Case of the Month: Thymus

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2015, case 18 and is thymic follicular hyperplasia.

Microscopic examination of the thymus shows hyperplastic thymic tissue. Most of the thymic islands are expanded by lymphocytes with prominent follicle formation, most with germinal centers. Many prominent Hassall corpuscles are noted throughout. In addition, the islands contain multiple cystic spaces which vary in size. A preserved epithelial lining in some of the cysts shows low cuboidal cells which appear benign. Aggregates of hemosiderin-laden macrophages are associated with cholesterol clefts. Some sections show thickened fibrous bands coursing between lobules.

Thymic hyperplasia is an entity that results in enlargement of the thymus, often to the extent that it may simulate neoplasia. There are two types of hyperplasia: true thymic hyperplasia and thymic follicular hyperplasia. A brief discussion of thymus anatomy is necessary to understand the distinction between the two. The thymus is composed of two compartments. The epithelial compartment contains the cortex and medulla and is the site of T-lymphocyte maturation within the thymus. The second compartment is the perivascular space, which is the portion of tissue that is within the thymic capsule but outside the epithelial compartment. In infancy, the perivascular space is more of a virtual space; however, beginning in early childhood the perivascular space increases as it is infiltrated by peripheral lymphocytes and adipose tissue, while the epithelial compartment decreases correspondingly. The two compartments are usually not obvious on H&E-stained slides but may be distinguished by use of a cytokeratin immunostain, which highlights epithelial cells present in the epithelial compartment. In addition, CD1a and Ki-67 can be used to demonstrate active thymopoiesis in the epithelial compartment.

In true thymic hyperplasia the thymus is too large for age. The diagnosis is based on the demonstration of an increased thymic weight with normal histology; useful reference tables are available that define normal thymus weight ranges by age, although there is wide variation in normal subjects. Generally speaking, normal thymus can weigh up to 50 grams between birth and age 30, and up to 30 grams between ages 30 and 60 years.

Table 1: Approximate mean weights

Reference: Adapted from Stanford Surgical Pathology Criteria surgpathcriteria.stanford.edu

With most forms of true thymic hyperplasia there is an increase in active thymopoiesis because the hyperplasia occurs by expansion of the thymic epithelial space. True thymic hyperplasia may occur in patients who have received chemotherapy or antiretroviral therapy. In this setting, the hyperplasia is often referred to as thymic rebound hyperplasia. An increase in active thymopoiesis in these patients is likely a compensatory mechanism to normalize the immune system.

Thymic follicular hyperplasia (TFH), also referred to as thymic lymphoid hyperplasia, is defined as thymic enlargement by increased migration of mature T and B lymphocytes into the perivascular space with subsequent follicle formation. It should be noted that the term ‘thymic hyperplasia’ as defined in the literature refers to TFH but is discouraged from use due to its vague implications. The diagnosis of TFH is based on the histologic demonstration of increased numbers of lymphoid follicles with active germinal centers in the thymus. There is no strict definition for how many active follicles constitute a true increase, as occasional germinal centers may be seen in the normal thymus. Generally speaking, more than an occasional lymphoid follicle is sufficient to support a diagnosis of TFH. Immunostains such as CD21, CD20, CD10 and bcl6 may confirm the presence of germinal centers in difficult cases.

Thymic follicular hyperplasia is classically associated with myasthenia gravis (MG), a disease in which circulating autoantibodies target nicotinic acetylcholine receptors present in the membrane of the neuromuscular junction, resulting in disruption of neuromuscular transmission and subsequent muscular weakness. The distribution of thymic pathology in patients with MG is as follows: 65% thymic follicular hyperplasia, 25% normal thymus, 10% thymomas. For reasons that are not completely understood, thymectomy results in clinical improvement in some patients with MG; there is some evidence that the ectopic germinal centers participate in auto-antibody production in these patients. In addition to MG, thymic follicular hyperplasia has also been associated with other autoimmune conditions including systemic lupus erythematosus, scleroderma and rheumatoid arthritis. None of the conditions were present in this patient, although limited history was available. Germinal centers may also be associated with neoplastic processes within the thymus, so adequate sampling is necessary.

In the current case, the presence of many cysts raises the possibility of a multilocular thymic cyst, although the cysts are a secondary feature in this case. Many thymic conditions may induce cystic change, including both non-neoplastic and neoplastic processes, so adequate sampling is critical to rule out underlying neoplasia. True thymic cysts may present at any age and may be congenital or acquired. The diagnosis of a thymic cyst can be made in instances of a predominantly cystic thymic lesion, which at least focally contains thymic tissue within the wall of the cyst. The cyst wall has an epithelial lining that is either squamous or columnar in the acquired type, and may also be glandular or ciliated in the congenital type. In acquired multilocular cysts, germinal centers may be present within the cyst wall. Cholesterol clefts are common in all types of thymic cysts. When cystic change occurs secondarily as in the current case, the main importance is to distinguish benign cystic change from a cystic thymoma. In the latter, no epithelial lining is present as they are not true cysts but rather distended perivascular spaces. In the current case, the cysts are lined by epithelium that is focally appreciable. In difficult cases, a cytokeratin immunostain may be used to highlight the presence of epithelium.

