eTable 1. Three levels of axillary lymphadenectomy
eTable 2. Three levels or less of neck lymphadenectomy
eTable 3. Four levels or more of neck lymphadenectomy
eTable 4. Inguinal lymphadenectomy
eTable 5. Ilioinguinal lymphadenectomy
Rossi CR, Mozzillo N, Maurichi A, Pasquali S, Macripò G, Borgognoni L, Solari N, Piazzalunga D, Mascheroni L, Giudice G, Mocellin S, Patuzzo R, Caracò C, Ribero S, Marone U, Santinami M. Number of Excised Lymph Nodes as a Quality Assurance Measure for Lymphadenectomy in Melanoma. JAMA Surg. 2014;149(7):700-706. doi:10.1001/jamasurg.2013.5676
Although the number of excised lymph nodes (LNs) represents a quality assurance measure in lymphadenectomy for many solid tumors, the minimum number of LNs to be dissected has not been established for melanoma.
To investigate the distribution of the number of excised LNs in a large patient series (N = 2526) to identify values that may serve as benchmarks for monitoring the quality of lymphadenectomy in patients with melanoma.
Design, Setting, and Participants
A retrospective multicenter study was conducted (1992-2010) in tertiary referral centers for treatment of cutaneous melanoma. Medical records on 2526 patients who underwent lymphadenectomy for regional LN metastasis associated with cutaneous melanoma were examined.
Patients had undergone lymphadenectomy for regional LN metastasis.
Main Outcomes and Measures
The mean, median, and 10th percentile of the number of excised LNs were calculated for the axilla (3 levels), neck (≤3 or ≥4 dissected levels), inguinal, and ilioinguinal LN fields.
After 3-level axillary (n = 1150), 3-level or less neck (n = 77), 4-level or more neck (n = 135), inguinal (n = 209), and ilioinguinal (n = 955) dissections, the median (interquartile range [IQR]) and mean (SD) number of excised LNs were as follows: 3-level axillary dissection, 20 (15-27) and 22 (8); 3-level or less neck, 21 (14-33) and 24 (15); 4-level or more neck, 29 (21-41) and 31 (14); inguinal, 11 ( 9-14) and 12 (5); and ilioinguinal, 21 (16-26) and 22 (4). A total of 90% of the patients had 12, 7, 14, 6, and 13 excised LNs (10th percentile of the distribution) after 3-level axillary, 3-level or less neck, 4-level or more neck, inguinal, and ilioinguinal dissections, respectively. More excised LNs were detected in younger (21 for those <54 years of age and 19 for ≥54 years, P < .001) and male (21 for male sex and 19 for female sex, P < .001) patients from high-volume institutions (21 for volume of ≥300 vs 18 for volume <300, P < .001) with a more recent year of diagnosis (21 for years 2002-2010 vs 18 for years 1992-2001, P < .001), LN micrometastasis vs macrometastasis (20 vs 19, P = .005), and more positive LNs (R2 = 0.03, P < .001); however, the differences between median values were small.
Conclusions and Relevance
These minimum numbers of excised LNs are reproducible across the institution, patient, and tumor factors evaluated. They can be taken into consideration when monitoring the quality of lymphadenectomy in melanoma and can represent entry criteria for randomized trials investigating adjuvant therapies.
