Introduction

Calcifying epithelial odontogenic tumor (CEOT, Pindborg tumor) is an uncommon odontogenic tumor, mainly affecting the mandibular body of individuals during the fifth decade of life with equal sex distribution [1, 2]. Most tumors are asymptomatic and slow-growing with a well-defined radiographic appearance, ranging from unilocular to multilocular radiolucencies or mixed radiolucent–radiopaque lesions often showing cortical bone expansion. Approximately 50% of the reported cases are associated to an unerupted tooth [3, 4].

The diagnosis of CEOT is based on the microscopic identification of variable number of nests, sheets or cords of polyhedral epithelial cells with ample eosinophilic cytoplasm surrounded by a well-defined cellular membrane [1,2,3,4]. Prominent intercellular bridges and nuclear pleomorphism are common findings. Often, neoplastic epithelial cells secrete odontogenic amyloid protein, which tends to calcify forming characteristic concentric structures morphologically resembling Liesegang rings [1,2,3,4]. Complete surgical removal including a narrow rim of surrounding bone is the current recommended treatment for CEOT. Long-term follow-up is recommended considering a recurrence rate of up to 15% [5].

Since the first report 70 years ago, different histomorphological features of CEOT have been described, including peripheral location (6%), clear cell variant, variable quantity of Langerhans cells and calcified material, multifocal presentation and an exceedingly rare malignant variant [5,6,7,8,9]. Additionally, CEOT-like areas have been described in adenomatoid odontogenic tumors (AOT), but they are considered part of the spectrum of AOT, with its same biological potential. Often, CEOT-like epithelial nests may be observed in dental follicles, and its significance even not completely understood, are not considered early stages of CEOT [1, 2, 7]. Although most cases are solid tumors, rare predominantly cystic CEOT cases have been reported (Table 1) [10,11,12,13,14]. We herein present a well-documented case of microcystic CEOT located in the posterior mandible of a 42-year-old female.

Table 1 Clinicopathological features of CEOT with extensive cystic component published in English-language literature
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Case Report

A 42-year-old female presented with an intra-osseous asymptomatic lesion in the right posterior mandible discovered 3 months prior to consultation. Patient had an otherwise non-contributory past medical history. Cortical bone expansion was evident during intra-oral examination, covered by intact mucosa. Panoramic X-ray revealed a well-defined and corticated mixed radiolucent–radiopaque lesion, measuring approximately 4 × 3 cm. The lesion was related to an unerupted third molar, which was posteriorly displaced close to the coronoid process. The mandibular nerve canal was basally displaced. Adjacent molars showed intact roots without resorption (Fig. 1). An incisional intraoral biopsy was performed under local anesthesia. Microscopic examination revealed multiple nests and cords of eosinophilic polyhedral epithelial cells supported by fibromyxoid stroma, exhibiting multiple microcystic spaces of varying size, with amyloid-like deposits, which were positive for Congo red and showed green birefringence under polarized light. Prominent intercellular bridges were clearly evident. Nuclei showed mild to moderate pleomorphism, mainly those surrounding the pseudo-ductal spaces. This unusual pattern may mimic metastatic adenocarcinoma or a primary carcinoma of the jaws. Occasional clear cells and minimal concentric calcifications were found (Fig. 2). More than 80% of the tumor cells showed immunohistochemical positivity for AE1/AE3 (dilution 1:500, clone AE1/AE3, Dako, Carpinteria, CA, USA), CK14 (dilution 1:200, clone LL002, Novocastra, Newcastle upon Tyne, UK), and CK19 (dilution 1:200, clone RCK108, Dako) in a cytoplasmic pattern, for p63 (dilution 1:300, clone 4A4, Dako) in a nuclear pattern, and for CD138 (dilution 1:100, clone MI15, Dako), and beta-catenin (dilution 1:200, clone 17C2, Novocastra) in a membrane pattern. Tumor cells were negative for CK7 (dilution 1:300, clone OV-TL 12/30, Dako) (Fig. 3). The Ki-67 (dilution 1:100, clone MIB-1, Dako) labelling index was less than 1% after evaluation of 1000 cells per five high-power fields. The histomorphological and radiographical findings supported a final diagnosis of CEOT, microcystic variant. The patient was treated by conservative surgical resection and microscopic examination of the resected specimen confirmed the initial diagnosis. After 1 year follow-up there is no evidence of recurrence.

