Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature. The Thymus: The Forgotten Organ The objectives of today’s talk are to briefly discuss the historical aspects regarding the thymus as well as detailed embryology, anatomy, and physiology of the thymus, and then specifically to discuss the etiology, pathogenesis, evaluation and management of aberrant cervical thymic tissue in the pediatric population. The word thymus comes from a Latin derivation of the Greek thymos, which means warty excrescent, because of its resemblance to the flowers of the thyme plant; however, after looking at pictures of the thyme plant, I do not really see the resemblance. It can also be interpreted as soul or spirit and was misrepresented as the seat of the soul by Greek physicians. The first notable physician to mention the thymus was Galen and he felt, wrongly, that it played a role in the purification of the nervous system; however, he was correct in noting that it was proportionally largest during infancy. He actually referenced it as the organ of mystery, which held up for several centuries thereafter. That is evidenced by in the 1600s when the predominant thinking was that the thymus was simply a protective thoracic cushion. In the 1700s, it was felt that it somehow regulated fetal and neonatal pulmonary function and became known as the organ of vicarious respiration in several articles. In 1777, William Hewson was the first to correctly identify the thymus gland as some sort of modified lymph gland and in 1832 Sir Astley Cooper devoted a whole book to the anatomy of the thymus gland which contained detailed cadaveric dissections. In 1846, a major breakthrough came in the study of the thymus when Hassall and Vanarsdale used improvements in compound microscopy to study the thymus more thoroughly and described differences between the thymus and other lymphoid tissues, specifically the characteristic histological feature that became known as Hassall’s corpuscles. This slide shows the very complex interactions of the embryology of the head and neck in fetal development, and we will be focus on the third branchial apparatus in the development of the thymus. During the sixth week of gestation, epithelial out pouching from the ventral aspect of the third branchial arch starts to develop and move caudally, forming what is known as the thymopharyngeal duct. Also, the dorsal aspect of the third branchial arch develops into the inferior parathyroid gland. This is actually mislabeled: it should be “parathyroid” here, as well. The superior parathyroid develops from the dorsal aspect of the fourth branchial pouch. There is a very minor and rudimentary portion of the thymic tissue, which develops from the ventral aspect of the fourth pharyngeal pouch; however, this is thought to completely degenerate and add nothing to the thymus in its development. It is also notable that the connection of the thymopharyngeal duct to the pharynx at the level of the pyriform sinus can have implications when these masses present in the neck, which will be discussed later. During the seventh to ninth week of gestation, the parathymic primordia start to move to the midline and eventually fuse and start their descent toward the mediastinum. A capsule surrounds the developing thymus and maintains the gland in close association with the parietal pericardium, which is key in it decent to the mediastinum. During the tenth week of gestation, lymphocyte invasion occurs from the fetal liver and yolk sac and Hassall’s corpuscles form from endodermal regression with the gland. The usual pathway of descent of the thymus gland is that typical of a third branchial arch derivative. A tract starts at the pyriform sinus and pierces the thyrohyoid membrane, exiting between the common carotid artery and the vagus nerve. It then passes posteriorly to the glossopharyngeal nerve and lateral to the thyroid and into the mediastinum. As stated before, this is closely associated with the inferior parathyroid gland, which explains why sometimes The normal anatomy in a neonate or infant is that of a midline structure composed of two lobes, situated in the anterior superior mediastinum. It normally extends from the fourth costal cartilage upward all the way to the level of the thyroid gland in some cases. It normally rests upon the pericardium below and on the front and sides of the trachea. It is pinkish/gray in color, soft, and multilobulated. Each lateral lobe is composed of numerous lobules, which vary in size from a pinhead to that of a small pea, and the lobules are composed of hundreds of follicles, which are each 1mm - 2mm in diameter. Each one of these follicles consists of a medullary and a cortical portion, which is surrounded by a vascular plexus that feeds vessels into the medulla to feed the developing lymphocytes. The arterial supply is from the internal mammary and superior and inferior thyroid arteries, and the venous drainage is into the innominate and thyroid veins. This is a histologic picture of a standard H&E stain, which is a good representation of the very basophilic staining cortex and more eosinophilic appearing medulla with the lobules separated here by the striae. This is a higher power picture of the medulla and the characteristic Hassall’s corpuscles are shown here. As stated, the cortex is surrounded by a capsule and it predominantly populated by lymphocytes of the T-cell lineage. Lymphoblasts are produced in the outer cortex, as can be seen by mitochondrial bodies here, and as they are pushed deeper into the cortex they develop further maturation and become more mature T-lymphocytes. The