Keywords vulvar cancer - sentinel - groin - vulva
Schlüsselwörter Vulvakrebs - Sentinel - Leiste - Vulva
What is already known on this topic
Inguinal sentinel lymph node dissection has been shown to be safe in early unifocal
vulvar cancer in several studies and is considered or even recommended in many guidelines.
What this study adds
Sentinel lymphadenectomy in vulvar cancer patients is a safe procedure in daily practice
in a real-world setting.
How this study might affect research, practice or policy
Sentinel lymphadenectomy in vulvar cancer can be routinely used in daily practice.
Introduction
Vulvar cancer is a rare gynecologic malignancy, but its incidence has been shown to
increase in recent decades [1 ]
[2 ]. Inguinal lymph node involvement is the most important prognostic factor for disease-free
and overall survival, with a reduction in three-year disease-free survival and overall
survival rates from 75% to 35% and from 90% to 56%, respectively, in patients with
node-positive disease [3 ].
The standard therapy for early vulvar cancer is surgery, with a local excision of
the tumor up to complete vulvectomy. Inguinofemoral nodal staging is mandatory for
all vulvar cancers, with an infiltration depth > 1 mm (> pT1a). The risk of inguinal
metastasis correlates with the depth of infiltration and increases rapidly from infiltration
over 1 mm. Complete groin dissection (inguinofemoral lymphadenectomy) is associated
with considerable short-term and long-term morbidity, with wound breakdown/infections
in up to 30% of patients and lymphoceles and lymph edema in up to 40% [4 ].
Inguinal sentinel lymph node dissection has been shown to be safe in early unifocal
vulvar cancer in several studies and is considered or even recommended in many guidelines
[5 ]
[6 ]
[7 ]
[8 ]. In the GROINSS-V study, the isolated groin recurrence rate was 2.5% at 5 years
[7 ]. The prognosis of inguinal recurrence is often poor and associated with significant
mortality [7 ]
[9 ]. To ensure an acceptably low false-negative rate, vulvar sentinel lymph node dissection
should only be performed in patients with a unifocal tumor up to a tumor size of 4 cm
and clinically unsuspicious lymph nodes through a clinical and/or sonographic examination,
with the availability of histologic ultrastaging of the sentinel lymph nodes and a
team trained for this procedure [8 ]. The gold standard of sentinel mapping in vulvar cancer is the use of radioactive
technetium-99m (Tc-99m)-labelled nanocolloid. In addition, mapping with patent blue
or indocyanine green (ICG) may be performed [8 ]
[10 ].
This retrospective study aimed to investigate the incidence of isolated groin recurrence
in daily practice in six large cancer centers in Germany. Ensuring a low rate in this
setting further emphasized the safety of the procedure.
Methods
Ethical review
The study was conducted according to the guidelines of the Declaration of Helsinki
and approved by the Institutional Review Board and Ethics Committee of Hannover Medical
School, with reference number 7898.
Patients
The study was performed in six large gynecologic centers, all members of the AGO-Kommission
Vulva/Vagina group (Dusseldorf, Hamburg, Munich, Hanover, Altötting, and Cologne-Kalk).
In a retrospective setting, we identified all patients with early vulvar cancer treated
between 2009 and 2015 who underwent inguinal sentinel lymphonodectomy and presented
with final node-negative histologic results. The patient details regarding disease
stage, sentinel procedure, and follow-up were examined using local cancer databases
and patient registries. Patients with no available follow-up were excluded from further
analysis.
Statistical analysis
Statistical analysis was performed using Microsoft Excel 2019 (Microsoft Corp., Redmond,
USA) and XLSTAT 2020 (Addinsoft, Paris, France). The Kaplan–Meier curves were calculated
for isolated groin recurrence. Special attention has been given to the analysis of
the quality parameters derived from previous studies and the German guidelines on
vulvar cancer (unifocal tumor, tumor size ≤ 4 cm, unsuspicious clinical groin examination,
and histologic ultrastaging) [6 ]
[8 ].
