Ann Surg Oncol DOI 10.1245/s10434-012-2417-0
ORIGINAL ARTICLE – COLORECTAL CANCER
Systematic Review of Sentinel Lymph Node Mapping Procedure in Colorectal Cancer Edwin S. van der Zaag, MD, PhD1, Wim H. Bouma, MD, PhD1, Pieter J. Tanis, MD, PhD2, Dirk T. Ubbink, MD, PhD3, Willem A. Bemelman, MD, PhD2, and Christianne J. Buskens, MD, PhD2 Department of Surgery, Gelre Ziekenhuizen, Apeldoorn, The Netherlands; 2Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands; 3Department of Quality Assurance & Process Innovation, Academic Medical Center, Amsterdam, The Netherlands 1
ABSTRACT Background. The clinical impact of sentinel lymph node (SN) biopsy in colorectal cancer is still controversial. The aim of our study was to determine the accuracy of this procedure from published data and to identify factors that contribute to the conflicting reports. Methods. A systematic search of the Medline, Embase, and Cochrane databases up to July 2011 revealed 98 potentially eligible studies, of which 57 were analyzed including 3,934 patients (3,944 specimens). Results. The pooled SN identification rate was 90.7 % (95 % CI 88.2–93.3), with a significant higher identification rate in studies including more than 100 patients or studies using the ex vivo SN technique. The pooled sensitivity of the SN procedure was 69.6 % (95 % CI 64.7–74.6). Including the immunohistochemical findings increased the pooled sensitivity of SN procedure to 80.2 % (95 % CI 4.7–10.7). Subgroups with significantly higher sensitivity could be identified: C4 SNs versus \4 SNs (85.2 vs. 66.3 %, p = 0.003), colon versus rectal cancer (77.6 vs. 65.7 %, p = 0.04), early T1 or T2 versus advanced T3 or T4 carcinomas (93.4 vs. 58.8 %, p = 0.01). Serial sectioning and immunohistochemistry resulted in a mean upstaging of 18.9 % (range 0–50 %). True upstaging defined as micrometastases (pN1mi?) rather than isolated tumor cells (pN0itc?) was 7.7 %. Conclusions. The SN procedure in colorectal cancer has an overall sensitivity of 70 %, with increased sensitivity and refined staging in early-stage colon cancer. Because the
Ó Society of Surgical Oncology 2012 First Received: 25 August 2011 E. S. van der Zaag, MD, PhD e-mail:
[email protected]
ex vivo SN mapping is an easy technique it should be considered in addition to conventional resection in colon cancer. Although improvements in screening and treatment have contributed to reduced disease-specific incidence and mortality, colorectal cancer (CRC) remains the third leading cause of cancer-related deaths.1 Primary treatment for nonmetastatic CRC is surgical resection of the primary tumor with en bloc resection of the regional node bearing mesentery. The role for regional lymphadenectomy in CRC is well established: It involves local-regional control, cancer staging, and adjuvant treatment planning, and it affects overall survival. Nodal involvement is the most important prognostic parameter and is the pillar in consensus-driven treatment decision making for adjuvant chemotherapy.2 The AJCC recommends at least 12 harvested nodes per resection specimen for accurate nodal staging, but in daily clinical practice the nodal yield varies with more than 50 % of resection specimens containing fewer than 12 nodes.3 This relates to a clinically significant understaging in CRC. Up to 30 % of early node-negative CRC will recur following potentially curative resection.4 Apart from incomplete surgical resection, inadequate staging of CRC may result from insufficient pathologic regional nodal retrieval, sampling error, or overlooked small-volume nodal disease. Serial sectioning and additional immunohistochemistry or RT-PCR could diagnose lymphatic spread more accurately.5 Ideally, all regional lymph nodes should be examined with these techniques, but this would be too expensive and time-consuming and therefore not feasible in everyday practice. The sentinel lymph node (SN) concept could offer a solution.6 This procedure allows the pathologist to study the few SNs removed in greater detail for tumor burden
