G. W. Milton

The classification of malignant melanoma and its histologic reporting

Apart from the rare malignant melanomas occurring in blue nevi, primary cutaneous malignant melanoma arises in 1 of 3 ways, regardless of the presence or absence of a pre‐existing nevus. These three types have been designated: 1. Malignant melanoma, invasive, with adjacent intra‐epidermal component of Hutchinsons melanotic freckle type; 2. Malignant melanoma, invasive, with adjacent intra‐epidermal component of superficial spreading type; and 3. Malignant melanoma, invasive, without adjacent intra‐epidermal component. Occasionally, both clinically and histologically, there may be difficulty in deciding whether a malignant melanoma belongs to category 1 or 2, but, in the majority of cases, these 2 types can be quite readily distinguished. In addition to recording the histogenetic mode of development of a malignant melanoma, a histologic system of reporting is recommended which includes mitotic activity, levels of invasion, and vascular involvement. There are other parameters such as the cell type, pigmentation, lymphocytic infiltrates, evidence of spontaneous regression, associated nevi, and solar changes in the dermis, all of which are of unknown significance. The recording of these features, which are clearly of interest for research purposes, is left to individual discretion. It is emphasized that all the usual macroscopic descriptions and measurements should continue to be recorded.

Cutaneous factors related to the risk of malignant melanoma.

In a case‐control study, 287 women with malignant melanoma were compared with 574 age‐matched controls. Red hair colour at age 5 years was associated with a tripling of risk [relative risk (RR) = 3.0], blonde hair with a 60% increase (RR=1.6) and fair skin with a doubling (RR = 2.1). Women with melanoma also reported that they tended to burn (RR = 1.4) and to freckle (RR =1.9) after exposure to sunlight. Since fair skin, red hair, and the tendency to burn or freckle after exposure to sunlight all cluster in the same individuals, the extent to which each of these factors had an independent influence on susceptibility to melanoma was investigated. Hair colour, especially red hair, proved to be the major determinant, followed by skin colour.

Prognostic significance of the histological features of malignant melanoma

A review of 694 patients with localized cutaneous malignant melanoma (clinical stage I) revealed that three histological features of the primary lesion had no effect of their own on survival rate but derived their prognostic significance only because of their close correlation with tumour thickness. Primary lesions of superficial spreading histogenetic type, or of low mitotic activity or showing evidence of partial regression appeared to have a more favourable prognosis than lesions of nodular histogenetic type or of high mitotic activity or showing no regression. However, the former three histological features were predominant in thin lesions which had a better prognosis than thicker lesions. It was concluded that these features exerted only an indirect effect upon survival, tumour thickness being the most important prognostic determinant.

The influence of surgical margins and prognostic factors predicting the risk of local recurrence in 3445 patients with primary cutaneous melanoma

Risk factors associated with local recurrences were analyzed from a series of 3445 clinical Stage I melanoma patients. In single‐factor analysis, tumor thickness, ulceration, and increasing age were highly significantly predictive of recurrence (p < 0.00001). After 5 years of follow‐up, local recurrence rates were 0.2% for tumors less than 0.76 mm thick, 2.1% for tumors 0.76 to 1.49 mm thick, 6.4% for tumors 1.5 to 3.99 mm thick, and 13.2% for tumors 4.0 mm or greater in thickness. Ulcerated melanomas recurred more often than nonulcerated lesions (11.5% versus 1.9%). When analyzed as a continuous variable, increasing age increased the risk of local failure. In multifactorial analysis, all of these three factors remained independently predictive of local recurrence. Recurrences were more common with nodular melanomas (5.6%) compared to superficial spreading (2.5%) or lentigo maligna melanoma (2.5%), but this difference did not reach statistical significance (P = 0.115). Lower extremity (4.7%) and head and neck lesions (4.4%) recurred more frequently than upper extremity (1.6%) or trunk (1.2%) melanomas (P = 0.0217). The highest recurrence rates were observed in patients with melanomas located on the foot (11.6%) and hand (11.1%). The safety of conservative margins for the excision of low‐risk melanomas was demonstrated in a review of 1151 consecutive patients with melanomas less than 1 mm thick where only one local recurrence was observed. Sixty‐two percent of these patients had resection margins of 2 cm or less. In 95 patients local recurrence developed as the first site of relapse and were treated with surgical excision. The median survival for this group was 3 years, whereas 20% of this group survived 10 years. These data demonstrate that: (1) the risk of local recurrence rises with increasing tumor thickness, presence of ulceration, and age; (2) melanomas less than 1 mm thick have a very low local recurrence rate, even when excised with margins of 2 cm or less; and (3) local recurrence is a poor prognostic sign because regional and systemic metastases subsequently develop in many patients. Cancer 55:1398‐1402, 1985.

