Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma

INTRODUCTION — In order to be useful, a staging system must be simple and practical, and must 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 has been incorporated into a staging system that was developed by the American Joint Committee on Cancer (AJCC) in collaboration with the Union for International Cancer Control (UICC). This system relies upon assessments of the primary tumor (T), regional lymph nodes (N), and distant metastatic sites (M).

The eighth edition of the AJCC staging system is based upon 43,792 patients diagnosed with stage I to III melanoma since 1998 (table 1) [1]. The disease-specific survival results from this database are prognostic rather than predictive and predate a number of important advances in the treatment of advanced melanoma, such as checkpoint inhibitor immunotherapy and molecularly targeted therapy, that are likely to have a major impact on outcomes for both rates of relapse and death. Staging markers that not only define risk of recurrence but also predict potential benefit from treatment will need to be developed.

The eighth edition AJCC melanoma staging system is presented here, along with key changes from the seventh edition. Other significant prognostic factors for cutaneous melanoma are also presented here. The clinical approach to staging a newly diagnosed patient is reviewed separately. (See "Staging work-up and surveillance of cutaneous melanoma".)

EIGHTH EDITION AJCC TNM STAGING — The eighth edition of the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system is based upon an evaluation of the primary tumor, the regional lymph nodes and lymphatic drainage, and the presence or absence of distant metastases. The information from TNM staging is then combined to classify patients into AJCC prognostic stage groups. (See 'Prognostic stage group' below.)

The eighth versus the seventh edition AJCC staging system shows greater reproducibility and higher concordance with a reference standard, though these still remain low [2].

Primary tumor (T) — The eighth edition AJCC staging system uses the same parameters that were used in the seventh edition AJCC staging system except that mitotic rate has been removed as a staging criterion for T1 tumors [1,3]. However, mitotic rate remains an important prognostic factor that should be recorded for all patients with T1 to T4 primary cutaneous melanoma.

Tumor thickness measured in mm (Breslow thickness) is a continuous variable that is associated with risk. Staging systems subdivide tumor thickness integer levels primarily for convenience.

The eighth edition AJCC staging system (table 1) defines T category as follows [1]:

●Tumor thickness is recorded to the nearest 0.1 mm rather than 0.01 mm (as was done in the seventh edition), even when tumor thickness is measured to the nearest 0.01 mm. For example, a tumor measuring 0.75 mm thick would be rounded to 0.8 mm, and one measuring 0.74 mm thick would be rounded to 0.7 mm [4].

●T0 melanomas have an unknown or completely regressed primary tumor.

●Tis is used for melanoma in situ.

●TX tumors are those in which the tumor thickness cannot be assessed (for example, if the diagnosis was established by curettage).

●T1 is ≤1 mm, with T1a <0.8 mm without ulceration, and T1b <0.8 mm with ulceration or 0.8 to 1.0 mm with or without ulceration.

●T2 is >1.0 to 2.0 mm, which is subdivided into T2a or T2b based upon the absence or presence of ulceration.

●T3 is >2.0 to 4.0 mm, which is subdivided into T3a or T3b based upon the absence or presence of ulceration.

●T4 is >4.0 mm, which is subdivided into T4a or T4b based upon the absence or presence of ulceration if ulceration status is known.

The impact of T subcategory on melanoma-specific survival is illustrated in the figure (figure 1).

Tumor thickness — Evaluation of the entire tumor from an excisional biopsy, rather than a wedge or punch biopsy, is preferable to ensure measurement of the thickest part of the lesion; a shave biopsy can compromise this evaluation and is therefore discouraged.

The maximal tumor thickness is measured at a right angle to the surface of the skin over the tumor mass. Tumor thickness is measured either from the top of the granular layer of the epidermis or from the base of ulcer (if the surface overlying the entire dermal component is ulcerated) to the deepest invasive cell across the broad base of the tumor in the dermis or subcutis [1]. The deepest point of invasion may be represented by "detached" cell clusters beneath the mass. (See "Pathologic characteristics of melanoma".)

