstetrics (FIGO) changed the vulvar cancer staging to a surgico-pathological system in. This staging system provided better discrimination of survival between stages than the 0 FIGO staging system []. In, stage IA was added to the staging system as studies showed that the risk of lymph node metastases in tumors with a depth of invasion mm was negligible []. In 00, FIGO staging and TNM classification were adjusted in order to allow for better prognostic discrimination between stages and less heterogeneity within stages. The number of lymph node metastases was shown to have a major impact on survival. In, the results of a Gynecologic Oncology Group (GOG) study showed a -year survival of >0% for patients with negative nodes, % for patients with one to two positive nodes, % for patients with three to four positive nodes, % for patients with five to six positive nodes, and 0% for patients with seven or more positive nodes []. In, Origoni was the first to report on the impact of the size of lymph node metastases on survival. He demonstrated -year cancerrelated survival rates of 0.% for patients with metastases < mm,.% for those with metastases > to < mm, and 0.0% for those with metastases > mm. He also demonstrated the impact of extracapsular tumor growth (.% vs. %) []. These results were confirmed by others [] and led to the incorporation of the number and size of lymph node metastases in the most recent staging system. Finally, bilaterality of lymph node metastases has been abolished, and the former stages I and II are combined in the revised classification system []. For an overview of the latest vulvar cancer TNM and FIGO classification, see Table. Treatment The cornerstone of treatment of patients with vulvar cancer is surgery. A Canadian study on patterns of care in patients with vulvar cancer showed that % had at least one surgical procedure, and approximately % received radiotherapy []. The standard treatment for squamous cell cancer of the vulva has changed dramatically over the last decades. Early in the 0th century, Basset was the first to propose en bloc dissection of the vulva and inguinofemoral lymph nodes []. Taussig and Way clinically applied the principles proposed by Basset and developed radical vulvectomy with inguinofemoral lymphadenectomy en bloc. [,] The radical approach replaced simple local excision in the second half of the last century and became the standard of care for a prolonged period. The rationale for this approach was the assumption that the prognosis is better after elective inguinofemoral lymphadenectomy compared to surveillance of the groins, despite the fact that only about 0% of patients will have lymph node metastases. Although highly effective, the morbidity of this treatment modality was very high. Wound breakdown, infections, and lymphedema were of great concern and they often for staging, Best Practice & Research Clinical Obstetrics and Gynaecology (0),

3 YBEOG_proof April 0 / Q Table TNM staging and FIGO staging. TNM FIGO T Confined to vulva/perineum Stage IA Ta N0 M0 Ta cm with stromal invasion mm Stage IB Tb N0 M0 Tb > cm or stromal invasion > mm Stage II T N0 M0 Stage IIIA T, T Na, b M0 T Lower urethra/vagina/anus involved Stage IIIB T, T Na, b M0 Stage IIIC T, T Nc M0 T Involvement of upper urethra/vagina, Stage IVA T, T N M0 bladder, rectal/mucosa, bone, fixed to T Any N M0 the pelvic bone Stage IVB Any T Any N M N0 Node negative Na Lymph node metastases, One to two nodes mm Nb One node > mm Na Three or more nodes < mm Nb Two or more nodes mm Nc Extracapsular spread N Fixed ulcerated nodes M0 No distant metastases M Distant metastases prolonged hospitalization. Since then, many modifications of surgery have been proposed in the treatment of patients with vulvar cancer. The aim of all modifications was to reduce the morbidity of vulvar cancer treatment without compromising survival rates. Strides were made with the introduction of inguinofemoral lymphadenectomy through separate groin incisions [], replacement of radical vulvectomy by wide local excision [], abandonment of bilateral lymphadenectomy in lateralized tumors < cm[0,], and abandonment of inguinofemoral lymphadenectomy in microinvasive tumors (<-mm depth of invasion) []. Due to these modifications, treatment-related morbidity has decreased, but is still significant for patients undergoing inguinofemoral lymphadenectomy, with longterm lymphedema and discomfort of the legs described in up to 0% of the patients [,]. At this moment, wide local excision with a tumor-free margin of e cm is advised for local treatment, with uni- or bilateral inguinofemoral lymphadenectomy, depending on the location of the tumor with respect to the midline. Only 0e0% of the patients with early-stage vulvar cancer will have lymph node metastases. The other 0e0% will probably not benefit from the inguinofemoral