BONE AND GALLIUM S C A N S IN POSTRADIOTHERAPY OSTEONECROSIS OF THE J A W Joel B. Epstein, DMD, MSD, Frances L. Wong, MD, FRCPC, Alan Dickens, DMD, Ivan Szasz, MD, FRCSC, FRCPC, and Michael Lepawsky, BA, MD
The role of radiographic and nuclear imaging in evaluation of postradiotherapy osteonecrosis of the jaw was studied. Patients who had received imaging at diagnosis and following hyperbaric oxygen therapy were studied. Radiographic changes did not correlate with the clinical status Of patients. All bone scans were abnormal at the time of diagnosis of osteonecrosis, but remained abnormal following changes in the clinical status of patients. Thus, the bone scan may aid in the detection of osteonecrosis. Gallium uptake did not aid i diagnosis, but did correlate with clinical findings following treatment. Persisting positive gallium scans may indicate the need for surgery following hyperbaric oxygen therapy. 0 1992 John Wiley & Sons, Inc. HEAD & NECK 1992;14:288-292
Head and neck radiotherapy is well known to induce vascular and cellular damage in bone and soft This results in an impaired reparative and regenerative capacity of the involved tissue^.^ Physical trauma and irritation, surgical manipulation, and infection are secondary factors that stress the healing ~ a p a c i t yTissue .~ ne~
~~
~
~~
From the Departments of Dentistry (Drs. Epstein and Dickens) and Radiation Oncology (Dr. Wong), BC Cancer Agency, Vancouver; and Nuclear Medicine Department (Dr. Szasz) and Hyperbaric Unit (Dr. Lepawsky), Vancouver General Hospital, Vancouver, British Columbia, Canada. Address reprint requests to Dr. Epstein at the Department of Dentistry, BC Cancer Agency, 600 West 10th Avenue, Vancouver, BC, V5Z 4E6, Canada. Accepted for publication December 9, 1991 CCC 0148-6403/92/040288-05 $04.00 0 1992 John Wiiey & Sons,inc.
288
Nuclear Imaging in Osteonecrosis
crosis occurs when ths rate of tissue breakdown exceeds the rate Of The most common site of bone m.3CrOsis after a COUIXe of radiotherapy is the This is due to its frequent position within the high-dose volume and its limited vascular supply. In addition, dental manipulation' and localtissue irritation are common in the Oral envi~O~ment. If postradiotherapy 0steonecrosis (PRON) develops, the condition can result in unremitting pain and dysfunction, fistula formation, and may lead to pathologic fract ~ r eThe . ~ diagnosis of PRON is based primarily upon clinical signs of ulceration of the mucous membrane with exposure of necrotic bone. The lesion may be accompanied by symptoms of pain, dysesthesia, fetor oris, dysgeusia, and food impaction in the area.' Radiographic evidence of PRON is generally delayed until 30% to 60% of calcium salts are lost in an adequate three-dimensional volume to be visualized.2,6 Nuclear medicine imaging will record osteoid changes before radiographic changes are seen and t h e extent and activity of the change can be determined*7 Radionuclide bone scanning using technetium (Tc-99m-labeled diphosphonate) can identify pathophysiologic changes in bone earlier than conventional radiography because scan changes reflect osteoblastic aAivity.2>6i8 Gallium-67citrate (GA-67) will localize in bone, liver, and large bowel. In addition, it will localize in certain pathologic pro-
HEAD & NECK
JulyiAugust 1992
cesses, which includes tumors and inflammatory lesion^.^ While Tc-99m and GA-67 are highly sensitive for increased osteoblastic activity and inflammatory lesions, respectively, they are both relatively nonspecific. Tc-99m and GA-67 have different mechanisms of concentration in involved bone and, therefore, indicate different aspects of the pathophysiology. Bone scintigraphy may provide earlier indications and extent of PRON and may allow quantitative analysis of the degree of abnormality and, thus, provide an accurate method of monitoring the disease for progression or regression. The purposes of this study were (1) to determine if bone or gallium scans would provide diagnostic information in patients with PRON; (2) to determine if bone or gallium scans interpreted alone or together would correlate with the clinical status of patients; and (3) to determine if bone or gallium scans interpreted alone or together would provide evidence of change following hyperbaric oxygen therapy (HBO). PATIENTS AND METHODS
Cases of PRON of the mandible were identified in the medical records of the Vancouver Clinic of the British Columbia Cancer Agency. As part of the workup for these patients, radiographic study and nuclear medicine imaging were obtained. Treatment for these cases of osteonecrosis consisted of HBO, surgery, or a combination of these modalities. After treatment patients were followed with repeat clinical examination, radiography, and nuclear imaging. The clinical status of the patients was classified as described by Epstein et a1.l’ Patients undergoing bone scans were administered intravenously 10 MBq/kg body weight of Tc-99m methylene diphosphonate (Tc-99m MDP). The average dose was 750 MBq or 20 mCi. A three-phase bone scan was obtained in most cases with the delay being imaged by tomography performed with a tomographic gamma camera (SPECT). Cameras used were either Siemens dual-headed ROTA camera or ADAC tomographic camera. In a similar fashion, patients receiving a gallium scan were administered 185 MBq (5 mCi) of GA-67 citrate intravenously and were imaged 48 hours postinfection with a SPECT camera. The nuclear medicine imaging was interpreted by three different nuclear medicine physicians in a blinded manner. Where there was disagreement in the interpretation of bone and gallium scans, the opinion of two of three physi-
Nuclear Imaging in Osteonecrosis
