Thymectomy for non-thymomatous myasthenia gravis: the end of controversy, albeit fifty years late

The recent publication of the first international, multicenter, prospective, singled-blinded, and randomized trial (MGTX trial) comparing extended transsternal thymectomy plus alternate-day prednisone with prednisone alone in generalized non-thymomatous myasthenia gravis (MG) provides an answer and ends a long-running debate on the role and effectiveness of thymectomy in the treatment of non-thymomatous MG patients (1). An initial reading of the results for a three-year period confirms that thymic resection is superior to medical treatment with prednisone alone in these patients. This trial has provided evidence that thymectomy still has an important role to play in the standard treatment of MG.

Thymectomy gained widespread acceptance as a modality of treatment in patients with MG after Blalock et al. reported their landmark series demonstrating relief from MG symptoms after removal of the thymus (2). The findings supported thymectomy as a treatment option in myasthenic patients, especially in those with milder forms of generalized MG (3-6). However the precise mechanism of action of thymectomy is unknown, although possible explanations include removal of the source of continued antigen stimulation, removal of acetylcholine receptor (AChR) antibody-secreting B cells and immunomodulation (7-15).

The effectiveness of thymectomy has been called into question over the last four decades, basically due to the absence of controlled randomized prospective studies, despite evidence that the condition of many patients improved and their reduced requirements of prednisone and pyridostigmine after surgery. In general, the benefits of thymectomy are delayed for months or years (10,16-24). According to life table analyses of remission rates comparing the results after six different types of resectional technique (T1-a or cervical basic, T-1b or extended cervical, T-2a or classic video-assisted thoracic surgery thymectomy-VATS, T-2b or video-assisted thoracoscopic extended thymectomy-VATET, T-3b or extended transsternal, and T-4 or combined transcervical-transsternal), between 3% and 24% of the thymectomized patients achieve remission in the first year after thymus resection. This variable success depends on the thymectomy technique used. Significantly, the highest remission rates are achieved in the fifth year after surgery, ranging between 25% and 55% of patients. Most experts believe that post-thymectomy evaluation at 5 years is a good starting point to evaluate remission rates and effectiveness after thymus resection. Rates of remission continue to increase in the next five years (ranging between 40% and 75%) (20). Some authors have even reported positive effects 15 years after thymectomy (10,16). The type of thymectomy technique also plays a role in this respect. The major differences in remission rates obtained depending on the thymectomy technique used suggests that “the more extensive the thymus resection, the better the results obtained” (20). However, these results must be considered with caution as it is difficult to ascertain whether the symptoms improve as a result of the surgery or due to the natural course of MG, as spontaneous remissions may occur in 10–20% of patients in the long term (9,16).

