Video-assisted thoracoscopic thymectomy for myasthenia gravis: where we are

Introduction

German surgeon Sauerbruch performed the first thymectomy more than 100 years ago. In 1903, in Breslau, a low-pressure chamber for operating on the open thorax was developed by Sauerbruch. In this way, he introduced advances in thoracic surgery. He developed the transcervical approach for thymectomy in 1911, in Zurich, Switzerland (1). Although the first thymectomy was performed by Sauerbruch, Alfred Blalock described the anatomical basis for the surgical technique 20 years later. In 1936, Blalock performed a transsternal complete thymectomy on a patient for a thymoma associated with severe MG. The patient’s MG markedly improved for several years. After this successful case, Blalock and his associates reported treating patients with MG by thymectomy (2). In 1939, he demonstrated a positive clinical response in patients with MG after thymectomy, with or without thymoma. By 1954, Keynes had completed and presented more than 200 thymectomies for MG (3).

Keynes was the first to show that MG responds poorly to surgery for thymoma, although the tumour needs to be removed (3). This finding created some confusion and controversy. He described that MG responded better in younger patients when a thymoma was present. From then on, MG was routinely treated by thymectomy.

It was believed that many patients showed some improvement 6 to 12 months after surgery. In Europe, MG specialists began to report that MG was remitted in 25% of patients, improved in another 50% and unchanged in 25%. The exact mechanism was not completely understood, but it was thought that pathogenetic events in the hyperplastic thymus were interrupted.

Myasthenia gravis (MG): a brief overview of the disease

MG is an autoimmune disease. It affects the neuromuscular junctions (NMJs) of skeletal muscles, causing muscle weakness and a tendency towards easy fatigability. In most patients (85%), autoantibodies directed against acetylcholine receptors (AChRs) are the cause of the disease (4). Patients with AChR-MG experience delay or blockage of normal signalling by way of complement activation, by causing receptor antigenic modulation or by directly blocking receptor function (5).

It has been demonstrated that in 6% of MG patients, autoantibodies target the muscle-specific kinase (MuSK) protein (MuSK-MG) (6). The rest of MG patients are double-seronegative (dSN-MG), because a detectable level of AChR or MuSK antibodies is absent. In dSN-MG, some patients have low-affinity antibodies against AChR (7).

It has been recently shown that some dSN-MG patients have autoantibodies against low-density lipoprotein receptor-related protein 4 (LRP4), which is a novel autoantigen in MG (8-10). In thymectomy-studied populations, measured level of these autoantigens is not seen. Even if these autoantigens are present, due to various factors (differences in antigens, assays used, ethnic origins of the patient and the prescribed medicine prior to thymectomy such as immunosuppressants and corticosteroids), the proportion of LRP4-MG, AChR-MG and MuSK-MG will vary greatly. Clinical data for patient outcomes may be strongly related to the presence of these autoantibodies, and yet the levels present may not be known at the time of the thymectomy. Especially for LRP4-MG, incidence of this novel MG subgroup and thymectomy has rarely been reported (11).

In the NMJ, there is a synapse between the nerve terminal and muscle that is responsible for carrying the nerve signals into muscle contractions. To have the best signal transmission, the AChRs must function properly. AChRs are responsible for depolarisation in response to nerve stimulation, and they are clustered within the NMJ (12). Clustering of AChRs is mediated by muscle membrane proteins, MuSK proteins and LRP4. For a long time, MuSK has been known to play a key role in all aspects of postsynaptic differentiation. LRP4 is one of the membrane proteins with an effect on neuronal and synaptic development. Specifically, LRP4 is necessary for the development of NMJ (13).

MG is not a homogenous disease. Patients with AChR-MG show more thymic pathological findings than patients with MuSK-MG, and differences in the pattern of affected muscles can also be seen in these patients. Furthermore, the response to therapy may vary. For instance, patients with MuSK-MG may demonstrate hypersensitivity when treated with the acetylcholinesterase inhibitor pyridostigmine, whereas they receive great therapeutic benefit from plasma exchange. These MG patients are not good surgical candidates. It is imperative to differentiate the MG subgroups and the unique characteristics of each. This approach may help in both diagnosis and management, especially when thymectomy is the choice of treatment.

