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Originally published as Ann Surg Oncol Early Release 10.1245/ASO.2004.07.014 on March 15, 2004

Annals of Surgical Oncology 11:426-433 (2004)
© 2004 Society of Surgical Oncology
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ORIGINAL ARTICLES

The Prognostic Importance of Tumor Mitotic Rate Confirmed in 1317 Patients With Primary Cutaneous Melanoma and Long Follow-Up

Anne Brecht Francken, MD, Helen M. Shaw, PhD, John F. Thompson, MD, Seng-jaw Soong, PhD, Neil A. Accortt, PhD, Manuela F. Azzola, MD, Richard A. Scolyer, MBBS, Gerald W. Milton, MBBS, William H. McCarthy, MBBS, Marjorie H. Colman, BSc and Vincent J. McGovern, MD{ddagger}

From the Sydney Melanoma Unit (ABF, HMS, JFT, MFA, GWM, WHMcC, MHC) and Department of Anatomical Pathology (RAS, VJMcG), Royal Prince Alfred Hospital, Sydney, NSW, Australia; and the Biostatistics and Bioinformatic Unit (S-JS, NAA), Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama.

Correspondence: Address correspondence and reprint requests to: John F. Thompson, MD, Sydney Melanoma Unit, Royal Prince Alfred Hospital, Missenden Rd., Camperdown, New South Wales 2050, Australia; Fax: 61-2-9550-6316; E-mail: thompson{at}smu.org.au


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The late Dr. Vincent McGovern (1915 to 1983) was an international authority on melanoma pathology and one of the first to suggest that assessment of tumor mitotic rate (TMR) might provide useful prognostic information. Data for a large cohort of patients, now with extended follow-up, whose tumors had been assessed by Dr. McGovern were analyzed to reassess the independent prognostic value of TMR in primary localized, cutaneous melanoma.

Methods: Information was extracted from the Sydney Melanoma Unit database for 1317 patients treated between 1957 and 1982 for whom there was complete clinical information and whose primary lesion pathology, which included tumor thickness, ulcerative state, and TMR, had been assessed by Dr. McGovern. All these assessments were made according to the recommendations of the Eighth International Pigment Cell Conference, held in Sydney in 1972 under the auspices of the International Union Against Cancer. Factors predicting melanoma-specific survival were analyzed with the Cox proportional hazards regression model.

Results: Stage, according to the recently revised American Joint Committee on Cancer Staging System (which is based on tumor thickness and ulceration) was the most predictive factor for survival (P < .0001). This was followed by primary lesion site (P < .0001), patient age (P = .0005), and TMR (P = .008).

Conclusions: TMR was confirmed to be an important independent predictor of survival of patients with primary cutaneous melanoma. However, its predictive value was less than it was when assessed according to the 1982 revisions of the 1972 TMR recommendations.

Key Words: Primary melanoma • Prognosis • Staging • Thickness • Tumor mitotic rate


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
When the International Union Against Cancer decided to hold its 1972 Interim Meeting in Sydney with the themes of Leukemia and Skin Cancer–Melanoma, it was thought appropriate that the Eighth International Pigment Cell Conference be held concurrently. The Australian Cancer Society appointed a Sydney-based histopathologist, Dr. Vincent McGovern,1 Chairman of the Pigment Cell Subcommittee. An internationally recognized authority on the histopathology of melanoma, he had developed a close association with the Sydney Melanoma Unit (SMU) by virtue of this expertise.

At this 1972 meeting the first organized discussion among histopathologists took place to consider ways of assessing prognosis based on features of a primary cutaneous melanoma, and it was agreed that the level of invasion, as proposed by Drs. Wallace Clark and McGovern, correlated well with prognosis. Although subsequently referred to as Clark levels, McGovern had previously made fundamentally important contributions to the concept and later undertook major studies validating it.2,3 The present study is based on other work undertaken by McGovern prior to his untimely death in a road accident on December 30, 1983.

