1 Introduction

Multiple hereditary exostoses (MHE) is a rare condition in which multiple benign bony tumors called osteochondromas develop throughout the body.^1,2 The disorder occurs in about 1 or 2 of every 100,000 people and is transmitted via an autosomal dominant inheritance pattern due to mutations in the EXT tumor suppressor genes. That leads to disruption of the cartilage structure synthesis at the physis in a mechanism not yet fully understood.¹ Almost any bone but the calvarium can be affected, with a predilection for areas of the body where cartilage eventually converts to bone, such as the metaphyseal side of physes. Osteochondromas have a predication for recurrence if incompletely resected, and in those for which surgical treatment is not pursued or those that are incompletely resected, malignant transformation can occur.^3,4

The majority of MHE patients are diagnosed as children, with 96% of diagnoses occurring between two and 12 years of age.¹ The most common presenting feature of MHE is pain at the site of an osteochondroma, occurring in up to 84% of patients.⁵ Additional presenting features are related to complications from osteochondroma formation, including compression of surrounding structures such as nerves, tendons, and vessels.⁵ The most feared complication of osteochondroma formation is malignant transformation, occurring in 1%–5% of patients and more commonly in the pelvis.^5,6 Treatment of persistently symptomatic MHE-associated osteochondromas is mostly surgical with excision of the lesions. Diagnosis involves a combination of imaging studies and genetic testing, generally starting with a plain radiograph, followed by possible computed tomography (CT) or magnetic resonance imaging (MRI) to better characterize the lesion and its proximity to soft tissue structures when planning for surgical removal.¹

The evaluation and treatment of patients with MHE necessitates multiple imaging studies and involves potential exposure to high cumulative lifetime doses of ionizing radiation. Additionally, although malignant transformation of osteochondromas is rare, radiographic screening may detect malignancy early. The negative effects of exposure to high levels of ionizing radiation are well documented and include increased risks of developing malignancy, including hematologic and central organ tumors, as well as increased pregnancy loss and birth defects in pregnancy.^7–14 In addition, younger age of exposure increases malignancy risk.¹⁴ The purpose of this study was to quantify the ionizing radiation exposure in patients of various ages with MHE to better understand their radiation risks.

2 Materials and methods

Approval for this project was obtained from our institution's Institutional Review Board. A retrospective review was conducted of all patients with a diagnosis of MHE who were treated at our institution and partner hospitals from January 2015 through August 2020. Patients were identified using specific International Classification of Diseases (ICD) −9 and ICD-10 codes, and by reviewing medical record documentation. The ICD-9 codes included 2130 through 2139, which represent “benign neoplasm of” a specific anatomic location. The ICD-10 code used was Q78.6, which is the specific diagnosis code for “multiple congenital exostoses.” Diagnostic radiographs, CTs, intraoperative fluoroscopy, and nuclear medicine studies were identified and analyzed for ionizing radiation exposure. Total radiation exposure from diagnostic imaging was determined for each patient.

The diagnostic imaging that was available in the healthcare systems that we accessed was reviewed for each patient. Imaging was separated to include imaging related to MHE and imaging unrelated to MHE. Imaging unrelated to MHE was determined by reviewing the ordering provider notes and visit diagnoses; it included imaging such as chest radiographs for pneumonia and CT scans for abdominal disease. Radiation dosage was determined by using reference values for each image obtained.¹⁵ (Table 1). Fluoroscopic imaging exposure was recorded for each osteochondroma procedure, if available.

