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. 2018 Sep 3;18:146. doi: 10.1186/s12890-018-0713-6

Clinical updates of approaches for biopsy of pulmonary lesions based on systematic review

Chuan-Jiang Deng 1,#, Fu-Qiang Dai 1,#, Kai Qian 1, Qun-You Tan 1, Ru-Wen Wang 1, Bo Deng 1,✉, Jing-Hai Zhou 1,✉
PMCID: PMC6122670  PMID: 30176840

Abstract

Background

Convenient approaches for accurate biopsy are extremely important to the diagnosis of lung cancer. We aimed to systematically review the clinical updates and development trends of approaches for biopsy, i.e., CT-guided PTNB (Percutaneous Transthoracic Needle Biopsy), ENB (Electromagnetic Navigation Bronchoscopy), EBUS-TBNA (Endobroncheal Ultrasonography-Transbronchial Needle Aspiration), mediastinoscopy and CTC (Circulating Tumor Cell).

Methods

Medline and manual searches were performed. We identified the relevant studies, assessed study eligibility, evaluated methodological quality, and summarized diagnostic yields and complications regarding CT-guided PTNB (22 citations), ENB(31 citations), EBUS-TBNA(66 citations), Mediastinoscopy(15 citations) and CTC (19 citations), respectively.

Results

The overall sensitivity and specificity of CT-guided PTNB were reported to be 92.52% ± 3.14% and 97.98% ± 3.28%, respectively. The top two complications of CT-guided PTNB was pneumothorax (946/4170:22.69%) and hemorrhage (138/1949:7.08%). The detection rate of lung cancer by ENB increased gradually to 79.79% ± 15.34% with pneumothorax as the top one complication (86/1648:5.2%). Detection rate of EBUS-TBNA was 86.06% ± 9.70% with the top three complications, i.e., hemorrhage (53/8662:0.61%), pneumothorax (46/12432:0.37%) and infection (34/11250:0.30%). The detection rate of mediastinoscopy gradually increased to 92.77% ± 3.99% with .hoarseness as the refractory complication (4/2137:0.19%). Sensitivity and specificity of CTCs detection by using PCR (Polymerase Chain Reaction) were reported to be 78.81% ± 14.72% and 90.88% ± 0.53%, respectively.

Conclusion

The biopsy approaches should be chosen considering a variety of location and situation of lesions. CT-guided PTNB is effective to reach lung parenchyma, however, diagnostic accuracy and incidence of complications may be impacted by lesion size or needle path length. ENB has an advantage for biopsy of smaller and deeper lesions in lung parenchyma. ENB plus EBUS imaging can further improve the detection rate of lesion in lung parenchyma. EBUS-TBNA is relatively safer and mediastinoscopy provides more tissue acquisition and better diagnostic yield of 4R and 7th lymph node. CTC detection can be considered for adjuvant diagnosis.

Keywords: Lung cancer, Percutaneous transthoracic needle biopsy, Electromagnetic navigation bronchoscopy, Endobroncheal ultrasonography, Circulating tumor cell

Background

Lung cancer is the most frequently diagnosed cancer and continues to be the leading cause of cancer mortality among both males and females [1]. The 5-year survival rate of lung cancer is only 18%, largely due to late-stage diagnosis [1]. Thus, early diagnosis is especially critical to improve long-term survival. Biopsy is important for identification and confirmation of lung cancer. In clinical practice, conventional flexible bronchoscopy is supposed to be difficult for biopsy of small lesions in lung parenchyma or mediastinum. Therefore, we focused on the following approaches for biopsy according to a variety of lesion location in lung parenchyma, i.e., CT-guided PTNB(Percutaneous Transthoracic Needle Biopsy), ENB (Electromagnetic Navigation Bronchoscopy), EBUS-TBNA (Endobroncheal Ultrasonography-Transbronchial Needle Aspitation) and mediastinoscopy. Furthermore, the studies regarding liquid biopsies, e.g., CTC (Circulating Tumor Cell) detection are timely and hot, and warrant to be systematically reviewed.

Therefore, we evaluated the published studies in the last 20 years which focused on CT-guided PTNB, ENB, EBUS-TBNA, mediastinoscopy and CTC, aiming to reveal the clinical updates, development trends, detection rates and complications.