The subdivision of T1 tumors based upon primary tumor thickness in the eighth edition is based upon an analysis of 7568 patients with T1N0 melanoma [4]. In multivariate analysis, melanoma-specific survival was worse for patients with a melanoma ≥0.8 mm thick compared with <0.8 mm (hazard ratio [HR] 1.7). Melanoma-specific survival was also worse for those with ulceration compared with those with nonulcerated melanoma (HR 2.6). Mitotic rate (as a dichotomous variable comparing <1 mitosis/mm² with ≥1 mitosis/mm², as was incorporated as a T1 subcategory criterion in the seventh edition) was not an independent factor on multivariate analysis in these T1 melanoma patients when ulceration and the tumor thickness stratification (<0.8 mm versus 0.8 to 1.0 mm) were also included in the analysis. The distinction using the 0.8 mm threshold was also predictive of positivity on sentinel lymph node biopsy; overall, less than 5 percent of those with a melanoma <0.8 mm thick had a positive sentinel lymph node biopsy, compared with 5 to 12 percent in those with melanoma 0.8 to 1.0 mm thick.

Additional supportive data for the subdivision of T1 tumors come from the following studies, among others [5-7]:

●In a population-based prospective registry of 26,736 patients with thin melanomas, the overall melanoma-specific survival at 20 years was 96 percent [8]. The original cutoff described by Breslow (<0.75 versus >0.75 mm) showed a powerful separation in melanoma-specific survival: the melanoma-specific survival rates at 20 years for depths <0.25, 0.25 to 0.49, 0.50 to 0.74, and 0.75 to 1 mm were 98.3, 98.1, 96.2, and 89.0 percent, respectively. In multivariate analysis, the most important factors associated with survival were tumor thickness (≥0.75 versus <0.25 mm, HR 4.3, 95% CI 2.8-6.8) and age at diagnosis (>65 versus <25 years, HR 2.8, 95% CI 1.8-4.5).

●Another multicenter database series of thin melanoma in 2243 patients with a median follow-up of 10 years correlated unadjusted estimates of survival with clinicopathologic parameters [9]. This study confirmed the importance of Breslow thickness (12-year overall survival rates 97, 92, and 71 percent for melanomas ≤0.5, >0.5 to ≤0.75, and >0.75 to ≤1 mm, respectively). Other important prognostic factors negatively influencing 12-year overall survival included mitotic rate (95 versus 75 percent for <1 versus ≥1 mitoses/mm²), ulceration (58 percent with ulceration versus 95 percent without ulceration), regression ≥50 percent (49 versus 95 percent for ≥50 versus <50 percent), lymphovascular invasion (66 versus 95 percent for present versus absent), and sentinel lymph node status (HR 2.97 positive versus negative).

●The use of a ≤0.8 mm cutoff was also supported by an analysis of 6263 patients from a single institution with a minimum of 10 years of follow-up that included 2117 patients with T1 lesions [10]. The 10- and 20-year melanoma-specific survival rates for those with lesions ≤0.8 mm thick were 93.4 and 85.7 percent, while for those with lesions 0.9 to 1.0 mm thick, the melanoma-specific survival rates were 81.1 and 71.4 percent, respectively. Despite the favorable prognosis for most patients, survival curves continued to decline 10 years after the initial diagnosis.

Ulceration — Ulceration is defined as the absence of an intact epithelium over the melanoma. Ulceration is an important prognostic factor of the primary tumor in the AJCC staging system; it is used to define patient subsets for each tumor thickness group. Outcomes in patients with ulcerated primary tumors are worse than in patients with primary melanomas of the same thickness but without ulceration.

Mitotic rate — Mitotic rate is a significant prognostic factor within all tumor thickness categories, and it should be assessed and recorded in all primary melanomas (figure 2). The recommended approach to determining mitotic rate is described in detail in the eighth edition of the AJCC Cancer Staging Manual [1]. In brief, the area of dermis containing the most mitoses (the "hot spot") is identified. Once the hot spot is identified, mitoses in adjacent fields within a total area of 1 mm² are counted to determine the mitotic rate.

