Malignant Melanoma With Monster Cells Showing Massive Cyclin D1 Amplification (2009)

To the Editor: Recently, there have been reports of melanomas containing very large and anaplastic melanocytes, termed “monster cells.” Although the data are limited, these cases may behave more aggressively with worse clinical outcomes.1,2 Little is known about the biology of these cells and their significance. We recently encountered a case of cutaneous melanoma with monster cells and would like to report some unique observations in our case, identified with fluorescence in situ hybridization (FISH). These findings may assist in furthering our understanding of this entity. Recently, FISH targeting chromosomal loci known to be altered in melanoma, such as cyclin D1, has emerged as a potential diagnostic aid.3 FISH allows for evaluation of copy number changes within each individual cell, facilitating integration and correlation of molecular with morphologic findings. We applied this technique to a case of melanoma with monster cells. Interestingly, the massive size of the nuclei in these cases correlated with an excessive number of DNA amplifications in specific chromosomal loci known to be altered in melanoma, including cyclin D1. We report the findings in this case and speculate as to the significance of cytogenetic changes. An 85-year-old women with a history of heavy sun exposure, presented with an enlarging 4-cm violaceous nodule on her right mid-forearm and several new small black macules on her right upper arm. Excision of the large mid-forearm lesion revealed a large exophytic and pedunculated mass with a fairly nodular dermal proliferation composed of sheets of atypical and large epithelioid melanocytes. The overlying epidermis showed prominent pagetoid scatter of atypical melanocytes, without ulceration. The melanoma cells had markedly enlarged and pleomorphic nuclei (Fig. 1). The lesion was deeply invasive into the reticular dermis, extending to a Breslow's depth of 29.0 mm. Angiolymphatic invasion was also noted. Analysis of the primary skin excision specimen with FISH revealed gains of at least 30 gene copies of cyclin D1 within the nuclei of the melanoma monster cells (Fig. 2). One of the upper arm macular lesions was biopsied and the histopathology was consistent with in-transit cutaneous metastatic melanoma, making her at least stage IIIB (T4bN2cMx) on presentation.FIGURE 1: High-power view of melanoma containing monster cells (hematoxylin-eosin, original magnification ×400).FIGURE 2: FISH analysis with green-labeled probe for cyclin D1. The white arrow shows gains of at least 30 gene copies of cyclin D1 integrated into the chromosome of a melanoma monster cell nucleus (original magnification ×1000).Over the last year, we have studied more than 50 melanomas on chronically sun-damaged skin with FISH. Those cases showing gains or amplifications in cyclin D1 most often show average copy number gains of approximately 4-5 per cell and may range from 2.5 and, more rarely, up to 15 copies per cell. The finding of greater than 30 copies of the cyclin D1 gene in a single cell is unique and a far outlier from our previous observations. Our findings in this case showed an interesting correlation in the molecular and morphologic changes. The level of aneuploidy observed in this type of melanoma is usually associated with profound genomic instability, which is typically incompatible with cell survival, activating pathways leading to cell death.4 Therefore, we postulate that melanomas with monster cells may have acquired a unique capacity to tolerate this extreme genomic instability and continue to have high level activation of the proliferative pathways. This profound uninhibited activation of the cell cycle pathways through amplification of cyclin D1 may possibly explain the aggressive course and presentation of melanomas with monster cells. Pedram Pouryazdanparast, MD Department of Pathology Feinberg School of Medicine, Northwestern University, Chicago, IL Marissa Newman, MD Mariam Mafee, BS Joan Guitart, MD Pedram Gerami, MD Department of Dermatology Feinberg School of Medicine, Northwestern University, Chicago, IL