A narrative review of clinical outcome measures in the management of odontogenic keratocystic lesions

Introduction

Background

Odontogenic keratocysts (OKCs) are benign developmental cysts that arise from the dental lamina and are most commonly found in the posterior mandible (1). Although benign, OKCs are locally aggressive and are associated with a high recurrence rate if not treated adequately. These lesions account for approximately 11–15% of all jaw cysts and are most frequently diagnosed in individuals between the second and fifth decades of life, with a slight male predominance (1). In 2005, the World Health Organization (WHO) reclassified the lesion as a keratocystic odontogenic tumor (KCOT) based on its neoplastic behavior and histologic characteristics. However, in 2015, the WHO reverted the nomenclature to OKC (1,2). Despite the terminological changes, the lesion’s clinical behavior remains consistent with that of a tumor, and many clinicians continue to view it as such due to its biological aggressiveness and potential for recurrence. Based on molecular and genetic markers, the authors support the nomenclature of the 2005 tumor-based naming.

Rationale and knowledge gap

The optimal management of OKCs remains a point of debate within the oral and maxillofacial surgery field. While several treatment strategies have been described—including marsupialization, enucleation, curettage, cryotherapy, peripheral ostectomy, and resection—there is no clear consensus on which approach consistently results in the lowest recurrence while minimizing morbidity (3-5). Moreover, newer adjunctive treatments such as 5-fluorouracil (5-FU) have shown early promise, but long-term outcomes are still being established (4,6-9). The literature is filled with variability in technique, follow-up duration, and outcome reporting, making it difficult to draw definitive conclusions across studies. This inconsistency highlights a clear gap in standardized treatment protocols and comparative data on recurrence rates between traditional and emerging modalities.

Objective

The primary objective of this review is to evaluate the clinical outcomes and recurrence rates associated with various treatment modalities for OKCs. By analyzing the current literature on conservative techniques, adjunctive therapies, and radical resections, this paper aims to identify which treatments are associated with the most favorable outcomes and where further research is still needed. Ultimately, the goal is to help inform evidence-based decision-making and contribute toward more standardized treatment approaches for this challenging pathology. We present this article in accordance with the Narrative Review reporting checklist (available at https://fomm.amegroups.com/article/view/10.21037/fomm-24-57/rc).

Methods

A literature review was conducted using PubMed, Google Scholar, and Cochrane Library databases to identify relevant studies published from January 1980 through June 2025. Priority was given to retrospective cohort studies, prospective trials, and systematic reviews focusing on treatment outcomes for odontogenic keratocystic lesions. Only studies that clearly reported recurrence rates and follow-up periods were included for analysis (Table 1).

Conservative techniques

Marsupialization

Marsupialization is the decompression of a lesion, which decreases hydrostatic forces placed on surrounding structures. A Polish professor, Carl Franz Maria Partsch, is credited with first introducing the concept of marsupialization in 1892 (10). In addition to decreasing the size of the lesion, some clinicians have argued that marsupialization changes the composition of odontogenic keratocystic lesions at the histological level, returning the lining to normal epithelium (11). The article describing this change histologically argues that after marsupialization, the pathology is no longer an odontogenic keratocystic lesion. To further investigate this concept, Schlieve, Miloro, and Kolokythas, in 2014, conducted a retrospective cohort study in which patients with benign odontogenic cyst-like lesions treated with marsupialization were evaluated at the histological level. It was found that 10 of 11 (91%) odontogenic keratocystic lesions had post-decompression histologic diagnosis consistent with the preoperative biopsy diagnosis (12). Thus, marsupialization alone seems to be inadequate to treat odontogenic keratocystic lesions.

In 2021, a retrospective study was published evaluating odontogenic keratocystic lesions treated with marsupialization followed by enucleation. Of 266 patients diagnosed with an odontogenic keratocystic lesion between 1993 and 2013 and treated with decompression and enucleation, 35.8% had a recurrence (13).

Although marsupialization can successfully decrease the physical size of an odontogenic keratocystic lesion, research has demonstrated that it does not have the consistent ability to change the histologic makeup of the lesion, and its high rate of recurrence when combined with enucleation leaves other treatment modalities as a better standard of care (12,13).