The tumor mitotic rate is not incorporated into the eighth edition AJCC melanoma staging system for the primary tumor [1], unlike the seventh edition [3], where it was a criterion used as a dichotomous variable (ie, <1 mitosis/mm² versus ≥1 mitosis/mm²) in separating T1a and T1b tumors and was the second most important prognostic factor on multivariate analysis. In the analysis of the eighth edition database, univariate analysis for all T1 to T4 melanomas, melanoma-specific survival decreased progressively with increasing mitotic rate (from 97 to 99 percent for those with <1 mitosis/mm² to 77 percent for those with ≥11 mitoses/mm²) (figure 2) [4]. In another observational study of 1918 patients with AJCC eighth edition stage III melanoma, higher mitotic rate was associated with an increased risk of central nervous system (CNS) metastases [11].

Mitotic rate is continuing to be explored across its continuum for its role in the development of clinical tools and further changes in the staging system [12].

Regional involvement — The regional lymph nodes are a common site of metastatic disease from cutaneous melanoma, and regional lymph node spread has a major negative impact on long-term outcome. The clinical approach to the evaluation and management of regional lymph nodes is discussed in detail separately. (See "Evaluation and management of regional nodes in primary cutaneous melanoma".)

N category — For staging purposes, all patients with histologic confirmation of nodal disease (including microsatellites, satellites, and in-transit cutaneous and/or subcutaneous metastases) and without distant metastases are classified as stage III, regardless of the extent of nodal tumor burden. Although all patients with nodal and/or non-nodal regional involvement are classified as stage III (table 1), the prognostic implications vary depending upon the extent of the regional nodal and non-nodal involvement and other features of the primary tumor (figure 3 and figure 4).

In the eighth edition AJCC melanoma staging system, regional lymph node involvement is classified as either "clinically occult" (found microscopically, usually based upon a sentinel lymph node biopsy) or "clinically detected" (on physical examination or by imaging). In the seventh edition AJCC melanoma staging system, regional lymph node involvement was classified as either "microscopic" or "macroscopic," and those terms are no longer used.

In the eighth edition, the AJCC Melanoma Expert Panel continues to note that it is acceptable to classify node-positive metastases based solely on immunohistochemical staining, even for aggregates of a few cells [1].

In the eighth edition, microsatellites, satellites, and in-transit cutaneous and/or subcutaneous metastases are formally stratified according to the number of tumor-involved lymph nodes (table 1). The distinction between satellite lesions and in-transit metastases is not necessary from a clinical perspective since both represent a manifestation of intralymphatic disease. Satellite lesions and in-transit metastases are grouped together and considered intralymphatic in the AJCC staging system [1].

●NX – Nodes not assessable (eg, sentinel node biopsy not performed, previously resected for other reasons).

●N0 – No regional metastases.

●N1 – One involved lymph node, or in-transit, satellite, and/or microsatellite metastases with no tumor-involved nodes. This is subdivided into N1a, N1b, and N1c depending upon the method of detection (clinical versus sentinel node biopsy [eg, clinically occult]) and the location of disease.

●N2 – Two or three tumor-involved nodes, or in-transit, satellite, and/or microsatellite metastases with one tumor-involved node. This is subdivided into N2a, N2b, and N2c depending upon the method of detection of the regional nodal involvement (clinical versus sentinel node biopsy) and the location of disease.

●N3 – Four or more tumor-involved nodes, in-transit, satellite, and/or microsatellite metastases with two or more tumor-involved nodes, or any number of matted nodes with or without in-transit, satellite, and/or microsatellite metastases. This is subdivided into N3a, N3b, and N3c depending upon the method of detection of the nodal involvement (clinical versus sentinel node biopsy), whether or not the nodes are matted, and the location of disease.

