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Ann Thorac Surg 2001;72:197-202
© 2001 The Society of Thoracic Surgeons
Address reprint requests to Dr Miller, Division of Cardiothoracic Surgery, Emory University, The Emory Clinic, Building A, 1365 Clifton Rd, Atlanta, GA 30322
e-mail: jmille{at}aol.com
Presented at the Forty-seventh Annual Meeting of the Southern Thoracic Surgical Association, Marco Island, FL, Nov 9–11, 2000.
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Abstract |
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Methods. A 25-year retrospective review (1974 to 1999) of all thymectomies performed at a single institution was undertaken.
Results. In 113 consecutive thymectomies for MG, women comprised 79% (89 of 113 patients), and mean age was 40 ± 15 years. Complications occurred in 14% of patients (16 of 113). In-hospital mortality was 0, but 90-day hospital mortality was 0.88% (1 of 113 patients). Follow-up was obtained in 81% (92 of 113 patients) at a mean of 51 ± 59 months postoperatively. Complete remission was achieved in 21% of patients (19 of 92), and marked improvement of MG in 54% (50 of 92), for a total benefit rate of 75%. Fourteen percent (13 of 92) were unchanged, and 11% (10 of 92) were worse. Using univariate analysis, sex, age, and pathology correlated significantly with outcome (p < 0.05): 80% of women (57 of 70) benefited from the procedure, versus 57% of men (12 of 21). Eighty percent (57 of 70) of patients less than 51 years of age were improved or in remission, versus 57% (12 of 22) older than 50. Twenty-three percent (5 of 22) of patients with thymoma deteriorated, versus 7.1% (5 of 70) without thymoma. Sex did not significantly correlate in the multivariate model.
Conclusions. Sex, age, and thymic pathology are potential predictors of outcome in thymectomy for MG, and may shape treatment decisions and target higher-risk patients.
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Introduction |
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Material and methods |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsDiscussionReferences |
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Techniques
Preoperative stabilization before thymectomy included anticholinesterase (AC) therapy and one or more of the three following modalities: plasmapheresis as the primary adjunctive preoperative treatment from 1974 to 1985, steroids during the period of 1985 to 1994, and intravenous 
-globulin most commonly used during the last 5 years of the study.
Surgical exposure of choice at our institution consists of the T incision with limited upper sternotomy, first described by Miller and colleagues in 1982 [4] (Fig 1). The operative procedure, which did not change during the 25 years of the study, was carried out as follows: a 2 x 2-inch T-shaped skin incision is made midsternally. The horizontal limb extends over the second intercostal space, and the vertical limb extends from the midpoint of the T down to the level of the fourth intercostal space. A superior skin flap is developed and an upper sternotomy made from the sternal notch to the fourth intercostal space, followed by placement of a small chest retractor. This exposure allows for visualization of the entire thymus. A radical en bloc thymectomy can then be performed. The superior poles are totally mobilized, as well as all mediastinal fat and inferior poles. All thymic, fatty, and nodal tissues between the pleural reflections are excised. The space is drained postoperatively by a single chest tube. Eighty-four percent (95 of 113) of thymectomies were performed by this approach; the remainder were performed by extended or full sternotomy (n = 14) or by thoracotomy (n = 4), mainly because of the presence of a thymoma.
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2 and Fisher’s exact in contingency tables. Univariate and multivariate analyses were then performed on all patient variables listed in Table 2, using a logistics regression model. Significance was assigned at a p less than 0.05. |
Results |
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Morbidity and mortality
Morbidity and mortality in our study are detailed in Table 3. There were no in-hospital deaths, but 1 patient died suddenly 2 weeks postoperatively, of unknown causes. Therefore, our 30-day and 90-day mortality were both 0.88% (1 of 113). Four additional patients died (mortality of 4.4%) up to 12 years postoperatively (mean 61 months). Forty percent (2 of 5) of the deaths were attributed to MG. The complication rate was 14% (16 of 113); 4 patients had perioperative pneumonia and 4 had respiratory distress, 1 of these with a pulmonary embolus and infarct. Of these 8 patients with respiratory complications, 4 had experienced preoperative respiratory symptoms with MG (modified Osserman type 4), and the remainder had none.
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Predictors of outcome
Preoperative symptom duration did not correlate with outcome from thymectomy. Contrary to the findings of many other studies, there was a nonsignificant inverse relationship between symptom duration and outcome: the average length of symptoms for worse patients was the lowest (12.8 months), compared with unchanged, 45 months; improved, 35.1 months; and remission, 18.8 months (p = 0.44).
Modified Osserman classification did not correlate with outcomes; however, patients in class 2 or 3 tended to benefit more from thymectomy (19 of 24 and 26 of 33, or 79%, respectively). Patients in class 4 were improved or in remission 71% of the time (12 of 17); meanwhile, patients with exclusively ocular symptoms, typically resistant to thymectomy, had a 60% benefit rate (6 of 10).
