Clear and Spindle Cell Dedifferentiation in Ameloblastic Carcinoma: A Case Report on a Uncommon Phenomenon

Abstract

Ameloblastic carcinoma is a rare malignant neoplasm with characteristic histopathological features that are directed towards an aggressive surgical approach than benign odontogenic lesions. It affects people of all ages, mostly in the posterior mandible, without a preference for race or gender. De novo cancer is one of its primary types, while the second type is defined as a malignant change from an antecedent case of benign ameloblastoma. The rapid progression of molecular biology led to the revelation that ameloblastoma contains a BRAF-V600E genetic mutation over 60%. Besides conventional ameloblastic carcinomas, rare histologic variants have also been described in the literature, including clear and spindle cells. These variants pose diagnostic challenges as to whether it is a dedifferentiation or a distinct entity. The dearth of data lends credence to the notion that these histologic variations are related to high-grade neoplasms and more aggressive outcomes. As a result, the current report intends to analyze a series of patients diagnosed with conventional ameloblastic carcinoma of the head and neck region with spindle and clear cell types along with a brief assessment of the literature.

Introduction

Ameloblastic carcinoma (AC) is characterized as a tumor that has some features of ameloblastoma but shows traditional histological features of malignancy and acts more aggressively than ameloblastoma. It may appear de novo or originate from a pre-existing ameloblastoma usually exhibiting bizarre behavior and a poor prognosis. Dedifferentiation towards more poorly differentiated lesions is one of the unwanted pursuits in the pathogenesis of AC and poses great challenges to pathologists because of their little or no resemblance to any of the odontogenic tumors [1]. According to Elzay's classification, if the primary tumor of the jaw presents with some histopathological characteristics of odontogenic tumors and has clear and squamous cell differentiation, then it is sufficient to consider them to be of odontogenic origin, and preferably designated as clear cell AC and AC with squamous differentiation respectively [2]. Many would prefer to diagnose these clear cell variants as clear cell odontogenic carcinoma, following the guidelines given by the World Health Organization classification of odontogenic tumors [3]. Extensive squamous differentiation in AC, a characteristic more typical of primary intraosseous carcinoma, can be related to more aggressive clinical behavior [4]. Therefore, we are presenting two highly aggressive cases, the first of which even resulted in the death of the patient. Classifying these as a variant of AC or a distinct entity was a conundrum. Here we attempted to diagnose these highly aggressive variants of AC with a combined approach of clinical history and histopathology along with specific immunohistochemical markers which might help in the timely identification and intervention of these tumors.

Case I

The first case was a 65-year-old male referred to our department who complained of extensive swelling in the left posterior mandible for one year along with intermittent pain, trismus, and dysphagia. Level I, II, and III lymph nodes were fixed and palpable. Intraoral examination showed firm swelling extending from 33 to pterygomandibular raphe. In the orthopantogram, poorly defined or irregularly marginated radiolucency of about 11–12.5 cm in size, with cortical expansion, perforation, and infiltration into adjacent structures was seen (Fig. 1A, B). An incisional biopsy intraorally from the anterior border revealed plexiform ameloblastoma. Furthermore, Ki67 immunohistochemistry was done, which revealed less than 5% proliferative activity, which could be attributed to the biopsy being obtained from the periphery of the lesion. Subsequently, complete excision was done with radical neck dissection (Fig. 1C), and fine needle aspiration cytology was done which revealed fluid mixed with hemorrhagic background, along with occasional scattered squamous cells and macrophages. With no evidence of atypical cells rendering it to be a benign cystic lesion (Fig. 1D–F) Subsequent serial sectioning of biopsy revealed a cluster of diffuse intermingled ameloblast-like cells with evident dysplastic features suggesting it as AC (Fig. 2A, B). Other areas of highly collagenized connective tissue stroma with cord and strand-like odontogenic epithelium with retraction artifacts were evident. (Fig. 2C, D) The epithelium revealed nests of clear cells with centrally placed round nuclei showing positivity for beta-catenin and Ki67. The clear cell islands of AC depicted amelogenin positivity. (Fig. 2E, F). After 24 months of follow-up, the patient succumbed to death due to metastasis in the lungs secondarily along with various sites.

Fig. 1.

A Extraoral view; B CBCT revealing poorly defined radiolucencies, with cortical expansion; C Resected specimen of the left mandibular region and level I, II, and III lymph nodes. D Gross specimen with straw-colored cystic fluid; E Cystic fluid; F Smear prepared from cystic fluid depicting mixed inflammatory cells with hemorrhagic background with few squamous cells and macrophages

Fig. 2.