After the delineation by Dr. Alexander Breslow (1970) of tumor thickness as the most important predictor of survival,4 McGovern had been the first to undertake detailed analyses of the histologic features of primary melanomas that were potentially of prognostic significance.5–12 These studies had included an examination of tumor mitotic rate (TMR) as a possible independent prognostic variable in a large cohort of SMU patients treated between 1957 and 1982. It was therefore considered useful to employ this unique dataset, now with very long patient follow-up, to confirm the prognostic value of TMR that we recently demonstrated in a completely separate group of 3661 SMU patients treated from 1983 onward.13 Also, this seemed a valuable method of determining if TMR assessment according to 1982 recommendations,14 used in the latter study, was more predictive of its prognostic strength than assessment according to the 1972 recommendations,15 used in the present study.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
All patients with cutaneous melanoma whose primary lesion pathology had been reviewed by McGovern were identified from the SMU database. There were approximately 4500 patients in total. Selected for detailed analysis were (1) patients who had definitive treatment, i.e., wide excision of the primary lesion, by SMU surgeons (GWM or WHMcC) between 1957 and 1982 at Royal Prince Alfred, St. Vincent’s, or Sydney Hospital (patients initially treated elsewhere and presenting to the SMU later in the course of their disease because of recurrence were excluded from the analysis to minimize referral bias); (2) patients who had only one primary, invasive, cutaneous melanoma; and (3) patients who had localized disease, i.e., clinical and/or pathologic stage I or II according to the most recent American Joint Committee on Cancer (AJCC) Melanoma Staging System.16

Pathology
The microscope used by McGovern was a Zeiss instrument with a high-power magnification of x300. For the purpose of the present study, this microscope’s high-power field (HPF) diameter was determined and found to be .79 mm. For each melanoma reported, McGovern recorded 14 pathologic variables; these included tumor thickness, presence or absence of ulceration, TMR and, where practical, Clark level of invasion.

For the present study tumor thickness results were grouped as recommended in the most recent revision of the AJCC staging system and coded as follows: 1, <=1.0 mm; 2, 1.01–2.0 mm; 3, 2.01–4.0 mm; and 4, >4.0 mm. Ulceration was coded as 0 (absent) or 1 (present). The AJCC staging (combining tumor thickness and ulceration) was used as a covariate in the Cox model, because it is now becoming generally accepted that this provides a far more accurate indicator of survival than is achieved by considering tumor thickness and ulceration separately. Coding for this variable was as follows: 1, stage IA; 2, stage IB; 3, stage IIA; 4, stage IIB; and 5, stage IIC.

The method used by McGovern to determine TMR was based on the recommendations of the 1972 International Pigment Cell Conference for the classification of malignant melanoma.15 The average number of mitoses in at least 10 high-power (x300) fields over the entire dermal component of the lesion was obtained and then expressed as the number of mitoses/5 HPF. In the case of small melanomas, where the dermal component was <10 HPF, the entire melanoma was assessed. The TMR was coded as follows: 1, 0 mitoses/5 HPF; 2, 1–4 mitoses/5 HPF; and 3, >=5 mitoses/5 HPF. Because the microscope used by McGovern had an HPF diameter of .79 mm, the area of its HPF was .49 mm2, which in the subsequent 1982 Pathology Workshop recommendations approximated to the following: 1, <=2 mitoses/mm2; 2, >2 to 8 mitoses/mm2; and 3, >8 mitoses/mm2.14

Other Putative Prognostic Variables
Age was coded in deciles as follows: 1, 10–19 years; 2, 20–29 years;...7, 70–79 years; and 8, >=80 years. Gender was coded as follows: 0, male; 1, female; anatomic site of primary lesion: 0, extremities; 1, trunk, head, or neck; and Clark level, 2, 3, 4, or 5.

Survival
Follow-up status was taken from the patient’s last follow-up date and was coded as follows: 1, alive or dead of an unrelated cause; or 2, dead of melanoma.

