Keratocystic odontogenic tumor: a recurrence analysis of clinical and radiographic parameters

Vol. 114 No. 1 July 2012

Keratocystic odontogenic tumor: a recurrence analysis of clinical and radiographic parameters Fadi Titinchi, BChD, and Christoffel J. Nortje, BChD, PhD, DSc, DipABOMR Objective. The aim of this study was to analyze the clinical and radiologic features of keratocystic odontogenic tumors (KCOT) and their recurrence patterns. Study Design. The authors undertook a retrospective analysis of 145 histopathologically proven KCOT. Recurrence was analyzed for age, sex, site, size, radiographic appearance, treatment, and association with nevoid basal cell carcinoma syndrome (NBCCS). Results. The mean age at presentation was 34.5 years, with a male predilection. Most KCOT (75.2%) were located in the mandible, with the posterior regions being most commonly affected. Radiographically, the majority of KCOT were unilocular (71.0%) in appearance, and 16.5% had scalloped margins. There was no significant association of recurrence rate with sex, site, size, radiographic appearance, and treatment. However, KCOT had significantly higher recurrence associated with age (P ⬍ .01) and NBCCS (P ⫽ .001). Conclusions. Most clinical and radiologic features of KCOT were similar to earlier reports. Recurrence was significantly associated with second and eighth decades of life and NBCCS. (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114: 136-142)

Keratocystic odontogenic tumors (KCOT), previously known as odontogenic keratocysts (OKC), are developmental cysts of epithelial origin first described by Philipsen in 1956.1 Since then, the lesion has been of particular interest due to its high recurrence rate and aggressive nature.2 Recently, OKC has been reclassified by the World Health Organization (WHO) as KCOT owing to its behavior as a locally destructive and highly recurrent lesion.3 Further reasons for its reclassification into a benign tumor include budding of the basal cell layer of KCOT into connective tissue and mutation of the PTCH gene.4 The reclassification of this lesion as a tumor serves to highlight its aggressive nature and to emphasize the need to manage it in a correspondingly aggressive manner.4 The frequency of occurrence of KCOT ranges from 3% to 11% of odontogenic cysts.5,6 It has a slight male predilection and occurs mainly in the second and third decades of life.2 Although any area of the jaws may be affected, the majority of lesions occur in the mandibular posterior regions.5 KCOT are usually solitary lesions except when they are associated with nevoid basal cell carcinoma syndrome (NBCCS), where multiple tumors are a common feature.7 Diagnosis of NBCCS relies mainly on the presence of ⱖ2 major (including KCOT, basal cell Department of Diagnostics and Radiology, Faculty of Dentistry, University of the Western Cape, Cape Town, South Africa. Received for publication Nov 17, 2011; returned for revision Jan 5, 2012; accepted for publication Jan 18, 2012. © 2012 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2012.01.032

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carcinomas, ectopic calcifications) or 1 major and 2 minor (including skeletal anomalies, frontal bossing, medulloblastoma) criteria as outlined by Evans et al.8 Owing to their high recurrence rate and aggressive nature, KCOT are of particular interest to dental specialists involved in their management. Because there are few extensive reports on the presentation and recurrence of KCOT, it was the aim of the present study: 1) to retrospectively analyze the clinical and radiographic features of KCOT; and 2) to analyze the recurrence rate of clinical and radiographic parameters over a 40-year period.

MATERIALS AND METHODS The material consisted of clinical records and radiographs of 106 patients with 145 KCOT from 1971 to 2011. In each of the cases, the clinical records and panoramic radiographs were analyzed for demographic, clinical, and radiologic features. Treatment method used as well as recurrence rates were recorded. Recurrence of KCOT was independently compared with age, sex, site, size, radiographic appearance, treatment, and association with NBCCS. All data collected were

Statement of Clinical Relevance Most manifestations of keratocystic odontogenic tumors were similar to earlier reports. Recurrence was significantly associated with the second and eighth decades of life and nevoid basal cell carcinoma syndrome and not with sex, site, size, radiographic appearance, and treatment.

