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  • Research article
  • Open Access
  • Open Peer Review

Tumor necrosis as a prognostic variable for the clinical outcome in patients with renal cell carcinoma: a systematic review and meta-analysis

  • 1,
  • 1,
  • 2,
  • 1,
  • 1,
  • 1 and
  • 1Email author
Contributed equally
BMC Cancer201818:870

https://doi.org/10.1186/s12885-018-4773-z

  • Received: 2 April 2018
  • Accepted: 23 August 2018
  • Published:
Open Peer Review reports

Abstract

Background

Tumor necrosis (TN) correlates with adverse outcomes in numerous solid tumors. However, its prognostic value in renal cell carcinoma (RCC) remains unclear. In this study, we performed a meta-analysis to evaluate associations between TN and cancer-specific survival (CSS), overall survival (OS), recurrence-free survival (RFS) and progression-free-survival (PFS) in RCC.

Methods

Electronic searches in PubMed, EMBASE and Web of Science were conducted according to the PRISMA statement. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated to evaluate relationships between TN and RCC. A fixed- or random-effects model was used to calculate pooled HRs and 95%CIs according to heterogeneity.

Results

A total of 34 cohort studies met the eligibility criteria of this meta-analysis. The results showed that TN was significantly predictive of poorer CSS (HR = 1.37, 95% CI: 1.23–1.53, p < 0.001), OS (HR = 1.29, 95% CI: 1.20–1.40, p < 0.001), RFS (HR = 1.55, 95% CI: 1.39–1.72, p < 0.001) and PFS (HR = 1.31, 95% CI: 1.17–1.46, p < 0.001) in patients with RCC. All the findings were robust when stratified by geographical region, pathological type, staging system, number of patients, and median follow-up.

Conclusions

The present study suggests that TN is associated with CSS, OS, RFS and PFS clinical outcomes of RCC patients and may serve as a predictor of poor prognosis in these patients.

Keywords

  • Renal cell carcinoma
  • Tumor necrosis
  • Prognosis
  • Meta-analysis

Background

Renal cell carcinoma (RCC), the third most common urologic tumor, accounts for 2–3% of all adult malignancies [1], and its incidence has continuously increased over the past few decades [2]. Although most RCC cases are diagnosed at an early stage, approximately 20% of patients undergoing curative nephrectomy will subsequently develop metastasis during the follow-up period [3]. Due to the varying efficacy of adjuvant therapies in RC, it is necessary to define more prognostic factors that will allow identification of patients at high risk of recurrence who may benefit from such treatment.

Currently, TNM stage classification [4] and the Fuhrman grade system [5] are the most important factors affecting the prognosis of patients with RCC. Additionally, several integrated prognostic models and histologic characteristics have been studied for their prognostic impact, including the American Joint Committee on Cancer (AJCC) staging system [6], International Society of Urologic Pathologists (ISUP) [7] and Mayo Clinic Stage, Size, Grade and Necrosis (SSIGN) Score [8], though these parameters are not entirely reliable. Tumor necrosis (TN) is believed to define regions of severe and chronic hypoxia, and there is renewed interest in using TN to predict prognosis after tumor resection. However, the prognostic impact of TN in RCC remains controversial, and there is increasing debate on whether TN can provide any additional information beyond grade and stage [9].

Hence, to further clarify the prognostic value of TN in RCC, we performed a systematic review and meta-analysis of the available published literature to evaluate whether the presence of TN has a prognostic impact on cancer-specific survival (CSS), overall survival (OS), recurrence-free survival (RFS) and progression-free-survival (PFS) in RCC patients.

Methods

Literature search strategy

According to the PRISMA guidelines [10], a comprehensive literature search was conducted using the electronic databases of PubMed, EMBASE and Web of Science up to April 2018. The MeSH terms and full text terms adopted were as follows: “kidney neoplasms”, “renal cell cancer”, “renal cell carcinoma”, “necrosis”, “tumor necrosis”, “prognosis”, “prognostic outcome”, “survival outcome”, “oncologic outcome” and their combinations. We also manually searched the reference lists of reviews, meta-analyses, and selected research articles to identify other “gray literature”. The language of the publications was restricted to English.

