Pediatric bone lesions, particularly non-ossifying fibromas(NOFs), are among the most prevalent skeletal abnormalities observed in children and adolescents.1 Despite their benign nature, differentiating these lesions from malignant tumors can pose a challenge, and NOFs frequently cause significant anxiety for patients and families, often leading to unnecessary referrals and unwarranted interventions,according to R. Lor Randall, MD, FACS.
“The take-home message is that these [lesions] are benign and self-limiting, but they are a very common cause for alarm in people who are not educated about them,” Randall said in an interview with OncLive®. “These lesions are very common; [if present, pediatric oncologists should review] the imaging with a musculoskeletal radiologist.”
Randall also noted that the self-correcting nature of these lesions is of interest in translational oncology. Although the exact etiology of NOFs is not fully understood, early molecular research has indicated that NOFs may be driven by activating mutations in the RAS/MAPK pathway.2,3 These mutations typically burn out, leading to the spontaneous regression of the lesions as patients reach skeletal maturity.1 Further investigation into the mechanisms of spontaneous regression in NOF could improve the management of tumors with RAS/MAPK mutations.3
During the interview, Randall highlighted the evolving epidemiological understanding of NOFs, outlined common diagnostic criteria and approaches to the management of these lesions, and emphasized emerging molecular insights that are of interest to the oncology community.
Randall is the David Linn Endowed Chair for Orthopedic Surgery, the chair of the Department of Orthopedic Surgery, and a professor at UC Davis Comprehensive Cancer Center in Sacramento, California.
OncLive: What are NOFs, and why are they commonly confused for sarcomas?
Randall:NOFs are probably the most common form of benign bone lesion in children that get referred to an orthopedic oncologist. [That referral can cause] heightened anxiety [because the family is left] wondering if it’s cancer. They are the most common benign bone lesion in children and adolescents. Usually, they’re incidentally found on imaging; [a child] sprains their knee or ankle or what have you, they get a radiograph, and lo and behold, there’s this spot on the bone. That is to say that they’re generally asymptomatic ahead of time, and [affected individuals] really don’t have any issues with it. [However, when] the emergency doctor or the pediatrician sees either the report or the actual image, they say, ‘There’s a hole in the bone in this child. Could this be cancer?’
To the more trained eye, on radiographic appearance, these tend to be more well-demarcated. They are radiolucent and tend to be eccentric and cortically based in the bone. For those of us who are specialists, we can look at a radiograph and say, ‘That is nothing to be worried about.’
What is currently known about the etiology and molecular mechanisms of NOFs? Why is this lesion of interest to oncologists?
[NOF] is an interesting lesion in and of itself, especially for a pediatric oncologist. This was first described in 1941 by Sontag and Pyle, who started getting radiographs of kids when fluoride was going into the water, and they noticed a large preponderance of these lesions. Although this is not cancer, it is interesting to those of us who are interested in the molecular biology of cancer. These defects in the bone are benign, but we do know that they’re driven by mutations in the RAS/MAPK pathway, involving KRAS, FGFR1, and NF1. In those that have been sampled, we do see this pathway aberrancy. What’s interesting is that they are self-limited. These pathway mutations seem to burn out, and these lesions seem to abate and normalize over time, as patients reach skeletal maturity and the bone fills in. There might be something interesting there, from a molecular biology standpoint, to tease out.
How prevalent are these lesions among pediatric populations, and how are they diagnosed?
Having said all that about the epidemiology and clinical impact, we think that these NOFs are present in 30% to 40% of kids at some point during their life. We’re not routinely screening kids, but when fluoride was going into the water and kids were being screened at that point, that’s when it was approximated. They’re most common in the distal femur, the proximal tibia, and distal tibia, which are areas of high mechanical stress and tendon insertion.
Approximately 60% of referrals to us are for these benign lesions that really heighten a lot of anxiety. I’ll see a lot of patients coming in with MRIs or CT scans, and there is additional radiation exposure with the latter for what is clearly just a benign process. The families have been waiting for a week or 2 to get in to see us, and they’re very anxious about the fact that their child may have cancer when they certainly do not and do not need any further workup.
How are these lesions typically managed?