E. S. van der Zaag et al.
compared with the conventional hematoxylin and eosin (H&E) staining currently used in routine daily practice. Therefore, SN procedure could refine staging, possibly identifying a patient group that might benefit from adjuvant chemotherapy. In contrast to breast cancer and melanoma, regional lymphadenectomy is an integral part of primary resection in CRC.7,8 Therefore, SN biopsy is only an adjunct potentially improving staging without clearly defined prognostic impact and therapeutic implications so far. Numerous, generally small and single-institution studies assessed the feasibility of SN with varying conclusions. The SN procedure for CRC has not been standardized, and the methods, materials, and patient selection vary by institution and surgeon. In this report, we present a systematic review of all published studies of SN in CRC to analyze the diagnostic accuracy of this procedure. Our study provides a thorough assessment of the test performance characteristics of the SN procedure reported in the literature and explores the reasons for the observed heterogeneity in study results. MATERIAL AND METHODS Literature Search The PubMed and Embase databases and The Cochrane Library were searched until July 2011 to identify relevant publications regarding lymphatic mapping in CRC patients. The following expanded Medical Subject Headings terms were used: ‘‘sentinel node,’’ ‘‘lymphatic mapping,’’ ‘‘colon cancer,’’ ‘‘rectal cancer,’’ ‘‘colorectal cancer/tumo(u)r.’’ References from included studies, review articles, and editorials were cross-checked for additional relevant publications. Data from meeting abstracts were not studied as these were judged unlikely to present sufficient detail for data extraction required by our study protocol. Selection of eligible studies was undertaken independently by 2 investigators. Any discrepancies were resolved by discussion. Inclusion and Exclusion Criteria English language publications analyzing lymphatic mapping in human patients with colorectal cancer were included. Duplicate articles based on the same group of patients were identified and excluded. For follow-up studies that included a subset of previously reported patients, only the most recent article was included. Studies describing the use of indocyanine green were judged to be experimental and therefore excluded. Finally, if quantitative results were not presented or SN performance parameters could not be extracted from the presented data, studies were also excluded.
Assessment of Methodological Quality Each of the studies identified was assessed for validity criteria laid down by QUADRAS (an evidence base tool for the assessment of the quality of diagnostic studies).9 The following items were scored as yes, no, or not mentioned: 1, prospective study; 2, consecutive patients; 3, inclusion and exclusion specification; 4, SN criteria and detection procedures (i.e., procedure described sufficiently detailed to permit replication); 5, valid reference test (histology); 6, [20 SN procedures per year; 7, outcome parameters reduced to stage of disease or location of disease; 8, use of additional immunohistochemistry or PCRtechniques with subclassification of upstaging. Data Extraction All data extraction was performed by 2 authors (ESZ and CJB) independently, with cross-checking to ensure validation. The fields for data capture were prespecified before analysis and included extensive information on publication details, patient demographics, methodology, and SN efficacy. In case of discrepancies in the results, the original article was reanalyzed. The quantitative results were used to build 2 9 2 contingency tables comprising true positives, true negatives, and false negatives. The term ‘‘false positive’’ (and hence the calculation of specificity) is not appropriate because the presence of metastases in the SN confers node positivity. The term is also not appropriate for the detection of