A Histopathological view (H&E;100X); B Highly dysplastic region showing spindle and epitheloid-like cells with dysplastic features (H&E; 400x) C Odontogenic cords and strands with retraction artifact areas in highly collagenized sclerotic connective tissue stroma (H&E;400X); D The epithelium revealed cluster of clear cells with centrally placed round nucleus (arrow mark) (H&E;400X); E Odontogenic islands showing nuclear positivity for beta-catenin (β catenin;200X); F Clear cell islands of AC depicting amelogenin positivity (Amelogenin;200X)

Case II

The second instance reported a 55-year-old female referred to our department having a chief complaint of swelling in the anterior mandible for two months. Clinical examination revealed a mild swelling in the symphyseal region of the mandible with no alterations in the surrounding cutaneous tissue and cervical lymph nodes, whereas the intraoral examination revealed a tiny smooth-surfaced nodule without any significant vestibular expansion (Fig. 3A). The orthopantogram revealed a well-defined unilocular radiolucency in the anterior mandible in relation to lower central incisors and CBCT showed superficial cortical bone erosion in relation to 33–44 (Fig. 3B). An excisional biopsy was performed and a microscopic examination confirmed the diagnosis of AC having highly dysplastic spindle and squamous cells with abundant keratinization, aberrant mitotic figures, large nucleoli, and a high proliferative index, with little morphologic resemblance to an AC (Fig. 3D, E). Positive immunohistochemical expression of CK5 and CK18 was observed. The patient was then referred to the Department of Oral Surgery for further treatment where resection was planned accordingly. No recurrence was reported after two years of follow-up.

Fig. 3.

A Intraoral view; B CBCT showing erosion of the cortical bone in relation to 33 till 44; C Histopathological view (H&E; 200X); D Extensive areas of squamous islands in the form of sheets with abundant keratinization (H&E; 200X); Positive immunohistochemical expression; E CK5; 200X; F CK18; 200X

Discussion

Odontogenic tumors are a broad category of lesions with varying histological characteristics and clinical symptoms. Malignant odontogenic tumors are relatively uncommon, constituting less than 6% of all odontogenic neoplasms. AC is the most prevalent variant with an annual incidence of roughly 1.79 instances per 10 million person-years overall, including malignant ameloblastoma [5]. AC shows male predominance and a mean age between 40 and 50 years [6]. Clinical features include mainly pain, ulceration, edema, and accelerated growth whereas the posterior mandible is the most afflicted site [7]. Cortical bone perforation ensuing expansion of intraoral soft tissues of labial or buccal mucosa are frequent findings radiographically [8].

According to the WHO, AC can be classified as either de novo/primary or secondary, based on whether it originated from a preexisting ameloblastoma [9]. The first case in the current situation is better classified as an AC secondary type with clear cell differentiation because ameloblastoma had been identified in the same region eight years ago. The second instance, with subsequent dedifferentiation to spindle cells and squamous epithelial sheets, appeared de novo in the region. However, an AC can develop due to a previously undiagnosed case of ameloblastoma, it can be challenging to accurately determine if it is primary. As a result, the primary and secondary categories of subclassification are inaccurate and ineffectual [10]. In both cases of AC, malignant cytological features such as nuclear pleomorphism and hyperchromatism, tissue necrosis, atypical mitoses, and vascular and neural invasion were present. Additionally, very few areas (< 1%) displayed plexiform architectural patterns as well as reverse nuclear polarization with subnuclear vacuolization. Spindle cell variants and clear cells have been outlined, and an increase in clear cells has been linked to more aggressive behavior in ameloblastomas and AC [11]. The significant aspect of the current cases is the high-grade transformation towards clear and spindle cells in AC, exhibiting extremely pleomorphic cells, abnormal mitotic figures, and a high proliferative index of 60%. Due to the rarity of these characteristics in the literature and the scarcity of microscopic evidence [7], we believe that these features of dedifferentiation of AC must be taken into consideration. High-grade evolution or dedifferentiation is typically associated with more aggressive clinical behavior, as seen in other neoplasms such as epithelial carcinoma, salivary gland tumors, or even sarcomas. A similar theory applies to AC, as the first case reported here had very aggressive clinical behavior and a poor prognosis due to metastasis to the lungs and various sites [12]. Meanwhile, the second, shorter-duration example revealed a high degree of dedifferentiation into spindle cell types.

There is no reliable diagnostic marker for the diagnosis and prognosis of AC, but recent research analyzed the expression of several molecules and their usefulness to distinguish it from ameloblastoma, as it was malignant in the current case and not explicitly necessary [13]. Cytokeratin expression found in the current cases revealed a moderate to strong staining for AE1/AE3 and an increased expression of CK5 and CK18 in the spindle cell variant. (Fig. 3E, F) Ki67 is the most often used molecular marker for distinguishing ameloblastoma from its malignant counterpart, and it must be employed in incisional biopsies. The clear cell variant demonstrated islands of abundant glycogen-rich cells, positive to PAS. Neoplastic cells were nuclear positive for beta-catenin, amelogenin (Fig. 2E, F), and 40% for Ki67.

Conclusion

AC is an uncommon condition, and reports of new cases may reveal previously unknown clinical and microscopic aspects that can aid in a better understanding of its clinical and biological characteristics, resulting in a straightforward, practical, and objective classification. In the current report, we highlight the significance of effectively diagnosing AC and its variants with the help of immunohistochemistry as they may exhibit extensive squamous, spindle, and clear cell differentiation as well as areas of dedifferentiation that may be associated with more aggressive clinical behavior.

Author Contributions

All the authors contributed significantly to this manuscript.

Funding

Not applicable.

Declarations

Conflict of interest

The authors declare that they have no known conflict of interest.