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Micrometastasis to In-Transit Lymph Nodes From Extremity and Truncal Malignant Melanoma

From the Departments of Surgery (MCT, LHN, REA, SPLL), Nuclear Medicine (ETM), and Pathology (PAT), and Melanoma Center (RWS, MK-S), University of California at San Francisco Medical Center at Mount Zion and UCSF Comprehensive Cancer Center, San Francisco, California.

Correspondence: Address correspondence and reprint requests to: Stanley P.L. Leong, MD, Director of Sentinel Lymph Node Program, Department of Surgery, Member, UCSF Comprehensive Cancer Center, 1600 Divisadero Street, Suite C333, San Francisco, CA 94115; Fax: 415-353-7721; E-mail: leongs{at}surgery.ucsf.edu

	ABSTRACT

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Background: The sentinel lymph node (SLN) is the first lymph node in the regional nodal basin to receive metastatic cells. In-transit nodes are found between the primary melanoma site and regional nodal basins. To date, this is one of the first reports on micrometastasis to in-transit nodes.

Methods: Retrospective database and medical records were reviewed from October 21, 1993, to November 19, 1999. At the UCSF Melanoma Center, patients with tumor thickness >1 mm or <1 mm with high-risk features are managed with preoperative lymphoscintigraphy, selective SLN dissection, and wide local excision.

Results: Thirty (5%) out of 557 extremity and truncal melanoma patients had in-transit SLNs. Three patients had positive in-transit SLNs and negative SLNs in the regional nodal basin. Two patients had positive in-transit and regional SLNs. Three patients had negative in-transit SLNs but positive regional SLNs. The remaining 22 patients were negative for in-transit and regional SLNs.

Conclusions: In-transit SLNs may harbor micrometastasis. About 10% of the time, micrometastasis may involve the in-transit and not the regional SLN. Therefore, both in-transit and regional SLNs should be harvested.

Key Words: Melanoma • Micrometastasis • In-transit sentinel lymph node

	INTRODUCTION

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Metastatic spread of primary cutaneous melanomas frequently follows an orderly progression via the lymphatic system.¹ The sentinel lymph node (SLN) is the first lymph node to receive direct lymphatic drainage from a primary tumor site.² The SLN may be identified by either the accumulation of isosulfan blue dye, radiocolloid, or both.^3,4

Recent studies have provided further insights into lymphatic anatomy and have identified the presence of second-tier and interval lymph nodes. The second-tier lymph node is defined as any node that receives tracer that has previously passed through a sentinel (first-tier) lymph node.⁵ In other words, the first- and second-tier lymph nodes are in series. An interval or in-transit node is a node that occurs anywhere between a primary melanoma site and a recognized draining lymph node field.^6,7 Thus, in-transit nodes can either be in parallel or series with respect to the primary SLN basin.

Consequently, accurate identification of the SLN is very important in the staging and subsequent treatment of melanoma. Lymphoscintigraphy identifies SLN drainage basins that do not necessarily follow clinical predictions, including in-transit SLNs. Several recent studies have shown discordancy between preoperative lymphoscintigraphy and clinical predictions of regional draining lymph nodes for a primary melanoma.^6,8,9

The purpose of this paper is to report our experience on micrometastasis to in-transit lymph nodes from extremity and truncal primary cutaneous melanoma and to compare the incidence of micrometastasis in in-transit and regional SLNs.

	PATIENTS AND METHODS

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The UCSF Medical Center at Mount Zion Surgical Oncology database contains detailed information on melanoma patients treated from October 21, 1993, to November 19, 1999. These patients underwent preoperative lymphoscintigraphy. Lymphatic channels were described as serial, parallel, or a combination of both. A serial lymphatic channel is one that passes directly through the in-transit to the regional basin. In contrast, parallel lymphatic channels are at least two in number with at least two separate and distinct destinations to the in-transit and regional basin, respectively. Following lymphoscintigraphy, patients then underwent selective SLN dissection and local re-excision. SLNs were identified intraoperatively as those with either elevated radioactivity counts, blue lymph nodes, or both. In certain cases where blue dye was injected, SLNs were classified on a scale of 1 to 5, with 1 being the faintest blue and 5 being the bluest. If no blue color was apparent, then a grade of 0 was given. The technical details of SLN dissection have been previously described.^4,10,11 Surgical specimens were reviewed by the UCSF Medical Center at Mount Zion Pathology Department. Immunohistochemical staining for S-100 and HMB-45 was performed on all the sentinel lymph node specimens. Retrospective database and medical record review of 557 extremity and truncal melanoma patients identified 30 patients with in-transit SLNs.

	RESULTS

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Thirty (5%) out of 557 extremity and truncal melanoma patients had in-transit SLNs (Table 1). In-transit and regional lymph node status was determined by immunohistochemical staining for S-100 and HMB-45. Patients were subdivided into the following four groups: positive in-transit SLNs and negative regional basin SLNs, negative in-transit SLNs and positive regional basin SLNs, positive in-transit and positive regional basin SLNs, and negative in-transit SLNs and negative regional basin SLNs.

Negative In-Transit SLNs and Positive Regional Basins SLNs
Another three patients (10%), two lower extremity and one trunk, had negative in-transit SLNs but positive regional SLNs. Of this group, the patients with the lower extremity melanomas had parallel lymphatic channels to the in-transit and regional basins. The patient with the 6-mm lower extremity melanoma had elevated in-transit and regional SLN counts without any evidence of blue-colored lymph nodes. The other patient with the 2.7-mm lower extremity melanoma had elevated in-transit and regional SLN radioactivity counts (no blue dye injection). In these two patients, there may be more than one lymphatic channel present for this to occur. This would partially explain the occurrence of having a simultaneous negative in-transit SLN and a positive regional basin SLN. Both patients had elevated radiotracer counts. However, one patient had elevated radiotracer counts and no evidence of any blue-dye stained lymph nodes. On the other hand, the patient with the truncal melanoma had parallel and serial lymphatic channels to the in-transit and regional basins as well as elevated radiotracer counts and blue-stained SLNs in both basins. In this case, confluent channels from the chest wall were traveling to the regional basins.