Comparison of Results from the Two SMU Studies of TMR
The 1983–2001 series13 analyzed data for patients treated at the SMU from 1983 onward and was therefore based on a patient population completely separate from the present analysis. Comparisons were made of clinical and pathologic factors between the two series, as well as the 10-year survival rates according to AJCC stage. Results of the Cox model analysis of prognostic factors derived from the present study were compared to the two Cox model results derived from the 1983 to 2001 series, in which two methods of grouping TMR were tested, to determine which would provide the more useful way of demonstrating the prognostic strength of this variable. These methods of grouping were A (mitosis groupings 1, for 0 mitoses/mm2; 2, for 1–4 mitoses/mm2; 3, for 5–10 mitoses/mm2; and 4, for >= 11/mm2) and B (mitosis groupings 1, for 0 or 1 mitoses/mm2; 2, for 2–4 mitoses/mm2; and 3, for >=5 mitoses/mm2).

Statistical Analysis
The methods for statistical analysis used in the present study were identical to those used in the 1983 to 2001 series13 and those used to validate the most recent AJCC staging system.17


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
A total of 1317 patients satisfied the study selection criteria, but 106 were excluded from the Cox analysis because of missing variables, most notably the Clark level of invasion (n = 100). A positive result (uncensored in the Cox analysis) was recorded for 204 patients, yielding a .168 ratio of uncensored to total patients. Median follow-up since 1957 for uncensored patients was 4.5 years (range, .4 to 27.5 years), and for censored patients, 13.8 years (range, .02 to 41.5 years).

Figure 1 shows the cumulative proportion of 204 stage I and stage II uncensored patients dying, according to time. Deaths due to melanoma continued to occur even after 15 years among stage I patients.



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  		FIG. 1. The cumulative proportion of 204 stage I and stage II uncensored patients dying according to time.

 
Table 1 shows the distribution of clinical and pathologic factors in the present study in comparison with their distribution in the 1983 to 2001 series. There were no marked differences in these distributions.


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  		TABLE 1. Comparison between present (1957–1982) study and 1983–2001 study13
 
Figure 2 shows the stepwise decline in 10-year survival rates according to the revised AJCC pathologic stage groupings in each study. There were no significant variations in these survival rates between the two series.



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  		FIG. 2. A comparison of 10-year survival rates according to AJCC stage for 1317 patients with localized, cutaneous melanoma in the present (1957 to 1982) study and 3661 patients with localized, cutaneous melanoma in the 1983 to 2001 study.

 
Figure 3 shows the decline in proportion of patients surviving according to TMR groups in the present study. There was a significant difference in survival between each group (P < .0001).



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  		FIG. 3. Melanoma-specific survival curves for the 1317 patients with localized, cutaneous melanoma in the present study according to TMR groupings.

 
The Cox model analysis of prognostic factors derived in the present study indicated that AJCC stage (based on tumor thickness and ulceration) was the most important predictor of survival, followed by primary lesion site, age of the patient, and, to a slightly lesser extent, TMR (Table 2). Clark level and patient gender were not significant as independent prognostic factors. In comparison, from the Cox models of prognostic factors derived from methods A and B groupings of TMR in the 1983 to 2001 series, AJCC stage was again the most important determinant of survival in both methods of grouping (Tables 3 and 4Go, respectively). However, TMR was the second most dominant prognostic variable with method A grouping, whereas it fell to third in rank importance with method B grouping.


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  		TABLE 2. Cox regression analysis of prognosis for 1211 melanoma patients with localized disease in the present (1957–1982) study
 

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  		TABLE 3. Cox regression analysis of prognosis for 3575 melanoma patients with localized disease according to method A in the 1983–2001 study
 

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  		TABLE 4. Cox regression analysis of prognosis for 3575 melanoma patients with localized disease according to method B in the 1983–2001 study
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The present analysis of TMR as assessed by McGovern with use of the 1972 consensus classification criteria confirmed that this variable was an important prognostic factor. It was a less dominant determinant of outcome than demonstrated in the 1983 to 2001 series, and it seems most likely that the different method of assessing TMR (1972 versus 1982 recommendations) was responsible for this reduction in prognostic importance. However, there were other factors that may have been responsible for this. It is instructive to examine these issues in detail.

