Current Surgical Management Of Primary
Cutaneous Malignant Melanoma

John B. Harris, M.D. and Mark E. Freeman, M.D.
John B. Harris, M.D. is with the Section of Plastic and Reconstructive Surgery,
Mayo Clinic Jacksonville.
Mark E. Freeman, M.D. is a Surgical Resident, Mayo Clinic Jacksonville.

After years of little change, recently there have been proposed advances in the surgical management of patients with primary cutaneous malignant melanoma. Issues related to margins of resection of the primary tumor have been resolved to most physicians satisfaction and little controversy currently exist in this area of melanoma management. However, the development of the concept and technique of sentinel lymph node biopsy along with reports of successful adjuvant treatment for melanoma has created new pathways to evaluate.

The purpose of addressing the regional lymph node basin and performing an elective lymph node dissection has been to remove the theoretical first site of metastatic spread of melanoma. A lymph node dissection such as an axillary lymph node dissection or inguinal lymph node dissection carries significant morbidity and can only be justified if there is improvement in survival for the group of patients that it is being proposed. There has been unanimous support for withholding elective lymph node dissection for patients with thin melanomas (less than 1 mm thick), with the thought that there is very low risk for regional metastasis in this group of patients. Similarly, there has been agreement that elective lymph node dissection is not of benefit for patients with thick melanomas (greater than 4 mm thick) who are at significant risk for systemic metastatic disease. The sub-group of patients for whom the procedure has been proposed to benefit is the intermediate thickness melanoma group (1 to 4 mm) who are at low risk for systemic spread, but may have metastasis to the adjacent regional lymph node basin. An improvement in overall survival with elective lymph node dissection has been proposed for this group of patients for whom the initial metastatic spread has theoretically been attended to.

Historically, surgeons who have not supported elective lymph node dissection for intermediate thickness melanoma have pointed to two prospective randomized trials conducted by the World Health Organization Melanoma Group and the Mayo Clinic. Neither study showed significant improvement in survival after elective lymph node dissection. Critics of both studies point to a lack of consistent pre-operative lymphoscintigraphy as well as patient selection factors. Regardless, these reports have represented the only good randomized prospective studies of the value of elective lymph node dissection in the management of melanoma. Surgeons who have supported elective lymph node dissection have relied on retrospective data from large melanoma centers such as the Sidney Melanoma Unit and the MD Anderson Cancer Center. In 1996, Balch et al reported on the first prospective randomized trial that found some benefit from elective lymph node dissection. However, the sub-group that benefited was limited to patients less than 60 years of age with melanoma 1.1 mm to 2.2 mm in thickness. This study, therefore did little to settle the issue of the overall value of elective lymph node dissection. The development of the technique of sentinel lymph node biopsy and reports of successful adjuvant treatment for melanoma may have made this debate irrelevant.

In 1993, Morton reported on the technique of the identification and biopsy of the sentinel lymph node. The basis of this technique is the supposition that there is a linear or sequential spread of melanoma through the cutaneous lymphatic system. Because of this drainage pattern, skip metastasis are felt to be very unlikely as originally proposed by Halsted. By removing what is felt to be the first lymph node in the chain of drainage, an indication of the status of the remaining lymph nodes is therefore feasible. Morton and others have shown that if the sentinel lymph node is found to be negative for melanoma then the remaining lymphatic basin is likely to be free of metastatic disease as well. If the sentinel lymph node is found to be positive for metastatic disease then a therapeutic lymph node dissection is recommended. In addition to being minimally invasive and cost-effective, the sentinel lymph node biopsy approach has decreased the number of unnecessary lymph node dissections.

The actual technique of sentinel lymph node biopsy is relatively straight forward. If the anatomic location of the primary melanoma indicates possible multiple pathways of lymphatic spread, a preoperative lymphoscintogram can be performed to assist in preoperative planning (Figure 1). A vital blue dye and radionucleotide labeled colloid are injected into the dermis surrounding the primary lesion (Figure 2). The patient is then taken to the operating room and a probe is utilized to identify the location of greatest radioactive intensity. An incision is made over this site and the sentinel lymph node located. The blue staining of the afferent lymphatics can be traced into the node further confirming the identity of the sentinel lymph node (Figure 3). The procedure can be performed though small incisions with minimum morbidity on an outpatient basis. Of great importance is cooperation with the pathology and nuclear medicine departments.

