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Ann Thorac Surg 2002;74:1658-1662
© 2002 The Society of Thoracic Surgeons

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Original article: general thoracic

Prognostic significance of thymomas in patients with myasthenia gravis

^a Divisions of Thoracic Surgery, Toronto General Hospital and Princess Margaret Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
^b Division ofNeurology, Toronto General Hospital and Princess Margaret Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
^c DepartmentAnesthesia, Toronto General Hospital and Princess Margaret Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
^d Department of Radiation Oncology, Toronto General Hospital and Princess Margaret Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada

* Address reprint requests to Dr Keshavjee, Division of Thoracic Surgery, E10-224, Toronto General Hospital, 200 Elizabeth St, Toronto, M5G2C4 Ontario, Canada.
e-mail: shaf.keshavjee{at}uhn.on.ca

Presented at the Poster Session of the Thirty-eighth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28–30, 2002.

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
BACKGROUND: The presence of thymoma may be a negative prognostic factor with respect to the outcome of myasthenia gravis (MG).

METHODS: Of 122 consecutive patients with MG undergoing thymectomy between August 1994 and September 2000, 37 had a thymoma. Postoperative radiation was administered to all patients with stage II thymoma and higher. To determine differences in presentation and outcome, thymoma patients were compared with patients with atrophic (n = 49) or hyperplastic (n = 36) thymus gland on final pathology.

RESULTS: Thymoma patients were significantly older (52 ± 14 vs 36 ± 15 years, p < 0.0001) and included a significantly higher proportion of males (54% vs 28%, p = 0.006) than patients without thymoma. However, the preoperative Osserman grade and the duration of symptoms before surgery were not significantly different between groups. Mean follow-up after thymectomy was not significantly different between patients with or without thymoma (32 ± 23 vs 37 ± 19 months, respectively, p = 0.3). At last follow-up, the proportion of asymptomatic patients (63% vs 70%, respectively, p = 0.5) and the mean Osserman grade (0.6 ± 0.9 vs 0.5 ± 0.9, respectively, p = 0.6) were similar in both groups. In addition, the rate of complete remission reached 36% at 5 years in patients with or without thymoma (p = 0.8).

CONCLUSIONS: Although myasthenic patients with thymoma are significantly older and include a greater proportion of males, the overall outcome, including the rate of complete remission, was similar between patients with or without thymoma. Therefore, the presence of a thymoma should not necessarily be viewed as a negative prognostic factor regarding recovery from myasthenia gravis.

	Introduction

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Myathenia gravis (MG) is an autoimmune disorder first diagnosed clinically at the end of the 17th century and currently affecting approximately 25,000 people in the United-States [1]. The association between thymoma and MG was first recognized in 1901 by Weigert, and can be observed in up to 44% of MG patients undergoing thymectomy [2, 3]. Although it has frequently been reported that thymoma is a factor associated with poor remission in patients with MG [4–6], only a few studies have specifically analyzed the outcome of MG after thymectomy in patients with or without thymoma, and their results have been controversial [3, 7, 8]. Some authors have observed that remission of MG in patients with thymoma may be influenced by postoperative radiation therapy and by the degree of extrathymic extension of the tumor [3, 6, 8]. Therefore, the purpose of this study was to evaluate whether thymoma had an effect on the outcome of MG when compared with a group of patients without thymoma and to determine whether the effect could be attributed to postoperative radiation therapy or to the stage of the tumor.

	Material and methods

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After approval by the Institutional Ethics Review Board, we retrospectively reviewed the charts of all patients with MG who underwent thymectomy in our institution between August 1994 and September 2000. All thymectomies were performed by a single staff surgeon (S.K.). Patient’s age, gender, duration of symptoms before surgery, and type of treatment were retrieved from hospital charts. MG was graded according to the referring neurologist’s assessment, as 0 = asymptomatic; 1 = ocular signs and symptoms; 2 = mild generalized symptoms; 3 = moderate generalized symptoms, bulbar dysfunction, or both; and 4 = severe generalized weakness, respiratory dysfunction, or both (modified Osserman classification).

