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Impact of Ulceration in Stages I to III Cutaneous Melanoma As Staged by the American Joint Committee on Cancer Staging System: An Analysis of the German Central Malignant Melanoma Registry

From the Department of Dermatology, Skin Cancer Program, Central Malignant Melanoma Registry of the German Dermatological Society, Eberhard-Karls-University of Tuebingen, Tuebingen, Germany; and Skin Cancer Research Group, School of Public Health and Tropical Medicine, James Cook University, Townsville, Australia

Address reprint requests to Claus Garbe, MD, Department of Dermatology, Eberhard-Karls-University, Liebermeisterstrasse 25, D-72076 Tuebingen, Germany; e-mail: claus.garbe{at}med.uni-tuebingen.de

	ABSTRACT

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PURPOSE: In 2001, the new American Joint Committee on Cancer classification of cutaneous melanoma (CM) introduced ulceration of the primary melanoma as a new key parameter being represented in respective subcategories of the tumor (T) classification. The present study was performed to validate the prognostic significance of ulceration in relation to T thickness and clinical stages of CM (stages I to III).

PATIENTS AND METHODS: Patients (N = 15,158) with incident invasive primary nonmetastatic CM and follow-up data recorded between 1976 and 2000 by the German Central Malignant Melanoma Registry were investigated using survival analysis to evaluate prognostic factors such as T thickness, level of invasion, body site, histologic subtype, ulceration, regression, age, and sex.

RESULTS: Comparisons of survival probabilities according to the Kaplan-Meier method between ulcerated and nonulcerated CM were not statistically significant for subgroups with T thickness 1 mm and more than 4.00 mm (P = .2601 and P = .0699, respectively) but were significant for T thickness of 1.01 to 2.00 mm and 2.01 to 4.00 mm (P < .0001 for both). This result was confirmed in the multivariate analysis. For stage III CM, the impact of ulceration on overall survival was statistically significant in the bivariate Cox model (P = .0111) but not in the multivariate Cox model (P = .0522).

CONCLUSION: Whereas ulceration seems to have a negative impact on the prognosis of patients with stages T2 and T3, a potential influence for patients with stages T1 and T4 could not be established. If factors of the primary CM were to be taken into consideration to judge prognosis of stage III CM, T thickness but not ulceration should be the focus.

	INTRODUCTION

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In 2001, an updated staging system for cutaneous melanoma (CM) was proposed by the American Joint Committee on Cancer (AJCC) melanoma group,¹ replacing the former classification dating back to 1987.² Basically, the new staging system still depends on the well-established tumor-node-metastasis system classification, but significant changes were introduced. For nondistant CM, the current classification covers tumor (T) thickness, ulceration, satellite and distant metastasis, the number of involved lymph nodes, and the kind of lymph node metastasis (micro- v macrometastases). Clark’s level of invasion is currently only considered for CM with a T thickness 1.0 mm.

Especially in the T classification, major changes concerning the cutoffs of T thickness were performed in the T1 to T3 categories, whereas the T4 category remained the same. In the new staging system, the T category thresholds were chosen in whole integers (1.0, 2.0, and 4.0 mm) as initially suggested by Büttner et al³ and Buzaid et al.⁴ Accordingly, the new T classification differentiates between four different subgroups of T thickness ( 1.0 mm, 1.01 to 2.0 mm, 2.01 to 4.00 mm, and > 4.0 mm).

Ulceration was introduced as a new key parameter because of its significant impact in the multivariate analysis of the data on which the new classification was based.⁵ Ulceration is now represented by its own subgroups (T1b, T2b, T3b, and T4b). The detection of ulceration now implies, in two cases, an upgrade in the subcategories (T1a/b: IA to IB; T3a/b: IIA to IIB) and, in one case, an upgrade in the major categories (T2a/b: IB to IIA). Additionally, a new subcategory for T4b (IIc) was established. It has been estimated that approximately one fourth of patients are upstaged as result of ulceration according to the new classification system.⁶

The prognostic relevance of ulceration in primary CM concerning overall survival was first noticed by Allen and Spitz⁷ and by Tompkins⁸ in 1953 and was confirmed by numerous reports published in following decades.^9-12 However, this prognostic significance could not be verified by all investigators.^13-15 In a meta-analysis of 54 studies on prognostic factors of CM, Vollmer¹⁶ found 20 studies in which ulceration was considered a significant parameter, whereas in 25 studies, ulceration was considered nonsignificant. Nine studies were not assessable.

