Reclassification of the Odontogenic Keratocyst from Cyst to Tumour

(1)

JCDA • www.cda-adc.ca/jcda • March 2008, Vol. 74, No. 2 • 165

Clinical

P r a c t i c e

Contact Author

Keratocystic Odontogenic Tumour:

Reclassification of the Odontogenic Keratocyst from Cyst to Tumour

Jonathan Madras, BSc (Hons), DDS; Henry Lapointe, DDS, PhD, FRCD(C)

ABSTRACT

The purpose of this paper is to review the features and behaviour of the odontogenic keratocyst (OKC), now officially known as the keratocystic odontogenic tumour (KCOT);

to analyze a series of histologically confirmed KCOT cases; and to review and discuss the redesignation of KCOT and the implications for treatment. Based on a literature review, more aggressive treatment — either resection or enucleation supplemented with Carnoy’s solution with or without peripheral ostectomy — results in a lower recurrence rate than enucleation alone or marsupialization. However, the recurrence rate after marsupialization followed by enucleation is not significantly higher than that after aggressive modalities. In a case series of 21 patients (27 KCOTs), recurrence rate was 29%, consistent with published data; all recurrences occurred within 2 years after intervention. The size of most lesions was 0–15 cm² (average 14 cm²) measured radiographically. WHO’s reclassification of this lesion from cyst to tumour underscores its aggressive nature and should motivate clinicians to manage the disease in a correspondingly aggressive manner. The most effective treatments are enucleation supplemented with Carnoy’s solution, or marsupialization with later cystectomy. Future treatment may involve molecular-based modalities, which may reduce or eliminate the need for aggressive surgical management.

For citation purposes, the electronic version is the definitive version of this article: www.cda-adc.ca/jcda/vol-74/issue-2/165.html

F

irst described by Philipsen in 1956,¹ the odontogenic keratocyst (OKC) is now designated by the World Health Organization (WHO) as a keratocystic odontogenic tumour (KCOT) and is defined as “a benign uni- or multicystic, intraosseous tumour of odontogenic origin, with a characteristic lining of parakeratinized stratified squamous epithelium and potential for aggressive, infil- trative behaviour.”² WHO “recommends the term keratocystic odontogenic tumour as it better reflects its neoplastic nature.”² In light

of the reclassification, it is appropriate to review the salient features of this well-known lesion and to consider the implications for treatment.

Case Series

To assess the impact of treatment modality and lesion size on KCOT recurrence, 21 patient files on 27 histologically confirmed KCOTs were reviewed (Table 1). The 27 KCOTs in- cluded 5 recurrences of a lesion treated elsewhere, 16 de novo lesions and 6 recurrences

Dr. Lapointe

Email: hlapoint@uwo.ca

(2)

Table 1 Description of keratocystic odontogenic tumours and treatment in a series of 21 patients

Patient’s date of birth

Tumour

Treatment Follow-up period Location Size; cm

Surface area; cm²

1912-08-18 Anterior mandible 8 × 3 24 Curettage 1 year

1918-01-13 Left mandibular body

and ramus^a 6.5 × 3 19.5 Marsupialization 1 year

1921-11-16 Right posterior maxilla 3 × 1.5 4.5 Curettage Recurrence at 1.5 years

Right posterior maxilla 1 × 1 1 Curettage 5.5 years

1922-07-17 Right mandibular body 4.5 × 1.5 6.75 Curettage 5 years 1925-07-22 Left mandibular ramus^a 5.5 × 3.5 19.25 Marsupialization 3.5 years 1925-11-27 Right mandibular body

