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Home All issues Volume 31 / No 3 (2025) J Oral Med Oral Surg, 31 3 (2025) 27 Full HTML
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J Oral Med Oral Surg
Volume 31, Number 3, 2025
Article Number 27
Number of page(s) 5
DOI https://doi.org/10.1051/mbcb/2025031
Published online 28 August 2025

© The authors, 2025

Licence Creative CommonsThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction

Clear Cell Odontogenic Carcinoma (CCOC) is a rare intraosseous tumor of the jaws. Malignant odontogenic tumors represents 6% of all odontogenic tumors [1]. Many cases evidenced a pathology often misdiagnosed due to its low frequency, poor knowledge in literature, and a lack of specificity with differential diagnoses. Moreover, clear cells are present in several different tumors. They are usually the results of fixation artefacts, intracellular storage of several substances (i.e. glycogen, mucin, lipid), or from a paucity of organelles [2]. Thus the lesion diagnosis is difficult to its low specificity.

The aim of this case-report was to put forward the difficulty of diagnosis of this pathology and to provide detailed data for upcoming studies, such as epidemiological, clinical, radiological, histopathological, immunohistochemical, and therapeutic aspects.

Observation

A 64-year-old woman was referred to our Department of Oral and Maxillofacial surgery by her dentist for the management of a mandibular lesion. The lesion was asymptomatic, and was discovered incidentally. The lesion was located in the anterior region, close to the teeth #41, #31, #32, #33. The patient had no medical history outside a gastroesophageal reflux disease; there was no alcohol or tobacco consumption.

Clinical examination revealed no asymmetry, no restriction in mandibular movement, no visible swelling, no neurosensory disturbance, and no palpable adenopathy. Oral inspection identified a well-defined, indurated mass located on the left submandibular lingual region. The overlying mucosa appeared healthy. Teeth #41, #31, #32, and #33 were responsive to cold sensitivity testing and did not present pathological mobility.

Additional diagnostic tests included panoramic radiography and cone-beam computed tomography (CBCT), which revealed a 22 × 18 × 17 mm radiolucent lesion localized to the mandibular symphysis. The lesion exhibited well-defined margins, a spherical and unilobular configuration, lingual cortical fenestration, and evidence of dental root resorption affecting teeth 31 and 32 (Figs. 1–3).

An initial incisional biopsy performed under local anesthesia suggested a diagnosis of desmoplastic ameloblastoma. Based on this preliminary finding, the decision was made to perform enucleation of the lesion and conduct a thorough histopathological analysis. During the procedure, abnormal adhesion of the lesion to the genioglossus muscle was noticed, raising concerns among the surgical team.

Subsequent investigations, including entire analysis of the lesion, revealed a diagnosis of CCOC. This diagnosis was confirmed through the following findings:

  • Histology: Biphasic variant with clear cells and hyperchromatic polygonal cells. No necrosis or mitotic activity was observed.

  • Immunohistochemistry: Tumor cells tested positive for CK5-6, p63, and EMA, and negative for SOX10, PS100, CD34, HMGA2, PLAG1, AML, and desmin. AML was also negative. The Ki67 proliferation index was low (<1%).

  • Molecular Biology: Detection of EWSR1 translocation.

A multidisciplinary tumor board recommended definitive treatment comprising interruptive pelvi-glosso-mandibulectomy with bilateral lymph node dissection, followed by reconstruction with a left fibula free flap. This surgical approach was combined with adjuvant radiotherapy. Final histopathological analysis confirmed a pT4N0M0 tumor with clear resection margins and no evidence of lymph node involvement. At 1-year postoperative follow-up, there were no signs of tumor recurrence.

thumbnail Fig. 1

Orthopantomogram with 22 × 17 mm well-defined radiolucent lesion, anterior from mental foramina, and associated with dental root resorption.
thumbnail Fig. 2

Sagittal section from CBCT defining the lesion and its lingual extension.
thumbnail Fig. 3

3D-modeling generated through segmentation highlighting the tumor among mandibular bone.

Discussion

CCOC was first described in 1985 by Hansen et al. as a benign odontogenic and locally aggressive neoplasm [3,4]. It is defined as a low-grade malignant tumor from odontogenic origin in the 2024 WHO classification of odontogenic bone tumor [5], due to its aggressive behavior, predilection for local recurrence, evidence of distant metastasis and histologically distinct features [6,7]. Any discussion about this tumor is limited by the lack of available data. Moreover, it represents a diagnostic challenge for physicians due to its uncharacteristic features. Clear cell changes have been identified in various benign and malignant tumors but remain as a rare occurrence in the head and neck region [6]. It is crucial to establish the correct diagnosis to develop appropriate treatment strategies, coupled to the fact that misdiagnosis stays as a loss of chance for patients.