Although [NOFs are] relatively rare compared with the common cold, they do sometimes get bigger, and they can weaken the bone and predispose to fracture. If it gets more than half the width of the bone, they can break. There can be some cortical thinning. These are commonly seen in the lower extremity, but having practiced for 30 years, I’ve [rarely] had to surgically intervene. It’s very rare that we need to do anything because these will self-limit. Observation is the rule; most regress, and surveillance may not be necessary. Once you establish that it’s stable or on the mend, you don’t need to continue to follow these kids, and less than 5% overall need any sort of intervention, like curettage and bone grafting.
Non-musculoskeletal radiologists may still sound the alarm, but treatment should be avoided because they often will resolve, and you just need to follow these patients to demonstrate stability. Even in this era of modern information and dissemination of knowledge, I still see so many families who have been anxious. [Despite good intentions], these families have been through real psychological stress because of the lack of understanding around these benign lesions.
What is the potential for misdiagnosis of NOFs based on imaging, and what can be done to help minimize this?
[NOFs] tend to be characterized by having a sclerotic border and being eccentric in the bones, sort of cortically based on the wall of the bone. The problem is that sometimes you don’t get images orthogonally or tangentially to the lesion, so it doesn’t have that classic appearance. Also, some bones aren’t completely tubular, so two views don’t really tell you what you need to know. For example, in the distal femur or the proximal tibia, it might be around the corner.
We live in a society where everyone is anxious about making the wrong diagnosis. If a radiologist doesn’t get those classic findings, they, being very well-intended, will say, ‘We can’t rule out [cancer],’ and then suggest getting a CT [scan] or an MRI. If a radiologist lists something as possibly NOF, the answer is to refer the patient to a pediatric orthopedist or a pediatric orthopedic oncologist before ordering additional tests, to avoid all that extra work and anxiety.
What is the typical timeline for these lesions from presentation to spontaneous regression and normalization?
It depends on the age of presentation. Many of these kids will have it and will never know about it. A patient [could] develop it by age 5, live with it through age 10 or 11, never get a radiograph, and by the time they are age 12 or 13, it dissipated. If you see that kid when they’re 5 and you get another radiograph, it might be a little bit bigger, and you’re going to follow them a little longer. By the time patients start to approach skeletal maturity—in girls, that’s [approximately] 12 [years of age] and for boys, that’s 16 to 18 [years of age]—they really should be dissipating and filling in.
In terms of molecular biology, how could continued investigation of the factors driving the formation and subsequent regression of NOFs be relevant to the field of oncology?
This is one fascinating [presentation of] an established oncogenic pathway. It forms a tumor, but then it invariably self-corrects. [A select] few will go on to be aggressive and go into adulthood, but it still self-corrects. It is interesting to ask, ‘What is it about this mutation that allows it to self-correct? Is there something we can learn there about oncogenesis and reversibility therein?’
[There is substantial interest in these lesions by translational scientists], especially since it’s so common. [Investigators] could easily develop a clinical trial. We’d hate to be invasive for something that doesn’t need anything, but if [researchers] could potentially perform a small needle biopsy to get a little bit of tissue from these kids to study, they could get large numbers of samples to observe at different time points, such as when you start to see radiographic regression. Performing deep sequencing on that tissue, compared with samples from someone younger where it’s still growing, could reveal what is happening there. Is there anything in that data that signals a treatment [avenue] for something that doesn’t know how to self-correct?
What are some other benign lesions that may be mistaken for sarcoma?
There’s a whole potpourri of them, but they tend to be much less common compared with NOF. There are osteochondromas, which are surface lesions of the bone and can be sessile, that are sometimes misdiagnosed as periosteal or low-grade osteosarcomas. There are lesions such as chondroblastoma, which tends to happen in the epiphysis and is sometimes misdiagnosed as a chondrosarcoma. Then there are a few others, like chondromyxoid fibroma, which can sometimes be erroneously diagnosed as a sarcoma of the bone. However, the incidence of NOF is 100 to 1 compared with these others.
References
- Walker KE, Smith JB, Todi NT, Brown D, Randall LR. Non‐ossifying fibromas: a 2025 review. doi:10.20944/preprints202507.2472.v1
- Baumhoer D, Kovac M, Sperveslage J, et al. Activating mutations in the MAP-kinase pathway define non-ossifying fibroma of bone. J Pathol. 2019;248(1):116-122. doi:10.1002/path.5216
- Bovée JV, Hogendoorn PC. Non-ossifying fibroma: a RAS-MAPK driven benign bone neoplasm. J Pathol. 2019;248(2):127-130. doi:10.1002/path.5259