Calcifying Epithelial Odontogenic Tumor ( Ceot )

Calcifying epithelial odontogenic tumor is a rare benign epithelial odontogenic lesion that comprises from 0.2% to 1.1 of all odontogenic tumors. In the past a number of different names have been given to this lesion, such as calcifying ameloblastoma, cystic complex odontoma, uncommon ameloblastoma with calcifications and others. There is a need to study and explore various aspects of this tumour, this article gives a broad idea of the various aspects of this tumor and which aspect of this tumour needs more investigation

tumor for the purpose of understanding this tumor better.
CEOT as a benign tumor under the heading neoplasms and other tumors related to odontogenic apparatus 5 .Histologic classification, they consider CEOT to be a benign neoplasm or tumor related to the odontogenic apparatus with odontogenic epithelium without odontogenic ectomesenchyme.Latest histologic classification there is no difference and they consider CEOT to be a bening neoplasm or tumor line lesion arising from the odontogenic apparatus, with odontogenic epithelium with mature, fibrous stroma and without odontogenic ectomesenchyme 6 .

Incidence & prevalence and relative frequency
The CEOT has one of the lowest frequency ranking on a "hit list" of odontogenic tumors.The peripheral or extra osseous variant constitutes about 6% of the total number of CEOTS.

Age
According to Neville 7 and Shafer 3 the mean age of occurrence is 40 years.According to Regezi 8 and Everson 9 it occurs more in young & middle aged persons in between 30 & 50 years and according to Riechart 10 it occurs in young & middle aged adults 8-92 years at the time of diagnosis with mean 36.9 years.Intra osseous type = 8 to 92 years, Extra osseous type = 12 to 64 years Sex According to Neville 7 , Regezi 8 and Everson 9 CEOT does not show sex predilection.According to Shafer 3 CEOT show no significant difference in gender with men = 49% and women = 51%, and according to Riechart 10 male: Female, for intraosseous = 80:81 and Male: Female, for extra osseous = 6.5, peak incidence for men = 3 rd decade, peak incidence for female = 4 th decade.

Pathogenesis
Pindborg was initially of the opinion that the CEOT was of odontogenic origin and developed from, the reduced enamel organ of the unerupted tooth 11 .The cells from which these tumors are derived are unknown, although the dental lamina remnant and the stratum intermedium of the enamel organ have been suggested 3,8 , tumor cells also bear close morphologic resemblance to cells of the stratum intermedium of enamel organ 8 .The appearance of report of cases of intra osseous CEOTs without an associated unerupted tooth and particular case of the peripheral variant -it became evident that other sources than reduced enamel epithelium should be considered when discussing the histogenesis of CEOTS, the peripheral location strongly suggests the possibility that the tumor arises from rests of the dental lamina or from the basal cells of oral epithelium 10 .

Macroscope
The intraosseous located CEOT is often easily enucleated, and the tumor size varies from 1 to 4cm in diameter.The mass varies in color from grayish white or yellow to tan pink.Bisecting the specimen usually reveals calcified particles that make a crumbling sound during cutting.The tumor may be solid or contain minute cystic spaces.If associated with an unerupted tooth, the crown (or hard dental structures of an odontoma) can be found embedded in the tumor mass.

Microscopy Histologic definitions:
According to the WHO classification 16 a CEOT is "a locally invasive epithelial neoplasm characterized by the development of intra epithelial structure, probably of an amyloid like nature, which may become calcified and which may be liberated as the cells break down".

Histology
The CEOT has a unique and sometimes bizarre microscopic pattern 8 .It has discrete islands, strands or sheets or polyhedral epithelial cells in fibrous stroma 7 .Occasionally, the cells are arranged in cords or results, mimicking adenocarcinoma, the nuclei are frequently pleomorphic, with giant nuclei and multinucleation being quite common but mitotic figures rare.The tumor cells in some lesions are characterized by extreme morphologic variation with severe cellular abnormalities, minimizing those often seen in some highly malignant neoplasm, while other cases of the CEOT are composed of very monomorphic, innocuous appearing tumor cells; yet, the biologic behavior does not differ between the two 3 .
There is no fundamental difference in histomorphol-ogy between the intraosseous and extra osseous variants of CEOT except for the minimal amount or total lack of calcified material in the later 10 .

