Prognostic Role of Inguinal Lymphadenectomy in Vulvar Squamous Carcinoma: Younger and Older Patients Should Be Equally Treated

YGYNO-975835; No. of pages: 7; 4C: Gynecologic Oncology xxx (2015) xxx–xxx

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Gynecologic Oncology

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Prognostic role of inguinal lymphadenectomy in vulvar squamous carcinoma: younger and older patients should be equally treated. A prospective study and literature review

Pierluigi Benedetti Panici a,FedericaTomaoa,⁎, Lavinia Domenici a, Andrea Giannini a, Diana Giannarelli b, Innocenza Palaia a, Violante Di Donato a, Angela Musella a, Roberto Angioli c, Ludovico Muzii a a Department of Gynecologic Oncology, University “Sapienza”, Viale del Policlinico 155, 00161 Rome, Italy b Service of Biostatistics, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy c Department of Gynecologic Oncology, University “Campus Biomedico”, Via Alvaro del Portillo 21, 00128 Rome, Italy

HIGHLIGHTS

• Prognostic role of nodal status in very elderly patients also. • Number of positive nodes and of lymphnodes removed impact survival. • Literature review about variable associated to nodal status and lymphadenectomy.

article info abstract

Article history: Objective. This study analyzed the prognostic significance of nodal involvement in vulvar squamous carcinoma Received 16 October 2014 and its correlation with other prognostic factors, focusing the research on comparison between b75 and ≥75 years Accepted 9 March 2015 old patients. Available online xxxx Methods. We prospectively enrolled patients with N1-mm-deep stromal invasion, Ib–III stage vulvar cancer. Patients underwent unilateral or bilateral inguinal lymphadenectomy, according to tumor localization. Keywords: Results. In total, 131 patients met inclusion criteria; 93 (71%) underwent bilateral and 38 (29%) unilateral Squamous vulvar cancer lymphadenectomy with 36 (27%) of them presenting nodal disease. At Kaplan–Meier analysis factors associated Lymphadenectomy Nodal status to prognosis were nodal status (in very elderly patients also) and number of resected nodes both in bilateral Prognosis and unilateral lymphadenectomy groups. In univariate analysis, covariates associated with survival included age, Survival in terms of overall survival (OS) but not with disease free-survival (DFS) and disease-specific survival (DSS), Very elderly patients grading, nodal status, the presence of bilateral nodal metastases, the number of resected nodes in both unilateral, in terms of OS and DSS but not of DFS and bilateral lymphadenectomy and the number of metastatic nodes. In multivariate analysis covariates associated with survival were age, the number of positive nodes and the number of resected nodes in bilateral lymphadenectomy. Conclusions. Results confirm the prognostic role of nodal status in very elderly patients also. Although DSS in older patients resulted worse, lymphadenectomy is not associated with more complications, suggesting its importance in older patients too. Furthermore, the resection of less than 15 lymph nodes in bilateral lymphadenectomy seems to have a negative impact on survival. © 2015 Elsevier Inc. All rights reserved.

1. Introduction

Vulvar cancer represents 4% of all female gynecologic malignancies with 4580 estimated new cases and 1030 deaths in USA in 2014 [1]. Most of vulvar carcinomas are squamous cell carcinomas (SCC). ⁎ Corresponding author at: Department of Gynecologic Oncology, University This tumor predominantly occurs in elderly women; 54% of patients “Sapienza”, Viale del Policlinico 155, 00161 Rome, Italy. Tel.: +39 3202956365, +39 064990550. with the diagnosis of vulvar carcinoma are 70 years or older; no more E-mail address: [email protected] (F. Tomao). than 15% are younger than 50 years [2,3].

