Thymectomy in Children

Abstract

Surgical diseases of the thymus are rare in childhood. Although thymic hyperplasia, myasthenia gravis (MG), and ectopic thymic cysts/tissues are relatively more frequent among these ones, thymectomy is commonly performed during congenital cardiac surgery and for thymoma. The indication and timing for thymectomy in thymic hyperplasia and non-thymomatous MG is controversial due to their unpredictable course. Such complex cases should be evaluated by a multidisciplinary team at a tertiary center. In thymic hyperplasia and MG, as a general management policy, thymectomy is recommended when all conservative approaches fail. Excision is the first option in symptomatic ectopic thymic cysts or tissues. There are three basic access routes for thymectomy: (I) transsternal, (II) transcervical, and (III) endoscopic (thoracoscopic/robotic). Additionally, when the extent and limits of the excision procedure are considered, the surgical techniques can be further classified in three groups: (I) simple/standard thymectomy, (II) extended thymectomy, (III) radical/maximal thymectomy. Most of the thymic disorders in children are treated with simple thymectomy, which can be performed through thoracoscopic approach. Transsternal access is usually preferred for a large thymus or advanced thymomas. Available literature supports that thymectomy can make a significant contribution to relieving generalized symptoms in selected cases of thymic hyperplasia and MG. Morbidity after thymectomy in children is minimal and mortality is negligible.

1. Introduction

Thymectomy is the basic surgical procedure in the treatment of disorders affecting the morphologic structure of the thymus gland. In order to understand better the surgical philosophy of thymectomy, first, it will be useful to mention briefly basic embryogenesis, anatomy and physiology of the thymus gland, and the history of thymectomy.

In the 5th intrauterine week, the thymic buds begin to differentiate as a diverticulum from the ventral surface (endodermal) of the third branchial pouches on the right and left sides, in close relationship with the inferior parathyroid glands’ ducts. Later, the buds that migrate dorsally and inferiorly around the thyroid gland, leaving the thymopharyngeal canal behind, merge and settle in the anterior–superior mediastinum. Meanwhile, the thymopharyngeal duct undergoes involution, and the relationship between the thymus and the pharynx disappears [1, 2].

Anatomically, the thymus is an organ located in the anterior mediastinum, posterior to the sternum, anterior to the trachea, main vascular structures and pericardium, consisting of two lobes and surrounded by a fibrocollagenous capsule. The right lobe is slightly larger and is joined in the middle by a loose areolar tissue. However, it might show significant variations in terms of shape, size, and borders [3]. Their size decreases significantly with puberty. The cortex and medulla of each lobe contain thymocytes (lymphocytes), stromal (epithelial, dendritic) cells, and Hassall’s corpuscles. The thymus is often fed by the internal mammary artery and inferior thyroid artery. Although the venous drainage of the gland is usually to the brachiocephalic and internal thoracic veins, it may also connect with the superior vena cava on the right side. Lymphatic drainage is in the direction of the anterior mediastinal and hilar lymph nodes [1, 3]. It is important to know the anatomical areas where ectopic thymic tissues may be found during thymectomy. The rate of ectopic thymic tissues located outside the anatomical capsule can reach up to 70%. The most common ectopic locations are cervical and mediastinal fatty tissues and the aortopulmonary window. Additionally, it has been reported that there may be ectopic thymic tissue within the thyroid gland [4].

The thymus gland has an important role in the development and functioning of T lymphocytes, especially in the first years of life. Because of this role, it is an important component of the immune system, especially in children. This role gradually decreases in parallel with the volume loss that occurs with adolescence [5].

The first thymus surgery in modern medicine is attributed to Ludwig REHN (a German surgeon) in 1896 [6]. He performed transcervical thymopexy on a patient whose thymus was enlarged and caused choking attacks. Until the 1930s, the principal access route for thymic surgery was the transcervical approach. The first successful transsternal thymectomy was performed by Alfred BLALOCK in 1936 via upper median sternotomy in a patient with MG and a large anterior superior mediastinal tumor [7]. Subsequently, median sternotomy became a standard method for accessing the thymus gland, and transcervical procedures followed sternotomy. Thoracoscopic thymectomy was first described in an adult population in 1995 and in a pediatric population in 2000 [8].

Thymectomy is an uncommon surgical procedure in children but it is performed throughout childhood, starting from the neonatal period. Despite its lower incidence and prevalence in children, the diseases originating from the thymus and requiring surgical intervention have a broader spectrum when compared to adults. Among these diseases, acquired ones are more common, and congenital ones are less common. Therefore, adult experiences are prioritized in thymus-related surgical interventions in children. This situation gains importance especially in the care of pediatric patients with lymphoid hyperplasia, refractory MG, and thymoma which is more common in older ages [9]. In this chapter, surgical treatment of thymic disorders in children, specifically thymectomy, will be reviewed taking into account emerging pediatric management strategies as well as the data obtained from adult patients.

2. Indications for thymectomy

While there is remarkable debate about the necessity of thymectomy in some cases, there is a certain consensus in the literature in other cases. In this context, it is important that complex or complicated cases should be evaluated with a multidisciplinary approach by a team consisting of pediatricians (pediatric neurologist, pediatric infection specialist, pediatric oncologist, etc.), pediatric radiologist and a surgeon experienced in both open and thoracoscopic thymectomy techniques. The main diseases for which thymectomy should be considered are explained below in detail.