and ramus 6.5 × 2.5 16.25 Curettage 2.5 years

1927-07-07 At teeth 44 and 45 1 × 1 1 Curettage Recurrence at 1 year

At teeth 44 and 45 1 × 1 1 Curettage Recurrence at 2 years

At teeth 44 and 45 1 × 1 1 Curettage 6 years

1929-01-19 Left mandibular coronoid

process^a 4.5 × 1.5 6.75 Resection 5 years

1959-09-07 Right mandibular ramus 4 × 3 12 Curettage 2 months

1933-05-15 Right mandibular body

and ramus 2.5 × 1.5 3.75 Curettage 5.5 years

1936-06-08 Right mandibular body,

at teeth 41–47 6.5 × 3 19.5 Curettage Recurrence at 8 months

At teeth 44–46 2.5 × 2 5 Curettage 5 years

and ramus 9 × 2.5 22.5 Curettage 1 year

and ramus^a 10 × 4.5 45 Resection 6 years

1949-03-22 Anterior mandible 6 × 3 18 Curettage Recurrence at 9 months

Anterior mandible 4 × 2 8 Curettage 7 years

1957-08-28 Left mandibular body

and ramus^a 7 × 3 21 Marsupialization 1.5 years

1957-12-01 Left mandibular angle

and ramus 2.5 × 3.5 8.75 Curettage 16 months

1960-07-18 At tooth 23, left maxilla

and sinus 4.5 × 4.5 20.25 Curettage 18 months

and ramus 8 × 4.5 36 Curettage 1 year

1966-09-23 Left posterior maxilla 4 × 3 12 Curettage Recurrence at 1.5 years

Left posterior maxilla 3.5 × 1.5 5.25 Curettage 2 years 1975-12-26 Left mandibular body

and ramus 6 × 4 24 Curettage 2.5 years

1986-05-06 Right maxilla 5 × 2 10 Curettage 2 years

a Initial presentation due to recurrence of previous tumour.

165a JCDA • www.cda-adc.ca/jcda • March 2008, Vol. 74, No. 2 •

(3)

of lesions treated in our clinic. There were 18 lesions in the posterior mandible, 3 in the anterior mandible and 6 in the posterior maxilla (Fig. 1). Treatment consisted of enucleation and curettage for 22 of the lesions, resection for 2 and marsupialization for 3. Follow-up periods varied from 2 months to 7 years. Overall, the recurrence rate was approximately 29%.

Figure 2 depicts the percentage of patients who re- mained free of recurrent KCOTs after the initial intervention at our clinic. Included are the 5 patients who presented with recurrence of a lesion treated elsewhere, as well as patients whose lesion recurred after initial treatment at our clinic. All recurrences of lesions (previously recurrent or new lesions) treated at our clinic were within 2 years.

The average surface area of the lesions measured radiographically was 14 cm². Most lesions were within the 0–15 cm² range and lesions in this range resulted in the greatest number and proportion of recurrences (Fig 3).

No relation was found between age and number of primary lesions among our patient group (Fig. 4).

Sample Cases

Patient 1 (born 1949, date of surgery: Dec. 16, 1999) This patient presented initially with recurrence of a KCOT (treated elsewhere 10 years earlier) of the right mandible. The tumour measured 45 cm²radiographically (Fig. 5). Because of the size, multilocularity and extent of soft tissue involvement in the lesion, resection was deter- mined to be the most appropriate treatment method. This included complete removal of the right mandible from the condyle to the bone distal to tooth 44. The tumour did not recur during the 6-year follow-up period.

Patient 2 (born 1925, date of surgery: Nov. 22, 2001) This patient presented with a primary KCOT measuring 19 cm² radiographically and involving the left man- dibular ramus (Fig. 6). The cyst was marsupialized and followed up for 3.5 years. Bone fill proceeded normally and there were no recurrences during that period.

Patient 3 (born 1949, date of surgery: Sept. 17, 1993) This patient presented with a de novo KCOT of the anterior mandible, measuring 18 cm² radiographically (Fig. 7). It was treated by curettage. Nine months later,

02 46 108 1214 1618 20

Posterior

maxilla Anterior

maxilla Posterior

mandible Anterior mandible KCOT location

Number of lesions

100 2030 4050 6070 8090 100

Time since surgery; years

% of disease-free patients

1 2 3 4 5 6

0 2 4 6 8 10 12 14 16

0–15 > 15–30 > 30

KCOT size; cm²

Number of lesions

Total lesions Recurences

0 1 2 3 4 5 6 7

10–19 20–29 30–39 40–49 50–59 60–69 70–79 80+

Patient age; in years

Number of primary lesions

Figure 1: Keratocystic odontogenic tumour (KCOT) location among patients in our study group.