Inclusion and exclusion criteria

Eligible studies were selected only if they met the following criteria: (i) RCC and TN were pathologically confirmed, with all patients undergoing surgical resection; (ii) the potential prognostic value of TN for CSS, OS, RFS and PFS were reported; (iii) the authors categorically reported hazard ratios (HRs) and 95% confidence intervals (95%CIs), or they could be computed from the given data. Studies were excluded if the following criteria were met: (i) animal models or cancer cell lines were used; (ii) reviews, letters, commentaries, case reports and non-original articles; (iii) TN, clinical features and survival outcome were not analyzed; (iv) lacking sufficient data to acquire HRs and 95%CIs; (v) not in English. Additionally, when duplicate articles were found, only the most informative and recent article was adopted.

Data extraction and quality assessments

Two investigators independently extracted data of eligible studies using a standardized form for the following information: author identification, year of publication, country, period of recruitment, study design, age of patients, gender ratio, sample size, follow-up time, study design, interpretation of TN, histology and survival end point. For HRs and 95% CIs, multivariate analysis data were preferentially adopted. If these data were not available, then univariate analysis of survival outcomes was extracted instead. All discrepancies between the investigators reached a consensus through discussion. The methodological quality of the included cohort studies was assessed using the Newcastle-Ottawa scale (NOS) [11]. Each study was assessed using 8 methodology items in 3 domains with a score ranging from 0 to 9. High scores indicated high quality, a study with a score ≥ 6 was regarded as high quality, a score < 6 was regarded as low quality.

Statistical analysis

Statistical analyses were performed using Stata 12.0 software (Stat Corp, College Station, TX, USA). Dichotomous variables were calculated using HRs, and pooled HRs with 95% CI were used to evaluate the association of TN with RCC prognosis (CSS, OS, RFS and PFS). A heterogeneity test of the pooled HR was conducted using a Chi-square-based Q test and Higgins I2 statistic. When I2 < 50% or Pheterogeneity > 0.1, no obvious heterogeneity existed among the studies, and the fixed-effects (FE) model would be applied; otherwise, the random-effects (RE) model was applied. To obtain a more precise evaluation of heterogeneity, subgroup analysis was performed for CSS, OS and RFS based on geographical region, pathological types, staging system, No. of patients and median follow-up. Publication bias was examined using funnel plots and Egger’s linear regression test. Additionally, sensitivity analysis was used to estimate the robustness of the results via sequential omission of individual studies. A p value of < 0.05 was considered to indicate significance.

Results

Search and eligible studies

A diagram of the selection process is shown in Fig. 1. According to the search strategy, 2715 articles were retrieved from the electronic databases. By excluding 1563 duplicate reports, 1152 articles were considered potentially relevant based on screening of the titles and abstracts. The remaining articles were further excluded upon full-text review for several reasons, such as a lack of sufficient data to estimate HRs or duplicate publication in repeated cohorts. Ultimately, 34 studies [3, 1244] that focused on the association between RCC and TN were included for meta-analysis. The outcomes were CSS in 22 studies, OS in 17 studies, RFS in 9 studies and PFS in 5 studies.
Fig. 1
Fig. 1

Diagram of the literature search used in this meta-analysis

Characteristics of the included studies

The main characteristics of the 34 eligible studies are listed in Table 1. All of the studies were published between 2005 and 2017, with a mean duration of follow-up varying from 11.7 to 102 months. The present meta-analysis was based on a total sample size of 14,084 patients, ranging from 59 to 3062 patients. The NOS was applied to assess the methodological quality of the included studies, and the results showed that all studies were of high quality (Additional file 1: Table S1). All of the included studies were based on data for retrospective analyses of survival (CSS, OS, RFS, PFS). The characteristics, including tumor features and pathologic outcomes, are summarized in Table 2. TN was detected in 31.6% (4452/14,084) of the pathological specimens from the included patients. A total of 13 of the included studies were limited to clear cell renal cell carcinoma (ccRCC), whereas 21 studies involved various tumor types, including ccRCC, papillary renal cell carcinoma, chromophobe renal cell carcinoma and unclassified tumor.
Table 1

Main characteristics of the eligible studies

Study

Country

Recruitment period

No. of patients

Age (years)