lymphadenectomy, but they are at a risk of the high morbidity associated with the procedure. Therefore, the most ideal approach would be a noninvasive procedure that is able to exclude lymph node metastases with a very high negative predictive value, resulting in about 0% of the patients who can safely be excluded from undergoing inguinofemoral lymphadenectomy. Until now, the results of imaging, such as computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, and positron emission tomography (PET), were not good enough to exclude lymph node metastases with a high enough negative predictive value []. The introduction of the sentinel node procedure provides a minimally invasive tool to assess lymph node status. Sentinel node biopsy M.H.M. Oonk et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (0) e The term sentinel node was first described by Gould et al. in their report on parotid gland cancer []. In, Cabanas performed lymphangiograms in 0 cases of penile cancer and demonstrated the existence of a specific lymph node center, the so-called sentinel lymph node (SLN). He described that this appeared to be the primary site of metastases from penile cancer []. The first application in vulvar cancer was reported in by Levenback et al., who used only blue dye in nine patients with vulvar cancer []. In their following paper in which they extended their series to patients, an identification rate of % was shown and intraoperative lymphatic mapping appeared to be safe and simple to perform []. In, De Hullu et al. published our results of a pilot study on the combined technique (blue dye and radioactive tracer) for SLN detection in patients with vulvar cancer [].Anidentification rate of 0% and no false negatives were demonstrated. Subsequently larger studies (in which the sentinel node for staging, Best Practice & Research Clinical Obstetrics and Gynaecology (0),

4 YBEOG_proof April 0 / M.H.M. Oonk et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (0) e Q procedure was always followed by a full lymphadenectomy) were designed in order to investigate the diagnostic accuracy of the SLN procedure in patients with early-stage vulvar cancer. In, Ansink et al. published their results of the sentinel node procedure with only blue dye in patients with vulvar cancer. This technique appeared to be inaccurate with only a % identification rate of a sentinel node and two false negatives [0]. In 000, de Hullu et al. presented our extended results of the combined procedure for sentinel node detection. A radioactive tracer and blue dye were used in patients with vulvar cancer. With an identification rate of 0% and no false negatives, this seemed a promising technique []. Subsequently, many other centers published their results on the application of the sentinel node procedure, followed by inguinofemoral lymphadenectomy. Identification rates were high, especially with the combined procedure, and false-negative rates low. In 00, a German multicenter study that included patients showed an identification rate of % and a false-negative rate of.%. The false-negative rate was high compared with the results reported in the literature until then. One explanation might be the inclusion of patients with TeT tumors on the condition that radical excision was possible. Two out of three false-negative cases occurred in patients with tumors of at least cm (0 and mm), indicating that larger tumors might be less suitable for sentinel node biopsy. Experience with the sentinel node procedure was not a requirement to participate in this multicenter study, which might be another explanation for the higher false-negative rate []. A Polish study including patients with vulvar cancer using the same inclusion criteria as GROINSS-V (Groningen International Study on Sentinel nodes in Vulvar cancer) also showed a very high false-negative rate. They described a falsenegative rate of %. The authors conclude that it is highly probable that the main factor responsible for the high false-negative rate was the surgeons' experience []. Table shows an overview of accuracy studies on the sentinel node application in vulvar cancer [0e]. In 00, the results of the first large prospective validation study were published, GROINSS-V. In this study, patients with squamous cell cancers of the vulva < cm and non-suspicious groin nodes at palpation were included. In these patients, sentinel node detection was performed using a radioactive tracer and blue dye. When the sentinel node was negative, inguinofemoral lymphadenectomy was omitted, and the patient was observed with follow-up every months for the first years after treatment. In the course of the study, groin recurrences occurred in a small proportion of patients with vulvar cancer having multifocal disease. We hypothesized that lymph flow in these tumors is more complex and not accurately