Clinical Radiology xxx (2014) 1e9
Contents lists available at ScienceDirect
Clinical Radiology journal homepage: www.clinicalradiologyonline.net
Pictorial Review
Osteoradionecrosis of the mandible: through a radiologist’s eyes S.S. Deshpande a, M.H. Thakur b, K. Dholam c, *, A. Mahajan b, S. Arya b, S. Juvekar b a
Department of Radiology, Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai 400022, India b Department of Radiodiagnosis, Tata Memorial Hospital, Parel, Mumbai 400012, India c Department of Dental and Prosthetic Surgery, Tata Memorial Hospital, Parel, Mumbai 400012, India
art icl e i nformat ion Article history: Received 15 April 2014 Received in revised form 1 September 2014 Accepted 17 September 2014
Head and neck malignancies constitute a major cause of morbidity and mortality all over the world. Radiotherapy plays a pivotal role in the management of these tumours; however, it has associated complications, with mandibular osteoradionecrosis (ORN) being one of the gravest orofacial complications. Early diagnosis, extent evaluation, and detection of complications of ORN are imperative for instituting an appropriate management protocol. ORN can closely mimic tumour recurrence, the differentiation of which has obvious clinical implications. The purpose of the present review is to acquaint the radiologist with the imaging features of mandibular ORN and the ways to differentiate ORN from tumour recurrence. Ó 2014 Published by Elsevier Ltd on behalf of The Royal College of Radiologists.
Introduction Head and neck tumours constitute a heterogeneous group of malignancies involving various anatomical sites and with different clinical, pathological, and treatment considerations. Overall, they account for approximately 560,000 new cases worldwide annually. Also, they are a major cause of morbidity and mortality, responsible for about 300,000 deaths each year.1 Radiotherapy (RT) plays a vital role in the management of head and neck cancers. It is used either as a primary treatment modality or as an adjuvant to surgery for local control of the disease. It can also be used with concurrent chemotherapy or as a
* Guarantor and correspondent: K. Dholam, Department of Dental and Prosthetic Surgery, Tata Memorial Hospital, Parel, Mumbai 400012, India. Tel.: þ91 9820945150. E-mail address: [email protected] (K. Dholam).
palliative treatment modality for unresectable tumours. RT is an extremely potent treatment modality; however, it has side effects on the adjacent normal tissues. Mandibular osteoradionecrosis (ORN) is one of the most serious orofacial complications of RT for head and neck cancers.2e4 As accurate evaluation of ORN has considerable clinical implications, the purpose of this review was to depict the varied radiological presentations of ORN.
Clinical considerations Mandibular ORN is defined as an area of exposed bone through an opening in the overlying skin or mucosa, persisting as a non-healing region for a period of 3 months5,6 (Fig 1). This may present clinically with symptoms such as pain, swelling, malocclusion, dysphagia, orocutaneous fistula, trismus, or facial disfiguration.7 Severe cases can lead to death.8
http://dx.doi.org/10.1016/j.crad.2014.09.012 0009-9260/Ó 2014 Published by Elsevier Ltd on behalf of The Royal College of Radiologists.
Please cite this article in press as: Deshpande SS, et al., Osteoradionecrosis of the mandible: through a radiologist’s eyes, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.012
2
S.S. Deshpande et al. / Clinical Radiology xxx (2014) 1e9
Figure 1 Post-RT oral ulcer with exposure of the underlying bone. The ulcer persisted for more than 3 months, and hence, was clinically diagnosed as ORN.
There are a few factors that determine the risk of ORN, such as primary site and stage of the tumour, total radiation dose, brachytherapy, extent of mandible included in the radiation field, fractionation, dentition status and oral hygiene, acute or chronic trauma, nutritional status, concomitant chemoradiation, alcohol or tobacco use, etc.7 Radiation-related factors form one of the major determinants of the possibility of ORN in patients receiving RT. Newer RT techniques, such as intensity-modulated radiation therapy (IMRT), have been introduced, which reduce the overall incidence of ORN.9e11 IMRT is a high-precision technique, which uses computer-controlled linear accelerators to deliver precise radiation doses to a malignant tumour or specific areas within the tumour. It thus allows higher radiation doses to be focused on the tumour, while minimizing the dose to the adjacent normal structures.12,13 Ben-David et al.10 reported no case of mandibular ORN after IMRT for head and neck cancer, using a strict prophylactic dental care policy. Peterson et al.11 reviewed 18-years of literature regarding the impact of cancer therapies on the prevalence of ORN, and reported a weighted ORN prevalence of 7.4% for conventional RT, 6.8% for chemoradiotherapy, 5.3% for brachytherapy, and 5.1% for IMRT. New RT techniques have thus contributed in reducing the incidence of ORN in head and neck RT.
Early and late-onset ORN Based on the onset of symptoms, ORN can be classified as early and late-onset ORN.14 Early-onset ORN is defined as clinical features noted within 2 years of RT. It is predominantly caused due to high radiation doses that are >70 Gy.6,14 Late-onset ORN is postulated due to trauma in a chronically hypoxic environment.14
osseous changes associated with RT in 1926, and called it “radiation osteitis”. Watson and Scarborough16 in 1938, postulated the causes of “radiation osteitis” to be radiation, trauma, and infection. However, Marx et al.5 put forth the idea of “endarteritis due to radiation therapy” as the cause for ORN. He proposed that endarteritis leads to hypoxia, hypocellularity, and hypovascularity, which in turn lead to tissue breakdown and chronic non-healing wounds. Another recently proposed theory suggests that osteoclastic injury due to radiation, leads to hampered osteoclast-mediated bone turnover. This in turn leads to ORN.17,18 A new theory, called the “fibro-atrophic theory” states that the radiationinduced fibro-atrophic mechanism leads to ORN. This constitutes three phases: the prefibrotic phase, the constitutive organized phase, and the late fibro-atrophic phase.19
Radiological considerations Radiological investigations are required in ORN to detect the presence, severity, and extent of ORN, and to monitor the progress of conservative treatment, if instituted. Major diagnostic concern in a suspected case of ORN is to exclude tumour recurrence. The various morphological imaging techniques that contribute to the evaluation of ORN are conventional radiographic techniques [mainly panoramic radiography (PR), multidetector CT (MDCT), and MRI].
PR Conventional radiography, most commonly PR, has been widely used for evaluation of suspected ORN. PR depicts osseous changes of ORN, however, with lesser sensitivity than cross-sectional imaging techniques.20 Early osseous changes are not easily detected, as it requires at least 30e50% reduction in the bone mineral density to be detected on conventional radiographs.21 PR is also not able to depict accurately the soft-tissue changes associated with ORN. As a two-dimensional (2D) projection, PR suffers from several limitations, such as magnification, superimposition, misrepresentation, and distortion of structures. However, PR is a readily available, fast, and convenient technique, which involves reduced radiation exposure. Hence, PR is recommended for follow-up and monitoring patients who are at risk of ORN; but is not very accurate for evaluation of extent.20 Radiation damage to the mandible can lead to loss of bone mass with resorption of the osseous trabeculae. On OPG, it is seen initially as rarefaction of the affected bone, or later, as lytic areas within the mandible (Fig 2). Disorganization and thickening of trabeculae can also be one of the features of radiation damage (Fig 3). Sequestrum, which is defined as “dead bone”, may be seen as a radiodense area amidst the affected rarefied portion of the mandible. Progression of the disease can lead to pathological fracture in severe cases, which is seen as a cortical break (Fig 4).
Pathogenesis
MDCT
Various theories have been proposed to explain the pathogenesis of ORN. Ewing15 was the first to identify the
MDCT can accurately evaluate the extent and severity of the osseous changes, along with the associated soft-tissue
Please cite this article in press as: Deshpande SS, et al., Osteoradionecrosis of the mandible: through a radiologist’s eyes, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.012
S.S. Deshpande et al. / Clinical Radiology xxx (2014) 1e9
Figure 2 Cropped image of the PR of a 25-year-old male patient having undergone external beam RT (EBRT) for left sinonasal teratoma. There is evidence of an ill-defined lytic lesion (arrow) in the mandibular body on the left side involving the mandibular canal, representing changes of ORN.
changes, if any.7,20,22,23 Store and Larheim20 compared the efficacy of CT and PR in the diagnosis and pre-surgical evaluation of mandibular ORN, by evaluating 31 cases. They concluded that CT is superior to PR in visualizing the radiological features of ORN and the anterioreposterior extent of the lesion. They recommended CT in a diagnostic dilemma or when surgical intervention is contemplated. At CT, ORN may present as loss of osseous trabeculae in the spongiosa. It can manifest as osteolytic mandibular lesions (Fig 5) or cortical erosions, involving the buccal (Fig 6) or lingual surface. Bicortical involvement (Fig 7) can occur in severe cases, leading to pathological fractures (Fig 8). Bone sequestrum (Fig 9) may be seen as sclerotic fragments in the involved region of the mandible that are separated from the adjacent cortex. Bone fragmentation and gas bubbles (Fig 10) may also be encountered in areas of ORN. The osseous changes of ORN can be associated with adjacent soft-tissue changes. An enhancing soft-tissue mass may be a frequent association. Enhancement may also
Figure 3 PR shows coarsening of the mandibular trabeculae with mixed lytic and sclerotic areas (arrow) in a 55-year-old male patient having undergone EBRT for adenocarcinoma of left maxilla, suggestive of ORN.
