21
Članek prispel / Received
15. 8. 2020
Članek sprejet / Accepted
11.03.2021
Abstract
Purpose: Vulvar cancer is one of the 
rarest forms of cancer. Vulvar cancer 
represents 3%–7% of all gynecologic 
cancers. Eighty percent of patients with 
vulvar cancer are > 60 years of age. The 
purpose of the current study was to eva-
luate the characteristics of patients with 
vulvar cancer, analyze the epidemiology, 
and describe the clinical characteristics, 
treatment modalities, and factors that in-
fluence the development of vulvar cancer.
Methods: This retrospective study in-
cluded patients treated at the University 
Medical Centre Maribor for vulvar can-
cer between 1994 and 2017. Patient de-
Izvleček
Namen: Rak zunanjega spolovila je 
ena najredkejših oblik raka. Predstavlja 
3–7 % vseh rakov rodil. Osemdeset od-
stotkov žensk, ki zbolijo, je starejših od 
60 let. Namen raziskave je bil oceniti 
značilnosti bolnic z rakom zunanjega 
spolovila, analizirati epidemiologijo, 
opisati klinične značilnosti, načine zdra-
vljenja in dejavnike, ki vplivajo na ra-
zvoj raka zunanjega spolovila.
Metode: Retrospektivna raziskava je 
zajela bolnice, ki smo jih obravnavali v 
Univerzitetnem kliničnem centru Mari-
bor zaradi raka zunanjega spolovila v 
obdobju od leta 1994 do 2017. Zbrali 
Ključne besede: 
rak zunanjega spolovila, 
epidemiologija, histologija, HPV
Key words: 
vulvar cancer, epidemiology, 
histology, HPV
Klinično-patološke značilnosti pacientk z rakom 
zunanjega spolovila, zdravljenih v obdobju od 1994 
do 2017 v Univerzitetnem kliničnem centru Maribor
Clinicopathologic characteristics of patients with 
vulvar cancer treated between 1994 and 2017 at the 
University Medical Centre Maribor
Avtor / Author Vida Gavrić Lovrec1,2, Nejc Kozar1,2, Iztok Takač1,2, Špela Stangler 
Herodež3,4
Ustanova / Institute 1Univerzitetni klinični center Maribor, Klinika za ginekologijo in perinatologijo, Maribor, 
Slovenija; 2Univerza v Mariboru, Medicinska fakulteta, Katedra za ginekologijo, Maribor, 
Slovenija; 3Univerzitetni klinični center Maribor, Klinika za ginekologijo in perinatologijo, 
Laboratorij za medicinsko genetiko, Maribor, Slovenija; 4Univerza v Mariboru, Medicinska 
fakulteta, Katedra za molekularno biologijo, Maribor, Slovenija.
1University Medical Centre Maribor, Division of Gynecology and Perinatology, Maribor, 
Slovenia; 2University of Maribor, Faculty of Medicine, Department of Gynecology, Maribor, 
Slovenia; 3University Medical Centre Maribor, Division of Gynecology and Perinatology, 
Medical Genetics Laboratory, Maribor, Slovenia; 4University of Maribor, Faculty of 
Medicine, Department of Molecular Biology, Maribor, Slovenia.
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2021; 14 (1): 25–37
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INTRODUCTION
Vulvar cancer is a rare malignancy and represents 
3%–7% of gynecologic cancers (1–3). The number 
of newly diagnosed cases in Slovenia per year from 
2010-2014 was 44 [4.2/100.000] (1). Vulvar cancer 
most often affects women > 70 years of age (2). 
Over the past few decades, the incidence of vulvar 
intraepithelial neoplasia (VIN) and invasive vulvar 
cancer (IVC) has increased in European countries and 
worldwide, particularly among younger women (2–6). 