Distant metastases (M) — In the eighth edition AJCC melanoma staging system, patients with distant metastases are subcategorized according to the site(s) of disease involvement (table 1) [1]. Key changes compared with the seventh edition (2010) AJCC staging system include the use of serum lactate dehydrogenase (LDH) level to further define each M category and the creation of a fourth category (M1d) based upon the presence of CNS metastases:

●M1a – Metastasis to distant skin, subcutaneous, or lymph node sites

●M1b – Lung metastasis

●M1c – Metastasis to other visceral sites, excluding the CNS

●M1d – Metastasis to the CNS, with or without involvement of other sites

Serum LDH is an important independent prognostic factor in patients with disseminated melanoma; however, an elevated serum LDH no longer automatically places the patient in the M1c category. In the eighth edition, each of the four M1 categories is subdivided with the notation (0) for non-elevated LDH and (1) for elevated LDH (eg, M1b(0) for a patient with lung metastasis only and a non-elevated serum LDH).

PROGNOSTIC STAGE GROUP — The eighth edition American Joint Committee on Cancer (AJCC) melanoma staging system groups patients into four prognostic stage groups based upon the tumor (T), node (N), and metastases (M) parameters [1]. The eighth edition AJCC staging system distinguishes between clinical and pathologic staging.

The details of prognostic group staging are presented in the table (table 2). In brief:

●Stage I – Stage I melanoma is limited to patients with low-risk primary melanomas (T1a, T1b, and T2a) without evidence of regional or distant metastases. Stage I is divided into stages IA and IB based on the thickness of the primary tumor and the presence or absence of primary tumor ulceration. (See 'Primary tumor (T)' above.)

●Stage II – Stage II disease includes primary tumors that are at higher risk of recurrence (T2b, T3a, T3b, T4a, and T4b) but do not have any evidence of lymphatic disease or distant metastases. Stage II is divided into stage IIA, IIB, and IIC depending upon tumor thickness and the presence or absence of primary tumor ulceration. (See 'Primary tumor (T)' above.)

●Stage III – Stage III disease includes pathologically documented involvement of regional lymph nodes and/or the presence of in-transit or satellite metastases (incorporated using N subcategory). Patients with stage III disease are substaged as having stage IIIA, IIIB, IIIC, or IIID disease depending upon the extent of regional lymphatic disease as well as the status of primary tumor ulceration and thickness (incorporated using T subcategory) (figure 5). (See 'Regional involvement' above.)

•Unknown primary – Patients with isolated metastases identified in the lymph nodes, skin, or subcutaneous tissue who do not have an identifiable primary cutaneous melanoma (T0) are classified as pathologic stage III, assuming no other sites of disease are identified after an appropriate staging evaluation. Other sites of metastases from an unknown primary melanoma are classified as stage IV. (See 'Melanoma with unknown primary' below.)

The melanoma-specific survival by substage for patients with stage III melanoma in the eighth edition staging system database is shown in the figure (figure 6).

●Stage IV – The presence of distant metastases defines stage IV disease (M1a to M1d). Central nervous system metastases (M1d) are associated with a particularly poor prognosis. There are no subgroups. (See 'Distant metastases (M)' above.)

OTHER PROGNOSTIC FACTORS — A number of other clinical and pathologic parameters have been analyzed for their ability to predict long-term outcome in patients with cutaneous melanoma. Some of these factors are independent predictors of outcome but are not included in the American Joint Committee on Cancer (AJCC) staging system. Data continues to evolve for the role of integrated risk models that build upon the AJCC staging system, enhance predictive and prognostic assessment, and support clinical decision-making [13].

Age — Advancing age is associated with worse prognosis. Young patients, despite often having aggressive features associated with their tumor at the time of diagnosis, have a better prognosis, which suggests that their tumors may have a distinct biology. Additionally, age-related immune competence in young patients may also influence prognosis.

