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Original Article |
1 Sydney Melanoma Unit, Sydney Cancer Centre, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia
2 Discipline of Surgery, The University of Sydney, Sydney, New South Wales 2006, Australia
3 Department of Anatomical Pathology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia
4 Discipline of Medicine, The University of Sydney, Sydney, New South Wales 2006, Australia
Correspondence: Address correspondence and reprint requests to: John F. Thompson, MD, Sydney Melanoma Unit, Sydney Cancer Centre, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia; E-mail: thompson{at}smu.org.au.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Methods: ITM rates for 2018 patients with primary melanomas 
1.0 mm thick treated at a single institution between 1991 and 2000 according to 3 protocols were compared: wide local excision (WLE) only (n = 1035), WLE plus SNB (n = 754), and WLE plus elective lymph node dissection (n = 229).
Results: The incidence of ITM for the three protocols was 4.9%, 3.6%, and 5.7%, respectively (not significant), and as a first site of recurrent disease the incidence was 2.5%, 2.4%, and 4.4%, respectively (not significant). The subset of patients who were node positive after SNB and after elective lymph node dissection also had similar ITM rates (10.8% and 7.1%, respectively; P = .11). On multivariate analysis, primary tumor thickness and patient age predicted ITM as a first recurrence, but type of treatment did not. Patients who underwent WLE only and who had a subsequent therapeutic lymph node dissection (n = 149) had an ITM rate of 24.2%, compared with 10.8% in patients with a tumor-positive sentinel node treated with immediate dissection (n = 102; P = .03).
Conclusions: Performing an SNB in patients with melanoma treated by WLE does not increase the incidence of ITM.
Key Words: Melanoma • In-transit metastasis • Recurrence • Sentinel node • Regional lymph node
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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1 mm thick. However, although SNB provides accurate staging and important prognostic information, the results of clinical trials designed to show whether it has any influence on ultimate outcomes are not yet published, and the possibility that significant adverse consequences are associated with SNB has not been eliminated. An important theoretical concern raised in the 1970s and 1980s was that removal of lymph nodes from a regional node field (causing impairment of lymphatic drainage from the primary tumor) could result in an increased rate of locoregional recurrence of the melanoma.1–4 It was suggested that tumor cells could become trapped in lymphatics draining the tumor site, causing in-transit metastasis (ITM) to develop between the primary tumor site and the regional lymph node field in a later phase of the disease. A similar concern has been raised recently by a report of high ITM rates after wide local excision (WLE) and SNB.5
Because of concern about high ITM rates after elective lymph node dissection (ELND) in some series,6 several studies compared ITM rates after WLE and ELND with and without a planned delay between primary excision and lymph node removal.1,7,8 However, these studies produced contradictory results, and none of them included a control group of patients who did not undergo any form of lymph node dissection. An additional consideration is that in most of these studies, preoperative lymphoscin-tigraphy was not performed. This means that meta-static disease foci that developed within "interval" sentinel nodes9 (i.e., sentinel nodes not located in recognized lymph node fields) could have been recorded as ITMs and not as nodal metastases. Nodes located in the triangular intermuscular space on the back10 and in the mid and upper arm11 are good examples of metastatic sites that could have been misinterpreted as ITMs if the possibility of sentinel nodes being located in these locations was not recognized.