Occurrence of amyloid
In the CEOT the tumor island frequently enclose masses of hyaline (amyloid -like) material.This results in cribriform appearance 7 .This eosinophilic substance has been variously interpreted as amyloid comparable glycoprotein, basal lamina, keratin of enamel matrix.In most cases, it stains metachromatically with crystal violet, positively with Congo red, and fluorescence under ultraviolet light with thioflavin T, all in a fashion similar to amyloid.
Though there have been several views about this amyloid like (Psuedoamyloid) materials, like its origin from light chain fragment of immunoglobin molecule 17 , origin from immune amyloid or amyloid of unknown origin 18 and its similarity to enamel matrix 19 and few stain & technique which proved the similarity of this material to amyloid, there has been no proof by any technique that it is amyloid.So there has to be more research done on two with never & promising technique.

Occurrence of cementum like components of CEOT stroma
These calcifications are sometimes in large amounts and often in the form of liesengang rings.The calcification actually appears and occur in some instances in globules of amyloid like material, many of which have coalesced and are transformed from being PAS (periodic acid -Schiff)-Negative to PAS -Positive during this calcification process 3 .It has been suggested that the amyloid-like material is an inductive stimulus for the stromal cells to differentiate towards production of a collagenous matrix that is destined to mineralize and resembles cementum.It should, however, be remembered that the majority of calcified homogenous matter of CEOT stroma is thought to be dystrophic calcification 10 .

The future
Study should be done as to whether the globules of amyloid like material from which calcification occur resembles or have any of the properties of cells of dental follicle

Occurrence of clear cells:
In this type, the tumor cells exhibit a clear vacuolated cytoplasm rather than on eosinophilic cytoplasm.The nucleus may remain round or oval in the center of the cells or be flattened against the cell mem-brane.Most of the clear cells are mucicarmine negative, the clear cells may comprise the bulk of the tumor cells while, in others, they consists of only a few scattered foci 3 .It is believed that clear tumor cells represent a simple degenerative phenomenon 6 .In a case of clear cell variant showed positive Immunohistochemical staining for wide spectrum cks, ck8, 13 and 19 indicating an odontogenic origin 20 .

The future
If the clear cell are considered to be a degenerative phenomenon why does it have a specific age range of 45.9 years and if the IHC indicates it to be odontogenic origin why is it less related to unerupted tooth needs to be ascertained in future studies.

Occurrence of Langerhans cells
In two cases reported the tumor chiefly consisted of scattered small islands of epithelial cells.In some nests there were few, occasionally several, clear cells positive for S-100 protein, lysozome, MT1 LN-3, and OMT 6 antibodies, but not for keratin antibody.Almost no calcification of homogenous eosinophilic material was observed.Ultra structurally the S-100 positive cells were identified as Langerhans cells based on the finding of rod and tennis, racket shaped Birbeck granules 21,22 .
It has been clearly ascertained that Langerhans cells function as antigen presenting cells and as allogenic stimulator cells to primed T lymphocytes in the epithelium 23,24 .Langerhans cells -rich variant of CEOT may have distinct predilection for occurrence in the anterior and premolar region of maxilla, compared to clinical CEOTs occurring usually in the molar and ascending ramus area of the mandible.

Occurrence of myoepithelial cells
In a study, one population constituted the classic polyhedral epithelial cells, and the others comprised cells arranged peripherally with elongated profiles and juxtaposed to the tumor epithelial cells.The later cells exhibited a large number of cytoplasmic fine filaments with occasional electron dense areas similar to those seen in the smooth muscle type cell.These cells found to extend basally around the tumor epithelium in most of the epithelial islands examined.They showed a lamina densa continous with that of the neighboring epithelial cells and demonstrated a large number of hemidesrnosoms.However desmosormes between these cell and tumor epithelial cells were not present.The ultra structural char-acteristics of these cells were interpreted to those of myoepithelial cells.This cell type, although found in tumors of glandular origin, has not been described previously in any of the odontogenic tumors and its occurrence in CEOT has so far not been confined in other electron microscopic studies of this tumor 10 .

Combined epithelial odontogenic tumors
First case of presence of CEOT like areas within two cases of adenamatoid odontogenic tumors was reported in 1983 & later which was named as combined epithelial odontogenic tumors 25 .A total of 24 cases of histologic CEOT /AOT variant have been reported 26 .

Recommendation and Conclusions
There is nothing to indicate that a CEOT/AOT lesion reflect a true combination of two distinct and separate odontogenic tumor entities and there are no reported cases of AOT in which CEOT -like areas predominate lastly, all published cases of the CEOT/AOT variant show a biological behavior identical to that of an AOT; that is, truely benign (harmartomatous) odontogenic lesions.Apart from histologically combined appearance of this lesion, the radiographic pattern can also help in analyzing & to differentiate this lesion to a minimal level.