predictable by the sentinel node procedure. This led to a protocol amendment, in which multifocal disease became an exclusion criterion. In patients with unifocal Table SN biopsy in vulvar cancer: an overview of accuracy studies. Author (year) Patients (n) Blue dye Radioactive tracer Lymphoscintigram Identification rate (%) False negatives Ansink Yes No No [0] DeCicco 000 No Yes Yes 0 0 [] De Hullu 000 Yes Yes Yes 0 0 [] Levenback 00 Yes No No 0 [] Sliutz 00 Yes a Yes Yes 0 0 [] Puig Tintore 00 Yes Yes Yes 0 [] Hauspy 00 Yes Yes No 0 [] Rob 00 Yes No No [] Yes Yes Yes 0 0 Vidal-Sicart 00 0 Yes Yes Yes 0 [0] Nyberg 00 Yes b Yes No [] Hampl 00 Yes c Yes Yes [] Radziszewski 0 Yes Yes Yes [] Levenback 0 Yes Yes d Yes d. [] Only studies with > patients were included. a Blue dye was only used in / cases. b Blue dye alone in / cases. c Radioactive tracer and blue dye in / cases. Radioactive tracer alone in / cases, eight blue dye alone. d All women underwent the procedure with blue dye. Preoperative lymphoscintigram and intraoperative radiolocalization were required beginning years after study activation. Ref. for staging, Best Practice & Research Clinical Obstetrics and Gynaecology (0),

5 YBEOG_proof April 0 / M.H.M. Oonk et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (0) e vulvar disease and a negative sentinel node, six groin recurrences were diagnosed after a median follow-up of months (.%; % confidence interval (CI) 0.e%), and the -year disease-specific survival rate was %. This study also showed a major decrease in treatment-related morbidity after sentinel node dissection compared with inguinofemoral lymphadenectomy (lymphedema.% vs..%, and recurrent erysipelas 0.% vs..%) []. Shortly after, Levenback et al. published their results of GOG, a large accuracy study on sentinel nodes and vulvar cancer, in which patients with tumors cm and cm were included. All patients underwent sentinel node biopsy, followed by inguinofemoral lymphadenectomy. In patients with a negative sentinel node, the false-negative predictive value was.%, and in women with a tumor cm.0% []. These results closely replicated those of GROINSS-V. Based on these two large studies, we recommend the application of the sentinel node procedure in the treatment of patients with early-stage vulvar cancer. However, in order to prevent fatal groin recurrences, the following criteria should be met: e Histologically proven primary squamous cell vulvar cancer with a depth of invasion > mm. e Tumors < cm, not involving anus/vagina/urethra e Unifocal tumor e No clinically suspicious lymph nodes e Enlarged lymph nodes excluded by preoperative imaging (CT/ultrasound/MRI) A major issue when performing the sentinel node procedure in vulvar cancer is the experience of the team that performs this multidisciplinary procedure. Only when high quality is ensured at each step of the procedure will fatal groin recurrences be avoided. Therefore, centers that wish to offer this procedure to their patients should have high enough exposure to guarantee good quality at every step of this multidisciplinary procedure. We advise an exposure of at least patients with vulvar cancer per year to maintain experience at a high enough level. Two recent studies showed that SLN biopsy is the most cost-effective strategy for the management of patients with early-stage vulvar cancer due to lower treatment costs and lower costs due to complications and its impact on quality of life [,]. Currently, GROINSS-V-II is ongoing. This observational study investigates whether radiotherapy to the groins is a safe alternative for inguinofemoral lymphadenectomy in patients with a positive sentinel node. The final results of this study are expected at the end of 0. Sentinel node detection protocol The day before the operation or the morning of the day of the operation, 0. ml of 0e0 MBq (depending on the local situation, interval between injection and surgery, sensitivity of the probe, etc.) m technetium-labeled nanocolloid (e.g., Solco Nuclear, Birsfelden, Switzerland) is injected circumferentially intradermally on four locations around the primary tumor. Half an hour before the injections, an anesthetic cream (e.g., lidocaineeprilocaine %) is applied on the vulva for pain relief. Anterior images are obtained using a single-head gamma camera with a low-energy high-resolution collimator. Within min after injection, dynamic imaging is started during 0 min. An anterior and lateral static image is obtained after. h. The first-appearing persistent focal accumulation is considered to be a sentinel node, especially when a direct connection from the injection site to the sentinel node is visible. On the day or the afternoon after the injection of the radioactive tracer, following induction of anesthesia,.0 ml of blue dye (e.g., Patent Blue V; Guerbet, Paris, France) is injected