Key words
vulva - cancer - therapy
Schlüsselwörter
Vulva - Karzinom - Therapie
Introduction
With an incidence of 4 % of all malignancies of the female genital tract, vulvar carcinoma is rather a
rare form of cancer. From the histopathological point of view it is usually a squamous cell carcinoma,
but adenocarcinomas, melanomas and carcinomas of the Bartholin glands may also occur in the vulvar
region. Current projections for Germany assume about 3400–4000 new cases of vulvar cancer per year (A.
Katalinic/U. Gerdemann: current statistics on vulvar cancer in Germany March 2011, cancer register
[Aktuelle Zahlen zum Vulvakarzinom in Deutschland März 2011, Krebsregister]). These figures reflect the
increasing occurrence of vulvar cancer over the past years [1], [2], [3], [4]. In the past,
especially women aged 70 years or more were afflicted, but in recent years the proportion of afflicted
younger women has increased markedly. This is probably related to the fact that 40–60 % of vulvar cancer
and up to 90 % of VIN cases are associated with HPV [1], [2], [5]. Among the vulvar cancers the following HPV subtypes in
order of frequency have been identified: HPV subtypes 16, 33, 6, 18 and 31, with HPV 16 having the
largest proportion of over 50 % [6]. Other factors that may be involved in the
development of vulvar cancer are, especially for older patients, lichen sclerosus et atrophicans,
inherited or acquired immune deficiency, nicotine abuse or anogenital intraepithelial neoplasias. Thus,
in the past few years a bimodal age distribution has become increasingly apparent: a first peak at 45 to
50 years and a second peak at 70 to 75 years of age [7]. Staging is done in
accordance with the FIGO and the TNM classifications. Decisive factors are the surgical findings and
results of the histopathological analysis of surgical specimens.
Operative Therapy
Stage-adapted therapy
In principle, in the primary situation of surgical therapy for vulvar cancer, attempts should always
be made to achieve an R0 resection. Only in exceptional cases such as, for example, an unacceptable
risk of narcosis or in a palliative situation is primary radio(chemo)therapy indicated. For decades
the standard surgical therapy consisted of an en-bloc resection of the vulva with bilateral inguinal
lymphadenectomy (LNE). Because of the mutilating nature of this procedure and the numerous
postoperative complications such wound-healing disorders (especially in obese female patients with
diabetes), disturbances of bladder function, vaginal stenosis and chronic pain, a paradigm shift in
favour of reduced surgical radicality has taken place during the past 10 to 15 years. Accordingly in
most large centres the traditional en-bloc resection has been replaced by the so-called triple
incision. Besides the vulvectomy dissection-shaped incision ([Fig. 1]),
two separate incisions in the groin area are made for the inguinal LNE. This procedure, which has in
the meantime advanced to be the standard, exhibits a markedly lower rate of wound-healing disorders.
Since this procedure also leads to loss of the clitoris, in the sense of a further reduction in the
radicality, at least in early tumour stages the triple incision is supplemented or, respectively,
substituted by a radical local excision. In this procedure the tumour is resected macroscopically on
all sides into healthy tissue. When this resection is widely performed it is also referred to as a
partial vulvectomy. In a meta-analysis of data from 11 studies involving a total of 530 patients
with T1 vulvar cancer, comparable rates of local recurrences were found for patients who underwent a
radical local excision and those who, respectively, underwent a radical vulvectomy. The
cancer-related mortality rates were also similar (0.6 vs. 0.5 %) (7.2 vs. 6.3 %) [8]. Depending on the localisation of the tumour, the radical local excision
is classified as a partial anterior or a posterior vulvectomy or a hemivulvectomy. Although the
radical local excision is now generally accepted it should be noted that only limited data are
available on the progression-free or overall survival.
Fig. 1 Advanced vulvar cancer before and after radical vulvectomy. On the left one can see
the preoperative situation with multifocal tumour disease with the resection shape including
removal of the clitoris. On the right one can see the postoperative result after placement of a
bladder catheter.
In clinical routine the following stage-adapted procedures are now established:
-
T1a: radical local excision
-
T1b: radical local excision, when in a median position with ipsi- or bilateral inguinal
LNE
-
T2: radical local excision with bilateral inguinal LNE and, if necessary, with pelvic LNE
-
T3/4: radical vulvectomy with bilateral inguinal LNE and, if necessary, with pelvic LNE or
also anterior/posterior or total exenteration
Independent of the surgical procedure, intraoperative macroscopic safety margins of 10 mm are
recommended. In this way it is ensured that the 8-mm margins required by histology are still
detectable even after artefacts from shrinking [9].
