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10.1245/ASO.2005.05.025
Annals of Surgical Oncology 12:587-596 (2005)
© 2005 Society of Surgical Oncology
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Original Article

Predictors and Natural History of In-Transit Melanoma After Sentinel Lymphadenectomy

Timothy M. Pawlik, MD, MPH1, Merrick I. Ross, MD1, Marcella M. Johnson, MS2, Christopher W. Schacherer, PhD1, Dana M. McClain, BS1, Paul F. Mansfield, MD1, Jeffrey E. Lee, MD1, Janice N. Cormier, MD, MPH1 and Jeffrey E. Gershenwald, MD, FACS1

1 Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Unit 444, PO Box 301402, Houston, Texas 77230-1402
2 Department of Biostatistics and Applied Mathematics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 0447, Houston, Texas 77230-1402

Correspondence: Address correspondence and reprint requests to: Jeffrey E. Gershenwald, MD; E-mail: jgershen{at}mdanderson.org.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: In-transit recurrence is a unique and uncommon pattern of treatment failure in patients with melanoma. Little information exists concerning the incidence, predictors, and natural history of in-transit disease since the introduction of sentinel lymph node biopsy (SLNB).

Methods: Between 1991 and 2001, 1395 patients with primary melanoma underwent SLNB. Univariate and multivariate logistic regression analyses were performed to examine the association among known clinicopathologic factors, in-transit recurrence, and distant meta-static failure after the development of in-transit disease.

Results: With a median follow-up of 3.9 years, 241 patients (17.3%) experienced disease recurrence, including 91 (6.6%) who developed in-transit recurrence. Independent predictors of in-transit recurrence included age >50 years, a lower extremity location of the primary tumor, Breslow depth, ulceration, and sentinel lymph node (SLN) status. Of the 69 patients who presented with in-transit disease as the sole site of first recurrence, 39 developed distant disease. By univariate analysis, predictors of distant failure among patients with in-transit disease included SLN status, largest metastatic focus in the SLN >2.5 mm2, subcutaneous location of in-transit disease, in-transit tumor size ≥ 2 cm, and a disease-free interval before intransit recurrence of <12 months. In-transit tumor size remained a significant predictor of distant metastasis by multivariate analysis (odds ratio, 9.69).

Conclusions: The overall incidence of in-transit metastases in patients undergoing SLNB is low and does not seem to have increased since the introduction of the SLNB technique. Intransit recurrence, as well as subsequent distant metastatic failure, can be predicted on the basis of adverse tumor factors and SLN status.

Key Words: In transit • Melanoma • Sentinel lymph node biopsy • Recurrence • Lymph node


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Traditionally, in-transit metastases have been regarded as recurrent locoregional disease found in the dermis or subcutaneous tissue between the primary melanoma and the regional lymph node basin. This pattern of recurrence is unique and has a reported incidence of 5% to 10%.1 Although the molecular determinants and pathophysiology of in-transit disease are poorly understood, in-transit recurrences are most likely an intralymphatic manifestation of melanoma metastases.2,3

It has been theorized that in-transit metastases are secondary to shed melanoma cells that enter the lymphatics only to be trapped at the time of regional lymph node dissection.4 Therefore, early lymphadenectomy—either electively or guided by a sentinel lymph node biopsy (SLNB)—may cause lymphatic stasis and trapping of melanoma cells, thereby increasing the risk of in-transit disease.5 The concern that SLNB may disturb lymph flow and lead to intransit metastases is of particular concern, because SLNB has been adopted as the standard of care for many patients with clinically localized melanoma. It has been difficult to address this question, however, because little information regarding the incidence and natural history of in-transit metastases has been published since the introduction of SLNB. The objective of this study, therefore, was to determine the incidence, predictors, and natural history of intransit disease in a large cohort of patients after SLNB.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
A database analysis was performed on 1395 patients with primary cutaneous melanoma who underwent SLNB and wide local excision at The University of Texas M. D. Anderson Cancer Center between January 1991 and May 2001. Data regarding demographics (age and sex), primary-tumor characteristics (site, tumor thickness, Clark level, and ulceration), sentinel lymph node (SLN) features (pathologic status and microscopic tumor burden), and recurrence were collected for all patients. With regard to recurrence, both the sequence and overall pattern of metastasis were noted.