Please cite this article as: Panici PB, et al, Prognostic role of inguinal lymphadenectomy in vulvar squamous carcinoma: younger and older patients should be equally treated. A ..., Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.03.013 2 P.B. Panici et al. / Gynecologic Oncology xxx (2015) xxx–xxx

Until 1980, the standard treatment of vulvar cancer consisted of en tumor extension. Patients with lateralizing lesions underwent unilateral bloc radical vulvectomy and bilateral dissection of the upper and deep superficial and deep inguino-femoral lymphadenectomy if ipsilateral groin lymph nodes, even if associated with high morbidity rates. From nodes were negative at frozen section analysis; in the other cases a that time on, surgeons began to implement a less invasive surgery, try- bilateral nodal resection has been carried out. ing to ensure better aesthetic results with the development of different Lymphadenectomy started with a 7–9-cm-long skin incision parallel techniques without compromising cancer-related outcome. to the inguinal ligament. The incision was performed about 3 cm above These surgical innovations have led to lower morbidity and compli- the inguinal cutaneous fold. cation rates while the local recurrence rate has remained unchanged. The subcutaneous tissue was cut down to Camper's fascia, which Lymph-nodal spread represents one of the most important prognos- was identified, incised, exposed, and tapered by Kelly clamps. tic factors for vulvar carcinoma, such as FIGO staging system revised the Inguinal skin flaps were prepared by resecting all the lympho-fatty classification in 2009, including all cases with nodal involvement in all tissue from the inferior border of the superficial Camper's fascia, stage (irrespective of tumor diameter) [4]. whereas the tissue above was not resected, in order to obtain two Lymph-nodal status is strictly related to other parameters such as well-perfused skin flaps to avoid skin necrosis. tumor size, depth of stromal invasion, histological grade, and lymph Clinical data analyzed were age, type of vulvar surgery and lymphad- vascular space involvement [5–12]. Generally, lateralizing lesions enectomy. Pathological evaluation included tumor size, depth of (N1 cm beyond the midline) drain to the ipsilateral superficial inguinal invasion, number of resected nodes, tumor stage, grading and nodal in- lymph nodes, whereas midline lesions can drain to either side [9]. volvement. All data were accurately stored in an appropriate database. Therefore, the indication to inguino-femoral lymphadenectomy Disease-free survival (DFS) was defined as the time from surgery to is limited to patients with more than 1 mm of stromal invasion and the date of recurrence or last follow-up. Overall survival (OS) was de- contralateral inguinal lymphadenectomy could be safely omitted for fined as the time from surgery to the date of death or last follow-up. lateral tumors when ipsilateral lymph nodes are negative [13]. Disease-specific survival (DSS) was the time from surgery to the Furthermore, in an effort to reduce the almost inevitable inguinal date of death due to vulvar cancer or last follow-up. The association be- dehiscence, other variations were proposed regarding groin lymphade- tween parametric variables was assessed by chi-square or Fischer's nectomy technique. exact test. Overall survival was estimated by the Kaplan–Meier method. Some authors have recommended either the use of sentinel node Survival curves were constructed by life table with log-rank significance sampling [14] or superficial nodal dissection with saphenous vein test. A Cox proportional hazards model was used to adjust the prognos- preservation [15]. tic role of the factors considered for multiple parameters. Due to the lack of established long-term oncologic outcomes as well The results had been considered statistically significant when as experience with sentinel node procedures in most centers, this p value was less than 0.05. approach remains experimental. On the other hand, patients undergoing superficial inguinal node 3. Results dissections have been reported to have a slight but significant