Vulva R Cancer

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Vulvar cancer: a review for dermatologists
Article in Wiener Medizinische Wochenschrift · April 2015

DOI: 10.1007/s10354-015-0354-9
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Re: Wiener Medizinische Wochenschrift (10.1007/s10354-015-0354-9)

Anastasiya Atanasova Chokoeva

Georgi Tchernev
Elena Castelli
Elisabetta Orlando
Shyam B. Verma
Markus Grebe
Uwe Wollina
I have checked the proofs of my article and
❑ I have no corrections. The article is ready to be published without changes.

❑ I have a few corrections. I am enclosing the following pages:
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Metadata of the article that will be visualized online
Article Title Vulvar cancer: a review for dermatologists
Article CopyRight - Year Springer-Verlag Wien 2015
Journal Name Wiener Medizinische Wochenschrift
Corresponding Author Family name Wollina

Particle
Given name Uwe
Suffix
Division Department of Dermatology and Allergology
Organization Academic Teaching Hospital Dresden-Friedrichstadt
Address Friedrichstrasse 41, 01067 Dresden, Germany
email wollina-uw@khdf.de
Author Family name Chokoeva
Particle
Given name Anastasiya Atanasova
Suffix
Division
Organization Onkoderma - Policlinic for Dermatology and Dermatologic Surgery
Address General Skobelev Nr 26, 1407 Sofia, Bulgaria
email assia_chokoeva@abv.bg
Author Family name Tchernev
Particle
Given name Georgi
Suffix
Division Medical Faculty
Organization University Hospital Lozenetz, Policlinic for Dermatology and
Venerology, Saint Kliment Ohridski University
Address Koziak street 1, 1407 Sofia, Bulgaria
email georgi_tchernev@yahoo.de
Author Family name Castelli
Particle
Given name Elena
Suffix
Division Department of Biomedicine, Internal Medicine,and Specialized
Medicin (DIBIMIS), Section Dermatology
Organization University of Palermo/AOUP Paolo Giaccone
Address Via del Vespro 131, 90127 Palermo, PR, Italy
email elena.castelli@unipa.it
Author Family name Orlando
Particle
Given name Elisabetta
Suffix
Division Department of Sciences for Health Promotion and Mother and Child
Care “Giuseppe D’Alessandro” – Section of Pathology
Organization AOUP Paolo Giaccone
Address Via del vespro 129, 90127 Palermo, PR, Italy
email orlabetta@tiscali.it
Author Family name Verma
Particle
Given name Shyam B.
Suffix
Author's Proof
Division
Organization
Address 18 Amee Society, Near Rajnigandha Apartments, Diwalipura, 390
015 Vadodara, Gujarat, India
email skindiaverma@gmail.com
Author Family name Grebe
Particle
Given name Markus
Suffix
Division Department of Gynecology
Organization Academic Teaching Hospital Dresden-Friedrichstadt
Address Friedrichstrasse 41, 01067 Dresden, Germany
email grebe-ma@khdf.de
Schedule Received 18 March 2015
Revised
Accepted 7 April 2015
Summary Vulvar malignancies are important tumors of the female reproductive
system. They represent a serious health issue with an incidence
between 2 and 7 per 100,000 and year. We provide a review about
most important cancer entities, i.e., melanoma, squamous cell
carcinoma, basal cell carcinoma, neuroendocrine cancer, and skin
adnexal malignancies.
Squamous cell carcinoma is the most common vulvar malignancy
that can develop from vulvar intraepithelial neoplasia or de novo.
Basal cell carcinoma represents only 2 % of all vulvar cancers.
Melanoma of the vulva exists in two major types—superficial
spreading and acral lentiginous. A special feature is the occurrence
of multiple vulvar melanomas. Of the adnexal cancer types Paget’s
disease and carcinoma are seen more frequently than other adnexal
malignancies. The dermatologist should be aware of this problem,
since he might be the first to be consulted by patients for vulvar
disease. Treatment should be interdisciplinary in close association to
gynecologists, oncologists, and radiologists.
Keywords Vulva - Squamous cell carcinoma - Basal cell carcinoma - Melanoma
- Paget’s disease - Adnexal carcinomas
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Wien Med Wochenschr

DOI 10.1007/s10354-015-0354-9
F
O
Anastasiya Atanasova Chokoeva · Georgi Tchernev · Elena Castelli ·
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Elisabetta Orlando · Shyam B. Verma · Markus Grebe · Uwe Wollina
PR
Received: 18 March 2015 / Accepted: 7 April 2015
D
© Springer-Verlag Wien 2015
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43 Summary Vulvar malignancies are important tumors of acral lentiginous. A special feature is the occurrence of 55
44 the female reproductive system. They represent a seri- multiple vulvar melanomas. Of the adnexal cancer types 56
45 ous health issue with an incidence between 2 and 7 per Paget’s disease and carcinoma are seen more frequently 57
46 100,000 and year. We provide a review about most impor- than other adnexal malignancies. The dermatologist 58
47 tant cancer entities, i.e., melanoma, squamous cell carci- should be aware of this problem, since he might be the 59
EC
48 noma, basal cell carcinoma, neuroendocrine cancer, and first to be consulted by patients for vulvar disease. Treat- 60
49 skin adnexal malignancies. ment should be interdisciplinary in close association to 61
50 Squamous cell carcinoma is the most common vulvar gynecologists, oncologists, and radiologists. 62
51 malignancy that can develop from vulvar intraepithelial
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52 neoplasia or de novo. Basal cell carcinoma represents Keywords Vulva · Squamous cell carcinoma · Basal cell 63
53 only 2 % of all vulvar cancers. Melanoma of the vulva carcinoma · Melanoma · Paget’s disease · Adnexal car- 64
54 exists in two major types—superficial spreading and cinomas 65
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Prof U. Wollina, MD () E. Orlando, MD
Department of Dermatology and Allergology, Academic Teaching Department of Sciences for Health Promotion and Mother and
Hospital Dresden-Friedrichstadt, Child Care “Giuseppe D’Alessandro” – Section of Pathology, AOUP
Friedrichstrasse 41, Paolo Giaccone,
01067 Dresden, Germany Via del vespro 129,
N
e-mail: wollina-uw@khdf.de 90127 Palermo, PR, Italy

e-mail: orlabetta@tiscali.it
A. A. Chokoeva, MD
Onkoderma - Policlinic for Dermatology and Dermatologic S. B. Verma, MBBS, DV & D
U
Surgery, 18 Amee Society, Near Rajnigandha Apartments, Diwalipura,

General Skobelev Nr 26, Vadodara Gujarat, 390 015, India
1407 Sofia, Bulgaria e-mail: skindiaverma@gmail.com
e-mail: assia_chokoeva@abv.bg
M. Grebe, MD
Prof G. Tchernev, MD Department of Gynecology, Academic Teaching Hospital Dresden-
Medical Faculty, University Hospital Lozenetz, Policlinic for Friedrichstadt,
Dermatology and Venerology, Saint Kliment Ohridski University, Friedrichstrasse 41,
Koziak street 1, 01067 Dresden, Germany
1407 Sofia, Bulgaria e-mail: grebe-ma@khdf.de
e-mail: georgi_tchernev@yahoo.de
E. Castelli, MD
Department of Biomedicine, Internal Medicine,and Specialized
Medicin (DIBIMIS), Section Dermatology,
University of Palermo/AOUP Paolo Giaccone,
Via del Vespro 131,
90127 Palermo, PR, Italy
e-mail: elena.castelli@unipa.it
13 Vulvar cancer: a review for dermatologists 1

Dictionary: English-US
JournalID:10354 ArticleID:354 Dispatch Date:16/04/2015 ProofNo: 1
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66 Introduction more numerous and dilated vessels. In addition, it lacks 121

adnexal structures, except for a few sebaceous glands, 122
AQ1
67 Malignant tumors of the female reproductive system are a whose ducts open directly on its surface and for the pres- 123
AQ2
68 serious health issue as they are the second cause of death ence of mammary-like glands, small skin appendages 124
69 among women, after breast cancer [1]. Their incidence with the structure of mammary lobules, mainly located 125
F
70 has increased dramatically during the past few years, with at the interlabial sulci. In contrast to labia major labia 126
71 significant variability in different geographic areas, reach- minora are missing subcutaneous adipose tissue. The 127
ing close to 32 % in Africa and 13 % in North America [1, 2] vestibule, the central portion of the vulva that contains
O
72 128
73 This is likely due to differences in socioeconomic status of the urethral meatus and the vaginal introitus, presents 129
74 the countries, health care, and the integration of screen- a mucosal layer lined by a nonkeratinizing squamous 130
O
75 ing programs, sexual habits, and the degree of HIV/AIDS epithelium that lies on a loose connective tissue. The 131
76 and human papilloma virus (HPV) carriers [1, 3]. epithelium lacks a granular and a horny layer and is char- 132
77 Vulvar tumors constitute only 4 % of all gynecologi- acterized by large suprabasal keratinocytes with a clear, 133
PR
78 cal neoplasms [3]. The overall incidence of the tumors glycogen-laden cytoplasm, positive to the periodic acid- 134
79 with vulvar location is between 2 and 7 cases per 100,000 Schiff stain [6]. Blood supply derives mainly from puden- 135
80 women, but it increases with age [2, 4]. Changes of clas- dal arteries and drainage occurs via internal pudendal 136
81 sification of disease also influence their incidence as for veins. Lymphatic drainage goes to inguinal lymph nodes 137
82 instance in vulvar intraepithelial neoplasia (VIN), whose and from the clitoris to iliac lymph nodes. Nerve supply 138
D
83 incidence has increased dramatically since 1970 [3, 4]. In originates from different sources including ilioinguinal 139
AQ3
84 US National Cancer Institute, vulvar carcinoma is among and genitofemoral nerves, branches from the pudendal 140
85 the 12 malignant tumors, whose incidence has increased and lateral femoral nerve of the thigh [6]. 141
TE
86 rapidly in the last few years [1]. Incidence of both carci-
87 noma of the vulva and VIN is increasing on average by
88 2.4 % every year. The mortality rate in Germany has been Malignant melanoma of the vulva (MM) 142
89 estimated as 0.8 per 100,000 women for 2010 [2].
EC
90 The most common vulvar cancer is squamous cell Pigmented vulvar lesions occur in up to 12 % of women. 143
91 carcinoma (SCC) (90 %) followed by malignant mela- Most are benign nevi, atypical melanocytic nevi of the 144
92 noma (MM) (< 5 %) [4]. Almost 2 % of vulvar neoplasias genital type or vulvar melanotic macules. MM is a rare 145
93 are basal cell carcinomas (BCCs) [5]. Vascular tumors of tumor in this anatomical region, with an aggressive 146
94 the vulva and sarcomas occur significantly less often [2]. behavior and poor prognosis [7, 8]. It constitutes < 5 % of 147
RR
95 Primary carcinoma of the Bartholin’s gland constitutes all cases of melanoma in women. The vulvar to cutane- 148
96 around 5 % of the vulvar tumors, whereas the sarcomas ous melanoma ratio is 1:71 [9]. MM accounts between 3 149
97 constitute barely 1–2 % of the tumors in that area [4, 5]. and 10 % of all the malignant tumors with vulvar location 150
98 The prognosis of vulvar neoplasias depends on the [8]. Vulva is the most common location for occurrence 151
99 clinical stage, the tumor thickness, and the status of the of MM in the female reproductive system followed by 152
CO
100 lymph nodes. Five-year survival constitutes of above 70 % vagina [7–9]. Due to delayed diagnosis and early spread 153 AQ4
101 in cases with early diagnosed vulvar cancer, with sub- 5-year survival is less than 50 % [8, 9]. 154
102 sequently adequate therapy. In case of vulvar MM, the A higher MM risk is seen in Caucasian women com- 155
103 prognosis is poor [1, 2, 4]. pared to Afro-American women (relative risks 2.6:1) [10]. 156
The peak is between 60 and 70 years of age, although 157
N
there are isolated cases of occurrence in adolescents 158