In-transit disease was defined broadly as any locoregional non-nodal metastasis regardless of the distance from the primary-tumor site, including local, satellite, and in-transit metastases. The appearance of disease as a result of assumed persistence of in situ or invasive melanoma at the margins of the initial surgical specimen was defined as a true locally recurrent process and was therefore not regarded as an intransit recurrence.6,7 Information regarding the nature of the in-transit disease was also collected: location (dermal vs. subcutaneous), number of in-transit lesions (≤ 10 vs. >10), diameter of the largest intransit lesion (≤ 2 vs. >2 cm), and disease-free interval from the date of the initial operation to the development of in-transit disease (<12 vs. ≥ 12 months).

Clinicopathologic factors, including age and sex, as well as tumor characteristics such as tumor thickness, ulceration, Clark level, anatomical site, and lymph node involvement were assessed as potential predictors of in-transit disease. For the cohort of patients with positive SLN involvement, the nodal tumor burden was defined by using three SLN tumor characteristics: largest focus (≤ 2.5 vs. >2.5 mm2), square area, and location. Cut-points for largest focus and square area were defined by recursive partitioning procedures by using previously defined values.8,9 For the cohort of patients who developed distant disease, all of the above-mentioned factors, including data on the nature of the in-transit disease, were used for purposes of analysis. The association of clinicopathologic factors with in-transit disease and subsequent distant failure was evaluated with {chi}2 or Fisher’s exact tests, as appropriate. Factors with a significant univariate association (P < .05) were further evaluated in multivariate models.10 In addition, Kaplan-Meier methodology and the log-rank test were used to compare disease-specific survival among various disease groups. All reported P values were two sided. Analyses were performed with S-PLUS (MathSoft Inc., Seattle, WA) and SAS (SAS Institute, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Clinicopathologic Characteristics
The clinicopathologic characteristics of the 1395 patients in this study are listed in Table 1Go. The ratio of men to women was 1.34:1. The median age was 51 years (range, 7–90 years). The most common site of the primary tumor was the trunk (46.5%). The median Breslow depth was 1.5 mm. Most tumors were either Clark level III or IV, and 21.2% of patients had an ulcerated primary tumor. Overall, 17.1% of patients had a positive SLN.


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  		TABLE 1. Clinical and pathologic characteristics of melanoma patients (n =1,395)
 
Patterns of Recurrence
With a median follow-up of 3.9 years, 241 (17.3%) of 1395 patients developed a recurrence. Among all patients, 155 (11.1%) developed distant or regional nodal disease as a first site of recurrence; 5 of these patients (.4%) later developed in-transit disease as a second site of failure. In contrast, 86 patients (6.2%) developed in-transit metastases as a component of the first site of recurrence (Table 2Go). Seventeen of these patients (1.2%) initially experienced recurrence with synchronous in-transit and distant disease, whereas 69 (5%) had in-transit disease only (Fig. 1Go). Of the 69 patients who initially experienced recurrence with in-transit disease only, 39 (56.5%) subsequently had treatment failure with distant metastases, whereas 30 (43.5%) remained free of distant disease (Fig. 2Go).


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  		TABLE 2. Clinical and pathologic characteristics of patients who developed in-transit metastases as a component of the first site of recurrence (n = 86)
 

Figure 1
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  		FIG. 1. Overall pattern of recurrence. At a median follow-up of 3.9 years, 241 (17.3%) of 1395 patients had recurrent disease. Most patients (11.1%) had either distant or regional nodal disease as a first site of recurrence, and fewer patients (6.2%) presented with intransit metastases as a component of the first site of recurrence.

 

Figure 2
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  		FIG. 2. Overall pattern of recurrence in patients who initially presented with in-transit–only disease. Of the 69 patients who initially had recurrence with in-transit–only disease, 39 (56.5%) of 69 subsequently developed distant metastases. Thirty patients were still free of distant disease at last follow-up.

 
Predictors of Recurrence
Overall Recurrence
Several clinicopathologic factors predicted any recurrence after primary wide excision and SLNB. By univariate analysis, patient age >50 years, Breslow depth, Clark level >III, ulceration, and positive SLN status were all significant predictors of overall recurrence. By multivariate analysis, only Breslow depth, ulceration, and positive SLN status maintained prognostic significance (Table 3Go).


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  		TABLE 3. Prognostic factors influencing overall recurrence
 
In-Transit Recurrence as a First Site of Failure
Among all patients (n = 1395), univariate analysis revealed that the same factors that predicted overall recurrence predicted in-transit recurrence. Specifically, age >50 years, Breslow depth, Clark level >III, ulceration, and positive SLN status were significant predictors of in-transit recurrence. In addition, a lower extremity location of the primary tumor was also significantly associated with in-transit disease. By multivariate analysis, age >50 years, Breslow depth, ulceration, and a lower extremity primary-tumor location maintained significance. Positive SLN status also remained an independent predictor of in-transit recurrence (Table 4Go).