increase in the rate of inguinal recurrences compared to those having a complete In total, 163 consecutive patients affected by histologically docu- groin dissection [4,16]. mented invasive squamous vulvar carcinoma were enrolled into the In this prospective study we reported our experience about lymph- study. adenectomy in vulvar squamous carcinoma, evaluating characteristics Among these patients 32 did not meet inclusion criteria: 22 presented of lymph-nodal involvement in this tumor, its prognostic role and its too extensive and/or metastatic disease (16 of these underwent neoadju- possible correlation with other prognostic factors. Moreover we vant chemotherapy), 10 were excluded for poor performance status or analyzed the role of nodal status in patients older than 75 years, usually for important concomitant pathologies leading them to be not amenable defined as very elderly population [17]. to surgical procedure. Median age was 69,5 (range 48–90). Seventy-nine patients (60%) were younger than 75 years, while 52 2. Materials and methods patients (40%) were older than 75 years (thus considered as very elderly patients). We prospectively enrolled patients affected by invasive SCC of the Eight patients (6%) underwent wide local excision, 57 (44%) vulva who were amenable to radical surgery comprehensive of inguinal hemivulvectomy and 66 (50%) radical vulvectomy; in all cases unilater- lymphadenectomy. Patients were afferent to “Campus Biomedico” al or bilateral lymphadenectomy was performed. Lymphadenectomy University of Rome and “Sapienza” University of Rome and were was bilateral in most of the cases (93 patients, 71%) and unilateral in recruited from 1998 to 2012. The study protocol was approved by the the remaining (38 patients, 29%). Clinical, surgical and pathological ethical committee. Written informed consent was obtained from all pa- characteristics are reported in Table 1. Postoperative complications, tients. Eligibility criteria were as follows: histologically documented related to inguinal lymphadenectomy, occurred in 43 patients (33%): squamous vulvar carcinoma with N1-mm-deep stromal invasion; stages in 24 out of 79 (30%) patients younger than 75 years and in 19 out of Ib–III, according to the International Federation of Gynecology and 52 (33%) patients older than 75 years, with no statistically significant Obstetrics (FIGO) new classification (all patients treated before 2009 difference (p = NS). Among these 43 patients, 45 complications oc- were restaged according to the new criteria), performance status 0–2 curred consisting of 26 (58%) wound breakdown, 11 (24%) lymphede- according to ECOG classification, and informed consent to treatment ma, 4 lymphocyst (9%) and 4 deep venous thrombosis (9%); and follow-up. Ineligibility criteria were as follows: unresectable dis- 2 patients had both wound breakdown and lymphedema. No intra ease; distant metastasis (other than pelvic lymph-nodes); impaired or postoperative death occurred. Median follow-up was 80 months renal (creatinine clearance b50 ml/min) or hepatic function tests (1–187). In total, 47 (36%) deaths have been recorded, of which 35 (transaminase level elevated more than 1.5 times the upper limit of were due to cancer. The median number of resected nodes was 18 normal range); other severe systemic diseases significantly limiting (range, 4–43) per patient: 23 (range, 10–43), when a bilateral lymphad- treatment feasibility or other concomitant malignancies. Preoperatively, enectomy was performed, 12 (range 4–19) when the lymphadenecto- all patients underwent complete diagnostic workup, consisting of my was unilateral. complete history, physical and gynecologic examination, complete All patients amenable to unilateral lymphadenectomy, having laboratory analyses, electrocardiogram and chest X-ray. Total-body metastatic nodes at frozen section, were subjected to contralateral computed tomography (CT) scan was carried out in order to exclude lymphadenectomy and consecutively to adjuvant chemotherapy. In distant metastases and vulvoscopy was performed to estimate local total lymph-nodal metastases were histologically verified in 36 (27%)