cians was accepted as final. Radiographs were interpreted by two independent radiologists to be normal, sclerotic, or lytic and consistent with PRON. If the two opinions did not agree, additional review was conducted and the majority report accepted as final. The imaging results were analyzed together with the clinical data. Bone scans were considered as “abnormal three phase” if there was increased blood flow and blood pool activity, as well as focally increased concentration of the radiopharmaceutical or delayed SPECT. When the blood flow and blood pool phases of the study were normal, and only the delayed imaging showed increased uptake, the results were termed “abnormal delayed scan.” The former category signifies active inflammatory process, whereas the latter is not specific and only related to active osteoblastic activity. Gallium scans were also performed in a tomographic manner similar to bone scans. They were termed “abnormal” if the activity was focally increased. Twelve patients met the study criteria of having the diagnosis of PRON and availability of imaging records. All patients had been treated by radiotherapy as a primary treatment modality for oral squamous cell carcinoma. The median age was 64 years (range 39-83 years), there were equal numbers of men and women. Patient demographics and stage of the tumor are reported in Table 1. The radiotherapy treatment planning films were reviewed for those who received external-beam therapy. The dose of radiotherapy, taking into account the fractionation and time, was calculated and expressed as a single value (TDF), according to Orton and Ellis” (Table 1).In the case of interstitial brachyther~~~~~~
~
~
Table 1. Patient demographic and radiotherapy dose No.
Age
Stage
TDP
1 2 3 4 5 6 7 8 9 10 11 12
83 49 77 39 47 60 65 70 53 76 70 64
T2N1 T2NO T i NO T2NO T1 N1 T i NO T4N1 T2N3 T2N1 T2NO T2NO T3NO
109* 117* 109* t6,490 cGy 109* t7,450 CGY t.5500 cGy 1O Y 108* t3,OOO cGy 125* 1OY
*Dose of radotherapy, takrng Info account fracbonabon and time tDenotes approximate implant dose
HEAD & NECK
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289
apy, a TDF would not be calculated, thus total implantation dose was recorded. RESULTS
The time of recognition of PRON from the radiotherapy ranged from 3 to 114 months. The mean was 35 months. All cases of necrosis occurred in the mandible. No identifiable precipitating factors were noted in four cases. Dental extractions and other surgical procedures were identified as the stimulus in five cases. Denture trauma was identified as the probably etiologic factor in two cases. In one case, severe caries was identified as the putative irritant. Ten patients received HBO as part of the treatment. HBO was delivered in a multiplace chamber, at 2.5 atm and 100% oxygen for 90 minutes per dive. One patient received 15 dives, another 25 dives, and the remaining eight patients 30 or more dives. Following HBO, six patients received surgical intervention. This consisted of mandibular resection in three cases and sequestrectomy in three. The remaining cases did not have surgery. The pre- and posttreatment clinical status and the management course are summarized in Table 2. All patients were symptomatic prior to therapy for PRON, at follow-up six patients had complete resolution of symptoms and intact mandibular arch, four were stable without progressive symptoms, and two had persisting symptoms. A total of 20 bone scans and 16 gallium scans were completed (Table 3). Prior to therapy, all bone scans done were positive. Two of nine panoramic radiographs were referred to as
within normal limits, four of nine were suggestive of necrosis, and three of nine were consistent with necrosis. Fifty percent of the pre-HBO gallium scans were reported as normal. Following treatment, all bone scans, but one, remained positive. One patient’s radiograph reverted to normal after treatment, correlating with his clinical course; however, all of the other patients’ radiographs were reported as abnormal. Seven patients received a gallium scan after HBO. Two scans were abnormal corresponding to the clinical stages of I1 and 111. The remaining five scans were normal corresponding to the clinical staging of the patients. DISCUSSION
The age range of the patient population is in keeping with those at risk for oral squamous carcinoma. Tumor staging showed that only two patients had T3 or T4 primary tumor. The risk of necrosis in more advanced stages of tumor has been previously described.1,2~10In the majority of studies, the principle factor related to subsequent risk of PRON was the dose of interstitial implant and the dose and fractionation of external-beam radiotherapy where the mandible was within the treatment v ~ l u m e . ~ ’ A ~ ’dose ~ ” ~of greater than TDF 109 correlating with an increased risk of necrosis has been described.” In this group of patients, the calculated TDF factor was 109 or greater in all but one of the cases. The time from radiotherapy to the diagnosis of PRON was from 3 to 114 months. The wide range and persisting risk of necrosis is known
Table 2. Management of PRON and pre- and posttreatment clinical status. No. 1 2 3 4 5 6 7
a 9 10 11 12
Interval from radiotherapy to PRON (mo)
Initial clinical stage‘
No. of HBOt
Surgery
Present clinical stage*
72 5 42 19
Ill lllb 111 Ila 111 111 II I1 II Ill I1 I1
Nil 33 25 15 44 42 Nil 30 30 40 30 40
SEQU$ SEQU Nil SEQU SEQU/MAND§ Nil Nil Nil Nil MAND MAND Nil
Ill I Ill I I I II I II II I I1
a 37 4 3 114 26 28 61
*As per Epstein et a/. fHyperbaric oxygen treatments #Sequesfrecfomy §Mandibular resection
290
Nuclear Imaging in Osteonecrosis
HEAD & NECK
July/August 1992
Table 3. Imaging results of patients before and after treatment. Bone scan*
Gallium scant
Radiographs+
No.