3
Figure 4 Cropped image of the PR shows pathological fracture (arrow) in the mandibular body with background changes of radiation damage, suggestive of advanced ORN.
involve the masticator muscles and form a “pseudo-mass”. It was initially believed that the absence of soft tissue associated with bone changes in the irradiated field suggests ORN, whereas its presence suggests tumour recurrence or sarcomatous change. However, Chong et al.24 studied the CT and MRI findings in five patients documented to have ORN. They found that four out of the five patients with ORN had associated soft-tissue thickening and enhancement in the adjacent masticator muscles, which can appear “mass-like”.
Cone-beam CT (CBCT) CBCT uses a divergent cone-shaped beam, obtaining multiple planar projections in a single rotation.25 CBCT provides accurate images in formats that allow
Figure 5 Axial CT image (bone window) demonstrates multiple lytic areas (arrow) involving the mandible with associated cortical erosions, in a 25-year-old man having received EBRT for sinonasal teratoma. Features are suggestive of ORN.
Please cite this article in press as: Deshpande SS, et al., Osteoradionecrosis of the mandible: through a radiologist’s eyes, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.012
4
S.S. Deshpande et al. / Clinical Radiology xxx (2014) 1e9
Figure 6 Coronal CT image (bone window) of a 76-year-old woman having received RT for tongue malignancy. It reveals unicortical erosion (arrow) involving the buccal cortex of the mandible.
three-dimensional (3D) visualization of the maxillofacial region, thus achieving a transition of dental imaging from 2D to 3D images. However, it has limited soft-tissue contrast resolution compared to MDCT.26 So, where evaluation of soft tissues is required, such as in suspected mandibular ORN, the appropriate imaging technique is MDCT or MRI, rather than CBCT.26
MRI MRI meticulously depicts marrow alterations, cortical erosions, soft-tissue changes, and complications of ORN.7,23,24 MRI of patients with ORN reveals altered marrow signal intensity in the involved part of the mandible, usually appearing hypointense on T1-weighted images (Fig 11a),
Figure 8 Axial CT image (bone window) of a 60-year-old man having received RT for tonsillar malignancy. It shows advanced ORN changes in the mandible in the form of loss of osseous trabeculae in the spongiosa with mixed lytic sclerotic areas. A pathological fracture is seen in the left hemi-mandible (arrow).
hyperintense on T2-weighted and short-tau inversion recovery (STIR) images (Fig 11b). These areas show intense post-contrast enhancement (Fig 11c). Chong et al.24 and Bachmann et al.27 found similar marrow signal intensity changes. However, Fujita et al.28 studied 13 patients with mandibular ORN and classified their MRI findings into three groups. They found the commonest MRI presentation to be homogeneous low signal intensity on both T1-weighted and T2-weighted images in the involved portion of the mandible. They postulated this to be suggestive of fibrosis of bone marrow due to long-standing ORN, inflammatory changes having settled down by the time of the MRI investigation. The second group showed low signal intensity on T1-weighted images and inhomogeneous high
Figure 7 (a) Axial and (b) coronal CT images (bone window) showing bicortical erosion of the mandible (arrow), in a known case of left pyriform sinus malignancy, post-RT. Please cite this article in press as: Deshpande SS, et al., Osteoradionecrosis of the mandible: through a radiologist’s eyes, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.012
S.S. Deshpande et al. / Clinical Radiology xxx (2014) 1e9
5
show intense post-contrast enhancement. Post-contrast enhancement may also be seen in the masticator muscles, giving a “pseudo-mass appearance” (Fig 13), as in CT.24
Radiological differentiation of mandibular ORN and tumour recurrence
Figure 9 Coronal CT image (bone window) showing sequestrum (arrow) in the form of a bone fragment separated from the involved cortex by an erosion.
signal intensity in a diffuse surrounding area of low signal intensity on T2-weighted images. This was suggested to be due to acute inflammatory changes in the irradiated fibrous bone marrow. The third pattern was of homogeneous low signal intensity on T1-weighted images and high signal intensity on T2-weighted images; which they postulated to be due to either inflammatory changes or loose fibrosis associated with marked cellularity. Further osseous changes associated with ORN include cortical erosions, which can be appreciated as loss of the hypointense cortical definition. Bone sequestrum (Fig 12), fragmentation (Fig 13), and pathological fractures can be appreciated at MRI; however, these osseous changes are better evaluated at CT.22,23 The osseous lesions may be associated with soft-tissue abnormalities, which appear hypointense on T1-weighted images, hyperintense on T2-weighted and STIR images, and
The major concern in patients presenting with radiological features of ORN is to exclude tumour recurrence. Tumour recurrence also commonly presents as osteolytic lesions with associated soft-tissue mass. It may be associated with pathological fracture (Fig 14). However, Hermans et al.22,23 found that cortical defects distant from the position of the original tumour and on the contralateral side, present the possibility of mandibular ORN. Tumour recurrence is usually encountered within 2 years of treatment of the primary tumour; whereas the time to presentation of ORN can be variable (early or late ORN). The introduction of functional imaging techniques such as diffusion-weighted imaging (DWI), PET, and SPECT, however, has added a new dimension to the radiological evaluation of ORN.
DWI DWI is a technique that capitalizes on the diffusion properties of water protons in a given tissue. As tumour recurrence comprises densely cellular tissue with an increased nuclear-to-cytoplasmic ratio and decreased intercellular space, this restricts water motion, and hence, shows restricted diffusion with decreased ADC values. However, post-treatment changes are less cellular and with increased interstitial space. This is responsible for higher ADC values seen in areas of post-treatment changes. This forms the basis of differentiation of ORN from tumour recurrence on DWI.29e32 Abdel Razek et al.32 evaluated the role of DWI in the differentiation of residual or recurrent head and neck tumours and post-treatment changes. They concluded that the mean ADC value of residual or recurrent lesions was significantly less than that of post-treatment changes (p < 0.001). They found that bone marrow infiltration also shows reduced ADC values, and hence appear low signal on ADC maps. Vandecaveye et al. found similar results and concluded that the ADC maps exhibit a high sensitivity (94.6%), specificity (95.9%), and accuracy (95.5%) in the discrimination of tumoural and non-tumoural tissues. DWI yielded fewer false-positive rates when compared to CT or PET.33
PET
Figure 10 Axial CT image (bone window) shows advanced ORN changes in the mandible with gas (arrow) noted in the region of the pathological fracture. This is a finding noted in ORN, as also seen in infective aetiologies.
FDG-PET, being a functional imaging technique, has been advocated to detect tumour recurrence and differentiate it from ORN. The sensitivity and specificity of PET-CT has been found to be better than CT in detecting tumour recurrence in many studies (92.9e100% versus 72% and 64e96% versus 88%, respectively).34e36 However, there have been a few recent reports showing avid FDG uptake in areas of ORN, thus giving false-positive results in evaluation of tumour
Please cite this article in press as: Deshpande SS, et al., Osteoradionecrosis of the mandible: through a radiologist’s eyes, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.012
6
S.S. Deshpande et al. / Clinical Radiology xxx (2014) 1e9
Figure 11 Coronal MRI image showing marrow signal intensity changes in ORN. (a) T1-weighted MRI image shows decreased marrow signal intensity in the right hemi-mandible (arrow) as compared to the left hemi-mandible. (b) Coronal STIR MRI image shows increased marrow signal intensity in the right hemi-mandible (arrow) as compared to the left hemi-mandible. (c) Coronal post-contrast T1-weighted fat-saturated MRI image shows post-contrast enhancement in the involved portion of the right hemi-mandible (arrow) and the adjacent soft tissues.
recurrence in irradiated regions.37,38 FDG is known to accumulate in areas of inflammation, due to uptake by the inflammatory cells. They show marked increase in FDG uptake in the presence of hypoxia and inflammatory mediators.39 This is postulated to be the cause of false-positive uptake in ORN cases. Dual-phase semi-quantitative PET studies have been suggested, as the washout of FDG-6phosphate is delayed from malignant lesions as compared with benign lesions.40,41 Wang et al.42 found that 75% of patients with false-positive visually interpreted FDG-PET, showed decreased SUV over time, and hence, dual-phase FDG-PET may aid in reducing false-positive PET studies. This may thus improve the specificity of FDG-PET in differentiating recurrence from ORN.
tumour recurrence. 99Tcm-sestamibi is a marker that has shown differential uptake in tumour recurrence and post-RT necrosis.43 Methoxy-isobutyl-isonitrile (MIBI) accumulates in cells rich in mitochondrial content and is influenced by the electric potentials generated across mitochondrial plasma membrane.44 Tan and Ng45 reported a case where 99Tcmsestamibi-SPECT/CT aided in the differentiation of tumour recurrence and ORN in a case of nasopharyngeal carcinoma post-RT. Tl-201 is another radiopharmaceutical that has been evaluated by Wang et al. for this purpose. They found that Tl-201-SPECT clarified 75% (three of the four) of the false-positive PETs to be ORN. Thus, SPECT-CT may be used to reduce false-positive rates and improve specificity.42
Other sites of ORN in the head and neck SPECT Utility of SPECT using various radio-pharmaceuticals has been evaluated to diagnose ORN and differentiate it from
Figure 12 Coronal post-contrast T1-weighted MRI image showing sequestrum (arrow) in the form of a bone fragment separated from the involved cortex by erosion.