Lymphadenectomy plays a significant role in cancer staging because thorough dissection allows identification of potential lymph node (LN) metastasis for patients who would benefit from adjuvant treatments.1- 6 This evidence has fostered care providers to establish quality assurance measures used to judge the appropriateness of lymphadenectomy.7 Although several indicators might be considered when monitoring the quality of lymphadenectomy, the number of excised LNs represents an easy-to-obtain factor that is supposed to reflect the accuracy of staging as well as the quality of the surgery and pathological examination.8,9
In cutaneous melanoma, lymphadenectomy provides important prognostic information. Five-year patient survival ranges from 25% in cases of multiple positive LNs to 70% in cases of a single positive LN after sentinel LN biopsy (SLNB) and completion lymphadenectomy.10,11 The clearance of all metastatic LNs in the regional field may have therapeutic implications because patients may benefit from an early (SLNB-guided) dissection when metastatic disease is harbored within the regional LN field.12,13 Quality assurance measures for lymphadenectomy, such as the minimum number of LNs to be excised, are thus of great importance when judging the appropriateness of surgery and serve as entry criteria for randomized trials investigating adjuvant therapies.14,15 The clinical practice guidelines for the treatment of melanoma from the National Comprehensive Cancer Network16 reported that there is insufficient evidence to identify a minimum number of LNs that must be excised to consider a dissection adequate, and attempts at providing new evidence have been encouraged. However, as shown by a recent survey17 conducted among surgical oncologists treating melanoma, the number of excised LNs is still the preferred indicator for monitoring the quality of lymphadenectomy. To identify cutoff values for this metric, Spillane and colleagues15,18 suggested that the desirable number of excised LNs should be greater than the 10th percentile of the number of LNs that had been excised in their practice (ie, 90% of patients need to have a number of excised LNs ≥10th percentile). This approach can identify patients who received a possibly low-quality lymphadenectomy, but it remains to be verified in an independent series. The present study investigated an Italian multicenter series to assess the minimum number of excised LNs that should be dissected after lymphadenectomy according to the extent of surgery within each regional LN field.
The study protocol was approved by the Research Committee of the Italian Melanoma Intergroup (IMI). Retrospective data on patients with melanoma and LN metastasis who underwent lymphadenectomy at 9 IMI institutions between January 1992 and January 2010 were gathered in a multicenter database.
Data were extracted according to the following selection criteria: (1) LN metastasis from a single primary tumor, (2) absence of in-transit and distant metastasis at the time of primary melanoma diagnosis, (3) lymphadenectomy of a single lymphatic field, and (4) availability of information regarding tumor thickness, LN tumor burden (ie, micrometastasis and macrometastasis), number of excised and positive sentinel LNs, and number of excised and positive LNs. Patients who had an epitrochlear, popliteal, or single iliac dissection were excluded from the analyses.
The following variables were considered for each patient: age at primary melanoma diagnosis, sex, tumor thickness, ulceration, mitotic rate of the dermal component,19,20 LN tumor burden (micrometastasis [ie, lymphadenectomy performed for positive SLNB specimens] vs macrometastasis [ie, lymphadenectomy performed for clinically positive LNs]), nodal field of lymphadenectomy, number of excised and positive LNs at lymphadenectomy, and extent of lymphadenectomy for each nodal field.
Lymphadenectomies were performed by general surgeons, and the extent was classified as follows: (1) 3 levels of axillary lymphadenectomy (always involved the 3 anatomical levels as suggested by Italian national guidelines21), (2) 3 or fewer levels of neck lymphadenectomy, (3) 4 or more levels of neck lymphadenectomy, (4) inguinal lymphadenectomy, and (5) ilioinguinal lymphadenectomy.
Of 2526 medical records, data on the Clark level of invasion and ulceration were missing in 111 cases (4.4%) and 299 cases (11.8%), respectively. The multiple imputation method was used to predict the missing values by using variables with nonmissing values as predictors (ie, age, sex, tumor thickness, American Joint Committee on Cancer N category, and LN tumor burden).
Mean (SD), median (interquartile range [IQR]), and 10th percentile were calculated according to the extent of lymphadenectomy for each institution, for individual IMI institutions, and for IMI as a group. The Mann-Whitney test (2-sided P values) for binary variables and linear regression for continuous variables were used to compare the number of excised LNs across covariates, including high-volume (≥300 patients) and low-volume (<300 patients) institutions. Multivariable regression analysis was fitted to data to identify factors associated with the number of excised LNs. Analyses were conducted considering an α error rate of .05 and computed with Stata SE, version 11.0 (StataCorp).
A total of 2526 patients who underwent treatment at 9 Italian IMI-affiliated centers were considered eligible for this study (Table 1). Of the participating institutions, 5 belonged to cancer centers, 3 of which are melanoma-specific units, and the remaining 4 units were general surgery departments in university hospitals. Three institutions entered more than 300 patients in the study, 2 institutions entered 200 to 300 patients, and 4 institutions included fewer than 100 patients. The results of each institution are reported in the Supplement (eTables 1-5).
