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ScienceDirect EJSO 41 (2015) 823e829

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Factors predictive of pelvic lymph node involvement and outcomes in melanoma patients with metastatic sentinel lymph node of the groin: A multicentre study N. Mozzillo a, S. Pasquali b, M. Santinami c, A. Testori d, M. Di Marzo a, A. Crispo e, R. Patuzzo c, F. Verrecchia d, G. Botti f, M. Montella e, C.R. Rossi b, C. Carac o a,* a

Dipartimento Melanoma, Istituto Nazione Tumori “Fondazione Pascale”, Napoli, Italy b Divisione Melanoma e Sarcomi, Istituto Oncologico Veneto, Padova, Italy c Divisione Melanoma e Sarcomi, Istituto Nazionale Tumori, Milano, Italy d Divisione Melanoma, Istituto Oncologico Europeo, Milano, Italy e Divisione di Epidemiologia, Istituto Nazione Tumori “Fondazione Pascale”, Napoli, Italy f Divisione di Anatomia Patologica, Istituto Nazione Tumori “Fondazione Pascale”, Napoli, Italy Accepted 20 February 2015 Available online 11 March 2015

Abstract Introduction: The optimal extent of the groin lymph node (LN) dissection for melanoma patients with positive sentinel LN biopsy is still debated and no agreement exist on dissection of pelvic LN. This study aimed at investigating predictors of pelvic LN metastasis and prognostic significance of having metastasis in the pelvic LNs. Methods: Clinicopathologic data of 740 patients with positive groin sentinel LN who underwent ilioinguinal completion LN dissection at four Italian centre were analysed. Multivariable logistic and Cox regression analysis was used to identify independent predictors of pelvic LN metastasis and to adjust prognostic significance of pelvic LN metastasis. Results: More than a quarter (26%) of patients had positive non-SLNs after inguinal and pelvic lymphadenectomy, which were located in their pelvis in the 12% of cases. Older patients [(OR) 1.69; 95% confidence interval (CI) 1.02e2.78] having thick primary (OR 1.6; 95% CI, 1.01e2.53) and  2 positive SLNs (OR 2.5; 95% CI, 1.4e4.47) were more likely to harbour pelvic LN metastasis. Interestingly, 4% of all patients (34% of patients with positive pelvic LNs) had pelvic LN metastasis with negative inguinal LNs. Pelvic LN metastasis was independently associated with higher risk of recurrence and lower survival. 5-year disease free and overall survival was 30% and 50%, respectively, for patients with pelvic LN metastasis. Conclusions: Pelvic LNs are frequently positive after ilioinguinal lymphadenectomy and it should be considered for all patients, especially those who are older, have thick primary and  2 positive SLN. Patients with pelvic LN metastasis have worse prognosis. Ó 2015 Elsevier Ltd. All rights reserved.

Keywords: Melanoma; Sentinel lymph node; Node metastasis; Deep disease

Introduction Lymphatic mapping and sentinel lymph node biopsy (SLNB) for patients with skin melanoma have become widely accepted procedures for staging regional lymph (LN) node field.1e3 Although SLNB does not improve survival when compared with nodal observation in clinically * Corresponding author. E-mail address: [email protected] (C. Caraco). http://dx.doi.org/10.1016/j.ejso.2015.02.005 0748-7983/Ó 2015 Elsevier Ltd. All rights reserved.

lymph node negative melanoma patients, completion lymph node dissection (CLND) in sentinel lymph node (SLN) positive patient showed a 20% 10-year survival benefit compared to lymphadenectomy for clinically positive LN metastasis.4,5 The evidence supporting SLNB and CLND survival benefit was observed in non-randomized patients of the Multicentre Selective Lymphadenectomy Trial (MSLT) and given the lack of evidence from randomized studies

