Robert J. Friedman

The incidence of malignant melanoma in the United States: Issues as we approach the 21st century

The risk of malignant melanoma developing in an American in the United States has now reached 1 in 87 (up more than 1800% since the 1930s). This rising incidence of malignant melanoma is, in fact, real because (1) it is not due to increased surveillance; (2) it is not due to better cancer-counting methods in general; (3) it is not due to changes in histologic diagnostic criteria; (4) it is being noted worldwide; and (5) most importantly, despite rising survival percentages, the mortality rate from malignant melanoma also continues to rise. On the basis of these trends, incidence rates for malignant melanoma will continue to rise for at least the next 10 to 20 years, although the demographics of those affected may change. Effective programs to improve public and professional education must be developed to enhance early clinical detection and behavioral changes. An establishment of a National Melanoma Registry is needed to more effectively assess the magnitude and impact of future incidence and the success of prevention program efforts into the next century.

The evolution of melanoma diagnosis: 25 years beyond the ABCDs.

Early detection of malignant melanoma remains the key factor in lowering mortality from this cancer. Recognizing the importance of this issue 25 years ago, our group at New York University published in CA: A Cancer Journal for Clinicians the mnemonic “ABCD” to facilitate the early diagnosis of melanoma. Studies have demonstrated the usefulness of this paradigm in enhancing early melanoma diagnosis as a part of clinical examinations, mass screenings, and public education programs. Approaches to melanoma diagnosis have dynamically evolved during the ensuing quarter century. In the 1990s, dermoscopy enabled the recognition of new subsurface features to differentiate between malignant and benign pigmented lesions. During the last decade, new computer‐based technologies have improved diagnostic sensitivity and specificity and may result in optimizing lesion selection for biopsy and pathology review. Despite all of the advances in melanoma diagnosis, timely recognition, detection, and rapid treatment of melanoma remain critical. Although pathologic examination remains the gold standard for diagnosis, this cancer has the potential to be diagnosed through noninvasive approaches because of its cutaneous location. From the development of the ABCDs through current attempts that use complex computer algorithms and genetic markers, a clinicians ability to detect melanoma in its earliest form has been augmented. However, a “good clinical eye” is still fundamental to selecting the lesions for evaluation among the sea of those that are prevalent. As current approaches are refined and new techniques are developed, the improved ability to diagnose this cancer will hopefully enhance reaching the goal of reducing melanoma mortality. CA Cancer J Clin 2010.

Prognostic Factors for Patients with Clinical Stage I Melanoma of Intermediate Thickness (1.51–3.99 mm)* A Conceptual Model for Tumor Growth and Metastasis

Fourteen variables were tested for their ability to predict visceral or bony metastases in 177 patients with clinical Stage I melanoma of intermediate thickness (1.51–3.99 mm). A Cox multivariate analysis yielded a combination of four variables that best predicted bony or visceral metastases for these patients: 1) mitoses > 6/mm2 (p = 0.0007), 2) location other than the forearm or leg) p = 0.009), 3) ulceration width > 3 mm (p = 0.04), and 4) microscopic satellites (p = 0.05). The overall prognostic model chi square was 32.40 with 4° of freedom (p < 10-5). Combinations of the above variables were used to separate these patients into at least two risk groups. The high risk patients had at least a 35% or greater chance of developing visceral metastases within five years, while the low risk group had greater than an 85% chance of being disease free at five years. Criteria for the high risk group were as follows: 1) mitoses > 6/mm2 in at least one area of the tumor, irrespective of primary tumor location, or 2) a melanoma located at some site other than the forearm or leg and histologic evidence in the primary tumor of either ulceration > 3 mm wide or microscopic satellites. The low risk group was defined as follows: 1) mitoses ≤ 6/mm2 and a location on the leg or forearm, or 2) mitoses ≤ 6/mm2 and the absence in histologic sections of the primary tumor of both microscopic satellites and ulceration ≥ 3 mm wide. The number of patients in this series who did not undergo elective regional node dissection (N = 47) was probably too small to detect any benefit from this procedure. Based on survival rates from this and other studies, it is estimated that approximately 1500 patients with clinical Stage I melanoma of intermediate thickness in each arm of a randomized clinical trial would be needed to detect an increase in survival rates from elective regional node dissection.

Prognostic factors for melanoma patients with lesions 0.76 - 1.69 mm in thickness. An appraisal of "thin" level IV lesions.

Fourteen variables were tested for their prognostic usefulness in 203 patients with clinical Stage I melanoma and primary tumors 0.76–1.69 mm thick. Only two variables, primary tumor location and level of invasion, were useful in predicting death from melanoma for these patients. Of the 12 deaths from melanoma, 11 occurred in patients with primary tumors located on the upper back, posterior arm, posterior neck, and posterior scalp (= BANS). There has been only one death from melanoma in 136 patients with melanoma located at other sites (11/67 vs 1/136, p < 0.0001 Fishers Exact Test). Of the 67 BANS patients, 51 had level II or level III lesions and five (10%) died of melanoma. This compares with six deaths from melanoma in 16 patients (37.5%) with level IV BANS lesions (5/51 vs 6/16, p = 0.01 Fishers Exact Test). The relatively high incidence of both melanoma deaths and regional node metastases for the BANS group merits consideration for testing the efficacy of elective regional node dissection for these patients.

