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Eur J Cardiothorac Surg 2008;34:1062-1067. doi:10.1016/j.ejcts.2008.07.049
Copyright © 2008, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
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Influence of ectopic thymic tissue on clinical outcome following extended thymectomy in generalized seropositive nonthymomatous myasthenia gravis

José M. Ponsetia,b,*, Josep Gameza,c, Ramón Vilallongaa,b, Carmen Ruizd, Jamal Azema,b, Manuel López-Canoa,b, Manuel Armengola,b

a Unit of Myasthenia Gravis, Hospital General Universitari Vall d’Hebron, Autonomous University of Barcelona, Barcelona, Spain
b Department of Surgery, Hospital General Universitari Vall d’Hebron, Autonomous University of Barcelona, Barcelona, Spain
c Department of Neurology, Hospital General Universitari Vall d’Hebron, Autonomous University of Barcelona, Barcelona, Spain
d Department of Pathology, Hospital General Universitari Vall d’Hebron, Autonomous University of Barcelona, Barcelona, Spain

Received 25 February 2008; received in revised form 18 July 2008; accepted 21 July 2008.

* Corresponding author. Address: Unit of Myasthenia Gravis, Department of Surgery, Hospital General Universitari Vall d’Hebron, Passeig Vall d’Hebron 119–129, E-08035 Barcelona, Spain. Tel.: +34 93 2746000x6587; fax: +34 93 2746224. (Email: jmponseti{at}vhebron.net; 5012jpb{at}comb.es).


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Objective: We determined the effect of detecting ectopic thymic tissue in thymectomy specimens on the long-term outcome of patients with myasthenia gravis. Methods: A total of 83 consecutive patients with generalized seropositive nonthymomatous myasthenia gravis underwent transsternal extended thymectomy (T-3b according to Myasthenia Gravis Foundation of America). Ectopic thymic tissue was only accepted when Hassal's corpuscles in the excised cervicomediastinal fat were documented. The primary endpoint was to assess differences in time to obtain complete stable remission (CSR) according to the presence or absence of ectopic thymus. Results: Thirty-five patients (42.2%) had ectopic thymic tissue. The mean follow-up was 88.4 ± 36.3 months (range 20–144). By the Kaplan–Meier analysis method, the estimated median follow-up to obtain a CSR in the group without ectopic thymic tissue was 32.9 months (95% confidence interval [CI] 21.1–44.8 months) and 117.8 months (95% CI 98.0–137.6 months) for the group with ectopic thymic tissue (log-rank test, p = 0.0002). The probability over time of obtaining CSR for the groups without and with ectopic thymic tissue was 65% vs 26% at 5 years. After stratification by hyperplasia or involution of the thymus as well as by post-thymectomy immunomodulating regimen (prednisone and prednisone–tacrolimus), the probability over time of obtaining CSR at 5 years was also significantly higher for patients without ectopic thymic tissue than for those with ectopic thymic tissue. Conclusions: The clinical outcome of patients with nonthymomatous seropositive myasthenia gravis is significantly affected by the presence of ectopic thymic tissue in the mediastinal fat.

Key Words: Myasthenia gravis • Thymectomy • Prednisone • Tacrolimus


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
Thymectomy has become increasingly accepted as an efficacious procedure for myasthenia gravis, with high rates of complete clinical remission, particularly in patients with nonthymomatous disease [1,2]. Although the efficacy of surgery is contingent upon complete excision of the thymus, surgical strategy and patient selection remain controversial, especially since the introduction of minimally invasive approaches [3]. Variations in the surgical anatomy of the thymus, including extraglandular thymic tissue [4], have propitiated the debate regarding which technique is preferable. Some investigators have recommended maximal thymectomy with extensive neck and mediastinal dissection to assure complete resection of all thymic tissue [5–7], whereas others advocated reduced invasiveness resulting in low morbidity and improved cosmesis, particularly in young women. The issue regarding the choice of thymectomy technique is not resolved, in part, because of small and heterogeneous patient populations, lack of long-term follow-up, and unclear definitions of predictors of outcome [8–10], including the significance of removing ectopic thymic tissue [11–14]. In this respect, transsternal thymectomy with an extended anterior mediastinal dissection, classified as T-3b according to the Myasthenia Gravis Foundation of America (MGFA) [15], is an embryologically sound procedure whereby thymic tissue is extracted from multiple sites of deposition that occur during migration of the third and fourth brachial arches.