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  		TABLE 4. Prognostic factors influencing in-transit recurrence as a first site of failure
 
In-Transit Recurrence as a Function of SLN Status
Because SLN status was one of the strongest predictors of in-transit disease, a subset analysis was performed to assess the risk of in-transit recurrence as it specifically related to SLN status. Looking at the entire cohort, the incidence of in-transit disease as a first site of recurrence was 3.5% in patients with a negative SLN compared with 12.0% in patients with a positive SLN (P < .0001).

SLN-Negative Patients
Of the patients with a negative SLN (n = 1136; 82.9%), only 40 (3.5%) developed in-transit disease as a first site of recurrence. By univariate analysis, patients with a negative SLN who were >50 years old (odds ratio [OR], 2.51; 95% confidence interval [CI], 1.31–4.82; P = .005) or who had a lower extremity primary tumor (OR, 2.71; 95% CI, 1.49–4.92; P = .001) were more likely to have recurrence with intransit disease. Additionally, patients with a negative SLN but who had an ulcerated (OR, 3.84; 95% CI, 2.06–7.17; P < .0001) or thick (OR, 1.23; 95% CI, 1.13–1.35; P < .0001) primary tumor were also more likely to experience recurrence with in-transit metastases. By multivariate analysis, independent predictors of in-transit recurrence in patients with a negative SLN included age >50 years (OR, 2.07; 95% CI, 1.05–4.07; P = .04), Breslow depth >2 to 4 mm (OR, 11.4; 95% CI, 3.33–39.32; P = .0001) or >4 mm (OR, 17.5; 95% CI, 4.74–64.80; P < .0001), and lower extremity tumor location (OR, 3.13; 95% CI, 1.68–5.85; P = .0003).

SLN-Positive Patients
Of the patients with a positive SLN (n = 234; 17.1%), 28 (12.0%) developed in-transit disease as a first site of recurrence. For patients with a positive SLN, in-transit recurrence was associated not only with primary-tumor factors, but also with the histological location and burden of micrometastatic disease in the sentinel node. Specifically, by univariate analysis, a lower extremity primary-tumor location (OR, 3.98; 95% CI, 2.01–7.90; P < .0001) and Breslow depth (OR, 1.17; 95% CI, 1.04–1.31; P = .009) were significant predictors of in-transit recurrence, whereas Clark level >III (OR, 2.47; 95% CI, .98–6.20; P = .05) and ulceration (OR, 1.84; 95% CI, .94–3.61; P = .07) approached statistical significance. The location and burden of the micrometastatic disease within the SLN were also associated with in-transit recurrence. A micrometastatic focus >2.5 mm2 (OR, 2.40; 95% CI, 1.21–4.78; P = .01), SLN extracapsular extension (OR, 3.10; 95% CI, 1.24–7.75; P = .02), and a combined subcapsular and intramedullary location of the SLN metastasis (OR, 3.35; 95% CI, 1.61–6.95; P = .001) all increased the risk of in-transit recurrence. By multivariate analysis, however, only a lower extremity primary-tumor location (OR, 4.73; 95% CI, 2.20–10.16; P<.0001) and a combined subcapsular and intramedullary location of the SLN metastasis (OR, 2.50; 95% CI, 1.13–5.55; P = .02) maintained significance. Ulceration again trended toward significance (OR, 1.90; 95% CI, .88–4.12; P = .10).

Disease-Specific Survival Based on the First Site of Recurrence
Among the entire cohort of patients who had disease recurrence (n = 241), the patients who developed distant-only disease experienced a 5-year disease-specific survival rate of 46% (Fig. 3Go). It is interesting to note that patients who presented with synchronous in-transit and distant disease had a shorter median survival (1.95 years; 95% CI, 1.38–6.26 years) than patients who presented with distant disease alone (4.09 years; 95% CI, 3.46–5.96) (P = .05). Patients with synchronous disease had a 5-year disease-specific survival rate of 24%; few patients survived longer than 6 years.


Figure 3
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  		FIG. 3. Disease-specific survival based on first site of recurrence. Patients with in-transit–only disease as a first site of recurrence had a longer median survival (6.19 years) than patients who presented with distant-only disease (4.09 years) and patients with synchronous in-transit and distant disease (1.95 years) (P = .002 for all 3 survival curves compared simultaneously).