Onset and etiology of MG

Ocular MG is diagnosed in patients with ocular symptoms lasting for at least 2 years. Approximately 15% of all AChR-MG patients have this type of disease. It has long been proposed that patients with ocular MG are not good candidates for thymectomy. However, several articles have recently proposed that thymectomy is a viable option in the treatment of ocular MG (14). In the generalised form, MG disease can be divided into three groups according to the age of onset, and thymectomy has been the most important treatment modality. In the early-onset form (EOMG), the age of onset is before 50 years. Most patients with EOMG have high levels of anti-AChR antibodies. They also have thymic follicular hyperplasia (15). It is suspected that sex hormones may play a role in this form of the disease, as more than 80% of patients with follicular hyperplasia are women (16). These patients may also have other autoantibodies and have the potential to develop other autoimmune diseases, such as thyroiditis (17). In the late-onset form (LOMG), the age of onset is more than 50 years. This group more commonly has thymoma. In patients with LOMG, autoantibodies against striated muscle proteins (ryanodine or titin) may be more common (18). The role these proteins play in recurrences of thymoma is not clear.

LOMG is mostly generalised and severe, with bulbar signs and frequent severe respiratory crises (19). In the very-late-onset form, the age of onset is after 60 years. In the last few decades, MG appearing after age 60 years has been described. Very-late-onset MG predominantly affects males, and it is different than LOMG, because patients do not present with thymoma (20). In a study analysing the 20-year period between 1987 and 2007, it has been demonstrated that the number of patients older than 50 years without thymoma has tripled (21).

During this 20-year period, the incidence of EOMG has not increased in parallel. The increased incidence of very-late-onset MG may be attributed to increased longevity. As autoimmunity increases with age, elderly individuals are more likely to develop an autoimmune disorder such as MG. Although patients with late-onset and very-late-onset MG are routinely thought to be unsuitable candidates for thymectomy, increased longevity may change this perception. These patients may become thymectomy candidates if research studies demonstrate the benefits. Long-term data for these patients are needed.

A single-centre, non-randomised, non-controlled study compared the long-term post-thymectomy results in patients with anti-AChR-positive, anti-AChR-negative and anti-MuSK-positive non-thymomatous MG (22).

Long-term post-thymectomy results were better in patients with anti-AChR antibodies than in those with seronegative disease (22). In seronegative anti-MuSK-positive MG, thymectomy seems to be less effective than in anti-MuSK-negative MG. The role of the thymus in the production of MuSK antibody is not clear, and there is increasing evidence suggesting that thymectomy may not be beneficial in patients with anti-MuSK MG (22).

Different pathogenic mechanisms have been proposed on the basis of the antibody target. Identification of these antibodies created a new classification, which was determined by the type of antibodies. Certainly, these antibodies have implications for the diagnosis, management and prognosis of MG. In EOMG, which is associated with AChR antibodies, it is known that the disease involves the thymus. This may explain why thymectomy is beneficial in the clinical trial reported by Wolfes (23).

With recent developments in patient selection for thymectomy, surgery may be performed in patients who have better potential for positive outcomes. If this occurs, it may be generalised to different subtypes of the disease. Currently, thymectomy is usually recommended for a limited group of patients with AChR antibodies. Remaining patients may benefit from targeted therapies such as rituximab, which has been shown to be effective in the treatment of anti-MuSK-positive patients (24).

It is thought that women have better outcomes after thymectomy. Two articles questioning this belief found no difference in outcome based on gender (25,26). Ironically, the presence of antibody may affect the outcome in patients with anti-MuSK, which is more common in women (27). Some patients with thymoma with MG may not respond very well after surgery, and dismal outcomes may be explained by autoantibodies. Paraneoplasia-associated antibodies may be present in thymomatous MG, which includes anti-voltage-gated K⁺ and Ca²⁺ channel, anti-Hu (antineuronal nuclear autoantibody 1), anti-dihydropyrimidinase-related protein 5 and anti-glutamic acid decarboxylase antibodies (28). Autoantibodies to a voltage-gated K⁺ channel, KCNA4, were demonstrated in Japanese patients with MG with thymoma, along with associated myocarditis and/or myositis (29). In patients with thymoma, even if thymothymectomy completely and permanently removes the tumour tissue, symptoms of MG usually persist and treatment generally requires chronic immunotherapy (4).

What is new in the effects of thymectomy?