Figure 2: Percentage of disease-free patients over time.

Figure 3: Relation between KCOT size and recurrence. Figure 4: KCOT distribution by age.

JCDA • www.cda-adc.ca/jcda • March 2008, Vol. 74, No. 2 • 165b

(4)

recurrence was observed. This was curetted and followed up for 7 years.

Clinical Features

KCOTs comprise approximately 11% of all cysts of the jaws.³ They occur most commonly in the mandible, especially in the posterior body and ramus regions.^2,4,5 They almost always occur within bone, although a small number of cases of peripheral KCOT have been reported.^6–11 Patients may present with swelling, pain and discharge or may be asymptomatic. Distinctive clinical features include a potential for local destruction and a tendency for multiplicity, especially when the lesion is associated with nevoid basal cell carcinoma syndrome (NBCCS) or Gorlin-Goltz syndrome. KCOTs have a high

recurrence rate, reportedly between 25% and 60%¹²(when associated with NBCCS, the recurrence rate is about 82%¹³). In addition to multiple KCOTs, NBCCS is also characterized by nevoid basal cell carcinomas, bifid ribs, calcification of the falx cerebri, frontal bossing, multiple epidermoid cysts and medulloblastoma.¹⁴

In 1976, Brannon⁵ proposed 3 mechanisms for KCOT recurrence: incomplete removal of the cyst lining, growth of a new KCOT from satellite cysts (or odontogenic rests left behind after surgery) and development of a new KCOT in an adjacent area that is interpreted as a recurrence.¹⁵ The wide range in reported recurrence rates has been attributed to the variation in follow-up times used by examiners, the surgical technique used and the number of cases incorporated into the studies.¹⁶ Most

Figure 5: Partial panoramic radiograph taken (a) pre-operatively and (b) 6 days and (c) 6 years after resection.

b c

a

Figure 6: Partial panoramic radiograph taken (a) pre-operatively, (b) 9 days, (c) 3 months and (d) 3.5 years after marsupialization.

b c

a d

b c

a d

Figure 7: (a) Pre-operative radiographic appearance of the lesion. (b) Recurrence at 9 months after curettage; and (c) 16 months and (d) 7 years after curettage of the recurring tumour.

165c JCDA • www.cda-adc.ca/jcda • March 2008, Vol. 74, No. 2 •

(5)

Table 2 Review of literature relating treatment to recurrence rate

Study Cysts Treatment Follow-up period

Recurrence rate; %

Kondell and Wiberg²¹ 29 Enucleation 1–8 years 24

Chow²² 70 Enucleation + Carnoy’s + peripheral

ostectomy ≥ 5 years 10

Meara and others²³ 49 Enucleation 1–15 years 35

Bataineh and al Qudah¹⁶ 31 Resection 2–8 years 0

Stoelinga²⁰ 82 Enucleation + Carnoy’s 1–25 years 11

el-Hajj and Anneroth²⁴ 63 Enucleation > 5 years 29

16 Enucleation + cryosurgery > 5 years 38

1 Enucleation + surgical bur > 5 years 0

2 Enucleation + cryosurgery + surgical bur > 5 years 50

3 Resection > 5 years 0

Marker and others²⁵ 23 Marsupialization + enucleation 1–19 years 9

Pogrel and Jordan²⁶ 10 Marsupialization + later cystectomy 1.8–4.8 years 0 Maurette and others³ 30 Decompression then curettage Approx. 25 months 14