medulla contains fewer lymphocytes than the cortex, which explains its more eosinophilic appearance on slides and it contains a large amount of epithelial cells, as can be seen here; however, the characteristic feature is the Hassall’s corpuscles, which first appear in fetal life and increase in number thereafter and are thought to be degenerated epithelial cells. The thymus serves many functions and is very important in immunologic function in the neonate and infant. Some of the functions are the development of immunocompetent T-cells from lymphocytes derived from the bone marrow as well as the fetal yolk sac and liver. It involves differentiation of the two T-cell subsets, a very complex interaction shown here, into T-helper cells or CD-4 or cytotoxic suppressor cells, CD8s. Also a function is the proliferation of clones of mature naïve T-cells, which move into the circulating lymphocyte pool and the peripheral tissues to help fight against infections. The development of immunologic self-tolerance and the prevention of autoimmune diseases is another important function of the thymus, as well as the secretion of hormones and other soluble factors, the most notable being thymolin, thymopoietin, and thymosin alpha-1. These hormones act in concert through many complex interactions to regulate T-cell maturation, proliferation, and function within the thymus and peripheral tissues, and it is also an important organ in hematopoiesis during fetal development. As for the natural history of the thymus, at birth it weighs about 15 gm and it continues to enlarge throughout childhood into puberty. At the age of 2- to 3-years, it reaches its largest relative size at 20gm - 25gm. It continues to grow, however, slower than the rest of the body. It actually reaches it largest size at puberty. Thereafter it starts to involute and is replaced by fibrofatty tissue until, by the age of 70-years, it is only a mere 6gm. Cervical thymic anomalies are an uncommon cause of neck masses in children. There are only about 100 cases reported in children who presented with a primary neck mass; however, it is felt that, because of the asymptomatic nature, this is a much more common lesion than is reported. In fact, in a study from the Journal of Pediatric Surgery in 1988 by Wagner, he quoted an incidence of 30% of asymptomatic cervical thymic tissue in children at autopsy. For unknown reasons, it occurs more commonly in males with a ratio of 3:1 and occurs more common on the left side of the neck. Two-thirds of these lesions present in the first decade of life with the remaining third presenting by the age of 20; however, there are sporadic reports in adults with the oldest case reported being that of a 71-year-old man. When thinking about thymic lesions in the neck, they can be divided into either cystic or solid. The vast majority of these lesions are cystic and can occur anywhere along the embryologic path of descent from the angle of the mandible to the mediastinum. Half of these will connect with normal thymic tissue in the mediastinum. There are, however, reports of ectopic tissue that occur elsewhere in the body off the path of embryologic descent. In 1983, Zarbo, in the Annals of Otology, Rhinology and Laryngology, proposed a scheme for deciphering the various reported types as solid and cystic thymic abnormalities. He distinguished these abnormalities into seven different categories by the anatomic location and the nature, either cystic or solid, of the thymic gland tissue. The first is an accessory cervical thymus, which is defined as solid cervical thymic tissue, which is sequestered from the main gland along the normal descent of the embryologic path. It may or may not have inferior parathyroids associated with it and other terms in the literature that are found include aberrant, ectopic, undescended, persistent, or accessory thymus. The important feature of this lesion is that it is only sequestered from the main gland and there will still be normal thymus in the mediastinum. A cervical thymic cyst is essentially the same lesion as an accessory cervical thymus except that it is cystic in nature. Again, it may or may not have parathyroids associated with it and there will be normal mediastinal thymic tissue present. An undescended cervical thymus occurs when a whole lobe of the thymus completely fails to descend. Again, it may or may not have parathyroids associated with it and it differs obviously from these two in that no thymic tissue will be present in the mediastinum. It may also become cystic and present as a cystic neck mass. As stated, the thymopharyngeal duct connects to the pharynx at the level of the pyriform sinus and there may be a persistent thymopharyngeal duct, which forms a cystic structure. It is essentially the same as an undescended cervical thymus. If there is solid thymic tissue associated with it, it usually represents the undescended thymus. A variant of this would be a cervical cystic duct leading to a normal thymus within the mediastinum. A persistent thymic cord is a cervical prolongation of a solid thymic cord, which is continuous with a mediastinal thymus, and there is a cystic variant of this lesion, which may overlap histologically and clinically with the appearance of the cervical thymic cyst, which is the second one described. This is only if there is no true connection to the mediastinum. If the thymus does descend into the mediastinum, but does not descend entirely, there may be a small rim of tissue that is pushed through the thoracic inlet and presents as a neck mass. What is different about this one is that it may increase