An increased incidence of VIN and IVC was evident 
in Slovenia in 2003, which coincided with the launch 
of the Slovenian cervical cancer screening program 
and registry [ZORA] (1). 
Squamous cell carcinoma (SCC) accounts for > 90% 
of malignant vulvar tumors. Basaloid and warty 
variants associated with the regular type of VIN are 
more common in younger women and are associated 
with human papilloma virus (HPV) infection (7). HPV 
16 and 18 are the most frequently reported genotypes 
that induce these lesions (8). In contrast, keratinizing 
Naslov za dopisovanje /  
Correspondence
Dr. Vida Gavrić Lovrec, dr. med., 
Univerzitetni klinični center Maribor, 
Klinika za ginekologijo in perinatologijo, 
Ljubljanska ul. 5, 2000 Maribor, 
Slovenija.
Telefon: +386 23212435
Faks: +386 23212085 
E-pošta: vida.ga.lo.1@gmail.com
smo podatke, ki so se nanašali na demo-
grafske značilnosti, značilnosti bolezni, 
klinične značilnosti, histopatološke ka-
rakteristike ter način zdravljenja. Po-
datke smo statistično obdelali in ocenili 
povezavo med različnimi demografskimi 
značilnostmi, tumorskimi karakteristika-
mi, zdravljenjem in dejavniki tveganja.
Rezultati: Zbrali smo podatke 124 
bolnic, ki so bile stare od 22 do 92 let. 
Povprečna starost bolnic je bila 71 let. 
Prepoznali smo 6 različnih vrst tumor-
jev, med katerimi je bil ploščatocelični 
karcinom najpogosteje zabeležen histolo-
ški tip raka. Pri 45 bolnicah je bil od-
vzet bris za testiranje na okužbo z viru-
som HPV. Okužbo s HPV smo odkrili 
pri 71 % (32/45) testiranih bolnic.
Zaklju~ek: Ugotovili smo, da je pri 
bolnicah, zdravljenih zaradi raka zu-
nanjega spolovila v UKC Maribor, 
najpogostejša oblika raka ploščatocelič-
ni karcinom. Eden izmed dejavnikov 
tveganja za raka zunanjega spolovila je 
nedvomno tudi okužba z virusom HPV. 
HPV 16 je bil najpogosteje diagnostici-
ran tip HPV med našimi bolnicami. Za 
celovitejše in reprezentativnejše zaključ-
ke bi bilo potrebno vključiti še bolnice iz 
drugih predelov Slovenije.
mographics, disease characteristics, clini-
cal features, histologic findings, and type 
of therapy were recorded. Associations 
among various demographic factors, tu-
mor characteristics, treatments, and risk 
factors of vulvar cancer were evaluated.
Results: We collected data from 124 
patients between 22 and 92 years of 
age. The average age of the patients 
was 71 years. Six different tumor types 
were identified, of which the most com-
mon histologic type of vulvar cancer 
was squamous cell carcinoma. Forty-fi-
ve patients were tested for the presence 
of HPV types, which was confirmed in 
71% (32/45) of the tested patients.
Conclusion: Squamous cell carci-
noma was the most common form of 
vulvar cancer in patients treated at the 
University Medical Centre Maribor. 
Undoubtedly, one of the risk factors for 
vulvar cancer is HPV infection. HPV 
16 was the most frequently diagnosed 
HPV type in our patients. For more 
comprehensive and more representative 
conclusions, data from other medical 
centers in Slovenia should be included.
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variants arising from chronic vulvar dermatosis, such 
as lichen sclerosus, are associated with differentiated 