Historical data on the impact of age were analyzed in 11,088 cases of stage I, II, and III melanoma in the AJCC Melanoma Staging Database used for the seventh edition AJCC melanoma staging system [14]. Contemporary studies are planned to further analyze the impact of age.

●In the entire study group, increasing age was associated with thicker primary tumors, increased mitotic rate, and an increasing percentage of tumors with ulceration.

●In younger patients, the most common location of the primary tumor was the trunk, with lesions of the head and neck the least common. By contrast, this pattern was reversed in those more than 80 years old, with the trunk the least common site and the head and neck the most common.

●For the 10,233 patients with stage I or II disease (ie, negative regional nodes) at presentation, multivariate analysis found that age was an independent prognostic feature for survival, along with sex, primary tumor thickness, mitotic rate, ulceration of the primary tumor, and anatomic site.

●In the 775 patients with stage III disease, multivariate analysis identified four factors independently associated with survival: age, number of involved lymph nodes, presence of ulceration, and mitotic rate.

●Melanoma occurring in patients less than 20 years old tended to have more aggressive features in the primary tumor (high mitotic rate, ulceration) compared with that occurring in patients more than 20 years old, but survival outcomes were better than those seen with older patients. Patients more than 70 years old had the most aggressive findings in their primary tumor and have a worse overall survival.

●Other studies have also suggested that older patients are less likely to have tumors that contain mutations in BRAF [15]. (See "The molecular biology of melanoma", section on 'Genetic abnormalities in melanoma'.)

In another analysis of the seventh edition AJCC Melanoma Staging Database, the impact of age on sentinel lymph node involvement was studied in patients with clinical stage I or II disease who underwent sentinel lymph node biopsy as part of their initial evaluation [16]. Increasing age was associated with decreasing incidence of sentinel lymph node involvement on multifactorial analysis; the highest incidence of sentinel lymph node involvement was 25.8 percent for those <20 years of age, compared with 15.5 percent in those 80 years old. Despite this, older age was associated with increased five-year mortality for patients with stage II disease (38 percent for those over 70 years of age compared with 20 percent for those age 20 to 40 years).

Sex — Females are more likely than males to have thin lesions that are not ulcerated and are located on the extremities, all favorable prognostic factors. Even after allowing for these differences, female sex appears to be associated with a better prognosis for patients with stage I or II melanoma:

●In a multivariate analysis of 10,233 patients in the seventh edition AJCC Melanoma Staging Database, female sex was significantly associated with better prognosis after incorporating data from other prognostic factors [17].

●In an analysis of 2672 patients with stage I/II melanoma enrolled in four adjuvant therapy trials conducted by the European Organisation for Research and Treatment of Cancer (EORTC), female sex was associated with significantly better overall and disease-specific survival (hazard ratios [HRs] 0.70 and 0.74, respectively) [18].

●In the Sunbelt Melanoma Trial, a multivariate analysis of 1829 patients (all of whom had undergone sentinel lymph node biopsy) found that male sex was an independent risk factor for worse overall survival (relative risk [RR] 1.45, 95% CI 1.21-1.77) [19].

In patients with stage III or IV disease, a pooled analysis of five randomized trials conducted by the EORTC (including 2734 patients with stage III disease and 1306 with stage IV disease) found that females had significantly better relapse-free and disease-specific survivals compared with males [20].

Anatomic location — Cutaneous melanomas arising on the head and neck area, trunk, and possibly, the lower extremity have a worse prognosis than those arising on the upper extremity [17,21,22]. However, the site of the primary tumor is less important than the factors included in the AJCC staging system (eg, tumor thickness, mitotic rate, ulceration, nodal involvement).

