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Ann Thorac Surg 2006;82:1234-1239
© 2006 The Society of Thoracic Surgeons

Original Articles: General Thoracic

Pleuropneumonectomy for the Treatment of Masaoka Stage IVA Thymoma

Cameron D. Wright, MD*

Division of Thoracic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

Accepted for publication May 8, 2006.

* Address correspondence to Dr Wright, Division of Thoracic Surgery, Massachusetts General Hospital, Harvard Medical School, Blake 1570, 55 Fruit St, Boston, MA 02114 (Email: cameron{at}mgh.harvard.edu).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
BACKGROUND: The treatment of locally advanced Masaoka stage IVA thymoma is not standardized and is problematic.

METHODS: A single-institution retrospective study was made of 5 patients with World Health Organization B3 thymomas who underwent pleuropneumonectomy for locally advanced thymoma. Two patients had recurrent thymoma and 3 presented de novo with stage IVA disease. Patients had a variety of induction and adjuvant treatments.

RESULTS: There was no operative mortality, and only 1 patient had a major complication. Several patients had relatively prolonged disease-free survival. The median survival was 86 months, and the Kaplan-Meier survival was 75% (95% confidence interval: 53% to 97%) at 5 years and 50% (95% confidence interval: 25% to 75%) at 10 years.

CONCLUSIONS: Pleuropneumonectomy can be performed safely in patients with advanced thymomas and may improve survival. Highly selected patients might be cured with this approach if a complete resection is performed. While the optimal multimodality strategy for these patients is unknown, induction chemotherapy followed by resection then chemoradiotherapy seems promising.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 References
 
The treatment of locally advanced (Masaoka stage IVA), often recurrent, thymoma is not standardized and controversial. Treatment can be palliative or with curative intent and may involve all three common treatment modalities: surgery, radiation, and chemotherapy. Surgery may entail piecemeal resection of all gross disease with excision of all pleural implants or an en-bloc approach by pleuropneumonectomy. An aggressive approach with curative intent would seem to be warranted for a small number of highly selected patients with recurrent or locally advanced thymomas that extensively involve the pleural space. Our experience with pleuropneumonectomy for thymoma in 5 patients is reported.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
From our database of thymoma patients, which spans from 1972 to 2006 and includes 190 patients, 5 patients (2.6%) were located that underwent pleuropneumonectomy for advanced thymoma. The Human Studies Committee gave permission on November 8, 2005, and individual consent was waived for this retrospective study. Patient characteristics are given in Table 1. Patients 1 and 2 were treated for a recurrent thymoma whereas the other 3 presented with a new mediastinal thymoma and multiple pleural implants. All patients had a careful search for extrathoracic metastatic disease, which was negative. Two patients had pleural effusions that were sampled and found to be cytologically negative (patients 4 and 5). All patients had a paralyzed diaphragm as a result of the thymoma. All patients were relatively young, had no significant comorbidities, and had normal lung and heart function. Pleuropneumonectomy was performed in a standard fashion with reconstruction of the pericardium and diaphragm with a polytetrafluoroethylene (PTFE) patch. Survival was calculated from the date of resection and was estimated by the Kaplan-Meier method.


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  		Table 1. Patient Characteristics and Treatment
 

   Results
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 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
Representative imaging is seen in Figures 1 through 4, Go Go Go which show a spectrum of disease that is amenable to pleuropneumonectomy. There were no postoperative deaths, and only 1 patient had a complication. Patient 4 developed tamponade physiology several days after operation, requiring reexploration and removal of the pericardial patch. This patient also had findings consistent with right ventricular dysfunction that were present before operation and became quite symptomatic after operation. In retrospect, this was thought to be radiation related. The mean length of stay was 8 days (range, 5 to 15).


Figure 1
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  		Fig 1. Chest computed tomography scan of patient 1 with recurrent thymoma with confluent pleural disease in the left posterolateral hemithorax.

 

Figure 2
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  		Fig 2. Chest computed tomography scan of patient 4 before induction chemoradiotherapy. (A) Computed tomography scan at level of carina demonstrating extensive lobulated mediastinal mass with central area of necrosis and calcification and thick confluent rim of tumor surrounding lung and major fissure. A small area of loculated pleural effusion is seen anteriorly. (B) Computed tomography scan at level of inferior pulmonary vein demonstrating nearly confluent pleural tumor and large loculated pleural effusion.

 

Figure 3
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  		Fig 3. Chest computed tomography scan of patient 4 after induction chemoradiotherapy. (A) Computed tomography scan at level of carina demonstrating only very minimal reduction in size of tumor but with resolution of pleural effusion. (C) Computed tomography scan at level of inferior pulmonary vein demonstrating only minimal reduction in tumor thickness but near complete resolution of pleural effusion.