Please cite this article as: Panici PB, et al, Prognostic role of inguinal lymphadenectomy in vulvar squamous carcinoma: younger and older patients should be equally treated. A ..., Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.03.013 P.B. Panici et al. / Gynecologic Oncology xxx (2015) xxx–xxx 3

Table 1 grade 4 neutropenia. Such as it concerns the possible association Clinical, surgical and pathological characteristics. between nodal status and characteristics of patients, there was no sta- Variable Median (range) tistically significant difference in age between patients with nodal metastases and patients without nodal metastases: the median age were Median age (range) 69,5 years (48–86) • b75 years (%) 79 (60%) 70,5 and 72 (p = NS) respectively. Histologically, 99 patients (76%) • ≥75 years (%) 52 (40%) had G1–G2 disease and 32 (24%) had G3 disease. In N− group 80 patients (84%) had G1–G2 tumor whereas 15 (16%) had G3 tumor; in Variable Number of patients (%) N+ group 19 patients (53%) had G1–2 tumor whereas 17 patients Type of surgery (47%) had G3 tumor (p = 0.007). We did not analyze possible correla- • Radical vulvectomy 66 (50%) tions between stage and nodal involvement, considering that new • Hemivulvectomy 57 (44%) FIGO staging system classifies only nodal metastatic disease as stage • Local wild excision 8 (6%) Inguinal Lymphadenectomy III. In total, 5-year OS and DFS were 69% and 44% respectively. • Bilateral 93 (71%) OS was higher in patients affected by G1–G2 disease than in patients • Unilateral 38 (29%) affected by G3 disease (p = 0.001) and also in patients affected by stages I–II disease than in patients affected by stage III disease (p = Variable Median (range) 0.005). Consequently, patients with N+ disease had both worst DFS – Median tumor size (mm) 40 (7 70) and OS (p b 0.0001 and b0.0001 respectively): 5-year OS of patients – Depth of invasion (mm) 4 (0,8 20) − Number of resected lymph nodes N was 86%, whereas 5-year OS of patients N+ was 36%. Survival • Total 18 (4–43) curves according to nodal status are reported in Fig. 1. Furthermore, • Bilateral lymphadenectomy 23 (10–43) we compared survivals between patients with negative nodes and pa- • Unilateral lymphadenectomy 11 (4–19) tients with positive nodes older than 75 years, observing that DFS and OS are significantly better in N− disease also in this group of patients Variable Number of patients (%) (p b 0.0001 and b0.0001 respectively). Stage Since very elderly patients tend to have more co-morbidities • Stage I 51 (39%) fi • Stage II 44 (34%) resulting in a shorter life expectancy, in order to con rm these data, • Stage III 36 (27%) we also analyzed DSS obtaining the same results (p b 0.0001). Fig. 2 re- Grading ports DSS according to nodal status in very elderly patients. Regarding • G1 30 (23%) the number of resected nodes, we observed that removing ≥15 nodes • G2 69 (53%) at bilateral lymphadenectomy improves both DFS and OS (p b 0.0001 • G3 32 (24%) b Nodal status and 0.0001 respectively). • N+ 36 (27%) This occurred also when unilateral lymphadenectomy was carried • N− 95 (73%) out: the resection of ≥10 lymph nodes correlated with better DFS and OS (p = 0.04 and 0.006 respectively). Fig. 3 reports both OS according to the number of resected nodes in bilateral and unilateral lymphadenectomy. Moreover we tried to con- patients (N+). On the contrary, 95 patients (73%) had negative nodes firm if the number of positive nodes significantly correlates with surviv- (N−). Since scientific evidences showed that vulvar cancer is a al. We did not find any statistical correlation between the number of chemo-sensitive tumor and that adjuvant chemotherapy could be a positive lymph nodes and survival (p = NS), using the Kaplan–Meier valid choice for the treatment of nodal disease with acceptable toxicity method and log-rank test. However, in univariate analysis, covariates [12], patients with metastatic nodes were treated with 4 cycles of associated with survival included age (with OS but not with DFS and cisplatin (100 mg/mq). All patients completed the treatment that over- DSS), grading, nodal status, the presence of bilateral nodal metastases, all was well-tolerated with 5 out of 36 (14%) patients suffering from the number of resected nodes in both unilateral (even if with OS and

Fig. 1. OS and DFS according to nodal status.

Please cite this article as: Panici PB, et al, Prognostic role of inguinal lymphadenectomy in vulvar squamous carcinoma: younger and older patients should be equally treated. A ..., Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.03.013 4 P.B. Panici et al. / Gynecologic Oncology xxx (2015) xxx–xxx