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strictly confidential and available only to the researchers involved. All diagnoses of KCOT were histopathologically confirmed before enrollment in this study according to the diagnostic criteria proposed by Pindborg and Hansen.9 Each panoramic radiograph was viewed under the same conditions in a darkened room by 2 independent and calibrated observers with training in oral and maxillofacial radiology. Details of the age, sex, and ethnic origin of the affected patients were recorded. Clinical data that were recorded included the presenting signs and symptoms, clinical history, and presence of NBCCS according to the criteria of Evans et al.8 The radiographic features recorded were site (maxilla/mandible), locularity, scalloping of the margins, whether root resorption of permanent dentition was present, and association with impacted tooth/ teeth. The lesions were also measured in millimeters on panoramic radiographs along the longest axis of the tumor to determine the maximal extent of tumor growth. To determine the location of a lesion, the mandible was divided into 2 halves and each half further divided into 3 anatomic regions: 1) the “anterior” region, extending from the midline to the distal surface of the canine; 2) the “posterior” region, extending from the mesial aspect of the first premolar to the angle of the mandible; and 3) the “ramus” region, extending from the angle of the mandible to the sigmoid notch. The maxilla was divided into 2 halves with 2 anatomic regions on each side: 1) the “anterior” region, extending from the midline to the distal surface of the canine; and 2) the “posterior” region, extending from the mesial aspect of the first premolar to the distal surface of the maxillary tuberosity. Extensive lesions were classified in all of the regions they were located in. Regarding locularity, the lesions were classified as either unilocular or multilocular: unilocular when lesions had a single radiolucent cavity, multilocular when septa divided the lesion into ⱖ2 separate compartments. Treatment modalities employed were classified as: 1) marsupialization; 2) enucleation; 3) enucleation and application of Carnoy solution; and 4) resection. The follow-up period for each patient was recorded and recurrence rates calculated. Data were analyzed using the SPSS package (v. 14.0; SPSS, Chicago, Illinois) to calculate means, percentages, and correlations. Comparison between different variables (such as age, site, NBCCS) was determined with the use of the ␹2 or t test. Statistical significance was considered at a P level of ⱕ.05.

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Table I. Age and sex distribution of patients with keratocystic odontogenic tumors, n (%) Age (y)

Male

Female

Total

0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 Not recorded Total

1 (0.9) 11 (10.4) 16 (15.1) 7 (6.6) 10 (9.4) 7 (6.6) 3 (2.8) 0 (0.0) 1 (0.9) 11 (10.4) 67 (62.2)

0 (0.0) 12 (11.3) 7 (6.6) 7 (6.6) 3 (2.8) 2 (1.9) 3 (2.8) 4 (3.7) 0 (0.0) 1 (0.9) 39 (37.8)

1 (0.9) 23 (21.7) 23 (21.7) 14 (13.2) 13 (12.2) 9 (8.5) 6 (5.6) 4 (3.7) 1 (0.9) 12 (11.3) 106 (100)

RESULTS Patient demographics The ages of patients at the time of diagnosis ranged from 9 to 82 years (mean 34.5 years). For male patients, the age ranged from 9 to 82 years (mean 34.1 years), and for female patients, the age ranged from 11 to 75 years (mean 34.9 years). Patients in their second and third decades of life were most commonly affected (Table I). Ninety of the 145 cases (62.2%) occurred in male patients, and 55 (37.8%) occurred in female patients. The male-to-female ratio was 1:0.6, showing a male predilection. Regarding ethnic distribution, patients of mixed race (43.4%) and Caucasians (42.5%) were almost equally affected by KCOT, whereas only 15 (14.2%) patients were African. Clinical manifestations Patients with KCOT had variable clinical signs and symptoms at the time of presentation (Table II). The most common complaint associated with KCOT was a slow-growing swelling (50.9%) in the affected area. Of those patients who had signs and symptoms, the mean period of suffering from these symptoms to first presentation was 14 months. Fifteen of the 106 patients (14.1%) had NBCCS, characterized by the presence of multiple KCOT along with other features, including basal cell carcinomas, nevi, falx cerebri calcifications, bifid ribs, etc. Ten of these patients (66.7%) were male and 5 (33.3%) female, with a mean age of 22.7 years. These patients were considerably younger than patients without NBCCS. Radiologic manifestations One hundred nine of the 145 KCOT (75.2%) were located in the mandible and 36 (24.8%) in the maxilla (Table III). The mandibular posterior region was found to be the most commonly affected. In the mandible, 9