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it is not totally surprising that controversies still exist on performing a lymphadenectomy in SLN-positive patients.4e8 Several population-based studies in Europe the US showed that roughly 40e50% of SLNB-positive patients have not been submitted to CLND.9,10 Furthermore, the optimal technique of lymphadenectomy is still to be established and the optimal extension of surgery within each nodal field (neck, axilla and groin) to be determined, particularly when LN metastasis involved the groin.11e13 Groin lymphadenectomy is at greater risk of postoperative morbidity when compared with neck and axillary dissection.14,15 Wound infection and dehiscence, seroma and lymphedema are the most frequently occurring postoperative adverse events and can happen in up to 80% of the patients with detrimental effects on long-term quality of life. Although it is commonly believed that pelvic dissection can increase morbidity of inguinal lymphadenectomy, there is no agreement about lesser morbidity when only the inguinal LNs are dissected. Surgeons agree to remove the inguinal LNs during groin lymphadenectomy, but have different opinions on whether or not also pelvic LNs should be dissected particularly when patients have positive SLNB.16 Some considered adequate the simply removal of the inguinal LNs, given the doubtful survival benefit and the risk of increasing morbidity.17 Other surgeons performed routinely an inguinal and pelvic dissection, accounting for the risk of pelvic disease, which is roughly 10e15% in case of positive SLNB and the relatively small benefit of currently available adjuvant treatments.11,18,19 Finally, some surgeons perform pelvic dissection when the number of positive inguinal LN is three or more, there are suspicious pelvic LNs at computed tomography (CT) scan, the Cloquet’s LN is involved or there are second-tier LNs seen at lymphoscintigram.20e23 Clearly these heterogeneity mirrors the lack of randomized trials investigating the survival benefit and the morbidity associated with pelvic dissection and the lack of effective selection criteria since most of the selection criteria for pelvic lymphadenectomy have been established in the pre-SLNB era and have low accuracy.24e27 Establishing predictive factors of pelvic LNs metastasis and understanding the prognostic significance of having melanoma cells located in these LNs can offer more information for counselling patients on the extent of their surgery. We designed a retrospective multi-centre study within four melanoma centres, where inguinal and pelvic dissection are routinely performed in for a positive groin SLNB, to investigate predictors of pelvic LN metastasis and the prognostic significance of having metastasis in the pelvic LNs. Methods Patients The study was approved by the Research Committee of the Italian Melanoma Intergroup.

Patients who underwent a inguinal and pelvic lymphadenectomy for positive groin SLNB between January 1996 and December 2013 at four Italian Institutions were included in this study. Patients were excluded when 1) they underwent pelvic dissection in delayed fashion following inguinal dissection; 2) received adjuvant radiotherapy or systemic treatment; and 3) had clinical evidence of involvement of the pelvic LNs or distant metastasis were found at the time of preoperative staging. All patients were staged with ultrasound scan and computed tomography (CT) to detect metastatic involvement of pelvic lymph nodes and distant metastasis. Higher risk patients in the most recent period also underwent a PET-CT scan. The following data were extracted from the prospectively collected data-base of the participating institutions: patients age and sex, primary tumour site, thickness, level of invasion and ulceration, number of excised and positive SLN, inguinal LNs and pelvic. Lymphatic mapping and SNB Lymphatic mapping and SLNB were performed according to an established protocol.28 Briefly, SLNB was performed in patients with melanoma thicker than 1 mm. In case of thin melanoma, SLNB have been performed in case of ulceration and Clark’s level IVeV. Tumours mitotic rate >1 has been introduced as selection criteria since the publication of the seventh edition of the AJCC TNM staging system. The SLN was identified by preoperative cutaneous lymphoscintigraphy using technetium 99 labeled colloidal albumin (Nanocoll, Sorin Biomedica, Saluggia, Italy) injected around the bioptic scar and planar gamma camera, intradermal injections of patent blue dye (Laboratoire Guerbet, Anenay- Sons Bois, France) and a g probe (C-trak, care Wise Medical Products, California, Usa) at the time of surgery. Groin lymphadenectomy An S-shaped or a straight skin incision was carried from the apex of Scarpa’s triangle to about 5 cm superomedial to the superior anterior iliac spine. In the inguinal LNs, the dissection was carried through adipose tissue to the femoral vascular sheath. The femoral vessels were exposed, the saphenous vein divided at the femoral entrance and at the apex of Scarpa’s triangle and the LNs excised. The retroperitoneal space was entered through dividing the lower abdominal muscles, leaving the inguinal ligament intact to dissect the pelvic LNs. External iliac vessels were exposed by blunt dissection and retraction of the peritoneum. Dissection of the iliac lymphatic tissue was extended up to the common iliac bifurcation. The obturator LNs were accessed through mobilizing the external iliac vein. Obturator LNs were freed from obturator nerve and vessels and excised. LN specimens were marked according to their

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LN field (inguinal, iliac, or obturator) before being sent for histology. In some cases, the operation was completed with transposition of the sartorius muscle. A suction drain was placed and patients were invited to wear compression socks from the day after the operation until up to threeesix months later. Pathology Description of the pathologic examination has been reported elsewhere.29,30 Briefly, the specimens were analysed in a routine manner, with LNs bisected or trisected, according their size, and stained with hematoxylin and eosin.

