Allen Postel

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.

Malignant melanoma patients with positive nodes and relatively good prognoses: Microstaging retains prognostic significance in clinical stage I melanoma patients with metastases to regional nodes

Fifteen yariables were tested for their value in predicting recurrent disease in 46 clinical Stage I melanoma patients with metastases to regional nodes. A stepwise proportional hazards general linear model (Cox multivariate analysis) separated these melanoma patients with regional node metastases into at least two risk groups. Twenty patients in the relatively low‐risk group had a five‐year disease‐free survival of 80% (in spite of having nodal metastases). This compares to a five‐year disease‐free survival of 17.5% for 26 patients in the high‐risk group (P < 0.001, Lee‐Desu Statistic). Criteria for the high‐risk group required that a patient have only one of the following two values: (1) The number of regional lymph nodes that contained tumor divided by the total number of nodes removed × 100% (percentage of positive nodes) ≥20%; or (2) a primary tumor thickness of >3.5 mm (regardless of node percentage). Conversely, patients in the low‐risk group had neither of the above features. The high‐risk group could further be stratified by the lymphocytic response at the base of the tumor. These findings have direct immediate application to the elective regional node dissection controversy and to adjuvant therapy studies containing these patients. Cancer 47:955–962, 1981.

“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 prognostic model for clinical stage I melanoma of the upper extremity. The importance of anatomic subsites in predicting recurrent disease.

Thirteen variables were studied for their relative usefulness in predicting recurrent disease in 107 patients with clinical Stage I melanoma of the upper extremity. After a mean follow-up period of 54 months, the only patients who have had recurrent disease to date are those whose primary lesions were located either on the hand or posterior upper arm. The five-year, disease-free survival role for 44 patients with melanoma at these sites was 68%. None of 63 patients with melanoma located on the forearm of anterior upper arm have had recurrent disease (i.e., the five-year, disease-free survival rate was 100% (p = 0.00004), compared with the hand or posterior arm group). A Cox proportional hazards (multivariate) analysis demonstrated that two primary tumor histologic variables, thickness in millimeters and ulceration, interacted to produce the best prognostic model for those 44 patients with melanoma of the hand or posterior upper arm. Twenty-one

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%).

A prognostic model for clinical stage I melanoma of the trunk: Location near the midline is not an independent risk factor for recurrent disease☆☆☆

Fifteen variables were studied for their usefulness in predicting recurrent disease in 254 patients with clinical stage I melanoma of the trunk. Thickness of the primary tumor correctly predicted outcome with an accuracy of 90 percent or greater in 176 patients with melanoma primaries with a thickness of less than 1.70 mm or 5.5 mm or greater. No other variables significantly increased predictive accuracy over these ranges of thickness. A Cox proportional hazards analysis of the remaining 78 patients with primary tumors 1.70 to 5.49 mm thick demonstrated that the following four variables functioned as independent risk factors for recurrent disease: (1) thickness of the primary tumor (p = 0.0005), (2) mitoses/mm2 greater than 6 (p = 0.006), (3) a nearly absent or minimal lymphocyte response at the base of the tumor (p = 0.009), and (4) location on the upper trunk (p = 0.03). Trunk lesions located near the midline did not have a worse prognosis than more lateral melanomas of similar thickness.

Volume of malignant melanoma is superior to thickness as a prognostic indicator : preliminary observation

There are many clinical and histologic factors that are known to be valuable in predicting survival rates for patients with cutaneous malignant melanomas. Breslow thickness is considered to be the most reliable prognostic factor; however, thickness is a unidimensional measurement. A more accurate mensuration to predict biologic behavior might be one that takes into account the three-dimensional volume of the neoplasm. In a study of 35 primary malignant melanomas, the volumes of the dermal components of the tumors were calculated. Those patients with tumor volumes of 200 mm3 or less had a 91.4% 5-year disease-free survival rate, compared with survival rate of only 16.7% for those patients whose lesions had tumor volumes exceeding 200 mm3. On multivariate analysis, tumor volume exceeded thickness as a prognostic indicator. Thus, measurement of tumor volume proved to be of greater significance than thickness in predicting the outcome for patients with malignant melanomas.

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.

Induced remission of malignant melanoma with actinomycin D. Immunologic implications

Five patients with malignant melanoma of the extremities experienced tumor regression while being treated with intravenous actinomycin D. Each had responded to a prior isolated perfusion with actinomycin D with transient tumor regression and drug toxicity in the perfused limb. Three patients are free of demonstrable melanoma for more than 4 1/2 years. These patients exhibited intense delayed skin hypersensitivity to test antigens; however, patients with melanoma exhibited a greater sensitivity to these antigens than did patients with carcinoma. Two other patients died of metastases to the brain without recurrent melanoma elsewhere. Five other patients similarly treated did not respond with tumor regression. No similar regression of melanoma has been observed in 23 patients treated with actinomycin D alone or among 101 other patients treated with 18 other chemotherapeutic agents.