Multilocular thymic cyst associated with follicular hyperplasia: clinicopathologic study of 4 resected cases

Human Pathology (2005) 36, 841 – 844

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Case report

Multilocular thymic cyst associated with follicular hyperplasia: clinicopathologic study of 4 resected cases Hiroshi Izumi MDa,*, Bunsei Nobukawa MDa, Kazuhisa Takahashi MDb, Toshio Kumasaka MDa, Hideaki Miyamoto MDc, Akio Yamazaki MDc, Satoshi Sonobe MDc, Toshimasa Uekusa MDd, Koichi Suda MDa a

Department of First Pathology, Juntendo University, School of Medicine, Tokyo 113-8421, Japan Respiratory Medicine, Juntendo University, School of Medicine, Tokyo 113-8421, Japan c General Thoracic Surgery, Juntendo University, School of Medicine, Tokyo 113-8421, Japan d Department of Laboratory, Labour Welfare Corporation Kanto Rousai Hospital, Kawasaki 211-8510, Japan b

Received 27 April 2005; accepted 4 May 2005

Keywords: Thymic cyst; Follicular hyperplasia; Sjogren syndrome

Summary We report here 4 cases of multilocular thymic cysts (MTCs) with reactive lymphoid follicular hyperplasia. They were admitted to our hospital to examine anterior mediastinal masses demonstrated on chest computed tomographic scans. Three patients presented high-grade intermittent fever, and 2 patients were associated with Sjogren syndrome with elevated serum antinuclear antibody levels. All patients were subjected to extended thymectomy. Interestingly, their fever disappeared immediately after surgery. Histologically, the lesions were characterized by several cystic spaces separated by various thick walls with dense lymphoid tissue containing large reactive germinal centers. The inner cyst walls were lined by flattened cuboidal epithelia in some portions. Columnar epithelia with focal cilia were partially observed in 2 cases. These pathological findings led to a diagnosis of MTCs that were thought to result from cystic transformation of medullary duct derivatives by acquired inflammatory processes. The pathological findings, together with clinical courses of our cases, suggest that inflammation accompanied by autoimmune diseases may play, in part, an important role in the development of MTCs. D 2005 Elsevier Inc. All rights reserved.

1. Introduction Benign thymic cysts are rare diseases that account for approximately 1% to 3% of anterior mediastinal masses [1]. Such cysts are classified into 2 groups: congenital and

T Corresponding author. E-mail address: [email protected] (H. Izumi). 0046-8177/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.humpath.2005.05.004

acquired. The former group commonly occurs and consists of a simple unilocular cyst with thin translucent wall. Thymic tissue attached to the cyst walls is frequently atrophied [2] and lacks inflammation [3]. In contrast, the latter group, called multilocular thymic cysts (MTCs), is rare and consists of multilocular cysts with thick walls and pericystic fibrous adhesions. Reactive lymphoid hyperplasia with germinal centers is frequently observed in the cysts of patients with acquired multilocular cysts [3,4],

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Table 1

Clinical and pathological findings in 4 cases of MTC

Case Age (y)/sex

Clinical presentation

1

65/male

Fever (39.28C)

2

57/female Asymptomatic

3

49/female Fever (39.48C)

4

35/female Fever (38.78C) Sjogren syndrome swelling of parotid gland

a b

Associated Serum ANA level Operation disease Preoperative Postoperative

Sjogren syndrome

2560

80a

Extended thymectomy

2560a

Extended thymectomy

40

160

Extended thymectomy

320b

Extended thymectomy

Gross description

Lining epithelia of cysts

Follow-up

15  9  4 cm Well circumscribed Adherent to pleura 6  4.8  1.8 cm Well circumscribed Adherent to pleura 5  3.8  0.8 cm Thinly encapsulated elastic mass 11.5  8.5  2 cm Well circumscribed

Flattened, Alive, 3 y 9 mo cuboidal columnar epithelia with cilia Flattened cuboidal