VIN, but not HPV, and generally affect older women 
(7). It is important to note, however, that all women 
with oncogenic HPV do not develop vulvar cancer. 
Therefore, additional factors, such as lifestyle data 
and decreased immune function, might be important 
risk factors (8).
Although the incidence of vulvar cancer is low, it is an 
important disease with an impact on women's health 
and quality of life that should not be underestimated. 
No retrospective studies have been conducted in 
Slovenian patients with vulvar cancer to date. As the 
second largest tertiary center in Slovenia, our patients 
receive primary surgical treatment in the Department 
of Gynecologic and Breast Oncology of University 
Medical Centre Maribor and are referred to the 
Institute of Oncology Ljubljana for radiotherapy and/
or chemotherapy, if required. 
The aim of this study was to review vulvar cancers 
recorded in our tertiary center over a 24-year period 
(1994–2017) to document the vulvar cancer status in 
the population of northeastern Slovenia.
PATIENTS AND METHODS 
This retrospective study included 124 patients from 
northeastern Slovenia treated in the Division of 
Gynecology and Perinatology of University Medical 
Centre Maribor for vulvar cancer from January 1994 
to December 2017. The study 
included all cases of vulvar 
cancer histologically-confirmed 
by biopsy or excised tissue 
specimens. Demographic data, 
medical histories, and cancer 
treatment data were collected 
using pre-defined written forms 
digitalized by custom Microsoft 
Access databases. IBM SPSS 
Statistics (version 21) was used 
for statistical evaluation. 
Due to the retrospective nature of 
this study, approval by the Ethics 
Committee was not required.
RESULTS
A total of 124 patients diagnosed with vulvar cancer 
between 1994 and 2017 were identified. The highest 
number of patients treated per year at UKC Maribor 
was between 2015 and 2017 (n=24; Figure 1). Time-
series analysis using Holt’s trend method showed a 
trend toward an increased incidence from 2003.
Patients ranged in age from 22–92 years (median age, 
71 years), with the majority between 72 and 81 years 
(Figure 2). The medical histories of 20 patients were 
significant for a previous malignancy. Only 17 patients 
(14%) had no co-morbidities. Co-morbidity data 
were obtained from the patient histories and medical 
records. The most common co-morbidities among 
patients with vulvar cancer were arterial hypertension 
(36%), diabetes mellitus (15%), and obesity (8%).
Patients usually presented with a lesion (46%), pain 
(28%), vaginal discharge (27%), and pruritus (27%). 
Other symptoms were less frequent (Figure 3).
The most frequently diagnosed histologic type of vulvar 
tumor was SCC (88.7%), followed by basocellular 
carcinoma (4%) and non-defined carcinoma (3.2%). 
The remaining 4% of patients had rare histologic 
types, including adenocarcinoma of cylindrical cells, 
malignant melanoma, and endodermal sinus tumor. 
The stage of vulvar cancer was assessed according to 
the 2009 International Federation of Gynecology and 
Obstetrics (FIGO) stage classification system (Figure 
4). Cases diagnosed prior to the new classification 
were translated into the 2009 FIGO stage classification 
 
