Ghost cell lesions.

Ghost cells have been a controversy for a long time. Ghost cell is a swollen/enlarged epithelial cell with eosnophilic cytoplasm, but without a nucleus. In routine H and E staining these cells give a shadowy appearance. Hence these cells are also called as shadow cells or translucent cells. The appearance of these cells varies from lesion to lesion involving odontogenic and nonodontogenic lesions. This article review about the origin, nature and significance of ghost cells in different neoplasms.

Ghost cells are found in groups, particularly in the thicker areas of the epithelial lining. The spinous cells may be widely separated by intercellular edema and the epithelium around the ghost cell is often convoluted. The ghost cells are enlarged, ballooned, ovoid or elongated, elliptoid epithelial cells.[1] They are eosinophlic and are usually well-defined, they may sometimes be blurred, and hence that groups of them appear fused. These epithelial cells devoid of nuclei and they retain their basic cell outline. Ghost cells may undergo calcification and lose their cellular outline to form sheet-like area.[2]

Ghost cells appear, especially in a group of neoplasms including odontogenic and nonodontogenic neoplasms such as calcifying cystic odontogenic tumor (CCOT), dentinogenic ghost cell tumor and odontogenic ghost cell carcinoma. Occasionally these cells are also seen in odontomas,[34] ameloblastoma,[5] adenomatoid odontogenic tumor,[6] ameloblastic fibroma, and pilomatricomas.

Sedano and Pindborg[7] found presence of ghost cells in inner enamel epithelium of a normal developing human tooth and eruption cyst. It was found that these cells also have a tendency to induce granulomas, potential to calcify and resistance to resorption.[89]

Ghost Cells – History Behind

Highman and Ogden (1944)[10] first described ghost cell in pilomatricomas. They described ghost cells as dyskeratotic cells, which are similar to viable cells, but have a distinct outline. Hashimoto et al.[11] found a gradual increase in keratinization from basaloid cells to shadow cells and considered these cells are in advanced stages of keratinization.

It was also found that the origin of ghost cells were from the epithelium. It can originate from any layer of the epithelium.[89121314] These cells do not have intercellular junctions[15]

Gorlin et al.[12] believed that ghost cells represent normal or abnormal keratinization. He also suggested that they represent squamous metaplasia with subsequent calcification caused by ischemia. Sedano and Pindborg[7] thought the ghost cells represented different stages of normal and aberrant keratin formation, and they were derived from the metaplastic transformation of odontogenic epithelium. Other investigations suggest that ghost cells may represent the product of abortive enamel matrix in odontogenic epithelium.

Lesions Associated with Ghost Cells

Ghost cells generally lack nuclear and cytoplasmic details and are characteristically seen in CCOT, craniopharyngiomas and pilomatricomas. Other lesions exhibiting ghost cells are odontomas, dentinogenic ghost cell tumor, dentinogenic ghost cell carcinoma, amelobalstoma, ameloblastic fibroma.

Calcifying Cystic Odontogenic Tumor

Calcifying cystic odontogenic tumor was previously named as calcifying odontogenic cyst (COC). Gorlin et al.[12] discussed the development of CCOT and ghost cells in 1962. During the development of CCOT, the transformation of an odontogenic epithelial cell into a ghost cell firstly starts by enlargement of mural cells, followed by other epithelial cells in cystic lining into abnormally keratinized cells. The basal cells transform toward the end, and this transformation leads to loss of distinction between epithelium and connective tissue. Since ghost cells are abnormally keratinized, they are considered as foreign bodies if they reach the connective tissue. This theory was supported by Abrams and Howell. Freedman et al.[16] found only the central portion of the epithelial lining of CCOT transforming into ghost cells. Whereas Ebling and Ephrain observed ghost cells only at places of epithelium where basal membrane had disappeared.