occult tumor cells in SNs given the uncertainty of the clinical significance of these cells. Instead the term upstaging is used to describe the immunohistochemical or PCR findings in SNs. The AJCC definition for occult tumor cells classifies only micrometastases (lesions between 0.2 and 2.0 mm) as true upstaging to pN1, whereas patients with isolated tumor cells (ITC) (tumor cell deposits smaller than 0.2 mm) are still considered N0 (pN0itc?).10 SN accuracy parameters were recalculated from the quantitative data presented in the original publication with and without taking immunohistochemical or PCR results into account. Standard definitions were used to facilitate comparison across studies. Outcome parameters may, therefore, differ from the original manuscript. The following definitions were used: Detection rate Accuracy rate
(Number of successful attempts to retrieve SNs/number of attempts to retrieve SNs) 9 100 % (Number of correct predictions of the nodal status by SN biopsy/number of patients with successful SN biopsy) 9 100 %
Sentinel Node Procedure in Colorectal Cancer
Sensitivity
Upstaging rate
(Number of patients with tumor involved SNs/number of patients with any lymph node containing tumor) 9 100 % (Number of patients with micrometastases or ITC/number of patients classified as N0 with routine histopathological examination) 9 100 %
Statistical Analysis If pooling was feasible, a random effects model with an exact likelihood approach was used to calculate summary SN accuracy parameters with 95 % confidence intervals (95 % CIs). The variation in sensitivity in studies was displayed graphically as a forest plot using Review Manager version 5.0 (Cochrane Collaboration, Copenhagen, Denmark). Bivariate correlations between continuous measures with normal distribution were based on the Pearson correlation coefficient. To correlate sensitivity results to various study parameters, a linear regression model was used. For sensitivity analysis of individual patient data, a logistic-regression analysis was applied. When appropriate, cutoff points for continuous variables were selected a priori based on clinically relevant criteria or reporting convention. All data were analyzed with SPSS version 16.0 (SPSS Inc., Chicago, IL), and a p value of \0.05 was considered significant. RESULTS Included Studies The literature search yielded 98 publications on SN biopsy in humans with CRC between January 1999 (the year of the earliest series) and July 2011. Of these, 2 articles did not assess the SN procedure, 2 articles were not in English, 34 articles were either duplicate studies or had more recent data updating the principal studies, and from 3 articles the quantitative data could not be retrieved. The remainder of this analysis is based on the 57 included studies that were available for data extraction (Fig. 1).11–68 Study Characteristics Selected study characteristics from the 57 articles are presented in Table 1. In total, 3934 patients were enrolled across all studies with 3944 SN procedures performed. There were 10 multicenter studies.23,27–29,31,39,41,49,54,56 Most studies analyzed a limited number of patients, with only 10 studies including more than 100 patients. There were 21 studies that solely included patients with colon cancer, and 3 studies that examined rectal cancer in
Medline and Embase search SN studies colorectal cancer Reports excluded based on title or abstract Review articles (n = 94) Irrelevant or non-comparitive (n = 251) Publications retrieved for detailed assessment Not in English (n = 2) Duplicate/updates available (n =34) SN procedure not used (n = 2) Publications analysed for SN performance parameters No quantitative data available (n = 3) Publications analysed for SN (n = 57)
FIG. 1 Flowchart showing the selection and exclusion of publications for this review
