Thymus pathology in myasthenia gravis with anti-acetylcholine receptor antibodies and concomitant Hashimoto's thyroiditis. A four-case series and literature review

Abstract

Objective: Identifying the morphological features of thymus in patients with myasthenia gravis (MG) with anti-acetylcholine receptor (AChR) antibodies and concomitant Hashimoto's thyroiditis (HT), which were recruited from a single surgical unit of a tertiary referral hospital located in the North-Eastern region of Romania, over a period of 11 years.

Patients, materials and methods: We retrospectively reviewed clinical, imaging, laboratory, thymic pathology, and outcome data that were obtained from medical records of patients with MG and concomitant HT, to whom a thymectomy was performed for a suspected thymic lesion. All the surgical interventions were done in the Third Clinic of Surgery, St. Spiridon Emergency County Hospital, Iaşi, Romania, for an 11 years' period, i.e., from January 1, 2000 and December 31, 2010.

Results: Four patients (three females and one male) were included. The mean age of the patients at the time of their thymectomy was 40.25 years. Of all patients, 75% had moderate or severe MG, 100% had anti-AChR antibodies, and an electromyographic decrement greater than 25%. All patients have been diagnosed with HT in their past medical history by a full thyroid panel [high thyroid-stimulating hormone (TSH) values, low free thyroxine (fT4) values, and the presence of the anti-thyroid antibodies] and all of them have been treated with Euthyrox. Our four patients expressed different MG subtypes, each of them being associated with different thymus pathology. Thoracic computed tomography (CT) scan revealed heterogeneous mediastinal masses and established the correct diagnosis only in 25% of cases. The pathological exams also revealed a heterogeneous pattern of thymic lesions. In contrast with other studies, our patients with MG with anti-AChR antibodies and concomitant HT presented atrophic thymus more frequently (50%), but with particular morphological changes of Hassall's corpuscles. Also, 25% of cases were diagnosed with thymic lympho-follicular hyperplasia (TLFH) associated with thymic epithelial hyperplasia. In B2 thymoma, neoplastic epithelial cells expressed cytokeratin 19 (CK19) immunoreactivity, high Ki67 labeling index and strong p63 immunopositivity.

Conclusions: In our series, MG and HT occurred simultaneously, or one of them was diagnosed before the other, raising some new questions regarding the immune mechanism of these two autoimmune diseases. Due to the heterogeneous morphological changes of the thymus that we found in this study, we can hypothesize that thymus is involved in the pathogenic mechanism of MG with anti-AChR-antibodies and concomitant HT development.

Figure 1

Case No. 1. F, 54-year-old. (a) Surgical specimen – nodular aspect of the thymus gland; (b) Morphological features – atrophy of the thymus with calcification of a Hassall’s corpuscle (HE staining, ×40). F: Female; HE: Hematoxylin–Eosin

Figure 2

Case No. 2. F, 28-year-old. Thymic follicular hyperplasia, thoracic CT scan: (a) Enlarged heterogeneous thymus (coronal plane); (b) Some nodules may be distinguished from adipose tissue (axial plane). CT: Computed tomography; F: Female

Figure 3

Case No. 2. F, 28-year-old. The resected thymectomy specimen was 9.5×5.5×2.5 cm in size and weighed 65 g. F: Female

Figure 4

Case No. 2. F, 28-year-old. Thymic follicular hyperplasia. Morphological and immunohistochemical features: (a) Thymic tissue with increased density of lymphoid follicles with hyperplastic germinal centers and occasional Hassall’s corpuscles; (b) The same image, but at higher magnification, revealed active germinal center; (c) Many lymphoid follicles, small and big, with prominent germinal centers expanded thymic medulla; (d) Lymphoid follicles from thymic medullary area showed CD23 immunopositivity in the follicular dendritic cell network (brown staining); (e) Immunopositivity for CK AE1/AE3 of the thymic epithelial cells revealed the fact that hyperplastic lymphoid follicles disrupted the normally epithelial network, but at the same time a thymic epithelial hyperplasia could be seen around each reactive follicle; (f) CD68 immunopositivity identified few macrophages in cortical and medullary regions. HE staining: (a) ×40; (b) ×100. Van Gieson staining: (c) ×40. Anti-CD23 antibody immunomarking: (d) ×40. Anti-CK AE1/AE3 antibody immunomarking: (e) ×40. Anti-CD68 antibody immunomarking: (f) ×40. CD: Cluster of differentiation; CK: Cytokeratin; HE: Hematoxylin–Eosin; F: Female