The purpose of this study was to investigate the concern about a potentially increased rate of ITM resulting from surgical intervention in the regional lymph node field in another way: by determining whether the incidence of ITM in patients with primary cutaneous melanomas who underwent SNB or ELND was higher than that in patients who underwent WLE only.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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After exclusion of these patients, 2018 remained and constituted the final study population. Within this cohort, 1035 were treated by WLE only, 754 were treated by WLE plus SNB, and 229 were treated by WLE plus ELND. All three groups contained patients treated between January 1991 and December 2000 except for the SNB group, which included only patients who received treatment after February 1992 (when SNB procedures were first performed at the SMU in those who agreed to participate in a validation study12). Between January 1991 and February 1992, patients were treated either by WLE only (if their primary tumor was <1.5 mm in Breslow thickness or was <2.0 mm on the lower limb of a woman) or by WLE plus ELND (if their primary tumor was 1.5 mm thick or was 2.0 mm on the lower limb of a woman).13 Between April 1994 and October 2000, 946 SMU patients were randomized to be treated by WLE only or by WLE plus SNB as part of an international multicenter trial to assess SNB—the Multicenter Selective Lymphadenectomy Trial.14 Patients eligible for this trial were those with a primary tumor 1.0 mm thick or <1.0 mm thick but with invasion to Clark level IV or V. After October 2000, SNB was recommended as a staging procedure to determine eligibility for a clinical trial of an adjuvant vaccine, but some patients requested WLE only, whereas others requested WLE plus ELND. A few patients treated after April 1994 were treated by WLE plus ELND because they were ineligible for the randomized trial assessing SNB or because they specifically requested ELND rather than trial participation. Some other patients requested WLE only or WLE plus SNB during this period. Patients found to have a positive sentinel node had a completion lymph node dissection of the regional node field within 3 to 4 weeks of the SNB procedure in all but a few instances.
The excision margins used for patients with similar primary tumor thicknesses were uniform for the three study groups, and treatment was undertaken using the same surgical protocols over the 10-year study period. Preoperative lymphoscintigraphy was performed in all patients treated by WLE plus SNB, in approximately 50% of those treated by WLE only, and in approximately 25% of those treated by WLE plus ELND.
Classification and Definitions
The frequencies of local, in-transit, regional, and distant melanoma recurrences were analyzed by using the following definitions. Recurrences within 3 cm of the original primary tumor were classified as local recurrences; intradermal and subcutaneous metastases between the excision scar and the regional lymph node field, >3 cm from the primary tumor site, were classified as ITMs; a recurrence found within the regional node field was recorded as a regional node field recurrence; and metastases beyond the regional node field or in a visceral organ were considered distant metastases. In describing patients with multiple sites of first recurrence, only the most prognostically adverse location was recorded, in the following descending order: distant, in transit, regional node field, and local. In addition to the recurrence data, the following patient and tumor characteristics were recorded and analyzed: sex, age, tumor thickness, presence or absence of ulceration, Clark level of invasion, primary tumor site, and follow-up period.
Statistical Analysis
Results for the three treatment groups were compared by univariate analysis with the 
2 test, Fisher’s exact test, the Wilcoxon rank test, the Mann-Whitney test, and Student’s t-test where appropriate. Results were compared by multivariate analysis with logistical regression. The Yates correction was applied to the 2 test when subgroups with small numbers were evaluated.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. There were no statistically significant differences in age or sex distribution between the WLE plus SNB and WLE plus ELND groups. However, the WLE-only patients were different in that the average age at diagnosis was older ( P = .02) and the proportion of men was significantly lower ( P = .03).
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The distribution of the primary melanomas over different body sites was similar for the compared groups, except for the proportion of melanomas in the head and neck region. This was significantly lower in the SNB group (12% vs. 20% and 24% for the WLE-only and WLE plus ELND groups, respectively; P < .001).
Incidence of ITM
There were no statistically significant differences on univariate analysis in the incidence of ITM for patients who had undergone WLE only, WLE plus SNB, or WLE plus ELND. This was also the case on multivariate analysis after adjusting for Breslow thickness, ulceration, sex, age, and follow-up time (Table 2). Neither when comparing the total figures for ITM occurring at any time during follow-up (4.9%, 3.6%, and 5.7%, respectively; Table 3) nor when comparing those occurring as first recurrences (2.5%, 2.4%, and 4.4%, respectively) were there any statistically significant differences. The median interval between excision of the primary tumor and diagnosis of ITM was 16 months (range, 2–83 months) and was similar for all three groups. More than 80% of all ITM diagnoses were within 35 months of the initial definitive operation. Actuarial ITM-free survival curves for the three treatment groups (calculated with the Kaplan-Meier method) are shown in Fig. 1.