The application of RT in head and neck tumours predisposes multiple other sites to ORN. Apart from mandible,
Figure 13 Coronal post-contrast T1-weighted MRI image showing advanced ORN changes in the form of bone fragmentation (short arrow). There is “pseudo-mass-like” enhancement in the adjacent soft tissues (long arrow).
Please cite this article in press as: Deshpande SS, et al., Osteoradionecrosis of the mandible: through a radiologist’s eyes, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.012
S.S. Deshpande et al. / Clinical Radiology xxx (2014) 1e9
7
Figure 14 Images of a 74-year-old male patient having received RT for malignancy of the right buccal mucosa. (a) Axial CT image (bone window) after 2 years reveals loss of osseous trabeculae in the mandibular spongiosa with lytic and sclerotic lesions. A pathological fracture (arrow) is seen involving the mandibular body on the left side. (b) Contrast-enhanced CT image shows an enhancing soft-tissue mass (arrow) adjacent to the pathological fracture. Histopathology proved this to be tumour recurrence.
which remains the commonest site of ORN in the head and neck, a few other sites are also affected by radiation damage. These include the maxillae, skull base, and the hyoid.
Radiological features of hyoid ORN are the same as elsewhere.
Maxillae Skull base ORN of the skull base may involve the sphenoid bone, clivus, internal carotid canal, and the temporal bone. The imaging features of ORN affecting the skull base are similar as seen elsewhere, such as bone destruction with sequestrum formation, which may be associated with air foci in the bone and adjacent tissue. The involvement may be classified as extensive and symmetric or localized.46 Huang et al.46 concluded that histopathological evaluation is very important, as it is difficult to differentiate tumour recurrence from ORN at this site; with the two entities sometimes being co-existent.
Temporal bone ORN of the temporal bone has been reported extensively following RT for carcinoma of the nasopharynx and external auditory canal. Ramsden et al.47 studied a series of 29 cases of temporal bone ORN and described two patterns of involvement1: localized involvement of the tympanic plate, which occurs commonly when the temporal bone is in the periphery of an irradiated field. It clinically presents with dermatitis, otalgia, otorrhoea, and hearing loss; and2 diffuse ORN of the temporal bone, which occurs when irradiation is primarily directed at the temporal bone. It extends to the skull base and presents commonly with CSF otorrhoea. It is more prone to complications such as hearing loss, chronic otomastoiditis, lateral sinus thrombosis, meningitis, intradural and/or extradural abscesses, brain abscesses, cranial nerve palsies (facial nerve), and fistula formation into the parotid gland or temporomandibular joint.
Maxillary ORN is a dreaded complication of RT used for maxillary malignancies, with imaging features being similar to ORN at other sites. Features such as bony sclerosis and destruction of maxillary antral walls help to diagnose ORN.49
Treatment of ORN The management of mandibular ORN includes mainly conservative measures, hyperbaric oxygen therapy and surgery. The initial approach to the treatment of ORN is conservative,50e52 with various measures that have been recommended in the literature, such as stringent oral hygiene, regular wound irrigation with saline and 0.02% aqueous chlorhexidine,53 antibiotics such as tetracyclines,54,55 and drugs that reduce post-RT fibrosis such as pentoxifylline and tocopherol.56 Hyperbaric oxygen therapy involves breathing 100% oxygen in a pressure chamber at 1.5 atmospheres or greater.57 Hyperbaric oxygen therapy benefits ORN by promoting angiogenesis, and hence, increasing tissue oxygenation, by controlling infection, predominantly through enhanced bacterial killing and by stimulating fibroblast replication and development of a collagen matrix.58 The protocol that is followed is that of 2e2.5 atmospheres of 100% oxygen in a hyperbaric chamber for 90e120 min per session.2,7,14,58,59 Surgical intervention is indicated in severe cases that present with large intra-oral ulcerations and/or fistula formation,60 radiographically detected osteolysis of the inferior mandibular border or a pathological fracture.61
Hyoid bone
Conclusion
RT administered for neoplasms abutting or in close proximity to the hyoid bone impose a risk of hyoid ORN.48
ORN is a dreaded complication of head and neck RT. Early and accurate diagnosis of ORN with detection of
Please cite this article in press as: Deshpande SS, et al., Osteoradionecrosis of the mandible: through a radiologist’s eyes, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.012
8
S.S. Deshpande et al. / Clinical Radiology xxx (2014) 1e9
complications is imperative for optimal patient management. Conclusive exclusion of local tumour recurrence is mandatory due to obvious therapeutic and prognostic implications. Radiologists play a pivotal role in this regards, and hence, should be well acquainted with the imaging of ORN.
References 1. Boyle P, Levin B. World Cancer Report. Lyon, France: International Agency for Research on Cancer; 2008. http://www.iarc.fr/en/publications/pdfsonline/wcr/2008/wcr_2008.pdf. 2. Sulaiman F, Huryn JM, Zlotolow IM. Dental extractions in irradiated head and neck patient: a retrospective analysis of Memorial Sloan-Kettering Cancer Center protocols, criteria and end results. J Oral Maxillofac Surg 2003;61:1123e31. 3. Hutchinson IL. Complications of radiotherapy in the head and neck: an orofacial surgeon’s view. In: Tobias JS, Thomas PRM, editors. Current Radiation Oncology. London: Arnold; 1996. p. 144e77. 4. Thorn JJ, Hansen HS, Specht L, et al. Osteoradionecrosis of the jaws: clinical characteristics and relation to the field of irradiation. J Oral Maxillofac Surg 2000;58:1088e93. 5. Marx RE. A new concept in the treatment of osteoradionecrosis. J Oral Maxillofac Surg 1983;41:351e7. 6. Jacobson A, Buchbinder D, Hu K, et al. Paradigm shifts in the management of osteoradionecrosis of the mandible. Oral Oncol 2010;46:795e801. 7. Chrcanovic B, Reher P, Sousa A, et al. Osteoradionecrosis of the jawsda current overviewdpart 1: physiopathology and risk and predisposing factors. Oral Maxillofac Surg 2010;14:3e16. 8. Marx RE, Johnson RP. Studies in the radiobiology of osteoradionecrosis and their clinical significance. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1987;644:379e90. 9. Gevorgyan A, Wong K, Poon I, et al. Osteoradionecrosis of the mandible: a case series at a single institution. J Otolaryngol Head Neck Surg 2013;42:46. 10. Ben-David MA, Diamante M, Radawski JD, et al. Lack of osteoradionecrosis of the mandible after intensity-modulated radiotherapy for head and neck cancer: likely contributions of both dental care and improved dose distributions. Int J Radiat Oncol Biol Phys 2007;68:396e402. 11. Peterson DE, Doerr W, Hovan A, et al. Osteoradionecrosis in cancer patients: the evidence base for treatment-dependent frequency, current management strategies, and future studies. Support Care Cancer 2010;18:1089e98. 12. Teh BS, Woo SY, Woo, et al. Intensity modulated radiation therapy (IMRT): a new promising technology in radiation oncology. Oncologist 1999;4:433e42. 13. Purdy JA. Intensity modulated radiation therapy. Int J Radiat Oncol Biol Phys 1996;35:845e6. 14. Reuther T, Schuster T, Mende U, et al. Osteoradionecrosis of the jaws as a side effect of radiotherapy of head and neck tumour patientsda report of a thirty year retrospective review. Int J Oral Maxillofac Surg 2003;32:289e95. 15. Ewing J. Radiation osteitis. Acta Radiol 1926;6:399e412. 16. Watson WL, Scarborough JE. Osteoradionecrosis in intra-oral cancer. Am J Roentgenol Radiat Ther 1938;40:524e34. 17. Ruggiero SL, Mehrotra B, Rosenberg TJ, et al. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62:527e34. 18. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003;61:1115e7. 19. Delanian S, Lefaix JL. The radiation-induced fibroatrophic process: therapeutic perspective via the antioxidant pathway. Radiother Oncol 2004;73:119e31. 20. Store G, Larheim TA. Mandibular osteoradionecrosis: a comparison of computed tomography with panoramic radiography. Dentomaxillofac Radiol 1999;28:295e300. 21. Worth HM, Stoneman DW. Osteomyelitis, malignant disease, and fibrous dysplasia. Some radiologic similarities and differences. Dent Radiogr 1977;50:1e9.
