I Guideline Information
Guidelines program of the DGGG, OEGGG and SGGG
For information on the guidelines program, please refer to the end of the guideline.
Citation format
Diagnosis, Therapy and Follow-up of Vaginal Cancer and Its Precursors. Guideline of
the DGGG and the DKG (S2k-Level, AWMF Registry No. 032/042, October 2018). Geburtsh
Frauenheilk 2019: 79: 1060–1078
Guideline documents
The complete long version in German, the short version and a German-language PDF slide
version for PowerPoint presentations are available on the homepage of the AWMF: https://www.awmf.org/leitlinien/detail/ll/032-042.html
Numbering
This text version of the guideline is a concise abridged version which has omitted
generally applicable chapters (12 Supportive Therapy, 13 Psycho-oncology and Quality
of Life, 14 Rehabilitation, 15 Integrative Medicine, 18 Palliative Medical Support).
The numbering of the chapters after “IV Guideline” and the numbering of the recommendations
and statements in this short version corresponds to the numbering used in the long
version, despite the obvious gaps in numbering. This was done to make it easier to
find the text in the long version if further information is desired.
Guideline group
The members of the guideline group are listed under “Authors”. The group is composed
of authors and mandate holders. The latter are representatives of the medical societies,
working groups, organizations, and associations who stated their interest in being
involved in the compilation of the guideline text and participated in the consensus
conference. The authors and mandate holders and their functions are listed in [Table 1 ].
Table 1 Guideline authors and mandate holders (listed alphabetically).
Author, mandate holder
Function*
Group, body
* A = author, M = mandate holder
Ackermann, PD Dr. med. Sven
A
German Society of Gynecology and Obstetrics [Deutsche Gesellschaft für Gynäkologie
und Geburtshilfe] (DGGG), German Cancer Society [Deutsche Krebsgesellschaft] (DKG),
Gynecological Oncology Working Group [Arbeitsgemeinschaft Gynäkologische Onkologie]
(AGO)
Alt-Radtke, Dr. med. Celine Desirée
A, M
German Roentgen Society [Deutsche Röntgengesellschaft] (DRG), Uroradiology Working
Group [AG Uroradiologie]
Angleitner, Prof. Dr. Lukas
M
Austrian Society of Gynecology and Obstetrics [Österreichische Gesellschaft für Gynäkologie
und Geburtshilfe] (OEGGG)
Barinoff, Dr. med. Jana
A
DGGG, DKG, AGO
Beckmann, Prof. Dr. med. Matthias W.
A
DGGG, DKG, German Cancer Aid [Deutsche Krebshilfe] (DKH), German Society for Senology
[Deutsche Gesellschaft für Senologie] (DGS), AGO, Comprehensive Cancer Center Erlangen
EMN (CCC ER-EMN)
Böing, Dr. med. Carsten
A
DGGG, DKG, AGO
Dannecker, Prof. Dr. med. Christian
A
DGGG, DKG, AGO
Fehm, Prof. Dr. med. Tanja
M
AGO Executive Board
Gaase, Dr. med. Rüdiger
M
Professional Association of Gynecologists [Berufsverband der Frauenärzte e. V.] (BVF)
Gaß, Dr. med. Paul
A
DGGG-Leitliniensekretariat
Gebhardt, Marion
M
Federal Association of Womenʼs Self-help Groups After Cancer [Bundesverband Frauenselbsthilfe
nach Krebs e. V.] (FSH)
Gieseking, Dr. med. Friederike
A, M
DGGG, DKG, AGO, Cervical Pathology and Colposcopy Working Group [AG Cervix-Pathologie
und Colposcopie] (AGCPC)
Günthert, Prof. Dr. med. Andreas
A
DGGG, DKG, AGO
Hack, PD Dr. med. Caroline C.
A, M
DGGG, DKG, AGO
Hampl, Prof. Dr. med. Monika
A, M
DGGG, DKG, AGO
Hantschmann, Dr. med. Peer
A
DGGG, DKG, AGO
Horn, Prof. Dr. med. Lars Christian
A, M
German Society of Pathology [Deutsche Gesellschaft für Pathologie] (DGP), DKG, AGO
Koch, Dr. med. Martin C.
A
DGGG, DKG, AGO
Letsch, Dr. med. Anne
A, M
German Society for Hematology and Medical Oncology [Deutsche Gesellschaft für Hämatologie
und medizinische Onkologie] (DGHO), German Society for Palliative Medicine [Deutsche
Gesellschaft für Palliativmedizin] (DGPm)
Mallmann, Prof. Dr. med. Peter
A, M
DGGG, DKG, AGO
Mangold, Dr. med. Bernhard
A, M
German Society for Cytology [Deutsche Gesellschaft für Zytologie] (DGZ)
Marnitz, Prof. Dr. med. Simone
A, M
German Society for Radio-oncology [Deutsche Gesellschaft für Radioonkologie] (DEGRO),
DKG, AGO
Mehlhorn, PD Dr. med. Grit
A
DGGG, DKG, AGO
Paradies, Kerstin
M
Conference for Oncological Nursing Care and Nursing Care of Children [Konferenz onkologischer
Kranken- und Kinderkrankenpflege e. V.] (KOK)
Reinhardt, Prof. Dr. med. Michael J.
M
German Society of Nuclear Medicine [Deutsche Gesellschaft für Nuklearmedizin e. V.]
(DGN)
Schnürch, Prof. Dr. med. Hans-Georg
A, M
DGGG, DKG, AGO
Tholen, Reina
M
German Association for Physiotherapy [Deutscher Verband für Physiotherapie]
Torsten, PD Dr. med. Uwe
A
DGGG, DKG, AGO
Weikel, Prof. Dr. med. Wolfgang
A
DGGG, DKG, AGO
Wetzig, PD Dr. med. Tino
M
German Dermatological Society [Deutsche Dermatologische Gesellschaft] (DDG)
Wölber, Prof. Dr. med. Linn
A
DGGG, DKG, AGO
Zraik, Dr. med. Isabella
M
German Society for Urology [Deutsche Gesellschaft für Urologie] (DGU)
Dr. M. Nothacker (an AWMF-certified guidelines advisor/moderator) kindly agreed to
moderate the guideline. Dr. P. Gaß (DGGG Guidelines Office, Erlangen) contributed
substantially to the compilation of the long and short versions of this guideline.