Gender (m/f)

Follow-up (months)

Study design

Survival analysis

Surgery

Xia et al.2017 [12]

China

2005–2007

293

Median (range)

55 (15–86)

90/203

Median (range)

99.1 (2.63–120.47)

Retrospective

OS,PFS

nephrectomy

Wu et al.2017 [13]

China

2004–2012

301

Median (range)

53 (4–83)

206/95

Median (range)

51.6 (3–121)

Retrospective

OS

nephrectomy

Niu et al.2017 [14]

China

2008–2009

384

Mean ± SD

53.9 ± 14.9

273/111

Median (range)

73 (42–74)

Retrospective

OS,RFS

RN and PN

Kim et al.2017 [15]

Korea

2006–2012

177

Mean ± SD

62 ± 10.9

136/41

Median (range)

19.2 (0.2–63.8)

Retrospective

OS,PFS

nephrectomy

Gu et al.2017 [16]

China

2006–2014

184

Mean ± SD

54.3 ± 13

142/42

Mean ± SD

23.3 ± 14.6

Retrospective

OS, PFS

nephrectomy

Gershman et al.2017 [17]

USA

1980–2010

138

Mean (range)

63 (54–72)

91/47

Median (IQR)

102(67.2–130.8)

Retrospective

CSS, OS

RN and PN

Chen et al.2017 [18]

China

2006–2015

172

Mean ± SD

56.5 ± 12.4

123/40

Mean ± SD

34.4 ± 22.9

Retrospective

CSS,RFS

RN

Chang1 et al.2016 [19]

China

2008–2014

233

Median (IQR)

56(48–62)

170/63

Median (IQR)

68(41–71)

Retrospective

RFS

nephrectomy

Volpe et al.2016 [3]

Italy

2000–2010

308

Median (IQR)

65(57–73)

110/80

Median (IQR)

72(39–108)

Retrospective

CSS

RN

Khor et al.2016 [20]

USA

1985–2003

842

Median(range)

61.5(22.4–89)

527/315

Median (range)

73.2 (0.12–273.6)

Retrospective

OS

RN and PN

NguyenHoang et al.2016 [21]

China

2008–2009

392

Mean ± SD

55.2 ± 12.1

116/276

Median (range)

73 (39–74)

Retrospective

OS, RFS

RN and PN

Errarte et al.2016 [22]

Spain

NA

59

Mean (range)

59 (25–83)

45/14

Mean (range)

65 (1–240)

Retrospective

OS

nephrectomy

Byun et al.2016 [23]

Korea

2000–2014

1284

Mean ± SD

55.9 ± 12.9

913/371

Median (IQR)

39(19–69)

Retrospective

CSS

RN and PN

Huang et al.2015 [24]

China

1991–2011

218

Mean ± SD

58.9 ± 12.2

169/49

Median (IQR)

43(17.8–67.5)

Retrospective

RFS

RN and PN

Cornejo et al.2015 [25]

USA

1984–2010

154

Mean (range)

62.7 (26–86)

125/29

Mean (range)

73.9 (0.13–222)

Retrospective

CSS, OS

RN and PN

Teng et al.2014 [26]

China

2004–2009

378

Mean ± SD

53.4 ± 12.4

272/106

Median (range)

60 (2–97)

Retrospective

CSS, RFS

RN and PN

Park et al.2014 [27]

Korea

2006–2011

83

Mean ± SD

56.3 ± 10.5

60/23

Median (range)

18 (1–62)

Retrospective

OS, PFS

RN and PN

Oliveira et al.2014 [28]

Brazil

1988–2006

94

Mean ± SD

59.7 ± 12.3

67/27

Median

11.7

Retrospective

CSS

RN and PN

Can et al.2014 [29]

Turkey

1995–2012

127

Mean (range)

56 (26–80)

70/57

Mean (range)

46 (3–169)

Retrospective

CSS

RN and PN

Pichler et al.2013 [30]

Austria

2000–2010

994

Mean ± SD

63.2 ± 11.9

599/395

Mean (range)

48.1 (0–132)

Retrospective

CSS, OS

RN and PN

Kruck et al.2013 [31]

Germany

1993–2006

278

Mean ± SD

62.2 ± 12.5

194/84

Median (IQR)