Alive, 5 y 7 mo

Flattened cuboidal

Alive, 7y

Flattened, Alive, 14 y cuboidal 3 mo columnar epithelia with cilia

ANA level 2 years after thymectomy. ANA level 4 years after thymectomy.

suggesting the involvement of acquired reactive inflammatory processes in the development of MTCs [1,3]. It is occasionally seen not only in the thymus of myasthenia gravis, but also in various autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis, and Hashimoto thyroiditis [4,5]. However, the clinical and pathological features of MTCs have not been well described. We recently encountered 4 cases of MTCs, some of which were accompanied with intermittent fever and/or associated with Sjogren syndrome. We therefore

Fig. 1 Multilocular thymic cyst in a 65-year-old man (case 1). Contrast-enhanced CT scan at level of the carina showed a sharply demarcated multilocular cystic mass in the anterior mediastinum.

report here their clinical and pathological features and refer to the potential pathogenesis in the development of MTCs.

2. Case reports 2.1. Clinical findings The subjects consist of 4 patients (1 man and 3 women) with MTCs. Their clinical and pathological characteristics

Fig. 2 Gross appearance of MTCs. The cut surface demonstrated multilocular cysts, up to 2 cm in diameter, filled with yellowish green colloid, and having tan-yellow solid thick walls. Surrounding lymph nodes of the thymus were swollen (case 1).

Multilocular thymic cyst are shown in Table 1. Their age at diagnosis ranged from 35 to 65 years (mean age, 51.5 years). Three patients presented high-grade intermittent fever before surgery. An anterior mediastinal mass was demonstrated in all patients on chest computed tomographic (CT) scan (Fig. 1). On laboratory data, the serum antinuclear antibody (ANA) level was elevated in 2 patients associated with Sjogren syndrome. All patients underwent extended thymectomy.

843 Interestingly, intermittent fever in 3 patients has disappeared immediately after surgery. There has been no recurrence for 3 years and 9 months to 14 years and 3 months of follow-up. Although 2 patients continued to be observed for Sjogren syndrome without aggravation of their condition after surgery, their serum ANA levels have remained high.

2.2. Pathological findings The resected mass ranged from 5 to 15 cm in maximum dimension and did not extend beyond the capsule of the thymus in any cases, as shown in Table 1. These masses consisted of various-sized rubbery fluctuant nodules with elastic solid areas. On cut surfaces, multilocular cysts filled with transparent fluid or turbid yellowish green colloidal material and unevenly thickened gray-white cyst walls were observed (Fig. 2). In 2 patients, the lesions grossly adhered to the pleura, and slight enlargement of the surrounding lymph nodes was demonstrated. Histologically, the lesions were characterized by several cystic spaces separated from each other by various thick walls containing dense lymphoid tissue accompanied by large reactive germinal centers (Fig. 3A). In some areas, the cyst walls showed fibrous hyalinization, clusters of foamy macrophages, and foreign body granulomas. Cholesterol clefts were variously found within the lumen or in the walls. In the lymphoid tissue of the walls, Hassall corpuscles with various calcifying tendencies and thymic epithelia were diffusely scattered (Fig. 3B). Some Hassall corpuscles showed cystic degeneration and were connected with larger cystic cavities. The inner surfaces of the cyst were lined by flattened cuboidal epithelia in some portions but denuded in many other portions. In cases 1 and 4, columnar epithelia with focal cilia were found on parts of the cyst surfaces (Fig. 3C). Immunohistochemically, the lining epithelia of the cyst were strongly positive for epithelial marker. CD20-positive B lymphocytes were arranged as germinal center aggregates and CD3-positive T lymphocytes arranged as interfollicular region aggregates, which suggested polyclonal lymphocyte expansion. In all cases, the residual thymic tissue surrounding multicystic lesions exhibited not only lipomatous atrophy by age involution, but also had some lymphoid follicles associated with germinal centers.

