Prognostic factors in melanoma outcome and survival

Facial Plast Surg Clin N Am 11 (2003) 33 – 41

Prognostic factors in melanoma outcome and survival Thong T. Le, MD*, Karen T. Pitman, MD, FACS Department of Otolaryngology—Head and Neck Surgery, St. Louis University Health Sciences Center, 3635 Vista at Grand Boulevard, St. Louis, MO 63110, USA

Clinical and pathologic variables that predict the outcome of patients with cutaneous malignant melanoma (CMM) have been extensively investigated for more than 30 years. Recently, the American Joint Commission on Cancer (AJCC) approved the latest revision of the AJCC staging system for cutaneous melanoma to be published in the 2002 Staging Manual [1]. Please refer to the first article of this issue for a full discussion of the new staging system. This revision was based on a critical review of previously identified prognostic factors and an analysis of new prognostic information including data gained from the recent advent of sentinel lymph node biopsy (SLNB) [2,3]. This article reviews the major clinicopathologic factors that influence outcome and survival in various stages of melanoma.

Prognostic factors in localized disease Tumor thickness Since the introduction of the Breslow staging system in 1970 [4], numerous studies have demonstrated that tumor thickness is the single most powerful prognostic factor in localized melanoma [5 – 12]. Tumor thickness correlates with the risk for local recurrence and metastatic involvement [13,14]. For instance, Averbrook et al reported that half of their patients with a tumor thickness greater than 4.0 mm had nodal metastases [15]. The relation of tumor

* Corresponding author. E-mail address: [email protected] (T.T. Le).

thickness to 10-year mortality can be predicted by a nonlinear mathematical model derived from the AJCC melanoma database, which depicts a smooth curve that has no discernable breakpoints (Fig. 1) [2]. Given this relationship of survival to tumor thickness, the AJCC has adopted the use of whole integers (1.0, 2.0, and 4.0 mm) to define the thickness thresholds for the tumor (T)-category in the 2002 melanoma staging system [1]. Ten-year survival rates for patients with tumor thicknesses of less than or equal to 1.0, 1.0 to 2.0, 2.0 to 4.0, and greater than 4.0 mm are 94.5%, 83.3%, 59.9%, and 46.6%, respectively, according to Buttner et al [16]. Ulceration Within tumor thickness categories, ulceration is the most significant predictor of outcome. Ulceration is defined as the absence of an epidermis overlying the major portion of the primary lesion and does not necessarily involve an ulcer crater per se [5,17,18]. Although ulceration is strongly associated with tumor thickness, it is an independent prognostic factor in multivariate analysis [2,19]. Survival rates for patients with ulcerated melanomas diminish to a level equivalent to that for thicker melanomas that are not ulcerated (Fig. 2). In fact, thicker, ulcerated, localized melanomas have worse survival rates compared with some substages of nodal metastases [2]. Ulceration is associated with increased mitotic rate in the primary lesion, evidence that the lesion might be more aggressive and more likely to metastasize [20]. Ulceration has been shown to be a highly reproducible histopathologic feature; it is therefore a highly practical staging tool [21].

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Fig. 1. Observed and predicted 10-year mortality rates of patients with clinically localized melanoma based on a mathematical model from the AJCC melanoma database (n = 15,320; P < 0.0001). (From 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(16):3622 – 34; with permission.)

Level of invasion In 1969, Clark et al [22] developed a widely referenced melanoma classification system based on the level of microinvasion through the layers of dermis and subcutaneous tissue. Later publications have shown that the level of invasion does not reflect prognosis as accurately as tumor thickness [2,3,5, 16,23]. In the subgroup consisting of thin melanomas ( V 1.0 mm), however, the level of invasion provides additional prognostic information. In this subgroup, the level of invasion is more predictive of survival than tumor ulceration, with deep levels of invasion (Clark’s level IV or V) being predictive of worse outcomes [2,16,24]. Pontikes et al [25] reported that thin melanomas with level IV or V invasion were 3.1 times more likely to recur than less invasive lesions. Accordingly, the 10-year survival rates for patients with thin, ulcerated melanomas with level II, III, and IV invasion has been reported to be 85%, 75%, and 70%, respectively [2]. For melanomas thicker than 1.0 mm, level of invasion is not a significant survival predictor compared with other such factors as ulceration, age, or anatomic site. Age and gender Age is an independent prognostic factor for overall survival rate within each of the thickness sub-