65(20–100)

Retrospective

CSS, OS

RN and PN

Fukatsu et al.2013 [32]

Japan

1986–2008

561

Median(range)

60(21–89)

442/119

Median (range)

55.7 (1–246)

Retrospective

CSS

nephrectomy

Sukov et al.2013 [33]

USA

1970–2002

395

Median(range)

65(25–89)

327/68

NA

Retrospective

CSS

RN and PN

Chang2 et al.2011 [34]

China

2001–2006

328

Mean (range)

59.2 (23–89)

216/112

Mean (range)

46.5 (1.0–97.2)

Retrospective

OS

RN and PN

Leibovich et al.2010 [35]

USA

1970–2003

3062

NA

2,0160/1002

Median (range)

97.2 (0–432)

Retrospective

CSS

RN and PN

Katz et al.2010 [36]

USA

1989–2004

586

Median

61

530/311

Median (range)

61 (1–209)

Retrospective

CSS, OS

RN and PN

Roos et al.2009 [37]

Germany

1990–2006

118

Mean (range)

64.5 (37.8–84.9)

76/42

Median (range)

3.2 (0.3–16.1)

Retrospective

CSS, PFS

nephrectomy

Coons et al.2009 [38]

USA

1988–2006

128

Median(range)

64(35–87)

95/33

Median (range)

25.2 (0–124)

Retrospective

CSS, OS, RFS

nephrectomy

Pflanz et al.2008 [39]

Germany

1992–2006

607

Mean (range)

61.6 (18–84)

387/220

Median

54

Retrospective

CSS, OS

RN and PN

Lee et al.2006 [40]

Korea

1993–2003

485

Median(range)

55(26–81)

360/125

Median(range)

50.9(1–148.6)

Retrospective

CSS

RN and PN

Lam et al.2005 [41]

USA

1989–2000

311

Median(range)

62(27–89)

208/103

Median (range)

45 (0.3–117)

Retrospective

CSS

nephrectomy

Tornberg et al.2016 [42]

Finland

2006–2014

142

Median(range)

65(41–89)

95/47

Median (range)

31 (0–111)

Prospective

CSS

RN and cytoreductive

Schiavina et al.2015 [43]

Italy

2000–2013

185

Mean ± SD

63.3 ± 11.8

149/36

Median (IQR)

32(18–62)

Prospective

CSS

RN and PN

Ramsey et al.2008 [44]

UK

2001–2005

83

NA

50/33

Median

38

Prospective

CSS, RFS

nephrectomy

total numbers rows:36; SD standard deviation, NA data not applicable, CSS cancer-specific survival, OS overall survival, RFS recurrence-free survival, PFS progression-free survival, RD radical nephrectomy, PN partial nephrectomy

Table 2

Tumor characteristics of the eligible studies

Study

Staging system

Grading system

TN+/TN-

Stage 1–2/ 3–4

Grade 1–2/ 3–4

ccRCC/no-ccRCC

Tumor size (cm)

Xia et al.2017 [12]

2010 AJCC

Furman

41/252

212/81

248/45

293/0

NA

Wu et al.2017 [13]

2010 AJCC

Furman

77/224

265/36

225/76

301/0

NA

Niu et al.2017 [14]

2010 AJCC

Furman

75/309

295/89

255/129

384/0

Mean ± SD

4.1 ± 2.1

Kim et al.2017 [15]

2009 AJCC

Furman

46/131

60/82

44/105

159/3

Median (range)

8 (1–117)

Gu et al.2017 [16]

2010 AJCC

Furman

90/94

NA

70/94

161/23

NA

Gershman et al.2017 [17]

2010 AJCC

WHO/ ISUP

111/27

31/106

6/132

105/33

Median (range)

10(8–13)

Chen et al.2017 [18]

2010 AJCC

Furman

53/110

0/163

83/55

135/8

Mean ± SD

6.8 ± 3.5

Chang1 et al.2016 [19]

2010 AJCC

Furman

182/51

169/64

135/96

233/0

NA

Volpe et al.2016 [3]

2002 AJCC

Furman

60/130

190/0

155/35

156/34

Median (IQR)

4.9(3.5–7)

