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The Risk of In-Transit Melanoma Metastasis Depends on Tumor Biology and Not the Surgical Approach to Regional Lymph Nodes

Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, The Sydney Melanoma Unit, Royal Prince Alfred Hospital, and the University of Sydney, Sydney, Australia, and the Department of Surgical Oncology, Erasmus University Medical Center, Rotterdam, the Netherlands

Although the majority of patients newly diagnosed with cutaneous melanoma present with clinically negative regional nodal basins, many of these patients harbor occult regional lymph node metastases. Historically, the initial treatment strategy for patients with clinically negative regional lymph nodes has been controversial. Treatments have included elective dissection, the goal of which was improved survival, and observation followed by dissection when clinical relapse developed. A more rational selective approach, involving lymphatic mapping and sentinel lymph node biopsy (SLNB), has now been widely adopted. SLNB is a minimally invasive technique for identifying the approximately 20% of patients who harbor occult metastatic disease and who may therefore benefit from completion lymphadenectomy.^1-4

Some authors have suggested that SLNB should not be employed outside the confines of a formal clinical investigation^5-9 because results are not yet available from completed clinical trials designed to assess whether SLNB affects survival. Among the authors' concerns is the possibility that SLNB may increase the risk of in-transit metastasis (ITM), thereby reducing, eliminating, or reversing any potential survival advantage associated with the SLNB technique.^5,10 The hypothesis that the SLNB technique and subsequent completion lymph node dissection in SLN-positive patients may disturb lymph flow and lead to increased rates of ITM—if the hypothesis is accurate—is of particular concern because SLNB has been widely adopted as the standard of care for many patients with clinically localized melanoma. When considering whether ITM is promoted by regional lymph node basin intervention, a full appreciation of the biology and incidence of ITM in melanoma patients before the advent of SLNB would be helpful.

ITM is defined as a unique manifestation of intralymphatic tumor dissemination, characterized by the presence of melanoma in either cutaneous or subcutaneous tissue situated between the primary tumor and the draining regional lymph node basin. In the pre-SLNB era, ITMs were reported to develop in 2.3% to 13% of patients with American Joint Committee on Cancer stage I and II melanoma treated by either wide local excision (WLE) alone or WLE plus elective lymph node dissection (ELND).^11,12 The appearance of ITM has serious prognostic implications: the reported 5-year survival rates in patients with ITM range from 12% to 37%.^13-15 Notoriously difficult to treat, ITMs are usually managed by simple excision, intralesional injection, or limb perfusion. Important risk factors for the development of ITM include thicker primary tumors, ulceration, lower-extremity location of the primary tumor, and regional lymph node metastasis.^12,13,16,17

It has been theorized that ITMs occur as a result of melanoma cells detaching from the primary tumor, entering dermal and subcutaneous lymphatic channels, and then becoming lodged in these vessels before reaching a regional lymph node.¹⁸ Mechanical interruption of lymphatic flow to the regional nodes, either by metastatic nodal disease obstructing normal lymph flow or by removal of the regional nodes, could then predispose to ITM by causing impairment of lymphatic drainage from the primary tumor.¹⁹ In one study,¹⁶ 27% of patients treated with WLE plus ELND developed ITM, compared with only 10% of patients treated with WLE plus a delayed therapeutic lymph node dissection performed after the lymph nodes became palpable. These remarkable findings led to speculation that early intervention in the lymph node basin using ELND or SLNB could result in an increased risk of ITM. Concern that SLNB may cause ITM has been heightened by several recent studies^9,10 reporting ITM rates as high as 23% after WLE and SLNB. Others⁵ have suggested that the incidence of local or in-transit recurrence following SLNB and completion lymphadenectomy in SLN-positive patients may be greater than four times the incidence expected in patients undergoing WLE alone. However, a critical analysis of the data from previous ELND trials, as well as data from more recent multi-institutional studies from both the United States and Australia, provides compelling evidence that the SLNB procedure and completion lymph node dissection in SLN-positive patients does not increase the incidence of ITM.

First, comparisons of the incidence of ITM in patients with positive SLNs with those patients undergoing WLE alone can be inappropriate and misleading. In general, patients included in SLNB studies have less favorable primary tumor characteristics than patients who undergo WLE alone. Thus it is probable that in patients who undergo SLNB, the biology of the tumor, rather than the SLNB procedure itself, contributes to the increased incidence of ITM. This is particularly true for the SLN-positive group of patients, who are significantly more likely to have thicker tumors and ulceration. More importantly, given the presence of metastatic nodal disease within the lymphatic compartment, patients with positive SLNs will predictably have higher recurrence rates at all sites. A recent small study by Estourgie et al⁹ exemplifies this point. The 61 patients who underwent WLE and SLNB and had positive SLNs had a particularly poor risk profile (median tumor thickness, 3.8 mm; incidence of ulceration, 50%) and, reflective of these adverse prognostic factors, had a high rate of ITM (23%). It is not surprising that other studies^11,19,20 including patients with more favorable primary tumor characteristics have reported substantially lower rates of ITM (6% to 10%).