Advocates of thymectomy as the standard treatment in myasthenia have pointed to observations that thymectomized patients had higher rates of remission and improvement, fewer myasthenic crises and needed less prednisone and pyridostigmine after surgery than those receiving conservative medical treatment (3-5,9,21). Various thymectomy techniques have been used since Blalock. Many aimed to avoid post-sternotomy scarring, while others aimed to avoid injuries in the recurrent laryngeal, left vagus or the phrenic nerves. Although the objective is to remove as much thymus tissue as possible, complete removal is sometimes impossible, especially in cases with microscopic ectopic thymic tissue foci. According to the MGFA, thymectomies are classified in five groups: T-1 or transcervical thymectomy, T-2 or videoscopic thymectomy, T-3 or transsternal thymectomy, T-4 or transcervical & transsternal thymectomy, and T-5 infrasternal thymectomy. Each operating technique also has several surgical variations; for example, there is the standard technique and the (more aggressive) extended technique for T-3 (transsternal thymectomy). Although resection of the thymus should be as extensive as possible, a comparative analysis of the different resectional techniques is very difficult, as the studies are neither prospective nor controlled, some have design problems and others do not comply with the standard recommendations of the Task Force of the MG Foundation of America (2). In the MGTX trial, the thymectomy technique chosen was Extended Transsternal Thymectomy (T-3b). Removal of almost all the mediastinal tissue, including cervical tissue, is achieved with this technique. This is the most aggressive form of transsternal thymectomy. However, this technique often leaves small amounts of thymus in the neck. Shortcomings in the choice of surgical technique were deemed to be the main cause of persistent incapacitating myasthenic symptoms in patients after thymectomy. In specific terms, incomplete resections, leading to the presence of residual or active ectopic thymic tissue, were accompanied by poor results. Rethymectomy may be justified for these patients. Thoracic surgeons needed to reconsider which of the various thymectomy techniques achieved complete excision of the thymic tissue (13). The number of thymectomies fell dramatically with the appearance of the immunoglobulins, plasma exchange therapy, alternate-day prednisone, azathioprine, cyclophosphamide, cyclosporin A, mycophenolate mofetil, tacrolimus, rituximab and other immunosuppressant drugs in the therapeutic arsenal for treating MG, calling into question whether surgical resection was superior to medical treatment. These controversies over whether patients should undergo surgery or not were based on the fact that all the observations of the effectiveness of thymectomy came from non-randomized controlled trials (i.e., non-class I studies). This criticism is more evident in the meta-analysis performed in four recent reviews of the medical literature. The main objective of these reviews was to assess the efficacy of thymectomy in non-thymomatous MG (17,25-27). More than 500 articles were reviewed, containing data from more than 4,000 patients who underwent surgery. Numerous risks of bias were identified in the design of most of the studies, especially a lack of randomization (class II trial), incomplete follow-up, an absence of blind evaluator investigators, an absence of standardized methods for assessing patient status before and after thymectomy, conflictive clinical classifications of patients, a lack of uniform post-interventional status criteria, different definitions of remission and improvement, and defective statistical methods. Most were retrospective case series or retrospective cohort type studies (class III trials). Others were anecdotal reports and narrative reviews (17,26,27). Given these shortcomings in the study design, the remission rates range from 13.7% to 50.0% and improvement rates range from 46.6% to 93.2%. However, different definitions of remission were used. In many cases of improvement, the authors do not specify whether the thymectomized patients are taking immunosuppressive drugs or cholinesterase inhibitors. As a result, despite the relative risk (RR) of clinical remission, pharmacological remission and improvement rate suggesting the superiority of thymectomy compared to medical treatment, these reports should be considered with caution (17,25-27).

The major confounding factors in the multivariate analysis of the real effects of thymectomy included the patient’s age, the disease duration prior to surgery, the choice of surgical technique for maximum removal of thymus tissue, gender, prednisone therapy before and after surgery, doses of pyridostigmine before and after surgery, disease severity, thymus histology, and the possibility of spontaneous improvement during the natural course of the disease (see Table 1). As a consequence, comparative analysis of the results of thymectomy remains problematic (28-36).

However, when we analyzed the QMG score results of the MGTX Study Group for the 126 patients randomized between 2006 and 2012, the differences between the two groups were moderate. A difference of 2.84 points was observed (8.99 points in the group of patients with prednisone, versus 6.15 points in the group of patients who had undergone surgery). None of the patients achieved complete stable remission (CSR), one of the MGFA primary therapeutic objectives in the treatment of MG. The minimal manifestations (MM) category of post-interventional status was achieved by 67% of the surgery group vs. 47% of the patients receiving medical treatment alone. The MG therapy status in both branches requires much higher doses of prednisone (44 mg on alternate days in the thymectomized group versus 60 mg on alternate days in the prednisone group) than those habitually used in neuromuscular clinics (37). Whether using other immunosuppressant drugs would have achieved a reduction in the amount of prednisone to consolidate the benefits of thymectomy and reach CSR will never be known (15,35,38).

Another shortcoming of this randomized clinical trial was the fact that it analyzed the results over a three-year period, when most experts believe that post-thymectomy evaluation at 5 years is a good starting point to evaluate remission rates and effectiveness after thymus resection. A further shortcoming is that it includes patients up to 65 years old. There is no rationale for thymectomy in non-thymomatous MG patients aged over 60 years old, as the results are poor, unlike in younger patients (4,5,9,10,19,33,34).

In conclusion, this study provides a partial response to the doubts over the effectiveness of thymectomy that have persisted for the last fifty years. A controlled trial of thymectomy, despite being long overdue, would have the merit of being “better late than never”. Future studies could analyze whether any of the subgroups of non-thymomatous MG patients analyzed respond better than the others, or whether the effects of the thymectomy are improved in the fifth year post-surgery (Table 2).

Acknowledgments

Funding: J Gamez is the recipient of a grant from the Spanish Fondo de Investigaciones Sanitarias (FIS PI16-01673-FEDER), and an Interlaken Research Awards Program (2012-12094537).

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Xiangya Medicine. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jxym.2017.01.02). The authors have no 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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