Abbreviations
AG:
working group [Arbeitsgemeinschaft]
AG-CPC:
Cervical Pathology and Colposcopy Working Group [Arbeitsgemeinschaft für Cervixpathologie
und Colposkopie]
AGO:
Gynecological Oncology Working Group [Arbeitsgemeinschaft Gynäkologische Onkologie]
AWMF:
Association of the Scientific Medical Societies in Germany [Arbeitsgemeinschaft der
Wissenschaftlichen Medizinischen Fachgesellschaften]
CAM:
complementary and alternative medicine
CCC:
comprehensive cancer center
CIN:
cervical intraepithelial neoplasia
CT:
computed tomography
DHCD:
data-sparing homogeneous cancer documentation
DGGG:
German Society of Gynecology and Obstetrics [Deutsche Gesellschaft für Gynäkologie
und Geburtshilfe]
DKG:
German Cancer Society [Deutsche Krebsgesellschaft]
EORTC:
European Organisation for Research and Treatment of Cancer
FDG-PET:
fluorodeoxyglucose-positron emission tomography
FIGO:
Fédération Internationale de Gynécologie et dʼObstétrique
H&E:
hematoxylin and eosin
HPV:
human papillomaviruses
HSIL:
high-grade squamous intraepithelial lesion
LDA:
lymph drainage area
LN:
lymph node
LNE:
lymph node excision
LN status:
lymph node status
LSIL:
low grade squamous intraepithelial lesion
MRI:
magnetic resonance imaging
NCCAM:
National Center of Complementary and Alternative Medicine
NCDB:
National Cancer Data Base
OEGGG:
Austrian Society of Gynecology and Obstetrics [Österreichische Gesellschaft für Gynäkologie
und Geburtshilfe]
OL:
Oncology Guidelines Program [Leitlinienprogramm Onkologie]
PE:
biopsy [Probe-Exzision]
PET:
positron emission tomography
PNI status:
perineural invasion status
QI:
quality indicator
QLQ:
quality of life questionnaire
R1:
microscopic residual disease
R2:
macroscopic residual disease
RCTX:
radio(chemo)therapy
SGB:
(German) Social Security Statute Book [Sozialgesetzbuch]
SGGG:
Swiss Society of Gynecology and Obstetrics [Schweizerische Gesellschaft für Gynäkologie
und Geburtshilfe]
SLN:
sentinel lymph node
SLNB:
sentinel lymph node biopsy
SPECT:
single-photon emission computed tomography
TNM system:
tumor-node-metastasis staging system
UICC:
Union internationale contre le cancer
VaIN:
vaginal intraepithelial neoplasia
VIN:
vulvar intraepithelial neoplasia
V status:
vessel status
WHO:
World Health Organization
WLE:
wide local excision
III Method
The method used to prepare this guideline was determined by the class to which this
guideline was assigned. The AWMF Guidance Manual (version 1.0) has set out the respective
rules and requirements for different classes of guidelines. Guidelines are differentiated
into lowest (S1), intermediate (S2) and highest (S3) class. The lowest class is defined
as a set of recommendations for action compiled by a non-representative group of experts.
In 2004, the S2 class was divided into two subclasses: a systematic evidence-based
subclass (S2e) and a structural consensus-based subclass (S2k). The highest S3 class
combines both approaches.
This guideline is classified as: S2k
Grading of recommendations
The grading of evidence and of recommendations is not envisaged for S2k-level guidelines.
The individual Statements and Recommendations are differentiated by syntax, not by
symbols ([Table 2 ]).
Table 2 Grading of recommendations.
Level of recommendation
Syntax
Strong recommendation, highly binding
must/must not
Simple recommendation, moderately binding
should/should not
Open recommendation, not binding
may/may not
Statements
Scientific statements given in this guideline which do not consist of any direct recommendations
for action but are simple statements of fact are referred to as “Statements”. It is
not possible to provide any information about the grading of evidence for these Statements.
Achieving consensus and strength of consensus
As part of the structured process to achieve consensus (S2k/S3 level), authorized
participants attending the consensus conference vote on draft Statements and Recommendations.
This can lead to significant changes in the wording, etc. Finally, the extent of consensus
is determined based on the number of participants who voted and the number of participants
who voted in favor ([Table 3 ]).
Table 3 Grading of strength of consensus.
Symbol
Strength of consensus
Extent of agreement in percent
+++
Strong consensus
> 95% of participants agree
++
Consensus
> 75 – 95% of participants agree
+
Majority agreement
> 50 – 75% of participants agree
–
No consensus
< 51% of participants agree
Expert consensus
As the name already implies, this term refers particularly to consensus decisions
on Recommendations/Statements where the decision was taken without a prior systematic
search of the literature (S2k) or for which evidence is lacking (S2e/S3). The term
“expert consensus” (EC) used here is synonymous with terms used in other guidelines
such as “good clinical practice” (GCP) or “clinical consensus point” (CCP). The strength
of the recommendation is graded as previously described in the chapter “Grading of
recommendations”, i.e., purely semantically (“must”/“must not” or “should”/“should
not” or “may”/“may not”) without the use of symbols.
Quality indicator
The QI working group of the Vulva and Vagina Commission has proposed that histological
confirmation of the primary vaginal cancer prior to planning therapy in a tumor conference
should be the only quality indicator for this rare entity.
IV Guideline
1 Epidemiology
Vaginal cancer is a rare tumor with only around 500 new cases reported annually in
Germany [1 ]. The majority of all invasive vaginal cancers are squamous cell carcinomas (> 95%),
followed by adenocarcinomas (< 5%) and melanomas (< 1%) [2 ]. The majority of clear cell adenocarcinomas are associated with maternal intake
of the drug diethylstilbestrol (DES) during pregnancy [3 ]. Vaginal metastasis and recurrence and vaginal infiltration caused by direct expansion
of an adjacent malignancy of the cervix, vulva, endometrium or rectum are more common
than primary vaginal cancer, and primary vaginal carcinoma must be differentiated
from all of these entities.
1.1 Age distribution
In more than 50% of cases, the age at onset of primary vaginal cancer is 70 years
and above. Only 15% of these carcinomas are diagnosed in patients between the ages
of 20 and 49 years [4 ].