Enucleation and curettage

The clinical outcomes of enucleation and curettage of odontogenic keratocystic lesions have been well documented. In 1998, Meara et al. conducted a 20-year retrospective study that evaluated 49 patients with odontogenic keratocystic lesions. Follow-up ranged from 1 to 15 years, and the overall recurrence rate of these lesions treated with enucleation was 35% (14). In 1999, Francone conducted a retrospective study that evaluated 40 cases of odontogenic keratocystic lesions. Nineteen of the cases were treated with simple cystectomy, 8 of which (42%) led to recurrence (15). In 2001, Myoung evaluated 256 cases of odontogenic keratocystic lesions. Two hundred and thirty-two of the patients were treated with enucleation, and 22 patients were treated with marsupialization followed by enucleation. One hundred and twenty-four patients were lost to follow-up for various reasons, but of the 132 patients who were followed, 77 (58.3%) of the patients had a recurrence (16). Each of these articles demonstrates that enucleation and curettage of odontogenic keratocystic lesions has a high recurrence rate.

With the understanding that odontogenic keratocystic lesions recur when treated with enucleation alone, a variety of adjunctive therapies have been trialed. Some of the therapies include cryotherapy, peripheral ostectomy, Carnoy’s solution, modified Carnoy’s solution, and 5-FU.

Adjunctive techniques

Curettage and cryotherapy

An adjunctive therapy trialed with enucleation and curettage for the treatment of odontogenic keratocystic lesions is cryotherapy. Cryotherapy involves applying liquid nitrogen or other refrigerant gas mixture spray to the cavity of the enucleated lesion to induce necrosis of affected cells via temperature. The typical temperatures achieved with cryotherapy are −20 ℃ (17,18). In 2001, a retrospective study out of the University of California at San Francisco evaluated 26 lesions treated with enucleation followed by liquid nitrogen cryotherapy. The method included spraying the cavity twice for 1 minute with liquid nitrogen with a 5-minute interval between sprays. Results demonstrated a recurrence rate of 11.5% with an average follow-up time of only 3.5 years (19). It should be noted that of these 26 patients, 22 had previous treatment with enucleation alone and had a recurrence after an average of 6.2 years after treatment.

In 1990, a paper out of Denmark compared recurrence rates of odontogenic keratocystic lesions after enucleation alone, enucleation and cryotherapy, and enucleation with fixation of Carnoy’s solution to the cystic membrane before enucleation (20). The preliminary report demonstrated that with enucleation alone, 5 of 14 lesions (36%) had a recurrence after 17-39 months. Similarly, 5 of 14 lesions (36%) treated with enucleation followed by cryotherapy had a recurrence after 22–59 months (20). Jensen, in 1988, evaluated 25 odontogenic keratocystic lesions in 22 patients from 1981 to 1984, none of which had Gorlin’s syndrome. Twelve lesions in 12 patients were treated with enucleation alone. Thirteen lesions in 10 patients were treated with enucleation with cryotherapy. In this study, the cavity was frozen to −70 ℃ twice with nitrous oxide for 1 minute, including adjacent soft tissue structures for 30 seconds. The overall recurrence rate of enucleation alone versus enucleation and cryotherapy was 33% and 38%, respectively (21).

In 1996, a study from the University of Umea in Sweden retrospectively compared recurrence rates of odontogenic keratocystic lesions treated with enucleation alone versus enucleation after cryotherapy. The study found that of 63 odontogenic keratocystic lesions treated with enucleation alone, 18 (28.5%) recurred. Of the lesions treated with enucleation after cryotherapy, 6 of 16 (37.5%) recurred (22).

More recently, Carneiro et al. in 2014 conducted a retrospective study where 29 patients with mandibular tumors were treated with a mixture of propane, butane, and isobutane gas. Nine of the lesions were proven OKCs, and 2 of 9 (22.22%) treated with cryotherapy after enucleation developed a recurrence during a 54–120-month follow-up period (23). In 2017, de Souza Cruz et al. conducted a retrospective in which 10 patients with OKCs were treated with a similar refrigerant propane/butane/isobutane gas mixture as cryotherapy after enucleation. The follow-up time for the 10 patients was 24–120 months, and 2 (20%) developed a recurrence (18).

