Cell proliferation markers in predicting metastases in malignant melanoma

Abstract

It is often difficult to predict the outcome of melanoma in patients with Clark level III-IV disease. We sought to identify markers of cell proliferation which may be useful in predicting prognosis. Patients with Clark's level III-IV malignant melanoma who had no local recurrences or metastases were matched with patients of comparable level and thickness who did experience recurrences of metastases. Cell proliferation markers p53, proliferating cell nuclear antigen (PCNA), and Ki-67 were assessed by immunohistochemistry. DNA ploidy was determined by flow cytometry. There was no difference in the expression of p53, PCNA, and Ki-67 between patients with metastases and patients without metastases. However, patients with metastases were more likely to have an aneuploid tumor cell population than were patients without metastases (p < 0.03). Expression of cell proliferation markers do not appear to help predict prognosis in advanced level melanoma; however, aneuploidy may be associated with a greater probability of metastasis.

Mitotic rate and S-phase fraction as prognostic factors in stage I cutaneous malignant melanoma

“…In addition, immunostaining for Ki-67 antigen is helpful in identifying individuals with thick nodular melanomas who are at risk of metastatic disease (Vogt et al, 1997). PCNA expression in cutaneous melanomas seems to be a marker of tumour progression (Takahashi et al, 1991;Evans et al, 1992), but it may not help in predicting prognosis in these tumours (Reddy et al, 1995). AgNOR counts often correlate with other markers of cell proliferation, but the staining techniques and the counting methods suffer standardization problems (Cross and Start, 1996).…”

Immunohistochemical characteristics of melanoma

“…57,62,[67][68][69] Many studies have shown an increase in recurrence rate and mortality that directly correlates with increasing positivity for Ki-67; however, others have shown that this correlation is not independent of Breslow thickness. 60,61,63,[69][70][71][72][73] Reddy et al 74 did not find any correlation at all, although they only studied 14 cases.…”

“…56,76,77 Niezabitowski et al found increased PCNA expression to be an independent prognostic factor for increased mortality and decreased diseasefree survival, although others have been unable to confirm this finding. 72,74,75,78 Cyclins Cyclins are proteins, approximately 100 amino acids long, which bind and activate cyclin dependent kinases causing the cell to progress through the various stages of the cell cycle. 63,65,[79][80][81] Cyclins C, D1, D2, D3 and E help the cell progress from G 1 to S phase; cyclin A from S to G 2 phase; cyclin B from G 2 to mitosis.…”

“…55,65,66,88,96,97 Most reports claim that there is no correlation between P53 staining and likelihood of metastasis, disease recurrence or overall melanomaspecific survival; the minority of reports that claim a linkage between P53 staining and outcome state that such staining is not independent of tumor thickness as a prognostic factor. 57,72,74,89,90,95,97 Some of the more recently studied proliferation markers include HDM2 and the Growth arrest DNA damage (GADD) proteins. HDM2 is a 90-kDa zinc finger protein that binds to the transcription activation domain of P53 to inhibit its function and ubiquinates p53 so that it is degraded by proteosomes.…”

Prognosticators of melanoma, the melanoma report, and the sentinel lymph node

“…70 One study of level III and IV melanomas found no correlation of survivorship with PCNA or Ki-67 expression; however, in that study, flow cytometric analysis showing an aneuploid DNA content was associated with a higher risk of metastatic progression. 71 …”