Pretreatment
Posttreatment
Pretreatment
Posttreatment
Pretreatment
Posttreatment
1 2 3 4 5 6 7
2 2 2 2 2 3 3 2 3 3 -
-
1 2 1 2 1 2 2 1 -
1 2 1 -
3
-
2 2
3 3
3
-
2 2 1 3
3 3 2 -
a
9 10
17 12
3
3 1 3 3 3 3 3 3
-
1 1 2 1 -
-
1
1
1 = Normal; 2 = abnormal thress-phase scan; 3 = abnormal delayed scan t l = Normal; 2 = abnormal. $1 = Normal; 2 = suggestive of PRON; 3 = consistent with PRON.
following r a d i ~ t h e r a p y . l > The ~ ~ ~ probable ~~,~~ stimulating factor leading to subsequent necrosis was identified in eight of our 12 patients. These potential stimuli have been recognized and are similar to those reported in previous s t ~ d i e s . ~ , ' ~ The initial clinical presentation in six cases was active and progressive (stage 111) and in the other six cases chronic persisting necrosis (stage
11). Conservative therapy was recommended in all cases. This included attention to dietary status, smoking and alcohol consumption, use of tetracycline or chlorhexidine rinse, frequent oral rinsing with saline, and analgesics when required. Ten of these cases were also managed with HBO, which has been recognized to be useful in promotion of healing.12314-16Following therapy, complete resolution or symptomatic improvement was noted in seven patients. One patient continued to have progressive symptoms. These results are not as dramatic as those reported by Marx.14 However, it demonstrated the value of HBO and conservative surgery in the complete resolution of some cases of PRON. Imaging for these 12 patients included radiographic and nuclear imaging using bone and gallium scans. Initial imaging was conducted at the time of recognition of necrosis. Patients in whom posttherapy nuclear medicine imaging had not been previously completed were recalled and upto-date imaging was Completed and clinical status was assessed. Quantitative assessment of uptake on nuclear imaging is possible3>'; however, this was not completed in these cases, but may
Nuclear Imaging in Osteonecrosis
be useful in future studies. Computerized assessment of nuclear imaging provides more detailed detection of small changes in uptake; however, visual determinations, particularly as conducted in this study, would be expected to identify greater changes which may be of greater clinical ~ignificance.~ The use of bone scintigraphy to image previously radiated sites may provide earlier indications of postradiotherapy changes than radiography.3,17-20 Inflammatory bone diseases can be demonstrated by scintigraphy weeks prior t o evidence of radiographic ~ h a n g e . ~ lFollowing -~~ radiotherapy, bone scan uptake may increase.3,17,18925 Excessive increased uptake in PRON of the mandible and also in acute osteomyelitis has been d e m ~ n s t r a t e d Bone .~ resorption and deposition appear to correlate with the intensity of the uptake on bone scan. Hattner and co-workers26 reviewed patients postradiotherapy with bone scintigraphy and identified osteopenic changes on the scan. It appears that irradiation can induce increased or decreased uptake on the bone scan. However, excessive degree of uptake may indicate development of clinical necrosis. Our study showed all bone scans were abnormal with excessive uptake at diagnosis of PRON. However, the three-phase and the delayed bone scanning technique failed t o correlate with the degree of initial clinical symptoms. Of the nine cases in whom radiographs were available for review, two were reported as normal, four suggestive of PRON, and three consistent with the clinical diagnosis of necrosis. This
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291
suggests that nuclear imaging is more sensitive than radiographic findings for the diagnosis of PRON. Similarly, the radiographic findings did not correlate with the clinical status of patients. The variable findings on gallium scan are consistent with the fact that PRON is not necessarily associated with inflammation within bone. Thus, the mechanisms necessary for gallium uptake may not be present and, thus, may not be diagnostic in necrosis. After therapy, the radiographs failed to correlate with the clinical status. All except one follow-up bone scan remained abnormal. Again, this did not ccorrelate with the clinical status. It is possible that the osteoblastic activity continued irrespective of the clinical symptoms. All of the patients who underwent follow-up gallium scans received HBO as part of the treatment. All of the patients who had complete resolution of PRON (stage I) had normal gallium scans. One patient, who had persistent osteonecrosis as evident on x-ray only, also had a normal gallium scan. In contrast, two patients who remained symptomatic developed abnormal uptake. The findings suggest that gallium may not correlate with symptoms prior to HBO,but may be a good marker after HBO. A persistent abnormal gallium scan may indicate the need for further therapy and surgical intervention. In conclusion, bone scans are more sensitive than radiographs in the diagnosis of PRON. Following HBO, the gallium scan correlates with the clinical development of the patients. For future studies, computer analysis of the scans may provide additional quantitative data.
