Gerald W. Milton

Determinants of Outcome in Melanoma Patients With Cerebral Metastases

PURPOSEnTo analyze prognostic factors, effects of treatment, and survival for patients with cerebral metastases from melanoma.nnnPATIENTS AND METHODSnAll melanoma patients with cerebral metastases treated at the Sydney Melanoma Unit between 1952 and 2000 were identified. From 1985 to 2000, patients were diagnosed and treated using consistent modern techniques and this cohort was analyzed in detail. Multivariate analysis of prognostic factors for survival was performed.nnnRESULTSnA total of 1137 patients with cerebral metastases were identified; 686 were treated between 1985 and 2000. For these 686 patients, the median time from primary diagnosis to cerebral metastasis was 3.1 years (range, 0 to 41 years). A total of 646 patients (94%) have died as a result of melanoma. The median survival from the time of diagnosis of cerebral metastasis was 4.1 months (range, 0 to 17.2 years). Treatment was as follows: surgery and postoperative radiotherapy, 158 patients; surgery alone, 47 patients; radiotherapy alone, 236 patients; and supportive care alone, 210 patients. Median survival according to treatment received for these four groups was 8.9, 8.7, 3.4, and 2.1 months, respectively; the differences between surgery and nonsurgery groups were statistically significant. On multivariate analysis, significant factors associated with improved survival were surgical treatment (P <.0001), no concurrent extracerebral metastases (P <.0001), younger age (P =.0007), and longer disease-free interval (P =.036). Prognostic factors analysis confirmed the important influence of patient selection on treatment received.nnnCONCLUSIONnThis large series documents the characteristics of patients who developed cerebral metastases from melanoma. Median survival was dependent on treatment, which in turn was dependent on patient selection.

Experience with 998 cutaneous melanomas of the head and neck over 30 years

Between 1960 and 1990, a total of 998 patients were treated at the Sydney Melanoma Unit for cutaneous melanoma of the head and neck. There were 595 male and 403 female patients, with a median age of 53 years. The most common primary lesion site was the face (47%), followed by the neck (29%), scalp (14%), and ear (10%). Histologic types were as follows: superficial spreading 30%, nodular melanoma 28%, lentigo maligna melanoma 16%, and other 26%. All patients underwent surgical treatment. Primary closure of wounds was achieved in 52% of patients, and excision margins were 2 cm or less in 45%. A total of 152 patients had therapeutic neck dissections, and 234 had elective neck dissections. The overall local recurrence rate was 13%, and this was significantly influenced by increasing tumor thickness and Clark level. The recurrence rate in the neck after neck dissection was 24%, and the rate of parotid recurrences was 14%. Melanoma-specific survival was 77% at 5 years and 66% at 10 years for the entire group. By univariate analysis, survival varied significantly with age, tumor thickness, ulceration, anatomic sub-site, histologically positive nodes, and the presence of distant metastases. A diagnosis of lentigo maligna melanoma and elective lymph node dissection both appeared to improve survival. With multivariate analysis, all of these factors remained significant prognostic factors except elective node dissection, which lost its beneficial influence.

Head and neck melanoma in 534 clinical Stage I patients. A prognostic factors analysis and results of surgical treatment

Single and multifactorial analyses were used to evaluate prognosis and results of surgical treatment in 534 clinical Stage I patients with head and neck cutaneous melanoma treated at the University of Alabama in Birmingham (U.S.A.) and the University of Sydney (Australia). This computerized data base was prospectively accumulated in over 90% of cases. Melanomas were about equally distributed between men and women. They were located on the skin of the face in 47%, neck in 27%, scalp in 13%, and the ear in 13% of patients. Both the results of the prognostic factors analyses and the surgical treatment demonstrated that lentigo maligna melanoma (LMM) was distinct from the other two growth patterns, superficial spreading melanoma and nodular melanoma (SSM and NM). In a multifactorial analysis of the 453 patients with SSM and NM, the dominant prognostic variables were tumor thickness (p less than 0.00001), anatomic subsite (p = 0.0213), and ulceration (p = 0.0289). Patients with melanomas on the scalp or neck subsites fared worse than those with tumors located on the face or ear. The results differed for LMM, where thickness was not a significant predictor of survival, and the most dominant prognostic variable was ulceration (p = 0.0042). Local recurrence rates were low, being 2.4% for tumors less than 2.5 mm in thickness, but were 12.3% for tumors greater than or equal to 4.0 mm in thickness. Patients with SSM and NM lesions located on the head and neck had a lower survival rate than those with extremity melanomas in every tumor thickness category, although only those in the 0.76 to 1.49 mm thickness subgroup were significantly different (p = 0.0007). After 5 years of follow-up, patients who underwent an elective lymph node dissection for SSM and NM with a thickness range of 1.5 to 3.99 mm had a better survival (72%) than patients with melanomas of equivalent thickness whose initial treatment was wide excision alone (45%). LMM had a less aggressive biologic behavior compared to SSM or NM and was treated more conservatively. Thus, LMM lesions had an 85% 10-year survival rate with wide excision only, and there was no significant improvement in survival with ELND. Growth patterns, tumor thickness, ulceration, and anatomic subsites should be considered when evaluating risk factors and when making treatment decisions in head and neck melanoma patients.

