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Final Version of the American Joint Committee on Cancer Staging System for Cutaneous Melanoma

From the Johns Hopkins Medical Institutions, Baltimore, MD; American Society of Clinical Oncology, Alexandria, VA; Hospital Sirio Libanes, San Paulo, Brazil; University of Alabama at Birmingham, Birmingham, AL; Beth Israel Deaconess Medical Center and Massachusetts General Hospital, Boston, MA; Istituto Nazionale Tumori and World Health Organization Melanoma Program, Milan, Italy; Memorial Sloan-Kettering Cancer Center, New York, NY; Methodist Hospital Cancer Center, Memphis, TN; University of Texas, M.D. Anderson Cancer Center, Houston, TX; University of Pittsburgh Medical Center, Pittsburgh, PA; University of Louisville Medical Center, Louisville, KY; John Wayne Cancer Institute, Santa Monica, CA; H. Lee Moffit Cancer Center, University of South Florida, Tampa, FL; University of Washington Medical Center, Seattle, WA; and Sydney Melanoma Unit, University of Sydney, Sydney, New South Wales, Australia.

Address reprint requests to Charles M. Balch, MD, American Society of Clinical Oncology, 1900 Duke St, Ste 200, Alexandria, VA 22314; email: balchc{at}asco.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION STATISTICAL METHODS STAGING FOR LOCALIZED MELANOMA:... STAGING FOR REGIONAL METASTATIC... STAGING FOR DISTANT METASTATIC... DISCUSSION REFERENCES

 
PURPOSE: To revise the staging system for cutaneous melanoma under the auspices of the American Joint Committee on Cancer (AJCC).

MATERIALS AND METHODS: The prognostic factors analysis described in the companion publication (this issue), as well as evidence from the published literature, was used to assemble the tumor-node-metastasis criteria and stage grouping for the melanoma staging system.

RESULTS: Major changes include (1) melanoma thickness and ulceration but not level of invasion to be used in the T category (except for T1 melanomas); (2) the number of metastatic lymph nodes rather than their gross dimensions and the delineation of clinically occult (ie, microscopic) versus clinically apparent (ie, macroscopic) nodal metastases to be used in the N category; (3) the site of distant metastases and the presence of elevated serum lactic dehydrogenase to be used in the M category; (4) an upstaging of all patients with stage I, II, and III disease when a primary melanoma is ulcerated; (5) a merging of satellite metastases around a primary melanoma and in-transit metastases into a single staging entity that is grouped into stage III disease; and (6) a new convention for defining clinical and pathologic staging so as to take into account the staging information gained from intraoperative lymphatic mapping and sentinel node biopsy.

CONCLUSION: This revision will become official with publication of the sixth edition of the AJCC Cancer Staging Manual in the year 2002.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION STATISTICAL METHODS STAGING FOR LOCALIZED MELANOMA:... STAGING FOR REGIONAL METASTATIC... STAGING FOR DISTANT METASTATIC... DISCUSSION REFERENCES

 
THE AMERICAN JOINT Committee on Cancer (AJCC) has now formally approved the final version of a revised melanoma staging system, which is described herein, along with operational definitions. The final version is similar to the initial recommendations from the AJCC Melanoma Staging Committee published last year.¹ Subsequent to the published recommendations, a number of clinicians made comments and recommendations to members of the AJCC Melanoma Staging Committee. In addition, a major database analysis of prognostic factors involving 17,600 patients from 13 cancer centers and organizations was performed to validate the original proposal.² Results from the prognostics factors analyses, as well as input from melanoma clinicians, were used by the AJCC Melanoma Staging Committee to make final adjustments to the melanoma staging system, changes that largely impacted the stage grouping criteria. The AJCC Executive Committee has approved the final version of the melanoma staging system. It will become official with publication of the sixth edition of the AJCC Cancer Staging Manual in the year 2002.