2.1 Congenital cardiac surgery

In the last decades, the number of operated congenital heart diseases is gradually increasing in parallel to advances in diagnostic methods, surgery, and intensive care facilities. In this context, today, complex and serious cardiovascular malformations generally require open-heart surgery more frequently at an earlier in age. Partial or complete removal of the thymus gland to improve surgical access is a common procedure during corrective or palliative cardiac operations [10]. However, the amount of eliminated tissue highly depends on the individual anatomy, surgeon’s preference, type of surgery, and patient age. Thymectomy in young children implies removal of the main source of T-cell differentiation, although other sources of differentiation have been described [11]. Cavalcanti et al. suggested that early thymectomy, either partial or complete, may be also associated with a reduction in many T cell subpopulations and TCR diversity, and these alterations may persist during long-term follow-up [12]. To overcome the negative immunological effects of thymectomy, they proposed some alternative solutions, such as modifications of surgical techniques with partial preservation of the thymus or autografting of gland fragments [12, 13].

2.2 Thymic hyperplasia

Thymic hyperplasia has several clinico-pathological manifestations. “Thymic lymphoid hyperplasia” involves germinal center. It is rare in children and associated with MG. In most pediatric cases, there is a reactionary/physiological growth of the thymus gland, known as “true thymic hyperplasia”, in which the thymus gland is histopathologically normal. “Rebound thymic hyperplasia” is a true hyperplasia characterized by rapid and excessive growth of the thymus gland. This condition can be seen after severe thermal burns or cardiac surgery, in tuberculosis, following chemotherapy, or after stopping steroid treatment [1, 3]. “Non-lymphoid thymic hyperplasia” cases are often asymptomatic and do not cause respiratory distress. The majority of cases are seen in the first year of life, and the thymus gland returns to its normal volume over time [3].

Thymic hyperplasia has been detected in 50–70% of patients with MG [14]. Hyperplasic thymus tissue can sometimes reach quite large sizes and put pressure on the surrounding tissues. If necessary, a short-term steroid (prednisolone) treatment may be administered to shrink the thymus. Such a therapy also allows thymic hyperplasia to be differentiated from non-lymphoid mediastinal masses. CT, MR imaging, and mediastinoscopy can also be used for diagnosis [1]. Thymectomy should be performed in symptomatic cases with rapid growth. Mediastinal radiotherapy is no longer performed because it carries a high risk of thyroid carcinoma. In cases where residual/recurrent lymphoma or a malignant tumor such as nodular thymic hyperplasia cannot be excluded, first PET and then, if necessary, exploration is recommended [3]. Nodular thymic hyperplasia is usually asymptomatic and is detected incidentally as a superior mediastinal mass on imaging methods. Complete blood and bone marrow examinations are normal. During surgery, a lesion originating from one lobe of the thymus and suppressing the adjacent normal tissue is observed. In histopathological examination, T and B lymphocyte ratios are normal. Today, thoracoscopic thymectomy is performed in most cases of thymic hyperplasia that do not respond to conservative approach [2, 9].

2.3 Myasthenia gravis (MG)

MG is an autoimmune disorder that affects the postsynaptic neuromuscular junction and results in fatigue in voluntary muscles. Although the relationship between the thymus gland and MG is not fully understood, the thymus is held responsible for the production of acetyl cholinesterase receptor (AChR) antibodies [15].

MG is frequently seen in women aged 20–30 and men over 60–70. Only, 10–30% of immune MG is seen in children [3]. The clinical picture in children is classified in three subgroups as “neonatal MG”, “congenital myasthenic syndrome”, and “juvenile MG”. Neonatal MG resolves spontaneously in the first few months. Congenital myasthenic syndrome remains relatively stable throughout life and does not respond to treatment methods (immunotherapy and thymectomy). Juvenile MG has similar features to the adult disease. According to the Osserman-Genkins grading used to determine the clinical picture of MG, findings may vary from mild ocular MG to severe myasthenic crisis [16].

Measurements of AChR and muscle-specific tyrosine kinase (MuSK) antibodies and edrophonium test give significant information for diagnosis and management. AChR antibodies are present in approximately 80% of cases. MuSK antibodies are detected in approximately 50% of the remaining patients. EMG and single fiber EMG are highly predictive of diagnosis [17]. After the neurological diagnosis is made, it should be investigated whether there is thymic pathology with CT (Figure 1) [1].

Figure 1.

Two cases of MG with thymic hyperplasia. Hyperplastic thymus (T) is seen in the thorax CT of a 14-year-old patient (A). Thorax MR shows hyperplasic/hypertrophic left lobe in a 15-year-old patient with MG (from the author’s own archive).

A possible association between the thymus and MG first suggested by chance observation of improved symptoms in several myasthenic patients undergoing thyroidectomy for goiters with concomitant resection of adjacent thymus gland in the early 1900s [18]. After that, remarkable progress made in the understanding surgical treatment of MG.

Although there are no controlled studies with high-evidence level on surgical treatment of MG, certain indications for thymectomy have been reported [17, 19]. These are listed below.

• Presence of thymoma.

• Early onset anti-AChR positive MG.

• Progressive widespread muscle weakness.

• Treatment-resistant non-thymomatous autoimmune MG.