1.2 Survival rate
The absolute 5-year survival rate correlates with the histological subtype: it is
54% for squamous cell carcinoma, 60% for adenocarcinoma, and 13% for patients with
malignant melanoma [4 ]. The 5-year survival rate also correlates with the tumor stage at primary diagnosis:
it is 20% for stage IV.
1.3 Risk factors
Consensus-based Statement 1.S1
Expert consensus
Strength of consensus +++
The risk factors for developing vaginal cancer are similar to those for cervical cancer.
Consensus-based Statement 1.S2
Expert consensus
Strength of consensus +++
Infection with human high-risk papillomavirus (HR-HPV) is one of the most important
risk factors.
Consensus-based Statement 1.S3
Expert consensus
Strength of consensus +++
Vaginal cancer has been reported to develop in up to 5% of cases with VaIN. A VaIN
2 – 3/HSIL is a precancerous lesion.
The risk factors for developing squamous cell tumors of the vagina are the same as
those for cervical cancer:
infection with high-risk human papillomavirus
previous treatment for preinvasive or invasive HPV-induced lesions
multiple sexual partners
early age at first intercourse
smoking [5 ]
1.3.1 HPV
HPV DNA was detected in 74% of vaginal carcinomas and in 96% of VaIN 2/3 lesions.
HPV 16 is the most commonly detected subtype both for VaIN and invasive tumors (59%).
1.3.3 VaIN
A vaginal intraepithelial neoplasia (VaIN) may be found sequentially or simultaneously
with vaginal cancer. The precise incidence of VaIN ist not clear. It is often reported
as 0.2 to 0.3 cases per 100 000 women and year [6 ]. There is a coincidence with other neoplasias of the lower anogenital tract [7 ], [14 ]. The data show that long-term follow-up is necessary in all cases with VaIN. The
rate of progression for VaIN developing into vaginal carcinoma is 2 – 5%. The same
chapter in the long version of this guideline provides more details on the above data
on the rate of progression.
2 Prevention and screening
2.1 Primary prevention
Consensus-based Statement 2.S4
Expert consensus
Strength of consensus +++
Because of the heterogeneity of the data, it is not possible to provide a final statement
on whether targeted sexual hygiene, which is recommended for other sexually transmissible
diseases, has a preventative effect on vaginal neoplasia.
Based on the distribution of HPV types, up to 60% of all vaginal carcinomas could
theoretically be prevented by HPV vaccination [8 ]. According to the current recommendations of the STIKO, HPV vaccination is also
useful with respect to the primary prevention of vaginal cancer and its precursors.
As smoking increases the risk of women who test positive for HPV (high-risk types)
developing a VaIN [9 ], women who smoke should always be provided with appropriate information in the context
of preventing VaIN. The long version of this chapter includes details on the role
of specific protective measures.
2.2 Screening (secondary prevention)
Consensus-based Statement 2.S5
Expert consensus
Strength of consensus +++
The legally mandated screening program for cervical cancer offers the opportunity
to diagnose vaginal cancers and their precursors at an early stage.
3 Healthcare structures
3.2 Treatment in oncology centers
Consensus-based Recommendation 3.E1
Expert consensus
Strength of consensus +++
Patients with vaginal cancer should be treated by an interdisciplinary, interprofessional
team. The team should have access to all necessary medical specialties and occupations
in a cross-sectoral network. A certified center is most likely to be able to provide
this extensive access.
3.2.2 Centers – interdisciplinary tumor board
Consensus-based Recommendation 3.E2
Expert consensus
Strength of consensus +++
All patients with vaginal cancer must be presented to an interdisciplinary tumor board.
4 Pathology
4.1 Classification of precancerous lesions ([Table 4 ])
Table 4 Nomenclature of HPV-associated precancerous vaginal lesions [10 ], [11 ], [12 ].
Description
Condylomatous lesion
Low-grade dysplasia
Intermediate-grade dysplasia
High-grade dysplasia
Carcinoma in situ
* LAST = Lower Anogenital Squamous Terminology Standardization project of the College
of American Pathologists and the American Society of Colposcopy and Cervical Pathology
[13 ].
WHO (2003)
VaIN 1
VaIN 2
VaIN 3
LAST project*
Low-grade squamous intraepithelial lesion (LSIL)
High-grade squamous intraepithelial lesion (HSIL)
WHO (2014)
Low-grade squamous intraepithelial lesion (LSIL)
syn.: VaIN 1
High-grade squamous intraepithelial lesion (HSIL)
syn.: VaIN 2 and VaIN 3
4.2 Morphology of precancerous vaginal lesions
Consensus-based Recommendation 4.E3
Expert consensus
Strength of consensus +++
The clinical terminology and morphological workup of a precancerous vaginal lesion
(vaginal intraepithelial neoplasia; VaIN) must be based on the most recent valid version
of the WHO classification.
In addition to its classification as LSIL or HSIL, HPV-associated changes (e.g. condylomas)
should be specified and the lesion should be graded (VaIN 1 to 3).
4.3 Vaginal Pagetʼs disease
Consensus-based Recommendation 4.E4
Expert consensus
Strength of consensus +++
If histological examination detects pagetoid changes in a vaginal biopsy specimen,
locoregional cancer and vulvar Pagetʼs disease with vaginal involvement must be clinically
excluded.
4.4 Morphology of malignant vaginal tumors
4.4.1 Tumor typing
Consensus-based Recommendation 4.E5
Expert consensus
Strength of consensus +++
The histological classification of malignant vaginal tumors must be based on the most
current version of the WHO classification.
4.4.2 Staging of vaginal carcinoma
Postoperative staging is done using the pTNM classification system [14 ]; citing the FIGO stage [15 ] is optional (s. Chapter 5.7).
From a morphological standpoint, the WHO definition of vaginal cancer is problematic.
According to this definition, squamous cell cancer of the vagina is defined as a vaginal
carcinoma without a previous cervical or vulvar carcinoma in the 10 years before the
current diagnosis [11 ], [16 ], [17 ]. Otherwise the vaginal cancer is considered to be a recurrence of a previously treated
carcinoma. Equally problematic is the statement by FIGO that squamous cell cancer
of the vagina with involvement of the cervix should be classified as a cervical carcinoma
[17 ].
