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The odontogenic keratocyst revisited

  • P.J.W. Stoelinga
    Correspondence
    Address: Paul J. W. Stoelinga, Department of Oral and Maxillofacial Surgery, Radboud University, Nijmegen, The Netherlands.
    Affiliations
    Department of Oral and Maxillofacial Surgery, Radboud University, Nijmegen, The Netherlands
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Open AccessPublished:March 08, 2022DOI:https://doi.org/10.1016/j.ijom.2022.02.005

      Abstract

      The treatment of odontogenic keratocysts is reviewed in light of the aetiology and pathogenesis of these lesions. The role of the dental lamina and submucosal hamartias, as frequently seen in nevoid basal cell carcinoma syndrome, is discussed, and the implications for treatment are emphasized.

      Key words

      Since the introduction of the term ‘keratocyst’ by Philipsen in 1956
      • Philipsen H.P.
      Om keratocyster (Kolesteatomer) i kaebaerne.
      , a large number of publications have been devoted to this subject. The aetiology, pathogenesis, presentation, and the various modes of treatment, as suggested by several authors, have resulted in hundreds of articles in various journals. It is particularly the tendency of keratocysts to recur after surgical treatment that has prompted many follow-up studies, all but one of which have been retrospective in nature
      • Stoelinga P.J.W.
      Long-term follow-up on keratocysts treated according to a defined protocol.
      . In the 1960s and 1970s, the reported recurrence rates were in the order of 40% to 60%, which probably reflected the fact that surgeons were not familiar with the potential aggressiveness of this newly discovered entity
      • Pindborg J.J.
      • Hansen J.
      Clinical and roentgenologic aspects of odontogenic keratocysts.
      • Hansen J.
      Keratocysts in the jaws.
      • Vedtofte P.
      • Praetorius F.
      Recurrences of the odontogenic keratocyst in relation to clinical and histological features.
      . In all of these reports, the cyst was just enucleated or removed by curettage.
      Current follow-up studies are still reporting fairly high recurrence rates despite attempts to remove possible epithelial cell nests from the cyst membrane by peripheral ostectomies, the use of Carnoy’s solution, or marsupialization and secondary enucleation of the lesion. Blanas et al.
      • Blanas N.
      • Freund B.
      • Schwartz M.
      • Furst J.
      Systematic review of the treatment and prognosis of the odontogenic keratocyst.
      performed a systematic review to summarize the results of these interventions up until the year 2000, and found only 14 studies that met their inclusion criteria. The reported recurrence rates varied from 17% to 56% when just an enucleation was performed. If any adjunctive treatment was applied, such as the use of Carnoy’s solution or decompression before enucleation, the recurrence rates went down to 1% to 8.7%. The follow-up periods, however, varied from 6 months to 21 years. They did not specify how many of them recurred within the first 5 years. It is generally assumed that most recurrences occur in the first 5 years, but this is difficult to prove since most studies have only included a few cases with follow-up of more than 10 years. There is, however, a fair amount of evidence that late recurrences may occur after 10–25 years
      • Stoelinga P.J.W.
      Long-term follow-up on keratocysts treated according to a defined protocol.
      • Stoelinga P.J.W.
      • da Silva Y.S.
      The significance of recurrent odontogenic keratocyts in bone grafts.
      . It is also likely that in most of these studies the orthokeratotic variant had been included
      • Chirapathomsakul D.
      • Sastravaha P.
      • Jansisyanont P.
      A review of odontogenic keratocysts and the behavior of recurrences.
      • Pitak-Arnnop P.
      • Chaine A.
      • Oprean N.
      • Dhanuthai K.
      • Bertrand J.C.
      • Bertolus C.
      Management of odontogenic keratocysts of the jaws: a ten-year experience with 120 consecutive lesions.
      . This would have affected the recurrence rates favourably, since it is known that this type of keratocyst does not give rise to recurrences
      • Siar C.H.
      • Ng K.H.
      Othokeratinised odontogenic keratocysts in Malaysians.
      • Crowley T.E.
      • Kaugars G.E.
      • Cunsolley J.C.
      Odontogenic keratocysts: a clinical and histologic comparison of the parakeratin and orthokeratin variants.
      .
      A more recent systematic review by Al-Moraissi et al.
      • Al-Moraissi E.A.
      • Pogrel M.A.
      • Ellis III, E.
      Enucleation with or without adjuvant therapy versus marsupialisation with or without secondary enucleation in the treatment of keratocystic tumors: a systematic review and meta-analysis.
      showed lower recurrence rates in patients who underwent primary enucleation with or without adjuvant therapy versus a group who underwent decompression ± secondary enucleation. A total of 997 odontogenic keratocysts (OKCs) were included in the review, of which 843 underwent primary enucleation and 154 underwent decompression ± secondary enucleation. The recurrence rates were 18.2% and 27.1%, respectively. Follow-up in both groups, however, varied from 1 to 29 years, and this was reported as either an average follow-up time or by mentioning the shortest and longest follow-up time. The fairly moderate recurrence rates are probably due to a substantial number of cases that were not followed up for longer than 5 years.
      It is only fair to say that little progress has been made over the last 40 years with regard to the recurrence rates of OKCs. One may easily become confused by the variety of opinions and treatment protocols that have been presented. It is the aim of this review to put all aspects of this intriguing lesion into perspective, including the aetiology, pathogenesis, and treatment. Both the solitary OKC and OKCs occurring in the context of nevoid basal cell carcinoma syndrome (NBCCS) will be addressed.

