Clear cell Odontogenic Carcinoma Mandible Mimicking oral Cavity Squamous cell Carcinoma: An Intriguing case with Review of Literature

Abstract

Clear cell odontogenic carcinoma (CCOC) is a rare odontogenic neoplasm with high risk of recurrence and aggressive behaviour. Presence of clear cells in head and neck is hallmark, but not pathognomic for the entity. Deceptive behaviour admist wide range of differentials, poses an immense diagnostic challenge. An incisional biopsy with appropriate immunohistochemistry is prudent for diagnosis. We herein report atypical case of CCOC mimicking squamous cell carcinoma, in a tertiary cancer center in North Eastern part of India.

Introduction

Clear cell odontogenic carcinoma (CCOC) is a rare odontogenic neoplasm. It was described as clear cell odontogenic tumor (CCOT) for the first time by Hansen et al. in 1985 [1]. In 1992, WHO classified the entity as benign neoplasm with locally invasive potential [2]. In 2005, CCOC was reclassified by WHO as a low grade malignancy, [3] owing to infiltrative behaviour with tendency of local recurrence, regional nodal metastasis, and rarely distant metastasis [4].

CCOC is characterised by islands of clear cells. Presence of clear cells in head and neck region evokes a list of diverse differential diagnosis which can be solved by immunohistochemistry.

The present case is unique one with respect to the ethnicity (North Eastern part of India), size and histology of the lesion.

Case Report

A 48-year-old woman presented to the Department of Head and Neck Surgery with a 6-month history of a painless and gradually growing swelling of the right lower jaw. Patient had history of betel quid chewing. The patient had been previously assessed by a general practitioner who referred the patient to a dedicated cancer care center for a second opinion. Detailed history and thorough examination was done.

The extra-oral examination showed 3.5*3 cm hard, fixed, non tender swelling which was present at ramus of mandible on right side. The intraoral examination revealed loose teeth (molars) along with ulceration in right lower alveolus. Intra orally fullness was palpable in lateral part of right floor of mouth from incisor to last molar as shown in Fig. 1. Clinically there was no palpable neck node.

Fig. 1.

From right to left, first and second image in first row depict pre operative picture of extra oral swelling of right mandible, and intra oral ulceration of right lower alveolus with right lateral half of floor of mouth fullness.Third image shows the picture after the primary excision of tumor

First and second image in second row depicts the harvesting of island nasolabial flap and the final picture after skin closure. Last image is the resected specimen showing tumor with right segmental mandible with coronoid process

A computed tomography scan with contrast revealed osteolytic bony lesion involving right hemi mandible with mentum, ramus and body, effacing right lateral border tongue and involving right hyoglossus, mylohyoid and buccal and alveolar mucosa as shown in Fig. 2.

Fig. 2.

Pre operative axial contrast enhanced computed tomography scan oral cavity and neck depicting osteolytic bony lesion involving right hemi mandible with mentum, ramus and body, effacing right lateral border tongue and involving right hyoglossus, mylohyoid and buccal and alveolar mucosa

Pre operative punch biopsy under local anaesthesia showed moderately differentiated squamous cell carcinoma oral cavity. After adequate investigations, patient underwent wide local excision with right segmental mandibulectomy with bilateral neck dissection as disease was reaching midline. Repair was done using island nasolabial flap depicted in Fig. 1. The choice of local flap for such defect offered minimal morbidity and good cosmetic and functional outcome. Post op period was uneventful and patient was discharged on 5th post operative day without tracheostomy.

Final histopathology revealed 7*4.5 cm grey white nodular growth showing nests, trabaculae, and focal sheets of polygonal cells with variable clear cytoplasm. At places squamous differentiation with basaloid features and comedo necrosis was seen in background of thick fibrous stroma. overlying mucosa did not show any dysplasia or carcinoma. All the cut margins were free. Perineural invasion and lymphovascular emboli were absent. No (0/30) lymph node showed metastasis. Imunohistochemical analysis revealed positive staining for CK and EMA and negative staining for vimentin, S-100, and PAX-8. Based on these findings, tumor was diagnosed as Clear cell odontogenic carcinoma.