Methods

We used systematic review to identify relevant studies, assess study eligibility, evaluate methodological quality, and summarize findings regarding postoperative clinical outcomes. Medline and manual searches were performed by investigators CJD and FQD independently and jointly to identify all published articles in English journals from January 1, 2000 to November 9, 2017 that addressed the issues regarding detection of lung cancers by using CT-guided PTNB, ENB, EBUS-TBNA, mediastinoscopy and CTCs, respectively. The Medline search was done on PubMed (http://www.ncbi.nlm.nih.gov). The search strategies and yielded citations were shown in Tables 1 and 2, respectively. Investigators CJD and FQD performed the actual search and data abstraction.

Table 1.

Data sources and searches regarding Clinical updates of approaches for biopsy

Methods Search term Period Additional filters Citation number after filtration Citation number after Manual verification
CT-guided PTNB ct guided transthoracic needle biopsy[All Fields] AND lung neoplasms[MeSH Terms] From January 1, 2000 To November 9, 2017 English, humans without review 106 22
ENB ‘electromagnetic navigation
bronchoscopy (ENB)’[All Fields]		 From January 1, 2000 To November 9, 2017 English, humans without review 91 31
EBUS-TBNA EBUS[All Fields] AND “lung neoplasms” [MeSH Terms] From January 1, 2000 To November 9, 2017 English, humans without review 613 66
Mediastinoscopy Mediastinoscopy[Mesh Terms]
AND “lung neoplasms”[MeSH Terms]		 From January 1, 2000 To November 9, 2017 English, humans without review 333 15
CTC ‘Neoplastic Cells, Circulating’[Mesh Terms] AND “lung neoplasms”[MeSH Terms] From January 1, 2000 To November 9, 2017 English, humans without review 459 19
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Table 2.