Is malignant melanoma arising in a Hutchinson's melanotic freckle a separate disease entity?

Several features which distinguish malignant melanoma arising in a Hutchinsons melanotic freckle (HMFM) from other types of malignant melanoma (MM) are described. Forty‐eight patients with HMFM of the head and neck region were compared with 98 patients with MM of the head and neck region. All patients were clinical stage I. There was a preponderance of women amongst HMFM patients but not MM patients and HMFM patients were significantly older than MM patients. Although HMFM patients had thicker tumours than MM patients, these thicker lesions had a lower degree of mitotic activity and a higher incidence of partial regression. Overall prognosis for HMFM patients was significantly better than for MM patients, this being particularly so for women, none of whom died of melanoma. There was no close correlation between prognosis of HMFM patients and the thickness of their tumours. Every one of the HMFM in this study displayed evidence of severe solar degeneration, but such degeneration per se did not appear to confer upon these lesions their benign biological behaviour.

Endocrine influences on survival from malignant melanoma.

A series of 1861 patients with malignant melanoma was reviewed to determine if there were endocrine influences on survival from the disease. No change in prognosis for melanoma patients was detected during times of hormonal upheaval such as puberty, menopause or estrogen administration. Parous women, however, irrespective of whether their pregnancies occurred prior to or coincident with diagnosis of melanoma, tended to present at an earlier clinical stage of the disease and have a higher 5‐year survival rate than non‐parous women. In addition, there was a statistically significant sex difference in prognosis, more women than men surviving 5 years. Two factors possibly contributing to this longer survival were that women first presented at an earlier clinical stage of the disease and had primary lesions confined to more prognostically favorable anatomical sites than men. The disease seemed to develop the capacity to metastasize more slowly in women than in men. However, the sex of the patient played an imortant role in prognosis only in patients first presenting with localized Stage I melanoma. Five‐year survival rate in women first presenting with metastases was less than in men first presenting with metastases and thus endocrine influences that may previously have delayed growth had no further effect on the behavior of the tumor. We concluded from the present study that there may be endocrine influences on the rate of formation of metastases and the distributions of anatomical sites of primary lesions.

Prognosis in patients with thin malignant melanoma: influence of regression

It has been suggested that patients with thin malignant melanoma displaying evidence of histological regression may have a poor prognosis. In the present study, the case histories of 353 patients with clinical stage I cutaneous malignant melanoma up to 0.7 mm thick were reviewed to determine if either active or past regression in these lesions was a poor prognostic sign. Lesions were reported as displaying evidence of partial regression if either (a) a portion of the melanoma had a heavy lymphocytic infiltrate associated with loss of tumour cells or the presence of degenerating tumour cells, or (b) a portion of the melanoma was replaced by vascular fibrous tissue with or without pigment‐containing phagocytes. The incidence of regression in this study (58%) was similar to that reported in another recent large study on thin lesions (53%). Only slightly more regressed than unregressed lesions metastasized (8% versus 5% respectively). A high proportion of first recurrences from these thin lesions developed at sites remote from the primary lesion (lung, bone or in subcutaneous tissues or lymph nodes wide of the line of spread). However, the presence or absence of regression in thin lesions did not appear to influence the site of first recurrence. Cumulative 10‐year survival rates for patients whose lesions displayed or did not display evidence of either active or past regression were nearly identical. We concluded that in patients with long‐term follow‐up, prognosis was not less favourable if there was presence of regression in their thin lesions.

