Keywords vulvar cancer - squamous cell cancer - resection margins
Schlüsselwörter Vulvakrebs - Plattenepithelkarzinom - Resektionsrand
Introduction
Vulvar cancers are relatively rare, ranking as the nineteenth most common cause of
cancer among women in Europe, with around 16500 new cases in 2020 [1 ]. In Germany, 3293 new cases were reported in 2019. These cancers primarily affect
older women [2 ], but the incidence of vulvar cancer in women under the age of 60 years has been
increasing in recent decades [3 ]. The term “vulvar cancer” can encompass various types of cancer that originate from
different cells in the genital region. The labia majora are most often affected, and
less frequently the labia minora and clitoral region [4 ]. The vast majority of the lesions involve squamous cell carcinoma.
Epidemiological risk factors associated with vulvar cancer include age, the prevalence
of human papillomavirus (HPV) infection, smoking, human immunodeficiency virus (HIV)
infection, vulvar intraepithelial neoplasia, and lichen sclerosus [4 ]
[5 ].
The diagnosis of vulvar cancer typically involves a physical examination, vulvoscopy,
and histological analysis of any suspicious areas [6 ].
For treatment planning and selection of appropriate therapy, the tumors are classified
in accordance with internationally recognized criteria that assess the lesion’s anatomic
spread and assign it to different stages [7 ]. Vulvar cancer is staged using both the International Federation of Gynecology and
Obstetrics (FIGO) system and the TNM classification system [8 ]
[9 ]. The latest revision of the FIGO staging system was published in 2021 by the FIGO
Committee on Gynecologic Oncology. This updated staging was informed by an analysis
of data from the National Cancer Database for the period 2010–2017 [8 ]. The revised staging for vulvar carcinoma now comprises two substages in stage I,
lacks a substage
in stage II, incorporates three substages in stage III, and features two substages
in stage IV. Notably, the update introduces a fresh definition of depth of invasion,
aligns with the definition of lymph-node metastases used in cervical cancer, and allows
the inclusion of findings from cross-sectional imaging in the staging of vulvar cancer
[8 ]. The eighth edition of the TNM staging system for vulvar cancer was published in
2017 by the American Joint Committee on Cancer (AJCC) and the International Union
Against Cancer (UICC) and applies to primary carcinomas [9 ].
The primary treatment for local disease without metastasis is surgery [10 ]. Radical local excision is recommended, with the aim of achieving histologically
tumor-free margins. Over the years, the primary goal has been to secure tumor-free
margin distances of at least 10 mm, allowing even narrower margins if the lesion is
close to critical structures. However, recent extensive studies have failed to establish
a clear link between the extent of tumor-free margins and the rates of local recurrence
or overall survival improvement. Consequently, the evidence supporting the 10-mm margin
distance requirement is now quite weak. Debate on the optimal tumor-free margin distance
to reduce the risk of local recurrences and improve patients’ overall survival is
still ongoing [11 ]
[12 ]
[13 ]
[14 ]
[15 ]
[16 ]
[17 ]
[18 ]
[19 ]
[20 ]. It appears that a minimum margin larger than 2–3 mm on histopathology might be
sufficient, allowing better functionality with acceptable oncological outcomes.
However, determining the optimal size for the tumor-free margin distance is a continuing
topic of discussion. The various guidelines for treating vulvar cancer used in Germany,
the United States, and Europe illustrate the lack of a consensus on the matter. In
Germany, the expert consensus guideline published by the German Society for Gynecology
and Obstetrics (Deutsche Gesellschaft für Gynäkologie und Geburtshilfe, DGGG) and the German Cancer Society (Deutsche Krebsgesellschaft, DKG) suggests a minimum tumor-free margin distance of 3 mm on histological examination
[21 ]. Unfortunately, an S3 guideline for vulvar carcinoma is not available in Germany.
As a result, the S3 guideline for cervical carcinoma is often referred to by analogy
[22 ]
[23 ]. In contrast, the National Comprehensive Cancer Network (NCCN) guidelines in the
United States recommend tumor-free margin distances of 1–2 cm for early-stage vulvar
squamous cell carcinoma [24 ]. The European Society of Gynaecological Oncology (ESGO) advises that a narrow margin
distance should be considered in order to preserve critical structures such as the
clitoris, urethra, or anus [25 ].