Morgan and others¹⁷ 11 Enucleation 13–288 months 55

11 Peripheral ostectomy 13–288 months 18

13 Peripheral ostectomy + Carnoy’s 13–288 months 0

2 Enucleation + Carnoy’s 13–288 months 50

3 Resection 13–288 months 0

Brøndum and Jensen²⁷ 44 Decompression + later cystectomy 7–19 years 18

Browne⁴ 12 Marsupialization > 16 months 25

72 Enucleation > 16 months 23

Forssell and others²⁸ 28 Enucleation in 1 piece 5–17 years 18

41 Enucleation in > 1 piece 5–17 years 56

5 Marsupialization 5–17 years 60

Jensen and others²⁹ 12 Enucleation 17–58 months 33

13 Enucleation + cryotherapy 21–59 months 38

Voorsmit and others³⁰ 52 Enucleation 1–21 years 14

40 Enucleation + Carnoy’s 1–10 years 3

Chuong and others³¹ 22 Enucleation 19 months to 10 years 18

1 Resection 19 months to 10 years 0

Vedtofte and Praetorius³² 57 Enucleation ≥ 5 years 51

Zachariades and others³³ 13 Enucleation > 5 years 31

1 Resection > 5 years 0

1 Marsupialization > 5 years 0

1 Decompression + enucleation > 5 years 0

JCDA • www.cda-adc.ca/jcda • March 2008, Vol. 74, No. 2 • 165d

(6)

recurrences take place within 5–7 years after treatment, although some have been reported more than 10 years following initial intervention.¹⁷ These findings emphasize the importance of long-term follow-up as an essential aspect of the KCOT treatment plan.

Common Treatment Modalities

Morgan and colleagues¹⁷ categorize surgical treatment methods for KCOT as conservative or aggressive.

Conservative treatment is “cyst-oriented” and, thus, includes enucleation, with or without curettage, or marsupialization. Its advantage is preservation of anatomical structures (including teeth), which is advocated because KCOTs commonly present in younger patients. It has been asserted that a conservative approach is applicable not only to all age groups, but also to patients with NBCCS.¹⁸

Aggressive treatment addresses the “neoplastic nature” of the KCOT and includes peripheral ostectomy, chemical curettage with Carnoy’s solution or en bloc resection. Aggressive modalities have generally been recommended for NBCCS cases, large KCOTs and recurrent lesions.¹⁸

Some authors advocate a site- and size-based approach to KCOT treatment planning. For example, Dammer and others¹⁹ suggest that “small keratocysts near the al- veolar process a maximum of 1 cm in diameter should be treated by simple excision, but large keratocysts near the base of the skull which have invaded soft tissue should be treated by radical excision.” This is presumably because of the potential for local invasion of the skull base, which can have catastrophic consequences.

With surgical treatment, removal of the mucosa overlying the lesion has been recommended, based on histologic evidence that clusters of epithelial islands and microcysts — presumably with the potential to cause

recurrence — have been found in the area where the KCOT was connected with the mucosa.²⁰

Recurrence

A review of the literature suggests that recurrence rate is relatively low with aggressive treatment, whereas more conservative methods tend to result in more recurrences (Tables 2 and 3). Articles reviewed were required to meet the following inclusion criteria: histologic diagnosis of OKC, a defined follow-up period and a clear description of treatment.

If a difference in recurrence rate between 2 modalities of ≥ 15% (arbitrarily chosen) is considered the threshold for clinical signifi- cance, a few simple inferences are possible.

First, enucleation plus Carnoy’s solution, with or without peripheral ostectomy, results in a significantly lower rate of recurrence than enucleation alone. Second, the use of cryotherapy with enucleation appears to have no significant effect on the recurrence rate compared with enucleation alone. Third, marsupialization as a definitive treatment is associated with a significantly higher recurrence rate than when the KCOT is subsequently enucle- ated. Finally, resection, despite a recurrence rate of 0, is not significantly better at eliminating recurrences than enucleation plus Carnoy’s solution or marsupialization plus cystectomy. Therefore, to minimize invasiveness and recurrence, the most effective treatment option appears to be enucleation of the KCOT and subsequent applica- tion of Carnoy’s solution. Alternatively, marsupialization followed by cystectomy is likewise effective, as this treatment does not result in a significantly higher rate of recurrence than enucleation plus Carnoy’s solution.