 
Compared with patients who developed either distant-only or synchronous distant and in-transit disease, patients who initially presented with intransit disease alone had a better prognosis. Patients with in-transit–only disease as a first site of recurrence had a longer median survival (6.19 years; 95% CI, 4.00 years to not yet attained) and an improved 5-year survival rate (54%) (P = .017 compared with patients who had distant-only disease; P = .0009 compared with patients who had synchronous distant plus in-transit disease) (Fig. 3Go). More than 40% of patients (n = 30; 43.5%) who presented with in-transit–only disease had not developed distant metastatic disease at the time of last follow-up. Therefore, an analysis of patients with in-transit–only disease was performed to investigate whether predictors of distant metastatic failure after in-transit recurrence could be identified.

Predictors of Distant Metastases After In-Transit Recurrence
The pattern of distant failure after in-transit recurrence was initially examined according to SLN status. Of the 28 patients with a positive SLN, 20 (71%) developed distant metastatic disease. In contrast, 18 (45%) of 40 patients with a negative SLN developed distant metastatic disease (P = .03). By univariate analysis, both a positive SLN status and a focus of micrometastatic disease >2.5 mm2 in the SLN were predictive of distant metastatic failure. In addition, factors related to the in-transit disease itself were significant. In particular, subcutaneous location, in-transit lesion ≥ 2 cm in diameter, and a disease-free interval from the date of the initial operation to intransit recurrence of < 12 months were all strongly predictive of distant failure. The number of in-transit lesions, however, was not significant (Table 5Go). By multivariate analysis, only in-transit lesion diameter ≥ 2 cm remained an independent predictor of distant metastasis (OR, 9.69; 95% CI, 1.74–54.11; P = .01), and subcutaneous location of the in-transit disease approached significance (OR, 3.87; 95% CI, .93–16.06; P = .06).


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  		TABLE 5. Factors predictive of distant metastatic failure after presentation with in-transit-only disease: univariate analysis
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In-transit metastases are a distinct form of locoregional recurrent disease that may develop in patients with melanoma. This type of recurrence can be very difficult to treat, may be associated with significant morbidity, and may be a source of eventual distant failure. Although the actual mechanism that leads to the development of in-transit metastases remains unknown, in-transit recurrence is believed to result from arrested tumor emboli in congested intradermal lymphatic vessels situated between the primary tumor and the regional lymph node basin.3,5,11 These intralymphatic tumor emboli originate at the site of the primary melanoma. Evidence of lymphatic invasion may sometimes be found by careful histopathologic examination of the primary tumor.1 Emboli of melanoma cells traveling through lymphatic vessels may be more likely to become trapped in the lymphatics after regional node dissection or SLNB. The theoretical risk of SLNB inducing lymphatic stasis and subsequent intransit disease has generated significant concern because SLNB is currently the standard of care in the treatment of many patients with clinically node-negative melanoma. To our knowledge, this study is the largest to date that specifically examined the natural history and predictors of in-transit recurrence after SLNB.

Among all patients (n = 1395), 241 (17.3%) experienced some form of recurrence. Not surprisingly, and consistent with previous studies,12,13 primary-tumor factors such as tumor thickness and ulceration, as well as positive SLN status, were associated with an increased risk of recurrence by multivariate analysis.

In this study, in-transit disease was relatively uncommon (overall incidence, 6.6%). Although most studies have reported a similarly low incidence of intransit metastases (5%–10%),1,5,14–16 some have reported a higher range (15%–20%).17,18 Several factors may account for this apparent discrepancy. It is important to note that the definition of in-transit disease itself has been inconsistent and, at times, confusing. Although the American Joint Committee on Cancer (AJCC)19 currently classifies satellite and in-transit disease together in stage III, the inconsistent application of these terms in some previous articles has led to heterogeneous study populations, thus complicating comparisons among trials. The higher reported rates of in-transit disease in some studies may also be attributable to varying risk in the cohorts being studied because of differing patient and primary-tumor factors.