intradermally on the same four locations around the primary tumor approximately e min prior to the surgical procedure. The surgical procedure starts with identification and removal of the sentinel nodes. During operation, a handheld gamma ray detection probe (Neoprobe) is used to find the area of greatest activity in the groin. A small skin incision is made at this point and a sentinel node excision biopsy is performed using the handheld gamma ray detector and by dissection of blue-stained lymph vessels. Sentinel nodes are sent to the pathologist. Subsequently, resection of the vulvar lesion is performed. When identification of the sentinel node is not successful because of low radioactivity, the primary tumor is removed first. By resection of the primary tumor together with the primary for staging, Best Practice & Research Clinical Obstetrics and Gynaecology (0),

6 YBEOG_proof April 0 / M.H.M. Oonk et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (0) e nanocolloid injection sites, the radiation background is greatly reduced, allowing easier identification of the sentinel nodes, especially when the primary tumor is near the groin. After removal of the sentinel nodes, the biopsy bed is reexamined for radioactivity, and if higher than % of the first excised lymph node, the dissection is continued in search of additional sentinel nodes. Micrometastases The sentinel node procedure is rapidly gaining popularity, not only in vulvar cancer. In breast cancer and melanoma, the procedure is well documented and part of the standard of care for these patients [,]. However, the sentinel node procedure is upcoming in other solid tumors as well such as cervical cancer, colorectal cancer, and head and neck cancer [e0]. An important side effect of the procedure is that it enables pathologic ultrastaging of the first tumor-draining lymph node. Accurate examination of the sentinel node is thought to be crucial as this determines further therapy planning. False-negative sentinel node assessment leads to omission of lymphadenectomy, which may lead to tumor outgrowth of metastatic lymph nodes that have been left behind. Especially in vulvar cancer, missing lymph node metastases are extremely harmful as tumor recurrences in the groin are very hard to treat and often fatal []. Therefore, sentinel nodes are not only subjected to routine pathological examination with hematoxylin/eosin (H&E) sections. When routine examination shows no metastases, ultrastaging will be performed with multiple sectioning and immunohistochemistry (with AE/ antibodies). The optimal protocol for sentinel node assessment has not yet been established. A compromise has to be made between workload and sensitivity. In our protocol (GROINSS-V), after negative routine histopathological examination, additional pairs of sections are cut with three sections per millimeter (one section per 00 mm). One section of each pair is stained with H&E, and the other section is immunostained with AE/. When lymph nodes that are negative on routine pathological examination are subjected to ultrastaging, about e% of the patients will be found to have metastases [e]. With ultrastaging, more and smaller metastases are detected compared to routine H&E staining. No definition exists for which metastases should be called micrometastasis. Analysis of GROINSS-V data showed that the size of sentinel node metastases has important prognostic value. Our data suggest that mm would be an appropriate cutoff for micrometastases, as prognosis was especially worse for those patients with sentinel node metastases > mm[]. This is in agreement with the definitions of breast cancer. In breast cancer, micrometastases are defined by size: the maximum dimension of the largest tumor deposit in the lymph node can be no larger than.0 mm. In breast cancer, there is also a separate term for the considerably small metastases: submicrometastases; this term is reserved for metastases no larger than 0. mm. In breast cancer, submicrometastases are classified as N0 and are treated in the same way as SLN-negative patients []. The clinical significance of micrometastases in vulvar cancer is unclear. Micrometastases would be clinically significant when they are associated with non-sentinel node metastases (indicating inguinofemoral lymphadenectomy). In an in-depth analysis of the sentinel nodes from GROINSS-V, it was shown that the proportion of patients with non-sentinel node metastases increases with the size of sentinel node metastasis. One of patients with only isolated tumor cells in the sentinel node had non-sentinel node metastases (.%), two of with metastases mm (.%), two of with metastases > mm and mm (.%), and of with metastases > mm (.