Extra osseous type
Extra osseous type of CEOT was first observed by Pindborg 2 .The lesion is less infiltrative in character than their central counter part 10 .The opinion that tumor arises from the reduced enamel epithelium or possibly that the oral epithelium may be site of origin needs greater amplification 27 .The peripheral location further suggests the possibly that it arises from rests of dental lamina which are located in the gingival, or from the basal cells of the surface epithelium.In a case, connection between the tumor and mucosal epithelium was noted 28,29 .The mean age for occurrence is 34.4 years and mostly shows female predilection 30,31 , why there is predominance of clear cells in most extra osseous types should be prodded and the level of aggressiveness in extra osseous CEOT with increased clear cells should be compared.

IHC (Immunohistochemistry)
In a study examination of CEOT immunohistochemically for localization of intermediate filament proteins, the tumor epithelium cells were slightly positive or negative for (monoclonal keratin bodies) PKKI detectable keratins, but slightly to strong pos-itive for KLI (monoclonal keratin bodies) and TK (polyclonal anti-keratin antibodies), tumor epithelium was slightly positive for vimentin but negative for desmin 32 .Two enamel proteins, amelogenin and enamelin were located in small foci in a case of CEOT when detected immunohistochemically 33 .Localization of fibroblast growth factor FGR -1 and FGF -2 and receptor FGFR2 and FGFR3 in the epithelium of human odontogenic tumors was done immunohistochemically, CEOT showed positivity for FGF 2 and receptor FGFR -2 while FGF and the receptor FGFR3 were absent or weakly detected 34 one case demonstrated reactivity for hepatocyte growth factor (HGF); transforming growth factor ? (TGF-?) and their receptor by neoplastic cells of CEOT immunohistochemically 20 .P63, CK 5/6, calponin low molecular weight cytokeratin (CK7) and glial fibrillary acidic protein in one case were positive 35 .

Recommendations
Though CEOT shows positivity for many tissue specific lineage markers, its importance in immediate and precise identification & in prediction of prognosis and response therapy should be seriously considered.

Ultra structural study:
Studies have been conducted on ultra structural localization of alkaline phosphatase in calcifying epithelial odontogenic tumor 35 .The majority of enzyme activity was associated with the adjacent stromal tissue.The reaction product of alkaline phosphatase was also detected in same membrane bound vacuoles (lysosomes) and the Golgi apparatus of tumor cells.It suggested that the appearance of enzyme activity associated mostly with epithelial cells membranes may be related to transport function of cell membranes.Is alkaline phosphate related to calcification process in case of CEOT still needs to be studied in future with greater interest.

J. Treatment & recurrence
It is evident that long term follow up information is required for the CEOT in order to choose the best treatment modality and assess the incidence of recurrence.Some authors have seen recurrences even after several decades and recommend a radical line of treatment others consider conservative surgery as the treatment of choice.In its ability to recur if treatment is not adequate, the CEOT is similar to the solid/ multicystic ameloblastoma, and although its growth pattern may be slower, some believe that the two should be treated with an identical approach.As reported by Waldron 36 and Hansen 37 , the occurrence of clear cells may prove to be sign of increased tumor aggressiveness indicating the need for more radical surgical approach.

k. Recommendations and conclusions
Correlation between the prognosis of CEOT and occurrence of Langerhans cells also needs further investigation.In view of the biological behavior of the CEOT destructive procedures such as a wide resection or hemi resection of mandible seen unwarranted.Enucleation with a margin of macroscopic normal tissue is therefore the recommended treatment for lesions involving the mandible.CEOT of maxilla however, should be treated more aggressively, as maxillary tumors generally tend to grow more rapidly than their mandibular counterparts and not usually remain well confined.Treatment should be individualized for each because the radiographic and histologic features may differ from one lesion to another.Although it has not been established in the literature, 5 years should be absolute minimum follow-up necessary to assess the care for CEOT.Although many more cases are needed to evaluate the prognosis for the extra osseous or peripheral variant of the CEOT, none of the 11 cases published so far has shown signs of recurrence after conservative Enucleation.Treatment should also include the awareness of the people of their responsibilities regarding their own health, it is important that people should be encouraged to immediately report to a doctor whenever they see any unusual swelling any discomfort and not wait for the swelling to grow and cause great discomfort & jeopardy to themselves in future.The rapid growth of the mass usually imposes additional challenges to the treating team as it will compromise airway and feeding 38 .