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The Clinical Features and Expression of bcl-2, Cyclin D1, p53, and Proliferating Cell Nuclear Antigen in Syndromic and Nonsyndromic Keratocystic Odontogenic Tumor

Ibrahim, Norliwati BDS, MClinDent; Nazimi, Abdul Jabar MFDSRCS, MClinDent; Ajura, Abdul Jalil BDS, MClinDent; Nordin, Rifqah MFDSRCS, MClinDent; Latiff, Zarina Abdul M.MED(PAED), MSc Medical Genetics; Ramli, Roszalina FDSRCS, FFDRCS

Journal of Craniofacial Surgery: July 2016 - Volume 27 - Issue 5 - p 1361–1366
doi: 10.1097/SCS.0000000000002792
Scientific Foundations
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The aim of this study was to describe the clinical features and expression of bcl-2, cyclin D1, p53, and proliferating cell nuclear antigen (PCNA) antibodies in syndromic (nevoid basal cell carcinoma syndrome [NBCCS]) and nonsyndromic patients diagnosed with keratocystic odontogenic tumor (KCOT).

Methods: This descriptive study comprised 5 patients of KCOT associated with NBCCS and 8 patients of nonsyndromic type treated in the Department of Oral Maxillofacial Surgery, Universiti Kebangsaan Malaysia Medical Centre between years 1998 and 2011. The clinical features (site, size, treatment, and recurrence), demographic characteristics, and immunohistochemistry results using antibodies of bcl-2, cyclin D1, p53, and PCNA were examined. The association of the antibody expression and the type of KCOT was analyzed using Fisher exact test.

Results: Altogether there were 13 patients, 5 with syndromic KCOT (1 patient met 3 major criteria of NBCCS) and 8 with sporadic KCOT. The age range for syndromic KCT was 11 to 21 years (mean 16.00 years, SD 4.36) and 10 to 54 years (median 24.50 years, interquartile range 19.00) for the nonsyndromic KCOT. Tumor recurrence occurred in 3 patients (7.7%); 1 patient from the syndromic and 2 patients from the nonsyndromic. The most positive expression was observed in PCNA for both the syndromic and nonsyndromic samples and the least positive expression involved the p53.

Conclusion: PCNA, bcl-2 protein, and cyclin D1 expressions could be useful in evaluating the proliferative activity of the tumor and the aggressiveness of the clinical presentation; however, the authors would propose for larger sample size research for more definitive results.

*Departments of Oral Medicine and Oral Pathology

Oral Maxillofacial Surgery, Faculty of Dentistry, Universiti Kebangsaan Malaysia, Selangor

Department of Oral Maxillofacial Surgery, Universiti Kebangsaan Malaysia Medical Centre

§Stomatology Unit, Cancer Research Centre, Institute for Medical Research

||Pediatrics Department, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia.

Address correspondence and reprint requests to Dr Norliwati Ibrahim, BDS, MClinDent, Lecturer at the Department of Oral Medicine and Oral Pathology, Faculty of Dentistry, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia; E-mail: norliibrahim@gmail.com

Received 28 October, 2015

Accepted 20 March, 2016

This study protocol was approved by Faculty of Dentistry, Universiti Kebangsaan Malaysia (DD/035/2009). The research was conducted in accordance with the World Medical Association Declaration of Helsinki.

This work was funded by Universiti Kebangsaan Malaysia Research Grant, Project code DD/035/2009.

