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10.1245/ASO.2006.07.020
Annals of Surgical Oncology 13:1105-1112 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Factors Predicting the Risk of In-Transit Recurrence After Sentinel Lymphonodectomy in Patients With Cutaneous Malignant Melanoma

Lutz Kretschmer, MD, Iris Beckmann, MD, Kai-Martin Thoms, MD, Christina Mitteldorf, MD, Hans Peter Bertsch, MD and Christine Neumann, MD

Department of Dermatology, Georg-August-University Göttingen, v. Siebold-Str. 3, D-37075 Göttingen, Germany

Correspondence: Address correspondence and reprint requests to: Lutz Kretschmer, MD; E-mail: lkre{at}med.uni-goettingen.de.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: In-transit metastasis is an important morbidity factor after sentinel lymphonodectomy (SLNE). So far, factors posing an increased risk after SLNE have not been adequately analyzed.

Methods: Using Kaplan-Meier estimations and the Cox proportional hazards model, we analyzed the risk of developing in-transit metastases after SLNE for 328 consecutive patients (median tumor thickness, 2.0 mm; median follow-up period, 40 months).

Results: The 5-year probability of developing in-transit metastases as a first recurrence was 11.2%. After negative and positive SLNE, the probabilities were 6.3% and 24%, respectively. Patients in whom satellite metastases were excised concurrently with the primary tumor had a probability of recurrence with in-transit metastases of 41%. In sentinel lymph node (SLN)-negative patients with primary tumors having a thickness of more than 4 mm, the probability was 22.1%. Among the group of SLN-positive patients, significantly increased in-transit probabilities were observed in those with primary tumors that were thicker than 4 mm (41.8%), with tumors located on the distal extremities (42.1%), and with penetration of the nodal metastasis of >1 mm into the SLN (36%) and in patients with capsular breakthrough (63.3%). By using multifactorial analysis, the SLN status (P = .005), Breslow thickness (P = .0009), and extremity location of the primary melanoma (P = .005) significantly predicted the risk of in-transit recurrence. Satellite metastasis (P < .089), Clark level, and ulceration did not reach significance.

Conclusions: Subgroups of patients can be identified who seem to have an increased risk of developing in-transit metastases as a first recurrence after SLNE. Individualized therapeutic strategies should be developed for these patients.

Key Words: Cutaneous melanoma • Sentinel lymphonodectomy • In-transit metastases • Lymph node excision • Prognostic factors


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In-transit metastases, i.e., cutaneous metastases localized between a primary tumor and its regional lymph nodes, are typical manifestations of metastasizing, cutaneous malignant melanomas. Clinically, they appear as cutaneous or subcutaneous tumors or, when situated in the upper dermis, as small, dome-shaped papules or nodules, which may be black, brown, purple, pink, or skin colored. In-transit metastases are believed to develop as a result of a tumor cell embolus becoming entrapped in the dermal lymphatic vessels. The first-line treatment is complete surgical excision of single cutaneous metastases or, if necessary, en-bloc excision of grouped lesions within a circumscribed area. Unfortunately, in-transit metastases tend to recur, and clinical management remains unsatisfactory. Some preventive therapies, such as wider safety margins around the primary melanoma1 or adjuvant cytostatic limb perfusion,2 have been proven to decrease the risk of in-transit recurrences without, however, improving survival rates. Until now, the value of adjuvant radiotherapy has not been adequately established.

After wide local excision (WLE) of a primary melanoma, several clinical and pathologic factors have been reported to increase the risk of in-transit recurrences: Breslow thickness, Clark level, epidermal ulceration, lymphatic invasion, the presence of microsatellites, leg location of the primary melanoma, and older age.3–9 The introduction of sentinel lymphonodectomy (SLNE) into clinical practice has changed the situation. With respect to in-transit metastases, there are presently three reasons for reassessing the known risk factors. (1) Previous studies have demonstrated that the pathologic status of the sentinel lymph node (SLN) strongly influences in-transit probability.10–19 When SLNE is used, this important risk factor is already known at the time of the primary tumor excision. (2) Preventive lymph node dissection avoids nodal recurrences, thereby prolonging the recurrence-free interval.19 Thus, SLNE directly affects the outcome variable when the probability of developing in-transit metastases as a first recurrence is calculated. (3) In addition to this bias, the sentinel procedure itself has been suspected of causing in-transit metastases by inducing lymphatic stasis or entrapment of melanoma cells.10,20,21 Recently published data, however, seem to refute this assumption.18,19,22–25