      Syndrome OKCs

      Despite the fact that solitary OKCs and syndrome OKCs appear alike when studied histologically, they probably have a different origin in many instances. There was and still is a general belief that all OKCs derive from remnants of the dental lamina. This hypothesis was first suggested by Hjörting-Hansen et al.
      • Hjörting-Hansen E.
      • Andreasen J.O.
      • Robinson L.H.
      A study of odontogenic cysts, with special reference to location of keratocysts.
      in 1969 and was reiterated by Toller
      • Toller P.A.
      Newer concepts of odontogenic cysts.
      , who even suggested the name ‘laminar cysts’. This may be true for many of the solitary OKCs, but is not likely the case with the syndrome cysts
      • Stoelinga P.J.
      • Peters J.H.
      • van de Staak W.J.
      • Cohen Jr, M.M.
      Some new findings in the basal-cell nevus syndrome.
      . A study on syndrome cysts that were removed with inclusion of the attached oral mucosa or gingiva, showed that the OKCs were derived from hamartias in the submucosa in 12 of 13 cases (Fig. 1)
      • Stoelinga P.J.W.
      • Cohen Jr., M.M.
      • Morgan A.F.
      The origin of keratocysts in the basal cell nevus syndrome.
      . These hamartias are almost certainly derived from offshoots of the basal layer of the epithelium covering the mucosa, since in many cases they were connected to this basal layer. This theory was endorsed by Gorlin et al.
      • Gorlin R.J.
      • Cohen Jr., M.M.
      • Levin L.S.
      Syndromes of the head and neck.
      . The similarity with the basal cell nevi in the skin that occur in this syndrome is striking. The penetration of the OKC into the bone has to be caused by an induction process
      • Stoelinga P.J.W.
      • Cohen Jr., M.M.
      • Morgan A.F.
      The origin of keratocysts in the basal cell nevus syndrome.
      (see further). The syndrome cysts arise at a much earlier age than the solitary OKCs and they may affect children in the first decade of life (Fig. 2)
      • Gorlin R.J.
      • Cohen Jr., M.M.
      • Levin L.S.
      Syndromes of the head and neck.
      . The aetiology and pathogenesis of the syndrome OKCs make the adjective ‘odontogenic’ questionable.
      Fig. 1
      Fig. 1High power view of a biopsy from the maxillary tuberosity of a patient with nevoid basal cell carcinoma syndrome, showing a typical hamartia (haematoxylin–eosin, ×90).
      Fig. 2
      Fig. 2Pseudo-dentigerous odontogenic keratocyst (OKC) in a 9-year-old boy suffering from nevoid basal cell carcinoma syndrome. Note the two small OKCs on top of the main OKC, which were located in the submucosa.