%). These data show low risk of non-sentinel node involvement in the case of minimal sentinel node involvement; however, they do not support a cutoff below which chances of non-sentinel node metastases are so low that inguinofemoral lymphadenectomy can be omitted. Furthermore, disease-specific survival for patients with sentinel node metastases > mm was lower than for those with sentinel node metastases mm (.% vs..%, p ¼ 0.00) []. Further data are needed to learn about the clinical significance of these small metastases, and to establish their possible role in clinical decision making. Implications for staging The literature on micrometastases in vulvar cancer is scarce. In a study reanalyzing lymph nodes by immunohistochemistry that were previously negative with standard H&E, Narayansingh et al. showed for staging, Best Practice & Research Clinical Obstetrics and Gynaecology (0),

7 YBEOG_proof April 0 / Q that after immunohistochemistry % (/) of women were found to have micrometastases. Nine women (%) developed recurrent disease; eight were in the group with the micrometastases. Of the remaining women without micrometastases, only one recurred (hazard ratio (HR)., CI.e) []. Micrometastases in this study were related to the development of recurrent disease. However, the side of recurrences was not mentioned (local/groin?) and the sample size was very small. As a consequence of ultrastaging, more and smaller metastases are found in lymph nodes, implicating that approximately e% of women with previously FIGO stage I disease will be upstaged to FIGO stage III. The clinical implications of these micrometastases are not clear, but there is evidence that smaller metastases have a better prognosis compared to larger metastases [,,]. This stage migration will therefore lead to better survival for the group patients with stage III disease, because patients with smaller metastases that were previously not diagnosed are classified stage III now. Probably, this will also lead to better survival for patients with stage I disease, because more patients with previously occult metastases are no longer in this stage. As the size of nodal metastases is an important prognostic factor for patients with vulvar cancer, the seventh edition of the TNM classification is a step forward, because for the first time vulvar cancer classification takes the size of lymph node metastases into account. However, micrometastases are not a specific subcategory in this staging system, and this is probably the group with the best prognosis. In the N category of the TNM classification, the distinction is made between metastases smaller or larger than mm. In the future, a new TNM classification should also include a separate category for micrometastases. What the exact size limits of these metastases will be and whether there will also be a subcategory for isolated tumor cells need further investigation. Data indicate that the prognosis for patients with only isolated tumor cells in the sentinel node is comparable to that of node-negative patients []. This supports a separate category for these patients in the next TNM classification. Postoperatively, radiotherapy is indicated for vulvar cancer patients with more than one lymph node metastasis, or in the presence of extranodal tumor growth. This policy is based on a study by Homesley et al., in which vulvar cancer patients with lymph node metastases at inguinofemoral lymphadenectomy were randomized between pelvic lymph node dissection and postoperative radiotherapy. The results of survival were in favor of the radiation group, and the benefit was most pronounced in those patients who presented with clinically suspicious or fixed ulcerated groin nodes, or two or more positive lymph nodes [,]. It seems that adjuvant radiotherapy is not beneficial in patients with only one intranodal lymph node metastasis []; however, data are conflicting on this subject []. Treatment guidelines are based on data obtained in the pre-sentinel node era. Whereas the rationale for postoperative radiotherapy in the case of two lymph node metastases > mmis argued by none, the evidence for postoperative radiotherapy in the case of two SLNs with only isolated tumor cells is at least questionable. Data on this subject in vulvar cancer are not available. In other tumors, indications for postoperative treatment are not comparable to vulvar cancer, and therefore comparable data in other tumors are not available. GROINSS-V-II is investigating the use of radiotherapy in sentinel node-positive patients. The size of sentinel node metastases is determined in all participating patients. We recommend all investigators performing clinical studies in patients with early-stage vulvar cancer to incorporate assessment of the size of (sentinel) lymph node metastases in their protocol. Hopefully, with time, more data will become available on the clinical significance of sentinel node micrometastases in vulvar cancer. Until then, lymph node metastases should