This study was undertaken to analyze the clinical and pathologic risk factors for the development of intransit metastases after SLNE by using multivariate analysis and, more importantly, to identify subgroups of patients with a high risk of developing in-transit recurrences.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Nomenclature
In-transit metastases of malignant melanomas (including microscopic and macroscopic satellite lesions, metastases in the primary tumor excision scar, and true in-transit metastases) are defined as cutaneous or subcutaneous metastases located between a primary melanoma and its regional lymph nodes. Satellite metastases that were excised concurrently with the primary tumor (mostly microsatellites) are considered as a prognostic factor and not regarded as a recurrence. Regrowth of an incompletely excised primary tumor bearing a junctional component is not regarded as intransit metastasis. Recurrent disease within the scar of a complete regional lymphadenectomy (nodal and soft tissue) is defined as nodal basin recurrence and, thus, is also not regarded as in-transit metastasis.

Patient Population
Between September 1993 and December 2004, SLNE was performed on 328 consecutive patients with primary cutaneous malignant melanoma. Indications for SLNE were a Breslow thickness of ≥1 or <1 mm if the Clark level was IV or V or if regression or ulceration was histologically documented. In-transit metastasis in the close vicinity of a primary tumor (satellite metastasis) was not considered a contraindication for SLNE. The clinical and histological data were collected prospectively by using an electronic database.

Therapeutic Approaches
For a population of 247 patients, both blue dye and a handheld gamma probe were used to localize the SLNs. In 81 early patients, intraoperative lymphatic mapping was performed by applying blue dye alone. Lymph nodes that stained blue and had blue afferent lymph channels were generally defined as SLNs. Radioactive lymph node(s) that first appeared during dynamic lymphoscintigraphy or for which there was lymphoscintigraphic evidence of an own afferent lymphatic vessel were also defined as SLN(s).

The standard treatment for a primary melanoma is WLE with adequate safety margins, depending on tumor thickness. Lesions <1, 1 to 4, and >4 mm thick receive safety margins of 1, 2, and 3 cm, respectively. For primary melanomas near vital structures, reduced margins are often applied. En-bloc resection of a primary tumor, together with the in-transit area and the SLN(s), was performed in 45 patients who had a primary melanoma in close proximity to the draining nodal basin.

Of the 96 patients with positive SLNs, 80 underwent complete lymph node dissection. Seven patients did not receive a complete node dissection because of increased general morbidity. Three patients decided not to undergo the operation. Six patients who were upstaged by reevaluation of their SLNs after the diagnosis of a tumor recurrence also did not undergo complete node dissection. For the analysis of in-transit probability, these histological false-negative results were reassigned to the group with positive SLNE. The complete lymph node dissections were performed by using established surgical techniques. In the case of axillary metastases, levels I to III of the axillary lymph nodes were excised. Regarding the extent of groin dissection, the procedure followed was an ilioinguinal dissection. Patients with neck metastases received a modified neck dissection.

Only eight patients (2.4%) received different regimens of adjuvant interferon, and six of them did so within controlled studies. It therefore seems very unlikely that adjuvant therapy might have biased our results. One patient received adjuvant radiotherapy in lieu of complete lymph node dissection. During the follow-up, whenever possible, our strategy for treatment of in-transit recurrences was surgical excision. For palliative purposes, four patients received radiotherapy, and five patients underwent hyperthermic cytostatic limb perfusion for multiple in-transit metastases.

Histological Analysis
Primary tumors and specimens from complete lymphadenectomies were examined by using routine histological procedures. SLNs were submitted for step sections. Hematoxylin and eosin staining, as well as immunohistochemical methods with anti-protein S-100 serum (Dako, Glostrup, Denmark; diluted 1/5000), anti–HMB-45 (Dako; undiluted), and anti-Mart-1 (Zymed; San Francisco, California, diluted 1/500), were applied.

