[Show abstract][Hide abstract] ABSTRACT: To compare the distribution of International Federation for Cervical Pathology and Colposcopy (IFCPC) transformation zone (TZ) types among women in different age groups referred to 8 colposcopy clinics.
[Show abstract][Hide abstract] ABSTRACT: Carcinogenesis of squamous cell carcinomas (SCC) in the anogenital tract and head and neck region is heterogeneous. A substantial proportion of SCC in the vulva, anus and head and neck follows an HPV-induced carcinogenic pathway. However, the molecular pathways of carcinogenesis in the HPV-independent lesions are not completely understood. We hypothesized that oncogenic KRAS mutations might represent a carcinogenic mechanism in a proportion of those HPV-negative cancers. Considering the repeated observation of KRAS-associated p16INK4a overexpression in human tumors, it was assumed that KRAS mutations might be particularly present in the group of HPV-negative, p16INK4a-positive cancers. To test this hypothesis, we analyzed 66 anal, vulvar and head and neck SCC with known immunohistochemical p16INK4a and HPV DNA status for KRAS mutations in exon 2 (codons 12, 13 and 15). We enriched the tumor collection with HPV DNA-negative, p16INK4a-positive cancers. A subset of 37 cancers was also analyzed for mutations in the BRAF gene. None of the 66 tumors harbored mutations in KRAS exon 2, thus excluding KRAS mutations as a common event in SCC of the anogenital and head and neck region and as a cause of p16INK4a expression in these tumors. In addition, no BRAF mutations were detected in the 37 analyzed tumors. Further studies are required to determine the molecular events underlying HPV-negative anal, vulvar and head and neck carcinogenesis. Considering HPV-independent p16INK4a overexpression in some of these tumors, particular focus should be placed on alternative upstream activators and potential downstream disruption of the p16INK4a pathway.
[Show abstract][Hide abstract] ABSTRACT: Die Inzidenz des Vulvakarzinoms hat in den letzten Jahren deutlich zugenommen. Während früher diese Tumorentität bevorzugt bei älteren Frauen diagnostiziert wurde, werden heutzutage zunehmend jüngere Frauen mit Vulvakarzinomen operiert.Literaturrecherche und Auswertung eigener Daten.Bei den jungen Patientinnen ist in 30–50 % eine Infektion mit humanen Papillomviren (HPV) Auslöser für die Tumorentstehung. Prädilektionsstelle der Tumoren ist die Region zwischen Klitoris und Urethra (> 50 % aller Tumoren, eigene Daten).Die Behandlung ist die Resektion in sano oder (partielle) Vulvektomie und eine inguinofemorale Lymphknotenentfernung ein- oder beidseitig, ggf. Sentinellymphonodektomie in ausgewählten Zentren. Die Deckung des Vulvadefekts mit lokoregionären Lappen zur Verbesserung des ästhetisch-funktionellen Ergebnisses ist eine Therapieoption, die v. a. jungen, sexuell aktiven Frauen angeboten werden sollte. Beispiele werden dargestellt.
[Show abstract][Hide abstract] ABSTRACT: Human papillomavirus (HPV) contribution in vulvar intraepithelial lesions (VIN) and invasive vulvar cancer (IVC) is not clearly established. This study provides novel data on HPV markers in a large series of VIN and IVC lesions.
Histologically confirmed VIN and IVC from 39 countries were assembled at the Catalan Institute of Oncology (ICO). HPV-DNA detection was done by polymerase chain reaction using SPF-10 broad-spectrum primers and genotyping by reverse hybridisation line probe assay (LiPA25) (version 1). IVC cases were tested for p16(INK4a) by immunohistochemistry (CINtec histology kit, ROCHE). An IVC was considered HPV driven if both HPV-DNA and p16(INK4a) overexpression were observed simultaneously. Data analyses included algorithms allocating multiple infections to calculate type-specific contribution and logistic regression models to estimate adjusted prevalence (AP) and its 95% confidence intervals (CI).
Of 2296 cases, 587 were VIN and 1709 IVC. HPV-DNA was detected in 86.7% and 28.6% of the cases respectively. Amongst IVC cases, 25.1% were both HPV-DNA and p16(INK4a) positive. IVC cases were largely keratinising squamous cell carcinoma (KSCC) (N=1234). Overall prevalence of HPV related IVC cases was highest in younger women for any histological subtype. SCC with warty or basaloid features (SCC_WB) (N=326) were more likely to be HPV and p16(INK4a) positive (AP=69.5%, CI=63.6-74.8) versus KSCC (AP=11.5%, CI=9.7-13.5). HPV 16 was the commonest type (72.5%) followed by HPV 33 (6.5%) and HPV 18 (4.6%). Enrichment from VIN to IVC was significantly high for HPV 45 (8.5-fold).