Fig. 3 A, The lesion was characterized by large cystic spaces separated from each other by thick walls and exhibited prominent lymphoid hyperplasia with well-developed germinal centers. Cyst lumens contained eosinophilic fluid and various cholesterol clefts (case 1; hematoxylin-eosin, original magnification 1.2). B, Cyst walls of MTCs. Hassall corpuscles with various calcifying tendencies were observed in the lymphoid tissue of the walls. The surrounding epithelia of the corpuscles were continuous with flattened cuboidal epithelium of the cystic cavity (case 4; hematoxylin-eosin, original magnification 50). C, Columnar epithelium with focal cilia lined the inner surfaces of cyst walls (case 4; hematoxylin-eosin; original magnification 100).

3. Discussion In this study, we report 4 cases of typical MTCs. In our cases, diagnosis of MTCs was made by both radiological and pathological findings. On chest CT scan, the lesion is characteristically demonstrated as a mediastinal mass containing multiple cysts accompanied by soft-tissue attenuation portion. However, this radiological finding is not specific for MTCs [6], indicating the importance of pathological investigation for accurate diagnosis. Pathologically, several cystic spaces separated by thick walls containing dense lymphoid tissue are frequently seen in MTCs; however, the

844 possibility of other cystic thymic lesions such as cystic degeneration of thymoma [7] must always be considered. In addition, a similar pathological change is seen in about half of the thymuses harboring nodular sclerotic Hodgkin disease [8], germ cell tumors [9,10], and mucosa-associated lymphoid tissue lymphoma [11,12]. Moreover, some cases of MTCs are associated with thymic neoplasm including thymoma [3,6,13], thymic carcinoma [3], and neoplastic tissue. Consequently, in suspicious cases of MTCs, thorough sampling of every bthymic cystQ must be carried out not only to establish an accurate diagnosis, but also to exclude the possibility of neoplasm especially in case the cyst wall is focally thickened. Since Suster and Rosai [3] reported 18 cases of MTCs, several cases have been described. Although most cases were asymptomatic and identified on routine chest radiograph, some patients have been reported to associate with autoimmune disorders such as Sjogren syndrome [3,14], aplastic anemia [3], systemic lupus erythematosus [6], and myasthemia gravis [6]. In our study, 2 patients with MTCs were associated with Sjogren syndrome, and 3 patients presented high intermittent fever, suggesting the existence of autoimmune diseases. These results indicate that inflammation caused by autoimmune diseases may play, in part, an important role in the development of MTCs. In fact, microscopic findings of all patients demonstrated dense lymphoid tissue containing germinal centers, which is reminiscent of inflammation. Thymic epithelial cells consist of 2 different components, reticular epithelium and medullary duct epithelium, which were endodermal pharyngeal pouch derivatives [15]. It is speculated that MTCs were developed by dilatation of medullary duct epithelium-derived structures including Hassall corpuscles [3]. Hassall corpuscles may show cystic degeneration, mainly because of reactive changes secondary to inflammation [5]. The flattened cuboidal epithelia lining the cyst walls might be fragments of degenerative Hassall corpuscles and epithelia connected with Hassall corpuscles. In fact, Hassall corpuscles with various calcifying tendency and around epithelia of corpuscles were continuous with flattened cuboidal epithelium in all patients of this study. Glandular change such as columnar epithelium appears to suggest the embryologic origin of thymus. In the head and neck areas, cystic enlargements of pharyngeal pouch derivatives might be developed in branchial cleft cysts, branchial cleftlike cysts in chronic thyroiditis, and lymphoepithelial cysts. Branchial cleft cysts are characterized by abundant lymphoid tissue and lining epithelium in the cyst walls. Cystic enlargements observed in MTCs might be pathogenetically analogous to the

H. Izumi et al. development of the branchial cleft and lymphoepithelial cysts. It seems to be the result of pharyngeal pouch derivatives caused by acquired inflammatory reaction. In conclusion, we reported 4 cases of MTCs accompanied by reactive lymphoid follicular hyperplasia. Pathological findings were essential to establish the diagnosis of MTCs. Multilocular thymic cysts could be the result of the cystic transformation of pharyngeal pouch derivatives caused by chronic inflammation accompanied by autoimmune disorders. However, careful pathological examinations should be carried out to exclude coexisting malignancy.

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