104 Vulvar anatomy and young women [9, 10]. Advanced age, tumor size, 159
tumor thickness, ulceration, presence of satellite lesions, 160
U
105 The vulva is composed of various parts. The outer lining involvement of adjacent organs (vagina, urethra), and 161
106 is by labia majora, mons pubis, and posterior labial com- regional or distant metastases are identified as the most 162
107 missure. Labia minora, clitoris with prepuce, introitus important prognostic markers [7, 10]. Unlike cutaneous 163
108 vaginae, hymen, and orificium urethrae represent the melanoma in which the major known risk factor is UV 164
109 inner parts of the vulva. Paraurethral Skene’s glands and radiation, nonultraviolet carcinogenesis dominates the 165
110 greater vestibular Bartholin’s glands complete the vulva. pathogenesis of vulvar MM [11, 12]. Other factors such as 166
111 Macro- and micromorphology of the vulva is influenced family history or hormonal status seem to be not related 167
112 by sexual hormones. During reproductive years, vulvar to vulvar MM risk [11]. 168
113 skin and vulvar mucosa change with the menstrual cycle Vulvar melanoma can assume two main clinically 169
114 [6]. The lining of the labia minora and the inner surface and histologically distinct forms: the acral/lentiginous 170
115 of the labia majora is not constituted by mucosa, but skin form, with a pattern reminiscent of typical, lentiginous 171
116 with a regularly keratinizing stratified squamous epithe- mucosal, palmoplantar and subungual melanoma, and 172
117 lium. In comparison to other cutaneous regions, how- the superficial spreading form, which looks not different 173
118 ever, this skin, is characterized by a more delicate dermal from superficial spreading melanoma of other cutane- 174
119 network of collagen bundles, with a poorly defined ous regions. These should be distinguished from nodular 175
120 interface between papillary and reticular dermis, and melanoma, a much rarer form that is directly infiltrative 176

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177 and is not associated with a pre-existing radially growing asymmetrical in color and structure, with polycyclic bor- 185
178 component [7, 11, 13]. In our records and in accordance ders (Fig. 1a). The macule gradually enlarges peripher- 186
179 with Massi and LeBoit (2014) [14] the lentiginous type is ally while becoming progressively more palpable. With 187
180 by far the most frequent form. the passage of time, it develops bluish and white areas 188
181 Vulvar melanoma most commonly occurs on the labia of discoloration, the latter representing a sign of focal 189
F
182 minora and clitoris, although it can also primarily involve regressive changes in its context [7, 8, 14]. 190
183 the vestibule, the labia majora, and the mons pubis. The The macule of acral/lentiginous/mucosal melanoma 191
O
184 lesion presents itself as a flat, black or brown macule, is usually black with markedly irregular contours [7, 192
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Fig. 1 Vulvar melanoma. a Vulvar melanoma of the acral len- and suprabasal layers of the epidermis by highly atypical me-
tiginous type in its nodular, invasive phase. The tumor involves lanocytes. A few apoptotic figures are observable (hematox-
the inner surface of the labia majora and extends to the labia ylin-eosin; × 250). d Acral lentiginous melanoma at the inner
minora and presents a large achromic nodule. Streaming of surface of labia minora. Continuous row of melanocytes with
melanin is well visible on both sides of the vulva (Courtesy of moderately long dendrites, highlighted with silver impregna-
Dr. M.F. Guarneri. Department of Gynecology and Obstetrics, tion, in an area of clinically evident “melanin streaming” (sil-
University of Palermo School of Medicine). b Acral lentiginous ver impregnation; × 250). e Acral lentiginous melanoma at the
melanoma in situ at the outer surface of the labia minora. In- inner surface of labia minora in its vertical invasive phase. An
crease in number and palisade alignment of the basal mela- endo-exophitic nodule, in continuity with the superficial/radial
nocytes. Some of the cells are obviously atypical, with angular component of the proliferation is visible (hematoxylin-eosin;
contours and large, hyperchromic nuclei (hematoxylin-eosin; × 10). f Noticeable pleomorphism in the nodule, resulting from
× 100). c Acral lentiginous melanoma in situ at the outer sur- the presence of multisized spindled, epithelioid and multinu-
face of the labia minora. Festoon-like colonization of the basal cleated bizarre cells (hematoxylin-eosin; × 250)

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193 8, 14]. Vulvar melanoma may sometimes be partly or Table 1 Immunohistologic markers for malignant melano-
194 entirely amelanotic thus resulting in a deceptive achro- ma (MM) of the vulva
195 mic variant. In the early phases, it appears as a pruritic Marker Percent Remarks
196 patch or plaque, sometimes scaling, which simulates positivity
197 chronic dermatitis or extramammary Paget’s disease, in primary
F
198 while late, nodular lesions resemble epithelial or soft tis- and meta-
199 sue neoplasms [9, 10]. static MM
O
200 Another unusual variant is represented by multiple (%)
201 vulvar melanoma, which is reported to be expression of
S100 protein 94–100 Lacks specificity, being largely
202 the lentiginous pattern, and is characterized by the con- distributed in normal human tissues
O
203 currence of several pigmented macules and/or plaques and derived tumors, is expressed with
204 irregularly strewn over the vulva. Early macules resemble varied intensity and distribution in blue
205 vulvar melanotic macules. The lesions can occur simul- nevi and in Spitz nevi
PR
206 taneously or one after the other as time passes. For this Gp100/PMel 17 83–92 More specific than S100, their
207 reason, macules and plaques may coexist in the same antigenic group sensitivity is variably decreased in its
HMB-45, spindle cell component, they also mark
208 case, expressing the concurrent presence of different
MART-1/melan-A dysplastic nevi and the superficial
209 phases of development [14]. reaches of Spitz nevi
210 Melanoma on vulvar lichen sclerosus et atrophicus has Ki-67 and Mib-1 ≤ 25 Unspecific, proliferation marker, the
D
211 been reported in a few cases. However, on the real neo- proliferative index is related, although
212 plastic nature of these lesions, especially the ones occur- not precisely, to the mitotic rate,
213 ring in young people, there is little agreement [7, 14]. The and has been demonstrated to be a
TE
214 doubts have been raised by the observation that in lichen prognostic factor independent of the
tumor thickness
215 sclerosus and atrophicus, melanocytes can acquire an
216 “activated” phenotype, thus giving rise to atypical vulvar
217 nevi that closely mimic melanoma [15]. plump-spindled type, but other types can be present, 252
EC
218 Dermoscopy of vulvar melanoma shows a compos- possibly resulting in remarkable pleomorphism (Fig. 1f ). 253
219 ite picture, which consist of blue white veil, atypical Numerous mitoses, apoptotic cells, and areas of necro- 254
220 network of streaks, irregularly shaped, multisized black sis can be seen. Desmoplasia and neurotropism are pos- 255
221 dots, and a recently described reticular depigmenta- sible features of this tumor, which through the infiltration 256
222 tion, which appears as a fine network-like crisscross of of the perineural spaces is able to reach and extensively 257
RR
223 thin white lines. The vessels are atypical, with a dotted invade the deep structures of the vulva [14]. 258
224 and linear-irregular pattern [8, 16]. Digital dermoscopy Because of the micro-anatomic characteristics of the 259
225 is an efficient tool to aid a precise diagnosis of suspicious region, the vertical, infiltrative phase occurs directly, 260
226 melanocytic lesions [17]. straight after a hardly detectable stage of microinvasion 261
227 The hallmark of MM diagnosis is histology. In less [14]. 262
CO
228 recent, but still in situ, lesions, the basal layer of the Immunohistochemistry is a useful support in the dif- 263
229 epidermis is virtually replaced by continuous palisades ferential diagnosis with dysplastic nevi and anomalous 264
230 of atypical melanocytes with noticeable cytoplasmic nevi of the genital area, and it is required in the ultimate 265
231 fixation retraction artifact and well-formed pericellular recognition of amelanotic variants without detectable 266
232 lacunae (Fig. 1b). Melanin is partially transferred to the junctional activity and in their distinction from undiffer- 267
N
233 epidermis, where it can be seen up to the horny layer in entiated carcinomas and sarcomas [7]. The markers most 268
234 the form of clumps and irregular columns [14] commonly utilized in ordinary immunohistologic prac- 269
235 With time, the epidermis becomes hyperplastic and tice are summarized in Table 1. 270
U
236 hyperkeratotic, while the multiplying melanocytes form Mutations in vulvar MM are common with NRAS 271
237 a ribbon that gradually replaces its basal and suprabasal mutations as the leading one. NRAS mutations occur in 272
238 layers with a festoon-like pattern (Fig. 1c). A number 21 %. C-KIT amplifications were detected in 4 %. In con- 273
239 of apoptotic cells and a few mitoses may be scattered trast to cutaneous MM, BRAF mutations are less typical in 274
240 throughout the lesion [14]. In the nearby areas of stream- vulvar MM. C-KIT (CD117) can be evaluated by immuno- 275
241 ing pigmentation there is a slight increase in melanocyte histochemistry. PCR and DNA analysis for the detection 276
242 numbers with prominent dendrites, particularly well vis- of BRAF and NRAS mutations and KIT amplifications is 277
243 ible with silver impregnation and specific immunostains appropriate [13, 18]. 278
244 (Fig. 1d) [14]. Because of the dense blood vessels and lymphatic ves- 279
245 The in situ stage is directly followed by the vertical, sel supply in the vulvar region early metastatic spread is 280
246 infiltrative phase. Here, large and irregular aggregates of commonly seen—to urethra, vagina and anus, and the 281
247 atypical melanocytes cells invade the whole tissue and regional lymph nodes with clitorial MM demonstrating a 282
248 consume the epidermis. Ultimately, these aggregates can worse prognosis. Distant metastases are found predomi- 283
249 give shape to the endo-exophytic mass that represents nantly in liver, lungs, and bones [7, 10]. Lymphatic inva- 284
250 the histologic counterpart of the clinical nodule (Fig. 1e) sion occurs in 30–40 % of cases [10, 11]. About 45 % of MM 285
251 [14]. The neoplastic cells in this phase are usually of the will relapse [10]. 286