 
19. Virgili A, Borghi A, Cazzaniga S, Di Landro A, Naldi L, Minghetti S et al. New insight into 
potential risk factors and associations i  genit l lich n scler sus: data fr m a multicenter 
Italian study on 729 consecutive cases. J Eur Dermatol Venereol 2017; 31(4): 699-704. 
 
 
 
Figure 1: Yearly occurrence of vulvar cancer between 1994 and 2017 at UKC Maribor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 20170
24
68
1012
1416
Year
Number
 of cases
 (N)
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 20170
24
68
1012
1416
Year
Number
 of cases
 (N)
19
94
19
95
19
96
19
97
19
98
19
99
20
00
20
01
20
02
20
03
20
04
20
05
20
06
20
07
20
08
20
09
20
10
20
11
20
12
20
13
20
14
20
15
20
16
20
17
0
2
4
6
8
10
12
14
16
Year
N
um
be
r o
f c
as
es
 (N
)
Figure 1. Yearly occurrence of vulvar cancer between 1994 and 2017 
at UKC Maribor.
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system using the clinical parameters in our database.
HPV testing was performed in 45 patients. Thirteen 
patients were HPV-negative (29%), while the remaining 
patients tested positive for one or more HPV types. The 
most common type was HPV 16, followed by HPV 18, 
31, and 33 (Table 1). 
Surgical treatment, including wide local excision and 
inguinofemoral lymphadenectomy or sentinel node 
biopsy, were the most common primary treatment 
modalities performed in 86% of the patients. The initial 
treatment was primary radiotherapy 
in 5% of the patients and the 
initial treatment was a combination 
of primary radiotherapy and 
chemotherapy in 2% of the patients. 
The initial surgical treatment was 
followed by adjuvant radiotherapy 
or a combination of radiotherapy 
and chemotherapy in 7% of the 
patients.
DISCUSSION
The current study is the first 
retrospective analysis to address 
the epidemiologic, clinical, and 
pathologic characteristics of patients 
with vulvar cancer treated in a 
single clinical center in Slovenia. 
The epidemiologic characteristics 
of the patients in this study were 
consistent with recent international 
data, which usually involve 
postmenopausal women with an 
age range of 65–70 years (8). The 
average age in our population was 
slightly higher (71 years). Figure 1 
shows a tendency toward a growing 
number of cases diagnosed per year 
from 2003, which was confirmed 
using the Holt’s trend method. 
This observation is in agreement 
with previously published data and 
was attributed to the increasing 
incidence of vulvar cancer to the 
implementation of ZORA, the Slovenian cervical 
cancer screening program and registry (1).  
In most cases, genital cancer is a lesion accompanied by 
symptoms, such as pruritus, bleeding, discharge, and pain, 
which was also confirmed in our study population (9). 
A typical distribution by histologic type of cancer was 
depicted in a retrospective study conducted in the 
Netherlands based on cancer registry data of 5680 
women, as follows: 81% of cases were SCCs; 8% 
were basal cell carcinomas; 6% were melanomas; and 
 
 
 
 
Figure 2: Age distribution of patients with vulvar cancer at UKC Maribor between 1994 and 2017.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2. Age distribution of patients with vulvar cancer at UKC 
Maribor between 1994 and 2017.
 
 
 
 
Figure 3: Presenting symptoms in patients with vulvar cancer. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3. Presenting symptoms in patients with vulvar cancer.
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5% were other types of cancer 
(10). Like other studies, we also 
confirmed that vulvar SCC was 
the most common histologic type 
of vulvar cancer (confirmed in 
88.7% of our patients). In contrast, 
vulvar melanoma, which has been 
reported to be the second most 
common neoplasm of the vulva, 
occurred in only 1.6% of our study 
patients (10).
Because the most common 
symptoms of vulvar cancer are 
lesions in 46% of patients, pain in 
28%, and discharge and pruritus 
in 27%, vulvar cancer is usually 
diagnosed in an early stage when 
the cancer is still confined to the 
primary site. According to the 
Netherlands Cancer Registry, 
patients are most often diagnosed 
at an early stage [59% in stages I 
and II] (11). The Cancer Registry of 
the Republic of Slovenia reported 
58 new cases of vaginal cancer in 
2017 (12). Cancer was diagnosed 
at a localized stage in 26 women 
(44.8%), while in 29 patients 
(50.0%) the tumor growth was 
regional (12). In the current study, 
63% of patients were classified in 
the first two stages according to the 
FIGO stage classification system. 
HPV is involved in one of at least 
two pathways leading to vulvar SCC: HPV-associated; 
and HPV-independent (13). According to del Pino 
(13), these two types of vulvar SCC have different 
epidemiologic, pathologic, and clinical characteristics, 
and should therefore be considered two separate entities. 
Rakislova et al. (14) stated that the percentage of HPV-
positive vulvar SCCs range from 18%–75% depending 
on the geographic area. HPV-associated tumors affect 
relatively young women and arise from high-grade 
intraepithelial lesions that are identical to other HPV-
associated pre-malignant lesions of the anogenital 
region. HPV-positive tumors tend to be of the basaloid 
(prevalence of HPV = 84%) or warty types (prevalence 
of HPV = 76.5%), whereas HPV-independent tumors 
tend to be the keratinizing type (prevalence of HPV = 
13.8%); however, there is a frequent overlap between 
these histologic types (15). The prognostic role of HPV 
in vulvar SCC is still a matter of debate; however, 
increasing evidence suggests that HPV-associated 
tumors are less aggressive (14). A large meta-analysis by 
Faber et al. (16) included > 5000 vulvar cancer patients; 
the prevalence of HPV was 39.7%. Our HPV-tested 
patients had a higher percentage of positive results. 
Table 1. HPV type distribution in 45 vulvar cancer specimens tested for HPV
HPV type N (45) %
No HPV infection 13 29
Single HPV infection 2 4.4
HPV16 2 4.4
HPV18 0 0
HPV31 0 0
HPV33 0 0
Multiple HPV infection 30 66.6
HPV16&HPV18 16 53
HPV16&HPV18&HPV31 0 0
HPV16&HPV18&HPV31&HPV33 14 47
 