The tumor burden to an SLN was classified on the basis of the maximum distance of intranodal melanoma cells from the interior margin of the nodal capsule. The depth of penetration into the SLN was measured according to the method of Starz et al.26 We chose a penetration depth of 1 mm as a reference point. Capsular breakthrough was defined as a metastasis extending through the capsule of a SLN, in contrast to tumor emboli in perinodal or intra-capsular lymphatic vessels.

Follow-Up
In accordance with guidelines applicable in Germany, the patients were routinely monitored at 3-month intervals for the first 2 years, every 6 months for the next 3 years, and annually thereafter. During the follow-up, the status of the in-transit area was known in 433 patients (97.8%). The median follow-up was 40 months (range, 1–102 months).

Statistical Analysis
Statistical comparison of the potential prognostic factors was performed by using the nonparametric Mann-Whitney U-test. The time until the appearance of the first in-transit recurrence was calculated from the primary tumor excision by using the nonparametric Kaplan-Meier method. In the analysis of the time to the first in-transit recurrence, follow-up was interrupted at the time of the first regional cutaneous, nodal, or distant recurrence. In the analysis of the overall probability of in-transit recurrence, the end point for follow-up was set at the time of the first regional cutaneous recurrence, independently of whether a nodal or distant recurrence had already appeared. The log-rank test was used to determine differences in subgroups defined by different levels of risk factors. Multiple covariate analyses were performed by using the Cox proportional hazards regression model and incorporating the factors that were found to be significant by univariate analysis. The Cox proportional hazards model was also used to test the significance of single variables. Individual model covariates were characterized with 95% confidence intervals (CIs) on the hazard ratio scale. Significance was determined at the P < .05 level.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
In-Transit Metastases as First Recurrence After SLNE
The probability of developing in-transit metastases as a first recurrence is important for studies whose aim is to improve locoregional tumor control. In our study, the probability of developing in-transit metastasis as a first recurrence was 11.2%. Table 1Go summarizes the patients’ characteristics according to the pathologic status of the SLN. Of the 65 first recurrences, 25 (38.5%) were in-transit metastases, which occurred after a median interval of 12 months (range, 4–54 months). Univariate risk factors significantly predicting the risk of developing in-transit recurrence as a first recurrence were metastasis to the SLN, increasing Breslow thickness, Clark level, ulceration, and location of the primary tumor on the extremities. The 16 patients who had in-transit metastasis (satellites) already at the time of the primary tumor excision had a significantly increased probability of recurrence with in-transit metastases. Age (P = .11) and sex were not significant.


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  		TABLE 1. Clinical and pathologic characteristics of the patient population
 
En-bloc excision of a primary tumor, in-transit area, and SLN, which was performed in 14.3% of the cases, did not significantly decrease the in-transit risk (10.7% probability after en-bloc dissection vs. 17.1% after WLE). The fact has to be taken into consideration, however, that the median Breslow thickness was significantly higher in the group with en-bloc dissections (2.5 vs. 1.9 mm; P = .005). Paradoxically, patients with safety margins around the primary melanoma of ≥ 2 cm had a significantly higher incidence of in-transit recurrences than patients with safety margins of <2 cm (P = .01; log-rank test). Because the margins were not a random feature but were strictly related to tumor thickness, we did not further analyze this factor.

The in-transit probabilities according to different levels of the significant risk factors are listed in detail in Table 2Go. In a multivariate analysis (Table 3Go), we included the risk factors that were significant with univariate analysis. The following factors could independently predict the risk of in-transit recurrence: site of the primary tumor, pathologic status of the SLN, and Breslow thickness. Satellite metastasis also tended to be significant.


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  		TABLE 2. Significant univariate factors predicting the probability of in-transit recurrences after sentinel lymphonodectomy
 

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  		TABLE 3. Prognostic factors for the probability of developing in-transit metastasis as a first recurrence (multifactorial analysis including 294 patients with complete data)
 
In-Transit Metastases as First Recurrence in the Subgroup of SLN-Negative Patients
In the SLN-negative subpopulation (n = 232), the 5-year probability of developing in-transit metastasis as a first recurrence was 6.3%. Only patients with primary tumors thicker than 4 mm (n = 28) had a relatively high in-transit probability of 22.1% (relative risk [RR], 7.0; 95% CI, 5.7–26.0; Fig. 1Go).