The diagnosis and treatment of vulvar cancer has substantial physical and psychological
effects on women. Several studies indicate that there is a risk of persistent sexual
dysfunction after radiotherapy or vulvar surgery, potentially linked to the extent
of vulvar tissue removal [26 ]
[27 ]
[28 ]. Reports of incontinence issues have also appeared after radical vulvectomy in cases
in which a portion of the urethra is removed or the vulvectomy excision comes close
to the urethra (within 1 cm) [29 ].
The goal of this two-center retrospective study was to assess the influence of the
tumor-free margin distance on patient survival and local recurrence rates, while identifying
additional prognostic factors for overall survival.
Methods
The retrospective two-center cohort analysis involved a review of clinical records
and histopathological reports for patients who had undergone surgical treatment for
primary vulvar squamous cell carcinoma between 2009 and 2021 at ANregiomed Hospital
in Ansbach, Germany, and Erlangen University Hospital/Comprehensive Cancer Center
Erlangen–European Metropolitan Region Nuremberg (CCC ER-EMN), Germany. The study was
approved by the Ethics Committee of Friedrich-Alexander-Universität Erlangen-Nürnberg
(FAU) (reference number: 23–169-Br).
The inclusion criteria for the study consisted of age over 18, primary radical local
excision with an R0 resection, no distant metastases, and availability of a complete
histopathological report and follow-up data ([Fig. 1 ]). In the next step, we conducted a separate analysis of patients with local recurrence.
Fig. 1
Flowchart illustrating the patient selection process for the study. The diagram outlines
the steps taken to identify eligible patients from the initial cohort. VSCC: vulvar
squamous cell carcinoma.
Oncology data collection
The database systematically recorded tumor characteristics and various aspects of
surgical treatment, including pathological staging (pTNM), tumor dimensions, histological
type, depth of invasion, tumor margin distance status, presence or absence of lymphovascular
space invasion, and perineural invasion, as well as the presence or absence of premalignant
disease. The type of groin surgery performed and the date of last contact with the
patient or death were also documented. The comprehensive data were extracted from
both hospitals’ internal registries and the registry of the Oncological Center at
ANregiomed Hospital and Erlangen University Hospital/CCC ER-EMN. The data were compiled
in an irreversibly anonymized format and exclusively analyzed using computers in the
respective hospitals.
Classification of pathological margin distance
For analytical purposes, patients were further subclassified into three groups on
the basis of the pathological resection margin distance: 1 to ≤ 3 mm, 3 to ≤ 8 mm,
and > 8 mm. These three groups were selected on the basis of recommendations regarding
the minimum histological margin distance found in the relevant specialist literature.
Although achieving tumor-free margins of at least 8 mm is a long-standing goal, the
evidence for it is sparse. Data suggest that histological margins of 5 mm or even
3 mm represent the minimum necessary to ensure oncological safety and long-term survival
[16 ]
[25 ]. In the present study, all gross specimens were processed in accordance with local
protocols. Resection margin distances were determined on the basis of the smallest
values indicated in the histopathological reports. In the event of
uncertainties, the pathologist conducted a reassessment of the resection margin distance.
The margin refers to the “ultimate” margin after the completion of surgical treatment,
encompassing the thickness of any additional resections performed in the same surgical
session or during a subsequent operation.
Treatment approach
Treatment was carried out in accordance with the guidelines, given that both centers
are certified gynecological facilities. Surgical treatment for vulvar squamous cell
carcinoma consisted either of partial or complete (radical) vulvectomy or of wide
resection of the tumor. Lymph-node staging involved a sentinel lymph-node procedure
for unifocal tumors < 4 cm in size with a depth of invasion > 1 mm, without clinical
evidence of lymph-node metastases. For tumors near the median line (< 1 cm), the sentinel
lymph-node procedure was carried out bilaterally. In cases of tumors > 4 cm with clinically
presumed or pathologically confirmed lymph-node metastases, or a sentinel lymph-node
metastasis before the validation of the sentinel lymph-node procedure in vulvar cancer,
a systematic inguinofemoral lymphadenectomy was conducted. After the surgical procedure,
all of the patients’ cases were discussed in the multidisciplinary tumor board to
explore further therapy
options. None of the patients included in the analysis received neoadjuvant radio(chemo)therapy
or systemic therapy. Adjuvant therapy was administered on the decision of the local
multidisciplinary tumor board.