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AQ8 Table 2 TNM classification of cutaneous melanoma stag- and 2 cm in cases of thicker MM [7]. In recent years, less 306
ing [19] radical surgery has become a trend and presents a more 307
Classification Tumor thickness (mm) Ulceration status/mitoses realistic option for many patients without decreasing 308
their survival rates [7, 20]. There is no evidence that 309
T
radical resection and prophylactic lymphadenectomy 310
Tis NA NA
F
improve the survival rate or decrease the risk of recur- 311
T1 ≤ 1.00 a: Without ulceration and rence [7]. 312
mitosis < 1/mm2
O
A positive SLN was found in 50 % of vulvar MM. In 313
b: With ulceration or mito- about 90 % of these cases no further positive nodes were 314
ses ≥ 1/mm2
detected [21, 22]. In SLNB-negative patients, the average 315
O
T2 1.01–2.00 a: Without ulceration tumor thickness lowers; i.e., 2.06 mm (0.60–7.10) com- 316
b: With ulceration pared to 4.33 mm (1.8–6.0) in SLNB-positive patients 317
T3 2.01–4.00 a: Without ulceration [22]. According to these data, SLNB has predictive value 318
PR
b: With ulceration in cases of a vulvar MM, while in negative SLNB lymph 319
T4 > 4.00 a: Without ulceration

node dissection is unnecessary [21]. 320
Radiation therapy with or without concurrent immu- 321
b: With ulceration
notherapy is considered in locally advanced cases as well 322
N No. of metastatic nodes Nodal metastatic burden as for recurrences [21]. Adjuvant systemic chemotherapy 323
D
N0 0 NA does not improve the prognosis [21]. Novel immuno- 324
N1 1 a: Micrometastasis* therapeutic and targeted agents have been reported to 325
b: Macrometastasis † improve survival in cutaneous melanoma. Therefore, 326
TE
N2 2–3 a: Micrometastasis * these drugs may be considered in advanced vulvar MM 327
but controlled trials for this peculiar subtype are still 328
b: Macrometastasis†
missing [10, 21]. 329
c: In transit metastases/satel-
lites without metastatic nodes
The most important factor for survival is the depth of 330
EC
invasion [7, 9]. The 10-year survival rate of 64.5 % that is 331
N3 4 + metastatic nodes, or
matted nodes, or in tran-
double as much as for other mucosal MM. This under- 332
sit metastases/satellites scores the importance of early diagnosis and timely treat- 333
with metastatic nodes ment [18, 19]. A 10-year follow-up is recommended by 334
M Site Serum LDH German guidelines for all melanoma patients [19]. 335
RR
M0 No distant metastases NA
M1a Distant skin, subcutane- Normal
ous, or nodal metastases Bowen’s disease (BD) 336
M1b Lung metastases Normal

BD of the vulva represents an in situ SCC but has a poten- 337
CO
M1c All other visceral me- Normal

tial to transform into invasive SCC. BD lesions develop 338
tastases
as a solitary slowly enlarging erythematous pale or pig- 339
Any distant metastasis Elevated
mented spot or plaque with irregular edges [23, 24]. 340
Histologically, the disease shows signs of VIN 3, in the 341
287 Clinical staging is performed by Union for Interna- presence of full thickness atypia within the lesion. The 342
N
288 tional Cancer Control (UICC) classification systems, risk of transformation into SCC is greater in females after 343
AQ5
289 the American Joint Committee on Cancer (AJCC) stag- the age of 45 [23, 24]. 344
290 ing system for cutaneous melanomas and the Interna- BD usually affects young women between 20 and 345
U
291 tional Federation of Obstetrics and Gynecology (FIGO) 50 years, and its incidence is increasing in recent years 346
292 system, in which regional lymph nodes were assessed probably owing to changes in sexual behavior [23]. BD is 347
AQ6
293 clinically, not surgically [19, 20]. TNM classification also associated with HPV 16 infections, more rarely 18, 348
294 for staging of a cutaneous melanoma is also applicable 31, or 33 infections [23, 24]. Other risk factors include 349
AQ7
295 (Table 2) [19]. Clark and Breslow classification can be early initiation of sexual activity with multiple sex part- 350
296 used only in cases with locations in the hairy part of the ners, immunosuppression, immunodeficiency, and 351
297 labia majora [4, 12]. smoking [23, 25]. Clinically, it can affect both the skin 352
298 The AJCC staging has greater prognostic value in com- and vulvar mucosa, most often the labia majora. How- 353
299 parison to FIGO staging in cases of MM on the vulva [13, ever, other parts of the vulva and areas with squamous 354
300 20]. For melanomas of at least 1 mm thickness sentinel epithelium such as the vagina, cervix, and anal mucosa 355
301 lymph node biopsy (SLNB) is recommended to improve can be involved [23]. 356
302 staging [19]. Treatment options include topical imiquimod, abla- 357
303 Therapeutic options are primarily surgical [20, 21]. tive laser therapy, surgery, and photodynamic therapy 358
304 Recommended excision margins are 0.5 cm for in situ with Mohs surgery achieving > 90 % complete response 359
305 MM, 1 cm for MM with up to 2 mm tumor thickness, [25]. 360

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361 Vulvar intraepithelial neoplasia (VIN)
362 The 2004 International Society for the Study of Vulvo-

363 vaginal Disease (ISSVD) classification distinguished two
364 types of VIN: a usual type (HPV-related) and a differenti-
F
365 ated (non-HPV-related) type [26]. Usual VIN tends to be
366 multifocal and multicenter distributed, is more frequent
among younger women and has a lower invasive poten-
O
367
368 tial. VIN in association with lichen sclerosis is more com-
369 mon with the differentiated type [26–28].
O
370 Undifferentiated VIN is characterized histologically
371 by a loss of squamous epithelial architecture, with vary-
372 ing degrees of cell atypia. Undifferentiated VIN is divided
PR
373 into VIN 1, 2, and 3 depending on the degree of cellular
374 disarray [26–29]. It has been found that MIB 1 staining is
375 useful for accurate staging of VIN [26, 27]. Differentiated
376 VIN is verified as VIN 3 because of its potentially invasive
377 nature [29].
D
378 Since usual VIN is HPV-related prophylactic, vac-
379 cination of adolescents is a tool of primary prevention.
380 Quadrivalent HPV vaccine reached an efficacy of 79 % for
TE
381 VIN2 + lesions in the intention-to-treat-group [30]. Cur-
382 rent data on catch-up vaccination in young women also
383 demonstrated a reduced rate of VIN2 + lesions [31].
384 The traditional treatment for VIN 2/3 is surgical exci-
EC
385 sion, however with high relapse rates between 30 and

386 50 % [29]. Adjuvant topical imiquimod after complete
387 excision reduced the relapse rate in a recent prospec-
388 tive trial from 48.4 to 44.8 % [32]. In a phase 2 trial, both
389 cidofovir and imiquimod achieved complete remis-
RR
390 sions in 46 % with less adverse effects in the cidofovir

391 group [33].
Fig. 2 Squamous cell carcinoma of the vulva. a HPV-associ-
ated type of younger smoking female. b Non-HPV-associated
392 Squamous cell carcinoma of the vulva (SCC) tumor in a 71-year-old female. c Advanced squamous cell
CO
carcinoma of the vulva with complete destruction of perineum

and infiltration of rectal ampulla. d Squamous cell carcinoma
393 SCC of the vulva is the most common malignancy seen in of the vulva, keratinizing type with dyskeratosis and multiple,
394 this area with a reported incidence between 2 and 7 per and atypical mitoses (hematoxylin-eosin; × 4)
395 100,000 women [1, 5, 34]. SCC is usually associated with
396 pre-existing VIN and/or HPV infection [35]. Known risk 37]. On the other hand, the HPV-independent pathway 416
N
397 factors for SCC are nicotine abuse, chronic inflammatory results in patients presenting with differentiated VIN 3 417
398 vulvar diseases, obesity, sexually transmitted diseases, lesions and chronic inflammatory vulvar dystrophy or 418
399 and low socioeconomic status [36, 37]. lichen sclerosus, specifically the elderly (Fig. 2b) [29, 39]. 419
U
400 There is a significant difference in the incidence in dif- Immunohistochemical expression of p14 (ARF) and 420
401 ferent age groups. The most significant increase in VIN p16 (INK4A) is associated with HPV DNA, typical for 421
402 has been reported for 40- to 49-year old females, while usual VIN, and which is not detected in differentiated 422
403 the risk of SCC is highest after 50 years of age [1, 34]. VIN [40]. P53 gene mutation is found in HPV-negative 423
404 Around 60 % of vulvar SCC appear after menopause, patients. HPV-associated lesions are less prone to relapse 424
405 between 50 and 80 years of age (average 62 years) [34]. [40]. CDKN2A (p16), HRAS, and PIK3CA-mutations are 425
406 An early appearance between ages of 20 and 30 years was also common in HPV-negative patients. The presence of 426
407 reported in rare cases, some of which associated with HRAS mutations is associated with a less favorable prog- 427
408 HIV infection and rarely with pregnancy [36–38]. nosis [41]. An increased expression of the endogenous 428
409 SCC may develop by two different mechanisms from hypoxia markers (HIF-1α, GLUT-1, CA-9, and VEGF] 429
410 premalignant lesions [29]. One of these is the human have been reported in vulvar SCC and less frequent in 430
411 papillomavirus (HPV)-dependent pathway which con- VIN, suggesting their potential involvement in the pro- 431
412 stitutes about 60 % of cases, caused by infection with cess of malignant transformation [42]. 432
413 HPV 16 and 33 as predominant subtypes (55 %) [29]. This According to the depth of invasion, the carcinoma of 433
414 is more commonly seen in younger women (< 50 years the vulva is divided into early invasive (stage 1) or inva- 434
415 old) usually with VIN who are smoking (Fig. 2a) [29, 36, sive carcinoma (stage 2, 3) (Table 3) [29, 43]. The FIGO 435 AQ9