Khor et al.2016 [20]

2010 AJCC

Furman

665/177

630/212

265/577

842/0

Median (range)

4.2(0.6–20)

NguyenHoang et al.2016 [21]

2010 AJCC

Furman

78/294

292/100

259/133

392/0

Mean ± SD

4.3 ± 2.6

Errarte et al.2016 [22]

2010 AJCC

Furman

30/29

32/27

24/35

59/0

Median (range)

7.9(2–19)

Byun et al.2016 [23]

2002 AJCC

Furman

208/1076

1105/179

664/620

1114/170

Mean ± SD

4.08 ± 2.68

Huang et al.2015 [24]

2010 AJCC

Furman

34/184

160/58

155/63

0/218

Median (IQR)

3.5(2.5–6)

Cornejo et al.2015 [25]

NA

Fuhrman/ ISUP

40/114

121/33

103/51

0/154

Mean (range)

5.1(0.4–17)

Teng et al.2014 [26]

2009 AJCC

Furman

38/340

346/32

200/178

378/0

Mean ± SD

4.6 ± 2.6

Park et al.2014 [27]

NA

Furman

37/46

NA

13/70

83/0

NA

Oliveira et al.2014 [28]

2010 AJCC

Furman

18/76

77/17

65/29

94/0

Mean ± SD

4.7 ± 2.6

Can et al.2014 [29]

2010 AJCC

Furman

42/85

84/43

72/55

127/0

NA

Pichler et al.2013 [30]

2010 AJCC

Furman

277/717

723/271

839

804/190

NA

Kruck et al.2013 [31]

2010 AJCC

Furman

114/164

169/109

234/44

278/0

Mean ± SD

5.26 ± 2.91

Fukatsu et al.2013 [32]

2010 AJCC

Furman

57/104

508/53

341/220

561/0

NA

Sukov et al.2013 [33]

2010 AJCC

Furman

186/209

346/49

247/148

0/395

NA

Chang2 et al.2011 [34]

2002 AJCC

Furman

139/189

240/88

216/112

232/96

NA

Leibovich et al.2010 [35]

2002 AJCC

Furman

792/2090

1992/1070

1649/1413

1781/1281

NA

Katz et al.2010 [36]

2002 AJCC

Furman

253/586

575/194

589/252

641/198

NA

Roos et al.2009 [37]

2002 AJCC

Furman

10/108

0/118

63/55

109/16

Median (range)

8(2.5–20)

Coons et al.2009 [38]

2002 AJCC

Furman

57/71

0/128

40/103

105/23

Median (range)

9.9 (3.5–21)

Pflanz et al.2008 [39]

2002WHO

Thoenes

155/452

515/92

532/75

479/128

NA

Lee et al.2006 [40]

1997 AJCC

Furman

131/354

382/103

364/221

419/66

NA

Lam et al.2005 [41]

1997 AJCC

Fuhrman

168/143

157/153

186/119

270/41

NA

Tornberg et al.2016 [42]

2009 AJCC

Furman

84/58

0/132

38/104

129/13

Mean ± SD

10.3 ± 3.6

Schiavina et al.2015 [43]

2009 AJCC

Furman

49/136

0/185

46/139

150/35

Mean ± SD

8.05 ± 2.8

Ramsey et al.2008 [44]

1997 AJCC

Furman

55/28

48/35

37/40

33/50

NA

total numbers rows:36; TN+/TN tumor necrosis positive/ tumor necrosis negative, SD standard deviation, NA data not applicable, ccRCC/no-ccRCC clear cell renal cell carcinoma/non- clear cell renal cell carcinoma