Positive In-Transit and Positive Regional Basin SLNs
Two patients (7%) with upper extremity melanoma had positive in-transit SLNs and positive regional SLN basins. One of these patients had parallel in-transit and regional basins as evidenced by two separate lymphatic channels emanating from the injection site to the epitrochlear in-transit node and to the axillary node, respectively. This patient also had elevated radiotracer counts and blue-stained SLNs in both basins. The other patient had a combination of parallel and serial channels. In this case, preoperative lymphoscintigraphy demonstrated a single serial lymphatic vessel from the injection site leading to the epitrochlear node and to the axillary node as well as another separate parallel lymphatic vessel from the epitrochlear region to the axilla. This patient had elevated radiotracer counts in both in-transit and regional SLN basins. Blue dye was not used in this case.

Of these melanoma patients with positive in-transit SLNs or regional SLNs or both sites, three patients (37.5%) had serial basins, four patients (50%) had parallel basins, and one patient (12.5%) had a combination of serial and parallel channels. The average Breslow thickness was 3.6 mm.

Negative In-Transit SLNs and Negative Regional Basin SLNs
Twenty-two patients (73%), 11 trunk, 6 upper extremity, 5 lower extremity, had negative in-transit and negative regional basin SLNs (Table 2). Of this group, 16 patients (73%) had serial channels and six patients (27%) had parallel channels. Ten patients underwent SLN identification and harvesting using radiotracer as the sole intraoperative modality whereas the remaining 12 patients had both radiotracer and blue dye injection. Of the latter group, six patients had serial lymphatic channels with elevated radioactivity counts and blue-stained lymph nodes in both in-transit and regional basins. The average Breslow thickness was 2.0 mm.

	DISCUSSION

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Thompson et al.⁶ reviewed lymphatic drainage pathways demonstrated by preoperative lymphoscintigraphy for 1759 patients with primary cutaneous melanoma. They found that the cutaneous lymphatic drainage pathways were at variance with longheld concepts of lymphatic anatomy. New pathways were identified draining to SLNs in unexpected sites in a minority of patients. These SLNs were identified as interval nodes. They occurred anywhere between a primary melanoma site and a recognized draining lymph node field.

Uren et al.⁷ reported the incidence of interval or in-transit nodes in 2045 patients with primary cutaneous melanoma. Out of this group, 148 patients were found to have interval or in-transit nodes. Twenty-one patients had their interval nodes excised for histological examination. In this subgroup, micrometastatic disease was found in 14% of the interval nodes in their series as compared to 10% in ours. Thus, interval nodes should be harvested.

Preoperative lymphoscintigraphy allows identification of serial and parallel lymphatic channels leading to SLNs. However, the resolution is such that if more than two serial nodes are identified, the possibility of another parallel channel passing directly over or around the serial channel cannot be excluded (by lymphoscintigraphy alone or by intraoperative detection of elevated radiotracer counts for identifying the SLNs). Although uncommon, this phenomenon has been visualized with the intraoperative use of isosulfan blue dye. But generally, only a single afferent channel is noted (Allen, personal communication, 2000).

In this study, we examined the incidence of micrometastasis in in-transit SLNs in extremity and truncal melanoma. The SLNs were identified with either elevated radiotracer counts or elevated radiotracer counts and blue dye. Ten percent of our patients had positive in-transit SLNs and negative regional SLN basins. Another 10% of our patients had negative in-transit SLNs and positive regional SLN basins. Seven percent of our patients had both positive in-transit and regional SLN basins. Seventy-three percent of our patients had negative in-transit and negative regional SLN basins. In our group of 30 patients, there appears to be a pass-through phenomenon in serial lymphatic channels as evidenced by the appearance of blue-stained lymph nodes in both in-transit and regional basins. However, as previously mentioned, the possibility of an unrecognized parallel lymphatic channel cannot be excluded at this time. All patients with positive SLNs had parallel channels. Apparently, parallel channels were most likely to be the conduits for micrometastasis.

It is evident that micrometastatic disease would have been missed if the SLN dissection was based solely on anatomic site. This study further emphasizes the importance of preoperative lymphoscintigraphy in the detection of in-transit SLNs. Due to the lack of microanatomical detail in present-day lymphoscintigraphy technology, it cannot be determined if lymph nodes are truly in series because the possibility of parallel channels cannot be excluded. At this time, however, parallel channels are detected only if two or more channels are identified in preoperative lymphoscintigraphy. This, in turn, emphasizes the importance of dynamic lymphoscintigraphic studies to visualize channels.

Our findings are consistent with those of Uren et al.’s⁷ 14% incidence of in-transit nodes harboring micrometastasis. With fewer patients in our database, we observed an incidence of 10% micrometastasis in in-transit SLNs. It appears that micrometastasis may involve either serial or parallel lymphatic channels. Therefore, we recommend that all in-transit and regional SLNs should be harvested. Furthermore, considerable research is needed to define lymphatic anatomy at the cellular, microscopic, and ultrastructural levels.

	Footnotes

 
Supported in part by a grant from the Eva B. Buck Charitable Trust.

Received for publication July 17, 2000. Accepted for publication January 24, 2001.

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