REFERENCES
1. Beumer J 111, Curtis T, Morrison RE. Radiation therapy of the oral cavity; sequelae and management, part 1 and part 2. Head Neck Surg 1979;1:301-302,392-408. 2. Murray CG, Daly TE, Zimmerman SO. The relationship between dental disease and radiation necrosis of the mandible. Oral Surg 1980;49:99-104. 3. Aitasalo K, Ruotsalainen P. Effects of irradiation on mandibular scintigraphy. J Nucl Med 1985;26:12631269. 4. Marx RE. Osteoradionecrosis: a new concept of its pathophysiology. J Oral Maxillofac Surg 1983;41:283-288. 5. Epstein JB, Wong F, Stevenson-Moore P. Osteonecrosis:
292
Nuclear Imaging in Osteonecrosis
study of the relationship of dental extractions in patients receiving radiotherapy. Head Neck Surg 1987;10:48-54. 6. Alexander JM. Radionuclide bone scanning in the diagnosis of lesions of the maxillofacial region. J Oral Surg 1976;34:249-256. 7. Epstein JB, Hatcher DC, Graham M. Bone scintigraphy of fibro-osseous lesions of the jaw. Oral Surg Oral Med Oral Pathol 1981;51:346-350. 8. Ahuja RB, et al: Comparative study of technetium-99m bone scans and orthopantomography in determining mandible invasion in intraoral squamous cell carcinoma. Head Neck 1990;6:237-242. 9. Weiner R. The role of transferrin and other receptors in the mechanism of GA-67 localization. Nucl Med Biol 1990;17:141- 149. 10. Eastein JB. Woncr F. Stevenson-Moore P. Osteoradionecrbsis: clinical experience and a proposal for classification. J Oral Maxillofac Surg 1987;45:104-110. 11. Orton CG, Ellis F. A simplification in the use of the NSD concept in practical radiotherapy. Br J Radiol 1973;46:529-537. 12. Mainous EG, Hart GB. Osteoradionecrosis of the mandiArch Otolaryngol ble: treatment with hyperbaric oxygen. .-_ 1975;101:173- 177. 13. Marx RE. Johnson RP. Kline SN. Prevention of osteoradionecrosis: a randomized prospective clinical trial of hyperbaric oxygen versus penicillin. J A m Dent Assoc 1985;111:49-54. 14. Marx RE. A new concept in the treatment of osteoradionecrosis. J Oral Maxillofac Surg 1983;41:351-357. 15. Hart GB, Mainous EG. The treatment of radiation necrosis with hyperbaric oxygen. Cancer 1976;37:2580-2585. 16. Hunt TK, Federfeldt B, Goldstick TK. Oxygen and healing. Am J Surg 1969;118:521-525. 17. Bell EG, McAfee JG, Constable WC. Local radiation damage to bone marrow demonstrated by radioisotopic imaging. Radiology 1969;92:1083- 1088. 18. Cox PH. Abnormalities in skeletal uptake of 99MTCpolyphosphate complexes in areas of bone associated with times which have been subjected to radiation therapy. Br J Radiol 1974;47:851-856. 19. Fordham EW, Ramachandan PC. Radionuclide imaging of osseous trauma. Semin Nucl Med 1974;4:411- 429. 20. Marty R, Denny JD, McKamey MR, et al. Bone trauma and related benign disease: assessment by bone scanning. Semin Nucl Med 1976;6:107- 120. 21. Handmarker H, Leonards R. The bone scan in inflammatory osseous disease. Semin Nucl Med 1976;6:95- 105. 22. Feine U, zum Winkel K. Nuklearmedizin-szintigraphische diagnostik. Stuttgark George Thieme Verlag, 1980~435-481. 23. Noyek AM, Kirsch JC, Wortszman G, et al. The clinical significance of radionuclide bone and gallium scanning in osteomyelitis of the head and neck. Laryngoscope 1984;94(~~ppl 34):1-21. 24. Thrall JH, Jeslien GE, Corcoron RJ, et al. Abnormal radionuclide position patterns adjacent to focal skeletal lesions. Radiology 1975;115:659-664. 25. King MA, Casarett GW, Weber D. A study of irradiated bone: 1. histopathologic and physiologic - _ - changes. - J Nucl Med 1979;20:i142-1i49. 26. Hattner RS. Hartmever J. Wara WM. Characterization of radiation-induced ” photopenic abnormalities of bone scans. Radiology 1982;145:161- 163.