The AJCC Melanoma Staging Committee used the following guidelines to determine which criteria should be used in the tumor-node-metastasis (TNM) classification and the stage groupings. First, the staging system must be practical, reproducible, and applicable to the diverse needs of all medical disciplines. Second, the criteria must accurately reflect the biology of melanoma based on consistent outcome results of patients treated at multiple institutions from multiple countries. Third, the criteria used must be evidence-based and reflect the dominant prognostic factors consistently identified in Cox multivariate regression analyses. Fourth, the criteria must be relevant to current clinical practice and regularly incorporated in clinical trials. Fifth, the required data must be sufficiently easy for tumor registrars to identify in medical records to code staging information.

The final version of the TNM categories is defined in Table 1, and the final stage groupings are in Table 2. All survival rates are actuarial calculations of melanoma-specific survival. Fifteen-year survival rates for patients with stages I to IV melanoma are shown in Fig 1. A summary of survival rates and the demographics of the melanoma patient database used to validate the staging criteria is listed in Table 3 and described in the companion publication (this issue).² These definitions, as recommended by the AJCC Melanoma Staging Committee and approved by both the AJCC Executive Committee and the International Union Against Cancer (UICC) TNM Committee, incorporate substantial revisions from the previous (1997) version of the melanoma staging categories and classifications. In addition, the revised melanoma staging system has been approved by the World Health Organization Melanoma Program as well as the European Organization for Research and Treatment of Cancer Melanoma Group in a recent publication.³

View larger version (19K): [in this window] [in a new window]   Fig 1. Fifteen-year survival curves comparing localized melanoma (stages II and I), regional metastases (stage III), and distant metastases (stage IV). The numbers in parentheses are patients from the AJCC melanoma staging database used to calculate the survival rates. The differences between the curves are significant (P < .0001).

	STATISTICAL METHODS

TOP ABSTRACT INTRODUCTION STATISTICAL METHODS STAGING FOR LOCALIZED MELANOMA:... STAGING FOR REGIONAL METASTATIC... STAGING FOR DISTANT METASTATIC... DISCUSSION REFERENCES

	STAGING FOR LOCALIZED MELANOMA: STAGES I AND II

TOP ABSTRACT INTRODUCTION STATISTICAL METHODS STAGING FOR LOCALIZED MELANOMA:... STAGING FOR REGIONAL METASTATIC... STAGING FOR DISTANT METASTATIC... DISCUSSION REFERENCES

 
The primary criteria for the T classification are tumor thickness (measured in millimeters) and the presence or absence of ulceration (determined histopathologically). Ten-year survival rates for each of the T categories in clinically staged patients are shown in Fig 2. Stage groupings for localized melanomas are defined in Table 2. The sole difference in the definitions of clinical versus pathologic stage grouping is whether the regional lymph nodes are staged by clinical/radiologic examination or by pathologic examination (after partial or complete lymphadenectomy). Fifteen-year survival rates for the entire group of clinically localized melanoma patients are shown in Fig 3.

View larger version (66K): [in this window] [in a new window]   Fig 2. Ten-year survival rates comparing the different T categories and the stage groupings for stages I and II melanoma. Note that the groupings upstage patients with melanoma ulceration with the next level T substage of patients with thicker, nonulcerated melanomas.

View larger version (18K): [in this window] [in a new window]   Fig 3. Fifteen-year survival curves for the stage groupings of patients with localized melanoma. See Table 2 for the stage grouping definitions. Numbers of patients from the AJCC melanoma staging database are shown in parentheses. The differences between the survival curves are significant (P < .0001)

Because the majority of patients with clinically localized melanoma present with T1 melanomas, a separate statistical analysis was performed to examine different thresholds at 0.1-mm increments of measured thickness between 0.90 mm and 1.1 mm. Because no significant survival differences were observed, a more clinically convenient and widely used threshold of 1.0 mm could appropriately be used for the threshold of T1 melanomas, while T2 melanomas were defined as those measuring 1.01 mm to 2.0 mm in thickness. T3 melanomas are defined as those with a thickness of 2.01 to 4.0 mm and T4 melanomas as those with a thickness of more than 4.0 mm.