Another problem in interpreting published data on the occurrence of in-transit recurrence is the issue of local recurrence. In contrast to in-transit metastases, true local recurrences occur at the site of the primary tumor, within or continuous with the scar, are likely the result of incomplete excision of the primary tumor, and are relatively rare. In many cases, such local recurrences may more appropriately be considered persistence of melanoma from the primary tumor.6,7 The prognosis after a true local recurrence is significantly better than that after an in-transit recurrence; therefore, the distinction between local recurrence and in-transit metastasis is important in treatment planning.7 The inclusion of local recurrences with intransit metastases may erroneously inflate the incidence of in-transit disease.20–23

In this study, all patients with a true local recurrence, as identified by established histological criteria,24–26 were excluded from our analyses. In the absence of these histological criteria, recurrent events contiguous with the scar after an appropriate wide local excision were considered as local metastases and were therefore included in our analyses. Previous studies have also demonstrated that the distance of a locoregional recurrence from the primary-tumor site is arbitrary and prognostically meaningless3,27; given this, the AJCC has merged satellite and in-transit disease in the most recent (6th) edition of the AJCC staging system.19 Therefore, in this study, all non-nodal locoregional metastases—regardless of the distance from the primary tumor—were considered collectively as in-transit disease.

Several clinical factors predicted in-transit recurrence in this study. Tumor thickness and ulceration were both associated with an increased risk of intransit disease. This finding is consistent with those of other studies in which an increased incidence of locoregional relapse was associated with deeply invasive ulcerated lesions.28–30 Greater tumor depth may increase the potential for tumor cells to come into contact with and gain entrance to the dermal lymphatics.1

Another risk factor for in-transit recurrence was a lower extremity primary-tumor location. Although the trunk was the most common site for a primary melanoma, the incidence of in-transit disease was greatest on the lower extremity. This finding is consistent with those of Karakousis et al.,5 Roses et al.,14 and Wong et al.,28 who reported an increased risk for in-transit disease with primary tumors located on the lower extremity. The reason that the lower extremity is at an increased risk for in-transit recurrence, however, remains unclear. Some have postulated that this risk is associated with the relatively more numerous and longer lymphatic vessels involved in the drainage of the skin from the leg.5,14 Another plausible reason is that the increased lymphatic stasis associated with the lower extremity due to gravity makes it more susceptible to in-transit disease.5,14

One of the most powerful predictors of in-transit recurrence was SLN status. Patients with a positive SLN were significantly more likely to develop intransit metastases than patients with a negative SLN. Borgstein et al.1 reported that the incidence of intransit recurrence was more than four times as high in patients with a positive SLNB compared with patients who had no SLN involvement. The association between positive SLN status and in-transit recurrence has been corroborated by other investigators.3,31

Recently, Estourgie et al.18 reported that the incidence of in-transit metastases was higher after a completion lymph node dissection (CLND) in SLN-positive patients (23.0%) than after therapeutic lymph node dissection (TLND) performed for clinically palpable nodal disease (8.3%). The results of this study, however, were difficult to interpret. The two patient cohorts were not comparable, because patients with a positive SLN had primary tumors that were both thicker and more ulcerated than those in the patients who underwent TLND.18 In addition, the study suffered from potential selection bias. Because patients who had established in-transit or distant disease in all probability never presented for TLND, the patients who did undergo TLND possibly had a tumor biology that was less regionally aggressive and, therefore, were less likely to develop intransit metastases.

In this study, every patient underwent SLNB. Our observation that patients with a positive SLN had a higher rate of in-transit metastases (12%) compared with patients with a negative SLN (3.5%) failed to substantiate the view that the SLNB technique alone induces subsequent in-transit disease. If this were true, one would have expected a relatively equal rate of in-transit recurrence after SLNB regardless of the pathologic status of the SLN. Although we cannot necessarily exclude a contribution from SLNB to the risk of development of in-transit disease, because all patients in this series underwent that procedure, the higher recurrence rate in patients with a positive SLN suggests that in-transit disease is the result of adverse biological factors and lymphatic tumor burden rather than adoption of the SLNB technique. The finding that microscopic tumor burden within the positive SLN also predicted locoregional recurrence further corroborates the concept that biology—not surgical technique—establishes risk for in-transit disease.

It could be argued, however, that the more extensive CLND, which virtually all SLN-positive patients undergo and which is more disruptive of the upstream lymph node basin than SLNB, is the real reason for the higher incidence of in-transit recurrence in SLN-positive patients. In fact, some retrospective series have demonstrated that patients who have undergone elective lymph node dissection (ELND) and who have microscopic nodal disease have an increased rate of in-transit disease compared with patients who have undergone a delayed TLND.31 These retrospective studies, however, can be misleading because the two groups being compared often have very different risk profiles for recurrence. Therefore, the most appropriate published experience to assess whether CLND is responsible for in-transit disease is the results of prospective randomized ELND trials. It is important to note that neither the Intergroup ELND trial32 nor the European Organization for Research and Treatment of Cancer elective limb perfusion trial,33 in which almost 50% of the patients had had ELND, demonstrated an increased incidence of in-transit disease in patients who underwent ELND. Of particular interest are the results of the European Organization for Research and Treatment of Cancer limb perfusion trial, which demonstrated a non-nodal locoregional relapse rate of 6.6% in the control arm.33 These results are identical to the overall rate of intransit recurrence that we report in this study.