After a 3-level axillary, 3-level or less neck, 4-level or more neck, inguinal, and ilioinguinal dissection, the median (IQR) number of excised LNs was 20 (15-27), 21 (14-33), 29 (21-41), 11 (9-14), and 21 (16-26), respectively. Ninety percent of the patients had 12, 7, 14, 6, and 13 excised LNs (10th percentile of the distribution) after 3-level axillary, 3-level or less neck, 4-level or more neck, inguinal, and ilioinguinal dissection, respectively (Table 2).
Univariate and multivariable analyses were performed to identify differences in the distribution of the number of excised LNs across specific institution, patient, and tumor features. Upon univariate analysis, the associations between the number of excised LNs and more recent year of diagnosis (P < .001), higher-volume centers (P < .001), younger age (P < .001), male sex (P < .001), micrometastasis (P = .005), and more positive LNs (P < .001) were statistically significant, although the differences between the median values were small (Table 3). Primary tumor features were not associated with the number of excised LNs.
Upon multivariable analysis, more recent year of diagnosis (correlation coefficient, 1.96; 95% CI, 1.01 to 2.90; P < .0001), high-volume institution (1.75; 0.95 to 2.55; P < .001), male sex (1.61; 95% CI, 1.13 to 2.76; P < .001), micrometastasis (1.95; 95% CI, 1.13 to 2.76; P < .001), and more positive LNs (0.46; 95% CI, 0.36 to 0.56; P < .001) were associated independently with a greater number of excised LNs. Age 54 years or older was associated with fewer excised LNs (−1.54; −2.26 to −0.82; P < .001).
The distribution of the number of LNs across significant covariates was analyzed according to the dissected lymphatic fields. Patients who received treatment in high-volume institutions had 3 more excised LNs (median values) than did patients who underwent lymphadenectomy in a low-volume institution. Considering the extent of surgery within each nodal field, the statistical significance was maintained for axillary dissections (low-volume: median [IQR], 19 [15-25]; high-volume: 21 [16-27]; P = .009), but the institution’s volume was no longer significant when a 3-level or less and 4-level or more neck (P = .54), inguinal (P = .37), and ilioinguinal (P = .74) dissection was performed.
Patients who received treatment in more recent years had 3 more excised LNs (median values) compared with patients who underwent lymphadenectomy in earlier years. Considering the extent of surgery within each nodal field, the difference was maintained for axillary (more recent years: median [IQR], 21 [16-27]; earlier years: 18 [14-24]; P = .004) and ilioinguinal (more recent years: 21 [16-27]; earlier years: 19 [15-24]; P = .001) dissections, but was no longer significant in cases of 3 or fewer (P = .28) and 4 or more (P = .08) levels of neck and inguinal (P = .28) dissection.
Younger patients had 2 more excised LNs (median values) compared with patients who were older at the time of their primary melanoma diagnosis. This significant difference was maintained for patients who had an axillary lymphadenectomy (age <54 years: median [IQR], 21 [16-27]; age ≥54 years: 19 [14-26]; P < .001) but not in those who had 3 or fewer (P = .90) and 4 or more (P = .53) levels of neck, inguinal (P = .39), or ilioinguinal (P = .49) dissection.
Male patients had 2 more excised LNs (median values) compared with female patients. This significant difference was maintained for patients who had an axillary lymphadenectomy (male: median [IQR], 21 [16-27]; female: 19 [14-24]; P < .001) but not in those who had 3 or fewer (P = .80) and 4 or more (P = .62) levels of neck, inguinal (P = .26), or ilioinguinal (P = .54) dissection.
Patients with micrometastasis had 1 more excised LN (median value) than did patients with macrometastasis. This significant difference was maintained for patients who had an inguinal (micrometastasis: median [IQR], 12 [10-14]; macrometastasis: 10 [7-13]; P = .001) or ilioinguinal (micrometastasis: 21 [17-27]; macrometastasis: 19 [14-25]; P < .001) lymphadenectomy but not an axillary (P = .54) and 3 or fewer (P = .20) or 4 or more (P = .10) levels of neck dissection.
A large patient series from 9 Italian centers was investigated to identify the minimum number of excised LNs that may serve as a quality assurance measure for lymphadenectomies performed for LN metastasis associated with melanoma. The mean numbers of excised LNs for axillary dissection, neck dissection involving 3 or fewer or 4 or more anatomical levels, inguinal, and ilioinguinal lymphadenectomy were 22, 24, 31, 12, and 22, respectively. Ninety percent of patients (ie, the 10th percentile) who underwent an axillary dissection, a neck dissection involving 3 or fewer or 4 or more anatomical levels, an inguinal, and an ilioinguinal lymphadenectomy had at least 12, 7, 14, 6, and 13 excised LNs, respectively.