Of the 1,395 patients who underwent SLNB at The University of Texas M.D. Anderson Cancer Center (Houston, TX), an overall 6.2% incidence of ITM as a first site of recurrence was observed. Patients with a positive SLN (15% of the entire cohort) had a higher rate of ITM (12%) than patients with a negative SLN (3.5%). As expected, the median tumor thickness and incidence of ulceration were significantly different for SLN-negative patients (1.3 mm and 12%, respectively) versus SLN-positive patients (3.0 mm and 45%, respectively); supporting the concept that tumor biology determines metastatic pattern.²⁰ In a recent review of 2,018 patients with primary melanomas 1.0 mm in thickness treated over a 10-year period at the Sydney Melanoma Unit of the University of Sydney (Sydney, Australia), there was no statistically significant difference in the rate of ITM among patients treated with WLE alone (4.9%) and those patients treated with WLE plus SLNB (3.6%).²¹ Because the WLE-alone and WLE-plus-SLNB groups were similar in terms of the constellation of primary tumor factors (median tumor depth, 2.31 mm v 2.34 mm, respectively; rate of ulceration, 25% v 23%; Clark level IV or V, 66% v 65%), these data strongly support the concept that early nodal intervention has little impact on the natural history of ITM. Recent data from the Sydney Melanoma Unit experience²¹ also showed that the incidence of local or in-transit recurrence in the group of patients undergoing ELND was 5.7%, which was not significantly different from the rate of local or in-transit recurrence in the WLE-alone (4.9%) or WLE-plus-SLNB (3.6%) groups (P = .27). The overall ITM rate was also assessed in a recent German study²² comparing 244 patients who had positive SLNs detected on SLNB with 199 patients treated with WLE alone followed by delayed lymphadenectomy for clinically palpable nodes. In the German study, the 5-year overall ITM rate as measured from the time of diagnosis of the primary tumor was identical in the two groups (33.7% in SLNB group v 33.3% in the delayed lymphadenectomy group). Because the SLNB and delayed lymphadenectomy groups were similar with respect to clinically relevant primary tumor factors (median tumor depth, 2.9 mm v 3.0 mm, respectively; rate of ulceration, 42.9% v 44.1%), these data also support the concept that early nodal intervention has little impact on the natural history of ITM. Interestingly, the probability of developing ITM as a first site of recurrence was higher in the SLNB group than in the delayed lymphadenectomy group (27.3% v 17.6%; P < .03). Although at first assessment this finding might seem incongruous with the other study findings described here, the finding is actually quite logical; in patients who have undergone SLNB, nodal basin failure is exceedingly rare as the first manifestation of recurrence, and thus the chance that ITMs would be the first manifestation of recurrence would be augmented.

Other current data^21,23 suggest that waiting for clinical nodal disease to develop may be ill advised. The development of clinical nodal disease itself can cause lymphatic obstruction that may be worsened after therapeutic lymph node dissection. Furthermore, the period of waiting for the development of nodal disease may allow for the growth of cell clones that are inherently more adherent to the lymphatic endothelium, and in turn could actually increase the incidence of clinical ITM.

Abandoning the SLNB technique in favor of a delayed approach to the regional lymph node basin may also have a negative impact on overall survival and regional disease control. A World Health Organization Melanoma Programme study²⁴ and a recently published multicenter trial from Germany²⁵ evaluated the impact of ELND on survival in patients with occult node-positive disease. Interestingly, both studies demonstrated a survival advantage for node-positive patients treated with SLNB compared with node-positive patients treated with delayed therapeutic lymphadenectomy. Additionally, long-term control of regional nodal basin disease is more commonly achieved in patients undergoing dissection for microscopic disease than in patients undergoing dissection for macroscopic disease.

Taken together, the current data provide compelling evidence that SLNB and completion lymph node dissection in SLN-positive patients does not increase the incidence of ITM. It seems most likely that ITM is the result of inherently adverse biology rather than mechanical disruption of the proximal nodal basin caused by either SLNB or subsequent completion lymphadenectomy. In consideration of this conclusion, the SLNB technique should be performed in patients with high-risk primary melanomas, with the goals of providing an optimal chance for cure, accurate staging, and durable regional control with minimal morbidity. A more definitive assessment of the impact of SLNB on the natural history of ITM and the role of this procedure in the overall treatment of melanoma patients will be possible with the publication of the long-term results of prospective randomized trials such as the Multicenter Selective Lymphadenectomy Trial. Recently presented unpublished preliminary results of this trial²³ support the conclusion that there is indeed no increase in the incidence of ITM in patients treated with SLNB.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

Acknowledgment

This publication was made possible by Grant Number P50 CA93459 from the UT M.D. Anderson Cancer Center SPORE in Melanoma, and its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. We thank M.D. Anderson Cancer Center's Department of Scientific Publications for their assistance with this manuscript.

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