Statistical analysis
The analyses were conducted using the Prism program, version 9.5.0 (GraphPad Software,
Boston, Massachusetts, USA). In a univariate investigation of factors influencing
survival time, a survival rate was calculated and depicted graphically for each level
of the input variable, using the Kaplan–Meier estimator [30 ]. The trajectories of survival probabilities for different groups were compared using
the log-rank test [31 ]. A significance level of 5% was applied.
A proportional hazards regression model (Cox model) was used to model survival time
[32 ]. In this context, the hazard of individuals (hazard rate) was modeled on the basis
of multiple covariates. The selection of relevant factors was carried out using a
“best-subset selection” approach [33 ] with the Akaike information criterion (AIC) [31 ]. This involved considering all possible subsets of influencing factors and selecting
the subset that provided the best model fit, according to the criterion used. The
analysis was performed using JMP Pro, version 17.0 (JMP Statistical Discovery LLC,
Cary, North Carolina, USA).
Results
Descriptive analysis
Of the 533 patients treated in the two hospitals during the study period, 232 met
the inclusion criteria. Among the patients analyzed, 80 were affiliated with the ANregiomed
Hospital in Ansbach, while 152 were associated with Erlangen University Hospital.
Their overall median age was 69, with patients from ANregiomed Hospital having a notably
higher median age of 74.5 years in comparison with those from Erlangen University
Hospital, where the median age was 67.
Survival analysis
To calculate the survival time in years, the period between the date of surgery and
the date of death (or the end of the study on December 31, 2022) was divided by 365 days.
In total, 82 patients (35.34%) died within a period of up to 10.5 years after surgery.
Notably, a significantly higher percentage of patients at ANregiomed Hospital died
(n = 39, 48.8%), in comparison with Erlangen University Hospital (n = 43, 28.3%).
The mortality rate remained relatively stable during the first 2.5 years after surgery.
Between 2.5 and 4.5 years postoperatively, there was only a modest number of recorded
deaths, followed by a subsequent increase in fatalities from 4.5 years to approximately
7 years after surgery.
Resection margins
The resection margins in the operations ranged from 1 mm to 24 mm, with a mean of
5.6 mm. In the majority of cases, the resection margin was less than 8 mm. However,
there were cases in which patients had considerably higher values, reaching up to
24 mm. The distribution also showed variation between the two hospitals; at ANregiomed
Hospital in Ansbach, the mean resection margin was significantly larger at 7.87 mm
in comparison with Erlangen University Hospital (4.4 mm).
[Table 1 ] shows the distribution of patients across the different resection margin categories.
At Erlangen University Hospital, the resection margin was less than 8 mm in over 80%
of the operations. In contrast, at ANregiomed Hospital, the resection margins in nearly
half of the operations were more than 8 mm.
Table 1
Distribution of patients by resection margin distance (RMD) categories at ANregiomed
Hospital in Ansbach and Erlangen University Hospital. Patients are grouped into three
RMD categories: 1 to ≤ 3 mm, 3 to ≤ 8 mm, and > 8 mm. For each hospital, the table
shows the number of patients (n) and the corresponding percentage (%) relative to
the hospital’s total cohort. The “Total” row combines data from both hospitals, presenting
the total number and percentage of patients in each RMD category across the entire
study population (n = 232).
RMD (mm)
Hospital
Total
Ansbach
Erlangen
n
%
n
%
n
%
Total
80
100
152
100
232
100
1 to ≤ 3 mm
14
16
63
41
77
33
3 to ≤ 8 mm
29
45
64
44
93
44
> 8 mm
37
39
25
15
62
23
Tumor classification
The distribution of tumor classifications before treatment shows that a significant
majority of the patients belonged to a single class for each evaluation criterion.