Information of yielded citations regarding approaches for biopsy

PMID Year Method Corresponding author Cases Diagnostic sensitivity
28,415,930 2017 CT-guided PTNB Feride Fatma Go¨rgu¨lu¨ 65 90.80%
28,063,634 2016 CT-guided PTNB C. Fontaine-Delaruelle 929 N/A
26,980,483 2016 CT-guided PTNB Mickey Sachdeva 203 N/A
26,397,325 2015 CT-guided PTNB M. Petranovic 52 N/A
26,110,775 2015 CT-guided PTNB Wen Yang 311 77%
25,903,714 2015 CT-guided PTNB Matthew Koslow 181 94.40%
25,816,042 2015 CT-guided PTNB Fabio Pagni N/A 97.60%
25,662,328 2015 CT-guided PTNB Anna Galluzzo 23 87%
25,569,025 2015 CT-guided PTNB Sébastien Couraud 980 90%
25,051,977 2014 CT-guided PTNB Tingyang Hu 341 N/A
24,581,458 2014 CT-guided PTNB Jeffrey S. Klein 32 N/A
24,475,839 2014 CT-guided PTNB Chang Min Park 1108 97%
25,763,320 2014 CT-guided PTNB Sanjay Piplani 74 95.94%
23,510,132 2013 CT-guided PTNB Antonio Bugalho 123 N/A
23,079,048 2013 CT-guided PTNB Yi-Ping Zhuang 102 96.10%
22,951,610 2012 CT-guided PTNB Ragulin IuA 107 N/A
22,124,475 2012 CT-guided PTNB Yeun-Chung Chang 55 N/A
21,537,657 2012 CT-guided PTNB Lu CH 89 91.50%
21,098,171 2010 CT-guided PTNB Hye Sun Hwang 27 94%
15,246,522 2004 CT-guided PTNB Ohno Y N/A 96.90%
14,595,149 2003 CT-guided PTNB Stephen T. Kee 846 96%
14,595,149 2003 CT-guided PTNB Stephen T. Kee 846 92%
12,118,196 2002 CT-guided PTNB Adnan Yilmaz 294 88%
28,410,635 2017 ENB Christopher W. Towe 341 N/A
27,623,421 2017 ENB Michael Chacey 31 96.80%
28,459,951 2017 ENB Kongjia Luo 24 100.00%
28,449,489 2017 ENB Hiran C. Fernando 17 79.00%
28,399,830 2017 ENB Erik E. Folch 1000 N/A
26,944,363 2016 ENB Mohammed Al-Jaghbeer 92 60.00%
27,157,054 2016 ENB Arjun Pennathur 29 100.00%
27,424,820 2016 ENB Fumihiro Asano 932 71.00%
25,849,298 2015 ENB Demet Karnak 44 72.80%
25,590,477 2015 ENB Mark R. Bowling 107 73.60%
24,739,685 2014 ENB Nima Nabavizadeh 31 N/A
24,401,166 2014 ENB Gregoire Gex 971 64.90%
23,440,066 2013 ENB Demet Karnak 76 89.50%
24,323,803 2013 ENB Rana S Hoda 40 94.00%
23,649,436 2013 ENB M. Patricia Rivera 932 71.00%
22,391,437 2012 ENB B.Lamprecht 112 83.90%
22,277,964 2012 ENB Daryl Phillip Pearlstein 104 85.00%
23,207,529 2012 ENB Christopher R Dale 100 N/A
23,207,349 2012 ENB Kyle R. Brownback 55 74.50%
23,207,460 2012 ENB Kurt W. Jensen 92 65.00%
23,169,081 2011 ENB Amit K. Mahajan 49 77.00%
20,850,809 2010 ENB Carsten Schroeder 52 N/A
20,802,352 2010 ENB Felix J. F. Herth 25 80.00%
20,435,658 2010 ENB Luis M. Seijo 51 67.00%
19,648,733 2010 ENB med. Ralf Eberhardt 54 75.50%
19,546,519 2009 ENB Jean-Michel Vergnon 54 71.40%
17,400,670 2007 ENB Armin Ernst 92 67.00%
17,360,724 2007 ENB C-H. Marquette 40 62.50%
17,532,538 2007 ENB Motoko Tachihara 94 62.50%
17,379,850 2007 ENB Armin Ernst 120 59.00%
16,873,767 2006 ENB Thomas R. Gildea 60 74.00%
29,054,229 2017 EBUS-TBNA Chen-Yoshikawa 413 N/A
27,710,975 2016 EBUS-TBNA Fumihiro Tanaka 20 75.00%
27,435,209 2016 EBUS-TBNA João Pedro Steinhauser Motta 84 61.00%
27,409,724 2015 EBUS-TBNA Whittney A. Warren 333 98.86%
27,150,855 2016 EBUS-TBNA Sang-Won Um 161 94.00%
26,656,954 2015 EBUS-TBNA Baijiang Zhang 114 81.20%
26,545,094 2015 EBUS-TBNA Wen-Chien Cheng 2527 N/A
26,386,084 2015 EBUS-TBNA Massimo Barberis 291 95.53%
26,176,519 2015 EBUS-TBNA Sebastián Fernández-Bussy 145 91.17%
25,611,227 2015 EBUS-TBNA Sang-Won Um 138 92.90%
25,584,815 2014 EBUS-TBNA Roberto F. Casal 220 N/A
25,170,748 2014 EBUS-TBNA Andrew R.L. Medford 70 90.00%
25,149,044 2014 EBUS-TBNA Masato Shingyoji 113 88.40%
24,930,616 2014 EBUS-TBNA Masahide Oki 150 89%
24,853,017 2014 EBUS-TBNA Yasushi Murakami 100 97.00%
24,419,182 2013 EBUS-TBNA Paul F. Clementsen 76 88.16%
24,340,058 2013 EBUS-TBNA Takayuki Shiroyama 178 73.60%
24,238,520 2014 EBUS-TBNA Zhao H 66 89.40%
24,172,712 2013 EBUS-TBNA Kang HJ 74 93.20%
24,125,976 2013 EBUS-TBNA Ozgül MA 40 94.70%
24,079,724 2013 EBUS-TBNA Lonny Yarmus 85 100.00%
24,075,565 2013 EBUS-TBNA Yinin Hu 231 90.00%
23,994,976 2013 EBUS-TBNA Sang-Won Um 42 95.30%
23,953,728 2013 EBUS-TBNA Konstantinos Syrigos 981 76.20%
