Charles M. Balch, MD
Professor of Surgery, Oncology and DermatologyJohns Hopkins Medical Institutions Baltimore, MD

Martin C. Mihm, Jr., MD
Director, Melanoma Program in DermatologyAssociate Director, Melanoma ProgramDana Farber Brigham and Women’s Cancer CenterHarvard Medical School, Boston, MA

Jeffrey E. Gershenwald, MD
Professor, Department of Surgical OncologyDivision of Surgery, and Professor, Department of Cancer BiologyThe University of Texas MD Anderson Cancer Center, Houston, TX

Seng-jaw Soong, PhD
Professor EmeritusComprehensive Cancer CenterUniversity of Alabama at Birmingham

Revisions to the Melanoma Staging System were published in the 7th edi­tion of the American Joint Committee on Cancer (AJCC) in 2009 and imple­mented January, 2010.^1,2,3,4 Though the changes are not great in number, they are of considerable significance. [The latest TNM criteria and stage groupings are shown in Tables 1a and 1b, while survival rates according to disease stage are shown in Figure 1.]

Highlights of the Revised Melanoma Staging System:

1. Primary melanoma thickness and tumor ulceration continue to define T category strata (Tables 1a and 1b). Survival rates for patients with localized melanoma stratified by T category are shown in Figure 2.
   
   
2. Primary tumor mitotic rate (his­tologically defined as the number of mitoses/mm²) is an important independent adverse predictor of survival. For T1 melanomas, a mi­totic rate of at least 1 mitosis/mm² replaces Clark‘ s level of invasion as a primary criterion for defining the subcategory of T1b (Table 1a). Presence of primary tumor ulcer­ation remains an adverse predictor of survival, and is included along with mitotic rate as a primary cri­terion for defining T1b melanomas.
    
3. The presence of nodal micrometas­tases can be defined using either hematoxylin & eosin (H&E) or immunohistochemical staining. (Previously, only the H&E could beused for formal staging purposes.)
    
4. There is no lower threshold of tumor burden used to define the presence of regional nodal metas­tasis. Specifically, based on the consensus that volumes of regional metastatic tumor even less than 0.2mm in diameter (previously used as the threshold for defining nodal metastasis in the overall 6th edition AJCC Staging System) are clinically significant, nodal tu­mor deposits of any size are to be included in staging nodal disease. An evidence-based lower threshold of clinically “insignificant” nodal metastases has not been defined.
    
5. M-category strata continue to be defined by the site(s) of distant metastases: non-visceral (i.e., skin/soft tissue/distant nodal) (M1a); lung (M1b); and all other visceral metastatic sites (M1c). An elevated serum lactic dehydrogenase (LDH) level also remains a powerful adverse predictor of survival;
   pa­tients with an elevated LDH level are all categorized as M1c, regard­less of site(s) of distant disease.
    
6. Survival estimates for patients with intralymphatic regional metastases (i.e., satellite and in-transit metastases) are somewhat better than for the remaining co­hort of stage IIIB patients. Howev­er, since stage IIIB represents the closest statistical fit for this group, the current staging definition for intralymphatic regional metastasis has been retained.
    
7. Based on the lack of sufficient data to substantiate revision of the definitions used in the 6th edition staging manual, microsatellites (i.e., discontinuous nests of meta­static cells more than 0.05 mm in diameter that are clearly separated by normal dermis [not fibrosis or inflammation] from the main invasive component of melanoma by a distance of at least 0.3 mm) are retained in the N2c category. This feature is retained in the N2c category largely because the published literature is insufficient to substantiate revision of the definitions used in the 6th edition staging manual.
    
8. The staging definition for patients with metastatic melanoma from an unknown primary site was clarified; patients with metastatic melanoma arising in lymph nodes, skin or subcutaneous tissues with­out a known associated primary melanoma are categorized as stage III, not stage IV.
    
9. Lymphatic mapping and senti­nel lymph node biopsy (sentinel lymphadenectomy) remain im­portant components of melanoma staging and should be used (or discussed with the patient) to identify occult stage III regional nodal disease among patients who present with clinical stage IB or II melanoma.

