V. J. McGovern

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.

A comparison of prognostic factors and surgical results in 1,786 patients with localized (stage I) melanoma treated in Alabama, USA, and New South Wales, Australia

Twelve clinical and pathologic parameters were compared in two series of Stage I melanoma patients treated at the University of Alabama in Birmingham, USA (676 patients) and at the University of Sydney in New South Wales, Australia (1,110 patients). Actuarial survival rates were virtually the same at the two institutions over a 25-year follow-up period. The incidence of thin melanomas (<0.76 mm) was also similar at both geographic locations (25% vs. 26%). Other similarities of these two patient populations included the following: 1) tumor thickness (Breslow Microstaging), 2) level of invasion (Clark Microstaging), 3) surgical results, 4) sex distribution, and 5) age distribution. The greatest differences between the two patient populations were their 1) anatomic distribution, 2) growth pattern, and 3) incidence of ulceration. The trunk was the most common site of melanoma, and occurred more frequently among Australian patients (37% vs. 28%). A multifactorial analysis (Coxs regression model) was then performed that included a comparison of the two institutions as a variable (Alabama vs. Australia). The dominant prognostic factors (p < 0.0001) were 1) ulceration, 2) tumor thickness, 3) initial surgical management (wide excision ± node dissection), 4) anatomic location, 5) pathologic stage (I vs. II), and 6) level of invasion. The benefit of elective lymph node dissection was demonstrated in both series for patients with intermediate thickness melanoma (0.76 to 3.99 mm). For melanomas ranging from 0.76 to 1.5 mm in thickness, the benefit of node dissection was primarily in male patients. Survival rates for melanoma at the two institutions were not significantly different in the multifactorial analysis, even after adjusting for all other variables. Thus, the biologic behavior of melanoma in these two different parts of the world was virtually the same, with only minor differences that did not significantly influence survival rates. Long-term follow-up exceeding eight to ten years after surgery is critical in the interpretation of these prognostic factors and the surgical results.

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. 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. 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). 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.

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.

The female superiority in survival in clinical stage. II. Cutaneous malignant melanoma

Five‐year survival rates were similar in men and women with nodal metastases from malignant melanoma (clinical Stage II). This is in contrast to our previous studies on patients with localized disease (clinical Stage I) which indicated a marked female superiority in survival. To seek explanations for this, we examined in these patients with regional lymph node metastases, four factors which we previously showed to be of prognostic importance in patients with localized disease: (1) Age of patient: overall survival rate in Stage II women was markedly reduced due to an extremely poor prognosis for postmenopausal women; (2) Site of primary lesion: Stage II women had a preponderance of extremity lesions, but these were not more prognostically favorable anatomic locations than axial locations; (3) Tumor thickness: women with metastatic malignant melanoma had a significantly higher proportion of very thick lesions than men; and (4) Evidence of tumor regression: although men with very thin regressing tumors had a poor prognosis, there were too few lesions of this thickness in patients with Stage II melanoma to markedly influence overall survival. It was concluded that although overall five‐year survival rates in men and women with clinical Stage II malignant melanoma were similar, if these patients were matched by age and thickness of primary lesion, a female superiority in survival did exist for young patients with very thick tumors.

Terminology of Vertebrate Melanin-Containing Cells, Their Precursors, and Related Cells: A Report of the Nomenclature Committee of the Sixth International Pigment Cell Conference

In 1953, Fitzpatrick and Lerner (“Terminology of Pigment Cells”, Science 117, 640, 1953) summarized the terminology recommended at the Third Conference on the Biology of the Normal and Atypical Pigment Cell held in New York in the fall of 1951. At this conference a group of investigators met and decided on the terminology that subsequently received wide acceptance and use by scientists throughout the world. In the last decade, however, it has become evident that current terminology should be revised in the light of new findings in the biochemistry, ultrastructure and cytophysiology of melanin-forming cells.

THE PATHOLOGICAL NATURE OF MYCOSIS FUNGOIDES

Throughout the connective tissue of the body there exist primitive mesenchymal cells (reticulum cells) which can differentiate towards whatever type of cell is required for these purposes. In addition there are aggregations of reticulo-endothelial tissues and their derivatives forming certain organs, namely the spleen, lymphoid tissue and bone marrow. The cells produced by the primitive reticulum ceU are blood cells, fibroblasts, vascular endothelium, tissue histiocytes and the phagocytic cells which line the sinuses of the spleen,, lymph nodes and bone marrow. On mathematical grounds it would be expected, and is found, that disorders and neoplasias of reticulo-endothelial tissues are more common in the spleen, lymphoid tissue and bone marrow than in other tissues such as the skin, in which the reticulo-endothelial system is represented by relatively few cells. However, the isolated reticulum cells of connective tissue can with the appropriate stimulus produce cells which are normally produced elsewhere, as in certain anaemias where blood cells may be produced in the spleen, lymph nodes and even the skin ; and in certain circumstances undergo hyperplasia or neoplastic change.

AN EXPREIMENTAL APPROACH TO THE PROBLEM OF PHOTOSENSITIVITY

UNTIL recent years, photosensitization was observed more frequently in domestic animals than in humans. However, we are now seeing increasing numbers of patients with light-sensitivity. This is due partly, I think, to increasing recognition, but there is probably a real increase as well which is due, at least in part, to the introduction of certain new drugs. There have been few experimental investigations of the problem of photosensitivity. The earliest was that of Eaab (1900), who found that paramecia in a solution of acridine hydrochloride 1 : 20,000 died within six minutes on exposure to bright daylight, but were unharmed by the dye in the dark. The experiments of Hausmann (1911) and Levy (1926) have all been confined to clinical and histological observations and have contributed little to elucidation of the mechanism of photosensitiAdty.