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Journal of Clinical Oncology, Vol 23, No 16 (June 1), 2005: pp. 3864-3865 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.382
In Reply:Surgery Branch, National Cancer Institute, National Institutes of Health Bethesda, MD
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY We thank Dr Wascher for his comments on our article. He raises several important concerns that we share and have described in the discussion of our manuscript. It is critical, however, to place these issues in context with the goals of our serial investigation and, thus, we will address each of his main points. With respect to concerns regarding our histologic analysis, appropriate clinical conduct prevented retrospectively performing step-sectioning and immunohistochemistry (IHC) on sentinel lymph nodes (SLNs) from patients who had originally been found to have negative SLNs with hematoxylin and eosin (H&E) and who were still free of recurrence. Nevertheless, our total percentage of patients found to have disease detected in their SLN by histologic methods (13%) is consistent with six previously published studies (range, 11% to 23%; Table 6 in Kammula et al).1 Further, the percentage of patients in our polymerase chain reaction (PCR) and histology-stratified cohorts is similar to those from multiple other institutions.2-5 Dr Wascher expressed concern that our recent cohort of patients evaluated with IHC did not show "upstaging" when compared to the older H&E cohort. Absence of upstaging, however, is impossible to determine from two temporally different cohorts, unless the same cohort of patients underwent both H&E and IHC in a blinded fashion. Further, it is unclear from broad multi-institutional experience whether histologic upstaging with advanced pathologic analysis (IHC) has truly demonstrated increased prognostic relevance when compared with traditional H&E analysis. In fact, reverse-transcriptase (RT) -PCR staging studies of melanoma SLNs from a single center performed in the era before IHC2 and, subsequently, with IHC4 showed comparable prognostic findings, although there was pathologic upstaging noted with the use of IHC. For these reasons, we believe that our histologic analysis is acceptable for the purpose of evaluating the impact of RT-PCR staging on our cohort. With regard to the main methodological concern, our study did focus on only tyrosinase mRNA expression as a marker of occult melanoma SLN metastases. Evaluation of this single melanoma-associated gene served to validate and provide long-term clinical follow-up to similarly designed and reported trials,2-5 which found prognostic benefit for a single-marker tyrosinase mRNA assay. In fact, the stratified recurrence rates between our series, calculated at the 42-month period, were quite remarkably comparable to outcomes from the six previously published studies with equal or less follow-up (Table 6 in Kammula et al). However, after an additional 2 years of observation of our cohort (median follow-up of 67 months), we found the predictive value for the presence of tyrosinase mRNA was no longer significant. With respect to technical concerns, there certainly exist limitations that we have described involving this RT-PCR assay, as well as, with other molecular assays that have been published. In fact, our reporting of a defined false-positive rate for our assay is a critical disclosure that has not been commonplace with other reports utilizing RT-PCR staging. These limitations further emphasize the importance of our sequential comparison of a single cohort of patients staged by a uniform molecular methodology. This type of analysis serves to highlight the experimental variable of duration of follow-up and exemplifies the potential pitfalls of early data reporting. We agree that both multimarker RT-PCR assays and quantitative RT-PCR represent novel methods to potentially enhance the sensitivity and specificity of occult disease detection in SLN evaluation. The important cutting-edge application of these technologies and the evaluation of paraffin-embedded specimens in retrospective SLN analyses have been reported6 but their clinical relevance is only now being evaluated broadly in prospective SLN trials and, thus, remains insufficiently validated. Invariably, certain older technologies will and should be justifiably superceded by newer ones that have proven evidence of clinical relevance. This, in fact, represents the true nature of sound research and development. New technology, however, should not be misconstrued as necessarily better without comprehensive validation studies conducted by different research groups. As a consequence, the desire for advancement of technology should not distract the reporting of long-term prospective studies involving older technologies that attempt to validate previous observations, generate new hypotheses, and reintroduce important "old" concepts, such as the value of mature follow-up. Although the aforementioned newer techniques as well as the next generation of molecular assays (such as microarray profiling) may prove to be more accurate in the detection and characterization of occult metastases, we conclude from the results of our analysis a technology-independent phenomenon, "Future studies evaluating molecular staging will necessitate suitable long-term median follow-up (approximately 5 years) to provide clinically relevant information to define outcome for patients with occult melanoma metastases."1 In essence, the technologies may advance, but the biology stays the same. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Kammula US, Ghossein R, Bhattacharya S, et al: Serial follow-up and the prognostic significance of reverse transcriptase-polymerase chain reaction–staged sentinel lymph nodes from melanoma patients. J Clin Oncol 22:3989-3996, 2004
2. Shivers SC, Wang X, Li W, et al: Molecular staging of malignant melanoma: Correlation with clinical outcome. JAMA 280:1410-1415, 1998 3. Blaheta HJ, Ellwanger U, Schittek B, et al: Examination of regional lymph nodes by sentinel node biopsy and molecular analysis provides new staging facilities in primary cutaneous melanoma. J Invest Dermatol 114:637-642, 2000[CrossRef][Medline] 4. Li W, Stall A, Shivers SC, et al: Clinical relevance of molecular staging for melanoma: Comparison of RT-PCR and immunohistochemistry staining in sentinel lymph nodes of patients with melanoma. Ann Surg 231:795-803, 2000[CrossRef][Medline] 5. Goydos JS, Patel KN, Shih WJ, et al: Patterns of recurrence in patients with melanoma and histologically negative but RT-PCR-positive sentinel lymph nodes. J Am Coll Surg 196:196-204, 2003[CrossRef][Medline]
6. Takeuchi H, Morton DL, Kuo C, et al: Prognostic significance of molecular upstaging of paraffin-embedded sentinel lymph nodes in melanoma patients. J Clin Oncol 22:2671-2680, 2004
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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