We hypothesized that it happened for the more complete represen- tation of the sample of patients through the Cox proportional hazards model. Up to now nodal status represents one of the most important prognostic factors for vulvar carcinoma [5]. However, there are no data in the international literature suggesting its importance also in patients older than 75 years. As previously defined, demographers consider the “older population” to be over 55 years of age. Within this group they dis- tinguish the “elderly” (from 65 until 74 years) from the “very elderly” (over 75 years) [17]. In the present study the lymphadenectomy was carried out in very elderly patients also, showing that in these patients it seems to be feasi- ble with no higher complication rates than in younger patients. There- fore, as concerns surgical complications following lymphadenectomy, we reported a complication rate of 33%, similar to those reported in the international literature [22–35,15]. Most common complications were wound breakdown and lymphedema. As previously reported, complication rates were similar between patients older than 75 years and those younger. Moreover, the nodal status represents a very important prognostic factor, in terms of DSS also, in very elderly patients such Fig. 2. DSS according to nodal status in very elderly patients (≥ 75 years). as in patients younger than 75 years. Analyzing the impact of nodal status on survival of very elderly patients, the presence of negative nodes DSS but not with DFS) and bilateral lymphadenectomy and the number at lymphadenectomy resulted in better OS, DFS and overall in DSS. At of metastatic nodes (with particularly higher HR when the number of univariate analysis the age seems related to OS only, showing a higher positive nodes was major than 3). hazard ratio in patients older than 75 years (1.0 vs 1.82; CI 1.02–3.24, In multivariate analysis covariates mainly associated with OS, DFS p=0.04). and DSS were age, the number of positive nodes (particularly when However, at multivariate analysis those patients seem to have a N N 3) and the number of resected nodes in bilateral lymphadenectomy. worse survival also in terms of DFS and DSS, even if in DSS, the differ- Results of univariate and multivariate analysis are reported in Table 2. ence is lower (p = 0.001 vs 0.007). These data suggest the importance of obtaining a complete lymph nodal dissection with resection of both superficial and deep lymph 4. Discussion nodes in older patients too. Nevertheless, the worse DSS obtained at multivariate analysis leads In this prospective study we confirmed that nodal status represents to better investigate the role of nodal status and the meaning of a radical a very important prognostic factor in very elderly patients also. inguinal lymphadenectomy in these patients. Regarding the number Moreover we demonstrated, according to other studies [18–21], that of resected nodes, different studies established that the number of the number of removed lymph nodes impacts both DFS and OS. removed lymph nodes represents an important prognostic factor in Results were similar in bilateral and unilateral lymphadenectomies vulvar cancer [18–21]. leading to conclude that when bilateral lymphadenectomy is carried Le T et al. [18] established that the number of removed lymph nodes out, more than 15 nodes should be removed, and in unilateral nodal is an important prognostic factor in vulvar cancer and the authors dissection the number of resected nodes should be at least 10. arbitrarily proposed a cut-off value of at least 10 nodes in total to define On the contrary, the number of metastatic nodes did not have a sta- optimal bilateral inguino-femoral lymphadenectomy. tistical significance in terms of survival at Kaplan–Meier evaluation, Another study published by Courtney-Brooks M et al. [19] analyzed even if it showed a statistically significant correlation with OS, DFS the impact of lymph nodal count on survival of 1030 patients with vul- and DSS both at univariate and multivariate analysis. var cancer and negative nodes.

Fig. 3. OS according to number of resected nodes in unilateral and bilateral lymphadenectomy.

Please cite this article as: Panici PB, et al, Prognostic role of inguinal lymphadenectomy in vulvar squamous carcinoma: younger and older patients should be equally treated. A ..., Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.03.013 P.B. Panici et al. / Gynecologic Oncology xxx (2015) xxx–xxx 5

Table 2 Univariate and multivariate analysis of OS, DFS and DSS by different prognosis factors.

Prognostic Univariate Multivariate factors OS DFS DSS OS DFS DSS

HR (95% CI) P HR (95% CI) P HR (95% CI) P HR (95% CI) r HR (95% CI) P HR (95% CI) P

Age b75 years 1.0 (referent) .04 1.0 (referent) .10 1.0 (referent) .41 1.0 (referent) .001 1.0 (referent) .001 1.0 (referent) .007 ≥75 years 1.82 (1.02–3.24) 1.62 (0.91–2.88) 1.32 (0.68–2.57) 3.39 (1.74–6.61) 2.89 2.84 (1.33–6.03) (1.51–5.52)

Grading 1–2 1.0 (referent) .009 1.0 (referent) .005 1.0 (referent) .001 ––– 3 2.25 (1.22–4.13) 2.38 (1.22–4.13) 2.98 (1.52–5.82)

