Lymphoepithelial Cysts of the Thyroid Gland: A Case Report and Review of the Literature

Originally reported by Louis et al1 in 1989, lymphoepithelial cysts of the thyroid gland are rare lesions with, to our knowledge, only 16 cases described in the medical literature.1–8 Histologically similar to branchial cleft cysts of the lateral neck, intrathyroidal lymphoepithelial cysts are lined predominantly by attenuated or stratified squamous epithelium with occasional reports of respiratory-type epithelium present in the cyst lining.1,8 Dense aggregates of lymphoid tissue with well-formed germinal centers are present beneath the lining epithelium of the cysts. Proposed theories for the occurrence of these lesions in the thyroid gland include origin from intrathyroidal branchiae-derived remnants,1 such as the ultimobranchial body.3 Although only a small number of cases have been reported, these cysts appear to be associated with chronic thyroiditis.

A 55-year-old white woman with a history of hyperthyroidism for which she received levothyroxine presented to her primary care physician because of an enlarging neck mass and dysphagia. An ultrasound study revealed a mass in the right lobe of the thyroid gland. The results of thyroid function tests at the time of presentation were within reference limits. The patient was admitted to our institution for further evaluation, and a computed tomography scan of the neck revealed a mass of the right lobe of the thyroid. Because of her symptoms of dysphagia, the patient elected to undergo total thyroidectomy. Surgical findings consisted of an enlarged, nodular right thyroid lobe and an unremarkable left thyroid lobe.

The tissue was fixed in 10% buffered formalin, routinely processed, and embedded in paraffin. Histologic sections were cut at 4-μm thickness and stained with hematoxylin-eosin. Immunohistochemical studies were performed on the formalin-fixed tissue with antibodies against cytokeratin (CAM 5.2, Becton Dickinson, Franklin Lake, NJ), epithelial membrane antigen (EMA, monoclonal, Dako Corp, Carpinteria, Calif), carcinoembryonic antigen (CEA, monoclonal, Dako), thyroglobulin (polyclonal, Dako), calcitonin (polyclonal, Dako), and leukocyte common antigen (LCA, monoclonal, Dako).

The right lobe of the thyroid measured 5.0 × 3.0 × 2.0 cm and had a maroon, nodular capsular surface. Sectioning revealed multiple smoothly lined cystic spaces that measured up to 1.4 cm in greatest dimension. At the time of sectioning, dark brown, thick material extruded from the larger multilocular cysts, giving the gross impression of an epithelial inclusion cyst or a teratoma. The smaller unilocular cysts contained clear to red-tinged fluid. Calcification was noted in the walls of some of the cysts, and the tissue between the cysts was firm and fibrotic.

The left lobe of the thyroid measured 3.5 × 2.0 × 0.5 cm and had a relatively smooth maroon capsular surface. Sectioning revealed multiple small, smoothly lined unilocular cysts in the red-tan parenchyma; these cysts measured up to 0.4 cm in greatest dimension. A calcified nodule measuring 1.0 × 0.5 cm was noted in the upper pole. The stroma between the cysts was red-gray and fibrotic.

The cysts in both lobes of the thyroid were lined predominantly by stratified squamous epithelium that was attenuated in some areas and stratified in others (Figure 1). Focally, in the epithelium lining the larger multiloculated cysts in the right lobe, respiratory-type epithelium with goblet cells was present (Figure 2). In areas adjacent to the respiratory-type epithelium, goblet cells were seen in apparently metaplastic squamous epithelium. The goblet cells in the epithelium stained for mucin. Deep to the epithelial lining, there was abundant lymphoid tissue with many reactive follicles containing well-defined germinal centers (Figure 3). Fibrous tissue encircled each cyst, and no thyroid tissue was identified in the walls of the cysts. The larger cystic cavities were filled with a mixture of sloughed keratinous debris, blood, and hemosiderin-laden macrophages, corresponding to the thick brown intracystic material seen at the time of sectioning. Numerous cholesterol clefts were also present in the intracystic material. The smaller cysts contained some keratinous debris but were filled mostly with pale eosinophilic fluid.