Fig. 1
figure 1

An expansive and well-defined mixed radiolucent–radiopaque lesion located in the ascending ramus of the mandible, in relation to an unerupted third molar. Cortical bone expansion and thinning of the inferior cortical bone is evident

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Fig. 2
figure 2

a, b Microcystic compartments of varying size resembling pseudo-glandular structures in a fibromyxoid stroma. c Extracellular amyloid deposits within a pseudo-ductal structure were d intermingled with typical cords of polyhedral eosinophilic epithelial cells and close to calcified material. e, f Congo red positive for amyloid material, which showed green birefringence under polarized light (HE, a ×25, b–f ×200)

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Fig. 3
figure 3

Tumor cells were positive for a AE1/AE3, b CK14, c CK19, d p63, e CD138, and f beta-catenin (IHC, ×200)

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Discussion

Virtually any epithelial lesion has the potential to develop cystic or pseudo-cystic spaces, particularly, epithelial odontogenic tumors such as ameloblastoma and adenomatoid odontogenic tumor [10]. On the other hand, cystic lesions e.g. calcifying odontogenic cyst, odontogenic keratocyst or glandular odontogenic cyst, often have aggressive biological behavior, comparable to a solid neoplasm. The difference between an odontogenic cyst and an odontogenic neoplasm may be subtle and difficult. Therefore, close correlation between clinical, radiographic, and gross features are required for proper diagnosis, treatment, and follow-up.

In 2006, Gopalakrishnan et al. reported the first case of cystic variant of CEOT in a 15-year-old male with an expansive mixed lesion of the posterior maxilla [10]. Since then, only three additional CEOT cases showing considerable cystic or microcystic pattern have been reported [11,12,13]. All patients were males with a median age of 24.5 years (ranging from 15 to 31). Radiographically, all CEOT with cystic spaces, showed a mixed radiolucent–radiopaque appearance. Two cases were located in the posterior maxilla, related to an unerupted displaced tooth, and showing maxillary sinus extension [10, 11], which is also a common finding in conventional maxillary CEOTs [5]. Other two cases were located in the tooth-bearing regions of the body of the mandible with root displacement or resorption, one of them extending posteriorly into the ramus [12, 13]. Interestingly, all cystic CEOT cases showed gross expansion of cortical bone, average size was 3.3 cm in the greatest diameter. To the best of our knowledge, our case is the second microcystic variant of CEOT reported [13].

Microscopically, most CEOT can be readily diagnosed on routine H-E sections, which in some cases required Congo red stain, in order to demonstrate amyloid deposits. Immunohistochemistry is mainly performed for academic reasons and to better understand the pathogenesis of these tumors. At present, the different histologic variants described so far, do not have any impact on prognosis or treatment. However, we consider that is important to describe them, for the benefit of morphologic diagnosis and to prevent potential confusion with other epithelial tumors affecting gnathic bones. For this specific case report, our interest is to highlight this unusual microcystic variant, which may be confused mainly with metastatic adenocarcinoma or other benign or malignant odontogenic tumors. Variable amounts of polyhedral eosinophilic epithelial cells, clear cells, amyloid material and calcifications can be observed in CEOT [10,11,12,13]. These features may help to confirm the diagnosis of microcystic CEOT.

As previously mentioned, the diagnostic value of immunohistochemistry in odontogenic lesions is limited [14]. Our results confirmed previously reported findings showing positivity for AE1/AE3, CK14 and CK19. At present, only six reported cases of CEOT were positive for p63 protein [6, 15, 16], which was also expressed in our case. Similarly, the positivity for syndecan-1 (CD138) and beta-catenin in CEOT were observed in only few studies [6, 7], which were both strongly positive in the present case. Therefore, the immunohistochemical profile seems to be similar in all variants of CEOT.

Additional cases of microcystic and other variants of CEOT may contribute to better understand the clinical, histological and biological spectrum of this tumor.