Key words Vulvar cancer - sentinel lymph node dissection - complete inguino-femoral lymphadenectomy
Schlüsselwörter Vulvamalignom - Sentinellymphonodektomie - komplette inguinofemorale Lymphonodektomie
Introduction
In Germany, approximately 1600 women develop vulvar cancer every year, and around 620
women die of it. The incidence of vulvar cancer is approx. 2.5/100 000 and the
mortality is 1.3/100 000 (RKI, 2006), although recent calculations by the
Association of Population-based Cancer Registries in Germany indicate that the
number of new cases every year in Germany may range between 3400 and 4000. The most
common entity is squamous cell carcinoma (80–90 %) [1 ].
The data from the Cancer Registries shows enormous differences between federal
states in Germany with regard to age-specific incidence of vulvar cancer, which
ranges from 2.1 to 8.1 (http://www.krebsregister-sh.de/datenbank/Vulva2011.pdf). The
incidence of higher-grade HPV-associated vulvar intraepithelial neoplasias (VIN 3)
is increasing, particularly among younger women [2 ], [3 ], [4 ]. One of the most
significant prognostic factors for vulvar cancer is the presence or absence of lymph
node metastasis. Depending on tumour size and infiltration depth, the standard
surgical therapy for vulvar cancer consists of radical local tumour excision or
complete/partial vulvectomy with unilateral or bilateral inguino-femoral
lymphadenectomy. Excision of the inguinal lymph nodes does not merely remove
potential lymph node metastasis, it also facilitates the correct staging for
subsequent therapies and provides important information for disease prognosis. The
argument for aggressive surgery in vulvar cancer is the high risk of death from
missed inguinal involvement with subsequent regional or systemic metastasis. The
argument against radical surgery is that approx. 70 % of patients treated by
complete removal of the inguinal lymph nodes had no metastasis [5 ], [6 ], [7 ], [8 ]. Moreover, the radical surgical approach has a high
morbidity: two thirds of patients subsequently have problems with wound healing, or
go on to develop infections, lymphoceles or lymphoedema of the legs after removal of
the inguinal lymph nodes [8 ], [9 ], [10 ], [11 ], [21 ], [22 ].
Use of the sentinel lymph node technique could potentially be a less radical
alternative in patients with vulvar cancer.
Forty-one hospitals treating differing numbers of patients for vulvar cancer were
investigated. The survey aimed to evaluate the use of the sentinel lymph node
technique to treat patients with vulvar cancer in Germany and compare the use of
this technique with complete inguino-femoral lymphadenectomy. The survey
investigated the extent to which hospitals complied with consensus recommendations
and the willingness of hospitals to participate in a prospective clinical
multicentre study to evaluate the oncological effectiveness of the sentinel lymph
node technique in patients with vulvar cancer under real conditions.
Methods
In a survey of hospitals performed by the Study Group for Gynaecological Oncology
(AGO) in 2010, 41 hospitals in Germany answered questions on their use of the
sentinel lymph node technique compared with complete inguino-femoral lymphadenectomy
in patients with invasive vulvar cancer. The hospitals were divided into 4
categories: university hospitals, hospitals offering maximum care, tertiary care
facilities and general hospitals. The hospitals were also differentiated into 4
groups according to the numbers of patients with vulvar cancer operated on annually:
> 10 patients/year, 7–10 patients/year, 4–6 patients/year and < 3
patients/year. The gynaecological surgeons were asked about their experience with
the sentinel lymph node technique for the treatment of breast cancer, endometrial
cancer, cervical and vulvar cancer and about the surgical procedures used for lymph
node dissection in patients with invasive vulvar neoplasias (inguino-femoral
lymphadenectomy alone, full removal of lymph nodes with extirpation of the sentinel
lymph nodes, or the sentinel lymph node technique alone, where indicated). If
sentinel lymph node dissection alone was done, the preoperative criteria used in the
respective hospital were investigated together with the incidence of inguinal
lymphadenectomies performed to complete the procedure. Hospitals were also asked
whether they were prepared to participate in a prospective clinical multicentre
study to evaluate the oncological effectiveness of the sentinel lymph node technique
in patients with vulvar cancer. The results of the survey were analysed using
descriptive statistics.