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Table 3 FIGO staging system: staging classifications and clinical practice guidelines of gynecologic cancers [44]. Stage 0 (Tis,
N0, M0) is a very early cancer found on the surface of the skin of the vulva only. It is also known as carcinoma in situ and as
Bowen’s disease. This stage is not included in the FIGO system
Stage I Tumor confined to the vulva
IA Lesions ≤ 2 cm in size, confined to the vulva or perineum and with stromal invasion ≤ 1.0 mmb, no nodal metastasis
F
IB Lesions > 2 cm in size or with stromal invasion > 1.0 mmb, confined to the vulva or perineum, with negative nodes
Stage II Tumor of any size with extension to adjacent perineal structures (1/3 lower urethra, 1/3 lower vagina, anus) with negative nodes
O
Stage III Tumor of any size with or without extension to adjacent perineal structures (1/3 lower urethra, 1/3 lower vagina, anus) with positive
inguinofemoral lymph nodes
O
IIIA (i) With 1 lymph node metastasis (≥ 5 mm), or
(ii) 1–2 lymph node metastasis(es) (< 5 mm)
IIIB (i) With 2 or more lymph node metastases (≥ 5 mm), or
PR
(ii) 3 or more lymph node metastases (< 5 mm)
IIIC With positive nodes with extracapsular spread
Stage IV Tumor invades other regional (2/3 upper urethra, 2/3 upper vagina), or distant structures
IVA Tumor invades any of the following:
D
(i) Upper urethral and/or vaginal mucosa, bladder mucosa, rectal mucosa, or fixed to pelvic bone, or
(ii) Fixed or ulcerated inguinofemoral lymph nodes
IVB Any distant metastasis including pelvic lymph nodes
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436 classification is used for the accurate staging [44]. Tumor inguinal lymph nodes are positive for metastatic spread. 472
437 thickness, stage, presence of lymph node metastasis, his- For stage III and IV radical vulvectomy, bilateral lymph 473
EC
438 tological grade, and vascular or perineural invasion are node excision and if necessary excision of other lymph 474
439 major prognostic factors [45]. nodes stations is recommended [50, 52]. 475
440 Clinically, SCC is characterized by a tumor forma- Neoadjuvant chemotherapy and radiotherapy are 476
441 tion, localized in labia majora and minora in 2/3 of cases considered to obtain resectability of the primary tumor 477
442 (Fig. 2c). It tends to shift its location to the clitoris with [50–57]. Locoregionally advanced SCC may benefit from 478
RR
443 age. Longstanding tumors are accompanied by itch- chemoradiation [54]. For advanced cases chemother- 479
444 ing [34, 36]. Localized pain, burning, or bleeding occur apy—mainly based on paclitaxel and cisplatin—is used. 480
445 less frequently, and are more common in advanced and Targeted therapy with erlotinib is a more recent option 481
446 invasive tumors. Dysuria and dyspareunia are possible in [53, 56]. The most important factors for local and regional 482
447 cases involving of the urethra [36, 37]. treatment failure are stromal invasion of more than 2 mm 483
CO
448 Three main variants of SCC have been identified [36]: and extracapsular spread from affected lymph nodes [55, 484
449 Keratinizing types of vulvar carcinoma is most common 57]. 485
450 (around 78 % of cases) and occurs predominantly in Verrucous carcinoma (VC) of the vulva is described 486
451 elderly females (older than 70 years of age). It is usually as an uncommon subtype of SCC that usually occurs in 487
452 preceded by lichen sclerosus et atrophicus or squamous elderly women [58]. It usually presents as an exophytic 488
N
453 hyperplasia, which is not associated with HPV (Fig. 2d). wart-like tumor mass and is histologically a variant of 489
454 Warty type is observed in 13 % and basaloid type in 8 % of well-differentiated, low-grade SCC. Some consider it a 490
455 cases. The warty and basaloid SCCs are usually preceded separate entity [59]. It is associated with low-risk HPV 491
U
456 by the usual VIN, whereas keratinizing SCCs are more types. The tumor exhibits a very low tendency to metas- 492
457 often associated with differentiated VIN. An important tasize, has slow growth and locally invasive behavior. 493
458 differential diagnosis is condyloma acuminatum [46]. A Treatment consists of wide excision after histological 494
459 rare variant of SCC is acantholytic SCC characterized by verification by a deep diagnostic biopsy (Fig. 3a) [58, 59]. 495
460 focal loss of desmosomal proteins (Fig. 3b) [47]. Buschke–Löwenstein tumor (BLT) represents a rare 496
461 SCC metastasizes mainly by lymphogenous route and sexually transmitted disease, with a prevalence rate of 497
462 can involve and invade neighboring vagina, urethra, and about 0.1 % [60, 61]. BLT is characterized by slow-grow- 498
463 rectum and also spread along the path of their lymphatic ing giant warts with a cauliflower-like morphology and 499
464 drainage [48]. SNLB is a staging method in vulvar SCC is associated with HPV-genotype 6 or 11 and tends to 500
465 that reduces the need of inguinofemoral lymph node infiltrate underlying tissue (Fig. 3c, 3d) [60, 61]. Bleed- 501
466 excision by 70 % [49]. ing, pain, and a rapid increase in tumor sizes are alarm- 502
467 The treatment of SCC is individualized and stage- ing signs of malignant transformation [62]. The average 503
468 dependent [48, 50]. For stage Ia local excision with 10 mm period of such transformation is about 5 years, as the risk 504
469 safety margins is sufficient. In stage Ib and II inguinal of recurrence is approximately 60 % [63]. The probability 505
470 local lymph node excision is added. Pelvic lymph node of metastasis is low and the overall mortality rate is about 506
471 excision may be necessary in stage II patients when

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accounts for about 1–4 % of all vulvar cancers [67]. BCC 521
affects mainly elderly women with an average age of 522
68 years [66, 67]. Ultraviolet radiation and sun exposure 523
are no risk factors for vulvar BCC [66]. But chronic inflam- 524
matory disorders like lichen sclerosus et atrophicus are 525
F
known predisposing factors [66, 67]. Previous radiother- 526
apy, burn scars, exposure to arsenic, and certain genetic 527
conditions as nevoid basal cell carcinoma syndrome and
O
528
xeroderma pigmentosum are further risk factors for the 529
development of vulvar BCC [66, 68]. 530
O
Clinical manifestation of BCC varies with vegetating, 531
ulcerated, pedunculated, infiltrated, nodular, morphe- 532
mic, pigmented, or depigmented lesions [69, 70]. Subjec- 533
PR
tive symptoms include itching and discomfort [69]. Pain 534
and bleeding can be seen in ulcerated lesions [67]. 535
Vulvar BCC usually affects the skin surface of labia 536
minora and majora, but can also affect the lining, as well 537
as the clitoris or the orificium urethrae [66, 67]. It usu- 538
D
ally presents as a single lesion, but may be bilateral or 539
multifocal, even disseminated [66, 68]. Vulvar BCC has 540
a good prognosis with a low mortality rate, but invasive 541
TE
or destructive growth has been documented too [68, 69]. 542
Histological features of vulvar BCC are identical to what is 543
seen in BCC of skin elsewhere [71]. Metatypic (basosqua- 544
mous) carcinoma is a high-risk subtype with metastatic 545
EC
potential, aggressive behavior, and higher mortality [72, 546

73]. About 85 % of vulvar BCCs show a diffuse expression 547
of the BerEP4 and patchy p16 using immunohistology in 548
contrast to SCC [74]. These results indicate that Ber EP4 549
Fig. 3 Rarer types of vulvar carcinoma. a Verrucous vulvar car- expression may be useful in the differentiation of BCC 550
RR
cinoma developing on pre-existent chronic lichen sclerosus. b and basaloid SCC. 551
Acantholytic pseudoglandular carcinoma (external aspect of BCC has minimal metastatic potential, but can recur 552
the labium majus). Tumor islands with central pseudo-lumina after excision in about 20 % of cases. Therefore, Mohs 553
containing acantholytic and dyskeratotic cells (hematoxylin- surgery is recommend to reduce the relapse rate [67, 75]. 554
eosin; × 10). c Buschke–Löwenstein tumor—panoramic view Distant metastases have been observed in metatypic BCC 555
CO
of a bioptic fragment: huge papillomatous, endo-exophytic

[73]. The differential diagnosis of vulvar BCC includes 556
epithelial growth with well-developed fibrovascular cores. In
Bowen’s disease, Paget’s disease, SCC, leukoplakia, 557
spite of the apparent inversion of polarity, the lesion can be
considered entirely benign, since it is composed of differenti- lichen planus, lichen sclerosus, melanocytic nevus, or 558
ated squamous cells, without atypia and mitoses (hematoxy- melanoma [68]. The diagnosis is confirmed by histologi- 559
lin-eosin; × 1). d Detail of (c). Modest but typical koilocytotic cal examination [69]. 560
N
changes are visible in this field (hematoxylin-eosin, × 10) Treatment of vulvar BCC is usually surgical. Mohs 561
surgery, despite higher costs than wide excision, is rec- 562
507 30 % [61, 63]. The treatment of choice is complete surgical ommended at least for relapsed and high-risk BCC [66]. 563
U
508 removal [60]. Radical or partial vulvectomy is used in rare cases of 564
509 Spindle cell or sarcomatoid squamous cell car- invading, advanced lesions [75]. 565
510 cinoma is a very rare variant of SCC. The tumor can Topical immunomodulator imiquimod is an alterna- 566
511 develop de novo or after radiotherapy of previous SCC. tive treatment option for thin BCC when surgery is contra- 567
512 This tumor type develops preferably on chronic lichen indicated. In other cases, radiotherapy may be considered 568
513 sclerosus et atrophicus and may be associated with [75]. There is no published data on targeted therapies with 569
514 differentiated-type VIN. Unlike most vulvar cancers no sonic hedgehog inhibitors for vulvar BCC [72]. 570
515 association to HPV has been found. These tumors seem The prognosis depends on the stage of invasion of the 571
516 to be more aggressive than other types of vulvar SCC [64, underlying tissues [67, 68]. The nature of the disease is 572
517 65]. generally more favorable than other cancers in this area 573
with a low mortality when promptly diagnosed and care- 574
fully treated [69]. The prognosis is worse in metatypic 575
518 Basal cell carcinoma of the vulva (BCC) types with metastatic potential, as well as recurrent BCCs 576
[69–71]. There should be a regular annual follow-up [72]. 577
519 BCC, the most frequent cutaneous tumor, is much less
520 commonly observed on female genitalia [66]. BCC