In the AJCC staging system, ulceration of the primary CM is defined as "an absence of an intact epidermis overlying a major portion of the primary CM based on microscopic examination of the histologic sections."¹ However, an absence of the epidermis could also be an artifactual result of scratching by the patient, or it could imply previous traumatic surgery. The pathologist is left with the uneasy task to distinguish between trauma-induced, artifactual, or T-related ulceration.⁶ The present definition of ulceration does not seem to guarantee either precise diagnosis or high interobserver reproducibility.⁶ In the present evaluation, the role of ulceration as a prognostic factor of invasive CM and the disjunctive ability of the newly introduced categories of T thickness were investigated based on data of the German Central Malignant Melanoma Registry.

	PATIENTS AND METHODS

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Patients
The German Dermatological Society officially founded the Central Malignant Melanoma Registry as a clinical-based melanoma registry. It developed into a large multicenter project. During the 25 years between 1976 and 2000, a total of 25,737 incident invasive CMs with follow-up were recorded from over 80 departments of dermatology in Germany (including data from the former German Democratic Republic and from the former Federal Republic of Germany), Austria, and Switzerland. The current analysis included only the first invasive CM per patient with recorded follow-up time of 3 months or greater. Patients with multiple lesions were excluded. Follow-up time was cut to a maximum of 10 years because patients usually participate in the CM follow-up program for a maximum of 10 years, whereas afterwards, only patients with progressive disease are regularly documented, and little information can be retrieved for patients without recurrences. Histopathologic reports of the responsible dermatopathologist of the respective hospitals were documented within the present study. No independent review process of the histopathologic reports was performed; however, there is a continuous medical education of dermatopathologist as organized by the German Dermatologic Society.

Statistical Analysis
Follow-up time was defined as date of last follow-up or date of death minus date of operation. Follow-up time was truncated after 10 years and was described as a median value with interquartile range (IQR). Only deaths caused by malignant CM as recorded in the registry were considered during survival analysis. Ten-year survival probabilities with respective 95% CIs were calculated according to the Kaplan-Meier method and were compared with log-rank test statistics. Figures of survival probabilities were calculated according to the actuarial method using 1-year intervals for reasons of convenience.

Multivariate Cox modeling was used to compare the former and current T classifications statistically with respect to their prognostic impact by adjusting for other prognostic factors. In preparation, categoric prognostic variables (sex, body site, histologic type, and ulceration) were dummy coded. T thickness, level of invasion, and the two classification variables were stepwise coded to allow a statistical judgment of separation. Stepwise coding implies that a given P value refers to a statistical judgment of the difference to the previous category. Hierarchical models were directly compared by means of overall log-likelihood (LL) values (–2 LL).¹⁷ Multivariate Cox modeling was also used to judge the impact of ulceration in the strata of T thickness (1 mm, 1.01 to 2.00 mm, 2.01 to 4.00 mm, and > 4.00 mm). Other potential prognostic factors considered in this process were age, sex, body site, histologic type, level of invasion, and T thickness.

Comparisons of T classifications and impact of ulceration were initially conducted using exclusively complete data sets (n = 15,158 of 23,868 incident invasive primary nonmetastatic CM). In particular, there were 7,101 CM (29.8% of 23,868) missing values for ulceration, mainly in the early-registered patients. Therefore, for a second analysis, the missing values of ulceration were estimated by using the result of a multivariate logistic regression analysis that was constructed to predict ulceration (yes or no) by means of the other prognostic factors. This logistic regression model was based on 16,691 patients and predicted the log(odds) for ulceration with the following formula: –5.7021 + 0.0189 x (age) + 0.1873 x (male sex) + 0.5684 x (anterior trunk) + 0.3077 x (posterior trunk) + 0.3659 x (lower extremities) + 1.4935 x (level III) + 2.4566 x (level IV) + 2.9147 x (level V) + 1.7418 x (level missing) + 1.4847 x (nodular melanoma) + 1.3282 x (acral lentiginous melanoma) + 0.4635 x (histologic type missing) + 0.0415 x (T thickness). The overall correctness of prediction of this model was 86.1%. Of the 7,101 missing values for ulceration, this model predicted 347 (4.9%) to be ulcerated CM. The lower percentage of patients with estimated ulceration in the group with missing data on ulceration may be a result of the following effect. If ulceration is present, it is highly likely that it will be recorded in the histopathologic report. However, if ulceration is absent, this may be reported less frequently. This may be the explanation for why the group with missing values for ulceration overall had a lower prevalence of (estimated) ulceration.

Statistical analysis was performed using SPSS for Windows, version 6.3.1 (SPSS, Inc, Chicago, IL). Throughout the analysis, a significance level of P = .05 was assumed.

	RESULTS

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Of the 25,737 patients with incident invasive CM with follow-up, 23,868 patients (93.7%) had a primary nonmetastatic CM, 2.0% had satellite or in-transit metastases, 3.3% had regional lymph node metastases, and 1.0% had distant metastases.