22. Hermans R, Fossion E, Ioannides C, et al. CT findings in osteoradionecrosis of the mandible. Skel Radiol 1996;25:31e6. 23. Hermans R. Imaging of mandibular osteoradionecrosis. Neuroimaging Clin N Am 2003;13:597e604. 24. Chong J, Hinckley LK, Ginsberg LE. Masticator space abnormalities associated with mandibular osteoradionecrosis: MR and CT findings in five patients. AJNR Am J Neuroradiol 2000;21:175e8. 25. Koong B. Cone beam imaging: is this the ultimate imaging modality? Clin Oral Impl Res 2010;21:1201e8. 26. Watanabe H, Honda E, Tetsumura A, et al. A comparative study for spatial resolution and subjective image characteristics of a multislice CT and a cone-beam CT for dental use. Eur J Radiol 2011;77: 397e402. 27. Bachmann G, Robler R, Klett R, et al. The role of magnetic resonance imaging and scintigraphy in the diagnosis of pathologic changes of the mandible after radiation therapy. Int J Oral Maxillofac Surg 1996;25: 189e95. 28. Fujita M, Harada K, Masaki N, et al. MR imaging of osteoradionecrosis of the mandible following radiotherapy for head and neck cancers. Nippon Acta Radiol 1991;51:892e900. 29. Wang J, Takashima S, Takayama F, et al. Head and neck lesions: characterization with diffusion-weighted echo-planar MR imaging. Radiology 2001;220:621e30. 30. Baur A, Huber A, Arbogast S, et al. Diffusion-weighted imaging of tumor recurrences and posttheraputical soft tissue changes in humans. Eur Radiol 2001;11:828e33. 31. Hein P, Eskey C, Dunn J, et al. Diffusion-weighted imaging in the followup of treated high-grade gliomas: tumor recurrence versus radiation injury. AJNR Am J Neuroradiol 2004;25:201e9. 32. Abdel Razek AA, Kandeel AY, Soliman N, et al. Role of diffusion-weighted echo-planar MR imaging in differentiation of residual or recurrent head and neck tumors and post treatment changes. AJNR Am J Neuroradiol 2007;28(6):1146e52. 33. Vandecaveye V, De Keyzer F, Nuyts S, et al. Detection of head and neck squamous cell carcinoma with diffusion weighted MRI after (chemo) radiotherapy: correlation between radiologic and histopathologic findings. Int J Radiat Oncol Biol Phys 2007;67:960e71. 34. Fischbein NJ, AAssar OS, Caputo GR, et al. Clinical utility of positron emission tomography with 18F-fluorodeoxyglucose in detecting residual/recurrent squamous cell carcinoma of the head and neck. AJNR Am J Neuroradiol 1998;19:1189e96. 35. Kao CH, Chang Lai SP, Chieng PU, et al. Detection of recurrent or persistent nasopharyngeal carcinomas after radiotherapy with 18fluoro-2-deoxyglucose positron emission tomography and comparison with computed tomography. J Clin Oncol 1998;16:3550e5. 36. Mitsuhashi N, Hayakawa K, Hasegawa M, et al. Clinical FDG-PET in diagnosis and evaluation of radiation response of patients with nasopharyngeal tumor. Anticancer Res 1998;18:2827e32. 37. Hung GU, Tsai SH, Lin WY. Extraordinarily high F-18 FDG uptake caused by radiation necrosis in a patient with nasopharyngeal carcinoma. Clin Nucl Med 2005;30:558e9. 38. Liu SH, Chang JT, Ng SH, et al. False positive fluorine-18 fluodeoxy-dglucose positron emission tomography finding caused by osteoradionecrosis in a nasopharyngeal carcinoma patient. Br J Radiol 2004;77:257e60. 39. Yamada S, Kubota K, Kubota R, et al. High accumulation of fluorine-18fluorodeoxyglucose in turpentine-induced inflammatory tissue. J Nucl Med 1995;36:1301e6. 40. Zhuang H, Pourdehnad M, Lambright ES, et al. Dual time point 18F-FDGPET imaging for differentiating malignant from inflammatory processes. J Nucl Med 2001;42:1412e7. 41. Hustinx R, Smith RJ, Benard F, et al. Dual time point fluorine-18 fluorodeoxyglucose positron emission tomography: a potential method to differentiate malignancy from inflammation and normal tissue in the head and neck. Eur J Nucl Med 1999;26:1345e8. 42. Wang CH, Liang JA, Ding HJ, et al. Utility of TL-201 SPECT in clarifying false-positive FDG-PET findings due to osteoradionecrosis in head and neck cancer. Head Neck 2010;32:1648e54. 43. Ohira H, Kubota K, Ohuchi N, et al. Comparison of intratumoral distribution of 99mTc-Mibi and deoxyglucose in mouse breast cancer models. J Nucl Med 2000;41:1561e8.
Please cite this article in press as: Deshpande SS, et al., Osteoradionecrosis of the mandible: through a radiologist’s eyes, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.012
S.S. Deshpande et al. / Clinical Radiology xxx (2014) 1e9 44. Ciu ML, Kronauge JF, Piwnica-Worms D. Effects of mitochondrial and plasma membrane potentials on accumulation of hexakis (2-methoxyisobutyl isonitrile) technetium in cultured mouse fibroblast. J Nucl Med 1990;31:1646e53. 45. Tan AE, Ng DC. Differentiating osteoradionecrosis from nasopharyngeal carcinoma tumour recurrence using 99Tcm-sestamibi SPECT/CT. Br J Radiol 2011;84:172e5. 46. Huang XM, Zheng YIQ, Zhang XM, et al. Diagnosis and management of skull base osteoradionecrosis after radiotherapy for nasopharyngeal carcinoma. Laryngoscope 2006;116:1626e31. 47. Ramsden RT, Bulman CH, Lorigan BP. Osteoradionecrosis of the temporal bone. J Laryngol Otol 1975;89:941e55. 48. Yoo JS, Rosenthal DI, Mitchell K, et al. Osteoradionecrosis of the hyoid bone: imaging findings. AJNR Am J Neuroradiol 2010;31:761e6. 49. Komisar A, Silver C, Kalnicki S. Osteoradionecrosis of the maxilla and skull base. Laryngoscope 1985;95:24e8. 50. Morrish Jr RB, Chan E, Silverman Jr S, et al. Osteonecrosis in patients irradiated for head and neck carcinoma. Cancer 1981;47:1980e3. 51. Epstein JB, Wong FLW, Stevenson-Moore P. Osteoradionecrosis: clinical experience and a proposal for classification. J Oral Maxillofac Surg 1987;45:104e10. 52. Beumer 3rd J, Harrison R, Sanders B, et al. Osteoradionecrosis: predisposing factors and outcomes of therapy. Head Neck Surg 1984;64:819e27.
9
53. Scully C, Epstein JB. Oral health care for the cancer patient. Eur J Cancer B Oral Oncol 1996;32B:281e92. 54. Rankow RM, Weissman B. Osteoradionecrosis of the mandible. Ann Otolaryngol 1971;80:603e11. 55. Coffin F. The incidence and management of osteoradionecrosis of the jaws following head and neck radiotherapy. Br J Radiol 1983;56:851e7. 56. Delanian S, Depondt J, Lefaix JL. Major healing of refractory mandible osteoradionecrosis after treatment combining pentoxifylline and tocopherol: a phase II trial. Head Neck 2005;27:114e23. 57. Grime PD, Bryson PRe, Maier, et al. Review of severe osteoradionecrosis treated by surgery alone or surgery with postoperative hyperbaric oxygen (Br J Oral Maxillofac Surg 2000;38:167e246). Br J Oral Maxillofac Surg 2001;39:242e3. 58. Thorn JJ, Kallehave F, Westergaard P, et al. The effect of hyperbaric oxygen on irradiated tissues: transmucosal oxygen tension measurements. J Oral Maxillofac Surg 1997;55:1103e7. 59. Chavez JA, Adkinson CD. Adjunctive hyperbaric oxygen in irradiated patients requiring dental extractions: outcomes and complications. J Oral Maxillofac Surg 2001;59:518e22. 60. Zarem HA, Carr R. Salvage of the exposed irradiated mandible. Plast Reconstr Surg 1983;72:648e55. 61. Maier A, Gaggl A, Klemen H, et al. Review of severe osteoradionecrosis treated by surgery alone or surgery with postoperative hyperbaric oxygenation. Br J Oral Maxillofac Surg 2000;38:173e6.