Results
Of the 41 German hospitals which participated in the survey, 44 % (n = 18) were
university hospitals, 19 % (n = 8) were hospitals offering maximum care, 22 %
(n = 9) were tertiary care facilities, and 15 % (n = 6) were general hospitals. As
regards the number of patients with invasive vulvar cancer treated, 54 % (n = 22) of
the hospitals treated > 10 patients/year, 22 % (n = 9) of hospitals treated
between 7 and 10 patients/year, 19 % (n = 8) treated 6–4 cases/year and 5 % (n = 2)
of hospitals treated < 4 patients/year ([Fig. 1 ]).
Almost all of the hospitals had some experience of the sentinel lymph node
technique, particularly in the treatment of breast cancer (97 %; n = 40). In the
survey, 73 % (n = 30) of gynaecologists reported that they were experienced in
treating patients with vulvar cancer, although the extent of experience depended on
the hospitalʼs status. In contrast, only 41 % of gynaecologists (n = 17) were
experienced in treating patients with cervical/endometrial cancer ([Fig. 2 ]). The surgical procedure used to treat patients
with vulvar cancer was then differentiated further. In 2010, 27 % of hospitals
(n = 11) carried out only complete inguino-femoral lymphadenectomy while 10 % of
hospitals (n = 3) performed only sentinel lymph node extirpation, and 63 % of
hospitals (n = 26) routinely used both methods. 24 % of hospitals (n = 11) carried
out complete inguino-femoral lymphadenectomy after sentinel lymph node dissection in
patients with advanced vulvar cancer. If sentinel lymph node biopsy alone was done,
only 20 % (n = 6) of surgeons complied fully with consensus recommendations ([Fig. 3 ]).
Fig. 1 What is the average number of patients with vulvar cancer you have
operated on in the past year?
Fig. 2 How experienced are you in sentinel lymph node dissection?
Fig. 3 What is your technique for lymphadenectomy in patients with vulvar
cancer?
73 % of hospitals surveyed in the study were willing to participate in a prospective
clinical study to evaluate the effectiveness of the sentinel lymph node technique in
patients with invasive vulvar cancer.
Discussion
Use of the sentinel lymph node technique to treat patients with vulvar cancer ([Fig. 4 ]) could reduce surgery-associated morbidity.
However, this approach should only be used after careful diagnosis and in strict
accordance with oncological guidelines. The patient must be fully informed about the
potentially lethal consequences of inguino-femoral recurrence.
Fig. 4 Vulvar cancer extending from the left labium majus.
Our results showed that use of the sentinel lymph node procedure alone in the
treatment of vulvar cancer was still not very common at the time of our survey in
2010, although a prospective observational study showed a clear benefit of this
method, provided the oncological guidelines were strictly complied with [12 ]. It should be noted, however, that use of the sentinel
lymph node technique in vulvar cancer was only included in the S2 guidelines in
2009. The reported rates for sentinel lymph node detection are between 95 and 98 %
using combined labelling compared to the use of patent blue labelling alone (69 %).
Radionuclide labelling and intraoperative detection were reported to have a high
sensitivity, a high negative predictive value and a low false-negative rate of less
than 3 % [13 ].
127 patients who underwent supplementary lymphadenectomy were included in the German
multicentre sentinel lymph node study of the AGO Vulva. The sensitivity was 92.3 %
and the false-negative rate was 7.7 % [14 ]. The results
of the prospective observational GROINSS-V1 study for the period 2000 to 2006 were
published in 2008. A total of 457 patients from 15 large gynaecological-oncological
centres were included in this study. However, follow-up was short, with 276 patients
followed up for 35 months and a total of 202 patients followed up for at least 24
months. The rate of inguino-femoral local recurrence was 2.9 % and the median
interval to recurrence was 12 months. However, the detection of metastasis in the
sentinel lymph node was only possible using pathologic ultrastaging, (i.e. serial
processing and immunohistochemical staining for cytokeratin [[Figs. 5 ] and [6 ]]), otherwise metastasis would
have been missed in 42 % of cases.
Fig. 5 Conventional H & E staining shows no indication of sentinel
lymph node metastasis.
Fig. 6 Ultrastaging of the same sentinel lymph node: serial processing and
immunohistochemistry (cytokeratin CK 05/14) shows metastatic involvement.