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578 Neuroendocrine tumors of the vulva
579 Neuroendocrine tumors of the vulva are rare malignant

580 tumors which are localized in the female genital tract
581 in about 2 % of the cases, affecting cervix, ovary, vagina,
F
582 and vulva [76]. They have a poor prognosis due to aggres-
583 sive behavior, high metastatic potential, and frequent
O
584 relapses [76, 77].
585 Merkel cell carcinoma (MCC) of the vulva is
586 extremely rare with about 15 cases described in the world
O
587 literature [78, 79]. In general old age, immunosuppres-
588 sion, and UV radiation are considered as risk factors for
589 its occurrence [79, 80]. It is particular aggressive and has
PR
590 a high potential for early dissemination [81].
591 MCC usually affects women between 69 and 75 years
592 of age. The clinical manifestation is nonspecific, often
593 presented as a painless lump or nodule over the labia or
594 vestibule [78, 79].
D
595 Histologically, a trabecular pattern of uniform cells
596 with neurosecretory granules is seen with high mitotic
597 index and frequent apoptosis (Fig. 4a, 4b) [80]. Differen-
TE
598 tial diagnosis includes SCC and metastases of lung can-
599 cer [78, 79, 81].
600 Three main variants of MCC are described, small,
601 large, and intermediate cell type variants. Intermediate-
EC
602 cell type is the commonest occurring of the three [80].

603 Positivity for wide spectrum low molecular weight cyto-
604 keratins, epithelial membrane antigen, neurofilaments,
605 neuron specific enolase, and chromogranin A was found
606 immunohistochemically. Positivity for cytokeratin 20
RR
607 and neurofilaments in typical globular paranuclear

608 arrangement are of diagnostic importance [80]
609 DNA of MCC polyoma virus (MCPyV) is detected in
610 43–85 % of cases of MCC, suggesting viral oncogenesis
611 [80]. However, MCPyV has not been studied systemati-
CO
612 cally in vulvar MCC.

613 The prognosis is poor with 60 % of cases recurring
614 or metastasizing [78, 79]. The 5-year survival ranges
615 between 30 and 60 %; in relapsing cases, it is as low as
616 17 % [78, 81].
N
617 In general, the recommended therapeutic approach is

618 wide excision with 3 cm margins, with bilateral lymphad-
619 enectomy and radiotherapy of tumor basin and regional Fig. 4 a Merkel cell carcinoma, trabecular pattern: uniform
U
620 lymph nodes [80]. proliferation of small basophilic cells arranged in arciform
ribbons. There is colonization of the epidermis (hematoxylin-
621 Small cell carcinoma (SmCC) represents a cancer
eosin; ×10). b Parallel alignment of the nuclear membranes.
622 type that occurs most often in the lungs. Extrapulmonary
Several mitotic figures are visible in this field (hematoxylin-
623 location is rare—only 2 % are seen on female genitalia eosin; × 40)
624 [82, 83]. Vulvar location is extremely rare with less than
625 10 cases reported in the literature [84]. Vulvar SmCC is
626 a potentially lethal disease due to its propensity of early Histologically, SmCC on the vulva does not differ 635
627 metastatic spread [82, 84]. Symptoms of SmCC are non- from the pulmonary form [85]. Expression of at least one 636
628 specific. The patient is usually asymptomatic or presents immunohistochemical neuroendocrine marker con- 637
629 with complaints of pain and nonspecific vaginal dis- firms the diagnosis [83]. 638
630 charge may occur [82, 83]. Advanced cases are seen with Therapy includes a total wide excision or vulvectomy, 639
631 non-specific tumors in the vulva, usually the labia, with depending on the stage of invasion. Bilateral lymphad- 640
632 enlarged inguinal lymph nodes [83]. A case of small cell enectomy is mandatory due to high metastatic potential 641
633 carcinoma that derived from SCC of the vulva has been [85]. Adjuvant chemotherapy with cisplatin and eto- 642
634 described [84]. poside, and adjuvant radiotherapy are used but do not 643
affect long-term prognosis [85]. Trimodal regimen of 644

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645 radiochemotherapy plus regional hyperthermia showed and seem to originate from mammary-like glands of the 701
646 partial regression of the tumor in cases refractory to stan- vulva. Wide excision is the treatment of choice [104]. 702
647 dard chemotherapy [86]. Since this tumor is an orphan Extramammary Paget’s disease (EPD) is a rare vari- 703
648 disease, no standardized treatment has been established. ant of classical Paget’s disease, which accounts for about 704
6 % of all cases of Paget’s disease and about 1 % of neo- 705
F
plasms with vulvar location [105]. EPD represents an 706
649 Adenocarcinomas of the vulva (AC) intraepithelial adenocarcinoma, which affects the areas 707
rich in apocrine sweat glands, the most common being
O
708
650 Primary AC of the vulva are very rare, consisting about the anogenital region [106, 107]. EPD is the most com- 709
651 2 % of all vulvar neoplasms [2, 3]. They primarily affect mon type of vulvar AA. EPD usually spreads in an insidi- 710
O
652 women of postmenopausal age [87]. The classification of ous fashion with histological boundaries often exceeding 711
653 AC is diverse and includes extramammary Paget’s dis- those of the clinical lesion. That explains the frequent 712
654 ease, sweat gland carcinomas, breast-like adenocarcino- recurrences [107]. It is more common in postmenopausal 713
PR
655 mas, apocrine adenocarcinomas, and Bartholin’s gland women (average 70 years) and although there is little 714
656 AC [88]. Adenocarcinomas of the vulva run an aggressive potential for malignant transformation to invasive carci- 715
657 course with a high propensity for recurrence and metas- noma, EPD tends to relapse in 40 % of cases [108]. Unlike 716
658 tasis. The prognosis is unfavorable in advanced cases and the classical variant of the disease, extra-mammary loca- 717
659 metastases are found in lungs and bones. The 5-year sur- tion is associated with an underlying neoplasia in 30 % 718
D
660 vival is estimated on average to be about 0 % [88]. of cases, including tumors of breast or genital tract [107, 719
661 Apocrine adenocarcinoma of the vulva (AA) rep- 108]. Several cases have been described suffering from 720
662 resents a rare tumor [87–89]. AA develop from native simultaneous mammary Paget’s disease and EPD [109]. 721
TE
663 apocrine sweat glands are histologically composed of Vulvar EPD clinically presents as an erythematous 722
664 adenopapillary cords and tubules, accompanied by plaque, with or without ulceration, localized mostly on 723
665 occasional pagetoid components. They are negative for the labia [107]. EPD can be accompanied by subjective 724
666 estrogen (ER) and progesterone (PR) receptors [88]. AA symptoms such as itch or being completely asymptom- 725
EC
667 express carcinoembryonic antigen (CEA), cytokeratin atic [106]. Bowen’s disease, intertrigo, eczema, psoria- 726
668 (CK) 7, epithelial membrane antigen (EMA), and gross sis, dermatomycosis, and MM are important differential 727
669 cystic disease fluid protein (GCDFP)-15 [88]. diagnoses [107, 110]. 728
670 Breast-like vulvar adenocarcinomas originate from EPD is composed of intraepithelial large pale cells or 729
671 anogenital mammary-like glands in the interlabial sulci, cell nests. Tumor cells are positive for CK7 and CEA but 730
RR
672 and usually express ER and PR receptors [90]. lack CK20 [107, 111]. Immunohistochemical study is help- 731
673 Adenoid cystic carcinoma of the vulvar sweat glands ful for the distinction from BD and superficial spreading 732
674 (ACCSG) also called hydradenoid carcinoma of the vulva melanoma [111]. Pigmented EPD represents a rare vari- 733
675 is an extremely rare disease. The tumor cells express CK7, ant of EPD with rare vulvar localization [112]. Usually, it 734
676 CAM 5.2, EMA, ER/PR, and GCDFP-15. ACCSG shows an occurs among postmenopausal women and presents clin- 735
CO
677 aggressive course and high propensity to relapse [91, 92]. ically as a macular pigment surface with mild desquama- 736
678 All types of AA metastasize lymphogenic and hema- tion. Hyperpigmentation is due to an increased amount 737
679 togenous mainly to heart, lungs, abdominal organs, and of melanocytes between the Paget cells [112]. EPD can 738
680 bones. The presence of metastases was associated with advance into Paget carcinoma with infiltrative growth. 739
681 a significantly poorer prognosis, and high mortality [90]. Standard therapy for EPD is wide excision to obtain 740
N
682 Adenoid cystic carcinoma of Bartholin’s gland tumor-free margins [113]. Topical imiquimod is a non- 741
683 (ACC) is very rare with about 80 cases reported in the surgical alternative with only 52.4 % complete remission 742
684 world literature [93, 94]. The tumor runs an aggressive [114]. Photodynamic therapy with topical or intravenous 743
U
685 curse with a strong metastatic potential and frequent photosensitizers achieved a complete remission in about 744
686 relapses, which determines the relatively high mortality 58 % [115]. Radiation therapy is appropriate in cases 745
687 [95]. Clinically, it presents as a slowly increasing nodular where surgical procedures are contraindicated [113]. 746
688 lesion, located in the rear part of the labia, with a ten- Adjuvant radiation therapy improves tumor control. 747
689 dency to local invasion and perineural infiltration [92, Cause-specific 5-year survival rates of 71 % have been 748
690 93]. Subjectively, it is accompanied by pain [94]. reported [115]. Due to high relapse rates a long term fol- 749
691 Optimal therapeutic approach is radical hemi or radi- low-up is recommended [116]. 750
AQ10
692 cal vulvectomy with lymph node dissection, followed by
693 external beam radiation. Administration of antiestrogen
694 therapy after the initiating surgery improves the quality Conclusions 751
695 of life of patients [93–99].
696 Mucinous adenocarcinoma is a rare variant of AA, Dermatologists should have a detailed knowledge about 752
697 breast-like AA, and ACC than stain positive for CEA malignant tumors of the vulva, since they are often con- 753
698 [100–103]. sulted for unspecific symptoms like pigmentary changes, 754
699 Phyllodes tumors of the vulva are rare neoplasias pruritus, or discharge. Biopsy for histological investiga- 755
700 sharing morphologic similarities with breast tumors tions is important for early diagnosis. Introducing proper 756