Results
Study population
Between 2009 and 2015, we identified 743 patients with vulvar cancer who underwent
a sentinel procedure. After excluding patients with nodal involvement and subsequent
further therapy, we found 414 patients with available follow-up data (Dusseldorf,
n = 163; Munich, n = 94; Hamburg, n = 80; Hanover, n = 49, Altötting, n = 20; Cologne-Kalk,
n = 8) ([Fig. 1 ]). The mean age at diagnosis was 60.5 years (range 23–94).
Fig. 1
Proportion of patient cases among the different recruiting centers.
The mean follow-up time was 38.4 months (range 1–115).
Primary tumor
The final tumor stage of the primary tumor was available in 398 patients. pT1b was
the most frequent stage (n = 330; 82.9%), while pT1a (n = 42; 10.6%), pT2 (n = 24;
6.0%) and pT3 (n = 2; 0.5%) were less common ([Fig. 2 ]).
Fig. 2
Distribution of the primary tumor stages.
Among the patients, 95.9% showed unifocal tumors, while 3.1% had multifocal invasive
diseases (no information on 1% of the cases).
In 115 patients, a local excision was performed (29.7%), while 241 patients received
a partial vulvectomy (62.3%) and 31 patients (8.0%) received a complete vulvectomy.
The mean tumor size, measured in the dermal plane before surgery, was 40.0 mm (range
2–150 mm, data from 333 patients), with a median tumor size of 36 mm ([Fig. 3 ]). The postoperative histologically measured mean tumor size was significantly smaller
at 18.3 mm (range 1– 220 mm).
Fig. 3
Distribution of the preoperatively measured tumor size. Red dots indicate cases of
isolated groin recurrence.
Preoperative groin assessment
All 414 patients had either a preoperative clinical examination of the groin, sonography,
or both. Clinical examination was carried out in 254 patients (61.4%). Among them,
252 showed a normal result (99.2%), and the remaining two patients had suspicion of
nodal involvement (0.8%). Sonography of the groins was conducted in 307 patients (76.0%).
Among these patients, 295 (96.1%) had unsuspicious groin sonography before surgery,
while 12 patients (3.9%) had suspicious findings in groin sonography.
Sentinel procedure and workup
Sentinel lymphonodectomy was performed unilaterally in 48 cases (11.6%) and bilaterally
in 363 cases (87.7%). In 405 of the 414 cases, information on the substance used for
the sentinel mapping was available. Tc-99m-labeled nanocolloid was used in all 405
cases, with additional marking with patent blue in 42 cases (10.4%) and ICG in two
cases (0.5%).
The mean number of removed sentinel nodes was 2.2 per side (range 0–9; right groin
2.16; left groin 2.26, n.s.). In 181 of 414 patients (43.7%), additional non-sentinel
lymph nodes were removed (mean 3.7 per patient; median 2.0; range 1–18), leading to
a mean of 1.6 non-sentinel lymph nodes in all patients.
In 408 of 414 cases, we gathered information about histologic ultrastaging, which
was performed in 404 cases (97.6%), with four cases without histologic ultrastaging
and six cases with no information available. Frozen section analysis was performed
in 82.4% of all cases.
Recurrence
Among the 414 patients, 65 experienced recurrent disease (15.7%). The mean time to
recurrence was 22.7 months (range 2–77). Moreover, 21 and 5 patients developed a second
(21/65 = 32.3%) and third recurrence (5/21 = 23.8%), respectively. No significant
differences in the overall recurrence rate between patients who fulfilled the guideline
quality requirements and those who did not were observed ([Fig. 4 ]).
Fig. 4
Recurrence-free survival, depending on whether the quality criteria of the German
guidelines for the treatment of vulvar cancer [8 ] are fulfilled (group 1) or not (group 0); p = 0.20.