Combined data from HPV-DNA and p16(INK4a) testing are likely to represent a closer estimate of the real fraction of IVC induced by HPV. Our results indicate that HPV contribution in invasive vulvar cancer has probably been overestimated. HPV 16 remains the major player worldwide.
European journal of cancer (Oxford, England: 1990) 07/2013; · 4.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: The incidence of vulvar squamous cell carcinomas located between the clitoris and urethra in young women is rising in distinct geographic regions, but characteristics of the tumors indicating certain carcinogenic mechanisms are unknown. The present study aimed at characterizing these vulvar cancers for their human papillomavirus (HPV), p16, and p53 status, revealing potential pathways of carcinogenesis. MATERIALS AND METHODS: Squamous cell vulvar cancers of the anterior fourchette were retrospectively collected from 8 German hospitals, with additional squamous cell cancers located at other sites of the vulva from 2 of the hospitals. All tumors were analyzed for HPV DNA by polymerase chain reaction and for p16 and p53 expression by immunohistochemistry. RESULTS: Potentially HPV-associated tumors (HPV and p16 positive, 21.4% [27/126] of the anterior fourchette and 27.7% [13/47] from other locations), p53-overexpressing tumors (35.7% [45/126] and 29.8% [14/47]), and a third group (HPV/p16 negative/p53 not overexpressed, 42.9% [54/126] and 42.6% [20/47]) were observed among tumors from the anterior fourchette as well as among vulvar cancers from other locations. Women with vulvar cancers of the anterior fourchette were of young age irrespective of the HPV/p16/p53 status. CONCLUSIONS: Different types of vulvar cancers can be found in squamous cell tumors of the anterior fourchette, similar to the finding in vulvar cancers from other locations and to what has previously been reported for vulvar squamous cell carcinomas in general.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: To describe the (a) symptom experience of women with vulvar intraepithelial neoplasia and vulvar cancer (vulvar neoplasia) during the first week after hospital discharge, and (b) associations between age, type of disease, stage of disease, the extent of surgical treatment and symptom experience. METHODS: This cross-sectional study was conducted in eight hospitals in Germany and Switzerland (Clinical Trial ID: NCT01300663). Symptom experience after surgical treatment in women with vulvar neoplasia was measured with our newly developed WOMAN-PRO instrument. Outpatients (n=65) rated 31 items. We used descriptive statistics and regression analysis. RESULTS: The average number of symptoms reported per patient was 20.2 (SD 5.77) with a range of 5 to 31 symptoms. The three most prevalent wound-related symptoms were 'swelling' (n=56), 'drainage' (n=54) and 'pain' (n=52). The three most prevalent difficulties in daily life were 'sitting' (n=63), 'wearing clothes' (n=56) and 'carrying out my daily activities' (n=51). 'Tiredness' (n=62), 'insecurity' (n=54) and 'feeling that my body has changed' (n=50) were the three most prevalent psychosocial symptoms/issues. The most distressing symptoms were 'sitting' (Mean 2.03, SD 0.88), 'open spot (e.g. opening of skin or suture)' (Mean 1.91, SD 0.93), and 'carrying out my daily activities' (Mean 1.86, SD 0.87), which were on average reported as 'quite a bit' distressing. Negative associations were found between psychosocial symptom experience and age. CONCLUSIONS: WOMAN-PRO data showed a high symptom prevalence and distress, call for a comprehensive symptom assessment, and may allow identification of relevant areas in symptom management.
[Show abstract][Hide abstract] ABSTRACT: Die Inzidenz des Vulvakarzinoms hat in den letzten Jahren deutlich zugenommen. Während diese Tumorentität früher vor allem bei älteren Frauen diagnostiziert wurde, werden inzwischen viele junge Vulvakarzinompatientinnen operiert, bei denen in 30–50% eine Infektion mit humanen Papillomviren (HPV) die Tumorentstehung auslöst. Prädilektionsstelle ist die Region zwischen Klitoris und Urethra (>50% aller Tumoren, eigene Daten). Die Behandlung ist die Resektion in sano oder eine (partielle) Vulvektomie und eine inguinofemorale Lymphknotenentfernung ein- oder beidseitig, ggf. Sentinel-Lymphonodektomie in ausgewählten Zentren. Die Deckung des Vulvadefektes mit lokoregionären Lappen zur Verbesserung des ästhetisch/funktionellen Ergebnisses ist eine Therapieoptionen, die vor allem jungen, sexuell aktiven Frauen angeboten werden sollte; im Beitrag werden Beispiele dargestellt.