As with cervical and vulvar carcinomas, the depth of invasion should be defined as the extent of stromal invasion measured from the epithelial-stromal
border at the most superficial dermal papilla adjacent to invasion to the deepest
point of invasion [13 ], [14 ], [18 ]. Lymph node infiltration which extends beyond the deepest point of invasion must
not be included in the measured depth of invasion or the tumor thickness but must
be classified as L1 [13 ], [14 ], [18 ]. Tumor thickness is measured from the surface of the tumor or, in the case of (strongly) keratinized
squamous cell carcinomas, from the granular cell layer to the deepest point of invasion
[13 ], [19 ].
4.4.4 Evaluation of tissue specimens
Consensus-based Recommendation 4.E6
Expert consensus
Strength of consensus +++
Biopsy specimens obtained from areas suspicious for VaIN must be processed and sliced
into sections for further evaluation.
4.4.4.1 Diagnostic biopsies
Consensus-based Recommendation 4.E7
Expert consensus
Strength of consensus +++
The biopsy findings report must provide information about the confirmation and type
of VaIN, the presence of any dermatological disease, any virus-associated changes,
and possible invasion.
4.4.4.2 Specimens after local excision, colpectomy, hysterocolpectomy and lymph node
status
Consensus-based Recommendation 4.E8
Expert consensus
Strength of consensus +++
Morphological processing of colpectomy specimens in vaginal cancer must be carried
out in such a way that all therapeutic and prognostically relevant parameters can
be evaluated. The findings report must use the most recent valid WHO classification
of tumor types and the most current TNM classification for staging.
Consensus-based Recommendation 4.E9
Expert consensus
Strength of consensus +++
The report detailing the histological findings of (radical) colpectomy specimens resected
for vaginal cancer must include the following information:
histological type using the WHO classification
grading
proof/absence of lymph node or vascular invasion (LN und V status)
proof/absence of perineural infiltration (PNI status)
staging (pTNM)
depth of invasion in mm
three-dimensional tumor size in cm
minimum metric distance between the carcinoma and any associated VaIN measured from
the edge of the resection to the VaIN
minimum metric distance between the tumor and the soft-tissue edge of the resection
(paracolpic tissue)
R classification (UICC)
Consensus-based Recommendation 4.E10
Expert consensus
Strength of consensus +++
All resected lymph nodes obtained by lymphadenectomy during the surgical treatment
of vaginal cancer must be examined histologically.
Consensus-based Recommendation 4.E11
Expert consensus
Strength of consensus +++
Lymph nodes up to a diameter of approx. 0.3 cm should be entirely embedded; larger
lymph nodes should be cut in half along their longitudinal axis and also completely
embedded.
According to the UICC and TNM classification systems, micrometastasis is defined as the histological confirmation of tumor cells measuring ≥ 0.2 mm and
no larger than 0.2 cm in lymph nodes [20 ], [21 ]. Tumor cells with a total length of < 0.2 mm are defined as isolated tumor cells in lymph nodes [20 ], [21 ]. The detection of isolated tumor cells and evidence of micrometastasis are not relevant
for the staging of vaginal cancer.
Consensus-based Recommendation 4.E12
Expert consensus
Strength of consensus +++
The report on the findings for lymphadenectomy specimens resected for vaginal cancer
must include the following information:
The number of affected lymph nodes compared to the number of resected lymph nodes
together with information on the biopsy location and side (pelvic, poss. inguinofemoral)
The size of the largest lymph node metastasis in mm
Information whether lymph node metastasis has spread beyond the capsule or not
Information on the presence/absence of isolated tumor cells in the lymph node, in
lymphatic vessels in perinodal adipose tissue, and/or in the lymph node capsule
4.4.4.3 Sentinel lymph nodes
Consensus-based Recommendation 4.E13
Expert consensus
Strength of consensus +++
In cases with vaginal cancer, the sentinel lymph nodes must be completely embedded
and cut into slides for examination. Sentinel lymph nodes which are found to be negative
based on an examination of their morphology using H & E staining, must additionally
be investigated by immunohistochemistry (ultrastaging).
4.4.5 Morphological prognostic factors
The prognostic contribution of individual morphological tumor characteristics is summarized
in [Table 5 ].
Table 5 Prognostic factors for vaginal cancer.
Name
Standard factor
Risk/prognostic factor
Relevant for treatment
Tumor stage
Yes
Yes
Yes
Lymph node status
Yes
Yes
Yes
Size of respective lymph node metastasis
Yes
Unclear
Yes
Number of inguinal lymph nodes with metastatic disease
Yes
Unclear
Yes
Extracapsular extension of inguinal lymph node metastasis
Yes
Unclear
Yes
Perineural infiltration (PNI status)
Yes
Unclear
No
Lymph node infiltration (LN status)
Yes
Unclear
No
Venous invasion (V status)
Yes
Unclear
No
Resection margins (residual tumor status; R classification)
Yes
Yes
Yes
Depth of invasion in mm
Yes
Unclear
No
Grading
Yes
Unclear
No
Three-dimensional tumor size in cm
Yes
Unclear
Yes
Location of the cancer in the vagina
Yes
Unclear
Yes (poss. surgical approach)
Macroscopic type of growth of the carcinoma
Yes
Unclear
No
Multifocal carcinoma
Yes
Unclear
Yes (surgical approach)
Peritumoral VaIN
Yes
Unclear
Yes (surgical approach)
Histological tumor type
Yes
Unclear
No (pure adenocarcinoma, poss. not radiosensitive)
HPV confirmation in the carcinoma
No
Unclear
No
Pattern of invasion
No
Unclear
No
Immunohistochemical ultrastaging of lymph nodes for metastasis
No
Unclear
Unclear
Molecular markers
No
Unclear
Unclear
5 Diagnostic workup
5.2 Clinical workup
Consensus-based Statement 5.S6
Expert consensus
Strength of consensus +++
The diagnostic workup of a suspicious vaginal lesion must consist of clinical, cytological
and colposcopic examinations depending on the manifestation of the lesion. The lesion
must be biopsied if the findings are suspicious.
5.3 Histological workup
All suspicious lesions must be examined histologically.
