Ann Thorac Surg 2004;78:253-258
© 2004 The Society of Thoracic Surgeons
Original article: general thoracic
Comparison of late results of basic transsternal and extended transsternal thymectomies in the treatment of myasthenia gravis
Marcin Zieli
ski, MD, PhDa*,
Jaros
aw Ku
da, MD, PhDa,
Artur Szlubowski, MDa,
Jerzy Soja, MD, PhDb
a Department of Thoracic Surgery, Pulmonary Hospital, Zakopane, Poland
b Department of Interventional Pulmonology, Jagiellonian University, Kraków, Poland
Accepted for publication November 25, 2003.
* Address reprint requests to Dr Zieli
ski, ul. Gladkie, 134-500 Zakopane, Poland
e-mail: marcinz{at}mp.pl
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Abstract
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BACKGROUND: The influence of the technique of thymectomy on late results in the treatment of myasthenia gravis remains controversial.
METHODS: Results of 60 basic transsternal thymectomies and 58 extended transsternal thymectomies were compared. Both positive results (complete remissions or improvement) and negative results (no improvement, deterioration, or death from myasthenia) were analyzed.
RESULTS: There were no differences between both groups according to patient's characteristics and postoperative complications rate. Ectopic foci of the thymic tissue were discovered in the fat of the neck and the mediastinum in 56.9% of patients from the extended thymectomy group. The foci occurred in all areas of dissection of the neck and the mediastinum. Complete remission rates in the basic thymectomy group were 8.3%, 11.7%, 15.0%, 16.7%, 20.0%, and 21.7% after 1, 2, 3, 4, 5, and 6 years of follow-up, respectively, and 29.3%, 37.9%, 41.4%. and 46.6% after 1, 2, 3, and 4 years, respectively, in the extended thymectomy group. The differences between both groups after 1, 2, 3, and 4 years were statistically significant (p = 0.0093, p = 0.0013, p = 0.0018, and p = 0.0007, respectively). Negative results were noted in 23.3% of patients in the basic thymectomy group and in 6.9% of patients in the extended thymectomy group (p = 0.0613). No other factors had any influence on the results.
CONCLUSIONS: Late results, both positive and negative, were considerably better in the extended thymectomy group. The difference can be explained by the removal of ectopic foci of the thymic tissue from the neck and the mediastinum in these patients.
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Introduction
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Myasthenia gravis (MG) is a neurologic disease of unique pathogenesis, characterized by the production of abnormal autoantibodies directed against nicotinic acetylcholine receptors (AChR) in neuromuscular junctions by the thymus gland. The thymectomy has been recognized as a mainstay of treatment in myasthenia gravis since 1939, when Blalock performed a transsternal thymectomy in MG caused by a cystic tumor in a young woman, which resulted in the complete remission of MG symptoms. Subsequently, Blalock introduced the thymectomy for patients with MG and without thymoma. Medical treatment consists of anticholinesterase inhibitors, corticosteroids, immunosupressive drugs (azathioprine, cyclophosphamide, cyclosporine), intravenous immunoglobulins (IVI,) and plasmapheresis. Although no randomized trial comparing the effectiveness of the thymectomy to medical treatment was undertaken, the thymectomy became a standard modality in MG patients. The choice of technique of the thymectomy has been a matter of debate. Several transsternal, transcervical, and videothoracoscopic (VTS) or video-assisted (VATS) techniques of the thymectomy have been described with varying extents of extirpation of the fatty tissue of the neck and the mediastinum, but there is still no consensus as to which method should be regarded as the standard [1–10]. For 30 years the basic thymectomy performed through the upper median sternotomy approach was an accepted type of procedure at the Department of Thoracic Surgery in Zakopane. From 1967 to the end of 1997 more than 500 such operations were performed for MG without thymoma. When we analyzed the results of these operations, however, we found that the complete remission rate was only 28.8% after a follow-up period of 3 to 30 years (mean, 10 years) (unpublished data). For this reason, we changed our practice and, from Jan 1,1998 to Dec 31,1999 all MG patients were operated on by the complete median sternotomy approach with the transsternal extended thymectomy, similar to the technique described by Bulkley and colleagues [11]. All consecutive patients operated on for MG from Jan 1, 1996 to Dec 31, 1999 by the basic transsternal and the extended transsternal thymectomies were followed up. The aim of this nonrandomized study is to compare the late results of the basic transsternal thymectomies and the extended transsternal thymectomies.