The Importance of Mitotic Rate

Tumor thickness and ulceration have both been formally used since 2002 for staging melanoma patients based on an evidence-based approach. More recently, cellular proliferation within the primary tumor, as reflected by the tumor’s mitotic rate, has emerged as another important predictor of survival.^5,6,7,8,9

Primary tumor mitotic rate was in­troduced this year as a major criterion for melanoma staging and prognosis. Detailed analysis of the AJCC Mela­noma Staging Database demonstrated a significant inverse correlation between primary tumor mitotic rate (histo­logically defined as mitoses/mm2) and survival^1,2,9 (Table 2). Thus, primary tumor mitotic rate is now acknowl­edged to be an important independent adverse predictor of survival; as the number of mitoses/mm² increases, melanoma survival decreases. Indeed, in a multivariate analysis, mitotic rate was the second most powerful predic­tor of survival outcome after tumor thickness in patients with localized melanoma (Table 3) and fourth after the number of metastatic lymph nodes, age, and tumor ulceration in patients with regional node micrometastases (Table 4). It is noteworthy that al­though mitotic rate is a continuous variable (as is melanoma tumor thick­ness), no discernible overall thresholds that delineate a particularly increased metastatic risk could be identified be­yond 1 mitosis/mm². In contrast, when no mitotic activity was identified —indicative of a more slowly growing primary melanoma — the prognosis was more favorable than for patients whose primary tumor had at least 1 mitosis/mm². This was particularly significant in the subgroup of patients with T1 tumors.

Based on this analysis, primary melanoma mitotic rate was incorpo­rated into the 7th edition of the AJCC Cancer Staging Manual as a required element for melanoma staging. These recommendations were made after reviewing the statistical informa­tion involving 4,861 T1 melanomas from the updated AJCC Melanoma Staging Database demonstrating that mitotic rate was the most powerful predictor of survival outcome for T1 melanoma patients, and conversely, that the Clark’s level of invasion was no longer statistically significant when mitotic rate and ulceration were in­cluded.¹ Ten-year survival rates were 97 percent for T1 melanomas 0.1-0.50 mm in thickness and <1 mitosis/mm², 95 percent for T1 melanomas 0.1-0.50 mm in thickness and ≥1 mitosis/mm², 93 percent for T1 melanomas 0.51-1.0 mm and <1 mitosis/mm², and 87 per­cent for 0.51-1.00 mm melanomas and ≥1 mitosis/mm². In the latter group, the 10-year survival rates dropped to 85 percent if the T1 melanoma was also ulcerated.¹

The AJCC Melanoma Staging Com­mittee concluded that histologic assess­ment of all primary melanomas should now include a determination of mitotic rate, using a standardized approach. For staging purposes, mitotic rate has been added as a secondary criterion for defining T1b melanoma and replaces the Clark level of invasion, which had been used in melanoma staging for 40 years. Specifically, for T1 melanomas, the pres­ence of ulceration overlying an invasive melanoma and/or at least 1 mitosis/mm² define the subcategory of T1b among patients with T1 primary tumors (i.e., ≤1.0 mm thickness).

The Hot Spot Method

As detailed in the 7th edition of the AJCC Cancer Staging Manual,¹ the recommended approach, employing the so-called “hot spot,” is to enumer­ate mitoses in the tumoral areas in the dermis containing the most mitotic fig­ures, if any. After counting the mitoses in the hot spot, with the 40x lens or at 400x magnification, the count is then extended to adjacent contiguous fields until an area corresponding to 1 mm² is assessed. If no hot spot can be found and mitoses are sparse and randomly scattered throughout the lesion, any mi­tosis is chosen, and the field containing it becomes the first field, then additional contiguous fields are counted to achieve the equivalent of 1 mm² of tissue. The count is expressed as the number of mitoses/mm². Calibration of individual microscopes is recommended to record mitoses accurately; as a guide, 1 mm² corresponds to approximately four 400x fields in most, but not all, microscopes.

When the invasive component of the melanoma is <1/mm², the number of mitoses in 1 mm² of dermal tissue that includes the tumor should be enumer­ated and recorded as a number of mito­ses per mm². In tumors whose invasive component comprises an area <1 mm², it is recommended to designate the pres­ence or absence of a mitosis as “at least 1/mm² “ (i.e., “mitogenic”) or as 0/mm² (i.e., “nonmitogenic”), respectively. At some institutions, when mitotic figures are not found after examining numer­ous fields, the mitotic count has been described as “<1/mm².” For most tumor registries, the designation “<1/mm²” is synonymous with zero, as has been customarily used in the past. While this practice may be continued for histori­cal data, the AJCC Melanoma Staging Committee strongly recommends that pathologists use the approach outlined above, “0/mm²,“ beginning in 2010.¹ In the Azzola article,⁵ the only persistent significant survival was in patients without mitoses after long-term follow-up.
 

