Gen Thorac Cardiovasc Surg (2014) 62:157–162 DOI 10.1007/s11748-013-0345-y
ORIGINAL ARTICLE
FDG PET/CT is useful for detecting infiltration to the port site in patients with malignant pleural mesothelioma Koji Kawaguchi • Tetsuo Taniguchi • Noriyasu Usami Takayuki Fukui • Futoshi Ishiguro • Shota Nakamura Kohei Yokoi
• •
Received: 4 September 2013 / Accepted: 3 November 2013 / Published online: 27 November 2013 Ó The Japanese Association for Thoracic Surgery 2013
Abstract Objective One reason for the poor outcomes of multimodality therapies, including macroscopic complete resection, in patients with malignant pleural mesothelioma (MPM) is the difficulty of correctly staging the disease, which can result in incomplete resection. The purpose of this study was to investigate the aspects of tumor infiltration to the port site and the usefulness of preoperative FDG PET/CT for diagnosing MPM. Methods Between June 2007 and May 2013, 21 patients who underwent surgical treatment with curative intent for MPM that had been previously diagnosed on a videoassisted thoracic surgery (VATS) biopsy were included in this study. Results There were 17 males and four females, with a mean age of 63 years. The accumulation of FDG at the port site was observed in all nine patients with tumor infiltration to the port site, whereas this feature was not noted in 15 patients without tumor extension to the port site. There were more positive lymph node cases in the infiltration group than in the non-infiltration group (p = 0.02). No significant differences in survival were observed between the patients with and without tumor infiltration to the port site. Conclusions FDG PET/CT is useful for detecting tumor infiltration of MPM to the port site and may help to prevent
K. Kawaguchi (&) T. Taniguchi N. Usami T. Fukui F. Ishiguro S. Nakamura K. Yokoi Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan e-mail: [email protected]
local recurrence, especially port site relapse, following macroscopic complete resection. However, this condition is related to tumor aggressiveness; therefore, performing careful staging and determining the appropriate treatment strategy are required in such patients. Keywords Malignant pleural mesothelioma Port site infiltration FDG PET/CT Staging
Introduction The surgical outcomes of extrapleural pneumonectomy (EPP) for malignant pleural mesothelioma (MPM) are far from satisfactory [1]. One reason for the poor outcomes is the difficulty of correctly staging the disease, which can result in incomplete resection [2]. Tumor extension to port sites created for the purpose of performing biopsies of tumors or drainage of pleural effusion has been reported to be a poor prognostic factor [3, 4]. Therefore, thoracic surgeons must excise all port sites with the specimens. However, it is difficult to confirm whether the tumor has infiltrated to the port site or only fibrous changes are present during surgery, which may result in a positive surgical margin at the port site [5]. If preliminary findings of tumor infiltration at the port site could be accurately obtained, then the ability to perform selective excision of port sites with an adequate margin would thus be expected to reduce the incidence of pathological positive surgical margins and local relapse. The purpose of this study was to investigate the aspects of tumor infiltration to the port site and the usefulness of preoperative [18F]-fluorodeoxyglucose positron emission tomography (FDG PET)/computed tomography (CT) for diagnosing MPM.
123
158
Patients and methods Between June 2007 and May 2013, 21 patients underwent surgical treatment with curative intent for MPM that had been pathologically diagnosed using a video-assisted thoracic surgery (VATS) biopsy. Surgical cases in which the diagnosis of MPM was made based on the findings of a needle biopsy, and those in which macroscopic complete resection was not accomplished were excluded from this study. Patient characteristics and clinical information were collected from the hospital database, and the study was approved by the Institutional Review Board of Nagoya University Hospital. We evaluated the perioperative findings and prognoses of the MPM patients with tumor infiltration to the port site, which represents an extension of the tumor into the soft tissue of the chest wall around the port site. Regarding preoperative staging procedures, all patients routinely underwent thin-slice contrast-enhanced CT and FDG PET/CT. These examinations were performed at both pre- and post-neoadjuvant chemotherapy when patients received it. The details of the FDG PET/CT scanners are the same as those described previously for evaluating thymic epithelial tumors [6]. In brief, the patients received an intravenous injection of 3.7–4.07 MBq/kg of FDG. Image acquisition was performed using a PET/CT scanner (Biograph16; Siemens Medical Solutions, Erlangen, Germany). The emission PET images were reconstructed using iterative ordered subset expectation maximization with non-contrast CT. For the semiquantitative assessment, regions of interest (ROIs) were overlaid on FDG-avid tumors, and the SUVmax [the maximum ROI activity (MBq/g)/injected dose (MBq)/body weight (g)] of each tumor was measured. The positive accumulation of FDG was defined as a SUVmax value [2.0 [7]. The staging system of the International Mesothelioma Interest Group (IMIG) for MPM was adopted in this study [8]. Tumor infiltration to the port site is staged as T3 in this system. The clinical staging was determined based on the radiological findings and the indications for the surgical procedures were judged carefully by multidisciplinary physicians. Regarding the preoperative evaluations of lymph node metastasis on FDG PET/CT, findings of a short diameter of the lymph node [1 cm and FDG accumulation were considered to be signs of lymph node metastasis. Our surgical treatment for MPM has changed during the study period. After the results of the MARS trial [9] were published, a feasibility study of pleurectomy/decortication (P/D) after neoadjuvant chemotherapy for resectable MPM was conducted in Japan. Our institution participated in this study and adopted the surgical method of P/D, especially in patients with an advanced stage of MPM. All patients underwent diaphragmatic resection and en bloc excision of
123
Gen Thorac Cardiovasc Surg (2014) 62:157–162
each port site from the skin, chest wall (muscles and fat tissue, without ribs) and uninterrupted to the parietal pleura in addition to EPP or P/D (Fig. 2). Reconstruction of the diaphragm and pericardium was performed using GoretexÒ patches (2 and 0.1 mm, respectively), if necessary. Neoadjuvant chemotherapy was usually administered and consisted of three courses of cisplatin and pemetrexed. Patients who underwent EPP were recommended to receive 54 Gy of postoperative radiotherapy for hemithorax approximately 2 months after the surgery. When the presence of tumor infiltration to the port site was proven on a pathologic examination, the administration of additional dose (usually 10 Gy/5 Fr) of radiation to the area was recommended. Comparisons of the preoperative findings were made using the Chi Square test. The survival time was measured from the date of surgery to the date of death or the last follow-up. Survival curves were estimated according to the Kaplan–Meier method, and differences in survival were assessed using the log-rank test. A p value of \0.05 was considered to be significant. The data were analyzed using the SPSS 20.0 software program (SPSS, Inc., Chicago, IL, USA).
Table 1 Characteristics of the patients who underwent macroscopic complete resection for malignant pleural mesothelioma Variable
Number of patients
Mean age (range)
63 (46–72)
%
Gender Male
17
81
Female
4
19
Epithelioid
16
76
Biphasic
5
24
Extrapleural pneumonectomy
17
81
Extended pleurectomy/decortication
4
19
13
62
Histology
Surgical procedure
pN status N0 N1
2
9
N2
6
29
Yes
15
71
No
6
29
Induction chemotherapy
Adjuvant therapy CT ? RT
3
14
RT
9
43
CT
1
5
None
8
38
CT chemotherapy, RT radiotherapy
Gen Thorac Cardiovasc Surg (2014) 62:157–162
159
Table 2 Comparison of the patients with and without tumor infiltration at the port site Variable
Positive
Negative
Gender
0.149
Male
6
11
Female
3
1
Yes
3
5
No
6
7
2.1
1.2
1–3
1–2
Chest pain
Number of the ports at VATS biopsy Mean Range
p
0.697
0.062
\0.001
Accumulation of FDG at the port sites on PET/CT Positive
9
0
Negative
0
12
Epithelioid
7
9
Biphasic
2
3
Positive
6
2
Negative
3
10
Histology
0.882
Lymph node metastasis
0.020
Results The characteristics of the 21 patients are shown in Table 1. There were 17 males and four females, with a mean age of 63 years. The epithelial subtype was most frequent, followed by the biphasic subtype. Preoperative FDG PET/CT for the purpose of staging or restaging following the administration of neoadjuvant therapy was performed approximately 17 days before the surgical treatment. A total of nine patients were found to have positive accumulation of FDG at the port site. Macroscopic complete resection with excision of all port sites was performed in all patients. Postoperative radiotherapy was administered in 12 patients with EPP, five of whom received additional radiation to port sites with proven tumor infiltration. On the other hand, only one patient who underwent P/D received postoperative radiotherapy to the site of the superior vena cava where the tumor was exposed during surgery. Table 2 shows the correlations between the patients with and without tumor infiltration to the port site according to various perioperative factors. Three (75 %) of the four females with MPM exhibited tumor infiltration to the port site, while positive infiltration was observed in six (35 %) of 17 male patients (p = 0.149). The histological subtype had no relationship to the presence of infiltration at the port site. The number of port sites used for biopsies was greater in the patients with tumor infiltration. The accumulation of FDG at the port site was observed in all nine patients with
positive infiltration; however, this feature was not detected in the 12 patients with negative infiltration. In addition, there were more positive lymph node cases in the infiltration group than in the non-infiltration group. Figure 1 shows the preoperative PET/CT and CT findings of three patients with tumor infiltration of the port site. Neither radiologists nor thoracic surgeons were able to detect tumor infiltration to the port site on contrastenhanced CT and/or with palpation; such cases were strongly suspected of involving infiltration on PET/CT only. All port sites were excised en bloc with the specimen in spite of the PET/CT and CT findings, and the pathologic results of them were carefully compared with the accumulation of FDG on preoperative PET/CT. Thirteen of 33 excised port sites were proven to be infiltrated with MPM, and 11 port sites were found to exhibit accumulation of FDG; the mean SUVmax was 3.8 (2.0–6.9). Five of the nine patients with positive port sites were proven to have positive surgical margins, although the surgeons tended to excise the port sites with an ‘adequate’ margin (Fig. 2). The median follow-up period was 9 months. Eight patients died of recurrent disease. The median survival and two-year survival rate were 37 months and 54 %, respectively. The survival curves of the patients with and without tumor infiltration to the port site are presented in Fig. 3. There were no significant differences in survival between the two groups.
Discussion Although multimodality therapies, including macroscopic complete resection, are administered in patients with MPM, the prognosis of the disease remains dismal [1, 5]. One reason for the poor outcomes is the difficulty of correctly staging the disease, which can result in incomplete resection [2]. In addition, it is impossible to excise the tumor with an adequately safe margin based on anatomical characteristics, that is, the pleura is not a parenchymatous organ and is widely adjacent to vital structures. It is well known that MPM easily infiltrates to port sites created for the purpose of performing biopsies of tumors or drainage of pleural effusion [3, 4]. The incidence of port site infiltration in this study was 43 % (nine of 21 patients), while that observed in patients with stage III MPM reported by Bolukbas and coworkers was up to 69 % [3]. Therefore, thoracic surgeons must excise all port sites during surgical resection; however, it is difficult to confirm whether the tumor has infiltrated to the port site or only fibrous changes are present during surgery [10]. As a result, in our study, five of the nine patients with tumor infiltration had a positive surgical margin at the port site. If preliminary findings of tumor infiltration at the port site could
123
160
Fig. 1 Preoperative PET/CT and CT findings of three patients with infiltration of malignant pleural mesothelioma (MPM) to the port site. Contrast-enhanced CT revealed no abnormal findings at the port sites, whereas the accumulation of FDG was clearly demonstrated on PET/ CT in each case (arrow). Pathologic examinations revealed tumor
Gen Thorac Cardiovasc Surg (2014) 62:157–162
infiltration to the port site in all cases. Left column 70-year-old female with the epithelioid subtype. Middle 60-year-old female with the epithelioid subtype. Right 67-year-old male with the epithelioid subtype
Fig. 2 Resected specimens with the skin and chest wall of the port sites. Left A specimen obtained via extrapleural pneumonectomy in concordance with the port site. Right A tumor infiltrating to the extrathoracic serratus anterior muscle of the port site (arrow)
be accurately diagnosed using PET/CT, the ability to perform selective excision of port sites with adequate margin would decrease the incidence of pathological positive surgical margins and perhaps local relapse. PET/CT is a useful tool for diagnosis, staging and conducting assessments of the efficacy of chemotherapy in patients with malignant diseases, including MPM. However, the sensitivity and specificity for intrathoracic staging of MPM are relatively low [2, 11–13]. In this study, findings of tumor infiltration at the port site were detected on
123
PET/CT with high accuracy. This is because the port sites were located outside of the thoracic cavity, where the effects of respiratory motion or inflammatory pleuritis are low. As it is difficult to diagnose MPM based on the results of cytological examinations of pleural effusion only, biopsies of the tumor or pleura using VATS are usually performed. In this study, the mean number of ports used for VATS biopsies in the 12 patients without tumor infiltration was only 1.2; therefore, the use of a lower number of ports may
Gen Thorac Cardiovasc Surg (2014) 62:157–162
161 Acknowledgments The authors wish to thank Takashi Nihashi and Katsuhiko Kato (Department of Radiology, Nagoya University Graduate School of Medicine) for their contribution to the measurement of SUVmax in each tumor. Conflict of interest interest exists.
The authors have declared that no conflict of
References
Fig. 3 Survival curves of the patients with and without tumor infiltration to the port site. There were no significant differences in survival between the two groups (p = 0.934)
be associated with the prevention of tumor extension into such areas. There were no significant differences in survival between the patients with and those without tumor infiltration to the port site in this study, in contrast to the findings of previous reports [3, 4]. Possible reasons for this discrepancy include the effectiveness of additional radiation to the port site and the short follow-up period. Nevertheless, the use of local therapies, including excision and radiation, is fundamental for overcoming MPM, as the disease exhibits a predilection for local progression rather than distant metastasis. There were more cases of positive lymph node metastasis in the patients with tumor infiltration, which may reflect tumor aggressiveness or malignant characteristics. Because the sensitivity and specificity for detecting mediastinal lymph node metastasis using PET/ CT and CT are extremely low in patients with MPM based on the findings of previous reports and this study (data not shown), performing additional histological examinations, such as mediastinoscopy or endobronchial ultrasound bronchoscopy, to evaluate the mediastinal lymph nodes is recommended in patients with aggressive disease [2, 14]. In conclusion, FDG PET/CT is useful for detecting tumor infiltration of MPM to the port site and may help to prevent local recurrence, especially port site relapse, after macroscopic complete resection. However, this condition is related to tumor aggressiveness; therefore, performing careful staging and determining the appropriate treatment strategy which sometimes includes non-surgical therapy is required in such patients.
1. Rusch VW, Giroux D, Kennedy C, Ruffini E, Cangir AK, Rice D, et al. Initial analysis of the international association for the study of lung cancer mesothelioma database. J Thorac Oncol. 2012;7:1631–9. 2. Flores RM, Akhurst T, Gonen M, Larson SM, Rusch VW. Positron emission tomography defines metastatic disease but not locoregional disease in patients with malignant pleural mesothelioma. J Thorac Cardiovasc Surg. 2003;126:11–6. 3. Bolukbas S, Eberlein M, Kudelin N, Demes M, Stallmann S, Fisseler-Eckhoff A, et al. Factors predicting poor survival after lung-sparing radical pleurectomy of IMIG stage III malignant pleural mesothelioma. Eur J Cardiothorac Surg. 2013;44:119–23. 4. Richards WG, Godleski JJ, Yeap BY, Corson JM, Chirieac LR, Zellos L, et al. Proposed adjustments to pathologic staging of epithelial malignant pleural mesothelioma based on analysis of 354 cases. Cancer. 2010;116:1510–7. 5. Krug LM, Pass HI, Rusch VW, Kindler HL, Sugarbaker DJ, Rosenzweig KE, et al. Multicenter phase II trial of neoadjuvant pemetrexed plus cisplatin followed by extrapleural pneumonectomy and radiation for malignant pleural mesothelioma. J Clin Oncol. 2009;27:3007–13. 6. Fukumoto K, Taniguchi T, Ishikawa Y, Kawaguchi K, Fukui T, Kato K, et al. The utility of [18F]-fluorodeoxyglucose positron emission tomography-computed tomography in thymic epithelial tumours. Eur J Cardiothorac Surg. 2012;42:e152–6. 7. Benard F, Sterman D, Smith RJ, Kaiser LR, Albelda SM, Alavi A. Metabolic imaging of malignant pleural mesothelioma with fluorodeoxyglucose positron emission tomography. Chest. 1998;114:713–22. 8. Rusch VW. A proposed new international TNM staging system for malignant pleural mesothelioma. From the International Mesothelioma Interest Group. Chest. 1995;108:1122–8. 9. Treasure T, Lang-Lazdunski L, Waller D, Bliss JM, Tan C, Entwisle J, et al. Extra-pleural pneumonectomy versus no extrapleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study. Lancet Oncol. 2011;12:763–72. 10. Husain AN, Colby T, Ordonez N, Krausz T, Attanoos R, Beasley MB, et al. Guidelines for pathologic diagnosis of malignant mesothelioma: 2012 update of the consensus statement from the International Mesothelioma Interest Group. Arch Pathol Lab Med. 2013;137:647–67. 11. Pilling J, Dartnell JA, Lang-Lazdunski L. Integrated positron emission tomography-computed tomography does not accurately stage intrathoracic disease of patients undergoing trimodality therapy for malignant pleural mesothelioma. Thorac Cardiovasc Surg. 2010;58:215–9. 12. Gerbaudo VH, Sugarbaker DJ, Britz-Cunningham S, Di Carli MF, Mauceri C, Treves ST. Assessment of malignant pleural mesothelioma with (18)F-FDG dual-head gamma-camera coincidence imaging: comparison with histopathology. J Nucl Med. 2002;43:1144–9.
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162 13. Erasmus JJ, Truong MT, Smythe WR, Munden RF, Marom EM, Rice DC, et al. Integrated computed tomography-positron emission tomography in patients with potentially resectable malignant pleural mesothelioma: staging implications. J Thorac Cardiovasc Surg. 2005;129:1364–70. 14. Schaefer NG, Veit-Haibach P, Soyka JD, Steinert HC, Stahel RA. Continued pemetrexed and platin-based chemotherapy in patients
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Gen Thorac Cardiovasc Surg (2014) 62:157–162 with malignant pleural mesothelioma (MPM): value of 18F-FDGPET/CT. Eur J Radiol. 2012;81:e19–25.
ORIGINAL ARTICLE
FDG PET/CT is useful for detecting infiltration to the port site in patients with malignant pleural mesothelioma Koji Kawaguchi • Tetsuo Taniguchi • Noriyasu Usami Takayuki Fukui • Futoshi Ishiguro • Shota Nakamura Kohei Yokoi
• •
Received: 4 September 2013 / Accepted: 3 November 2013 / Published online: 27 November 2013 Ó The Japanese Association for Thoracic Surgery 2013
Abstract Objective One reason for the poor outcomes of multimodality therapies, including macroscopic complete resection, in patients with malignant pleural mesothelioma (MPM) is the difficulty of correctly staging the disease, which can result in incomplete resection. The purpose of this study was to investigate the aspects of tumor infiltration to the port site and the usefulness of preoperative FDG PET/CT for diagnosing MPM. Methods Between June 2007 and May 2013, 21 patients who underwent surgical treatment with curative intent for MPM that had been previously diagnosed on a videoassisted thoracic surgery (VATS) biopsy were included in this study. Results There were 17 males and four females, with a mean age of 63 years. The accumulation of FDG at the port site was observed in all nine patients with tumor infiltration to the port site, whereas this feature was not noted in 15 patients without tumor extension to the port site. There were more positive lymph node cases in the infiltration group than in the non-infiltration group (p = 0.02). No significant differences in survival were observed between the patients with and without tumor infiltration to the port site. Conclusions FDG PET/CT is useful for detecting tumor infiltration of MPM to the port site and may help to prevent
K. Kawaguchi (&) T. Taniguchi N. Usami T. Fukui F. Ishiguro S. Nakamura K. Yokoi Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan e-mail: [email protected]
local recurrence, especially port site relapse, following macroscopic complete resection. However, this condition is related to tumor aggressiveness; therefore, performing careful staging and determining the appropriate treatment strategy are required in such patients. Keywords Malignant pleural mesothelioma Port site infiltration FDG PET/CT Staging
Introduction The surgical outcomes of extrapleural pneumonectomy (EPP) for malignant pleural mesothelioma (MPM) are far from satisfactory [1]. One reason for the poor outcomes is the difficulty of correctly staging the disease, which can result in incomplete resection [2]. Tumor extension to port sites created for the purpose of performing biopsies of tumors or drainage of pleural effusion has been reported to be a poor prognostic factor [3, 4]. Therefore, thoracic surgeons must excise all port sites with the specimens. However, it is difficult to confirm whether the tumor has infiltrated to the port site or only fibrous changes are present during surgery, which may result in a positive surgical margin at the port site [5]. If preliminary findings of tumor infiltration at the port site could be accurately obtained, then the ability to perform selective excision of port sites with an adequate margin would thus be expected to reduce the incidence of pathological positive surgical margins and local relapse. The purpose of this study was to investigate the aspects of tumor infiltration to the port site and the usefulness of preoperative [18F]-fluorodeoxyglucose positron emission tomography (FDG PET)/computed tomography (CT) for diagnosing MPM.
123
158
Patients and methods Between June 2007 and May 2013, 21 patients underwent surgical treatment with curative intent for MPM that had been pathologically diagnosed using a video-assisted thoracic surgery (VATS) biopsy. Surgical cases in which the diagnosis of MPM was made based on the findings of a needle biopsy, and those in which macroscopic complete resection was not accomplished were excluded from this study. Patient characteristics and clinical information were collected from the hospital database, and the study was approved by the Institutional Review Board of Nagoya University Hospital. We evaluated the perioperative findings and prognoses of the MPM patients with tumor infiltration to the port site, which represents an extension of the tumor into the soft tissue of the chest wall around the port site. Regarding preoperative staging procedures, all patients routinely underwent thin-slice contrast-enhanced CT and FDG PET/CT. These examinations were performed at both pre- and post-neoadjuvant chemotherapy when patients received it. The details of the FDG PET/CT scanners are the same as those described previously for evaluating thymic epithelial tumors [6]. In brief, the patients received an intravenous injection of 3.7–4.07 MBq/kg of FDG. Image acquisition was performed using a PET/CT scanner (Biograph16; Siemens Medical Solutions, Erlangen, Germany). The emission PET images were reconstructed using iterative ordered subset expectation maximization with non-contrast CT. For the semiquantitative assessment, regions of interest (ROIs) were overlaid on FDG-avid tumors, and the SUVmax [the maximum ROI activity (MBq/g)/injected dose (MBq)/body weight (g)] of each tumor was measured. The positive accumulation of FDG was defined as a SUVmax value [2.0 [7]. The staging system of the International Mesothelioma Interest Group (IMIG) for MPM was adopted in this study [8]. Tumor infiltration to the port site is staged as T3 in this system. The clinical staging was determined based on the radiological findings and the indications for the surgical procedures were judged carefully by multidisciplinary physicians. Regarding the preoperative evaluations of lymph node metastasis on FDG PET/CT, findings of a short diameter of the lymph node [1 cm and FDG accumulation were considered to be signs of lymph node metastasis. Our surgical treatment for MPM has changed during the study period. After the results of the MARS trial [9] were published, a feasibility study of pleurectomy/decortication (P/D) after neoadjuvant chemotherapy for resectable MPM was conducted in Japan. Our institution participated in this study and adopted the surgical method of P/D, especially in patients with an advanced stage of MPM. All patients underwent diaphragmatic resection and en bloc excision of
123
Gen Thorac Cardiovasc Surg (2014) 62:157–162
each port site from the skin, chest wall (muscles and fat tissue, without ribs) and uninterrupted to the parietal pleura in addition to EPP or P/D (Fig. 2). Reconstruction of the diaphragm and pericardium was performed using GoretexÒ patches (2 and 0.1 mm, respectively), if necessary. Neoadjuvant chemotherapy was usually administered and consisted of three courses of cisplatin and pemetrexed. Patients who underwent EPP were recommended to receive 54 Gy of postoperative radiotherapy for hemithorax approximately 2 months after the surgery. When the presence of tumor infiltration to the port site was proven on a pathologic examination, the administration of additional dose (usually 10 Gy/5 Fr) of radiation to the area was recommended. Comparisons of the preoperative findings were made using the Chi Square test. The survival time was measured from the date of surgery to the date of death or the last follow-up. Survival curves were estimated according to the Kaplan–Meier method, and differences in survival were assessed using the log-rank test. A p value of \0.05 was considered to be significant. The data were analyzed using the SPSS 20.0 software program (SPSS, Inc., Chicago, IL, USA).
Table 1 Characteristics of the patients who underwent macroscopic complete resection for malignant pleural mesothelioma Variable
Number of patients
Mean age (range)
63 (46–72)
%
Gender Male
17
81
Female
4
19
Epithelioid
16
76
Biphasic
5
24
Extrapleural pneumonectomy
17
81
Extended pleurectomy/decortication
4
19
13
62
Histology
Surgical procedure
pN status N0 N1
2
9
N2
6
29
Yes
15
71
No
6
29
Induction chemotherapy
Adjuvant therapy CT ? RT
3
14
RT
9
43
CT
1
5
None
8
38
CT chemotherapy, RT radiotherapy
Gen Thorac Cardiovasc Surg (2014) 62:157–162
159
Table 2 Comparison of the patients with and without tumor infiltration at the port site Variable
Positive
Negative
Gender
0.149
Male
6
11
Female
3
1
Yes
3
5
No
6
7
2.1
1.2
1–3
1–2
Chest pain
Number of the ports at VATS biopsy Mean Range
p
0.697
0.062
\0.001
Accumulation of FDG at the port sites on PET/CT Positive
9
0
Negative
0
12
Epithelioid
7
9
Biphasic
2
3
Positive
6
2
Negative
3
10
Histology
0.882
Lymph node metastasis
0.020
Results The characteristics of the 21 patients are shown in Table 1. There were 17 males and four females, with a mean age of 63 years. The epithelial subtype was most frequent, followed by the biphasic subtype. Preoperative FDG PET/CT for the purpose of staging or restaging following the administration of neoadjuvant therapy was performed approximately 17 days before the surgical treatment. A total of nine patients were found to have positive accumulation of FDG at the port site. Macroscopic complete resection with excision of all port sites was performed in all patients. Postoperative radiotherapy was administered in 12 patients with EPP, five of whom received additional radiation to port sites with proven tumor infiltration. On the other hand, only one patient who underwent P/D received postoperative radiotherapy to the site of the superior vena cava where the tumor was exposed during surgery. Table 2 shows the correlations between the patients with and without tumor infiltration to the port site according to various perioperative factors. Three (75 %) of the four females with MPM exhibited tumor infiltration to the port site, while positive infiltration was observed in six (35 %) of 17 male patients (p = 0.149). The histological subtype had no relationship to the presence of infiltration at the port site. The number of port sites used for biopsies was greater in the patients with tumor infiltration. The accumulation of FDG at the port site was observed in all nine patients with
positive infiltration; however, this feature was not detected in the 12 patients with negative infiltration. In addition, there were more positive lymph node cases in the infiltration group than in the non-infiltration group. Figure 1 shows the preoperative PET/CT and CT findings of three patients with tumor infiltration of the port site. Neither radiologists nor thoracic surgeons were able to detect tumor infiltration to the port site on contrastenhanced CT and/or with palpation; such cases were strongly suspected of involving infiltration on PET/CT only. All port sites were excised en bloc with the specimen in spite of the PET/CT and CT findings, and the pathologic results of them were carefully compared with the accumulation of FDG on preoperative PET/CT. Thirteen of 33 excised port sites were proven to be infiltrated with MPM, and 11 port sites were found to exhibit accumulation of FDG; the mean SUVmax was 3.8 (2.0–6.9). Five of the nine patients with positive port sites were proven to have positive surgical margins, although the surgeons tended to excise the port sites with an ‘adequate’ margin (Fig. 2). The median follow-up period was 9 months. Eight patients died of recurrent disease. The median survival and two-year survival rate were 37 months and 54 %, respectively. The survival curves of the patients with and without tumor infiltration to the port site are presented in Fig. 3. There were no significant differences in survival between the two groups.
Discussion Although multimodality therapies, including macroscopic complete resection, are administered in patients with MPM, the prognosis of the disease remains dismal [1, 5]. One reason for the poor outcomes is the difficulty of correctly staging the disease, which can result in incomplete resection [2]. In addition, it is impossible to excise the tumor with an adequately safe margin based on anatomical characteristics, that is, the pleura is not a parenchymatous organ and is widely adjacent to vital structures. It is well known that MPM easily infiltrates to port sites created for the purpose of performing biopsies of tumors or drainage of pleural effusion [3, 4]. The incidence of port site infiltration in this study was 43 % (nine of 21 patients), while that observed in patients with stage III MPM reported by Bolukbas and coworkers was up to 69 % [3]. Therefore, thoracic surgeons must excise all port sites during surgical resection; however, it is difficult to confirm whether the tumor has infiltrated to the port site or only fibrous changes are present during surgery [10]. As a result, in our study, five of the nine patients with tumor infiltration had a positive surgical margin at the port site. If preliminary findings of tumor infiltration at the port site could
123
160
Fig. 1 Preoperative PET/CT and CT findings of three patients with infiltration of malignant pleural mesothelioma (MPM) to the port site. Contrast-enhanced CT revealed no abnormal findings at the port sites, whereas the accumulation of FDG was clearly demonstrated on PET/ CT in each case (arrow). Pathologic examinations revealed tumor
Gen Thorac Cardiovasc Surg (2014) 62:157–162
infiltration to the port site in all cases. Left column 70-year-old female with the epithelioid subtype. Middle 60-year-old female with the epithelioid subtype. Right 67-year-old male with the epithelioid subtype
Fig. 2 Resected specimens with the skin and chest wall of the port sites. Left A specimen obtained via extrapleural pneumonectomy in concordance with the port site. Right A tumor infiltrating to the extrathoracic serratus anterior muscle of the port site (arrow)
be accurately diagnosed using PET/CT, the ability to perform selective excision of port sites with adequate margin would decrease the incidence of pathological positive surgical margins and perhaps local relapse. PET/CT is a useful tool for diagnosis, staging and conducting assessments of the efficacy of chemotherapy in patients with malignant diseases, including MPM. However, the sensitivity and specificity for intrathoracic staging of MPM are relatively low [2, 11–13]. In this study, findings of tumor infiltration at the port site were detected on
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PET/CT with high accuracy. This is because the port sites were located outside of the thoracic cavity, where the effects of respiratory motion or inflammatory pleuritis are low. As it is difficult to diagnose MPM based on the results of cytological examinations of pleural effusion only, biopsies of the tumor or pleura using VATS are usually performed. In this study, the mean number of ports used for VATS biopsies in the 12 patients without tumor infiltration was only 1.2; therefore, the use of a lower number of ports may
Gen Thorac Cardiovasc Surg (2014) 62:157–162
161 Acknowledgments The authors wish to thank Takashi Nihashi and Katsuhiko Kato (Department of Radiology, Nagoya University Graduate School of Medicine) for their contribution to the measurement of SUVmax in each tumor. Conflict of interest interest exists.
The authors have declared that no conflict of
References
Fig. 3 Survival curves of the patients with and without tumor infiltration to the port site. There were no significant differences in survival between the two groups (p = 0.934)
be associated with the prevention of tumor extension into such areas. There were no significant differences in survival between the patients with and those without tumor infiltration to the port site in this study, in contrast to the findings of previous reports [3, 4]. Possible reasons for this discrepancy include the effectiveness of additional radiation to the port site and the short follow-up period. Nevertheless, the use of local therapies, including excision and radiation, is fundamental for overcoming MPM, as the disease exhibits a predilection for local progression rather than distant metastasis. There were more cases of positive lymph node metastasis in the patients with tumor infiltration, which may reflect tumor aggressiveness or malignant characteristics. Because the sensitivity and specificity for detecting mediastinal lymph node metastasis using PET/ CT and CT are extremely low in patients with MPM based on the findings of previous reports and this study (data not shown), performing additional histological examinations, such as mediastinoscopy or endobronchial ultrasound bronchoscopy, to evaluate the mediastinal lymph nodes is recommended in patients with aggressive disease [2, 14]. In conclusion, FDG PET/CT is useful for detecting tumor infiltration of MPM to the port site and may help to prevent local recurrence, especially port site relapse, after macroscopic complete resection. However, this condition is related to tumor aggressiveness; therefore, performing careful staging and determining the appropriate treatment strategy which sometimes includes non-surgical therapy is required in such patients.
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