Pathologic factors — A number of pathologic factors that are not formally included in the AJCC staging system have been studied for their potential effect on prognosis:

●Tumor burden within a sentinel lymph node – As noted above, pathologic involvement of a sentinel lymph node (eg, largest diameter of metastatic sentinel lymph node deposit) is one of the key prognostic factors [23]. In addition, a larger tumor burden within a tumor-involved sentinel lymph node (eg, size >1 mm, nonsubcapsular location, increasing tumor penetrative depth) appears to be associated with worse disease-free and melanoma-specific survival (MSS) [24]. In the International Melanoma Database and Discovery Platform analysis that informed the eighth edition AJCC melanoma staging system, univariate analysis demonstrated that increasing sentinel lymph node tumor burden (based on the greatest maximum dimension of the largest discrete, deposit of metastatic melanoma) was associated with worse MSS. The prognostic significance of tumor features within a sentinel lymph node remains an area of active investigation [4].

●Growth pattern – The four major growth patterns (or histologic subtypes) are lentigo maligna melanoma, nodular melanoma, superficial spreading melanoma, and acral lentiginous melanoma. An observational study of close to 120,000 patients with melanoma suggested that the nodular growth pattern was an independent risk factor for death, controlling for thickness, ulceration, and stage (although the seventh edition AJCC staging system, which was the most recent at the time, was used in this study) [25]. The same staging criteria, however, should be used for melanomas of any growth pattern.

●Lymphatic invasion – Lymphatic invasion within the tumor was identified as a negative prognostic factor in a retrospective analysis of 251 patients treated for vertical growth phase melanoma between 1972 and 1991 [26]. Patients did not have regional lymph node involvement at presentation and had at least a 10-year follow-up. The endpoint was metastasis-free survival at 10 years. A multivariate analysis that included thickness of the primary lesion, mitotic rate, and anatomic site found that lymphatic invasion was a statistically significant independent negative prognostic factor (odds ratio 2.2).

●Nevus association – The clinical significance of atypical nevi lies in their association with an increased risk of melanoma, and individuals with atypical nevi have a 3- to 20-fold higher risk of developing a melanoma compared with individuals without atypical nevi. Approximately 20 to 30 percent of melanomas are histopathologically associated with a nevus. (See "Atypical (dysplastic) nevi".)

Nevus-associated melanomas appear to be associated with a better prognosis than those arising de novo [27]. A retrospective analysis of two cohorts included a total of 547 nevus-associated melanomas and 1602 de novo melanomas. The de novo melanomas were associated with increased tumor thickness, higher stage, older age, ulceration, nodular subtype, and worse overall survival. In multivariate analysis, de novo classification was an independent poor prognostic indicator in one of the two cohorts (HR 1.70, 95% CI 1.19-2.44, in one cohort and HR 1.27, 95% CI 0.93-1.75, in the other cohort).

●Other histopathologic findings – Other pathologic factors that have been associated with an improved prognosis in some reports include the presence of lymphocyte infiltration in a tumor and histologic evidence of regression in the primary tumor [28-32]. However, multivariate analyses of large series (assessed in an era prior to the availability of more contemporary treatments such as immunotherapy) have not established a definitive relationship with these factors.

●Desmoplastic melanoma – Desmoplastic melanoma is a rare variant that comprises less than 5 percent of cases. Although desmoplastic melanomas may be locally aggressive, the prognosis appears to be better than with other advanced lesions. Although there may be prognostic differences for patients with desmoplastic melanoma, the same AJCC staging system is used in these cases [3]. The clinical features of desmoplastic melanomas and desmoplastic neurotropic melanomas are discussed separately.

Mutation status — The presence of characteristic mutations in the mitogen-activated protein kinase (MAPK) pathway is associated with other poor prognosis features. However, as these studies were conducted in the era before the availability of effective molecularly targeted therapy for patients with BRAF mutations, further investigation is warranted to re-evaluate these observations.

As an example, in a series of 912 patients with a first primary melanoma diagnosed in 2000 and a median follow-up of 7.6 years, BRAF and NRAS mutations were identified in 30 and 13 percent of cases, respectively, and 57 percent were wild type [33]. Compared with wild-type melanomas, those with BRAF and NRAS mutations were more likely to present with higher stage primary tumors. There was a statistically nonsignificant trend toward increased melanoma-specific mortality in those with mutations and T2b or higher primary tumors, but the number of deaths was limited.