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Material and methods
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There were 784 thymectomies performed overall at the Department of Thoracic Surgery of the Pulmonary Hospital in Zakopane during the period 1967 to 2003, including thymoma cases. In this study we compared the results of 61 consecutive basic transsternal thymectomies performed in 1996 and 1997 with the results of 58 consecutive extended transsternal thymectomies performed for MG in 1998 and 1999. One patient was excluded from the basic thymectomy group because her diagnosis of MG was abandoned in favor of polymyalgia, so ultimately there were 60 patients in the basic thymectomy group and 58 patients in the extended thymectomy group. All patients with MG in the course of thymoma or who underwent rethymectomy, operated on during this period, were excluded from the analysis.
The operative technique of the basic transsternal thymectomy is as follows: a 10 cm longitudinal incision is done above the upper part of the sternum, which is divided in the standard manner. The sternal edges are retracted for several centimeters with a small sternal retractor. The whole thymus gland is dissected free by blunt and sharp dissection from the mediastinal fat and removed. Generally, any pleural cavity is entered and the mediastinal fat is not removed. After hemostasis is achieved a single chest tube is inserted through a separate incision in the parasternal area and placed in the anterior mediastinum. The sternal edges are approximated with two or three steel wire sutures and the wound is closed in the standard fashion. The technique of the extended transsternal thymectomy is similar to the method described by Bulkley and colleagues [11] and is as follows: a complete longitudinal sternotomy is performed; all the fatty tissue of the anterior and (partly) the middle mediastinum is removed by sharp dissection from the level of the lower poles of the thyroid gland to the level of the diaphragm. The mediastinal pleura are widely incised below the inner surface of the sternum and parallel to the phrenic nerves, at a distance of 1 cm from each nerve. The sheets of mediastinal pleura are bilaterally removed en bloc with the specimen. Both phrenic nerves are the margins of dissection although in the region of the aortopulmonary window the left phrenic nerve is retracted laterally and the adipose tissue beneath this area is removed, reaching the level of the left vagus and recurrent nerves. No effort is made to dissect the thymus gland separately, but it is always removed with the whole specimen. One to four thymic veins and 1 to 4 inferior thyroid veins are ligated and divided near the left innominate vein. The adipose tissue of the lower part of the neck is totally removed from between both carotid arteries, which are dissected free along their anterior surfaces with visualization of both laryngeal recurrent nerves and lower parathyroid glands, all of which are carefully preserved. The fatty tissue from the aortocaval groove (a space situated posterior to the aorta and vena cava, superior and lateral to the trachea) and the aortopulmonary window are dissected separately, and the rest of the specimen (containing the adipose tissue from the pretracheal and the cervical regions, the space behind the left innominate vein, the anterior mediastinum, and the right and the left epiphrenic fat pads) is removed. Hemostasis is achieved and one chest tube is placed through separate incisions in each pleural cavity. The sternal edges are approximated with steel wire sutures and the wound is closed in the standard manner. The policy of postoperative care at our department is to place all patients who undergo thymectomy in the intensive care unit (ICU). In patients from the basic thymectomy group a single mediastinal suction drain is used for 24 hours. In the extended thymectomy group chest tubes are placed in both pleural cavities for 48 hours. Postoperative analgesia in patients of the basic thymectomy group included narcotic drug use for the first 24 hours and non-narcotic drugs subsequently. At the beginning of 1998 the policy of postoperative analgesia changed in our department with the introduction of the epidural analgesia used in almost all patients of the extended thymectomy group. Therefore, any comparisons of postoperative pain between both groups are not possible.
In pathologic studies the histologic types of the thymus were described as hyperplastic, involuted, or normal, and foci of the ectopic thymic tissue were searched for with hematoxillin-eosin staining. To all patients from both groups questionnaires were sent every year with questions about symptoms (or lack of symptoms), medications (anticholinergic, corticosteroids, or immunosuppresive drugs, and the doses of drugs), improvement, stabilization or worsening, and (in women) the effect of pregnancy on the myasthenia. In selected cases the patients or their physicians were interviewed by phone. Outcomes were based on the patients answers and were defined as follows: (1) complete remission (no symptoms of MG and no need of antimyasthenic medication); (2) improvement (myasthenic symptoms less severe or absent using antimyasthenic drugs); (3) positive results (complete remission or improvement); (4) negative results (no improvement, deterioration, or death from myasthenia).
Statistical analysis was performed with the STATISTICA software package (StatSoft, Tulsa, OK). Probability values were generated with the 
2 test and the Student's t test or the Mann-Whitney u test. Probability values, p less than 0.05, were considered to be statistically significant. The complete remission rate for 1, 2, 3, and 4 years of follow-up and negative results rate were compared between both groups. Impact of age, sex, duration of symptoms, severity of symptoms (Osserman classification) [12], the histologic type of the thymus (hyperplasia, involution, normal), and the presence of ectopic foci of the thymic tissue were examined. The study was approved by the Scientific Committee of our hospital.