isolation. However, the majority of studies (33) included both patient with colon and rectal cancer. In 32 studies the in vivo technique was used, in 17 studies the ex vivo technique, and in 8 studies both methods were used to identify SNs. The 2 methods used to identify SNs were blue dyes or radiolabeled tracers. There were 3 blue dyes used: patent blue dye V (25 studies), isosulfan blue 1 % (lymphazurin) (15 studies), and 1 % methylene blue (4 studies). In 2 studies, 99mTc sulfur colloid for SN was used for identification, and 11 studies used a combination of blue dye and radioactive colloid. The mean number of harvested lymph nodes reported was 16.7, and ranged from 7.5 to 30.0 across studies. The overall average number of SNs identified was 2.8 (range between studies from 1.0 to 7.1). All studies had a prospective design and used a valid reference test (histology) with clear SN criteria and detection protocols. However, only 20 of the 57 eligible studies met at least 3 of the 5 other validity criteria (consecutive patients, inclusion and exclusion criteria clearly described, [20 studies per year, separate presentation of outcome parameters, use of additional upstaging techniques with subclassification of upstaging).11,18–21,24,25,28,29,32,39,41,43–45,56,57,59,64,67
E. S. van der Zaag et al. TABLE 1 Results of lymphatic mapping in patients with colorectal cancer Study
No. Colon Rectum No. patients ln
Tracer
Method
No. True True False Analysis SN SN pos neg neg
Methylene blue
In vivo/ex vivo 1.0
Upstaging (%)
Vilcea11
43
22
21
NR
8
19
5
HE, IHC of SN
9.4
Ceranic12
45
NR
NR
22.9 Methylene blue
Ex vivo
1.7
14
23
7
HE, IHC of SN
22.0
Retter13
31
31
0
21.5 Patent blue
In vivo
1.3
4
16
8
HE, IHC of SN
20.8
Finan14
58
0
58
12.1 Isosulfan blue
Ex vivo
2.2
15
27
7
HE, IHC of SN
0
Sommariva15
69
54
15
12.4 Patent blue
Ex vivo
5.0
12
46
9
HE, IHC of SN
12.0
Dragan16
60
60
0
NR
Isosulfan blue
Ex vivo
4.1
32
26
0
HE, IHC of SN
26.9
Ivanov17
103
48
55
NR
Patent blue
In vivo
NR
48
52
3
HE, IHC of SN
20.0
Nordga¨rd18
131
131
0
13.8 Patent blue
Ex vivo
4.0
29
83
13
HE, RT-PCR of SN
21.4
19
Van der Zaag
132
100
32
15.4 Patent blue
Ex vivo
2.0
33
11
73
HE, IHC of SN
28.8
Park20
69
45
24
18.5 Methylene blue
In vivo/ex vivo 2.5
26
27
6
HE, IHC of SN
18.5
Chan21
31
19
12
7.5
In vivo
1.3
11
11
3
HE, IHC of SN
0
Quadros22
52
22
30
19.0 Patent blue/99mTc
In vivo
3.5
15
16
8
HE, IHC of SN
37.5
Faerden23
199
200
0
13.0 Patent blue
In vivo
4.0
32
125
28
HE, IHC of all ln
29.8
Lim24
120
120
0
20.0 Isosulfan blue/99mTc In vivo
4.0
29
71
20
HE, IHC of SN
11.3
Sandrucci25
Methylene blue
Patent blue/99mTc
35
30
5
8.7
2.2
21
11
3
HE, IHC of SN
36.4
26
Ko¨ksal
19
13
6
10.0 Isosulfan blue
In vivo/ex vivo 1.8
2
13
3
HE, IHC of SN
18.7
Kelder27
69
69
0
11.0 Patent blue
In vivo
2.3
15
49
3
HE, IHC of SN
18.4
315
315
0
20.0 Patent blue
In vivo
2.0
74
156
38
HE, IHC of SN
21.3
Stojadinovic29
84
84
0
18.2 Isosulfan blue
Ex vivo
2.7
18
56
8
HE, IHC of SN
26.8
Matter30
52
36
12
30.0 Patent blue
In vivo
2.7
8
30
10
HE, IHC of all ln
19.4
Tiffet31
64
49
15
18.0 Patent blue/99mTc
In vivo
2.8
12
35
12
HE, IHC of SN
5.7
Van schaik32
44
27
17
10.5 Patent blue
Ex vivo
5.0
26
16
0
HE, IHC of SN
30.3
Murawa33
27
13
14
NR
In vivo
NR
2
22
1
HE, IHC of SN
9.1
Liberale34
118
71
47
20.0 Patent blue
In vivo/ex vivo 2.0
22
76
14
HE, IHC of SN
9.5
Covarelli35
20
20
0
17.1 Patent blue/99mTc
In vivo
1.3
6
12
1
HE, IHC of SN
7.7
Bianchi
22
22
0
23.3 Patent blue
In vivo
2.3
5
16
1
HE, IHC of SN
12.5
Yagci37
47
20
27
18.6 Patent blue
Ex vivo
5.9
16
27
4
HE, IHC of SN
14.8
Thomas38
69
63
6
15.8 Isosulfan blue
Terwisscha39
53
56
0
9.0
Bembenek28
36
Patent blue
Patent blue/99mTc
In vivo
In vivo
2.1
12
38
14
In vivo
2.2
12
35
2
HE, IHC of SN
5.3
HE, IHC of all ln
14.8
Smith40
17
17
0
16.0 Isosulfan blue
Ex vivo
1.8
8
0
8
HE, IHC of SN
10.0
Saha41
500
408
92
15.0 Isosulfan blue
In vivo
2.2 186
211
21
HE, IHC of SN
261
Tuech42
30
34
0
20.0 Patent blue
In vivo/ex vivo 1.8
10
20
2
HE, IHC of SN
12.0
Khafagy43
53
0
53
NR
Patent blue
In vivo
NR
31
8
8
HE, IHC of all ln
46.0
