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© 2002 American Society for Clinical Oncology Implications of Microscopic Satellites of the Primary and Extracapsular Lymph Node Spread in Patients With High-Risk Melanoma: Pathologic Corollary of Eastern Cooperative Oncology Group Trial E1690ByFrom the Departments of Pathology and Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Melanoma Center, University of Pittsburgh Cancer Institute Pittsburgh, PA; Department of Biostatistics, Dana-Farber Cancer Institute, Boston, MA; Wayne State University, Harper-Grace Hospitals, Detroit, MI; and University of Chicago Medical Center, Chicago, IL. Address reprint requests to Uma N.M. Rao, MD, Professor of Pathology, University of Pittsburgh School of Medicine, Presbyterian-University Hospital, 200 Lothrop St, Pittsburgh, PA 15213-2582; email: raounm{at}msx.upmc.edu
PURPOSE: To correlate the presence of extracapsular spread (ECS) of regional nodal metastases, and micrometastasis near the primary tumor, with disease outcome in the intergroup study E1690 in relation to the impact of recombinant interferon-alfa (rIFN  )-2b.
PATIENTS AND METHODS: E1690 included 642 patients with American Joint Committee on Cancer stage IIB or III cutaneous melanoma. Patients were randomized into high- and low-dose rIFN RESULTS: Ulceration, mitotic activity, thickness, and size of tumor-bearing lymph nodes did not show a statistically significant correlation with either OS or RFS across all treatment arms. The presence of MS was correlated with RFS (P = .0008) and OS (P = .05). ECS correlated with RFS (hazard ratio = 1.44, P = .032) but not OS (P = .11). CONCLUSION: The presence of MS (in 6% [18 of 308 patients]) had a significant adverse impact on both RFS (P = .0008) and OS (P = .053). Ulceration, mitotic activity, thickness, and number of positive lymph nodes had no significant effect on OS in this subset study (univariate or multivariate Cox analysis). The presence of ECS in lymph nodes had a significant adverse effect on RFS (P = .032) but not on OS.
MELANOMA COMMONLY metastasizes to lymph nodes, and occult metastases are detected in up to 25% of patients when appropriately studied.1-6 The prognosis of lymph node metastatic melanoma (stage III) is dependent on the number of the nodes involved and the extent of involvement within nodes, not the size of involved lymph nodes.7-12 In almost all multifactorial analyses of melanoma, the presence of lymph node metastases and the number of lymph nodes involved with tumor have proved to be the most important predictors of survival.7 New parameters of prognostic significance are needed to dissect and further refine the pathologic assessment of melanoma. A number of pathologic features associated with the biologic behavior of a tumor may be important in determining clinical outcome beyond the current algorithm. One of these features is the histologic presence of extracapsular spread (ECS) of tumor in regional lymph nodes. The exact relationship of ECS to the characteristics of the primary tumor is not known.4,13-17 Although small nodes with tumor can demonstrate ECS, it is more common with a larger nodal tumor burden in patients with squamous cell carcinoma. ECS is associated with an increased risk of regional recurrence and has been taken as an indication for postoperative adjuvant radiation therapy for head and neck, vulvar, and bronchogenic squamous cell carcinoma.18-24 There are no known primary histologic features in primary melanoma that predict ECS. In the new American Joint Committee on Cancer (AJCC) staging system, nodal disease is stratified into two groups on the basis of the presence of microscopic, as opposed to macroscopic, metastases including ECS in the latter category of lymph node disease.11,12,25 These data, based on analysis of 17,600 melanoma patients, show 5-year overall survival (OS) of 69.5% and 63%, respectively, for patients with microscopic involvement in 1, 2, or 3 (IIIA) nodes in the absence of ulceration and a 5-year survival of 52.8% and 49.6% when the primary tumor was ulcerated (IIIB). Diverse clinical courses may be observed in patients with nodal involvement that exhibits similar characteristics when judged by current criteria in AJCC stages IIIA, B, and C.12 Although satellite lesions, defined as cutaneous metastases occurring within 2 cm of the primary in the older AJCC staging system, were categorized as T4b, the presence of microscopic satellites (MS) in the vicinity of the primary tumor has not been evaluated systematically.26-28 In this study, we evaluated the presence of MS, ulceration, and mitotic activity in the primary and ECS in lymph nodes in a series of uniformly treated and completely staged patients who participated in the intergroup trial E1690.