 

Figure 4
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  		Fig 4. Chest computed tomography scan of patient 5 after induction chemotherapy. (A) Computed tomography scan demonstrating anterior mediastinal tumor with lobulated contour, lack of fat planes and calcification. (B) Computed tomography scan at level of inferior pulmonary vein demonstrating mass invading lung, small focus of consolidation in the lower lobe, and loculated pleural effusion with pleural thickening. (C) Computed tomography scan at level of diaphragm demonstrating two pleural implants (I) at the medial heart border and confluent pleural implant (I) along the posterior gutter. The liver (L) is seen in cross section.

 
All patients had World Health Organization (WHO) type B3 tumors (so called well-differentiated thymic carcinoma or atypical thymoma). The first 2 patients presented originally with large tumors (Masoaka stage III) at high risk for pleural dissemination. Both underwent a complete resection including the phrenic nerve, and patient 1 had adjuvant radiotherapy. Patient 1 had recurrence in the pleura 6 years after the first resection, then had 2 cycles of chemotherapy followed by pleuropneumonectomy and then 2 more cycles of the same chemotherapy (Fig 1). Patient 2 had recurrence in the pleura 7 years, 10 months after the first resection and then underwent pleuropneumonectomy followed by adjuvant mediastinal radiation. Patients 3, 4, and 5 underwent resection of the primary thymoma in conjunction with their pleural disease. Two of the resections had positive microscopic resection margins—patient 4 at the chest wall and patient 5 on the pericardium and adventitia of the superior vena cava. Patient 3 underwent pleuropneumonectomy followed by adjuvant chemotherapy (4 cycles) and radiation. Patient 4 had induction concurrent chemoradiotherapy (4 cycles) followed by pleuropneumonectomy followed by adjuvant chemotherapy (6 cycles; Figs 2 and 3). Patient 5 had 5 cycles of induction chemotherapy followed by pleuropneumonectomy followed by concurrent chemoradiotherapy (low-dose radiation–sensitizing cisplatin; Figs 4 and 5).Go The Kaplan-Meier 5-year survival was 75% (95% confidence interval: 53% to 97%), and 10-year survival was 50% (95% confidence interval: 25% to 75%). The median survival was 86 months. There were no recurrences in the chest. Three patients had recurrences in the abdominal cavity, and 1 of these also had metastatic bone disease.


Figure 5
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  		Fig 5. Chest positron emission tomography scan of patient 5 before and after chemotherapy. (A) Positron emission tomography scan at the level of the lower chest demonstrating very bright uptake in tumor. (B) Positron emission tomography scan at the level of the lower chest demonstrating marked decrease in uptake after chemotherapy.

 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
Thymomas are most likely to recur in the pleural space as droplet metastases after resection of a thymoma that abuts that pleural space [1–5]. Likewise, the first site of spread of an unresected thymoma is the pleural space. The treatment of patients with pleural implants is not standardized and is controversial. There is no question that thymomas respond well to complete resection, radiation, and chemotherapy [1–7]. How these modalities are integrated to provide a favorable outcome in this rare subset of patients is always going to remain problematic as each case is almost unique.

We have come to the conclusion pleuropneumonectomy is probably beneficial to these patients, and that the optimal treatment also involves induction chemotherapy and then adjuvant chemoradiotherapy. This regimen is best typified by patient 5, the patient we most recently treated (Figs 4 and 5). This patient had a partial response to chemotherapy with a reduction in size of his tumor and a reduction in positron emission tomography activity. He then went on to resection of his tumor along with the pericardium, the superior vena cava (which was replaced with a PTFE ringed graft), the pleura and lung, and the diaphragm. After satisfactory recovery, he underwent adjuvant mediastinal radiation with low-dose cisplatin. Although we prefer to do induction concurrent chemoradiotherapy for clinical stage III thymomas to achieve maximal downstaging, we now do not recommend it in this scenario in which a pneumonectomy is going to be part of the resection. Several reports suggest elevated perioperative mortality from induction chemoradiotherapy for lung cancer from damage to the remaining lung [8]. Our fourth patient also had right heart dysfunction during therapy that worsened postoperatively, which is not unexpected since there was a huge tumor covering the anterior and lateral aspects of her heart that were in the radiation field. This strategy of induction chemotherapy alone is used by most centers to treat locally advanced or "unresectable" thymomas within the context of multimodality therapy [2, 7].