The objective of this study was to determine the effect of detecting ectopic thymic tissue in thymectomy specimens on the long-term outcome of patients with myasthenia gravis. To this purpose, a homogeneous population of patients with generalized seropositive nonthymomatous myasthenia gravis undergoing transsternal extended thymectomy in a single-center institution was selected.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
Between January 1995 and December 2005, 142 consecutive patients with generalized myasthenia gravis were scheduled for transsternal thymectomy at the Unit of Myasthenia Gravis of a tertiary care, university-affiliated hospital in Barcelona, Spain. All patients gave written informed consent to be operated on.

The diagnosis of myasthenia gravis was established by history, signs and symptoms, electromyography (single fiber and repetitive nerve stimulation), edrophonium test (Tensilon Roche Laboratories, Hoffmann-La Roche Inc., Nutley, NJ), serum anti-acetylcholine receptor (AChR) antibodies (AChR-Ab RIA kit, RSR Ltd., Cardiff, UK), and anti-MuSK antibodies (MuSK-Ab RIA kit, RSR Ltd., Cardiff, UK) in seronegative patients. In patients with negative anti-AChR and anti-MuSK antibodies, the diagnosis was made by clinical findings, EMG, and edrophonium test. The preoperative diagnosis of thymoma was based on clinical symptoms, conventional radiographs, and computed tomographic scans. Thymectomy was indicated in all patients with thymoma and in patients with moderate or severe generalized myasthenia without thymoma under 60 years old.

In all patients, preoperative preparation for thymectomy, in the hospital setting, included withdrawal of anticholinesterase agents, administration of high-dose intravenous immunoglobulin (Endobulin®, Baxter S.L., San Fernando de Henares, Madrid, Spain) (400 mg/kg per day) during the 5 days before surgery, and administration of prednisone (1.5 mg/kg per day) during the 6 days before surgery [2]. The procedure consisted of an extended thymectomy [16,17], classified as T-3b according to MGFA [15], in which an en bloc resection of the anterior mediastinal fat tissue, including the thymus, was performed. The adipose tissue around the upper poles of thymus, behind the innominate vein, and on the pericardium were resected meticulously. If necessary, the pleural cavity was entered. The borders of the resection were the diaphragm caudally, the thyroid gland orally, and the phrenic nerves laterally. Details of the surgical procedure and perioperative care have been previously reported [2,18]. In order to identify the location of the ectopic thymic tissue, the perithymic fat was sent for histopathological examination, divided and classified into five separate groups: pretracheal infrathyroid fat, fatty tissue in the aortopulmonary window, mediastinal fat lateral to right and left phrenic nerves, and pericardial fat up to the diaphragm. Microscopically, the histologic types of the thymus were described as hyperplastic, involuted, and thymoma. The foci of ectopic thymic tissue with Hassall bodies in the excised cervicomediastinal fat were searched for with hematoxylin–eosin staining (Fig. 1 ). Pathological samples of all patients were retrieved and reassessed by an independent pathologist (CR) who was unaware of the purpose of the study.


Figure 1
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  		Fig. 1. (A) Microscopic foci of ectopic thymus in the anterior mediastinal fat (hematoxylin & eosin x100); (B) Hassall corpuscle (hematoxylin & eosin, x400).

 
Treatment with prednisone was maintained over the immediate postoperative period, to which tacrolimus (FK506, Prograf, Astellas Pharma SA, Madrid, Spain) was added 24 h after thymectomy or during the post-thymectomy latency period until complete remission was fully consolidated, starting at doses of 0.1 mg/kg per day b.i.d. and then adjusted to achieve plasma drug concentrations between 7 and 8 ng/ml (EMIT 2000, Dade Behring, Milton Keyes, UK). At follow-up, doses of immunosuppressants were progressively reduced following a previously described protocol [2,18] and finally withdrawn if complete stable remission (CSR) was achieved. According to MGFA postintervention status [15], CSR was defined as no symptoms or signs of myasthenia gravis for at least 1 year and no therapy for myasthenia during that time.

Assessments were performed at baseline during the preoperative preparation days, during the first postoperative week and at 15 days, and 1–3 months after surgery, and every 3 months until the first year; thereafter, follow-up visits were scheduled at 6-month intervals. Clinical state according to MFGA postintervention status [15] and adverse events were assessed at each visit.