Please cite this article in press as: Deshpande SS, et al., Osteoradionecrosis of the mandible: through a radiologist’s eyes, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.012
Contents lists available at ScienceDirect
Clinical Radiology journal homepage: www.clinicalradiologyonline.net
Pictorial Review
Osteoradionecrosis of the mandible: through a radiologist’s eyes S.S. Deshpande a, M.H. Thakur b, K. Dholam c, *, A. Mahajan b, S. Arya b, S. Juvekar b a
Department of Radiology, Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai 400022, India b Department of Radiodiagnosis, Tata Memorial Hospital, Parel, Mumbai 400012, India c Department of Dental and Prosthetic Surgery, Tata Memorial Hospital, Parel, Mumbai 400012, India
art icl e i nformat ion Article history: Received 15 April 2014 Received in revised form 1 September 2014 Accepted 17 September 2014
Head and neck malignancies constitute a major cause of morbidity and mortality all over the world. Radiotherapy plays a pivotal role in the management of these tumours; however, it has associated complications, with mandibular osteoradionecrosis (ORN) being one of the gravest orofacial complications. Early diagnosis, extent evaluation, and detection of complications of ORN are imperative for instituting an appropriate management protocol. ORN can closely mimic tumour recurrence, the differentiation of which has obvious clinical implications. The purpose of the present review is to acquaint the radiologist with the imaging features of mandibular ORN and the ways to differentiate ORN from tumour recurrence. Ó 2014 Published by Elsevier Ltd on behalf of The Royal College of Radiologists.
Introduction Head and neck tumours constitute a heterogeneous group of malignancies involving various anatomical sites and with different clinical, pathological, and treatment considerations. Overall, they account for approximately 560,000 new cases worldwide annually. Also, they are a major cause of morbidity and mortality, responsible for about 300,000 deaths each year.1 Radiotherapy (RT) plays a vital role in the management of head and neck cancers. It is used either as a primary treatment modality or as an adjuvant to surgery for local control of the disease. It can also be used with concurrent chemotherapy or as a
* Guarantor and correspondent: K. Dholam, Department of Dental and Prosthetic Surgery, Tata Memorial Hospital, Parel, Mumbai 400012, India. Tel.: þ91 9820945150. E-mail address: [email protected] (K. Dholam).
palliative treatment modality for unresectable tumours. RT is an extremely potent treatment modality; however, it has side effects on the adjacent normal tissues. Mandibular osteoradionecrosis (ORN) is one of the most serious orofacial complications of RT for head and neck cancers.2e4 As accurate evaluation of ORN has considerable clinical implications, the purpose of this review was to depict the varied radiological presentations of ORN.
Clinical considerations Mandibular ORN is defined as an area of exposed bone through an opening in the overlying skin or mucosa, persisting as a non-healing region for a period of 3 months5,6 (Fig 1). This may present clinically with symptoms such as pain, swelling, malocclusion, dysphagia, orocutaneous fistula, trismus, or facial disfiguration.7 Severe cases can lead to death.8
http://dx.doi.org/10.1016/j.crad.2014.09.012 0009-9260/Ó 2014 Published by Elsevier Ltd on behalf of The Royal College of Radiologists.
Please cite this article in press as: Deshpande SS, et al., Osteoradionecrosis of the mandible: through a radiologist’s eyes, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.012
2
S.S. Deshpande et al. / Clinical Radiology xxx (2014) 1e9
Figure 1 Post-RT oral ulcer with exposure of the underlying bone. The ulcer persisted for more than 3 months, and hence, was clinically diagnosed as ORN.
There are a few factors that determine the risk of ORN, such as primary site and stage of the tumour, total radiation dose, brachytherapy, extent of mandible included in the radiation field, fractionation, dentition status and oral hygiene, acute or chronic trauma, nutritional status, concomitant chemoradiation, alcohol or tobacco use, etc.7 Radiation-related factors form one of the major determinants of the possibility of ORN in patients receiving RT. Newer RT techniques, such as intensity-modulated radiation therapy (IMRT), have been introduced, which reduce the overall incidence of ORN.9e11 IMRT is a high-precision technique, which uses computer-controlled linear accelerators to deliver precise radiation doses to a malignant tumour or specific areas within the tumour. It thus allows higher radiation doses to be focused on the tumour, while minimizing the dose to the adjacent normal structures.12,13 Ben-David et al.10 reported no case of mandibular ORN after IMRT for head and neck cancer, using a strict prophylactic dental care policy. Peterson et al.11 reviewed 18-years of literature regarding the impact of cancer therapies on the prevalence of ORN, and reported a weighted ORN prevalence of 7.4% for conventional RT, 6.8% for chemoradiotherapy, 5.3% for brachytherapy, and 5.1% for IMRT. New RT techniques have thus contributed in reducing the incidence of ORN in head and neck RT.
Early and late-onset ORN Based on the onset of symptoms, ORN can be classified as early and late-onset ORN.14 Early-onset ORN is defined as clinical features noted within 2 years of RT. It is predominantly caused due to high radiation doses that are >70 Gy.6,14 Late-onset ORN is postulated due to trauma in a chronically hypoxic environment.14
osseous changes associated with RT in 1926, and called it “radiation osteitis”. Watson and Scarborough16 in 1938, postulated the causes of “radiation osteitis” to be radiation, trauma, and infection. However, Marx et al.5 put forth the idea of “endarteritis due to radiation therapy” as the cause for ORN. He proposed that endarteritis leads to hypoxia, hypocellularity, and hypovascularity, which in turn lead to tissue breakdown and chronic non-healing wounds. Another recently proposed theory suggests that osteoclastic injury due to radiation, leads to hampered osteoclast-mediated bone turnover. This in turn leads to ORN.17,18 A new theory, called the “fibro-atrophic theory” states that the radiationinduced fibro-atrophic mechanism leads to ORN. This constitutes three phases: the prefibrotic phase, the constitutive organized phase, and the late fibro-atrophic phase.19
Radiological considerations Radiological investigations are required in ORN to detect the presence, severity, and extent of ORN, and to monitor the progress of conservative treatment, if instituted. Major diagnostic concern in a suspected case of ORN is to exclude tumour recurrence. The various morphological imaging techniques that contribute to the evaluation of ORN are conventional radiographic techniques [mainly panoramic radiography (PR), multidetector CT (MDCT), and MRI].
PR Conventional radiography, most commonly PR, has been widely used for evaluation of suspected ORN. PR depicts osseous changes of ORN, however, with lesser sensitivity than cross-sectional imaging techniques.20 Early osseous changes are not easily detected, as it requires at least 30e50% reduction in the bone mineral density to be detected on conventional radiographs.21 PR is also not able to depict accurately the soft-tissue changes associated with ORN. As a two-dimensional (2D) projection, PR suffers from several limitations, such as magnification, superimposition, misrepresentation, and distortion of structures. However, PR is a readily available, fast, and convenient technique, which involves reduced radiation exposure. Hence, PR is recommended for follow-up and monitoring patients who are at risk of ORN; but is not very accurate for evaluation of extent.20 Radiation damage to the mandible can lead to loss of bone mass with resorption of the osseous trabeculae. On OPG, it is seen initially as rarefaction of the affected bone, or later, as lytic areas within the mandible (Fig 2). Disorganization and thickening of trabeculae can also be one of the features of radiation damage (Fig 3). Sequestrum, which is defined as “dead bone”, may be seen as a radiodense area amidst the affected rarefied portion of the mandible. Progression of the disease can lead to pathological fracture in severe cases, which is seen as a cortical break (Fig 4).
Pathogenesis
MDCT
Various theories have been proposed to explain the pathogenesis of ORN. Ewing15 was the first to identify the
MDCT can accurately evaluate the extent and severity of the osseous changes, along with the associated soft-tissue
Please cite this article in press as: Deshpande SS, et al., Osteoradionecrosis of the mandible: through a radiologist’s eyes, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.012
S.S. Deshpande et al. / Clinical Radiology xxx (2014) 1e9
Figure 2 Cropped image of the PR of a 25-year-old male patient having undergone external beam RT (EBRT) for left sinonasal teratoma. There is evidence of an ill-defined lytic lesion (arrow) in the mandibular body on the left side involving the mandibular canal, representing changes of ORN.
changes, if any.7,20,22,23 Store and Larheim20 compared the efficacy of CT and PR in the diagnosis and pre-surgical evaluation of mandibular ORN, by evaluating 31 cases. They concluded that CT is superior to PR in visualizing the radiological features of ORN and the anterioreposterior extent of the lesion. They recommended CT in a diagnostic dilemma or when surgical intervention is contemplated. At CT, ORN may present as loss of osseous trabeculae in the spongiosa. It can manifest as osteolytic mandibular lesions (Fig 5) or cortical erosions, involving the buccal (Fig 6) or lingual surface. Bicortical involvement (Fig 7) can occur in severe cases, leading to pathological fractures (Fig 8). Bone sequestrum (Fig 9) may be seen as sclerotic fragments in the involved region of the mandible that are separated from the adjacent cortex. Bone fragmentation and gas bubbles (Fig 10) may also be encountered in areas of ORN. The osseous changes of ORN can be associated with adjacent soft-tissue changes. An enhancing soft-tissue mass may be a frequent association. Enhancement may also
Figure 3 PR shows coarsening of the mandibular trabeculae with mixed lytic and sclerotic areas (arrow) in a 55-year-old male patient having undergone EBRT for adenocarcinoma of left maxilla, suggestive of ORN.
