Identification of higher risk thin melanomas should be based on Breslow depth not Clark level IV

BACKGROUND: There is good prognostic correlation for the two microstaging systems, Breslow depth and Clark level, commonly used to stage melanomas. Many investigators have reported that Breslow depth is the superior microstaging method. Although Clark level has been dropped from most of the proposed American Joint Committee on Cancer (AJCC) melanoma staging system, the AJCC system still includes Clark Level IV as a criterion for upstaging thin melanomas. The authors sought to determine whether this is appropriate, based on melanoma patient data in the Duke Comprehensive Cancer Center database. METHODS: Of the 8833 patients registered between January 1, 1970 and December 31, 1995, complete data on Breslow depth and Clark level was available for 4560 patients who were without nodal or metastatic disease at presentation. Ten-year survival was measured from the date of excision of the primary tumor until death from melanoma and analyzed using Kaplan-Meier and Cox proportional hazard methodologies. RESULTS: When analyzed separately, both increased Breslow thickness and Clark level correlated with shorter survival times. During subgroup analysis, Breslow thickness remained a significant prognostic indicator of survival at Clark Levels III and IV. Conversely, at narrow levels of Breslow thickness (i.e., 0-0.75 mm, > 0.75 -1.0 mm, > 1.0-1.5 mm) survival times were indistinguishable between Clark Levels III and IV. For the broader Breslow thickness interval of 0-1.0 mm, a barely significant difference between Clark Levels III and IV could be obtained. However, for this thickness range, even greater differences in survival could be obtained by merely comparing Breslow subgroups (i.e., < or = 0.8 mm vs. > 0.8-1.0 mm, < or = 0.9 mm vs. > 0.9-1.0 mm). CONCLUSION: The authors' data suggested that, after controlling for Breslow depth, Clark level was not a good prognostic indicator for survival. If the AJCC's objective is to design a classification system that will reliably predict the higher risk melanomas, then the system should be based on tumor thickness, which is clearly a better prognostic indicator, and should not be modified because of Clark level.     

Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system.

PURPOSE: The American Joint Committee on Cancer (AJCC) recently proposed major revisions of the tumor-node-metastases (TNM) categories and stage groupings for cutaneous melanoma. Thirteen cancer centers and cancer cooperative groups contributed staging and survival data from a total of 30,450 melanoma patients from their databases in order to validate this staging proposal. PATIENTS AND METHODS: There were 17,600 melanoma patients with complete clinical, pathologic, and follow-up information. Factors predicting melanoma-specific survival rates were analyzed using the Cox proportional hazards regression model. Follow-up survival data for 5 years or longer were available for 73% of the patients. RESULTS: This analysis demonstrated that (1) in the T category, tumor thickness and ulceration were the most powerful predictors of survival, and the level of invasion had a significant impact only within the subgroup of thin (< or = 1 mm) melanomas; (2) in the N category, the following three independent factors were identified: the number of metastatic nodes, whether nodal metastases were clinically occult or clinically apparent, and the presence or absence of primary tumor ulceration; and (3) in the M category, nonvisceral metastases was associated with a better survival compared with visceral metastases. A marked diversity in the natural history of pathologic stage III melanoma was demonstrated by five-fold differences in 5-year survival rates for defined subgroups. This analysis also demonstrated that large and complex data sets could be used effectively to examine prognosis and survival outcome in melanoma patients. CONCLUSION: The results of this evidence-based methodology were incorporated into the AJCC melanoma staging as described in the companion publication.     

Earlier diagnosis of second primary melanoma confirms the benefits of patient education and routine postoperative follow-up

