It's not often that a pathologist gets to make a diagnosis that works for the patient by preventing treatment from occurring. But thanks to a Johns Hopkins Medicine doctor and his newly reported definition and classification of a previously unknown, novel type of benign soft tissue tumor, that's exactly the desired outcome.
In a paper appearing in the December 2025 issue of the journal Modern Pathology, John Gross, M.D., associate professor of pathology and orthopedic surgery at the Johns Hopkins University School of Medicine, describes in detail for the first time a slow-growing, bone-covered, noncancerous mass that he named the ossifying spindled and epithelioid tumor, or OSET. The danger for patients with an OSET, he explains, is not from the tumor itself, but that it could be mistaken for a malignant growth and lead to a patient receiving unnecessary chemotherapy or radiation treatments.
"The index case biopsy sample that led to the OSET discovery was from a patient with a bone-covered tumor that a colleague sent to me in consultation," Gross says. "Under the microscope, it had traits that mimicked those of cancerous tissue, such as being hypercellular [composed of many tumor cells] and being positive for cytokeratins [proteins commonly seen in epithelial, or surface-lining, cells]; however, there were other features, such as the indolent bony shell that made me believe it was not likely a malignancy."
"In fact, the sample looked totally different from any bone-covered tumor I had seen before," Gross recalls.
The tumor's nonmalignancy was confirmed, Gross says, by a comprehensive, commercially available molecular genetics assay which subsequently turned up negative for gene fusions, mergings of genetic material between two chromosomes commonly seen in cancer cells.
A few months later, Gross watched an online presentation in which Roberto Garcia, M.D., associate professor of clinical pathology and laboratory medicine at the Weill Cornell Medicine, attending pathologist at its Hospital for Special Surgery and a co-author on this study, discussed a bone-covered tumor "that everyone thought was a sarcoma [malignant tumor] but no one could identify," says Gross.
Similar to the index case, Garcia's tumor also tested negative for gene fusions. So, Gross asked Garcia if he could further study a sample from it.
That evaluation revealed that the tumor had the same characteristics as the first bone-encased mass Gross had investigated. Two more tumors that Gross examined — sent by this study's eventual senior author Andrew Rosenberg, M.D., professor of pathology at the University of Miami's Miller School of Medicine, and co-author Gregory Charville, M.D., Ph.D., associate professor of pathology at Stanford Medicine — followed suit.
Convinced that he had something unique, Gross decided to name the tumor OSET. "O for 'ossifying' to categorize the bony shell surrounding the tumor; S for 'spindled' to reflect that the cells have an elongated, spindly appearance; and E for 'epithelioid' to indicate the plump, round cells that are positive for cytokeratins," he explains.
Gross first presented his new tumor at an international pathology meeting in Baltimore in 2024. Afterward, he began hearing from other pathologists who had seen similar tumors. Utilizing tissues from the samples they sent and others, Gross decided to have colleagues at the Johns Hopkins Kimmel Cancer Center perform an in-depth genomic analysis to see if the tumors shared a common molecular genetic link.
"What we found was the majority of the tumors had a molecular abnormality leading to a pathogenic fusion of two different genes, the SRSF7 gene on chromosome 2 and the NFATC3 gene on chromosome 16, and that this was likely the driver of the OSET's development," says Gross. "Neither of these two genes has been known to be involved in cancer, so the fusion between them didn't show up with traditional, commercially available genomic assays — tests that only look for genetic abnormalities linked to known malignancies."
Gross and his colleagues believe that a piece of the SRSF7 gene breaks away from chromosome 2 and "gets squished" into the NFATC3 gene on chromosome 16. This translocation results in a genetic aberration, but not one damaging enough to lead to cancer or potentially lethal outcomes.
"I will always remember the excitement I felt when the call came in from Kimmel saying, 'Dr. Gross, we have several tumors with the same aberrant genetic fusion,'" he says. "It was such a thrilling moment; the point at which I knew we had identified something very special."
Building upon the Kimmel work, study co-author Ying Zou, Ph.D., associate professor of pathology at the Johns Hopkins University School of Medicine, and her team at the Johns Hopkins Cytogenetics and Cytogenomics Laboratory custom-designed a diagnostic tool to detect the SRSF7-NFATC3 fusion using a technique called fluorescence in situ hybridization, or FISH.
Additionally, study co-authors Daniel Baumhoer, M.D., professor in bone and soft tissue pathology, and Baptiste Ameline, Ph.D., postdoctoral fellow, at the University of Basel in Switzerland, developed a molecular test for analyzing the methylation traits of cells from an OSET.
A methylation test analyzes a person's genetic blueprint to reveal how efficiently the body carries out the vital process of methylation. This process affects key functions such as DNA repair, cellular detoxification and the production of neurotransmitters.
The methylation test developed by Baumhoer and Ameline analyzes the epigenetic characteristics of an OSET, proving to be a valuable diagnostic tool for showing that an OSET is not a malignant tumor. Epigenetic characteristics — a hallmark of cancer cells — are the chemical changes in a gene's expression (protein production) and function that occur even though the gene's DNA sequence remains unaltered.
"Similar to my excitement learning about the recurrent and novel SRSF7-NFATC3 fusion in OSETs, I was thrilled — but not surprised — to find out that OSET harbors a unique epigenetic molecular 'fingerprint' as well," says Gross.
In the OSETs diagnosed to date, Gross says, there haven't been reports of any serious health problems for patients. However, they can be considered cosmetically unappealing and in some cases, may cause pain if pressing on surrounding nerves. Surgical removal is the current treatment of choice.
The study authors emphasize, however, that even after treatment, clinical follow-ups and analyses of any future OSETs are needed.
Gross explains that the Modern Pathology paper comprehensively details the OSET, so that pathologists and other diagnosticians can accurately and reliably identify these bone-covered tumors from their more dangerous relatives.
"Having a distinct classification category for OSET is important, because without it, it would be difficult to diagnose and determine that a biopsied tumor sample is malignant," he says. "A mistaken diagnosis could result in a patient receiving unnecessary chemotherapy, radiation treatment and other anticancer measures."
"The work done in this study has solidified OSET's place in the scientific literature," Gross adds. "We have shown that OSET is unique, unlike anything previously reported and definitely warrants more study."
Along with Gross, the members of the research team from the Johns Hopkins University School of Medicine are Pedram Argani, Ezra Baraban, Jonathan Dudley, Melanie Klausner, Laura Morsberger Lisa Rooper and Ying Zou.
Other team members are Leslie Cope, Jennifer Meyers, Kornel Schuebel, Alyza Skaist, Srinivasan Yegnasubramanian and Yan Zhang from the Johns Hopkins Kimmel Cancer Center; Nasir Ud Din from the Aga Khan University Hospital (Pakistan); Ali Alani from the Baylor University Medical Center; Michael Michal from Charles University (Czech Republic); Josephine Dermawan, Karen Fritchie and Brian Rubin from the Cleveland Clinic; Christopher Hysell from the Corewell Health William Beaumont University Hospital; Abbas Agaimy from Erlangen University (Germany); David Suster from Rutgers University; Gregory Charville from the Stanford University School of Medicine; Daniel Baumhoer and Baptiste Ameline from the University Hospital Basel (Switzerland); Andrew Rosenberg from the University of Miami; and Roberto Garcia from Weill Cornell Medicine.