Melanoma Ulceration
Melanoma ulceration is defined as the absence of an intact epidermis overlying a major portion of the primary melanoma based on microscopic examination of the histologic sections.^6,7,13,14 It can easily be distinguished from artifactual or traumatic disruption of the epidermis. Traumatically induced defects are associated with hemorrhage, brightly eosinophilic fibrin exudation at the site, and an architectural defect that usually defines the agent leading to the trauma, such as an insect bite or an excoriation. In fact, the interpretation of melanoma ulceration among pathologists is one of the most reproducible of all the major histopathologic features.^15,16 This definition encompasses surface defects from a total absence of the epidermis overlying the tumor to an excavated area including the epidermis and a portion of the tumor. The surface may exhibit scattered debris.

Melanoma ulceration heralds such a high risk for metastases that its presence upstages the prognosis of all such patients, compared with patients who have melanomas of equivalent thickness without ulceration. Thus, survival rates for patients with an ulcerated melanoma are proportionately lower than those of patients with a nonulcerated melanoma of equivalent T category but are remarkably similar to those of patients with a nonulcerated melanoma of the next highest T category (Fig 2, Table 3).

Melanoma Level of Invasion
Our prognostic factors analysis in the companion publication demonstrated that the level of invasion, as defined by Wallace Clark, MD,¹⁷ is an independent predictive feature of thin (T1) melanoma but not for thicker lesions.² As a result, the level of invasion is incorporated only into the staging definitions of T1 melanomas. In this cohort, the assignment of T1a is restricted to patients who meet the following three criteria: (1) melanoma 1.0 mm thick, (2) absence of ulceration, and (3) depth of invasion limited to level II or level III. Those melanomas with a thickness > 1.0 mm and with the more aggressive features of level IV or V or with ulceration (regardless of level) are defined as T1b melanomas. About three quarters of patients with T1 melanomas are T1a and have a 95% 5-year survival rate, while the remaining T1 patients have T1b lesions and experience a somewhat lower 91% 5-year survival rate (Table 3).

Melanoma-in-Situ, Indeterminate Melanomas, and Multiple Primary Melanomas
Patients with melanoma-in-situ are categorized as Tis. Those patients with melanoma presentations that are indeterminate or cannot be microstaged should be categorized as Tx. Two examples of indeterminate staging of melanoma would be a diagnosis with a shave or a curettage biopsy that transected the base of the melanoma or when an unknown primary melanoma presents with regional or distant metastases. When patients present with multiple primary melanomas, the T-category staging is based on the melanoma with the worst prognostic features.

Melanoma Growth Patterns
The data used to derive the TNM categories were largely based on melanomas with superficial spreading and nodular growth patterns. There is some evidence that other growth patterns, namely lentigo maligna melanoma, acral lentiginous melanoma, and desmoplastic melanoma, may have a different etiology and prognosis.^9,18-22 At present, the same staging criteria should be used for melanomas with these growth patterns, even though their prognosis may differ somewhat from the more commonly occurring superficial spreading and nodular growth patterns.

Stage Grouping
Patients with primary melanomas with no evidence of regional or distant metastases (either clinically or pathologically) are divided into the following two stages: stage I for early-stage patients with low risk for metastases and melanoma-specific mortality and stage II for those with intermediate risk for metastases and melanoma-specific mortality. Furthermore, stage I patients constitute the following two subgroups: (1) stage IA are T1 melanomas without ulceration or level IV or V depth of invasion (T1aN0M0 melanomas) and (2) stage IB are either T1 melanomas with histopathologic evidence of level IV/V depth of invasion or ulceration of their surface (T1bN0M0) or those T2 melanomas without ulceration (T2aN0M0). Stage II patients constitute the following three subgroups: (1) stage IIA are T2 melanomas with ulceration (T2bN0M0) or T3 melanomas without ulceration (T3aN0M0), (2) stage IIB are either T3 melanomas with ulceration (T3bN0M0) or T4 melanomas without ulceration (T4aN0M0), and (3) stage IIC are T4 melanomas with ulceration (T4bN0M0). Survival rates for these stage groupings are shown in Figs 2 and 3 and listed in Table 3.