BACKGROUND: Rising health care costs have caused providers to question the benefit of regular follow-up after treatment for patients with early stage cutaneous melanoma. The authors hypothesized that routine reassessment and careful education of these patients would facilitate earlier diagnosis of a subsequent second primary melanoma, as reflected by reduced thickness of that lesion. METHODS: A prospective melanoma data base was used to identify patients who developed a second primary melanoma after treatment for American Joint Committee on Cancer (AJCC) Stage I or II cutaneous melanoma. After excision of the initial primary melanoma, all patients underwent routine biannual follow-up for new primary lesions. Follow-up consisted of a questionnaire and a complete skin examination by a physician. In addition, patients were regularly educated regarding the increased risk of developing a second melanoma. A paired t test was used to examine AJCC stage, thickness, and level of invasion of the initial melanoma compared with the second primary melanoma. RESULTS: Of 3310 patients with AJCC Stage I or II melanoma, 114 patients (3.4%) developed a second primary melanoma. AJCC staging of both first and second melanomas was available in 82 patients (72%). When the AJCC stages of first and second melanomas were compared, 39 of 82 patients (48%) had lower stage second primary lesions, and 41 (50%) had same-stage second primary lesions. The mean tumor thickness was 1.32 +/- 1.02 mm for the initial melanoma, decreasing to 0.63 +/- 0.52 mm for the second melanoma; in fact, tumor thickness increased in only 4 of 51 patients (8%) whose records contained data for both first and second melanomas. Similarly, the level of invasion decreased in 60% of patients, remained the same in 27% of patients, and increased in only 13% of patients. By paired t test, the differences in AJCC stage, tumor thickness, and level of invasion between first and second melanomas were each highly significant (P = 0.0001). CONCLUSIONS: In this study, the second primary melanoma in patients with a prior cutaneous melanoma was significantly thinner than the initial primary lesion. This is evidence that careful follow-up and patient education allow earlier diagnosis. All patients diagnosed with cutaneous melanoma should be counseled regarding the risks of second melanoma and should undergo lifelong follow-up at biannual intervals.     

Review of the 2001 AJCC staging system for cutaneous malignant melanoma

The American Joint Committee on Cancer (AJCC) staging system for melanoma has recently been revised and published. The previous staging system had not been substantially modified since the late 1980s. In a series of papers, the staging system for melanoma was critically analyzed, and many shortcomings were identified. Many well-established prognostic factors were not used in the staging system. This assessment has led to a substantially modified staging system for cutaneous melanoma in 2001 that is a considerable improvement over past staging systems, albeit more complex. The following modifications are the most important: 1) The primary determinant of tumor (T) staging is tumor thickness as measured in millimeters. The Clark level of invasion is now used only for defining T1 (< or = 1mm) melanomas; 2) The cutpoints for tumor thickness are less than or equal to 1 mm, 1 to 2 mm, 2 to 4 mm, and greater than 4 mm; 3) Ulceration has been added in describing the primary tumor; 4) Local recurrence, satellite disease, and in-transit metastases have similar prognosis and are now all classified together as regional stage III disease; 5) Size of lymph node as prognostic factor has been eliminated and replaced with the number of positive nodes; 6) The presence of an elevated serum lactic dehyrogenase level is used in the metastasis (M) category. This revised staging system more precisely defines prognosis and will improve the stratification of patients in future clinical trials.     

Prognostic factors in localized invasive cutaneous melanoma: high value of mitotic rate, vascular invasion and microscopic satellitosis

The aim of this study was to determine independent clinical and pathological prognostic factors for overall and disease-free survival in Spanish melanoma patients. Eight hundred and twenty-three patients with localized melanoma and complete clinical and pathological information were evaluated. The age at diagnosis, gender, location, tumour thickness, invasion level, ulceration, histological subtype, inflammatory infiltrate, mitotic rate, vascular invasion, microscopic satellitosis, regression and cell type were all included. Univariate and multivariate Cox regression analyses were performed for overall and disease-free survival. Gender, histological subtype, tumour thickness, invasion level, ulceration, inflammatory infiltrate, microscopic satellitosis, vascular invasion and mitotic rate were related to overall and disease-free survival in univariate analysis. Age and location were only related to disease-free survival. Only tumour thickness, vascular invasion and gender exhibited independent significance for overall survival in multivariate analysis. For disease-free survival, tumour thickness, location, mitotic rate, vascular invasion and microscopic satellitosis were the sole independent factors. It can be concluded that the Breslow thickness remains the most significant prognostic factor for the survival of patients with localized cutaneous melanoma. Our results support the inclusion of microscopic satellitosis and vascular invasion in the current American Joint Committee on Cancer (AJCC) staging system, although further studies evaluating their separate influence are needed. Mitotic rate is confirmed as an objective and independent predictor of disease-free survival for melanoma patients that should be considered in further revisions of the mentioned staging system.     