5.4 Pretreatment staging of a carcinoma
Consensus-based Recommendation 5.E14
Expert consensus
Strength of consensus +++
Prior to treatment of a confirmed carcinoma, the following examinations must be carried
out:
gynecological examination of the entire anogenital area (multicentric/multifocal)
determination of the location, spread and size of the tumor (colposcopy)
assessment of the infiltration depth (palpation and poss. histological examination)
assessment of spread to neighboring organs
urethrocystoscopy, rectoscopy, poss. anal sonography depending on the location
imaging examination depending on the clinical spread of the tumor
5.5 Diagnostic workup of advanced tumors
Because of the close proximity of neighboring organs and because surgical treatment
often requires extensive excision to obtain healthy margins, the indications for exploration
using endoscopy and imaging should be interpreted liberally.
For this reason, screening for distant metastasis in cases with large tumors must
be done prior to starting treatment (see 5.6).
5.6 Imaging workup for vaginal cancer
5.6.1 Diagnostic workup of the primary tumor
Consensus-based Statement 5.S7
Expert consensus
Strength of consensus +++
Pelvic MRI is the imaging modality of choice for the local staging of histologically
confirmed vaginal carcinoma from FIGO stage II onwards.
Consensus-based Recommendation 5.E15
Expert consensus
Strength of consensus +++
The current recommendations (protocol) for gynecological pelvic tumors must be followed
when carrying out a functional pelvic MRI to achieve the best possible diagnostic
accuracy.
Consensus-based Statement 5.S8
Expert consensus
Strength of consensus +++
The value of FDG-PET/CT for the staging of vaginal cancer has not been confirmed in
the primary setting.
5.6.2 Diagnostic workup of lymph nodes
Consensus-based Statement 5.S9
Expert consensus
Strength of consensus +++
The amount of information which can be obtained from imaging procedures to assess
pelvic lymphatic drainage in cases with primary vaginal carcinoma is higher with functional
MRI than with CT or standard MRI.
5.6.3 Distant metastasis
Consensus-based Recommendation 5.E16
Expert consensus
Strength of consensus +++
For complete staging, a CT scan of the abdomen and chest using contrast medium should
be carried out in cases with advanced vaginal carcinoma (≥ FIGO II) or if there is
a reasonable suspicion of metastasis.
Consensus-based Recommendation 5.E17
Expert consensus
Strength of consensus +++
Prior to any planned pelvic exenteration, PET/CT may be used in patients with primary vaginal cancer to exclude distant metastasis insofar
as this is possible.
5.6.4 Imaging in radiation therapy
Consensus-based Recommendation 5.E18
Expert consensus
Strength of consensus +++
Patients who are treated with percutaneous radiotherapy, combined radiochemotherapy
or brachytherapy must have an MRI scan at the start of planning treatment and to monitor
therapy; where possible, the scan should be a functional MRI scan.
5.6.5 Diagnostic workup for recurrence
Consensus-based Recommendation 5.E19
Expert consensus
Strength of consensus +++
Patients with a suspicion of local recurrence of vaginal cancer should have a functional
pelvic MRI scan to assess the extent of local spread in the pelvis.
Consensus-based Recommendation 5.E20
Expert consensus
Strength of consensus +++
Prior to planning treatment, PET/CT may be indicated in patients with a suspicion
of extensive recurrence of vaginal carcinoma extending beyond the pelvic area.
5.7 Staging
Staging is carried out using the FIGO and TNM classification systems ([Table 6 ]). The findings at surgery together with the results of the histopathological examination
of the surgical specimens will determine the staging.
Table 6 Vaginal cancer staging according to AJCC 2017 [22 ]/FIGO (2018) [15 ]/TNM 2017 [14 ].
UICC
FIGO
Tumor spread
1) The FIGO classification does not envisage a stage 0 (Tis).
2) The presence of a bullous edema in the bladder mucosa is not enough to classify a
tumor as T4.
TX
Primary tumor cannot be assessed due to lack of information
T0
No evidence of a primary tumor
Tis
1)
Carcinoma in situ, vaginal intraepithelial neoplasia (VaIN) grade 3
T1a
I
Tumor is limited to the vagina and no larger than 2 cm, it has not spread (N0, M0)
T1b
I
Tumor is limited to the vagina and larger than 2 cm, it has not spread (N0, M0)
T2a
II
Tumor has infiltrated paravaginal tissue (paracolpium), is not larger than 2 cm, has
not reached the pelvic wall, it has not spread (N0, M0)
T2b
II
Tumor has infiltrated paravaginal tissue (paracolpium), is larger than 2 cm but has
not reached the pelvic wall, it has not spread (N0, M0)
T1 bis T3
N1
T3
N0
M0
III
III
Tumor is growing into the pelvic wall and/or the lower third of the vagina and/or
blocks the flow of urine, which is causing kidney problems
Tumor has spread into regional pelvic or inguinal LNs, no distant metastasis
Tumor is growing into the pelvic wall and/or the lower third of the vagina and/or
blocks the flow of urine
Tumor has not spread (N0, M0)
T4
Any N
M0
IVA
Tumor has infiltrated the bladder mucosa and/or rectum and/or has spread beyond the
pelvis2)
Tumor may or may not have spread to regional LNs, no distant metastasis
Any T
Any N
M1
IVB
Tumor has spread to distant organs (incl. pelvic LN metastasis), may or may not be
infiltrating adjacent structures
Tumor may or may not have spread to regional LNs
The pelvic lymph nodes (obturator, internal iliac, external iliac and other unspecified
pelvic LNs) are the regional lymph nodes for tumors in the upper two-thirds of the
vagina. The inguinofemoral LNs are the regional LNs for tumors in the lower third
of the vagina.
7 Treatment of vaginal intraepithelial neoplasia (VaIN)
7.1 Local surgical therapy
Consensus-based Statement 7.S10
Expert consensus
Strength of consensus +++
Before starting any superficial treatment for VaIN, one or more biopsies must be carried
out to exclude invasive carcinoma where possible. If there is a cytological suspicion
of invasion, destructive therapy must not be carried out and treatment must consist
of excision instead.
[Table 7 ] shows the optimal treatment approaches for high-grade VaIN according to their HPV
status and vaginal location.
Table 7 Treatment options for high-grade VaIN depending on the location of the lesion.
VaIN
2 – 3 (HSIL)
Lower third
Intermediate third
Vaginal vault
Entire vagina
HPV-induced
Excision, PE/laser vaporization, local drug therapy
Excision, PE/laser vaporization, local drug therapy
Excision, PE/laser vaporization, upper colpectomy
Skinning resection of vaginal epithelium, colpectomy, local drug therapy
HPV-negative
Excision
Excision
Excision, upper colpectomy
Colpectomy, skinning resection of vaginal epithelium
Consensus-based Recommendation 7.E21
Expert consensus
Strength of consensus +++
The decision which of the available guideline-based treatment options for VaIN to
apply must be made on an individual basis.