23,723,003 2013 EBUS-TBNA Guo-liang Xu 128 93.00%
23,663,438 2013 EBUS-TBNA Fumihiro Asano 7345 N/A
23,639,784 2013 EBUS-TBNA Riccardo Inchingolo 662 77.00%
23,609,248 2013 EBUS-TBNA Christian B. Gindesgaard 116 87.00%
23,609,243 2013 EBUS-TBNA Hammad A. Bhatti 13 94.00%
23,571,718 2013 EBUS-TBNA Masahide Oki 108 88.00%
23,549,813 2013 EBUS-TBNA Sang-Won Um 37 86.40%
23,245,441 2012 EBUS-TBNA Kazuhiro Yasufuku 438 96.50%
23,117,878 2014 EBUS-TBNA George A. Eapen 1317 N/A
24,632,834 2014 EBUS-TBNA Sang-Won Um 44 79.00%
24,603,902 2013 EBUS-TBNA Moishe Liberman 161 72.00%
22,219,613 2012 EBUS-TBNA Sang-Won Um 151 91.60%
22,154,791 2011 EBUS-TBNA Benjamin E. Lee 73 95.00%
21,963,329 2011 EBUS-TBNA Kazuhiro Yasufuku 153 81.00%
21,792,077 2011 EBUS-TBNA Sam M. Janes 161 87.00%
21,718,857 2011 EBUS-TBNA Alexander Chen 50 81.00%
21,651,742 2011 EBUS-TBNA Shahab Nozohoo 243 66.00%
21,592,457 2010 EBUS-TBNA Kazuhiro Yasufuku 450 93.10%
20,819,667 2010 EBUS-TBNA Tian Q 33 69.70%
20,740,503 2010 EBUS-TBNA Qing Kay Li 47 89.50%
20,609,781 2010 EBUS-TBNA Kazuhiro Yasufuku N/A 96.40%
20,372,904 2010 EBUS-TBNA J. Eckardt 308 72.00%
20,138,390 2010 EBUS-TBNA Bin Hwangbo 126 97.20%
20,037,856 2010 EBUS-TBNA Sökücü SN N/A 88.20%
20,022,759 2010 EBUS-TBNA Artur Szlubowski 61 67.00%
19,890,836 2009 EBUS-TBNA Wei Sun 64 88.90%
19,789,210 2009 EBUS-TBNA Andrew RL Medford 54 89.00%
19,699,917 2009 EBUS-TBNA Sebastien Gilbert 172 86.60%
19,590,457 2009 EBUS-TBNA Armin Ernst N/A 91.00%
19,502,074 2009 EBUS-TBNA Henrik Ømark Petersen 157 85.00%
19,447,014 2009 EBUS-TBNA Devanand Anantham N/A 90.00%
19,371,395 2008 EBUS-TBNA David Fielding 68 94.00%
19,068,672 2008 EBUS-TBNA Marie-Paule Jacob-Ampuero 48 77.00%
18,952,453 2009 EBUS-TBNA Jarosław Kuzdza 226 89.00%
18,263,680 2007 EBUS-TBNA Armin Ernst 100 89.00%
17,916,175 2008 EBUS-TBNA Mariko Siyue Koh 38 62.00%
17,379,850 2006 EBUS-TBNA Armin Erns 120 69.00%
17,035,455 2007 EBUS-TBNA Meng-Chih Lin 151 73.80%
16,963,667 2006 EBUS-TBNA Takehiko Fujisawa 102 92.30%
16,807,262 2005 EBUS-TBNA F.J.F. Herth 100 92.30%
16,171,897 2005 EBUS-TBNA Takehiko Fujisawa 105 94.60%
27,385,137 2016 Mediastinoscopy Necati C¸itak 261 96.00%
27,385,137 2016 Mediastinoscopy Necati C¸itak 187 95.00%
24,751,152 2014 Mediastinoscopy Benjamin Wei 721 87.10%
23,778,084 2013 Mediastinoscopy Akif Turna 344 92.20%
23,778,084 2013 Mediastinoscopy Akif Turna 89 96.60%
23,008,924 2012 Mediastinoscopy Ashutosh Chauhan 39 87.50%
22,219,461 2012 Mediastinoscopy Carme Obiolsa 221 95.00%
21,601,176 2011 Mediastinoscopy Young Mog Shim 521 95.90%
20,417,780 2010 Mediastinoscopy Yaron Shargall 104 98.90%
20,417,780 2010 Mediastinoscopy Yaron Shargall 396 97.20%
18,520,794 2008 Mediastinoscopy Armin Ernst 66 78.00%
18,687,697 2008 Mediastinoscopy Elias A. Karfis 139 88.40%
18,054,494 2007 Mediastinoscopy Gunda Leschber 377 87.90%
12,842,542 2003 Mediastinoscopy Jèrôme Mouroux 154 98.00%
12,683,545 2003 Mediastinoscopy Didier Lardinois 195 95.60%
11,321,666 2001 Mediastinoscopy Reidar Grénman 249 84.30%
26,913,536 2016 CTC María Jose Serrano 56 51.80%
26,951,195 2016 CTC Noriyoshi Sawabata 23 30.40%
27,206,795 2016 CTC Binlei Liu 40 55.00%
27,206,795 2016 CTC Binlei Liu 40 75.00%
25,996,878 2015 CTC Wei Li 169 23.70%
25,678,504 2014 CTC Mario Santini 16 89.00%
23,861,795 2013 CTC Viswam S. Nair 43 60.47%
21,098,695 2011 CTC Paul Hofman 208 49.00%
21,215,651 2011 CTC Noriyoshi Sawabata 75 69.33%
21,683,606 2011 CTC Renato Franco 45 23.90%
21,128,227 2010 CTC Paul Hofman 210 39.00%
21,128,227 2010 CTC Paul Hofman 210 50.00%
20,471,712 2010 CTC Chul-Woo Kim 61 42.60%
20,471,712 2010 CTC Chul-Woo Kim 61 36.10%
19,887,487 2009 CTC Fumihiro Tanaka 125 71.00%
18,514,066 2008 CTC Yan-hui Yin 134 84.30%
18,606,477 2008 CTC Shang-mian Yie 67 38.80%
17,554,991 2007 CTC Noriyoshi Sawabata 9 11.10%
16,642,481 2006 CTC Inn-Wen Chong 100 90.00%
15,801,980 2005 CTC Katharina Pachmann 29 86.21%
12,167,790 2002 CTC Michio Ogawa 57 38.60%
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Data abstraction