The authors report no conflicts of interest.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0

In 2005, the World Health Organization has reclassified odontogenic keratocyst into keratocystic odontogenic tumor (KCOT) due to their true neoplasm behavior. It displays high proliferative activity and protein expression associated with inhibition of apoptosis, haplo-insufficiency, and loss of heterozygosity of the tumoral suppressor gene PTCH. Keratocystic odontogenic tumor was shown to be associated with a syndrome, known as the nevoid basal cell carcinoma syndrome (NBCCS) with an incidence of 1 in 56,000 to 164,000 patients.1 Syndromic KCOT was proposed to behave more aggressively compared with the nonsyndromic type.2,3

It has been shown that the expression of some proliferative markers of the epithelium is consistent with the aggressiveness of the KCOT;4 however, other studies claimed that some apoptotic and proliferative markers were not good prognostic markers and recurrences should be well related to the clinical presentations and surgical procedures rather than the biological features.5,6

In this study, we described the clinical characteristics and demonstrated the expression of bcl-2, cyclin D1, p53, and proliferating cell nuclear antigen (PCNA) antibodies using the immunohistochemistry technique. The selection of these antibodies was made based on the findings in the literature.7–9

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METHODS

Patients and Clinical Characteristics

Clinical descriptions of patients with syndromic or familial and nonsyndromic or sporadic KCOT were traced retrospectively from medical records at the Universiti Kebangsaan Malaysia Medical Centre between 1998 and 2011. The surgical or biopsy specimens were traced and processed from the laboratory archives at the Oral Medicine and Oral Pathology and the General Pathology Department, Universiti Kebangsaan Malaysia. The range of follow-up as stated in the clinical descriptions, was between 2 and 8 years. The treatment for the syndromic and nonsyndromic KCOT was assessed.

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Immunohistochemistry Procedure

The specimens were evaluated by 2 pathologists (NI and AAJ). All specimens were fixed in 10% neutral buffered formalin solution and serial of 4 μm sections from the paraffin-embedded blocks of formalin-fixed were cut for each patient. Immunohistochemical analysis was performed using commercially available monoclonal antibodies of bcl-2, cyclin D1, p53, and PCNA. For comparison the following positive controls were used; breast carcinoma tissue for bcl-2, normal tonsil tissue for cyclin D1 and PCNA, and colon cancer tissue for p53. The negative controls were the same tissues as the above but without incubation with the primary antibodies.

The dilutions for both bcl-2 and cylin D1 were determined to be 1:50, while PCNA and p53 were for 1:200. Immunohistochemical staining was conducted using Dako Cytomation Chemmate System. Dewaxing and antigen retrieval was performed, followed by incubation with primary antibodies with appropriate dilution within 30 minutes. The sections were exposed to Chemmate Envision polymer for 30 minutes followed by diaminobenzidine substrate incubation for 10 minutes and counterstained in hematoxylin. The sections were then dehydrated, cleared, and mounted. All the stained slides were visualized using light microscope for immunoreactivity assessment and comparison was made with the positive and negative controls.

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Assessment of Immunostaining

The immunohistochemical staining pattern, intensity, and distribution between the samples and controls were initially assessed by 2 pathologists (NI and AAJ) using light microscopy under various magnifications and then analyzed using 3DHISTECH digital slide scanner. Kappa value of interexaminer evaluation is 0.92.

The calculation of immunoreactive score was based on Koo et al.10 Staining intensity and area of immune-positivity were assessed and the following scores were given: 0 indicates no staining; 1 indicates weak intensity; 2 indicates moderate intensity; and 3 with strong intensity. These intensity scores were set according to the “gray level” of the 3DHISTECH digital slide scanner. For the extent of positively stained cells, the score was given as the following: 0% for negative staining; 1 for 1% to 10%; 2 for 11% to 50%; 3 for 51% to 80%; and 4 for 81% to 100%. Final immunoreactive score was determined by multiplying the intensity scores with the extent of positivity scores of stained cells, with the minimum score of 0 and a maximum score of 12. Interpretation of the immunoreactive scores was as follows:

  1. 0 to 3 indicates negative staining
  2. 4 to 12 indicates positive staining
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Statistical Analysis

The association between the expression of the antibodies and KCOT (syndromic versus nonsyndromic) was performed using Fisher exact test as the expected cell frequency was less than 5. The level of significance was set at P < 0.05.