Codignola44
56
52
4
21.0 Patent blue
In vivo
2.0
37
13
6
HE, IHC of SN
37.5
Braat45
91
57
34
7.7
Ex vivo
1.8
23
51
8
HE, IHC of SN
10.5
Smith46
40
29
8
16.9 Isosulfan blue
Ex vivo
4.4
10
23
6
HE, IHC of SN
24.0
Dahl47
30
30
0
17.4 Patent blue/99mTc
In vivo
2.2
10
18
2
HE only
Bell48
58
46
12
29.9 Patent blue
Ex vivo
2.9
9
33
14
HE, IHC of SN and equal no of other ln
Bertagnolli49
72
72
0
17.3 Isosulfan blue
In vivo
2.1
10
42
14
HE, serial sections of all ln
Demirbas50
Patent blue
41
25
16
8.6
124
110
12
30.0 Isosulfan blue
57
57
0
14.4 Isosulfan blue/99mTc In vivo
Bembenek
48
0
48
18.0
Bertoglio54
26
20
6
12.4 Patent blue
Roseano55
23
14
9
14.6 Patent blue
In vivo/ex vivo 2.5
2
19
2
HE, IHC of SN
0
Viehl56
31
31
0
21.6 Isosulfan blue
In vivo
6
15
6
HE, IHC of SN
NR
Wong51 Patten52 53
Patent blue
99m
Tc
Ex vivo
3.0
18
17
2
Ex vivo
3.8
27
69
24
61
HE, IHC of SN
11.8
HE, IHC of all ln
27.3
3.5
14
31
11
HE, IHC of SN
14.3
Ex vivo
3.0
7
30
9
HE, IHC of SN
0
In vivo
2.9
7
15
2
HE, serial section of SN only
2.5
Sentinel Node Procedure in Colorectal Cancer TABLE 1 continued Study
No. Colon Rectum No. patients ln
Bilchik57
Tracer
Method
No. True True False Analysis SN SN pos neg neg
Upstaging (%)
120
102
18
14.0 Isosulfan blue/99mTc In vivo
1.8
37
73
5
HE, IHC of SN
29.5
50
46
5
NR
Isosulfan blue
In vivo/ex vivo 1.5
10
27
10
HE, IHC of SN
NR
56
19
37
23.9
99m
In vivo
3.5
18
29
4
HE only
Nastro60
8
8
0
NR
Patent blue/99mTc
In vivo
NR
4
2
0
HE, IHC of SN
50.0
Paramo61
55
55
0
12.1 Isosulfan blue
In vivo
1.9
14
30
1
HE, IHC of SN
20.0
62
Cox
17
17
0
17.5 Isosulfan blue
In vivo/ex vivo 5.5
3
14
0
HE, IHC of SN
24.0
Gandy63
19
8
11
16.0 Patent blue
Ex vivo
5
6
1
HE only
Esser64
31
26
5
15.0 Isosulfan blue
In vivo
1.7
2
15
1
HE only
Merrie65
25
26
0
17.5 Patent blue/99mTc
In vivo
3.0
4
16
3
HE, RT-PCR of all ln 25.0
Cserni66
25
NR
NR
15.5 Patent blue
In vivo
4.0
8
11
5
HE only
Joosten67
50
44
6
14.0 Patent blue
In vivo
3.0
8
15
12
Broderick-Villa Kitagawa59
58
Tc
7.1
HE, IHC of SN
13.3
SN sentinel lymph node, HE hematoxylin and eosin staining, IHC immunohistochemistry, RT-PCR real-time polymerase chain reaction, NR not reported
SN Identification In 3643 specimens (92.4 %) 1 or more SNs could be identified. The proportion of successful lymphatic mapping across studies ranged from 58 to 100 %, with the majority of studies (41 of 57) demonstrating an identification rate higher than 90 %. The detection rate in studies analyzing colon carcinomas was significantly higher than in studies including only rectal cancers (93.1 vs. 83.1 %, respectively, p = 0.03). Identification rate was significantly higher in studies including more than 100 patients (mean 94.6 %) than in smaller studies (89.5 %, p = 0.02). In the 32 studies employing the in vivo method, the SN was significantly less often successfully identified than in the 18 studies with ex vivo procedures (89.2 vs. 93.7 %, respectively, p = 0.04). In vivo identification results did not improve in the 11 studies where colloid was added to blue dye. Also, 18 in vivo studies commented on aberrant lymphatic drainage with a mean rate of 3.9 %.13,24,25,27,28,30,31,34–36,42,44,47,49,61–63,67 No SNs were found outside the planned resection area in 11 studies, and the percentage of aberrant drainage ranged from 1.6 to 15.0 % in the remaining 7 studies. When analyzing other parameters, no predictive factors for identification rate could be identified (i.e., multicenter studies, tracer used). Test Performance Measures The pooled sensitivity as derived from the recalculated outcome parameters was 69.6 % (95 % CI 64.7–74.6), with an accompanying false negative rate of 30.4 (95 % CI 25.5–35.3). The overall pooled accuracy of the SN proce-