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and 5 and Fig. 2). Univariate analysis showed that the tumor-negative SNB group had a significantly lower rate of ITM as a first recurrence when compared with the tumor-negative ELND group. Rates for total ITM were 2.5% for SNB-negative and 5.5% for ELND-negative patients ( P = .04), whereas first-recurrence ITM rates were 1.7 % and 4.5%, respectively ( P = .03). However, multivariate analysis showed that Breslow thickness ( P = .039) and patient age at diagnosis ( P = .014) were the only significant independent predictors of ITM, and treatment did not have a significant effect (Table 2
). The tumor-positive groups had similar rates for both first and total ITM, and no significant factors predicting ITM were found on multivariate analysis.
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. This analysis showed a relatively low ITM rate for the upper extremity (2.4%), intermediate rates for the trunk (3.5%) and the head and neck region (4.0%), and the highest overall ITM rate for the lower extremity (8.0%).
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). One was treated with WLE only and a subsequent (delayed) therapeutic lymph node dissection when metastatic disease in the regional nodes became clinically apparent, and the other subgroup was treated with WLE plus SNB followed by a completion lymph node dissection, normally within 3 to 4 weeks, because a sentinel node was tumor positive. The total ITM rate was significantly higher in the group treated with a delayed therapeutic regional node dissection (24.2%) than in the group that underwent immediate regional node dissection (10.8%; P = .008; Fig. 3). Median follow-up times in these groups were 34 and 29 months, respectively (significantly different; P = .025), but on multivariate analysis, treatment was the only significant factor that predicted ITM ( P = .006).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Although much is known about the characteristics of this prognostically ominous type of metastasis, little is known about its pathophysiology. It has generally been assumed that ITMs occur as a result of malignant cells detaching from the primary tumor, entering dermal and subcutaneous lymphatic channels, and subsequently lodging in these vessels before reaching a regional lymph node. However, alternative mechanisms are also possible, such as the recently described extravascular migratory metastasis model.18–20 Some have suggested that mechanical interruption of the lymphatic flow to the regional nodes, either by metastatic nodal disease obstructing normal lymph flow or by their surgical excision, could predispose to ITM by trapping malignant cells present in the static lymph.1–4
This concern was first raised several decades ago and has been investigated in several studies. McCarthy et al.,1 Fortner et al.,7 and Petersen et al.8 compared patients undergoing regional node dissections several weeks after the primary excision with those who had immediate dissections. However, none of these studies provided convincing support for the tumor-entrapment hypothesis.
Subsequently, a large retrospective series reported a 10% incidence of ITM in lymph node–positive patients.6 A higher incidence of ITM would be expected in patients with more advanced disease, such as palpable lymph node metastases. However, the results were quite the opposite: an unexpectedly high ITM rate of 27% was found in a group of patients undergoing WLE plus ELND in whom tumor-positive lymph nodes were found in the regional node field. By comparison, there was a remarkably low ITM rate of only 4% in patients treated with a therapeutic lymph node dissection after lymph nodes became palpable ( P < .001). This observation led to further speculation that performing a regional node dissection some time after excision of the primary tumor might be beneficial to allow for clearance of any melanoma cells in the afferent lymphatics draining to regional nodes.
The same argument concerning ITM caused by tumor cell entrapment could be applied to SNB. Results reported recently from the Netherlands Cancer Institute raised concern about this possibility,5 with an ITM rate of 7% in sentinel node–negative patients and 23% in sentinel node–positive patients. However, Clary et al.21 reported ITM rates of 2.8% in sentinel node–negative patients and 12.5% in sentinel node–positive patients, whereas Doting et al.22 reported ITM rates of 4% in sentinel node–negative patients and 8% in sentinel node–positive patients. Gershenwald et al.23 reported an ITM rate of 7.6% in sentinel node–positive patients, and Pawlik et al.,24 from the same institution, subsequently reported an overall ITM rate of 6.6% in a larger cohort of 1395 patients with longer follow-up who underwent SNB. In the last study, the ITM rate for sentinel node–negative patients was 3.5%, and for those who had positive sentinel nodes it was 12%. In 710 patients followed up for a median of 29 months, Cascinelli et al.25 observed an ITM rate of 3%. Discussing interim results from the Sunbelt Melanoma Trial, Chao et al.26 reported ITM rates of .95% in 950 sentinel node–negative patients and 2.1% in 233 sentinel node–positive patients, but with a median follow-up time of only 16 months.