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RESULTS

Clinical Characteristics of Familial/Syndromic Patients

In total, there were 5 patients with 16 different locations of syndromic KCOT. All the patients were young, aged between 11 and 21-year old (mean 16.00, SD 4.36). They were all Malay with 3 males and 2 females. The sites involved bilateral maxilla and unilateral mandibular bones. Only 1 patient was diagnosed with bilateral maxilla and bilateral mandible lesions.

Patient 1 presented with the largest lesion, measuring 6.0 cm in the mandible. All other lesions in Patient 1 and other patients ranged 1.5 to 5.0 cm in size. Recurrence was observed in Patient 1 involving the right maxilla. No recurrence was documented for the other 4 patients. All these patients were with various clinical manifestations consistent with minor and/or major criteria for diagnosing NBCCS. This included abnormality in the skull, face, eyes and mouth, spine, skin, and neck. Patient 2 presented with the most clinical characteristics and met 3 major criteria of NBCCS. The treatment for the syndromic KCOT was in a combined form: extensive enucleation with peripheral ostectomy and cryosurgery (Table 1).

TABLE 1

TABLE 1

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Clinical Characteristics of Nonsyndromic Patients

There were 8 patients of nonsyndromic KCOT. Five were males and 3 were females. The age was between 10 and 54-year old (median 24.50 years, interquartile range [IQR] = 19.00). There were 6 Malays, 1 Chinese, and 1 Indian. The locations of the KCOT involved left mandible (1 patient), right maxilla (1 patient), and left maxilla (6 patient s).

All patients had extensive enucleation. Two patients (22.2%) were diagnosed with recurrence, between 3 to 7 years following first surgery (Table 2).

TABLE 2

TABLE 2

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Immunohistochemistry Antibodies Expressions

Bcl-2

Expression of Bcl-2 was seen within the cytoplasm and mainly distributed on the basal region. Specimens from the syndromic and nonsyndromic displayed 20% (1 of 5 patients) and 37.5% (3 of 8 patients) of positive staining respectively (Table 2). Patient 2 (syndromic) specimen showed strong staining with immunoreactive score of 9 (Fig. 1).

FIGURE 1

FIGURE 1

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p53

p53 revealed nuclear staining visualized mostly on the basal or suprabasal regions of the epithelium. Positive staining involved 20% (1 of 5 patients) of the syndromic and 12.5% (1 of 8 patients) of the nonsyndromic specimens (Table 2). The highest immunoreactive score for both syndromic and nonsyndromic specimens was 4 (1 patient for each) (Fig. 1).

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Cyclin D1

Cyclin D1 showed nuclear staining exhibited at the suprabasal region or could involve full thickness of the epithelium. Positive staining for syndromic and nonsyndromic specimens was 20% (1 of 5 patients) and 37.5% (3 of 8 patients) respectively with highest score of 6 for both the syndromic (1 patient) and nonsyndromic (3 patients) specimens (Table 2) (Fig. 1).

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Proliferating Cell Nuclear Antigen

The positive nuclear PCNA immunostaining involved full thickness of the epithelium for the syndromic group while for the nonsyndromic, the positive staining was observed at the suprabasal layer. The nonsyndromic patients showed positivity of 62.5% (5 of 8 patients), while the syndromic patients who exhibited 60% (3 of 5 patients) positivity (Table 2). Patients 2 and 5 (syndromic patients) showed immunoreactive score of 9 while Patient 11 (nonsyndromic patient), a 12 (Fig. 1).

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Association of bcl-2, p53, Cyclin D1, and Proliferating Cell Nuclear Antigen and Keratocystic Odontogenic Tumor (Syndromic and Nonsyndromic)

Fisher exact test did not show any significant difference between the proteins and KCOT (P > 0.05).