HEAD 8, NECK
July/August 1992
The role of radiographic and nuclear imaging in evaluation of postradiotherapy osteonecrosis of the jaw was studied. Patients who had received imaging at diagnosis and following hyperbaric oxygen therapy were studied. Radiographic changes did not correlate with the clinical status Of patients. All bone scans were abnormal at the time of diagnosis of osteonecrosis, but remained abnormal following changes in the clinical status of patients. Thus, the bone scan may aid in the detection of osteonecrosis. Gallium uptake did not aid i diagnosis, but did correlate with clinical findings following treatment. Persisting positive gallium scans may indicate the need for surgery following hyperbaric oxygen therapy. 0 1992 John Wiley & Sons, Inc. HEAD & NECK 1992;14:288-292
Head and neck radiotherapy is well known to induce vascular and cellular damage in bone and soft This results in an impaired reparative and regenerative capacity of the involved tissue^.^ Physical trauma and irritation, surgical manipulation, and infection are secondary factors that stress the healing ~ a p a c i t yTissue .~ ne~
~~
~
~~
From the Departments of Dentistry (Drs. Epstein and Dickens) and Radiation Oncology (Dr. Wong), BC Cancer Agency, Vancouver; and Nuclear Medicine Department (Dr. Szasz) and Hyperbaric Unit (Dr. Lepawsky), Vancouver General Hospital, Vancouver, British Columbia, Canada. Address reprint requests to Dr. Epstein at the Department of Dentistry, BC Cancer Agency, 600 West 10th Avenue, Vancouver, BC, V5Z 4E6, Canada. Accepted for publication December 9, 1991 CCC 0148-6403/92/040288-05 $04.00 0 1992 John Wiiey & Sons,inc.
288
Nuclear Imaging in Osteonecrosis
crosis occurs when ths rate of tissue breakdown exceeds the rate Of The most common site of bone m.3CrOsis after a COUIXe of radiotherapy is the This is due to its frequent position within the high-dose volume and its limited vascular supply. In addition, dental manipulation' and localtissue irritation are common in the Oral envi~O~ment. If postradiotherapy 0steonecrosis (PRON) develops, the condition can result in unremitting pain and dysfunction, fistula formation, and may lead to pathologic fract ~ r eThe . ~ diagnosis of PRON is based primarily upon clinical signs of ulceration of the mucous membrane with exposure of necrotic bone. The lesion may be accompanied by symptoms of pain, dysesthesia, fetor oris, dysgeusia, and food impaction in the area.' Radiographic evidence of PRON is generally delayed until 30% to 60% of calcium salts are lost in an adequate three-dimensional volume to be visualized.2,6 Nuclear medicine imaging will record osteoid changes before radiographic changes are seen and t h e extent and activity of the change can be determined*7 Radionuclide bone scanning using technetium (Tc-99m-labeled diphosphonate) can identify pathophysiologic changes in bone earlier than conventional radiography because scan changes reflect osteoblastic aAivity.2>6i8 Gallium-67citrate (GA-67) will localize in bone, liver, and large bowel. In addition, it will localize in certain pathologic pro-
HEAD & NECK
JulyiAugust 1992
cesses, which includes tumors and inflammatory lesion^.^ While Tc-99m and GA-67 are highly sensitive for increased osteoblastic activity and inflammatory lesions, respectively, they are both relatively nonspecific. Tc-99m and GA-67 have different mechanisms of concentration in involved bone and, therefore, indicate different aspects of the pathophysiology. Bone scintigraphy may provide earlier indications and extent of PRON and may allow quantitative analysis of the degree of abnormality and, thus, provide an accurate method of monitoring the disease for progression or regression. The purposes of this study were (1) to determine if bone or gallium scans would provide diagnostic information in patients with PRON; (2) to determine if bone or gallium scans interpreted alone or together would correlate with the clinical status of patients; and (3) to determine if bone or gallium scans interpreted alone or together would provide evidence of change following hyperbaric oxygen therapy (HBO). PATIENTS AND METHODS
Cases of PRON of the mandible were identified in the medical records of the Vancouver Clinic of the British Columbia Cancer Agency. As part of the workup for these patients, radiographic study and nuclear medicine imaging were obtained. Treatment for these cases of osteonecrosis consisted of HBO, surgery, or a combination of these modalities. After treatment patients were followed with repeat clinical examination, radiography, and nuclear imaging. The clinical status of the patients was classified as described by Epstein et a1.l’ Patients undergoing bone scans were administered intravenously 10 MBq/kg body weight of Tc-99m methylene diphosphonate (Tc-99m MDP). The average dose was 750 MBq or 20 mCi. A three-phase bone scan was obtained in most cases with the delay being imaged by tomography performed with a tomographic gamma camera (SPECT). Cameras used were either Siemens dual-headed ROTA camera or ADAC tomographic camera. In a similar fashion, patients receiving a gallium scan were administered 185 MBq (5 mCi) of GA-67 citrate intravenously and were imaged 48 hours postinfection with a SPECT camera. The nuclear medicine imaging was interpreted by three different nuclear medicine physicians in a blinded manner. Where there was disagreement in the interpretation of bone and gallium scans, the opinion of two of three physi-
Nuclear Imaging in Osteonecrosis