in size with Valsalva maneuver or increased intrathoracic pressure. Finally, ectopic thymus is a very rare lesion, which is solid thymic tissue in abnormal locations off the normal embryologic path of descent. Examples reported in the literature include within the pharynx or the trachea and also at the base of the skull. As everyone knows, the differential diagnoses for a pediatric neck mass are very extensive and it is probably the rarest lesion in the pediatric neck mass category and so the diagnosis of a thymic cyst is rarely made preoperatively. Common considerations in the differential diagnosis are branchial cleft cysts and cystic hygromas. The less common considerations are these here. There are differentiating factors between a thymic cyst and cystic hygromas and branchial cleft cysts. As stated, they are more rare than cystic hygromas or branchial cleft cysts and they occur in an intermediate age group with most patients presenting younger in cystic hygromas and most older and up to adults in the third decade with branchial cleft cysts. Also, the thymic cysts, because of their embryologic derivation, are usually located in the lower neck in the anterior triangle whereas cystic hygromas are in the posterior triangle and branchial cleft cysts are in the upper neck since most of these, as you remember, are derived from the second branchial apparatus. As stated, half of these will have the connection to the mediastinum whereas 10% of cystic hygromas may move into the mediastinum and no branchial cleft cysts should. Most of these will present as an asymptomatic neck mass; up to 90% in some studies, with just an asymptomatic neck swelling as shown here. However, there are reported symptoms and these include hoarseness, dysphagia, and occasionally stridor. Large thymic cysts have been reported to cause respiratory compromise in neonates with subsequent death. When evaluating these lesions, as always, a thorough history and physical examination is the most important factor; however, radiologic imaging is usually obtained in the form of either ultrasound, CT, or MRI. MRI is a very good study because it is often able to demonstrate a connection to the mediastinal thymus. FNA is sometimes useful in the diagnosis; however, this is not always available or commonly performed at most institutions in children. It may assist in the preoperative diagnosis. If an ultrasound is obtained, the echogenicity of thymic tissue lies between that of surrounding muscle and thyroid and has been described as having a starry sky appearance, as can be seen here, which is presumably related to the presence of large Hassall’s corpuscles within the thymus. This is a good example of thymic tissue along its normal embryologic path of descent along the carotid sheath in between the jugular vein and the carotid artery with the thyroid gland just medial to that. On CT scan, these lesions are fairly homogenous. They are usually non-enhancing with contrast, anterior to the sternocleidomastoid muscle, and usually do not show significant mass effect on surrounding structures. In contrast again to second branchial cleft cyst and lymphangiomas, thymic cysts will maintain a relationship with the carotid sheath based on their embryologic path of migration and this is obviously not the case in ectopic thymic tissue that is off the embryologic path of descent. Second branchial cleft cysts occur superficial and lateral to the internal jugular vein and the common carotid arteries, and cystic hygromas most commonly occur in the posterior triangle and often violate normal fascial planes, neither of which will not be seen with thymic cysts. These are just CT scans demonstrating the variability of cervical thymic tissue; sometimes presenting as a very large multicystic structure. On T1 weighted images, if an MRI is obtained, the lesion is usually isointense or slightly hyperintense when compared with muscle and only has mild enhancement with gadolinium contrast. The T2 weighted images are slightly less intense or isointense relative to fat, as can be seen easily here. This is actually an interesting MRI that shows ectopic thymus tissue in the retropharyngeal space. The arguments for a FNA are that is does provide rapid results and if a diagnosis can be obtained of thymic tissue, it may avoid the need for surgery. On standard pathology stains, it consists of a dominant population of small, round, non-activated lymphocytes with associated epithelial cells. Occasionally you may see Hassall’s corpuscles, which will be the characteristic histologic feature. However, the disadvantages of a FNA are that it is very difficult to distinguish thymic tissue from a low grade lymphoma on FNA without the architectural context for the pathologist. When talking about the management of these lesions, you can either observe them or take them out. When choosing observation, if these lesions are completely asymptomatic and/or if the diagnosis is known with an FNA, then it is most likely safe to observe; however, FNA is not routinely performed in children in most situations and hence the diagnosis is rarely made preoperatively. As with any neck mass, the indications for surgical excision are if it is symptomatic, recurrently infected, or for cosmetic purposes. Polloson and Chiari first described an attempted partial excision of a thymic cyst in 1901; however, the child died shortly after the operation and it was not until 1944 that the first successful excision of a thymic cyst was reported by Hyde. The cysts were mostly multilocular – this is a good example here – and usually had clear or straw-colored fluid