Isolated groin recurrence (IGR)
Isolated groin recurrence was seen in 13 of 414 cases, leading to an isolated groin
recurrence rate of 3.1%. The mean time to isolated groin recurrence was 17.7 months
(range 5–39). With a mean age of 67 years (range 46–80), the difference in the whole
study population (60 years) did not reach statistical significance (p = 0.1). The
mean preoperative tumor size was 41 mm, and the mean histologic tumor size was 21.4 mm,
both not statistically different from the group of all patients (40 mm and 18.3 mm,
respectively). The tumor stage also did not statistically differ (pT1a, n = 1; pT1b,
n = 11; pT2, n = 1). All of these patients were marked with TC-99m-nanocolloid, with
additional blue dye marking in two cases. In 12 of the 13 patients in this group,
an intraoperative frozen section was obtained, which was not significantly higher
than in the whole study population (92% vs. 82%, p = 0.3). All patients in the IGR
group underwent histologic ultrastaging. The mean number of
sentinels removed per groin did not statistically differ from that of the whole study
group (1.95 vs. 2.25; p = 0.37). Furthermore, the mean number of removed non-sentinel
lymph nodes per patient did not statistically differ from that of the other study
population (2.2 vs. 1.6; p = 0.56).
Fulfillment of the requirements of the German guidelines
[Table 1 ] shows the proportion of fulfillment of the requirements of the German guidelines
for the treatment of vulvar cancer [8 ]. Information for all different parameters was available in 333 of the 414 patients
(80.4%). Among these patients, all the requirements of the German guidelines were
followed by 55.3%.
Table 1
Fulfilment of quality requirements for vulvar sentinel lymphadenectomy according to
the German guideline in all patients, as in patients with and without isolated groin
recurrence.
All patients
Patients without isolated groin recurrence
Patients with isolated groin recurrence
Den.
yes
%
no
%
Den.
yes
%
no
%
Den.
yes
%
no
%
Den. = Denominator; * without tumor size postoperatively
Unifocal tumor
403
389
96.5
14
3.5
390
377
96.7
13
3.3
13
12
92.3
1
7.7
Tumor size ≤ 4 cm, preoperative
333
187
56.2
146
43.8
322
181
56.2
141
43.8
11
6
54.5
5
45.5
Tumor size ≤ 4 cm, postoperative
352
333
94.6
19
5.4
339
320
94.4
19
5.6
13
13
100
0
0
Ultrastaging
414
403
97.3
10
2.4
400
390
97.5
10
2.5
13
13
100
0
0
Unsuspicious groin in palpation/sonography
414
397
95.9
17
4.1
401
384
95.8
17
4.2
13
13
100
0
0
Combined*
333
184
55.3
149
44.7
322
178
55.3
144
44.7
11
6
54.5
5
45.5
Combined* without pT1a cases
291
143
49.1
148
50.9
281
138
49.1
143
50.9
10
5
50.0
5
50.0
In this subgroup of 184 patients, there were six isolated recurrences, leading to
an isolated recurrence rate of 3.3%, with a mean follow-up time of 43 months. There
were no statistically significant differences in the different quality requirements
in any of the patient groups, with or without an isolated groin recurrence ([Fig. 5 ]). After removing the pT1a cases who had been treated with the sentinel procedure,
no statistically significant difference was found.
Fig. 5
Isolated groin recurrence-free survival, depending on whether the quality criteria
of the German guidelines for the treatment of vulvar cancer [8 ] are fulfilled (group 1) or not (group 0); p = 0.75.
Discussion
The feasibility and the oncological safety of the sentinel node procedure in vulvar
cancer have been shown in several prospective trials [5 ]
[6 ]
[7 ]. This procedure has been considered the most effective method to reduce treatment-related
morbidity for patients with early-stage vulvar cancer in recent decades. However,
data from real-life settings outside the framework of prospective studies are limited.
This study confirms that vulvar sentinel dissection is also safe in this context.
