Editing Thymus (section)

==Clinical significance==
===Immunodeficiency===
As the thymus is where T cells develop, congenital problems with the development of the thymus can lead to [[immunodeficiency]], whether because of a problem with the development of the thymus gland, or a problem specific to thymocyte development. Immunodeficiency can be profound.{{sfn|Davidson's|2018|p=67}} Loss of the thymus at an early age through genetic mutation (as in [[DiGeorge syndrome]], [[CHARGE syndrome]], or a very rare "nude" thymus causing absence of hair and the thymus{{sfn|Harrison's|2015|pp=2493}}) results in severe immunodeficiency and subsequent high susceptibility to infection by viruses, [[protozoa]], and [[fungi]].{{sfn|Davidson's|2018|pp=79-80}} [[Nude mouse|Nude mice]] with the very rare "nude" deficiency as a result of [[FOXN1]] mutation are a strain of research mice as a model of T cell deficiency.<ref>{{cite book |last1=Fox |first1=James G. | name-list-style = vanc |title=The Mouse in Biomedical Research: Immunology |date=2006 |publisher=Elsevier |isbn=978-0-08-046908-9 |pages=277 |url=https://books.google.com/books?id=63K0IifQIrgC&pg=PA277 |language=en}}</ref>

The most common congenital cause of thymus-related immune deficiency results from the deletion of the [[Chromosome 22 (human)|22nd chromosome]], called [[DiGeorge syndrome]].{{sfn|Harrison's|2015|pp=2493}}{{sfn|Davidson's|2018|pp=79-80}} This results in a failure of development of the third and fourth pharyngeal pouches, resulting in failure of development of the thymus, and variable other associated problems, such as [[congenital heart disease]], and abnormalities of mouth (such as [[cleft palate]] and [[cleft lip]]), failure of development of the [[parathyroid glands]], and the presence of a fistula between the [[trachea]] and the [[oesophagus]].{{sfn|Davidson's|2018|pp=79-80}} Very low numbers of circulating T cells are seen.{{sfn|Davidson's|2018|pp=79-80}} The condition is diagnosed by [[fluorescence in situ hybridization|fluorescent in situ hybridization]] and treated with [[thymus transplantation]].{{sfn|Harrison's|2015|pp=2493}}

[[Severe combined immunodeficiency]] (SCID) are group of rare congenital genetic diseases that can result in combined T, B, and [[NK cell]] deficiencies.{{sfn|Davidson's|2018|pp=79-80}} These syndromes are caused by mutations that affect the maturation of the [[hematopoietic progenitor cell]]s, which are the precursors of both B and T cells.{{sfn|Davidson's|2018|pp=79-80}} A number of genetic defects can cause SCID, including [[IL-2 receptor]] gene loss of function, and mutation resulting in deficiency of the [[enzyme]] [[adenine deaminase]].{{sfn|Davidson's|2018|pp=79-80}}

===Autoimmune disease===
====Autoimmune polyendocrine syndrome====
[[Autoimmune polyendocrine syndrome type 1]] is a rare genetic autoimmune syndrome that results from a genetic defect of the thymus tissues.{{sfn|Harrison's|2015|pp=2756-7}} Specifically, the disease results from defects in the [[autoimmune regulator]] (AIRE) gene, which stimulates expression of self antigens in the epithelial cells within the medulla of the thymus. Because of defects in this condition, self antigens are not expressed, resulting in T cells that are not conditioned to tolerate tissues of the body, and may treat them as foreign, stimulating an immune response and resulting in autoimmunity.{{sfn|Harrison's|2015|pp=2756-7}}  People with APECED develop an autoimmune disease that affects multiple [[endocrine]] tissues, with the commonly affected organs being [[hypothyroidism]] of the [[thyroid gland]], [[Addison's disease]] of the [[adrenal gland]]s, and [[candida infection]] of body surfaces including the [[oral mucosa|inner lining of the mouth]] and of the [[nail (anatomy)|nail]]s due to dysfunction of [[T helper 17 cell|TH17 cells]], and symptoms often beginning in childhood. Many other autoimmune diseases may also occur.{{sfn|Harrison's|2015|pp=2756-7}} Treatment is directed at the affected organs.{{sfn|Harrison's|2015|pp=2756-7}}

