SLN biopsy and lymphadenectomy performance
A total of 75 consecutive patients were enrolled in this study and all were eligible for analysis. The patients’ characteristics were listed in Table 1. The median age of them was 46 years (range 24 to 61). The FIGO 2009 stages were IA2, IB1, IB2, IIA1, IIA2 and IIB in 4, 44, 9, 10, 3 and 5 patients, respectively. Fifteen patients with stage IIA2, IB2 or IIB disease received 2-3 cycles of neoadjuvant chemotherapy prior to surgeries and achieved partial or complete response. The surgical approaches were laparoscopic in 19 and laparotomic in 56 patients. Methylene blue was used alone in 49 patients and carbon nanoparticles suspension in 24, while in 2 patients they were used together. Of the 75 patients, at least one SLN was detected in 69. Thus, the overall detection rate was 92.0% (69/75), with an accumulated number of 414 for SLNs totally dissected (median: 5, range: 0~19).
Table 1
The clinic-pathological characteristics of 75 patients with cervical cancer
Clinic-pathological characteristics
|
Number
|
Patient age
|
|
≤45 years
|
35
|
>45 years
|
40
|
FIGO stage
|
|
IA2
|
4
|
IB1
|
44
|
IB2
|
9
|
IIA1
|
10
|
IIA2
|
3
|
IIB
|
5
|
Histological grade
|
|
G1
|
2
|
G2
|
37
|
G3
|
36
|
Histological type
|
|
Squamous cell carcinoma
|
58
|
Adenocarcinoma
|
15
|
Adenosquamous carcinoma
|
1
|
Big cell neuroendocrine carcinoma
|
1
|
Neoadjuvant chemotherapy
|
|
Yes
|
15
|
No
|
60
|
Surgical approach
|
|
Laparotomic
|
60
|
Laparoscopic
|
15
|
Of the 69 patients with at least one SLN detected, 33 (47.8%) were bilateral and 36 (52.2%) were unilateral (17 on left side and 19 on right). The median time from injection to detection was 12 (ranged 1 to 30) minutes. The most stained nodes were obturator nodes (stained in 52 of 69 patients, 75.4%), followed by external iliac (66.7%), common iliac (28.9%), internal iliac (17.4%) and parametrial nodes (11.5%). Besides, one patient had SLN detected in the presacral area. Twenty-six (37.7%) patients had more than one area of SLNs detected in their hemipelvis. All patients underwent bilateral pelvic lymphadenectomy and 15 underwent additional paraaortic lymphadenectomy as well. A total of 2363 lymph nodes were removed with an average of 31.5 per patient (range: 10~63).
We classified unilateral (n=36) and failed (n=6) SLN detections together as unsuccessful. Then the association between detection results and clinic-pathological factors were analyzed. As shown in Table 2, the only factor affecting the detection results was lymphovascular invasion. This result was further validated by multivariate logistic regression, in which lymphovascular invasion remained the only independent predictor of unsuccessful SLN detection (adjusted odds ratio=12.59, 95% CI 2.42–65.39, P=0.003). The bilateral detection rate in patients with lymphovascular invasion was significantly lower compared with that in patients without (9.1% versus 58.5%, P<0.001). In patients with lymphovascular invasion, only 2 out of 22 achieved successful detection. In addition, the differences by other factors, including neoadjuvant chemotherapy history, tumor diameter, histological grade, deep stromal invasion, and growth type, were not significant.