A total of 642 patients were accrued in the intergroup protocol E1690/S9512/C9190. Eligibility criteria included T4N0M0 primary melanoma with or without lymphadenectomy, T1 to 4 primary N1M0 with nonpalpable nodal involvement proved at lymphadenectomy, T1 to 4 primary melanoma with clinically overt regional lymph node metastases confirmed by lymphadenectomy, and T1 to 4 primary tumors with regionally recurrent lymph node metastasis. The older version (1997) of the AJCC staging system for cutaneous melanoma was used in this study, which was conducted between 1990 to 1995. The pathology material included histologic slides of the primary lesion containing its deepest level of invasion, all surgical margins and sections of tumor-bearing lymph node, and uninvolved nodes. The pathology material was accompanied by the corresponding pathology report from the primary originating institution. The pathology report specified the site and total number of nodes removed and the number that contained metastases. The data were entered and analyzed by the Eastern Cooperative Oncology Group biostatistics facility (J.I.). The submitted pathology slides were evaluated by the pathologist (U.N.M.R.) who had no knowledge of patient outcome. All observations, including presence of ulceration, tumor thickness, mitotic activity, and MS, were recorded on a standard pathology form. Mitotic activity was evaluated in 10 nonoverlapping (40x) high-power fields in the sections submitted. The presence of ulceration and MS near the primary tumor was identified using previously defined criteria.26 On evaluation of a positive lymph node, any histologic breach of the capsule with tumor extension into adjacent soft tissue was regarded as ECS. In most cases, at least two sections of the tumor-bearing lymph node were evaluated. However, in some instances, the lymph node capsule was not sampled; therefore, ECS could not be determined with certainty and these sections were excluded. Artifacts attributable to knife carry-over were excluded. The completed pathology forms were submitted for multivariate statistical analysis and correlated with relapse-free survival (RFS) and OS using logistic regression. Of 642 patients accrued, information for all four parameters—ulceration of primary lesion, mitotic activity, MS, and ECS—was available for half of the patients. The three arms of the clinical trial (A = high-dose interferon [IFN; HDI], B = low-dose IFN [LDI], and C = observation only [OBS]) were categorized separately. The number of patients with missing information for each parameter (ulceration, mitotic activity, thickness, ECS, and MS) was variable, probably attributable in part to the reasons cited earlier, and not all of the categories had the same degree of missing information, which accounted for the slight discrepancies in the actual number analyzed in each category.
The 642 patients accrued in E1690 included approximately 200 patients who were T4N0M0. In the remaining patients, a total of 324 were identified with ulceration in arm A (66 of 114), arm B (69 of 101), and arm C (66 of 109). The presence of ECS in lymph nodes was evaluated in 291 patients, in whom ECS was found among arm A (27 of 89), arm B (29 of 110), and arm C (19 of 92). MS were assessable in 308 patients, who were equally distributed in all three arms. A total of 18 patients across all treatment arms fulfilled the criteria for the diagnosis of MS. When examined across all treatment arms, the presence of ulceration and mitotic activity was not a significant predictor of either RFS or OS in this data set. The presence of MS was significantly correlated with RFS (P = .0008) and OS (P = .05). ECS was correlated with RFS (hazard ratio [HR] = 1.44; P = .032) but not with OS (P = .11). The number of positive nodes did not correlate with the presence of ECS or with the presence of ulceration. No other feature studied showed a significant correlation with OS or RFS (Table 1). A multivariate model was developed to examine the impact of HDI and LDI, adjusting for the influence of these factors. The HRs and P values for individual treatment arms for all of the variables studied are listed in Table 2. Details of the Cox regression analysis and Kaplan-Meier plots are displayed in Figs 1 through 6. Presence of MS was determinant across all treatment arms of RFS (HR = 2.49; P = .0008) and OS (HR = 1.80; P = .053). Breslow thickness was analyzed for each arm and for all arms combined. Tumor thickness was not significant in univariate or multivariate Cox analysis in relation to either RFS or OS. A Cox regression analysis, adjusting for prognostic variables, including ulceration, mitotic activity, MS, and ECS, found differences in RFS between LDI and HDI when compared with OBS as previously reported.29 RFS and OS differences in the pathology subset evaluated mirrored the results of the larger study from which this sample was drawn but did not achieve significance in the pathology study subset because of the small numbers involved.