Table 1 Patient clinicopathological characteristics. Factor

Characteristic

Number (%)

Gender

Male Female 55 >55 Unknwon Lower extremity Lumbar/Trunk T1 T2 T3 T4 Unknown Yes No 1 2 SLN only Inguinal LNs only Inguinal and pelvic LNs Pelvic LNs only

313 (42.3) 427 (57.7) 279 (37.7) 455 (61.5) 6 548 (74.7) 192 (25.3) 51 (6.9) 187 (25.3) 256 (34.6) 240 (32.4) 6 468 (63.3) 272 (36.7) 661 (89.3) 79 (10.7) 515 (69.6) 135 (18.2) 59 (8.0) 31 (4.2)

Age (yrs.)

Primary site AJCC T stage

Ulceration

Follow-up No. positive SLN

Patients have been evaluated with follow-up visits every threeefour months for the first two years, every 4 months during the third year, and every 6 months thereafter. Follow-up consisted of clinical evaluation, ultrasound of the lymph node basin and the liver, chest X-ray, and positron-emission tomography (PET)-CT scan, if deemed necessary. Statistical analysis Estimation of the likelihood of local-regional relapse and disease-free and melanoma-specific survival were calculated according to the KaplaneMeier method for the entire patient population. Statistical differences between curves were calculated using the log-rank test. Main clinicopathological characteristics, as well laterality were analysed in univariate model to correlate with deep nodal involvement. Multiple regression analysis was performed using the Cox proportional hazard model, with a stepwise approach to estimate hazard ratio (HR) and relative 95% confidence intervals (95% CI) for each covariate. A p value of  0.05 was considered statistically significant. All time intervals were calculated from the date of stage III diagnosis. Statistical analysis was performed with SPSS (version 10.0; SPSS, Inc., Chicago, IL). The nodal involvement variable was categorized into two groups: “only superficial” vs “superficial and deep and/or only deep” to be evaluate as the dependent variable in a logistic analyses. Results There were 740 patients eligible for this study. Patients’ and tumours’ features are reported in Table 1. Inguinal and pelvic LN A mean of 1.14 positive SLNs were found for each patient (range 1e4). A mean of 0.62 positive LN nodes from inguinal dissection and a mean of 0.27 LNs from pelvic dissection were removed.

825

Nodal involvement

Pathologic evaluation of the 740 surgical specimens demonstrated that metastatic disease was limited to the inguinal LNs in 650 patients (87.8%) and extended to the pelvic LNs in 90 patients (12.2%). Interestingly, among the 90 patients with pelvic metastasis, 31, representing 4.2% of all patients and 34.4% of patients with positive pelvic LNs had no involvement of inguinal LNs other than the SLNs. Prediction of pelvic LN metastasis Older patients [Odds ratio, (OR) 1.69; 95% confidence interval (CI) 1.02e2.78], those having a primary tumour thicker than 4 mm (OR 1.6; 95% CI, 1.01e2.53) and more than one positive SLN (OR 2.5; 95% CI, 1.4e4.47) were at higher risk of having pelvic LN metastasis (Table 2). Disease-free survival (DFS) The median follow-up was 62.6 months (range 1.43e241.8 months). 260 patients (35.1%) had disease recurrence. The median time to relapse was 40.2 months (range 1.1e241.8 months). KaplaneMeier analysis of disease-free survival was done according to clinical and pathologic features (Table 3). The 5-yearDFS was worse for patients with pelvic LN metastasis compared to patients who had only inguinal LN disease (p ¼ 0.0001) (Fig. 1). The 5-year DFS rate also differed significantly according to the extent of nodal involvement, with a 74.1% for patients who had only the SLN involved and 30.0% for patients who had involvement of pelvic LNs (p ¼ 0.0001) (Table 3).

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Table 2 Multivariate analysis for the prediction of pelvic lymph node metastasis in patients with a positive inguinal SLNB. Risk factors

Total Age 55yrs >55 yrs Gender Males Females Breslow 4 mm >4 mm No. of positive SLN 1 2 Primary site Extremity Lumbar trunk Laterality Right Left Centre 1 2 3 4

Negative pelvic LNS

Positive pelvic LNS

No.

%

No.