Figure 1
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  		FIG. 1. Among the sentinel lymph node–negative patients, those with primary tumors thicker than 4 mm had a considerable risk of in-transit recurrence. Br, Breslow thickness.

 
In-Transit Metastases as First Recurrence in the Subgroup of SLN-Positive Patients
In the SLN-positive subpopulation (n = 96), the 5-year probability of developing in-transit metastasis as a first recurrence was 24.1%. In SLN-positive patients with primary tumors thicker than 4 mm (n = 27), the probability of developing in-transit metastases as a first recurrence was as high as 44.2% (RR, 2.9; 95% CI, 1.1–7.7; P = .03). SLN-positive patients whose primary tumors were located below the knee or elbow (n = 38) had a similarly high in-transit probability of 42.2% (RR, 4.6; 95% CI, 1.54–13.9; P = .007). Micromorphologic features of the SLN were also important. The probability of developing in-transit metastases was associated with deep penetration of a nodal metastasis into the SLN (Fig. 2Go), as measured from the internal margin of the nodal capsule.26 When the nodal metastasis penetrated deeper than 1 mm into the SLN, the in-transit probability reached 36% (RR, 3.3; 95% CI, 1.26–10.46; P = .006). The 13 patients with capsular breakthrough had a probability of 63.3% (RR, 12.1; 95% CI, 4.01–36.50; P = .00007). Actually, these patients tended to have macrometastasis, because the mean penetration depth from the nodal capsule was 4.5 mm in this group.


Figure 2
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  		FIG. 2. Patients with lymphatic metastasis penetrating deeper than 1.01 mm into the sentinel lymph node had a significantly higher risk of in-transit recurrence.

 
Overall Probability of In-Transit Recurrence for the Entire Study Population
The overall probability of in-transit recurrence (also taking into account the in-transit recurrences that occurred after the onset of nodal or distant recurrences) was 16.1%. By using multifactorial analysis, SLN status (adjusted RR, 3.1; 95% CI, 1.52–6.2; P = .002), Breslow thickness (adjusted RR, 1.3/mm; 95% CI, 1.10–1.48/mm; P = .001), and extremity location of the primary melanoma (adjusted RR, 3.6; 95% CI, 1.51–11.10; P = .004) retained their significance. Satellite metastasis around the primary lesion (P < .06), Clark level, and ulceration were not significant.

Survival Analysis
Patients who developed only in-transit metastases as a first event had a 5-year overall survival probability (calculated from the excision of the primary tumor) of 59.9%. The overall survival of patients who presented with distant metastases or synchronous intransit and distant metastases as the first site of recurrence was significantly worse (Fig. 3Go).


Figure 3
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  		FIG. 3. Overall survival according to the pattern of first recurrence.

 
The probability of surviving 5 years after the first in-transit metastasis was 50.7%. In accordance with the American Joint Committee on Cancer classification, the survival after in-transit metastasis was significantly better in SLN-negative patients compared with SLN-positive patients (Fig. 4Go).


Figure 4
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  		FIG. 4. Probability of survival after the first in-transit metastasis, according to the pathologic status of the sentinel lymph node (SLN).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
After WLE of primary melanomas, the incidence of in-transit metastasis is currently estimated to be <5%, whereas an unexpectedly high incidence of 9% (11.2% in this study) has been described for patients with WLE plus SLNE. After positive SLNE, in-transit rates exceeding 20% have been reported.10 The explanation for this, at first sight, surprising observation is relatively simple: by using SLNE, nodal recurrences are reduced to a negligible number, and this prolongs the time period during which in-transit metastases are able to manifest as a first recurrence.19

Using multiple logistic regression, Pawlik et al. recently identified age >50 years, lower extremity location of the primary melanoma, Breslow thickness, ulceration, and SLN status as predictors of in-transit recurrence after SLNE.27 In this study, using the (from the biometric standpoint) preferable Cox proportional hazards model, we have demonstrated that the pathologic status of the SLN, Breslow thickness, and extremity location of the primary tumor are independent predictors of in-transit risk after SLNE. The presence of satellite metastasis at the time of the primary tumor also tended to be significant. The 5-year probabilities of developing in-transit metastases as a first recurrence for SLN-positive and SLN-negative patients were 24% and 6.3%, respectively.