be treated according to current treatment guidelines, independent of their size. Summary M.H.M. Oonk et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (0) e Treatment of vulvar cancer has greatly improved in the last decades, with the introduction of the sentinel node procedure as the last introduced major advantage for decreasing treatment-related morbidity. A part of the sentinel node procedure is the detailed examination of the removed sentinel nodes. Subsequently, more and smaller metastases are diagnosed. Studies show that the chances of non-sentinel node metastases increase and those of survival decrease with increasing size of the sentinel node metastasis. The size of metastases is included in the latest staging system for vulvar cancer, however without clinical implications. Further research is needed to determine the clinical consequences of the size of (sentinel) lymph node metastases. for staging, Best Practice & Research Clinical Obstetrics and Gynaecology (0),

8 YBEOG_proof April 0 / M.H.M. Oonk et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (0) e Conflicts of interest The authors indicated no potential conflicts of interest. Practical points The sentinel node procedure can be considered as the standard of care in well-selected patients with unifocal squamous cell cancers < cm without suspicious inguinofemoral nodes at imaging and performed by an experienced multidisciplinary team. As a consequence of the sentinel node procedure, more and smaller metastases are diagnosed, of which the clinical significance is not clear yet. Until more data are available on this subject, all patients with sentinel lymph node metastases should be treated by inguinofemoral lymphadenectomy, independent of their size. Research agenda Future clinical studies in vulvar cancer are encouraged to incorporate the size of metastases in their protocol in order to create more data on this subject. Indications for radiotherapy in the case of micrometastases. References [] Bodelon C, Madeleine MM, Voigt LF, et al. Is the incidence of invasive vulvar cancer increasing in the United States? Cancer Causes Control 00;0:e. [] Lai J, Elleray R, Nordin A, et al. Vulval cancer incidence, mortality and survival in England: age-related trends. BJOG 0; :e. [] Akhtar-Danesh N, Elit L, Lytwyn A. Trends in incidence and survival of women with invasive vulvar cancer in the United States and Canada: a population-based study. Gynecol Oncol 0;:e. [] Schuurman MS, van den Einden LC, Massuger LF, et al. Trends in incidence and survival of Dutch women with vulvar squamous cell carcinoma. Eur J Cancer 0;:e0. *[] Paladini D, Cross P, Lopes A, et al. Prognostic significance of lymph node variables in squamous cell carcinoma of the vulva. Cancer ;:e. *[] Woelber L, Eulenburg C, Choschzich M, et al. Prognostic role of lymph node metastases in vulvar cancer and implications for adjuvant treatment. Int J Gynecol Cancer 0;:0e. [] Prodratz KC, Symmonds RE, Taylor WF, et al. Carcinoma of the vulva: analysis of treatment and survival. Obstet Gynecol ;:e. [] Homesley HD, Bundy BN, Sedlis A, et al. Prognostic factors for groin node metastasis in squamous cell carcinoma of the vulva (A Gynecologic Oncology Group study). Gynecol Oncol ;:e. [] Hopkins MP, Reid GC, Johnston CM, et al. A comparison of staging systems for squamous cell carcinoma of the vulva. Gynecol Oncol ;:e. [] Hacker NF, Berek JS, Lagasse LD, et al. Individualization of treatment for stage I squamous cell vulvar carcinoma. Obstet Gynecol ;:e. [] Homesley HD, Bundy BN, Sedlis A, et al. Assessment of current International Federation of Gynecologic and Obstetrics staging of vulvar carcinoma relative to prognostic factors for survival (A Gynecologic Oncology Group study). Am J Obstet Gynecol ;:e0. *[] Origoni M, Sideri M, Garsia S, et al. Prognostic value of pathological patterns of lymph node positivity in squamous cell carcinoma of the vulva stage III and IVA FIGO. Gynecol Oncol ;:e. *[] Hacker NF. Revised FIGO staging for carcinoma of the vulva. Int J Gynecol Obstet 00;:e. [] Barbera L, Thomas G, Elit L, et al. Treating vulvar cancer in the new millennium: are patients receiving optimal care? Gynecol Oncol 00;:e. [] Basset A. Traitement chirurgical operatiore de l'epithelioma primitif du clitoris: indications, technique, resultats. Rev Chir ;:e. [] Taussig FJ. Cancer of the vulva: an analysis of cases (e0). Am J Obstet Gynecol ;0:e. [] Way S. Carcinoma of the vulva. Am J Obstet Gynecol 0;:e. [] Hacker NF, Leuchter RS, Berek JS, et al. Radical vulvectomy and bilateral inguinal lymphadenectomy through separate incisions. Obstet Gynecol ;:e. [] Hacker NF, van der Velden J. Conservative management of early vulvar cancer. Cancer ;:e. for staging, Best Practice & Research Clinical Obstetrics and Gynaecology (0),

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