The determination of stage grouping for patients with T4bN0M0 melanomas was a dilemma because they are at a particularly high risk for harboring both regional and distant metastases. These thick, ulcerated melanomas are biologically aggressive and are associated with mortality rates that are the same or even larger than those for some groups of patients with nodal metastases (Tables 3 and 5). Such patients were grouped as stage III in the 1997 version of the melanoma staging system because of commensurate risk for melanoma-specific mortality. The Melanoma Staging Committee concluded that such a categorization would add significant complexity to the new stage groupings. To stay within the conventional anatomic definitions, T4 melanomas were therefore assigned to stage II in the final version. This includes T4b melanomas that would still be grouped with other localized melanomas but designated separately as stage IIC, since these patients are at an especially high risk for clinically occult nodal and systemic metastases. The 10-year survival rate for such clinically staged IIC patients is 32% (Table 3, Fig 2).

Data Recording Criteria for Stages I and II Melanoma
When entering melanoma TNM data into tumor registries for the purposes of stage grouping, the electronic data fields must record the measured tumor thickness (in millimeters), the presence or absence of ulceration (based on histopathologic examination), and the level of invasion to derive stage groupings for localized melanomas. In those circumstances where there has been an incisional (or punch) biopsy, generally the maximum tumor thickness in either the biopsy or definitive excision should be recorded (ie, the measurements should not be added). Other prognostic features of localized melanomas were not incorporated into the new TNM categories. Nevertheless, these are potentially important for other types of data analysis and for stratification of patients in clinical trials and should be recorded in medical records and tumor registries. These features include the patient’s age and sex, the anatomic site of the primary melanoma (ie, trunk, extremities, or head and neck), regression (if present), and the growth pattern (superficial spreading, nodular, lentigo maligna melanoma, acral lentiginous melanoma, or desmoplastic melanoma).

	STAGING FOR REGIONAL METASTATIC MELANOMA: STAGE III

TOP ABSTRACT INTRODUCTION STATISTICAL METHODS STAGING FOR LOCALIZED MELANOMA:... STAGING FOR REGIONAL METASTATIC... STAGING FOR DISTANT METASTATIC... DISCUSSION REFERENCES

 
Stage III melanoma patients include those with regional metastases, either in the regional lymph nodes or intralymphatic metastases manifesting as either satellite or in-transit metastases. The definitions for clinical and pathologic staging for stage III are more complicated than for the other stages because of the need to accommodate advances in staging for lymph node metastases (Table 2). In response to more precise nodal staging of melanoma patients using the technology of sentinel node biopsy, separate designations must be applied for patients who have clinical/radiologic staging of the regional lymph nodes compared with the more accurate method of pathologic staging using lymphatic mapping and sentinel node lymphadenectomy.

Clinical Staging of Regional Mesastases
Clinical stage III groupings rely on clinical and/or radiologic assessment of the regional lymph nodes. Clinical staging of nodal metastases is inherently difficult, especially with respect to assessing the number of metastatic nodes present. The Melanoma Staging Committee, therefore, made no subgroup definitions of clinically staged patients with nodal or intralymphatic regional metastases. They are all categorized as clinical stage III disease (Table 2)

Pathologic Staging of Regional Mesastases
In contrast to clinical staging of regional metastases, there is greater accuracy (both qualitatively and quantitatively) in finding distinctive prognostic subgroups within pathologic stage III using information from pathologic examination of the regional lymph nodes after lymphadenectomy. The numerical classification for pathologic staging requires that pathologists perform a careful examination of the surgically resected nodal basin and report on the actual number of nodal metastases identified.

These are the following four major determinants of outcome for pathologic stage III melanoma: (1) the number of metastatic lymph nodes, (2) whether the tumor burden is microscopic (ie, clinically occult and detected pathologically by sentinel or elective lymphadenectomy) or macroscopic (ie, clinically apparent by physical or radiologic examination and verified pathologically), (3) the presence or absence of ulceration of the primary melanoma, and (4) the presence or absence of satellite or in-transit metastases.^2,4,9,23-36 The effect of ulceration on survival rates of stage III patients is shown in Fig 4, with additional data described in the companion publication.² The stage groupings for stage III melanoma are defined in Table 2 and survival rates for these patients are shown in Fig 5.

