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September 2025

Circulating Tumor Cells: A Step Forward for Melanoma Detection

Because many solid tumors are populated by cells that no longer have strict controls on where they are supposed to be in the body, malignant cells often leave the tumor and enter circulation (reviewed in Lin et al 2018 and Deng et al 2022). First observed in the late 1800’s by Ashworth (1869), these cells are referred to as circulating tumor cells (CTC’s). These released cells can settle down into another tissue in a process called metastasis. If the tumor cells are shedding from the tumor at a high enough rate, they can be detected in the blood with modern analytical tools. Note that there are two types of bloodwork tests used to assess the presence of a tumor: circulating tumor cell assays and circulating tumor DNA assays. Circulating tumor DNA assays are designed to detect only tumor DNA in patient serum from which the cells have been removed, and circulating tumor cell assays are designed to detect live cells purified from the patient’s serum. Both techniques then use polymerase chain reaction (PCR) to detect mutant genes characteristic of the tumor. While seemingly subtle, the difference is important because the presence of circulating tumor DNA does not allow practitioners to conclude that there are or aren’t circulating tumor cells; in other words, it tells you nothing about whether or not cells are being shed from the tumor. While still in the early stages of characterization and widespread application, the presence or absence of circulating tumor cells is beginning to have prognostic value. In some cancers, such as neuroblastoma and hepatocellular carcinoma, these tumor cells released into circulation have low metastatic potential (Kojima and Hiyama 2023; Lin et al 2021; Ahn et al 2020). With other cancers, such as breast cancer and cutaneous melanoma, the circulating tumor cells have been reported to have high metastatic potential (Bidard et al 2016; Huang and Hoon 2016). Because of predictive (prognostic) value with regard to outcomes, assays for circulating tumor cells are becoming routine for a number of cancer types, including breast cancer, prostate cancer, colorectal cancer, pancreatic cancer, cutaneous melanoma, and lung cancer (Cen et al 2012; Maly et al 2019; Shoji et al 2022).  

There has been much work exploring the diagnostic and prognostic benefits of assaying for circulating melanoma cells, which have been observed in a significant fraction of early- and late-stage melanomas (Mocellin 2006; Ireland et al 2011; Itakura et al 2011 and Clawson et al 2012; Lucci et al 2020). While circulating tumor cells in early melanoma have not been studied to the same extent as later metastatic disease, an older meta-study by Mocellin and colleagues (2006), has firmly established that circulating tumor cells are observed in 32-42% of stage I/II melanoma patients at time of diagnosis.  The circulating tumor cell assays are primarily useful for detecting the presence of a tumor; in other words, if the circulating tumor cells are present, then there is a parent tumor somewhere in the body. Conversely, if the test does not detect circulating tumor cells it suggests that there is not a parent tumor, but importantly DOES NOT PROVE the absence of a parent tumor. The detection assays also provide valuable information about the number of cells being shed by the parent tumor because the number of cells shed from the parent tumor (hence in circulation) is an important predictor of metastatic potential and long-term survival (Lucci et al 2020; Shoji 2022). The final utility of the circulating tumor cells test is that it provides information about the molecular markers of the parent melanoma, including targets for monoclonal antibodies, tumor specific antigens for ex vivo dendritic cell stimulation, and targeted therapies such as BRAF/MEK inhibitors. They will also inform us in the future about the possibility of treatments with so far incompletely understood but promising therapies such as methylene blue, near infrared light, and mistletoe (Cwalinski et al 2020; Hamblin et al 2018; Thronike et al 2022). Thus, as we move into the age of personalized cancer diagnosis and treatment, information about the molecular aspects of the cancer cells is providing information that allows patients and clinicians to make highly informed decisions when customizing the therapy regime.

There are a number of different published assay systems, or platforms, for detecting circulating melanoma cells. Circulating tumor cell counts are known to vary with detection method (platform) and timing of blood draws (reviewed in Vidlarova 2023), and the different detection platforms target different combinations of the melanoma markers. This has led to a generalized lack of standardization across trials and clinics. One test by CellSearch (FDA approved for breast, prostate, and colorectal cancers) is beginning to provide a standardized platform for detection of circulating melanoma cells (Circulating Melanoma Cell Assay). While not yet FDA approved, this platform has been used in a number of studies to analyze circulating melanoma cells and is in routine use in many cancer clinics here in the U.S. Another commercial test, the Signatera Melanoma Test marketed by Natera, detects circulating tumor DNA rather than the tumor cells, making this test useful for detecting tumors and understanding their genetic profile (mutations) but not for assessing the potential for metastasis. 

In summary, circulating tumor cells are becoming a critical component of precision medicine approaches used to treat and eliminate melanoma. Specifically, the assay for circulating melanoma cells provides personalized diagnostic and prognostic information about the melanoma and potential treatment options. In addition, the possibility of early detection of distant metastases is exciting because it has the potential to significantly increase long term survival of melanoma patients because more effective immediate treatment and often less toxic long-term modes of prevention (such as natural light therapies, stress reduction, and diet optimization) can be used most effectively early on. Current limitations of the CTC approach include the finite limit of detection for any given cancer, and the fact that not all tumors (such as well-encapsulated tumors like liposarcomas) are guaranteed to shed cells, or are necessarily shedding at the time of blood draw. This suggests that caution be used when utilizing CTC’s to draw conclusions about the absence of an active tumor, and that in general the information gained should be considered in conjunction with other tests such as imaging, sentinel lymph node biopsies, and blood markers such as glucose 6-phosphate dehydrogenase/UDP-glucose 6- dehydrogenase. In addition, because of the lack of standardization discussed above, clinicians and patients should understand the advantages and limitations of each assay approach as they make decisions about treatment options.

References

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