In-transit disease has traditionally been associated with a poor prognosis characterized by progressive disease, systemic metastases, and death.28 The prognostic implications of in-transit recurrence were described by Day et al.,34 who noted that the 5-year disease-free survival rate for patients with microscopic satellites was 36%, compared with 89% for patients without satellites. Leon et al.35 reaffirmed this finding a decade later when they reported that the presence of in-transit disease correlated with a significantly decreased survival rate (37% vs. 65% at 10 years). Urist et al.36 reported a median survival duration of 3 years in patients with locoregional recurrence: only 20% survived 10 years. Similarly, Roses et al.14 found that 71% of patients with intransit metastases developed systemic metastases at an average of 9.7 months. Others, however, have noted that a substantial proportion of patients with in-transit disease can be successfully treated by aggressive locoregional therapy, with 5-year survival rates of 30% to 40%.1

In this study, in-transit disease adversely affected survival. In particular, patients who presented with synchronous distant metastases and in-transit disease had the shortest median survival, even when compared with patients with distant-only metastases. In contrast, the natural history for patients who presented with in-transit–only disease was more heterogeneous. Although some patients developed distant metastases, a large subset had yet to develop distant metastases, and most were alive at last follow-up. The divergent survival outcome and metastatic pattern for patients with in-transit–only disease exemplified the need for better predictors of prognosis for this group of patients.

On the basis of AJCC staging criteria, patients with nodal and in-transit metastases have a less favorable survival than those with in-transit disease alone.19 The pattern of distant failure after in-transit recurrence was therefore initially examined according to SLN status. Nearly three fourths of patients who had not developed distant disease had a negative SLN. Conversely, more than half of the patients who eventually had a recurrence at a distant site had a positive SLN. Not surprisingly, by univariate analysis, positive SLN status was associated with distant metastasis; it is interesting to note that the extent of the microscopic tumor burden in the SLN also predicted distant metastases.

On univariate analysis, certain in-transit disease characteristics were also associated with distant metastatic disease. These include subcutaneous location, lesions with a diameter ≥ 2 cm, and a disease-free interval before in-transit recurrence of <12 months. Singletary et al.27 reported a similar difference in prognosis based on an intradermal versus subcutaneous location of the in-transit lesion. Subcutaneous in-transit lesions may represent a distinct, more aggressive pattern of dissemination indicative of disease that has escaped the confines of the lymphatic system, thus leading to a worse prognosis. In-transit tumor burden, as reflected by in-transit lesion size, has also previously been shown to be prognostically important.37 Zogakis et al.37 reported that the risk of death after in-transit recurrence was significantly greater in patients with a lesion size ≥ 1.4 cm2. Although in other studies the number of in-transit lesions has reportedly influenced clinical outcome,28 an association between the number of in-transit lesions and distant metastatic failure was not observed in this study. Consistent with previous reports, however, a short disease-free interval before the development of in-transit melanoma was associated with an increased risk of distant disease. Both Wong et al.28 and Balch et al.38 found that remission duration was an important prognostic variable in patients with in-transit disease.

Multivariate analysis demonstrated that only an intransit lesion size of ≥ 2 cm (OR, 9.69; P = .01) was predictive of distant metastatic failure. The fact that only this one factor was shown to be significant may be due in part to the small number of patients (n = 69) and the large number of risk factors included in the multivariate analysis. It may, therefore, be inappropriate to assume that the other factors that were predictive of distant disease on univariate analysis are unimportant. Future studies with larger sample sizes are needed to determine more thoroughly which factors are most predictive of distant relapse after recurrence of in-transit disease.

In summary, the overall incidence of in-transit metastases in patients undergoing SLNB is low and can be predicted by adverse tumor factors, SLN status, and the burden of disease in the SLN. Although in-transit disease as a first site of recurrence has traditionally been viewed as portending a poor prognosis, in this study, more than 40% of patients who presented in this manner have not developed distant metastases. In addition, several factors, including intransit location and size, SLN status, and disease-free interval, were strongly associated with eventual distant metastatic failure. It is therefore likely that intransit disease is the result of inherent adverse biology rather than a mechanical disruption of the proximal nodal basin caused by either the SLNB or the subsequent CLND. Patients who present with in-transit disease alone and who are at high risk for distant failure can be identified. This information may be helpful in prioritizing systemic versus locoregional therapy for patients with in-transit disease.