Reflecting on the 2001 American Joint Committee on Cancer Staging System for melanoma

The Melanoma Staging Committee of the American Joint Committee on Cancer (AJCC) promulgated in 2001 major revisions of the melanoma tumor-node-metastasis (TNM) categories and stage grouping criteria, for a new staging system of cutaneous melanoma. The Committee invited data analyses relevant to the proposed new melanoma staging for validation of the system. Validation studies that were published subsequently confirmed most of the parameters of the new staging system, identified new prognostic factors that had not been included in the revised AJCC staging, whereas the prognostic power of some parameters could not be confirmed in the data of other institutions. This article provides an in-depth analysis of the current AJCC staging for melanoma, addresses areas of controversy, and offers proposals for consideration at the next revision of the system.     

The new staging system for cutaneous melanoma in the era of lymphatic mapping

In 2002, the American Joint Committee on Cancer (AJCC) revised the staging system for cutaneous melanoma on the basis of a survival analysis of important melanoma prognostic factors. Features of the revised system include new strata for primary tumor thickness, incorporation of primary tumor ulceration as an important staging criterion in both the tumor (T) and node (N) classifications, revision of the N classification to reflect the prognostic significance of regional nodal tumor burden, and new categories for distant metastatic disease. These changes reflect evolving insight into melanoma arising from the results of numerous clinical investigations and database analyses. One of the most important recent changes in melanoma care is the establishment of lymphatic mapping and sentinel lymph node (SLN) biopsy as a highly accurate and minimally morbid technique for pathologic regional nodal staging. In this article, the salient features of the revised melanoma staging system are examined, with specific attention paid to its use in this era of lymphatic mapping and SLN biopsy.     

Staging and prognosis of cutaneous melanoma

Staging of cutaneous melanoma continues to evolve through identification and rigorous analysis of potential prognostic factors. In 1998, the American Joint Committee on Cancer (AJCC) Melanoma Staging Committee developed the AJCC melanoma staging database, an international integrated compilation of prospectively accumulated melanoma outcome data from several centers and clinical trial cooperative groups. Analysis of this database resulted in major revisions to the TNM staging system reflected in the sixth edition of the AJCC Cancer Staging Manual published in 2002. More recently, the committee's analysis of an updated melanoma staging database, including prospective data on more than 50,000 patients, led to staging revisions adopted in the seventh edition of the AJCC Cancer Staging Manual published in 2009. This article highlights these revisions, reviews relevant prognostic factors and their impact on staging, and discusses emerging tools that will likely affect future staging systems and clinical practice.     

A population-based validation of the American Joint Committee on Cancer melanoma staging system.

PURPOSE: A major revision of the American Joint Committee on Cancer (AJCC) stages for melanoma was implemented in 2002 after its validation in multinational cohorts including patients from cancer centers and cooperative groups. This staging system has not been validated in a US population-based cohort. PATIENTS AND METHODS: We used 41,417 patients with primary invasive cutaneous melanoma diagnosed between 1988 and 2001 from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) cancer registry to validate the revised AJCC staging system. Survival rates computed from stage-specific Kaplan-Meier curves (time to melanoma-specific death) were compared with the survival rates from 17,600 patients in the original AJCC validation study. RESULTS: In the SEER cohort, 65% of reported melanomas were < or = 1.00 mm in thickness and 8.7% were more than 4.00 mm compared with 39% and 10% in the AJCC cohort (P < .001), respectively. AJCC stages were able to discriminate among SEER patient groups with different prognosis. However, SEER survival rates were significantly higher than those in the AJCC study and notably so in patients with T1a lesions (< or = 1 mm without ulceration). This population-specific effect remained significant after controlling for lesion thickness in all substages except stage IIA. CONCLUSION: Although this national population-based study validates the most recent revision of AJCC stages for melanoma, it emphasizes that survival rates are population specific and found them to be generally higher for SEER compared with AJCC patients. Population-specific survival rates should be used in study designs and decisions about patient-specific interventions.     

Impact of ulceration in stages I to III cutaneous melanoma as staged by the American Joint Committee on Cancer Staging System: an analysis of the German Central Malignant Melanoma Registry.