Compartment model
Similar to colon and cervix cancer, the compartment model is also under discussion for vulvar cancer.
This model is based on the following theory.
Malignancies spread over a relatively long period of time within the tissue compartments
predetermined by embryonic development. In spite of their close spatial relationships, neighbouring
compartments are at first not infiltrated by the tumour. The complete removal of the respective
morphogenetic unit or a segment of this compartment with minimal surgical trauma and retention of
the neighbouring structures of different embryonic origin can result in an increased surgical
radicality with reduced mortality. In cases of vulvar cancer three compartments can be
distinguished:
The deep compartment, that originates embryonically from the genital tubercle and from which the
clitoris, bulbus and vestibulum develop, the superficial compartment originating from the urogenital
folds which differentiate into the glans clitoridis, the labia minor and the inner sides of the
labia major, and the lateral compartment, the origin of the outer sides of the labia major.
Consideration of these embryonically predefined structures during the surgical or therapeutic
planning in the sense of a vulvar field resection offers an enormous potential for increasing the
surgical-oncological radicality and efficacy. It has been shown prospectively that, in about 50 % of
the patients in tumour stage T1–3, who underwent such a vulvar field resection with up to 50 months
follow-up observation and 5 % local morbidity, not one single local recurrence developed (with
radical vulvectomy over all stages the rate is 25–35 %) [10]. However,
since the available data are limited and these results are all from a single centre, this procedure
is not yet established as a standard and must still prove its value in the future.
The surgical procedure in the framework of a posterior vulvar field resection with reconstruction is
shown in [Fig. 2].
Fig. 2 a to c Posterior vulvar field resection with reconstruction: a vulvar
cancer in the region of the posterior commissure after marking the incision lines. Laterally the
respective flaps to be rotated are marked (Limberg flaps). b After resection of the
posterior vulvar field. c Postoperative result after plastic reconstruction by rotation
of the flaps.
Relevance of (Sentinel) Lymphadenectomy
Relevance of (Sentinel) Lymphadenectomy
In principle the lymph outflow of the vulva proceeds through the lymph nodes of the groin, which include
both the superficial inguinal and the deeper femoral lymph nodes. The probability of lymphatic
metastatic spread in this region does not depend on the tumour stage or, respectively, the visible
tumour size. Solely for the infiltration depth has a positive correlation with positive groin lymph
nodes been detected in numerous studies [11], [12], [13]. Thus, at an infiltration depth of > 1 mm (pT1b) the
groin lymph nodes should be removed. This should be done in the sense of a bilateral systematic
inguinofemoral lymphadenectomy, since removal of merely the superficial inguinal lymph nodes carries a
markedly higher risk of a prognostically very unfavourable groin recurrence. In such cases the removal
of at least 6 lymph nodes of each type is recommended [14], [15]. Only for very small cancers with a far lateral localisation and free
ipsilateral lymph nodes is it possible to omit the contralateral lymphadenectomy, since a very low rate
(< 0.5 %) of positive lymph nodes can be assumed [16], [17], [18], [19].
Relevance of the pelvic lymphadenectomy
Lymph drainage of the vulva occurs almost exclusively via the inguinofemoral lymph nodes. Only in
cases of extensive disease is lymphatic metastatic spread via the femoral drainage pathways through
to the external iliac veins and arteries in the direction of the pelvic lymph nodes to be expected.
A communication via the plexus venosus vaginalis with the internal lymph nodes as is known in cases
of vaginal carcinoma has not been described for vulvar cancer. Thus, with an incidence of 2 % pelvic
lymph node metastases are rather rare in early vulvar cancer of stage T1/T2 [20], [21], [22].
This results in a possible indication for pelvic lymphadenectomy only in cases with confirmed
lymphogenic metastatic spread in the groin. Accordingly pelvic lymphadenectomy is recommended in
cases with 3 or more positive unilateral groin lymph nodes, with capsule rupture, or with
macrometastasis > 10 mm.