3
Figure 4 Cropped image of the PR shows pathological fracture (arrow) in the mandibular body with background changes of radiation damage, suggestive of advanced ORN.
involve the masticator muscles and form a “pseudo-mass”. It was initially believed that the absence of soft tissue associated with bone changes in the irradiated field suggests ORN, whereas its presence suggests tumour recurrence or sarcomatous change. However, Chong et al.24 studied the CT and MRI findings in five patients documented to have ORN. They found that four out of the five patients with ORN had associated soft-tissue thickening and enhancement in the adjacent masticator muscles, which can appear “mass-like”.
Cone-beam CT (CBCT) CBCT uses a divergent cone-shaped beam, obtaining multiple planar projections in a single rotation.25 CBCT provides accurate images in formats that allow
Figure 5 Axial CT image (bone window) demonstrates multiple lytic areas (arrow) involving the mandible with associated cortical erosions, in a 25-year-old man having received EBRT for sinonasal teratoma. Features are suggestive of ORN.
Please cite this article in press as: Deshpande SS, et al., Osteoradionecrosis of the mandible: through a radiologist’s eyes, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.012
4
S.S. Deshpande et al. / Clinical Radiology xxx (2014) 1e9
Figure 6 Coronal CT image (bone window) of a 76-year-old woman having received RT for tongue malignancy. It reveals unicortical erosion (arrow) involving the buccal cortex of the mandible.
three-dimensional (3D) visualization of the maxillofacial region, thus achieving a transition of dental imaging from 2D to 3D images. However, it has limited soft-tissue contrast resolution compared to MDCT.26 So, where evaluation of soft tissues is required, such as in suspected mandibular ORN, the appropriate imaging technique is MDCT or MRI, rather than CBCT.26
MRI MRI meticulously depicts marrow alterations, cortical erosions, soft-tissue changes, and complications of ORN.7,23,24 MRI of patients with ORN reveals altered marrow signal intensity in the involved part of the mandible, usually appearing hypointense on T1-weighted images (Fig 11a),
Figure 8 Axial CT image (bone window) of a 60-year-old man having received RT for tonsillar malignancy. It shows advanced ORN changes in the mandible in the form of loss of osseous trabeculae in the spongiosa with mixed lytic sclerotic areas. A pathological fracture is seen in the left hemi-mandible (arrow).
hyperintense on T2-weighted and short-tau inversion recovery (STIR) images (Fig 11b). These areas show intense post-contrast enhancement (Fig 11c). Chong et al.24 and Bachmann et al.27 found similar marrow signal intensity changes. However, Fujita et al.28 studied 13 patients with mandibular ORN and classified their MRI findings into three groups. They found the commonest MRI presentation to be homogeneous low signal intensity on both T1-weighted and T2-weighted images in the involved portion of the mandible. They postulated this to be suggestive of fibrosis of bone marrow due to long-standing ORN, inflammatory changes having settled down by the time of the MRI investigation. The second group showed low signal intensity on T1-weighted images and inhomogeneous high
Figure 7 (a) Axial and (b) coronal CT images (bone window) showing bicortical erosion of the mandible (arrow), in a known case of left pyriform sinus malignancy, post-RT. Please cite this article in press as: Deshpande SS, et al., Osteoradionecrosis of the mandible: through a radiologist’s eyes, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.012
S.S. Deshpande et al. / Clinical Radiology xxx (2014) 1e9
5
show intense post-contrast enhancement. Post-contrast enhancement may also be seen in the masticator muscles, giving a “pseudo-mass appearance” (Fig 13), as in CT.24
Radiological differentiation of mandibular ORN and tumour recurrence
Figure 9 Coronal CT image (bone window) showing sequestrum (arrow) in the form of a bone fragment separated from the involved cortex by an erosion.
signal intensity in a diffuse surrounding area of low signal intensity on T2-weighted images. This was suggested to be due to acute inflammatory changes in the irradiated fibrous bone marrow. The third pattern was of homogeneous low signal intensity on T1-weighted images and high signal intensity on T2-weighted images; which they postulated to be due to either inflammatory changes or loose fibrosis associated with marked cellularity. Further osseous changes associated with ORN include cortical erosions, which can be appreciated as loss of the hypointense cortical definition. Bone sequestrum (Fig 12), fragmentation (Fig 13), and pathological fractures can be appreciated at MRI; however, these osseous changes are better evaluated at CT.22,23 The osseous lesions may be associated with soft-tissue abnormalities, which appear hypointense on T1-weighted images, hyperintense on T2-weighted and STIR images, and
The major concern in patients presenting with radiological features of ORN is to exclude tumour recurrence. Tumour recurrence also commonly presents as osteolytic lesions with associated soft-tissue mass. It may be associated with pathological fracture (Fig 14). However, Hermans et al.22,23 found that cortical defects distant from the position of the original tumour and on the contralateral side, present the possibility of mandibular ORN. Tumour recurrence is usually encountered within 2 years of treatment of the primary tumour; whereas the time to presentation of ORN can be variable (early or late ORN). The introduction of functional imaging techniques such as diffusion-weighted imaging (DWI), PET, and SPECT, however, has added a new dimension to the radiological evaluation of ORN.
DWI DWI is a technique that capitalizes on the diffusion properties of water protons in a given tissue. As tumour recurrence comprises densely cellular tissue with an increased nuclear-to-cytoplasmic ratio and decreased intercellular space, this restricts water motion, and hence, shows restricted diffusion with decreased ADC values. However, post-treatment changes are less cellular and with increased interstitial space. This is responsible for higher ADC values seen in areas of post-treatment changes. This forms the basis of differentiation of ORN from tumour recurrence on DWI.29e32 Abdel Razek et al.32 evaluated the role of DWI in the differentiation of residual or recurrent head and neck tumours and post-treatment changes. They concluded that the mean ADC value of residual or recurrent lesions was significantly less than that of post-treatment changes (p < 0.001). They found that bone marrow infiltration also shows reduced ADC values, and hence appear low signal on ADC maps. Vandecaveye et al. found similar results and concluded that the ADC maps exhibit a high sensitivity (94.6%), specificity (95.9%), and accuracy (95.5%) in the discrimination of tumoural and non-tumoural tissues. DWI yielded fewer false-positive rates when compared to CT or PET.33
PET
Figure 10 Axial CT image (bone window) shows advanced ORN changes in the mandible with gas (arrow) noted in the region of the pathological fracture. This is a finding noted in ORN, as also seen in infective aetiologies.
FDG-PET, being a functional imaging technique, has been advocated to detect tumour recurrence and differentiate it from ORN. The sensitivity and specificity of PET-CT has been found to be better than CT in detecting tumour recurrence in many studies (92.9e100% versus 72% and 64e96% versus 88%, respectively).34e36 However, there have been a few recent reports showing avid FDG uptake in areas of ORN, thus giving false-positive results in evaluation of tumour
Please cite this article in press as: Deshpande SS, et al., Osteoradionecrosis of the mandible: through a radiologist’s eyes, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.012
6
S.S. Deshpande et al. / Clinical Radiology xxx (2014) 1e9
Figure 11 Coronal MRI image showing marrow signal intensity changes in ORN. (a) T1-weighted MRI image shows decreased marrow signal intensity in the right hemi-mandible (arrow) as compared to the left hemi-mandible. (b) Coronal STIR MRI image shows increased marrow signal intensity in the right hemi-mandible (arrow) as compared to the left hemi-mandible. (c) Coronal post-contrast T1-weighted fat-saturated MRI image shows post-contrast enhancement in the involved portion of the right hemi-mandible (arrow) and the adjacent soft tissues.
recurrence in irradiated regions.37,38 FDG is known to accumulate in areas of inflammation, due to uptake by the inflammatory cells. They show marked increase in FDG uptake in the presence of hypoxia and inflammatory mediators.39 This is postulated to be the cause of false-positive uptake in ORN cases. Dual-phase semi-quantitative PET studies have been suggested, as the washout of FDG-6phosphate is delayed from malignant lesions as compared with benign lesions.40,41 Wang et al.42 found that 75% of patients with false-positive visually interpreted FDG-PET, showed decreased SUV over time, and hence, dual-phase FDG-PET may aid in reducing false-positive PET studies. This may thus improve the specificity of FDG-PET in differentiating recurrence from ORN.
tumour recurrence. 99Tcm-sestamibi is a marker that has shown differential uptake in tumour recurrence and post-RT necrosis.43 Methoxy-isobutyl-isonitrile (MIBI) accumulates in cells rich in mitochondrial content and is influenced by the electric potentials generated across mitochondrial plasma membrane.44 Tan and Ng45 reported a case where 99Tcmsestamibi-SPECT/CT aided in the differentiation of tumour recurrence and ORN in a case of nasopharyngeal carcinoma post-RT. Tl-201 is another radiopharmaceutical that has been evaluated by Wang et al. for this purpose. They found that Tl-201-SPECT clarified 75% (three of the four) of the false-positive PETs to be ORN. Thus, SPECT-CT may be used to reduce false-positive rates and improve specificity.42
Other sites of ORN in the head and neck SPECT Utility of SPECT using various radio-pharmaceuticals has been evaluated to diagnose ORN and differentiate it from
Figure 12 Coronal post-contrast T1-weighted MRI image showing sequestrum (arrow) in the form of a bone fragment separated from the involved cortex by erosion.