PURPOSE: In 2001, the new American Joint Committee on Cancer classification of cutaneous melanoma (CM) introduced ulceration of the primary melanoma as a new key parameter being represented in respective subcategories of the tumor (T) classification. The present study was performed to validate the prognostic significance of ulceration in relation to T thickness and clinical stages of CM (stages I to III). PATIENTS AND METHODS: Patients (N = 15,158) with incident invasive primary nonmetastatic CM and follow-up data recorded between 1976 and 2000 by the German Central Malignant Melanoma Registry were investigated using survival analysis to evaluate prognostic factors such as T thickness, level of invasion, body site, histologic subtype, ulceration, regression, age, and sex. RESULTS: Comparisons of survival probabilities according to the Kaplan-Meier method between ulcerated and nonulcerated CM were not statistically significant for subgroups with T thickness < or = 1 mm and more than 4.00 mm (P = .2601 and P = .0699, respectively) but were significant for T thickness of 1.01 to 2.00 mm and 2.01 to 4.00 mm (P < .0001 for both). This result was confirmed in the multivariate analysis. For stage III CM, the impact of ulceration on overall survival was statistically significant in the bivariate Cox model (P = .0111) but not in the multivariate Cox model (P = .0522). CONCLUSION: Whereas ulceration seems to have a negative impact on the prognosis of patients with stages T2 and T3, a potential influence for patients with stages T1 and T4 could not be established. If factors of the primary CM were to be taken into consideration to judge prognosis of stage III CM, T thickness but not ulceration should be the focus.     

A new American Joint Committee on Cancer staging system for cutaneous melanoma

The Melanoma Staging Committee of the AJCC has proposed major revisions of the melanoma TNM and stage grouping criteria. The committee members represent most of the major cooperative groups and cancer centers worldwide with a special interest in melanoma; the committee also collectively has had clinical experience with over 40,000 patients. The new staging system better reflects independent prognostic factors that are used in clinical trials and in reporting the outcomes of various melanoma treatment modalities. Major revisions include 1) melanoma thickness and ulceration, but not level of invasion, to be used in the T classification; 2) the number of metastatic lymph nodes, rather than their gross dimensions, the delineation of microscopic versus macroscopic lymph node metastases, and presence of ulceration of the primary melanoma to be used in the N classification; 3) the site of distant metastases and the presence of elevated serum LDH, to be used in the M classification; 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 new staging information gained from intraoperative lymphatic mapping and sentinel lymph node biopsy. The AJC Melanoma Staging Committee invites comments and suggestions regarding this proposed staging system before a final recommendation is made.     

An evidence-based staging system for cutaneous melanoma

A completely revised staging system for cutaneous melanoma was implemented in 2003. The changes were validated with a prognostic factors analysis involving 17,600 melanoma patients from prospective databases. This major collaborative study of predicting melanoma outcome was conducted specifically for this project, and the results were used to finalize the criteria for this evidence-based staging system. In fact, this was the largest prognostic factors analysis of prospectively followed melanoma patients ever conducted. Important results that shaped the staging criteria involved both the tumor-node-metastasis (TNM) criteria and stage grouping for all four stages of melanoma. Major changes in the staging include: (1) melanoma thickness and ulceration are the dominant predictors of survival in patients with localized melanoma (Stages I and II); deeper level of invasion (ie, IV and V) was independently associated with reduced survival only in patients with thin or T1 melanomas. (2) The number of metastatic lymph nodes and the tumor burden were the most dominant predictors of survival in patients with Stage III melanoma; patients with metastatic nodes detected by palpation had a shorter survival compared with patients whose nodal metastases were first detected by sentinel node excision of clinically occult or "microscopic" metastases. (3) The site of distant metastases (nonvisceral versus lung versus all other visceral metastatic sites) and the presence of elevated serum lactate dehydrogenase (LDH) were the dominant predictors of outcome in patients with Stage IV or distant metastases. (4) An upstaging was implemented for all patients with Stage I, II, and III disease when a primary melanoma is ulcerated by histopathological criteria. (5) Satellite metastases around a primary melanoma and in-transit metastases were merged into a single staging entity that is grouped into Stage III disease. (6) A new convention was implemented for defining clinical and pathological staging so as to take into account the new staging information gained from lymphatic mapping and sentinel node biopsy.     