7.2 Local drug therapy
Local treatment may be used as an alternative to surgical treatment. This includes
therapy with 5-FU or imiquimod (both are off-label uses). There are also reports of
using brachytherapy.
The choice of treatment is based on the grade of the VaIN lesion ([Table 8 ]).
Table 8 Recommendations for treatment according to VaIN grade.
VaIN 1 (condylomatous lesion)
Low-grade squamous intraepithelial lesion LGSIL, flat condyloma
VaIN 2 – 3
High-grade intraepithelial neoplasia HGSIL
Regular monitoring, in exceptional cases destruction, excision, local application
of imiquimod (off-label use)
Extensive PEs, followed by destruction or surgical removal (excision, skinning colpectomy,
skinning excision, partial/total colpectomy) or radiotherapy
7.3 Recurrence and progression rates
Consensus-based Recommendation 7.E22
Expert consensus
Strength of consensus +++
Patients treated for VaIN must be offered regular follow-up examinations for the rest
of their lives because the rate of recurrence for VaIN is high.
More information on the rates of recurrence and progression is available in the long
version of the guideline.
8 Surgical treatment of invasive carcinoma
The majority of invasive vaginal cancers are treated with radio(chemo)therapy [8 ], [23 ], [24 ], [25 ]. Local surgical treatment ranges from local excision to partial or total colpectomy
to anterior and/or posterior exenteration [26 ].
8.1 FIGO stage I
Consensus-based Statement 8.S11
Expert consensus
Strength of consensus +++
Surgery may be used to treat FIGO stage I vaginal carcinoma.
Consensus-based Recommendation 8.E23
Expert consensus
Strength of consensus +++
Circumscribed FIGO stage I tumors should be excised locally with tumor-free margins;
the surgical treatment of larger tumors should consist of colpectomy or hysterectomy,
if necessary.
8.2 FIGO stage II
Consensus-based Statement 8.S12
Expert consensus
Strength of consensus +++
Radio(chemo)therapy is the standard therapy for tumor stages II to IV. Exenteration
to treat stage IV vaginal carcinoma is an individual therapy decision.
8.3 Stage III/IV
The standard therapy consists of radio(chemo)therapy. In cases with infiltration through
the wall into adjacent organs (bladder and/or rectum), anterior and/or posterior exenteration
with creation of a neobladder and/or a colostomy is a surgical option which has to
be decided on in the context of an individual therapy decision.
8.4 Plastic reconstruction
Consensus-based Recommendation 8.E24
Expert consensus
Strength of consensus +++
Before undergoing colpectomy, the patient should be informed about the possibility
of vaginal plastic reconstruction.
9 Surgery of lymph drainage areas
9.1 Introduction
To date, sentinel lymph node imaging has not played any significant role in the diagnosis
and treatment of vaginal cancer. The lack of information about lymphatic drainage
in vaginal cancer is why lymphatic imaging with sentinel node analysis is necessary.
The current practice of treating all regional lymph node stations either surgically
or with radiotherapy is probably overtreatment and could be reduced in individual
cases with targeted imaging and biopsies of sentinel lymph nodes.
9.2 Indication
The issue whether to lymph node (LN) staging should be carried out in cases with vaginal
carcinoma or not is a question which affects both patients for whom primary surgery
is indicated and patients for whom primary radio(chemo)therapy is indicated. If surgical
examination of the lymph node areas is not possible or the patient does not want it,
then primary radio(chemo)therapy is indicated and should potentially also include
the site of the primary tumor (see Chapter 10).
9.3 Lymphatic drainage from the vagina
Consensus-based Statement 9.S13
Expert consensus
Strength of consensus +++
Because the correlation between tumor location and the direction of lymphatic flow
is not clear due to extensive lymphatic anastomosis in the vagina and lesser pelvis,
it is not possible in individual cases to clearly link the vaginal tumor site with
the direction of lymphatic flow.
The literature on this issue is discussed in the long version of the guideline.
9.4 Vaginal cancer and risk of lymphatic metastasis
Consensus-based Statement 9.S14
Expert consensus
Strength of consensus +++
There are no evidence-based parameters which show a close correlation between vaginal
cancer and the risk of lymphatic metastasis. As with vulvar cancer, an infiltration
depth of > 1 mm may be an indication of an incipient risk of lymphatic metastasis.
9.5 Sentinel node procedures
9.5.1 Benefit of sentinel node procedures
Because of the lack of studies on the benefits of sentinel node procedures in vaginal
cancer, the use of these procedures in vaginal cancer is still experimental. Studies
of adjacent primary tumors of the uterine cervix and vulva provide some positive evidence
for the use of sentinel node procedures in vaginal cancer. The flow chart in [Fig. 1 ] shows the conventional and the experimental sequence for diagnosis and treatment;
the sequence to be followed is described in Chapter 9.6.
Fig. 1 Flowchart for the diagnostic workup and treatment of vaginal carcinoma with the option
of carrying out a sentinel LN procedure or not. [rerif]
9.5.2 Lymph node mapping using sentinel lymph node technique
Consensus-based Statement 9.S15
Expert consensus
Strength of consensus +++
Sentinel lymph node mapping and tracing the lymphatic drainage pathway in cases with
vaginal cancer is the precondition for carrying out SLNB and for planning any subsequent
surgical and/or radiotherapeutic treatment.
Consensus-based Recommendation 9.E25
Expert consensus
Strength of consensus +++
The following preconditions must be adhered to when using the sentinel lymph node
technique in cases with vaginal cancer:
No clinically suspicious lymph nodes and/or nodes suspicious on imaging.
The diameter of the primary tumor is no larger than 4 cm in the vaginal plane and
the tumor has not infiltrated any structures beyond the vagina (FIGO I).
The patient has not undergone any prior operations in the lymphatic drainage area
to be treated.
Imaging is done using 99 m technetium nanocolloid.
A gamma probe must be used during surgical LN exploration; patent blue or – particularly
when carrying out laparoscopic exploration – indocyanine green (ICG) may also be used
for staining.
