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EDITORIALS |
From the Roy E. Coats Research Laboratories of the John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica, California.
Correspondence: Address correspondence and reprint requests to: Richard Essner, MD, John Wayne Cancer Institute, 2200 Santa Monica Blvd, Santa Monica, CA 90404; Fax 310-449-5259; E-mail: essnerr{at}jwci.org
Over the last hundred years, there has been great debate among surgeons regarding the management of clinically negative regional lymph nodes in patients with cutaneous melanoma. The debate is based on the concept that if melanoma metastasizes, it spreads first to the regional lymph nodes and then to distant sites. Intuitive thinking suggests that the lymphatic pathways represent a clear and defined connection from the primary to the regional lymph nodes, and that physical soiling of the regional lymph nodes with tumor metastases likely occurs before any spread to distant sites. This theory is based on clinical observation of the natural history and progression of metastatic melanoma. If melanoma uniformly metastasizes first to the regional lymph nodes, then removal of these nodes early in the course of the disease should halt the metastatic progression and improve prognosis. Both single- and multiple-institutional retrospective studies have identified subgroups of patients who achieve a survival benefit from early elective lymph node dissection (ELND). However, the four randomized prospective studies1–4 have failed to demonstrate any conclusive evidence that routine ELND in all melanoma patients is therapeutic, in part because a majority of patients do not have nodal metastases. Cost, potential morbidity, and lack of therapeutic value have made ELND impractical for the routine care of patients with clinically localized primary melanoma. However, if we can identify the subgroup of patients who have subclinical metastases limited to the regional lymph nodes, can we improve their survival by complete lymphadenectomy?
With the development of the technique of intraoperative lymphatic mapping and sentinel lymphadenectomy (LM/SL) more than 10 years ago,5 surgeons have renewed their interest in evaluation of the tumor status of regional lymph nodes.6 Unlike staging based on clinical exam or conventional ELND, LM/SL allows pathologists to focus on a single lymph node. Very small volumes of tumor can be identified (by immunohistochemistry and RT-PCR to melanoma-specific genes) in this sentinel lymph node. But what if the sentinel node is free of tumor? Does the absence of nodal involvement improve survival?
The study reported in this issue of Annals of Surgical Oncology by Dessureault et al.7 from the American Joint Committee on Cancer (AJCC) Melanoma Staging Committee addresses the role of lymph node staging for melanoma and the potential survival benefit associated with tumor-free lymph nodes. Of over 30,000 patients with melanoma (from 12 institutions) from the AJCC database, Dessureault et al. identified 15,767 with clinically negative nodes. Unfortunately, in a collective database like this, there is no way to determine the thought process of the clinicians and the various radiographic staging modalities that may have been employed to identify individuals who had clinically negative nodes. Obviously there was no prospective attempt to standardize the treatment from the multiple centers and the years in which the patients were treated. In fact, only 854 (5.4%) patients were subsequently found to have N1 disease, which left 14,914 for this analysis. A majority (69.4%) of patients were treated by wide excision alone, which greatly exceeded the number of patients undergoing either ELND (13.5%) or LM/SL (17.1%). The 5-year survival estimates were statistically lower for those patients with primaries thicker than 1 mm (with or without ulceration) who underwent wide excision alone (69.8 ± 0.8%) versus those undergoing ELND (77.1 ± 1.0%) or LM/SL (90.5 ± 1.1%). The conclusion of these investigators is that LM/SL is superior to other staging procedures, and those patients with tumor-negative regional lymph nodes are less likely to have recurrence and die.
We commend the investigators from the AJCC for collecting and analyzing such a large set of data, but we are skeptical of any conclusions drawn in the absence of measures to standardize treatment. We understand how LM/SL is a superior staging technique to clinical exam, but any comparison of these two patient groups must consider that the follow-up of patients who underwent wide excision alone is probably several years longer than the follow-up of those who underwent LM/SL. In our experience, approximately 12% of patients with intermediate-thickness melanomas and tumor-negative sentinel nodes ultimately develop recurrence of their disease. We have observed recurrences 5 years after tumor-negative LM/SL. The cumulative number of recurrences and deaths may increase with further follow-up.
Another question raised by these results is why ELND was associated with a worse prognosis than LM/SL. In a matched-pair statistical analysis from the John Wayne Cancer Institute, we found no difference in survival for patients undergoing ELND versus LM/SL.8 We would expect that complete removal of the entire nodal basin by ELND would be therapeutic, and in the few cases where nodal metastases are missed by the pathologists, we would expect little or no worse outcome than that for individuals undergoing LM/SL. Could their results reflect only differences in follow-up time between the two groups? It seems more likely that the survival differences reflect the greater accuracy of LM/SL to detect nodal metastases. LM/SL reduces the specimen size to a small number of nodes, which allows the use of special immunochemical stains to detect micrometastases that would be missed during routine hematoxylin and eosin (H&E) examination of the 15–30 nodes in a complete lymphadenectomy specimen. Thus, the designation of node-negative by LM/SL is more accurate than node-negative by ELND, because the latter group includes not only truly node-negative patients but also patients who have pathologically undetected nodal metastases (AJCC stage III melanoma). Our group has reported that approximately 14% of ELND specimens that are tumor-negative by routine H&E staining will become tumor-positive when examined by immunohistochemical staining with antibodies to S-100/HMB-45.9
Throughout the last 20 years, there have been great advances in the development of radiological techniques, including magnetic resonance imaging, computed tomography, and ultrasonography; these procedures may have altered the initial staging of these patients. It is likely that patient selection provides a great deal of bias. Patients with any suspicion of distant metastases on radiographic studies, or those with high-risk primaries on the head and neck or torso who can have multiple lymphatic drainage patterns, may have only been offered wide excision alone.
Although the diagnostic utility of LM/SL has been well established,10 its therapeutic value remains unproven. The Multicenter Selective Lymphadenectomy Trial (MSLT), currently in its 7th year, is comparing the survival benefit of adding LM/SL to wide excision as a primary endpoint. We have demonstrated through the creation of a learning phase for this trial that the technique can be transferred from institution to institution; but even with a high degree of accuracy, LM/SL can be technically challenging and is not foolproof.10 Although the MSLT continues with its follow-up (now with >1800 patients entered), we advocate LM/SL as a minimally invasive diagnostic technique to evaluate the tumor status of the regional lymph nodes. However, given our current regimens of adjuvant therapy, it is unclear whether knowing the tumor status of the sentinel node can be parlayed into a survival advantage. Furthermore, the premise that a tumor-negative sentinel node leads to cure is untested, but that is suggested by Dessureault et al. The rapid development of sensitive immunological and molecular techniques eventually may eliminate the need for lymph node sampling and thereby lay to rest the concept of lymph node staging for early-stage melanoma.11,12
(Editorial Note: In the article by Dessureault et al.,7 P values in figures do not match values in text.)
Footnotes
Supported by grant CA29605 from the National Cancer Institute.
Received for publication August 29, 2001. Accepted for publication September 4, 2001.
REFERENCES
This article has been cited by other articles:
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  D. S. Reintgen, J. W. Jakub, S. Pendas, G. Swor, R. Giuliano, and S. Shivers The Staging of Malignant Melanoma and the Florida Melanoma Trial Ann. Surg. Oncol., March 1, 2004; 11(3_suppl): 186S - 191S. [Abstract] [Full Text] [PDF]
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