Figure 5

Case No. 3. F, 60-year-old. B2 thymoma: (a) Thoracic CT scan at the level of the thymus showing a lobular anterior mediastinal mass, infiltrating the adjacent pleura (axial plane); (b) Gross features of the surgical specimen – pink-tan, solid tumor showing multiple nodules and having the greatest diameter of 6.1×3.5 cm. CT: Computed tomography; F: Female

Figure 6

Case No. 3. F, 60-year-old. B2 thymoma. Morphological and immunohistochemical features: (a) Tumor made up of two distinct cellular populations – clusters of large polygonal neoplastic epithelial cells setting on a background of numerous lymphocytes; the tumor presented a fibrous capsule infiltrated by tumoral cells; (b) Admixture of clusters of polygonal epithelial cells and lymphoid cells; the epithelial cells were larger than the lymphoid cells and presented hypochromatic nuclei with small nucleoli; the lymphocytes were uniform, with scant cytoplasm, round nuclei, and inconspicuous nucleoli; (c) Within the tumor there were some perivascular spaces centered by a venule surrounded by a clear space containing proteinaceous fluid; (d) CK19 immunoreactivity of neoplastic epithelial cells setting in a background of abundant lymphocytes; (e) CD20 immunostaining was positive in B-lymphocytes infiltrate and negative in the epithelial neoplastic component (immunoperoxidase with Hematoxylin counterstaining); (f) Strong CD5 immunopositivity of T-lymphocytes infiltrate, but negative in the epithelial neoplastic component (immunoperoxidase with Hematoxylin counterstaining); (g) Ki67 labeling index showed high values (>80%), but most of the nuclear staining represented T-lymphocytes; however, some larger epithelial cells were also immunopositive for Ki67; (h) Strong and diffuse immunopositivity for p63 in the tumoral epithelial cells. HE staining: (a and c) ×40; (b) ×100. Anti-CK19 antibody immunomarking: (d) ×100. Anti-CD20 antibody immunomarking: (e) ×400. Anti-CD5 antibody immunomarking: (f) ×400. Anti-Ki67 antibody immunomarking: (g) ×200. Anti-p63 antibody immunomarking: (h) ×100. CD: Cluster of differentiation; CK: Cytokeratin; HE: Hematoxylin–Eosin; F: Female

Figure 7

Case No. 4. M, 19-year-old. Thymic atrophy with cystic degeneration of Hassall’s corpuscles: (a) CT scan of the neck demonstrated a heterogeneously enlarged thyroid gland (axial view); (b) Thoracic CT scan revealed a nodular mediastinal mass suggestive for thymoma (axial view). CT: Computed tomography; M: Male

Figure 8

Case No. 4. M, 19-year-old. Thymic atrophy with cystic degeneration of Hassall’s corpuscles. Morphological and immunohistochemical features: (a) Extensive reduction in the thymic cortex with many cystic structures, filled with homogeneous eosinophilic material; (b) Huge cystic dilatation filled up with cellular detritus; (c) Thymic medulla with extremely large cystic dilatation filled with heterogeneous amorphous material; (d) Strong immunopositivity for CK AE1/AE3 revealed the thymic epithelial cells lining inner surface of the cyst and confirmed the cystic transformation of Hassall’s corpuscles. HE staining: (a) ×40; (b) ×100. Van Gieson staining: (c) ×40. Anti-CK AE1/AE3 antibody immunomarking: (d) ×40. CK: Cytokeratin; HE: Hematoxylin–Eosin; M: Male