1

What is the thymus?

The thymus is a primary lymphoid organ that receives immature T lymphocytes (prothymocytes) from the bone marrow and allows them to develop into fully active T lymphocytes, which express a tolerance to all tissues of the host.

2

Describe the embryological development of the thymus

The thymus is formed at week 6 embryologically from elements of all three geminal layers, including:

a)

endodermal and ectodermal cells from the left and right 3rd and 4th branchial pouches;

b)

mesenchymal cells from the neural crest.

After week 8, these structures begin to migrate caudally and ventrally, to form a single midline thymus.

As the thymus descends towards the mediastinum, the connective tissue septa begin to develop, dividing the thymus into lobes and lobules.

Blood vessels and nerve fibres migrate in along the developing connective tissue septa.

This new vascular supply allows the migration of lymphoid precursor cells into the developing thymic tissue.

By week 10, the thymus gland mostly consists of lymphoid tissue.

Other cells, such as macrophages, are generally initially seen at week 12, as the medulla begins to become distinct from the cortex.

By week 17, the thymus is completely differentiated and contains fully formed thymocytes.

Approximately 25% of the general population will have some ectopic thymic tissue, which can be found anywhere along its path during its caudal migration.

The thymus increases in weight from approximately 10g at birth to 35g at the age of 15, after which there is no more development of lymphatic tissue.

From the age of 15, there is no significant decrease in the size of the thymus but actually a shift from being predominantly composed of lymphoid tissue to being predominantly composed of adipose tissue.

3

Describe the anatomy of the thymus (Figure 1)

The thymus is a bilobed pyramidal-shaped gland, which largely lies in the superior and anterior mediastinum.

The lower border roughly corresponds to the level of the 4th costal cartilage.

The upper border is often less defined, and the upper poles can reach the neck and occasionally the lower aspect of the thyroid gland.

Anatomical relations of the thymus include:

a)

anterior – sternum, costal cartilages, and origins of sternohyoid and sternothyroid muscles;

b)

posterior – pericardium, aortic arch, great vessels, trachea and brachiocephalic vein.

4

Describe the anatomical structure of the thymus (Figure 2)

Microscopically, the thymus can be divided into two distinct zones:

a)

outer cortex – which is mainly packed with cells derived from the T lymphocyte lineage;

b)

inner medulla – which contains far fewer T-cells and mostly consists of epithelial cells.

A loose capsule of connective tissue surrounds these zones and infiltrates into the cortex and medulla, splitting the thymus into lobules.

These infiltrations of the capsule allow access for the blood and lymphatic vessels to supply the thymus.

5

What is the blood supply of the thymus (Figure 3)?

Arterial supply:

a)

internal thoracic arteries;

b)

inferior thyroid arteries;

c)

superior thyroid arteries (in some cases).

Venous drainage:

a)

left innominate veins;

b)

internal thoracic veins;

c)

superior vena cava;

d)

inferior thyroid veins.

6

What is the lymphatic drainage of the thymus?

Unlike many other lymphoid organs, the thymus receives no afferent lymphatic supply.

Efferent lymphatic drainage follows the major vessels, draining into the brachiocephalic and tracheobronchial nodes, as well as lymph nodes adjacent to the internal thoracic artery.

7

What is the nerve supply of the thymus?

Sympathetic nerve fibres – from the stellate ganglion.

Parasympathetic nerve fibres – from the vagus nerve.

Phrenic nerve.

The exact roles of these neural inputs to the thymus is poorly understood.

8

Which cell types are found in the thymus?

Thymocytes (90% of the thymus) – which originate from the bone marrow. The most immature thymocytes are found in the cortex, whereas more mature thymocytes are seen in the medulla.

Epithelial cells (10% of the thymus), such as vascular and pharyngeal epithelial cells. They are spread throughout the cortex and medulla, and form a framework that surrounds the maturing thymocytes. Epithelial cells play a vital role in creating the environment for the maturation of the thymocytes via cell-cell contacts and the release of chemical mediators and hormones.

Other cell types that are present in smaller numbers in the thymus include fibroblasts, myoid cells and phagocytes.

9

Describe the physiology of the thymus (Figure 4)

The primary function of the thymus is the maturation and selection of T-cells, which are specialised lymphocytes that regulate and execute the cell-mediated immune defence system.

Although pro-thymocytes express both CD4 and CD8 ligands, maturation and differentiation result in some thymocytes only expressing the CD4 ligand (regulatory or helper T-cells) and others the CD8 ligand (effector or cytotoxic T-cells).

Only those T lymphocytes which have survived the selection process leave the thymus via the bloodstream or lymphatic system to form part of the host immune defence.

With age, the thymus becomes less active and the functional tissue is replaced by adipose tissue. Some functional islets, however, still exist in the thymus well into adult life.