Pregnancy — The influence of pregnancy on melanoma is discussed separately. (See "Melanoma and pregnancy".)

Circulating melanoma cells and circulating tumor DNA (ctDNA) — The presence of circulating melanoma cells [34-37] or circulating tumor DNA (ctDNA) [38-40] in the peripheral blood may identify patients with melanoma at increased risk for relapse. However, this approach has not been validated for general use, and further data are necessary. (See "Initial management of uveal and conjunctival melanomas", section on 'Prognosis'.)

●Circulating melanoma cells – Several studies and a systematic review of the literature suggest that the presence of circulating melanoma tumor cells (using reverse transcriptase polymerase chain reaction [RT-PCR] for tyrosinase and other markers) may identify patients at increased risk for relapse [34-37,41]. As an example, samples from 320 patients with stage III melanoma were analyzed with a panel of three markers (MART-1, MAGE-A3, GalNAc-T) [41]. All patients had undergone a complete lymph node dissection and were enrolled in an adjuvant trial. Patients whose samples were positive for two or more of these biomarkers had significantly worse distant metastasis-free survival and reduced recurrence-free survival (HRs 2.1 and 1.7, respectively).

●Circulating tumor DNA – Similarly, in a separate observational study, detection of preoperative ctDNA was associated with reduced melanoma-specific survival in a cohort of 174 patients with stage III melanoma receiving completion lymph node dissection [38].

Gene expression profiling and proteomics — We do not routinely use gene expression profiling (GEP) in the risk classification or management of cutaneous melanoma. Although the use of GEP in patients with cutaneous melanoma is controversial, as some studies suggest that GEP offers improved diagnostic and prognostic utility [42,43], this approach is consistent with consensus guidelines from the Melanoma Prevention Working Group (MPWG) and the National Comprehensive Cancer Network (NCCN) [44,45]. By contrast, GEP is used in the routine management of uveal melanoma, which is discussed separately. (See "Initial management of uveal and conjunctival melanomas", section on 'Prognosis' and "Initial management of uveal and conjunctival melanomas", section on 'Posttreatment systemic surveillance'.)

GEP and proteomics have been used to characterize tumor, serum, and other biologic samples from patients with cutaneous melanoma. While these have improved our understanding of the molecular complexities in melanoma [43], there are limited prospective data regarding the clinical applications of GEP in modern, unselected patient populations with cutaneous melanoma [46]. Further data are required to confirm their prognostic value in patients with melanoma and to evaluate their use to guide therapy [47,48]. (See "Pathologic characteristics of melanoma", section on 'Gene expression profiling'.)

Various commercial gene expression profile testing platforms are available for clinical use; these platforms have been developed (or are in development) in patients with local (stage I and II) or locoregional (stage III) cutaneous melanoma [49-52]. However, in such patients, we agree with the MPWG and NCCN that there are insufficient prospective data to support the use of GEP for either risk classification or routine management (eg, post-treatment surveillance, eligibility for sentinel lymph node biopsy, or choice of adjuvant therapy) [44,45]. Therefore, we await further data before incorporating this approach into our standard clinical practice.

AMELANOTIC MELANOMA — In approximately 2 percent of cases, melanoma can present without clinical or histopathologic evidence of pigmentation [53]. As such, amelanotic melanomas can present a difficult challenge that may result in a significant delay in diagnosis and implementation of treatment, which may contribute to a worse prognosis. (See "Dermoscopic evaluation of skin lesions".)

An analysis of 628 patients with amelanotic melanoma identified in the Surveillance, Epidemiology, and End Results (SEER) database found that amelanotic melanomas are significantly more likely to present with regional or distant metastases, as well as other unfavorable prognostic factors, compared with melanotic melanoma [54]. These factors may all contribute to the poorer survival seen in amelanotic melanoma, rather than reflecting an increased biologic aggressiveness. For patients with regional or distant metastases, there were no statistically significant differences in the five-year melanoma-specific survival.

