2021, Number 3
Adjuvant therapy with topic 5-fluorouracil for odontogenic keratocyst, case report and literature review
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References: 20
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ABSTRACT
Odontogenic keratocyst is the third most common maxillary region cyst after periapical and dentigerous cysts. It is characterized by presenting a thin epithelium. Therefore, it is hard to combat its high recurrence rate with conservative treatments and eradicate it with a simple enucleation or curettage. It occurs most frequently in the posterior mandibular area; clinically, it can cause cortical expansion and displacement of the tooth involved in the injury. Currently, different treatments have been described for these entities to reduce the morbidities created by the surgeon through the chosen treatment. 5-fluoruracil is an anti-metabolite used to treat basal cell carcinomas, inhibiting the Sonic Hedgehog (SHH) signaling pathway. Because its molecular pathogenesis is shared with keratocysts, it has been proposed to treat them by topical application of this anti-metabolite, thanks to its lower morbidity, its null neurotoxicity, and the possibility of preserving more of the adjacent tissues compared to other treatments. A 19 years old female patient case is presented, treated with decompression, enucleation of the lesion, and topical 5-fluorouracil applying.INTRODUCTION
Odontogenic keratocyst (OKC) is a cyst of odontogenic origin characterized by a thin layer of parakeratinized squamous epithelium.1 The term "odontogenic keratocyst" was first used by Philipson (1956), and subsequently, Browne (1970-1971) confirmed its clinical and histological features. It was believed to be a benign but potentially aggressive and recurrent cyst.2 In 2005 the World Health Organization (WHO) renamed this lesion as "keratocystic odontogenic tumor" because it was considered that its clinical behavior was more similar to that than a neoplasm, with a high recurrence rate after its simple enucleation, its histological features, and more recently to the presence of markers within the cyst. These markers consist of proliferating cell nuclear antigen, Ki67, BCE 2 sequence of the enzyme dihydrolipoyl acetyltransferase, matrix metalloproteinase 2 and 9, and p53.3
In 2017 the WHO reclassified keratocyst within the section of odontogenic cysts since there was not enough evidence to classify it as a neoplasm. While there is a sea of changes in the molecular pathogenesis of this entity, most definitions of neoplasia include the concept of autonomy, whereby it can continue to grow even if the causative agent is removed. Neoplasms cannot remit spontaneously. However, it has been widely described that keratocysts can give way after their decompression, and unexpectedly, the lining of many of the decompressed cysts appear to be histologically similar to that of the buccal mucosa.4
This work aims to review the treatments available for this entity, the benefits of using a conservative treatment with adjuvant therapy with 5-fluorouracil, and present a clinical case in which 5-fluorouracil was used topically for the treatment of an OKC.
CASE REPORT
A 19-year-old female patient attended the Oral and Maxillofacial Surgery Clinic (Division de Estudios de Posgrado e Investigación –DEPeI- de la UNAM) to extract her third molars, with no vital history for the treatment. The orthopantomography showed the right upper third molar (#18 D.O.) moved to the ipsilateral orbit floor, with a radiolucent zone associated with its crown that occupied the entire maxillary sinus and extended to the same side's tuberosity, measuring approximately 3.3 × 5.0 cm. The tomography (cone beam) revealed the close relationship between the third molar apex and the orbital floor (Figure 1). Initially, an exploratory puncture evidenced a yellowish content compatible with keratin. Subsequently, an incisional biopsy of the lesion was performed, and the involved third molar was removed for histopathological study. Drainage was placed using a Foley No. 18 probe, and strict hygiene was indicated (Figure 2).
The sample was sent to the Department of Pathology (DEPeI), and the diagnosis of odontogenic keratocyst was issued. It was decided to continue with the decompression of the cystic cavity until it reached the optimal size for enucleation and extraction. The patient was scheduled for monthly monitoring and every four months for radiographic follow-up of the lesion. Eight months after the cystic drainage was placed, it was observed that density around the lesion had changed in the orthopantomography and a greater delimitation of the lesion, so enucleation and topical application of 5-fluorouracil was performed (Figure 3A). Starting with an approach through the anterior wall of the maxillary sinus, enucleation and curettage of the cystic epithelium was performed. Once the tissue was removed entirely, a gauze soaked in 5% 5-fluorouracil (Efudix®) was placed using approximately 1 g, and the patient was summoned to remove the gauze after 24 hours (Figure 4). After that time, the material placed at the enucleation site was removed, and the buccal mucosa was hermetically sealed.
