Tumor node metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma
- Antonio C Buzaid, MD
Antonio C Buzaid, MD
- Chairman, Steering Committee Member
- Centro Oncológico
- Hospital Israelita Albert Einstein, Brazil
- Jeffrey E Gershenwald, MD, FACS
Jeffrey E Gershenwald, MD, FACS
- Professor of Surgery and Cancer Biology
- The University of Texas MD Anderson Cancer Center
In order to be useful, a staging system must be simple, practical, and accurately reflect the prognosis of the patients to whom it is being applied. Detailed analyses of large databases of patients presenting with newly diagnosed cutaneous melanoma have allowed the correlation of pathologic and clinical parameters with long-term outcome.
This information is incorporated into a staging system that was originally developed by the American Joint Committee on Cancer (AJCC) subsequently adopted by the International Union for Cancer Control (UICC). This tumor, node, metastasis (TNM) system relies upon assessments of the primary tumor (T), regional lymph nodes (N), and distant metastatic sites (M). The seventh (2010) edition of this staging system is based upon an analysis of over 38,900 patients with cutaneous melanoma from the AJCC Melanoma Staging Database [1,2].
The 2010 TNM staging system and other prognostic factors for cutaneous melanoma are discussed here. The approach to staging is reviewed separately. (See "Staging work-up and surveillance after treatment of melanoma".)
PROGNOSTIC FACTORS AFFECTING STAGING
Primary tumor (T) — The histopathologic factors incorporated into the 2010 TNM staging system are the thickness of the primary tumor (originally described by Breslow ), the presence or absence of ulceration of the overlying epithelium, and the mitotic rate [1,2]. The prognostic implications of these parameters were derived from the American Joint Committee on Cancer (AJCC) Melanoma Staging Database, which included over 27,000 patients who had clinically or pathologically localized melanoma (figure 1).
The thickness of the primary tumor (T) defines four categories (table 1):
- Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009; 27:6199.
- Melanoma of the Skin. In: American Joint Committee on Cancer Staging Manual, 7th, Edge SB, Byrd DR, Compton CC, et al (Eds), Springer, New York 2010. p.325.
- Breslow A. Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg 1970; 172:902.
- Thompson JF, Soong SJ, Balch CM, et al. Prognostic significance of mitotic rate in localized primary cutaneous melanoma: an analysis of patients in the multi-institutional American Joint Committee on Cancer melanoma staging database. J Clin Oncol 2011; 29:2199.
- Shen S, Wolfe R, McLean CA, et al. Characteristics and associations of high-mitotic-rate melanoma. JAMA Dermatol 2014; 150:1048.
- Green AC, Baade P, Coory M, et al. Population-based 20-year survival among people diagnosed with thin melanomas in Queensland, Australia. J Clin Oncol 2012; 30:1462.
- Maurichi A, Miceli R, Camerini T, et al. Prediction of survival in patients with thin melanoma: results from a multi-institution study. J Clin Oncol 2014; 32:2479.
- Balch CM, Gershenwald JE, Soong SJ, et al. Multivariate analysis of prognostic factors among 2,313 patients with stage III melanoma: comparison of nodal micrometastases versus macrometastases. J Clin Oncol 2010; 28:2452.
- León P, Daly JM, Synnestvedt M, et al. The prognostic implications of microscopic satellites in patients with clinical stage I melanoma. Arch Surg 1991; 126:1461.
- Soong SJ, Ding S, Coit D, et al. Predicting survival outcome of localized melanoma: an electronic prediction tool based on the AJCC Melanoma Database. Ann Surg Oncol 2010; 17:2006.
- Balch CM, Soong SJ, Gershenwald JE, et al. Age as a prognostic factor in patients with localized melanoma and regional metastases. Ann Surg Oncol 2013; 20:3961.
- Balch CM, Thompson JF, Gershenwald JE, et al. Age as a predictor of sentinel node metastasis among patients with localized melanoma: an inverse correlation of melanoma mortality and incidence of sentinel node metastasis among young and old patients. Ann Surg Oncol 2014; 21:1075.
- Joosse A, Collette S, Suciu S, et al. Superior outcome of women with stage I/II cutaneous melanoma: pooled analysis of four European Organisation for Research and Treatment of Cancer phase III trials. J Clin Oncol 2012; 30:2240.
- Scoggins CR, Ross MI, Reintgen DS, et al. Gender-related differences in outcome for melanoma patients. Ann Surg 2006; 243:693.