It is important to carefully evaluate respiratory functions in these patients before thymectomy. In the treatment of non-thymomatous MG, anticholinergics (pyridostigmine) and corticosteroids are used primarily. In selected cases, immunoglobulins, immunosuppressors, and plasmapheresis may be useful [17]. In (highly) active generalized MG, complement inhibitors (currently eculizumab and ravulizumab) or neonatal Fc receptor modulators (currently efgartigimod) are recommended for AChR-Ab-positive status and rituximab for muscle-specific receptor tyrosine kinase (MuSK)-Ab-positive status [20]. In cases of failure and in the presence of generalized symptoms, thymectomy has begun to be applied to children as an effective method [16, 21]. However, there is no consensus in the literature regarding the timing of thymectomy, which is a procedure that can be performed safely in children [22]. The general approach is to perform thymectomy in cases where there is no response to pharmacotherapy within 1 or 2 year [23]. The thoracoscopic approach for thymectomy has attracted attention in recent years. The goal is to remove all thymic tissue. It has been stated that even an amount of 3 g of residual thymus tissue can cause MG symptoms [24]. In their series including 12 cases, Ashfaq et al. stated that thoracoscopic thymectomy is an effective option to control the disease with low morbidity and short hospitalization time [16]. Goldstein et al. obtained similar findings in terms of effectiveness in their study comparing cases in which thoracoscopy, sternotomy, and thymectomy were performed [21].

2.4 Thymic cysts

While these cysts can be located within the mediastinal thymus tissue, they can also be seen anywhere from the neck to the diaphragm in anterior or posterior mediastinum where ectopic thymic tissue may be present. Most cases are diagnosed after pathological examination. Histopathologically, cysts are lined with ciliated columnar (respiratory) epithelium and characteristically contain Hassall corpuscles. They may contain lymphocyte infiltration and normal thymic tissue, and both inflammatory and granulomatous changes may be seen [9]. Their location in the neck region is lateral to the midline and may vary from the submandibular area to the suprasternal fossa along the sternocleidomastoid muscle line [25]. The cysts can be congenital or acquired. Congenital ones are usually located on the left side and originate from the thymopharyngeal duct. They can be unilocular or multilocular [26]. Acquired ones may coexist with inflammatory or neoplastic diseases (thymoma, germ cell tumors) [3].

Thymic cysts are usually asymptomatic. However, the cysts become symptomatic when microorganisms reach the cyst through remnants of the thymopharyngeal duct (i.e., when they infected), bleeding occurs into the cyst, and the cyst grows and causes pressure on surrounding tissues and organs. Those with large dimensions in the neck may also cause cosmetic problems.

Findings on chest radiography are mostly non-diagnostic. On CT or MRI, a well-circumscribed, fluid-dense mass is detected in the original or ectopic location of the thymus [1]. Cyst excision is recommended in ectopic locations, and thymectomy is recommended in original locations [2, 8].

2.5 Ectopic thymic tissues

Since ectopic thymic tissues are usually asymptomatic, the majority of cases are detected incidentally during ultrasonography, which is frequently used for the differential diagnosis of patients presenting with neck-related symptoms [27]. Most ectopic tissues are located in the thyroid gland. Ultrasound has a high predictivity for diagnosing ectopic thymus, providing a unique appearance and allowing specific diagnosis [28]. In childhood, ectopic intrathyroidal thymus tissues generally remain stable, but sometimes their size may decrease or grow. Stable ectopic tissues can be safely followed without the need for excision and physicians should reassure parents about its benign course. However, microcalcified intrathyroidal nodules that grow during follow-up, which may mimic thyroid cancer, ultimately require invasive diagnostic procedures or surgery [4].

2.6 Thymolipoma

Thymolipoma is a slowly progressing benign tumor that is more common in young adults and rare in children. It is considered a hamartomatous lesion consisting of a mixture of thymic and mature fatty tissues. Although approximately half of the cases are asymptomatic, the tumor can reach very large sizes over time [3]. CT and MRI show a tumor structure mostly consisting of fatty tissue, but the tumor also contains different soft tissue components scattered throughout [1]. Excision is both a diagnostic and therapeutic method in patients who have a progressive course and cause mass effect on neighboring structures [9].

2.7 Thymoma

Thymomas are mediastinal masses that are rarely seen in children. They are mostly seen in the third and fourth decades of life. Only 2% of all thymomas are diagnosed in childhood, and these account for less than 1% of all mediastinal tumors [3]. Thymomas originate from the thymic epithelium and can vary markedly in both size and appearance. Histopathologically, they are low-grade malignant tumors. In 30–40% of cases, there is a tendency to invade the surrounding tissues (pericardium, pleura, lung, and large vessels) [29, 30]. This type of tumor tissue that spreads beyond the capsule is called invasive thymoma. Lymphatic and hematogenous metastases are rare, but transdiaphragmatic spread may occur. The recent WHO classification of thymic epithelial tumors including thymomas, thymic carcinomas, and neuroendocrine tumors is summarized in Table 1 [31]. Thymic carcinomas and neuroendocrine tumors are exceedingly rare and constitute 1% of all thymic tumors.

Behavior Code	Histological Description
3*	Thymomas**
3	Squamous carcinomas
3	Adenocarcinomas
3	Adenosquamous carcinomas
3	Salivary gland-like carcinomas
3	Undifferentiated carcinomas
3	Thymic carcinomas
3	Thymic neuroendocrine neoplasms
3	Neuroendocrine tumors
3	Neuroendocrine carcinomas

Table 1.

Main thymic epithelial tumors according to the 2021 WHO classification [31].

*

Behavior code 3: malignant tumor, primary site.

**

Except for lipofibroadenoma and micronodular thymoma with lymphoid stroma.