For instance, 174 patients (69%) had unaffected lymph nodes, and the tumor extension
was classified as T1b in 173 patients (68.7%). All other tumor extensions were relatively
rare, except for T1a, which was observed 48 times (20.69%).
Univariate analysis
In the univariate analysis, the influence of both the resection margin distance and
the tumor assessment criteria (T stage and N stage) on the overall survival time following
surgery was assessed.
Survival time in relation to the resection margin
The estimated survival probabilities showed notable variations across the different
classes ([Fig. 2 ]). The group with a resection margin distance of 1 to ≤ 3 mm was associated with
the highest survival rate. During the initial 4 years, the group with a resection
margin distance of 3 to ≤ 8 mm closely mirrored the outcomes in the group with smaller
resection distances. Nevertheless, a significant rise in fatalities occurred between
the fourth and seventh year post-treatment. The group with a resection margin distance
of > 8 mm consistently showed a lower survival rate throughout the entire period in
comparison with the other cohorts. The log-rank test yielded a p value of 0.0022.
Fig. 2
Estimated survival probabilities based on the Kaplan–Meier method across resection
margin distance categories. The figure depicts the estimated survival probabilities
over time, calculated using the Kaplan–Meier method, and stratified by resection margin
distance categories. The x-axis represents time in years since surgical resection,
while the y-axis shows survival probability, ranging from 0% to 100%. Each curve corresponds
to a specific resection margin category: 1 to ≤ 3 mm, 3 to ≤ 8 mm, > 8 mm.
Survival time in relation to tumor size (T stage)
Noticeable variations in estimated survival probabilities were also apparent across
different groups. The smallest tumor size (T1a) was associated with the highest survival
rate, while the survival probability for the largest (T1b) consistently lagged behind
the reference at all time points. In this category, 61.3% of the patients survived
overall. Although there were only 11 patients, the survival probability associated
with a large tumor size (T2, T3) was significantly lower. The log-rank test indicated
a p value of 0.0001, indicating a statistically significant difference in survival
among the groups.
Due to the very low number of patients with large tumors (T2, T3), the main focus
for the assessment of significant differences lay between groups T1a and T1b. These
specific groups are examined individually in [Fig. 3 ]. Once again, a distinct difference between the two groups was evident. The log-rank
test yielded a p value of 0.0009 in the analysis of these two groups, indicating that
the differences in survival were statistically significant in this case as well.
Fig. 3
Estimated survival probabilities according to the Kaplan–Meier method for tumor stages
T1a and T1b. The figure illustrates the estimated survival probabilities over time
for patients with tumor stages T1a and T1b, calculated using the Kaplan–Meier method.
The x‑axis represents time in years since surgical intervention, while the y‑axis
shows survival probability, ranging from 0% to 100%. The survival curves correspond
to tumor stages T1a and T1b.
The correlation between larger tumor sizes and increased resection margin distances
was also examined. The case numbers for T2 and T3 are limited, but the resection margin
distances in group T1b were significantly larger than those in group T1a.
Survival time in relation to lymph-node involvement (N stage)
Examining lymph-node involvement presented a challenge, due to a substantial imbalance
in the group sizes. Among the patients, 173 (68.7%) did not have any lymph-node issues
(N0), while the remaining individuals were distributed across six distinct classes.
Survival periods were lower among patients with lymph-node involvement in comparison
with those without. In view of the low case numbers in the groups, the subsequent
analysis focused on comparing survival probabilities between patients without lymph-node
involvement and all patients with lymph-node involvement ([Fig. 4 ]). The log-rank test confirmed a statistically significant difference (p < 0.0001).
Fig. 4
Estimated survival probabilities according to the Kaplan–Meier method for patients
with or without lymph-node involvement (N). The figure shows estimated survival probabilities
over time for patients with or without lymph-node involvement (N), calculated using
the Kaplan–Meier method. The x-axis represents time in years since surgical intervention,
and the y-axis shows survival probability (0% to 100%). Survival curves are stratified
by lymph-node involvement: one for patients with lymph-node involvement (N positive)
and one for patients without (N negative).