Thus there are wide variations in reported ITM rates after SNB. It is likely that the explanation of these variations is multifactorial and involves differences in primary tumor characteristics such as Breslow thickness and ulceration, as well as differences in the duration and completeness of follow-up and perhaps also systematic differences in excision margins and even in the precise definition of ITM among individual centers. Final answers should be provided by large-scale multicenter clinical trials with clearly defined eligibility criteria and treatment protocols and accurate and complete long-term follow up.
If the tumor-entrapment theory were correct, then a higher incidence of ITM would be predicted in patients undergoing SNB or ELND compared with patients who had only a WLE of their primary melanoma. To investigate this, we examined the ITM rate in three groups of patients treated at a single institution over the same time period by the same surgical team. One group of patients was treated with WLE only, the second was treated with WLE plus SNB, and the third was treated with WLE plus ELND. Because of the possibility that patients who presented with ITM as a first recurrence might have a better chance of curative treatment, both first-recurrence ITM rates and overall ITM rates were examined.
Our study showed no significant difference in the overall or first-recurrence ITM rates among three large groups of patients. Median follow-up ranged from 35 months for the WLE-only group to 61 months for the WLE plus ELND group. Although there was no significant difference from the WLE-only group, the WLE plus ELND group did seem to show a trend toward an increased incidence of ITM, both for overall recurrence and first recurrence only. However, factors other than lymphatic blockage seem likely to have caused this increase (and this was borne out by multivariate analysis). First, there was a substantially greater average primary tumor thickness and a considerably higher proportion of ulcerated tumors in the ELND group: a median of 2.8 vs. 1.8 mm for the WLE-only group and 40% vs. 25% ulcerated in the WLE-only group. Both tumor thickness and ulceration are known to be important prognostic factors for a higher incidence of ITM.2,27 These differences are likely to have resulted from the selection criteria applied to patients treated early in the study period, which assigned those with thick tumors to be treated by ELND at the time of WLE. Follow-up times were significantly longer in the WLE plus ELND group (median, 61 vs. 35 months for the WLE-only group) because most of the ELND procedures were performed early in the study period. However, logistical regression showed no significant effect of follow-up time. This result was expected because, as previously indicated, the great majority of ITM events occur within 3 years of initial definitive melanoma treatment.17 The logistical regression analysis indicated that the somewhat higher ITM incidence in the WLE plus ELND group was due to tumor thickness and patient age and not to follow-up time or treatment category.
The significantly lower incidence of ITMs observed in tumor-negative SNB patients when compared with tumor-negative ELND patients is likely to have resulted from more accurate staging of the SNB patients. Previous studies have consistently shown superior staging because of more comprehensive histological examination of the regional lymph nodes after SNB.28–34 The pathologist examining the sentinel node specimen is provided with a specifically selected and markedly reduced amount of material, which can therefore be examined in greater detail. Thus, it is probable that the "tumor-negative" ELND group contained more false-negative patients, who would have been at considerably higher risk of developing ITM.3 As stated previously, the higher incidence of ITM in the ELND patients was attributable to differences in primary tumor thickness and age at diagnosis. The median thickness of the primary melanoma in the SNB group was 1.85 vs. 2.80 mm in the WLE plus ELND group, and age at diagnosis was 54 vs. 58 years, respectively.
The relatively high incidence of ITM in node-positive ELND and SNB patients was expected, both on the basis of previous reports and on theoretical grounds, because regional node positivity identifies patients whose tumors have developed metastatic potential. Regional node metastases are undoubtedly the result of migration of metastatic tumor cells through the lymphatics, and it is therefore logical to assume that there will be an increased likelihood that other tumor cells might be arrested in the lymphatics to produce ITM. In previous studies, similar increases were found in the incidence of ITM when metastases were present in the regional node field.15,21,35
The ITM rates that we observed in different parts of the body are closely comparable to those described previously.6 The higher ITM rates in the lower extremity may be a consequence of the relatively more abundant and longer lymphatic vessels that are present in this part of the body.35,36 However, lymphatic flow rates are far greater in the lower extremity than in other body sites,37 which might be expected to reduce ITM rates if the process involves mechanical trapping of metastatic cells in the lymphatics.