According to adult data, 30–50% of patients with thymoma have MG, while thymoma is detected in 10–25% of patients with MG [29]. Advanced imaging methods such as CT, MR, and PET-CT are used for diagnosis and surgical planning [1]. A staging system (Masaoka) has also been developed to determine the treatment method and prognosis of thymomas. There may be progression from stage I, without capsule invasion, to stage IV, with distant metastases [14]. A multidisciplinary approach should be applied at diagnosis and during therapy [32].

Thymectomy with no adjuvant approach is the best treatment option in early stages, which accounts for 85–90% of cases are at the time of diagnosis. Recently, it has been suggested that robotic thymectomy has better cosmetic results and morbidity in early noninvasive thymoma [33]. Since incomplete tumor resection is associated with a high-recurrence rate and poor outcome, it should be avoided. While anterior region lymph node dissection is recommended for non-invasive thymomas, an additional systemic sampling of deep lymph nodes should be performed for invasive thymomas. Neo-adjuvant chemotherapy is recommended for advanced tumors but the prognosis is still poor [9, 30]. Radiotherapy is also applied as a palliative or adjuvant therapy because of the radiosensitive nature of the tumors. In the EXPeRT study, which included one of the largest series of children, it was reported that two of 16 thymoma cases and 15 of 20 thymic carcinoma cases were mortal, and the 5-year survival rate in thymic carcinoma was 21% [29]. Additionally, a need for multicenter, multidisciplinary studies in collaboration with adult thoracic surgeons.

2.8 Other tumors of the thymus

Thymic carcinoids are very rare and develop from normally existing neuroendocrine cells in the thymus gland. Approximately half of the tumors are functionally active and may present with Cushing’s syndrome. Less than 5% of primary thymic carcinoids are seen in children. They may show aggressive behavior with tendency to metastasis and local recurrences after thymectomy [1, 3].

Germ cell tumors, including mature or immature teratomas located in the anterior mediastinum, lymphoma, and leukemic infiltrates are topographically related to the thymus and should be considered in the differential diagnosis. Although lymphoma is the most common anterior mediastinal mass in children, isolated thymic involvement is extremely rare. Thymic involvement associated with advanced stage of Hodgkin or non-Hodgkin lymphoma is more likely [1, 14].

3. Preoperative evaluation and preparation

The preoperative evaluation should include safe surgery guidelines and standard institutional protocols, comprising a comprehensive history and physical examination. The extent of work-up depends on the disease necessitating a thymectomy and should be individualized. Radiological identification of adjacent structures and blood vessels (especially, innominate vein) during preoperative evaluation has utmost importance to avoid from intraoperative complications [14, 34].

Specific anesthesiologic measures in patients with an anterior mediastinal mass should be strictly followed to avoid airway compressing during induction phase. For anesthetic management, placement of a double-lumen endotracheal tube for sequential lung isolation in older children and adolescents, or a standard single lumen endotracheal tube in young children can be used. Single lung ventilation with selective bronchial intubation or with a blocker can be also preferred in selected patients [35].

Medical history should include any past-history of coagulation disorders, allergic conditions, medications used, radiation to the neck or chest, and prior surgery in the neck, mediastinum, or thorax. The patient should be examined systematically to detect any neurological deficits, cervical/supraclavicular lymphadenopathy, cervical/thoracal spine anomalies, and chest wall deformities, including sternum.

Preoperative work-up consists of routine baseline tests (complete blood count, chemistry, and coagulation studies), ECG, and other studies, as indicated. Further laboratory studies, such as thyroid function tests, tumor markers (alpha fetoprotein and beta-hCG), or myasthenia gravis antibodies (anti-AChR, anti-MuSK), can also be obtained if necessary. Pulmonary function tests help stratifying risk for pulmonary complications and serve as a baseline for postoperative comparison in patients with a coexisting lung disease. Simple or sophisticated radiological imaging methods such as chest x-ray, ultrasound, CT, MRI, and PET-CT are helpful to establish diagnosis or differential diagnosis [35].

First-generation cephalosporins are used for prophylaxis unless there is a known immunological disorder or susceptibility to infection. Aminoglycosides are contraindicated in patients with MG because they increase neuromuscular blockade.

4. Thymectomy techniques

Although the term thymectomy simply defines the surgical removal/excision of the thymus gland, detailed literature review reveals that there are different definitions and practices in terms of access routes used and the extend/limits of the excision [34, 36]. In this context, there are three basic access methods for thymectomy (Table 2): (I) transsternal, (II) transcervical, (III) thoracoscopic (VATS). Each of these can be used individually or in different combinations. On the other hand, when the prevalence and limits of the excision procedures are considered, defining thymectomy becomes more complicated. It may be informative to summarize these procedures in three groups [3]: (I) Simple/Standard thymectomy, (II) Extended thymectomy, (III) Radical/Maximal thymectomy.

Surgical techniques for thymic disorders
Thymectomy Techniques	Transcervical Thymectomy
	Simple
	Extended
	Thoracoscopic Thymectomy
	Conventional
	Video Assisted Extended Thymectomy
	Transsternal Thymectomy
	Simple
	Extended
	Combined (Transcervical + Transsternal) Thymectomy (Radical Thymectomy)
Surgical Techniques Other Than Thymectomy	Excision of Ectopic Thymic Cyst
	Transcervical (for cervical ectopic cysts)
	Transsternal/Thoracoscopic (for mediastinal ectopic cyts)
	Excision of Ectopic Thymic Tissue
	Thyroidectomy/Thyroid Lobectomy (for intrathyroidal location)
	Transcervical/Transsternal/Thoracoscopic (for extrathyroidal location)

Table 2.