“Microscopic satellites” are more highly associated with regional lymph node metastases than is primary melanoma thickness

A multivariate analysis was performed on 20 clinical and histologic variables from 327 Stage I prospectively studied melanoma patients who underwent elective regional lymph node dissection (ERLD). Primary tumor thickness, microscopic satellites, and the elapsed interval between diagnosis and ERLD, were selected as the combination of variables that were most highly associated with clinically occult regional lymph node metastases (P = 10−15, model chi‐square). Microscopic satellites were defined as tumor nests, >0.05 mm in diameter, in the reticular dermis, panniculus, or vessels beneath the principal invasive tumor mass but separated from it by normal tissue on the section in which the Breslow measurement was taken. The probability of finding nodal metastases for melanomas <0.75 mm thick was 0% (0/41 patients); for those 0.76–1.50 mm, 4% (4/108); 1.51–3.0 mm, 14% (14/102); and >3.0 mm, 39.5% (30/76). Primary melanomas >1.50 mm thick with microscopic satellites were more often associated with nodal metastases than those of similar thickness without satellites (30/57 (53%) versus 14/121 (12%), P = 0.01). Some satellites probably represent intraspecimen metastases, while others do not. Any predictive model for occult regional lymph node metastases based on data from ERLD done <50 days after diagnosis may underestimate the prevalence of metastases.

Importance of complete cutaneous examination for the detection of malignant melanoma.

With the rate of melanoma increasing 1,000% in the past 50 years, the early detection of the disease is becoming more important. Data from 2,239 persons seen at the Manhattan Melanoma/Skin Cancer Detection Screening Program were analyzed to determine if a complete cutaneous examination would significantly increase the chance of detecting melanoma. Thirteen of the fourteen melanomas detected were on anatomic sites normally covered by clothing. Patients having complete skin examinations were 6.4 times more likely to have a melanoma detected than those having partial examinations (p = 0.025). These findings reinforce the importance of complete skin examination for the early detection of malignant melanoma.

A multivariate analysis of prognostic factors for melanoma patients with lesions greater than or equal to 3.65 mm in thickness. The importance of revealing alternative Cox models.

Fourteen prognostic factors were examined in 79 patients with clinical Stage I melanoma greater than or equal to 3.65 mm in thickness. All nine patients with melanoma of the hands or feet died of melanoma. A Cox proportional hazards (multivariate) analysis of the remaining 70 patients showed that a combination of the following four variables best predicted bony or visceral metastases: 1) a nearly absent or minimal lymphocyte response at the base of the tumor, 2) histologic type other than superficial spreading melanoma, 3) location on the trunk, and 4) positive nodes or no initial node dissection. Ulceration and/or ulceration width were not useful in predicting outcome either singly or in combination with other variables. Patients with negative lymph nodes and primary tumors of the trunk, hands, and feet did not do better than patients with positive nodes at those sites. Conversely, non of 16 patients with negative lymph nodes and extremity melanomas (excluding the hands and feet) or head and neck melanomas developed visceral or bony metastases (i.e., five-year disease-free survival rate 100%).

Local and in-transit metastases following definitive excision for primary cutaneous malignant melanoma.

A total of 672 consecutive patients with clinical stage I and stage II primary cutaneous malignant melanoma were treated by excision of 3.0 to 5.0 cm of surrounding skin down to and including the underlying fascia when the lesion exceeded 0.5 mm thickness (Breslow measurement). More conservative margins were taken in locations where such excisions would result in significant cosmetic or functional morbidity and for thinner lesions (<0.5 mm). Seven of 658 patients with clinical stage I disease (1.1%) and three of 14 patients with clinical stage II disease (21.4%) developed histologically verified local metastases within 5 cm of the primary excision scar or skin graft. Fifteen patients wth stage I disease developed in-transit metastases (2.3%) at a site more than 5.0 cm proximal to the surgical scar or skin graft but not beyond the regional nodal group. Two patients with stage II disease who had developed local metastases also developed in-transit metastases (14.3%). No patient with a lesion less than 1.0 mm thick has had a local recurrence. Nine of the ten pattients (90%) who developed local metastases and 12 of the 17 patients (70.6%) who developed in-transit metastases have also developed systemic metastases to date. Local and in-transit metastases following such definitive excision is a significant indicator of disseminated systemic metastatic melanoma.

Prognostic index for malignant melanoma

This report verifies the ability of a Prognostic Index (PI) to accurately predict 5‐year survival rates for 879 Stage I cutaneous malignant melanoma (MM) patients seen at New York University Medical Center. The PI used in this study was first reported from Munich, West Germany, and is calculated from standard histologic sections by multiplying the MM thickness in millimeters (Breslow method) by the number of MM mitoses per square millimeter. A PI value of <19 versus ≥19 was found to be a significant and independent prognostic variable for Stage I MM when compared with seven other predictive variables (including Breslow thickness). These PI intervals identified a subgroup of patients with MM of intermediate thicknesses (1.50–3.49 mm) whose significantly worse survival would not have been anticipated if prognosis were determined by Breslow thickness alone. For example, patients with MM 1.50 to 2.49 mm thick have a 5‐year survival rate of 84.1% determined by Breslow thickness alone; however, among these patients exists a subgroup with PI ≥ 19 whose survival rate is only 57.6%. This study verifies the additive usefulness of the PI in predicting survival rates of patients with Stage I cutaneous MM. Cancer 59:1236‐1241, 1987.

Regression in malignant melanoma

A multiple stepwise logistic regression analysis shows that histologic regression is more likely to be found in a malignant melanoma that is level III or less, more than 10 mm in diameter, associated with solar elastosis, located on an anatomic area other than the head or neck, and when there are areas of whiteness clinically. Although patients with malignant melanomas displaying signs of regression histologically have a slightly better 5-year disease-free survival, this may be attributed to a difference in tumor thickness.