3 Results

Out of 856 patients identified using specific ICD codes, 37 patients met inclusion criteria as having a diagnosis of MHE treated at our institution between 2015 and 2020. Patients identified by ICD-9 codes who did not have a diagnosis of MHE, and duplicate patients were excluded. The study group included 20 male patients and 17 female patients, with an average age of 20 years (range: 7–33 years). These 37 patients received a total of 1200 imaging studies with a mean of 32 per patient. 976 (81%) of the imaging studies were related to MHE, and 224 (19%) were unrelated. The mean estimated cumulative radiation dose per patient was 5.23 mSv (Table 2). The greatest contributors of radiation were radiographs and CTs related to MHE. Forty percent of radiation exposure came from radiographs related to MHE, and 38% of radiation exposure came from CTs related to MHE (Table 2). CT scan accounted for 49% (73.5 mSv total, mean 1.99 mSv) of MHE-related exposure. Patients from ages 10–24 years old received the most imaging studies and exposure to ionizing radiation, especially compared to those under age 10 (Table 3). Radiation exposure in the 10- to 24-years age group was significantly greater than in the under 10-years age group for both cumulative radiation exposure, which includes MHE-related imaging and non-MHE imaging (P = 0.016), and for MHE-related imaging (P = 0.037). The 37 patients also received 53 surgical-excision procedures, with a mean of 1.4 per person (Table 2). The 10- to 24-years age group underwent the highest number of surgical-excision procedures, with a mean of 1.7 procedures which was significantly greater than the mean of 0.4 procedures in the 25-years-and-over age group (P = 0.030).

4 Discussion

Our study demonstrates radiation exposure for patients receiving imaging related to their MHE diagnosis. Radiation exposure affects patient-population groups differently, with children being much more sensitive to the carcinogenic effects of radiation than adults, having a longer life expectancy in which to express risk, and having developing organs that are more susceptible to the effects of radiation.^6,16,17 Numerous epidemiologic cohort studies of childhood exposure to radiation for treatment of benign diseases have demonstrated radiation-related risks of cancer of the thyroid, breast, brain, and skin, as well as leukemia.¹² Despite a low radiation dose for a single image or procedure, pediatric patients often receive serial exams over time to evaluate their conditions, leading to relatively high cumulative doses.¹⁶ One study analyzing radiation exposure and cancer risk in scoliosis patients found that female patients had a statistically significant higher cancer rate than male patients who experienced the same spine-imaging protocol, suggesting that there may also be a different response to radiation in women versus men.^18–20 Additionally, the frequency of pediatric CT examinations is rapidly increasing among the general pediatric population.²¹ Overall, those studies highlight the presence and potential dangers of serial imaging early in life.

Ionizing radiation is an inevitable risk of the diagnosis and treatment of MHE; MHE patients undergo a broad spectrum of both number and type of diagnostic imaging.¹ Possibly due to the wide range of presenting features and range of age at presentation, no clear radiographic workup has been detailed regarding MHE, and no consensus exists for monitoring for malignant transformation.^1,19,22 MHE patients undergoing osteochondroma surgical excision are typically exposed to additional radiation in the form of intraoperative fluoroscopic imaging. In many cases, fewer fluoroscopic exams can contribute higher overall radiation exposure than a greater number of radiographs.¹⁰ CT scans are also sometimes used to better characterize the osteochondroma and to evaluate the surrounding structures in osteochondral lesions in preoperative planning.²³ By adulthood, 70% of MHE patients have undergone a surgical-excision procedure, with 67% of those adults requiring surgery.¹ Our study mirrors this data, with 65% of (24) patients having undergone osteochondroma excision by time of inclusion.

In this study, all patients underwent MHE-related XR imaging with only six patients (16.2%) having MHE-related CT scans. CT scans accounted for nearly half of the MHE-related exposure (49%) in our cohort, thus half of the radiation exposure was generated by 6 of 37 patients’ CT scans. Our study shows the importance of conservative use of CT scan in this patient population. Further study should focus on identifying which lesions most benefit from CT evaluation so that other imaging modalities like MRI could be used instead to avoid ionizing radiation.

The youngest children (under 10 years old) received the lowest amount of MHE-related radiation exposure because their tumors are often not yet large enough to cause symptoms that prompt diagnostic imaging.¹ Following that logic, adolescents and young adults experience most symptomatic lesions, resulting in higher rates of imaging. This was represented in our study population, with patients aged 10- to 24-years-old receiving higher levels of radiation compared to the younger and older age groups. Likely for the same reason, the 10- to 24-year-old age group also had the highest number of surgical-excision procedures. Serial imaging is also a concern with MHE patients, including those in this study with one patient having 44 MHE-related XR images of his forearm alone. Since ionizing radiation is of cumulative significance and risks increase with increased exposure,¹⁰ limiting cumulative exposure in young patients is of utmost importance. From a biological standpoint, no dose of radiation is “safe.“¹⁷ Background radiation accounts for approximately 3.31 mSv per year in the United States.²⁴ Thus, MHE patients are receiving nearly 2 years of additional background radiation.