From the eligible articles, investigators CJD and FQD reviewed the following information, i.e., PMID, year of publication, study design, number of patients, average age of patients, nodules size and location, operation time, biomarkers for detection, diagnostic sensitivity, relative complication morbidity, treatment of complications, outcome and follow-up period.

Statistical analysis

The association between detection rate of ENB and nodule size, number of cases, operation time, average age of patients, sex, and mean distance of the lesions from the pleura was performed using Pearson’s correlation analysis. The impact of nodule location on detection rate of ENB was analyzed by using ANOVA analysis. The association between morbidity of pneumothorax following ENB and nodule size was performed using Pearson’s correlation analysis. The analyses were performed using SPSS Version 11.0 software for Windows (SPSS, Inc., Chicago, IL, USA). P < 0.05 (two-sided) was considered to indicate a statistically significant difference.

Results

CT-guided PTNB: Biopsy of lesion in lung parenchyma mapped on CT images

In last 20 years, the overall sensitivity, specificity, and accuracy of CT-guided PTNB were 92.52 ± 3.14%, 97.98 ± 3.28%, and 92.28% ± 5.40%, respectively. The top two complications of CT-guided PTNB were pneumothorax (1111/4822:23.04%) and hemorrhage (287/3503:8.19%), respectively. Two cases with severe complications were reported [2, 3]. Bronchial artery embolization was performed in one patient due to massive hemoptysis [3]. The other one suffered from cardiopulmonary arrest leading to death [2].

Diagnostic accuracy and incidence of complications seemed to be decreased [3–5] and increased [2–9], respectively, by smaller lesion size or longer needle path length (P < 0.05).