dure was 88.2 % (95 % CI 86.0–90.3). Sensitivity of the SN procedure ranged from 33.3 to 100 % across studies (Fig. 2). If the immunohistochemical findings of the SN were included in the accuracy parameters, an increased mean sensitivity of 80.2 % was found (20 studies11–15,18,19,30,33,35,39,43–46,48,49,52,57,60) (Table 2). There was a strong correlation between sensitivity and the number of identified SNs (Pearson correlation coefficient 0.37, p = 0.007, Fig. 3), with a good predictive accuracy for lymph node involvement when 4 or more SNs were identified (mean sensitivity \4 SNs = 66.3 % vs. C4 SNs = 85.2 %, p = 0.003). There was no correlation between sensitivity and the method of SN detection or tracer used. Apart from the 24 studies only analyzing colon or rectal malignancies, another 10 studies presented separate sensitivity results for the 2 types of cancer.9–12,15,32,37,41,45,64 After combing the outcome parameters a significantly higher sensitivity of SN procedures in colon carcinomas was found (77.6 vs. 65.7% for rectal carcinomas, p = 0.04). In 6 studies, sensitivity results could be calculated separately for early (T1/T2) and advanced (T3/T4) carcinomas.15,21,31,41,53,59 Statistically, a significantly higher sensitivity was seen in the early group compared with advanced carcinomas (93.4 vs. 58.8%, p = 0.01), but the number of patients with positive lymph nodes in early carcinomas in these studies was small. Unfortunately, the reported parameters associated with heterogeneity in the sensitivity results could not be analyzed in a prediction model since different studies commented on different variables. Overall, the sensitivity of 20 high-quality studies was higher than the other studies, although not statistically
E. S. van der Zaag et al. FIG. 2 Individual study results on diagnostic accuracy of 57 SN studies included in the metaanalysis
Study TP 8 1. Vilcea 14 2. Ceranic 4 3. Retter 15 4. Finan 12 5. Sommariva 32 6. Dragan 48 7. Ivanov 29 8. Norgard 33 9. Van der Zaag 18 10. Park 11 11. Chan 15 12. Quadros 32 13. Faerden 29 14. Lim 21 15. Sandrucci 2 16. Koksai 15 17. Kelder 74 18. Bembenek 18 19. Stojadinovic 8 20. Matter 12 21. Tiffet 26 22. Van Schaik 2 23. Murawa 22 24. Liberale 6 25. Covarelli 5 26. Bianchi 16 27. Yagci 12 28. Thomas 12 29. Terwisscha 8 30. Smith 186 31. Saha 10 32. Teuch 31 33. Khafagy 37 34. Codignola 23 35. Braat 10 36. Smith 10 37. Dahl 9 38. Bell 10 39. Bertagnolli 18 40. Demirbass 27 41. Wong 14 42. Patten 7 43. Benbenek 7 44. Bertoglio 2 45. Roseano 6 46. Viehl 37 47. Bilchik 48. Broderick-Villa 10 18 49. Kitagawa 4 50. Nastro 14 51. Paramo 3 52. Cox 5 53. Gandy 2 54. Esser 4 55. Merrie 8 56. Cserni 8 57. Joosten
FP 0 0 0 0 0 0 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
FN 5 7 8 7 9 0 0 13 11 4 3 8 28 20 3 3 3 38 8 10 12 0 1 14 1 1 4 14 2 0 21 2 8 6 8 6 2 14 14 2 24 11 9 2 2 6 5 10 4 0 1 0 1 1 3 5 12
TN 19 23 16 27 46 26 52 83 73 29 11 16 125 71 11 13 49 156 56 30 35 16 22 76 12 16 27 38 35 8 282 20 8 13 51 23 18 33 42 17 69 31 30 15 19 15 73 27 29 2 30 14 6 15 16 11 15
Sensitivity 1.00 [0.63, 1.00] 0.67 [0.43, 0.85] 0.33 [0.10, 0.65] 0.68 [0.45, 0.86] 0.57 [0.34, 0.78] 1.00 [0.89, 1.00] 1.00 [0.93, 1.00] 0.69 [0.53, 0.82] 0.75 [0.60, 0.87] 0.82 [0.60, 0.95] 0.79 [0.49, 0.95] 0.65 [0.43, 0.84] 0.53 [0.40, 0.66] 0.59 [0.44, 0.73] 0.88 [0.68, 0.97] 0.40 [0.05, 0.85] 0.83 [0.59, 0.96] 0.66 [0.57, 0.75] 0.69 [0.48, 0.86] 0.44 [0.22, 0.69] 0.50 [0.29, 0.71] 1.00 [0.89, 1.00] 0.67 [0.09, 0.99] 0.61 [0.43, 0.77] 0.86 [0.42, 1.00] 0.83 [0.36, 1.00] 0.80 [0.56, 0.94] 0.46 [0.27, 0.67] 0.86 [0.57, 0.98] 1.00 [0.63, 1.00] 0.90 [0.85, 0.94] 0.83 [0.52, 0.98] 0.79 [0.64, 0.91] 0.86 [0.72, 0.95] 0.74 [0.55, 0.88] 0.63 [0.35, 0.85] 0.83 [0.52, 0.98] 0.39 [0.20, 0.61] 0.42 [0.22, 0.63] 0.90 [0.68, 0.99] 0.53 [0.38, 0.67] 0.56 [0.35, 0.76] 0.44 [0.20, 0.70] 0.78 [0.40, 0.97] 0.50 [0.07, 0.93] 0.50 [0.21, 0.79] 0.88 [0.74, 0.96] 0.50 [0.27, 0.73] 0.82 [0.60, 0.95] 1.00 [0.40, 1.00] 0.93 [0.68, 1.00] 1.00 [0.29, 1.00] 0.83 [0.36, 1.00] 0.67 [0.09, 0.99] 0.57 [0.18, 0.90] 0.62 [0.32, 0.86] 0.40 [0.19,0.64]
Sensitivity
0.0
