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Melanocytic Tumors: Malignant Melanoma or Benign Nevi?

November 2013


Melanoma comprises only 10% of all skin cancers, but is responsible for approximately 90% of all skin-cancer mortality. This malignant tumor typically originates from melanocytes in the basal layer of the epidermis or from melanocytic nevus cells at the dermal-epidermal junction and can appear on sun-exposed or hidden areas, including under nails, in the mouth, digestive tract, urinary tract, or vagina, and in the eye. Melanoma in the setting of dysplastic nevi is associated with a strong family history and is typically present on the upper body.

Melanocytic tumors arising in the skin can present a significant diagnostic challenge. They are some of the most commonly biopsied tumor types in pathology and are often underdiagnosed. While many lesions can be easily classified as benign nevi or malignant melanoma based on histologic features alone, a significant subset of lesions cannot be clearly defined as either benign or malignant. Since the course of treatment for malignant melanoma relative to benign lesions varies significantly, accuracy and expediency of the diagnosis are of paramount importance.

Assay Development and Method Description

Mayo Clinic Cytogenetic Laboratory has developed a fluorescence in situ hybridization (FISH)-based test panel (FMEL / Melanoma FISH, Tissue) that, when used in conjunction with clinical and pathologic information, can assist the pathologist in the differentiation of benign from malignant melanocytic lesions.

FISH is a highly sensitive and specific laboratory technique to identify gain or loss of DNA sequences in nuclei. DNA sequences labeled with fluorescent molecules (“probes”) are hybridized and bind to complementary DNA sequences in cells. The probes target specific genes or chromosome regions that may be altered in malignancy.

The Mayo Clinic-developed assay utilizes a multicolored 8-probe FISH-based strategy that is more sensitive (86%) than conventional 4-probe strategy tests (75%) offered in other laboratories. The test is performed on formalin-fixed paraffin-embedded tissue sections within areas of the tumor as identified by a pathologist. The 8 probes are combined into 3 probe sets that are hybridized to the tissue following standard FISH protocols with results expressed as the percent of abnormal nuclei.

The 3 probe sets include:

  1. RREB1/D6Z1/MYB/CCND1 to identify gain and  loss of DNA material on chromosomes 6 and 11  (Figure 1a and 1b)
  2. CDKN2A/D9Z1 to identify loss of the tumor suppressor gene on chromosome 9p (Figure 2a  and 2b)
  3. D8Z2/MYC to identify gain of the oncogene on chromosome 8q (Figure 3a and 3b)

The FISH-based test panel is considered abnormal if certain parameters are met that have been shown to be observed in malignant melanocytic lesions. The test is reported as within normal limits if these parameters are not met. An abnormal result is not diagnostic of malignancy, nor does a normal result exclude malignancy. The results are intended to be interpreted in the context of the pathologic and clinical findings.

Figure 1. RREB1/D6Z1/MYB/CCND1 probe set
Figure 2. CDKN2A/D9Z1 probe set
Figure 3. D8Z2/MYC probe set


The melanoma FISH assay is intended for use as an ancillary test to assist in the diagnosis of malignant melanoma. A diagnosis can usually be made from tumor tissue on the basis of histopathology. In cases where  the diagnosis is unclear, this FISH-based assay can assist in differentiating malignant melanoma from benign melanocytic lesions.