Basic Description of Invasive Primary Nonmetastatic CM
Overall, 57.1% of patients were female (Table 1). The majority (56.4%) of CM was 1 mm in thickness, and 62.7% were superficial spreading melanomas. The median follow-up time was 4.0 years (IQR, 2.0 to 7.3 years), and 6.9% of the patients died from CM.

View larger version (24K): [in this window] [in a new window]   Fig 1. Cumulative survival probabilities of 15,158 incident invasive primary nonmetastatic melanoma patients with complete data stratified according to the old T classification. P value was result of a log-rank test.

View larger version (33K): [in this window] [in a new window]   Fig 2. Cumulative survival probabilities of 15,158 incident invasive primary nonmetastatic melanoma patients with complete data stratified according to the new T classification. P value was result of a log-rank test.

View larger version (22K): [in this window] [in a new window]   Fig 3. Prevalence of melanoma ulceration in categories of tumor thickness for 15,158 patients with incident primary invasive melanoma.

Using the predicted and observed ulceration allowed us to repeat the analysis with 21,191 incident invasive primary nonmetastatic CMs with complete data sets. The results in the section Prognostic Importance of Predicted and Observed Ulceration Together, were all confirmed for this data set, but survival probabilities according to the Kaplan-Meier method were significantly different for ulceration (yes v no) for CM greater than 4.00 mm (P = .0173). However, in multivariate Cox modeling for this T thickness, ulceration remained nonsignificant (P = .0820).

Prognostic Importance of Ulceration in Stage of Lymph Node Metastases: Clinical Stage III
In 1,195 patients (63.9%) who developed lymph node metastases (n = 1,869), the presence or absence of ulceration of the primary lesion was documented (median observation period from time of diagnosis of lymph node metastasis, 1.8 years; IQR, 0.9 to 3.9 years). Of these patients, 44.4% died as result of CM. In the bivariate analysis,there was a significant decline in 10-year survival probabilities from the time point of diagnosis of lymph node metastases for patients with ulceration of the primary CM compared with patients with absence of ulceration (P = .0111). However, in the multivariate Cox model, ulceration remained nonsignificant (P = .0970), whereas T thickness remained the strongest negative parameter (P = .0211; Table 5).

	DISCUSSION

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In general, ulceration in thin CM is a rare attribute. In the present cohort of 8,961 CM patients with a T thickness 1.00 mm, the prevalence of ulceration was 2.5% and clearly lower compared with the previously published results of the AJCC (6%)⁵ and data by McKinnon et al²⁰ (4.2%). However, there was an overlap between those two cohorts from surgical departments.

The prognostic relevance of ulceration in thin CM is currently controversially discussed. In the present analysis, the 10-year survival rate for patients was not significantly different for patients with (95.5%) or without (96.4%) ulcerated thin primary CM. In contrast, Balch et al,⁵ McKinnon et al,²⁰ and McCarthy et al²¹ reported a significant impact of ulceration concerning overall survival or disease-free survival for patients with thin CM in their evaluations. In the study of Balch et al,⁵ the 10-year survival rate was 76% for patients with ulcerated primary CM compared with 86% for patients with nonulcerated primary CM (P < .0001). Similarly, the analysis by McKinnon et al²⁰ of 2,187 patients of the Sydney Melanoma Unit showed that the 10-year survival rate for patients with ulceration was significantly worse than for patients without ulceration (84% v 92.3%, respectively). However, because of the embedding of the Australian data of McKinnon et al²⁰ into the cohort of Balch et al,⁵ these two studies cannot be considered as completely independent. Similarly, a study of thin CM conducted by Kalady et al²² showed that the presence of ulceration did not deteriorate the overall survival significantly.

The prevalence of ulceration is strictly increasing with incremental T thickness,⁵ and in the present cohort, the prevalence of ulceration in T2 and T3 CM increased in parallel with T thickness as expected. Within the present study in patients with ulcerated T2 CM, a significant decline was detected in the 10-year survival rate by 6.3%. These results were more favorable than in the data presented by Balch et al.¹ Concerning patients with a T thickness of 2.01 to 4.00 mm, the present study found a prevalence of ulceration of the primary CM in 38.7% of our patients. Patients without ulceration of the primary CM had a significantly advantageous 10-year survival rate compared with patients with ulcerated CM (76.9% v 67.1%, respectively). Again, these results were more favorable than comparable data by Balch et al.¹

Expectedly, the prevalence of ulceration was highest for thick CM (> 4.00 mm T thickness). In the present cohort, 55.2% of these thick CM were ulcerated. In their cohort of 126 patients with thick CM, Ferrone et al²³ found a prevalence of ulceration of 42.8%. In the present cohort, the 10-year survival rate for patients with nonulcerated thick CM was 65.7% compared with 61.7% for patients with ulcerated thick CM, whereas the 10-year survival rates in the evaluation by Balch et al⁵ were 53.9% and 32.3%, respectively, and therefore, dramatically inferior to the present results. Additionally, in contrast to observations by Balch et al,⁵ the present results of ulceration of thick CM were nonsignificant in bivariate and multivariate analysis.