- Joosse A, Collette S, Suciu S, et al. Sex is an independent prognostic indicator for survival and relapse/progression-free survival in metastasized stage III to IV melanoma: a pooled analysis of five European organisation for research and treatment of cancer randomized controlled trials. J Clin Oncol 2013; 31:2337.
- Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2001; 19:3622.
- Callender GG, Egger ME, Burton AL, et al. Prognostic implications of anatomic location of primary cutaneous melanoma of 1 mm or thicker. Am J Surg 2011; 202:659.
- Bello DM, Chou JF, Panageas KS, et al. Prognosis of acral melanoma: a series of 281 patients. Ann Surg Oncol 2013; 20:3618.
- Nguyen JT, Bakri K, Nguyen EC, et al. Surgical management of subungual melanoma: mayo clinic experience of 124 cases. Ann Plast Surg 2013; 71:346.
- van der Ploeg AP, van Akkooi AC, Haydu LE, et al. The prognostic significance of sentinel node tumour burden in melanoma patients: an international, multicenter study of 1539 sentinel node-positive melanoma patients. Eur J Cancer 2014; 50:111.
- Xu X, Chen L, Guerry D, et al. Lymphatic invasion is independently prognostic of metastasis in primary cutaneous melanoma. Clin Cancer Res 2012; 18:229.
- Cymerman RM, Shao Y, Wang K, et al. De Novo vs Nevus-Associated Melanomas: Differences in Associations With Prognostic Indicators and Survival. J Natl Cancer Inst 2016; 108.
- Balch CM, Soong SJ, Murad TM, et al. A multifactorial analysis of melanoma: III. Prognostic factors in melanoma patients with lymph node metastases (stage II). Ann Surg 1981; 193:377.
- Botella-Estrada R, Traves V, Requena C, et al. Correlation of histologic regression in primary melanoma with sentinel node status. JAMA Dermatol 2014; 150:828.
- Ribero S, Osella-Abate S, Sanlorenzo M, et al. Favourable prognostic role of regression of primary melanoma in AJCC stage I-II patients. Br J Dermatol 2013; 169:1240.
- Socrier Y, Lauwers-Cances V, Lamant L, et al. Histological regression in primary melanoma: not a predictor of sentinel lymph node metastasis in a cohort of 397 patients. Br J Dermatol 2010; 162:830.
- Thomas NE, Edmiston SN, Alexander A, et al. Association Between NRAS and BRAF Mutational Status and Melanoma-Specific Survival Among Patients With Higher-Risk Primary Melanoma. JAMA Oncol 2015.
- PACK GT, SCHARNAGEL IM. The prognosis for malignant melanoma in the pregnant woman. Cancer 1951; 4:324.
- Stensheim H, Møller B, van Dijk T, Fosså SD. Cause-specific survival for women diagnosed with cancer during pregnancy or lactation: a registry-based cohort study. J Clin Oncol 2009; 27:45.
- O'Meara AT, Cress R, Xing G, et al. Malignant melanoma in pregnancy. A population-based evaluation. Cancer 2005; 103:1217.
- Daryanani D, Plukker JT, De Hullu JA, et al. Pregnancy and early-stage melanoma. Cancer 2003; 97:2248.
- Lens MB, Rosdahl I, Ahlbom A, et al. Effect of pregnancy on survival in women with cutaneous malignant melanoma. J Clin Oncol 2004; 22:4369.
- Tellez A, Rueda S, Conic RZ, et al. Risk factors and outcomes of cutaneous melanoma in women less than 50 years of age. J Am Acad Dermatol 2016; 74:731.
- Koyanagi K, O'Day SJ, Gonzalez R, et al. Serial monitoring of circulating melanoma cells during neoadjuvant biochemotherapy for stage III melanoma: outcome prediction in a multicenter trial. J Clin Oncol 2005; 23:8057.
- Mocellin S, Hoon D, Ambrosi A, et al. The prognostic value of circulating tumor cells in patients with melanoma: a systematic review and meta-analysis. Clin Cancer Res 2006; 12:4605.
- Fusi A, Collette S, Busse A, et al. Circulating melanoma cells and distant metastasis-free survival in stage III melanoma patients with or without adjuvant interferon treatment (EORTC 18991 side study). Eur J Cancer 2009; 45:3189.
- Hoshimoto S, Shingai T, Morton DL, et al. Association between circulating tumor cells and prognosis in patients with stage III melanoma with sentinel lymph node metastasis in a phase III international multicenter trial. J Clin Oncol 2012; 30:3819.