We conducted a bibliographic search of the English language literature in the National Institutes of Health PubMed database using the terms “clear cell odontogenic carcinoma”, and a total of 82 results between 1985 and 2024 was observed.

Local symptoms were commonly reported as a painless swelling mass, tooth mobility, inconstant pain, periodontal issues, non-healing ulceration, numbness, bleeding, oral mucosal expansion, and more rarely decreased mouth opening [4,8]. Radiological analysis always showed an osteolytic lesion, unilocular or multilocular, with inconstant root resorption. According to studies, radiolucent lesions with ill-defined margins are observed in 66.3% of cases, while well-defined radiolucent lesions are reported in 22.5% of cases [8,9].

In this case, radiology could be a warning sign but most of the symptoms were not specific.

In the majority of the cases, the preferred location of the tumor is the mandible with an occurrence of 43% in the mandibular body, 31% in the anterior mandible, and 26% in the maxilla or palate [4,9]. The mean calculated size of the lesion is around 4 cm diameter [9,10].

Most cases commonly occur in patients during their 5th and 6th decades of life, with a female preponderance (male-female-ratio of 1:1,8) [7,8,11,12]. No ethnic specificity has been highlighted yet [4].

Our case-report seems to present similar characteristics to the scientific literature.

The presence of clear cells in odontogenic cysts and tumors is due to their origin from the dental lamina. This cells mainly resulted from artifactual changes, cytoplasmic accumulation of water, glycogen, mucopolysaccharides, mucin, lipids, phagocytized foreign body material in the cytoplasm, hydropic degeneration of organelles, paucity of cellular organelles, and intermediate filaments and immature zymogen granules [10,13]. Indeed pathognomonicity of clear cells' presence is hard to demonstrate.

Histologically, three variants are distinguished: biphasic pattern, monophasic pattern, and ameloblastomatous pattern [7].

The biphasic variants (80%) consists of islands and strands containing two populations of cells : clear cells with well-defined borders and a centrally placed nucleus, and hyperchromatic polygonal cells with eosinophilic cytoplasm and eccentrically placed nuclei, both embedded in a fibrous stroma. The monophasic variant (3%) is composed almost entirely of clear cells. The ameloblastomatous variant (12%) is composed predominantly of columnar cells with ameloblast-like differentiation at the periphery of the tumor islands [4].

Immunohistochemistry is obviously helpful for diagnosis. It responds positive for cytokeratin CK8, CK13, CK14, CK18, CK19 and for epithelial membrane antigen (EMA) in clear and eosinophil cells. Immunohistochemistry should be negative for vimentin, S-100 protein, desmin, smooth muscle actin, HMB-45, alpha-chymotrypsin, CD31, CD45 and GFAP. The values for p53 and Ki-67 are low [9,11,13], which was in close correlation with the biopsy's report of our patient.

The improvement of molecular biology and knowledge of genetics enables complementary fields for diagnosis. A DNA microarray technique has allowed for more accurate diagnosis of CCOC through genetic profiling. It results in a frequent translocation of the EWSR1 gene (Ewing Sarcoma RNA Binding Protein 1) commonly with ATF1 gene (Activating Transcription Factor 1) [7,11,14,15]. Alberto Jose Peraza Labrador et al. described the EWSR1 gene rearrangement affection in over 80% of cases [9].

To summarize, combination of histology, immunohistochemistry, and molecular biology can improve the diagnostic precision. CK14, CK19 and EMA immunostaining patterns added to cellular distribution may help the diagnosis, and the negativity of CK7, vimentin and SMA remained important in the exclusion of other tumors presenting clear cells. EWSR1 translocation status remains helpful in the diagnosis of CCOC [7,9].

The complexity of positive diagnosis resides in the plethora of other pathologies with similar characteristics. Differential diagnosis includes other tumors that exhibit histopathological feature similar to those of clear cells, such as: calcifying epithelial odontogenic tumor, hyalinizing clear cell carcinoma, odontogenic cysts, ameloblastic carcinoma, intraosseous clear-cell variant of mucoepidermoid carcinoma, acinic cell carcinoma, squamous cell carcinoma, clear cell oncocytoma, glycogen-rich salivary tumors, clear cell variant of adenocarcinoma of salivary gland origin, intraosseous variant of melanoma, and metastatic tumors of kidney, thyroid, prostate, colon, breast, and lung origins. The kidney is the most closely similar clear cell odontogenic carcinoma histologically [7,8,12,13,16].