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DISCUSSION

Keratocystic odontogenic tumor affects both sexes almost equally and could occur sporadically at any age, normally during third decade of life.2 The age ranges from 6 to 78-year old.2 The prevalence of KCOT in Malaysia was between 3.1% and 17% of all the cystic lesions of the jaw bones11–14 with mean age of 26.9 years.15

Keratocystic odontogenic tumor may be associated with NBCCS which is also known as the Gorlin Goltz syndrome, an autosomal dominant disorder that usually occurs at an earlier age compared with the sporadic type.16 Patients with NBCCS are diagnosed when 2 major or 1 major and 2 minor clinical criteria are present16,17 and these included multiple basal cell carcinomas, KCOT, palmar or plantar pits, calcification of the falx cerebri, medulloblastoma, ovarian fibromas, and skeletal abnormalities. About 6% of KCOT are associated with NBCCS.7 In contrast, KCOTs is the most consistent and common finding of the syndrome occurring in about 65% to 100% of NBCCS patients.18 The site of occurrence involved the mandible, mainly on the posterior region.3,19 The recurrence rate of KCOT was about 13% and it was reported to be related to NBCCS and associated with second or eighth decade of life.3,19

Our syndromic KCOT patients were mostly in their second decade of life. Although only 1 patient (Patient 1) showed recurrence, longer duration of follow-up is needed for all the patients since KCOT recurrences may be observed from 5 to 7 years after treatment.20,21 In addition, there are reported patients of recurrence 10 years or more following initial treatment.22,23

Tumor size could have influence on the recurrence rate as seen in Patient 1 and this was consistent with a study by Gosau et al,24 while Kuroyanagi et al25 showed the opposite. Recent report suggested that smaller lesion is associated with higher recurrence rate.26

In relation to the location, similarities were observed in both the syndromic and nonsyndromic patients; bilateral mandible and right maxilla in all the syndromic patients (100%) and left maxilla (75%) in the nonsyndromic patients.

There is no consensus for treatment plan of KCOT in different jaw locations or provide the details of the morbidity associated with different treatment modalities.27,28 We used all the adjunctive therapies for KCOT that have been proposed in the literature29 together with the standard method of extensive enucleation in all the patients. However, the use of Carnoy solution and electrocautery is not included in our treatment protocol.

In relation to immunohistochemistry, previous report on proliferative activity and apoptosis-related factors such as p53, ki 67, bcl-2, and PCNA in the lining epithelium of KCOT showed that these factors were associated with recurrences, especially with the syndromic KCOT.7,8,30 They were described as determinant for tumor aggressiveness, although some studies showed low expression of these proteins.7 This has to be interpreted carefully taking into consideration demographic characteristics, tumor site, and size and different treatment methods.

Bcl-2 is the protein that stops apoptosis without promoting cell proliferation.8 Inhibition of apoptosis results in tumorigenesis and bcl-2 is physiologically being expressed by haematopoetic precursors such as small B lymphocytes and many T cells that can be found in the basal layers of the nasopharynx and skin.8 Overexpression of bcl-2 was observed in most human low-grade tumors for example in KCOT and other odontogenic cyst/tumor. In this study, antiapoptotic activity measured by bcl-2 expression was mostly evident in the basal cell region, which is consistent with previous studies.8,9 Patient 2 showed very strong bcl-2 expression. Patient 2 exhibited 3 major criteria of NBCCS including cystic lesion of the jaw, bifid ribs and has a first degree relative affected with NBCCS. We therefore propose that strong bcl-2 expression could be associated with NBCCS-related SKOT. In addition, strong bcl-2 expression was inconsistent with tumor size or tumor aggressiveness as it was not observed in Patient 1 which has the largest lesion and showed recurrence. In addition, sporadic KCOT with recurrences also showed either no staining or moderate staining with the bcl-2.

p53 is a tumor suppressor gene in which its mutation has been reported in a wide range of human tumors, and thus reflects its potent role in tumorigenesis.31,32 Under normal condition, p53 is synthesized continuously in the nucleus.29,33 Its concentration is kept low where it is degraded by proteases.31,32 The concentration increases when its half-life is extended, which may occur due to mutation, association of wild-type p53 with other proteins, or disruption of its degradation pathway.31,32 p53 has been reported in odontogenic cysts where the overexpression of p53 was observed to be higher in the KCOT compared with other odontogenic cysts.9 On the contrary, our study showed mostly negative results and this was in agreement with studies by Malcić et al34 and Figuerao et al.7 Only 2 patients of the nonsyndromic and 1 of the syndromic patient showed positive results with p53.