Sentinel lymphadenectomy
In principle, the concept of sentinel lymphadenectomy seems to be attractive also for vulvar cancer
on account of the highly relevant postoperative morbidity of a systematic inguinofemoral
lymphadenectomy. Unfortunately, however, groin recurrences after sentinel lymphadenectomy alone have
been reported in numerous publications [23], [24], [25], [26]. Even so, the
sentinel procedure is justified in tumour stages T1 and T2 according to the data of Zee et al. [27]. In the framework of this work involving over 400 patients the authors
demonstrated a marked in morbidity with a 2.3 % rate of groin recurrence. Since in the meantime also
prospective data on this topic have become available [28], sentinel
lymphadenectomy can be considered as an alternative to systematic bilateral inguinofemoral
lymphadenectomy in cases of vulvar cancer when the patients are informed adequately.
Systemic Therapy
On the whole, systemic therapy for primary vulvar cancer in the form of adjuvant or neoadjuvant
chemotherapy has not had a history of success. Even so there have been isolated publications in the past
few years concerning, above all, cisplatin, 5-FU or bleomycin that may possibly redefine the role of
systemic therapy for vulvar cancer.
In the adjuvant situation it has been shown that a cisplatin monotherapy subsequent to surgical treatment
may in individual cases with afflicted groin lymph nodes be a reasonable option also with regard to
survival [29]. However, due to the small number of cases, the results of
further studies must certainly be awaited.
Neoadjuvant therapy is an interesting therapeutic concept, especially for advanced or, respectively,
inoperable vulvar cancer [30], [31], [32]. The first objective here is a reduction of tumour size, which can then
facilitate a subsequent local therapy or even change a primarily inoperable situation into a resectable
finding, in such a case exenteration can be avoided and the patientʼs quality of life improved. In
addition, neoadjuvant chemotherapy can treat possibly present micrometastases and thus reduce the
chances for distant metastatic spread [33], [34], [35]. However, due to the small number of patients, the use
of neoadjuvant chemotherapy for vulvar cancer is still restricted to individual cases and further
studies are needed.
Radiation
Primary radiochemotherapy
In cases of local advanced vulvar cancer a primary radiochemotherapy, usually with cisplatin, 5-FU or
also mitomycin C, may be employed. This may be indicated in patients with inoperable findings or to
avoid a radical surgical intervention (exenteration) [36]. In spite of
the high rate of clinical remissions of 46–91 % [37], [38], [39], [40], [41], residual tumours are frequently found on
histopathology [40], [41], [42]. Thus, surgical sanitation should also follow directly after the
primary radiochemotherapy; thus it is better in this context to refer to it as a neoadjuvant
radiochemotherapy. All of the studies, although very heterogeneous with respect to study population
and treatment schemes, have in common reported pronounced skin toxicity. Furthermore, randomised
studies have shown no benefit in comparison with primary operations with regard to recurrence-free
and overall survival [43], but they did reveal markedly higher rates of
complications. Under consideration of the facts that the surgical procedure is more difficult after
a prior radiation and that the option for radiation is still open in the case of a recurrence, a
neoadjuvant radiochemotherapy remains reserved for exceptional cases.
Adjuvant radiation
Together with macrometastases > 10 mm and a capsule rupture in the region of the inguinal lymph
nodes and since the GOG study of Homesley et al. 1986, irradiation of the inguinal and pelvic lymph
drainage pathways or a pelvic lymphadenectomy in combination with an inguinal radiotherapy are
recommended in cases with 3 or more afflicted inguinal lymph nodes [44].
This procedure was the gold standard for a long time; however, since the ASCO 2012 and the results
of the as yet largest multicentre study on nodal-positive vulvar cancer presented there, the
indication for adjuvant radiation of the lymph drainage pathways has been expanded. In the AGO Care
1 Study a benefit of adjuvant radiation was observed independent of the number of positive lymph
nodes. For this reason radiotherapy is now being discussed already for patients with just one
afflicted inguinal lymph node. In addition, for R1 resection or marginal R0 resection without
further surgical options, a subsequent radiation of the tumour bed should be carried out [45].
Perspectives and Conclusion
Perspectives and Conclusion
The management of vulvar cancer requires an interdisciplinary therapy in which surgery and radiotherapy
play important roles. The precise significance of neoadjuvant chemotherapy needs to be clarified in
further studies. Adjuvant radiation of the groin in the case of only one positive inguinal lymph node
will certainly be a topic for future discussion.
Acknowledgements
We are grateful to Dr. Wolfgang Schmitt for provision of the graphic material.