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757 treatment requires an interdisciplinary approach of der- 16. Ferrari A, Zalaudek I, Argenziano G, et al. Dermoscopy of 819
758 matologists with gynecologists, urologists, radiothera- pigmented lesions of the vulva: a retrospective morpho- 820
logical study. Dermatology. 2011;222:157–66. 821
759 pists, and oncologists.
17. Wollina U, Burroni M, Torricelli R, et al. Digital dermos- 822
copy in clinical practise: a three-centre analysis. Skin Res 823
760 Conflict of interest Technol. 2007;13:133–42. 824
F
761 None declared. 18. van Engen-van Grunsven AC, Küsters-Vandevelde HV, De 825
Hullu J, et al. NRAS mutations are more prevalent than KIT 826
mutations in melanoma of the female urogenital tract—a
O
827
762 References study of 24 cases from the Netherlands. Gynecol Oncol. 828
2014;134:10–4. 829
19. Mehra T, Grözinger G, Mann S, et al. Primary localiza- 830
O
763 1. Akhtar-Danesh N, Elit L, Lytwyn A. Trends in incidence
tion and tumor thickness as prognostic factors of sur- 831
764 and survival of women with invasive vulvar cancer in the
vival in patients with mucosal melanoma. PLoS One. 832
765 United States and Canada: a population-based study.
2014;9:e112535. 833
PR
766 Gynecol Oncol 2014;134:314–8.
20. Balch CM, Gershenwald JE, Soong S, et al. Final version 834
767 2. Robert Koch-Institut & Gesellschaft der epidemiologischen
of 2009 AJCC melanoma staging and classification. J Clin 835
768 Krebsregister in Deutschland e. V. Krebs in Deutschland
Oncol. 2009;27:6199–206. 836
769 2009/2010. Beiträge zur Gesundheitsberichterstattung des
21. Pflugfelder A, Kochs C, Blum A, et al. Malignant melanoma 837
770 Bundes, 9. Ausgabe. Berlin: Robert-Koch-Institut; 2013.
S3-guideline “Diagnosis, therapy and follow-up of mela- 838
771 pp. 72–6.
noma”. J Dtsch Dermatol Ges. 2013;6:1–116, 1–126. 839
D
772 3. Pathak D, Agrawal S, Dhali TK. Prevalences of and risk fac-
22. Leitao MM Jr. Management of vulvar and vaginal melano- 840
773 tors for vulvar diseases in Nepal: a hospital-based study.
mas: current and future strategies. Am Soc Clin Oncol Educ 841
774 Int J Dermatol 2011;50:161–7.
Book. 2014:e277–81. 842
775
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4. Dittmer C, Katalinic A, Mundhenke C, Thill M, Fischer D.
23. Trifirò G, Travaini LL, Sanvito F, et al. Sentinel node detec- 843
776 Epidemiology of vulvar and vaginal cancer in Germany.
tion by lymphoscintigraphy and sentinel lymph node 844
777 Arch Gynecol Obstet 2011;284:169–74.
biopsy in vulvar melanoma. Eur J Nucl Med Mol Imaging. 845
778 5. Bromfield ME, Gibson TN, Hanchard B, Waugh N,
2010;37:736–41. 846
779 McNaughton D. A Thirty-year review of vulvar cancer in
24. Moxley KM, Fader AN, Rose PG, et al. Malignant melanoma 847
780 Jamaica, 1978 to 2007. West Indian Med J 2014;63:138–41.
EC
of the vulva: an extension of cutaneous melanoma? Gyne- 848

781 6. Deliveliotou A, Creatsas G. Anatomy of the vulva. In: Far-
col Oncol. 2011;122:612–7. 849
782 age MA, Maibach HI, editors. The vulva. Anatomy, physiol-
25. Yuan GW, Wu LY, Zhang R, Li XG. Clinical analysis for 18 850
783 ogy, and pathology. Informa Healthcare, New York; 2006.
cases of vulvar Bowen’s disease. Zhonghua Fu Chan Ke Za 851
784 pp. 1–8.
Zhi. 2013;48:925–8. 852
785 7. Wollina U, Hansel G, Koch A, et al. Diagnostik und thera-
26. Lazaridou E, Fotiadou C, Giannopoulou C, Ioannides D. 853
RR
786 peutisches Vorgehen bei extrakutanem Melanom und

Persistent erythematous lesion of the vulva: a diagnostic 854
787 unbekanntem Primarius. In: Szeimies R-M, Hauschild A,
and treatment challenge. J Drugs Dermatol. 2012;11:110–2. 855
788 Garbe C, Kaufmann R, Landthaler M, editors. Tumoren der
27. Kang HK, Yun JH, Son YM, Roh JY, Lee JR. Photodynamic 856
789 Haut. Grundlagen, Diagnostik und Therapie in der derma-
therapy for Bowen’s disease of the vulva area. Ann Derma- 857
790 tologischen Onkologie. G Thieme Verlag, Stuttgart; 2010.
tol. 2014;26:241–5. 858
791 pp. 404–14.
CO
28. van de Nieuwenhof HP, van der Avoort IA, de Hullu JA. 859
792 8. Murzaku EC, Penn LA, Hale CS, Keltz Pomeranz M, Polsky
Review of squamous premalignant vulvar lesions. Crit Rev 860
793 D. Vulvar nevi, melanosis, and melanoma: an epidemio-
Oncol Hematol. 2008;68:131–56. 861
794 logic, clinical, and histopathologic review. J Am Acad Der-
29. Preti M, Scurry J, Marchitelli CE, Micheletti L. Vulvar 862
795 matol 2014;71:12412–9.
intraepithelial neoplasia. Best Pract Res Clin Obstet Gyn- 863
796 9. Tcheung WJ, Selim MA, Herndon JE 2nd, et al. Clinicopath-
aecol. 2014;28:1051–62 (pii: S1521-6934(14)00134-5). 864
797 ologic study of 85 cases of melanoma of the female genita-
N
30. Léonard B, Kridelka F, Delbecque K, et al. A clinical and 865

798 lia. J Am Acad Dermatol 2012;67:598–605.
pathological overview of vulvar condyloma acuminatum, 866
799 10. Baderca F, Cojocaru S, Lazăr E, et al. Amelanotic vulvar
intraepithelial neoplasia, and squamous cell carcinoma. 867
800 melanoma: case report and review of the literature. Rom J
U
Biomed Res Int. 2014;2014:480573. 868

801 Morphol Embryol 2008;49:219–28.
31. Chiesa-Vottero A, Dvoretsky PM, Hart WR. Histopathologic 869
802 11. Moan J, Porojnicu AC, Dahlback A, Grant WB, Juzeniene
study of thin vulvar squamous cell carcinomas and associ- 870
803 A. Where the sun does not shine: is sunshine protective
ated cutaneous lesions: a correlative study of 48 tumors in 871
804 against melanoma of the vulva? J Photochem Photobiol B
44 patients with analysis of adjacent vulvar intraepithelial 872
805 2010;101:179–83.
neoplasia types and lichen sclerosus. Am J Surg Pathol. 873
806 12. Ragnarsson-Olding BK. Spatial density of primary malig-
2006;30:310–8. 874
807 nant melanoma in sun-shielded body sites: a potential
32. Kjaer SK, Sigurdsson K, Iversen OE, et al. A pooled analysis 875
808 guide to melanoma genesis. Acta Oncol 2011;50:323–8.
of continued prophylactic efficacy of quadrivalent human 876
809 13. Aulmann S, Sinn HP, Penzel R, et al. Comparison of molec-
papillomavirus (Types 6/11/16/18) vaccine against high- 877
810 ular abnormalities in vulvar and vaginal melanomas. Mod
grade cervical and external genital lesions. Cancer Prev Res 878
811 Pathol 2014;27:1386–93.
(Phila). 2009;2:868–78. 879
812 14. Massi G, LeBoit PE. Melanoma on genital skin. In: Massi
33. Couto E, Sæterdal I, Juvet LK, Klemp M. HPV catch-up vac- 880
813 G, LeBoit PE, editors. Histological diagnosis of nevi and
cination of young women: a systematic review and meta- 881
814 melanoma. 2nd Edn. Heidelberg—Berlin: Springer; 2014.
analysis. BMC Public Health. 2014;14:867. 882
815 pp 653–62.
34. Gentile M, Bianchi P, Sesti F, et al. Adjuvant topical treat- 883
816 15. Carlson JA, Mu XC, Slominski A, Weismann K, et al. Mela-
ment with imiquimod 5 % after excisional surgery for VIN 884
817 nocytic proliferations associated with lichen sclerosus.
2/3. Eur Rev Med Pharmacol Sci. 2014;18:2949–52. 885
818 Arch Dermatol 2002;138:77–87.

