asian cardiovascular and thoracic annals 2010 agasthian 234 9

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DOI: 10.1177/0218492310369017

2010 18: 234Asian Cardiovascular and Thoracic Annals Thirugnanam Agasthian and Soon Jia Lin

Clinical Outcome of Video-Assisted Thymectomy for Myasthenia Gravis and Thymoma

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O RIGINAL ARTICLE

Clinical Outcome of Video-AssistedThymectomy for Myasthenia Gravisand ThymomaThirugnanam Agasthian, FRCS, Soon Jia Lin, FRCS 1

National Cancer Center 1 National Heart Center Singapore

ABSTRACTWe reviewed our experience of video-assisted thoracoscopic thymectomy for myasthenia gravis and thymomas in 119 patients, aged 1283 years, who were treated between 1998 and 2007. Disease severity was graded using the Osserman classifi-

cation. To prevent rupture of the tumor capsule and tumor seeding, thymomas wereresected using a modified no-touch technique. Thymoma diameters were 1090 mm(mean, 50 mm). There were no operative deaths, 12 (10%) patients had complications,and 87 (73.1%) improved by 1 or more Osserman grades postoperatively. After follow-up of 1.910 years (mean, 4.9 years), 74 (62%) patients remained asymptom-atic, with 21% in complete stable remission. Using multivariate regression analysis,there were no statistical differences in median pre- and postoperative Osserman gradeswith regards to age, sex, duration of symptoms, and presence of thymoma. Video-assisted thoracoscopic thymectomy for myasthenia gravis and selected thymomas canachieve long-term clinical outcomes comparable to those of standard approaches.

(Asian Cardiovasc Thorac Ann 2010;18:2349)

KEYWORDS: Myasthenia Gravis, Thoracic Surgery, Video-Assisted, Thymectomy,Thymoma

INTRODUCTIONThymectomy is a well-established treatment for myas-thenia gravis and thymomas. There are many methods of thymectomy, but the optimal approach is unclear. 1

Minimally invasive techniques such as video-assisted thoracoscopic surgery (VATS) were introduced to pro-vide the benefits of less pain, faster recovery, and superior cosmesis. However, whether complete thymec-

tomy for myasthenia gravis can be achieved throughVATS, when this approach is indicated, and its safetyand long-term oncological efficacy for thymomasremain unclear. We reviewed our experience of VATSin patients with myasthenia gravis and thymoma.

PATIENTS AND METHODSThe records of 119 patients undergoing VATS thymec-tomy between 1998 and 2007 were reviewed

retrospectively. Institutional and ethics review board approval was obtained for the study. The mean age of the patients was 44 years (range, 1283 years) and 56.8% were female. Indications for thymectomy weremyasthenia gravis in 61 patients, thymoma associated with myasthenia gravis in 32, and thymoma alone in 26.All data, including contact telephone numbers, werekept in a master SPSS data spreadsheet (SPSS, Inc.,

Chicago, IL, USA) and updated every 6 months toensure that no patient was lost to follow-up. Myastheniagravis symptom severity was graded preoperatively bythe attending neurologists, using the Osserman classifi-cation: grade 0 asymptomatic; grade I ocular myas-thenia gravis; grade IIA slow onset, frequently ocular;grade III rapid onset of severe bulbar and skeletalmuscle weakness, with respiratory dysfunction gradu-ally spreading to skeletal and bulbar muscles; grade

Thirugnanam Agasthian, FRCS Tel: 65 64368232 Fax: 65 62257559 Email: [email protected] National Cancer Center, 11 Hospital Drive, Singapore 16960.doi: 10.1177/0218492310369017

SAGE Publications 2010 Los Angeles, London, New Delhi and Singapore ASIAN C ARDIOVASCULAR & T HORACIC ANNALS 2010, V OL. 18, N O . 3234

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IIB gradual onset of bulbar muscle involvement; and grade IV severe myasthenia gravis developing at least2 years after the onset of grade I or II symptoms. Onlywell-encapsulated noninvasive thymomas screened on preoperative computed tomography of the thorax wereselected for VATS. Thymectomy for ocular myastheniagravis was carried out when it was associated withthymoma or failure to control symptoms with medicaltherapy. All patients were optimally prepared for surgery medically by the neurologist: 54.7% were onsteroids, 78.7% on anticholinesterases, and 16% onimmunosuppressives (azathioprine or mycophenolate).Two patients in Osserman grade III needed preoperative plasmapheresis or intravenous immunoglobulin therapy.

Patients were assessed at 46 month intervals postoper-atively for clinical improvement in muscle strength.Detailed postoperative clinical outcomes were graded by the referring neurologist, using the Myasthenia

Gravis Foundation of America postintervention statusclassification. Complete remission was defined asasymptomatic and off all medications. The Ossermangrade and postintervention status at the last follow-upwere used to assess improvement rates. In addition, allthymoma patients underwent follow-up by the surgeonwith 6-monthly computed tomography of the thorax for the first 2 years, and yearly for the rest of their lives, for detection of tumor recurrence. Modified Masaoka stag-ing was used for staging: stage 1 no invasion and anintact capsule; stage 2 macro- or microscopic capsular invasion into perithymic fat; stage 3 invasion intosurrounding organs; and stage 4 pleural/pericardialdissemination. 2,3 Thymic carcinomas and WHO classB3 or C tumors were excluded from this series.

