Introduction

The word thymus means "soul" in Greek (stemmed from the belief that it houses the soul). However, its importance has long generated debate.[1]  Many species have a thymus, which indicates this organ is ancient and has been conserved throughout evolution.[2] It is an essential organ of the immune system, and its dysfunction can drastically affect a patient’s quality of life.[1]

Structure and Function

The thymus is a superior mediastinal retrosternal organ. It is bilobed and has two subcomponents: the cortex and the medulla and is made up of epithelial, dendritic, mesenchymal, and endothelial cells.[3] The thymus is one organ that has already reached its maturity in utero and involutes as people age. Involution of the thymus involves changes in its architecture, as it loses its organized structure replaced by adipose tissue as it becomes functionally less active.  Several studies since the 1960s demonstrate that the thymus is necessary for life. Mice that received a thymectomy had an immunodeficiency with a decreased number of lymphocytes.[1] The thymus is the organ primarily responsible for the production and maturation of immune cells; including small lymphocytes that protect the body against foreign antigens. The thymus is the source of cells that will live in the lymphoid tissues and supports their maturation and proper function.

Positive selection is used by the thymus to select self-antigen-recognizing t-cells to be destined for apoptosis. The thymus is where T-cells get exposure to self-antigen, and 95% of all created T cells undergo apoptosis due to their recognition of self-antigen. The non-reactive T-cells then go through negative selection for those that bind to antigen with high affinity.[1] Only lymphocytes that pass both positive and negative selection are allowed to travel out of the thymus. These T-cells are activated by bacteria, viruses, or other foreign antigens and then undergo mitosis. After the pathogen dies, the cells go through apoptosis, and the ones that do not continue as memory cells. These cells allow the immune system to respond quicker and stronger the next time they interact with the same antigen.[1] Hassall’s bodies, cells unique to the thymus, are involved in maturing thymocytes and clearing apoptotic cells. They are a vital part of lymphopoiesis.[2]

Embryology

Originally derived from the ventral third pharyngeal pouch, the thymus grows from embryogenesis to 3 years of age and then involutes during puberty.[1]  During embryogenesis, the thymus migrates from the third pharyngeal pouch down into the superior mediastinum posterior to the manubrium. The thymus is large in infants and young children and coalesces over time, and thymic tissue is replaced by fat by early adulthood. Thymic involution is suggested to be caused by the increased levels of androgens present in the bloodstream during puberty.[2][4][2]

Blood Supply and Lymphatics

The thymus’ blood supply is complicated and widely varies. Most often the blood is supplied by the inferior thyroid, internal thoracic, pericardiacophrenic, or anterior intercostal arteries. Rarely, the thymus can obtain blood from the middle thyroid artery.[2] Laterally, the thymus receives blood from branches of the internal mammary artery. These branches are named the lateral thymic arteries; they vary in number and are asymmetric. Posterior thymic arteries derive from the brachiocephalic artery and the aorta; however, they are rare. Accessory thymic arteries are diverse but have been documented to originate from the thyrocervical trunk, subclavian or superior thyroid arteries. Venous drainage variation is common, but most often the thymus is drained by left brachiocephalic and internal thoracic tributary veins. Thymic venous supply runs in the interlobular septa, into the thymic capsule, and leaves the cortex via a plexus on the posterior side of the organ. These veins then join together and drain each lobe separately.[2][5][2]

Nerves

Sympathetic innervation of the thymus originates from the superior cervical and stellate ganglion. These fibers travel in a plexus along large blood vessels until they enter the thymic capsule. Parasympathetic fibers arise from the vagus, recurrent laryngeal, and phrenic nerves. Several rodent studies have found that thymocytes respond to stimuli via norepinephrine, dopamine, acetylcholine, neuropeptide Y, vasoactive intestinal peptide, calcitonin gene-related peptide, and substance P.[2][6][2]

Muscles

The thymus sits in the mediastinum just posterior to the manubrium. The muscles that depress the hyoid bone that attach to the sternum are near the thymus. These muscles include the sternohyoid and sternothyroid, and both muscles are bilateral. The thyrohyoid and sternocleidomastoid muscles are close to any ectopic thymic tissue or any superior extensions of the thymus. The thymus also lies anterior to the cardiac muscle and pericardium.[7]