Joint Tumor Board discussion suggested to consider adjuvant radiotherapy in view of > 4 cm size. The present case is one year post treatment, disease free and in still under regular follow up.

Discussion

To the best of our knowledge, 108 cases (excluding the present one) have been reported in English literature till date. History dates back to 1985, when it was first described by Hansen et al. [1] as benign odontogenic tumor. Due to the invasive potential, it was reclassified as malignant by WHO in 2005. The paucity of the entity in head and neck creates room for uncertainty regarding its epidemiology, predictive factors, management protocols and treatment outcomes.

Literature suggests it to be more common in females in fifth decade. There seems to be no ethnicity predilection. Most frequent site of occurrence is posterior part of the mandible followed by anterior mandible and maxilla/palate [5].

CCOC generally are asymptomatic initially. Symptoms are often restricted to swelling with or without pain, loose tooth and periodontal issues. Bleeding, ulceration of oral mucosa ,paresthesia are less common. In the present case, patient presented with swelling and oral mucosal fullness. The first differential was squamous cell carcinoma (SCC) considering the huge burden of oral cancer in India, especially in North east part of country where betel quid consumption is rampant. Clinically, absence of oral ulceration, intraoral bleeding in the current case are points against SCC. CCOC has more of an indolent course when compared to SCC.

Radiographically, CCOC is similar to other osteolytic jaw lesions, manifesting as well or poorly demarcated radiolucency which can be unilocular or multilocular [6]. CCOC has no specific radiographic signs, further making its diagnosis a challenge. SCC presents as irregular soft tissue mass with heterogenous contrast enhancement associated with or without bone erosion.

Differential diagnosis of CCOC comprises of SCC, odontogenic, primary salivary and metastatic tumors and melanotic(amelanotic melanoma) as depicted in Table 1. Odontogenic tumors include clear cell variant of calcifying epithelial odontogenic tumor (CCCEOT), ameloblastoma with clear cell changes. Primary salivary tumors encompass mucoepidermoid carcinoma, hyalinising clear cell carcinoma, acinic cell carcinoma, epithelial myo-epithelial carcinoma. Metastatic tumors can be from kidney, thyroid and prostate.[7]. Presence of clear cells is not pathognomic. Due to conspicous nature of clear cells, overlap in histologic features and biological behavior, it poses a diagnostic challenge .Hence, a thorough workup is required to reach the correct differential. Table 1 highlights the important distinguishing features amongst various differentials of CCOC.

Table 1.

Differential Diagnosis of CCOC (Clear Cell Odontogenic Carcinoma)

Differential diagnosis	Histopathological Features	Immunochemical stain
Squamous cell carcinoma (SCC)	Dysplastic features (hyper chromatic nuclei, increased N/C ratio, keratin pearl, mitotic figures	EMA CK8 CK18
Calcifying Epithelial Odontogenic Tumor (CEOT)	Cords,nests or sheets of epithelial cells, calcifying concentric rings (Liesegang rings), Amyloid deposition in stroma	Congo red stain
Clear cell ameloblastoma	Peripheral tall columnar cells with palisading and reverse nuclear polarity	Calretinin+ CK19+
Mucoepidermoid carcinoma	Multiple cystic spaces lined by mucous, epidermoid, intermediate and clear cells(pale basophilic clear cytoplasm)	Mucicarmine stain+ Alcian Blue stain+ CK7, 19+
Hyalinising clear cell carcinoma	Peripheral palisading and hyalinisation of stroma	Pan CK+ EMA+
Epithelial Myoepithelial carcinoma	Group of clear cells (centrally placed nucleus with prominent outline) admixed with ductular epithelial cells	Calponin+ EMA+, CK+
Myoepithelial carcinoma	Clear cells arranged in nodules with necrotic area in centre and hyper cellular areas in periphery	S-100+ Alpha SMA+ Calponin+ Vimentin+
Acinic cell carcinoma	Interspersed basophilic granules	PTAH+ S100+ Pan CK+ CEA+ GFAP+
Metastasis from Renal Cell Carcinoma	Infilterative solid /organoid growth pattern	Sudan Black O stain+ CD10+ PAX-8+
Metastasis from thyroid carcinoma	Cytoplasmic clear cell changes in papillary and follicular arrangement	Thyroglobulin+
Amelanotic melanoma	Infilterative nests or sheets of clear cells	Masson Fontana stain+ Melan A+ HMB45+