significant (75.6 vs. 66.4 %, respectively, p = 0.07). The results are summarized in Table 2. Upstaging In 46 studies, immunohistochemical staining was performed on specimens histologically classified as N0.11–17,19–46,48,50–53,55,57,60–62,67 Most studies only
0.2
0.4
0.6
0.8
1.0
analyzed the SN when H&E staining results were negative. In 2 studies, RT-PCR of the SN was used after negative H&E staining result.18,65 Sectioning and staining of the lymph nodes was not uniformly undertaken. Serial sectioning was used in most studies with intervals ranging from 20 to 500 lm with a large variety of monoclonal and polyclonal antibodies used (e.g., cytokeratin markers, cell surface glycoproteins, tumor specific proteins).
Sentinel Node Procedure in Colorectal Cancer TABLE 2 Diagnostic accuracy results of SN mapping in patients with colorectal cancer Sensitivity (%)
95 % CI
69.6
64.7–74.6
80.2
74.3–86.1
72.9
63.1–80.9
Sensitivity (%)
95 % CI
p value
68.3
61.4–75.3
0.5
70.4
59.5–81.2
0.9
Overall results HE analysis 57 studies, n = 3934 HE ? IHC analysis 20 studies, n = 1477 Subgroup analysis Ex vivo
In vivo
18 studies, n = 1169 Blue dye
32 studies, n = 2415 69.4
63.7–75.2
Colloid
Number of SN C 4 10 studies, n = 434
85.2
73.5–96.9
Number of SN \4 45 studies, n = 3320
66.3
61.2–71.4
0.003
Colon carcinoma
77.6
71.3–83.8
Rectal carcinoma
65.7
54.7–76.7
0.04
58.8
37.1–80.5
0.01
66.4
59.9–73.0
0.07
44 studies, n = 3246
13 studies, n = 688
31 studies, n = 2224 Early carcinoma
14 studies, n = 468 93.1
73.7–100
Advanced carcinoma
6 studies, n = 156 High validity study
6 studies, n = 612 75.6
68.5–82.6
Low validity study
20 studies, n = 2009
37 studies, n = 1925
Monocenter study Multicenter study
Number of SNs 8
6
8
6
40
60
80
100
Sensitivity (%)
FIG. 3 Scatter plot illustrating the correlation between the sensitivity of the SN procedure across studies and the number of identified SNs (Pearson correlation coefficient 0.37, p = 0.004). A fitted linearregression equation is shown with 95 % confidence intervals
Mean upstaging was 18.9 % ± 11.8 (range 0–50 %). Thus, in almost 20 % of patients staged as N0 with conventional histopathological techniques, detailed investigation of the SN showed occult tumor cells. However, only 10 studies subclassified these finding into micrometastases or ITC as advised by the AJCC.13,19,22,27,28,31,34,36,38,59 In these studies the true upstaging rate was significantly lower with 7.7 % of stage I/II patients becoming stage III (range 0–15.4 %).
DISCUSSION This systematic review of 57 studies analyzing the SN procedure for CRC shows an overall acceptable identification rate (92 %) with higher identification rates for colon cancers than rectal cancers. The increased detection rate seen in studies including more than 100 patients indicates the existence of a learning-curve effect. It has been demonstrated that technical issues can influence the detection rate. The volume of injection was related to the detection rate for both in vivo and ex vivo techniques.56 However, further standardization of working definitions is needed. Usually, the in vivo technique is propagated since this procedure has the advantage of identifying aberrant lymphatic drainage with the possibility to adjust the planned resection.68 However, in 18 studies analyzing aberrant drainage, a SN outside the planned resection margins was only found in 4 % of the patients. The addition of radiocolloid to blue dye did not improve the in vivo results. Also, considering the complexity of the procedure, these observations will make ex vivo mapping the method of choice. A pooled sensitivity of 69.6 % for predicting lymph node metastases was found with an accompanying false negative rate of 30.4 %. This led us to conclude that pathological examination of only the SN cannot replace routine examination of the complete mesentery. However, it should be emphasized that SN mapping in colorectal patients, in contrast to breast cancer and melanomas, is not used for therapeutic purposes but mainly to refine staging.