Most reports of thymomas indicate that a complete resection is a strong predictor of freedom from recurrence [1]. Obtaining a complete resection when there are numerous pleural implants is problematic, as simple parietal pleurectomy leaves disease behind on the mediastinal, visceral, and diaphragmatic pleura. In addition, most cases where pleuropneumonectomy is considered have lung implants or direct extension rather deep into the lung. Although it is difficult to envision a true complete resection by means of a pleuropneumonectomy, this procedure can come very close and leave just microscopic disease behind. The fact that the tumor responds to both radiation and chemotherapy allows further treatment with possible curative intent of the remaining minimal disease.

The situation is somewhat analogous to mesothelioma, where again pleuropneumonectomy is used as an important cytoreductive adjunct along with radiation and chemotherapy. This strategy actually makes more oncologic sense for thymomas, which can have rather long disease containing intervals and better responses to chemoradiotherapy than mesothelioma. Patient 2 is a proof of the principle that surgery with a complete resection may lead to a cure. This patient was early in our experience, before chemotherapy played a major role in these patients. She had no chemotherapy and is disease free more than 15 years after pleuropneumonectomy (24 years after her first diagnosis). The recurrence pattern is also similar to mesothelioma with peritoneal recurrences, either from migration through the diaphragm before operation or from spillage during operation.

The operation can be performed through a large posterolateral thoracotomy, as is usually the case for a pleuropneumonectomy (patients 1, 2, 4), with a second lower intercostal incision for diaphragm resection if needed. Alternatively the resection can be performed through a mediansternotomy (patients 3, 5) for better exposure of the mediastinum. This exposure facilitated superior vena cava resection in patient 5, and was helpful to remove the large anterior thymoma in patient 3. Others have reported pleuropneumonectomy by a midline approach [9]. It is important to try to stay out of the other pleural space to minimize the chance of seeding the opposite side with pleural implants as well. Pleuropneumonectomy has been relatively standardized by surgeons removing mesotheliomas, and their technique was followed [10]. At the initial exploration, the pleura should be attempted to be stripped off the chest wall to make sure a relatively clean resection can be done before dividing the central structures. Similar to mesothelioma, if extensive invasion is present into the intercostal muscles, then a resection is not likely to be of benefit. Sites that have residual gross or microscopic disease should be marked with clips to facilitate postoperative radiation.

The selection criteria for pleuropneumonectomy are rather strict given the magnitude of the operation. In general, they are quite similar to those for mesothelioma. Patients should be relatively young and fit, with excellent cardiopulmonary function. Metastatic disease should be sought for and ruled out. We have found PET scans useful in this regard and would obtain combined whole body CT/PET scans to examine the most likely sites. There should be no disease in the opposite chest. If myasthenia gravis is present, it must be well controlled. Plasmapheresis and intravenous gamma globulin are used if active myasthenia is present. If induction therapy is given, recovery of the functional status, bone marrow, and nutrition must be assured. The CT scan should be of high quality with contrast enhancement, and the points of tumor abutment to important structures should be carefully scrutinized for subtle signs of invasion. In general, structures such as the innominate vein and the superior vena cava can be resected without much morbidity, but aortic or main pulmonary artery invasion seem too much in the context of the other disease. All of our patients had preexisting phrenic nerve paralysis, thus reducing the function of the affected lung and hence minimizing the impact of lung removal. Pleuropneumonectomy should not be performed in cases in which there are only limited, easily resected pleural droplets—in this case, a limited resection should be performed in conjunction with chemotherapy.

The survival of this group of patients with rather extensive disease seems fairly good when compared with either patients with stage IVA disease or B3 tumors from other series. In our own series of patients, there were 11 patients with stage IVA disease with a 10-year survival of 25%, and 51 patients with B3 tumors with a 10-year survival of 60% [1].

In a large collected Japanese series of 67 patients with stage IVA disease, the 10-year survival was 45% [11]. In another large collected Japanese series with 26 B3 tumors, the 10-year survival was 75% [12]. Our series survival seems especially good considering not only the advanced Masaoka stage of the patients but also that they were all B3, the worst histologic type of thymoma.

There have been several case reports in the Japanese literature on pleuropneumonectomy for stage IVA thymoma, but with only short follow-up [13–17]. These previous reports demonstrated it was technically feasible and had good short-term results. Haniuda and colleagues [5] reported 2 patients who had pleuropneumonectomy for recurrent thymoma involving the pleura who both had severe myasthenia gravis and required prednisone. Both patients, however, died of complications after operation. Repeated hemithorax radiation in 6 patients with recurrent pleural thymoma was reported by Ichinose and colleagues [18]. The estimated 5-year survival was very high at 88% [18]. A novel form of treatment for pleural dissemination of thymoma was reported by Terada and colleagues [19]. They reported use of trans-arterial infusion chemotherapy delivered through the intercostal and subphrenic arteries in 2 patients. The tumors did not subsequently grow over the 24 and 19 months that the patients were observed.