However, as the latter option requires a protracted course of treatment, patient compliance must be considered; lesions treated in this manner require several months of at-home irrigation by the patient as well as clinical obser- vation before enucleation.

KCOT: The Neoplasm

In 1967, Toller suggested that the OKC may best be re- garded as a benign neoplasm rather than a conventional cyst based on its clinical behaviour.³⁴ In 1984, Ahlfors and others³⁵ suggested that “if the OKC were recognized as a true, benign cystic epithelial neoplasia, the question of modified treatment schedules would be raised.” In the years since, published reports have influenced WHO to reclassify the lesion as a tumour. Several factors form the basis of this decision.

• Behaviour: As described earlier, the KCOT is locally destructive and highly recurrent.

• Histopathology: Studies such as that by Ahlfors and others³⁵ show the basal layer of the KCOT budding Table 3 Summary of treatment related to recurrence rate

Treatment Lesions Recurrences

Recurrence rate; %

Enucleation 465 141 30

Enucleation + Carnoy’s 122 11 9

Enucleation +

peripheral ostectomy 11 2 18

Enucleation + Carnoy’s +

peripheral ostectomy 83 7 8

Enucleation + cryotherapy 29 11 38

Marsupialization 18 6 33

Marsupialization +

cystectomy 108 14 13

Resection 39 0 0

165e JCDA • www.cda-adc.ca/jcda • March 2008, Vol. 74, No. 2 •

(7)

into connective tissue. In addition, WHO notes that mitotic figures are frequently found in the suprabasal layers.²

• Genetics: PTCH (“patched”), a tumour suppressor gene involved in both NBCCS and sporadic KCOTs, occurs on chromosome 9q22.3-q31.^36–40 Normally, PTCH forms a receptor complex with the oncogene SMO (“smoothened”) for the SHH (“sonic hedgehog”) ligand. PTCH binding to SMO inhibits growth-signal transduction (Fig. 8). SHH binding to PTCH releases this inhibition (Fig. 9).⁴¹ If normal functioning of PTCH is lost, the proliferation-stimulating effects of SMO are permitted to predominate.

Evidence has shown that the pathogenesis of NBCCS and sporadic KCOTs involves a “2-hit mechanism,” with allelic loss at 9q22.^42,43 The 2-hit mechanism refers to the process by which a tumour suppressor gene is inactivated.⁴⁴ The first hit is a mutation in one allele, which, although it can be dominantly inherited, has no phenotypic effect. The second hit refers to loss of the other allele and is known as

“loss of heterozygosity” (LOH). In KCOTs, this leads to the dysregulation of the oncoproteins cyclin D1 and p53.⁴³ Lench and others⁴⁵ indicate that LOH in the 9q22.3-q31 region has been reported for many epithelial tumours, including basal cell carcinomas, squamous cell carcinomas and transitional cell carcinomas; they note that LOH is,

“by definition a feature of tumorigenic tissue.”

Implications and the Future of KCOT Treatment The aggressive nature of the KCOT is universally acknowledged. WHO’s formal reclassification of it as a tumour underscores the fact that this lesion should not be managed as the simple cyst it was believed to be.

Although some studies advocate more conservative treat- ment, Table 3 shows that an aggressive approach is more likely to reduce the risk of recurrence (and therefore the risk of trauma caused by repeated surgeries). Although one study²⁶ suggests treating with marsupialization alone

and showed promising results (0 recurrences), the follow- up period (≤ 4.8 years) and sample size (10 patients) were inadequate to draw definitive conclusions.

Despite the fact that resection of the jaw results in the lowest recurrence rate, this procedure is extreme.

Thus, unless resection is deemed necessary, the most appropriate action would be enucleation of the KCOT plus use of Carnoy’s solution or marsupialization followed by enucleation.