Furthermore, we identified additional patient groups that had a considerably increased risk of developing in-transit metastases (as a first recurrence). Patients in whom surgically amenable satellite metastases were excised concurrently with the primary tumor had a recurrence probability of 41%. Among the patients with negative SLNs, those with primary tumors thicker than 4 mm had a risk of 22.1%. Among the patients with positive SLNs, those with primary tumors thicker than 4 mm had an in-transit risk of 44.2%. Penetration of the metastasis deeper than 1 mm into the SLN was associated with an in-transit risk of 36%. In patients with capsular breakthrough, the probability reached 63.3%.

So far, two retrospective studies have suggested that overall survival after positive SLNE may be superior to that of stage III patients who receive a delayed lymph node dissection only after the development of clinically enlarged node metastases.28,29 However, this potential survival benefit is compromised by the high risk of regional cutaneous metastases in the subgroups described previously. Moreover, radical therapeutic modalities providing wider safety margins,1 continuous dissection including the primary tumor and regional lymph nodes,30 preventive node dissection,31–33 adjuvant irradiation,34 or cytostatic limb perfusion2 have been shown to influence local or regional tumor control rather than overall survival. Nevertheless, it seems that a substantial proportion of patients can be successfully treated by adequate and aggressive surgical therapy. In our study, 50.7% of patients survived >5 years after in-transit metastasis appeared as a first event. In agreement with others,26 we observed that the probability of survival after intransit metastasis, occurring as a first event, depended on the pathologic status of the SLN. Overall, patients with in-transit recurrence fared better only than patients with distant recurrence or synchronous distant and in-transit recurrence.

So far, the effect of safety margins for the primary melanoma on the rate of in-transit-metastases has been evaluated with reference to Breslow thickness only. However, as shown by this study, the SLN status is also an independent predictor of in-transit risk, and the question of whether the recommended resection margins should be adjusted to SLN status remains unanswered.

Reasonably, the site of the primary tumor and its distance from the regional lymph nodes often affect further adjuvant strategies. Where a thick primary lesion is situated close to the regional lymph nodes, a continuity procedure, i.e., removing the peritumoral skin en bloc with the afferent lymph vessels and the SLN(s), may be considered. We performed continuity procedures in approximately 14% of our patients without significantly increasing the morbidity.35

It has been shown that in-transit metastases respond well to radiotherapy.36 This study has identified high-risk patients who are potential candidates for adjuvant irradiation. After positive SLNE plus complete lymph node dissection, a probability of tumor recurrence in the node dissection field of 25.3%32 seems to justify the application of adjuvant irradiation to the in-transit area and the nodal basin. Radiotherapy, however, increases morbidity after complete lymph node dissection.37 Therefore, one might also consider replacing complete node dissection by radiotherapy in certain cases.38

Until now, adjuvant cytostatic limb perfusion has been assessed only for patients with primary melanomas thicker than 1.5 mm.2 With this procedure, an in-transit rate of 6.6%, which is in any case low, was reduced by 50% without affecting overall survival. Consideration should be given to the fact that, after the introduction of tumor necrosis factor {alpha} to limb perfusion, the response rates further improved. 39 In our study, SLN-positive patients with primary tumors located distally to the knee or elbow had an in-transit probability of 42.2%; this might qualify this group as being more promising for studies dealing with cytostatic limb perfusion. The current practice of applying this relatively toxic procedure only for extensive or notoriously recurring in-transit metastasis to save the limb40 may have to be changed.

In conclusion, in-transit metastases are important in the era of the SLN. Our results show that the risk of developing in-transit metastasis differs considerably among various subgroups of patients. Individualized therapeutic approaches for the risk groups described should be evaluated in future controlled trials.

Received for publication July 22, 2005. Accepted for publication February 21, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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