2.1 Statistical analysis
Baseline characteristics and follow-up data in patients with and without ectopic thymic tissue were compared with the chi-square test ({chi} 2) for categorical variables and the non-parametric Mann–Whitney U test for continuous variables. The primary endpoint of the study was to assess differences in time to obtain CSR according to the presence or absence of ectopic thymus. Time to CSR was defined as time elapsed from operation to the first date that CSR patients were asymptomatic and off of all medications (start date). Patients who had not achieved CSR were censored and time to CSR was defined as time from operation to most recent patient contact. These non-CSR patients had to have at least 12 months of follow-up after operation to be included in the analysis. The Kaplan–Meier method was used for survival analysis. Survival curves were compared with the log-rank test. The Statistical Package for Social Sciences (SPSS), version 11.5 for Windows, was used to analyze the data. Statistical significance was set at p < 0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
Of the 142 patients included in the study, 59 were excluded for the following reasons: presence of thymoma in 46 and negative anti-AChR antibodies in 13 (anti-MuSK positive antibodies, n = 5; anti-MuSK negative antibodies, n = 8). Of the 83 AChR Ab-seropositive patients with nonthymomatous myasthenia gravis included in the study, 35 patients (42%) had ectopic thymic tissue and 48 had no ectopic thymic tissue. One woman without ectopic thymic tissue was excluded due to failure to attend a control visit at month 1. As shown in Table 1 , there were no statistically significant differences in the clinical characteristics of patients with and without ectopic thymic tissue at baseline. Extended transsternal thymectomy was feasible in all cases and operations were performed by the same surgeon (JMP). Postoperative complications occurred in eight patients. Seven patients required reintubation and mechanical ventilation because of postoperative myasthenic crisis associated with respiratory infection in one, and respiratory insufficiency secondary to paralysis of the phrenic nerve in another. Minor complications included atelectasis in four patients, thrombophlebitis in one and bronchorrhea in one. There was neither perioperative mortality nor late deaths.


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  		Table 1 Baseline characteristics of 83 thymectomized seropositive patients with nonthymomatous myasthenia gravis
 
Histopathologically, hyperplasia of the thymus was observed in 61 of the patients and thymic involution in 22. In the group of 35 patients with ectopic thymic tissue, ectopic tissue was located in one area in 10 patients, in two areas in 19, in three areas in 4, and in all four areas in 2. The highest incidence of ectopic foci was found in the pericardial fat up to the diaphragm (37%) followed by the mediastinal fat lateral to the left phrenic nerve (31%), the aortopulmonary window (19%), the mediastinal fat lateral to the right phrenic nerve (8%), and the pretracheal infrathyroid fatty tissue (5%).

Postoperatively, all patients received prednisone, either alone (n = 10) or combined with tacrolimus starting 24 h after thymectomy (n = 43) or on a later time (n = 30) after a mean (± standard deviation) interval of 31.2 ± 19.2 months (range 32.4–85.2) post-thymectomy. The mean follow-up was 87.9 ± 35.9 months (range 20–144) in the patients with ectopic thymic tissue and 88.8 ± 37.0 months (range 21–144) in patients without ectopic thymic tissue. The results of treatment are shown in Table 2 . Anti-AChR antibodies decreased significantly in both study groups from a mean of 34.2 ± 52.7 to 9.5 ± 14.5 nmol/l in patients with ectopic thymic tissue and from 43.5 ± 63.5 to 8.9 ± 11.3 nmol/l in patients without ectopic thymic tissue (Mann–Whitney U test, p < 0.001), although serum titers in the final visit were similar.


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  		Table 2 Results at the final visit in 83 thymectomized seropositive patients with nonthymomatous myasthenia gravis
 
According to the MGFA postintervention status [15], 33 out of 48 patients (69%) without ectopic thymic tissue and 9 out of 35 patients (26%) with ectopic thymic tissue achieved CSR. Thirteen patients in each group achieved pharmacological remission (PR) but 12 patients with ectopic thymic tissue had minimal manifestations (MM) compared with 2 patients in the group without foci of ectopic thymic tissue (Table 2).

By the Kaplan–Meier analysis method, the estimated median follow-up to obtain a CSR in the group without ectopic thymic tissue was 32.9 months (95% confidence interval [CI] 21.1–44.8 months) and 117.8 months (95% CI 98.0–137.6 months) for the group with ectopic thymic tissue (log-rank test, p = 0.0002). However, the probability over time of obtaining CSR (Kaplan–Meier plots) for the groups without and with ectopic thymic tissue was 10% vs 6% at 1 year post-thymectomy, 29% versus 17% at 2 years, 52% versus 23% at 3 years, 58% versus 23% at 4 years, and 65% versus 26% at 5 years (Fig. 2 ).


Figure 2
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  		Fig. 2. Kaplan–Meier curve for time to complete stable remission (CSR) for patients with and without ectopic thymic tissue in the mediastinal fat (log-rank test, p = 0.0002).