cians was accepted as final. Radiographs were interpreted by two independent radiologists to be normal, sclerotic, or lytic and consistent with PRON. If the two opinions did not agree, additional review was conducted and the majority report accepted as final. The imaging results were analyzed together with the clinical data. Bone scans were considered as “abnormal three phase” if there was increased blood flow and blood pool activity, as well as focally increased concentration of the radiopharmaceutical or delayed SPECT. When the blood flow and blood pool phases of the study were normal, and only the delayed imaging showed increased uptake, the results were termed “abnormal delayed scan.” The former category signifies active inflammatory process, whereas the latter is not specific and only related to active osteoblastic activity. Gallium scans were also performed in a tomographic manner similar to bone scans. They were termed “abnormal” if the activity was focally increased. Twelve patients met the study criteria of having the diagnosis of PRON and availability of imaging records. All patients had been treated by radiotherapy as a primary treatment modality for oral squamous cell carcinoma. The median age was 64 years (range 39-83 years), there were equal numbers of men and women. Patient demographics and stage of the tumor are reported in Table 1. The radiotherapy treatment planning films were reviewed for those who received external-beam therapy. The dose of radiotherapy, taking into account the fractionation and time, was calculated and expressed as a single value (TDF), according to Orton and Ellis” (Table 1).In the case of interstitial brachyther~~~~~~
~
~
Table 1. Patient demographic and radiotherapy dose No.
Age
Stage
TDP
1 2 3 4 5 6 7 8 9 10 11 12
83 49 77 39 47 60 65 70 53 76 70 64
T2N1 T2NO T i NO T2NO T1 N1 T i NO T4N1 T2N3 T2N1 T2NO T2NO T3NO
109* 117* 109* t6,490 cGy 109* t7,450 CGY t.5500 cGy 1O Y 108* t3,OOO cGy 125* 1OY
*Dose of radotherapy, takrng Info account fracbonabon and time tDenotes approximate implant dose
HEAD & NECK
July/August 1992
289
apy, a TDF would not be calculated, thus total implantation dose was recorded. RESULTS
The time of recognition of PRON from the radiotherapy ranged from 3 to 114 months. The mean was 35 months. All cases of necrosis occurred in the mandible. No identifiable precipitating factors were noted in four cases. Dental extractions and other surgical procedures were identified as the stimulus in five cases. Denture trauma was identified as the probably etiologic factor in two cases. In one case, severe caries was identified as the putative irritant. Ten patients received HBO as part of the treatment. HBO was delivered in a multiplace chamber, at 2.5 atm and 100% oxygen for 90 minutes per dive. One patient received 15 dives, another 25 dives, and the remaining eight patients 30 or more dives. Following HBO, six patients received surgical intervention. This consisted of mandibular resection in three cases and sequestrectomy in three. The remaining cases did not have surgery. The pre- and posttreatment clinical status and the management course are summarized in Table 2. All patients were symptomatic prior to therapy for PRON, at follow-up six patients had complete resolution of symptoms and intact mandibular arch, four were stable without progressive symptoms, and two had persisting symptoms. A total of 20 bone scans and 16 gallium scans were completed (Table 3). Prior to therapy, all bone scans done were positive. Two of nine panoramic radiographs were referred to as
within normal limits, four of nine were suggestive of necrosis, and three of nine were consistent with necrosis. Fifty percent of the pre-HBO gallium scans were reported as normal. Following treatment, all bone scans, but one, remained positive. One patient’s radiograph reverted to normal after treatment, correlating with his clinical course; however, all of the other patients’ radiographs were reported as abnormal. Seven patients received a gallium scan after HBO. Two scans were abnormal corresponding to the clinical stages of I1 and 111. The remaining five scans were normal corresponding to the clinical staging of the patients. DISCUSSION
The age range of the patient population is in keeping with those at risk for oral squamous carcinoma. Tumor staging showed that only two patients had T3 or T4 primary tumor. The risk of necrosis in more advanced stages of tumor has been previously described.1,2~10In the majority of studies, the principle factor related to subsequent risk of PRON was the dose of interstitial implant and the dose and fractionation of external-beam radiotherapy where the mandible was within the treatment v ~ l u m e . ~ ’ A ~ ’dose ~ ” ~of greater than TDF 109 correlating with an increased risk of necrosis has been described.” In this group of patients, the calculated TDF factor was 109 or greater in all but one of the cases. The time from radiotherapy to the diagnosis of PRON was from 3 to 114 months. The wide range and persisting risk of necrosis is known
Table 2. Management of PRON and pre- and posttreatment clinical status. No. 1 2 3 4 5 6 7
a 9 10 11 12
Interval from radiotherapy to PRON (mo)
Initial clinical stage‘
No. of HBOt
Surgery
Present clinical stage*
72 5 42 19
Ill lllb 111 Ila 111 111 II I1 II Ill I1 I1
Nil 33 25 15 44 42 Nil 30 30 40 30 40
SEQU$ SEQU Nil SEQU SEQU/MAND§ Nil Nil Nil Nil MAND MAND Nil
Ill I Ill I I I II I II II I I1
a 37 4 3 114 26 28 61
*As per Epstein et a/. fHyperbaric oxygen treatments #Sequesfrecfomy §Mandibular resection
290
Nuclear Imaging in Osteonecrosis
HEAD & NECK
July/August 1992
Table 3. Imaging results of patients before and after treatment. Bone scan*
Gallium scant
Radiographs+
No.
