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  • Research article
  • Open Access
  • Open Peer Review

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

Contributed equally
BMC Pulmonary Medicine201818:146

https://doi.org/10.1186/s12890-018-0713-6

  • Received: 21 June 2018
  • Accepted: 23 August 2018
  • Published:
Open Peer Review reports

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

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%

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 [35] and increased [29], 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 [1021], 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 [1030]. 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

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 [3235]. 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

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 [3745]. 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

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 [4765]. 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.

Notes

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

Declarations

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.

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.

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Authors’ Affiliations

(1)
Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing, 400042, People’s Republic of China

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