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Journal of Clinical Oncology, Vol 22, No 4 (February 15), 2004: pp. 617-623 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.06.047
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors' Disclosures of...REFERENCES |
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B in the vascular progression of melanoma.
PATIENTS AND METHODS: A data set of 526 patients from the University of California San Francisco Melanoma Center with 2 years of follow-up or first relapse was studied. The impact of the presence or absence of various prognostic factors on overall survival of melanoma patients was assessed using Cox regression and Kaplan-Meier analysis. A matched-pair analysis of NF-B expression was performed in cases with vascular involvement and increased tumor vascularity versus matched controls lacking these factors.
RESULTS: Cox regression analysis of factors evaluated by the American Joint Committee on Cancer Melanoma Staging Committee reproduced the powerful impact of tumor thickness and ulceration in this data set. With the inclusion of vascular factors such as tumor vascularity and vascular involvement, ulceration was no longer significant in predicting overall survival. By multivariate analysis, vascular involvement and tumor vascularity were the strongest predictors of melanoma outcome. Tumor vascularity seems to be a precursor of both vascular involvement and ulceration. A matched-pair tissue array analysis demonstrated the significant correlation between overexpression of NF-B–p65 and the development of vascular factors.
CONCLUSION: Vascular factors play an important role in the progression of malignant melanoma. Ulceration may be a surrogate marker for the interactions between melanoma and the tumor vasculature. NF-B seems to play an important role in the development of these factors.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors' Disclosures of...REFERENCES |
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Recently, ulceration has been incorporated into the American Joint Committee on Cancer (AJCC) staging classification for cutaneous melanoma [10]. This was based on analyses of large databases that showed reduced survival with the presence of ulceration given a range of tumor thickness [11,12]. In fact, in patients with primary cutaneous melanoma, tumor thickness and ulceration were the most powerful predictors of survival in the T (tumor) category of those analyzed by the AJCC. In the current AJCC staging classification, the T classification is largely stratified by tumor thickness (with breakpoints of 1 mm, 2 mm, and 4 mm) and presence or absence of ulceration. Thus ulceration has been proposed as an important factor that further refines the prognosis of tumors within various thickness ranges within the VGP. Although the prognostic significance of ulceration has been well known, factors that drive its development have been poorly understood. Our recent studies have suggested that ulceration is highly correlated with interactions occurring between the VGP of the primary melanoma and the tumor vasculature, namely vascularity of the primary melanoma [13] and vascular involvement, in which melanoma cells either invade or abut the tumor vasculature [14].
These studies have suggested a model of melanoma progression based on such tumor cell–tumor vasculature interactions. In addition, our recent studies using systemic ribozyme-based targeting in murine models identified the p65 subunit of NF-B as playing an important role in the metastasis of melanoma by virtue of its effects on melanoma cell invasiveness [15]. In this study, we explore the utility of a tumor progression model by further analyzing the interactions between these vascular factors and other prognostic factors in melanoma. Moreover, we examine the correlation between NF-B–p65 expression and the development of these vascular factors using tissue arrays.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors' Disclosures of...REFERENCES |
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Matched Pairs
Twenty-four cases of primary melanoma were selected from this data set (in which the primary tumor blocks were available for analysis) with evidence of vascular involvement and either the moderate or prominent pattern of vascularity. Each case was paired with a control from the data set lacking vascular involvement, demonstrating absent or sparse vascularity, and matched for age, sex, tumor location, histogenetic subtype, tumor thickness, and Clark level. The specifics of the matching are as follows: patients were matched perfectly for sex and tumor location (stratified into head and neck, axial, and extremity); age was matched within two deciles as described by the AJCC [11]. Patients with superficial spreading, nodular melanoma, and melanoma not otherwise classified were grouped together and matched with patients with similar histologies, whereas patients with acral melanoma were matched with patients with identical histology; patients were matched for tumor thickness by being within the same T stage of the AJCC (1 to 2 mm, 2 to 4 mm, and > 4 mm) and matched for Clark level (stratified into levels II and III, and IV and V).
Tissue Arrays
Tissue microarrays were created using methods previously described by Kallioniemi et al [16,17] by taking small tissue core biopsies from donor blocks and relocating them onto a recipient block. Initially, the target areas within the donor blocks containing representative tumor sections were marked on the corresponding hematoxylin and eosin slides. Using a Beecher arraying instrument, a 0.6-mm diameter tissue core was punched by lowering a cylindrical tube with a cutting edge into the donor paraffin block. Subsequently, the contents of the thin cylinder tube were placed in order into the recipient paraffin block. This step was repeated with other donor blocks until a complete grid of tissue cores was created onto the array block. After construction of the block, 5-µm sections were cut using a tissue microtomer. A special tape (Instrumedics, Hackensack, NJ) was placed on the tissue block, and the tape containing the tissue section was laminated onto an adhesive-coated microscope slide to transfer the tissue onto the slide. Finally, the section was UV cross-linked to the slide before removal of the tape using a degreasing agent. Cases were placed adjacent to their matched pair in a random fashion. Two tissue arrays were created to accommodate the 24 matched pairs used in this analysis.