10

What are the principal imaging modalities for the thymus?

Computed tomography (CT) (Figure 5) is the imaging modality of choice for assessing thymic anatomy and is best seen on coronal sections. The thymus can be seen as a triangular-shaped, bilobed structure in the anterior mediastinum, with the left lobe usually slightly larger than the right. Multiple lobes or irregular borders may indicate thymic pathology.

Magnetic resonance imaging (MRI) (Figure 6):

a)

T1-weighted images – where thymic tissue has a signal intensity between that of muscle and fat;

b)

T2-weighted images – where thymic tissue has a signal intensity greater than that of muscle and similar to that of fat.

As the adiposity of the thymus increases with age, differentiation from the surrounding structures becomes more difficult.

Positron emission tomography (PET) – which is the imaging modality of choice for assessing thymic function. It normally shows some areas of high uptake, especially in younger patients and usually shows higher uptake than the surrounding lungs. PET is useful in imaging thymic hyperplasia, lymphomas and carcinomas, due to high uptake (Figure 7). This can, however, be difficult to distinguish from normal activity in younger patients.

11

Describe the pathological classification of thymic tumours

Thymoma – which is a neoplasm derived from thymic epithelium, without overt malignant cytological features.

Thymic carcinoma – which is a neoplasm derived from thymic epithelium, with malignant cytological features.

Thymic lymphoma – which may involve the thymus primarily or as part of a diffuse lymphoma:

a)

Hodgkin lymphoma (mainly the nodular sclerosis type) tends to present as a large mediastinal mass, often with a cystic appearance;

b)

T-cell lymphoblastic lymphoma;

c)

mediastinal large B-cell lymphoma.

Thymolipoma – which is a rare (2-9%), benign tumour that presents in young adults. It is composed of normal thymic tissue and fat cells, grows slowly and presents as a large anterior mediastinal mass found incidentally on radiological imaging.

Germ cell tumour – which includes seminoma, teratoma, yolk sac tumour and choriocarcinoma.

12

What is the epidemiology of thymomas?

Thymomas are the most common thymic tumours in adults.

They account for 20% of all mediastinal tumours.

The peak incidence is in patients aged 40-60 years old.

13

What are the histological features of a thymoma?

The macroscopic appearance is typically a solid, encapsulated tumour with a lobulated appearance, which occasionally contains cystic structures.

The microscopic appearance is lobules separated by fibrous strands and neoplastic epithelial cells coexisting with non-neoplastic cells in varying proportions.

Thymomas can recur, metastasise or demonstrate malignant invasive properties.

14

Describe the WHO classification (2004) of thymomas and thymic carcinomas (Figure 8)

Type A (medullary thymoma, spindle-shaped thymoma) – which are characterised by neoplastic epithelial cells that have a spindle or oval shape and are arranged in fascicles or whorls. They can express the B-cell CD20 ligand. Type A thymomas are generally less invasive than Type B.

Type B – which are characterised by neoplastic epithelial cells that are polygonal, dendritic or epithelioid in shape. The lymphocytes are immature and cortical-type. They are subclassified according to the relative amount of lymphocytes in relation to epithelial cells, with B1 having the most lymphocytes and B3 the most epithelial cells:

a)

Type B1 (predominantly cortical thymoma) – which show localised areas of medullary differentiation, mimicking normal thymic appearance (hence ‘organoid’ thymoma). These tend to be at a low stage;

b)

Type B2 (cortical thymoma) – which have neoplastic epithelial cells that are larger and have a more prominent nucleus. The lymphocytes are rarer and have an immature, cortical-type appearance. Medullary differentiation is absent in Type B2 thymomas;

c)

Type B3 (epithelial thymoma) – which have the highest proportion of neoplastic epithelial cells that appear atypical with irregular nuclei and pale cytoplasm. They can show areas of squamous differentiation and almost always have genetic abnormalities (not seen in Types A, B1 or B2). Type B3 thymomas were previously known as well-differentiated thymic carcinoma.

Type AB (mixed thymoma) – which express both Type A and Type B (B1 mostly, B2 rarely) features, in distinct regions or more closely-linked areas.

Type C (high-grade thymic carcinoma) – where the neoplastic epithelial cells show malignant cytological features and express the CD5 ligand. They lack an encapsulated structure and can be found adherent to the surrounding structures or metastasised to nodes. They usually appear de novo and rarely represent progression from a thymoma. Thymic carcinomas can resemble carcinoma from other structures. They are named according to their differentiation, including squamous cell, basaloid, mucoepidermoid, lymphoepithelioma-like, sarcomatoid, clear-cell, papillary, neuroendocrine and undifferentiated carcinomas.