In our institution, all patients with generalized MG were referred for thymectomy unless they were more than 50 years of age with both mild symptoms and without a thymoma on computed tomography (CT) scan of the chest. The surgical approach was determined according to the CT scan findings. If a thymoma was detected, a trans-sternal thymectomy was chosen, whereas the video-assisted trans-cervical approach was the procedure of choice for all patients without thymoma. Complete thymectomy, which includes an extracapsular resection of the thymus with removal of visible mediastinal fat, was performed in all patients. Relative contraindication to the trans-cervical approach included prior cervico-mediastinal surgery or radiation therapy, and cervical spine pathology limiting extension of the neck. Postoperative complications included all events occurring within 30 days of surgery.

Thymomas were classified into four stages according to Masaoka and associates [9]: stage I, macroscopically encapsulated tumors and microscopically no capsular invasion; stage II, macroscopic invasion into surrounding fatty tissue or mediastinal pleura or microscopic invasion into the capsule; stage III, macroscopic invasion into neighboring organs (pericardium, great vessels, or lung); stage IVa, pleural or pericardial dissemination; or stage IVb, lymphogenous or hematogenous metastasis. In this report, noninvasive thymoma was defined as Masaoka stage I, whereas invasive thymoma was defined as Masaoka stage II to IV.

Patients were either followed by one of the authors on a regular basis, or were followed elsewhere and contacted by telephone. Follow-up was complete if the patient was seen or contacted between January and December 2001, and if they had at least 6 months of follow-up after the surgery. To compare our results with those of previous publications, we used definitions similar to those in other series. Complete remission from MG was defined as asymptomatic without weakness and without any MG medications for at least 6 months, and remission was defined as asymptomatic with normal strength or minimal ocular findings (ptosis) without any MG medication or with pyridostigmine only.

Statistical analysis
Data are expressed as means ± SD. Categorical variables were analyzed by Fisher’s exact test, and continuous variables by Student’s t test. Life-table analysis was tabulated by the Kaplan-Meier method, with complete remission as the event of interest [10]. The log-rank test was used to assess differences in the rate of complete remission between the different groups. Probability values of p < 0.05 were considered to be statistically significant.

	Results

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
A total of 122 consecutive patients with MG underwent thymectomy during the study period. There were 37 patients with a thymoma on final pathology. The remaining 85 patients presented with an hyperplastic thymus (n = 36) or with an atrophic thymus (n = 49) on histopathological examination. Thymomas were classified as stage I (n = 13), stage II (n = 15), stage III (n = 8), and stage IVa (n = 1). On histologic examination, the tumor was predominantly lymphocytic (n = 14), epithelial (n = 7), spindle (n = 4), or mixed (n = 12).

The group of patients with a thymoma were significantly older and included significantly more male patients than the group of patients without thymoma (Table 1). However, the duration of symptoms, preoperative Osserman grade, and medical management were not significantly different between the two groups (Table 1).

View larger version (19K): [in this window] [in a new window]   Fig 1. Surgical approach in myasthenia gravis patients with or without thymoma. A median sternotomy was performed in the majority of patients with thymoma, whereas the video-assisted transcervical approach was the procedure of choice in patients without thymoma. Note that the rate of conversion was significantly higher among patients with atrophic rather than hyperplastic thymus (p= 0.02).

Postoperative complications occurred in 7 patients (5.7%). Three patients (of whom, 2 had a thymoma) developed a myasthenic crisis after sternotomy and required invasive (n = 2) or noninvasive ventilatory support (n = 1). One patient developed a sternal wound infection after a trans-sternal approach, and another had a pneumothorax after a trans-cervical approach. In addition, a 72-year-old woman died from diffuse mesenteric infarction 8 days after a trans-sternal thymectomy for thymoma.