A systematic review by Tay et al. in 2021 evaluated chemical adjuncts and cryotherapy in the management of OKCs. In this review, 119 OKCs were treated with cryotherapy and a follow-up period ranging from 6 to 120 months. Analysis demonstrated a recurrence rate of about 30% in those treated with enucleation followed by cryotherapy (24). This review created an additional analysis of the articles that had explicit, detailed information on the management of the OKCs to minimize bias. Within this analysis, 24 OKCs were managed with enucleation followed by cryotherapy, and 7 (29.17%) had a recurrence over a follow-up time of 21–108 months. The authors state the data failed to demonstrate any statistically significant difference in outcome when comparing cryotherapy versus no adjunct therapy (24-26). From each of these studies, the outcomes demonstrate that enucleation with cryotherapy does not offer a significant benefit over enucleation alone.

Curettage and peripheral ostectomy

Curettage with peripheral ostectomy refers to the use of rotary instruments to remove the bone adjacent to a lesion. The primary goal of this technique is to remove all residual cells, epithelium, or cysts. Staining the bony cavity with methylene blue or another dye is a technique to help visualize which aspects of the cavity have been addressed during the ostectomy (27). This treatment is technique-sensitive, and the ability to consistently repeat the same method between providers is difficult. For this reason, no strong, reproducible studies demonstrate the effectiveness of peripheral ostectomy in treating odontogenic keratocystic lesions.

Kolokythas, Fernades, Pazoki, and Ord in 2007 documented eight patients who were treated with enucleation and peripheral ostectomy. With a follow-up ranging from 1.5 to 9 years, this study recorded no recurrences (28). Limitations to this study include sample size, duration of follow-up, and a lack of description of how the peripheral ostectomy was performed. A meta-analysis of different treatment modalities of odontogenic keratocystic lesions was conducted by Al-Moraissi et al. in 2023. Across 16 studies, 711 odontogenic keratocystic lesions were treated with enucleation with peripheral ostectomy. Among the studies, 102 lesions (14.3%) recurred; the shortest recurrence time was less than 24 months (4). Although a larger sample size across the 16 studies, it should be noted that it is impossible to discern the consistency in surgical technique and standardization across surgeons in each study. With this being said, a recurrence rate of 14% is an improved treatment modality compared to marsupialization versus enucleation and curettage or versus enucleation and curettage with cryotherapy described in this review thus far.

Curettage and application of Carnoy’s

Carnoy’s solution is another adjunct used with enucleation and curettage for the treatment of odontogenic keratocystic lesions. The solution consists of ethyl alcohol, chloroform, glacial acetic acid, and ferric chloride (29). Through initial utilization, clinicians found that neurotoxicity was a shortcoming of Carnoy’s solution. In 1994, Frerich et al. evaluated the critical time of exposure of the inferior alveolar nerve to Carnoy’s solution to address this concern. By exposing rabbits to Carnoy’s solution for a period of 30 seconds to 10 minutes and testing their somatosensory evoked potentials, Frerich determined that 3 minutes was the maximum amount of time the nerve could be exposed to Carnoy’s solution before developing some neurotoxicity (30).

The study out of Denmark in 1990, previously described in this review for cryotherapy, also evaluated Carnoy’s solution. Of the odontogenic keratocystic lesions treated with Carnoy’s solution, 0 of 10 patients had a recurrence (20). In 2000, a systematic review conducted by Blanas et al. found that 1 of 60 lesions (1.6%) treated with enucleation and Carnoy’s solution had a recurrence (31). In a second systematic review from 2013, the authors compared their findings for the treatment of odontogenic keratocystic lesions to the Blanas et al. review. In their report, 63 lesions were treated with enucleation with Carnoy’s solution, and 5 (7.9%) had a recurrence (32).

More recently, in 2023, Winters et al. conducted a systematic review for the safety and efficacy of adjunctive therapy in the treatment of odontogenic keratocystic lesions. A total of 62 patients were included through four studies that met the inclusion criteria. Of the 10 patients treated with Carnoy’s solution, there were no recurrences with follow-up times ranging from 41.8 to 60 months (6,33). Based on each of these systematic reviews, as well as the study from Denmark, the recurrence rates of less than 10% support that using Carnoy’s solution is a viable option for treating odontogenic keratocystic lesions.