Cyclin D1 is a regulatory subunit of a holoenzyme which plays an important role in tumorigenesis.35 It phosphorylates and inactivates retinoblastoma proteins that is important in the progression from G1 phase to S phase within a cell cycle.35 Studies revealed that cyclin D1 expression was significantly different between KCOT and other dentigerous cysts35 and between syndromic and nonsyndromic KCOT.8 Lo Muzio8 also showed that cyclin D1 is overexpressed at different stages of KCOT-associated NBCCS, but not in sporadic KCOT. However, our study showed the reverse. In addition, positive staining of cyclin D1 in the nuclei was distributed on the basal and parabasal regions and this was consistently observed in most studies.8,35 Similarly, our result showed nuclear staining that mainly involved the suprabasal (parabasal layer) but some patients exhibited nonspecific staining involving the full thickness of the epithelium. Our finding suggests a weak correlation of cyclin D1 protein and KCOT associated with the syndromic KCOT.

Proliferating cell nuclear antigen is a nuclear protein synthesized in the late G1 and S phase of the cell cycle.36 It is a useful marker for the proliferating fraction of cells in the tissue specimens.36 The staining is confined to the nucleus in diffuse or granular appearance and PCNA is the most common proliferation marker observed in all odontogenic cysts including KCOT.36 Expression of PCNA in different lesions had been observed at different levels of the epithelium.8 The staining of samples with KCOT associated with NBCCS was shown to involve the entire thickness of the epithelium compared with samples from the sporadic type.8

In contrast, overexpression of PCNA was mostly observed at the suprabasal region in the sporadic KCOT.32 This finding was consistent with our study. Therefore, we would like to propose for PCNA as a good protein marker to differentiate KCOT among the syndromic and nonsyndromic patients. Furthermore, the high expression of PCNA in KCOT may reflect the high level of cell-proliferative activity in the lining epithelium which supports the neoplastic nature of this lesion. It is difficult to associate the expression of these 4 antibodies with the NBCCS features and the recurrence pattern. Overall, the PCNA staining seems to be strongly expressed in both the syndromic and nonsyndromic KCOT specimens while the p53 was the least.

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Limitation and Future Research

The results of immunohistochemistry involving the 4 antibodies, bcl-2, cyclin D1, p53, and PCNA are variable and this correlates with the findings in the literature. The main limitation in this study was the sample size. Syndromic KCOT particularly involving the NBCCS is rare. A multicenter collaboration is advocated to improve the sample size. We would like to propose for genetic study to be performed alongside with the immunohistochemistry. Genetic study may contribute to the understanding of minor versus major type of NBCCS and the aggressiveness of KCOT associated with this syndrome could be much better predicted from the results of these 2 studies.

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CONCLUSION

Bcl-2, cyclin D1, and PCNA showed some positive results for both the syndromic and nonsyndromic KCOT samples; however, this requires further analysis with larger sample size.

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Acknowledgments

The authors acknowledge the Medical Laboratory Technicians (MLT) from the Stomatology Unit, Cancer Research Centre, Institute for Medical Research and MLT from the Oral Pathology Laboratory, Faculty of Dentistry, Universiti Kebangsaan Malaysia, for their help in slides preparation.

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Keywords:

Immunohistochemistry; KCOT; odontogenic tumor; syndrome

© 2016 by Mutaz B. Habal, MD.