Classification of surgical techniques for the treatment of thymic disorders (modified from Crabbe and Parikh [3]).

Simple thymectomy involves complete removal of both lobes of the gland using a single access method. In both extended transcervical thymectomy and extended transsternal thymectomy, excision margins progress toward potential locations where ectopic tissues outside both lobes may be found. Radical thymectomy is performed with the combined use of cervical incision and sternotomy. It describes the removal of all thymic tissues along with the pericardial fat pad in the region from the inferior thyroid gland to the diaphragm, including areas where ectopic thymic tissues may be present. The dissection is extended laterally toward the phrenic nerves and utmost care is taken to preserve it.

Besides the commonly used techniques of thymectomy, some rare surgical procedures have also been reported to treat thymic diseases. Pure mediastinoscopic thymectomy, subxiphoid thymectomy, and partial thymectomy can be mentioned among these ones, but will not be discussed here [37].

4.1 Transsternal approach

Median sternotomy provides excellent visibility for thymectomy (Figures 2 and 3). It is an approach especially suitable for large thymus and thymomas. Although there is a risk of complications related to the sternal bone, pleural injury is rarely encountered. It has also been reported that a simple thymectomy can be performed with a partial sternotomy that includes only the manubrium. Care should be taken to protect the phrenic and recurrent nerves on both sides, as well as the main vascular structures [3].

• The skin incision should be cosmetically located in the exact midline. The length of the incision is about half or two third of the length of the sternum.

• Before sternotomy, skin flaps are mobilized circumferentially. The mobility of the skin flaps allows easy access to the suprasternal notch and the manubrium with the appropriate retraction.

• The sternum is generally divided from top to bottom using a pneumatic or electrical sternal saw. Once the sternum is split, periosteal bleeding points from two edges are controlled with cautery, and bone wax is applied to seal the bone marrow.

• Then the sternal retractor is inserted, gradually opened, and sterno-pericardial ligaments are separated.

• The thymic dissection is begun by caudal and lateral aspects of the gland following visible plans between pericardium and thymus. The dissection is carried out cephalad along the pericardium toward the brachiocephalic vein. It encompasses mediastinal fat from the retrosternal space to the phrenic nerve. If there is pleural or pulmonary involvement, the mass is resected en bloc.

• The horizontal extent of dissection is widened from one phrenic nerve to other phrenic nerve. Exploration of aorto-pulmonary window is a critical step of procedure, especially in patients with thymoma.

• Care should be taken to avoid mechanical or electrocautery injury to the phrenic nerve.

• The thymic vein(s) are usually found at the lower border of the brachiocephalic vein, near the midline, and are cut after clip or suture ligation.

• Arterial blood supply from the internal thoracic artery or inferior thyroid artery may be encountered and these branches should be ligated/clipped and divided.

• Than the gland totally excised with or without surrounding mediastinal fat tissue [6].

• Before sternal closure, a drain is placed in the anterior mediastinum.

• If pleural space is entered as part of the en bloc resection, a separate chest tube is inserted.

• The sternum is closed using sternal wires.

• If necessary, a superficial drain can be placed under skin flaps before closing skin with subcuticular stitches.

Figure 2.

Transsternal approach to a case of thymoma associated with MG. Appearance of anterior surface of the thymus after median sternotomy (A), and dissection of posterior surface of the gland from pericardium and left innominate vein in another case (B) (from the author’s own archive; *left innominate vein anterior to the thymus).

Figure 3.

Transsternal approach to a case of thymoma associated with MG. Appearance of anterior mediastinum after extended thymectomy (A) and thymectomy material (B) (from the author’s own archive, *right innominate vein, **left innominate vein).

Indications: All thymic masses predicted to be resectable, regardless of their sizes and invasiveness (thymic hyperplasia, MG, thymoma, etc.).

Contraindications: Sternal anomalies and acute or chronic infections of breastbone. Inability to tolerate general anesthesia, hemodynamic instability, severe coagulopathy. Repeated sternotomies also pose a relative contraindication.

Advantages: Median sternotomy provides excellent visibility for thymectomy, allowing safe resection of huge thymic mases and invasive thymomas.

Disadvantages: Large scar tissue, more postoperative pain, prolonged drainage, and long hospital stay.

4.2 Transcervical approach

Although transcervical approach has a nice cosmetic appearance, rapid healing and is a good way to reach the upper-anterior mediastinum, it requires a high level of technical experience. It is more suitable for cases that are relatively small and do not show inferior growth/location [3]. When performing colon interposition for esophageal replacement, this approach can be used to make a space for the colon segment at the thoracic outlet and to eliminate external compression/obstruction during and after the cervical anastomosis [38]. We used this technique in three patients who underwent esophageal replacement due to isolated esophageal atresia (n = 2) and caustic esophageal stricture (n = 1).

• Appropriate position (hyperextension), field illumination (headlamp), and the presence of automatic retractors increase the success of the technique.

• A transverse, curved incision along the Langer lines is made just above the suprasternal notch. To reach the back of the manubrium, subplastimal plane is entered, upper and lower skin flaps are prepared, and the strep muscles are divided in the midline. If necessary, the sternal heads of both sternocleiodomastoid muscles can be partially transsected to provide a better exposure.