The possible effects of thymectomy and the selection of surgical technique are still debatable issues. In patients with thymic follicular hyperplasia, it has been claimed that thymectomy can be very helpful in changing the course of MG, potentially leading to decreased severity or remission in a significant number of patients (30). It has been consistently reported, and became a well-known reality, that the best outcome may be obtained when the patient has severe thymic hyperplasia and when thymectomy is performed soon after the onset of symptoms (31,32). Thymectomy has the potential to eliminate the main production site of anti-AChR autoantibodies. In this way, thymectomy may result in a decreased level of anti-AChR antibodies, perhaps correlating with the number of B cells available in the thymus of the patient (33). This finding may explain why thymectomy has a better outcome when the patient has severe follicular hyperplasia. However, it has not been shown that the antibody levels are consistently decreased after thymectomy. The long-living plasma cells generated in the thymus that migrate to the periphery may be a reason for this (34).

The possible benefits of thymectomy when compared with other medical therapies have been in the centre of the debate, and an international randomised clinical trial to address this debate was strongly encouraged by surgeons and neurologists (35). Enrolment was completed in 2012, and the results were presented in 2016 with a 3-year follow-up period. Before the presentation of the paper, it was thought that improvement after thymectomy was related to the elimination of thymic B cells, and it was claimed that other therapies had the potential to produce similar effects. For example, corticosteroids may cause a significant decrease in the size and number of germinal centres in the thymus (36).

Recently, the results of the Thymectomy Trial in Non-Thymomatous MG Patients Receiving Prednisone Therapy (MGTX) were presented (23). An extended transsternal thymectomy was the selected procedure, because the authors wanted to standardise the procedure for reproducibility and safety. This decision also prevented further discussion about the differences in surgical techniques. The surgery was combined with a standardised prednisone protocol, and the aim of the study was to evaluate if surgery was better than prednisone therapy alone after 3 years. The goal of treatment was to decrease the myasthenic weakness and the dose of prednisone while increasing quality of life.

This study was a randomised, medication-controlled, rater-blinded trial. It demonstrated benefits of thymectomy in MG patients over a period of 3 years. The surgical arm was superior with respect to clinical outcomes, prednisone and azathioprine use, symptoms and distress due to immunosuppressive agents and the need for hospitalisation for exacerbations. It is clear that this study reinforced the essential place of thymectomy in the treatment of MG (23).

Current situation

The gold standard technique for thymectomy has been described as the transsternal approach. The main advantages of this approach are optimal exposure, complete dissection of the thymus and mediastinal fatty tissue and reproducibility (37). With research claiming zero risk of incomplete thymectomy, a complete recovery from MG may be possible if the cellular (antibody production) and hormonal events occurring in and around the thymus are excluded (37). The risks of major vascular and phrenic nerve injuries should be very low (37). A partial or total sternal splitting technique has several disadvantages, including the splitting of the sternum, longer duration of surgery and longer postoperative hospitalisation. For these reasons, transsternal resections for non-thymomatous thymus have almost been abolished in major thoracic surgery centres and replaced by minimally invasive procedures (23).

Another approach that is rarely used is the transcervical thymectomy. It is popular with younger female patients and neurologists because of some advantages such as short hospitalisation, almost no pain and fewer complications (38). However, the main criticism includes possible incomplete resection of thymus or perithymic fatty tissue because of the crowding of instruments. Although long-term results are comparable with open techniques, most surgeons do not find this technique reproducible.

Video-assisted thoracoscopic surgery (VATS) thymectomy gained popularity after 2000s. It could be performed through a left- or right-sided approach or even subxiphoidal or bilateral approaches. VATS thymectomy has been shown to be an acceptable surgical technique. Meta-analyses and many articles demonstrate that the operation time and intraoperative bleeding is lower in VATS, as well as duration of postoperative ventilation and shorter mean length of stay in hospital when compared with transternal techniques (39,40). Recently, more support for VATS thymectomy was provided by several authors claiming that extended, or even maximal, thymectomies could be performed with VATS (41,42).

The extent of thymectomy remains a controversial topic. Although the presence of extracapsular thymic tissue is frequent and well described, the accessibility of these ectopic thymic foci is not clear. Also, their function and impact on outcome are not adequately described (43). Ectopic thymic foci are thought to be found more frequently in patients with an atrophic thymus. Their presence may result in a poor outcome, even after maximal thymectomy with resection of all potential sites of ectopic thymic foci in the neck and mediastinum (44,45). Because ectopic thymic foci are usually isolated to one or two sites and are most frequently found in the anterior mediastinal fat, an extended thymectomy involving the fat located between the pericardium, both pleura and the diaphragm can be safely accessible with minimally invasive surgery in the hands of experienced surgeons. It is recommended that these tissues be routinely resected regardless of the type of surgical approach. Extending the surgery to resect tissues in the pericardiophrenic angles, aorto-pulmonary window, aorto-caval groove and along the thyroid gland may cause a risk of phrenic or recurrent nerve injury; thus, some authors claim that there is limited evidence to recommend that it be routinely done (43-45). A randomised clinical trial would be needed to answer this question. Interestingly, positron emission tomography (PET) has shown a correlation between parathymic standardised uptake value and the presence of ectopic thymic tissue, but again, future research is needed to determine the clinical utility of PET/computed tomography in patients with MG.