Multivariate analysis
In the multivariate analysis, the overall survival time was examined in relation to
several influencing factors, including the resection margin distance (RMD), tumor
extension (T), lymph-node involvement (N), depth of invasion, lymphatic vessel invasion
(L), age, and hospital treating the patient. On the basis of the observations from
the univariate analysis, lymph-node involvement (N) was treated as a binary variable
(N > 0). In this context, a value of 0 indicated no lymph-node involvement, while
a value of 1 represented the presence of lymph-node involvement.
The resection margin distance was not further divided into three classes; instead,
the resection margin distance (RMD) in millimeters (mm) was treated as a continuous
variable. In addition, three variables were taken into consideration: lymphatic vessel
invasion (L), depth of invasion, and patient’s age. The correlation between these
variables and survival probability has not previously been investigated.
Modeling survival probability for all patients
Survival probability was initially modeled taking all patients into consideration.
However, due to missing data for 19 patients for the variables of lymphatic vessel
invasion and invasion depth, only 213 of the 232 patients were included in this analysis.
The most influential factors, identified with a best-subset selection approach [33 ] using the AIC criterion [31 ], included age, lymphatic vessel invasion, and resection margin distance in millimeters.
[Table 2 ] shows the parameter estimates from the Cox model and assesses influences using the
Wald test [31 ]. The full model, including all of the factors analyzed (on the right), and the best-subset
selection model (on the left) were compared. In the full model, only two factors —
age and resection margin distance— were deemed significant at the α = 5% level. In
the selected model, lymphatic vessel invasion emerged as significant, with a p value
well below 5%.
Table 2
Assessment of the significance of factors influencing survival time using the Wald
test for both the selected best-subset model (left) and the full Cox model (right),
which considers all potential factors for all patients. The table presents Wald test
statistics and corresponding p values for each variable in both models. Assessed variables
include hospital (Ansbach/Erlangen), age, tumor stage (pT1a vs. pT3, pT1b vs. pT3,
pT2 vs. pT3), lymphatic vessel invasion, depth of invasion, resection margin distance,
and lymph-node involvement. The p values in the “Best-subset selection” column reflect
the selected model, which includes only the most significant factors as determined
by the Akaike Information Criterion (AIC). The p values in the “Cox model” column
are derived from the full model, which incorporates all factors.
Variable
Best-subset selection
Wald test
p
Cox model
Wald test
p
* Lymphatic vessel invasion was not applicable in the full Cox model, due to a strong
correlation with positive lymph-node involvement.
Hospital (Ansbach/Erlangen)
0
0
1.000
0.0493
0.0324
0.857
Age (years)
0.0731
40.73
< 0.001
0.0689
33.6542
< 0.001
pT1a versus pT3
0
0
1.000
−1.6459
2.1907
0.139
pT1b versus pT3
0
0
1.000
−1.2586
1.4702
0.225
pT2 versus pT3
0
0
1.000
−0.8435
0.4998
0.48
Lymphatic vessel invasion
0.736
7.951
0.005
0.5436
3.0530
n/a *
Depth of invasion (cm)
0
0
1.000
0.0731
0.1546
0.694
Resection margin (mm)
0.1124
17.83
< 0.001
0.1077
13.0944
< 0.001
Lymph-node involvement (N-positive)
0
0
1.000
0.2315
0.4877
0.485
The effects of individual variables were interpreted using exponentiated parameter
estimates (hazard ratio) for the three most pivotal factors. All three variables showed
a hazard ratio exceeding 1, indicating an elevated risk of mortality and reduced probability
of survival. The 95% confidence intervals show a range of values providing the level
of confidence for these estimates. Alongside lymphatic vessel invasion, higher age
and larger resection margin distances similarly showed adverse effects on the likelihood
of survival.
Modeling survival probability for patients in Erlangen University Hospital
Survival times only among patients at Erlangen University Hospital were examined here.