The revised American Joint Committee on Cancer staging system for melanoma

Substantial progress has been made in identifying the most significant clinical and pathologic characteristics of melanoma that predict for metastasis and survival. The American Joint Committee on Cancer (AJCC) staging system for cutaneous melanoma was recently revised to include these prognostic variables. Major changes in the staging include: (1) melanoma thickness and ulceration but not level of invasion will 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 will be used in the N category; (3) the site of distant metastases and the presence of elevated serum lactate dehydrogenase (LDH) will be used in the M category; (4) all patients with stage I, II, or III disease will be upstaged when a primary melanoma is ulcerated; (5) satellite metastases around a primary melanoma and in-transit metastases will be merged into a single staging entity that is grouped into stage III disease; and (6) distinct definitions for clinical and pathologic staging will take into account the new staging information gained from intraoperative lymphatic mapping and sentinel node biopsy.     

New American Joint Commission on Cancer staging system for melanoma: prognostic impact and future directions

Accurate melanoma staging is critical in establishing management strategies and estimating disease relapse. Combined with assessment of comorbidities and understanding treatment toxicities, risk assessment is central to offering appropriate surgical or systemic therapies. The American Joint Commission on Cancer (AJCC) melanoma staging system provides survival estimates within anatomically defined disease categories. Newer prognostic factors and methods of prognostic analyses can augment predictions for the presence of micro-metastatic disease and further define the risk for relapse. This article highlights relevant changes, evidence supporting future incorporation of more recently defined prognostic variables, novel approaches used as adjuncts to the current staging system, and future directions of the AJCC staging committee.     

Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma.

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.     

Implementation of the 7th edition AJCC staging system: Effects on staging and survival for pT1 melanoma. A Dutch population based study

In the 7^th edition of the AJCC staging system, the mitotic rate criterion replaced Clark level to increase correct classification of high‐risk thin melanoma patients (pT1B). Additionally, sentinel node biopsy (SNB) was recommended for nodal staging of pT1B melanomas. The aim of this article was to evaluate the effects on pT1 substaging and clinical implications in the national pT1 melanoma population. All pT1 melanomas diagnosed in the Netherlands between 2003 and 2014 were selected from the Netherlands Cancer Registry (IKNL). Patients were stratified by cohort according to AJCC edition: (1) 2003–2009 (6^th) and (2) 2010–2014 (7^th). Relative survival was calculated to estimate melanoma‐specific survival. A total of 29.546 pT1 melanoma patients were included. The pT1b proportion increased from 10.1% in Cohort 1 to 21.5% in Cohort 2. The proportion of performed SNBs per cohort increased: for pT1b melanomas alone from 4.5% to 13.0%. SNB positivity rate decreased from 10.5% to 8.8% for the entire pT1 population, and for pT1b melanomas from 11.3% to 8.6%. At 5 years, the relative survival rate was similar for pT1a and pT1b in both cohorts, namely, pT1a 100% vs pT1b 97% (Cohort 1), and pT1a 100% vs pT1b 98% (Cohort 2). The 7^th edition of the AJCC staging system has caused an increased number of patients to undergo SNB, without an increase in SNB positivity rate. Survival between pT1 subgroups remains similar. The mitotic rate criterion for pT1b classification and the recommendation to perform SNB for pT1b melanomas should be reconsidered.     

Evidence and interdisciplinary consense-based German guidelines: diagnosis and surveillance of melanoma

Melanoma is a malignant tumor that arises from melanocytic cells and primarily involves the skin. The most important exogenous etiological factor is exposure to ultraviolet irradiation. Diagnosis of melanoma is based primarily on its clinical features, and the A-B-C-D rule is useful in identifying pigmented lesions, which are suspicious for melanoma (Asymmetry, Border irregular, Color inhomogeneous and Diameter more than 5 mm). Dermoscopy is very helpful in clarifying the differential diagnosis of pigmented lesions. About 90% of melanomas are diagnosed as primary tumors without any evidence for metastasis. The tumor-specific 10-year survival for all such tumors is about 75-85%. The most important prognostic factors for primary melanoma without metastases are vertical tumor thickness (Breslow depth) as measured on the histological specimen, presence of histopathologically recognized ulceration, invasion level (Clark level) and identification of micrometastases in the regional lymph nodes via sentinel lymph node biopsy. The current tumor node metastasis classification for the staging of primary melanoma is based on these factors. Melanomas can metastasize either by the lymphatic or by the hematogenous route. About two-thirds of metastases are originally confined to the drainage area of regional lymph nodes. A regional metastasis can appear as satellite metastases up to 2 cm from the primary tumor, as intransit metastases in the skin between the site of the primary tumor and the first lymph node and as regional lymph node metastases. In the stage of regional metastasis, the differentiation between micrometastasis and macrometastasis and the number of lymph nodes involved are crucial. As soon as distant metastasis develops, prognosis depends on the site of the metastasis and on the lactate dehydrogenase levels in the blood. The frequency and extent of follow-up examinations is based on the initial tumor parameters. In thin primary melanomas up to 1-mm tumor thickness, clinical examinations at 6-month intervals are sufficient and in thicker primary melanomas, at 3-month intervals. Lymph node sonography as well as determination of the tumor marker protein S100beta are recommended. Additionally, in the stage of regional metastasis, whole body imaging should be performed every 6 months; in the stage of distant metastasis, surveillance has to be scheduled individually.     