Odontomas

Ghost cells seen in odontomas have resemblance to poorly decalcified osteodentin.[17] Various authors described the nature of ghost cells in similar and confusing terminologies like; a form of true keratinization,[18] prekeratin,[19] stages in the process of orthokeratin, parakeratin and aberrant keratin formation,[1314] highly keratinized epithelial cells and cells, which have lost their developmental and inductive effect.[19] Pindborg suggested that ghost cells were found within odontogenic epithelium, generally near or at the surface of enamel matrix, entrapped within calcified tissue corresponding to either enamel or dentinal matrix and/or isolated within connective tissue. In a study by levy et al.[17] pathogenesis of ghost cells in odontomas was from metaplastic transformation of odontogenic epithelium, which occurs due to reduced oxygen supply caused by walling-off effect by the surrounding hard tissue calcification resulting in death of cells and keratinization. This suggests that ghost cells are formed due to cell death from local anoxia. Some found that these cells are probably a special form of degeneration with a marked aberrant keratinization.[20]

Dentinogenic Ghost Cell Tumor

Presence of ghost cells in dentinogenic ghost cell tumor was first observed by confocal laser scanning microscopy in 2007. Three different maturative stages of ghost cells were observed with varying extents of keratin expression, indicating accumulation of hard keratin in their cytoplasm during the pathological transformation process, thus indicating that ghost cells might represent differentiation into hair.[8]

Ameloblastic Fibroma

Ameloblastic fibroma is a rare odontogenic tumor, in which both epithelial and ectomesenchymal components are neoplastic.[21] Mixed odontogenic tumors with ameloblastic and fibromatous components comprise a heterogenous group of neoplasms. Ameloblastic fibroma containing ghost cells such as those seen in CCOT are reported less in number.[4] Ghost cells were seen in neoplastic epithelial nests. They tend to gather in small groups, and the calcification seemed to occur in the ghost cell background. Lining epithelium show ghost cell differentiation and calcification, other features of ameloblastic fibroma is seen in the cyst wall. Groups of ghost cells were also seen within ameloblastic epithelium in the area of ameloblastic fibroma.

Pilomatricoma

Pilomatricoma, previously known as Pilomatrixoma a benign tumor arising from hair cortex cells, it was initially thought to be a sebaceous gland neoplasm. It most commonly affects children and adolescents; however, it is also seen in elderly patients. It is more common in females.[22]

Histopathologicaly tumor is composed of nodules with nucleated basaloid cells peripherally and ghost cells centrally Early lesions tend to become cystic, whereas older become solid with prominent shadow cell component, keratin debris, multinucleated giant cells and dystrophic calcification with the incidence ranging from 69% to 85%.[2223] According to Lan et al.[24] the mechanism of development of ghost cells seems to arise from basaloid cells, some transitional cells are seen between the basalaoid cells and ghost cells and they were thus thought to represent apoptotic cells proceeding to ghost cells in pilomatricoma. Ghost cells show positive staining for Bax and negativity for Bcl2, which suggest their formation to be an apoptotic process. In pilomatricomas Bcl2 expression was seen to be decreasing from basaloid to transitional cells and finally reaches zero in ghost cells.

Ghost Cell Odontogenic Carcinoma

Ghost cell odontogenic carcinoma (GCOC) is an exceptionally rare and malignant odontogenic tumor with aggressive growth characteristics. GCOC has a low incidence. Ward and Cohen[25] suggested three possible explanations for the histogenesis of a cyst with lining epithelium and its associated carcinoma in jaws. First, carcinomas and cysts have different origins, the former possibly originating from adjacent epithelium or by distant metastasis of a primary tumor. Second, the primary lesion was a carcinoma, which partially underwent cystic degeneration. Third, the primary lesion was a cyst, and the lining epithelium subsequently underwent malignant transformation.

Histopathological examination showed that the tumor was composed of epithelial cell nests. The neoplastic cells showed cytological atypia, manifested mainly as hyperchromatic cells with variably sized nuclei, raised nuclear-cytoplasmic ratio and an increased number of mitotic ures. Clusters of ghost cells were diffusely distributed in the tumor nests.[26]