In view of the substantial variations between the hospitals, particularly with regard
to resection margin distances and age variables, which markedly affect the modeling
of survival probabilities, further investigation was needed to determine whether similar
effects were observed when focusing solely on a single hospital. In addition, eight
patients had missing data for the variables of lymphatic invasion or depth of invasion.
The analysis was consequently based on the data for only 144 of the 152 patients at
this point.
[Table 3 ] again shows the parameter estimates in the Cox model, encompassing both the model
selected using the procedure described and the comprehensive model incorporating all
covariates. Importantly, this analysis focused solely on patients from Erlangen University
Hospital. The findings indicate a substantial similarity to the broader analysis including
all patients. Age, resection margin in millimeters, and lymphatic invasion retained
a significant influence in the final model. In addition, despite a p value just above
the significance threshold of 5%, the depth of invasion was incorporated in the model
in this instance.
Table 3
Assessment of the significance of factors influencing survival time using the Wald
test for both the selected best-subset model (left) and the full Cox model (right),
which considers all potential factors for patients treated at Erlangen University
Hospital. The table presents Wald test statistics and corresponding p values for each
variable in both models. Assessed variables include age, tumor stage (pT1a vs. pT2,
pT1b vs. pT2), lymphatic vessel invasion, depth of invasion, resection margin distance,
and lymph-node involvement. The p values in the “Best-subset selection” column reflect
the selected model, which includes only the most significant factors as determined
by the Akaike Information Criterion (AIC). The p values in the “Cox model” column
are derived from the full model, which incorporates all factors.
Variable
Best-subset selection
Wald test
p
Cox model
Wald test
p
Age (years)
0.0847
28.03
< 0.001
0.0892
27.45
< 0.001
pT1a versus pT2
0
0
1.000
0.218
0.054
0.816
pT1b versus pT2
0
0
1.000
0.214
0.078
0.781
Lymphatic vessel invasion
0.764
4.603
0.032
0.983
4.944
0.026
Depth of invasion (cm)
0.468
3.462
0.063
0.566
3.963
0.047
Resection margin (mm)
0.1216
5.698
0.017
0.119
4.901
0.027
Lymph-node involvement (N-positive)
0
0
1.000
−0.399
0.801
0.371
All of the variables examined showed a hazard ratio exceeding 1. This implies that
a higher value for each respective covariate led to a lower probability of survival.
The 95% confidence intervals indicate a range of values providing a level of confidence
for these estimates.
Local recurrence
Out of 232 patients analyzed, 43 experienced a local recurrence. Of these, 18 were
from ANregiomed Hospital in Ansbach and 25 from Erlangen University Hospital. [Table 4 ] shows the distribution of patients with local recurrence based on resection margin
distance. In the group with tumor-free margins of 1 to ≤ 3 mm, 37% experienced a local
recurrence, with higher rates at Erlangen (44%) compared to Ansbach (28%). Among those
with margins of 3 to ≤ 8 mm, 44% had a recurrence, with similar rates at both hospitals.
In the group with margins > 8 mm, only 19% developed a recurrence, with lower rates
at Erlangen (12%) compared to Ansbach (28%).
Table 4
Distribution of patients with local recurrence by resection margin distance (RMD)
at ANregiomed Hospital in Ansbach and Erlangen University Hospital. The table categorizes
patients with local recurrence (n = 43) into three RMD groups: 1 to ≤ 3 mm, 3 to ≤ 8 mm,
and > 8 mm, reporting the absolute number (n) and percentage (%) of recurrences for
each hospital. The “Total” row aggregates data from both hospitals.
RMD (mm)
Hospital
Total
Ansbach
Erlangen
n
%
n
%
n
%
Total
18
100
25
100
43
100
1 to ≤ 3 mm
5
28
11
44
16
37
3 to ≤ 8 mm
8
44
11
44
19
44
> 8 mm
5
28
3
12
8
19
Discussion
This study examined a large two-center cohort of patients (n = 232) with primary vulvar
squamous cell carcinoma (VSCC), in order to assess the impact of pathological tumor-free
resection margin distances on the survival outcomes, while identifying additional
prognostic factors influencing overall survival. The data show a consistently lower
survival rate throughout the study period among patients with the largest resection
margin distances (> 8 mm). Conversely, patients with resection margin distances of
1 to ≤ 3 mm had the highest survival rates. The data reveal intriguing nuances that
warrant further discussion.
