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SUPPLEMENT |
From the Adelaide Melanoma Unit and Breast Endocrine and Surgical Oncology Unit, Department of Surgery (BJC, PGG), University of Adelaide, and Department of Nuclear Medicine (BC), Royal Adelaide Hospital, North Terrace; and Department of Pathology (FW, CJ), Institute of Medical and Veterinary Sciences, and Adelaide Pathology Partners, West Terrace, Adelaide, South Australia.
Correspondence: Address correspondence and reprint requests to: Brendon J. Coventry, BMBS, PhD, FRACS, Adelaide Melanoma Unit, Department of Surgery, University of Adelaide, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia; Fax: 61-2-8222-5896; E-mail: bcoventry{at}medicine.adelaide.edu.au
ABSTRACT
Lymphatic mapping and sentinel lymph node dissection (LM/SLND) for surgical staging of cutaneous primary melanoma is currently being evaluated, but the role of these techniques in recurrent (secondary) melanoma is largely unexplored. Our experience with 12 patients indicates the potential usefulness of LM/SLND in the management of locally recurrent melanoma at subcutaneous sites. We have even used mapping to localize the sentinel node draining a subcutaneous local recurrence after previous LM/SLND for primary melanoma. The application of LM/SLND may therefore be extended beyond primary melanoma management as we understand more about the technical issues and appropriate selection of patients.
Key Words: Lymphatic mapping • Secondary • Sentinel node biopsy • Subcutaneous melanoma recurrence
Lymphatic mapping and sentinel lymph node dissection (LM/SLND) for surgical staging of cutaneous primary melanoma can identify those patients likely to benefit from regional complete lymphadenectomy, but its role in recurrent (secondary) melanoma is largely unexplored. Local recurrence near the primary melanoma excision site is clinically problematic and correlates with poorer outcome in many cases. Local recurrence can be cutaneous, subcutaneous, or both, sometimes beneath or close to the wide-excision scar, and it has been associated with subsequent nodal lymphatic basin metastasis, systemic spread, and further local or in-transit metastasis.
Our group and others have used the LM/SLND technique since 1993 for primary melanoma and breast cancer treatment and as part of the international Multicenter Selective Lymphadenectomy Trial (MSLT) and other clinical trials.1 We have employed standard intradermal injection for cutaneous primary melanoma and peritumoral injection for primary breast cancers, with good results.2 Over the past few years we have utilized peritumoral injection techniques, similar to those used for breast cancer, for subcutaneous recurrent melanoma deposits and have identified a sentinel node (SN) in the majority of cases. We have hypothesized that LM/SLND can be used to map SNs from solitary, subcutaneous, locally recurrent melanoma deposits and that these techniques may be of benefit in identifying regional lymph node basin metastases, in a manner similar to their use for primary melanoma. In those patients with strictly regional metastases, complete lymph node dissection may offer containment of disease and, in some cases, potential cure. We present some follow-up data from our preliminary clinical experience with LM/SLND in the treatment of local subcutaneous melanoma recurrence.
METHODS
Patients
The 12 patients included in the study presented to our institution with solitary subcutaneous or cutaneous melanoma recurrences after previous wide local excision as sole treatment for primary melanoma. Eligible patients had solitary local recurrence of melanoma within 5 cm of the original excised primary melanoma and no demonstrable evidence of metastatic spread on whole-body computed tomographic (CT) scans or other investigations (blood tests, ultrasonography, and magnetic resonance imaging [MRI] or positron emission tomography [PET] where indicated and performed). All solitary nodules were less than 2 cm in diameter. Patients with clinically involved regional lymph nodes, more than one subcutaneous recurrence, or any other evidence of wider metastatic disease were excluded. Informed patient consent was obtained for the procedure, using an LM/SLND protocol approved by our institutional human ethics committee.
Patient age, lymphoscintigram result, sentinel node status, follow-up at February 2002, survival, and presence of local, nodal, or systemic recurrence were determined clinically, radiologically, and pathologically.
LM/SLND Technique
The methods used for LM/SLND were similar to those employed at our center for the MSLT studies.1,3 Injection of both radionuclide and blue dye was peritumoral, similar to that used in our breast cancer studies,2 rather than intradermal (as used in the MSLT for cutaneous melanoma). Peritumoral injection or injection around the excision site (if the recurrence had been resected to obtain the diagnosis) of Tc99m-labeled antimony sulfide colloid (Lymphflo, Adelaide, Australia) was performed using a 40-mBq dose via four standard injections, and lymphatic mapping was performed using the same criteria as for the MSLT. The first or sentinel node(s) were localized by lymphoscintigraphy in the nuclear medicine department with a gamma camera and marker source, and its position(s) marked with a triangulation method. Injection and localization were performed on the morning of the day of surgery. In one case of periocular subcutaneous melanoma recurrence, ultrasound localization was used for accurate injection of the radionuclide and blue dye. A period of 3 to 5 hours elapsed between radiopharmaceutical injection and the skin incision.