====Thymoma-associated multiorgan autoimmunity====
[[Thymoma-associated multiorgan autoimmunity]] can occur in people with thymoma. In this condition, the T cells developed in the thymus are directed against the tissues of the body. This is because the malignant thymus is incapable of appropriately educating developing thymocytes to eliminate self-reactive T cells. The condition is virtually indistinguishable from [[graft versus host disease]].<ref>{{cite journal | vauthors = Wadhera A, Maverakis E, Mitsiades N, Lara PN, Fung MA, Lynch PJ | title = Thymoma-associated multiorgan autoimmunity: a graft-versus-host-like disease | journal = Journal of the American Academy of Dermatology | volume = 57 | issue = 4 | pages = 683–9 | date = October 2007 | pmid = 17433850 | doi = 10.1016/j.jaad.2007.02.027 }}</ref>

====Myasthenia gravis====
[[Myasthenia gravis]] is an autoimmune disease most often due to antibodies that block [[acetylcholine receptors]], involved in signalling [[neuromuscular junction|between nerves and muscles]].{{sfn|Davidson's|2018|pp=1141-43}} It is often associated with thymic hyperplasia or thymoma,{{sfn|Davidson's|2018|pp=1141-43}} with antibodies produced probably because of T cells that develop abnormally.<ref name=":2">{{cite journal | vauthors = Engels EA | title = Epidemiology of thymoma and associated malignancies | journal = Journal of Thoracic Oncology | volume = 5 | issue = 10 Suppl 4 | pages = S260-5 | date = October 2010 | pmid = 20859116 | pmc = 2951303 | doi = 10.1097/JTO.0b013e3181f1f62d }}</ref> Myasthenia gravis most often develops between young and middle age, causing easy fatiguing of muscle movements.{{sfn|Davidson's|2018|pp=1141-43}} Investigations include demonstrating antibodies (such as against acetylcholine receptors or [[MuSK protein|muscle-specific kinase]]), and [[CT chest|CT scan]] to detect thymoma or thymectomy.{{sfn|Davidson's|2018|pp=1141-43}} With regard to the thymus, removal of the thymus, called [[thymectomy]] may be considered as a treatment, particularly if a thymoma is found.{{sfn|Davidson's|2018|pp=1141-43}} Other treatments include increasing the duration of acetylcholine action at nerve synapses by decreasing the rate of breakdown. This is done by [[acetylcholinesterase inhibitors]] such as [[pyridostigmine]].{{sfn|Davidson's|2018|pp=1141-43}}

===Cancer===
{{See also|Tumors of the hematopoietic and lymphoid tissues}}

====Thymomas====
Tumours originating from the thymic epithelial cells are called [[thymomas]].<ref name="Robbins9th" /> They most often occur in adults older than 40.<ref name="Robbins9th" /> Tumours are generally detected when they cause symptoms, such as a [[neck mass]] or affecting nearby structures such as the [[superior vena cava]];<ref name=":2" /> detected because of screening in patients with myasthenia gravis, which has a strong association with thymomas and hyperplasia;<ref name="Robbins9th" /> and detected as an [[Incidental medical findings|incidental finding]] on imaging such as [[chest X-ray]]s.<ref name=":2" /> [[Hyperplasia]] and tumours originating from the thymus are associated with other autoimmune diseases – such as [[hypogammaglobulinemia]], [[Graves disease]], [[pure red cell aplasia]], [[pernicious anaemia]] and [[dermatomyositis]], likely because of defects in negative selection in proliferating T cells.<ref name="Robbins9th" />{{sfn|Harrison's|2015|pp=2759}}

Thymomas can be benign; benign but by virtue of expansion, invading beyond the capsule of the thymus ("invasive thymoma"), or malignant (a [[carcinoma]]).<ref name="Robbins9th" /> This classification is based on the appearance of the cells.<ref name="Robbins9th" /> A [[World Health Organization|WHO]] classification also exists but is not used as part of standard clinical practice.<ref name="Robbins9th" /> Benign tumours confined to the thymus are most common; followed by locally invasive tumours, and then by carcinomas.<ref name="Robbins9th" /> There is variation in reporting, with some sources reporting malignant tumours as more common.{{sfn|Harrison's|2015|pp=2759}} Invasive tumours, although not technically malignant, can still spread ({{wt|en|metastasise}}) to other areas of the body.<ref name="Robbins9th" /> Even though thymomas occur of epithelial cells, they can also contain thymocytes.<ref name="Robbins9th" /> Treatment of thymomas often requires surgery to remove the entire thymus.{{sfn|Harrison's|2015|pp=2759}} This may also result in temporary remission of any associated autoimmune conditions.{{sfn|Harrison's|2015|pp=2759}}