All resected sentinel LNs negative on H & E staining are subjected to pathologic ultrastaging
with immunohistochemistry.
Those inguinal and pelvic lymphatic drainage areas not mapped using the sentinel LN
technique are systematically explored surgically or included in the primary therapy
(systematic LNE or RCTX).
9.5.3 Validity of sentinel lymph node biopsy
Consensus-based Recommendation 9.E26
Expert consensus
Strength of consensus +++
The sentinel lymph node technique may be used if the patient has consented after being
informed in detail about the limited validity of the method in vaginal cancer because
of the current lack of data.
Consensus-based Statement 9.S16
Expert consensus
Strength of consensus +++
Because of the rarity of these tumors, no valid data on the diagnostic certainty of
SLNB in vaginal cancer will be available in the foreseeable future.
Systematic inguinofemoral or pelvic lymphadenectomy or radio(chemo)therapy of the
respective areas probably offers greater oncological safety but patients will have
to accept a higher rate of side effects.
To evaluate the usefulness of sentinel lymph node biopsy in vaginal cancer, a new
central register has been set up to collect treatment data and the course of disease
of all patients with vaginal cancer in Germany (“knowledge-generating healthcare research”
by the DKG). This national interdisciplinary vaginal carcinoma register is supported
by the medical societies DGGG, AGO and DEGRO. All cases of vaginal cancer must be
reported to the Radiotherapy Department of Cologne University (email: martina.illig@uk-koeln.de ). All hospitals with a tumor board which discusses and treats cases of vaginal carcinoma
are requested to contact the registration office.
9.5.5 Planning primary radio(chemo)therapy
Consensus-based Recommendation 9.E27
Expert consensus
Strength of consensus +++
If SLN imaging is carried out preoperatively followed by intraoperative SLN biopsy,
the findings should be taken into consideration when planning the radiation fields
for primary radiotherapy.
Please refer to this chapter in the long version of the guideline to read how staging
results from sentinel lymph node procedures can improve the situation.
9.6 Diagnosis and therapy with and without sentinel lymph node procedures
9.6.1 Process description of diagnostic workup and treatment
This chapter describes the recommended treatment approach for primary vaginal carcinoma
with and without a sentinel lymph node procedure; the circled numbers correspond to
the respective steps shown in [Fig. 1 ].
9.7 Systematic lymphanedectomy
Lymphatic drainage areas relevant for vaginal cancer include the pelvic, anorectal
and inguinofemoral lymph nodes. In addition to these LNs, very advanced lymphogenic
metastatic vaginal cancer may also affect the paraaortic LNs. As with SLN procedures,
pretherapeutic systematic LNE in the above-mentioned lymphatic drainage areas may
be useful to determine the extent of the required radiation for subsequent primary
radio(chemo)therapy based on staging findings. Lymph node regions shown to have no
metastatic involvement should not be irradiated.
If metastatic involvement is found to be present in pelvic lymph nodes on one side,
it is important to ensure that both sides are treated with radiotherapy in accordance
with the uniform approach used to treat pelvic lymph node metastasis from other primary
tumors (carcinomas of the uterine cervix, prostate, endometrium, rectum, and anus),
There are no data available on hemipelvis radiotherapy for vaginal cancer.
9.8 Surgical tumor reduction (debulking) prior to radio(chemo)therapy
In cases with advanced vaginal carcinoma and large circumscribed lymph node metastases
in the groin or pelvis, the option to carry out preparatory surgical debulking as
a means of improving the response to radio(chemo)therapy should be considered. The
overall oncological situation, the patientʼs general operability, and local resectability
as well as the expected morbidity following therapy must all be taken into consideration.
Consensus-based Recommendation 9.E28
Expert consensus
Strength of consensus +++
Treatment planning for vaginal carcinoma should be based on the flowchart showing
the diagnostic workup and treatment of vaginal carcinoma ([Fig. 1 ]).
10 Radio(chemo)therapy for vaginal carcinoma
10.1 Introduction
Radiotherapy alone has been used since many decades to treat both local and advanced
squamous cell carcinoma and adenocarcinoma of the vagina.
Depending on the tumor stage, radiotherapy alone can achieve high local control rates,
ranging from 85 – 95% for FIGO stage I, to 70 – 80% for FIGO stage II and around 50 – 70%
for FIGO stages III–IVA [27 ], [28 ], [29 ], [30 ], [31 ].
Please refer to this chapter in the long version of the guideline for details on the
dose-response relationship, the different radiotherapy techniques and the target volume
definitions.
10.5 Radiotherapy of the tumor region
A second resection should be considered if the tumor was not resected in its entirety.
If this is not feasible or if the expected functional results of this second resection
are expected to be unsatisfactory, then local radiotherapy should be administered
to improve local control.
Consensus-based Recommendation 10.E29
Expert consensus
Strength of consensus +++
In primary radio(chemo)therapy, the target volume should cover the primary tumor including
the safety margin with a dose of > 70 Gy.
Consensus-based Statement 10.S17
Expert consensus
Strength of consensus +++
There is no evidence which specifies a minimal histological safety margin between
the tumor and the edge of the resected specimen nor that resection margins below such
a minimal histological safety margin represent an indication for administering radiotherapy
to the tumor region postoperatively.
Consensus-based Recommendation 10.E30
Expert consensus
Strength of consensus +++
Postoperative radiotherapy of the tumor region must be recommended after R1 and R2
resection if a second resection is not feasible.
10.6 Radiotherapy of the lymphatic drainage pathways
10.6.1 Inguinal lymph nodes
If inguinal lymph node metastasis has been confirmed histologically, the recommendations
to administer postoperative radiotherapy will be based on the recommendations used
to treat vulvar cancer. Radiotherapy planning should opt for modern proton therapy
in preference to electron therapy.
10.6.2 Pelvic lymph nodes
Radiotherapy with bilateral radiation of the pelvic lymph drainage pathways is recommended
if pelvic lymph node metastasis has been confirmed histologically. Even if metastasis
is only confirmed on one side, radiotherapy should always be administered to both
sides.
10.7 Radio(chemo)therapy
Consensus-based Recommendation 10.E31
Expert consensus
Strength of consensus +++
Primary radiotherapy should also be offered in the form of simultaneous radiochemotherapy.