TMR Assessment and Groupings
The recommendations of the 1972 consensus were followed in assembling the data used in the present study, because McGovern’s reviews of these 1317 primary melanomas were all performed prior to the 1982 meeting. The method used in the 1983 to 2001 series, conversely, was to count the total number of mitoses per square millimeter in the dermal area of the tumor with the highest TMR. This method of assessment was the recommendation of the 1982 pathology workshop held in Sydney, convened and chaired by McGovern and attended by other prominent international histopathologists with an interest in melanoma. The participants in this workshop considered that their revised method of assessing TMR would be independent of the microscope and magnification used and that results obtained in different parts of the world would therefore become more comparable.

The SMU histopathologists involved in the 1983 to 2001 series also believed that this method was more accurate and scientifically valid, being particularly useful in the assessment of tumors in which only rare or a single dermal mitosis was present in the entire specimen. With use of the 1972 classification, such cases would defy subgrouping, as the average TMR would be >0 but <1/10 HPF. Such cases would be classified in McGovern’s grouping as 0 mitoses/5 HPF. Also, in this earlier classification, there was a tacit assumption that there was not a wide variation in the area of a HPF for the microscopes used to assess TMR. This has clearly been shown to be incorrect, with TMR expressed as the number of mitoses/10 HPF varying by as much as 600%, depending on the particular microscope used.18 Furthermore, the 1982 consensus method is similar to that recommended for the counting of TMR in other solid tumors,19 and for these reasons the SMU histopathologists recommended its use in determining the TMR of cutaneous melanomas.

In the 1983 to 2001 series, there was a significant prognostic difference between a TMR of 0 mitoses/mm2 and a TMR of 1 mitosis/mm2 but not between 1 and 2 mitoses/mm2, 2 and 3 mitoses/mm2, 3 and 4 mitoses/mm2, and 4 and 5 mitoses/mm2. Attempts were made in that study to determine the optimal groupings of TMR that would demonstrate its true prognostic significance. Method A groupings were as follows: 1, 0 mitoses/mm2; 2, 1–4 mitoses/mm2; 3, 5–10 mitoses/mm2; and 4, >=11 mitoses/mm2. Method B groupings were as follows: 1, 0 or 1 mitoses/mm2; 2, 2–4 mitoses/mm2; and 3, >=5 mitoses/mm2. It was found that by grouping TMR according to method A, this variable proved to be second only to tumor thickness in prognostic importance. Conversely, grouping TMR according to method B, which combined 0 and 1 mitosis/mm2, caused TMR to fall to third in rank importance. It is important to note that the lower prognostic significance derived in the present study, in which 0, 1, and 2 mitoses/mm2 were grouped together, followed the same pattern as that previously obtained with use of method B in the 1983 to 2001 series.

Another difference between these two SMU studies was in the number of histopathologists involved in determining TMR in each case. In the 1983 to 2001 series, five histopathologists contributed, whereas in the current study, all reviews were made by McGovern, which may have reduced variability in assessing TMR. However, a recent SMU review carried out by six histopathologists with varying experience in assessing TMR in melanomas revealed that there was excellent concordance among these histopathologists in assessing this variable.20 Therefore, differences in the methods of assessing TMR and the TMR groupings used in each of the two studies, rather than interobserver variability, were probably the most important factors in determining the significance of the results.

Other Factors
Although the two series were superficially similar in patient composition, they were not identical, probably mainly because of temporal differences in referral patterns to the SMU. The present series spanned a period of time (1957 to 1982) when almost all patients were referred to a hospital for initial assessment and excision of their primary lesion. More recently, primary lesion excisions are commonly performed by family practitioners or dermatologists and patients are referred to a specialist treatment center such as the SMU only if more extensive definitive treatment is required. Thus, the present 1957 to 1982 series could be regarded as more population-based than the 1983 to 2001 series, reported previously.