In short, any resection has to include both mediastinal pleuras, a sharp dissection on the pericardium, complete removal of the horns without cutting or coagulating and excision of pericardiophrenic fatty tissues. All thoracic surgeons have to accept the need for a major shift from open surgery to video-assisted surgery and robotic-assisted surgery in non-thymomatous MG. Minimally invasive surgery can be done through a combination of cervicotomy, a transcervical-subxyphoid approach or unilateral or bilateral video-assisted or robotic-assisted thoracic surgery (RATS). The benefits of a minimally invasive approach have clearly demonstrated that it would be unwise to have a randomised trial comparing open and minimally invasive surgery (46-50).

What is our standard approach for thymectomy?

In our armamentarium, the approaches used for thymectomy for patients with MG are variable. VATS or robotic-assisted thymectomy is preferred, generally from the right side, even when a thymoma is located on the left side. The thymoma can be pulled to the right side after the dissection of the right thymus, or a two-incision exploration can be performed from the left side (51).

The patient is positioned in a 30° semi-supine position, supported with a roll placed under the right shoulder and the right arm abducted over a support attached to the table if the operation is a VATS thymectomy (51). In this technique, three ports are opened around the mammary gland without violating the mammalian tissue. The first port is always the camera port, and the other ports are opened with the help of a camera. The left port is opened in the anterior axillary fossa, lateral to the pectoralis major muscle. The right port is opened in the 5th–6th intercostal space lateral to the midclavicular line [Figure 1 (51)]. For robotic surgery, the arm is placed inferiorly on the ipsilateral side. Again, three ports are selected without an assistant port.

Our institution has extensive experience with VATS thymectomy. Our knowledge has been replicated and transferred to our experience with robotic surgery. In robotic surgery, an access incision is not opened, using only three ports for a completely robotic thymectomy. With our developing experience, it has been recognised that the left arm of the robot can be placed more anteriorly when compared with the VATS technique. Also, CO₂ with a pressure of 7–8 mmHg is routinely used during robotic surgery but not during VATS. A 30° up camera angle is used in the beginning, with a 0° camera angle during the dissection from pericardium and innominate vein, and 30° down camera angle when dissecting the left phrenic nerve side of the thymus. A single camera at a 30° angle is used in VATS. A Jackson-Pratt drainage system is used in both techniques after the operation.

Mineo et al. studied patients with left-sided thymectomy and preferred using four flexible trocars (52). Pardolesi et al. preferred RATS with a left-sided approach (53). Three incisions are used at the fifth intercostal space at the anterior axillary line, at the anterior axillary line in the third intercostal space and at the fifth intercostals space at the midclavicular line (53).

Literature findings

Two studies have compared clinical experience with a right-sided versus a left-sided VATS thymectomy approach in patients with non-thymomatous MG. These studies demonstrated no difference regarding surgical time, intraoperative blood loss, postoperative hospital stay and postoperative complications. Both approaches are feasible, effective and comparable in operative and long-term results for the treatment of non-thymomatous MG (54).

Another study compared a single-port approach from below the xiphoid process and conventional VATS thymectomy. This study demonstrated that operative time was comparable, but the subxiphoid single-port technique had advantages in blood loss, hospitalisation period and need for analgesia in the postoperative period (55). However, there are disadvantages in subxiphoid thymectomy in cases with obesity, cardiomegaly and decreased manoeuvrability of instruments (56).

Toker et al. demonstrated that catastrophic intraoperative complications could occur during VATS thymectomy or thymothymectomy. Although they are rare (1.5%), complications are life threatening. The surgical team should be proficient and always ready to convert to open surgery within seconds, managing complications to avoid mortality in these cases (57). Another retrospective study on VATS thymectomy showed that body mass index (BMI) was the sole significant factor related to longer operative time (58).