====Lymphomas====

Tumours originating from T cells of the thymus form a subset of [[acute lymphoblastic leukaemia]] (ALL).<ref name="Williams9eChapter91">{{cite book |last1=Larson |first1=Richard A. | name-list-style = vanc |title=Williams hematology (online) |date=2015 |publisher=McGraw-Hill Education |isbn=978-0071833004 |edition=9th |chapter=Chapter 91: Acute Lymphoblastic Leukemia}}</ref> These are similar in symptoms, investigation approach and management to other forms of ALL.<ref name="Williams9eChapter91" /> Symptoms that develop, like other forms of ALL, relate to deficiency of [[platelet]]s, resulting in bruising or bleeding; immunosuppression resulting in infections; or infiltration by cells into parts of the body, resulting in an [[hepatomegaly|enlarged liver]], [[splenomegaly|spleen]], [[lymphadenopathy|lymph nodes]] or other sites.<ref name="Williams9eChapter91" /> Blood test might reveal a large amount of white blood cells or [[lymphoblast]]s, and deficiency in other cell lines – such as low platelets or [[anaemia]].<ref name="Williams9eChapter91" /> [[Immunophenotyping]] will reveal cells that are [[CD3 (immunology)|CD3]], a protein found on T cells, and help further distinguish the maturity of the T cells. Genetic analysis including [[karyotyping]] may reveal specific abnormalities that may influence prognosis or treatment, such as the [[Philadelphia translocation]].<ref name="Williams9eChapter91" /> Management can include multiple courses of [[chemotherapy]], [[stem cell transplant]], and management of associated problems, such as treatment of infections with [[antibiotics]], and [[blood transfusions]]. Very high white cell counts may also require [[cytoreduction]] with [[apheresis]].<ref name="Williams9eChapter91" />

Tumours originating from the small population of B cells present in the thymus lead to [[primary mediastinal large B cell lymphoma]]s.<ref name="PMLBCL2014">{{cite journal | vauthors = Dabrowska-Iwanicka A, Walewski JA | title = Primary mediastinal large B-cell lymphoma | journal = Current Hematologic Malignancy Reports | volume = 9 | issue = 3 | pages = 273–83 | date = September 2014 | pmid = 24952250 | doi = 10.1007/s11899-014-0219-0 | pmc = 4180024 }}</ref> These are a rare subtype of [[Non-Hodgkin lymphoma]], although by the activity of genes and occasionally microscopic shape, unusually they also have the characteristics of [[Hodgkin lymphoma]]s.<ref name="Williams9eChapter98"/> that occur most commonly in young and middle-aged, more prominent in females.<ref name="Williams9eChapter98"/> Most often, when symptoms occur it is because of compression of structures near the thymus, such as the [[superior vena cava syndrome|superior vena cava]] or the [[upper respiratory tract]]; when lymph nodes are affected it is often in the mediastinum and [[cervical lymph nodes|neck]] groups.<ref name="Williams9eChapter98"/> Such tumours are often detected with a [[biopsy]] that is subject to [[immunohistochemistry]]. This will show the presence of [[clusters of differentiation]], cell surface proteins – namely [[CD30]], with [[CD19]], [[CD20]] and [[CD22]], and with the absence of [[CD15]]. Other markers may also be used to confirm the diagnosis.<ref name="Williams9eChapter98">{{cite book |last1=Smith |first1=Stephen D. |last2=Press |first2=Oliver W. | name-list-style = vanc |title=Williams hematology (online) |date=2015 |publisher=McGraw-Hill Education |isbn=978-0071833004 |edition=9th |chapter=Chapter 98. Diffuse Large B-Cell Lymphoma and Related Diseases}}</ref> Treatment usually includes the typical regimens of [[CHOP (chemotherapy)|CHOP]] or [[EPOCH (chemotherapy)|EPOCH]] or other regimens; regimens generally including [[cyclophosphamide]], an [[anthracycline]], [[prednisone]], and other chemotherapeutics; and potentially also a [[stem cell transplant]].<ref name="Williams9eChapter98"/>