Pretreatment
Posttreatment
Pretreatment
Posttreatment
Pretreatment
Posttreatment
1 2 3 4 5 6 7
2 2 2 2 2 3 3 2 3 3 -
-
1 2 1 2 1 2 2 1 -
1 2 1 -
3
-
2 2
3 3
3
-
2 2 1 3
3 3 2 -
a
9 10
17 12
3
3 1 3 3 3 3 3 3
-
1 1 2 1 -
-
1
1
1 = Normal; 2 = abnormal thress-phase scan; 3 = abnormal delayed scan t l = Normal; 2 = abnormal. $1 = Normal; 2 = suggestive of PRON; 3 = consistent with PRON.
following r a d i ~ t h e r a p y . l > The ~ ~ ~ probable ~~,~~ stimulating factor leading to subsequent necrosis was identified in eight of our 12 patients. These potential stimuli have been recognized and are similar to those reported in previous s t ~ d i e s . ~ , ' ~ The initial clinical presentation in six cases was active and progressive (stage 111) and in the other six cases chronic persisting necrosis (stage
11). Conservative therapy was recommended in all cases. This included attention to dietary status, smoking and alcohol consumption, use of tetracycline or chlorhexidine rinse, frequent oral rinsing with saline, and analgesics when required. Ten of these cases were also managed with HBO, which has been recognized to be useful in promotion of healing.12314-16Following therapy, complete resolution or symptomatic improvement was noted in seven patients. One patient continued to have progressive symptoms. These results are not as dramatic as those reported by Marx.14 However, it demonstrated the value of HBO and conservative surgery in the complete resolution of some cases of PRON. Imaging for these 12 patients included radiographic and nuclear imaging using bone and gallium scans. Initial imaging was conducted at the time of recognition of necrosis. Patients in whom posttherapy nuclear medicine imaging had not been previously completed were recalled and upto-date imaging was Completed and clinical status was assessed. Quantitative assessment of uptake on nuclear imaging is possible3>'; however, this was not completed in these cases, but may
Nuclear Imaging in Osteonecrosis
be useful in future studies. Computerized assessment of nuclear imaging provides more detailed detection of small changes in uptake; however, visual determinations, particularly as conducted in this study, would be expected to identify greater changes which may be of greater clinical ~ignificance.~ The use of bone scintigraphy to image previously radiated sites may provide earlier indications of postradiotherapy changes than radiography.3,17-20 Inflammatory bone diseases can be demonstrated by scintigraphy weeks prior t o evidence of radiographic ~ h a n g e . ~ lFollowing -~~ radiotherapy, bone scan uptake may increase.3,17,18925 Excessive increased uptake in PRON of the mandible and also in acute osteomyelitis has been d e m ~ n s t r a t e d Bone .~ resorption and deposition appear to correlate with the intensity of the uptake on bone scan. Hattner and co-workers26 reviewed patients postradiotherapy with bone scintigraphy and identified osteopenic changes on the scan. It appears that irradiation can induce increased or decreased uptake on the bone scan. However, excessive degree of uptake may indicate development of clinical necrosis. Our study showed all bone scans were abnormal with excessive uptake at diagnosis of PRON. However, the three-phase and the delayed bone scanning technique failed t o correlate with the degree of initial clinical symptoms. Of the nine cases in whom radiographs were available for review, two were reported as normal, four suggestive of PRON, and three consistent with the clinical diagnosis of necrosis. This
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suggests that nuclear imaging is more sensitive than radiographic findings for the diagnosis of PRON. Similarly, the radiographic findings did not correlate with the clinical status of patients. The variable findings on gallium scan are consistent with the fact that PRON is not necessarily associated with inflammation within bone. Thus, the mechanisms necessary for gallium uptake may not be present and, thus, may not be diagnostic in necrosis. After therapy, the radiographs failed to correlate with the clinical status. All except one follow-up bone scan remained abnormal. Again, this did not ccorrelate with the clinical status. It is possible that the osteoblastic activity continued irrespective of the clinical symptoms. All of the patients who underwent follow-up gallium scans received HBO as part of the treatment. All of the patients who had complete resolution of PRON (stage I) had normal gallium scans. One patient, who had persistent osteonecrosis as evident on x-ray only, also had a normal gallium scan. In contrast, two patients who remained symptomatic developed abnormal uptake. The findings suggest that gallium may not correlate with symptoms prior to HBO,but may be a good marker after HBO. A persistent abnormal gallium scan may indicate the need for further therapy and surgical intervention. In conclusion, bone scans are more sensitive than radiographs in the diagnosis of PRON. Following HBO, the gallium scan correlates with the clinical development of the patients. For future studies, computer analysis of the scans may provide additional quantitative data.