Table 2
Clinic-pathological factors for the performance of SLN detection
|
Unsuccessful detection(%)
|
Successful detection(%)
|
P-value
|
Number of patients
|
42
|
33
|
|
Neoadjuvant chemotherapy
|
|
|
|
Yes
|
9(21.4)
|
6(18.2)
|
|
No
|
33(78.6)
|
27(81.8)
|
0.727
|
Histological grade
|
|
|
|
G1-2
|
20 (47.6)
|
19 (57.6)
|
|
G3
|
22 (52.4)
|
14 (42.4)
|
0.392
|
Deep stromal invasion
|
|
|
|
Yes
|
23(54.8)
|
13(39.4)
|
|
No
|
19(45.2)
|
20(60.6)
|
0.186
|
Lymphovascular invasion
|
|
|
|
Yes
|
20(47.6)
|
2(6.06)
|
|
No
|
22(52.4)
|
31(94.0)
|
< 0.001
|
Tumor diameter
|
|
|
|
≥2 cm
|
26(61.9)
|
14(42.4)
|
|
<2 cm
|
16(38.1)
|
19(57.6)
|
0.093
|
Growth type
|
|
|
|
Exophytic
|
20(47.6)
|
22(66.7)
|
|
Endophytic
|
14(33.3)
|
6(18.2)
|
|
Ulcerative
|
8(19.0)
|
5(15.2)
|
0.229
|
Pathological results
A total of 16 metastatic SLNs were finally confirmed in 11 patients, comprising 6 unilateral and 5 bilateral metastases. None of the 6 patients with bilaterally failed SLN detection presented lymph node metastasis. The SLN metastases were detected both by intraoperative and final pathology in 9 patients, while in 2 patients they were detected by final pathology only. According to the standard, the SLN metastases were defined as macrometastases, micrometastases, and isolated tumor cells in 9, 1 and 1 patient, respectively. The 11 patients with nodal metastasis were numbered and their clinico-pathological data are listed in Table 3, showing that these patients were characteristized by young age (median: 32 years), high incidence of deep stromal invasion (100%, 11/11) and lymphovascular invasion (81.8%, 9/11). For patients with lymphovascular invasion, the metastatic rate (40.9%, 9/22) was significantly higher than those without (3.8%, 2/53).
Table 3
The clinic-pathological feature of the 11 patients with lymph node metastasis.
Patient Number
|
Age
|
FIGO 2009 stage
|
Tumor
volume (cm3)
|
Histological grade
|
Histological type
|
Deep stromal invasion
|
Lymphovascular invasion
|
Metastasis type
|
1
|
31
|
IB2
|
3 × 4 × 4.5
|
2
|
Adenocarcinoma
|
yes
|
yes
|
Macrometastasis
|
2
|
30
|
IB1
|
3 × 2.5 × 1
|
2
|
Adenocarcinoma
|
yes
|
yes
|
Macrometastasis
|
3
|
32
|
IA2
|
2.5 × 2 × 1
|
2
|
Squamous carcinoma
|
yes
|
yes
|
Micrometastasis
|
4
|
32
|
IB2
|
2.5 × 2 × 1
|
2
|
Adenocarcinoma
|
yes
|
no
|
Macrometastasis
|
5
|
51
|
IB1
|
1.5 × 1.5 × 1
|
2
|
Squamous carcinoma
|
yes
|
yes
|
Macrometastasis
|
6
|
32
|
IB1
|
2.5 × 2 × 1.5
|
2
|
Squamous carcinoma
|
yes
|
yes
|
Macrometastasis
|
7
|
31
|
IB2
|
3 × 3 × 4.0
|
2
|
Squamous carcinoma
|
yes
|
yes
|
Macrometastasis
|
8
|
44
|
IB1
|
3.5 × 3 × 1.3
|
2
|
Squamous carcinoma
|
yes
|
yes
|
Macrometastasis
|
9
|
37
|
IB1
|
1.8 × 0.9 × 0.9
|
3
|
Squamous carcinoma
|
yes
|
yes
|
Isolated tumor cells
|
10
|
55
|
IB1
|
2.5 × 2 × 1.3
|
3
|
Squamous carcinoma
|
yes
|
no
|
Macrometastasis
|
11
|
58
|
IB1
|
2 × 2 × 1
|
3
|
Squamous carcinoma
|
yes
|
yes
|
Macrometastasis
|
The details on SLN detection and pathological examination of the 11 patients are listed in Table 4. Additional non-SLN metastases were observed in 7 patients (No.1, 3, 4, 6, 7, 8 and 11), which were only revealed by pelvic lymphadenectomy. Accordingly, the risk of having residual metastases after a positive SLN biopsy was 63.6%. No patient with negative SLN presented ipsilateral nodal metastasis, while three patients presented metastases on the hemipelvis without SLN detected. The most frequently involved nodes were obturator (9/11, 81.8%) and external iliac nodes (6/11, 54.5%), which was similar to the tendency of SLN distribution. Notedly, the parametrial nodes also had high rate to be involved (4/11, 36.4%), although they were relatively less identified as SLN. The pre-sacral SLN detected in patient No.7 was also confirmed to be metastatic. No patient had paraaortic node metastasis and the overall rate of nodal metastasis in the whole cohort was 14.7% (11/75).