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Table II. Frequency of clinical manifestations of keratocystic odontogenic tumors Clinical manifestation

No. of patients (%)

Swelling Purulent discharge Combination of pain and swelling Pain Paresthesia Incidental/asymptomatic

54 (50.9) 18 (17.0) 9 (8.5) 8 (7.5) 1 (0.9) 16 (15.1)

Table III. Distribution of keratocystic odontogenic tumors by location in the jaws (n ⫽ 145), n (%) Region

Mandible

Maxilla

Total

Anterior Posterior Ramus Anterior and posterior Anterior/posterior/ ramus/condyle Total

12 (8.3) 49 (33.8) 22 (15.2) 9 (6.2) 17 (11.7)

16 (11.0) 19 (13.1) NA 1 (0.7) NA

28 (19.3) 68 (46.9) 22 (15.2) 10 (6.9) 17 (11.7)

109 (75.2)

36 (24.8)

145 (100)

NA, Not applicable.

lesions were very extensive, involving the anterior and posterior regions and crossing the midline. One hundred three KCOT (71.0%) were unilocular in appearance and 42 (29.0%) were multilocular. Thirtysix mandibular KCOT (33.0%) were multilocular in appearance, and only 6 maxillary KCOT (16.7%) were multilocular. Twenty-four KCOT (16.5%) showed signs of scalloping of the margins (Figure 1), and only 1 tumor caused root resorption (Figure 2). Three KCOT presented with poorly defined margins (Figure 3), and another 6 caused expansion of the cortex (Figure 4). Seventy-six KCOT (52.4%) were associated with impacted teeth. The mandibular third molar (44.7%) was the most commonly impacted tooth. On average, multilocular KCOT (63.0 mm) were significantly larger (P ⫽ .0001) in buccolingual width than unilocular KCOT (38.0 mm), which tended to be smaller. KCOT were also significantly larger (P ⫽ .02) in buccolingual width in patients ⬎50 years old (mean 52.3 mm) compared with patients ⬍15 years old (mean 37.3 mm). Treatment and recurrence The treatment records of 65 cases were available (Table IV). Enucleation was the most common form of treatment, with a recurrence rate of 30.0% after a mean follow-up period of 23.5 months. One KCOT was treated by resection and did not recur after a follow-up period of 30 months. The overall recurrence rate was 29.2% with a mean follow-up period of 19.8 months. Two cases (3.1%) experienced ⱖ2 recurrences.

Fig. 1. Multilocular keratocystic odontogenic tumor in the mandibular ramus region showing scalloped margins.

Fig. 2. Mandibular keratocystic odontogenic tumor causing root resorption of second lower left molar and displacement of third lower left molar.

For patients with NBCCS, the majority (70.0%) were treated by enucleation alone, and 30.0% were treated by enucleation and application of Carnoy solution. The overall recurrence rate was 50.0% after a mean follow-up period of 22.2 months. This recurrence rate was significantly higher than KCOT not associated with NBCCS (P ⫽ .001). Nineteen (29.2%) of the 65 KCOT that were followed recurred (Table V). The recurrence rates for different age groups ranged from 0 to 100%. Patients in

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Table IV. Treatment and recurrence rates of keratocystic odontogenic tumors (KCOT) Treatment

KCOT

Recurrent KCOT

Recurrence rate, %

Follow-up, mo

Marsupialization Enucleation Enucleation and Carnoy solution Resection Total

5 50 9

3 15 1

60.0% 30.0% 11.1%

13.0 23.5 12.6

1 65

0 19

0.0% 29.2%

30.0 19.8

Table V. Recurrence of keratocystic odontogenic tumors based on age, site, and radiographic appearance Parameter

Fig. 3. Poorly defined maxillary keratocystic odontogenic tumor invading the maxillary sinus.

