Oral lymphoepithelial cyst: A clinicopathological study of 26 cases and review of the literature

Introduction Τo describe the clinicopathological features of 26 oral lymphoepithelial cysts (LECs) and review the literature. Material and Methods Twenty-six cases of oral LECs diagnosed during a 37-year period were retrospectively collected. The patients’ gender and age, as well as the main clinical features of the cysts were retrieved from the requisition forms. The main microscopic features were recorded after reevaluation of all cases. Pubmed and Google Scholar electronic databases were searched with the key word “oral LEC”. Inclusion criteria were the microscopic confirmation of LEC diagnosis and the report at least two of three main clinical features (gender, age and cyst’s location). Results The 26 oral LECs represented 0.08% of 31,564 biopsies accessioned during the study period. They affected 25 patients, 14 females and 11 males with a mean age of 33.04±9.81 years. They appeared as smooth (92%) nodules, with soft (24%) or firm (76%) consistency and normal (28%), yellow to normal (20%), yellow (32%) or white (20%) hue, in the tongue (69.23%) or the floor of mouth (30.77%). They were covered by parakeratinized squamous (92.31%) or non-keratinized (7.69%) epithelium and contained desquamated epithelial cells, amorphous eosinophilic material and/or inflammatory cells (100%). The lymphoid tissue surrounded the cystic cavity partially (34.62%) or completely (65.38%), often in a follicular pattern with prominent germinal centers (53.85%). Literature review yielded 316 cases of oral LECs derived from 25 case reports, 3 case studies/retrospective studies with detailed information for each case and 7 studies with summarized data. Conclusions Oral LEC is a pathologic entity with discrete clinical presentation that is, however, commonly misdiagnosed in clinical practice as other, mostly benign, entities. Its pathogenesis remains obscure, as its clinicopathologic features are consistent with both theories suggested up to date. Key words:Oral lymphoepithelial cyst; developmental cyst; non odontogenic cyst; lymphoid tissue; oral tonsil.


Introduction
The oral lymphoepithelial cyst (LEC) is a rare, soft-tissue, developmental cyst (1,2), first described by Gold (3) in 1962 as "branchial cleft cyst". The name LEC that was in use for the description of branchial cysts of the neck (4,5) was proposed by Bhaskar (6) in 1966. Other names applied were "branchial cleft cyst" (7,8), "branchiogenic cyst" (9) or "tonsillar pseudocyst" (10). LECs arise in various organs, i.e. pancreas (11), stomach (12), thyroid (13), esophagus (14) and mediastinum (15). In the head and neck area it is most common in the lateral cervical region and the parotid glands, with LECs of major salivary glands associated with the human immunodeficiency virus (4,16). Oral LECs usually present in the floor of mouth or the lateral margin of tongue, as painless nodules of normal-yellow to white color and soft to firm consistency, measuring less than 1cm (17)(18)(19)(20)(21). Microscopically, the cystic cavity is lined by stratified squamous or/and pseudostratified columnar epithelium and contains desquamated epithelial cells and inflammatory cells. The fibrous connective tissue wall of the cyst is surrounded by lymphoid tissue, usually with a follicular pattern (6,17,18,20). The pathogenesis of intraoral LEC has not been settled (3,10,22). The objective of the present study is to describe the clinicopathological features of 26 oral LECs and review the pertinent literature with emphasis on its histopathogenesis.