In summary, this small series suggests that pleuropneumonectomy can be performed safely and probably improves survival in selected patients with extensive stage IVA thymoma. Although the optimal multimodality strategy is unknown, we suggest that induction chemotherapy followed by pleuropneumonectomy and then by chemoradiotherapy is safe and might be the best sequencing.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 

  1. Wright CD, Wain JC, Wong DR, et al. Predictors of recurrence in thymic tumors: importance of invasion, World Health Organization histology, and size J Thorac Cardiovasc Surg 2005;130:1413-1421.[Abstract/Free Full Text]
  2. Ciccone AM, Rendina EA. Treatment of recurrent thymic tumors Seminar Thorac Cadiovasc Surg 2005;17:27-31.
  3. Ruffini E, Mancuso M, Oliaro A, et al. Recurrence of thymoma: analysis of clinicopathologic features, treatment and outcome J Thorac Cardiovasc Surg 1997;113:55-63.[Abstract/Free Full Text]
  4. Regnard JF, Zinzindohoue F, Maggdeleinat P, et al. Results of re-resection for recurrent thymomas Ann Thorac Surg 1997;64:1593-1598.[Abstract/Free Full Text]
  5. Haniuda M, Kondo R, Numanami H, et al. Recurrence of thymoma: clinopathological features, re-operation and outcome J Surg Oncol 2001;78:183-188.[Medline]
  6. Eng TY, Thomas CR. Radiation therapy in the management of thymic tumors Semin Thorac Cardiovasc Surg 2005;17:32-40.[Medline]
  7. Evans TL, Lynch TJ. Role of chemotherapy in the management of advanced thymic tumors Semin Thorac Cardiovasc Surg 2005;17:41-50.[Medline]
  8. Albain KS, Swann RS, Rusch VR, et al. Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA (pN2) non-small cell lung cancer (NSCLC); outcomes update of North American Intergroup 0139 (RTOG 9309) J Clin Oncol 2005;23:7014abstract.
  9. Martin-Ucar AE, Stewart DJ, West KJ, Waller DA. A median sternotomy approach to right extrapleural pneumonectomy for mesothelioma Ann Thorac Surg 2005;80:1143-1145.[Abstract/Free Full Text]
  10. Chang MY, Sugarbaker DJ. Extrapleural pneumonectomy for diffuse malignant pleural mesothelioma: techniques and complications Thorac Surg Clin 2004;14:523-530.[Medline]
  11. Kondo K, Monden Y. Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan Ann Thorac Surg 2003;76:878-885.[Abstract/Free Full Text]
  12. Okumura M, Ohta M, Tateyama H, et al. The World Health Organization classification system reflects the oncologic behavior of thymoma Cancer 2002;94:624-632.[Medline]
  13. Suito T, Ikeda T, Sakai T, Fukayama M. Pleuropneumonectomy in malignant thymoma with pleural dissemination-a case report Nippon Kyobu Geka Gakkai Zasshi 1988;36:99-103.[Medline]
  14. Suzuki S, Okada S, Nagamoto N, et al. Pleuropneumonectomy with thymectomy for invasive thymoma with pleural disseminations-a case report Nippon Kyobu Geka Gakkai Zasshi 1990;38:1371-1374.[Medline]
  15. Shinada J, Yoshimura H, Hirai S, et al. Pleuropneumonectomy with combined resection of diaphragm, superior vena cava, and pericardium for invasive thymoma with pleural dissemination Kyobu Geka 1991;44:949-952.[Medline]
  16. Okada Y, Kondo T, Handa M, et al. Surgical treatment of stage IVA thymoma Kyobu Geka 1993;46:35-40.[Medline]
  17. Shih DF, Wang JS, Tseng HH, Tiao WM. Primary pleural thymoma Arch Pathol Lab Med 1997;121:79-82.[Medline]
  18. Ichinose Y, Ohta M, Yano T, et al. Treatment of invasive thymoma with pleural dissemination J Surg Oncol 1993;54:180-183.[Medline]
  19. Terada Y, Kambayashi T, Okahashi S, et al. Trans-arterial infusion chemotherapy for recurrence of pleural dissemination after thymectomy Ann Thorac Surg 2005;79:e32-e33.[Abstract/Free Full Text]



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