An important subgroup analysis was undertaken to assess the validity of the concept that ITM is due to trapping of melanoma cells in lymphatic channels. This involved a comparison of ITM rates in patients with evidence of regional lymph node metastasis who received either immediate or delayed regional node dissection. Contrary to what the entrapment theory would predict, the group of patients who received immediate regional lymph node dissection after a tumor-positive sentinel node had been found showed a lower incidence of ITM than the patients treated with WLE only who had a delayed dissection when metastatic disease in the lymph nodes became clinically apparent. Although part of this difference could be explained by the slightly shorter median follow-up time in the group that received immediate dissection (29 vs. 34 months in the group that received delayed dissection), it seems that allowing for a supposed "lymphatic clearance" before performing regional node dissection did not decrease the incidence of ITM. Thus, the results of our study do not support the hypothesis that mechanical entrapment of tumor cells in lymphatic channels due to surgical interference with the regional nodes is a significant factor in the development of ITM.
One of the difficulties in trying to interpret the ITM rates reported in the literature is that the definition of ITM varies from series to series. It is possible—indeed, probable—that the conventional definitions of in-transit and local recurrence do not truly represent the different forms of locoregional recurrence. Various biological mechanisms have been proposed to explain local recurrence; these include the persistence of dispersed primary tumor cells in the near vicinity of the primary tumor, instability of adjacent melanocytes, secreted wound healing and growth factors, so-called extravascular migratory metastasis, and hematogenous recirculation of cells.18–20,38–41 Whichever explanation is correct, it is debatable whether local recurrence (as conventionally defined) and scar recurrence should be considered together. True scar recurrence is thought to result from local retention of primary tumor cells due to inadequate primary surgical therapy. Conversely, local recurrence (within 3 cm of the original primary tumor), like in-transit disease, is considered to develop when tumor emboli adhere to and grow within the lymphatic channels draining the skin. Multivariate analysis has shown that an arbitrary division based on distance from the primary disease site has no prognostic value.12 Therefore, it may be more logical to categorize all locoregional recurrences between the primary tumor site and the regional node field as ITMs, perhaps with the exception of scar recurrences.
In our study, ITM was defined as metastatic disease that occurred >3 cm from the primary melanoma site, between that site and the regional lymph node field. Thus, we did not include local recurrences (i.e., recurrences at or close to the primary melanoma site) under the heading of ITMs. However, as already indicated, these are probably also due to lymphatic tumor embolization, with the exception of true scar recurrences. To ensure that our definition was not the reason why the observed ITM rates were lower than those reported by some other groups, we reanalyzed our data with all local recurrences (occurring <3 cm from the primary melanoma site) added to the previously determined ITMs. With this alternative definition, the "ITM" rate for WLE only was 6.5%, the rate for WLE plus SNB was 3.7%, and the rate for WLE plus ELND was 7.0%. Our conclusions are thus not changed by including local recurrences with true ITMs (as we defined them); indeed, proportionally fewer patients developed local recurrences and ITMs after WLE plus SNB than after WLE alone or WLE plus ELND.
A further difficulty arises when cutaneous or subcutaneous recurrence occurs close to or within an area designated as a node field. Should this nonnodal recurrence be classified as ITM or as node field recurrence? In our study, we recorded such disease as node field recurrence, but it is possible that other investigators have regarded it as ITM. Nevertheless, when we reanalyzed our data comparing local recurrence plus ITM (as originally recorded) plus node field recurrence for the WLE-only, WLE plus SNB, and WLE plus ELND groups, the figures were 7.0%, 4.4%, and 7.0%, respectively. The rate for WLE plus SNB was significantly lower than that for the WLE-only group ( P < .05) and was lower than but not significantly different from the WLE plus ELND group. Again, our conclusions were not changed by including node field recurrences with local recurrences and true ITMs (as we defined them), and, again, proportionally fewer patients developed local recurrences, ITMs, and node field recurrences after WLE plus SNB than they did after WLE alone or WLE plus ELND.