In the GROINSS-V study, the isolated groin recurrence rate was 2.5% at five years
for sentinel-negative patients [7 ]. In our data, the isolated groin recurrence rate was slightly higher at 3.1% at
a mean follow-up time of 38.4 months. The risk of recurrence was higher in our study
due to different factors often associated with real-life data.
The main factor was the significantly higher mean tumor size. The median diameter
in the GROINSS-V study was 17.5 mm in sentinel-negative patients [6 ]
[7 ]. Following the study protocol, this diameter was measured preoperatively. The primary
tumor was measured by tape or estimated preoperatively, although we have no data on
the specific measurement methods in a single patient. Postoperative measurements were
done by rulers or measuring tapes in pathology departments. GROINSS-V excluded patients
with a tumor size of > 4 cm, but these patients were included in our study population.
In our data, the median tumor size, measured in the dermal plane before surgery, was
36.0 mm (range 2–150 mm, data from 333 patients), with a mean tumor size of 40 mm.
The histologic measurement showed a mean tumor size of 18.3 mm. Among the patients,
43.8% and 5.4% had a preoperative and postoperative tumor size > 4 cm, respectively.
As shown in [Fig. 3 ], most of the cases had tumor sizes of 30–40 mm. In the 11 isolated groin recurrences,
five occurred in this group, leading to an isolated groin recurrence rate of 3.4%
in patients with tumor sizes > 4 cm, without a significant difference compared with
the whole population. Tumor size is the main predictive factor for lymphatic involvement
[11 ]
[12 ]
[13 ]. Therefore, the significantly higher tumor size is a convincing explanation for
the slightly higher isolated groin recurrence rate in our data compared with GROINSS-V
[6 ]
[7 ]. The reasons for performing sentinel procedures in patients with tumor sizes > 4 cm
were mainly higher age and co-morbidities.
In GROINSS-V, patients with multifocal tumors were excluded after amending the study
protocol [5 ]
[6 ]
[7 ]. Among the patients in our data, 3.5% had multifocal tumors who underwent sentinel
lymphonodectomy, mainly due to higher age and co-morbidities. One patient in this
group who had a tumor size of 15 mm and negative sentinel lymph nodes in both groins
had an isolated groin recurrence after 14 months.
As reported, all patients in GROINSS-V had unsuspicious groin during palpation/sonography
and histologic ultrastaging [7 ]. In our data, we found a small number of patients with suspicious groins preoperatively
(14/414 = 3.4%), or without ultrastaging (2.4%, no information on ultrastaging/no
ultrastaging). However, none of the 11 isolated groin recurrences occurred in these
patients.
An infiltration depth below 1 mm is associated with a low rate of inguinal lymph node
involvement [11 ]. In GROINSS-V, patients with an invasion depth ≤ 1 mm were excluded [6 ]
[7 ]. However, in our real-life setting, 42 patients had pT1a stage (10.6%). Interestingly,
one patient in this group experienced an isolated groin recurrence. This patient had
a unifocal vulvar cancer of 14 mm, which had a left-sided negative inguinal sentinel
(0/3). Twenty-six months after surgery, a unilateral, left-sided isolated groin and
pelvic recurrence was found, which was treated through surgery and radiotherapy.
To compare our dataset with the results of the GROINSS-V trial, we evaluated a subset
of patients who fulfilled all the requirements for vulvar sentinel lymphadenectomy
([Table 1 ]). No statistically significant difference was found between this group and the group
of patients in which one or more requirements were not met. However, the low number
of isolated groin recurrences is a restricting factor in analyzing the assumed difference.
Conclusions
Sentinel lymphadenectomy in vulvar cancer patients is a safe procedure in daily practice.
The requirements of the cancer guidelines (unifocal tumor, ≤ 4 cm, histologic ultrastaging,
and exclusion of suspicious groins preoperatively) should be followed to ensure a
low isolated groin recurrence rate. However, in this study, we could not find any
difference between the patients who fulfilled the guideline requirements and those
who did not.