One to 2 mL of Patent Blue V dye (Rhone-Poulenc, Fauldings, Adelaide, Australia) was injected peritumorally (or beneath the wound) immediately before surgery with use of the same injection sites as for the radioactive tracer. At least 15 to 20 minutes was allowed for adequate transit of the blue dye to the SN prior to excision.
LM/SLND was performed in all cases with use of blue dye and a hand-held gamma probe (Gammasonics, Sydney, Australia). Two experienced surgeons performed the studies. The results were collected prospectively, collated, and analyzed retrospectively. Standard descriptive statistical median estimations were used throughout.
Pathology included standard hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC) with S-100, HMB-45, and Melan-A. The same SN processing protocol was adopted as that used in the MSLT.1,3 SN positivity was based on H&E and IHC results.
Follow-Up
Patients were followed with clinical examinations every 3 months for 2 years, every 6 months for 2 years, and yearly thereafter. Interim examinations were undertaken if required. CT scans of head, chest, abdomen, and pelvis were performed prior to enrollment and at 6-month intervals, unless otherwise dictated clinically. Other investigations such as ultrasonography, MRI, PET scans, blood tests, and fine-needle aspirations were performed as clinically indicated.
RESULTS
The results are summarized in Table 1. The median age of the 12 patients was 60.5 years (range, 19 to 78 years). Pathology of the initial primary melanoma lesions ranged from in situ to 4.8 mm in Breslow thickness (Clark levels I to V). The melanoma recurrence was located on an extremity in eight patients, on the trunk in two patients, and on the head in two patients. All recurrences were less than 5 cm from the initial primary melanoma resection sites. Wider local excision and primary closure or skin grafting were performed in all cases after LM/SLND. Pathology of the recurrent lesions confirmed melanoma in all cases. None of the study patients had previously undergone LM/SLND or complete lymph node dissection (CLND).
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Three patients with tumor-positive SNs subsequently underwent CLND. In one case (patient 11, Table 1) CLND revealed further melanoma-involved lymph nodes. One patient with a positive SN refused subsequent CLND, but no melanoma recurrence has been evident to date (patient 10, Table 1). In patients 6 and 12 (Table 1) the SN was the only node positive for malignancy.
The clinical follow-up period ranged from 6 to 105 months, with a median of 23 months. The longest disease-free follow-up time was for the patient whose primary lesion had the deepest Breslow thickness. Seven patients (58.3%) remained melanoma-free at the time of follow-up, and five patients had further local, regional, or distant recurrence. Local recurrence (LR) occurred in four cases (two without systemic metastases); all of these were in-transit in nature, with no cases of recurrence in the draining lymphatic basin. Four patients developed systemic melanoma recurrence (SR). In the group with SR, there were three deaths (25%), at 18, 21, and 30 months after LM/SLND; two of these patients had negative SNs and one had a positive SN (the 18-month survivor). SR occurred in the brain (patients 1 and 11), lung (patients 1 and 4), small bowel (patient 2), and liver (patient 2); thus, two patients had two organ sites of recurrence. Subsequent treatment was systemic chemotherapy, radiotherapy, vaccine immunotherapy, and/or isolated limb infusion chemotherapy.
Patient 4 (Figs. 1–5
) underwent LM/SLND for a local subcutaneous recurrence close to the wide-excision site on the mid-calf and had a negative SN. This patient subsequently developed two further in-transit metastases 4–5 cm above and below the leg wide-excision site, and a subcutaneous in-transit (nodal?) nodule in the left mid-thigh. CLND was performed. No inguinal/pelvic regional recurrence has occurred at 37 months of follow-up in the basin from which the initial (negative) SN was excised. SR has occurred in the lungs, but these nodules remain quiescent after vaccine and chemotherapy.
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Two patients developed a second primary cancer (prostate and leukemia).
DISCUSSION
Some local melanoma recurrences are subcutaneous and/or intradermal, beneath or close to the primary melanoma wide-excision scar. We investigated the possible application of peritumoral injection, as used for breast cancer LM/SLND techniques, because of certain anatomic parallels between intraparenchymal breast cancer and subcutaneously located melanoma deposits. We found that LM/SLND was possible by peritumoral injection of radionuclide and blue dye around subcutaneously located melanoma deposits and that these methods could be utilized for some of these patients with minor technical modifications. LM and SLND techniques have significantly increased knowledge of lymphatic drainage patterns from primary lesions.4–7 We further reasoned that understanding the lymphatic drainage pattern from a subcutaneous metastasis may provide some guidance in deciding the type and potential usefulness of any further surgery. The recent American Joint Committee on Cancer (AJCC) staging system views locally recurrent cutaneous/subcutaneous melanoma (less than 2 cm from the primary melanoma site), in-transit melanoma nodules, and involved lymph nodes as prognostically similar.8,9
Local recurrence can occur intradermally, subcutaneously, and/or within deeper tissues, such as muscle and nerve. However, where dermal involvement is present, intradermal injection of radioactive tracer and blue dye may be just as effective as peritumoral subcutaneous injection. The pattern of lymphatic drainage close to the tumor is undoubtedly the most important aspect defined by the LM/SLND procedure in primary cutaneous melanomas and in locally recurrent melanoma. Local recurrences may be very close to the primary melanoma excision scar or a short distance away from it and represent metastatic tumor microemboli within lymphatic channels in surrounding soft tissues.