Six of the 8 patients with inguino-femoral recurrence died. Two of them had
multifocal recurrence, two patients had micrometastasis of the sentinel lymph node
not found at primary diagnosis, and in 2 only one sentinel lymph node was dissected
instead of the two detected at preoperative lymph scintigraphy. Thus,
inguino-femoral recurrence was associated with a fatal outcome in most patients with
vulvar cancer even after secondary surgery or radiotherapy. Surprisingly, the EORTC
observational study did not find a strong difference in quality of life between
patients treated with sentinel lymph node dissection and patients treated by
complete lymphadenectomy [12 ], [15 ].
The GROINSS-V2 study was initiated in January 2006, based on results of the
GROINSS-V1 study which had demonstrated the importance of adjuvant therapy in
patients with positive sentinel lymph node involvement. One of the conclusions of
the GROINSS-V1 study was that additional therapy was indicated if metastasis of any
size was detected during sentinel lymphadenectomy. Although elective radiotherapy is
already being used successfully in the therapy of squamous cell carcinoma of other
origin, the data on the safety of this method for the treatment of patients with
primary vulvar cancer and sentinel lymph node metastasis is controversial. In a
case-control study by Manavi et al., 65 patients with T1 vulvar cancer and
clinically unsuspicious inguino-femoral lymph nodes underwent inguino-femoral
radiotherapy. The local rate of recurrence was 4.6 % [16 ]. The study by Perez et al. [17 ] reported a
recurrence rate of 10.5 %, but tumour sizes in their study were larger (T1/T2) than
in the study by Manavi et al. In a randomised control study, Stehmann et al.
compared the outcomes after primary surgery for T1, T2 and T3 vulvar tumours with
those after inguino-femoral radiotherapy of clinically unsuspicious lymph nodes.
There was no recurrence after surgery (0/25), while 5/27 patients had recurrence
after primary radiotherapy (rate of recurrence: 18.5 %) [18 ]. The criticism that could be levelled at all of these studies is that
deep lymph nodes were probably not adequately irradiated. In a retrospective
analysis of 227 patients with vulvar cancer, the rates of local recurrence were
similar for patients treated with inguino-femoral lymphadenectomy alone, with
radiotherapy alone and with a combination of both methods. The authorsʼ conclusion
was that elective inguino-femoral radiotherapy in patients with vulvar cancer and
minimal or microscopic tumours could help prevent most cases of local recurrence
[19 ]. Based on the results of all studies to date,
irradiation therapy could be used to prevent local recurrence in patients with
vulvar cancer and minimal/microscopic inguino-femoral tumours, provided the dosage
is adequate, the target volume is correct and the penetration depth is
sufficient.
The rationale behind the GROINSS-V2 follow-up study on sentinel lymph node metastasis
was to evaluate the safety of combined sentinel lymph node dissection and radiation
compared with the standard procedure of additional inguino-femoral lymphadenectomy.
According to the study protocol of the GROINSS-V2 study, adjuvant radiotherapy with
50 Gy was indicated in cases with sentinel lymph node involvement. Inclusion
criteria for the study were squamous tumours with diameters of < 4 cm, an
infiltration depth > 1 mm and no clinical indications of tumours in the
inguino-femoral region. Criteria for terminating the study were defined prior to the
start of the study; the criterion was a rate of recurrence of between 4 and a
maximum of 6 % for a collective of 135 recruited patients with vulvar cancer. In
June 2010, no further patients were enrolled in the study as the upper limit for the
rate of recurrence of 6 % had been exceeded. At that point a total of 82 patients
had been enrolled in the study, and 10 of these had recurrence in the inguinal
region. An analysis of the cases in accordance with the study protocol showed that
the number of inguinal recurrences was significantly higher in patients with
sentinel lymph node metastases > 2 mm (9/45 vs. 1/46, p = 0.008). In addition,
extracapsular extension of a lymph node metastasis was also associated with a higher
risk of inguinal recurrence (4/15 vs. 5/74, p = 0.04).