New TNM melanoma staging system: linking biology and natural history to clinical outcomes

The American Joint Committee on Cancer (AJCC) implemented major revisions of the melanoma TNM and stage grouping criteria in the recently published 6th edition of the Staging Manual. The new staging system better reflects independent prognostic factors that are used in clinical trials and in reporting the outcomes of various melanoma treatment modalities. Major revisions include: 1) melanoma thickness and ulceration but not level of invasion to be used in the T classification, 2) the number of metastatic lymph nodes rather than their gross dimensions and the delineation of microscopic vs. macroscopic nodal metastases to be used in the N classification, 3) the site of distant metastases and the presence of elevated serum lactic dehydrogenase (LDH) to be used in the M classification, 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 pathological staging so as to take into account the new staging information gained from intraoperative lymphatic mapping and sentinel node biopsy.     

Update on the melanoma staging system: the importance of sentinel node staging and primary tumor mitotic rate

The 7(th) Edition of the AJCC Staging Manual includes a detailed summary of melanoma staging and prognosis. The revisions are summarized in this article, along with details on two key aspects of melanoma staging: the incorporation of mitotic rate of the primary melanoma and the key role of the sentinel lymph node biopsy (SLNB) in determining accurate staging for clinically occult nodal metastases. Primary tumor mitotic rate was introduced as a major criterion for melanoma staging and prognosis that replaces the Clark's level of invasion, and is now proven to be an important independent adverse predictor of survival. Analysis of the AJCC melanoma staging database demonstrated a significant inverse correlation between primary tumor mitotic rate (histologically defined as mitoses/mm(2) ) and survival. The use of SLNB reliably identifies melanoma patients with nodal micrometastases, enabling clinicians to identify patients with occult nodal metastases that would otherwise take months or years to become clinically palpable The number of nodal metastases was the most significant independent predictor of survival among all patients with stage III disease, including among patients with nodal micrometastases, and continues to be a primary criterion for defining Stage III melanoma. A clinical scoring system model and multivariate predictive tool under the auspices of the AJCC has led to a first-generation web-based predictive tool (www.melanomaprognosis.org).     

Objective histopathologic grading of cutaneous malignant melanomas by stereologic estimation of nuclear volume. Prediction of survival and disease-free period

Modern stereologic techniques enable unbiased and shape-independent estimation of the three-dimensional nuclear volume (Vv). This study investigates the prognostic impact of Vv in 47 patients with malignant melanomas (10 years of follow-up) and compares Vv to traditional prognostic parameters and two-dimensional morphometric estimates. The averaged Vv was 226 microns3 and 457 microns3 in Stage I and II melanomas, respectively. The Vv was significantly increased in the case of ulceration, nodular melanoma, and Clark's level greater than III. The Vv showed only poor correlation to two-dimensional morphometric estimates. Cox regression analysis indicated Vv to possess excellent prognostic information, only rivaled by tumor ulceration, the latter being a 100% predictor of metastatic spread. Histologic type, Clark's level of invasion, tumor thickness (according to Breslow), and patient sex were without independent prognostic significance, which may be due to attributes of the small data base. It is concluded that Vv may be a powerful prognostic indicator in cutaneous melanomas, suitable for objective malignancy grading. The clinical and prognostic value of nuclear Vv needs further investigation in a larger and contemporary series of patients with malignant melanomas.