Following standard lung isolation using a double-lumenendotracheal tube, the patient was propped up 30degrees in a semi-supine position with a roll under theshoulder, and the ipsilateral arm was held abducted over a padded L screen to expose the axilla for port placement. At the start of the procedure, transientcarbon dioxide insufflation at pressures of 58mm Hgwas used in some cases to enhance rapid and completecollapse of the lung. For a nonthymomatous gland, our

preferred approach was from the right side.4

Three5-mm ports and one 10-mm port were inserted. A30 -angled camera was placed in the most lateral 5-mm port (Figure 1). When dissecting the opposite side of thegland, the contralateral phrenic nerve and pleural cavitywere easily visualized by shifting the camera from themost lateral 5-mm port to the medial 10-mm port, and opening the contralateral pleura completely. Thus theopposite phrenic nerve can be identified, and the gland can be safely dissected from the nerve under directvision. Radicalness and completeness of thymectomywere assessed anatomically at surgery by inspecting the

resected gland and tumor for macroscopically clear margins, and the thymic bed for residual ectopic fat.Unlike the VATS approach for nonthymomatous glands,certain oncological modifications were adopted for thymomas to minimize the risk of breaching the tumor capsule and tumor seeding. We describe this as ano-touch tumor-last technique: the surgical approachwas always from the side of the tumor to enable safedissection under direct vision; the nontumorous part of the thymus and perithymic fat were always dissected first and used for grasping and traction when dissectingthe tumor, to minimize the risk of capsular damage. If the tumor is dissected first, it may obstruct the surgicalfield, making dissection of the rest of the gland not onlydifficult but oncologically hazardous. All specimenswere safely removed via an endobag by enlarging one of the anterior port incisions through which a 28F chesttube was placed at the end of the operation. A HarmonicScalpel (ultrasonic dissectors) or bipolar diathermy

dissectors were used routinely, especially when dissect-ing close to the phrenic nerves, to avoid thermal injury. 5

As experience with this technique increased, extended resections were performed, including limited resectionof adjacent perithymic fat. En-bloc resection of phrenicnerve, pericardium, and a wedge of lung was undertakenalong with the tumor if it was found to invade and deemed oncologically safe.

Statistical analysis was carried out using SPSS software.Chi-squared or Fischers exact tests were used for categorical variables, and a 2-sample test for continuous

variables. Probability values were derived using both theKruskal-Wallis analysis of variance and Wilcoxonsigned-rank nonparametric test. Multivariate linear regression analysis was performed for selected vari-ables; p < 0.05 was considered significant. Cumulativecomplete stable remission rates were calculated usingKaplan-Meier curves.

RESULTSOverall, the right-sided approach was used in 93.2% of cases; for thymomas the right-sided approach was used in 79.3% because the side of approach was always from

the side of the tumor for oncological reasons. The meanduration of surgery was 149.8min (range, 60289 min).Mean hospital stay was 5 days (range, 215 days). Most patients were fit for discharge on the 3 rd postoperativeday but stayed longer for social reasons and the lack of home- or community-based services in our country. The patient who stayed for 15 days had a myasthenic crisison the 3 rd postoperative day, which required extended hospitalization. Mean follow-up was 4.9 years (range,1.910 years) and it was complete in all patients. Therewere no operative deaths. Operative morbidity was 10%:3 patients had superficial wound infections, 1 had

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pneumothorax, 2 had minor bleeding, 1 had phrenicnerve injury, 4 had myasthenic crisis, and 1 had acholinergic crisis. The patient with phrenic nerve injurywas asymptomatic except for an elevated right-sided hemidiaphragm. The nerve injury was probably due tothermal damage arising from use of a monopolar

thoracoscopic hook dissector. Since then, we haveused either bipolar or ultrasonic dissectors when dis-secting the gland and fat from the phrenic nerves.Preoperatively, 24% of patients were in Osserman gradeI, 33% in grade 2, 35% in grade III, and 8% in grade IV.Postoperatively, clinical improvement of one or more

5MM 30degrees Camera

10MM Working port

5MM Working port

5MM Working port

Camera and instrument placements for right vats thymectomy

5MM Working port

10MM Working and extraction port

5MM Cameraport

5MM Working port

Right vats thymectomy

CRANIAL

(A)

(B)

Figure 1. Placement of the camera and instruments for right-sided thymectomies.