Immunohistochemistry
Immunohistochemical staining of the p65 subunit of NF-B was performed as described [15]. For polyclonal antibody against p65 (Zymed Laboratory, South San Francisco, CA), microwave antigen retrieval was used and blocked with normal goat serum. Rabbit polyclonal immunoglobulin G against a recombinant protein derived from the carboxyl terminal of the human NF-B-p65, diluted at 0.625 µg/mL, was incubated overnight at 4°C. Goat antirabbit immunoglobulin G antibody (Vector Laboratories, Burlingame, CA) was used as a secondary antibody for amplification. Expression of p65 protein was scored as absent (0), slight (1+, < 10% of tumor cells staining positive), moderate (2+, up to 50% of tumor cells staining positive), or prominent (3+, > 75% of tumor cells staining positive) for the candidate marker for the matched pair by a pathologist blinded to the identity of the cases. Specificity controls for p65 staining included the use of both tonsil and prostate tissue.
Statistical Analysis
Statistical methods used to assess the significance of various prognostic factors on the outcome associated with melanoma are as follows: survival curves were generated using the Kaplan-Meier method [18], and differences between Kaplan-Meier curves were assessed using both log-rank and generalized Wilcoxon tests. Multivariate comparisons of the relative contributions of various high-risk prognostic factors were assessed using Cox regression analysis, assuming proportional hazards. In the Cox regression analyses, the various prognostic factors were entered into the model according to data coding criteria previously used and described by the AJCC staging committee [11]. The primary outcome variable used was overall survival. However, because of the high-risk nature of this data set, it is likely that most deaths observed in this cohort were caused by metastatic melanoma. For the tissue array analysis, the potential correlation between NF-B overexpression and the development of vascular involvement and tumor vascularity was tested using the binomial sign test and the Wilcoxon matched-pairs signed-ranks test. Pearson's 
2 test and Fisher's exact test were used to assess the statistical significance of cross-tabulations. The significance of differences between means was assessed via one-way analysis of variance and Student's t test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors' Disclosures of...REFERENCES |
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2 values and associated statistical significance of the various clinical and histologic prognostic factors examined by the AJCC committee, with strikingly similar quantitative risk ratios for the six prognostic factors included in the AJCC analysis (Table 1). These results confirmed the comparability of our data set with the AJCC database for conducting such prognostic analyses.
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Subsequently, we performed a Cox regression analysis that included all factors examined by the AJCC staging committee, in addition to vascular involvement and tumor vascularity. When all eight factors were included in the model, surprisingly, vascular involvement and tumor vascularity emerged as the most significant prognostic factors (Table 2). Age and tumor location were also highly significant. Tumor thickness remained of substantial independent prognostic significance, though with a somewhat diminished impact on overall survival. We also evaluated the role of mitotic index, even though this factor was not analyzed by the AJCC. Addition of mitotic index to the model did not impact the independent prognostic significance of vascular involvement (P = .0044) or tumor vascularity (P = .0062) on overall survival. Intriguingly, mitotic index did not significantly impact survival (P = .57) in this analysis (data not shown). Finally, in the presence of nodal status, vascular involvement continued to have independent prognostic impact on overall survival (data not shown).