Figure 1 (Left). Lymphoscintogram of left posterior hip melanoma with single drainage pathway to left inguinal nodes.	Figure 2 (Center). Isosulfane blue dye injected into dermis surrounding biopsy site of primary lesion.	Figure 3 (Right). Intra operative view of blue dye in afferent lymphatics and three levels of radioactivity with the highest level identifying the sentinel node.

An associated advantage of the technique is the intense scrutiny the pathologist can now give to the sentinel lymph node(s). Serial sectioning of a complete lymph node dissection specimen is time consuming. By focusing the serial sectioning technique on one or two lymph nodes the pathologist is less likely to miss a micro-metastasis. The routine use of immunohistochemical staining along with serial sectioning has had the combined affect of minimizing missed micro metastatic disease and likely has upstaged many patients. Paralleling the development of the sentinel lymph node biopsy technique has been the evaluation of even more sensitive assays for micro-metastatic disease. The reverse transcription polymerase chain reaction technique (RT-PCR) can identify one melanoma cell in a field of one million lymphocytes. The cost effectiveness of RT-PCR and its potential affect on treatment choices is being evaluated and currently precludes routine use in most clinical practices.

Reports of the effectiveness of adjuvent interferon alpha-2b by the Eastern Cooperative Oncology Group (ECOG) 1684 trial has created interest in the role of sentinel lymph node biopsy as a staging procedure. The ECOG study evaluated overall survival and relapse-free survival for high-risk melanoma patients who had no evidence of disease after surgical therapy who were subsequently given adjuvent treatment with interferon alpha-2b. The conclusion of the study was that interferon prolongs the relapse-free interval and overall survival of high risk resected melanoma patients. A significant result of this study is that accurate staging of patients who are at high risk for metastatic disease is now more important. Patients who have intermediate thickness melanoma and are clinically node negative might all then undergo a minimally invasive surgical procedure for staging such as sentinel lymph node biopsy, and if necessary may benefit from interferon treatment. The significant toxicity of interferon alpha_2b has been well documented and current trials underway involve varying the timing and dosage in an effort to minimize side effects.

In conclusion, there have been recent changes in the surgical management of the patient with primary cutaneous melanoma with the development of the Sentinel Lymph Node Biopsy. With the advent of potentially effective adjuvent treatment for patients who are high risk for metastatic melanoma, accurate staging of the patient has become very important. In institutions where pathology and radiology departments allow for the use of lymphoscintigraphy and intraoperative radionucleotide lymphatic mapping then sentinel lymph node biopsy may be the new standard. For institutions where lymphatic mapping and sentinel lymph node biopsy are not feasible, then elective lymph node dissection for patients with clinically node negative intermediate thickness melanomas may still be appropriate. The acceptance of routine sentinel lymph node biopsy in the management of patients with melanoma must continue to be evaluated. The exact role that it may play, if any, in improving overall survival for melanoma patients remains to be determined.

Bibliography

Morton DL, Wen DR, Wong H, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg.1992;127:392-399.

Reintgen DS, Cruese CW, Bernam C, et al. An orderly progression of melanoma nodal metastasis. Ann Surg. 1994;220:759-767.

Wang X, Heller R, VanVoorhis N, et al. Detection of submicroscopic lymph node metastases in patients with malignant melanoma. Ann Surg. 1994; 220:768-774.

Veronesi U, Adamus J, Bandier DC, et al. Inefficacy of immediate node dissection in stage I melanoma of the limbs. N Engl J Med. 1977;297:627.

Sim FH, Taylor WF, Pritchard DJ, et al. Lymphadenectomy in the management of stage I malignant melanoma: a prospective randomized study. Mayo Clinic Proc. 1986;61:697.

Balch CM, Soong S-J, Milton GW, et al. A comparison of prognostic factors and surgical results in 1,786 patients with localized (stage I) melanoma treated in Alabama, USA, and New South Wales, Australia. Ann Surg. 1982; 156:677.

Balch CM, Soong S-J, Bartolucci A, et al. Efficacy of an elective regional lymph node dissection of 1 to 4 mm thick melanomas for patients 60 years of age younger. Ann Surg. 1996; 224:255-266.

Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;14:7-17.

October, 1999/ Jacksonville Medicine

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