Patient age in our study correlated with outcome. Myasthenic patients younger than 51 were significantly more likely to benefit from thymectomy than were those older than 50 (81% or 57 of 70 versus 55% or 12 of 22, p = 0.02). There was a strong but nonsignificant trend (p = 0.07) toward benefit for patients younger than 38 years of age. Conversely, a larger proportion of patients older than 50 years had poor outcomes—23% (5 of 22) versus 7.1% (5 of 70) (p = 0.02). The age of 50 proved to be the age cut-off value in our multivariable model (Fig 3).
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Sex correlated with outcome in the univariate analysis. Female MG patients were more likely to benefit from thymectomy, with 80% (57 of 71) in remission or improved versus 57% (12 of 21) of men, and 24% (5 of 21) of men worse versus 7% (5 of 71) of women, p = 0.045. However, on multivariate analysis, the p value was 0.34, with an odds ratio (OR) of 1.9 and a 95% confidence interval (CI 95%) of 0.49 to 7.5. Remission rates were the same across sex: men 24% (5 of 21) versus women 20% (14 of 71).
Thymic pathology is often reported as another predictor of response. Typically, hyperplastic thymus carries the best prognosis, thymoma the worst [6, 7]. In the present study 82% (36 of 44) of patients with hyperplastic thmus glands achieved remission or improvement in disease, compared with 82% (18 of 22) of those with normal thymus tissue. A significantly high percentage of patients with thymoma responded poorly to thymectomy (28%, 5 of 28) (p = 0.023).
The procedures were performed by 6 faculty surgeons, with 94% (106 of 113) performed by 2 surgeons. Eighty-four percent (92 of 113) of thymectomies in this study were performed by T incision. The rate of remission plus improvement in the T incision was 76% (57 of 75) versus 54% (7 of 13) for the extended sternotomies; there was no statistically significant difference.
Preoperative treatment did not correlate with outcomes. When considered alone or in combination with each other, the major forms of therapy did not predict response to thymectomy: rates of remission plus improvement were 67% (8 of 12) with plasmapheresis plus AC, 77% (40 of 52) with steroids plus AC, 62% (13 of 21) with intravenous -globulin plus AC, and 45% (9 of 20) with AC alone. No significant correlation was found between treatment and outcomes.
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Comment |
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The proportion of overall improvement (75%) in this study compares favorably with other large studies. The complete remission rate of 21% is slightly lower; however, comparison among studies is often difficult, because of differing patient exclusion criteria among series (eg, patients without thymoma [12]) and, as mentioned above, the variable nature of symptoms and multiple classification systems [8]. In addition, it is frequently observed that postoperative remission from MG may not be achieved for several years [6, 10–12], and this delay may have reduced our rate of observed remission. Complete remission in our study was achieved in patients at an average of 66 ± 71 months postoperatively, which is longer than our average follow-up of 51 months. Therefore, if longer follow-up had been achieved, we may have expected an increase in our rate of complete remission.
The proportion of positive response in patients with purely ocular symptoms (60%) was not significantly different from either the overall beneficial response rate (75%) or the rate of any other modified Osserman category. Therefore the use of thymectomy is indicated in resistant ocular MG, as is recommended by other authors.
Age at the time of thymectomy has shown a strong correlation with outcomes. The large, detailed study by Masaoka and coworkers [11] found better outcomes in younger patients, and this finding has been echoed by other researchers [9, 11, 13, 14]. Our study found a similar trend, with 81% of those 50 years of age or younger improving, versus 55% of those older than 50. Not surprisingly, there has been debate regarding surgical treatment in the elderly: whereas many studies have shown safe, effective relief from thymectomy in patients older than 60 years [15, 16], other studies do not recommend this procedure for this group [17]. We found a linear relationship with a strong trend (p = 0.05) toward deterioration in MG disease after thymectomy as age increased: 6.1% poor responders among those younger than 39 years of age, 8.3% among those 39 to 52 years, and 26% among those 53 years or older. Our results do demonstrate, however, that thymectomy in elderly patients may be safely performed without significant perioperative morbidity or mortality. Complication rate was not higher in those older than 50 years, with a 30-day mortality of 3.7%, the lone death occurring suddenly from unknown causes.
Patient sex is a factor that shows disparate associations among studies. Many studies have found improved outcome in female patients [7, 14], whereas others have found increased improvement in male patients [18] or no sex predilection [12, 19, 20]. On univariate analysis, we found a significantly increased proportion of improved female patients, 80% versus 57% in male patients, and that male patients more often had a poor response than female patients (24% versus 7%). The multivariate analysis, however, did not bear out this statistical significance (p = 0.34); age, symptom severity, and pathology ultimately proved to be confounding factors. These findings validate the importance of using a multivariable logistic regression to assess the outcome in such a complex disease as MG.