   ACKNOWLEDGMENTS
 
This publication was made possible by Grant P50 CA93459 from the University of Texas M. D. Anderson Cancer Center SPORE in Melanoma. 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 the manuscript.

Received for publication May 22, 2004. Accepted for publication November 19, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Borgstein PJ, Meijer S, van Diest PJ. Are locoregional cutaneous metastases in melanoma predictable? Ann Surg Oncol 1999;6:315–21.[Abstract]
  2. Gershenwald JE, Fidler IJ. Cancer. Targeting lymphatic metastasis. Science 2002;296:1811–2.[Abstract/Free Full Text]
  3. Cascinelli N, Bufalino R, Marolda R, et al. Regional non-nodal metastases of cutaneous melanoma. Eur J Surg Oncol 1986;12:175–80.[Medline]
  4. Attie JN, Khafif RA. Melanotic Tumors—Biology, Pathology and Clinical Features. Springfield, IL: Charles C. Thomas, 1964.
  5. Karakousis CP, Choe KJ, Holyoke ED. Biologic behavior and treatment of intransit metastasis of melanoma. Surg Gynecol Obstet 1980;150:29–32.[Medline]
  6. Yu LL, Heenan PJ. The morphological features of locally recurrent melanoma and cutaneous metastases of melanoma. Hum Pathol 1999;30:551–5.[Medline]
  7. Wolf IH, Richtig E, Kopera D, Kerl H. Locoregional cutaneous metastases of malignant melanoma and their management. Dermatol Surg 2004;30:244–7.[Medline]
  8. Carlson GW, Murray DR, Lyles RH, Staley CA, Hestley A, Cohen C. The amount of metastatic melanoma in a sentinel lymph node: does it have prognostic significance? Ann Surg Oncol 2003;10:575–81.[Abstract/Free Full Text]
  9. Gershenwald JE, Prieto VG, Colome-Grimmer MI, et al. The prognostic significance of microscopic tumor burden in 945 melanoma patients undergoing sentinel lymph node biopsy (abstract). Proc Am Soc Clin Oncol 2000;19:2169.
  10. Lemeshow S, Hosmer D. Applied Logistic Regression. New York: Wiley, 2000.
  11. Nakayama T, Taback B, Turner R, Morton DL, Hoon DS. Molecular clonality of in-transit melanoma metastasis. Am J Pathol 2001;158:1371–8.[Abstract/Free Full Text]
  12. Rousseau DL Jr, Ross MI, Johnson MM, et al. Revised American Joint Committee on Cancer staging criteria accurately predict sentinel lymph node positivity in clinically node-negative melanoma patients. Ann Surg Oncol 2003;10: 569–74.[Abstract/Free Full Text]
  13. McMasters KM, Wong SL, Edwards MJ, et al. Factors that predict the presence of sentinel lymph node metastasis in patients with melanoma. Surgery 2001;130:151–6.[CrossRef][Medline]
  14. Roses DF, Harris MN, Rigel D, Carrey Z, Friedman R, Kopf AW. Local and in-transit metastases following definitive excision for primary cutaneous malignant melanoma. Ann Surg 1983;198:65–9.[Medline]
  15. Karakousis CP, Balch CM, Urist MM, Ross MM, Smith TJ, Bartolucci AA. Local recurrence in malignant melanoma: long-term results of the multiinstitutional randomized surgical trial. Ann Surg Oncol 1996;3:446–52.[Abstract]
  16. Dong XD, Tyler D, Johnson JL, DeMatos P, Seigler HF. Analysis of prognosis and disease progression after local recurrence of melanoma. Cancer 2000;88:1063–71.[CrossRef][Medline]
  17. Estourgie SH, Nieweg OE, Valdes Olmos RA, Hoefnagel CA, Kroon BB. Review and evaluation of sentinel node procedures in 250 melanoma patients with a median follow-up of 6 years. Ann Surg Oncol 2003;10:681–8.[Abstract/Free Full Text]
  18. Estourgie SH, Nieweg OE, Kroon BB. High incidence of intransit metastases after sentinel node biopsy in melanoma. In: Estourgie SH (eds). Clinical Relevance and Refinement of the Sentinel Node Procedure in Breast Cancer and Melanoma. Amsterdam: Drukkerij Verhaag, 2004:91–4.
  19. AJCC Cancer Staging Manual. 6th ed. New York: Springer-Verlag, 2002.