View larger version (43K): [in this window] [in a new window]   Fig 4. Five-year survival rates from the AJCC melanoma staging database comparing the different N categories and the stage groupings for stage III melanoma. The survival results are significantly different when the primary melanoma is ulcerated compared with equivalent N category of patients without ulceration.

View larger version (16K): [in this window] [in a new window]   Fig 5. Fifteen-year survival curves for stage groupings of regional metastatic melanoma patients (pathologic stage III). Numbers of patients from the AJCC melanoma staging database are shown in parentheses. The differences between the survival curves are significant (P < .0001).

Micrometastases Versus Macrometastases
The second most significant prognostic feature for patients with nodal metastases is the tumor burden of nodal metastases, so designated operationally but not by actual measurements. Thus, those patients without clinical or radiologic evidence of lymph node metastases but who have pathologically documented nodal metastases are defined by convention as having microscopic or clinically occult nodal metastases. It is recognized that such nodal metastases may vary in dimensions (especially for deep-seated nodes or in obese patients), but such a delineation can be identified in the medical record, based on the preoperative clinical examination and the operative notation about the intent of the lymphadenectomy (ie, whether it is an elective, sentinel, or therapeutic lymphadenectomy). In contrast, melanoma patients with both clinical evidence of nodal metastases and pathologic examination documenting the number of nodal metastases (after therapeutic lymphadenectomy) are defined by convention as having having macroscopic or clinically apparent nodal metastases. Survival rates for these two patient groups are significantly different.^2,37,38

The previous melanoma staging systems used maximum measured dimensions of nodal metastases (< 5 cm in the 1987 version and < 3 cm in the 1992 and 1997 versions). However, the Melanoma Staging Committee found no compelling evidence in the literature that the measured size of nodal metastases had any independent prognostic value.^4,39

Primary Melanoma Ulceration
The third most significant prognostic factor in defining pathologic stage III melanoma is the presence or absence of melanoma ulceration.² Based on the analysis described in the companion publication and in the literature, the presence or absence of ulceration is the only prognostic feature of a primary melanoma that independently predicts outcome in stages I and II as well as in stage III melanoma.^2,4,23,33 The AJCC Melanoma Staging Committee accounted for this by upstaging all pathologic stage III patients by one substage when the primary melanoma was ulcerated. The survival correlation was remarkable when the stage subgroupings were analyzed using these definitions (Fig 4, Table 5).

Stage Groupings for Pathologic Stage III Melanoma
After these prognostic features in pathologic stage III melanoma are accounted for, there are the following three definable subgroups with statistically significant differences in survival: stages IIIA, IIIB, and IIIC (Fig 5, Table 3). Patients with pathologic stage IIIA are confined to those who have one to three microscopic lymph node metastases (detected by sentinel or elective lymphadenectomy), and whose primary melanoma is not ulcerated (T1-4aN1aM0 or T1-4aN2aM0). The 5- and 10-year survival rates for such patients are 67% and 60%, respectively (Fig 4, Table 5). With respect to pathologic stages IIIB and IIIC, the final version of the melanoma staging criteria varies slightly from that originally proposed.¹ In the prior proposal for stage grouping, all patients with pathologic evidence of lymph node metastases and an ulcerated melanoma would have been upstaged to N3 regardless of the number of metastatic nodes or the tumor burden, on the basis of the published literature at that time.¹ However, the actual data analysis demonstrated that patients with one to three macroscopic lymph node metastases and a nonulcerated primary melanoma (ie, T1-4aN1bM0 or T1-4aN2bM0) had approximately the same prognosis as those with one to three microscopic lymph node metastases and an ulcerated primary melanoma (T1-4bN1bM0 or T1-4bN2aM0) (Fig 4, Table 5).² In the final version, such patients are now grouped as pathologic stage IIIB melanoma, along with N2c patients (intralymphatic metastases without nodal metastases). The estimated 5-year survival rate for stage IIIB patients is 53% (Figs 4 and 5, Table 5). Patients grouped as stage IIIC melanoma are defined as those with a one to three macroscopic lymph node metastases and an ulcerated primary melanoma (T1-4bN1bM0 or T1-4bN2bM0) or any patient with N3 disease regardless of T status or whether the nodal metastases are microscopic or macroscopic (Table 2). The estimated 5-year survival rate for pathologic stage IIIC patients is significantly lower at 26% (Table 5, Figs 4 and 5).