The current S2 guidelines specifically emphasise the importance of careful
examination and dissection prior to and during sentinel lymph nodectomy in patients
with vulvar cancer. Prior to surgery the patient must be fully informed about the
potentially higher rate of recurrence and the associated poorer prognosis. Patients
must be followed up closely after surgery. According to the S2 guidelines, this
method should only be used in patients with a tumour size ≤ 4 cm (FIGO I) and no
clinical or sonographic evidence of lymph node metastasis. Surgeons must be
experienced in the use of technique, with at least 10 previous sentinel lymph node
dissections performed in patients with vulvar cancer. Biopsied tissue should be
fully embedded and serial sections cut at intervals of 200 µm for
immunohistochemical ultrastaging (anti-cytokeratin pan antibodies) to detect
micrometastasis. If histology is negative for metastasis, immunohistochemistry can
be used for the detection of epithelial markers [20 ]. The
patient should additionally be informed about the necessity for secondary
inguino-femoral lymphadenectomy in the event of micrometastasis. A review of all
currently available study results shows that the use of sentinel lymph node
dissection alone is acceptable provided that all of the above criteria as described
in the S2 guidelines are met.
The 6th Biennial International Sentinel Node Society Meeting 2008 held in Sydney,
Australia formulated similar consensus recommendations on the use of sentinel lymph
node dissection to treat patients with unifocal vulvar cancer. They found that the
experience of the surgical team played an important role, with better results
reported for surgeons who operated greater numbers of patients per year, generally
more than 5–10 cases annually. The criteria for performing the procedure in patients
with unifocal squamous cell carcinoma of the vulva were a maximum tumour diameter of
≤ 4 cm, preoperative lymph scintigraphy with identification and extirpation of all
sentinel lymph nodes and the identification of the sentinel lymph nodes on both
sides in cases with midline tumours. However, they recommended performing complete
lymphadenectomy when inconsistencies or suspicious lymph nodes were present. The
recommended postoperative follow-up of patients was at 3-month intervals.
In our survey of the criteria for sentinel lymph node dissection in patients with
vulvar cancer, only 20 % of the surveyed institutions stated that they carried out
sentinel lymph node extirpation in accordance with the above-listed criteria ([Fig. 3 ]). This could indicate these recommendations have
not been sufficiently disseminated and therefore that the preconditions for
performing sentinel lymphadenectomy alone in patients with vulvar cancer are
insufficiently known. However, our survey found that experience of the sentinel
lymph node technique was increasing, although experience largely depended on
hospital size ([Fig. 2 ]). 73 % of surveyed hospitals were
prepared to participate in further evaluations of this technique offering the
possibility of further prospective clinical multicentre studies. Finally, it is
important to qualify the results of our study by noting that only a limited number
of the questionnaires distributed using the email list of the AGO were returned, and
that this evaluation therefore does not reflect the real situation in German
hospitals.
The modified GROINSS-V2 study could provide new information. It aims to evaluate the
efficacy of adjuvant radiotherapy compared to supplementary inguino-femoral lymph
node dissection in patients with unifocal vulvar cancer and sentinel lymph node
metastasis of < 2 mm. AGO Vulva has planned a clinical observational study with
strict inclusion criteria to evaluate the oncological safety of sentinel lymph node
dissection alone in patients with vulvar cancer. In view of the rarity of this
tumour entity, it is almost impossible to carry out a prospective randomised study,
which would otherwise be preferable.
Conclusion
The sentinel lymph node technique is increasingly being used in Germany to treat
patients with invasive vulvar cancer. The current criteria for the comprehensive
implementation of the sentinel lymph node technique to treat patients with vulvar
cancer are based on the study of van der Zee et al. [12 ], [15 ]. Using the limited data available,
our 2010 study showed that only a few hospitals used the sentinel lymph node
technique in accordance with the guidelines on vulvar cancer or the strict
conditions prescribed by international consensus recommendations. The majority of
patients who had sentinel lymph node extirpation additionally underwent radical
resection of the inguino-femoral lymph nodes, a procedure which is associated with
increased morbidity. Only a few of the surveyed hospitals stated that they complied
strictly with the criteria of the S2 guidelines published in 2008 and with the
international consensus recommendations published in 2009. More information and a
better dissemination of information are necessary. AGO Vulva has planned a clinical
observational study to evaluate the oncological safety of the sentinel lymph node
technique in patients with vulvar cancer. More than 73 % of hospitals that took part
in our survey were prepared to participate in a prospective clinical observational
study. However, given that the incidence of invasive vulvar cancer is 2.5/100 000
per year, it will be difficult to recruit sufficient numbers of patients to obtain
statistically valid data.
