Myasthenia gravis (MG) is an autoimmune disease that affects neuromuscular transmission. Muscle weakness and fatigue are common in patients with MG due to reduced neuromuscular signaling. The dysfunction in autoimmune MG occurs due to autoantibodies targeting components of the neuromuscular junction. The most prevalent subtype of autoantibody-mediated MG involves antibodies targeting the nicotinic acetylcholine receptor (AChR), which is seen in about 85% of cases. Antibodies against muscle-specific kinase (MuSK) or lipoprotein receptor-related protein 4 (LRP4) can be identified in the remaining 15% of cases.1 Myasthenia gravis most commonly affects the muscles of the face, neck, throat, and limbs.2 Numerous autopsy case series have demonstrated the histopathologic alterations in skeletal muscle in people with MG.3 Thymic abnormalities that have been documented in MG include thymic follicular hyperplasia (TFH) (thymitis), thymic atrophy, thymoma, and thymolipoma.4 

Thymic Histology in Myasthenia Gravis

Thymic Follicular Hyperplasia

Myasthenia gravis typically improves following thymectomy in patients with early-onset anti-AChR antibody MG (EOMG), and typical thymic alterations are identified in 80% of cases. These include epithelial hyperplasia and extraparenchymal infiltration by lymph node-like tissue with T cell areas and germinal centers.5 

In cases of TFH, increased numbers of lymphoid follicles in the medulla and perivascular spaces are noted. Although single lymphoid follicles can be found in healthy people, follicles in more than one-third of the thymic lobules are most likely abnormal. TFH is linked to a variety of autoimmune illnesses, but it is most common in EOMG. The annual incidence of TFH caused by EOMG is 1 to 10 per 1,000,000 cases. TFH is also commonly found in remnant thymuses adjacent to thymomas in 30% to 50% of thymoma-associated MG (TAMG) cases, and it is believed to be the source of autoantibodies.4 

Thymoma 

Thymoma affects 10% to 20% of patients with MG, while 30% of thymoma patients have TAMG. Thymomas are epithelial tumors that are classified by the World Health Organization (WHO) as A, AB, B1, B2, B3, or other rare types.4 

Type A Thymoma

Histologically, type A thymomas can have a variety of patterns, such as fascicular, rosette-forming, storiform, glandular, or solid. The spindle or oval cells are bland with small, spindly, or oval nuclei, fine chromatin, and inconspicuous nucleoli. Thin-walled hemangiopericytoma-like vessels are identified in most cases. There is a scarcity of lymphoid cells. Type A thymoma is rarely associated with MG, as it is mostly lymphocyte-poor or lymphocyte-free. Hassall corpuscles are absent. Mitoses, apoptotic cells and perivascular spaces are rare. Coagulation necrosis is typical of the atypical variant.4 

Type AB Thymoma

Type A regions in type AB thymomas resemble type A thymomas histologically. Oval, spindled, or polygonal tumor cells with small nuclei and inconspicuous nucleoli are seen in the B-like regions. Type AB thymomas appear rich in epithelial cells on immunohistochemistry with keratin and p63/p40 stains. In 50% of cases, focal epithelial CD20 positivity occurs. Outside of medullary islands, lymphocytes are mostly immature CD3+ terminal deoxynucleotidyl transferase (TdT)-positive T cells with a Ki-67 index of >90%. Myasthenia gravis affects 20% to 40% of individuals with type AB thymomas, and other autoimmune disorders are also common.4 

Type B1 Thymoma

Type B1 thymomas have minimal or no lobulation on histological examination. The darker cortical regions take precedence over the lighter medullary islands. Clustering (ie, 3 or more contiguous tumor cells) should be absent, and the vast number of epithelial cells are comparable to that of a normal pediatric thymus. Tumor cells have vesicular chromatin and nucleoli that vary in size. Immunohistochemical staining reveals a delicate cytokeratin-positive epithelial network, which is diminished in the medullary islands. This type of thymoma is seen in around 45% of MG cases.4

Type B2 Thymoma

The histological appearance of type B2 thymoma involves small lobules of tumor cells delineated by fibrous septae. Immunohistochemistry using TdT shows positivity in T cells, imparting a blue impression, and keratin/p40 positivity is noted in tumor cells, which are more numerous than in type B1 thymomas. Individual tumor cells show vesicular nuclear chromatin and prominent nucleoli. Intratumoral lymphoid follicles are commonly seen in cases associated with MG. Myasthenia gravis is seen in up to 50% of cases of type B2 thymoma.4 

