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Odontogenic keratocyst: A benign cystic neoplasm?
Oral Oncology (2007) 43, 619–620
available at www.sciencedirect.com
journal homepage: http://intl.elsevierhealth.com/journals/oron/
LETTER TO THE EDITOR
Odontogenic keratocyst: A benign cystic neoplasm? There are some controversies regarding the nature of the odontogenic keratocyst (OKC), also known as keratocystic odontogenic tumour. This subject was addressed at the recent International Association of Oral Pathologists meeting held in Brisbane, Australia. The aggressive behaviour and high recurrence rate of OKC suggests a true neoplastic potential and prompted the World Health Organization Working Group to classify the OKC as a benign tumour with odontogenic epithelium and mature, fibrous stoma without odontogenic ectomesenchyme.1 Although the term tumour is not synonymous with neoplasm, since it also includes hamartomatous tissue proliferations, the authors believe that genetic alterations support the OKCs neoplastic nature. On the other hand, some clinical studies challenged this concept by demonstrating a good response of OKC to marsupialization. Even though this fact points to a non-neoplastic nature, some odontogenic neoplasms may show a positive response to conservative approaches. Recently, we observed a complete regression of the calcifying odontogenic cyst (calcifying cystic odontogenic tumour), a benign odontogenic neoplasm, to marsupialization.2 Mutations in the Patched (PTCH) tumour suppressor gene were identified as the underlying genetic event in nevoid basal cell carcinoma syndrome (NBCC, Gorlin’s syndrome) and sporadic OKCs.3 Until now, we do not know if the development of OKC follows the ‘two-hit’ or the haploinsufficiency models. According to the former, the OKC associated with NBCC would arise from precursor cells containing a hereditary ‘first hit’ followed by allelic loss of the second normal allele, while the sporadic OKC would arise from susceptible cells in which two somatic ‘hits’ have occurred. According to the haploinsufficiency model, the OKC would develop after the loss of only one PTCH allele, leading to reduction of gene dosage. The presence of normal PTCH protein in OKC cases with PTCH non-sense mutation (predicted to result in a truncated protein) suggests the retention of one wild PTCH allele and supports the haploinsufficiency model.4 As many developmental abnormalities described in the NBCC syndrome follow the haploinsufficiency of the PTCH gene, this genetic alteration in OKC is compatible with either a developmental or neoplastic nature. The demonstration that the PTCH alteration reported in OKC is still
compatible with a non-neoplastic condition is confirmed by the presence of loss of heterozygosity of this gene in the dentigerous cyst, a non-neoplastic odontogenic cystic lesion.5 However, the most important evidence that OKC is a neoplasm comes from genetic studies demonstrating loss of heterozygosity of other tumour suppressor genes in OKC cases, e.g.: p53 and p16.6,7 These genetic alterations were not reported in the developmental abnormalities associated with NBCC syndrome, but were commonly found in basal cell carcinoma lesions related to it. Taken together, these studies demonstrate nucleotide instability in OKC, which is characteristic of neoplastic conditions. In conclusion, although additional molecular investigations, including epigenetic studies, should be performed, the current scientific evidence supports the neoplastic nature of OKC.
References 1. Barnes L, Eveson JW, Reichart P, Sidransky D. World Health Organization classification of tumours. Pathology & genetics. Head and neck tumours. Lyon: IARC Press; 2005. 2. Souza LN, Souza ACRA, Gomes CC, Loyola AM, Durighetto-Junior AF, Gomez RS, et al. Conservative treatment of calcifying odontogenic cyst: Report of three cases. J Oral Maxillofac Surg accepted for publication. 3. 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. 4. Barreto DC, Bale AE, De Marco L, Gomez RS. Immunolocalization of PTCH protein in odontogenic cysts and tumors. J Dent Res 2002;81(11):757–60. 5. Pavelic B, Levanat S, Crnic I, Kobler P, Anic I, Manojinovic S, et al. PTCH gene altered in dentigerous cysts. J Oral Pathol Med 2001;30(9):569–76. 6. Agaram NP, Collins B, Barnes L, Lomago D, Aldeeb D, Swalsky P, et al. Molecular analysis to demonstrate that odontogenic keratocyst are neoplastic. Arch Pathol Lab Med 2004;128(3):313–7. 7. Henley J, Summerlin D-J, Tomich C, Zhang S, Cheng L. Molecular evidence supporting the neoplastic nature of odontogenic keratocyst: a laser capture microdissection study of 15 cases. Histopathology 2005;47(6):582–6.