In our case series, smaller lesions were more often associated with recurrence. This contradicts our expecta- tions, as larger lesions should be inherently more dif- ficult to excise in one piece and, therefore, should be more likely to recur. To date, the literature makes little mention of recurrence of large versus small lesions. The largest of our lesions was resected and, as supported by the literature, this method of treatment was associated with the lowest rate of recurrence. This could influence the results, making small lesions appear to recur more often. Thus, our results regarding lesion size and associated recurrence are inconclusive. Notably, Forssell and others²⁸ found that lesion size does not affect recurrence rate, confirming earlier observations.

Regarding a relation between treatment modality and recurrence, in the case series all recurrences followed enucleation and curettage.

In our study, the tumours presented primarily in the posterior mandible, in accordance with findings described above under “clinical features.” Likewise, in agreement with earlier research, the recurrence rate we observed was 29%.¹³ Our follow-up interval ranged from 2 months to 7 years, with the variability attributed to patient compliance and time since surgery. Although all recurrences took place within 2 years post-intervention, it remains prudent to suggest at least 5 years follow-up for KCOTs for reasons stated earlier.

In recent years, studies have hinted at possible new treatment methods for KCOT. According to Taipale and colleagues,⁴⁶ cyclopamine, a plant-based steroidal alka-

Figure 9: SHH releases PTCH from SMO, allowing signal transduction.

Figure 8: PTCH prevents the proliferation-inducing effect of SMO.

JCDA • www.cda-adc.ca/jcda • March 2008, Vol. 74, No. 2 • 165f

(8)

loid, inhibits the cellular response to the SHH signal.

They found that cyclopamine blocks activation of the SHH pathway caused by oncogenic mutation making it a potential “mechanism-based” therapeutic agent for human tumours whose pathogenesis involves excess SHH pathway activity. Zhang and others⁴⁷ postulate that antagonists of SHH signalling factors could effectively treat KCOTs. Their suggested strategies include the re- introduction of a wild-type form of PTCH, inhibiting the SMO molecule by synthetic antagonists and sup- pressing the downstream transcription factors of the SHH pathway. They suggest that intracystic injection of an SMO protein-antagonist has the greatest potential as a future treatment option (Fig. 10).

Conclusion

The aggressive nature of KCOT warrants an aggressive treatment strategy, and its recent reclassification by WHO as a neoplasm should further motivate clinicians in this direction. Resection of the jaw results in the lowest recurrence rate. However, considering the radical nature of the procedure, unless resection is necessary, it is ac- ceptable to use enucleation in combination with Carnoy’s solution or marsupialization.

As research continues, treatment may become molecular in nature. This could eventually reduce or eliminate the need for aggressive methods to manage the lesions. Currently, the novel designation of the OKC as a tumour and the research that influenced this change should serve as a compass by which clinicians can navi- gate future treatment plans. a

THE AUTHORS

Dr. Madras is a graduate of the Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario. He is currently a general practice resident at Mount Sinai Hospital, Toronto, Ontario.

Dr. Lapointe is associate professor and chair, division of oral and maxillofacial surgery, and assistant director of post- graduate studies, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario.

Correspondence to: Dr. Henry J. Lapointe, Schulich School of Medicine and Dentistry, University of Western Ontario, Dental Sciences Building, Room 0130, 1151 Richmond St., London ON N6A 5C1

The authors have no declared financial interests.

This article has been peer reviewed.

References

1. Philipsen HP. Om keratocystedr (Kolesteratomer) and kaeberne.

Tandlaegebladet 1956; 60:963–71.

2. Barnes L, Eveson JW, Reichart P, Sidransky D, editors. Pathology and genetics of head and neck tumours. Lyon: IARC Press; 2005. WHO classifica- tion of tumours series.

3. Maurette PE, Jorge J, de Moraes M. Conservative treatment protocol of odontogenic keratocyst: a preliminary study. J Oral Maxillofac Surg 2006;

64(3):379–83.

4. Browne RM. The odontogenic keratocyst: clinical aspects. Br Dent J 1970;

128(5):225–31.

5. Brannon RB. The odontogenic keratocyst. A clinicopathologic study of 312 cases. Part I. Clinical features. Oral Surg Oral Med Oral Pathol 1976;

42(1):54–72.