ENB: Biopsy of lesion in lung parenchyma and mediastinal area

The detection rate of lung cancer by ENB increased gradually (Fig. 1a) and was recently reported to be 96.8% [10]. There seemed to be no significant correlation between detection rate and number of cases, average age of patients, sex, nodule size, lobar location of nodule, mean distance from pleura to nodule and operation time. As shown in Fig. 1b, pneumothorax was the top one complication following ENB (86/1648:5.2%). In 86 pneumothorax cases, 34 cases (34/86) were administrated with closed drainage [10–21], and one case (1/86) was managed with manual aspiration and observation [19]. The other 51 cases with mild pneumothorax were discharged for rehabilitation. Intriguingly, the incidence of pneumothorax was significantly negatively correlated with nodule size (R = − 0.512, P = 0.018, Fig. 1c). The three hemorrhage cases were observed carefully without further intervention and were discharged for rehabilitation [16, 22]. Three cases of respiratory failure were reported without detailed depiction [16]. There were no ENB related death [10–30]. ENB plus EBUS imaging seemed to yield a higher detection rate as compared with sole use of ENB (59% vs. 88% [20] and 71.42% vs. 73.07% [11]). Surprisingly, studies combining fluoroscopy with ENB to confirm navigation success reported lower diagnostic yields (56.3 vs. 69.2% without fluoroscopy, p = 0.006) [31].

Fig. 1.

Fig. 1

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Analysis of clinical points regarding ENB. a Correlation between detection rate and publication time showing the detection rate increased gradually. b Pneumothorax was the top one complication following ENB (86/1648:5.2%). c The morbidity of pneumothorax was significantly negatively correlated with nodule size (R = −0.512, P = 0.018)

EBUS-TBNA: Biopsy of lesion in subcarinal and bilateral hilar area

The detection rate of lung node by EBUS-TBNA remained to be 86.06 ± 9.70%. The diagnostic sensitivity, specificity, accuracy, positive predictive value and negative predictive value of EBUS-TBNA for the mediastinal staging of lung cancer were 85.48% ± 12.89%, 99.09% ± 3.15%, 92.88% ± 4.99%, 98.70% ± 3.03%, 83.03% ± 15.46%, respectively. As shown in Fig. 2a, the top three complications following EBUS-TBNA were hemorrhage (53/8662:0.61%), pneumothorax (46/12432:0.37%) and infection (34/11250:0.30%), respectively. Four hemorrhage cases were administrated with further intervention with one perioperative death. The other 49 cases with mild hemorrhage were discharged for rehabilitation [32, 33]. In 46 pneumothorax cases, nine cases (9/46) and 37 cases (37/46) were administrated with closed drainage and conservative treatment, respectively [32–35]. Perioperative mortality was relatively low (4/11189:0.04%). Besides the above mentioned one case died of severe hemorrhage, there was one case died of cerebral infarction and two unexplained deaths [32, 33, 36].

Fig. 2.

Fig. 2

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Analysis of clinical points regarding EBUS-TBNA and mediastinoscopy. a The top three complications following EBUS-TBNA were hemorrhage (53/8662:0.61%), pneumothorax (46/12432:0.37%) and infection (34/11250:0.30%), respectively. b The detection rate by using mediastinoscopy increased slightly. c The positive rate of 4thR (91.5% ± 9.35%) and 7th (80.56% ± 19.47%) lymph node by using mediastinoscopy were significantly higher than others (P < 0.05). d Hoarseness (67/4387:1.53%) was the top one complication following mediastinoscopy

Mediastinoscopy: Biopsy of the lesion or lymph node in the vicinity of the trachea, the subcarinal and the bronchi area

The detection rate of lung cancer by mediastinoscopy increased slightly (Fig. 2b) which was reported to be 96% in recent years [37]. The diagnostic sensitivity, specificity, accuracy, positive predictive value and negative predictive value of mediastinoscopy for the mediastinal staging of lung cancer were 82.83% ± 10.63%, 100%, 93.98% ± 4.68%, 100%, 87.64% ± 13.00%, respectively. Intriguingly, the positive rates of 4thR (91.5% ± 9.35%) and 7th (80.56% ± 19.47%) lymph node were significantly higher than others (P = 0.03) (Fig. 2c). As shown in Fig. 2d, hoarseness (67/4387:1.53%) was the top one complication following mediastinoscopy. Among the abovementioned 67 cases with hoarseness, nine cases (9/67) suffered from permanent hoarseness, two cases (2/67) recovered partially by vocal cord medialization and six cases (6/67) recovered within a few months [37–45]. Perioperative mortality was relatively low (4/2137: 0.19%). The death causes among three cases were aortic laceration, stroke, and cardiac arrest, respectively, and one case die of unexplained cause [46].