Physiologic Variants

Variants in the number of lobes, size, and location of the thymus are common. The most common anatomic variant is an extension reaching up to the thyroid gland. During the descent of the thymus tissue may implant along the way and is then defined as an ectopic thymus. Fifty percent of people have ectopic thymic tissue. This variant is typically located in the anterior cervical region, deep to the sternocleidomastoid muscle, anterior to the carotid sheath, and can expand into the retropharyngeal space. Half of these masses connect to the thymus in the mediastinum.[2][8][2]

Surgical Considerations

The thymus poses difficulty for surgeons due to its high variation in size and arterial supply. Imaging of the gland is also difficult and rarely provides surgeons any insight. On standard chest radiographs, the thymus is barely discernible as it gets lost in the cardiac silhouette.  The gland has smooth borders and is more visible in x-rays of infants and young children. Ultrasound is mostly used to assess the thymic parenchyma, and a CT scan is most helpful to assess the location, size, shape, and its relationship to other structures.[2]

An ectopic thymus can be confused for lymphadenopathy or a tumor.  Since the difference is difficult to discern clinically, their benign nature is most often confirmed after resection. Another complication of ectopic thymic tissue is that it can compress nearby structures; this can cause swelling, decreased blood flow, discomfort, and impaired thyroid function. Resection of these masses possesses surgical difficulty due to many adhering to the carotid sheath and in close proximity to vital pharyngeal muscles and phrenic nerve.[1]

Clinical Significance

Insulin is known to play an essential role in thymic growth. Insulin, growth hormone, and insulin-like growth factor increase the development of lymphocytes, and insulin can be found in the medulla of the thymus. Type 1 diabetes adversely affects the thymus; these patients will have a decreased immune system in addition to their diabetes and other related complications. The supplementation with insulin can be protective of their thymic function and preserve their immune system maturation.[2]

Thymus hyperactivity secondary to hyperplasia of the organ is common in myasthenia gravis. However, thymus tumors, lymphomas, systemic lupus, or hyperthyroidism can also cause this clinical finding. Patients with thymus hyperactivity will have pallor, lymphadenopathy, rhinorrhea, and tonsillitis. This condition's treatment includes vitamins A and D, calcium, and iodine. Thalassotherapy, thymus radiotherapy, and heliotherapy may also be treatments.[1]

Myasthenia gravis (MG) is an autoimmune pathology resulting in muscle weakness. The thymus produces antibodies that interrupt the signaling of acetylcholine at the motor endplate. The patient’s muscle strength worsened with continued contractions and this is a clinical finding that differentiates MG from Lambert-Eaton syndrome. Thymic hypertrophy in MG is so common that it is considered a diagnostic criterion; along with the antibodies found in the blood to the acetylcholine receptors and anti-muscarinic antibodies. Physicians may use an MRI or CT scan to evaluate the size of the thymus. MG is treated depending on the severity of the disease. Treatments range from immunosuppression and corticosteroids to surgical thymectomy. In some patients, only pyridostigmine bromide, a medication that slows the breakdown of acetylcholine, is necessary for symptom control. In patients with this condition, it is essential to keep in mind the potential drug exacerbations of disease when treating acute illness or comorbidities.[1][9][1]

In contrast, atrophy of the thymus is present in several congenital conditions. DiGeorge syndrome is when the thymus fails to form in utero. This agenesis results in an immature immune system and recurrent infections. Severe combined immunodeficiency (SCID) is a genetic disorder where the thymus disappears early in childhood, and the patient lacks T and B cells. These children are also at significant risk for severe, recurrent infections.[1][10][1]

Other Issues

As humans age, and their thymus regresses, they have an increased susceptibility for disease. This decrease in thymus size and function leads to decreased circulating T cells and alteration of their role. This change in function can increase autoimmune diseases, bacterial and viral infections, and neoplasms. Restoring thymic function or intervening before involution could maintain the immune system throughout adult life.[2] The thymus is a current area of research with great promise. One study from Scottish researchers found they were able to re-grow an adult mouse thymus from stem cells. This new organ began to produce T-cells. Duke University in Durham, North Carolina, has successfully performed thymus transplants on children with DiGeorge syndrome.[1] Thymus research poses incredible medical breakthroughs for many diseases and the possibility to revamp adult immune systems.