groups, with a consistent decrease in survival for each increasing decade of life. In particular, patients with localized disease who are older than 60 years of age have a 9% to 18% decrease in disease-free survival rates compared with patients who are younger than 60 years of age [2,9,15]. Gender is also an independent predictor of survival based on multivariate analysis, albeit to a lesser degree than age; men most commonly have thick, ulcerated CMMs on the trunk, whereas women have thinner, less frequently ulcerated melanomas on the extremities [2,19,26].

Site In multivariate analysis, patients with melanoma of the trunk or head and neck have a poorer prognosis than patients with melanoma of the extremities [2,8,19,27,28]. Balch et al [19] found 10-year survival rates for patients with primary melanomas of the extremity to be 85% as opposed to 70% for patients with truncal and head and neck lesions, a finding that corroborated the association of truncal/ head and neck primaries to metastasize at a higher frequency than extremity primaries [27]. CMM of the head and neck per se bears 5- and 10-year survival rates of 77% and 66%, respectively [29]. The majority of lesions of the head and neck occur in the face, yet scalp lesions have been reported to carry a worse prognosis compared with other head and neck sites

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Fig. 2. Survival curves of patients with localized melanoma stratified according to melanoma thickness and presence or absence of ulceration. (From 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(16): 3622 – 34; with permission.)

[11,29 – 32]. Some studies have not supported this finding, however [33].

melanoma-specific survival rates ranging from 13% to 69% (Table 1). Number of metastatic nodes

Prognostic factors in regional and nodal disease Five-year survival rates for patients with malignant melanoma decrease considerably with the development of nodal metastases, falling to 49% at 5 years and 37% at 10 years [2]. Adding to the armamentarium of surgeons in the last 10 years, preoperative lymphoscintigraphy and SLNB have significantly impacted the staging of melanoma by allowing the determination of nodal status through conservative biopsy techniques, which involve less morbidity and cost [34 – 36]. Pathologic nodal status has been shown in many studies to be the most significant predictor of outcome in patients with clinical N0 disease who are pathologically staged with SLNB or elective lymphadenectomy [2,6,7,37]. According to Balch et al [2], the three most important independent prognosticators in patients with nodal disease are (1) the number of metastatic nodes, (2) nodal tumor burden, and (3) the presence of ulceration in the primary tumor. These three factors, when occurring in different combinations, result in a wide array of survival rates, with 5-year

The number of metastatic nodes is the most significant independent risk factor of regional disease, with an increasing number of nodes signifying a worse melanoma-specific survival rate [2,3]. The grouping for the number of metastatic nodes that correlates best with 5-year survival rates has been shown by Balch et al [2] to be one versus two to three versus greater than or equal to four metastatic nodes. According to a critical review by Buzaid et al [3], in contrast with previous melanoma staging systems, the size of the nodal mass as determined by physical examination does not yield significant prognostic information. Tumor burden Nodal tumor burden (microscopic versus macroscopic) represents the second most significant independent prognostic factor in regional disease. Microscopic tumor burden is defined as nodal metastasis that is not present on clinical examination but is detected pathologically. Macroscopic tumor burden is defined as clinically apparent nodal disease that is

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T.T. Le, K.T. Pitman / Facial Plast Surg Clin N Am 11 (2003) 33–41

Table 1 Five-year survival rates (% F SE) for 1148 stage III (nodal metastases) patients stratified by number of metastatic nodes, ulceration, and tumor burden Microscopic

Macroscopic

Ulceration

1 node

2 – 3 nodes

4 nodes

1 node

2 – 3 nodes

4 nodes

Absent Present

69 F 3.7 52 F 4.1

63 F 5.6 50 F 5.7

27 F 9.3 37 F 8.8

59 F 4.7 29 F 5.0

46 F 5.5 25 F 4.4

27 F 4.6 13 F 3.5

Adapted from 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(16):3622 – 34; with permission.