      Solitary OKCs

      The name ‘solitary OKC’ is somewhat misleading, because they may occur as multiple cysts in persons without the symptoms of NBCCS. Yet, this name is understood to be a keratocyst not related to NBCCS. Solitary OKCs may occur anywhere in the jaws, but the frequency is higher for the posterior mandible and somewhat less so for the posterior maxilla
      • Stoelinga P.J.W.
      Long-term follow-up on keratocysts treated according to a defined protocol.
      • Chirapathomsakul D.
      • Sastravaha P.
      • Jansisyanont P.
      A review of odontogenic keratocysts and the behavior of recurrences.
      • Pitak-Arnnop P.
      • Chaine A.
      • Oprean N.
      • Dhanuthai K.
      • Bertrand J.C.
      • Bertolus C.
      Management of odontogenic keratocysts of the jaws: a ten-year experience with 120 consecutive lesions.
      . However, a substantial number of OKCs occur in the tooth-bearing area
      • Slusarenko da Silva Y.
      • Stoelinga P.J.W.
      • Naclerio-Homen M.
      The presentation of odontogenic keratocysts in the jaws with an emphasis on the tooth bearing area: a systematic review and meta-analysis.
      . The aetiology and pathogenesis of solitary OKCs have been described extensively
      • Stoelinga P.J.W.
      • Peters J.H.
      A note on the origin of keratocysts of the jaws.
      • Stoelinga P.J.W.
      Studies on the dental lamina as related to its role in the etiology of cysts and tumors.
      . In short, the dental lamina disintegrates after it has laid down the tooth buds of the permanent teeth. The possible remnants are expected to be located in the gingiva or periodontium and certainly not in the bone
      • Stoelinga P.J.W.
      • Peters J.H.
      A note on the origin of keratocysts of the jaws.
      • Stoelinga P.J.W.
      Studies on the dental lamina as related to its role in the etiology of cysts and tumors.
      . The remote possibility exists that after the formation of the third molars, an offshoot of the distally growing dental lamina persists. It is fully understandable that remnants of the dental lamina, including a distal offshoot, would be responsible for the development of OKCs, and that is certainly true for the tooth-bearing area. The fact that many lateral periodontal cysts and lateral follicular cysts turn out to be OKCs fits with this picture
      • Stoelinga P.J.W.
      Long-term follow-up on keratocysts treated according to a defined protocol.
      • Pitak-Arnnop P.
      • Chaine A.
      • Oprean N.
      • Dhanuthai K.
      • Bertrand J.C.
      • Bertolus C.
      Management of odontogenic keratocysts of the jaws: a ten-year experience with 120 consecutive lesions.
      • Voorsmit R.A.C.A.
      The incredible keratocyst. Thesis.
      . There is, however, no actual proof of this hypothesis.
      An alternative theory might be that, like in the syndrome cysts, submucosal hamartias play a role. In a prospective study in which the overlying, attached mucosa was excised in 23 of the 44 cases, these hamartias were seen
      • Stoelinga P.J.W.
      Long-term follow-up on keratocysts treated according to a defined protocol.
      . They were almost all located in the retromolar area of the mandible or in the maxillary tuberosity. In only two cases were epithelial islands seen in other parts of the cyst wall
      • Stoelinga P.J.W.
      Long-term follow-up on keratocysts treated according to a defined protocol.
      . These islands were probably displaced when the cyst expanded and penetrated into the bone.
      The fact that the OKCs originate from an epithelial residue of the dental lamina located in the gingiva, or a hamartia in the submucosa, does not disprove the fact that they are located in the bone. This penetration into the bone has to be based on an induction phenomenon very similar to what happens when the permanent molars are developing. The dental lamina is growing distally in the submucosa to lay down the molar tooth buds. The epithelial–mesenchymal interaction apparently induces bone resorption, creating crypts in which the developing tooth buds will be positioned
      • Stoelinga P.J.W.
      Studies on the dental lamina as related to its role in the etiology of cysts and tumors.
      • Stoelinga P.J.W.
      Etiology and pathogenesis of keratocysts.
      . An example of the potential of the growing dental lamina to resorb even a bone graft and to lay down a tooth bud in the graft is shown in Fig. 3.
      Fig. 3
      Fig. 3(A) Radiograph of a 9-year-old boy with hemifacial microsomia who underwent an osteotomy in the right ascending ramus and received a rib graft on the left side. (B) The second radiograph, taken at 16 years old, shows the development of the second molar and the third molar, which developed in the grafted bone. Courtesy Dr D. Trimble.