CTC: Biopsies of tumor cells shed from solid tumor lesion into peripheral blood

The mean sensitivities of a variety of methods to detect CTC remained to be 63.05%. As shown in Fig. 3a, sensitivity of PCR seemed to be highest (78.81 ± 14.72%). Sensitivity of Density-gradient, ISET and Magnetic bead seemed to be higher than 60% (71.32% ± 2.8%, 67.75% ± 21.22% and 67.85% ± 25.24%, respectively). Specificity of ISET, PCR and Cell search was relatively high (100%, 90.88 ± 0.53% and 94.33% ± 9.82%, respectively). There was no published data regarding specificity of Magnetic bead and density-gradient.

Fig. 3.

Fig. 3

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Analysis of clinical points regarding CTCs. a Sensitivity of PCR seemed to be highest (78.81 ± 14.72%). Specificity of ISET, PCR and Cell search was relatively high (100%, 90.88 ± 0.53% and 94.33 ± 9.82%). b Sensitivity of Multimarker assay seemed to be highest(90%) including 17 target genes: AGR2, CEACAM5, MMP11, STRN3, CEACAM6, COL5A2, AMPH, CEACAM7, ABCC3, THY1, COL6A3, ENO1, PNN, SCFD1, KDELR3, KIAA0391, TACSTD1

Intriguingly, there are a variety of biomarker combination for CTCs identification by using PCR yielding different sensitivities. As shown in Fig. 3b, the sensitivity of Multimarker assay seemed to be highest (90%). Besides, the sensitivity of the combination of TSA-9, KRT-19, Pre-proGRP was satisfactory (84.3%).

Discussion

Considering the exquisite anatomy of the mediastinum, hilar and lung parenchyma, the equipment and technique, e.g., percutaneous lung biopsy, ENB, EBUS-TBNA, and Mediastinoscopy developed quickly. Furthermore, liquid biopsy, e.g., CTC detection has been introduced and a few pilot studies regarding early diagnosis of lung cancer have been published [47–65]. According to application in specific location and situation, we systemic reviewed clinical updates of these approaches focusing on development trends, detection rate and complications .

CT-guided PTNB is regarded as an effective and feasible procedure to detect a difficult nodule with advantage of accurate positioning and high detection accuracy. Nevertheless, once the lesion diameter is less than 2 cm or the needle path length is more than 8 cm, the detection rate will drop dramatically [4]. In addition, the lesions in the vicinity of mediastinum vessels are challengers to clinicians with regards to safety. Currently, ENB is developed for biopsy of the lesions in deep lung parenchyma or mediastinum.

ENB is recommended in patients with lesions in lung parenchyma difficult to reach with conventional bronchoscopy or CT-guided PTNB. The detection rate of ENB increased gradually probably due to improvement of software and hardware. Eberhardt et al. [20] found nodule location has been noted to be an important factor in diagnostic yield, e.g., the yields from the lower lobes were significantly lower (29%; p = 0.01). However, Jensen et al. [22] found lobar location of nodule did not affect the diagnostic yield (p = 0.59). Therefore, we systematically analyzed the results of six studies mentioning detection rate and nodule location [14, 20, 22, 27, 29, 66], and found that there seemed to be no association between them (p = 0.433). The highest incidence of complication is pneumothorax (5.2%). However, pneumothorax following ENB was reported to be unrelated with age or sex [16], accordant with our results. Intriguingly, the incidence of pneumothorax seemed to be significantly negatively correlated with nodule size, probably due to difficulties varying with the size. Additionally, there was no reported ENB associated death, proving that ENB is relatively safe.