E. S. van der Zaag et al.
In contrast to breast cancer, the complete nodal basis is resected in colorectal cancer, and all lymph nodes harvested will be examined by the pathologist. Therefore, a false negative SN will not lead to undertreatment of colorectal patients. Despite the overall disappointing sensitivity rate, subgroups could be identified with increased sensitivity rates. Sensitivity improved when the number of identified SNs was higher. The latter has been previously established as 1 of 2 independent predictive factors of false negative mapping in a prediction model created with Bayesian Network Analysis (the other being presence of tumor replaced nodes, which could not be analyzed in this meta-analysis).69 Another factor predictive of sensitivity in this study was depth of invasion. Early (T1/T2) carcinomas had higher accuracy parameters when compared with advanced carcinomas. A recent review with comparable overall sensitivity rates did not find a correlation with T stage, but the authors stratified for individual T stages in colon and rectal cancer separately, which might yield different results.70 In our review, the quantitative data of only a small number of early carcinomas could be retrieved, but our results are in line with a review of 2 prospectively maintained databases describing a sensitivity of 89 % in 193 patients with T1/T2 carcinomas.71 The lower sensitivity in advanced cancers is probably due to obstruction of afferent lymph vessels or nodes by tumor, changing lymphatic drainage. Since the aim of SN mapping is to refine staging, high accuracy is less important in advanced stage III and IV CRC that already meet criteria for adjuvant chemotherapy. Because of progress in diagnostic technology and screening programs, diagnosis of CRC will occur at earlier stages.72,73 It is especially important in these early cancers to identify the small subgroup of high-risk patients who may benefit from adjuvant systemic treatment. The final subgroup with improved results is colon versus rectal cancer patients. In rectal cancer, identification of the SN is more difficult, and radiotherapy has been demonstrated to induce fibrosis and alter lymphatic flow and lead to falsepositive staining of non-SNs.19 Previously, we demonstrated that occult tumor cells are predominantly found in SNs.74 The mean upstaging rate of 19 % found in this review, with most studies only analyzing the SN, is therefore probably an accurate estimate of the percentage of patients with occult tumor cells. However, only 10 studies classified these cells in ITC or micrometastases, which makes the upstaging results difficult to interpret.9 The prognostic value of ITC is still unclear. A reduced relative survival is described associated with the presence of occult tumor cells in 156 patients with stage II colon cancer, suggesting also clinical significance of ITC.75 This would be in line with the prognostic role of ITC established in metastasized breast, colon, and prostate cancer patients.76–78 However, it is conceivable that ITC in
patients with distant metastasis have different prognostic value when compared with N0 patients. Another report demonstrated that N0 patients with or without ITC in lymph nodes show similar survival rates, whereas patients with micrometastases had lower survival rates.79 As long as the prognostic significance is not sorted, the AJCC recommends additional treatment only in patients with micrometastases, and the 19 % upstaging found in this study should be regarded as overestimation. Apart from improving staging by additional staining, SN mapping has also been described to increase the yield of harvested lymph nodes with corresponding upstaging. The number of lymph nodes analyzed has been recognized as a prognostic factor for a long time.80 It has been demonstrated that SN mapping results in an increased proportion of N1 patients with a corresponding better prognosis of the N0 patient group, which would be an additional reason to recommend mapping in patients with colorectal cancer.29,81 A major drawback of our study is the tremendous clinical heterogeneity across studies as to patient selection, technical details of SN procedures, and pathological analysis. The results should therefore be interpreted with caution and used in an epidemiological sense. As with any systematic review, the possibility of publication bias should be taken into account. In conclusion, this systematic review demonstrates an overall sensitivity rate of SN mapping in patients with colorectal cancer of 70 %. Especially in early-stage colon cancer an increased accuracy rate was found that could lead to refined staging. Since no patients will be understaged, the SN procedure can be recommended in colon cancer in addition to conventional resection. CONFLICT OF INTEREST There are no financial interests or conflicts of interests to disclose in the subject of this study.
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