EMA- Epithelial Membrane Antigen; CK- Cytokeratin; N/C- Nuclear Cytoplasmic Ratio; SMA- Smooth Muscle Antigen; PTAH- Phosphotungstenic acid hematoxylin; CEA- Carcinoembryonic Antigen; GFAP- Glial Fibrillary Acidic Protein; CD- Cluster of Differentiation; PAX-Paired Box Gene; HMB- Homatorpine Methyl Bromide

Proliferation of neoplastic epithelial cells with clear cytoplasm arranged in islands are present in CCOC. Three types of cells can be found: basaloid to polygonal clear cells, basaloid to polygonal pale eosinophilic cells, and columnar cells with ameloblast-like differentiation. Depending on the proportion of these cells in the tumor, three different subtypes can be distinguished:

(1) monophasic: clear cells with well-defined borders and centrally placed nuclei;

(2) biphasic: identified by by oval and linear nests of large cells mixed with smaller islands of smaller polygonal cells with eosinophilic cytoplasm.

(3) ameloblastic : characterized by columnar cells with ameloblastic differentiation at the periphery of islands [8]. Biphasic is the most common subtype.

SCC pathologically has dysplastic features like hyper chromatic nuclei, nuclear and cytoplasmic pleomorphism, increased nuclear cytoplasmic ratio, keratin pearl formation, mitotic figures with varying degree if differentiation. Concentric whorled accumulation of keratin surrounded by dysplastic cells points towards SCC.

Immunohistochemistry is crucial for diagnosis. Immunophenotypically, CCOC are positive for cytokeratins (CK 14 ,19), p63, and PAS, are diastase-sensitive (demonstrating intracytoplasmic glycogen), and are negative for mucicarmine and myoepithelial markers such as S100, SMA, and calponin [9]. Positivity of epithelial membrane antigen p63 and the connection with the epithelial lining in CCOC directs towards the mucosal origin rather than a glandular one. Molecularly, CCOC has been shown to demonstrate Ewing sarcoma region 1 (EWSR1) rearrangement [10].

Owing to the rarity of the tumor, ideal approach and specific guidelines have not been conclusively determined. In general, treatment protocol similar to oral squamous cell cancers are adopted. Due to high recurrence rate [5], literature suggests early and aggressive surgical excision with clear margins. Due to paucity of cases, it is a challenge to outline risk factors predicting recurrence and metastasis. Medical fraternity has limited knowledge about its behaviour. We need to follow up the cases for long duration. Authors hope that reporting this case can add to the better understanding of this entity. Further, to identify the precise indications of radiotherapy and chemotherapy in adjuvant setting needs more cases, investigations and assessment of patterns of failure. The review by Loyola et al.[11] have reported a local recurrences rate of 41.0% and distant metastases in 31.0% of the cases .

Conclusion

CCOC is a rare malignant neoplasm. Clinical presentation may be non specific and misleading. Immunohistochemistry is the problem solving tool when CCOC needs to be differentiated from list of differentials. Surgical resection with clear margins is the gold standard treatment. Neck dissection should be considered in select cases. Owing to high recurrence risk, follow up is mandatory.

Funding

No funding required.

Declarations

Ethical Approval

All procedures were in accordance with the ethical standards of the institution.

Conflict of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The study is conducted according to the ethical standards. The informed consent of the participant was taken for the study.