The application of RT in head and neck tumours predisposes multiple other sites to ORN. Apart from mandible,
Figure 13 Coronal post-contrast T1-weighted MRI image showing advanced ORN changes in the form of bone fragmentation (short arrow). There is “pseudo-mass-like” enhancement in the adjacent soft tissues (long arrow).
Please cite this article in press as: Deshpande SS, et al., Osteoradionecrosis of the mandible: through a radiologist’s eyes, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.012
S.S. Deshpande et al. / Clinical Radiology xxx (2014) 1e9
7
Figure 14 Images of a 74-year-old male patient having received RT for malignancy of the right buccal mucosa. (a) Axial CT image (bone window) after 2 years reveals loss of osseous trabeculae in the mandibular spongiosa with lytic and sclerotic lesions. A pathological fracture (arrow) is seen involving the mandibular body on the left side. (b) Contrast-enhanced CT image shows an enhancing soft-tissue mass (arrow) adjacent to the pathological fracture. Histopathology proved this to be tumour recurrence.
which remains the commonest site of ORN in the head and neck, a few other sites are also affected by radiation damage. These include the maxillae, skull base, and the hyoid.
Radiological features of hyoid ORN are the same as elsewhere.
Maxillae Skull base ORN of the skull base may involve the sphenoid bone, clivus, internal carotid canal, and the temporal bone. The imaging features of ORN affecting the skull base are similar as seen elsewhere, such as bone destruction with sequestrum formation, which may be associated with air foci in the bone and adjacent tissue. The involvement may be classified as extensive and symmetric or localized.46 Huang et al.46 concluded that histopathological evaluation is very important, as it is difficult to differentiate tumour recurrence from ORN at this site; with the two entities sometimes being co-existent.
Temporal bone ORN of the temporal bone has been reported extensively following RT for carcinoma of the nasopharynx and external auditory canal. Ramsden et al.47 studied a series of 29 cases of temporal bone ORN and described two patterns of involvement1: localized involvement of the tympanic plate, which occurs commonly when the temporal bone is in the periphery of an irradiated field. It clinically presents with dermatitis, otalgia, otorrhoea, and hearing loss; and2 diffuse ORN of the temporal bone, which occurs when irradiation is primarily directed at the temporal bone. It extends to the skull base and presents commonly with CSF otorrhoea. It is more prone to complications such as hearing loss, chronic otomastoiditis, lateral sinus thrombosis, meningitis, intradural and/or extradural abscesses, brain abscesses, cranial nerve palsies (facial nerve), and fistula formation into the parotid gland or temporomandibular joint.
Maxillary ORN is a dreaded complication of RT used for maxillary malignancies, with imaging features being similar to ORN at other sites. Features such as bony sclerosis and destruction of maxillary antral walls help to diagnose ORN.49
Treatment of ORN The management of mandibular ORN includes mainly conservative measures, hyperbaric oxygen therapy and surgery. The initial approach to the treatment of ORN is conservative,50e52 with various measures that have been recommended in the literature, such as stringent oral hygiene, regular wound irrigation with saline and 0.02% aqueous chlorhexidine,53 antibiotics such as tetracyclines,54,55 and drugs that reduce post-RT fibrosis such as pentoxifylline and tocopherol.56 Hyperbaric oxygen therapy involves breathing 100% oxygen in a pressure chamber at 1.5 atmospheres or greater.57 Hyperbaric oxygen therapy benefits ORN by promoting angiogenesis, and hence, increasing tissue oxygenation, by controlling infection, predominantly through enhanced bacterial killing and by stimulating fibroblast replication and development of a collagen matrix.58 The protocol that is followed is that of 2e2.5 atmospheres of 100% oxygen in a hyperbaric chamber for 90e120 min per session.2,7,14,58,59 Surgical intervention is indicated in severe cases that present with large intra-oral ulcerations and/or fistula formation,60 radiographically detected osteolysis of the inferior mandibular border or a pathological fracture.61
Hyoid bone
Conclusion
RT administered for neoplasms abutting or in close proximity to the hyoid bone impose a risk of hyoid ORN.48
ORN is a dreaded complication of head and neck RT. Early and accurate diagnosis of ORN with detection of
Please cite this article in press as: Deshpande SS, et al., Osteoradionecrosis of the mandible: through a radiologist’s eyes, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.012
8
S.S. Deshpande et al. / Clinical Radiology xxx (2014) 1e9
complications is imperative for optimal patient management. Conclusive exclusion of local tumour recurrence is mandatory due to obvious therapeutic and prognostic implications. Radiologists play a pivotal role in this regards, and hence, should be well acquainted with the imaging of ORN.
References 1. Boyle P, Levin B. World Cancer Report. Lyon, France: International Agency for Research on Cancer; 2008. http://www.iarc.fr/en/publications/pdfsonline/wcr/2008/wcr_2008.pdf. 2. Sulaiman F, Huryn JM, Zlotolow IM. Dental extractions in irradiated head and neck patient: a retrospective analysis of Memorial Sloan-Kettering Cancer Center protocols, criteria and end results. J Oral Maxillofac Surg 2003;61:1123e31. 3. Hutchinson IL. Complications of radiotherapy in the head and neck: an orofacial surgeon’s view. In: Tobias JS, Thomas PRM, editors. Current Radiation Oncology. London: Arnold; 1996. p. 144e77. 4. Thorn JJ, Hansen HS, Specht L, et al. Osteoradionecrosis of the jaws: clinical characteristics and relation to the field of irradiation. J Oral Maxillofac Surg 2000;58:1088e93. 5. Marx RE. A new concept in the treatment of osteoradionecrosis. J Oral Maxillofac Surg 1983;41:351e7. 6. Jacobson A, Buchbinder D, Hu K, et al. Paradigm shifts in the management of osteoradionecrosis of the mandible. Oral Oncol 2010;46:795e801. 7. Chrcanovic B, Reher P, Sousa A, et al. Osteoradionecrosis of the jawsda current overviewdpart 1: physiopathology and risk and predisposing factors. Oral Maxillofac Surg 2010;14:3e16. 8. Marx RE, Johnson RP. Studies in the radiobiology of osteoradionecrosis and their clinical significance. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1987;644:379e90. 9. Gevorgyan A, Wong K, Poon I, et al. Osteoradionecrosis of the mandible: a case series at a single institution. J Otolaryngol Head Neck Surg 2013;42:46. 10. Ben-David MA, Diamante M, Radawski JD, et al. Lack of osteoradionecrosis of the mandible after intensity-modulated radiotherapy for head and neck cancer: likely contributions of both dental care and improved dose distributions. Int J Radiat Oncol Biol Phys 2007;68:396e402. 11. Peterson DE, Doerr W, Hovan A, et al. Osteoradionecrosis in cancer patients: the evidence base for treatment-dependent frequency, current management strategies, and future studies. Support Care Cancer 2010;18:1089e98. 12. Teh BS, Woo SY, Woo, et al. Intensity modulated radiation therapy (IMRT): a new promising technology in radiation oncology. Oncologist 1999;4:433e42. 13. Purdy JA. Intensity modulated radiation therapy. Int J Radiat Oncol Biol Phys 1996;35:845e6. 14. Reuther T, Schuster T, Mende U, et al. Osteoradionecrosis of the jaws as a side effect of radiotherapy of head and neck tumour patientsda report of a thirty year retrospective review. Int J Oral Maxillofac Surg 2003;32:289e95. 15. Ewing J. Radiation osteitis. Acta Radiol 1926;6:399e412. 16. Watson WL, Scarborough JE. Osteoradionecrosis in intra-oral cancer. Am J Roentgenol Radiat Ther 1938;40:524e34. 17. Ruggiero SL, Mehrotra B, Rosenberg TJ, et al. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62:527e34. 18. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003;61:1115e7. 19. Delanian S, Lefaix JL. The radiation-induced fibroatrophic process: therapeutic perspective via the antioxidant pathway. Radiother Oncol 2004;73:119e31. 20. Store G, Larheim TA. Mandibular osteoradionecrosis: a comparison of computed tomography with panoramic radiography. Dentomaxillofac Radiol 1999;28:295e300. 21. Worth HM, Stoneman DW. Osteomyelitis, malignant disease, and fibrous dysplasia. Some radiologic similarities and differences. Dent Radiogr 1977;50:1e9.