In summary, the stage grouping for pathologic stage III melanoma uses these four criteria to assign patients with regional metastases into one of three groups designated as stage IIIA, IIIB, or IIIC. Pathologic stage IIIA patients have three or fewer microscopic (clinically occult) nodal metastases and a nonulcerated melanoma (T1-4aN1aM0 and T1-4aN2aM0) identified after sentinel or elective lymphadenectomy (Table 2). Pathologic stage IIIB patients comprise the following three subgroups with equivalent survival rates: (1) those with three or fewer microscopic (clinically occult) nodes and an ulcerated primary melanoma (T1-4bN1aM0 and T1-4bN2aM0), (2) those with three or fewer macroscopic metastatic nodes and a nonulcerated primary (T1-4aN1bM0 and T1-4aN2bM0), or (3) those with satellite or in-transit metastases but no evidence of nodal or distant metastases (T1-4a/bN2cM0) (Table 2). Pathologic stage IIIC patients comprise the following three subgroups: (1) those with four metastatic nodes or matted nodes regardless of tumor burden or ulceration status (T1-4N3M0), (2) those with one to three macroscopic nodes and an ulcerated primary (T1-4bN1bM0, T1-4bN2bM0), or (3) any patient with any combination of satellites or in-transit metastases and nodal metastases.

Clinical Versus Pathologic Nodal Staging
Historically, the distinction between clinical staging and pathologic staging has not been emphasized because the definitions did not delineate any specific prognostic groups. With the widespread use of sentinel node lymphadenectomy, the range of survival rates among various subgroups of pathologic stage III patients is enormous (ranging from 13% to 69% 5-year survival rates and 9% to 63% 10-year survival rates) because of upstaging based on a direct examination of the sentinel lymph nodes by histopathologic examination.²

Our own prognostic factors analysis and those from many other institutions have consistently demonstrated that the nodal status is a significant prognostic feature of melanoma.^2,30,32-34 Thus, significant differences were identified using the survival rates for melanoma patients who were first clinically staged as having no evidence of nodal metastases and who were subsequently staged pathologically after either sentinel or elective node dissection (Table 6). These survival differences were statistically significant among all T substages except for T4b (Table 6). The differences were most striking in patients with clinical T2aN0M0, T2bN0M0, T3aN0M0, T3bN0M0, and T4aN0M0 disease, where 5-year survival rates for the clinically node-negative patients when staged based on their pathologic nodal status varied significantly, with diminished survival rates ranging from 14% to 30% among clinically versus pathologically staged patients of equivalent T categories (Table 6). These results highlight the compelling prognostic value of knowing the nodal status as identified by lymphatic mapping and sentinel lymphadenectomy in those situations where accurate staging is important.

Data Recording Criteria for Stage III Melanoma
Electronic data fields for melanoma should incorporate all the information listed above for the primary melanoma. In addition, they should incorporate the number of metastatic lymph nodes identified by the pathologist (out of a total number of lymph nodes examined), the presence or absence of intralymphatic metastases (satellites or in-transits), and the intent of the surgical procedure that led to the detection of the nodal metastases (ie, a therapeutic lymphadenectomy for clinically detectable metastatic lymph nodes or either a sentinel or elective lymphadenectomy that detected clinically occult metastases). The former would define macroscopic nodal disease while the latter would define microscopic nodal disease. It is acknowledged that these terms are operational definitions simply used for communicating a level of tumor burden and are not intended to be used as a more strict definition of microscopic disease that cannot be observed without a microscope. It is not necessary to measure the dimensions of the nodal metastases for the purposes of staging. Nevertheless, the extent of tumor involvement in a sentinel lymph node should be noted (and measured where possible) to examine whether future subgroups should account for this, which has been suggested by some investigators.⁴⁴

