Histopathological Comparative Analysis between Syndromic and Non-Syndromic Odontogenic Keratocysts: A Retrospective Study

Betancourt N.J., Qian M.F., Pickford J.R., Bailey-Healy I., Tang J.Y., Teng J.M.

PURPOSE Gorlin syndrome (GS) is a rare genetic disorder characterized by lifetime risk of basal cell carcinomas (BCCs), skeletal anomalies (SAs), and other extracutaneous neoplasms. There is great variation in disease severity, and a genotype-phenotype correlation has not been well established. Here, we investigate whether patients' clinical characteristics predict disease severity to inform clinical decision making. METHODS Data of 248 patients with GS were collected between 2014 and 2021 from three institutions. Multivariable regression analyses were performed to investigate whether clinical characteristics predicted disease burden. Genotype-phenotype correlations were investigated in 40 patients. RESULTS Patients with SAs had a mean increase of 120 lifetime BCCs (95% CI, 27.1 to 213) relative to patients without SAs. Those with ≥ 2 SAs had 2.45 increased odds (95% CI, 1.01 to 5.91) of advanced or metastatic BCCs. Moreover, the presence of multiple SAs was associated with 5.00 increased odds of having a keratocystic odontogenic tumor (95% CI, 2.22 to 11.3) and 2.79 increased odds of an ovarian fibroma (95% CI, 1.05 to 7.40). Genotype-phenotype analyses showed that missense/in-frame mutations were more likely to be hereditary compared with severe deleterious mutation types (100% v 27%; P = .004). In addition, heat map visualization illustrated that those with more deleterious variants, like large deletions, trended toward increased burden of SAs and BCCs per year. CONCLUSION GS patients with SAs may be at greater risk for developing more numerous and severe BCCs and other neoplastic growths including keratocystic odontogenic tumors and ovarian fibromas. Current clinical guidelines suggest yearly follow-up in individuals with GS. Since SAs are usually recognized at the time of diagnosis, our results suggest that more vigilant lifetime multidisciplinary surveillance should be considered for these patients starting in childhood.

Soluk-tekkesin M., Wright J.M.

Ravi J., Wadhwan V., Gotur S.

Vered M., Wright J.M.

The 5th edition of the World Health Organization (WHO) Classification of Head and Neck Tumours (2022) comes out only five years after the previous edition, however it presents important updates that run in parallel with the rapid progression involving the increasingly sophisticated molecular investigation and its interpretation, some of which already have therapy-related impact. This manuscript provides an overview of the leading changes introduced in the classification of Odontogenic and Maxillofacial Bone Tumours that encompasses cysts of the jaws, odontogenic tumours, giant cell lesions and bone cysts, and bone and cartilage tumours. This is the first edition that Essential and Desirable Diagnostic Features were added for each entity, so that the most important clinical, microscopic and/or radiologic features were encapsulated and briefly highlighted. Surgical ciliated cyst was added to the group of odontogenic cysts, adenoid ameloblastoma was a newly recognized benign epithelial odontogenic tumour, and segmental odontomaxillary dysplasia was introduced in the group of fibro-osseous tumours and dysplasia. In addition, rhabdomyosarcoma with TFCP2 rearrangement, was introduced into the group of malignant jawbone tumours. The unique genetic aberrations distinguish it from other types of rhabdomyosarcomas. On the other hand, melanotic neuroectodermal tumour of infancy and osteoid osteoma were deleted from the benign bone and cartilageneous tumours, as was the hematolymphoid tumour of solitary plasmacytoma of bone. We systematically reviewed each entity in this chapter and provided important updated findings for selected topics that can further aid in the diagnostic process for challenging cases, broaden insights on the logic of the present classification, and finally, emphasize the potential that some of the molecular results may have in the near future to set new treatment approaches.

Cserni D., Zombori T., Stájer A., Rimovszki A., Cserni G., Baráth Z.