Type B3 Thymoma

Histology of type B3 thymoma shows tumor cells with bland nuclei and inconspicuous nucleoli, or nuclei can show moderate atypia with prominent nucleoli. There are usually few, if any, lymphocytes among the tumor cells, and they may or may not be TdT(+). Conspicuous perivascular spaces are often noted. Immunohistochemistry shows diffuse and dense expression of keratin and p40/p63 with focal expression of GLUT1 (glucose transporter 1) and EMA (epithelial membrane antigen). CD20 expression is absent. Myasthenia gravis is observed in 40% to 50% of patients with type B3 thymomas.4 

Thymolipoma

Thymolipoma has been linked to MG in the past but mediastinal/thymic lipoma has not, implying that there is a pathogenetic link between the thymic component and thymolipoma-associated MG. On histological examination, the tumors are composed of a small component of thymic tissue embedded in a large component of mature adipose tissue encased in a fibrous, epithelial-free capsule. The thymic component is typically atrophic, but it can occasionally display follicular hyperplasia and neoplastic change (thymoma or carcinoid).4 

Muscle Histology in Myasthenia Gravis

Dorothy S. Russell categorized the muscle histopathology of MG into 3 types after reviewing 8 autopsy cases of MG in 1953. The architectural alterations in fibers were referred to as type I. In this type, acute alterations in muscles include coagulative necrosis. The development of lymphorrhage in the tissue was labeled as type II. Progressive atrophy occurs first and impacts solitary muscle fibers, resulting in basophilic staining of the sarcoplasm and a loss of cross striations. The nuclei show an increase in size and number, and they can occasionally become central in location. Type III shows simple atrophy that affects single muscle fibers or groups of fibers. The fibers’ distinctive eosinophilia is preserved, as opposed to type II in which altered staining reactivity occurs. There is a small increase in the bulk of the perimysium, as well as an increase in the number of nuclei that remain in their peripheral position.6 

In another study conducted in 1963, muscle histology in MG was divided into 3 types: (1) normal, (2) small group lesions, and (3) leukocytic infiltration.3

Normal: There is no change in the normal histology. For each case, the following features are noted: muscle fiber diameter; fiber distribution pattern; fiber structure; position, shape, and number of muscle nuclei; connective tissue and fat distribution; the presence of abnormal cells; and the structure of nerves and spindles, if present.3  

Small group lesions: Sets of muscle fibers are noted in many fascicles that are significantly smaller in size. On cross-section, their shape is typically elongated, and they are seen in a continuous stream through a fascicle of normal fibers.3 

Leukocytic infiltration: There is a compact cellular aggregation composed of lymphocytes. They are usually surrounded by a small blood vessel in the center. The periphery of the aggregate shows the cells extended out between normal fibers in a compact or diffuse manner.3 

References 

  1. ​​Fichtner ML, Jiang R, Bourke A, Nowak RJ, O’Connor KC. Autoimmune pathology in myasthenia gravis disease subtypes is governed by divergent mechanisms of immunopathology. Front Immunol. 2020;11:776. doi:10.3389/fimmu.2020.00776
  2. Myasthenia gravis: pathology. Britannica. Accessed February 24, 2022.
  3. Fenichel GM, Shy GM. Muscle biopsy experience in myasthenia gravis. Arch Neurol. 1963;9:237-243. doi:10.1001/archneur.1963.00460090043004
  4. Marx A, Ströbel P, Weis CA. The pathology of the thymus in myasthenia gravis. Mediastinum. 2018;2:66. doi:10.21037/med.2018.12.04
  5. Leite MI, Jones M, Ströbel P, et al. Myasthenia gravis thymus: complement vulnerability of epithelial and myoid cells, complement attack on them, and correlations with autoantibody status. Am J Pathol. 2007;171(3):893-905. doi:10.2353/ajpath.2007.070240
  6. Russell DS. Histological changes in the striped muscles in myasthenia gravis. J Pathol Bacteriol. 1953;65(2):279-289. doi:10.1002/path.1700650202

Reviewed by Debjyoti Talukdar, MD, on 2/26/2022.

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