6. Dayan D, Buchner A, Gorsky M, Harel-Raviv M. The peripheral odonto- genic keratocyst. Int J Oral Maxillofac Surg 1988; 17(2):81–3.

7. Worrall SF. Recurrent odontogenic keratocyst within the temporalis muscle. Br J Oral Maxillofac Surg 1992; 30(1):59–62.

8. Chehade A, Daley TD, Wysocki GP, Miller AS. Peripheral odontogenic keratocyst. Oral Surg Oral Med Oral Pathol 1994; 77(5):494–7.

9. Ide F, Shimoyama T, Horie N. Peripheral odontogenic keratocyst: a report of 2 cases. J Periodontol 2002; 73(9):1079–81.

10. Chi AC, Owings JR Jr, Muller S. Peripheral odontogenic keratocyst: report of two cases and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005; 99(1):71–78.

11. Preston RD, Narayana N. Peripheral odontogenic keratocyst. J Periodontol 2005; 76(12):2312–5.

12. Sapp JP, Eversole LR, Wysocki GP. Contemporary oral and maxillofacial pathology. 2nd ed. St. Louis: Mosby; 2004. p. 54.

13. Dominguez FV, Keszler A. Comparative study of keratocysts, associated and non-associated with nevoid basal cell carcinoma syndrome. J Oral Pathol 1988; 17(1):39–42.

14. Gorlin RJ. Nevoid basal-cell carcinoma syndrome. Medicine (Baltimore) 1987; 66(2):98–113.

15. Woolgar JA, Rippin JW, Browne RM. A comparative study of the clinical and histological features of recurrent and non-recurrent odontogenic kera- tocysts. J Oral Pathol 1987; 16(3):124–8.

16. Bataineh AB, al Qudah M. Treatment of mandibular odontogenic kerato- cysts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998; 86(1):42–7.

17. Morgan TA, Burton CC, Qian F. A retrospective review of treatment of the odontogenic keratocyst. J Oral Maxillofac Surg 2005; 63(5):635–9.

18. Meiselman F. Surgical management of the odontogenic keratocyst: con- servative approach. J Oral Maxillofac Surg 1994; 52(9):960–3.

19. Dammer R, Niederdellmann H, Dammer P, Nuebler-Moritz M.

Conservative or radical treatment of keratocysts: a retrospective review.

Br J Oral Maxillofac Surg 1997; 35(1):46–8.

20. Stoelinga PJ. Long-term follow-up on keratocysts treated according to a defined protocol. Int J Oral Maxillofac Surg 2001; 30(1):14–25.

21. Kondell PA, Wiberg J. Odontogenic keratocysts: a follow-up study of 29 cases. Swed Dent J 1988; 12(1-2):57–62.

22. Chow HT. Odontogenic keratocyst: a clinical experience in Singapore.

Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998; 86(5):573–7.

23. Meara JG, Shah S, Li KK, Cunningham MJ. The odontogenic keratocyst: a 20-year clinicopathologic review. Laryngoscope 1998; 108(2):280–3.

24. el-Hajj G, Anneroth G. Odontogenic keratocysts. A retrospective clinical and histologic study. Int J Oral Maxillofac Surg 1996; 25(2):124–9.

25. Marker P, Brøndum N, Clausen PP, Bastian HL. Treatment of large odontogenic keratocysts by decompression and later cystectomy: a long- Figure 10: Cyclopamine blocks SHH signal, preventing transduction;

SMO antagonist blocks SMO, preventing transduction.

165g JCDA • www.cda-adc.ca/jcda • March 2008, Vol. 74, No. 2 •

(9)

term follow-up and a histologic study of 23 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996; 82(2):122–31.

26. Pogrel MA, Jordan RC. Marsupialization as a definitive treatment for the odontogenic keratocyst. J Oral Maxillofac Surg 2004; 62(6):651–5.

27. Brødum N, Jensen VJ. Recurrence of keratocysts and decompression treatment. A long-term follow-up of forty-four cases. Oral Surg Oral Med Oral Pathol 1991; 72(3):265–9.