Odontogenic keratocysts (OKCs) have a diagnostic thin epithelial lining characterised by a linear epithelial connective tissue interface generally lacking inflammatory changes, basal palisading of the nuclei and a wavy parakeratotic layer on the surface. This typical epithelium may convert to a thicker non-keratinizing one with rete pegs and a relatively flat surface after operative decompression. The aim was to characterize this type of epithelial change by immunohistochemistry for bcl2, keratin17, 10 and 19. Eleven out of 33 archived OKCs demonstrated an altered epithelium related to previous biopsy, decompressing drainage or inflammation. The typical basal bcl2 staining was lost in 10/11 cases; transepithelial CK17 was lost or markedly reduced in 9/11 cases. CK10 displayed a segmental upper layer staining in OKCs, and its loss or partial loss in the altered epithelium did not differ from negative areas of OKCs. CK19 displayed various staining patterns in the altered epithelium from lost to maintained in a patchy transepithelial distribution, the latter of which did not differ from the typical OKC staining pattern. Three of four non-keratinizing epithelial linings with basal palisading displayed immunostaining reminiscent of typical OKC epithelium. The lack of a typical epithelium is not sufficient to exclude the diagnosis of OKC if the sampling is not generous (e.g. biopsy), and the presence of non-keratinizing epithelium with basal palisading and an immunophenotype characteristic of OKC (basal bcl2, patchy or diffuse CK17 and upper layer CK10 positivity) may be consistent with the OKC diagnosis even in the absence of typical epithelial lining.

Hoyos Cadavid A.M., Kaminagakura E., Rodrigues M.F., Pinto C.A., Teshima T.H., Alves F.A.

The aim of this study was to compare the clinical and demographic features of 62 patients presenting sporadic odontogenic keratocysts (OKCs) or OKCs associated with nevoid basal cell carcinoma syndrome (NBCCS). In conjunction with this, we also evaluated the immunohistochemical expression of Shh, Ptch1, Ptch2, Smo, Gli1, Gli2 and Gli3 proteins in 86 OKCs. By doing this, we add to the understanding of the biology of this type of lesion, providing tools that will help facilitate the early diagnosis of NBCCS in those patients where the first manifestation is that of OKCs. This is a retrospective study; patients were classified into two groups: group 1 which consisted of those who were not affected by NBCCS (49 patients and 57 OKCs) and group 2 which consisted of those who were diagnosed with NBCCS (13 patients and 29 OKCs). The clinical and demographic features were studied and the immunohistochemical expression of Sonic Hedgehog proteins (Shh, Ptch1, Ptch2, Smo, Gli1, Gli2, and Gli3) was analyzed in all samples. There was an increase in the expression of three proteins in the syndromic OKC, when compared to that of sporadic cysts. Shh and Gli1 showed higher cytoplasmic expression, while Smo revealed stronger nuclear and cytoplasmic expressions. Our findings suggest that the expression patterns of important Shh pathway proteins can represent valuable markers for early diagnosis of NBCCS-associated OKCs, as the major criterion for the diagnosis of NBCCS is currently based on the late appearance of basal cellular carcinomas. Thus, standardizing a new diagnostic tool for diagnosis of NBCCS could be of great importance in the identification of therapeutic targets. We therefore suggest, as based on our findings, that OKCs showing high expression of Shh, Smo, and Gli1 are potentially associated with NBCCS.

Selvamani M., Devi A., Basandi P., Madhushankari G.

Pogrel M.A.

In 2005, the World Health Organization renamed the lesion previously known as an odontogenic keratocyst as the keratocystic odontogenic tumor. The clinical features associated with the keratocystic odontogenic tumor show it to be a unilocular or multilocular radiolucency, occurring most frequently in the posterior mandible. These tumors are normally diagnosed histologically from a sample of the lining. With simple enucleation, it seems that the recurrence rate may be from 25% to 60%.

Bhargava D., Deshpande A., Pogrel M.A.

The World Health Organization (WHO) has reclassified ‘odontogenic keratocyst’ (OKC) to ‘keratocystic odontogenic tumour’ (KCOT) in 2005. Currently, this tumour is classified as a benign neoplasm of odontogenic origin and not as a cyst. This article reviews and discusses history, classification scheme, aetiology and pathogenesis, molecular and genetic basis, incidence, epidemiology and site, clinical features, imaging, histopathology, immunohistochemistry, treatment options, prognosis, recurrence and malignant transformation of KCOT, with emphasis on understanding the basis of reclassification as ‘keratocystic odontogenic tumour’. A systematic search and review of the literature was carried out in the online database of the United States National Library of Medicine to identify eligible titles for the study. Current evidence suggests that the scientific community still continues to use the term ‘odontogenic keratocyst’ more favourably than ‘keratocystic odontogenic tumour’. The online database search indicates that the scientific community still continues to use the term ‘odontogenic keratocyst’ more favourably than ‘keratocystic odontogenic tumour’. At this juncture, where the terminology has changed from a cyst to a tumour, a thorough review of literature on KCOT is presented.