Author's Proof
review
886 35. Tristram A, Hurt CN, Madden T, et al. Activity, safety, 54. Micheletti L, Preti M. Surgery of the vulva in vulvar cancer. 954
887 and feasibility of cidofovir and imiquimod for treatment Best Pract Res Clin Obstet Gynaecol. 2014;28:1074–87 (pii: 955
888 of vulval intraepithelial neoplasia (RT3VIN): a multicen- S1521-6934(14)00135-7). 956
889 tre, open-label, randomised, phase 2 trial. Lancet Oncol. 55. Bogani G, Cromi A, Serati M, et al. Predictors and patterns 957
890 2014;15:1361–8 (pii: S1470-2045(14)70456-5). of local, regional, and distant failure in squamous cell car- 958
891 36. Judson PL, Habermann EB, Baxter NN, Durham SB, Virnig cinoma of the vulva. Am J Clin Oncol. 2014 [Epub ahead of 959
F
892 BA. Trends in the incidence of invasive and in situ vulvar print]. 960
893 carcinoma. Obstet Gynecol. 2006;107:1018–22. 56. Graham K, Burton K. “Unresectable” vulval cancers: is 961
894 37. Hasanzadeh M, Zamiri-Akhlaghi A, Hassanpoor-Moghad- neoadjuvant chemotherapy the way forward? Curr Oncol 962
O
895 dam M, Shahidsales S. Vulvar carcinoma in pregnant Rep. 2013;15:573–80. 963
896 women aged less than 40 years: case report. Iran J Cancer 57. Expert Panel on Radiation Oncology-Gynecology, Kidd E, 964
897 Prev. 2014;7:175–8. Moore D, et al. ACR Appropriateness Criteria® management 965
O
898 38. Ciszko B, Pochwałowski M, St Gabryś M. Risk factors and of locoregionally advanced squamous cell carcinoma of the 966
899 clinical characteristic patients with vulvar cancer. Ginekol vulva. Am J Clin Oncol. 2013;36:415–22. 967
900 Pol. 2006;77:914–21. 58. Iavazzo C, Fotiou S, Salakos N, Bakalianou K, Kondi- 968
PR
901 39. Aragona AM, Cuneo NA, Soderini AH, Alcoba EB. An Pafiti A. HPV-related verrucous carcinoma of the vulva. A 969
902 analysis of reported independent prognostic factors case report and literature review. Eur J Gynaecol Oncol. 970
903 for survival in squamous cell carcinoma of the vulva: is 2011;32:680–1. 971
904 tumor size significance being underrated? Gynecol Oncol. 59. Boujoual M, Hachi H, Rimani M, El Khannoussi B, Bougtab 972
905 2014;132:643–8. A. Verrucous carcinoma of the vulva: report of four cases. 973
906 40. Simbiri KO, Jha HC, Kayembe MK, Kovarik C, Robertson Pan Afr Med J. 2014;17:303. 974
D
907 ES. Oncogenic viruses associated with vulva cancer in 60. Spinu D, Rădulescu A, Bratu O, Checheriţă IA, Ranetti AE, 975
908 HIV-1 patients in Botswana. Infect Agent Cancer. 2014;9:28. Mischianu D. Giant condyloma acuminatum—Buschke- 976
909 41. van Seters W, ten Kate FJW, van Beurden M, Verheijen Lowenstein disease—a literature review. Chirurgia 977
TE
910 RHM, et al. In the absence of (early) invasive carcinoma, (Bucur). 2014;109:445–50. 978
911 vulvar intraepithelial neoplasia associated with lichen 61. Levy A, Lebbe C. Buschke-Löwenstein tumor: diagnosis 979
912 sclerosus is mainly of undifferentiated type: new insights in and treatment. Ann Urol (Paris). 2006;7:175–8. 980
913 histology and aetiology. J Clin Pathol. 2007;60:504–9. 62. Indinnimeo M, Impagnatiello A, D’Ettorre G, et al. Buschke- 981
914 42. Chulvis do Val IC, Almeida Filho GL, Valiante PM, Gon- Löwenstein tumor with squamous cell carcinoma treated 982
EC
915 dim C, Takiya CM, Carvalho Mda G. Vulvar intraepithelial with chemo-radiation therapy and local surgical excision: 983
916 neoplasia p53 expression, p53 gene mutation and HPV in report of three cases. World J Surg Oncol. 2013;11:231. 984
917 recurrent/progressive cases. J Reprod Med. 2004;49:868–74. 63. Ulas M, Bostanci EB, Teke Z, et al. Giant anorectal con- 985
918 43. Trietsch MD, Spaans VM, Ter Haar NT, et al. CDKN2A (p16) dyloma acuminatum of Buschke-Löwenstein: suc- 986
919 and HRAS are frequently mutated in vulvar squamous cell cessful plastic reconstruction with bilateral gluteal 987
920 carcinoma. Gynecol Oncol. 2014;135:149–55. musculocutaneous v-y advancement flap. Indian J Surg. 988
RR
921 44. Li YZ, Li SL, Li X, et al. Expression of endogenous hypoxia 2013;75(Suppl 1):168–70. 989
922 markers in vulvar squamous cell carcinoma. Asian Pac J 64. Santos-Briz A, Antúnez P, López-Ríos F, Rodríguez-Peralto 990
923 Cancer Prev. 2012;13:3675–80. JL, Garzón A. Human papillomavirus-negative spindle cell 991
924 45. Zanvettor PH, Filho DF, Soares FA, Neves AR, Palmeira LO. carcinoma of the vulva associated with lichen sclerosus: 992
925 Study of biomolecular and clinical prognostic factors in case report and literature review. Am J Dermatopathol. 993
CO
926 patients with cancer of the vulva undergoing surgical treat- 2002;24:135–8. 994
927 ment. Int J Gynecol Cancer. 2014;24:766–72. 65. Bigby SM, Eva LJ, Jones RW. Spindle cell carcinoma of the 995
928 46. Pecorelli S. Revised FIGO staging for carcinoma of the vulva: a series of 4 cases and review of the literature. Int J 996
929 vulva, cervix, and endometrium. Int J Gynaecol Obstet. Gynecol Pathol. 2014;33:203–12. 997
930 2009;105:103–4. 66. Choi DS, Lee JW, Lee SJ, et al. Squamous cell carcinoma 998
931 47. O’Shea C, Fitzpatrick JE, Koch PJ. Desmosomal defects in with sarcomatoid features of the vulva: a case report and 999
N
932 acantholytic squamous cell carcinomas. J Cutan Pathol. review of literature. Gynecol Oncol. 2006;103:363–7. 1000
933 2014;41:873–9. 67. Kanitakis J, Arbona-Vidal E, Faure M. Extensive pigmented 1001
934 48. Sznurkowski JJ, Milczek T, Emerich J. Prognostic factors vulvar basal-cell carcinoma presenting as pruritus in an 1002
U
935 and a value of 2009 FIGO staging system in vulvar cancer. elderly woman. Dermatol Online J. 2011;17:8. 1003
936 Arch Gynecol Obstet. 2013;287:1211–8. 68. Saini R, Sarnoff DS. Basal cell carcinoma of the vulva 1004
937 49. Verma SB, Wollina U. Condyloma-like squamous cell car- presenting as unilateral pruritus. J Drugs Dermatol. 1005
938 cinoma of the vulva: report of two midline cases. Clin Cos- 2008;7:288–90. 1006
939 met Investig Dermatol. 2012;5:129–33. 69. Asuman C, Ozlem A, Burçak T, Onder P. An unusual loca- 1007
940 50. Deka P, Barmon D, Shribastava S, Kataki AC, Sharma JD, tion of basal cell carcinoma: the clitoris and the vulva. 1008
941 Bhattacharyya M. Prognosis of vulvar cancer with lymph Indian J Dermatol. 2008;53:192–4. 1009
942 node status and size of primary lesion: a survival study. J 70. Pisani C, Poggiali S, De Padova L, Andreassi A, Bilenchi 1010
943 Midlife Health. 2014;5:10–3. R. Basal cell carcinoma of the vulva. J Eur Acad Dermatol 1011
944 51. Lawrie TA, Patel A, Martin-Hirsch PP, et al. Sentinel node Venereol. 2006;20:446–8. 1012
945 assessment for diagnosis of groin lymph node involve- 71. Kara M, Colgecen E, Yildirim EN. Vulvar basal cell carci- 1013
946 ment in vulval cancer. Cochrane Database Syst Rev. noma. Indian J Pathol Microbiol. 2012;55:583–4. 1014
947 2014;6:CD010409. 72. Wollina U, Pabst F, Krönert C, et al. High-risk basal cell car- 1015
948 52. Robison K, Roque D, McCourt C, et al. Long-term follow- cinoma: an update. Exp Rev Dermatol. 2010;5:357–68. 1016
949 up of vulvar cancer patients evaluated with sentinel lymph 73. Perrone T, Twiggs LB, Adcock LL, Dehner LP. Vulvar basal 1017
950 node biopsy alone. Gynecol Oncol. 2014;133:416–20. cell carcinoma: an infrequently metastasizing neoplasm. 1018
951 53. Herr D, Juhasz-Boess I, Solomayer EF. Therapy for pri- Int J Gynecol Pathol. 1987;6:152–65. 1019
952 mary vulvar carcinoma. Geburtshilfe Frauenheilkd.
953 2014;74:271–5.