Age (y) 0-9 10-19* 20-29 30-39 40-49 50-59 60-69 70-79* 80-89 Site Maxillary anterior region Maxillary posterior region Mandibular anterior region Mandibular posterior region Mandibular ramus region Mandibular anterior and posterior regions Radiographic appearance Unilocular Multilocular Scalloping

Recurrence (%) 0/3 (0.0) 9/14 (64.3) 2/11 (18.2) 2/14 (14.3) 0/8 (0.0) 1/7 (14.3) 1/3 (33.3) 4/4 (100) 0/1 (0.0) 2/5 (40.0) 4/9 (44.4) 1/6 (16.7) 8/24 (33.3) 4/20 (20.0) 0/1 (0.0) 12/40 (30.0) 7/25 (28.0) 3/14 (21.4)

*Statistically significant difference (P ⬍ .05).

Fig. 4. Mandibular keratocystic odontogenic tumor causing expansion of the cortex.

their second and eighth decades of life experienced significantly more recurrences than patients of other age groups (P ⬍ .01 and P ⫽ .0001, respectively). Eight out of 32 male (25.0%) and 12 out of 33 female (36.4%) subjects developed recurrences; however, the difference was not statistically significant. Statistical analysis of the sites of recurrences was performed (Table V). The maxillary posterior region

was the most frequent site of recurrence (44.4%). This, however, was not statistically significant. The mandibular anterior region was associated with the lowest recurrence rate (16.7%). Twelve out of 40 unilocular KCOT (30.0%) recurred, and multilocular KCOT showed a slightly lower recurrence rate (28.0%). Three out of 14 KCOT with scalloped margins (21.4%) recurred. The difference in recurrence rates for these radiographic features was not statistically significant. Size (buccolingual width) of KCOT also was not a significant factor in recurrence.

DISCUSSION In the present study, we report the clinical and radiologic features of KCOT along with its management and recurrence. This is one of the larger series of cases to be studied. Moreover, this is one of the first reports to provide detailed view on the radiologic manifestations of these aggressive lesions.

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Table VI. Comparison of clinical and radiological features of keratocystic odontogenic tumors with previous reports

Mean age (y) Male:female Swelling Maxilla:mandible Most common site Unilocular:multilocular Association with teeth

This study

Habibi et al.24

Myoung et al.2

Chow10

Chirapathomsakul et al.6

Dong et al.16

34.5 1:0.6 50.9% 1:3.0 Mand. post. 1:0.4 52.4%

27.1 1:0.7 45.8% 1:2.1 Mand. post. NA 33.7%

30.8 1:0.7 46.1% 1:3.9 Mand. molar NA NA

32.8 1:0.6 50.0% 1:2.5 Mand. post. NA 52.8%

36.9 1:1.2 23.5% 1:2.2 Mand. post. 1:0.4 31.3%

38.9 1:0.4 75.4% 1:9.2 Mand. post. 1:0.1 50.0%

NA, Not available.

Patient demographics The demographics of patients at the time of presentation in this series were similar to earlier reports (Table VI). Patients in their second and third decades of life were most commonly affected. Most earlier studies have reported similar findings.2,10,11 The male-to-female ratio was also very similar to that of earlier reports, confirming the higher frequency of KCOT in male patients.2,10,12 South Africa’s population is predominantly (⬃80%) made up of Africans; however, in this study only 14.2% of the patients were African and patients of mixed race and Caucasians made up 85.8% of the affected sample. The lower frequency of KCOT in Africans has also been reported by Shear and Speight, who also studied a South African sample.13 Clinical manifestations Swelling was found to be the most common presenting complaint in more than half of all patients, as was also reported by Myoung et al.2 and Chirapathomsakul et al.6 More than 15% of patients did not have any symptoms and KCOT was discovered incidentally. This is consistent with an earlier report in that KCOT sometimes tend to enlarge silently without any swelling or pain to alert the patient or physician.10 Association of KCOT with NBCCS has been reported to occur in 1.4%-8.8% of patients.2,10,14 In the present sample, 14.1% of patients had NBCCS. This high association of KCOT with NBCCS could be due to the high number of Caucasian patients, in which the syndrome is known to occur more frequently compared with other race groups.15 Another possible reason for this finding is that this study was conducted at a tertiary-care academic hospital, so a larger number of NBCCS patients may have presented compared with primary-care facilities. Radiological manifestations Most reports agree that KCOT affect the mandible more frequently than the maxilla, with the mandibular posterior region being the most commonly affected site.2,6,10,16 In the present sample, too, 75.2% of KCOT