confirmed pathologically. Patients with microscopic involvement of one, two to three, and greater than or equal to four nodes have a 5-year survival rates of 61%, 56%, and 36%, respectively. These survival rates differed in a statistically significant manner from patients with macroscopic nodal involvement, in whom survival rates are 46%, 27% to 37%, and 24%, respectively [2]. Ulceration The third most significant predictor of poor outcome in regional disease is the presence of ulceration in the primary melanoma lesion [2]. Ulceration is a characteristic of the primary tumor that is predictive of mortality rates in localized and regional diseases, suggesting that ulcerated lesions might have a greater tendency for distant metastasis [15,18,38 – 41]. Age of patient and site of primary lesion Based on multivariate analyses, the patient’s age and the site of the primary lesion are independent prognostic predictors of survival in patients with nodal metastasis [2,42]. Messaris et al [42] reported statistically significant survival differences when examining these two factors in Stage III patients. Patients who were older than 50 years of age had a 5-year survival rate of 17% compared with 36% for patients who were younger than 50 years of age. Meanwhile, patients with primaries of the head and trunk had a 5-year survival rate of 20% compared with 40% for patients with primaries of the extremities. Intralymphatic metastasis Satellite lesions are defined as skin lesions within 2 cm of the primary tumor. In-transit metastases are defined as involving skin or subcutaneous tissue more than 2 cm from the primary tumor but not beyond the regional lymph nodes [43]. Data comparing patients with satellite metastasis, in-transit meta-

stasis, and nodal metastases support that these forms of metastasis have similar survival rates, suggesting that they represent the same disease process of lymphatic dissemination. The concurrent presence of satellite/in-transit metastases and nodal metastases portends a worse prognosis, however. In a review by Buzaid et al [3], previous reports of 10-year survival rates for patients with satellite/in-transit metastases without nodal involvement ranged from 41% to 56%, as opposed to 28% to 35% for patients with satellite/ in-transit metastases with nodal involvement.

Prognostic factors in distant metastasis Site of metastasis The survival of patients with distant metastasis is measured in months rather than years, with death occurring on average between 6 and 18 months after the progression of disease [44]. The site of metastasis has been shown to be the most significant prognostic factor in Stage IV melanoma [2,44 – 49]. Patients with nonvisceral metastasis sites (skin, subcutaneous, and distant lymph nodes) have better 1- and 2-year survival rates than patients with visceral metastasis sites. Patients with lung metastasis have a somewhat better prognosis compared with patients with other visceral sites, but this improved prognosis appears to be true only for 1-year survival, not for 2-year survival (Fig. 3) [2,44,48]. Lactate dehydrogenase level The serum lactate dehydrogenase (LDH) level has been shown in multivariate analyses to be an independent prognostic factor of survival in patients with distant metastasis [47 – 51]. Serum LDH is measured on two or more determinations at the time of staging and, if elevated above normal limits, it is predictive of a poor survival rate [1]. Patients with elevated pretreatment levels of LDH have been reported to have a

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Fig. 3. Survival curves of patients with metastatic melanomas at distant sites (n = 1158). Survival differences between patients with lung metastases and patients with metastases in other visceral sites are statistically significant ( P < 0.0001) for 1-year survival data but not for 2-year survival data. (From 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(16):3622 – 34; with permission.)

median survival time of 6 months as opposed to 11.5 months for patients with normal LDH values [47]. Number of metastases The number of distant metastatic sites also correlates with the survival rate, with the median duration of survival being 7 months for one site, 4 months for two sites, and 2 months for three or more sites [44]. Other more recent publications have confirmed the prognostic value of the number of metastases [45,46,48], but the determination of the number of metastases is highly dependent on the tests and imaging used to diagnose them; hence, its role in staging is controversial.

togenetic subtypes might merely reflect variations in tumor thickness [19,52,53]. A study by Balch et al [19] that stratified melanomas of equivalent thickness according to growth pattern revealed a 10-year survival of 90% for lentigo maligna melanoma, 65% for superficial spreading or nodular types, and 50% for the acral lentiginous type. With regard to CMM of the head and neck, O’Brien et al [29] found that lentigo maligna melanoma resulted in a better 10-year survival rate (86%) than superficial spreading melanoma (68%) and nodular melanoma (56%), confirming data from Urist et al [11] but conflicting with Ringborg et al [54], who did not find that the histogenetic subtype was an independent prognostic factor in head and neck melanoma. Mitotic rate