Prognostic value of TN for survival outcome

The present meta-analysis demonstrated that TN in RCC is associated with poor CSS (RE HR = 1.37, 95% CI: 1.23–1.53, p < 0.001, I2 = 76.5%, Pheterogeneity < 0.001; Fig. 2a), OS (RE HR = 1.29, 95% CI: 1.20–1.40, p < 0.001, I2 = 57.6%, Pheterogeneity = 0.02; Fig. 2b), RFS (FE HR = 1.55, 95% CI: 1.39–1.72, p < 0.001, I2 = 35.6%,Pheterogeneity = 0.133; Fig. 2c) and PFS (FE HR = 1.31, 95% CI: 1.17–1.46, p < 0.001, I2 = 32.9%, Pheterogeneity = 0.202; Fig. 2d). To explore the source of heterogeneity for CSS, OS and RFS, subgroup analysis was conducted according to geographical region (Asia vs. other regions), pathological type (ccRCC vs. other types), staging system (2010 AJCC vs. other system), No. of patients (≥ 300 vs. < 300) and median follow-up (≥ 40 months vs. < 40 months). The results of this subgroup analysis again suggested that TN is a prognostic factor, despite heterogeneity among some groups (Table 3). Notably, heterogeneity for CSS, OS and RFS was significantly decreased in some models, such as geographical region in Asia, ccRCC pathological type, 2010 AJCC staging system and ≥ 300 cases.
Fig. 2
Fig. 2

a Forest plots of studies evaluating the association between TN and CSS outcomes in RCC patients. b Forest plots of studies evaluating the association between TN and OS outcomes in RCC patients. c Forest plots of studies evaluating the association between TN and RFS outcomes in RCC patients. d Forest plots of studies evaluating the association between TN and PFS outcomes in RCC patients

Table 3

Summary and subgroup analysis for the eligible studies

Analysis specification

No. of studies

Study heterogeneity

Effects model

Pooled HR(95% CI)

p-Value

I2 (%)

Pheterogeneity

CSS

 Overall

22

76.5

< 0.001

Random

1.37(1.23,1.53)

< 0.001

 Geographical region

  Asian

7

51.7

0.053

Random

1.34(1.12,1.59)

0.001

  Other regions

15

80.8

< 0.001

Random

1.40(1.22,1.60)

< 0.001

 Pathological types

  ccRCC

6

0

0.775

Fixed

1.34(1.15,1.55)

< 0.001

  Other types

16

81.7

< 0.001

Random

1.38(1.22,1.58)

< 0.001

 Staging system

  2010 AJCC

8

0

0.981

Fixed

1.30(1.17,1.44)

< 0.001

  Other system

14

82.3

< 0.001

Random

1.42(1.23,1.64)

< 0.001

 No. of patients

   ≥ 300

13

82

< 0.001

Random

1.39(1.21,1.61)

< 0.001

   < 300

9

15,4

0.301

Fixed

1.33(1.16,1.51)

< 0.001

 Median follow-up

   ≥ 40 months

12

83.3

< 0.001

Random

1.36(1.16,1.60)

< 0.001

   < 40 months

9

30.2

0.177

Fixed

1.33(1.16,1.51)

< 0.001

OS

 Overall

17

57.6

0.002

Random

1.29(1.20,1.40)

< 0.001

 Geographical region

  Asian

9

30.2

0.177

Fixed

1.38(1.25,1.51)

< 0.001

  Other regions

8

58.6

0.017

Random

1.20(1.09,1.34)

< 0.001

 Pathological types

  ccRCC

8

48.8

0.057

Random

1.33(1.19,1.49)

< 0.001

  Other types

9

62.7

0.006

Random

1.26(1.13,1.41)

< 0.001

 Staging system

  2010 AJCC

10

63.6

0.003

Random

1.30(1.17,1.44)

< 0.001

  Other system

7

53.1

0.046

Random

1.30(1.14,1.47)

< 0.001

 No. of patients

   ≥ 300

8

67.5

0.003

Random

1.25(1.12,1.39)

< 0.001

   < 300

9

29.2

0.185

Fixed

1.35(1.22,1.49)

< 0.001

 Median follow-up

   ≥ 40 months

13

62.6

0.001

Random

1.27(1.16,1.39)

< 0.001

   < 40 months

4

0

0.412

Fixed

1.37(1.20,1.56)

< 0.001

RFS

 Overall

9

35.6

0.133

Fixed

1.55(1.39,1.72)

< 0.001

 Geographical region

  Asian

6

42.7

0.12

Fixed

1.48(1.31,1.66)

< 0.001

  Other regions

3

0

0.684

Fixed

1.87(1.41,2.37)

< 0.001

 Pathological types

  ccRCC

4

0

0.541

Fixed

1.61(1.40,1.86)