The background thyroid tissue showed changes of severe chronic lymphocytic thyroiditis. Only occasional foci of identifiable thyroid follicles were seen in either lobe of the thyroid gland. In the tissue not involved by cysts, extensive fibrosis and chronic inflammation were present. Lymphoid follicles with prominent germinal centers were identified in the stroma in areas distant from the cystic spaces, and the thyroid follicles present showed oxyphil cell change and marked atrophy. Groups of entrapped, markedly reactive follicular cells were seen in the lymphoid aggregates. Collections of basaloid squamous cells histologically similar to the squamous cells lining the cysts were present in the background thyroid tissue, a finding that has been seen in cases of chronic lymphocytic thyroiditis and has been postulated to represent either metaplastic follicular epithelium or variants of solid cell nests. These squamous collections manifested varying degrees of cystic change and, in areas, showed continuity with the squamous epithelium lining the cysts. Well-defined solid cell nests were present in the background thyroid tissue and in close proximity to the cysts. Occasional solid cell nests were seen within the walls of the cysts. Varying degrees of cystic change and occasional mucin-positive goblet cells were present in the solid cell nests. Some of the solid cell nests merged with the basaloid squamous cell nests, which in turn showed continuity with the cyst epithelium. Areas of calcification in the thyroid tissue adjacent to the cysts were noted, and 2 collections of intrathyroidal parathyroid tissue were identified adjacent to the cysts (Figure 4).

The squamous epithelium lining the cysts showed uniformly strong staining for cytokeratin, focally strong staining for EMA, and intermediately strong staining of the superficial lining cells for CEA and calcitonin. The areas of columnar epithelium and the areas of metaplasia with goblet cells reacted strongly for cytokeratin and CEA. In general, the solid cell nests stained somewhat weakly for EMA, but in the solid cell nests showing cystic change, the superficial cells lining the cyst cavity reacted very strongly for EMA. Staining did not show cytokeratin or CEA positivity in any of the solid cell nests. The lymphoid cells in the cyst wall and in the background thyroid tissue were strongly positive for CD45 (LCA). The entrapped follicular cells in the lymphoid aggregates stained strongly for thyroglobulin and EMA.

Lymphoepithelial cysts histologically similar to branchial cleft cysts of the lateral neck have been described at various sites, including the oral cavity,9 parotid gland,10 parathyroid glands,11 and pancreas.12 These cysts have been postulated to originate from solid cell nests of the thyroid, which are thought to be derivatives of the embryonic ultimobranchial body13,14; the ultimobranchial bodies also give rise to parafollicular (C) cells of the thyroid and possibly to other thyroid constituents as well.15 In 6 of the previously described cases, solid cell nests were identified in the thyroid gland (Table). In 3 additional cases, collections of basaloid squamous cells were identified in the thyroid parenchyma. These basaloid collections have been described previously, and in the current case, they merged with the squamous epithelium lining the cysts. Although the exact nature of these basaloid nests has yet to be completely defined, the possibility that they represent variations of solid cell nests of the thyroid is supported by the merging of cystic solid cell nests and cystic basaloid squamous nests in the current case. The fact that both types of squamous collections (solid cell nests and basaloid squamous nests) showed some degree of continuity with the squamous epithelium lining the cysts in the current case raises the possibility that all 3 structures may arise from a common source and represent various stages of a single lesion.

It is interesting to note that originally, the basaloid squamous nests reported in cases of chronic thyroiditis were thought to possibly represent metaplasia of follicular epithelium in response to inflammatory stimuli. Although this may be the case, these basaloid squamous collections could also represent reactive changes to inflammation in solid cell nests. This is an attractive proposition if one follows the possible scenario of intrathyroidal ultimobranchial remnants (solid cell nests) becoming reactive (basaloid squamous nests) and cystic, with resultant progression to lymphoepithelial cysts by the immune-mediated attraction of dense lymphoid aggregates to the cyst. The absence of inflammatory changes in some of the reported cases is not completely congruous with this theoretical sequence, and other unknown factors must come into play in the development of the lesions in those cases.

The theory that intrathyroidal lymphoepithelial cysts arise from branchial remnants1 is supported by the occasional intrathyroidal presence of other branchiae-derived structures, such as thymic and parathyroid tissue. Indeed, in one of the previously reported cases, by Apel et al,2 as well as in the current case, intrathyroidal branchial derivatives have been identified in proximity to the lymphoepithelial cysts. Further support for a branchial remnant origin of these cysts is provided in a case reported by Chetty and Forder,11 in which lymphoepithelial cysts were identified in the inferior parathyroid glands of a patient with chronic parathyroiditis, the parathyroid equivalent of chronic lymphocytic thyroiditis. The superior parathyroid glands were grossly normal. The occurrence of these cysts in the thyroid gland and inferior parathyroid glands support a branchial derivation of the cysts, given that each of these glandular tissues is derived from the third branchial pouch.