within the cyst itself. They are usually adherent to surrounding neural and vascular structures; however, blunt dissection is usually not difficult. In our case, it was grossly adherent to the thyroid gland and required partial removal of the left thyroid lobe; however, it was not adherent to the surrounding neural and vascular structures. Again, it is not unusual to encounter thymic tissue or fibrous cord, which tracts inferiorly to the superior mediastinum with a connection to normal thymic tissue. Histologically, the cyst wall contains variable linings and the cyst itself may have cholesterol crystals, occasional giant cells, and calcifications within it. There are usually frequent lymphocytes seen in germinal centers, and occasional Hassall’s corpuscles may be seen within the cyst wall. One argument for removing these lesions is that they do theoretically have a malignant potential. There are sporadic reports of malignant degeneration of thymic structures, Most of these are in solid cervical thymic anomalies, which only make up 10% of cervical anomalies anywhere, so it would be a very rare case of malignant degeneration; however, they have been reported. Also, a theoretical consequence of total thymectomy, which is very interesting, is that we do not really know what happens when you take out the whole thymus in a neonate or child. It is likely that it is very well tolerated; however, there is a theoretical potential of inducing immune dysfunction or autoimmune disease by taking out the whole thymus because of its importance in the immunologic development of the child. After an extensive review of the literature, there is really not much known about this subject. What is know is from a study in 1987 by Brilley in which he reviewed 18 patients that were less than 3-months of age who underwent a total thymectomy during cardiac bypass procedures. All he did was study the lymphocyte numbers and what he found were normal total lymphocyte numbers; however, there were significantly lower numbers of T-cells and T-cell subsets with diminished responses to a-hemagglutinin and concanavalin A. The clinical significance of this is unknown; however, the theoretical potential for immune dysfunction does exist in this situation. Another study in 1995 from the Journal of Immunology studied the effect of neonatal thymectomy in mice. They took out the whole thymus in mice at 3-days of age and what they found was that it induced autoimmune disease in these mice and it was felt that the altered immune function was probably due to the failure of development of suppressor T-cells, which usually occurs in mice at the age of 3-days. The disadvantage of this is that it is not known whether this immunologic system mimics that of a human system. So, after an extensive review of the literature and our general lack of knowledge regarding the immunologic dysfunction, if you take out the whole thymus, it appears prudent that mediastinal thymic tissue should be identified preoperatively in infants less than 3-months of age who are scheduled for excision of solid, symptomatic cervical masses. This can be done very easily by any radiological means. Least expensive is a chest x-ray and you will see a mediastinal shadow which is consistent with the thymus gland; however, in most cases in children that are going to the O.R. for an excision of a neck mass, a CT or an MRI will be obtained and it should always be in the back of your mind that this could be thymic tissue and to look for thymic tissue in the mediastinum. If there is no thymic tissue in the mediastinum preoperatively, then it could be recommended that a frozen section be obtained intraoperatively so that, if this is consistent with thymic tissue, the only thymus is not inadvertently removed - only a partial excision should be undertaken. In summary, cervical thymic anomalies are an uncommon diagnosis in the pediatric neck mass, but they should be considered in the differential diagnosis of pediatric neck masses. They are rarely diagnosed preoperatively and usually are mistaken for branchial cleft cysts or cystic hygromas. An MRI is an excellent tool not only for the diagnosis of a neck mass, but also for the determination of the presence of normal mediastinal thymic tissue. An FNA may aid in the diagnosis circumventing the need for surgical management; however, surgical excision is recommended for symptomatic or cosmetically unappealing lesions. The potential risk for immunologic dysfunction if all thymus tissue is removed exists, although not much is known about this subject. If no mediastinal thymic tissue is present, then a conservative approach should probably be undertaken.
The patient remained asymptomatic over the next several months and a repeat MRI was obtained 5/26/03, which revealed no change in the mass. After extensive discussions with the patient’s family regarding possible etiology of the lesion as well as risks and benefits of continued observation versus surgical excision, it was decided to remove the mass. The patient was taken to the OR on 7/14/03, and a 2.5cm x 1.8cm x 1.6cm, pinkish-tan cystic mass was excised through anterior midline neck incision without difficulty. The mass was adherent to left thyroid lobe, and portion of the thyroid was removed with the mass. Final pathology revealed thymic cyst, described as multilocular cyst lined by respiratory type epithelium with numerous reactive lymphoid follicles and plasma cells. There were lobules of thymic tissue, with characteristic Hassall’s corpuscles which composed much of the cyst wall. 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