PURPOSE: To revise the staging system for cutaneous melanoma under the auspices of the American Joint Committee on Cancer (AJCC). MATERIALS AND METHODS: The prognostic factors analysis described in the companion publication (this issue), as well as evidence from the published literature, was used to assemble the tumor-node-metastasis criteria and stage grouping for the melanoma staging system. RESULTS: Major changes include (1) melanoma thickness and ulceration but not level of invasion to be used in the T category (except for T1 melanomas); (2) the number of metastatic lymph nodes rather than their gross dimensions and the delineation of clinically occult (ie, microscopic) versus clinically apparent (ie, macroscopic) nodal metastases to be used in the N category; (3) the site of distant metastases and the presence of elevated serum lactic dehydrogenase to be used in the M category; (4) an upstaging of all patients with stage I, II, and III disease when a primary melanoma is ulcerated; (5) a merging of sa...

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Final Version of the American Joint Committee on Cancer Staging System for Cutaneous Melanoma

PURPOSE: The American Joint Committee on Cancer (AJCC) recently proposed major revisions of the tumor-node-metastases (TNM) categories and stage groupings for cutaneous melanoma. Thirteen cancer centers and cancer cooperative groups contributed staging and survival data from a total of 30,450 melanoma patients from their databases in order to validate this staging proposal. PATIENTS AND METHODS: There were 17,600 melanoma patients with complete clinical, pathologic, and follow-up information. Factors predicting melanoma-specific survival rates were analyzed using the Cox proportional hazards regression model. Follow-up survival data for 5 years or longer were available for 73% of the patients. RESULTS: This analysis demonstrated that (1) in the T category, tumor thickness and ulceration were the most powerful predictors of survival, and the level of invasion had a significant impact only within the subgroup of thin (≤ 1 mm) melanomas; (2) in the N category, the following three independent factors were ide...

Prognostic Factors Analysis of 17,600 Melanoma Patients: Validation of the American Joint Committee on Cancer Melanoma Staging System

Cutaneous melanin pigment plays a critical role in camouflage, mimicry, social communication, and protection against harmful effects of solar radiation. Melanogenesis is under complex regulatory control by multiple agents interacting via pathways activated by receptor-dependent and -independent mechanisms, in hormonal, auto-, para-, or intracrine fashion. Because of the multidirectional nature and heterogeneous character of the melanogenesis modifying agents, its controlling factors are not organized into simple linear sequences, but they interphase instead in a multidimensional network, with extensive functional overlapping with connections arranged both in series and in parallel. The most important positive regulator of melanogenesis is the MC1 receptor with its ligands melanocortins and ACTH, whereas among the negative regulators agouti protein stands out, determining intensity of melanogenesis and also the type of melanin synthesized. Within the context of the skin as a stress organ, melanogenic activity serves as a unique molecular sensor and transducer of noxious signals and as regulator of local homeostasis. In keeping with these multiple roles, melanogenesis is controlled by a highly structured system, active since early embryogenesis and capable of superselective functional regulation that may reach down to the cellular level represented by single melanocytes. Indeed, the significance of melanogenesis extends beyond the mere assignment of a color trait.

https://www.physiology.org/doi/pdf/10.1152/physrev.00044.2003

Melanin Pigmentation in Mammalian Skin and Its Hormonal Regulation

The combination of routine physician examination of the skin coupled with self-examination provides a realistic opportunity for the identification of early malignant melanomas. Removal of such thin lesions can significantly reduce the mortality rate from this potentially serious form of cutaneous cancer.

Early detection of malignant melanoma: The role of physician examination and self‐examination of the skin

In this study we demonstrate the presence of specific, high-affinity receptors for 1,25-dihydroxyvitamin D3 in malignant melanoma. Receptors are present both in cultured melanoma cells and in melanoma tumor tissue produced by inoculation of cells into athymic rats. The receptor sediments at 3.25 on sucrose density gradients, possesses a preferential affinity for 1,25-(OH)2D3 and has an apparent Kd of 0.18 nM by Scatchard analysis. We also demonstrate that human melanoma cells are responsive to 1,25-(OH)2D3 in vitro. Inclusion of 1,25-(OH)2D3 in the culture medium produced a marked increase in cell doubling time. This inhibitory effect of the hormone on melanoma cell proliferation was dose-related and represents the first demonstration of a 1,25-(OH)2D3 mediated action on tumor cells.

1,25-dihydroxyvitamin D3 and malignant melanoma: the presence of receptors and inhibition of cell growth in culture.

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.

Prognostic significance of the histological features of malignant melanoma

Several features which distinguish malignant melanoma arising in a Hutchinson's 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.

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

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 nonparous women. In addition there was a statistically significant sex difference in prognosis with more women than men surviving 5 years. 2 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 important role in prognosis only in patients first presenting with localized Stage 1 melanoma. 5-year survival rates in women first presenting with metastases were 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 that there may be endocrine influences on the rate of formation of metastases and the distributions of anatomical sites of primary lesions. (authors)

Endocrine influences on survival from malignant melanoma

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 women's 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.

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

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 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.

G. A. Farago

Papers

Prognostic significance of the histological features of malignant melanoma

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

Endocrine influences on survival from malignant melanoma

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

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