Ghost cell odontogenic carcinoma (GCOC) is a rare malignant odontogenic epithelial tumor with features of benign calcifying odontogenic cysts. Herein, we report two new cases of GCOC and systematically review the previous literature.

In case 1, a 46-year-old man complained of painless swelling of the right maxilla for 3 years, with a 1-mo history of hemorrhinia in the right nasal cavity. In case 2, a 72-year-old man was referred to our hospital with a chief complaint of painful swelling of the right mandible. Initially, the preliminary diagnoses were ameloblastomas. Thus, the two patients underwent resection of the tumor under general anesthesia. Finally, immunohistochemical examination confirmed the diagnosis of GCOC. The patient in case 1 was followed for 2 years, with no evidence of recurrence. However, the patient in case 2 was lost to follow-up.

GCOC is a rare malignant odontogenic epithelial tumor with high recurrence. Local extensive resection is necessary for the definitive treatment of GCOC.

Ghost cell odontogenic carcinoma (GCOC) is an extremely rare odontogenic epithelial malignant neoplasm within the maxillofacial bones that displays aggressive behavior[1]. It may be derived from de novo or two benign odontogenic neoplasms: Calcifying cystic odontogenic tumors (CCOT) or dentinogenic ghost cell tumors (DGCT)[2,3]. Since Ikemura et al[4] first well documented one case in 1985, about 50 cases have been described thus far. Although histologic diagnostic criteria have been established for CCOT, DGCT, and GCOC, these three tumors manifest diverse nonspecific clinical and radiologic characteristics, making the diagnosis challenging.

The natural history of GCOC is unpredictable, as it may vary from slow progression to rapid destructive growth, with highly local aggressive characteristics, recurrence, and occasional distant metastases. Herein, we report two cases of GCOC and describe their clinical features, histological characteristics, and treatment.

GCOC.

The patient with maxillary involvement underwent maxillectomy. Moreover, another patient with a mandibular lesion underwent segmental resection of the mandible.

The patient in case 1 was followed for 2 years without any sign of recurrence. However, the patient in case 2 was lost to follow-up.

GCOC is an extremely rare tumor with aggressive and destructive behavior. Various terminologies have been used to designate this disease owing to its diverse histopathological characteristics including calcifying GCOC, malignant epithelial odontogenic ghost cell tumor, carcinoma arising from the calcifying odontogenic cysts (COCs), aggressive epithelial ghost cell odontogenic tumor, malignant COC, and malignant calcifying ghost cell odontogenic tumor[5,6]. It is characterized by the presence of ‘‘ghost cells,” which are enlarged polygonal eosinophilic epithelial cells without a nucleus stained with hematoxylin and eosin. The formation of ghost cells is still unclear, and ischemia induced degeneration or metaplastic of epithelial cells may play an important role[7]. Nevertheless, the presence of ghost cells is not a specific feature, as they can also be seen in pilomatricoma, craniopharyngioma, odontoma, and ameloblastic fibro-odontoma[5,8]. These tumors are exclusively seen in an intraosseous location, with an occurrence of approximately 7% in the head and neck regions. Their incidence in the oral cavity is about 0.37% to 2.1% of all odontogenic tumors[5]. They occur most commonly in the maxilla, accounting for 67%[9]. Pathologically, it is reported to arise de novo (55%), followed by malignant transformation of CCOT and DGCT (32.5%), ameloblastoma, and other odontogenic tumors[10]. In the presented cases, both patients had an impacted tooth in the bone lesion, which suggested that the disease may originate from an odontogenic tumor progressing into a malignant GCOC.

Because of the rarity of such disease, less than 50 cases have been reported in the English literature[3-6,8-44] (Table 1). The Asian population appears to be more susceptible to such tumor (20/50), and men are at a higher risk than women with a ratio of 3.2:1. It can occur at any age, ranging from 10 to 89 years, with the peak incidence in the fourth and fifth decades of life. The maxilla is the most commonly involved site, with a ratio of 2.1:1. In addition, the molar area and ramus are the most affected parts of the mandible. Patients are often referred to the hospital with a chief complaint of painful or painless swelling of the bone, and local paresthesia, teeth mobility, and mucosal ulcer can be seen in some patients. Few patients showed enlarged neck lymph nodes, and lymph node metastasis was extremely rare. Pulmonary metastasis was found in two cases, and multiple metastases occurred only in one case. Local recurrence in patients who underwent local surgical resection or curettage was more common, and 56.25% of patients demonstrated recurrence from 3 mo to 7 years of follow-up. Given the rare occurrence of GCOC, most epidemiological information and clinical features are based on case reports; hence, the 5-year survival rate is not yet clear.

