Medwin M. Mintzis

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.

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%).

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.

Influence of anatomic location on prognosis of malignant melanoma: Attempt to verify the BANS model

Stage I cutaneous malignant melanomas between 0.76 and 1.69 mm thick (Breslow measurement) in BANS (upper part of the back, posterior aspects of the arms, posterior and lateral aspects of the neck, posterior aspect of the scalp) areas have been reported to portend a relatively poor prognosis compared to non-BANS sites. We were unable to confirm the 15% poorer survival for BANS area lesions (84% BANS, 99% non-BANS) originally reported. In this report of 211 patients, malignant melanomas in BANS sites had a 4.6% poorer 5-year cumulative survival rate (88.9% BANS, 93.5% non-BANS; p = 0.35). Although many more patients need to be studied, we believe this small difference in survival is insufficient to influence therapeutic management strategies.

Predictors of Late deaths among patients with clinical stage I melanoma who have not had bony or visceral metastases within the first 5 years after diagnosis

We studied fourteen prognostic factors in 340 patients with clinical stage I malignant melanoma who were free of bony or visceral metastases 60 months following diagnosis. The malignant melanoma survival rate (MMSR) was 95% for these patients during the ensuing 40 months (i.e., 100 months following diagnosis). Deaths from malignant melanoma occurred exclusively in the subset of patients with primary lesions 1.70 mm through 3.64 mm thick. The seventy-four patients in this thickness group who were free of bony or visceral metastases at 60 months had a 100-month MMSR of 73%. Patients in the other thickness groups, including nineteen patients with melanomas ≥23.65 mm thick, had a 100-month MMSR of 100% (if bony or visceral metastases had not occurred in the first 60 months following diagnosis). Within the 1.70 through 3.64 rnm thickness group, a Cox multivariate analysis found no other significant prognostic factors among the remaining thirteen variables. As a result of the continuing deaths after 60 months in the 1.70 through 3.64 rnrn thickness group, these patients had a cumulative 100-month MMSR (i.e., 1 through 60 months plus 61 through 100 months) that was only 17% higher than that for the thicker (≥3.65 mm) group. These data, when combined with published 1- through 60-month results, indicate that most melanomas do not become lethal until a critical volume is reached (indicated by a thickness of ≥1.70 mm), Inasmuch as primary melanomas continue to grow and increase in size after they attain this critical volume, the thickness measurement parallels the metastatic tumor burden. In other words, thickness is an index not only of the lethal potential but also of the survival interval (or rate of death) after surgical removal of the tumor.

Ultrastructural study of superficial spreading melanoma and benign simulants

Ultrastructural examination of the intraepidermal component of superficial spreading melanomas (SSM) and benign melanocytic lesions was undertaken to determine the diagnostic value of electron microscopy in clinically “borderline” melanoma problems. Seventeen SSMs and ten benign melanocytic nevi and lentigines which clinically resembled melanoma were studied. Melanocytes of the intraepidermal component of the SSMs showed a greater tendency for abnormal melanosome formation than did melanocytes of the benign simulants. However, the abnormalities were variable and were not limited to the SSMs. Our observations suggest that qualitative ultrastructural evaluation cannot be reliably used in differentiating SSMs from benign melanocytic lesions.

What Lies Beneath? A Lesson for the Clinician. Intraoperative Frozen Section Appearance of Persistent Basal Cell Carcinoma after Apparent Cure with Imiquimod 5% Cream

The Food and Drug Administration (FDA) has approved imiquimod 5% cream for the treatment of nonfacial superficial basal cell carcinoma (BCC), and it has increased in popularity as a nonsurgical approach for the treatment of BCC. Its use for the treatment of superficial BCCs on the trunk, neck, and extremities has been documented in the dermatology and family physician literature. Studies of imiquimod for nodular BCC, on the other hand, have demonstrated suboptimal cure rates according to both clinical and histologic criteria, but little is known about the efficacy of imiquimod cream in the treatment of more extensive lesions, more aggressive BCC subtypes, or treatment in higher risk locations like the face, although the off-label practice of treating facial BCCs with imiquimod is not rare.