22. Hermans R, Fossion E, Ioannides C, et al. CT findings in osteoradionecrosis of the mandible. Skel Radiol 1996;25:31e6. 23. Hermans R. Imaging of mandibular osteoradionecrosis. Neuroimaging Clin N Am 2003;13:597e604. 24. Chong J, Hinckley LK, Ginsberg LE. Masticator space abnormalities associated with mandibular osteoradionecrosis: MR and CT findings in five patients. AJNR Am J Neuroradiol 2000;21:175e8. 25. Koong B. Cone beam imaging: is this the ultimate imaging modality? Clin Oral Impl Res 2010;21:1201e8. 26. Watanabe H, Honda E, Tetsumura A, et al. A comparative study for spatial resolution and subjective image characteristics of a multislice CT and a cone-beam CT for dental use. Eur J Radiol 2011;77: 397e402. 27. Bachmann G, Robler R, Klett R, et al. The role of magnetic resonance imaging and scintigraphy in the diagnosis of pathologic changes of the mandible after radiation therapy. Int J Oral Maxillofac Surg 1996;25: 189e95. 28. Fujita M, Harada K, Masaki N, et al. MR imaging of osteoradionecrosis of the mandible following radiotherapy for head and neck cancers. Nippon Acta Radiol 1991;51:892e900. 29. Wang J, Takashima S, Takayama F, et al. Head and neck lesions: characterization with diffusion-weighted echo-planar MR imaging. Radiology 2001;220:621e30. 30. Baur A, Huber A, Arbogast S, et al. Diffusion-weighted imaging of tumor recurrences and posttheraputical soft tissue changes in humans. Eur Radiol 2001;11:828e33. 31. Hein P, Eskey C, Dunn J, et al. Diffusion-weighted imaging in the followup of treated high-grade gliomas: tumor recurrence versus radiation injury. AJNR Am J Neuroradiol 2004;25:201e9. 32. Abdel Razek AA, Kandeel AY, Soliman N, et al. Role of diffusion-weighted echo-planar MR imaging in differentiation of residual or recurrent head and neck tumors and post treatment changes. AJNR Am J Neuroradiol 2007;28(6):1146e52. 33. Vandecaveye V, De Keyzer F, Nuyts S, et al. Detection of head and neck squamous cell carcinoma with diffusion weighted MRI after (chemo) radiotherapy: correlation between radiologic and histopathologic findings. Int J Radiat Oncol Biol Phys 2007;67:960e71. 34. Fischbein NJ, AAssar OS, Caputo GR, et al. Clinical utility of positron emission tomography with 18F-fluorodeoxyglucose in detecting residual/recurrent squamous cell carcinoma of the head and neck. AJNR Am J Neuroradiol 1998;19:1189e96. 35. Kao CH, Chang Lai SP, Chieng PU, et al. Detection of recurrent or persistent nasopharyngeal carcinomas after radiotherapy with 18fluoro-2-deoxyglucose positron emission tomography and comparison with computed tomography. J Clin Oncol 1998;16:3550e5. 36. Mitsuhashi N, Hayakawa K, Hasegawa M, et al. Clinical FDG-PET in diagnosis and evaluation of radiation response of patients with nasopharyngeal tumor. Anticancer Res 1998;18:2827e32. 37. Hung GU, Tsai SH, Lin WY. Extraordinarily high F-18 FDG uptake caused by radiation necrosis in a patient with nasopharyngeal carcinoma. Clin Nucl Med 2005;30:558e9. 38. Liu SH, Chang JT, Ng SH, et al. False positive fluorine-18 fluodeoxy-dglucose positron emission tomography finding caused by osteoradionecrosis in a nasopharyngeal carcinoma patient. Br J Radiol 2004;77:257e60. 39. Yamada S, Kubota K, Kubota R, et al. High accumulation of fluorine-18fluorodeoxyglucose in turpentine-induced inflammatory tissue. J Nucl Med 1995;36:1301e6. 40. Zhuang H, Pourdehnad M, Lambright ES, et al. Dual time point 18F-FDGPET imaging for differentiating malignant from inflammatory processes. J Nucl Med 2001;42:1412e7. 41. Hustinx R, Smith RJ, Benard F, et al. Dual time point fluorine-18 fluorodeoxyglucose positron emission tomography: a potential method to differentiate malignancy from inflammation and normal tissue in the head and neck. Eur J Nucl Med 1999;26:1345e8. 42. Wang CH, Liang JA, Ding HJ, et al. Utility of TL-201 SPECT in clarifying false-positive FDG-PET findings due to osteoradionecrosis in head and neck cancer. Head Neck 2010;32:1648e54. 43. Ohira H, Kubota K, Ohuchi N, et al. Comparison of intratumoral distribution of 99mTc-Mibi and deoxyglucose in mouse breast cancer models. J Nucl Med 2000;41:1561e8.
Please cite this article in press as: Deshpande SS, et al., Osteoradionecrosis of the mandible: through a radiologist’s eyes, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.012
S.S. Deshpande et al. / Clinical Radiology xxx (2014) 1e9 44. Ciu ML, Kronauge JF, Piwnica-Worms D. Effects of mitochondrial and plasma membrane potentials on accumulation of hexakis (2-methoxyisobutyl isonitrile) technetium in cultured mouse fibroblast. J Nucl Med 1990;31:1646e53. 45. Tan AE, Ng DC. Differentiating osteoradionecrosis from nasopharyngeal carcinoma tumour recurrence using 99Tcm-sestamibi SPECT/CT. Br J Radiol 2011;84:172e5. 46. Huang XM, Zheng YIQ, Zhang XM, et al. Diagnosis and management of skull base osteoradionecrosis after radiotherapy for nasopharyngeal carcinoma. Laryngoscope 2006;116:1626e31. 47. Ramsden RT, Bulman CH, Lorigan BP. Osteoradionecrosis of the temporal bone. J Laryngol Otol 1975;89:941e55. 48. Yoo JS, Rosenthal DI, Mitchell K, et al. Osteoradionecrosis of the hyoid bone: imaging findings. AJNR Am J Neuroradiol 2010;31:761e6. 49. Komisar A, Silver C, Kalnicki S. Osteoradionecrosis of the maxilla and skull base. Laryngoscope 1985;95:24e8. 50. Morrish Jr RB, Chan E, Silverman Jr S, et al. Osteonecrosis in patients irradiated for head and neck carcinoma. Cancer 1981;47:1980e3. 51. Epstein JB, Wong FLW, Stevenson-Moore P. Osteoradionecrosis: clinical experience and a proposal for classification. J Oral Maxillofac Surg 1987;45:104e10. 52. Beumer 3rd J, Harrison R, Sanders B, et al. Osteoradionecrosis: predisposing factors and outcomes of therapy. Head Neck Surg 1984;64:819e27.
9
53. Scully C, Epstein JB. Oral health care for the cancer patient. Eur J Cancer B Oral Oncol 1996;32B:281e92. 54. Rankow RM, Weissman B. Osteoradionecrosis of the mandible. Ann Otolaryngol 1971;80:603e11. 55. Coffin F. The incidence and management of osteoradionecrosis of the jaws following head and neck radiotherapy. Br J Radiol 1983;56:851e7. 56. Delanian S, Depondt J, Lefaix JL. Major healing of refractory mandible osteoradionecrosis after treatment combining pentoxifylline and tocopherol: a phase II trial. Head Neck 2005;27:114e23. 57. Grime PD, Bryson PRe, Maier, et al. Review of severe osteoradionecrosis treated by surgery alone or surgery with postoperative hyperbaric oxygen (Br J Oral Maxillofac Surg 2000;38:167e246). Br J Oral Maxillofac Surg 2001;39:242e3. 58. Thorn JJ, Kallehave F, Westergaard P, et al. The effect of hyperbaric oxygen on irradiated tissues: transmucosal oxygen tension measurements. J Oral Maxillofac Surg 1997;55:1103e7. 59. Chavez JA, Adkinson CD. Adjunctive hyperbaric oxygen in irradiated patients requiring dental extractions: outcomes and complications. J Oral Maxillofac Surg 2001;59:518e22. 60. Zarem HA, Carr R. Salvage of the exposed irradiated mandible. Plast Reconstr Surg 1983;72:648e55. 61. Maier A, Gaggl A, Klemen H, et al. Review of severe osteoradionecrosis treated by surgery alone or surgery with postoperative hyperbaric oxygenation. Br J Oral Maxillofac Surg 2000;38:173e6.
Please cite this article in press as: Deshpande SS, et al., Osteoradionecrosis of the mandible: through a radiologist’s eyes, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.012