• Then, the upper border of thymus is identified, and the gland is dissected from top to bottom, close to thymus capsule.

• Special devices to provide better mediastinal exposure such as Cooper and Parker retractors

• Surrounding tissues, nerves, and vascularities are carefully separated from the gland. The dissection is deepened by gently pulling the gland upward. Thymectomy is completed after the thymic vessels are tied and divided.

• The incision is closed with subcuticular sutures, with or without a drain being placed in the wound.

Indications: Normal thymus or mild/moderate thymic hyperplasia by CT scan, early or small thymomas in which the masses are completely contain within the thymus, selected cases of retrosternal esophageal replacement to provide adequate mediastinal space.

Contraindications: Giant thymus or thymic hyperplasia and large/invasive thymomas. Inability to tolerate general anesthesia, hemodynamic instability, and severe coagulopathy. Relative contraindications are previous median sternotomy, thyroidectomy, and cervical spine surgery/trauma which may create added risk for extreme hyperextension of the neck.

Advantages: Better cosmetic appearance (less scar) than transsternal approach, no cutting of the sternum, minimal local pain without intercostal neuralgia, and rapid and better wound healing.

Disadvantages: Limited exposure of anterior mediastinum, difficulty to secure the surgical field even if the surgeon is familiar with the procedure, and necessity of a high level of technical experience. This technique is challenging when performed for removal of large tumors or for combined resection of adjacent organs. A relative disadvantage is that some patients do not like such an incision, which cannot be hidden by clothing.

4.3 Endoscopic approaches

Endoscopic or minimal invasive thymectomy can be carried out via the traditional thoracoscopic approach or, more recently, the robotic approach.

4.3.1 Thoracoscopic approach (VATS thymectomy)

It is an approach that has been used since the 1990s, first in adults and then in children (Figures 4 and 5). Its effectiveness is comparable to the transsternal approach and is more advantageous in terms of morbidity, which can be summarized as short hospital stay, less blood loss, good cosmetic appearance, and decreased need for analgesics. With appropriate patient selection, the risk of major vessel injuries and conversion to open surgery is low [15, 36].

Figure 4.

Thoracoscopic approach to a case of MG unresponsive to maximal medical treatment. Opening of anterior mediastinal window (A), and exploration and initial dissection of left lobe of thymus (B) (from the author’s own archive).

Figure 5.

Post-thoracoscopic appearance of port sites (A) and thymectomy material with a mass in the left lobe after thoracoscopic excision (B) (from the author’s own archive).

As an alternative to conventional left-sided thoracoscopic approach, thymectomy with subxiphoid access, whether single port or not, or a right-sided approach in cases where the thymic lesion was almost totally located on the right side has been reported [37].

Single lung ventilation with or without using a double lumen endotracheal tube may assist in good exposure to the thymus. Although VATS thymectomy can be applied from either side, the right-side approach is more popular in adults and vice versa in children. Venous connections with the inferior vena cava and brachiocephalic trunks can be better defined in right-side approach. The left side approach is more suitable to reach the fat tissue in the aorta-pulmonary window. If there is a significant hypertrophy or a large mass in one lobe, the ipsilateral approach should be preferred. However, if the opposite side cannot be safely explored and dissected from the ipsilateral side, a simultaneous bilateral approach can be applied. It is also possible to perform extended thymectomy from both sides with VATS and, if necessary, by adding a cervical approach.

We performed five thoracoscopic thymectomies in the last 15 years in which three of them suffered from intractable non-thymomatous MG, whereas two patients had thymoma associated with MG. The patients’ ages ranged between 11 and 16. There was no intra- or post-operative complication except contralateral pneumothorax in one patient. Thymectomy completely (n = 2) or remarkably (n = 2) resolved neurological symptoms in four but the last patient with thymoma associated with MG showed no improvement.

• As for the technical details of the procedure, the patient is positioned at 30–45° from horizontal plane with the ipsilateral right arm raised above the head [8, 34].

• In simple VATS thymectomy, three ports are generally used, one of which is for the camera.

• CO₂ insufflation is set to a pressure of 6–8 mmHg [8, 39].

• After opening an anterior mediastinal window via incision of parietal pleura, starting the procedure from lateral border of the thymus provides a better and safer dissection.

• The dissection is carried from inferior to superior, elevating the gland and ultimately exposing the vasculature. Maximal care must be taken to protect the phrenic nerve during the lateral dissection.

• The thymic branches of the internal thoracic artery originate cephalic and lateral to the gland, while the thymic vein branches drain posteriorly to the innominate vein. Blood vessels should be isolated and divided between clips or cauterized with an energy device.

• Next, the thymus is bluntly dissected from its contralateral pleural attachments taking care to avoid injury to the contralateral phrenic nerve.

• Once the entire gland has been dissected free, the thymus is inserted into a specimen bag to remove it free of seeding.

• In cases where the procedure proceeds smoothly, the routine use of a drain or chest tube may not be necessary [8].

• In order to better control postoperative analgesia, an intercostal nerve block is applied after the surgery is completed.

• Extubation is generally uneventful and the patient is then taken to the recovery room for observation. Patients are usually discharged home 48–72 h after the surgery.

Indications: Thymic hyperplasia, thymic cysts, non-thymomatous MG, and non-invasive thymoma.

