Prognostic Factors for Melanoma

The current melanoma staging system, as defined by the American Joint Committee on Cancer (AJCC), is the standard by which melanoma prognosis is determined. This article focuses on the components of the AJCC melanoma staging system regarding patient prognosis. In addition, this article summarizes the other commonly researched clinical and histologic melanoma prognostic factors and reviews the recent advancements in genetic biomarkers associated with prognosis.

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The AJCC melanoma staging system defines prognosis based on the standard TNM (tumor, regional nodes, distant metastasis) classification to create 4 (I–IV) clinical and pathologic stages.
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The tumor thickness serves as the main prognostic factor, with the mitotic rate and ulceration further subcategorizing the Breslow thickness to increase its prognostic accuracy.
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For advanced disease, the determination of lymph node involvement is the first step in evaluating for systemic involvement and predicting survivability.
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The AJCC has created an online melanoma prediction tool ( www.melanomaprognosis.org ) to more accurately determine melanoma prognosis for localized and regional disease.
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Research into identifying the major genetic pathways that contribute to the development of melanoma has created a new model to determine prognosis and develop new therapeutic options.

Key Points

Introduction

The pioneering work by Drs Wallace H. Clark, Jr and Alexander Breslow established the framework for today’s melanoma prognosis models. Following the establishment of the Clark levels of invasion and the Breslow thickness in 1969 and 1970, respectively, Clark and colleagues, in 1989, described 6 independently predictive factors (mitotic rate, tumor-infiltrating lymphocytes, tumor thickness, anatomic site, patient sex, and histologic regression) that, when analyzed with tumor thickness, became the standard melanoma prognostic model. Today, the American Joint Committee on Cancer (AJCC) serves as the dominant staging system for melanoma, with the Breslow thickness being the principle component in determining outcomes. As medical science evolves into a genetic approach to understanding the balance between disease and health, research on genetic biomarkers has introduced an additional factor that influences prognosis. This article summarizes the current melanoma AJCC staging system and predictive model, discusses the more recent larger clinical studies and current reviews on common prognostic factors, and summarizes recent genetic biomarker development to understand the current staging system and future implications.

2009 AJCC melanoma staging and classification

The AJCC melanoma staging system defines prognosis based on the standard TNM (tumor, regional nodes, distant metastasis) classification to create 4 (I–IV) clinical and pathologic stages ( Tables 1 and 2 ). This classification system is pivotal because it unifies the staging nomenclature to predict the prognosis and determine the appropriate treatment.

Table 1

TNM melanoma classification

Classification	Thickness (mm)	Ulceration Status/Mitoses
T
Tis	NA	NA
T1	≤1.00	a: Without ulceration and mitosis <1/mm ²
T1	≤1.00	b: With ulceration or mitoses ≥1/mm ²
T2	1.01–2.00	a: Without ulceration
T2	1.01–2.00	b: With ulceration
T3	2.01–4.00	a: Without ulceration
T3	2.01–4.00	b: With ulceration
T4	>4.00	a: Without ulceration
T4	>4.00	b: With ulceration
N	Number of Metastatic Nodes	Nodal Metastatic Burden
N0	0	NA
N1	1	a: Micrometastasis ^a
N1	1	b: Macrometastasis ^b
N2	2–3	a: Micrometastasis ^a
		b: Macrometastasis ^b
		c: In-transit metastases/satellites without metastatic nodes
N3	4+ metastatic nodes, or matted nodes, or in-transit metastases/satellites with metastatic nodes
M	Site	Serum LDH
M0	No distant metastases	NA
M1a	Distant skin, subcutaneous, of nodal metastases	Normal
M1b	Lung metastases	Normal
M1c	All other visceral metastases	Normal
M1c	Any distant metastasis	Elevated

Abbreviations: NA, not applicable; LDH, lactate dehydrogenase.

Adapted from Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009;27:6199–206; with permission.

a Micrometastases are diagnosed after sentinel lymph node biopsy.

b Macrometastases are defined as clinically detectable nodal metastases confirmed pathologically.