The etiology of GCOC is controversial, and an integrative genomic and transcriptomic analysis of GCOC revealed the expression of multiple oncogenes and changes in tumor suppressor genes. Although the gene expression in the GCOC is unique, no tumor markers have been identified. Because of the different compositions of GCOC tissues, the imaging of GCOC showed that mixed unicameral or multilocular radiolucent-radiopaque lesions with or without clear borders are more common than radioactive lesions[19]. Displacement of tooth roots and various degrees of bony destructions or infiltration of adjacent structures are common; tooth impaction and root resorption can also occur[21,45]. No typical or special presentation is found on CT of such lesions. Although bone destruction is frequently observed, the manifestation of tooth resorption was unusual. Possibly, various compositions of the cancellous bone, cortical bone, and cementum are related to the phenomenon.

Histologically, GCOC shows small, rounded cells with dark nuclei, larger cells with vesicular nuclei, or small cluster or large masses of “ghost cells” regardless of calcification. Mitoses are frequently observed. Immunohistochemical staining with a panel of antibodies demonstrated that neoplastic cells were strongly positive for cytokeratin and negative for vimentin, desmin, SMA, and CD34[43]. The expression of Ki-67 and MMP-9 may be associated with the proliferation, invasion, and prognosis of GCOC[33]. In our two cases, the Ki-67 staining was focally positive, which demonstrated the lower malignancy of GCOC. Moreover, the cytokeratins such as CK19 were present, which showed the nature of odontogenic epithelial tumor. In addition, Rappaport et al[39] reported that mutation of the β-catenin gene was noted at codon 33 in GCOC. Compared to CCOT and DGCT, GCOC demonstrates extensive bone destruction, and tartrate-resistant acid phosphatase and vitronectin receptor were strongly expressed in the ghost cells of GCOC[24]. Further research is required to determine if these biomarkers can be used to determine malignant transformation or high recurrence rate.

The diagnosis of GCOC should be based on clinical symptoms, radiological examination, and histopathology. Accurate diagnosis of GCOC requires extensive sampling of the specimen for the features of malignant epithelial tumors containing benign histology of CCOT or DGCT[42,46].

The recommended treatment for GCOC is wide surgical excision with clean margins[5,42]. No research to date has been able to draw definite conclusions on whether adjunctive radiotherapy with or without chemotherapy has efficient outcome. Adjuvant cetuximab may be an option; however, it has been used in only one case.

To develop a full picture of GCOC treatment, additional studies will be needed to obtain overall information about its pathological and biological features. Taken together, a multidisciplinary team is essential to determine proper therapy and optimal outcome. According to previous case reports, GCOC has a high recurrence rate and shows diverse biological behaviors. Therefore, long-term follow-up is recommended to track and assess clinical changes in such disease. The present cases emphasized the biological behavior of GCOC. Adequate biopsy with meticulous histopathological examination of multiple sections along with adjunctive immunohistochemistry is the key to definitive diagnosis and to differentiating from conventional squamous cell carcinoma. As recurrence and metastasis are very frequent in GCOC, long-term follow-up should be advised. According to some studies, the 5-year survival rate was about 73%[28]. However, the small number of cases made it difficult to determine the exact rate of recurrence, with half of them having a follow-up time shorter than 2 years and with almost half of the patients having a relapse during the follow-up period. Given the short follow-up time and obscure prognosis, it is hard to determine the recurrence rate, disease-free survival, and 5-year survival rate.

In summary, we have introduced another two cases of GCOC that affected the adjacent tooth, which suggested that the disease may originate from an odontogenic tumor progressing into malignant GCOC. During the 2-year follow-up period, no recurrence was reported in case 1. Further investigation is needed to elucidate the etiology and diagnosis, and its treatment remains to be improved.

GCOC is a rare tumor that has been reported mostly in case reports. The literature review as well as the clinical, imaging, and histochemical presentation suggests an odontogenic origin of this tumor. In addition, this carcinoma has high recurrence when treated with enucleation therapy only. It is commonly recognized that extended resection therapy with a negative margin is a comparatively radical cure for GCOC. However, there is no explicit evidence to indicate that adjunctive therapy is effective.

We fully appreciate the help from Professor Jia-Li Zhang in the histopathological diagnosis.