Contraindications: Invasion of large vessels, in particular, contraindicates for minimally invasive thymectomy and requires an open procedure. Additionally, if the patient is thought to be unable to tolerate one-lung ventilation, resection via sternotomy or transcervical approach is indicated [3].

Advantages: Nice cosmetic appearance (less scar), rapid healing, faster improvement of lung function, reduction of surgical trauma, short hospitalization, decreased postoperative pain, and no complications originated from breastbone.

Disadvantages: Limited surgical manipulation, transient intercostal neuralgia, and limited exposure of contralateral side during unilateral thoracoscopy.

4.3.2 Robotic thymectomy

The first robotic thymectomy was reported by Yoshino et al. for a small thymoma in 2001and followed by Rea et al. and Ashton et al., both described the first case series of robotic thymectomy for MG in 2003 (Figure 6) [40, 41, 42]. To date, many case series and several meta-analyses were published, mostly addressing the treatment of adult thymic disorders. In their meta-analysis, Xu et al. suggested that robotic video-assisted thoracoscopic surgery can be performed on both sides; however, left-side approach had significantly lower complications, regarding atrial fibrillation, open conversion, and air leaks [43]. Another meta-analysis found robotic thymectomy to be advantageous over conventional thoracoscopic VATS in terms of short-term outcomes such as shorter duration of drainage, less total drainage, and a lower rate of conversion [44]. The recurrence rate was comparable between the two techniques. In recent years, case series of children who underwent thymectomy with robotic VATS have also been published [3, 19].

• Patient position and port entry sites are similar to thoracoscopic procedure. Alternatively, robot-assisted thymectomy with subxiphoid access or a right-sided approach in cases where the thymic lesion was almost totally located on the right side can be used.

• In left-sided robotic thymectomy technique, which is a most common approach, a camera port for the 3-D camera (12 mm) is introduced and followed by other two or three working ports are positioned on the midaxillary or anterior axillary lines under its guidance. Forth trocar may be also used as an optional table-site assistant port. The arms of the robotic system are then connected to the ports [45].

• Whether left or right-side approach is used, following exploration of the anterior mediastinum and chest cavity, the dissection begins at a safe window between sternum and phrenic nerve or the level of cardiophrenic angle and moves upwards. The procedure then follows the basic principles of thoracoscopic thymectomy.

• Briefly, thymus and/or, if necessary, the entire mediastinal tissue is fully isolated from the anterior border of the phrenic nerve, pericardium, mammarian, and innominate vessels with great care.

• The connecting vessels or thymic veins/arteries are identified, coagulated/clipped, and divided.

• After removal of the specimen and hemostasis, a chest tube is usually placed (the anterior port site is preferred), the lung is fully inflated, and the other incisions are closed.

• Intercostal nerve block is applied to better control postoperative analgesia after the surgery is completed.

Figure 6.

General perspective of console, operating table, and robotic arms in robotic thymectomy. Sites of ports and robotic arms in left-sided robotic thymectomy (A). Sites of ports and robotic arms in subxiphoid approach for robotic thymectomy (B).

Indications: Similar to thoracoscopic thymectomy.

Contraindications: Similar to thoracoscopic thymectomy.

Advantages: Compared with traditional open approach surgery, robotic thymectomy has better cosmetic effect, faster improvement of lung function, reduction of surgical trauma and length of stay, and no complications originated from breastbone.

Disadvantages: Long set-up procedure, high cost (expensive equipment), and limited number of robotic centers.

5. Postoperative care and follow-up

Early postoperative care should be continued in collaboration with anesthesiologist, intensivist, and pediatricians. Extubation is generally uneventful, and the patient is then taken to the recovery room for observation. To evaluate lung expansion, chest tube position, and diaphragm, a postoperative chest x-ray should be taken in the recovery unit. Patients who undergo thoracoscopic/robotic thymectomy are usually discharged home 48–72 h after the surgery. Hospitalization is longer in the transsternal approach (5 to 7 days).

For transsternal thymectomy, sternal precautions such as avoiding heavy lifting and excessive shoulder movement should be maintained for at least 6 months [35]. Pain can be controlled with analgesic infusion or patient-controlled anesthesia and switched to oral medications once the patient tolerates the diet. After less invasive approaches, the need for analgesics is significantly reduced. Chest tubes are removed when the drainage is low, contents are not hemorrhagic, and air leakage has stopped, usually on 1st or 2nd postoperative day following minimally invasive surgery [35].

In patients with MG, the patient’s respiratory condition and ventilatory support require great attention in the early postoperative period. Respiratory complications can be minimized with careful preoperative preparation. As long as they are hospitalized, all MG and thymoma patients should be followed dynamically by a multidisciplinary team, including pediatric neurologists/oncologists as well as pediatric surgeons.

After discharge from the hospital, close follow-up should be continued in a multidisciplinary manner within the framework of a standardized protocol (Table 3).