In the present study, 34% of patients were pathologically staged. This figure is a reflection of the proportion of patients with intermediate-risk to high-risk tumors (>1.5 mm in thickness), 95% of whom underwent elective lymph node dissection (Table 1). The remaining 66% were clinically staged patients whose tumors were <=1.5 mm in thickness and who therefore would have had a relatively low risk of harboring lymph node metastases (6% in a recent unpublished review of SMU sentinel node biopsy data). In the 1983 to 2001 study, 34% of patients were also pathologically staged. However, the proportion of tumors >1.5 mm in thickness in this latter study was somewhat higher (46%) than the proportion pathologically staged (Table 1). This was because after 1992, according to the randomization requirements of the Multicenter Selective Lymphadenectomy Trial21 in which the SMU participated, only 60% of patients with tumors >=1 mm in thickness were pathologically staged, by sentinel lymph node biopsy. This could have had a bearing on the slight differences in clinical and histopathologic factors between the two series.

A major feature that varied between the two analyses and seems likely to have been responsible for differences in the rank importance of prognostic factors, however, was the prolonged follow-up in the present study (overall median of 13.8 years for censored patients). As an example, one can examine the prognostic prominence of primary lesion site in the present study and its relative lack of importance in the 1983 to 2001 series. It has been amply demonstrated that with long follow-up, 10-year survival rates for patients with extremity lesions are significantly higher than for patients with lesions on the trunk, head, or neck.22,23 In the present study, patients with extremity lesions and short follow-up (5 years) had a 4.3% higher survival rate than those with lesions on the trunk, head, or neck. However, the difference at 10 years rose to 12.7%. In contrast, in the 1983 to 2001 series, the prognostic advantage of this lesion location was less perceptible after 10 years (4.7%). Thus, the longer the follow-up, the more apparent will the prognostic significance of this variable become.

The present study confirmed our initial findings on the prognostic importance of TMR that was demonstrated in the 1983 to 2001 series. However, its relative strength as a prognostic factor was diminished, primarily because of the method used for its estimation. As described in detail in the 1983 to 2001 series, several recent studies have also attempted to assess its prognostic value.24–30 Nevertheless, since the submission for publication of the 1983 to 2001 series report, additional studies have appeared in the literature that support the role of TMR as a powerful prognostic variable. In their multivariate analysis of 1284 patients in stages I to III, Retsas et al.31 attempted to validate the AJCC proposal for the introduction of ulceration of the primary cutaneous melanoma as an independent prognostic factor. During the course of this study they found, by analyzing both tumor thickness and TMR as continuous variables, that TMR (assessed as the number of mitoses/mm2) was second only to tumor thickness in predicting overall survival (P < .005 and P < .0001, respectively).

The current consensus is that the status of sentinel nodes is the most important predictor of survival in patients with melanoma. The role of TMR in predicting sentinel lymph node positivity and positivity of nonsentinel nodes upon CLND is gradually emerging, as new information is reported. Sabel et al.,32 assessing TMR by recording the number of mitoses per HPF, found that in addition to tumor thickness, both TMR and younger age were highly predictive of sentinel node positivity in 423 patients in stage I–II (P < .0001, P < .0001, and P < .003, respectively). Similarly, a recent small study of six patients with thin primary tumors (<1.0 mm thick) and positive sentinel nodes33 revealed that ulceration, vertical growth phase, and high TMR rate were major factors in influencing sentinel node positivity (P = .019, P = .002, and P = .008, respectively).

A univariate analysis of histologic factors affecting nonsentinel node positivity in 191 patients from among the SMU patients with primary tumors of any thickness34 indicated that there was a trend for increasing TMR to be associated with a greater risk of nonsentinel node positivity.