In our study, we repeated LM/SLND in patient 4 to examine lymphatic flow from a second later subcutaneous recurrence. LM revealed pooling of radioactivity in the lower leg, typical of lymphedema, without demonstrating a SN more proximally. This patient had undergone an inguino-pelvic lymphadenectomy that altered lymphatic flow; the recurrence was distal to the graft site on the mid-calf, making the situation less than ideal for lymphoscintigraphic studies of this type. However, some recent experience with LM/SLND techniques for multiple primary lesions and for subcutaneous metastatic melanoma occurring distant to the primary melanoma site after previous LM/SLND has shown us that the methods can be successfully used to localize and remove SNs draining from different areas of skin (B. Coventry, unpublished data). Even LM/SLND can be repeated in the same basin. Therefore, in favorable clinical situations, we see no reason why LM/SLND could not be useful in specific cases for multiple (or repeated) subcutaneous metastases, despite the expected attendant technical and theoretical difficulties.
Solitary in-transit recurrent melanoma deposits present another problem where LM/SLND might be successfully utilized in special instances to trace and selectively sample the lymph nodes most likely to drain the in-transit deposit. We have performed this in one case, but this approach currently remains a tenuous, highly experimental method of treatment.
In cases of secondary subcutaneous melanoma, where LM/SLND was not performed for treatment of the primary lesion, tumor emboli to the SN could have occurred from either the original primary tumor or the locally recurrent melanoma. In either case, the purpose of LM/SLND would be to identify melanoma deposits in the SN(s) for staging purposes and for recommending CLND.
Local recurrence of melanoma (and other cancers) is often a harbinger of further metastatic disease and poorer clinical outcome. Systemic recurrence therefore remains the major limitation of LM/SLND in the setting of subcutaneous secondary melanoma recurrence. Two of the three patients who died in this series had systemic recurrence with a negative SN, without evidence of recurrence in the lymph node basin draining the site of the subcutaneous recurrent melanoma. This is most likely because of direct hematogenous metastasis of viable melanoma cells into the circulation and probable immunosuppression. Complete transit of melanoma cells through the lymph nodes without adhesion cannot be excluded as another possibility. Further local recurrence or in-transit recurrence also presents some limitation, although our experience suggests that this is sometimes amenable to further surgery (perhaps including LM/SLND), chemotherapy (including isolated limb infusion), vaccine immunotherapy, or radiotherapy.
It is interesting to note that in our series, the survivor with the longest follow-up (105 months) had the deepest invasive melanoma (Clark level V; Breslow thickness, 4.8 mm) and a negative SN, whereas two of the patients who died of systemic melanoma metastases had a negative SN and thin (in situ, 0.57-mm) primary melanomas (Table 1). This underlines the fact that individual tumor biology is extremely important in determining the pathways and propensity for metastatic spread.
Among patients with locally recurrent melanoma, the subgroup most likely to benefit from LM/SLND are patients without lymphatic spread beyond the regional lymphatic drainage basin and without direct hematogenous metastasis. This longer-term survival benefit may be less than the 12% predicted for LM/SLND and CLND in patients with intermediate-thickness primary melanoma. LM/SLND might prolong the disease-free interval, perhaps by reducing remetastasis from metachronous subcutaneous melanoma deposits, but this is currently unproven from the small sample size and (understandable) lack of untreated control patients. If so, then LM/SLND may have some survival advantage or may significantly improve quality of life by delaying or reducing melanoma recurrence and the need for more extensive treatment modalities.
Our preliminary experience and results indicate that LM/SLND is feasible in subcutaneous, locally recurrent melanoma, but further data are needed. In addition, in selected cases, these techniques may be used to map lymphatic drainage pathways and lymph node metastasis from in-transit melanoma recurrences. LM/SLND may even be useful for local recurrence after previous LM/SLND for primary melanoma treatment or for multiple local recurrences. Issues that remain to be resolved are the best technique, true validity, and clinical efficacy, together with appropriate selection of patients.
FOOTNOTES
Experience with 12 patients indicated the potential usefulness of lymphatic mapping and sentinel lymph node dissection in the management of locally recurrent melanoma at subcutaneous sites.
Received for publication November 24, 2003. Accepted for publication January 19, 2004.
REFERENCES
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