Consensus-based Recommendation 10.E32
Expert consensus
Strength of consensus +++
The inguinofemoral and pelvic lymphatic drainage areas on both sides should also be
irradiated if surgical lymph node staging was indicated but surgical staging was not
carried out.
Consensus-based Recommendation 10.E33
Expert consensus
Strength of consensus +++
The patientʼs comorbidities, own wishes, and clinical situation need to be considered
before administering cisplatin ± 5-FU or mitomycin ± 5-FU.
Consensus-based Statement 10.S18
Expert consensus
Strength of consensus +++
In primary radiotherapy, achieving sufficiently high tumor doses is decisive for the
success of therapy. Brachytherapy, possibly in combination with percutaneous radiotherapy,
plays an important role in this context.
Consensus-based Recommendation 10.E34
Expert consensus
Strength of consensus +++
As with vulvar cancer, adjuvant radio(chemo)therapy after R1/R2 resection should be
administered to the tumor area and the affected groin area if inguinal metastasis
is present and bilaterally if there is pelvic metastasis.
The recommendation to administer simultaneous radiochemotherapy to treat vaginal cancer
is a transfer of the experience with this approach in other tumors. Because of the
rarity of vaginal carcinoma, we recommend that vaginal cancer should be treated in
centers which deal with larger numbers of patients [32 ], [33 ], [34 ].
10.9 Side effects of therapy, their prophylaxis and treatment
10.9.2 Late radiogenic side effects
Please refer to this chapter in the long version of the guideline for details on therapy-related
toxicity, the choice of radiation technique and its impact on toxicity.
Symptomatic measures such as treatment for diarrhea, sitz baths, vaginal douching
and the intravaginal application of a topical ointment (poss. using a tampon) to prevent
adhesions are useful. Acute reactions are common but usually heal after the end of
radiotherapy with no further effects. Important prophylactic measures against chronic
consequences of scarring such as vaginal stenosis include the above-listed therapies
applied consistently to treat acute reactions and the early and regular use of vaginal
dilators, particularly in young and sexually active patients [35 ], [36 ], [37 ], [38 ].
10.9.3 Preservation of ovarian function and/or fertility
Young patients should be informed about the possibility of preserving ovarian function
using ovariopexy with clip marking and the use of the latest radio-oncology techniques
[39 ], [40 ], [41 ], [42 ], [43 ]. Please consult the German-language AWMF S2k guideline “Fertilitätserhalt bei onkologischen
Erkrankungen” on preserving fertility in patients with oncologic disease for more
information about indications and techniques [44 ].
11 Systemic therapy
The current data on the use of systemic therapy to treat vaginal cancer is based on
single case reports and small series which were analyzed retrospectively. Most therapeutic
concepts were adapted from the treatment concepts used for cervical cancer.
11.2 Neoadjuvant chemotherapy
Consensus-based Statement 11.S19
Expert consensus
Strength of consensus +++
The use of neoadjuvant chemotherapy to treat vaginal cancer is currently still an
experimental concept.
11.3 Radio(chemo)therapy
Consensus-based Statement 11.S20
Expert consensus
Strength of consensus +++
Using radio(chemo)therapy to treat vaginal cancer is analogous to using radio(chemo)therapy
to treat cervical and vulvar cancer.
11.4 Chemotherapy in the palliative setting (recurrence, secondary metastasis, primary
metastasizing vaginal carcinoma)
The references for the few available reports and studies on vaginal cancer are given
in the long version of the guideline.
For the general chapters 12 Supportive Therapy, 13 Psycho-oncology and Quality of Life, 14 Rehabilitation and 15 Integrative Medicine , please refer to the long version of the guideline on the homepage of the AWMF: https://www.awmf.org/leitlinien/detail/ll/032-042.html
16 Follow-up
Consensus-based Recommendation 16.E35
Expert consensus
Strength of consensus +++
Patients who were treated for vaginal HSIL should have regular risk-adapted follow-up
appointments for the rest of their lives.
Consensus-based Recommendation 16.E36
Expert consensus
Strength of consensus +++
References: Adapted from Salani R et al. 2011 [45 ], Dannecker C et al. 2016 [46 ], Oonk MH et al. 2003 [47 ]
Follow-up care of vaginal cancer should include the following routine examinations:
Examination
1st–3rd year
4th–5th year
From 6th year
Medical history
every 3 months
every 6 months
annually
Clinical examination
every 3 months
every 6 months
annually
Speculum examination, colposcopy (cervix/vagina/
every 3 months
every 6 months
annually
The long version of this guideline includes additional information on the clinical
follow-up, the short and long-term impact of the disease and its therapy, and the
effects of lifestyle choices and psychosexual and psychosocial follow-up care.
17 Therapy for locoregional recurrence and distant metastasis
Around 90% of recurrences occur within the first five years [8 ], [48 ], [49 ]. About 25% of all recurrences are local or locoregional [48 ].
A palliative concept is used to treat distant metastasis; it is important to exclude
any distant metastasis before deciding on the appropriate therapy to treat locoregional
recurrence.
17.1 Diagnostic workup
The following diagnostic workup should be carried out if there is a suspicion of locoregional
recurrence:
gynecological examination and histological examination
vaginal ultrasound imaging
pelvic MRI [48 ]
cystoscopy and rectoscopy, exclusion of fistula
CT scan of the thorax and abdomen to exclude distant metastasis
It should be noted in this context that it is not uncommon for primary therapy to
create long-term complications which can mimic recurrence, particularly fistula formation
[49 ].
17.2 Treatment of locoregional recurrence
Consensus-based Statement 17.S21
Expert consensus
Strength of consensus +++
The decision to treat local or locoregional recurrence depends on the previous therapy,
the extent of recurrence, and the patientʼs general condition. The decision is made
an individual basis; treatment options include surgery, radiotherapy, radio(chemo)therapy
and best supportive care.
Consensus-based Recommendation 17.E37
Expert consensus
Strength of consensus +++
The decision about the appropriate treatment approach for a patient with local or
locoregional recurrence must be made by an interdisciplinary tumor board.
The long version of the guideline has drafted some cornerstones for treating recurrence
which must be followed. The limited options to treat distant metastasis are explained
in the long version.
To read the general chapter 18 Palliative Medical Care, please refer to the long version on the homepage of the AWMF: https://www.awmf.org/leitlinien/detail/ll/032-042.html
