Mitotic rate, TIL, important variables in melanoma prognosis

Vancouver, British Columbia - The vertical growth phase of melanoma presents as a tumor nodule or tumor-infiltrating lesion.

The radial growth phase is a slightly raised or flat lesion associated with micro or single-cell invasion in the epidermis. Vertical growth phase cells look different from radial growth phase cells and they have different morphology, according to Martin Mihm, M.D., clinical professor of pathology at Massachusetts General Hospital. Mitoses are present and the host response is variable.

Multivariate analysis in the Clark model from 1989 identified mitotic rate and tumor infiltrating lymphocytes (TILs) as equally important prognostic variables.

"This study sponsored by Cancer Research Institute of New York at finish will have reviewed about 2,585 cases for all prognostic factors," he adds.

Study subjects

At present, the study population includes patients who had adjuvant therapy as well as those who had no therapy. Dr. Mihm says he and colleagues want to confirm again that TILs are significant.

"We're also quantifying for intensity and using <10, 10-20, >20 lymphocytes per high-powered field, using several fields for counts. In this manner we hope to better understand TILs and see if we can even better refine the prognostication of these lesions."

The receptor alpha V beta-3 or vitronectin is associated with the malignant potential of primary melanoma. The alpha-V-beta-3 integrin is a good marker to mark change from the radial to the vertical growth phase.

Dr. Mihm notes that chemokines in general can have a host of different effects. While initially thought to be involved only in recruitment of inflammatory cells, some recent studies have shown that they can also have a variety of other effects. Some chemokines are actually tumor growth factors and their presence has been associated with a poor prognosis in various studies. Others act as receptors, such as CCR7, necessary on dendritic cells for their migration to lymph nodes. Many other studies have revealed various important functions for these molecules.

E cadherin

Among the many cadherin molecules, E cadherin may be the most familiar. E cadherin is expressed on epidermal melanocytes and is associated with the adherence of melanocytes and keratinocytes. When invasion occurs, E cadherin expression is diminished and cells begin to express N cadherin; cells become noncohesive with the loss of E cadherin as they do not attach to the adjacent cells.

Dr. Mihm stresses that E cadherins are very important in keratinocyte-melanocyte interaction. E cadherin is expressed in the epidermis in the radial growth phase. As cells go into the vertical growth phase, E cadherin is lost.

Dr. Mihm points out that when E cadherin expression is lost, it is due to cleavage of the membrane from the extra-membranous component. The cells then express N cadherin.

A recent study has shown that the presence of P cadherin is associated with poor survival. P cadherin shows redundancy with other cadherin molecules.

"The active fragment isn't cleaved, but is produced apparently by the melanoma cells. There is so much redundancy in the cadherins; it's thought this acts as a competitive inhibitor for some of the other cadherins, but in a negative way. It was shown in multivariate analysis in a recent study to be associated as an independent factor with regard to prognostication," Dr. Mihm explains.

When melanoma cells express N cadherin, they can attach to the intracellular adhesion molecule (ICAM); they can enter into the endothelial cells and intravasate and also extravasate and metastasize. ICAM has been shown to be associated with tumor thickness and a reduction in disease-free survival.

Dr. Mihm says Thy-1 was recently found to be highly expressed on peritumoral and intratumoral endothelial cells in melanoma. The alpha V-beta-3 integrin which was previously known to be associated with fibronectin, vitronectin and so on, is also the receptor for a Thy-1 molecule, which is expressed in tumor vasculature or activated epithelium such as inflammation.

Activation molecule