Follow-up results after thymectomy

A meta-analysis compared VATS thymectomy with open thymectomy. Operation time and intensive care unit time were comparable, but intraoperative blood loss and length of hospital stay were lower in VATS. Total number of complications and myasthenic crises were also lower in VATS thymectomy; however, other complications were comparable (39). In a retrospective study of 90 patients who underwent VATS thymectomy, the mean length of chest tube duration and hospitalisation time was 26.7±18.6 h and 2.2±1.1 days (55). Another study demonstrated that BMI, age, duration of operation and length and duration of drainage are variables related to length of hospital stay in patients who underwent VATS thymectomy (59). As our group increased surgical skill in the VATS thymectomy procedure, we demonstrated that BMI was related to longer operative time and median duration of the operation decreased with increased experience of the surgeon (60).

A study comparing three approaches (RATS-VATS-open surgery) reported that postoperative drainage duration and volume were significantly lower in RATS (2.88 vs. 3.77 and 4.41 days, P<0.05; 352.2 vs. 613.9 and 980 mL, P<0.05). Hospital stay showed a trend towards shorter duration in RATS compared with the open surgery and VATS (4.3 vs. 5.5 and 6.6 days). However, postoperative complications occurred in three patients in the open surgery group, with no postoperative complications in the RATS and VATS groups (61).

Yu et al. analysed 8 years of follow-up in patients with MG after thymectomy, and they reported that 81.1% of patients gained satisfactory efficacy, 8.1% died and 10.8% remained unchanged or deteriorated. Patients with non-thymomatous MG showed significantly higher rates of complete stable remission and clinical remission than patients with thymomatous MG (62).

Liu et al. also reported that two good prognostic factors were preoperative prescription of anticholinesterase alone (P=0.035) and non-thymomatous MG (P=0.003). The 5-year complete stable remission rates in the VATS group and open group were 56.5% and 57.1%, respectively (47).

Age and thymectomy

Thymectomy became a routinely performed procedure for patients with MG. If patients have co-morbidities, surgery can become more complicated. Older age is another factor that complicates the procedure. Moreover, for the patients older than 60 years or with late- or very-late-onset MG, standard thymectomy for MG is not recommended, except in patients with a concomitant thymoma (63). Patients younger than 45 years have a higher rate of achieving complete stable remission during follow-up (64). However, increasing age in the population may soon create a platform for increasing the age limits of thymectomy in patients with MG and without a thymoma.

There seems to be no reported obstacle in younger patients, even in paediatric patients. In Toker et al. the average age was 14.8 (65), and it was 11.3 years in Christon-Lagay’s study (66). In both studies, all patients underwent thoracoscopic surgery, and this approach was deemed safe in paediatric patients with MG.

New perspectives

VATS has proved its reliability in thymectomy in MG disease. Usually a three-port approach from the right side is the preferable technique. Single-port thymectomies are also being performed in several minimally invasive surgery centres (67). Scarci et al. described performing a thymectomy from a 3-cm lateral muscle-sparing incision on the 5th intercostal space using a single-incision laparoscopic surgery port device (67). Another single-port technique is subxiphoid approach uni-portal thymectomy. This technique has advantages for bleeding, duration of operation and requirement of analgesia compared with conventional three-port VATS thymectomy technique (64).

Surgery of the thymic gland in the treatment of MG and thymoma is also entering a new era for robotic-assisted surgery (68,69). It has been shown that robotic thymectomy in patients with MG is safe and feasible. Neurological benefits and decreased need for steroids has been observed by Keijzers (70). A study that compared RATS and VATS thymectomy did not report any statistical difference in conversion to open, length of hospital stays or postoperative pneumonia (71). A meta-analysis on these issues found no significant differences in conversion rates, operation time and length of hospitalisation; however, a slightly higher blood loss was noted in RATS (72).

Conclusions

VATS has replaced open techniques for surgery of the thymic gland in the treatment of non-thymomatous MG with superiorities for postoperative pain, preserved pulmonary function, stay in hospital and cosmetic results.

Innovations such as RATS and uni-portal or subxiphoid approaches may produce similar results, if the extent of resection is like VATS with good patient selection and reproducibility. In the future, our understanding of MG may change on the basis of antibodies and new classifications and their relation to the thymus. We are sure this will refine the criteria for better patient selection for thymectomy. The extent of thymectomy will remain an open question. Until another surgical trial in MG demonstrates superiority, basic resection should include both pleura, both horns and mediastinal fatty tissue.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Tommaso Claudio Mineo) for the series “Mediastinal Surgery” published in Journal of Visualized Surgery. The article has undergone external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jovs.2018.07.11). The series “Mediastinal Surgery” was commissioned by the editorial office without any funding or sponsorship. AT serves as an unpaid editorial board member of Journal of Visualized Surgery from Jun 2017 to May 2019. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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