%

Or

650

88

90

12

255 389

39.6 60.4

24 66

26.7 73.3

272 378

41.8 58.2

41 49

45.6 54.4

442 208

68.0 32.0

52 38

57.8 42.2

1.0 1.6

590 60

90.8 9.2

71 19

78.9 21.1

1.0 2.5

480 164

74.5 25.5

68 22

75.6 24.4

236 247

48.9 51.1

31 38

44.9 55.1

54 455 113 28

8.3 70.0 17.4 4.3

9 68 12 1

10.0 75.6 13.3 1.1

(95% CI)**

p-value*

0.04 1.0 1.69

(1.02e2.78) 0.5

0.04 (1.01e2.53) 0.002 (1.40e4.47) 0.8

0.5

0.3

*ChieSquare test; ** Conditional multiple logistic regression analysis adjusted for terms of centre, gender, site, breslow and number of positive sentinel nodes. Values in bold represent the p-value of statistical analysis.

Interestingly, the extent of nodal involvement was still a prognostic factor, along with tumour thickness and age, when adjusted for other statistically significant prognosticator at univariate analysis. Patients with metastasis in the inguinal LNs (HR 2.83, 95% CI 1.87e4.28), both in their inguinal and pelvic LNs (HR 3.23, 95% CI 1.61e6.5) and with only pelvic metastasis (HR 4.62, 95% CI 2.73e7.8) did worse than SLN-positive patients with no further metastatic LNs. Melanoma-specific survival Patients with pelvic LN metastasis had lower survival rates compared to those who had only inguinal LN metastasis (p ¼ 0.0001) (Fig. 2). The 5-year melanoma-specific survival also differed significantly according to the extent of LN involvement, with a 80.9% for SLN-positive patients and 50.0% for patients who had metastasis in their pelvic LN (p ¼ 0.0001) (Table 3). Remarkably, nodal involvement was still an independent prognostic factor, along with tumour thickness, when adjusted for other statically significant prognostic factors at univariate analysis (p < 0.0001). Patients with metastasis both in their inguinal and pelvic LNs (HR 4.56, 95% CI 2.12e9.83) and with only pelvic metastasis (HR 3.22, 95% CI 1.63e6.36) did worse than SLN-positive patients with no further metastatic LNs. The melanoma-specific

survival of this latter group was similar to that of patients with LN metastasis confined to the inguinal LNs (HR 1.74, 95% CI 0.96e3.14). Discussion This multi-centre study analysed data of 740 melanoma patients with positive SLNB in their groin who underwent ilioinguinal lymphadenectomy. More than a quarter (26%) of these patients had positive non-SLNs, which were located in the pelvis in the 12% of the cases. Patients with pelvic LN metastasis were older, had thicker primary and two or more positive SLNs. There was also a group of patients (4% of all patients and 34% of patients with positive pelvic LNs) who had further LN metastasis detected in the pelvis but not in the inguinal LNs. Remarkably, pelvic LN-positive patients were at higher risk of recurrence and had worse prognosis after adjustment for other factors, with a 30% and a 50% 5-year DFS and OS rate, respectively. The results of this large multi-centre study underline some of the existing controversies about the extension of regional lymphadenectomy in SLNB-positive melanoma patients.31,32 Given the reported morbidity, including wound infection, seroma, flap necrosis and lymphedema up to 80%, and the potential increase from the extension of surgery to the pelvic basin, the benefit e risk ratio, in front of the perceived rarity of concomitant pelvic groin disease in

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Table 3 Univariate analysis for 5-year disease-free survival and melanoma-specific survival. Clinical and pathologic factors Age (yrs) 55 >55 p value Primary Site Trunk Lower extremity Unknown p value T stage T1eT2 T3 T4 p value Ulceration No Yes p value No. positive LNs 1 (N1) 2 or 3 (N2) 4 (N3) p value Extent of nodal involvement SLN only Inguinal LN only Inguinal and pelvic LNs Pelvic LNs only p value

Disease-free survival (%)

Melanoma-specific survival (%)

45.3 28.9 0.03

64.1 52.2 0.03

22.6 41.5 37.5 0.1

45.2 62.7 50 0.5

52.9 27.8 41.5 0.2

73.5 47.2 65.8 0.4

36.8 29.3 0.6

58.6 54.4 0.2

41.7 36.4 7.1 0.007

65.5 54.5 14.3 0.0009

74.1 46.8 34.5 30.0 0.001

80.9 68.2 63.8 50.0 0.001

Values in italics represent the results of statistical analysis, and differ from the numbers representig percentage of each category analysed.

patients with positive SLN, compels many surgeons to limit completion lymphadenectomy to the inguinal region.16,17,33 Others surgeons believe that the incidence of pelvic LN metastasis is sufficient to perform a pelvic dissection.11,34 This probably needs to be put in context with the small benefit of adjuvant treatment. Interferon alpha is still the

Figure 1. 5-year DFS rate according to the extent of nodal involvement.