With the availability of immunohistochemical staining, it is now possible to detect nodal metastases at a level of less than 0.1 mm in tumors or even aggregates of a few cells.⁴⁵ The reverse transcriptase polymerase chain reaction technique may even be able to detect metastases not identified by the light microscope.^46-48 Such sophisticated detection procedures may be incorporated into future staging criteria but are not sufficiently available or standardized to warrant their inclusion at this time. Immunohistochemical staining does help direct pathologists to suspicious areas and does help distinguish melanoma cells from other cell types in a lymph node. Nevertheless, for the purposes of staging for nodal metastases, there must be histopathologic confirmation using standard hematoxylin and eosin staining.

	STAGING FOR DISTANT METASTATIC MELANOMA: STAGE IV

TOP ABSTRACT INTRODUCTION STATISTICAL METHODS STAGING FOR LOCALIZED MELANOMA:... STAGING FOR REGIONAL METASTATIC... STAGING FOR DISTANT METASTATIC... DISCUSSION REFERENCES

 
In patients with distant metastases, the site(s) of metastases and elevated serum levels of lactic dehydrogenase (LDH) are used to delineate the M categories into three groups: M1a, M1b, and M1c, with 1-year survival rates ranging from 41% to 59% (Fig 6). Because the survival differences between the M categories are small, there are no subgroups of stage IV melanoma.

View larger version (52K): [in this window] [in a new window]   Fig 6. One-year survival rates from the AJCC melanoma staging database comparing the different M categories. There is a significant difference comparing skin, subcutaneous, and lung metastases to all other sites (P < .0001).

Elevated Serum LDH
Although it is uncommon in staging classifications to include serum factors, an exception was made for elevated levels of serum LDH. This factor was among the most predictive independent factors of diminished survival in all published studies when it was analyzed in a multivariate analysis, even after accounting for site and number of metastases.^52-56 Therefore, when the serum LDH is elevated above the upper limits of normal at the time of staging, such patients with distant metastases are assigned to M1c regardless of the site of their distant metastases. The use of an elevated serum LDH should be used only when there are two or more determinations obtained more than 24 hours apart because an elevated serum LDH on a single determination can be falsely positive due to hemolysis or other factors unrelated to melanoma metastases.

Number of Metastases
The number of metastases at distant sites has previously been documented as an important prognostic factor.^9,23,50,51 However, this feature was not incorporated into this version of the staging system as a result of the significant variability in the deployment of diagnostic tests to comprehensively search for distant metastases. These may range from a chest x-ray in some centers to positron emission tomography scanning in others. Until the indications and types of tests used are better standardized, the number of metastases cannot reliably be used for staging purposes.

Data Recording Criteria for Stage IV Melanoma
Electronic fields for patients with stage IV melanoma should include all the information listed above for the primary melanoma and regional metastases, plus the site(s) of distant metastases as well as the serum LDH level (normal v abnormal). Additional data to be considered include the number of distant metastases, and the patient’s age, sex, and performance status.

	DISCUSSION

TOP ABSTRACT INTRODUCTION STATISTICAL METHODS STAGING FOR LOCALIZED MELANOMA:... STAGING FOR REGIONAL METASTATIC... STAGING FOR DISTANT METASTATIC... DISCUSSION REFERENCES

 
Over the past 3 years, the AJCC Melanoma Staging Committee held a series of meetings to revise the melanoma staging system. They used an evidence-based methodology to create the TNM criteria and stage groupings, based on their own data and information published in the medical literature. The membership of the Committee included a representative of the UICC TNM Committee and comments were solicited from other UICC, World Health Organization Melanoma Program, and European Organization for Research and Treatment of Cancer representatives.

The proposed melanoma staging system was published in 2000.¹ Some changes to the original proposal were made, based on the prognostic factors analysis. These included (1) adding level of invasion to define T1a and T1b categories, and (2) incorporating primary melanoma ulceration into the stage grouping criteria for stages IIIB and IIIC instead of moving all patients with nodal metastases and an ulcerated primary melanoma into stage IIIC, and (3) eliminating all subgroups of clinical stage III.