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B plays an important role in the progression of melanoma in murine models by virtue of its effects on tumor invasiveness [15]. Given the powerful prognostic impact of vascular involvement and tumor vascularity on melanoma survival, we hypothesized that NF-B expression may impact the development of these vascular factors in human melanoma. To test this hypothesis, we performed a matched-pairs analysis of expression of NF-B–p65 in cases with and without the presence of vascular involvement and increased tumor vascularity. Twenty-four primary human melanomas demonstrating vascular involvement and increased tumor vascularity from this data set (cases) were paired with 24 melanomas without these features (controls) matched for age, sex, tumor location, histogenetic subtype, tumor thickness, and Clark level (Table 3) . Ulceration was not used as a matching criterion, given our data demonstrating the increased prevalence of ulceration with the presence of both vascular factors. The matched pairs were examined for levels of p65 expression using tissue arrays (Fig 2). Immunohistochemical staining of the matched-pair array demonstrated higher levels of p65 protein expression in 17 cases with vascular factors present compared with their matched pair (P = .03). Moreover, the cases more commonly expressed higher levels of p65 protein than the controls (P = .004; Table 4). Thus the level of p65 expression was correlated strongly with the presence of these vascular factors in the matched pairs.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors' Disclosures of...REFERENCES |
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2 values and associated statistical significance of prognostic factors analyzed by the AJCC staging committee, the addition of vascular involvement and tumor vascularity revealed these two prognostic factors to have the greatest impact on melanoma survival. With the inclusion of these factors in the model, ulceration was no longer of independent prognostic value. Taken together with results suggesting that ulceration occurs more commonly with increased tumor vascularity and vascular involvement, our results suggest that ulceration may act as a surrogate for these vascular interactions occurring at the base and within the vertical growth of the tumor. Furthermore, our analysis suggested that increasing tumor vascularity is a precursor of (and possibly a prerequisite for) vascular invasion and incipient invasion (vascular involvement) as well as ulceration. This was supported by the observation that few cases of ulceration or vascular involvement are present without increased vascularity. This suggests that vascular invasion may occur more commonly into angiogenic vessels than preexisting normal vessels. Intriguingly, when increased vascularity was absent, the presence of ulceration did not increase the risk of death. Although this observation may be attributed to a small sample size, it is tempting to speculate that the underlying vascularity of the tumor may be a guide to identifying biologically relevant cases of ulceration, given that ulceration can also be caused by external factors such as trauma and prior biopsy.
Taken together, these results have suggested a model of melanoma progression that attempts to describe crucial factors involved in melanoma metastasis. Our studies indicate that tumor vascularity represents an early step and potentially an initial requirement for further progression in melanoma. This is supported by other studies suggesting that increased vascularity occurs early in melanoma progression [19-21]. With increased tumor vascularity, further tumor progression can result in the development of vascular involvement, and the presence of both of these factors can increase the prevalence of ulceration. Although tumors can metastasize with the presence of increased tumor vascularity alone, the additional presence of either vascular involvement or ulceration further increases the risk of metastasis. Multiple prior studies have indicated that these factors are highly correlated with the development of both regional and distant metastasis [3,4,11-14,22-25].
Finally, these studies provide mechanistic insight into the pathways by which NF-B contributes to melanoma progression. Our results suggest that NF-B plays an important role in the interaction between melanoma cells and the tumor vasculature. Moreover, NF-B overexpression may be required for the development of tumor invasiveness in melanoma. This was suggested by our laboratory studies using ribozyme-based targeting of NF-B in mice that showed a correlation between level of NF-B–p65 expression and melanoma cell invasiveness [15]. Other investigators have shown a link between NF-B and vascularity in the metastasis of melanoma [26]. In addition, NF-B has been shown to be activated in various human melanoma cell lines [27,28], and activated in metastatic melanomas when compared with normal melanocytes [29]. To our knowledge, however, this is the first study to suggest the impact of NF-B on melanoma cell invasiveness, and on the development of vascular factors, directly in human melanoma samples. Given the dominant impact of vascular invasion on survival in this and other studies [14,24,25], these results suggest that NF-B may be a novel molecular marker of melanoma outcome. Moreover, given its role as a transcriptional activator, it will be important to determine genes downstream of the NF-B signaling pathway that mediate its effects on the vascular progression of melanoma. In this regard, recent studies indicating the role of tumor lymphangiogenesis as a novel mechanism of tumor progression are of interest in potentially characterizing the nature of the vessels recorded in this study [30]. Intriguingly, NF-B has been shown to regulate vascular endothelial growth factor C [31], which has been implicated in lymphangiogenesis [30]. Ultimately, NF-B may be important as a prognostic factor in melanoma because it can regulate several tumor progression pathways, including tumor cell adhesion, apoptosis, cell cycle, and lymph/angiogenesis [26,31-34]. Finally, other molecules with known importance in melanoma that may mediate some of the vascular effects observed here include interleukin-8 [35] and MUC18 [36].
In summary, we have explored the utility of a model of melanoma progression using vascular factors, given the powerful impact of these factors on the overall survival associated with melanoma. These studies suggest the requirement of increased tumor vascularity for melanoma progression, given that the development of both ulceration and vascular invasion are dependent on it. Moreover, these results suggest that ulceration may be a surrogate for these tumor cell-tumor vasculature interactions. Finally, our results implicate NF-B in the vascular progression of melanoma, suggesting its role as a possible molecular prognostic factor of melanoma outcome.
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Authors' Disclosures of Potential Conflicts of Interest |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors' Disclosures of...REFERENCES |
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Acknowledgment |
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NOTES |
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Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors' Disclosures of...REFERENCES |
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Submitted June 12, 2003; accepted December 4, 2003.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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B in the Vascular Progression of Melanoma