One interesting observation is related to the interplay among the various influencing
factors. In the univariate analysis, a correlation is seen between tumor size and
resection margin distances. Larger tumors were associated with wider resection margin
distances, probably with an adverse effect on survival. The mean age of patients with
larger tumors (T) was also higher. These associations suggest that the influences
observed may have been partly driven by other correlated variables, potentially explaining
why tumor size (T) was excluded from the final model. Alternatively, older patients
might have often had more advanced disease at the same time of surgery, potentially
necessitating larger resection margins. Several factors could have contributed to
this. Firstly, advanced age was frequently associated with delayed diagnosis, which
could lead to tumors being identified at a more advanced stage. Secondly, older patients
might have experienced different tumor behaviors or
more aggressive forms of cancer, influencing the surgical approach to ensure complete
tumor removal and minimize the risk of local recurrence. Additionally, the presence
of two distinct molecular subtypes of vulvar cancer – HPV-positive and HPV-negative
– could also have played a significant role. The HPV-related subtype, which is often
located in the anterior vulva near the clitoris and urethra, generally requires lower
resection margins [8 ].
In the multivariate analysis, age, lymphatic vessel invasion, and resection margin
distance (measured in millimeters) emerged as the most influential factors affecting
overall survival.
To date, only a limited number of studies have investigated the impact of the tumor-free
resection margin distance on survival in patients with VSCC. Woelber et al. analyzed
a much smaller cohort of 102 VSCC patients and suggested that the resection margin
did not have a significant influence on disease-free survival, after categorizing
the patients into three groups (< 3 mm, ≥ 3–8 mm, and ≥ 8 mm) [34 ]. However, the median follow-up period in the cohort analyzed was only 31 months
[34 ]. Raimond et al., who also separated the patients into three groups (< 3 mm, ≥ 3–8 mm,
and ≥ 8 mm) analyzed 112 VSCC patients and did not observe any significant effect
of the tumor-free resection margin distance on disease-free survival or overall survival
[19 ]. However, as in
the study by Woelber et al., the median follow-up in the cohort analyzed was only
25 months [19 ]. Micheletti et al. studied 114 patients with FIGO stages IB/II VSCC and postulated
that a histological margin of 5 mm is the minimum distance required to ensure oncological
safety and long-term survival in patients with lymph node-negative FIGO stage IB/II
VSCC. The cohort was divided into groups according to the size of the tumor-free histological
margin (< 5 mm and ≥ 5 mm, and later < 8 mm and ≥ 8 mm) to compare survival outcomes.
The median follow-up period was 80 months [16 ]. Taran et al. assigned 128 patients with node-negative VSCC, who were treated with
surgery alone and did not receive any adjuvant treatment, to three groups (1–3 mm,
> 3 to 8 mm, and > 8 mm) and did not observe a significant effect of the pathologically
tumor-free resection margin on disease-free or overall survival [35 ]. The median follow-up period for disease-free survival was 6.39 years, and for overall
survival 6.29 years [35 ].
Against the background of the continuing discussion regarding the optimal tumor-free
margin distance, the present study reassessed the significance of the pathological
resection margin size on overall survival in a much larger cohort with a longer follow-up
period. The most influential factors in the two-center cohort were identified. In
contrast to other studies that similarly categorized patients into three groups (1
to ≤ 3 mm, 3 to ≤ 8 mm, and > 8 mm), the present analysis of the estimated survival
probabilities found significant variations between the different resection margin
classes (p = 0.0022) [19 ]
[34 ]
[35 ]. The cohort with a resection margin distance of 1 to ≤ 3 mm was associated with
the longest overall survival, while the cohort with the widest
resection margin (> 8 mm) consistently had a lower survival rate throughout the entire
period.
In the multivariate analysis, a pronounced correlation of r = 0.53 emerged between
lymphatic vessel invasion (L) and lymph-node involvement (N). This close association
posed a challenge for pinpointing which of the two variables truly accounted for the
variations in survival probabilities. Despite this complexity, the study addressed
the issue by prioritizing lymphatic vessel invasion (L) as a more informative variable,
contributing to an enhanced model quality.