Routine follow-up protocol*
Follow-Up	Benign Conditions		Malign Conditions
	Thymic hyperplasia (not associated with MG), thymic cyst, thymolipoma, ectopic thymic tissue, etc.	Thymic hyperplasia associated with MG, non-thymomatous MG	Thymoma and other epithelial tumors
First month	Chest x ray; Outpatient exam. in pediatric surgery	Chest CT; Outpatient exam. in pediatric neurology; Outpatient exam. in pediatric surgery	Chest CT; Outpatient exam. in pediatric surgery; Outpatient exam. in pediatric neurology; Outpatient exam. in pediatric oncology
Sixth month	Chest x ray; Outpatient exam. in pediatric surgery	Outpatient exam. in pediatric neurology; Outpatient exam. in pediatric surgery	Chest CT; Outpatient exam. in pediatric surgery; Outpatient exam. in pediatric neurology; Outpatient exam. in pediatric oncology
First year	Chest CT; Outpatient exam. in pediatric surgery	Chest CT; Outpatient exam. in pediatric neurology; Outpatient exam. in pediatric surgery	Chest CT; Outpatient exam. in pediatric surgery; Outpatient exam. in pediatric neurology; pediatric oncology
Second year	Chest x ray; Outpatient exam. in pediatric surgery	Outpatient exam. in pediatric neurology; Outpatient exam. in pediatric surgery	Chest CT; Outpatient exam. in pediatric surgery; Outpatient exam. in pediatric neurology; Outpatient exam. in pediatric oncology
Third year	No routine follow-up; Check-up when there is a clinical complaint	Outpatient exam. in pediatric neurology; Outpatient exam. in pediatric surgery	Chest CT; Outpatient exam. in pediatric neurology; Outpatient exam. in pediatric oncology
Fourth year	No routine follow-up; Check-up when there is a clinical complaint	Outpatient exam. in pediatric neurology; Outpatient exam. in pediatric surgery	Chest CT; Outpatient exam. in pediatric neurology; Outpatient exam. in pediatric oncology
Fifth year	No routine follow-up; Check-up when there is a clinical complaint	Outpatient exam. in pediatric neurology; Outpatient exam. in pediatric surgery	Chest CT; Outpatient exam. in pediatric neurology; Outpatient exam. in pediatric oncology
After fifth year	No routine follow-up; Check-up when there is a clinical complaint	Outpatient exam. in pediatric neurology; Outpatient exam. in pediatric surgery	Lifelong monitoring; Outpatient exam. in pediatric neurology; Outpatient exam. in pediatric oncology

Table 3.

Follow-up protocol of pediatric patients who underwent thymectomy.

*

Our institutional follow-up protocol (Akdeniz University School of Medicine, Department of Pediatric Surgery).

6. Immunological changes and prognosis after thymectomy

After 1 year of age, T cell production in the thymus begins to decrease rapidly and reaches a minimal level, similar to that in healthy adults. After neonatal thymectomy, CD4+ and CD8+ T lymphocyte rates and numbers decrease significantly compared to those who underwent thymectomy at later ages [12]. This situation, in which there is a change in T cell composition at a very early period similar to that in adults, is defined as “premature immunosenescence”. However, there is not enough data to show that this has a negative impact on the health of the infant. Broek et al. suggest that 5–10 years after neonatal thymectomy, redevelopment of thymic components with adaptive mechanisms in the peripheral lymphoid tissue and an increase in T cell numbers indicate that the thymic tissue has regenerative capacity [5]. In a systematic review, it has been reported that early thymectomy, either partial or complete, may be associated with a reduction in many T cell subpopulations and TCR diversity, and these alterations may persist during long-term follow-up [13]. Alternative solutions should be studied, either in the operative technique with partial preservation of the thymus or through the autograft of fragments of the gland [12].

Despite these opposing views which are suggestive for laboratory based immunological impacts, according to our current knowledge, thymectomy has not been found to have a significant effect on susceptibility to infection, response to childhood vaccines, and the presence of organ-specific autoantibodies [19].

Mortality after thymectomy in children is negligible, and morbidity is minimal. It is difficult to determine the long-term effects of thymectomy in adults and even more difficult in children. This is due to heterogeneity in patient groups, differences in indications, and non-standardization of surgical treatment methods. Although there are pediatric cases in large series, there are no large case series consisting entirely of children. The long-term effects of thymectomy in patients with MG are also variable. Most cases begin to improve within 1 year, and some of them go into permanent remission but the remaining part of thymectomized patients still needs maximal medical care [21]. Christison-Lagay et al. reported that, as a result of long-term follow-up (average time: 38.5 months), the rate of improvement in symptoms was 75%, and the rate of asymptomatic patients was 47% in their juvenile MG series of 15 cases [46]. Tracy et al. found that thymectomy is an effective treatment in 62% of children with MG, and remission is complete in 31% [47]. In a large series with an average follow-up period of nearly 10 years, 34 thymectomized patients were examined, and it was suggested that thymectomy made a significant contribution to relieving generalized symptoms [22].

7. Conclusion

Aside from the fact that surgical diseases of the thymus such as intractable thymic hyperplasia, generalized myasthenia gravis, symptomatic ectopic thymic cysts/tissues, and thymoma are rare in childhood, the indication, timing, and technique of thymectomy are also controversial in a remarkable part of them. In this respect, it is important to evaluate such cases with a multidisciplinary approach, and the surgeon must be experienced in both open and thoracoscopic thymectomy techniques.

Thoracoscopic thymectomy is recommended in patients with thymic hyperplasia and MG resistant to conservative approach or in early stage thymoma. Excision is the first option in symptomatic ectopic thymic cysts/tissues, and transsternal extended/maximal thymectomy is the first option in cases of the advanced stage thymoma. Incidental thymectomy is a routine procedure in most of open-heart surgery for congenital heart diseases.

Postoperative morbidity is significantly lower in thoracoscopic thymectomy then in open thymectomy techniques. Mortality due to thymectomy is very low and comparable between thoracoscopic and open techniques.

Conflict of interest

The authors declare no conflict of interest.