 
 
 
Figure 4: FIGO stage classification of vulvar cancer diagnosed between 1994 and 2017 at UKC 
Maribor. 
 
 
 
Table 1: HPV type distribution in 45 vulvar cancer specimens tested for HPV  
HP   N (45) % 
No HPV infection 13 29 
Single HPV infection 2 4.4 
HPV16 2 4.4 
HPV18 0 0 
HPV31 0 0 
HPV33 0 0 
Multiple HPV infection 30 66.6 
HPV16&HPV18 16 53 
HPV16&HPV18&HPV31 0 0 
HPV16&HPV18&HPV31&HPV33 14 47 
 
Figure 4. FIGO stage classification of vulvar cancer diagnosed between 
1994 and 2017 at UKC Maribor.
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Among HPV-positive cases, the predominant high-risk 
HPV type was 16, followed by 33 and 18, once again 
demonstrating geographic heterogeneity. In a recent 
Austrian study, 23% of vulvar cancers tested positive 
for HPV DNA, and HPV 16 was present in 76%, 
followed by HPV 31 and HPV 33 (17). HPV 16 also 
had the highest prevalence in our population, followed 
by HPV 18. 
Lichen sclerosus is a chronic inflammatory disease that 
has traditionally been considered a pre-cancerous lesion, 
although malignant transformation is observed in only 
4%–6% of patients (18). Lichen sclerosus is a frequent 
finding in the skin adjacent to HPV-independent 
vulvar SCC; however, the mechanisms involved in the 
pathogenetic pathway from lichen sclerosus to cancer 
have not been elucidated (13, 18). Hypertension, 
hypothyroidism, and type II diabetes mellitus are more 
frequent in the Italian population with lichen sclerosus 
than among the general population. (19). These 
findings led Virgili et al. (19) to conclude that metabolic 
factors and lifestyle have key roles in the pathogenesis of 
genital lichen sclerosus among genetically-predisposed 
patients. Of note, some co-morbidities in the Virgili et 
al. (19) study were the most common co-morbidities in 
our vulvar cancer patients.
The gold standard for surgical treatment of vulvar 
carcinoma was previously a radical vulvectomy followed 
by en bloc resection of the inguinal, and sometimes, 
pelvic lymph nodes. Today, a more individualized 
and less radical approach is preferred, including wide 
excision and inguinofemoral lymphadenectomy or 
sentinel node biopsy. Operative treatment is preferred 
whenever feasible (stages I and II, locally advanced 
disease [stages III and IVA]), otherwise primary 
chemoradiation is recommended (10). Surgical 
treatment was feasible in 93% of our patients with 
vulvar carcinoma. Decisions about adjuvant treatment 
were based on the findings at the time of surgery, and 
was necessary in 7% of our patients.
CONCLUSIONS
Vulvar cancer most often affects older women; however, 
the incidence is on the rise across all age groups. Early 
detection and histologic examination of any suspicious 
lesion is required for early diagnosis and successful 
treatment. 
Because a high percentage of vulvar cancers is related 
to HPV infection, vulvar cancer may be prevented by 
prophylactic HPV vaccination. Although HPV 16 
accounts for the majority of cases, other HPV types 
play an important role in the development of HPV-
associated disease. Therefore, vaccines should cover 
a wide range of genotypes to reduce the incidence of 
vulvar pre-cancerous lesions and vulvar cancer. 
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