  20. Cruse CW, Wells KE, Schroer KR, Reintgen DS. Etiology and prognosis of local recurrence in malignant melanoma of the skin. Ann Plast Surg 1992;28:26–8.[Medline]
  21. Fusi S, Ariyan S, Sternlicht A. Data on first recurrence after treatment for malignant melanoma in a large patient population. Plast Reconstr Surg 1993;91:94–8.[Medline]
  22. Cohn-Cedermark G, Mansson-Brahme E, Rutqvist LE, Larsson O, Singnomklao T, Ringborg U. Outcomes of patients with local recurrence of cutaneous malignant melanoma: a population-based study. Cancer 1997;80:1418–25.[Medline]
  23. Kretschmer L, Preusser KP, Neumann C. Locoregional cutaneous metastasis in patients with therapeutic lymph node dissection for malignant melanoma: risk factors and prognostic impact. Melanoma Res 2002;12:499–504.[CrossRef][Medline]
  24. Heenan PJ. Local recurrence of melanoma. Australas J Dermatol 1997;38:S59–S62.
  25. Ackerman AB, Cerroni L, Kerl H. Pitfalls in Histopathologic Diagnosis of Malignant Melanoma. Philadelphia: Lea & Febiger, 1994.
  26. Garbe C, Cerroni L, Kerl H. Melanozytaere naevi und malignes melanom. In: Kerl H, Garbe C, Cerroni L (eds). Histopathologie der Haut. Berlin: Springer, 2003: 593–649.
  27. Singletary SE, Tucker SL, Boddie AW Jr. Multivariate analysis of prognostic factors in regional cutaneous metastases of extremity melanoma. Cancer 1988;61:1437–40.[Medline]
  28. Wong JH, Cagle LA, Kopald KH, Swisher SG, Morton DL. Natural history and selective management of in transit melanoma. J Surg Oncol 1990;44:146–50.[Medline]
  29. Storm FK, Sparks FC, Morton DL. Treatment for melanoma of the lower extremity with intralesional injection of bacille Calmette Guerin and hyperthermic perfusion. Surg Gynecol Obstet 1979;149:17–21.[Medline]
  30. Rampen FH, van Andel JG. Female sex is a risk factor for satellite and in-transit recurrences from cutaneous melanoma. Eur J Cancer Clin Oncol 1984;20:1151–3.[CrossRef][Medline]
  31. Calabro A, Singletary SE, Balch CM. Patterns of relapse in 1001 consecutive patients with melanoma nodal metastases. Arch Surg 1989;124:1051–5.[Abstract]
  32. Balch CM, Soong S, Ross MI, et al. Long-term results of a multi-institutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0 to 4.0 mm). Intergroup Melanoma Surgical Trial. Ann Surg Oncol 2000;7:87–97.[Abstract]
  33. Koops HS, Vaglini M, Suciu S, et al. Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593. J Clin Oncol 1998;16:2906–12.[Abstract/Free Full Text]
  34. Day CL Jr, Harrist TJ, Gorstein F, et al. Malignant melanoma. Prognostic significance of "microscopic satellites" in the reticular dermis and subcutaneous fat. Ann Surg 1981;194:108–12.[Medline]
  35. Leon P, Daly JM, Synnestvedt M, Schultz DJ, Elder DE, Clark WH Jr. The prognostic implications of microscopic satellites in patients with clinical stage I melanoma. Arch Surg 1991;126:1461–8.[Abstract]
  36. Urist MM, Balch CM, Soong S, Shaw HM, Milton GW, Maddox WA. The influence of surgical margins and prognostic factors predicting the risk of local recurrence in 3445 patients with primary cutaneous melanoma. Cancer 1985;55:1398–402.[CrossRef][Medline]
  37. Zogakis TG, Bartlett DL, Libutti SK, et al. Factors affecting survival after complete response to isolated limb perfusion in patients with in-transit melanoma. Ann Surg Oncol 2001;8:771–8.[Abstract/Free Full Text]
  38. Balch CM, Soong SJ, Murad TM, Smith JW, Maddox WA, Durant JR. A multifactorial analysis of melanoma. IV. Prognostic factors in 200 melanoma patients with distant metastases (stage III). J Clin Oncol 1983;1:126–34.[Abstract]



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