The significant disparities in age and resection margin distance between the ANregiomed
Hospital in Ansbach and Erlangen University Hospital prompted further discussion.
In the ANregiomed Hospital, the median age of the patients (74.5 years) and the mean
resection margin size (7.87 mm) were notably higher. These differences may have contributed
to the higher proportion of deceased patients. These variations highlighted the importance
of considering hospital-specific characteristics when interpreting the results. It
was crucial to determine whether the outcomes reflected inherent differences in the
patient population or hospital-specific practices.
To provide a comprehensive understanding of the variations observed, the analysis
was bifurcated: firstly for all patients, and then specifically for those from Erlangen
University Hospital. The aim was to discern whether potential influences were exclusively
tied to the distinctions between the two hospitals. Conducting separate analyses was
intended to ascertain whether any trends or outcomes that were observed were driven
primarily by hospital-specific factors rather than universal factors affecting all
patients.
The survival probability modeling in all VSCC patients identified three significant
influencing factors: age, lymphatic vessel invasion (L), and resection margin distance.
While age and lymphatic vessel invasion remained constant, the resection margin distance
could be influenced by the operating surgeon and was integral to active therapy planning.
These findings are consistent with observations in the study by Micheletti et al.,
which concluded that the highest long-term survival was observed in lymph node–negative
patients [16 ].
The modeling of survival probability was then specifically conducted for the patients
in Erlangen University Hospital. The results not only reinforced the consistency of
the overall dataset, but also confirmed the identification of age, lymphatic vessel
invasion, and resection margin distance (in millimeters) as primary determinants of
overall survival. These insights showed remarkable consistency in the influences across
different patient cohorts, emphasizing the relevance of these factors for the prognosis.
Our analysis of local recurrence data supported our earlier findings. Specifically,
smaller tumors with resection margins of 1 to ≤ 3 mm were associated with a lower
risk of local recurrence. Conversely, larger tumors treated with resection margins
greater than 8 mm also showed a reduced risk of recurrence. However, the group with
resection margins of 3 to ≤ 8 mm presented a more complex scenario. The optimal margin
distance for minimizing recurrence risk in this range was less clear-cut. The variability
in recurrence rates within this group suggested that a one-size-fits-all approach
might not be effective. Instead, individualized treatment strategies that considered
both tumor size and margin distance seemed necessary to optimize patient outcomes.
The study has several limitations. It was a retrospective analysis of patients who
underwent primary surgical treatment for VSCC at ANregiomed Hospital in Ansbach and
Erlangen University Hospital over a 13-year period. During this period, the surgical
management of VSCC evolved, mainly through the dissemination of the sentinel-node
procedure. Although VSCC is a disease mostly affecting older patients, information
on the cancer-specific mortality rate was not available. The strengths of the study
include the large, comprehensive cohort of patients with VSCC and the long follow-up
period.
Conclusion
The study underlines the importance of tumor-free margin distance as a prognostic
factor for survival in patients with VSCC. Patients with tumor-free margins exceeding
8 mm had notably higher mortality rates. This was likely due to the observed correlation
between resection margin distances, tumor sizes, and age, where larger resection margins
often signified more advanced disease and older age, both of which are linked to a
poorer prognosis. Smaller resection margins did not indicate worse or reduced survival
outcomes. Therefore, for smaller tumors and younger patients, resection with smaller
margins was deemed appropriate, provided that healthy margins were ensured.
Tumor-free margin distance and age, along with lymphatic vessel invasion as the primary
prognostic factor, played pivotal roles in predicting overall survival. Awareness
of these key determining factors allowed a more informed and nuanced approach to treatment
strategies, especially in order to customize surgical interventions to individual
patients’ characteristics. It may be useful to consider a more tailored surgical approach,
with the aim of minimizing morbidity and preserving both function and sensitive areas
on the vulva.
Financial Support
This study received no specific financial support from funding agencies in the public,
commercial, or non-profit sectors.
