Thymic hyperplasia with lymphoepithelial sialadenitis (LESA)-like features: a case report and literature review

In 2012, Weissferdt et al. first reported 4 patients with thymic hyperplasia similar to lymphoepithelial sialadenitis (LESA) of the salivary glands and named them “thymic hyperplasia with lymphoepithelial sialadenitis-like features” [1]. Currently, the disease is considered a rare form of thymic hyperplasia that commonly affects people in their fourth or fifth decades of life without a sex predilection [1‐4]. However, the incidence rate is unclear. Patients with LESA-like TH usually appear an anterior mediastinal mass discovered incidentally on imaging studies. Most patients are asymptomatic, and a few patients suffer from a series of symptoms due to mass compression of adjacent tissues.

Macroscopically, the mass of LESA-like TH is enlarged both in size and weight. The cut surfaces are gray-white in color and medium in texture, showing multinodular architecture and focal cystic changes. Microscopically, its histological morphology shows a characteristic pattern of lobulated structures divided by fibrofatty tissue septum. There is abundant lymphofollicular hyperplasia with germinal centers, bland thymic epithelium with reticular or cord hyperplasia, and proliferation of dilated Hassall corpuscles. Mature plasma cells are scattered in the interfollicular areas, and polytypic light chain expression is confirmed by Kappa and Lambda immunohistochemical staining. In addition, the presence of lymphoepithelial lesions, cholesterol clefts and their resulting cholesterol cleft granulomas, and cystic structures lined by squamous epithelium can be observed. Immunohistochemically, epithelial markers such as pan-cytokeratin and CK19 can clearly delineate the obvious hyperplasia of thymic epithelial cells as well as Hassall corpuscles, and lymphoepithelial lesions in the medullary region. Staining for lymphocyte markers reveals a massive proliferation of mature B and T lymphocytes, while an almost complete absence of cortical areas rich in immature T cells is detected.

Morphologically, LESA-like TH striking resembles LESA of the salivary gland. LESA is a component of SjÖgren’s syndrome, characterized by lobulated structure, reactive lymphoid follicles with germinal centers, hyperplasia of ducts, and lymphoepithelial lesions [6]. It is reported that patients with LESA had a 44-fold increased risk of developing lymphoma, with mucosa-associated lymphoid tissue lymphoma (MALT lymphoma) being the most common [7‐9]. Initially, Weissferdt et al. also suggested that LESA-like thymic hyperplasia might be a precursor lesion of thymic MALT lymphoma [1]. Until 2020, Porubsky et al. reported the largest cohort of patients with LESA-like TH and found that 10% of patients had concomitant lymphoma, especially MALT lymphoma, and 33% of patients were associated with non-myasthenic autoimmune diseases. Furthermore, residual LESA-like TH was found in a retrospective analysis of primary thymic MALT lymphoma. Therefore, Porubsky et al. suggested that LESA-like TH may be the precursor lesion of thymic MALT lymphoma as well [3]. However, more relevant case reports are warranted to confirm.

The primary differential diagnosis of LESA-like TH is thymic MALT lymphoma. The median age at onset of thymic MALT lymphoma is 63 years old, about a decade later than LESA-like TH [10]. Likewise, the presence of cystic changes, cholesterol granulomas, and lymphoid follicles can be observed in thymic MALT lymphoma, while thymic epithelium and Hassall corpuscles are occasionally seen. Most importantly, lymphoid follicles in thymic MALT lymphoma have prominent marginal zones, and lymphocytes are characterized by small atypical and monotonous sheets of lymphocytes. These heteromorphic lymphocytes percolate the residual epithelium to form lymphoepithelial lesions or destroy the germinal centers of lymphoid follicles—termed follicular “colonization”, which is absent in LESA-like TH [10]. It is known that thymic MALT lymphoma is a clonal B-cell proliferation lesion, while clonal B-cell proliferation can be detected in a few patients with LESA-like TH as well [3]. Therefore, it is important to underscore that the differential diagnosis from thymic MALT lymphoma cannot be based solely on molecular detection, but also needs to be combined with morphological features.

The thymus gland weighs about 25 g at birth and reaches a maximum weight of about 30-40 g at puberty, then begins to be gradually replaced by adipose tissue and degenerates, but does not disappear completely [11]. “Conventional” thymic hyperplasia mainly includes true thymic hyperplasia (TTH) and thymic follicular hyperplasia (TFH) [12]. TTH usually affects infants and children, and is defined as a remarkably enlarged both in size and weight above normal limits while preserving normal thymic architecture [13]. There are 2 types of TTH according to etiology and pathogenesis: (1) primary thymic hyperplasia without any other disease; (2) secondary thymic hyperplasia in association with other diseases including endocrine abnormalities, sarcoidosis, and Beckwith-Wiedemann syndrome [12]. On the other hand, TFH also shows abundant lymphoid follicles leading to expansion of the medullary region, but the normal architecture of the cortical region and clear corticomedullary boundary is preserved. Another notable feature that distinguishes it from LESA-like TH is the absence of apparent hyperplasia of the thymic epithelium and Hassall corpuscles. While cortical atrophy is sometimes seen in massive and long-standing TFH, there was almost complete absence of cortex in LESA-like TH [13]. In addition, TFH prefers younger female patients and is associated with myasthenia gravis [14].

Finally, LESA-like TH needs to be differentiated from the most common epithelial tumor of the thymus (thymoma) and benign cystic lesions of the thymus. Micronodular thymoma with lymphoid stroma (MNT) shares similar features with LESA-like TH, including cyst changes, lymphoid follicles, and the paucity of immature T cells. However, MNT shows islands of spindle-shaped neoplastic epithelium surrounded by lymphoid stroma free of epithelial cells [15]. Other subtypes of thymoma with lymphoid follicles were either associated with myasthenia gravis or enriched in TDT + immature T lymphocytes in corticosteroid naïve patients. In a similar pattern to LESA-like TH, multilocular thymic cysts (MTCs) are composed of multiple cysts lined by squamous or low cuboidal epithelium, and accompanied by inflammatory changes, lymphoid hyperplasia with germinal centers, the remnant of thymic tissue, cholesterol cleft granulomas, and dilated Hassall corpuscles. Although atypical epithelial pseudoepitheliomatous hyperplasia was reported in some MTCs, those changes are confined to the inner wall of cysts [16]. While nested or reticular hyperplasia of thymic epithelium, and lymphoepithelial lesions can be seen in the thymic parenchyma of patients with LESA-like TH.

In conclusion, we reported a Chinese patient with LESA-like TH and performed a literature review on the clinicopathological features of LESA-like TH. LESA-like TH is a rare thymic hyperplasia with tumor-like features. Due to its rare incidence, it is easy to be misdiagnosed in routine practice. Morphologically, it is characterized by a striking dilation of the thymic medullary area with lymphoid follicles containing germinal centers, hyperplastic thymic epithelial cells and Hassall bodies, lymphoepithelial lesions, plasma cell infiltration, and cystic changes, while the cortical area is mostly all absent. Therefore, LESA-like TH should be considered in the diagnosis of an anterior mediastinal mass characterized by hyperplasia of lymphoid follicular, hyperplasia of thymic epithelial cells, lymphoepithelial lesions, and the almost complete absence of the thymic cortex.