[Show abstract][Hide abstract] ABSTRACT: Human papillomavirus is responsible for a variety of diseases including grade 2 and 3 vulvar and vaginal intraepithelial neoplasia. The aim of this study was to assess parts of the burden of the last diseases including treatment costs. The direct medical resource use and cost of surgery associated with neoplasia and related diagnostic procedures (statutory health insurance perspective) were estimated, as were the indirect costs (productivity losses) associated with surgical treatment and related gynaecology visits for diagnostic purposes.
Data from 1991-2008 were retrospectively collected from patient records of the outpatient unit of the Gynaecological Dysplasia Clinic, Heinrich Heine University, Dusseldorf, Germany. Two subgroups of patients were analysed descriptively: women undergoing one surgical procedure related to a diagnosis of vulvar and/or vaginal intraepithelial neoplasia, and women undergoing two or more surgical procedures. Target measures were per-capita medical resource consumption, direct medical cost and indirect cost.
Of the 94 women analysed, 52 underwent one surgical intervention and 42 two or more interventions (mean of 3.0 interventions during the total period of analysis). Patients undergoing one surgical intervention accrued €881 in direct costs and €682 in indirect costs; patients undergoing more than one intervention accrued €2,605 in direct costs and €2,432 in indirect costs.
The economic burden on German statutory health insurance funds and society induced by surgical interventions and related diagnostic procedures for grade 2/3 vulvar and vaginal neoplasia should not be underrated. The cost burden is one part of the overall burden attributable to human papillomavirus infections.
[Show abstract][Hide abstract] ABSTRACT: Das Vulvakarzinom ist nicht mehr ein Alterskarzinom: Die Zunahme dieser Tumorentität um 300–400% in der letzten Dekade ist vor allem durch das gehäufte Auftreten dieser Tumoren bei jungen Frauen bedingt. Abhängig vom Alter der Patientin ist an diesen Tumoren in 30–60% eine Infektion mit humanen Papillomviren (HPV) ursächlich beteiligt. Die Prädilektionsstelle ist die Region zwischen Klitoris und Urethra (etwa 40%). Die Behandlung ist die Resektion in sano oder (partielle) Vulvektomie und eine inguinofemorale Lymphknotenentfernung. Als neue Therapieoptionen ist die Sentinel-Lymphonodektomie und die Deckung des Defektes mit lokoregionären Lappen zur Verbesserung des ästhetischen wie des funktionellen Ergebnisses zu sehen.
[Show abstract][Hide abstract] ABSTRACT: Die HPV-induzierte klassische vulväre intraepitheliale Neoplasie (VIN) ist die häufigste Präkanzerose der Vulva (90%). Die Inzidenz der Erkrankung hat zugenommen und liegt derzeit bei 5–7/100.000 Frauen/Jahr, der Altersmedian liegt bei 46 Jahren. Die Erkrankung kann multifokal auftreten und multizentrisch. Die nicht HPV-assoziierte differenzierte VIN ist selten und tritt v. a. bei älteren Frauen auf. Die Beschwerden sind unspezifisch mit Juckreiz, Brennen oder tastbarer Veränderung. Die Diagnose erfolgt kolposkopisch mittels Stanzbiopsie. Die Standardtherapie ist die chirurgische Entfernung im Gesunden (Exzision oder Lasertherapie). Das Immunmodulans Immiquimod zeigt gute Heilungsraten, ist aber für die Erkrankung nicht zugelassen und deshalb nur im ,,Off-Label-Use“ einsetzbar. Die zweithäufigste prämaligne Läsion ist der M. Paget. Die kolposkopische Verdachtsdiagnose wird über eine Biopsie gesichert. Auch hier besteht die Therapie in der weiten/tiefen Exzision oder Laservaporisation. Die Rezidivrate ist hoch.