These data demonstrate a close similarity between CCOC and clear cell carcinoma of minor salivary glands making it difficult to distinguish [9]. Approximately 84% of CCOCs express EWSR1-ATF1 rearrangement, the same rearrangement found in clear cell carcinoma of the salivary gland [8]. Immunohistochemistry may be beneficial in this respect, as CCOC presents negative results for vimentin and muscle actin, while clear cell salivary gland tumors react positively with vimentin, muscle actin, cytokeratin, and S-100 protein [12–14]. A clinical difference can also be made as the localization does not seem to occur in the same areas [12].

Even in cases of biphasic-pattern CCOC, differentiating it from metastatic renal cell carcinoma may be difficult without incorporating the glycogen-negative tendency of CCOC [14].

Treatment of choice is surgical resection with wide margins due to a higher recurrence rate in those treated conservatively (86.7% vs. 29%) [7,8]. Guastaldi et al. highlighted in his study that only 22% of surgeries included a neck dissection, and only 29% of them were positive on histological examination (6% overall) [4]. Few cases uses chemo-radiotherapy as treatment modality or as an adjuvant but there are no clear recommendations on this point [11]. Although the curative effect of radiotherapy and chemotherapy is not clear, adjuvant radiotherapy could be considered in the cases with soft tissue infiltrations (perineural or vascular), cortical erosion, positive lymph nodes, and if margins are unclear [1,7]. CT scans or MRI are helpful to evaluate the inferior alveolar nerve invasion, soft tissue involvement and bone erosion. TEP-scan has not shown to be useful as a diagnostic tool. Moreover, scientists could not identify any proper X-ray feature for CCOC [1,13]. In order to improve predictability, Gómez et al. performed a surgery planned virtually and intraoperatively navigated as radical resection with oncological margins remains as the gold standard of treatment [1].

Such as others aggressive pathologies, and despite a well-conducted therapeutic strategy, CCOC presents a significant recurrence’s risk.

The overall recurrence rate for these tumors is 55% [4,6,9]. Conservative therapy (enucleation or curettage) has higher local recurrence than resection surgery. The recurrence rate reach approximately 87% in patients treated with curettage only [7,8,10]. It remains difficult to identify risk factors for recurrence due to a lack of data published. Experiences with other tumors suggests that factors such as tissue involvement, size of lesion, location, and nodal or distant metastasis should be considered when developing treatment strategies. Presence of positive surgical margin is an important consideration for recurrence prevalence [1,17]. Compared with clear cell carcinoma of the salivary glands, CCOC has a higher recurrence rate related to the intraosseous component [12].

Most common sites of metastasis are the regional lymph nodes, kidney and lungs [1,2,18]. Lymph node metastasis on initial presentation is rare (10%) but swiftly evolve in those with recurrent disease (33%) [6,9].

The mortality rate is 14.3%, while survival rates at 5, 10, and 20 years is estimated 87%, 76%, and 46%, respectively [14].

CCOC remains a poorly known tumor that needs further disease etiology and predictive factors investigations in order to provide the best treatment strategy. Indeed misdiagnosis could be prejudicial for patients, with a loss of chance for survival, higher recurrence rate, and avoidable consecutive surgeries.

Funding

This research did not receive any specific funding.

Conflicts of interest

The authors declare that they have no conflict of interest.

Data Availability Statement

All data generated or analysed during this study are included in this published article. Additional information or raw data supporting the findings of this work are available from the corresponding author upon reasonable request.

Author Contribution Statement

V.M. conceived and designed the study. S.T-V. and V.M. collected clinical data, and performed the surgical procedure. V.M. carried out the literature review, analyzed and interpreted the histopathological and imaging findings, and drafted the manuscript. All authors contributed to the discussion, critically revised the manuscript for important intellectual content, and approved the final version of the manuscript for submission.

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Cite this article as: Metrop V, Tisne-Versailles S, Murcier G, Borgnat F. 2025. Clear cell odontogenic carcinoma, a rare tumor case-report and its complexity of diagnosis. J Oral Med Oral Surg. 31: 27. https://doi.org/10.1051/mbcb/2025031

All Figures

thumbnail Fig. 1

Orthopantomogram with 22 × 17 mm well-defined radiolucent lesion, anterior from mental foramina, and associated with dental root resorption.
In the text
thumbnail Fig. 2

Sagittal section from CBCT defining the lesion and its lingual extension.
In the text
thumbnail Fig. 3

3D-modeling generated through segmentation highlighting the tumor among mandibular bone.
In the text

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