Thymic follicular hyperplasia may be difficult to distinguish from a thymoma, especially the WHO type B1 thymoma (lymphocyte-rich thymoma, see Table 2). Type B1 thymoma resembles normal thymus with lymphocytic expanses resembling thymic cortex and areas of medullary differentiation; the neoplastic epithelial cells may be scant and inconspicuous. Useful features that favor thymoma over normal thymus or thymic hyperplasia include (1) dendritic epithelial cells scattered throughout broad lymphocyte-rich areas with only scattered medullary like foci, (2) only rare Hassall corpuscles, and (3) large lobules separated by fibrous bands. In the current case, the presence of many Hassall corpuscles with retained thymic architecture and the formation of lymphoid follicles is evidence against thymoma. While thick fibrous bands are seen in some sections, in this case it is likely a type of reactive fibrosis from cyst rupture.

Table 2: Summary of Major Thymoma Subtypes, WHO Classification

Reference: WHO Classification Tumours of the Lung, Pleura, Thymus and Heart. Ed. William T, Brambilla E, Muller-Hermelink H, and Harris C. Lyon: IARCPress Lyon, 2004.

In addition to type B1 thymoma, thymic follicular hyperplasia may resemble the less common micronodular thymoma with lymphoid stroma. This variant is characterized by well-formed epithelial nodules surrounded by B-cell rich areas which may contain germinal centers.

A variety of lymphomas may arise in the thymus, including primary mediastinal large B-cell lymphoma, T lymphoblastic leukemia/lymphoma, Hodgkin lymphoma, and extranodal marginal zone lymphoma. The key feature of thymic lymphoma is effacement of the normal thymic architecture with an atypical lymphocytic population, although entrapped elements of normal thymus may be present. In the current case, the normal thymic architecture is generally maintained with frequent follicle formation, not typical of a lymphoma. The differentiation between lymphoma and a lymphocyte-rich thymoma is often more problematic than the differentiation between a hyperplastic lesion.

1. Which of the following is true regarding thymic follicular hyperplasia?

   
   

   1. Cystic change is a feature specific to thymic follicular hyperplasia.
   2. Follicle formation occurs exclusively in thymic follicular hyperplasia and is not a feature of normal thymus.
   3. Follicle formation occurs in the epithelial compartment rather than the perivascular space.
   4. Thymic follicular hyperplasia has been associated with a variety of autoimmune diseases.
   5. Thymic weight is usually increased.
2. Which of the following is the most common thymic entity found in patients with myasthenia gravis?

   
   

   1. Lymphoma
   2. Normal thymus
   3. Thymic follicular hyperplasia
   4. Thymoma
   5. True thymic hyperplasia
3. Which of the following is a feature seen in thymoma and not in follicular thymic hyperplasia?

   
   

   1. Cystic change
   2. Effacement of normal thymic architecture
   3. Follicle formation
   4. Many Hassall corpuscles
   5. Normal distribution of cortex and medulla

1. den Bakker MA, Oosterhuis JW. Tumours and tumour-like conditions of the thymus other than thymoma; a practical approach. Histopathology. 2009;54(1):69-89.
2. Hale LP. Histologic and Molecular Assessment of Human Thymus. Ann Diagn Pathol. 2004;8:50-60.
3. Suster S. Diagnosis of thymoma. J Clin Pathol. 2006;59:1238-1244.
4. Suster S, Rosai J. Thymus. In: Mills SE ed. Histology for Pathologists. 4^th ed. Philadelphia, PA: Wolters Kluwer; 2012:505-526.
5. Rosai J. Rosai and Ackerman’s Surgical Pathology. 10^th ed. Philadelphia, PA: Elsevier; 2011.
   Wick MR. The mediastinum. In: Mills SE, Carter D, Greenson JK, Reuter VE, Stoler MH, eds. Sternberg’s Diagnostic Surgical Pathology. 5^th ed. Philadelphia, PA: Wolters Kluwer; 2010:1120-1177.

Amy M. Coffey, MD
Surgical Pathology Committee
Columbia University Medical Center
New York Presbyterian Hospital
Resident in Anatomic Pathology, PGY-3
New York, NY

1. Thymic follicular hyperplasia has been associated with a variety of autoimmune diseases. (d)
2. Thymic follicular hyperplasia (c)
3. Effacement of normal thymic architecture (b)