The prognostic importance of tumor mitotic rate confirmed in 1317 patients with primary cutaneous melanoma and long follow-up.

AbstractBackground: The late Dr. Vincent McGovern (1915 to 1983) was an international authority on melanoma pathology and one of the first to suggest that assessment of tumor mitotic rate (TMR) might provide useful prognostic information. Data for a large cohort of patients, now with extended follow-up, whose tumors had been assessed by Dr. McGovern were analyzed to reassess the independent prognostic value of TMR in primary localized, cutaneous melanoma.n Methods: Information was extracted from the Sydney Melanoma Unit database for 1317 patients treated between 1957 and 1982 for whom there was complete clinical information and whose primary lesion pathology, which included tumor thickness, ulcerative state, and TMR, had been assessed by Dr. McGovern. All these assessments were made according to the recommendations of the Eighth International Pigment Cell Conference, held in Sydney in 1972 under the auspices of the International Union Against Cancer. Factors predicting melanoma-specific survival were analyzed with the Cox proportional hazards regression model.n Results: Stage, according to the recently revised American Joint Committee on Cancer Staging System (which is based on tumor thickness and ulceration) was the most predictive factor for survival (P < .0001). This was followed by primary lesion site (P < .0001), patient age (P = .0005), and TMR (P = .008).n Conclusions: TMR was confirmed to be an important independent predictor of survival of patients with primary cutaneous melanoma. However, its predictive value was less than it was when assessed according to the 1982 revisions of the 1972 TMR recommendations.

Prognostic histopathological factors in malignant melanoma

&NA; An analysis of prognostic factors in 4000 patients with cutaneous malignant melanoma at the Sydney Melanoma Unit and the University of Alabama in Birmingham has demonstrated that the histological features of the primary melanoma become less predictive of survival the more advanced the disease becomes. Thus, whilst 4 features of primary lesions were independent predictors in localized disease (tumour thickness, ulceration, level of invasion and regression), only one of the stronger ones (ulceration) remained predictive in patients with regional lymph node metastases. Once distant spread was evident, there were no parameters of the primary lesion that predicted survival. Thus, in patients with advanced disease prognosis was dictated by the extent of metastatic involvement: the number of positive lymph nodes in stage II patients and the number and location of metastatic sites in stage III patients.

Evidence that treatment with vaccinia melanoma cell lysates (VMCL) may improve survival of patients with stage II melanoma

SummaryA total of 80 patients with melanoma metastases in regional lymph nodes were treated by i.d. injections with a vaccine prepared from a vaccinia virus-infected allogeneic melanoma cell line; 39 patients have been followed for a 2-year period. Interim results from comparison of the treated group with 151 historical controls treated without the vaccine from September 1978 to December 1981 at the same institution and 56 non-randomized concurrent controls suggest that survival was significantly prolonged in the vaccinated group. At the 2-year period overall survival was 75% in the treated compared to 57% in the historical control group. Subset analysis showed a greater apparent benefit of vaccine therapy among patients who had metastases detected at the time of treatment of the primary melanoma (synchronous metastases), while therapy appeared less effective in patients with metastases detected at some time after treatment of the primary (delayed metastases). In the latter only those with one lymph node appeared to benefit from the treatment whereas in patients with synchronous metastases patients with three or more nodes as well as one node appeared to have improved survival. The survival rates at 2 years for treated patients with synchronous metastases in one, two, three or more lymph nodes was 100%, 83% and 79% respectively compared with that of 82%, 86% and 47% respectively in the equivalent control groups. Survival rates in treated patients with delayed metastases in one, two, three or more lymph nodes was 70%, 70% and 65% compared with 47%, 42% and 35% in the equivalent control groups. Treatment and control groups appeared well matched for a number of known prognostic features, including number and size of involved nodes, sex and thickness of primary tumor. Multivariate analysis indicated the effect of treatment was independent of these factors. Despite the empiricism of this approach the present results suggest that this form of therapy warrants further evaluation in a randomized controlled trial.