Instead of simple mechanical explanations for the development of ITM, complex biological events involved in the metastatic process are more likely to be responsible. A wide range of studies have shed light on some of these biological mechanisms. For example, metastatic melanoma cells have been shown to exhibit organ specificity dependent on organ-specific growth factors42 and to produce immunosuppressive substances that downregulate lymph node functional activity, a process that could create conditions that permit the survival and growth of tumor cells in lymphatic tissue.43 Nip et al.44 showed that melanoma cells with the ability to adhere to vitronectin, an extracellular matrix protein in lymph nodes, showed increased expression of vitronectin-specific receptors on their surface. This mechanism represents another biological adaptation of melanoma cells that allows them to adhere to lymphatic tissue.
At an even more basic level, it has been shown that significant heterogeneity may exist within primary tumors, with only a minority of cells possessing the metastatic phenotype. It seems that establishment of clinically successful ITMs requires specific genetic events. This concept is supported by the studies of Nakayama et al.,45 who demonstrated that ITMs are clonal in origin. This was assessed by using loss of heterozygosity analysis for specific DNA microsatellite loci. The most common allelic loss noted in melanoma ITMs is 9p23, an allelic loss that differs from the one most commonly seen in regional lymph node metastases.45,46
Several histopathologic features that accurately predict the development of ITMs have been identified. Borgstein et al.35 found that lymphatic invasion was associated with ITMs in most patients, whereas patients with melanomas without this characteristic did not develop ITMs. This relationship was so strong that these authors suggested selection of patients for adjuvant treatment, for example, isolated limb perfusion, on the basis of this single feature. Recently, Lugassy, Barnhill, and their colleagues have proposed that the migration of tumor cells along the external surfaces of vessels (a phenomenon that they have termed extravascular migratory metastasis) may be an important mechanism by which some melanoma cells spread to nearby or distant sites.18,19,47,48 They have documented the presence of melanoma cells around small blood vessels (without evidence of tumor cells in the vessel lumen) at the periphery of melanomas, and they found that this strongly correlates with the presence of extravascular migratory metastasis. Although further, larger studies are required, initial results suggest that the presence of angiotropism may be an important prognostic factor for melanoma patients.49
All intralymphatic melanoma metastases situated between the primary tumor location and the regional lymph node field thus seem to represent a type of metastasis with a distinctive, genetically based biology. On the basis of this study, we conclude that the risk of developing these ITMs is not increased by either SNB or ELND and that these metastases cannot be prevented by performing a delayed regional node dissection days or even weeks after excision of the primary tumor. However, the likelihood of ITM can be predicted by detailed pathologic evaluation of the primary tumor. Further studies are required to determine whether patients who are at high risk of developing this type of metastasis, as judged by the histopathologic, clinical, and possibly also genetic features of the primary melanoma, can benefit from locoregional or systemic adjuvant treatment.
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ACKNOWLEDGMENTS |
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Received for publication August 12, 2004. Accepted for publication February 10, 2005.
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  J. L. Messina and V. K. Sondak Lymphangiogenesis Induced by Surgery: A Risk for Melanoma Metastasis--Reply Arch Dermatol, January 1, 2009; 145(1): 90 - 90. [Full Text] [PDF]
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 M. I. Ross and J. E. Gershenwald How Should We View the Results of the Multicenter Selective Lymphadenectomy Trial-1 (MSLT-1)? Ann. Surg. Oncol., March 1, 2008; 15(3): 670 - 673. [Full Text] [PDF]
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J. E. Gervasoni Jr., S. Sbayi, and B. Cady Role of lymphadenectomy in surgical treatment of solid tumors: an update on the clinical data. Ann. Surg. Oncol., September 1, 2007; 14(9): 2443 - 2462. [Abstract] [Full Text] [PDF]
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 R. F. Uren Sentinel Lymph Node Biopsy in Melanoma J. Nucl. Med., February 1, 2006; 47(2): 191 - 195. [Full Text] [PDF]
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