Unfortunately, in 2013, the Food and Drug Administration (FDA) banned the use of chloroform, and the production of Carnoy’s solution was terminated. As a result, a modified Carnoy’s solution without chloroform was formulated. A study out of the University of Michigan studied the rate of recurrence in odontogenic keratocystic lesions with enucleation and curettage with Carnoy’s versus modified Carnoy’s solution. From 1996 to 2014, 80 patients met the inclusion criteria (44 treated with Carnoy’s solution and 36 with modified Carnoy’s solution). The recurrence rate for Carnoy’s solution was 10%, with an average recurrence time of 41.5 months. The recurrence rate of modified Carnoy’s solution was 35%, with an average recurrence time of 30 months (34).

Worth a discussion is an 18-year retrospective cohort study conducted by Janas-Naze et al. in 2023, which compared the effectiveness of Carnoy’s versus modified Carnoy’s in the management of OKCs in 122 patients. The study’s method consisted of enucleation and curettage of the lesion with elective extraction of indicated teeth, peripheral ostectomy using a round bur, treatment with either Carnoy’s solution (73 patients) or modified Carnoy’s (49 patients) for 3 minutes followed by irrigation, and finally excision of overlying mucosa (35). The Carnoy’s arm had 6 (8.2%) recurrences, and the modified Carnoy’s arm had 5 (10.2%) recurrences (35). The study found no statistically significant difference between the two solutions. The writer highlights that the lack of surgical standardization could be a reason for the discrepancy from the Dashow et al. study out of the University of Michigan, which demonstrated a statistically significant difference between modified Carnoy’s and Carnoy’s solution. In the Janas-Naze et al. study, there was a single surgeon for all procedures, whereas the Dashow et al. study had three operating surgeons involved (34,35). With multiple operating surgeons, it is difficult to standardize the degree of peripheral ostectomy completed, as mentioned previously in the manuscript with the discussion of enucleation and curettage followed by peripheral ostectomy for the treatment of OKCs (36-38).

Recently, in 2024, a systematic review comparing modified Carnoy’s solution to 5-FU for the treatment of OKCs found that of 114 patients treated with modified Carnoy’s solution, 27 (23.7%) patients developed a recurrence in a median recurrence time of 42 months (39). Based on this study, modified Carnoy’s solution failed to provide consistently improved recurrence rates compared to enucleation and curettage, marsupialization, or cryotherapy.

Curettage and application of 5-FU

5-FU is a thymidylate synthase inhibitor that blocks the synthesis of pyrimidine thymidylate and prohibits DNA replication. Over the past 5–8 years, 5-FU has increased in popularity for treating odontogenic keratocystic lesions. In 2017, an ambispective cohort study out of the University of Toronto was conducted to evaluate the efficacy of topical 5-FU compared to modified Carnoy’s solution for the treatment of odontogenic keratocystic lesions. In this study, sterile quarter-inch ribbon gauze that was coated with 5% 5-FU was placed in the site of the enucleated lesion and left for 24 hours before removal. Of the 32 patients with 32 odontogenic keratocystic lesions, there were no recurrences in the 5-FU group (n=11), with a mean follow-up time of 35.0±8.5 months. There were four recurrences in the modified Carnoy’s solution group (n=21) after enucleation and peripheral ostectomy, with a mean follow-up time of 41.3±3.8 months. Additionally, there was a significantly lower incidence of paresthesia of the inferior alveolar nerve in the 5-FU group when compared to the modified Carnoy’s solution (7).

Akhter Lone et al., in 2020, conducted a prospective study over 7 years where odontogenic keratocystic lesions in 27 patients were treated with either (I) enucleation and modified Carnoy’s solution, (II) peripheral ostectomy and 5-FU, or (III) segmental resection. Eleven patients were treated with peripheral ostectomy and 5-FU, which was administered via coating on sterile ribbon gauze and left within the bony cavity for 24 hours postoperatively before removal. There were no recurrences in the 5-FU group, and only one patient had temporary paresthesia, which resolved over time (8).

Singh et al., in 2022, published in the British Journal of Oral and Maxillofacial Surgery a systematic review and meta-analysis on the effectiveness of 5-FU as an adjuvant in the management of odontogenic keratocystic lesions. Although the authors underscore the overall low quality of evidence of each study, a total of 56 cases were reviewed of patients treated with 5-FU, and no cases had recurrences or permanent paresthesia (9).