Comparison of two methods of treating primary malignant melanomas clark IV and V, thickness 1.5 mm and greater, localized on the extremities. Wide surgical excision with and without adjuvant regional perfusion

A comparative retrospective study of patients with primary malignant melanomas of the extremities, Clark level IV/V and tumor thickness ≤ 1.5 mm, was performed in Sydney (Australia) and Groningen (The Netherlands). The efficacy of wide local excision combined with adjuvant regional perfusion (Groningen) was compared with that of wide surgical excision only (Sydney). Patients were classified by sex and tumor location. There were only sufficient numbers of female patients with a tumor of the lower extremity available for this comparative study. All patients were stage I and none received prophylactic lymph node dissection. Age, tumor location, tumor thickness, depth of infiltration and ulceration were taken into account and the factors studied within this group were 10‐year disease‐free rate, 10‐year survival rate, and local and regional recurrences. Women with a melanoma of the leg (excluding the foot) who had been treated by excision and adjuvant regional perfusion, had a significantly better 10‐year disease‐free rate (P <0.0005), a significantly higher 10‐year survival rate (0.010

Cutaneous melanoma in childhood: Incidence and prognosis

The incidence and prognosis of cutaneous melanoma in children under 13 years of age has always been difficult to assess. The main reasons for this difficulty include the rarity of melanoma in children, referral biases from investigating institutions, changing conceptions in the histological diagnosis of true melanoma, and the lack of large enough study groups with sufficient follow-up to estimate 10-year survival rates. The present study documents 32 cases of childhood cutaneous melanoma drawn from the records of two large referral centres in New South Wales, Australia: the Sydney Melanoma Unit and the Newcastle Melanoma Unit in order to demonstrate some of the difficulties in the assessment of incidence and prognosis in children.

Histogenesis of Malignant Melanoma with an Adjacent Component of the Superficial Spreading Type

&NA; There has been a world‐wide exponential increase in the incidence of thin malignant melanoma. At the Sydney Melanoma Unit, the proportion of patients diagnosed as having superficial spreading melanoma has more than doubled from 33% prior to 1960 to 78% during 1980–83. A study was made of the non‐invasive component of malignant melanoma with an adjacent non‐invasive component of the superficial spreading type in an attempt to elucidate the pathogenetic mechanisms involved in these changing trends. In this study on 723 cases of melanoma with a superficial spreading component, there was evidence that 39% originated in a precursor lesion. In the remaining 61%, the adjacent superficial spreading component consisted of melanoma in situ, suggesting that these were melanomas from the beginning. The latter lesions were thinner and had a lower degree of mitotic activity than melanomas commencing in a precursor lesion. Despite the large increase in incidence of superficial spreading melanomas and the shift to thinner lesions over time, there appeared to be no difference in the proportion of lesions commencing de novo to those commencing in a precursor lesion. This suggests that the precursor lesion may be of genetic origin.

SUBUNGUAL MALIGNANT MELANOMA: A DISEASE ENTITY SEPARATE FROM OTHER FORMS OF CUTANEOUS MELANOMA

The characteristics and results of treatment of 30 patients with subungual malignant melanoma treated at the Sydney Melanoma Unit were studied. It was found that in several major respects subungual melanoma differed from other forms of cutaneous melanoma. Patients with subungual melanoma were considerably older than those with either superficial spreading or nodular melanoma and there was a preponderance of men with subungual melanoma of the upper extremity. Independent prognostic factors (such as tumour thickness) which are important in determining survival in patients with superficial spreading or nodular melanoma, had little consequence in patients with subungual melanoma. Despite the fact that the vast majority of subungual melanomas were very thick and ulcerated due to the delay in correctly diagnosing the disease clinically, overall survival rate was reasonably good, providing patients had an amputation of the entire digit together with either a prophylactic or therapeutic lymph node dissection. These findings indicate that subungual melanoma is a disease entity separate from other forms of cutaneous melanoma and that radical surgery is essential in all subungual melanoma patients.