Malignant melanoma: influence of site of lesion and age of patient in the female superiority in survival.

Efforts were made to further explain female superiority in survival of 753 patients with clinical Stage I malignant melanoma. Two factors contributing to this female superiority in survival drew some of their prognostic value from the correlation with tumor thickness. (1) More than twice as many women as men had primary lesions located on the extremities, which were prognostically favorable anatomical sites in both men and women. In addition, women with extremity lesions had a more favorable prognosis than men with extremity lesions. This sex differential in survival for patients with extremity lesions was partly attributable to the fact that the extremity lesions of women were significantly thinner than those of men. (2) Significantly more women than men were under age 50; this age group of women had a significantly better prognosis than the corresponding age group of men. The sex differential in survival for patients under 50 years was partly attributable to the fact that the womens lesions were significantly thinner than those of men. There was only a slight sex differential in the survival of patients 50 years and over, a finding in consonance with the smaller difference in tumor thickness between these older men and women. The association between decline in prognosis with increasing age and decline in proportion of thin lesions with increasing age was much closer in men than women. In men and women matched by age, site, and thickness of primary lesions, women with very thick tumors still survived longer.

Histologic features of tumors and the female superiority in survival from malignant melanoma

The primary tumors of 780 patients with clinical Stage I malignant melanoma were reviewed to seek reasons for the female superiority in survival. Histologic features of tumors believed to be of prognostic significance were examined: tumor thickness, evidence of regression, histogenetic type, and mitotic activity. The average tumor thickness was significantly less in women, due to a preponderance of very thin lesions in women and very thick lesions in men. In both men and women, there proved to be a direct correlation between five‐year survival rate and tumor thickness, but women had a higher survival rate than men at each thickness level. These latter two findings, in combination, could contribute to the overall female superiority in survival. No further insight into the sex difference in survival was obtained from the examination of the other histologic features. Although the incidence of partial lesion regression was significantly higher in men, prognosis for regressing and nonregressing lesions was not markedly different except for very thin lesions. There were no disparities between the sexes in the incidences of histogenetic types or grades of mitotic activity, two histologic features which drew their prognostic significance only from their correlation with tumor thickness.

Changing trends in cutaneous melanoma over a quarter century in Alabama, USA, and New South Wales, Australia

Clinical and pathologic characteristics of melanoma were compared among 1647 clinical Stage I patients treated at the University of Alabama in Birmingham (USA) and The University of Sydney (Australia) between 1955 and 1980 to determine what changes occurred over a quarter century. Over this period, the number of patients treated annually has increased substantially. There was a steady increase in the proportion of patients presenting with localized disease (clinical Stage I). Melanomas became thinner, less invasive, less ulcerative and thus more curable. They also exhibited more of a radial growth phase. The median thickness of melanomas decreased in Australia from 2.5 mm prior to 1960 to 1.1 mm during the period 1976 to 1980, while in Alabama it has decreased from 3.3 to 1.4 mm. There was a significant increase in melanomas located on the trunk in males and a corresponding decrease in male head and neck melanomas. No significant change in the site distribution was observed for any major anatomical area on female patients. There were minimal differences in the incidence of both clinical and pathologic parameters among melanoma patients in Alabama, USA and in New South Wales, Australia even when accounting for their year of diagnosis. Long‐term survival rates in patients with localized disease were found to increase slightly during the 25 year time frame of this analysis. The changes that have occurred are likely due to earlier diagnosis and changes in the biological nature of the disease.