Twenty of the 24 patients with an invasive thymoma underwent postoperative radiation therapy to the mediastinum in our institution for a total of 40 Gy in 20 fractions for more than 4 weeks. Radiation therapy did not exacerbate the symptoms of MG. Myasthenic symptoms deteriorated in only 1 patient during the radiation therapy, and this may have been due to poor patient compliance, because the symptoms improved rapidly after hospitalization with treatment by pyridostigmine only.

Follow-up was obtained for 116 patients (95%) and ranged between 3 and 74 months. Six patients were followed for less than 6 months and were thus excluded from outcome analysis. Mean follow-up was not significantly different between patients with or without thymoma (32 ± 23 vs 37 ± 19 months, respectively, p = 0.3). Two patients died during follow-up. One of them presented with a stage II thymoma. He had to be intubated 6 weeks postoperatively for severe MG and died of cardiac arrhythmia 3 months after surgery. The second patient died from perforated colon diverticulitis 9 months after a median sternotomy performed for an atrophic thymus. No patient died from recurrent thymoma.

At last follow-up, 63% of the patients with a thymoma were asymptomatic, which was not significantly different from patients with an atrophic or a hyperplastic thymus (65% and 71%, respectively). The mean Osserman grade at last follow-up (0.6 ± 0.9 vs 0.5 ± 0.9, respectively, p = 0.6) and the mean improvement rate in Osserman grade (2.1 ± 1.2 vs 1.9 ± 1.2, respectively, p = 0.5) was also not significantly different between patients with or without thymoma. The proportion of patients treated with immunosuppressive therapy was, however, higher in the group of patients with thymoma, but the difference did not reach statistical significance (67% in patients with thymoma vs 48% in patients without thymoma, p = 0.12). The rate of complete remission over time, which was determined by the life-table analysis, showed that 36% of the patients with a thymoma were in complete remission at 5 years, which was not significantly different from patients with an atrophic or a hyperplastic thymus (32% and 42%, respectively, p = 0.8) (Fig 2).

View larger version (17K): [in this window] [in a new window]   Fig 2. Rate of complete remission in myasthenia gravis patients with or without thymoma. The rate of complete remission over time was calculated by the Kaplan-Meier method. There was no difference between the group of patients with thymomatous, atrophic, or hyperplastic thymus (p = 0.8).

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
The purpose of this study was to determine whether thymoma was a negative prognostic factor in a series of 122 consecutive patients with MG undergoing thymectomy over a 6-year period. A total of 37 patients were found to have a thymoma on final pathology. This group of patients did not have any significant difference in outcome of MG when compared with the groups of patients presenting with a hyperplastic or an atrophic thymus. The rate of complete remission over time as well as the mean Osserman grade at last follow-up and the mean improvement rate in Osserman grade were similar between each group. The proportion of asymptomatic patients was also similar between each group.

Our results may be different from previous series published in the literature because the medical therapy for MG has improved dramatically over the past 20 years with the introduction of immunosuppressive drugs and better understanding of the disease. In addition, in our series, only 9 out of 37 patients had an invasive thymoma extending into neighboring organs, and adjuvant radiation therapy was likely an important factor reducing local recurrences in these patients.

We currently recommend radiation therapy to all patients presenting with a thymoma invading the thymic capsule or extending into the perithymic fatty tissue (Masaoka stage II and higher). A total of 20 patients with MG, of whom 12 were treated with immunosuppressive therapy, underwent postoperative radiation therapy for invasive thymoma in our series. We did not observed any exarcerbation of their MG symptoms or any complication related to their immunosuppressive therapy. Therefore, the combination of radiation and immunosuppressive therapy seems to be safe and can be recommended after thymectomy if necessary.

Monden and associates [11] observed deterioration of myasthenic symptoms in 35% of their patients during radiation. However, they administered radiation therapy to patients with unresectable stage III or IV thymoma, whereas we administered radiotherapy to patients with completely resected stage II and III thymoma. Therefore, their findings may have been related to the persistence of residual thymic tissue rather than to a direct effect of radiation on MG.