 
In the group of hyperplasia, the estimated median follow-up to obtain a CSR was 31.4 months (95% CI 23.2–39.6 months) for patients without ectopic thymic tissue and 107.0 months (95% CI 81.0–133.0 months) for those with ectopic thymic tissue (log-rank test, p = 0.0008), with the probability over time of obtaining CSR at 5 years post-thymectomy of 70% versus 33%. Similar results were observed among patients with thymic involution (37.0 months, 95% CI 29.8–61.1 months vs 141.6, 95% CI 121.6–161.7 months) (long-rank test, p = 0.0008), with the probability over time of obtaining CSR at 5 years post-thymectomy of 33% versus 9%. As shown in Fig. 3 , the behavior of the two study groups stratified by histology of the thymus showed statistically significant differences (log-rank test, p = 0.0008).


Figure 3
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  		Fig. 3. Kaplan–Meier curve for time to complete stable remission (CSR) for patients with and without ectopic thymic tissue in the mediastinal fat according to histology of the thymus (hyperplasia or thymic involution) (log-rank test, p = 0.0008).

 
On the other hand, the behavior of the two study groups stratified by post-thymectomy immunomodulating regimen showed a significantly higher probability over time of obtaining CSR at 5 years post-thymectomy for patients without ectopic thymic tissue than for patients with ectopic thymic tissue (77% vs 6% for prednisone-treated patients and starting tacrolimus at a later time and 72% vs 47% for prednisone combined with tacrolimus immediately after thymectomy) (log-rank test, p = 0.0002) (Fig. 4 ).


Figure 4
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  		Fig. 4. Kaplan–Meier curve for time to complete stable remission (CSR) for patients with and without ectopic thymic tissue in the mediastinal fat according to post-thymectomy immunomodulating regimen (prednisone between 1995 and 1999, and combined prednisone–tacrolimus between 2000 and 2005) (log-rank test, p = 0.0002).

 
Adverse events in patients treated with combined prednisone and tacrolimus were mostly observed at the beginning of treatment, including cushingoid habit in 36 cases, acne in 25, obesity in 21, paresthesias and muscular cramps in 21, headache in 18, hypertrichosis in 12, edemas in 9, tremor in 7, diarrhea in 4, and infection in 1. With regard to laboratory abnormalities, hypomagnesemia occurred in 16 cases, hypercholesterolemia in 12, anemia in 3, hyperglycemia in 2, and increased serum creatinine in 1. When patients discontinued prednisone and were treated with tacrolimus only, the following adverse events were observed: diarrhea in two cases, tremor in one, and paresthesias in one. Laboratory findings included hypercholesterolemia in five cases, anemia in two, hyperglycemia in one, and hypomagnesemia in one. In none of the patients had tacrolimus to be withdrawn due to drug-related adverse effects. The mean number of side effects of 7 during initial treatment decreased to 0.6 at the final visit.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
In a homogeneous series of patients with AChR Ab-seropositive nonthymomatous myasthenia gravis, this study provides evidence of the negative impact of detecting ectopic foci of thymic tissue in thymectomy specimens on the outcome of the disease. As far as we are aware, no previous study exclusively focused on the significance of extraglandular thymic tissue in the clinical course of patients with myasthenia gravis has been conducted. Other studies assessing predictors of clinical outcome following thymectomy in myasthenia gravis have identified a significant correlation with the clinical outcome of the presence of mediastinal ectopic thymic tissue [11–14]. However, in neither of these studies was the clinical response evaluated according to MGFA recommendations in terms of CSR as the primary endpoint of the study, nor was a survival analysis performed.

After a mean follow-up of 88 months, the group of patients with ectopic thymic tissue showed a significantly lower rate of CSR and higher rate of MM compared with those without ectopic thymic tissue. Moreover, the estimated median follow-up to obtain CSR was significantly shorter for patients without extraglandular thymic tissue. Patients without ectopic thymic tissue also showed a twofold probability over time of obtaining CSR at 1 year post-thymectomy compared with patients with ectopic thymic tissue. Differences at 5 years were 65% versus 26%. These findings of a higher CSR rate and, particularly, the possibility of reducing to more than half the post-thymectomy latency period until complete remission is fully consolidated is very relevant from a clinical point in patients with a disabling disease, such as myasthenia gravis. It should be noted that baseline characteristics of patients with and without extraglandular thymic tissue were similar, particularly in respect to the duration of preoperative symptoms and use of prednisone.