A highly significant and underreported feature of melanoma is the presence or absence of ulceration overlying the primary melanoma. An ulcerated melanoma (as defined histopathologically) is associated with such aggressive metastatic behavior that such lesions should be considered in the same category as a poorly differentiated or locally advanced cancer.^{6,7,13,14,33,36,37,57-68} The term ulceration is a descriptive term for this biologic event, in which the melanoma tumor invades through the overlying epidermis rather than pushing it upward, manifesting as an absent epidermis overlying the tumor (Fig 7). Such an event can clearly be distinguished from traumatic or artifactual events leading to a partial absence of the overlying epidermis. In most instances, an ulcerated melanoma does not have an ulcer crater¹³ (Fig 7). The results demonstrated, once again, a significant impact of melanoma ulceration that had to be accounted for in the stage groupings because ulceration negatively impacted survival rates in stages I, II, and III disease compared with nonulcerated melanomas. This was true for every combination of prognostic factors used to assemble various substages.

View larger version (153K): [in this window] [in a new window]   Fig 7. Photomicrograph of a typical ulcerated melanoma. The epidermis above the primary melanoma is absent, with a tapering of the epidermis at the periphery of the lesion.

Finally, the prognostic factors used to validate the melanoma staging system should be the primary stratification criteria and end-results reporting criteria of melanoma clinical trials. The AJCC Melanoma Committee recommends that all melanoma patients with clinically negative regional lymph nodes and who may be considered for later entry onto surgical and adjuvant therapy clinical trials should have pathologic staging with sentinel lymphadenectomy to ensure prognostic homogeneity within assigned treatment groups. In this way, investigators will be better able to discern between the impact of natural history and treatment when interpreting results of melanoma clinical trials. Moreover, the use of a consistent set of criteria will facilitate the comparability of melanoma clinical trials and thereby accelerate the progress of multidisciplinary melanoma treatment approaches.

It is evident that the next phase of staging melanoma will evolve as new technology allows the clinician to reliably diagnose metastatic melanoma at a level of tumor burden better than that achievable with the light microscope or routine x-rays. These include molecular diagnostic approaches, such as reverse transcriptase polymerase chain reaction, to detect relevant gene expression, positron emission tomography scanning, use of antimelanoma antibodies, and serum markers of tumor-related DNA and RNA species that will more accurately detect and stage metastatic melanoma.^{46-48,52,80-83} Some of these advances will no doubt be incorporated into subsequent revisions of the melanoma staging system.

	ACKNOWLEDGMENTS

 
Supported in part by an unrestricted educational grant from Schering Pharmaceutical, Kenilworth, NJ.

	REFERENCES

TOP ABSTRACT INTRODUCTION STATISTICAL METHODS STAGING FOR LOCALIZED MELANOMA:... STAGING FOR REGIONAL METASTATIC... STAGING FOR DISTANT METASTATIC... DISCUSSION REFERENCES

 
1. Balch CM, Buzaid AC, Atkins MB, et al: A new American Joint Committee on Cancer staging system for cutaneous melanoma. Cancer 88: 1484-1491, 2000[Medline]

2. Balch CM, Soong S-J, 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 19: 3622-3634, 2001[Abstract/Free Full Text]

3. Ruiter DJ, Testori A, Eggermont AM, et al: The AJCC staging proposal for cutaneous melanoma: Comments by the EORTC Melanoma Group. Ann Oncol 12: 9-11, 2001[Free Full Text]

4. Buzaid AC, Ross MI, Balch CM, et al: Critical analysis of the current American Joint Committee on Cancer staging system for cutaneous melanoma and proposal of a new staging system. J Clin Oncol 15: 1039-1051, 1997[Abstract/Free Full Text]

5. Breslow A: Thickness, cross-sectional areas, and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg 172: 902-908, 1970[Medline]

6. Balch CM, Murad TM, Soong SJ, et al: A multifactorial analysis of melanoma: Prognostic histopathological features comparing Clark’s and Breslow’s staging methods. Ann Surg 188: 732-742, 1978[Medline]

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Submitted February 1, 2001; accepted May 18, 2001.

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