< 0.001

  Other types

5

57.5

0.051

Random

1.46(1.25,1.71)

< 0.001

 Staging system

  2010 AJCC

5

54

0.069

Random

1.48(1.31,1.69)

< 0.001

  Other system

4

0

0.483

Fixed

1.69(1.40,2.04)

< 0.001

 No. of patients

   ≥ 300

4

0

0.702

Fixed

1.57(1.35,1.83)

< 0.001

   < 300

5

63.4

0.027

Random

1.52(1.32,1.76)

< 0.001

 Median follow-up

   ≥ 40 months

6

0

0.758

Fixed

1.62(1.43,1.84)

< 0.001

   < 40 months

3

75.3

0.018

Random

1.39(1.16,1.68)

0.001

PFS

 Overall

5

32.9

0.202

Fixed

1.31(1.17,1.46)

< 0.001

 Pathological types

  ccRCC

2

67.8

0.078

Random

1.44(1.20,1.71)

< 0.001

  Other types

3

0

0.6

Fixed

1.23(1.07,1.41)

0.004

 Staging system

  2010 AJCC

2

76.3

0.04

Random

1.35(1.18,1.54)

< 0.001

  Other system

3

0

0.582

Fixed

1.22(1.01,1.48)

0.036

Sensitivity analyses and publication bias

In sensitivity analysis excluding one study at a time, the pooled HR for CSS ranged from 1.29 (95% CI: 1.19–1.39) to 1.37 (95% CI: 1.22–1.54) (Additional file 2: Figure S1). Similarly, the pooled HR for OS ranged from 1.27 (95% CI: 1.17–1.37) to 1.31 (95% CI: 1.21–1.42) (Additional file 3: Figure S2), that for RFS from 1.52 (95% CI:1.32–1.76) to 1.66 (95% CI: 1.47–1.86) (Additional file 4: Figure S3), and that for PFS from 1.21 (95% CI:1.07–1.38) to 1.35 (95% CI: 1.12–1.63) (Additional file 5: Figure S4). These results indicate that the findings were reliable and robust. Although no statistical evidence of publication bias was observed for RFS (p-Egger = 0.135, Fig. 3c) and PFS (p-Egger = 0.932, Fig. 3d), publication bias was observed for CSS (p-Egger = 0.006, Fig. 3a) and OS (p-Egger = 0.001, Fig. 3b).
Fig. 3
Fig. 3

a Funnel plots and Egger’s tests for the publication bias of CSS in hazard ratios (HRs). b Funnel plots and Egger’s tests for the publication bias of OS in hazard ratios (HRs). c Funnel plots and Egger’s tests for the publication bias of RFS in hazard ratios (HRs). d Funnel plots and Egger’s tests for the publication bias of PFS in hazard ratios (HRs)

Discussion

RCC is the most common solid lesion of the kidney, and more than 40% of patients die from this type of cancer [2]. Despite significant improvements in systemic therapy for RCC, the prognosis of patients with RCC and treatment response rates have not substantially increased [17, 42, 44]. Although several pathologic parameters, including lymphatic vessel invasion [45], tumor fat invasion [26] and primary tumor size [43], provide independent prognostic information, the likely outcome for an individual patient remains uncertain. The TNM stage and Fuhrman grade system are the most widely used approaches for RCC; however, there have been many recent suggestions for modifications based on survival trends in large case series [46]. Additionally, RCC is a highly heterogeneous disease with different clinical presentations and characteristics that remain somewhat unpredictable [47]. Therefore, it is essential to optimize the treatment and prognosis of RCC and to provide better counseling for each RCC patient.

The presence of TN in pathologic specimens may reflect the tumor biology and may also provide additional useful prognostic information. As TN results from rapid tumor proliferation and consequent outgrowth of the blood supply [41], histologic TN has been proposed to be a sign of tumor aggressiveness that generally leads to poor clinical outcomes [48]. Previous studies have investigated the association of TN with various solid tumors, including breast cancer [49], colorectal cancer [50] and lung cancer [51]. Indeed, there is renewed interest in using TN, which can be assessed in every routine pathological examination without additional costs, to more accurately predict the clinical outcome of RCC. For example, Khor et al. [20] and Ito et al. [48] reported that TN is strongly associated with poor survival and should serve as an independent prognostic factor for patients with RCC. Nonetheless, some studies have shown that the presence of any TN is a negative predictor of survival in RCC [52, 53].