The negative impact of the presence of ectopic thymic tissue on the course of myasthenia gravis was also apparent when patients were analyzed according to histology of the thymus, both in the subsets of patients with hyperplasia and thymic involution, as well as in reference to post-thymectomy immunosuppressant regimen. In all cases, attainment of CSR occurred significantly more frequently among patients without foci of ectopic thymic tissue. The combined use of prednisone and tacrolimus starting 24 h after thymectomy was more favorable than starting tacrolimus at a later time both in patients with and without ectopic thymic tissue. In this respect, these data are consistent with previous studies of our group showing the beneficial effect of early post-thymectomy administration of tacrolimus combined with prednisone [2,18].

Besides the important role of the absence of ectopic thymic tissue on the clinical outcome of thymectomized patients with nonthymomatous myasthenia gravis, other factors reported to be related with a favorable outcome were female sex, young age, short duration of symptoms before surgery, and hyperplasia of the gland [8,19]. It has been generally accepted that female patients have better prognosis than men, and the younger the patient the more likely is CSR [9]. It is well known that nonthymomatous and thymomatous myasthenia gravis exhibited significant differences in population characteristics and CSR rates [2,7,16,17]. For this reason, it was appropriate to assess the significance of ectopic thymic tissue in a population of myasthenia gravis patients without thymoma.

The presence of mediastinal ectopic foci of thymic tissue may be observed in a range from 20% up to 72% [12] (42% in our series of AchR Ab-seropositive nonthymomatous patients) and may result in a failed procedure in cases undergoing simple thymectomy. In addition, anatomic variability of the thymic tissue has been reported as high as 98% of patients with myasthenia gravis [20]. An autopsy study in cases without myasthenia gravis revealed that 44% had ectopic thymic tissue in anterior mediastinal fat, and 7.4% in the retrocarinal area [14]. Aberrant foci of thymic tissue are found in approximately 20% of humans [21], the majority are located laterally in the neck, either fused or close to the parathyroid and thyroid gland. Ectopic foci of thymus have also been reported in the base of skull, main bronchi, and in the parathyroid gland [4]. Therefore, total and complete removal of the thymic tissue to achieve a favorable clinical outcome is theoretically impossible. The presence of ectopic thymic tissue has been proposed as a prognostic factor because the patients with ectopic thymic tissue not removed at the time of thymectomy continue producing anti-AChR antibodies, showing comparatively poorer clinical outcome than patients without ectopic thymic tissue [12,22]. In a series of 137 thymectomized patients with nonthymomatous myasthenia gravis reported by Masaoka et al. [23], six were reoperations. Thymectomy had initially been performed by the transcervical approach, but was ineffective. Extended thymectomy was then performed by median sternotomy. Rethymectomy revealed residual thymus in all cases but CSR was obtained in only 4.8% of patients. Other series of patients undergoing ‘maximal’ thymectomy at reoperation due to failure of the first procedure, such as those reported by Zielinski et al. [24] and Jaretzki and Wolf [20], revealed foci of ectopic thymus in 61.9% and 98%, respectively, but CSR was achieved in only 11.8% and 4% of cases after rethymectomy. In our experience, ‘maximal’ rethymectomy was performed in 10 patients operated on before 1995, and foci of ectopic thymus in the mediastinal fat were found in 80% of cases but in none of them was CSR achieved [25]. It seems that rethymectomy procedures with ‘maximal’ cervicomediastinal excision, despite the fact of finding and removing ectopic thymic tissue left in the first operation, provide scarce benefit in terms of attaining CSR.

Although the present results should be interpreted taking into account the limitations of the study related to its retrospective design, we studied a group of patients consecutively treated in a single center with extensive experience in the surgical, preoperative and postoperative management of myasthenia gravis and closely followed by the same research team. On the other hand, the presence of ectopic thymic tissue was only considered when characteristic Hassall corpuscles were observed microscopically. The study population was homogeneous since only patients with nonthymomatous and positive AChR antibodies were selected.

This study shows that the clinical outcome of patients with nonthymomatous seropositive myasthenia gravis is significantly affected by the presence of ectopic thymic tissue in the mediastinal fat. Patients without extraglandular thymic tissue have a significantly higher probability to attain CSR and in a shorter period of time than patients with ectopic thymic tissue. Given the potential presence of ectopic thymic tissue from the base of skull to the diaphragm, the finding of foci of ectopic thymic tissue in the mediastinal fat has a prognostic rather than curative significance. Transsternal extended thymectomy is sufficiently large for the surgical treatment of myasthenia gravis. The association of immunomodulating agents (prednisone–tacrolimus) immediately after thymectomy can improve the CSR rate even in cases in which foci of ectopic thymic tissue is present in the mediastinal fat.


   Acknowledgments
 
We thank Marta Pulido, MD, for editing the manuscript and for editorial assistance.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 

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