N status N− 1.0 (referent) b.001 1.0 (referent) b.001 1.0 (referent) b.001 ––– N+ 5.21 (2.90–9.36) 5.808 9.816 (3.18–10.61) (4.77–20.22)

No. of N+ N0 1.0 (referent) b.001 1.0 (referent) b.001 1.0 (referent) b.001 ––– N1 3.00 2.92 (0.87–9.83) 5.58 (1.55–20.12) (0.89–10.08) N N 15.82 6.84 (3.66–12.78) 11.02 (3.18–10.68) (5.27–23.08)

No. of N+ N0 1.0 (referent) b.001 1.0 (referent) b.001 1.0 (referent) b.001 ––– N1–2 4.73 (2.49–8.96) 5.61 (2.89–10.88) 9.14 (4.25–19.66) N N 26.96 6.30 (2.67–14.88) 12.01 (2.93–16.52) (4.61–31.30)

No. of N+ N0 1.0 (referent) b.001 1.0 (referent) b.001 1.0 (referent) b.001 1.0 (referent) b.001 1.0 (referent) .001 1.0 (referent) .001 N1–3 4.86 (2.63–8.97) 5.53 (2.93–10.44) 5.53 (2.93–10.44) 3.61 (1.61–8.11) 4.14 11.60 (3.25–41.46) (1.67–10.27) N N 38.06 7.34 (2.50–21.52) 7.34 (2.50–21.52) 9.89 8.12 33.58 (2.75–23.63) (3.07–31.90) (2.47–26.66) (7.32–154.08)

Laterality of N+ Monolateral 1.0 (referent) .009 1.0 (referent) .006 1.0 (referent) .009 ––– Bilateral 3.06 (1.31–7.10) 3.25 (1.40–7.55) 3.06 (1.31–7.10)

No. of resected N in UL ≥ 10 1.0 (referent) .01 1.0 (referent) .07 1.0 (referent) .04 ––– b 10 6.27 3.46 (0.89–13.38) 7.11 (1.12–45.08) (1.47–26.66)

No. of resected N in BL ≥ 15 1.0 (referent) b.001 1.0 (referent) b.001 1.0 (referent) b.001 1.0 (referent) b.001 1.0 (referent) b.001 1.0 (referent) b.001 b 15 12.27 12.01 12.27 10.91 9.16 10.09 (4.10–24.88) (5.44–27.69) (5.32–27.09) (5.44–27.69) (4.60–25.89) (4.00–20.96)

The authors concluded that the resection of more than 10 nodes cor- Nevertheless, in our trial all patients underwent the resection of more related significantly with better DSS and OS in former stage III node- than 10 nodes when a bilateral lymphadenectomy had been carried out, negative vulvar cancer patients. was less than 10; so we need a cut-off value higher than 10 in order to ob- However, in this study the stratification of patients was carried out tain statistically significant results. Thus we chose the number of 15 nodes with old FIGO staging system in which stage III included tumors of as cut-off of resected nodes that can be used to define an optimal bilateral any size with adjacent spread to the lower urethra, vagina or anus. lymphadenectomy, obtaining impressive differences in terms of HR, ac- Gadducci A et al. reported the same results with a higher cut-off cording to the results obtained by Gadducci A et al. [8]. value of lymph-node removal, demonstrating that among patients However, the number of lymph nodes removed seems to be prog- who underwent bilateral lymphadenectomy and who had negative nostic also when a unilateral lymphadenectomy was carried out in nodes, groin recurrence occurred in 12% of those who had ≤15 nodes those patients with unilateral lesions and homolateral negative lymph removed and 0% of those who had N15 nodes removed [8]. nodes. It probably happens because the removal of an adequate number Consecutively, Baiocchi G et al. [20] showed that the number of of lymph nodes may provide a better staging and eliminate the possibil- resected nodes at lymphadenectomy is a prognostic factor but only in ity of underestimated metastases. We furthermore observed that the those patients having nodal involvement. The authors reported that number of metastatic nodes did not represent a prognostic factor at the resection of fewer than 12 lymph nodes in vulvar cancer patients Kaplan–Meier analysis, leading to hypothesize that when an extensive has a negative impact on the outcome of patients with positive inguinal lymphadenectomy is carried out, eventually followed by appropriate lymph nodes, with a negative impact on the risk of recurrence (p = adjuvant treatment, the number of positive nodes does not represent 0.003) and death from cancer (p = 0.04). Finally, other authors [8,21] a factor able to modify the prognosis. However, at both univariate and showed that the overall risk of developing GR after negative inguino- multivariate analysis the number of metastatic nodes resulted in a femoral lymphadenectomy, in patients with vulvar SCC, is significantly worse prognosis, mainly when the number of positive nodes was higher higher in patients with lymph node count less than 9. than three. It probably happened because at Cox proportional hazards