There are many possibilities to mitigate radiation exposure in MHE patients. One way is to develop specific criteria and indications for imaging of MHE patients to ensure they receive the most necessary exposures to ionizing radiation. For example, Murphey et al.²³ suggests that to effectively screen for MHE, a skeletal survey must include radiographs of long bones, chest, and pelvis as well as “evaluation of areas with significant deformity … particularly the hips, knees, ankles, and wrists.” Sanchez et al.²⁵ suggest that bony scintigraphy may more useful in detecting the presence of new bone lesions since it enables whole-body images to be captured in a single examination versus multiple plan radiographic films to image the entire body. Both of these options may potentially lead to undue ionizing radiation exposure in situations where a thorough physical exam might have been able to eliminate the need for some of them. MRI screening has potential to be beneficial in limiting radiograph exposure. Several studies suggest that MRI screenings for MHE may be of value, but no consensus has been reached.^1,19,22,26 One study demonstrates that because 75% of malignant transformation occurs between ages 20 and 40, and because proximal lesions are more likely to undergo malignant transformation than distal lesions, patients in this age range may benefit from cervical spine to proximal femur MRI screenings.^1,22 Additionally, genetic testing is playing an increasingly important role in diagnostic medicine, and MHE patients will likely benefit. By correlating specific MHE genetic mutations with clinical manifestations, it may be possible to stratify patients into subtypes of hereditary multiple exostoses and identify genetic markers associated with malignant degeneration.²⁷ For example, the EXT1 mutation is associated with a higher rate of malignant transformation, as well as a more severe MHE phenotype with a higher number of exostoses, pelvic and flat bone involvement, and decreased joint range of motion.¹ Targeting patients with this specific mutation could maximize potential benefit of screening imaging while minimizing radiation exposure for patients with other mutations and less severe phenotypes.

An aspect of radiation-exposure research that makes data analysis difficult is that there are numerous ways to quantify radiation exposure, which leads to controversy when measuring and comparing radiation-induced cancer risks.^21,28 In addition, high-dose categories of imaging, such as CT and PET, more consistently are associated with increased risks, while the true risk of cumulative exposure of radiographs and fluoroscopy is not as clear.²¹ The retrospective nature of this data collection limited our study in two ways: we did not have complete fluoroscopic time data for all surgical procedures, and we were only able to collect data from the imaging studies performed in our local healthcare systems; this likely led to underestimation of the cumulative exposure of imaging in patients, both MHE- and non-MHE related. Future research into radiation exposure in MHE patients could focus on the effectiveness of strategies to limit radiation exposure.

5 Conclusions

Through retrospective review, we were able to define medical imaging ionizing radiation exposure to MHE patients in our cohort. While the full extent of the risk that ionizing radiation poses to MHE patients remains unclear, some risk does exist. Use of ionizing radiation in the treatment of MHE patients is common, so diagnostic imaging should be carefully selected. The risks of further imaging exposure versus improving pain, function, and monitoring for malignant transformation of lesions need to be weighed. Future studies should focus on further defining risk in the MHE populations and investigating the benefits of mitigation strategies, such as alternative imaging modalities and protocols for when ionizing radiation studies should and shouldn't be obtained.

Funding/sponsorship

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

7 Institutional ethical committee approval

Approval for this project was obtained from the University of Tennessee Health Science Center Institutional Review Board. (# 20-07663-XP).

Authors’ contribution

Nolan D. Farrell: Investigation. Data curation. Writing – original draft. Jennings H. Dooley: Investigation. Data curation. Writing – original draft. Benjamin W. Sheffer: Formal analysis. Writing - review and editing. Jeffrey R. Sawyer: Protocol development. Writing - review and editing. Derek M. Kelly: Conceptualization. Protocol development. Data curation. Supervision. Manuscript review and editing.

Financial disclosures

Dr. Sawyer has a consulting agreement with Orthopediatrics, receives royalties from Elsevier Publishing, and has a financial relationship with DePuy. Dr. Kelly has a consulting agreement with Orthopediatrics and receives royalties from Elsevier Publishing. Dr. Sheffer receives royalties from Elsevier Publishing. Drs. Jennings H. Dooley and Nolan D. Farrell report no conflicts of interest.