Novel CUX1::FLOT1 Fusion and Clinicopathological Features of Uterine Tumor Resembling Ovarian Sex Cord Tumor: A Six-Case Series with RNA Sequencing

Inside the human body, the uterus is a muscular organ that, in rare instances, can develop a peculiar type of growth. These growths are known as uterine tumors resembling ovarian sex cord tumors. For decades, doctors have found these masses difficult to classify because they look like a mix of different tissue types, behaving sometimes like benign lumps and other times like aggressive cancers. The challenge has been to understand what drives these tumors to form and why some remain harmless while others spread to other parts of the body. To solve this, modern medicine has turned to reading the genetic instructions inside cells. By analyzing the RNA, which acts as a messenger carrying out the cell's genetic plans, researchers can spot specific errors or rearrangements that cause the disease. Understanding these genetic clues is crucial because it helps doctors distinguish between a tumor that can be safely removed and one that requires long-term vigilance or different treatment.

A team of researchers recently examined six women who had been diagnosed with this rare condition. They gathered detailed information about the patients' health, the physical appearance of the tumors, and the specific proteins present on the cell surfaces. Most importantly, they used advanced sequencing technology to read the RNA from the tumor tissue, looking for broken or fused genes that might be the root cause of the cancer. The study, conducted over a period spanning from 2008 to 2023, involved women ranging in age from 31 to 67. In four of the six cases, the tumors were discovered accidentally during routine checkups, as the women had no symptoms. In the other two cases, the patients experienced abnormal bleeding after menopause. The tumors varied in size, with the largest measuring 15.2 centimeters, and were found in different locations within the uterine wall.

When the researchers looked at the tumors under a microscope, they saw a wide variety of shapes and patterns. The cells grew in cords, nests, tubes, and even papillary structures, often invading the surrounding muscle tissue. Some tumors contained cysts, while others had tiny calcium deposits or areas where cells had died. Despite this visual diversity, the cells shared a common chemical signature. Almost all the tumors produced specific proteins that act as receptors for hormones, as well as other markers typically found in muscle and nerve-related tissues. One case stood out because the cells displayed a protein called CD34 on their surface, a feature that had never been seen before in this specific type of tumor. This unusual finding suggests that these tumors can look and act in ways that doctors have not previously documented.

The most significant discovery came from the genetic analysis. In two of the six cases, the researchers found a specific fusion where the gene for an estrogen receptor, ESR1, was joined to a gene called NCOA2. This combination creates a constant signal that tells the cells to grow, driven by the body's natural estrogen. Another case showed a similar fusion involving a gene called GREB1 and NCOA2. However, in one patient, the team identified a completely new genetic error: a fusion between a gene named CUX1 and another named FLOT1. This CUX1::FLOT1 combination had never been reported in this type of tumor before. While the researchers do not yet know exactly how this new fusion works, its presence expands the known list of genetic causes for the disease. Two of the six patients did not have any detectable gene fusions, indicating that the disease might arise through different mechanisms in different people.

The long-term outcome of these patients provided a sobering lesson about the nature of the disease. Five of the six women remained healthy and free of cancer for the duration of the study, which lasted between 12 and 149 months. One patient, however, had a different fate. This woman, who carried the ESR1::NCOA2 fusion, remained disease-free for nearly eight years after her surgery. Then, at 97 months, she developed metastases in her abdomen. Over the next few years, the cancer spread to her diaphragm, colon, liver, and adrenal glands. She passed away 149 months after her initial diagnosis. This outcome suggests that even when a tumor appears to be behaving well for many years, it can eventually become aggressive. It also indicates that the presence of the ESR1::NCOA2 fusion, previously thought to be less dangerous than other types, might be linked to this late and severe recurrence.

The study concludes that these tumors are far more complex than previously understood, with a wide range of appearances and genetic causes. The discovery of the new CUX1::FLOT1 fusion adds a new piece to the puzzle, while the unexpected behavior of the patient with the ESR1::NCOA2 fusion warns doctors that no single genetic marker guarantees a benign course. Because these tumors can return many years after the initial treatment, the researchers emphasize that patients need to be monitored for a very long time, potentially for the rest of their lives. Accurate diagnosis now requires combining the visual inspection of the tissue with a search for these specific genetic changes, ensuring that every patient receives the care that matches the unique biology of their tumor.