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Results
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Patients characteristics (Table 1)
are as follows: mean age, 29.0 years (range,14 to 67) in the basic thymectomy group and 29.4 years (range, 15 to 70) in the extended thymectomy group (p = 0.8079); sex ratio (51 women and 9 men in the basic thymectomy group and 47 women and 11 men in the extended thymectomy group) (p = 0.5639); median duration of symptoms before an operation, 2.14 years (range, 4 months to 15 years) in the basic thymectomy group and 2.74 years (range, 1 month to 15 years) in the extended thymectomy group (p = 0.8107); Osserman score (I, 0 patients; IIa, 30 patients; IIb, 27 patients; III, 3 patients) in the basic thymectomy group and (I, 5 patients; IIa, 19 patients; IIb, 34 patients; III, 0 patients) in the extended thymectomy group; and use of steroids before an operation (19/60 to 31.7%) in the basic thymectomy group and (13/58 to 22.4%) in the extended thymectomy group (p = 0.2853). There is no significant difference between both groups in regard to any of these factors. The operative time was 35 to 165 minutes (mean, 90.1) in the basic thymectomy group and 115 to 235 minutes (mean, 171.0) in the extended thymectomy group (p = 0.005). No patient from either group required blood transfusion in the perioperative period. There was no postoperative mortality and there were only a few serious complications with no difference between groups. All postoperative complications are listed in Table 2.
Pathologic studies revealed ectopic thymic tissue in all areas of dissected fatty tissue of the neck and the mediastinum (Table 3).
No patient was lost from follow-up and all patients responded to the questionnaires. The mean follow-up was 6.0 years (range, 5.5 to 6.5 years) in the basic thymectomy group and 4.0 years (range, 3.5 to 4.5 years) in the extended thymectomy group. The results of the follow-up regarding complete remission rates are shown in Figure 1. The difference in complete remission rate between both groups was statistically significant in favor of the extended thymectomy group after 1, 2, 3, and 4 years of follow-up: after 1 year, 8.3% vs 29.3%, p = 0.0093; after 2 years, 11.7% vs 37.9%, p = 0.0013; after 3 years, 15.0% vs 41.4%, p = 0.0018; and after 4 years, 16.7% vs 46.6%, p = 0.0007). The results are also better in terms of the lower rate of negative results (23.3% [14/60] versus 6.9% [4/58]) in favor of the extended thymectomy group, but the difference is not significant (p = 0.0613) although it is close to the level of significance. Age (< 40 or > 40 years), sex, duration of disease (< 2 years or > 2 years), severity of disease in the Osserman classification, and histology of the thymus had no impact on the complete remission rates or negative results rates (Table 4).
Pathologic examination of the specimen revealed ectopic foci of the thymic tissue with Hassall's corpuscles in the adipose tissue of the neck and the mediastinum in 22.4% of patients and the foci highly probable for the presence of the thymic tissue, but without Hassall's corpuscles in 34.5% of patients. Overall, ectopic foci of the thymic, or probably thymic, tissue were found in 56.9% of patients. The localization of these foci is shown in Table 3. The ectopic foci were most prevalent in the aortopulmonary window (25.9%), the right pericardiophrenic fat pad (24.1%), the perithymic tissue (22.4%), and the left pericardiophrenic fat pad (22.4%). The ectopic foci were slightly less prevalent in the aorta-caval groove (17.2%) and in the neck (12.1%). In some patients the ectopic foci occurred in more than one location, so the numbers in Table 3 should not be added. The presence of proven (with Hassall's corpuscles) or suspected foci of the thymic tissue had no influence on the complete remission rate (Table 5).
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Table 1. Characteristics of Patients of Transsternal Basic Thymectomy and Transsternal Extended Thymectomy Groups
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Table 3. Occurrence and Localization of Ectopic Proven Foci (Hc+) or Suspected Foci (Hc-) in the Adipose Tissue of the Neck and Mediastinum in Patients From the Extended Thymectomy Group
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Table 4. Influence of Thymic Histology, Patient's Sex, Age, Duration of Symptoms, and Severity of MG on Complete Remission Rate After Basic and Extended Transsternal Thymectomy
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Table 5. The Influence of the Presence of Proven or Suspected Foci of the Thymic Tissue on the Complete Remission Rate in Patients of the Extended Thymectomy Group (n = 58)
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Comment
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Myasthenia gravis is so rare that there are only a few medical centers able to accumulate significant experience in surgical treatment of this disease. For this reason, several controversies in regard to the treatment of MG have arisen. Among the unresolved problems, the extent of the thymectomy is also a matter of discussion [13]. The aim of the thymectomy is to remove the whole thymic tissue, which was shown to generate an autoimmunologic process leading to the occurrence of myasthenic symptoms. Therefore, it seems logical that ectopic foci of the thymic tissue, described first by Wenglowski in 1912 [14], and afterwards rediscovered by Jaretzki and Wolff [15] and Masaoka and colleagues [16], should be removed as well. However, this presumption has never been proven. Additionally, there are opinions that the removal of the adipose tissue with ectopic foci of thymic tissue is of unproven value and that there is a lack of evidence that this procedure has an impact on the late results of a thymectomy. In Table 6
the late results of several important series of different techniques of thymectomy are presented, with complete remission rates for each of them, in various periods of postoperative follow-up. Complete remission was achieved in 24.0% to 30.0% of patients after the basic thymectomy [7, 13,] and in 34.2% to 62.0% of patients after the extended thymectomy [7, 13, 19, 21].