None of the above studies were particularly large, and if they included multivariate analyses, they may not have adhered to Vollmer’s strict guidelines for performing such analyses, as described in detail in the report of our 1983 to 2001 series.35 Nevertheless, at this stage it seems probable that TMR is an important independent indicator of the metastatic potential of a melanoma and the patient’s ultimate prognosis. If this is validated by rigorous analyses from other centers in which TMR is assessed according to the 1982 recommendations, TMR should logically be included in all determinations of prognosis and perhaps integrated into future melanoma staging systems.


   ACKNOWLEDGMENTS
 
The authors gratefully acknowledge the financial support of The Melanoma Foundation of The University of Sydney; The Melanoma and Skin Cancer Research Institute; Stichting VSB Fonds; Stichting Dr. Hendrik Muller’s Vaderlandsch Fonds; Stichting Fonds Doctor Catherine van Tussenbroek–Nell Ongerboer Fonds; Stichting Groninger Universiteits Fonds; Stichting De Korintiers; Nederlandse Kankerbestrijding–Koningin Wilhemina Fonds; and Marco Polo Fonds.


   FOOTNOTES
 
{ddagger}Died December 30, 1983. Back

The prognostic importance of tumor mitotic rate in localized primary melanomas was confirmed in a single-center study of 1317 patients treated prior to 1983.

Received for publication July 24, 2003. Accepted for publication December 21, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. McGovern VJ, Russell P. Mechanisms in pigmentation. In: Riley V, ed. Pigment Cell. Vol. 1. Basel: Karger, 1973.
  2. McGovern VJ. The classification of melanoma and its relationship with prognosis. Pathology 1970; 2: 85–98.[Medline]
  3. McGovern VJ. Melanoma: growth patterns, multiplicity and regression. In: McCarthy WH, ed. Melanoma and Skin Cancer: Proceedings of the International Cancer Conference. Sydney: Blight, Government Printer, 1972: 95–106.
  4. Breslow A. Thickness, cross sectional areas an depth of invasion in the prognosis of cutaneous melanoma. Ann Surg 1970; 172: 902–8.[Medline]
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  8. McGovern VJ, Shaw HM, Milton GW, Farago GA. Cell type and pigment content as prognostic indicators in cutaneous malignant melanoma. In: Ackerman AB, ed. Pathology of malignant melanoma. New York: Masson, 1981; 327–32.
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  21. Multicenter Selective Lymphadenectomy Trial. Bethesda, MD: National Cancer Institute (grant no. PO1 CA29605–12).
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  28. Wagner JD, Gordon MS, Chuang T-Y, et al. Predicting sentinel and residual lymph node basin disease after sentinel lymph node biopsy for melanoma. Cancer 2000; 89: 453–62.[CrossRef][Medline]
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J. Vaquerano, W. G. Kraybill, D. L. Driscoll, R. Cheney, and J. M. Kane III
American Joint Committee on Cancer Clinical Stage as a Selection Criterion for Sentinel Lymph Node Biopsy in Thin Melanoma
Ann. Surg. Oncol., February 1, 2006; 13(2): 198 - 204.
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P. A. Gimotty, P. Van Belle, D. E. Elder, T. Murry, K. T. Montone, X. Xu, S. Hotz, S. Raines, M. E. Ming, P. Wahl, et al.
Biologic and Prognostic Significance of Dermal Ki67 Expression, Mitoses, and Tumorigenicity in Thin Invasive Cutaneous Melanoma
J. Clin. Oncol., November 1, 2005; 23(31): 8048 - 8056.
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N. R. Abbasi, H. M. Shaw, D. S. Rigel, R. J. Friedman, W. H. McCarthy, I. Osman, A. W. Kopf, and D. Polsky
Early Diagnosis of Cutaneous Melanoma: Revisiting the ABCD Criteria
JAMA, December 8, 2004; 292(22): 2771 - 2776.
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K. J. Busam
Editorial: The Prognostic Importance of Tumor Mitotic Rate for Patients with Primary Cutaneous Melanoma
Ann. Surg. Oncol., April 1, 2004; 11(4): 360 - 361.
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