REFERENCES
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study of the relationship of dental extractions in patients receiving radiotherapy. Head Neck Surg 1987;10:48-54. 6. Alexander JM. Radionuclide bone scanning in the diagnosis of lesions of the maxillofacial region. J Oral Surg 1976;34:249-256. 7. Epstein JB, Hatcher DC, Graham M. Bone scintigraphy of fibro-osseous lesions of the jaw. Oral Surg Oral Med Oral Pathol 1981;51:346-350. 8. Ahuja RB, et al: Comparative study of technetium-99m bone scans and orthopantomography in determining mandible invasion in intraoral squamous cell carcinoma. Head Neck 1990;6:237-242. 9. Weiner R. The role of transferrin and other receptors in the mechanism of GA-67 localization. Nucl Med Biol 1990;17:141- 149. 10. Eastein JB. Woncr F. Stevenson-Moore P. Osteoradionecrbsis: clinical experience and a proposal for classification. J Oral Maxillofac Surg 1987;45:104-110. 11. Orton CG, Ellis F. A simplification in the use of the NSD concept in practical radiotherapy. Br J Radiol 1973;46:529-537. 12. Mainous EG, Hart GB. Osteoradionecrosis of the mandiArch Otolaryngol ble: treatment with hyperbaric oxygen. .-_ 1975;101:173- 177. 13. Marx RE. Johnson RP. Kline SN. Prevention of osteoradionecrosis: a randomized prospective clinical trial of hyperbaric oxygen versus penicillin. J A m Dent Assoc 1985;111:49-54. 14. Marx RE. A new concept in the treatment of osteoradionecrosis. J Oral Maxillofac Surg 1983;41:351-357. 15. Hart GB, Mainous EG. The treatment of radiation necrosis with hyperbaric oxygen. Cancer 1976;37:2580-2585. 16. Hunt TK, Federfeldt B, Goldstick TK. Oxygen and healing. Am J Surg 1969;118:521-525. 17. Bell EG, McAfee JG, Constable WC. Local radiation damage to bone marrow demonstrated by radioisotopic imaging. Radiology 1969;92:1083- 1088. 18. Cox PH. Abnormalities in skeletal uptake of 99MTCpolyphosphate complexes in areas of bone associated with times which have been subjected to radiation therapy. Br J Radiol 1974;47:851-856. 19. Fordham EW, Ramachandan PC. Radionuclide imaging of osseous trauma. Semin Nucl Med 1974;4:411- 429. 20. Marty R, Denny JD, McKamey MR, et al. Bone trauma and related benign disease: assessment by bone scanning. Semin Nucl Med 1976;6:107- 120. 21. Handmarker H, Leonards R. The bone scan in inflammatory osseous disease. Semin Nucl Med 1976;6:95- 105. 22. Feine U, zum Winkel K. Nuklearmedizin-szintigraphische diagnostik. Stuttgark George Thieme Verlag, 1980~435-481. 23. Noyek AM, Kirsch JC, Wortszman G, et al. The clinical significance of radionuclide bone and gallium scanning in osteomyelitis of the head and neck. Laryngoscope 1984;94(~~ppl 34):1-21. 24. Thrall JH, Jeslien GE, Corcoron RJ, et al. Abnormal radionuclide position patterns adjacent to focal skeletal lesions. Radiology 1975;115:659-664. 25. King MA, Casarett GW, Weber D. A study of irradiated bone: 1. histopathologic and physiologic - _ - changes. - J Nucl Med 1979;20:i142-1i49. 26. Hattner RS. Hartmever J. Wara WM. Characterization of radiation-induced ” photopenic abnormalities of bone scans. Radiology 1982;145:161- 163.
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