Matthew N. Harris

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.

Complications of Level I and II Axillary Dissection in the Treatment of Carcinoma of the Breast

OBJECTIVE To assess the complications of level I and II axillary lymph node dissection in the treatment of stage I and II breast cancer, with breast-conservation surgery and mastectomy. SUMMARY BACKGROUND DATA The role of axillary dissection for staging, and as an effective means of controlling regional nodal disease, has long been recognized. As small and low-grade lesions have been detected more frequently, and as its therapeutic impact has been questioned, axillary dissection has increasingly been perceived as associated with significant complications. METHODS Two hundred patients, 112 of whom had breast-conservation surgery with axillary dissection and 88 of whom had total mastectomy with axillary dissection, were evaluated 1 year or more after surgery for arm swelling as well as nonedema complications. All patients had arm circumference measurements at the same four sites on both the operated and nonoperated sides. RESULTS No patient had an axillary recurrence. The mean difference in circumference on the nonoperated versus operated side was 0.425 cm +/- 1.39 at the midbiceps (p < 0.001), 0.315 cm +/- 1.27 at the antecubital fossa (p < 0.001), 0.355 cm +/- 1.53 at the midforearm (p < 0.005), and 0.055 cm +/- 0.75 at the wrist (n.s.). Seven patients (3.5%) had mild swelling of the hand. Heavy and obese body habitus were the only significant predictors of edema on multivariate analysis. One hundred fifty-three (76.5%) patients had numbness or paresthesias of the medial arm and/or axilla after surgery; in 125 (82%) of these, the problem had lessened or had resolved on follow-up assessment. CONCLUSIONS The characterization of a level I and II axillary dissection as a procedure with significant complications does not appear justified based on this experience.

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%).

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.

Prognosis of patients with pathologic stage II cutaneous malignant melanoma.

The prognostic relevance of the extent of nodal metastases, lesion thickness, level of invasion, site of lesion, satellitosis, age, sex, and year of diagnosis and treatment were assessed in 213 consecutive patients with pathologic Stage II malignant melanoma (157 with clinical Stage I disease and 56 with clinical Stage II disease). Of these factors, only three were significant: 1) clinical status of the lymph nodes (p less than 0.0001); 2) thickness of the primary lesion in the ranges of less than 2.0 mm, 2.0 to 4.9 mm, and 5.0 mm or greater (p = 0.002); and 3) level of invasion (p = 0.0002). The extent of nodal metastases in those patients with clinical Stage I disease was not significant. The difference in survival between patients with clinically negative/histologically positive nodes (clinical Stage I) and clinically positive/histologically positive nodes (clinical Stage II) was apparent throughout the follow-up period. The 5- and 10-year survival rates for the clinical Stage I patients were 44% and 28%, respectively, and for the clinical Stage II patients 21% and 12%, respectively (p less than 0.0001). A 5-year cumulative survival rate of 65% was achieved for clinical Stage I patients having primary lesions of less than 2.0 mm in thickness, while it was 19% for patients having primary lesions of 5.0 mm or more in thickness. For pathologic Stage II malignant melanoma patients, prognosis is most dependent on the clinical status of the lymph nodes, not on the number of lymph nodes with micrometastases.

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.