The sample was sent for histopathological study, and the diagnosis of odontogenic keratocyst was confirmed. The patient remains in radiographic monitoring, with no signs of recurrence after three years. The lesion site is observed with adequate evolution and bone formation in the cystic cavity (Figure 3B). Long-term follow-up is required to confirm the success, so follow-up appointments are indicated for at least five years and radiographic control every three to four months.
DISCUSSION
OKCs account for 10 to 20% of all odontogenic cysts.1 Radiographically they look like a radiolucent image with well-defined cortical edges. They may be unilocular or multilocular and have cortical expansion and slight inflammation.2,3 About 59% of keratocysts in the mandible occur in the posterior region, and 41% can be found adjacent to the teeth. In the maxillary bone case, 75.5% are located in the teeth area and 24.5% in the posterior maxillary portion. Histologically, a parakeratinized epithelium of 5 to 8 layers of cells is observed, without interpapillary ridges, with a corrugated surface, basal cells arranged in palisade, with hyperchromatic nuclei and reverse polarization.4,5 The presence of parakeratin is unique among other lesions, making its diagnosis more accurate.6 Some of these lesions' genetic alterations are mainly in tumor suppressor genes such as p16, p53, PTCH, MCC, TSLC1, LTAS2, and FHIT. However, the drosophila patched gene (PTCH1), which encodes a transmembrane receptor for Sonic Hedgehog and other Hedgehog proteins, is (the most critical genetic alteration reported in keratocyst.7
Some of the treatments for this cyst are: enucleation, curettage, wide resections, and adjuvant therapies such as cryotherapy, Carnoy's solution, modified Carnoy's solution, and more recently, topical 5-fluorouracil applying. Enucleation and curettage are traditional methods for odontogenic cysts and some tumors of the maxillary region.8 The recurrence rate may be from 25 to 60% with enucleation. However, when the lesion is treated with resection and safety margins of one centimeter, it can achieve 0%, being inversely proportional to the excessive increase in patient morbidity.3,9 Another option is the marsupialization of the cyst, which consists of suturing the cystic epithelium to the oral mucosa to replace the epithelium and its thickening to facilitate its removal. For the same purposes of marsupialization, an incision can be made, and a decompression tube placed, achieving an epithelium replacement and reducing the lesion size. However, if decompression is performed, there may be a recurrence of 10%.3,9 In a study carried out by Da Silva et al., they compared simple enucleation and marsupialization with enucleation after decompression of the lesion without adjuvant therapy. It reduced recurrence by 52% compared to simple enucleation. Thus, performing a "delayed" enucleation before definitive treatment is recommended.3,9 Diniz et al. pointed out that in lesions treated with marsupialization, there is an alteration of the PTCH1 gene mutation and the SHH signaling pathway.10
In 2014 Gao et al. concluded that in OKCs, the mean decompression at one month was 2.87 cm2.11 A peripheral osteotomy of the lesion of about 1-2 mm can be performed for cyst enucleation. Its disadvantage is the bigger morbidity when removing a plus of tissue in addition to cystic injury.3,11 For physical treatment with cryotherapy, temperatures below -20 oC must be achieved. The only available agent that can achieve these temperatures is liquid nitrogen, which reaches temperatures down to -198 oC. The technique includes enucleation of the lesion. It should be applied to the cavity until it freezes, and it should be kept that way for a minute by applying it several times and then letting it thaw. It is recommended that it be applied three times. There seems to be a recurrence of 10% approximately using this technique.
Carnoy's solution is a chemical agent applied for 5 min in the bone cavity and then washed out. It is neurotoxic and can damage the alveolar or infraorbital nerve if it is in contact for two minutes. Another drawback of Carnoy's solution is that it contains chloroform, categorized as carcinogenic by the U.S. Environmental Protection Agency, so many people have stopped using it. Therefore, a modified Carnoy's solution was proposed, which excluded chloroform from the preparation. The American Association of Oral and Maxillofacial Surgeons reported that of 6,880 members in 2013, 56% used the solution with chloroform and 42% with the modification, not reporting any complications; hence its use continues to be defended.3,12 In another study, a group of patients (n = 44) was treated with Carnoy's solution and another group (n = 36) with modified Carnoy's solution. A recurrence of 10% was demonstrated in patients treated with Carnoy's solution and 35% with modified solution.13
In the study carried out in 2016 by Forteza et al., there was a recurrence of 26.8%, with marsupialization being the one with the highest recurrence rate with 45.8%.14 The article by Moraissi et al. found that with enucleation alone, there was a recurrence of 23.1%; with enucleation plus curettage 17.4%; enucleation and Carnoy's solution 11.5%; enucleation with cryotherapy 14.5%; marsupialization alone 32.3%; decompression followed by enucleation 14.6%, and wide resections 8.6%, obtaining a total recurrence rate in general of 16.6%.15 Due to some of the mentioned treatments causing high recurrence and morbidity, other conservative treatments for this type of lesion have been sought. Therefore, a therapy based on current knowledge of the molecular pathogenesis of keratocysts has been recently proposed. Molecular studies focused on the patched homologous protein tumor suppressor gene (PTCH) pathway have given us a targeted therapy for basal cell carcinomas. Keratocysts are known to develop from a mutation similar to basal cell carcinomas in the PTCH gene.