1368-8375/$ - see front matter c 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2006.09.008
620
Letter to the editor Carolina Cavalie ´ri Gomes Ricardo Santiago Gomez Department of Oral Surgery and Pathology, School of Dentistry, Universidade Federal de Minas Gerais, Avenida Antonio Carlos,
6627, 31270901 Belo Horizonte, Minas Gerais, Brazil Tel.: +55 31 34992477; fax: +55 31 34992472 E-mail address: [email protected] (R.S. Gomez) Available online 14 December 2006
available at www.sciencedirect.com
journal homepage: http://intl.elsevierhealth.com/journals/oron/
LETTER TO THE EDITOR
Odontogenic keratocyst: A benign cystic neoplasm? There are some controversies regarding the nature of the odontogenic keratocyst (OKC), also known as keratocystic odontogenic tumour. This subject was addressed at the recent International Association of Oral Pathologists meeting held in Brisbane, Australia. The aggressive behaviour and high recurrence rate of OKC suggests a true neoplastic potential and prompted the World Health Organization Working Group to classify the OKC as a benign tumour with odontogenic epithelium and mature, fibrous stoma without odontogenic ectomesenchyme.1 Although the term tumour is not synonymous with neoplasm, since it also includes hamartomatous tissue proliferations, the authors believe that genetic alterations support the OKCs neoplastic nature. On the other hand, some clinical studies challenged this concept by demonstrating a good response of OKC to marsupialization. Even though this fact points to a non-neoplastic nature, some odontogenic neoplasms may show a positive response to conservative approaches. Recently, we observed a complete regression of the calcifying odontogenic cyst (calcifying cystic odontogenic tumour), a benign odontogenic neoplasm, to marsupialization.2 Mutations in the Patched (PTCH) tumour suppressor gene were identified as the underlying genetic event in nevoid basal cell carcinoma syndrome (NBCC, Gorlin’s syndrome) and sporadic OKCs.3 Until now, we do not know if the development of OKC follows the ‘two-hit’ or the haploinsufficiency models. According to the former, the OKC associated with NBCC would arise from precursor cells containing a hereditary ‘first hit’ followed by allelic loss of the second normal allele, while the sporadic OKC would arise from susceptible cells in which two somatic ‘hits’ have occurred. According to the haploinsufficiency model, the OKC would develop after the loss of only one PTCH allele, leading to reduction of gene dosage. The presence of normal PTCH protein in OKC cases with PTCH non-sense mutation (predicted to result in a truncated protein) suggests the retention of one wild PTCH allele and supports the haploinsufficiency model.4 As many developmental abnormalities described in the NBCC syndrome follow the haploinsufficiency of the PTCH gene, this genetic alteration in OKC is compatible with either a developmental or neoplastic nature. The demonstration that the PTCH alteration reported in OKC is still
compatible with a non-neoplastic condition is confirmed by the presence of loss of heterozygosity of this gene in the dentigerous cyst, a non-neoplastic odontogenic cystic lesion.5 However, the most important evidence that OKC is a neoplasm comes from genetic studies demonstrating loss of heterozygosity of other tumour suppressor genes in OKC cases, e.g.: p53 and p16.6,7 These genetic alterations were not reported in the developmental abnormalities associated with NBCC syndrome, but were commonly found in basal cell carcinoma lesions related to it. Taken together, these studies demonstrate nucleotide instability in OKC, which is characteristic of neoplastic conditions. In conclusion, although additional molecular investigations, including epigenetic studies, should be performed, the current scientific evidence supports the neoplastic nature of OKC.
References 1. Barnes L, Eveson JW, Reichart P, Sidransky D. World Health Organization classification of tumours. Pathology & genetics. Head and neck tumours. Lyon: IARC Press; 2005. 2. Souza LN, Souza ACRA, Gomes CC, Loyola AM, Durighetto-Junior AF, Gomez RS, et al. Conservative treatment of calcifying odontogenic cyst: Report of three cases. J Oral Maxillofac Surg accepted for publication. 3. 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. 4. Barreto DC, Bale AE, De Marco L, Gomez RS. Immunolocalization of PTCH protein in odontogenic cysts and tumors. J Dent Res 2002;81(11):757–60. 5. Pavelic B, Levanat S, Crnic I, Kobler P, Anic I, Manojinovic S, et al. PTCH gene altered in dentigerous cysts. J Oral Pathol Med 2001;30(9):569–76. 6. Agaram NP, Collins B, Barnes L, Lomago D, Aldeeb D, Swalsky P, et al. Molecular analysis to demonstrate that odontogenic keratocyst are neoplastic. Arch Pathol Lab Med 2004;128(3):313–7. 7. Henley J, Summerlin D-J, Tomich C, Zhang S, Cheng L. Molecular evidence supporting the neoplastic nature of odontogenic keratocyst: a laser capture microdissection study of 15 cases. Histopathology 2005;47(6):582–6.
1368-8375/$ - see front matter c 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2006.09.008
620
Letter to the editor Carolina Cavalie ´ri Gomes Ricardo Santiago Gomez Department of Oral Surgery and Pathology, School of Dentistry, Universidade Federal de Minas Gerais, Avenida Antonio Carlos,
6627, 31270901 Belo Horizonte, Minas Gerais, Brazil Tel.: +55 31 34992477; fax: +55 31 34992472 E-mail address: [email protected] (R.S. Gomez) Available online 14 December 2006