were located in the mandible, with the mandibular posterior region being most commonly affected. Regarding the radiographic appearance, most KCOT in this series were unilocular, which is in accordance with earlier reports.6,16 Chirapathomsakul et al.6 reported that multilocular KCOT were found to be significantly more common in the maxilla compared with the mandible. This was not the case in the present sample, because the majority of multilocular KCOT were located in the mandible (33.0%) than in the maxilla (16.7%). Few KCOT (16.5%) showed signs of scalloping of the margins. Scalloping of the tumor margins may be indicative of unequal growth activity within the lining of the tumor and is generally observed in extensive lesions.13 A correlation between the buccolingual width and margin outline revealed that lesions with scalloped margins were significantly (P ⫽ .0001) larger than tumors without scalloping of the borders, thus confirming the findings of Shear and Speight.13 KCOT are commonly associated with impacted teeth.17 In the present sample, 52.4% of KCOT were associated with impacted teeth, which is similar to findings of Chow10 and Dong et al.,16 whereas Chirapathomsakul et al.6 reported a lower association (31.3%) of KCOT with impacted teeth. The mandibular third molar was the most commonly implicated tooth, owing to the high frequency of KCOT in the posterior regions of the mandible. Root resorption was not found to be a significant feature of KCOT; only 1 case was observed. Chirapathomsakul et al.6 also reported a low incidence of root resorption (1.3%). The overall radiographic appearance of KCOT can range from well-defined unilocular lesions to extensive multilocular lesions with ill-defined borders. This varied radiographic appearance may mimic ameloblastomas, ameloblastic fibromas, calcifying odontogenic cysts and adenomatoid odontogenic tumors amongst others.17 The later two lesions may mimic KCOT when lesions are small in size and calcifications are not easily apparent on a radiograph. The high association of KCOT with teeth may also give it a “dentigerous cyst”–like appearance, making it

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indistinguishable from a dentigerous cyst.17 In the present sample, 43 KCOT (29.6%) were initially diagnosed as dentigerous cysts. Tsukamoto et al.18 attempted to diffentiate between the appearance of KCOT and dentigerous cysts on panoramic radiographs. They found that KCOT presented with a significantly larger area on panoramic radiographs than dentigerous cysts. They also reported that dentigerous cysts cause more displacement of third molars compared with KCOT. Although these findings may be of some value in aiding to differentiate KCOT from dentigerous cysts, there are no clear radiographic features distinguishing the 2 lesions. The difficulty in differentiating KCOT radiographically from other cystic lesions of the jaws requires histopathologic confirmation by means of incisional biopsy or examination of frozen sections intraoperatively.2 Advanced imaging modalities (including computerized tomography and magnetic resonance imaging) may be of great aid in identifying the extents of the tumor and surgical planning.19 Regular panoramic radiographs can be used to aid in the detection of recurrent tumors on follow-up appointments. All recurrent KCOT in the present series were detected on panoramic radiographs, thus highlighting its usefulness in the detection of recurrent tumors. Recurrence rate One of the most important aspects of KCOT is its high recurrence rate and aggressive nature. Studies in the literature have reported recurrence rates to range from 0 to 62%.2,9,20 In the present sample, a recurrence rate of 29.2% was observed over a mean follow-up period of 19.8 months. This recurrence rate is lower than some reports, which may be due to a shorter follow-up period.10,16 Many patients (55.2%) were lost because they did not attend regular follow-up visits, because many of these patients come from distant rural areas in South Africa. Recurrence rate and treatment. The majority of patients in this sample (76.9%) were treated by enucleation. Enucleation alone was associated with a recurrence rate of 30.0% over a mean follow-up period of 23.5 months. In a systematic review of treatment of KCOT, Blanas et al.21 showed that enucleation alone was associated with a recurrence rate of 28.7%, which is very similar to our finding. Enucleation and application of Carnoy solution had a much lower recurrence rate (11.1%) in this series. Blanas et al.21 reported an even lower recurrence rate (1.6%) with enucleation and application of Carnoy solution, and resection was associated with no recurrence at all, as seen in 1 patient in the present sample. As previously mentioned, KCOT is an aggressive neoplasm with high recurrence rate. The WHO’s recent reclassification of this lesion as a tumor highlights the