Empirically, EBUS-TBNA is suitable for biopsy of lesion in subcarinal and bilateral hilar area. EBUS-TBNA is also well utilized in the peripheral area with radial probe EBUS and in conjunction with ENB. As EBUS-TBNA has relatively high false negative rates, especially at station 4R or 7 lymph node, mediastinoscopy is still required for patients with suspicious nodal disease in these stations [67]. Cytological samples are usually taken by EBUS-TBNA, however, larger histological tissue samples are possible to obtain by mediastinoscopy.

Mediastinoscopy is always recognized as the gold standard for surgical staging of lung cancer which is suitable for biopsy in the vicinity of the trachea, the subcarinal and the bronchi area. Especially, the positive rate of station 4Rth (91.5 ± 9.35%) and 7th (80.56 ± 19.47%) lymph node were significantly higher than other stations (Fig. 2c). Nevertheless, as mediastinoscopy is an invasive approach, the incidences of complications are relatively remarkable.

CTC is a kind of liquid biopsies of tumor cells shed from solid tumor lesions (primary foci and metastases) into peripheral blood. Although the mean sensitivities of CTC detection were not satisfactory, the convenience of this non-invasive method seems to be incomparable. Sensitivity of PCR remained to be highest (78.81% ± 14.72%) as compared with other methods. Intriguingly, the sensitivities of PCR varies with combined biomarkers. Expectedly, the sensitivity of combination of multimarkers assay is highest (90%). Furthermore, the specificity of the three methods, i.e., ISET, PCR and Cell search, was relatively high (100%, 90.88% ± 0.53% and 94.33% ± 9.82%, respectively). Currently, CTC can be used as an auxiliary diagnostic method to provide a higher detection rate.

Conclusions

The biopsy approaches should be chosen according to a variety of location and situation of lesions. CT-guided PTNB is regarded as an effective and feasible procedure for biopsy in lung parenchyma, however, diagnostic accuracy and incidence of complications may be impacted by lesion size or needle path length. ENB has an advantage for biopsy of smaller and deeper lesions in lung parenchyma. ENB plus EBUS imaging can further improve the detection rate. EBUS-TBNA and mediastinoscopy can be recommended for the biopsy in lower and upper mediastinum, respectively. The former is relatively safer and the latter provides more tissue acquisition and better diagnostic yield of 4R and 7th lymph node. CTC detection can be considered for adjuvant diagnosis.

Acknowledgements

We’d appreciated Drs. Mingzhou Guo, Riitta Kaarteenaho and J. Francis Turner for valuable comments which improves our manuscript greatly.

Funding

This study was supported by grants from the National Natural Science Foundations of China (NSFC) (No. 81101782 and 81572285), and National Natural Science Foundation of Chongqing City (No.cstc2018jcyjAX0592).

Availability of data and materials

The dataset was searched on PubMed (http://www.ncbi.nlm.nih.gov). The search strategies and yielded citations were shown in Tables 1 and 2, respectively.

Abbreviations

CTC

Circulating tumor cell

EBUS-TBNA

Endobroncheal Ultrasonography-Transbronchial Needle Aspitation

ENB

Electromagnetic navigation bronchoscopy

PCR

Polymerase chain reaction

PTNB

Percutaneous transthoracic needle biopsy

Authors’ contributions

BD conceived and designed the study. CJD and FQD searched the data and performed data analysis. CJD wrote the paper. BD, JHZ, KQ, QYT and RWW reviewed and edited the manuscript. All authors read and approved the manuscript.

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Chuan-Jiang Deng, Email: exc.dcj@foxmail.com.

Fu-Qiang Dai, Email: daifuqiangd@163.com.

Kai Qian, Email: qk1984@126.com.

Qun-You Tan, Email: tanqy001@163.com.

Ru-Wen Wang, Email: wangrw53@126.com.

Bo Deng, Email: dengbo@tmmu.edu.cn.

Jing-Hai Zhou, Email: zhzhlu1993@aliyun.com.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The dataset was searched on PubMed (http://www.ncbi.nlm.nih.gov). The search strategies and yielded citations were shown in Tables 1 and 2, respectively.

Articles from BMC Pulmonary Medicine are provided here courtesy of BMC

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