===Thymic cysts===
{{Further|Cervical thymic cyst}}
The thymus may contain cysts, usually less than 4&nbsp;cm in diameter. Thymic cysts are usually detected incidentally and do not generally cause symptoms.<ref name="Robbins9th" /> Thymic cysts can occur along the neck or in the chest ([[mediastinum]]).<ref name="Goldstein2015">{{cite journal |last1=Goldstein |first1=Alan J. |last2=Oliva |first2=Isabel |last3=Honarpisheh |first3=Hedieh |last4=Rubinowitz |first4=Ami |title=A Tour of the Thymus: A Review of Thymic Lesions with Radiologic and Pathologic Correlation |journal=Canadian Association of Radiologists Journal |date=1 February 2015 |volume=66 |issue=1 |pages=5–15 |doi=10.1016/j.carj.2013.09.003|pmid=24736228 |s2cid=33986973 |doi-access=free }}</ref> Cysts usually just contain fluid and are lined by either [[Stratified squamous epithelium|many layers of flat cells]] or [[columnar epithelium|column-shaped cells]].<ref name="Goldstein2015" /> Despite this, the presence of a cyst can cause problems similar to those of thymomas, by compressing nearby structures,<ref name="Robbins9th" /> and some may contact internal walls ({{wt|en|septa}}) and be difficult to distinguish from tumours.<ref name="Goldstein2015" /> When cysts are found, investigation may include a workup for tumours, which may include [[Computed tomography|CT]] or [[Magnetic resonance imaging|MRI scan]] of the area the cyst is suspected to be in.<ref name="Robbins9th" /><ref name="Goldstein2015" />

===Surgical removal===
[[Thymectomy]] is the surgical removal of the thymus.<ref name="Grays2016" /> The usual reason for removal is to gain access to the heart for surgery to correct [[congenital heart defects]] in the neonatal period.<ref name=":1">{{cite journal | vauthors = Eysteinsdottir JH, Freysdottir J, Haraldsson A, Stefansdottir J, Skaftadottir I, Helgason H, Ogmundsdottir HM | title = The influence of partial or total thymectomy during open heart surgery in infants on the immune function later in life | journal = Clinical and Experimental Immunology | volume = 136 | issue = 2 | pages = 349–55 | date = May 2004 | pmid = 15086401 | pmc = 1809033 | doi = 10.1111/j.1365-2249.2004.02437.x }}</ref> Other indications for thymectomy include the removal of thymomas and the treatment of myasthenia gravis.<ref name="Grays2016" /> In neonates the relative size of the thymus obstructs surgical access to the heart and its surrounding vessels.<ref name=":1" /> 

Removal of the thymus in infancy results in often fatal immunodeficiency, because functional T cells have not developed.<ref name="Grays2016" /><ref>{{Cite journal |last1=Prelog |first1=Martina |last2=Wilk |first2=Cordula |last3=Keller |first3=Michael |last4=Karall |first4=Thomas |last5=Orth |first5=Dorothea |last6=Geiger |first6=Ralf |last7=Walder |first7=Gernot |last8=Laufer |first8=Guenther |last9=Cottogni |first9=Marco |last10=Zimmerhackl Lothar |first10=Bernd |last11=Stein |first11=Joerg |last12=Grubeck-Loebenstein |first12=Beatrix |last13=Wuerzner |first13=Reinhard |date=2008-01-30 |title=Diminished response to tick-borne encephalitis vaccination in thymectomized children |url=https://www.sciencedirect.com/science/article/pii/S0264410X07013412 |journal=Vaccine |volume=26 |issue=5 |pages=595–600 |doi=10.1016/j.vaccine.2007.11.074 |pmid=18178293 |issn=0264-410X}}</ref> In older children and adults, which have a functioning lymphatic system with mature T cells also situated in other lymphoid organs, the effect is reduced, but includes failure to mount immune responses against new antigens,<ref name="Grays2016" /> an increase in cancers, and an increase in all-cause mortality.<ref>{{Cite journal |last1=Kooshesh |first1=Kameron A. |last2=Foy |first2=Brody H. |last3=Sykes |first3=David B. |last4=Gustafsson |first4=Karin |last5=Scadden |first5=David T. |date=2023-08-03 |title=Health Consequences of Thymus Removal in Adults |journal=New England Journal of Medicine |language=en |volume=389 |issue=5 |pages=406–417 |doi=10.1056/NEJMoa2302892 |pmid=37530823 |s2cid=260377788 |issn=0028-4793|pmc=10557034 }}</ref>