To our knowledge, the present study is the first meta-analysis on the association between TN and clinical outcomes of different types of RCC. In this analysis, 14,084 RCC patients were included from 34 cohort studies, and TN was detected in 31.6% of 4452 RCC patients. Robust evidence obtained from sensitivity analysis demonstrated that the presence of TN was associated with poor outcomes in terms of CSS (HR = 1.37, p < 0.001), OS (HR = 1.29, p < 0.0 01), RFS (HR = 1.55, p < 0.001) and PFS (HR = 1.31, p < 0.001) in patients with RCC. These findings were consistently independent of geographical region, pathological type, staging system, No. of patients and median follow-up. Although there was no evidence of heterogeneity in terms of CSS or PFS, significant heterogeneity was detected in analyses of OS and RFS models. To further explore the source of heterogeneity in OS and RFS, subgroup analysis was conducted, and the data showed that significant variations were reduced in OS and RFS within some items.

Notably, the present study has several limitations. First, all the included studies were retrospective cohort studies, and data extracted from those studies may have led to inherent potential bias. Second, the criteria for determining the presence of TN in a pathologic specimen were inconsistent in the included studies, which may contribute to heterogeneity. Thus, rigorous morphological criteria should be used to standardize the diagnosis of TN. Third, we only included published studies written in English, and the lack of “gray literature” may cause selection bias. Fourth, substantial heterogeneity was observed in meta-analysis of CSS and OS, and although we selected the RE model according to heterogeneity, this diversity remained. Using subgroup analysis, we propose that the heterogeneity likely reflected differences in factors, such as patient and tumor characteristics. Fifth, a statistical publication bias was observed for CSS and OS according to Egger’s test. In general, studies with negative results tend not to be submitted or published; therefore, a certain degree of publication bias was observed in the present study. Finally, it should be noted that factors, including age, sex, histology type and surgical method, that may affect survival outcomes were adequately controlled.

Nevertheless, the present study has several key strengths. First, the meta-analysis included 34 studies with large sample sizes, with the ability to detect more stable associations between TN and clinical outcomes of RCC patients. Second, with strict inclusion and exclusion criteria, we extracted available data from relevant studies. Furthermore, through subgroup and sensitivity analyses, the results were reliable and robust. Therefore, TN determination, with excellent accessibility and low costs, warrants wider application in patients with RCC for risk stratification and decision-making of individualized treatment.

Conclusions

In conclusion, the results of the present meta-analysis demonstrate that TN in histopathology is associated with poor CSS, OS, RFS and PFS in patients with RCC. Due to the limitations of the present study, large-scale, multicenter prospective studies with long-term follow-up are needed to verify these results.

Notes

Abbreviations

AJCC: 

American Joint Committee on Cancer

ccRCC: 

Clear cell renal cell carcinoma

CIs: 

Corresponding 95% confidence intervals

CSS: 

Cancer-specific survival

FE: 

Fixed-effects

HRs: 

Hazard ratios

ISUP: 

International Society of Urologic Pathologists

NOS: 

Newcastle Ottawa scale

OS: 

Overall survival

PFS: 

Progression-free-survival

PRISMA: 

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

RCC: 

Renal cell carcinoma

RE: 

Random-effects

RFS: 

Recurrence-free survival

SSIGN: 

Mayo Clinic Stage, Size, Grade and Necrosis

TN: 

Tumor necrosis

Declarations

Availability of data and materials

All data generated or analyzed during the present study are included in this published article (and its additional files).

Authors’ contributions

LJZ and BW designed the research. ZLZ, WQ and HZ performed the literature search. JY and YJF analyzed the data and interpreted the results. LJZ drafted the manuscript. All authors approved the final 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

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Urology, Affiliated Jiang-yin Hospital of the Southeast University Medical College, Jiang-yin, 214400, People’s Republic of China
(2)
Department of Pharmacy, Affiliated Jiang-yin Hospital of the Southeast University Medical College, Jiang-yin, 214400, People’s Republic of China

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