The mutation in this gene produces an activation of the Smoothened (SMO) and Sonic Hedgehog (SHH) signaling pathways, resulting in neoplastic growth. Recently, Rui et al.16 reported that alterations in the SMO gene play an essential role in developing keratocyst. This finding suggests that SHH signaling pathway antagonism may be an efficient conduit for treating keratocysts, inhibiting the SMO gene, and suppressing SHH transcription factors. The anti-metabolite drug 5-fluorouracil has been shown to induce apoptosis by inhibiting SHH in hepatocellular carcinoma cells, the same signaling pathway observed in odontogenic keratocyst, which is why its topical use is proposed for the treatment of the latter. In an ambispective cohort study on the treatment of keratocysts with topical 5-fluorouracil applying, in which a group of 32 patients was formed, 11 were treated with 5-fluorouracil and 21 with modified Carnoy's solution; it was found no evidence of recurrence and local or systemic damage using 5-fluorouracil.17
5-fluorouracil is activated through a triple enzymatic process by the sequential catalytic activity of carboxylesterase (liver), cytidine deaminase, and thymidine phosphorylase, this cascade results in the formation of 5-fluorouracil. 5-fluorouracil is further metabolized to 5-fluorodeoxyuridine monophosphate, inhibiting thymidylate synthase (TYMS). The latter converts deoxyuridine monophosphate into thymidine monophosphate, a key molecule for deoxyribonucleic acid (DNA) synthesis. In addition, 5-fluorouracil can be incorporated directly into ribonucleic acid (RNA), which interferes with RNA transcription, and, less frequently, into DNA, inhibiting its replication. Dihydropyrimidine dehydrogenase (DYPD) is the initial step in the catabolism of physiological pyrimidines and 5-fluorouracil and capecitabine. It is predominantly expressed in the liver and deactivates more than 80% of the administered drug. Up to 20% is excreted in the urine. Reduced activity of DYPD (DYPD deficiency) results in an increased half-life of DYPD. The increased concentration of 5-fluorouracil in the body can cause severe toxicity. The prevalence of partial DYPD deficiency is uncommon, ranging from 3% to 5% in the general population.18
There has never been a reported case of life-threatening toxicity from a patient receiving only topical 5-fluorouracil application. Several previous studies of the topical 5-fluorouracil application report a skin absorption rate of 10%. Therefore, it is estimated that the application of 2 g of 5% 5-fluorouracil cream applied twice daily would result in a total exposure of 20 mg/day of 5-fluorouracil (which means 0.33 mg/kg). This amount is well below the typical 500-550 mg/kg i.v. bolus 5-fluorouracil administered for cancer chemotherapy.19 For the 5-fluorouracil to be safe, a therapeutic range has been determined in an area under the curve (AUC), ranging from 20 to 30 mg/h/L. AUC is the pharmacokinetic parameter most closely associated with efficacy and toxicity. As for 5-fluorouracil therapy, the best response is in patients with AUC measurements from 20 to 30 mg/h/L. Outside these parameters, the patient runs the risk of toxicity by receiving toxic or inadequate therapeutic doses, so 5-fluorouracil was topically used, without any side effects, and it evolves satisfactorily without wide resections and maintaining all the structures adjacent to the pathology with minimal morbidity for the patient entirely.20
CONCLUSIONS
Keratocyst has a high recurrence rate if not treated correctly. Currently, there are multiple treatment options for this type of pathology, but the ideal treatment depends on each patient's condition. In addition to eliminating the lesion, the goal is to reduce morbidity, avoiding radical and extensive procedures. Due to its properties and lower morbidity, topical 5-fluorouracil application is a good adjuvant treatment option.
REFERENCES
AFFILIATIONS
1 Clínica de Cirugía Oral y Maxilofacial de la División de Estudios de Postgrado e Investigación, Facultad de Odontología, Universidad Nacional Autónoma de México.
CORRESPONDENCE
Óscar Rohel Hernández-Ortega. E-mail: oscarrohel@hotmail.comReceived: Mayo 2020. Accepted: Junio 2020.