ORIGINAL ARTICLE Titinchi and Nortje 141

need for a more aggressive approach in its treatment.4 Although some authors advocate a more conservative approach to its treatment, Madras and Lapointe4 and Blanas et al.21 have shown that a more aggressive approach is likely to lower the risk of recurrence. Because resection may be considered to be an aggressive and extreme form of therapy, enucleation and application of Carnoy solution seems to be an acceptable treatment modality with a low recurrence rate. Recurrence rate and NBCCS. Recurrence rate of KCOT in patients with NBCCS (50.0%) was significantly (P ⫽ .001) higher than that for KCOT that were not associated with the syndrome (29.2%). Manfredi et al.22 reported that up to 60% of patients with the syndrome may have recurrence of KCOT. However, one must be careful not to confuse new tumor development in these patients with recurrence of previous tumors; therefore, it may be difficult to estimate the exact recurrence rate of KCOT in these patients.22 Recurrence rate and age. Some reports have demonstrated that younger patients had significantly higher recurrence rates, whereas others have shown a significantly higher recurrence rate in older age.2,23 In the present series, patients in their second and eighth decades of life experienced significantly higher recurrences than patients of other age groups. Recurrence rate and sex. The association between recurrence rate and sex of patients is controversial. Ahlfors et al.5 reported that there was an association between sex and recurrence of KCOT; however, Myoung et al.2 and Habibi et al.24 found no relationship between them. In the present sample, sex was not established to be a significant factor in the recurrence rate. Recurrence rate and site. Habibi et al.24 reported no significant correlation between the site of KCOT and the recurrence rate. On the other hand, Myoung et al.2 and Chemli et al.25 reported that the mandibular molar region was significantly more prone to recurrence, possibly owing to reduced accessibility to the area. In the present study, the maxillary posterior region (44.4%) was associated with a higher recurrence rate than the mandibular posterior region (33.3%), as was reported by González-Alva et al.11 The maxillary posterior region also may pose such a surgical challenge, especially when the tumor may involve adjacent structures, such as the maxillary sinus. Recurrence rate and radiographic appearance. We also analyzed the relationship between radiographic appearance of KCOT with recurrence rate. No study has previously reported on this. Unilocular and multilocular KCOT had similar recurrence rates (30.0% and 28.0%, respectively) which were not statistically significant. One would have expected a higher recurrence rate with multilocular lesions, as reported by Chemli et al.,25 but this

ORAL AND MAXILLOFACIAL RADIOLOGY 142 Titinchi and Nortje

was not the case. This could be due to the use of more aggressive and adjunct therapy to manage these tumors, therefore reducing the overall recurrence rate compared with unilocular lesions. Scalloped margins were also not associated with a significantly higher recurrence rate. Recurrence rate and size. The size of KCOT on panoramic radiographs did not have any significant effect on the recurrence rate, as previous observed by Forssel et al.26

CONCLUSION The findings of this study were similar in many ways to earlier reports. 1) We found that KCOT presented mainly in the second and third decades of life with a male predilection; 2) KCOT occurred 3 times more commonly in the mandible than in the maxilla with a tendency for the posterior regions of the mandible; 3) radiographically, the majority of KCOT presented as unilocular lesions, with some having scalloped margins; 4) KCOT were frequently associated with impacted teeth, although root resorption was not found to be a common feature; and 5) recurrence was significantly associated with the patient’s age and presence of NBCCS, whereas sex, site, size, treatment, and radiographic appearance of tumors were not. Owing to their variable radiographic presentation and aggressive nature, histopathologic confirmation and advanced imaging modalities (such as computerized tomography and magnetic resonance imaging) should be used to aid in differentiation of KCOT from other lesions and in identification of tumor extent and content. Routine panoramic radiography and long-term follow-up are essential to detect any recurrences.

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9.

10.

11.

12. 13. 14.

15.

16.

17. 18.

19.

20.

21.

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Reprint requests: Christoffel J. Nortje Department of Diagnostics and Radiology Faculty of Dentistry University of the Western Cape Private Bag X1, Tygerberg 7505 South Africa [email protected]