Spillane et al15,18 reported similar results in their experience at the Melanoma Institute Australia. In their studies the mean value of the number of excised LNs after a lymphadenectomy performed in the axilla, neck with 3 or fewer and 4 or more levels, inguinal, and ilioinguinal nodal fields were 22, 19, 39, 12, and 22, respectively. These results are similar to those reported in our study for all types of lymphadenectomy except 4 or more dissected levels. A similar observation can be made for the 10th percentile of the value of the examined LNs; at the Melanoma Institute Australia, 90% of patients had 10, 6, 20, 8, and 14 excised LNs after axillary dissection, neck dissection involving 3 or fewer and 4 or more anatomical levels, inguinal, and ilioinguinal lymphadenectomy, respectively.
The difference in the distribution of the number of excised LNs among patients who underwent a dissection of 4 or more neck levels may result from a lower number of patients in our study (367 in the Australian study vs 135 in the present study) and by a potentially greater number of patients who underwent a 5-level dissection in the study by Spillane et al.15 This discrepancy should be further investigated. Furthermore, it appears difficult to compare the extent of surgery within neck anatomical levels across different institutions given the lack of guidelines suggesting the optimal extent for a neck dissection based on primary tumor location and features along with the location of LN metastasis in the neck lymphatic field.16
Moreover, the present study investigated the association between the number of excised LNs and institution, patient, and tumor characteristics. Although primary tumor features did not correlate with the number of excised LNs, more recent year of diagnosis (3 more excised LNs; P < .001), higher-volume institution (3 more excised LNs; P < .001), male sex (2 more excised LNs; P < .001), micrometastasis (1 more excised LN; P < .001), and more positive LNs (R2 = 0.03; P < .001) were associated independently with a greater number of excised LNs; older age was associated with fewer excised LNs (2 fewer LNs; P < .001). Despite the statistically significant results, the differences in the median and 10th percentile number of excised LNs were small, suggesting that the cutoff values calculated considering the 10th percentile of their distribution are reproducible across the considered institution, patient, and tumor categories.
Spillane at al15 considered only the expertise of the surgeons as a confounder of the number of excised LNs by categorizing surgeons according to whether they belonged to the Melanoma Institute Australia and reported that surgeons belonging to this institution retrieved more excised LNs than did the other surgeons.
To the best of our knowledge, the study of Spillane et al15,18 represents the only evidence-based attempt so far at identifying a minimum number of LNs that must be excised according to the extent of surgery within each nodal field. Xing et al22 investigated patients with LN metastases included in the Surveillance, Epidemiology, and End Results database and reported that 15, 8, and 6 LNs should be excised after neck, axillary, and groin dissections, respectively, to identify 1 positive LN; however, they did not consider the potentially different extent of surgery within each nodal field. Other authors7,14,23,24 suggested a minimum number of LNs that should be excised to monitor the quality of surgery based on expert opinion. Patients who underwent neck, axillary, or groin dissection should have 15 to 30, 10 to 15, and 5 to 6 excised LNs, respectively (Table 4).7,14,15,18,22- 25
These efforts to identify a minimum number of LNs may have high relevance for patients as well as for physicians involved in the treatment of melanoma. A recent survey17 conducted among 193 surgeons with recognized high skills in melanoma treatment noted that the indicators for quality assurance monitoring of lymphadenectomy were used by 72% of responders, with the number of excised LNs cited as the most frequent considered indicator (94% of responders).
Despite this interest, poor LN counts after lymphadenectomy have been reported by Bilimoria et al,7 who conducted a national assessment of melanoma care in the United States and set 15, 10, and 5 excised LNs as the minimum standard for neck, axilla, and groin dissections, respectively. At the patient level, only 29%, 27%, and 45% of patients had a sufficient LN count for each of the above-mentioned nodal fields, and the figures were even smaller when the hospital level was investigated.