Life-table analysis has been reported to be the most relevant statistical method to determine the rate of complete remission over time [12]. In our series, the rate of complete remission at 5 years was 32% in patients with an atrophic thymus, 36% in patients with a thymoma, and 42% in patients with a hyperplastic thymus. Similar results have been observed in other series, with a complete remission rate ranging between 30% and 45% after a mean of 5 years follow-up [13–15].

The incidence of thymoma in MG patients was 30% in our series, which is similar to other large surgical series [3, 6]. Patients with thymoma were predominantly men older than 40 years, whereas patients without thymoma were predominantly young women. This finding has been observed previously and is characteristic of the two peaks in the incidence of MG, one occurring in young women with benign disease and the other in elderly men with thymoma [16, 17]. The association between MG and thymoma progressively increased with age in our series, from 12% in patients less than 40 years, to 42% in patients between 40 and 60 years, and 63% in patients older than 60 years. In fact, 8 out of 10 women with MG older than 60 years had a thymoma. Therefore, older patients with new onset of MG should be examined carefully for the presence of thymoma.

In contrast to other reported series, the duration of symptoms and the type of preoperative therapy did not differ between patients with or without thymoma [6]. This likely reflects the rapid referral for thymectomy of all patients younger than 50 years old with generalized MG in our institution after the diagnosis of MG is confirmed and the symptoms are stabilized [18]. A CT scan of the chest is then performed and, if thymoma is not suspected, patients undergo video-assisted trans-cervical thymectomy, whereas if a thymoma is suspected, thymectomy is performed through a median sternotomy. In 2 cases, however, we performed a trans-cervical thymectomy for a small encapsulated thymoma located in the upper pole of the thymus, and both patients are alive without recurrence 39 and 72 months after their thymectomy, respectively. Although we would not recommend a trans-cervical approach as a routine procedure in patients with thymoma because of the risk of incomplete resection, it is worth noting that some authors have reported good results after trans-cervical thymectomy for noninvasive thymoma of less than 4 cm [19, 20].

A total of 13 patients had conversion from a transcervical approach to an upper sternotomy. The conversion rate was higher among patients with an atrophic rather than with a hyperplastic thymus. This finding may be related to the absence of clear margins between the thymic capsule and the perithymic fat in patients with atrophic thymus. In addition, although the use of video-assisted technologies provides better visualization of the mediastinum, sometimes this leads to visualization of additional mediastinal fatty tissue that would not ordinarily have been seen by direct vision alone. With increasing experience in the use of the video-camera, however, the conversion rate decreased from 20% in our early experience to less than 10% over the past 2 years.

Over two-thirds of MG patients presented with thymoma of stage I and II in our series and in that of others [6, 13]. Therefore, MG may have prompted early detection of thymoma as compared with thymomas without MG. However, during follow-up, exacerbation of MG symptoms was not associated with recurrence of thymoma. We observed an aggravation in MG symptoms in 4 patients during follow-up, but none of them was found to have recurrence on serial chest CT scan. In contrast, 1 patient presented with recurrent thymoma, but remained stable from a myasthenic point of view. Similarly, Monden and associates [11] observed no deterioration in MG in 4 patients with recurrent thymoma. MG is, therefore, not a reliable indicator to follow thymoma, and periodic CT scan is recommended in all patients.

In conclusion, we observed that patients presenting with MG and thymoma were significantly older and included a greater proportion of men. The large majority of the patients presented with thymoma of stage I and II, and the outcome in these patients was similar to patients without thymoma. Patients with tumors extending into neighboring organs may, however, have a lower rate of remission than patients with stage I and II thymoma. We also observed that radiotherapy did not adversely affect the outcome of MG symptoms, and that exacerbation of MG symptoms did not correlate with recurrence of thymoma.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
We thank Dr Robert J. Ginsberg for reviewing the manuscript.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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