Table 4
The details of SLN detection and pathological examination of the 11 patients with lymph node metastasis
Patient Number
|
Number of SLNs
|
SLN
lateral
|
Metastatic lateral
|
Locations of SLNs
|
Metastases on frozen examination
|
Metastases on final pathology
|
total
|
metastatic
|
SLNs
|
Non-SLNs
|
1
|
3
|
3
|
Bilateral
|
Bilateral
|
Left: E
Right: O
|
Left: E
Right: O
|
Left: E
Right: O
|
Right: M
|
2
|
12
|
3
|
Bilateral
|
Right
|
Left: E, O
Right: M
|
Right: M
|
Right: M
|
—
|
3*
|
8
|
1
|
Bilateral
|
Bilateral
|
Left: E, C
Right: O
|
None
|
Left: E
|
Right: E
|
4**
|
5
|
1
|
Right
|
Bilateral
|
Right: E, O
|
Right: E
|
Right: E
|
Left: O, M
|
5
|
15
|
1
|
Left
|
Left
|
Left: E, O
|
Left: O
|
Left: O
|
—
|
6**
|
2
|
1
|
Left
|
Bilateral
|
Left: O
|
Left: O
|
Left: O
|
Right: O
|
7
|
9
|
2
|
Bilateral
|
Bilateral
|
S; Left: O
Right: O
|
S
Right: O
|
S
Right: O
|
Left: O
|
8
|
1
|
1
|
Left
|
Left
|
Left: E
|
Left: E
|
Left: E
|
Left: M
|
9*
|
1
|
1
|
Right
|
Right
|
Right: O
|
None
|
Right: O
|
—
|
10
|
3
|
1
|
Bilateral
|
Left
|
Left: E
Right: E
|
Left: E
|
Left: E
|
—
|
11
|
0
|
0
|
Left
|
Left
|
Left: O
|
Left: O
|
Left: O
|
Left: E
|
Notes: E = external iliac, O = obturator, C = common iliac, M = para-metrial, S = pre-sacral. |
*indicates patients with false-negative frozen section examination. |
**indicates patients with unilateral SLN detection have bilateral node metastases. |
With the aid of ultrastaging procedures, two patients (No.3 and 9) were found to have occult metastases in SLNs which were omitted by frozen section examination. On the re-review of initial slices of the half-SLNs for frozen section examination, as before, neither of them showed metastasis. However, micrometastasis or isolated tumor cells were detected in their other half-SLNs by serial section examination. Therefore, the sensitivity of frozen section examination in our institution was 81.8% (9/11, 95%CI: 47.8%-97.8%), with 100% (9/9) for macrometastasis and 0% (0/2) for micrometastasis and isolated tumor cells.
Follow-up and recurrence
After surgeries, all treatments were planned according to patients’ pathological risks. Standard concurrent chemoradiotherapy were scheduled if patients had any of the high risks including parametrial invasion, positive surgical margins, and/or lymph node metastasis. In absence of any high risk, 3 to 4 cycles of chemotherapies were administrated to patients having prior neoadjuvant chemotherapy. Up to May 2020, the median follow-up time was 53 months (range 34-72), calculated by reverse Kaplan–Meier method. Five patients experienced recurrence, including 2 in lung, 1 in groin, 1 in vaginal stump and 1 in mediastinal lymph nodes. Their FIGO stages at initial diagnosis were IB2 in 2, IIA2 in 1, and IIB in 2 patients. Notedly, 4 of them had bilaterally failed SLN detection and one had positive SLN. The treatments after recurrences included pelvic exenteration, inguinal lymphadenectomy, and palliative chemotherapy. Up to the last follow-up, no retroperitoneal node recurrence was observed. Two patients died from the disease; one had lung metastasis treated by chemotherapy and another had vaginal stump recurrence treated by pelvic exenteration.