Why the cumulative survival rates differed to this degree between the AJCC database and the Central Malignant Melanoma Registry database is an interesting question. There are two possible explanations that may both contribute. First, the AJCC database obviously dates back from 1955 and compromises patients from decades with less standardized CM management procedures. Second, there may be differences between patient collectives primarily presenting to dermatologists or to surgical oncologists, with a tendency for less favorable prognostic factors and outcome for the patients first presenting to a surgeon. In addition, there is a general trend toward prognostically more favorable melanomas (Büttner et al, submitted for publication), implying that ulceration is likely to be less prevalent in future melanoma patients and further reducing its overall prognostic impact.

The new AJCC staging system also proposed to include ulceration as an independent prognostic factor concerning patients in stage III of the disease.¹ However, the analysis of the present cohort could not confirm the importance of ulceration in those patients. Similarly, Gershenwald et al²⁴ could not establish an impact of ulceration of the primary CM in patients with at least one positive sentinel node. The results of the present analysis suggest that T thickness, but not ulceration, should be considered an important prognostic factor for patients with stage III CM.

On the basis of our results, we would propose the following changes of the present AJCC/International Union Against Cancer staging system for CM. The difference between T1a and T1b based on ulceration should be removed. The difference between T4a and T4b should likewise be removed; therefore, the separate stage IIC can be waived. The upstaging in stages IIIA and IIIB based on the ulceration of the primary T should be cancelled. This would clearly simplify the AJCC/International Union Against Cancer staging system and make it easier to apply for the clinician.

In conclusion, the present analysis confirmed ulceration as a prognostic factor of CM. However, the prognostic impact of ulceration must be separately reviewed depending on the category of T thickness. Although there seems to be a significant decline in overall survival for patients with ulcerated CM and a T thickness between 1.01 and 4.00 mm, no important impact of ulceration could be detected for thin and thick CM. Additionally, for patients with lymph node metastases, the influence of ulceration of the primary CM on overall survival could not be confirmed in the multivariate analysis. According to the multivariate Cox model, T thickness was the most relevant parameter and should be assessed. We suggest including these considerations for an upcoming revision of the AJCC melanoma staging system to simplify this rather complicated and difficult to use classification.

	Authors’ Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Acknowledgment

 
The following Departments of Dermatology were major contributors (> 500 patients) to the Central Malignant Melanoma Registry of the German Dermatological Society: University of Berlin (Charité) (Chair: W. Sterry), Free University of Berlin (Chair: C.E. Orfanos), Berlin-Neukölln (Chair: P. Kohl), Chemnitz (Chair: J. Koch), Dortmund (Chair: P. Frosch), Dresden-Friedrichstadt (Chair: U. Wollina), University of Dresden (Chair: M. Meurer), Erfurt (Chair: R. Linse), University of Erlangen (Chair: G. Schuler), University of Essen (Chair: H. Goos), University of Freiburg (Chair: L. Bruckner-Tudermann), Gera (Chair: J. Meyer), University of Göttingen (Chair: Ch. Neumann), University of Graz (Chair: H. Kerl), University of Greifswald (Chair: M. Jünger), University of Hamburg (Chair: I. Moll), Hamburg-St. Georg (Chair: C. Sander), Hildesheim (Chair: H. Vakilzadeh), University of Heidelberg (Chair: D. Petzold), University of Heidelberg/Mannheim (Chair: S. Goerdt), University of Homburg (Chair: W. Tilgen), University of Jena (Chair: P. Elsner), Kassel (Chair: R. Rompel), University of Kiel (Chair: E. Christophers), Krefeld (Chair: S. Wassilew), University of Leipzig (Chair: J. Simon), University of Lübeck (Chair: H.H. Wolf), University of Magdeburg (Chair: H. Gollnick), Minden (Chair: R. Stadler), University of Munich (Chair: G. Plewig), University of Münster (Chair: Th. Luger), Nürnberg (Chair: E. Paul), University of Tuebingen (Chair: M. Röcken), University of Ulm (Chair: K. Scharfetter-Kochanek), Wiesbaden (Chair: J. Metz), University of Würzburg (Chair: E.B. Bröcker), University of Halle (Chair: W. Marsch), and University of Zürich (Chair: G. Burg).

	NOTES

 
Authors’ disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
1. Balch CM, Buzaid AC, Soong SJ, et al: Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 19:3635-3648, 2001[Abstract/Free Full Text]

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Submitted March 9, 2004; accepted August 16, 2004.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Eigentler, T. K. Articles by Garbe, C. Search for Related Content PubMed PubMed Citation Articles by Eigentler, T. K. Articles by Garbe, C. Social Bookmarking                            What's this?