VATS Thymectomy Agasthian

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Osserman grades was seen in 87 (73.1%) patients; 64(53.8%) improved by 2 or more grades. The medianOsserman grade improved from 3.0 (mean, 2.88; range,14) preoperatively to 0 (mean, 0.32; range, 03) postoperatively. At follow-up, 74 (62%) patientsremained asymptomatic. The postintervention statusclassification showed that 21% of patients were in

complete stable remission and off all medication, 42%had reduced medical therapy, 18% were in remissionwith medication unchanged, 14% improved but required more medication, and 5% did not improve. TheKaplan-Meier cumulative estimate for complete stableremission continued to improve with time: 28% of patients were in complete stable remission at 5 years,52% at 6 years, and 82% at 8 years (Figure 2). Usingmultivariate regression analysis, there were no statisticaldifferences in median pre- and postoperative Ossermangrade changes with regards to patient age ( p 0.20),sex ( p 0.03), duration of preoperative symptoms( p 0.01), and presence of thymoma ( p 0.04).Histology of the resected thymus showed normal/atro- phic glands in 18 cases, cyst/involution in 4, hyperplasiain 39, and thymomas in 58. The mean size of thethymomas was 50 mm (range, 1090mm; Figure 3).There were 25 (43%) patients in Masaoka stage 1, 25(43%) in stage 2, 7 (12%) in stage 3, and 1 (1.7%) in

stage 4a. All patients had clear resection margins on pathological analysis. The 7 patients in stage 3 had thymomas with a mean diameter of 2.5 cm on preoper-ative computed tomography. At surgery, they werefound to have only limited localized involvement of the surrounding structures; as they were deemed oncologically safe and easily amenable to resection byVATS, it encouraged us to complete the resection rather than covert to an open procedure. Among the stage 3 patients, 2 had cuff of pericardium, 2 had phrenic nervealone, 2 had wedge of lung with cuff of pericardium, and one had pericardium and phrenic nerve removed en bloc

with the thymus and perithymic fat at the time of

5 CM Thymoma

Figure 3. A resected 5-cm thymoma.

Kaplan meier cumulative estimateof complete stable remission rates

0

0.1

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C o m p

l e t e s

t a b l e r e m

i s s

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2 3 4 5 6 7 8 9 10 11

Figure 2. The Kaplan-Meier cumulative estimate for

complete stable remission.

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surgery. Postoperative adjuvant radiotherapy was un-dertaken in 32% of patients; all of them had invasivethymomas. There have been 2 local recurrences: oneMasaoka stage 1 thymoma recurred locally 4 years after resection of a 6-cm tumor; the other was in a 40-year-old woman with a 5.5-cm stage 3 invasive thymoma, whohad postoperative radiotherapy, but suffered a relapse onthe contralateral surface 8 years after the initial surgery.Both patients underwent successful repeat resectionthrough a transsternal approach. The stage 4 patientwas a 76-year-old woman who had a 5.5-cm invasivetumor with adjacent satellite pleural nodules that wereall resected completely via VATS, with no recurrence at8 years after the initial surgery. No port site recurrenceshave been detected in any of the patients. At the lastfollow-up, all 58 thymoma patients were alive and well.

D ISCUSSIONThere is no consensus on the optimal procedure for thymectomy, because all approaches seem to be equallyefficacious. 69 This is because of the lack of a proper definition of complete thymectomy, and a lack of dataon which approach allows complete thymectomy withthe best possible long-term clinical outcome. VATSthymectomy was introduced because of the potential benefits of a decreased immune-mediated surgical stressresponse, reduced pain and chest wall trauma with lessimpairment of postoperative pulmonary function, and superior cosmesis, which all translate into faster recov-ery and fewer complications. 1012 However, theseadvantages would be secondary if complete thymectomy

was not feasible through VATS; a complete radicalanatomical thymectomy is feasible due to the 30camera which offers superior magnified panoramicvisualization and exposure of all aspects of the chest,from the thoracic inlet to pericardial-diaphragmaticrecesses, and phrenic nerve to phrenic nerve. 13 Wefound that complete thymectomy with visualization of both phrenic nerves and aortopulmonary window fat can be achieved with unilateral VATS by moving thecamera to a medial port and opening the opposite pleura. Completeness was confirmed anatomically at thetime of surgery by inspecting the specimen and the

resected thymic bed.

Our results are comparable to those of other standard approaches, in terms of major clinical outcomes. 1012

VATS was considered safe with no operative mortalityand low morbidity; our results are similar to those of other VATS thymectomy series. 6,8,14 Five of our patients had a myasthenic crisis prior to 2001. Sincethen, there have been no further postoperative crises, dueto better preoperative pharmacological control withoutthe fear of sternotomy-related complications. Somereports noted outcome differences related to age, sex,

duration of preoperative symptoms, and histology,whereas we found no significant differences related tothese variables. 15

VATS has been confined to small well-encapsulated thymomas, mainly due to oncological concerns (possible breach of tumor capsule, risk of tumor seeding). 6,16

However, as we gained experience in VATS thymecto-my for nonthymomatous myasthenia gravis, we realized that less invasive large tumors could be resected bymodifying the VATS technique. Our first experience of VATS for large thymomas was in a 73-year-old manwith a 9-cm tumor, who was deemed unfit for opensurgery. Our 2 patients who had local recurrences weretreated early in our experience, before we adopted theno-touch tumor-last technique. All stage 2 tumorswere well encapsulated and could be resected easily byVATS; microscopic capsular invasion was noted onlyafter final postoperative pathological analysis. Our stage

3 tumors were all small (

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