Please cite this article as: Panici PB, et al, Prognostic role of inguinal lymphadenectomy in vulvar squamous carcinoma: younger and older patients should be equally treated. A ..., Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.03.013 6 P.B. Panici et al. / Gynecologic Oncology xxx (2015) xxx–xxx

Table 3 5-year OS in vulvar cancer patients related to number of positive nodes.

Author Study design Pts (n) Type of lymphadenectomy Resected nodes (n) 5 year OS p-Value

Hacker, 1983 [7] Retrospective 131 Bilateral (113 pts) & unilateral (18 pts) NA N− 96% NA 1 N+ 94% 2 N+ 80% N3 N+ 12% Homesley, 1991 [6] Retrospective 588 Bilateral & unilateral NA N− 90% NA 1–2 N+ 75.2% 3–4 N+ 36.1% 5–6 N+ 24% N7N+ 0% Paladini, 1994 [36] Retrospective 75 Bilateral (68 pts) & unilateral (7 pts) NA N− NA 0.006 1 N+ 46% 2–3 N+ 23% N3 N+ 20% Van der Velden, 1995 [37] Retrospective 71 Bilateral & unilateral NA 1 N+ 58% 0.021 N2 N+ 38% Raspagliesi, 2006 [38] Retrospective 110 Bilateral & unilateral 10 (6–14) N− 76% b0.05 N+ 39.5% No. of N+ not associated with prognosis NS Le T, 2007 [18] Retrospective 58 Bilateral 14 (NA) No. of resected nodes ≥10 associated 0.021 with prognosis Tabbaa, 2012 [39] Retrospective 468 Bilateral NA 2–3 N+ 52% NS Woelber, 2012 [40] Prospective 49 NA NA 1 N+ 55% b0.001 N2 N+ 25% Courtney-Brooks 2012 [19] Retrospective 1030 NA 11 (St I) No. of resected nodes N10 is prognostic 0.03 14 (St II) (but only in st III) 15 (St III) *St: Stage Gadducci A 2012 [8] Retrospective 87 Bilateral 15 No. of resected nodes ≥15 is prognostic NS Baiocchi, 2013 [20] Retrospective 234 Bilateral 22.5 1 N+ 45.3% NS (0.19) N2 N+ 33.3% No. of resected nodes ≥12 associated with prognosis (only in N+ pts) Van Beekhuizen 2014 [21] Retrospective 134 Bilateral & unilateral 9.8 No. of resected nodes ≥9 associated 0.04 with prognosis Bogani 2014 [41] Retrospective 101 NA NA OS (both N+/N−) 82%, N inﬂuence 0.0001 survival at multivariate analysis Our experience Prospective 131 Bilateral (93 pts) & unilateral (38 pts) 23(10–43) & 12(4–19) N0 86% b0.0001 N+ 36% • No. of resected nodes ≥15 associated b0.0001 with prognosis (BL) • No. of resected nodes ≥10 associated 0.0064 with prognosis (UL) • No. of N+ not associated with prognosis NS

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Please cite this article as: Panici PB, et al, Prognostic role of inguinal lymphadenectomy in vulvar squamous carcinoma: younger and older patients should be equally treated. A ..., Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.03.013 P.B. Panici et al. / Gynecologic Oncology xxx (2015) xxx–xxx 7

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