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Editorial

Should Tumor Mitotic Rate and Patient Age, As Well As Tumor Thickness, be Used to Select Melanoma Patients for Sentinel Node Biopsy?

From the Sydney Melanoma Unit, Royal Prince Alfred Hospital, and Department of Surgery, University of Sydney, Sydney, New South Wales, Australia.

Correspondence: Address correspondence to: John F. Thompson, MD, Sydney Melanoma Unit, Sydney Cancer Centre, Gloucester House, Royal Prince Alfred Hospital, Camperdown, NSW, 2050, Australia; Fax: +61-2-9550-6316, E-mail: thompson{at}smu.org.au

Until the results of large, well-designed clinical trials are available, uncertainty will remain as to whether a sentinel node biopsy procedure, with complete regional node clearance if metastatic disease is found in a sentinel node, is of any therapeutic value in patients with clinically localized primary melanoma. It is already abundantly clear, however, that sentinel node status is a powerful predictor of survival outcome.¹ Most physicians who treat patients with melanoma and, indeed most patients themselves, consider that the greatly improved staging and more reliable prognostic estimates that can be achieved by performing a procedure that is minimally invasive make sentinel node biopsy a worthwhile procedure, even if it does not confer a therapeutic benefit. As progress is made toward finding effective adjuvant therapies for melanoma, it becomes increasingly important to identify patients who are at greatest risk of disease recurrence. In 2004, this means identifying patients at greatest risk of having a positive sentinel node.

Analysis of a pooled dataset containing details of 17,600 patients with melanoma, undertaken to validate a proposed revision of the American Joint Committee on Cancer (AJCC) staging system, indicated that primary tumor thickness, its ulcerative state, and regional lymph node status (negative, microscopically positive, or clinically detectable) were the most important prognostic factors.² These variables, therefore, were incorporated into the new (2002) AJCC staging system.³ Tumor mitotic rate (TMR) as a prognostic variable was not considered in the AJCC dataset analysis, however. In a subsequent study of 3661 patients treated at the Sydney Melanoma Unit (SMU), TMR was found to be a more important independent prognostic factor than ulceration, second in importance only to Breslow thickness of the primary tumor as a predictor of outcome.⁴

Prognosis and sentinel node status are closely associated. Therefore, it came as no surprise that Sondak et al.,⁵ in an article published in this issue of the Annals of Surgical Oncology, found that both TMR and tumor thickness were predictors of sentinel node positivity. They also confirmed previous reports that younger age is a predictor of sentinel node positivity,^6–8 a paradoxic finding because younger patients have a significantly better overall prognosis than older patients.² Their study involved the application of elegant probabilistic modeling in a series of 419 patients, of whom 75 (17.9%) had positive sentinel nodes. They found on multivariate analysis that the only factors significantly associated with a positive sentinel node were Breslow thickness, TMR, and age. No other factor, including ulceration, was significantly associated with a positive sentinel node. The important practical implication of their results is that patients whose primary tumor is 1 mm in Breslow thickness, with a high TMR, and who are young (<35 years) should be considered for sentinel node biopsy. Currently, sentinel node biopsy is not usually recommended for patients with tumors 1 mm in thickness, regardless of age or TMR, although invasion to Clark level IV is sometimes considered an indication for sentinel node biopsy in those with thin tumors, because Clark level has been shown to be a significant prognostic factor in patients with thin melanomas.²

We have recently analyzed prognostic factors for sentinel node positivity in patients with melanoma treated at the SMU (unpublished data). Our results substantiate those of Sondak et al.,⁵ with tumor thickness (P < .00001), age (P = .0004), and TMR (P = .034) found to be independent predictors of sentinel node metastasis on multivariate binary logistic regression analysis. This SMU study involved 1303 patients with AJCC stage I and stage II disease who had lymphatic mapping and sentinel node biopsy, 207 of whom (15.8%) had at least one positive sentinel node.

In our analysis, patient age, tumor thickness, ulceration, TMR, Clark’s level of invasion, gender, anatomic site, and number of explored fields were used as covariates. Age and tumor thickness were analyzed both as continuous and categoric variables. Age categories were <20, 20–29, 30–39, 40–49, 50–59, 60–69, and 70 years. Tumor thickness categories were based on the AJCC staging system: 1.0 mm, 1.01–2.0 mm, 2.01–4.0 mm, and 4.0 mm. Ulceration, TMR, Clark’s level, gender, anatomic site, and number of explored fields were analyzed only as categoric variables. Ulceration was categorized as present or absent. In comparing the prognostic significance of the latter somewhat subjective pathologic variable between different series, it is essential that it be clearly defined. This problem is discussed in detail elsewhere.^4,9 Also critical is the method of assessing TMR. The method used in our study was that recommended by the participants in the 1982 Pathology Workshop.¹⁰ This stipulated that the number of mitoses/mm² be recorded in the area of tumor in which most mitoses were seen. The following TMR groups were used in our analysis: 0, 1–4, 5–10, and 11 mitoses/mm². These particular groups were used because significant survival differences between these groupings were demonstrated in the previous SMU study of prognosis in 3661 patients with stage I and II cutaneous melanoma referred to above.⁴ Not used in our present analysis was the pre-1982 method of TMR estimation,¹¹ in which the average number of mitoses in at least 10 high power fields (HPF) was recorded. This method was seriously flawed because the number of mitoses/10 HPF was found to vary by as much as 600%, depending on the microscope used.¹² Although this method also showed that TMR was prognostically important in a separate SMU series of 1317 patients with stage I and II cutaneous melanoma treated before 1982,¹³ the prognostic strength of TMR was considerably less than it was when assessed using the post-1982 method.

Univariate analysis of our data revealed that, in contrast to the findings of Sondak et al.,⁵ no linear trend existed between age and sentinel node positivity. The metastatic rates were as follows: <20 years, 21.7%; 20–29 years, 15.1%; 30–39 years, 22.5%; 40–49 years, 16.0%; 50–59 years, 15.1%; 60–69 years, 11.2%; and 70 years, 17.7%. Multivariate analyses were performed to find an age cut-off point for which the difference between age groups was most significant. The difference between <40 years and 40–69 years was found to be most significant (P = .0001, odds ratio [OR] = 2.3). Between groups with a TMR of 0 mitoses/mm² and a TMR of 5–10 mitoses/mm², a significant difference was seen in sentinel node metastatic rate (6.0% vs. 25.2%, respectively; P = .021, OR = 2.94). We found, as did Sondak et al.,⁵ that when tumor thickness, TMR, and age were included in the multivariate analysis, no other covariate analyzed, including ulceration, was significantly associated with sentinel node positivity. Only 82 patients had tumors 1.0 mm in thickness, preventing any valid multivariate analysis from being performed. By univariate analysis, however, the sentinel node metastatic rate was 5.0% and two of the four patients in that group with sentinel node metastases were <40 years of age.

The paradox—younger patients have a better prognosis, yet are more likely to harbor sentinel node metastases—has yet to be explained. Nevertheless, the SMU data generally corroborate the models of Sondak et al., ⁵ and support the proposal that in melanoma patients with tumors 1.0 mm thick, young age (<40 years) and a higher TMR (>5/mm²) should be considered as additional indications for lymphatic mapping and sentinel node biopsy, because such patients are at increased risk of having metastatic disease in a sentinel node.

Received for publication January 12, 2004. Accepted for publication January 19, 2004.

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