Do the New T1b Criteria Using Mitotic Rate Change the Staging Indications for SLNB?

For staging purposes, survival end­points are used de facto to evaluate potential prognostic factors. While the multifactorial analysis based on the AJCC Melanoma Staging Database of­fered compelling reasons to incorporate mitotic rate into the T1 staging criteria based on survival outcome data, it is not yet definitively established how to uti­lize this prognostic factor in predicting metastatic risk in a regional sentinel lymph node. Until such data become available, it is recommended that the considerable information on predicting sentinel node metastases — employing measured tumor thickness, level of invasion, presence or absence of ul­ceration, and other criteria currently in use — be employed. Nonetheless, it is worthwhile to note that preliminary data from a large cohort of patients have recently been presented, demon­strating a correlation between mitotic rate and sentinel lymph node status among patients with T1 melanoma.¹⁰

Conclusions

Since the histologic features of the primary melanoma — tumor thick­ness, mitotic rate and ulceration — are hallmarks of melanoma prognosis and staging, the initial biopsy is a criti­cal component of both diagnosis and staging. An excisional biopsy of the entire clinically apparent lesion, with a narrow 1 to 2 mm margin of adjacent normal-appearing skin, is the biopsy technique of choice when melanoma is suspected. An incisional biopsy may be acceptable for larger lesions. A deep saucerization (shave) biopsy may be satisfactory when the lesion is flat and suspicion of melanoma is not high.^1,2,11

The AJCC Melanoma Staging System recommends that the sentinel lymph node biopsy be performed as a staging procedure in patients for whom the information will be useful in planning subsequent treatments and follow-up regimens. Specifically, the procedure should be recommended for (and dis­cussed with) patients who have T2, T3 or T4 melanomas and clinically unin­volved regional lymph nodes (clinical stages IB and II), as well as for patients with T1 melanomas and secondary features associated with increased risk for nodal micrometastases: ulceration, mitotic rate ≥1/mm², or Clark's level IV, especially when the primary melanoma exceeds 0.7 mm in thickness.¹⁰

Increasingly, as new prognostic fac­tors are identified, particularly when multiple and continuous prognostic variables are included in predictive models, melanoma staging will re­quire the use of electronic predictive tools. The AJCC has initiated this step by launching a website, www.melanomaprognosis.org, that provides actuarial survival rates based on com­binations of prognostic features.¹² Mi­totic rate has not yet been incorporated into this predictive model, but will be included in the future.

Finally, the prognostic factors included in the Melanoma Staging System should be the primary strati­fication criteria and end-results re­porting criteria of melanoma clinical trials. The use of a consistent set of criteria will facilitate the reporting of melanoma treatment outcomes and the comparability of melanoma clinical trials. Potentially, it will also acceler­ate the progress of multidisciplinary melanoma treatment approaches.
 

*The authors would like to acknowledge the members of the AJCC Melanoma Committee that developed the new staging guidelines:

CHARLES M. BALCH, MD (Chair), Johns Hopkins Medical Institutions, Baltimore, MD; JEFFREY E. GERSHENWALD, MD (Vice-chair), The University of Texas MD Anderson Cancer Center, Houston, TX; SENG-JAW SOONG, MD (Vice-chair), University of Alabama at Birmingham; MICHAEL B. ATKINS, MD, Beth Israel Deaconess Medical Center, Boston, MA, Eastern Cooperative Oncology Group; DAVID R. BYRD, MD, University of Washington, Seattle, WA; ANTONIO C. BUZAID, MD, Hospital Sirio-Libanes, Sao Paulo, Brazil; NATALE CASCINELLI, MD, Istituto Nazionale Tumori, WHO Melanoma Program, San Pio X Hospital, Milan, Italy; ALISTAIR J. COCHRAN, MD, David Geffen School of Medicine at UCLA, Los Angeles, CA; DANIEL G. COIT, MD, Memorial Sloan-Kettering Cancer Center, New York, NY; ALEXANDER M. M. EGGERMONT, MD, Erasmus University MC – Director, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands; UICC representative DAVID P. FRISHBERG, MD, Cedars Sinai Medical Center, Los Angeles, CA (CAP representative); KEITH T. FLAHERTY, MD, Massachusetts General Hospital Cancer Center, Boston, MA; PHYLLIS A. GIMOTTY, PHD, University of Pennsylvania, Philadelphia, PA; ALLAN C. HALPERN, MD, Memorial Sloan-Kettering Cancer Center, New York, NY; ALAN N. HOUGHTON, Jr., MD, Memorial Sloan-Kettering Cancer Center, New York, NY; MARCELLA M. JOHNSON, University of Texas MD Anderson Cancer Center, Houston, TX; JOHN M. KIRKWOOD, MD, University of Pittsburgh Cancer Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, and Eastern Cooperative Oncology Group; KELLY M. MCMASTERS, MD, PhD, University of Louisville Medical Center, Louisville, KY, Sunbelt Melanoma Trial Group; MARTIN F. MIHM, Jr., MD, Dana Farber Brigham and Women’s Cancer Center, Harvard Medical School, Boston, MA; DONALD L. MORTON, MD, John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica, CA; MERRICK I. ROSS, MD, The University of Texas MD Anderson Cancer Center, Houston,TX; ARTHUR J. SOBER, MD, Massachusetts General Hospital, Boston MA; VERNON K. SONDAK, MD, H. Lee Moffitt Cancer Center and University of South Florida College of Medicine, Tampa, FL; KRISTEN STEPHENS, Roswell Park Cancer Institute, Buffalo, NY; JOHN F. THOMPSON, MD, Sydney Melanoma Unit, University of Sydney, Sydney, NSW, Australia.

References

1. Balch CM, Gershenwald JE, Soong S-j, et al. Mela­noma of the skin. In: Edge SB, Byrd DR, Compton CC, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY.: Springer, 2010.
    
2. Balch CM, Gershenwald JE, Soong S-j, et al. Final version of 2009 AJCC melanoma staging and clas­sification. J Clin Oncol 2009; 27:6199–206.
    
3. Gershenwald JE, Soong S-j, Balch CM, on behalf of the American Joint Committee on Cancer (AJCC). 2010 TNM staging system for cutaneous mela­noma...and beyond. Ann Surg Oncol 2010; 17: 6:1475-1477, DOI:10.1245/s10434-010-0986-3.
    
4. Balch CM, Gershenwald JE, Soong S-j, et al. Multi­variate analysis of prognostic factors among 2313 patients with stage III melanoma. J Clin Oncol 2010 May 28(14): 2452-2459.
    
5. Azzola MF, Shaw HM, Thompson JF, et al: Tumor mitotic rate is a more powerful prognostic indica­tor than ulceration in patients with primary cutaneous melanoma. Cancer 2003; 97:1488-98.
    
6. Scolyer RA, Shaw HM, Thompson JF, et al: Interobserver reproducibility of histopathologic prognostic variables in primary cutaneous mela­nomas. Am J Surg Pathol 2003; 27:1571-6.
    
7. Francken AB, Shaw HM, Thompson JF, et al: The prognostic importance of tumor mitotic rate con­firmed in 1317 patients with primary cutaneous melanoma and long follow-up. Ann Surg Oncol 2004; 11:426-33.
    
8. Gimotty PA, Guerry D, Ming ME, et al: Thin primary cutaneous malignant melanoma: a prog­nostic tree for 10-year metastasis is more accurate than American Joint Committee on Cancer stag­ing. J Clin Oncol 2004; 22:3668-76.
    
9. Thompson JF, Soong S-j, Balch CM, et al. The prognostic significance of mitotic rate in localized primary cutaneous melanoma: an analysis of patients in the multi-institutional AJCC melanoma staging database. Submitted for publication, 2011.
   
   
10. Caudle AS, Ross MI, Prieto VG, et al. Mitotic rate predicts sentinel lymph node involvement in mela­noma: Impact of the 7th edition AJCC Melanoma Staging System. Society of Surgical Oncology 63rd Annual Cancer Symposium. St Louis, MO, 2010.
     
11. Sober AJ, Balch CM. Method of biopsy and inci­dence of positive margins in primary melanoma. Ann Surg Oncol 2007; 14:274-275.
     
12. Soong S-j, Ding S, Coit D, et al., and the AJCC Mel­anoma Task Force. Predicting survival outcome of localized melanoma: an electronic prediction tool based on the AJCC Melanoma Database. Ann Surg Oncol 2010; August 17:2006-2014.