The clinical stage and thickness of primary cutaneous melanoma at initial diagnosis are the most important prognostic factors. Many studies have suggested that high mitotic activity and ulceration in cutaneous melanoma carry an adverse prognosis30-32 and that ulcerated primary melanoma has an increased risk of sentinel node involvement.33-37 Ulceration therefore has been included in the new AJCC staging system for melanoma.11,12 In a recent analysis of 1,062 patients who had primary melanomas thicker than 1 mm and underwent sentinel lymph node dissection, the status of the lymph node was the most important factor that determined survival. Tumor thickness of 4 mm also had an impact on survival, but the impact of ulceration in this study was of borderline significance.38 Our multivariate analysis, incorporating ulceration and mitotic activity, showed significant differences (P = .03) between the relapse outcome for those patients with ulceration as compared with those without. These data are at variance with the recently published version of the AJCC staging of cutaneous melanoma12 and may be because this study focused exclusively on patients who had lymph node involvement to determine the importance of ECS of nodal tumor and the presence of MS near the primary tumor. We correlated the presence of these features with ulceration and Breslow thickness of the primary tumor. Of the 642 patients, one-quarter were T4 with no evidence of regional lymph node metastases, and some were excluded from statistical analysis for various reasons. This decrease in total patients reviewed as well as the heterogeneous primary tumor population of different tumor thicknesses that had lymph node metastases (T1 to 4 N1) that were entered into this study might have had an impact on the lack of significance for ulceration and thickness because of the smaller number of patients in each category. One may also speculate that in tumors in this particular study that had a predominance of macrometastases in lymph nodes, ulceration and thickness were not statistically significant independent variables. Matting and confluence of adjacent nodes with ECS are widely regarded as ominous signs.10,15,17 ECS is not generally found with microscopic foci of lymph node involvement and, thus, may reflect tumor burden rather than the inherent biologic properties of the tumor. In this series drawn from a prospective intergroup trial, 75 of 290 patients had histologically documented ECS (approximately 27%). The presence of ECS also was not found to correlate with number of positive nodes or with the presence of ulceration. Although patients with ECS were more likely to relapse compared with those without ECS, ECS did not correlate with OS. In this study, the amount of tumor present within the lymph nodes was not quantitated objectively and thus will be evaluated prospectively in future studies. Considering the importance of this finding, however, we recommend careful histopathologic examination of all surgically excised tumor-bearing lymph nodes for presence of ECS. This study also evaluated the presence of MS, defined as a nodule of melanoma located in the reticular dermis or fat and clearly separated from the tumor in the same section in which the Breslow depth was measured but > 0.05 mm discontinuous from it. The incidence of MS ranges from 8% to 14% in the literature.26-28 Patients with MS have been reported to have an increased likelihood of regional cutaneous metastases, nodal metastases, overall relapse rate, and mortality. Only 18 patients from the three treatment arms of E1690 demonstrated MS. The Kaplan-Meier plots demonstrated significant differences (P < .001) for RFS and OS between patients with and without MS. The HR for relapse with MS in this study was 2.49 (P = .0008). The presence of MS might be anticipated to be associated with local or in transit regional recurrence, but the number of patients evaluated in this series is small, and this will bear further evaluation in future studies as efforts to reduce the current guidelines for surgical margins are undertaken. This finding also supports the inclusion of satellite lesions into pathologic stage III in the new AJCC staging system for cutaneous melanoma.12
A final objective for the assessment of the pathologic features of melanoma here has been to identify discriminants of therapeutic relevance: here, specifically the benefit from intervention from high-dose IFN
Supported in part by Public Health Service grant nos. CA23318, CA66636, CA21115, CA39229, CA14028, and CA32102 and from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services, Bethesda, MD.
The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