Jacobs et al., in 2024, referenced previously in this review during the discussion of modified Carnoy’s solution, conducted a systematic review and meta-analysis comparing 5-FU with modified Carnoy’s solution for the treatment of OKCs. Of the 6 studies that met the inclusion criteria, which included having at least 12 months of follow-up, there were 0 recurrences among 99 patients (39). Two of the six articles in the systematic review are the studies by Akhter Lone et al. and Ledderhof et al. discussed in this manuscript, and the remaining four studies included three randomized comparative studies (40-42) as well as one retrospective Cohort study (43). A limitation to the comparative study by Wanve et al., which was underscored in the Jacobs et al. systematic review, was the short follow-up time of 1 year (39,41). Through each of the studies, the clinical outcome measures have demonstrated promising results for 5-FU as a successful adjunct treatment for odontogenic keratocystic lesions.

Resection

Management of odontogenic keratocystic lesions through resection has the lowest rate of recurrence, but is also associated with significant morbidity. In a study evaluating 35 patients who underwent radical resection of mandibular odontogenic keratocystic lesions followed by immediate defect reconstruction, one patient had a recurrence (44). In this study, 28 of the 35 patients had immediate reconstruction with a vascularized flap, which may reduce the morbidity associated with the resection. Although an effective method for the treatment of odontogenic keratocystic lesions, it remains an excessively aggressive treatment option when compared to enucleation and peripheral ostectomy with or without 5-FU.

Fidele Bushabu et al. in 2023 conducted a systematic review for clinical indications for radical resection of OKCs. Of 10 studies that were included in the review, 221 OKCs underwent segmental or marginal resections. The study highlights that the main indications for resection were multilocular appearance, large OKCs (>5 cm), lesions with multiple recurrences, primary or recurrent lesions with radiolucencies extending beyond the thinned inferior border of the mandible, or malignant transformation (45). It should be noted that the overall level of evidence in these studies is low, but the review highlights that resection, whether marginal or segmental, has a place in the management of odontokeratocystic lesions.

Strengths and limitations

A strength of this review is its comprehensive approach in evaluating a wide range of treatment modalities for OKCs, from traditional techniques such as marsupialization and enucleation to more contemporary adjuncts like cryotherapy, Carnoy’s solution, and 5-FU. The inclusion of both historical context and recent advances offers a well-rounded perspective for clinicians navigating the complexities of OKC management. This paper also brings attention to emerging therapies, like topical 5-FU, which have demonstrated encouraging preliminary outcomes.

However, the most significant limitation of this review—and the current body of OKC literature as a whole—is the lack of randomized controlled trials. The overwhelming majority of available data comes from retrospective studies, which are subject to selection bias, limited control of confounding variables, and heterogeneity in surgical techniques and follow-up periods (46). The absence of prospective, randomized studies weakens the strength of evidence and limits the ability to draw definitive conclusions regarding treatment efficacy. Furthermore, variability in study design and inconsistent reporting of outcomes make it difficult to standardize treatment recommendations (46,47). As a result, while this review helps contextualize current practices, it also highlights the need for high-quality, multicenter prospective trials to establish evidence-based protocols for the management of OKCs.

Conclusions

This narrative review highlights the broad spectrum of management strategies for odontogenic keratocystic lesions, ranging from conservative to aggressive surgical approaches. Among the various modalities, 5-FU emerges as a particularly promising adjunctive therapy—showing low recurrence rates with reduced morbidity compared to more aggressive treatments like resection. While resection remains the most definitive option, its associated functional and aesthetic consequences make it less ideal as a first-line treatment for many patients. In contrast, 5-FU may offer a more balanced approach, though its application protocols remain highly variable and underexplored.

Prospective, randomized controlled trials are urgently needed to establish the comparative efficacy of these treatments. Future research should focus not only on the long-term outcomes of 5-FU, but also on the method of its application. Areas of future research should study whether the rate of recurrence of OKCs is influenced by the quantity of time 5-FU is exposed to the pathology. Can this adjunctive therapy be placed as briefly as minutes, or must it be placed in the enucleated cavity for an extended period of time?

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://fomm.amegroups.com/article/view/10.21037/fomm-24-57/rc

Peer Review File: Available at https://fomm.amegroups.com/article/view/10.21037/fomm-24-57/prf

Funding: None

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://fomm.amegroups.com/article/view/10.21037/fomm-24-57/coif). J.I.H. serves as an unpaid editorial board member of Frontiers of Oral and Maxillofacial Medicine from August 2025 to July 2027. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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