Author's Proof
review
1020 74. Elwood H, Kim J, Yemelyanova A, Ronnett BM, Taube JM. 93. Sahincioğlu O, Berker B, Güngör M, Kankaya D, Sertçelik 1085
1021 Basal cell carcinomas of the vulva: high-risk human papil- A. Adenoid cystic carcinoma of the Bartholin’s gland: a rare 1086
1022 lomavirus DNA detection, p16 and BerEP4 expression. Am tumor unmarked by persistent vulvar pain in a postmeno- 1087
1023 J Surg Pathol. 2014;38:542–7. pausal woman. Arch Gynecol Obstet. 2008;278:473–6. 1088
1024 75. Mulvany NJ, Rayoo M, Allen DG. Basal cell carcinoma of 94. Zhan P, Li G, Liu B, Mao XG. Bartholin gland carcinoma: a 1089
1025 the vulva: a case series. Pathology. 2012;44:528–33. case report. Oncol Lett. 2014;8:849–51. 1090
F
1026 76. Rouzbahman M, Clarke B. Neuroendocrine tumors of 95. Kajal B, Talati H, Daya D, Alowami S. Apocrine adenocarci- 1091
1027 the gynecologic tract: select topics. Semin Diagn Pathol. noma of the vulva. Rare Tumors. 2013;5:e40. 1092
2013;30:224–33. 96. Chraibi Z, Hebert T, Body G, Arbion F, Ouldamer L. Bartho-
O
1028 1093
1029 77. Sheikh ZA, Nair I, Vijaykumar DK, Jojo A, Nandeesh M. lin’s gland carcinoma. Gynecol Obstet Fertil. 2014;42:540–2. 1094
1030 Neuroendocrine tumor of vulva: a case report and review 97. Obermair A, Koller S, Crandon AJ, Perrin L, Nicklin JL. Pri- 1095
1031 of literature. J Cancer Res Ther. 2010;6:365–6. mary Bartholin gland carcinoma: a report of seven cases. 1096
O
1032 78. Hierro I, Blanes A, Matilla A, Muñoz S, Vicioso L, Nogales Aust N Z J Obstet Gynaecol. 2001;41:78–81. 1097
1033 FF. Merkel cell (neuroendocrine) carcinoma of the vulva. 98. Kozakiewicz B, Dmoch-Gajzlerska E, Roszkowska-Purska 1098
1034 A case report with immunohistochemical and ultrastruc- K. Carcinomas and sarcomas of Bartholin gland. A report 1099
PR
1035 tural findings and review of the literature. Pathol Res Pract. of nine cases and review of the literature. Eur J Gynaecol 1100
1036 2000;196:503–9. Oncol. 2014;35:243–9. 1101
1037 79. Jońska-Gmyrek J, Bobkiewicz P, Gmyrek L, Zółciak- 99. Agolli L, Osti MF, Armosini V, De Sanctis V, Valeriani M, 1102
1038 Siwińska A, Lindner B, Staniaszek J. Merkel cell carcinoma Enrici RM. Adenoid cystic carcinoma of Bartholin’s gland 1103
1039 of the vulva—case report and the literature review. Ginekol receiving adjuvant radiation therapy: case report. Eur J 1104
1040 Pol. 2013;84:385–9. Gynaecol Oncol. 2013;34:487–8. 1105
D
1041 80. Cardoso JC, Teixeira V, Tchernev G, Wollina U. Merkel cell 100. Ohno T, Nakano T, Abe A, Sano T, Niibe Y, Oka K. 1106
1042 carcinoma: a review and update on aetiopathogenesis, Mucinous adenocarcinoma of Bartholin gland treated 1107
1043 diagnosis and treatment approaches. Wien Med Wochen- with radiation therapy: a case report. Jpn J Clin Oncol. 1108
TE
1044 schr. 2013;163:359–67. 2001;31:226–30. 1109
1045 81. Iavazzo C, Terzi M, Arapantoni-Dadioti P, Dertimas V, Vor- 101. Chung-Park M, Zheng Liu C, Giampoli EJ, Emery JD, Sha- 1110
1046 gias G. Vulvar Merkel carcinoma: a case report. Case Rep lodi A. Mucinous adenocarcinoma of ectopic breast tissue 1111
1047 Med. 2011;2011:546972. of the vulva. Arch Pathol Lab Med. 2002;126:1216–8. 1112
1048 82. Mharrech A, Benchakroun N, Tawfiq N, et al. Small-cell 102. Alsaad KO, Obaidat N, Dube V, Chapman W, Ghazarian 1113
EC
1049 carcinoma of the vulva. J Gynecol Obstet Biol Reprod D. Vulvar apocrine adenocarcinoma: a case with nodal 1114
1050 (Paris). 2006;35:834–83. metastasis and intranodal mucinous differentiation. Pathol 1115
1051 83. Atienza-Amores M, Guerini-Rocco E, Soslow RA, Park Res Pract 2009;205:131–5. 1116
1052 KJ, Weigelt B. Small cell carcinoma of the gynecologic 103. Lee S, Nodit L. Phyllodes tumor of vulva: a brief diagnostic 1117
1053 tract: a multifaceted spectrum of lesions. Gynecol Oncol. review. Arch Pathol Lab Med. 2014;138:1546–50. 1118
2014;134:410–8. 104. Gavriilidis P, Chrysanthopoulos K, Gerasimidou D. Extra- 1119
RR
1054
1055 84. Matsumoto R, Bito T, Washio K, et al. Primary cutaneous mammary Paget’s disease of the vulva. BMJ Case Rep. 1120
1056 small cell carcinoma of the vulva arising from squamous 2013;pii:bcr2013200623. 1121
1057 cell carcinoma. Br J Dermatol. 2011;165:1147–8. 105. Wollina U. Extensive extramammary Paget’s disease: surgi- 1122
1058 85. Cohen J, Chan JK, Kapp DS. The management of small- cal treatment. J Cutan Aesthet Surg. 2013;6:40–4. 1123
1059 cell carcinomas of the gynecologic tract. Curr Opin Oncol. 106. Barmon D, Kataki AC, Imchen L, Sharma JD. Extra mam- 1124
CO
1060 2012;24:572–9. mary Paget’s disease of the vulva. J Midlife Health. 1125
1061 86. Eckert F, Fehm T, Bamberg M, Müller AC. Small cell car- 2012;3:100–2. 1126
1062 cinoma of vulva: curative multimodal treatment in face of 107. Cooper JC, Hew KE, Audlin KM, Im DD, Matsuo K. Syn- 1127
1063 resistance to initial standard chemotherapy. Strahlenther chronous of breast and vulvar Paget’s disease: a case 1128
1064 Onkol. 2010;186:521–4. report. Eur J Gynaecol Oncol. 2012;33:534–6. 1129
1065 87. Jiménez-Ayala M, Pinedo Moraleda F, Rodríguez Alvarez 108. Kim S-A, Kwon J-I, Jung H-R, Lee K-S, Cho J-W. Primary 1130
N
1066 MC. Glandular lesions of the vulva. Monogr Clin Cytol. extramammary Paget’s disease combined with Bowen’s 1131
1067 2011;20:77–86. disease in vulva. Ann Dermatol. 2011;23(Suppl 2):S222–5. 1132
1068 88. Robson A, Lazar AJ, Nagi JB, et al. Primary cutaneous apo- 109. Clayton EF, Rubin SC, Dumoff KL. Paget cells in endome- 1133
U
1069 crine carcinoma: a clinicopathologic analysis of 24 cases. trial and endocervical curettings in a patient with recurrent 1134
1070 Am J Surg Pathol. 2008;32:682–90. vulvar Paget’s disease. Int J Surg Pathol. 2013;22:374–7. 1135
1071 89. Bagwan IN, Taylor A, Dina R. Metastatic apocrine carci- 110. Ladak A, Bramley M, Titi S. Unilateral pigmented extra- 1136
1072 noma of female genital tract. J Clin Pathol. 2009;62:287–88. mammary Paget’s disease of the axilla associated with a 1137
1073 90. Van der Putte SCJ, van Gorp LHM. Adenocarcinoma of benign mole: a case study and a review of literature. Korean 1138
1074 the mammary-like glands of the vulva: A concept unifying J Pathol. 2014;48:292–6. 1139
1075 sweat gland carcinoma of the vulva, carcinoma of super- 111. Luyten A, Sörgel P, Clad A, et al. Interventions for the treat- 1140
1076 numerary mammary glands and extramammary Paget’s ment of Paget’s disease of the vulva. Cochrane Database 1141
1077 disease. J Cutan Pathol. 1994;21:157–63. Syst Rev. 2013;10:CD009245. 1142
1078 91. Hou JL, Wu LY, Zhang HT, Lv NN, Huang Y, Yu GZ. Clinico- 112. Lellé RJ, Harter P, Buttmann N, Petry KU. Treatment of 1143
1079 pathologic characteristics of 12 patients with vulvar sweat extramammary Paget disease of the vulva with imiquimod: 1144
1080 gland carcinoma. Int J Gynecol Cancer. 2010;20:874–8. a retrospective, multicenter study by the German Colpos- 1145
1081 92. Tang QL, Jiang XF, Lin ZQ, Li HG, Wang YA, Luo X. Primary copy Network. J Am Acad Dermatol. 2014;70:644–50. 1146
1082 adenoid cystic carcinoma of sweat glands in vulva: report 113. Nardelli AA, Stafinski T, Menon D. Effectiveness of photo- 1147
1083 of an unusual case and review of the literature. J Obstet dynamic therapy for mammary and extra-mammary Pag- 1148
1084 Gynaecol Res. 2011;37:1694–7. et’s disease: a state of the science review. BMC Dermatol. 1149
2011;11:13. 1150

Author's Proof
review
1151 114. Hata M, Koike I, Wada H, et al. Postoperative radiation 115. Nomura H, Matoda M, Okamoto S, Kondo E, Omatsu K, 1154
1152 therapy for extramammary Paget’s disease. Br J Dermatol. Kato K, Takeshima N. Clinicopathologic features and treat- 1155
1153 2014. doi:10.1111/bjd.13357. [Epub ahead of print]. ment outcomes of primary extramammary Paget disease of 1156
the vulva. J Low Genit Tract Dis. 2014 [Epub ahead of print]. 1157
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Vulvar cancer: a review for dermatologists

Article in Wiener Medizinische Wochenschrift · April 2015

Georgi Tchernev Elena Castelli

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Shyam B Verma Markus Grebe

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Journal Name Wiener Medizinische Wochenschrift

Corresponding Author Family name Wollina

Wien Med Wochenschr

e-mail: wollina-uw@khdf.de 90127 Palermo, PR, Italy

Surgery, 18 Amee Society, Near Rajnigandha Apartments, Diwalipura,

13 Vulvar cancer: a review for dermatologists 1

66 Introduction more numerous and dilated vessels. In addition, it lacks 121

there are isolated cases of occurrence in adolescents 158

2 Vulvar cancer: a review for dermatologists 13

13 Vulvar cancer: a review for dermatologists 3

4 Vulvar cancer: a review for dermatologists 13

T4 > 4.00 a: Without ulceration

M1b Lung metastases Normal

M1c All other visceral me- Normal

13 Vulvar cancer: a review for dermatologists 5

361 Vulvar intraepithelial neoplasia (VIN)

362 The 2004 International Society for the Study of Vulvo-

385 sion, however with high relapse rates between 30 and

390 sions in 46 % with less adverse effects in the cidofovir

carcinoma of the vulva with complete destruction of perineum

6 Vulvar cancer: a review for dermatologists 13

13 Vulvar cancer: a review for dermatologists 7

potential, aggressive behavior, and higher mortality [72, 546

of a bioptic fragment: huge papillomatous, endo-exophytic

8 Vulvar cancer: a review for dermatologists 13

578 Neuroendocrine tumors of the vulva

579 Neuroendocrine tumors of the vulva are rare malignant

602 cell type is the commonest occurring of the three [80].

607 and neurofilaments in typical globular paranuclear

612 cally in vulvar MCC.

617 In general, the recommended therapeutic approach is

13 Vulvar cancer: a review for dermatologists 9

10 Vulvar cancer: a review for dermatologists 13

of the vulva: an extension of cutaneous melanoma? Gyne- 848

786 peutisches Vorgehen bei extrakutanem Melanom und

30. Léonard B, Kridelka F, Delbecque K, et al. A clinical and 865

Biomed Res Int. 2014;2014:480573. 868

13 Vulvar cancer: a review for dermatologists 11

12 Vulvar cancer: a review for dermatologists 13

13 Vulvar cancer: a review for dermatologists 13

14 Vulvar cancer: a review for dermatologists 13

AQ1. Please provide a complete German version of the article title.

AQ2. Please provide keywords and abstract in German.

AQ6. Please provide the expanded form of the acronym TNM.

AQ7. Please provide the significance values of * and † in Table 2.

AQ8. Please check the styling of Table 2.

AQ9. Please provide the significance value of b in Table 3.