Figure 2. 5-year OS rate according to the extent of nodal involvement.

only approved drug for the adjuvant treatment of these patients and offers a 3% survival gain.35,36 Radiotherapy is considered in patients with high tumour burden and its efficacy is limited to the regional control.37 Finally some surgeons considered criteria such as  three positive inguinal LNs, the Cloquet’s LN status, the morphology of pelvic LNs at CT scan and the patter of lymphatic drainage as criteria to guide their decision of dissecting the pelvic LN field. Despite these measures are adopted in several guidelines, including those from the National Comprehensive Cancer Network22 and from the United Kingdom,38 their accuracy and particularly their negative predictive value (which describes the ability of a test to identify the patients with negative pelvic LNs) is relatively low.25e27 In this study, the presence of more than one positive SLN increased chances of having pelvic LN metastasis, suggesting that the minimum of three LNs recommended by the guidelines can lead to under treat patient. Moreover, the stage of the primary tumour should be considered, as patients having tumours thicker than 4 mm are at greater risk of pelvic metastasis. Interestingly, patients age is another criteria that should be taken into account. Recent studies have shown the inverse correlation between age and SLN positivity.39 Results from this series suggested that when the SLN is involved, older patients are more likely to experience tumour progression to their pelvic LNs. Another important result of this study is the occurrence of pelvic LN metastasis in absence of disease progression through the inguinal LNs. This finding underlines the importance of investigating the lymphatic drainage at lymphoscintigraphy and the possibility of tailoring the dissection upon the presence of second-tier LNs in the pelvis.20,23 Interestingly, a recent study demonstrated that almost 40% of patients undergoing groin SLNB have lymphatic drainage in the pelvis and this was associated with older age and tumour, which are the same predictors we identified for pelvic LN positivity.40

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This study investigated also prognosis of patients with pelvic metastasis. The presence of pelvic LNs involvement was associated with a significant worse overall survival which decreased to 50% from 81% in patients with positive SLN and negative non-SLN both in the inguinal and pelvic lymphatic fields. Consistently, increased disease recurrence and shorter DFS were observed in these patients, with only one third of them disease-free after five years. Previous studies19,34,41 reported 5-year survival similar or even lower to those we identified here. The adverse prognostic implications of having metastasis in the pelvic LN parallels the prognostic value of melanoma progression from the SLN to the non-SLN.42e44 Whether surgery represents a curative option in this patient is still matter of discussion. Considering the relatively low effectiveness of adjuvant treatment and the low but relevant survival rate after removal of pelvic LN metastasis showed in this study, surgery can offer a therapeutic opportunity for some of these patients. However, definitive evidence can be provided only with a randomized controlled trial. The Evaluation of Groin Lymphadenectomy Extent For Metastatic Melanoma study (EAGLEeFM) is going to randomized SLNB-positive patients to inguinal CLND or inguinal and pelvic CLND.45 Enrolment in this trial should be largely encouraged as it is going to standardize the treatment of melanoma patients with LN metastasis in the groin. Moreover, the MSLT-II which is comparing CLND and nodal observation in SLNB-positive patients, is going to provide more evidence on the therapeutic value of lymphadenectomy in melanoma.46 Conclusion The present study offered interesting insight for the identification of patients with positive SLNB in the groin at risk of pelvic nodal disease and their prognosis. Pelvic metastases were detected in 12% of these patients and let to a 30% and 50% 5-year disease free and overall survival rates, respectively, which was lower than patients with metastasis limited to their SLN or inguinal LNs. Older patients, those who have thicker primaries and more than one positive SLN are at higher risk pelvic metastasis. Given the lack of effective adjuvant treatments, pelvic dissection should be considered in patients with positive SLNB in the groin. Conflict of interest Authors have no conflict of interest.

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Factors predictive of pelvic lymph node involvement and outcomes in melanoma patients with metastatic sentinel lymph node of the groin: A multicentre study.

The optimal extent of the groin lymph node (LN) dissection for melanoma patients with positive sentinel LN biopsy is still debated and no agreement ex...
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