Material and Methods
All cases of LEC diagnosed in the pathology laboratory of the Department of Oral Medicine and Pathology between 1980 and 2016 were retrospectively collected. LECs of the major salivary glands were excluded. Patients' gender and age, location, clinical features (color, consistency, surface texture and maximum dimension), symptoms and duration of the lesion before diagnosis, as well as clinical diagnosis were collected from the requisition forms. The main clinical features of the cases studied are summarized in table 1. The histopathological features studied were type of the lining epithelium, cystic content, pattern of lymphoid tissue, type of adjacent anatomic structures and overlying mucosa. All patients at the time of their initial examination gave written consent for the future use of their data for study. The study was approved by the Research Ethics Committee (NKUOA code number 310).
Pubmed and Google Scholar electronic databases were searched on April 2017 with the key word "oral lymphoepithelial cyst" and the pertinent literature was collected. Studies included were those where the diagnosis had been confirmed by microscopic examination and at least two of three main clinical features (gender, age and location of the cyst) were reported. Cases located on the palatine tonsils, oropharynx or jawbones were excluded from evaluation.
-Histopathological features Table 2 summarizes the main histopathological data of the cases studied. The two adjacent LECs showed similar histopathological features ( fig. 2A). In 24 cases (92.31%) the cystic epithelium was parakeratinized and in 17 of them (70.83%) prominent hyperplasia of the parakeratin layer was noticed ( fig. 2B). In one of those cases transition from squamous to pseudostratified columnar epithelium was also seen. In 2/26 cases (7.69%) the cyst was lined by non-keratinized squamous epithelium with a superficial layer of cuboidal cells. Mucous cells   or goblet cells were not found. The inflammatory cells infiltrated focally the cystic epithelium in most cases.
The lymphoid tissue surrounded the cystic cavity partially (9 cases, 34.62%) or completely (17 cases, 65.38%) and was arranged in a follicular pattern with prominent germinal centers (14 cases, 53.85%, Fig. 3A,B). The cystic lumen in all cases was filled with desquamated epithelial cells, amorphous eosinophilic material and/or polymorphonuclear leukocytes, lymphocytes and plasma cells (Fig. 3A,B). The cystic wall consisted of non inflammatory, loose to dense fibrous connective tissue and exhibited areas of epithelial islands and minor salivary glands in one and six cases, respectively. The overlying mucosa was present in the histopathological sections of 22 cases (84.62%) and was covered by parakeratinized, stratified squamous epithelium. In 10 cases the cyst was located directly beneath the oral mucosa. Continuity of the cystic epithelium and the overlying mucosa was noticed in one case.
-Literature review  Forty-five papers were retrieved; 10 case-reports were excluded, 7 due to inability to access full-text (23-29) and 3 due to non-intraoral location (30)(31)(32). Only two cases from a report of multiple LECs in the same patient (33) were included, as the rest lacked histopathological confirmation, while for the same reason another case (34) included in previous reviews (35,36) was omitted. In total our review included 316 cases of oral LEC (Table 3, Table 3  with summarized sample data. In three of the latter studies (1,2,36) there were 8 cases in the palatine tonsil or the oropharynx that could not be excluded, due to the way the data were reported.

Discussion
The 26 LEC cases presented herein represent less than 0.1% of all biopsies accessioned in a single oral pathology laboratory during a 37-year period, while in two previous studies they respective figures were 0.11% in 53 years (2) and 0.1% in 40 years (1). The asymptomatic nature of LECs that make their recognition mostly an incidental finding (3,9,19,39,49), as well as their clinical misdiagnosis as normal anatomic structures, e.g. foliate papillae (53) may account for the rarity of recorded cases.
According to the obstruction theory, a traumatic event or a microbial invasion accompanied by inflammatory reaction may stimulate the parakeratinization of the crypt's non keratinized epithelium (17,18,20,36). With incomplete desquamation, the parakeratinized squamous epithelial cells along with bacteria and purulent material accumulate and obstruct the crypt's orifice, resulting in the formation of LEC (10,(18)(19)(20). According to this theory, LEC is a pseudocyst LEC. This theory is supported by the most common presence of oral lymphoid tissue ("oral tonsils") in the floor of mouth, tongue and soft palate (10), i.e. the three most frequent sites of intraoral; the presence of inflammatory infiltration of the LEC epithelium; and the continuity or the close proximity of the cystic epithelium with the superficial oral mucosa (19,21,46,53). Continuity, though, may disappear in advanced developmental stages of oral LEC (18) or may not be detected in sections evaluated; thus, lack of it does not necessarily reject the latter theory (53). There are cases, however, where pathogenesis in not consistent with either hypothesis (18) or consistent with both hypothesis (19). As in previous reports, the findings of our study may be interpreted by both theories. Excisional biopsy is usually recommended to confirm the diagnosis of oral LEC. Recurrence has not been reported in a follow up period up to 17 years (36).
In conclusion, oral LEC is a pathologic entity with discrete clinical presentation that is, however, commonly misdiagnosed in clinical practice as other, mostly benign, entities. Its pathogenesis remains obscure, as its clinicopathologic features are consistent with both theories suggested up to date.