Thymic histology is also a relatively consistent predictor of response: hyperplasia correlates in many studies with increased improvement rates [13, 15, 21, 22]. Overall, we detected no differences in proportion of benefit with respect to histologic type. However, the presence of thymoma has often been found to correlate with poorer response to thymectomy [9, 11, 23, 24]: Masaoka and colleagues [11] found, in their large study of 375 patients, significantly decreased remission or palliation rates in patients with thymomas after 15 years of follow-up; Jaretzki and coworkers [12] found a decreased remission rate and increased mortality among thymomatous patients with MG; and we found that patients with thymoma were significantly more likely to experience deterioration. Thymomas were more common in women (70%) and those patients younger than 50 years of age (70%), with no increase in the mean age of those with thymomas. The mortality rate among patients with thymomas was no different from either the nonthymomatous patients or the overall mortality rate.
Surgical exposure is another issue of debate regarding thymectomy for MG. Many have advocated the "total" or "maximal" thymectomy as optimal surgical therapy [3, 12, 22], but the MGFA task force has recently deemed the issue of fullness of resection to be unresolved. Remission rates in series involving traditional transsternal approaches have ranged from 24% to 36% [25], compared with our complete remission rate of 21%. At our institution we advocate a limited, upper median sternotomy with a 2-inch, sternal T-shaped skin incision, which allows for excellent access to mediastinal and cervical contents, but spares the patient the morbidity of either a cervical incision or a full sternotomy. We performed 84% of thymectomies by this T approach and found no significant difference in outcome compared with the extended or full sternotomies or thoracotomies. No myasthenic patient required reoperation for recurrent symptoms, and among six invasive thymomas, there were no recurrences after a mean follow-up of 55 months.
In summary, our review of 113 myasthenic patients undergoing thymectomies shows improvement and remission rates similar to other studies. Our data show that thymectomy may be safely and effectively performed by a limited sternotomy with a T upper sternal incision, and that two groups traditionally believed to have prohibitively low likelihood of response—myasthenics older than 60 and those with solely ocular symptoms—can benefit from this procedure. Female sex, age, and thymic histology were found to correlate statistically with patient outcomes. Despite their predictive values, these factors should not serve to absolutely indicate or contraindicate this procedure for certain candidates, but rather should assist in decision-making and expectations.
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Acknowledgments |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsDiscussionReferences |
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Discussion |
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First of all, in your retrospective review you found that as patients increase in age they have less of a response to thymectomy. I was wondering if you could comment to the audience, what is your current recommendation regarding the age of the patient, especially elderly patients who have ocular symptoms only?
My second question is in regard to your preoperative management. I know that during the time of this review, which covered 25 years, you changed preoperative treatment of these patients. You do not use plasmapheresis now but intravenous gammaglobulin. At the Mayo Clinic, most of our patients undergo preoperative plasmapheresis except patients with ocular symptoms only. I would like to know why your institution switched to gammaglobulin and how has this affected postoperative respiratory problem?
Thirdly, was there any correlation regarding response to thymectomy and antiacetylcholine receptor antibody level?
Finally, what patient would you not operate on for myasthenia gravis? It seems from your data that every patient on whom you operated had some benefit. I commend you for your hard work and Dr Miller for expertise.
DR BUDDE: Thank you, Dr Miller. Thank you for your comments and questions. Your first question, would you repeat it?
DR MILLER: Because you found that older patients did not respond to thymectomy as well as your younger patients, what is your current recommendation regarding the age of the patient who should undergo thymectomy for myasthenia gravis?
DR BUDDE: OK. In the two trouble groups, the elderly and the patients with ocular symptoms, as we talked about, a lot of studies have shown different predictors of response, but I am not sure that has definitely precluded anybody from surgery.
At Emory, I think the biggest part of the decision would come from discussion with the patient and the family. If the patient is comfortable on the medication regimen and is not just exasperated by symptoms, I think in a person who was of advanced age that age might come into play in the decision, but I do not think it would outright preclude anybody from surgery, and that would be my thinking on the patients with ocular disease also.
In terms of the decision to treat preoperatively with plasmapheresis versus immunoglobulin, from what I know, immunoglobulin has a longer lasting effect preoperatively and the patients may benefit more from that treatment. However, I can say among our patients, many of the patients receive multiple modalities. In fact, I think a great percentage, probably 70% of the patients in our study, were also on steroids. So our practice has reflected the trend, but there was certainly no strict exclusion of any patient from any preoperative modality.
One other comment I would make is that we do work jointly with our neurologists and leave a lot of the preoperative therapy and most of the postoperative therapy in their hands.
In terms of antiacetylcholine antibodies, there are many studies showing a great correlation with that; however, we did not examine that aspect.
DR JOSEPH I. MILLER (Atlanta, GA): Thank you, Dan; I appreciate your comments. What I would say is we have a very large myasthenic population attracted to the excellent neurology department at Emory. One, in the older patients, after age 55, they are referred for surgery only when medical therapy has totally failed and they are getting progressively worse. Also, the only ocular patients that are referred for surgery are those who have been stable for a while and are then getting progressively worse on medication. We stopped using plasmapheresis, that is, the neurology department did, about 1985. They became enamored with steroids and then since 1995 they have used gammaglobulin on all patients being sent to surgery. I think there is a little less morbidity associated with gammaglobulin therapy than with undergoing plasmapheresis.
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