In addition, in one series, patients with amelanotic melanoma were more likely to have BRAF or KIT mutations, which may have important implications for subsequent management [55].

MELANOMA WITH UNKNOWN PRIMARY — Occasional patients present with metastatic melanoma involving lymph nodes, cutaneous sites, or visceral sites. These patients should be staged using the same American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system as for those with a known primary (table 2). (See 'Eighth edition AJCC TNM staging' above and 'Prognostic stage group' above.)

Patients who present with only lymph node metastases have a survival similar to (or slightly better than) those with lymph node metastases and a known primary, and they should be treated as if they had stage III disease [56-58]. Patients who present with widely metastatic disease have a survival that is similar to or slightly better than those with metastatic disease and a known primary site, particularly if such an analysis incorporates other prognostic characteristics, such as stage or number of metastatic sites [59-61]. (See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites" and "Adjuvant and neoadjuvant therapy for cutaneous melanoma".)

A detailed history and physical examination to search for a potential primary, with a focus on the surrounding skin in patients presenting with nodal or soft tissue disease, is indicated for patients presenting with melanoma from an unknown primary. A detailed search for an occult mucosal or ocular primary melanoma is generally not indicated. Nonetheless, an occult anorectal melanoma may rarely be the origin of inguinal nodal basin metastatic melanoma with initially unknown primary melanoma.

Data on the molecular characterization of tumors from an unknown primary have observed that the frequency of BRAF and NRAS mutations is similar to that of cutaneous melanomas with a known primary, strongly suggesting that these tumors largely result from regressed cutaneous primaries [62-64]. (See "The molecular biology of melanoma", section on 'Genetic abnormalities in melanoma'.)

SUMMARY AND RECOMMENDATIONS

●Staging and prognosis of cutaneous melanoma – Staging and prognosis of cutaneous melanoma are based upon the eighth edition American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) system (table 1 and table 2).

This staging system incorporates information about the primary tumor (T), regional lymphatics (N), the potential distant metastatic sites (M), and (for patients with stage IV disease only) the nonanatomic factor serum lactate dehydrogenase (LDH). (See 'Eighth edition AJCC TNM staging' above and 'Prognostic stage group' above.)

●Melanoma of unknown primary – Patients with metastatic melanoma to lymph nodes, skin, or subcutaneous tissues without a known primary site of origin are likely of cutaneous origin (based on tumor mutation patterns) and should be classified and managed using a similar approach to patients with stage III disease. (See 'Melanoma with unknown primary' above and 'Prognostic stage group' above and "Adjuvant and neoadjuvant therapy for cutaneous melanoma".)

●Prognostic accuracy of AJCC staging system – Disease-specific survival outcomes that informed the eighth AJCC melanoma staging system are likely underestimated, as these analyses include patient data that largely predate a number of important advances in the treatment of advanced melanoma, such as checkpoint inhibitor immunotherapy and molecularly targeted therapy. These data will benefit from reassessment using studies that include patients treated with more contemporary regimens. (See 'Introduction' above.)

●Other prognostic factors – Other prognostic factors not formally included in the AJCC staging system remain areas of active investigation and will likely inform further staging system revisions and/or integrative risk models. Examples of such factors include age, sex, sentinel lymph node tumor burden, mitotic rate, and circulating tumor DNA (ctDNA) or melanoma cells. (See 'Other prognostic factors' above and 'Mitotic rate' above.)

●Is there a role for gene expression profiling? – We do not routinely use gene expression profiling (GEP) in the risk classification or management of cutaneous melanoma. The use of GEP in this patient population is controversial, and we await further prospective data before incorporating this approach into our standard clinical practice. (See 'Gene expression profiling and proteomics' above and "Initial management of uveal and conjunctival melanomas".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Merrick Ross, MD, who contributed to earlier versions of this topic review.