[Show abstract][Hide abstract] ABSTRACT: The number of women with vulvar carcinoma located in the anterior fourchette in immediate proximity to the urethral opening has increased. A retrospective analysis was performed in order to evaluate the risk of urinary incontinence after tumor-resection, standard inguinal lymphadenectomy and additional partial urethral resection.
Between 2002 and 2007, 19 women with vulvar carcinomas located close to the urethral opening and consequently treated by additional partial urethral resection of up to 1.5 cm, were evaluated for urinary loss postoperatively by standard incontinence questionnaire. All patients complaining about some kind of urinary loss underwent urodynamic measurement. Results were compared with 21 controls (women with anterior vulvar cancer treated without urethral resection).
Five of 19 women (26%) of the study group complained about urinary disturbances and received urodynamic evaluation. Ninety-five percent of the patients (18/19 women) were continent by urodynamic criteria; in one woman the measurement was unreliable. One patient in the control group (1/21 women) complained of an increase of urge symptoms that had been present preoperatively.
Twenty-six percent of our patients after partial urethral resection reported incontinence symptoms, though this was not always confirmed by urodynamics. We conclude that the risk of urinary stress incontinence after partial urethral resection in anterior vulvar carcinoma is acceptable.
European journal of obstetrics, gynecology, and reproductive biology 09/2010; 154(1):108-12. · 1.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate a vascular endothelial growth factor (VEGF)-targeted gene therapy for the treatment of endometriosis.
Analysis of the VEGF gene expression and promoter activity in ectopic and eutopic endometrium. Evaluation of the specific replication and cell-killing effect of a VEGF-targeted adenovirus (Ad5VEGFE1) in endometriotic cells.
Four patients who underwent hysterectomy for benign disease, 30 women with moderate superficial, and 30 women with deep infiltrating endometriosis.
Immunostaining and gene expression of VEGF was examined in eutopic endometrium, endometriotic lesions, and normal peritoneum. The VEGF promoter activity was evaluated in eutopic endometrium and endometriotic lesions. A VEGF-targeted conditionally replicative adenovirus (Ad5VEGFE1) was evaluated regarding specific viral replication in endometriosis cells and induction of apoptosis. The biodistribution of the VEGF-targeted conditionally replicative adenovirus was examined in a mouse model.
The VEGF gene was highly expressed in ectopic endometrium compared with eutopic endometrium and normal peritoneum. The VEGF promoter was active in endometriotic cells. Ad5VEGFE1 showed efficient viral replication and induction of apoptosis in purified primary endometriotic cells and demonstrated a similar lower targeting to the liver and the uterus in a mouse model.
Ad5VEGFE1 is a promising candidate for treating endometriosis and holds potential for clinical testing.
Fertility and sterility 07/2009; 93(8):2687-94. · 3.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Most cervical cancers are caused by human papillomavirus (HPV) genotypes 16 or 18, while almost all the anogenital warts are related to HPV 6 and 11. In placebo-controlled trials, a vaccine against HPV (6, 11, 16, 18) almost completely prevented infections and associated clinical lesions in primarily not infected women. Furthermore, new data demonstrate that sexually active women, as well as those with prior infection, also benefit from the vaccine. These results suggest that a general vaccination programme for sexually active women will be beneficial.
[Show abstract][Hide abstract] ABSTRACT: Der Lymphabfluss aus der Vulva und dem distalen Drittel der Vagina verläuft über die Leistenlymphknoten (Leisten-LK), der
aus den proximalen zwei Vaginaldritteln nach pelvin. Die Indikation zur Behandlung der Leisten-LK muss wegen hoher Komplikationsraten
streng indiziert werden. Ab einer Infiltrationstiefe von 1mm ist eine relevante Metastasierung zu erwarten. Bei Indikationsstellung
zur LNE (Lymphonodektomie) sollte grundsätzlich eine inguinofemorale LNE durchgeführt werden. Bei lateral gelegenen T1-Tumoren
der Vulva und freien ipsilateralen LK kann auf die kontralaterale LNE verzichtet werden. Bei fortgeschrittenem Befall der
Leiste ist eine Behandlung der pelvinen LK durch Operation oder Bestrahlung indiziert. Bei sehr großen LK-Metastasen ist eine
kombinierte Behandlung durch operatives Debulking und anschließende Radiochemotherapie zu diskutieren. Eine obligate postoperative
Bestrahlung ist bei erhöhtem Rezidivrisiko indiziert. