Clinical Imaging 39 (2015) 56–61
Contents lists available at ScienceDirect
Clinical Imaging journal homepage: http://www.clinicalimaging.org
Invasive lung cancer staging: influence of CT-guided core needle biopsy on onset of pleural carcinomatosis Paul Flechsig a,b,⁎, Josef Kunz b,c, Claus-Peter Heussel b,c, Farastuk Bozorgmehr b,d, Philipp Schnabel b,e, Hendrik Dienemann b,f, Hans-Ulrich Kauczor a,b, Oliver Sedlaczek a,b a
Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany Member of the German Center for Lung Research DZL, Translational Lung Research Center Heidelberg, Heidelberg, Germany Division of Diagnostic and Interventional Radiology with Nuclear Medicine, Thoraxklinik at Heidelberg University, Heidelberg, Germany d Division of Oncology, Thoraxklinik at Heidelberg University, Heidelberg, Germany e Department of General Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany f Division of Thoracic Surgery, Thoraxklinik at Heidelberg University, Heidelberg, Germany b c
a r t i c l e
i n f o
Article history: Received 3 February 2014 Received in revised form 18 September 2014 Accepted 9 October 2014 Keywords: Tumor spread Pleural carcinomatosis Lung cancer Computed tomography Biopsy
a b s t r a c t In lung cancer patients with single peripheral lesions, CT-guided needle biopsies (CTNBs) are common for histological sampling. Recently published studies showed conflicting results for the influence of CTNB on the onset of pleural carcinomatosis (PC). In order to estimate the influence of CTNB on pleural tumor spread, 146 histologically confirmed cases of lung cancer diagnosed by CTNB were retrospectively compared to 112 control lung cancer patients diagnosed by non-CTNB. CTNB was not associated with an earlier onset of PC, identifying CTNB as a safe procedure for minimally invasive lung cancer staging. © 2015 Elsevier Inc. All rights reserved.
1. Introduction In patients with suspected pulmonary cancer, the acquisition of histological samples is a prerequisite for the initiation of adequate treatment regimens. Invasive staging techniques such as transbronchial biopsy (TBB) and mediastinoscopy (MTS) are used for the initial tumor classification and for therapeutic planning. They are usually performed complementary to noninvasive methods such as computed tomography (CT), magnetic resonance imaging and particularly 18Ffluorodeoxyglucose/positron emission tomography–CT, which is the current standard for the noninvasive evaluation of mediastinal and hilar lymph node involvement in patients with lung cancer [1,2]. Besides TBB and MTS, CT-guided transthoracic needle biopsy (CTNB) plays an important role in the acquisition of tumor tissue, especially in patients with a single lesion in peripheral lung parenchyma [3,4]. Besides procedure-specific risks such as pneumothorax and hemorrhage, several case reports document tumor spread along the needle track which could be associated with progressive disease during follow-up [3,5–8]. Recently published studies show conflicting results for the onset of pleural metastasis after CT-guided biopsy and long⁎ Corresponding author. Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, INF 110, 69120 Heidelberg, Germany. Tel.: +49 6221 56 36497; fax: +49 6221 565730. E-mail address: paul.fl[email protected] (P. Flechsig). http://dx.doi.org/10.1016/j.clinimag.2014.10.005 0899-7071/© 2015 Elsevier Inc. All rights reserved.
term survival. At least for TNM stage I patients, rates of about 9% of pleural carcinomatosis (PC) were detected in long-term survivors [9–12]. The aim of the study was to evaluate the impact of CTNB on the incidence and onset of PC in lung cancer patients compared to patients diagnosed by methods other than CTNB (non-CTNB). In order to quantify the risk of pleural tumor spread for patients of all TNM stages, we retrospectively identified patients from a database with 422 patients after CT-guided lung biopsy with follow-up CT-imaging in order to detect the onset of PC and soft tissue metastasis after at least 3 months from the date of biopsy. The onset of ipsi- and contralateral PC was correlated to the histological subtype and to the initial tumor stage.
2. Materials and methods 2.1. Patients Of 422 consecutive patients who underwent CTNB for tissue acquisition and had adequate CT follow-up imaging between the years 2003 and 2010, the initial diagnosis of lung cancer was confirmed in 146 patients. The remaining 277 patients either had benign histological findings (35 patients) or were patients with rebiopsies after MTS or pneumonectomy (242 patients). Biopsies were performed after noninvasive staging and prior to surgery or radio-/chemotherapy.
P. Flechsig et al. / Clinical Imaging 39 (2015) 56–61 Table 1 Therapy regimen according to the initial tumor stage CTNB Stage
Therapy regimen Local
I II III IV Total
Table 2 Initial tumor stages according to the revised seventh edition of TNM classification for lung cancer
Non-CTNB n
26 22 32 66 146
20 (77%) 16 (73%) 24 (75%) 29 (44%) 89 (61%)
Stage
n
Systemic 6 (23%) 6 (27%) 8 (25%) 37 (56%) 57 (39%)
Therapy regimen Local
I II III IV Total
9 10 45 48 112
57
9 (100%) 10 (100%) 36 (80%) 24 (50%) 79 (71%)
Systemic 0 (0%) 0 (0%) 9 (20%) 24 (50%) 33 (29%)
As a control group for a matched pair analysis (matched by tumor stage, therapy regimen, histology, adequate follow-up imaging), we retrospectively analyzed 112 patients diagnosed in the identical time period between the years 2003 and 2010. Since patients in the CTNB group tended to be in lower tumor stages and patients in the non-CTNB group were diagnosed with more invasive regimens, we performed a subgroup analysis to control any bias caused by the initial tumor stage (Kaplan–Meier survival analysis using logrank test for correlation of patients with same tumor stages in both groups), therapy regimen (Kaplan–Meier survival analysis using logrank test for patients with same therapy regimens in both groups) and histology (Kaplan–Meier survival analysis using log-rank test for patients with same histological confirmations in both groups) on the onset of PC. The study was conducted according to the guidelines of the institutional review board and standards of good clinical practice according to the Declaration of Helsinki. 2.2. Therapy regimens In order to discriminate between patients that underwent local and/ or systemic therapy, the applied therapeutic regimens were divided into two groups (Table 1): • Local therapy: radiotherapy, lobectomy or pneumonectomy • Systemic therapy, i.e. chemotherapy • Patients who underwent a multimodal treatment (surgery and radio-/ chemotherapy) were classified as surgery (local). 2.3. CTNB CTNBs were performed in single-center (Thoraxklinik Heidelberg) setting using standard methods. Scans were performed at 120 kV, 30 mAs using a 4×1.25-mm collimation (Siemens Volume Zoom; Siemens Medical Solution, Forchheim, Germany). After an initial nonenhanced CT examination for biopsy planning, needle access was chosen individually targeting according to the tumor localization and considering organs such as scapula, vessels, mediastinum, and fissure. The procedure was undertaken in coaxial technique. Contact to the lower edge of the ribs was avoided if possible, in order to protect intercostals nerves and vessels. CT-guided two to four core-cut samples of the suspected mass were taken (Bard 15G, Tempe, AZ, USA). Pneumothorax and hemorrhage were ruled out in the concluding CT scan covering access channel, target lesion, and potential pneumothorax location. 2.4. Follow-up examinations Contrast-enhanced CT (CE-CT) scans were performed at restaging visits in order to observe local tumor response, potential lymphatic spread, and metastases. Assessments were performed using the CT scanner mentioned above with a biphasic injection of 40 ml at 2 ml/s contrast agent (Iopamidol-300; Bracco Imaging, Konstanz, Germany) followed by a second bolus of 60 ml at 2 ml/s after 40 s with 30 ml of saline flush at the CT scanner as mentioned before covering from below
CTNB Stage
I II III IV Total
Non-CTNB n
26 (18%) 22 (15%) 32 (22%) 66 (45%) 146 (100%)
Subgroup a
b
16 2 18
10 20 14
Stage
n
I II III IV Total
9 (8%) 10 (9%) 45 (40%) 48 (33%) 112 (100%)
Subgroup a
b
3 1 26
6 9 19
the adrenal glands through the lung apices. CT data sets were reconstructed at a slice thickness of 3.0 mm using a 2.5-mm increment with a B30 standard soft tissue kernel and a B70 high-resolution kernel. PC was defined as progressive growth or increase of pleural nodules, or as malignant pleural effusion in cytology, soft tissue seedings as growing nodules along the chest wall [10]. Patients underwent 2 to 20 follow-up CTs within a follow-up period of 3 to 98 months; the average duration between biopsy and last CT examination was 17 months. Images were interpreted by radiologists with more than 5 years of experience in oncologic chest imaging.
2.5. Statistical analysis Statistical analysis was performed using SPSS (Version 17 for Windows; SPSS Inc., Chicago, IL, USA), SAS (Version 9.2 for Windows; SAS Institute Inc, Cary, NC, USA), and SigmaPlot (Systat Software GmbH, Erkrath, Germany). Statistical analyses were supposed to be exploratory. The term “significant” refers to P values b.05. Differences between two independent samples of quantitative data were tested using the two-sample t test if the assumption of normality was not violated; otherwise, the Wilcoxon rank sum test was used. Median values±minimum and maximum were calculated and are illustrated in box-whisker plots. Failure time was analyzed using standard methods (Kaplan–Meier estimates of survivor curves, log-rank tests, and the Cox proportional hazards model). 3. Results 3.1. Patient demographics In correlation to the 146 CTNB-patients (33–86 years, 84 female, median age 64), the non-CTNB group consisted of 112 patients (28–75 years, 22 female, median age 61) diagnosed by means of TBB (n=51), MTS (n= 22), video-assisted thoracoscopy (n= 29), or biopsies of liver, brain, or bone metastases (n= 10) in the identical time period. Mean follow-up period of all included patients (CTNB, non-CTNB) was 17months. There was no significant difference between both groups in terms of age distribution (P=.31). 3.2. Histologies In the CTNB group, we detected 64 cases of adenocarcinoma (AC), 51 cases of squamous cell carcinoma (SCC), 9 cases of small cell lung cancer (SCLC), and 8 cases of neuroendocrine carcinoma (NET). Fourteen patients showed malignant histologies other than the above mentioned, i.e., basaloid carcinoma, mucoepidermoid carcinoma, and pleomorphic carcinomas. In the non-CTNB group, there were 67 cases of AC, 26 cases of SCC, 8 cases of SCLC, and 7 cases of NET. In four patients, histological entities other than the above mentioned were identified, i.e., basaloid carcinoma, mucoepidermoid carcinoma, and pleomorphic carcinomas.
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P. Flechsig et al. / Clinical Imaging 39 (2015) 56–61
P. Flechsig et al. / Clinical Imaging 39 (2015) 56–61
Fig. 2. Kaplan–Meier-plot of PC survival according to tumor histology. Patients with SCC had a significantly reduced risk for PC compared to patients with AC (P=.05).
3.3. Initial TNM According to the revised seventh edition of TNM classification for lung cancer, the patients presented the following clinical conditions at the time of the initial staging examination [13] (Table 2). Initial contact with pleural surface was found in 110 patients (75%) in the CTNB group and in 78 patients (70%) in the non-CTNB group. 3.4. Onset of PC after CTNB versus non-CTNB with PC-free survival rates Regarding CTNB patients, the incidence of PC was diagnosed in 18 out of 146 patients (12.4%) within the follow-up period of 98 months. In the control group, the onset of PC was diagnosed in 16 out of 112 cases (14.3%). Comparing the overall onset of PC after CTNB (n= 18/ 146) versus non-CTNB (n=16/112), there was no statistically significant difference between the compared methods (P= .49, hazard ratio=1.28, 95% confidence interval: 0.63 to 2.58; Fig. 1a). After subgroup analysis comparing patients with matched tumor stages, PC-free survival rates (PFS) was not significantly influenced by the choice of tissue acquisition [stage I (P= .386), stage II (P= .505), stage III (P=.567), stage IV (P=.609); Fig. 1b–e]. Regarding overall survival, there was a tendency toward a lower incidence of PC in patients undergoing non-CTNB. In long-term survivors after 60 months, patients with CTNB showed a tendency toward lower rates for the onset of PC (Fig. 1a). Subgroup analyses of different tumor histologies revealed a significantly reduced risk for PC in SCC patients compared to patients with AC (P=.05) (Fig. 2). Otherwise, the different types of tumor histologies had no significant influence on the onset of PC.
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Fig. 3. Kaplan–Meier-plot of PC survival according to the initial tumor stage. Patients with tumor stages 1 and 2 had a significantly reduced risk for PC compared to stage 3 and 4 patients.
CTNB), stage 2; P= .3] and within the higher tumor stages between stages 3 and 4 [n= 6/32 (CTNB) vs. 7/45 (non-CTNB), stage 3; 11/66 (CTNB) vs. 7/48 (non-CTNB), stage 4; P=.8] for PC-free survival (Fig. 3). 3.6. Onset of PC depending on therapy regimen Comparing systemic versus local therapy, we found a significantly reduced risk for PC with higher PFS in patients with local tumor therapy [mean PFS 81 months (20/168≙11.9%) (local) vs. mean PFS 53months (12/90≙13.3%) (syst); P=.01]. This difference was independent from the initial tumor stage since local therapy included patients undergoing both surgery (usually lower TNM stages) and radiotherapy (usually higher TNM stages; Fig. 4). 3.7. Seed metastases Out of the 146 patient with CTNB, there was one single case with a single nodule along the needle access infiltrating the intercostal chest wall muscles (0.7%) (Fig. 5). In no further follow-up, CT morphologic signs of seed metastases could be detected. 3.8. Pneumothorax, chest drainage, and hemorrhage The most common complications associated with CTNB was postinterventional pneumothorax in 30 out of 146 patients (20%), with 2 patients requiring pleural drainage (1.4%). There was no patient with any other severe post-CTNB complication such as hemoptysis, relevant hemorrhage requiring transfusion or intervention, prolonged hospitalization, or death.
3.5. Onset of PC depending on initial tumor stage 4. Discussion Subgroup analyses with regard to the initial tumor stage showed a significantly reduced risk for PC in patients presenting with stage 1 or 2 [n= 2/48 (CTNB) and 2/19 (non-CTNB)] versus stages 3 and 4 [n=16/98 (CTNB) and 14/93 (non-CTNB), P=.04]. No significant differences were seen within the lower stages between stages 1 and 2 [n=1/ 26 (CTNB) vs. 2/9 (non-CTNB), stage 1; 1/22 (CTNB) vs. 0/10 (non-
In our study, we did not detect an earlier or excessive onset of PC in patients after CTNB compared to non-CTNB. PC was not significantly increased after CTNB, even when analyzed according to TNM stage, histology, and therapy regimen. However, the onset of PC did depend on tumor histology.
Fig. 1. Kaplan–Meier-plot of PC-free survival. There is no significant difference in PC-free survival comparing patients with CTNB and patients with non-CTNB (a), even after subgroup analysis (b–e). Red line (CTNB), black line (non-CTNB). (a) overall PC-free survival (P=.29). (b) TNM stage I (P=.386). (c) TNM stage II (P=.505). (d) TNM stage III (P=.567). (e) TNM stage IV (P=.609).
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P. Flechsig et al. / Clinical Imaging 39 (2015) 56–61
Fig. 4. Kaplan–Meier-plot of PC survival depending on therapy regimen. Patients after local therapy had a significantly reduced risk for PC compared to patients with systemic therapy (P=.01).
Moreover, the study confirms the established correlation of a significantly reduced risk for PC in patients with a lower initial tumor stage (1 and 2) compared to stages 3 and 4. Accordingly, the specific risk for PC was significantly reduced after local therapy (surgery, radiotherapy) compared to systemic therapy (chemotherapy). The leaking influence of different biopsy types for all tumor stages on the onset of PC is in accordance with findings from Asakura et al. [12], who examined TNM stage I patients after surgery, comparing CTNB vs. bronchoscopy and thoracoscopic wedge resection. In their specific patient population, no evidence was found for an increased risk of pleural recurrence after CTNB. The data presented in this study suggest that this finding can be extended to patients of all TNM stages, irrespective of tumor histology and therapy regimen. This is noteworthy, since not all patients after CTNB are undergoing surgery. Concerning different therapy regimens, there was a tendency toward more invasive therapies in patients undergoing MTS or TBB instead of CTNB. This might be due to the fact that in our study center, patients with good physical condition
often proceeded with the more invasive staging techniques (MTS, TBB) while patients with concomitant diseases (chronic obstructive pulmonary disease, heart failure) may undergo the less demanding procedure of CTNB. Wisnivesky et al. [9] recently investigated postinterventional survival after preoperative percutaneous needle biopsy in stage I lung cancer patients, and could not find negative effects on overall and cancer deaths after CTNB. This seems to be quite in line with our findings, even though we examined PC-free survival and did not look at the overall survival of patients. Nevertheless, our results differ from findings by Matsuguma et al. [10] and Inoue et al. [11], who found an increased risk for pleural recurrence after CTNB for stage I NSCLC patients. We could not find a reason for this discrepancy, especially since the examined CT-guided biopsy techniques were quite similar. However, the incidence of other postinterventional complications (pneumothorax, hemorrhage) was within the previously reported ranges by Asakura et al. [12], Tsukada et al. [14], Saji et al. [15], and Yamauchi et al. [16]. Relevant limitations of this monocentric study are the retrospective design of the data and the relatively small number of patients. Even in this large center for thoracic surgery and oncology with more than 300 transthoracic needle biopsies per year, this was mainly due to the strict selection criteria and many patients being lost to follow-up due to early disease progression and outpatient care. The fact that we included patients in all TNM stages resulted in a relatively short mean follow-up period of 17 months, which was shorter than in comparable studies with 45 months [12], 60 months [11], and 80 months [10], who focused on stage I patients after surgery with much better prognosis. Nevertheless, the maximum follow-up period in our study was 98 months, indicating that healthy patients were followed up appropriately. Another limitation may be a potential selection bias between the CTNB and control groups. However, further subgroup analysis addressing site of intrapulmonal tumor localization and tumor size did not reveal significant differences, most likely due to the overall low incidence of PC. This issue was already emphasized in previously published studies [12] and could only be addressed by meta-analysis or analyzing larger cohorts in a multicenter setting. Our study indicates that the appropriate approach for tumor tissue acquisition in lung cancer patients should be chosen primarily depending on the clinically most feasible access road, with CTNB being a minimally invasive procedure, and thus safe to use in patients with relevant comorbidities. This is particularly true as excessive iatrogenic spread after CTNB is an extraordinarily rare event.
Fig. 5. *CT-image of access channel in lung cancer patient during biopsy. **Access channel of same patient 13 months post-biopsy and surgery. Needle track metastasis on the level of seventh rib in CE-CT highlighted by red lines.
P. Flechsig et al. / Clinical Imaging 39 (2015) 56–61
References [1] Kratochwil C, Haberkorn U, Giesel FL. PET/CT for diagnostics and therapy stratification of lung cancer. Radiologe 2010;50:684–91. [2] Abramyuk A, Appold S, Zophel K, Hietschold V, Baumann M, Abolmaali N. Quantitative modifications of TNM staging, clinical staging and therapeutic intent by FDGPET/CT in patients with non small cell lung cancer scheduled for radiotherapy — a retrospective study. Lung Cancer 2012;78:148–52. [3] Wu CC, Maher MM, Shepard JA. Complications of CT-guided percutaneous needle biopsy of the chest: prevention and management. AJR Am J Roentgenol 2011;196: W678–82. [4] Tomiyama N, Yasuhara Y, Nakajima Y, Adachi S, Arai Y, Kusumoto M, Eguchi K, Kuriyama K, Sakai F, Noguchi M, Murata K, Murayama S, Mochizuki T, Mori K, Yamada K. CT-guided needle biopsy of lung lesions: a survey of severe complication based on 9783 biopsies in Japan. Eur J Radiol 2006;59:60–4. [5] Kara M, Alver G, Sak SD, Kavukcu S. Implantation metastasis caused by fine needle aspiration biopsy following curative resection of stage IB non-small cell lung cancer. Eur J Cardiothorac Surg 2001;20:868–70. [6] Kim JH, Kim YT, Lim HK, Kim YH, Sung SW. Management for chest wall implantation of non-small cell lung cancer after fine-needle aspiration biopsy. Eur J Cardiothorac Surg 2003;23:828–32. [7] Redwood N, Beggs D, Morgan WE. Dissemination of tumour cells from fine needle biopsy. Thorax 1989;44:826–7. [8] Seyfer AE, Walsh DS, Graeber GM, Nuno IN, Eliasson AH. Chest wall implantation of lung cancer after thin-needle aspiration biopsy. Ann Thorac Surg 1989;48:284–6.
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[9] Wisnivesky JP, Henschke CI, Yankelevitz DF. Diagnostic percutaneous transthoracic needle biopsy does not affect survival in stage I lung cancer. Am J Respir Crit Care Med 2006;174:684–8. [10] Matsuguma H, Nakahara R, Kondo T, Kamiyama Y, Mori K, Yokoi K. Risk of pleural recurrence after needle biopsy in patients with resected early stage lung cancer. Ann Thorac Surg 2005;80:2026–31. [11] Inoue M, Honda O, Tomiyama N, Minami M, Sawabata N, Kadota Y, Shintani Y, Ohno Y, Okumura M. Risk of pleural recurrence after computed tomographic-guided percutaneous needle biopsy in stage I lung cancer patients. Ann Thorac Surg 2011;91: 1066–71. [12] Asakura K, Izumi Y, Yamauchi Y, Nakatsuka S, Inoue M, Yashiro H, Abe T, Sato Y, Nomori H. Incidence of pleural recurrence after computed tomography-guided needle biopsy in stage I lung cancer. PLoS One 2012;7:e42043-e42043. [13] Rami-Porta R, Crowley JJ, Goldstraw P. The revised TNM staging system for lung cancer. Ann Thorac Cardiovasc Surg 2009;15:4–9. [14] Tsukada H, Satou T, Iwashima A, Souma T. Diagnostic accuracy of CT-guided automated needle biopsy of lung nodules. AJR Am J Roentgenol 2000;175: 239–43. [15] Saji H, Nakamura H, Tsuchida T, Tsuboi M, Kawate N, Konaka C, Kato H. The incidence and the risk of pneumothorax and chest tube placement after percutaneous CT-guided lung biopsy: the angle of the needle trajectory is a novel predictor. Chest 2002;121:1521–6. [16] Yamauchi Y, Izumi Y, Nakatsuka S, Inoue M, Hayashi Y, Mukai M, Nomori H. Diagnostic performance of percutaneous core needle lung biopsy under multi-CT fluoroscopic guidance for ground-glass opacity pulmonary lesions. Eur J Radiol 2011;79:e85–9.
Contents lists available at ScienceDirect
Clinical Imaging journal homepage: http://www.clinicalimaging.org
Invasive lung cancer staging: influence of CT-guided core needle biopsy on onset of pleural carcinomatosis Paul Flechsig a,b,⁎, Josef Kunz b,c, Claus-Peter Heussel b,c, Farastuk Bozorgmehr b,d, Philipp Schnabel b,e, Hendrik Dienemann b,f, Hans-Ulrich Kauczor a,b, Oliver Sedlaczek a,b a
Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany Member of the German Center for Lung Research DZL, Translational Lung Research Center Heidelberg, Heidelberg, Germany Division of Diagnostic and Interventional Radiology with Nuclear Medicine, Thoraxklinik at Heidelberg University, Heidelberg, Germany d Division of Oncology, Thoraxklinik at Heidelberg University, Heidelberg, Germany e Department of General Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany f Division of Thoracic Surgery, Thoraxklinik at Heidelberg University, Heidelberg, Germany b c
a r t i c l e
i n f o
Article history: Received 3 February 2014 Received in revised form 18 September 2014 Accepted 9 October 2014 Keywords: Tumor spread Pleural carcinomatosis Lung cancer Computed tomography Biopsy
a b s t r a c t In lung cancer patients with single peripheral lesions, CT-guided needle biopsies (CTNBs) are common for histological sampling. Recently published studies showed conflicting results for the influence of CTNB on the onset of pleural carcinomatosis (PC). In order to estimate the influence of CTNB on pleural tumor spread, 146 histologically confirmed cases of lung cancer diagnosed by CTNB were retrospectively compared to 112 control lung cancer patients diagnosed by non-CTNB. CTNB was not associated with an earlier onset of PC, identifying CTNB as a safe procedure for minimally invasive lung cancer staging. © 2015 Elsevier Inc. All rights reserved.
1. Introduction In patients with suspected pulmonary cancer, the acquisition of histological samples is a prerequisite for the initiation of adequate treatment regimens. Invasive staging techniques such as transbronchial biopsy (TBB) and mediastinoscopy (MTS) are used for the initial tumor classification and for therapeutic planning. They are usually performed complementary to noninvasive methods such as computed tomography (CT), magnetic resonance imaging and particularly 18Ffluorodeoxyglucose/positron emission tomography–CT, which is the current standard for the noninvasive evaluation of mediastinal and hilar lymph node involvement in patients with lung cancer [1,2]. Besides TBB and MTS, CT-guided transthoracic needle biopsy (CTNB) plays an important role in the acquisition of tumor tissue, especially in patients with a single lesion in peripheral lung parenchyma [3,4]. Besides procedure-specific risks such as pneumothorax and hemorrhage, several case reports document tumor spread along the needle track which could be associated with progressive disease during follow-up [3,5–8]. Recently published studies show conflicting results for the onset of pleural metastasis after CT-guided biopsy and long⁎ Corresponding author. Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, INF 110, 69120 Heidelberg, Germany. Tel.: +49 6221 56 36497; fax: +49 6221 565730. E-mail address: paul.fl[email protected] (P. Flechsig). http://dx.doi.org/10.1016/j.clinimag.2014.10.005 0899-7071/© 2015 Elsevier Inc. All rights reserved.
term survival. At least for TNM stage I patients, rates of about 9% of pleural carcinomatosis (PC) were detected in long-term survivors [9–12]. The aim of the study was to evaluate the impact of CTNB on the incidence and onset of PC in lung cancer patients compared to patients diagnosed by methods other than CTNB (non-CTNB). In order to quantify the risk of pleural tumor spread for patients of all TNM stages, we retrospectively identified patients from a database with 422 patients after CT-guided lung biopsy with follow-up CT-imaging in order to detect the onset of PC and soft tissue metastasis after at least 3 months from the date of biopsy. The onset of ipsi- and contralateral PC was correlated to the histological subtype and to the initial tumor stage.
2. Materials and methods 2.1. Patients Of 422 consecutive patients who underwent CTNB for tissue acquisition and had adequate CT follow-up imaging between the years 2003 and 2010, the initial diagnosis of lung cancer was confirmed in 146 patients. The remaining 277 patients either had benign histological findings (35 patients) or were patients with rebiopsies after MTS or pneumonectomy (242 patients). Biopsies were performed after noninvasive staging and prior to surgery or radio-/chemotherapy.
P. Flechsig et al. / Clinical Imaging 39 (2015) 56–61 Table 1 Therapy regimen according to the initial tumor stage CTNB Stage
Therapy regimen Local
I II III IV Total
Table 2 Initial tumor stages according to the revised seventh edition of TNM classification for lung cancer
Non-CTNB n
26 22 32 66 146
20 (77%) 16 (73%) 24 (75%) 29 (44%) 89 (61%)
Stage
n
Systemic 6 (23%) 6 (27%) 8 (25%) 37 (56%) 57 (39%)
Therapy regimen Local
I II III IV Total
9 10 45 48 112
57
9 (100%) 10 (100%) 36 (80%) 24 (50%) 79 (71%)
Systemic 0 (0%) 0 (0%) 9 (20%) 24 (50%) 33 (29%)
As a control group for a matched pair analysis (matched by tumor stage, therapy regimen, histology, adequate follow-up imaging), we retrospectively analyzed 112 patients diagnosed in the identical time period between the years 2003 and 2010. Since patients in the CTNB group tended to be in lower tumor stages and patients in the non-CTNB group were diagnosed with more invasive regimens, we performed a subgroup analysis to control any bias caused by the initial tumor stage (Kaplan–Meier survival analysis using logrank test for correlation of patients with same tumor stages in both groups), therapy regimen (Kaplan–Meier survival analysis using logrank test for patients with same therapy regimens in both groups) and histology (Kaplan–Meier survival analysis using log-rank test for patients with same histological confirmations in both groups) on the onset of PC. The study was conducted according to the guidelines of the institutional review board and standards of good clinical practice according to the Declaration of Helsinki. 2.2. Therapy regimens In order to discriminate between patients that underwent local and/ or systemic therapy, the applied therapeutic regimens were divided into two groups (Table 1): • Local therapy: radiotherapy, lobectomy or pneumonectomy • Systemic therapy, i.e. chemotherapy • Patients who underwent a multimodal treatment (surgery and radio-/ chemotherapy) were classified as surgery (local). 2.3. CTNB CTNBs were performed in single-center (Thoraxklinik Heidelberg) setting using standard methods. Scans were performed at 120 kV, 30 mAs using a 4×1.25-mm collimation (Siemens Volume Zoom; Siemens Medical Solution, Forchheim, Germany). After an initial nonenhanced CT examination for biopsy planning, needle access was chosen individually targeting according to the tumor localization and considering organs such as scapula, vessels, mediastinum, and fissure. The procedure was undertaken in coaxial technique. Contact to the lower edge of the ribs was avoided if possible, in order to protect intercostals nerves and vessels. CT-guided two to four core-cut samples of the suspected mass were taken (Bard 15G, Tempe, AZ, USA). Pneumothorax and hemorrhage were ruled out in the concluding CT scan covering access channel, target lesion, and potential pneumothorax location. 2.4. Follow-up examinations Contrast-enhanced CT (CE-CT) scans were performed at restaging visits in order to observe local tumor response, potential lymphatic spread, and metastases. Assessments were performed using the CT scanner mentioned above with a biphasic injection of 40 ml at 2 ml/s contrast agent (Iopamidol-300; Bracco Imaging, Konstanz, Germany) followed by a second bolus of 60 ml at 2 ml/s after 40 s with 30 ml of saline flush at the CT scanner as mentioned before covering from below
CTNB Stage
I II III IV Total
Non-CTNB n
26 (18%) 22 (15%) 32 (22%) 66 (45%) 146 (100%)
Subgroup a
b
16 2 18
10 20 14
Stage
n
I II III IV Total
9 (8%) 10 (9%) 45 (40%) 48 (33%) 112 (100%)
Subgroup a
b
3 1 26
6 9 19
the adrenal glands through the lung apices. CT data sets were reconstructed at a slice thickness of 3.0 mm using a 2.5-mm increment with a B30 standard soft tissue kernel and a B70 high-resolution kernel. PC was defined as progressive growth or increase of pleural nodules, or as malignant pleural effusion in cytology, soft tissue seedings as growing nodules along the chest wall [10]. Patients underwent 2 to 20 follow-up CTs within a follow-up period of 3 to 98 months; the average duration between biopsy and last CT examination was 17 months. Images were interpreted by radiologists with more than 5 years of experience in oncologic chest imaging.
2.5. Statistical analysis Statistical analysis was performed using SPSS (Version 17 for Windows; SPSS Inc., Chicago, IL, USA), SAS (Version 9.2 for Windows; SAS Institute Inc, Cary, NC, USA), and SigmaPlot (Systat Software GmbH, Erkrath, Germany). Statistical analyses were supposed to be exploratory. The term “significant” refers to P values b.05. Differences between two independent samples of quantitative data were tested using the two-sample t test if the assumption of normality was not violated; otherwise, the Wilcoxon rank sum test was used. Median values±minimum and maximum were calculated and are illustrated in box-whisker plots. Failure time was analyzed using standard methods (Kaplan–Meier estimates of survivor curves, log-rank tests, and the Cox proportional hazards model). 3. Results 3.1. Patient demographics In correlation to the 146 CTNB-patients (33–86 years, 84 female, median age 64), the non-CTNB group consisted of 112 patients (28–75 years, 22 female, median age 61) diagnosed by means of TBB (n=51), MTS (n= 22), video-assisted thoracoscopy (n= 29), or biopsies of liver, brain, or bone metastases (n= 10) in the identical time period. Mean follow-up period of all included patients (CTNB, non-CTNB) was 17months. There was no significant difference between both groups in terms of age distribution (P=.31). 3.2. Histologies In the CTNB group, we detected 64 cases of adenocarcinoma (AC), 51 cases of squamous cell carcinoma (SCC), 9 cases of small cell lung cancer (SCLC), and 8 cases of neuroendocrine carcinoma (NET). Fourteen patients showed malignant histologies other than the above mentioned, i.e., basaloid carcinoma, mucoepidermoid carcinoma, and pleomorphic carcinomas. In the non-CTNB group, there were 67 cases of AC, 26 cases of SCC, 8 cases of SCLC, and 7 cases of NET. In four patients, histological entities other than the above mentioned were identified, i.e., basaloid carcinoma, mucoepidermoid carcinoma, and pleomorphic carcinomas.
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Fig. 2. Kaplan–Meier-plot of PC survival according to tumor histology. Patients with SCC had a significantly reduced risk for PC compared to patients with AC (P=.05).
3.3. Initial TNM According to the revised seventh edition of TNM classification for lung cancer, the patients presented the following clinical conditions at the time of the initial staging examination [13] (Table 2). Initial contact with pleural surface was found in 110 patients (75%) in the CTNB group and in 78 patients (70%) in the non-CTNB group. 3.4. Onset of PC after CTNB versus non-CTNB with PC-free survival rates Regarding CTNB patients, the incidence of PC was diagnosed in 18 out of 146 patients (12.4%) within the follow-up period of 98 months. In the control group, the onset of PC was diagnosed in 16 out of 112 cases (14.3%). Comparing the overall onset of PC after CTNB (n= 18/ 146) versus non-CTNB (n=16/112), there was no statistically significant difference between the compared methods (P= .49, hazard ratio=1.28, 95% confidence interval: 0.63 to 2.58; Fig. 1a). After subgroup analysis comparing patients with matched tumor stages, PC-free survival rates (PFS) was not significantly influenced by the choice of tissue acquisition [stage I (P= .386), stage II (P= .505), stage III (P=.567), stage IV (P=.609); Fig. 1b–e]. Regarding overall survival, there was a tendency toward a lower incidence of PC in patients undergoing non-CTNB. In long-term survivors after 60 months, patients with CTNB showed a tendency toward lower rates for the onset of PC (Fig. 1a). Subgroup analyses of different tumor histologies revealed a significantly reduced risk for PC in SCC patients compared to patients with AC (P=.05) (Fig. 2). Otherwise, the different types of tumor histologies had no significant influence on the onset of PC.
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Fig. 3. Kaplan–Meier-plot of PC survival according to the initial tumor stage. Patients with tumor stages 1 and 2 had a significantly reduced risk for PC compared to stage 3 and 4 patients.
CTNB), stage 2; P= .3] and within the higher tumor stages between stages 3 and 4 [n= 6/32 (CTNB) vs. 7/45 (non-CTNB), stage 3; 11/66 (CTNB) vs. 7/48 (non-CTNB), stage 4; P=.8] for PC-free survival (Fig. 3). 3.6. Onset of PC depending on therapy regimen Comparing systemic versus local therapy, we found a significantly reduced risk for PC with higher PFS in patients with local tumor therapy [mean PFS 81 months (20/168≙11.9%) (local) vs. mean PFS 53months (12/90≙13.3%) (syst); P=.01]. This difference was independent from the initial tumor stage since local therapy included patients undergoing both surgery (usually lower TNM stages) and radiotherapy (usually higher TNM stages; Fig. 4). 3.7. Seed metastases Out of the 146 patient with CTNB, there was one single case with a single nodule along the needle access infiltrating the intercostal chest wall muscles (0.7%) (Fig. 5). In no further follow-up, CT morphologic signs of seed metastases could be detected. 3.8. Pneumothorax, chest drainage, and hemorrhage The most common complications associated with CTNB was postinterventional pneumothorax in 30 out of 146 patients (20%), with 2 patients requiring pleural drainage (1.4%). There was no patient with any other severe post-CTNB complication such as hemoptysis, relevant hemorrhage requiring transfusion or intervention, prolonged hospitalization, or death.
3.5. Onset of PC depending on initial tumor stage 4. Discussion Subgroup analyses with regard to the initial tumor stage showed a significantly reduced risk for PC in patients presenting with stage 1 or 2 [n= 2/48 (CTNB) and 2/19 (non-CTNB)] versus stages 3 and 4 [n=16/98 (CTNB) and 14/93 (non-CTNB), P=.04]. No significant differences were seen within the lower stages between stages 1 and 2 [n=1/ 26 (CTNB) vs. 2/9 (non-CTNB), stage 1; 1/22 (CTNB) vs. 0/10 (non-
In our study, we did not detect an earlier or excessive onset of PC in patients after CTNB compared to non-CTNB. PC was not significantly increased after CTNB, even when analyzed according to TNM stage, histology, and therapy regimen. However, the onset of PC did depend on tumor histology.
Fig. 1. Kaplan–Meier-plot of PC-free survival. There is no significant difference in PC-free survival comparing patients with CTNB and patients with non-CTNB (a), even after subgroup analysis (b–e). Red line (CTNB), black line (non-CTNB). (a) overall PC-free survival (P=.29). (b) TNM stage I (P=.386). (c) TNM stage II (P=.505). (d) TNM stage III (P=.567). (e) TNM stage IV (P=.609).
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Fig. 4. Kaplan–Meier-plot of PC survival depending on therapy regimen. Patients after local therapy had a significantly reduced risk for PC compared to patients with systemic therapy (P=.01).
Moreover, the study confirms the established correlation of a significantly reduced risk for PC in patients with a lower initial tumor stage (1 and 2) compared to stages 3 and 4. Accordingly, the specific risk for PC was significantly reduced after local therapy (surgery, radiotherapy) compared to systemic therapy (chemotherapy). The leaking influence of different biopsy types for all tumor stages on the onset of PC is in accordance with findings from Asakura et al. [12], who examined TNM stage I patients after surgery, comparing CTNB vs. bronchoscopy and thoracoscopic wedge resection. In their specific patient population, no evidence was found for an increased risk of pleural recurrence after CTNB. The data presented in this study suggest that this finding can be extended to patients of all TNM stages, irrespective of tumor histology and therapy regimen. This is noteworthy, since not all patients after CTNB are undergoing surgery. Concerning different therapy regimens, there was a tendency toward more invasive therapies in patients undergoing MTS or TBB instead of CTNB. This might be due to the fact that in our study center, patients with good physical condition
often proceeded with the more invasive staging techniques (MTS, TBB) while patients with concomitant diseases (chronic obstructive pulmonary disease, heart failure) may undergo the less demanding procedure of CTNB. Wisnivesky et al. [9] recently investigated postinterventional survival after preoperative percutaneous needle biopsy in stage I lung cancer patients, and could not find negative effects on overall and cancer deaths after CTNB. This seems to be quite in line with our findings, even though we examined PC-free survival and did not look at the overall survival of patients. Nevertheless, our results differ from findings by Matsuguma et al. [10] and Inoue et al. [11], who found an increased risk for pleural recurrence after CTNB for stage I NSCLC patients. We could not find a reason for this discrepancy, especially since the examined CT-guided biopsy techniques were quite similar. However, the incidence of other postinterventional complications (pneumothorax, hemorrhage) was within the previously reported ranges by Asakura et al. [12], Tsukada et al. [14], Saji et al. [15], and Yamauchi et al. [16]. Relevant limitations of this monocentric study are the retrospective design of the data and the relatively small number of patients. Even in this large center for thoracic surgery and oncology with more than 300 transthoracic needle biopsies per year, this was mainly due to the strict selection criteria and many patients being lost to follow-up due to early disease progression and outpatient care. The fact that we included patients in all TNM stages resulted in a relatively short mean follow-up period of 17 months, which was shorter than in comparable studies with 45 months [12], 60 months [11], and 80 months [10], who focused on stage I patients after surgery with much better prognosis. Nevertheless, the maximum follow-up period in our study was 98 months, indicating that healthy patients were followed up appropriately. Another limitation may be a potential selection bias between the CTNB and control groups. However, further subgroup analysis addressing site of intrapulmonal tumor localization and tumor size did not reveal significant differences, most likely due to the overall low incidence of PC. This issue was already emphasized in previously published studies [12] and could only be addressed by meta-analysis or analyzing larger cohorts in a multicenter setting. Our study indicates that the appropriate approach for tumor tissue acquisition in lung cancer patients should be chosen primarily depending on the clinically most feasible access road, with CTNB being a minimally invasive procedure, and thus safe to use in patients with relevant comorbidities. This is particularly true as excessive iatrogenic spread after CTNB is an extraordinarily rare event.
Fig. 5. *CT-image of access channel in lung cancer patient during biopsy. **Access channel of same patient 13 months post-biopsy and surgery. Needle track metastasis on the level of seventh rib in CE-CT highlighted by red lines.
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