- Abraha HD, Fuller LC, Du Vivier AW, et al. Serum S-100 protein: a potentially useful prognostic marker in cutaneous melanoma. Br J Dermatol 1997; 137:381.
- Tarhini AA, Stuckert J, Lee S, et al. Prognostic significance of serum S100B protein in high-risk surgically resected melanoma patients participating in Intergroup Trial ECOG 1694. J Clin Oncol 2009; 27:38.
- Aukema TS, Olmos RA, Korse CM, et al. Utility of FDG PET/CT and brain MRI in melanoma patients with increased serum S-100B level during follow-up. Ann Surg Oncol 2010; 17:1657.
- Mårtenson ED, Hansson LO, Nilsson B, et al. Serum S-100b protein as a prognostic marker in malignant cutaneous melanoma. J Clin Oncol 2001; 19:824.
- Winnepenninckx V, Lazar V, Michiels S, et al. Gene expression profiling of primary cutaneous melanoma and clinical outcome. J Natl Cancer Inst 2006; 98:472.
- Gerami P, Cook RW, Russell MC, et al. Gene expression profiling for molecular staging of cutaneous melanoma in patients undergoing sentinel lymph node biopsy. J Am Acad Dermatol 2015; 72:780.
- Berger AC, Davidson RS, Poitras JK, et al. Clinical impact of a 31-gene expression profile test for cutaneous melanoma in 156 prospectively and consecutively tested patients. Curr Med Res Opin 2016; 32:1599.
- Huvos AG, Shah JP, Goldsmith HS. A clinicopathologic study of amelanotic melanoma. Surg Gynecol Obstet 1972; 135:917.
- Moreau JF, Weissfeld JL, Ferris LK. Characteristics and survival of patients with invasive amelanotic melanoma in the USA. Melanoma Res 2013; 23:408.
- Massi D, Pinzani P, Simi L, et al. BRAF and KIT somatic mutations are present in amelanotic melanoma. Melanoma Res 2013; 23:414.
- Cormier JN, Xing Y, Feng L, et al. Metastatic melanoma to lymph nodes in patients with unknown primary sites. Cancer 2006; 106:2012.
- Lee CC, Faries MB, Wanek LA, Morton DL. Improved survival after lymphadenectomy for nodal metastasis from an unknown primary melanoma. J Clin Oncol 2008; 26:535.
- van der Ploeg AP, Haydu LE, Spillane AJ, et al. Melanoma patients with an unknown primary tumor site have a better outcome than those with a known primary following therapeutic lymph node dissection for macroscopic (clinically palpable) nodal disease. Ann Surg Oncol 2014; 21:3108.
- Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 1998; 83:1664.
- Vijuk G, Coates AS. Survival of patients with visceral metastatic melanoma from an occult primary lesion: a retrospective matched cohort study. Ann Oncol 1998; 9:419.
- Lee CC, Faries MB, Wanek LA, Morton DL. Improved survival for stage IV melanoma from an unknown primary site. J Clin Oncol 2009; 27:3489.
- Egberts F, Bergner I, Krüger S, et al. Metastatic melanoma of unknown primary resembles the genotype of cutaneous melanomas. Ann Oncol 2014; 25:246.
- Gos A, Jurkowska M, van Akkooi A, et al. Molecular characterization and patient outcome of melanoma nodal metastases and an unknown primary site. Ann Surg Oncol 2014; 21:4317.
- Dutton-Regester K, Kakavand H, Aoude LG, et al. Melanomas of unknown primary have a mutation profile consistent with cutaneous sun-exposed melanoma. Pigment Cell Melanoma Res 2013; 26:852.
- PROGNOSTIC FACTORS AFFECTING STAGING
- Primary tumor (T)
- - Tumor thickness
- - Mitotic rate
- - Ulceration
- - Thin (T1) melanoma
- Lymphatic involvement (N)
- - Node classification
- - Satellite lesions and in transit metastases
- Distant metastases (M)
- STAGE GROUPING
- Stage I
- Stage II
- Stage III
- Stage IV
- Unknown primary
- DIFFERENCES FROM 2002 TNM SYSTEM
- PROGNOSIS AND SURVIVAL: PREDICTION TOOL
- OTHER PROGNOSTIC FACTORS
- Anatomic location
- Pathologic factors
- Mutation status
- Circulating melanoma cells
- Serum S-100 protein
- Gene expression profiling and proteomics
- AMELANOTIC MELANOMA
- MELANOMA WITH UNKNOWN PRIMARY