Abdullah W.A.

KCOT is one of the most aggressive odontogenic cysts with a high recurrence rate, this was explained histopathologically as it typically shows a thin, friable wall, which is often difficult to enucleate from the bone in one piece, and have small satellite cysts within the fibrous wall. Multiple surgical approaches were introduced including decompression, marsupilization, enucleation with or without adjunct (Carnoy’s solution, enucleation) and resection. Depending on other studies KCOT can be conservatively treated with enucleation and application of Carnoy’s solution or cryotherapy. This can be used specially in the large lesions that when treated with resection, the continuity of the jaw will be interrupted. This technique shows comparable results to other more aggressive techniques.

Vered M., Peleg O., Taicher S., Buchner A.

Background: The aggressive biological behavior of odontogenic keratocysts (OKCs), unlike that of other odontogenic cysts, has argued for its recent re-classification as a neoplasm, ‘keratocystic odontogenic tumor’. Identification of mutations in the PTCH gene in some of the OKCs that were expected to produce truncated proteins, resulting in loss of control of the cell cycle, provided additional support for OKCs having a neoplastic nature. Methods: We investigated the immunohistochemical expression of the sonic hedgehog (SHH) signaling pathway-related proteins, PTCH, smoothened (SMO) and GLI-1, and of the SHH–induced bcl-2 oncoprotein in a series of primary OKC (pOKC), recurrent OKC (rOKC) and nevoid basal cell carcinoma syndrome-associated OKCs (NBCCS-OKCs), and compared them to solid ameloblastomas (SAMs), unicystic ameloblastomas (UAMs), ‘orthokeratinized’ OKCs (oOKCs), dentigerous cysts (DCs) and radicular cysts (RCs). Results: All studied lesions expressed the SHH pathway-related proteins in a similar pattern. The expression of bcl-2 in OKCs (pOKCs and NBCCS-OKCs) and SAMs was significantly higher than in oOKCs, DCs and RCs (P < 0.001). Conclusions: The present results of the immunoprofile of OKCs (that includes the expression of the SHH-related proteins and the SHH-induced bcl-2 oncoprotein) further support the notion of OKC having a neoplastic nature. As OKCs vary considerably in their biologic behavior, it is suggested that the quality and quantity of interactions between the SHH and other cell cycle regulatory pathways are likely to work synergistically to define the individual phenotype and corresponding biological behavior of this lesion.

Eryilmaz T., Ozmen S., Findikcioglu K., Kandal S., Aral M.

Odontogenic keratocyst is an epithelial developmental odontogenic cyst most commonly occurring in the jaws. It comprises approximately 11% of all cysts of the jaws. It has an aggressive behavior including high rates of recurrence, rapid growth, and extension into adjacent tissues. Odontogenic keratocyst is commonly found in the mandible with a predilection for angle and ascending ramus of the mandible. We document a case of odontogenic keratocyst that is unusually originated from the temporomandibular joint and we review the existing literature concerning odontogenic keratocyst. As far we know this is the first case of the odontogenic keratocyst originating from the temporomandibular joint.

Habibi A., Saghravanian N., Habibi M., Mellati E., Habibi M.

Driemel O., Rieder J., Morsczeck C., Schwarz S., Hakim S.G., Müller-Richter U., Reichert T.E., Kosmehl H.