All of the reported cases have had a squamous epithelial lining of these cysts that was either attenuated or stratified; 3 of the previously reported cases as well as the current case exhibited foci of respiratory-type epithelium with goblet cells lining portions of the cysts.1,8 The presence of mucin-positive goblet cells in solid cell nests has been reported previously14 and was seen in the current case; their identification in the solid cell nests as well as in the foci of respiratory-type epithelium lining the cysts lends further support to a relationship between the 2 structures and their possible branchial origin. Since lymphoepithelial cysts of the lateral neck are believed to be branchial cleft derivatives and to contain a squamous to respiratory-type lining with goblet cells, the presence of similar cell types in solid cell nests and intrathyroidal lymphoepithelial cysts supports a common derivation.

The lymphoid tissue associated with the cysts that was present in all of the reported cases was located in the wall of the cyst, just beneath the epithelium, and exhibited multiple reactive germinal centers. Significant lymphoid infiltrates in the background thyroid parenchyma and cellular changes of Hashimoto thyroiditis were seen in 2 of the previously reported cases1 as well as in the current case (Table). In 6 additional cases, a diagnosis of chronic lymphocytic thyroiditis had been rendered.2 The 8 remaining cases showed varying degrees of chronic inflammation in the thyroid tissue, ranging from focal chronic inflammation to the complete absence of inflammation.3–8 It would seem, therefore, that the development of these cystic lesions may be influenced by the presence of chronic inflammation and its associated cellular mediators. Given the absence of demonstrable inflammation in some of the cases, however, the presence of these cysts cannot be completely ascribed to inflammatory changes.

Although these cysts are histologically benign, they may raise clinical suspicion of a neoplastic process. In 10 of the previously described 16 cases, lobectomy or thyroidectomy was performed because of thyroid masses that were detected by imaging or palpation but that proved histologically to be lymphoepithelial cysts (Table). Five of the remaining cases of lymphoepithelial cysts were incidental findings in thyroid glands removed for symptoms other than a demonstrable cystic nodule, and one case was an incidental finding at autopsy. Interestingly, 4 of the previously reported cases have occurred in thyroid glands containing a separate papillary carcinoma.2,8 Although this could suggest a causal relationship between the 2 entities, it seems more likely that these were coincidental findings.

A review of the 16 previously reported cases (Table) shows that 11 cases occurred in women, and 5 cases occurred in men. The mean patient age at the time of diagnosis in the 16 cases was 43.4 years. Of the 10 cases in which the cysts were not incidental findings and came to medical attention as masses that were eventually proven to be lymphoepithelial cysts, the mean patient age at the time of diagnosis was 45.9 years. The issue of the distribution of these cystic lesions in the thyroid gland is somewhat difficult to establish since total or subtotal thyroidectomy occurred in only 8 of the reported cases, while the remaining 8 cases consisted of lobectomies alone. Of the 8 cases in which total or subtotal thyroidectomy was performed, 3 showed bilateral involvement by lymphoepithelial cysts, and the remaining 5 showed unilateral involvement. In 13 of the 16 reported cases, lymphoepithelial cysts were grossly evident at the time of sectioning, while cysts in the remaining 3 cases were only identified microscopically.

In summary, lymphoepithelial cysts of the thyroid are relatively rare lesions that appear to arise from intrathyroidal solid cell nest remnants of branchial derivatives, such as the ultimobranchial bodies. These cysts may come to clinical attention as solitary or multiple, unilocular or multilocular masses of the thyroid that may simulate neoplasm. Although these lesions have been seen in thyroid glands affected by chronic inflammatory processes, they have also been reported in otherwise histologically unremarkable thyroid glands. Some cases have occurred in thyroid glands containing papillary neoplasms, but a definitive association between the two has not been established. As a relatively newly described entity with few cases reported, accrual of the data from future cases will no doubt improve our understanding of the pathogenesis of these interesting lesions.