Most studies analyzing results of thymectomy are retrospective and based on small groups of patients or patients who were operated on over relatively long periods of time. In fact, there was no prospective randomized trial comparing results of basic versus extended thymectomies conducted by one surgical team on a uniform group of patients during a relatively short period of time (to exclude any changes of management of MG that might occur if the study was conducted over a long period of time). The patients in our study were not randomized to the basic thymectomy or the extended thymectomy groups; however, both groups of patients were comparable in terms of age, sex ratio, duration of MG before an operation, severity of symptoms, and steroids use. The neurologists referring the patients for the operation and the surgeons performing the operation were the same during the years 1996 to 1999. The period of time when all operations were done is relatively short and no considerable changes in treatment of MG occurred during that time. There were no differences in postoperative morbidity in both groups despite the operative time being significantly longer in the extended thymectomy group. The duration of follow-up after the thymectomy is known to influence the number of complete remissions. We have shown a statistically significant difference in complete remission rates between the basic and the extended thymectomy groups after 1, 2, 3, and 4 years of follow-up. The only explanation for such a difference in results is the technique of thymectomy, with the removal of ectopic foci of the thymic tissue in the extended thymectomy group. Some authors [19, 22, 23] reported that the results of thymectomies were more favorable in young women, with mild myasthenia, the thymic hyperplasia and the short duration of symptoms. Conversely, we were unable to find any influence on results of factors such as sex, age (> 40 or < 40), duration of symptoms (< 2 years or > 2 years), thymic histology (hyperplasia, involution, or normal thymus), and severity of MG (estimated with the Osserman scale). We chose the age limit of 40 years because there was a significant number of patients more than 40 in the whole group, but there were only a few patients more than 50 or 60, so the analysis is, in our opinion, more reliable. The same age criteria were used by Cosi and colleagues [20].
Pathologic studies revealed proven ectopic foci of thymic tissue (containing Hassall's corpuscles) or highly probable ectopic foci of thymic tissue (resembling thymic tissue, but without Hassall's corpuscles) in 56.9% of specimens after the extended thymectomy. Regarding the relatively high incidence of ectopic foci of the thymic tissue in all the examined areas of the neck and mediastinum, it can be expected that omission of removal of the adipose tissue from these sites might negatively affect the results. However, it is possible that such foci can also be located in close proximity to the phrenic and laryngeal recurrent nerves and the remote areas of the neck and mediastinum. Removal of such foci might not be feasible. An incidence of ectopic foci of thymic tissue in the adipose tissue of the neck and the mediastinum reported by Jaretzki and Wolff [15] was 98.0%, 72.2% by Masaoka and colleagues [19], and 39.5% by Ashour [21]. Contrary to Ashour, we found no influence of the presence of the ectopic foci of the thymic tissue on the complete remission rates after the extended thymectomy. This finding supports the necessity of the extensive removal of the adipose tissue of the mediastinum and the neck because the high complete remission rate of MG may be achieved even if the ectopic foci are present. The importance of the removal of ectopic foci of thymic tissue is additionally supported by the results of 21 rethymectomies performed at our department. In 13 of 21 rethymectomy specimens ectopic foci of thymic tissue were found; in 4 cases a part of the thymus was also encountered, so finally the thymic tissue was found in 17 of 21 patients (81.0%) and in 4 cases no thymic tissue was discovered, including 2 patients reoperated on after an extended transsternal thymectomy. We plan to report the analysis of the results of rethymectomies in the future.
We conclude that the results of our study strongly support the importance of the removal of ectopic foci of the thymic tissue and, therefore, the necessity of performing a thymectomy with an extended technique. The choice of an operative approach in the performance of the extended thymectomy remains a matter of discussion.
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Top
Abstract
Introduction
= extended thymectomy; 
= basic thymectomy.