28. Forssell K, Forssell H, Kahnberg KE. Recurrence of keratocysts. A long- term follow-up study. Int J Oral Maxillofac Surg 1988; 17(1):25–8.

29. Jensen J, Sindet-Pedersen S, Simonsen EK. A comparative study of treatment of keratocysts by enucleation or enucleation combined with cryo- therapy. A preliminary report. J Craniomaxillofac Surg 1988; 16(8):362–5.

30. Voorsmit RA, Stoelinga PJ, van Haelst UJ. The management of kerato- cysts. J Maxillofac Surg 1981; 9(4):228–36.

31. Chuong R, Donoff RB, Guralnick W. The odontogenic keratocyst.

J Oral Maxillofac Surg 1982; 40(12):797–802.

32. Vedtofte P, Praetorius F. Recurrence of the odontogenic keratocyst in relation to clinical and histologic features. A 20-year follow-up study of 72 patients. Int J Oral Surg 1979; 8(6):412–20.

33. Zachariades N, Papanicolaou S, Triantafyllou D. Odontogenic kerato- cysts: review of the literature and report of sixteen cases. J Oral Maxillofac Surg 1985; 43(3):177–82.

34. Toller P. Origin and growth of cysts of the jaws. Ann R Coll Surg Engl 1967; 40(5):306–36.

35. Ahlfors E, Larsson A, Sjögren S. The odontogenic keratocyst: a benign cystic tumor? J Oral Maxillofac Surg 1984; 42(1):10–9.

36. Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, and others. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 1996; 85(6):841–51.

37. Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, and others. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 1996; 272(5268):1668–71.

38. Lench NJ, Telford EA, High AS, Markham AF, Wicking C, Wainwright BJ.

Characterisation of human patched germ line mutations in naevoid basal cell carcinoma syndrome. Hum Genet 1997; 100(5–6):497–502.

39. Agaram NP, Collins BM, Barnes L, Lomago D, Aldeeb D, Swalsky P, and others. Molecular analysis to demonstrate that odontogenic keratocysts are neoplastic. Arch Pathol Lab Med 2004; 128(3):313–7.

40. Barreto DC, Gomez RS, Bale AE, Boson WL, De Marco L. PTCH gene mutations in odontogenic keratocysts. J Dent Res 2000; 79(6):1418–22.

41. Cohen MM. Nevoid basal cell carcinoma syndrome: molecular biology and new hypotheses. Int J Oral Maxillofac Surg 1999; 28(3):216–23.

42. Levanat S, Gorlin RJ, Fallet S, Johnson DR, Fantasia JE, Bale AE. A two-hit model for developmental defects in Gorlin syndrome. Nat Genet 1996; 12(1):85–7.

43. Lo Muzio L, Staibano S, Pannone G, Bucci P, Nocini PF, Bucci E, and others. Expression of cell cycle and apoptosis-related proteins in sporadic odontogenic keratocysts and odontogenic keratocysts associated with the nevoid basal cell carcinoma syndrome. J Dent Res 1999; 78(7):1345–53.

44. Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma.

Proc Natl Acad Sci USA 1971; 68(4):820–3.

45. Lench NJ, High AS, Markham AF, Hume WJ, Robinson PA. Investigation of chromosome 9q22.3-q31 DNA marker loss in odontogenic keratocysts.

Eur J Cancer B Oral Oncol 1996; 32B(3):202–6.

46. Taipale J, Chen JK, Cooper MK, Wang B, Mann RK, Milenkovic L, Scott MP, and others. Effects of oncogenic mutation in Smoothened and Patched can be reversed by cyclopamine. Nature 2000; 406(6799):1005–9.

47. Zhang L, Sun ZJ, Zhao YF, Bian Z, Fan MW, Chen Z. Inhibition of SHH signaling pathway: molecular treatment strategy of odontogenic keratocyst.

Med Hypotheses 2006; 67(5) :1242–4. Epub 2006 June 27.

JCDA • www.cda-adc.ca/jcda • March 2008, Vol. 74, No. 2 • 165h