Other prognostic factors Histogenetic subtypes In localized disease, the survival rates associated with different growth patterns of CMM have been reported to vary, although some investigators have suggested that differences in prognosis between his-

Although related to tumor thickness, mitotic rate in the dermal component of a melanoma lesion has been shown to be an independent prognosticator for localized disease in multivariate analysis [55 – 57]. Clark et al [56] reported 8-year survival rates of 95% for patients with no mitoses, 79.4% for mitotic rates less than 6/mm2, and 38.2% for mitotic rates greater

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than 6/mm2. More recently, Karjalainen et al [57] reported a 5-year, recurrence-free survival rate of 91% in patients with a volume-corrected mitotic index of less than or equal to seven as opposed to 72% for patients with an index greater than seven. Other investigators have reported that the mitotic rate lacks prognostic value [58]. Tumor regression Current consensus defines tumor regression as the presence of extensive fibrosis with segmental replacement of tumor cells and the presence of new blood vessel formation, lymphohistiocytes, and melanophages [59]. In analyzing factors predictive of disease progression in the subgroup of thin melanomas ( V 1.0 mm), some studies have reported that the possible unfavorable impact of tumor regression could mask the original thickness of the tumor [8,60 – 62]. Other studies have failed to confirm these data [63], possibly reflecting the disparity among observers in the histopathologic definition of regression [59]. In a recent study of tumor morphometric parameters, tumor thickness plus regression thickness (T + R) was an independent prognosticator of disease progression [61]. Molecular markers Routine histopathologic (hematoxylin and eosin) examinations of specimens from SLNB and elective lymphadenectomy have reportedly missed 25% to 50% of regional metastatic disease [37,64]. To evaluate for the submicroscopic presence of melanoma cells in lymph nodes, highly sensitive immunohistochemical staining (HMB-45, S-100) and, more recently, molecular biology assays have been developed [65,66]. The prognostic importance of submicroscopic metastases is controversial, however. Shivers et al [66] recently used a reverse transcription – polymerase chain reaction (RT-PCR) assay to detect tyrosinase mRNA, a molecular marker uniquely expressed by normal melanocytes and a majority of melanoma cells. Disease-free and overall survival rates were lower in patients whose sentinel lymph nodes were histologically negative and RTPCR – positive compared with patients with negative results by both techniques. Hence, earlier detection of micrometastases through RT-PCR could yield more accurate prognostic information. The role of further therapeutic intervention (eg, elective lymph node dissection and chemotherapy) in patients who are positive only by the molecular assay is currently being investigated by the national multicenter Sunbelt Melanoma Trial [66,67].

DNA content DNA content is a controversial prognostic factor for localized disease. Aneuploidy has been shown to be a predictor of unfavorable recurrence and diseasefree survival rates, correlating with metastasis and death [68,69]. Its possible role as a prognosticator for regional disease has also been reported [70]. Other investigators have found DNA content to be of limited or insignificant prognostic importance [71,72]. Host cellular response The lack of a host inflammatory response at the tumor base has been described by some observers as yielding an unfavorable prognosis [8,19]. Others have demonstrated that the extent of lymphocytic inflammation at the tumor base is inversely related to tumor thickness [73]. In a series of 287 patients with thin melanomas, Massi et al [61] reported 5-year, disease-free survival rates based on the presence or absence of inflammatory response to be 93.4% and 63.8%, respectively.

Summary Several clinicopathological factors have been identified as influencing outcome and survival in patients with CMM. The most important prognostic determinants in localized disease are the tumor thickness and the presence of ulceration. In the subgroup of thin tumors ( < 1.0 mm), the level of invasion represents the most important prognosticator. In regional disease, the most significant independent predictors of survival are the number of metastatic nodes, the nodal tumor burden, and the presence of ulceration. In distant disease, the most important independent prognosticators are the site of metastatic involvement, the serum LDH level, and the number of metastases. Accordingly, the 2002 AJCC melanoma staging system represents an incorporation of the most recent prognostic data. In the future, further advances in diagnostic and staging techniques (eg, imaging and molecular staging) will undoubtedly lead to new and more accurate prognostic information.

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