      Implications for treatment

      Considering the aspects of the aetiology and pathogenesis of OKCs described, it is unlikely that the recurrence rate of these lesions can be brought down to zero. True recurrences might be due to remnants of the fragile cyst membrane that are left behind. The same is true for microcysts or epithelial islands, as sometimes seen in the connective tissue wall of the cyst. The use of Carnoy’s solution or, in certain cases, electrocauterization when the cyst has reached the soft tissues, be it mostly lingual in the mandible or buccal in the maxilla, may prevent this from happening. It is important to mention in this context that in many countries chloroform is no longer a permitted constituent of Carnoy’s solution. It follows that there is a need for a study on the efficacy of Carnoy’s solution without chloroform. A suitable substitute that has the same working mechanism as the original Carnoy’s solution would also be very welcome.
      Recurrences as a result of new cyst formation due to the presence of hamartias in the overlying mucosa, whether it concerns epithelial islands or microcysts, are more difficult to avoid. Even when the attached mucosa has been excised it cannot be ruled out that new offshoots of the mucosa will occur or that the excision has not included all epithelial islands or microcysts present. This obviously was the reason for some of the recurrences in a previous study
      • Stoelinga P.J.W.
      Long-term follow-up on keratocysts treated according to a defined protocol.
      .
      A rational approach to OKCs aimed at minimizing the number of recurrences has been presented in several publications
      • Stoelinga P.J.W.
      Long-term follow-up on keratocysts treated according to a defined protocol.
      • Slusarenko da Silva Y.
      • Stoelinga P.J.W.
      • Naclerio-Homen M.
      The presentation of odontogenic keratocysts in the jaws with an emphasis on the tooth bearing area: a systematic review and meta-analysis.
      • Voorsmit R.A.C.A.
      • Stoelinga P.J.W.
      • van Haelst U.J.G.M.
      The management of keratocysts.
      • Stoelinga P.J.W.
      The treatment of odontogenic keratocysts by excision of the overlying attached mucosa, enucleation and treatment of the bony defect with Carnoy solution.
      • Chapelle K.A.
      • Stoelinga P.J.
      • de Wilde P.C.
      • Brouns J.J.
      • Voorsmit R.A.
      Rational approach to diagnosis and treatment of ameloblastomas and odontogenic keratocysts.
      . In short, the usually small cysts in the dentate area that are just enucleated and turn out to be an OKC, could be treated in a second intervention with Carnoy’s solution. This would help to eliminate possible epithelial cell nests that were left behind. All unicystic lesions in the posterior mandible, including the third molar area and ascending ramus, are best treated as a possible OKC or unicystic ameloblastoma. This would require excision of the overlying attached mucosa after which the cyst is enucleated in conjunction with the excised mucosa and the defect wiped out with (a modified) Carnoy’s solution. The area where the mucosa is attached to the cyst wall can easily be located using modern imaging techniques, which will clearly show the anterior fenestration in the ascending ramus, when present. The defect is left to heal by secondary intention, which implies the use a ribbon soaked in Whiteheads varnish or iodoform Vaseline that is packed in the bony defect. This needs to be changed every 7–10 days until the defect can be kept clean by rinsing. Cysts in the maxilla that include the tuberosity area may be treated the same way. The use of Carnoy’s solution, however, should be limited to the tuberosity area. Many of these cysts have expanded into the maxillary sinus, which prevents the use of Carnoy’s solution in that area for obvious reasons. In those cases, the wound needs to be closed primarily. The fenestration is usually located on top of the tuberosity. When hamartias are seen in the attached mucosa, long-term follow-up is warranted since it will not be certain that all of the epithelial islands have been removed or that new ones will develop.
      The protocol described does not include multicystic lesions. They would require a preoperative biopsy to rule out another pathology.

      Funding

      None.

      Competing interests

      None.

      Ethical approval

      Not applicable.

      Patient consent

      Not applicable.

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