Table 2

TNM melanoma staging

	Clinical Staging ^a				Pathologic Stagingt ^b
	T	N	M		T	N	M
0	Tis	N0	M0	0	Tis	N0	M0
IA	T1a	N0	M0	IA	T1a	N0	M0
IB	T1b	N0	M0	IB	T1b	N0	M0
IB	T2a	N0	M0	IB	T2a	N0	M0
IIA	T2b	N0	M0	IIA	T2b	N0	M0
IIA	T3a	N0	M0	IIA	T3a	N0	M0
IIB	T3b	N0	M0	IIB	T3b	N0	M0
IIB	T4a	N0	M0	IIB	T4a	N0	M0
IIC	T4b	N0	M0	IIC	T4b	N0	M0
III	Any T	N > N0	M0	IIIA	T14a	N1a	M0
				IIIA	T14a	N2a	M0
				IIIB	T14b	N1a	M0
					T14b	N2a	M0
					T14a	N1b	M0
					T1-4a	N2b	M0
					T14a	N2c	M0
				IIIC	T1-4b	N1b	M0
					T14b	N2b	M0
					T14b	N2c	M0
					Any T	N3	M0
IV	Any T	Any N	M1	IV	Any T	Any N	M1

Adapted from Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009;27:6199–206; with permission.

a Clinical staging includes microstaging of the primary melanoma and clinical/radiologic evaluation for metastases. By convention, it should be used after complete excision of the primary melanoma with clinical assessment for regional and distant metastases.

b Pathologic staging includes microstaging of the primary melanoma and pathologic information about the regional lymph nodes after partial (ie, sentinel lode biopsy) or complete lymphadenectomy. Pathologic stage 0 or stage IA patients are the exception; they do not require pathologic evaluation of their lymph nodes.

The T classification describes the state of the primary tumor by the thickness, presence of ulceration, and mitotic rate. The N designation signifies the degree of regional lymph node involvement subcategorized by microscopic and macroscopic disease, and the M category defines the presence and location of distant metastatic disease. The current melanoma TNM classification system is predominantly an anatomic and pathologic staging system; the Breslow thickness continues to be the main prognostic factor. The 2009 classification introduced a few significant modifications to the 2002 classification ( Table 3 ). The mitotic rate in the T category replaces the Clark level of invasion in the 2009 staging system and the integration of immunohistochemical tumor detection with no lower tumor threshold in the N category has also been added. The AJCC’s prognosis determinations were based on a multivariate analysis, using the Cox proportional hazards model, of prospective data on 30,946 patients with stages I, II, and III melanoma and 7972 patients with stage IV disease in the AJCC melanoma staging database. Survival curves were created through the Kaplan-Meier product-limit method and compared using the log-rank test.

Table 3

Differences between the sixth edition (2002) and the seventh edition (2009) of the melanoma staging system

Factor	Sixth Edition Criteria	Recommended Seventh Edition Criteria	Comments
Thickness	Primary determinant of T staging	Same	Thresholds of 1.0, 2.0, and 4.0 mm
Level of invasion	Used only for defining T1 melanomas	Same	Used as a default criterion only if mitotic rate cannot be determined
Ulceration	Included as a secondary determinant of T and N staging	Same	Signifies a locally advanced lesion; dominant prognostic factor for grouping stages I, II, and III
Mitotic rate per square millimeter	Not used	Used for categorizing T1 melanoma	Mitosis ≥1/mm ²used as a primary criterion for defining T1b melanoma
Satellite metastases	In N category	Same	Merged with in-transit lesions
Immunochemical detection of nodal metastases	Not included	Included	Must include at least 1 melanoma-associated marker (eg, HMB-45, Melan-A, MART-1) unless diagnostic cellular morphology is present
0.2 mm threshold of defined N+	Implied	No lower threshold of staging N+ disease	Isolated tumor cells or tumor deposits <0.1 mm meeting the criteria for histologic or immunohistochemical detection of melanoma should be scored as N+
Number of nodal metastases	Primary determinant of N staging	Same	Thresholds of 1 v 2–3 v 4+ nodes
Metastatic volume	Included as a second determinant of N staging	Same	Clinically occult (microscopic) nodes are diagnosed at sentinel node biopsy v clinically apparent (macroscopic) nodes diagnosed by palpation or imaging studies or by the finding of gross (not microscopic) extracapsular extension in a clinically occult node
Lung metastases	Separate category as M1b	Same	Has a somewhat better prognosis than other visceral metastases
Elevated serum LDH	Included as a second determinant of M staging	Same	Recommend a second confirmatory LDH level if elevated
Clinical vs pathologic staging	Sentinel node results incorporated into definition of pathologic staging		Large variability in outcome between clinical and pathologic staging; sentinel node staging encouraged for standard patient care should be required before entry into clinical trials