These results suggest that, because surgery is still the most effective treatment of melanoma regional LN metastasis, further efforts are required to improve the quality of care delivered to these patients. The identification of a minimum number of LNs that should be excised may be part of a quality assurance process, as demonstrated by studies conducted in colorectal cancer.1,26 After the introduction of the minimum 12 excised LNs benchmark, an increase in the number of excised LNs at both the patient and hospital level has been observed,1,26- 30 with more patients receiving adjuvant therapies and entering clinical trials. However, whether such improvement would translate into the identification of more positive LNs and better survival for patients remains unclear.27,29- 31
In melanoma, other measures have been suggested for the quality assurance of treatment performed in patients with LN metastases, such as the thoroughness of the SLNB32,33 and the digital picture of the nodal field after the dissection.34 Clearly, further research is required to test the value of these indicators and evaluate whether these factors could improve the quality of care and patient outcome.
Our study, as well as others9,28,35 that have investigated the number of excised LNs, may be limited by deficiencies and differences in the surgical technique and the pathological workup of the LNs. Nonetheless, using the number of excised LNs as a quality measure provides the chance to improve the quality of the surgical and pathological processes. For instance, when few LNs are identified after dissection, the surgeon and pathologist should evaluate the procedures applied to identify the potential pitfalls, with the ultimate aim of improving the care for future patients. As a result of a similar process with colorectal carcinoma, the College of American Pathologists36 established precise guidelines for the pathological evaluation of LNs and recommended that, if fewer than 12 nodes are identified, additional techniques for visual enhancement should be implemented and this event should be stated in the pathology report.
Another factor that clearly influences the number of excised LNs is the extent of surgery within each nodal field. Although the 3-level dissection is generally accepted as the standard approach for axillary dissection,37 guidance on how a neck (which anatomical levels have to be dissected) or a groin (when pelvic LNs have to be dissected) dissection should be performed is still lacking,16 reflecting the low level of evidence supporting these operations. A study comparing different neck dissections may be difficult to design and conduct; however, a randomized study38 comparing inguinal and ilioinguinal dissections for patients with groin LN metastasis is in progress at the Melanoma Institute Australia and is expected to improve standardization of groin dissection.
The present study investigated the number of excised LNs that should be dissected after lymphadenectomy according to the extent of surgery within each nodal field. Ninety percent of patients in the series had 12, 7, 14, 6, and 13 excised LNs after axillary, 3-level or less neck, 4-level or more neck, inguinal, and ilioinguinal lymphadenectomy, respectively. These values are reproducible across the institution, patient, and tumor features evaluated and may serve to monitor the quality of surgery within audit processes and for patients who are eligible to be enrolled in trials investigating adjuvant therapies. Further research is needed to evaluate whether using the number of excised LNs as a quality assurance factor might affect patient outcomes and whether other metrics (eg, morbidity) might be suitable for quality assurance monitoring.
Accepted for Publication: August 1, 2013.
Corresponding Author: Carlo Riccardo Rossi, MD, Melanoma and Sarcoma Unit, Veneto Institute of Oncology, Via Gattamelata, 64, 35128 Padova, Italy (email@example.com).
Published Online: May 7, 2014. doi:10.1001/jamasurg.2013.5676.
Author Contributions: Dr Rossi had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Rossi, Pasquali, Macripò, Solari, Mocellin, Patuzzo, Ribero.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Rossi, Pasquali, Giudice, Mocellin, Ribero.
Critical revision of the manuscript for important intellectual content: Rossi, Mozzillo, Maurichi, Pasquali, Macripò, Borgognoni, Solari, Piazzalunga, Mascheroni, Mocellin, Patuzzo, Caracò, Ribero, Marone, Santinami.
Statistical analysis: Rossi, Pasquali, Giudice, Mocellin.
Obtained funding: Giudice.
Administrative, technical, or material support: Borgognoni, Ribero.
Study supervision: Maurichi, Macripò, Solari, Mascheroni, Patuzzo, Marone.
Conflict of Interest Disclosures: None reported.
Funding/Support: The study was supported by the Italian Melanoma Intergroup, the Italian network for melanoma treatment and research (http://www.melanomaimi.it).
Role of the Sponsor: The Italian Melanoma Intergroup had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: Valentina Rossi, MA, edited the manuscript and Marta Rotella, MS, provided project managing support. The contributors received no financial compensation.