With the new term “keratocystic odontogenic tumour” (KCOT) keratocyts are even in the nomenclature a close differential diagnosis to ameloblastomas (A). Recurrence of KCOT and A were retrospectively compared with regard to treatment and immunohistochemical markers of cell cycle and migration and cell architecture. Biopsies harvested over a period of 22 years of 101 patients (86 KCOT, 15 A) were examined. The histopathological slides were stained with H&E and with the immunohistochemical markers: Cyclin D1, Collagen IV, p16, Cox-2-Laminin-5 and Tenascin-C. Mean age KCOT 47 years (range 14–80 years), A 41 years (range 16–79 years). Gender KCOT: m:f = 2:1; A: m:f = 3:2. Region of origin mandible with predilection of the angle and the ramus: KCOT: 76; A: 12. Maxilla: KCOT: 18; A: 3. Multiple lesions were found in 5 KCOT patients. Treatment primary KCOT: cystectomy (46), cystostomy (6), cystectomy and curettage (17), cystectomy and marginal ostectomy (14), resection (11). A: resection (10), enucleation (5). Recurrence rate KCOT: 11,7% after 5,5 years. Recurrence after: cystostomy (4), cystectomy (6), cystectomy and curettage (3), cystectomy and marginal ostectomy (2). A: no recurrences. Immunohistochemistry Cell cycle associated and extracellular matrix proteins did not differ in quantity in KCOT and A, and did also not differ in recurrent and non-recurrent KCOT.

Chirapathomsakul D., Sastravaha P., Jansisyanont P.

The purpose of this study is to report experiences of odontogenic keratocysts (OKCs) and analyze information regarding recurrences to better understand the nature of recurrences.Fifty-one cases of OKC treated at the Faculty of Dentistry, Chulalongkorn University, from 1988 to 2003 were studied retrospectively. Clinicoradiographic features, histologic features, and methods of treatment were reviewed. Recurrences were analyzed and compared with respect to sites of involvement, relationship to the remaining teeth, and methods of treatment.OKCs occurred predominantly in the 11- to 40-year-old age group. The body-angle-ramus area of mandible was the most common site of occurrence. Radiographically, the unilocular to multilocular radiolucency ratio was 2.5:1. Multilocular lesions occurred more frequently in the mandible (P < .05). Most of the lesions were diagnosed histologically as parakeratinized OKC (93.7%). The patients were followed from 1-14.6 years. However, 20 patients were lost to follow-up after a short period of time, and recurrences were found in 7 out of 31 cases (22.6%). The recurrent tumors occurred more frequently in patients who had an OKC associated with the remaining teeth and were treated by enucleation or enucleation with adjuvant therapy.According to a high recurrent rate of OKCs treated by enucleation, clinicians should give more attention to the dentate area if the enucleation is chosen as the treatment of choice.

Szaraz D., Ksinan A.J., Machacek C., Borilova Linhartova P.

Abstract Background This retrospective study aims to evaluate the relative representation of individual types of developmental odontogenic cysts (DOCs), especially from the perspective of syndromic and non-syndromic multiple DOCs in the Czech population. In addition, we also summarize the previous studies on the occurrence of multiple DOCs and provide a literature review of case reports and case series on non-syndromic multiple DOCs, particularly dentigerous cysts (DCs) and odontogenic keratocysts (OKCs). Methods The study included histologically confirmed DOCs retrieved between January 1, 2012, and August 8, 2023, at the Clinic of Maxillofacial Surgery, University Hospital Brno, Czech Republic. All specimens were re-classified according to the fifth edition of the World Health Organization Classification of Head and Neck Tumors, 2022. Patients with an uncertain histological diagnosis were excluded from the study. Results Of a total of 377 patients, 286 had DCs, 85 OKCs, 5 orthokeratinizing odontogenic cysts (OOCs), 1 botryoid cyst, and 1 calcifying odontogenic cyst. The proportion of patients with multiple DCs in our study (6.6%) was higher than usually reported in the literature. The study also found that 100% of patients with multiple DCs did not exhibit any syndromic associations. On the other hand, 66% of multiple OKCs were associated with the Naevoid Basal Cell Carcinoma Syndrome (NBCCS) and the proportion of OKC patients with NBCCS (7%) was relatively higher than in other studies. Recurrence of OKCs was also significantly associated with NBCCS (p < 0.05). Only one patient presented with bilateral OOCs, without any association with a syndrome. Conclusion Multiple OKCs are more likely to develop in syndromic patients, while none of the multiple DCs were associated with a syndrome. The incidence of multiple OOCs and other DOCs is extremely rare. Still, we conclude that patients with multiple DOCs should be carefully considered for examination by other specialists to rule out possible syndromic involvement.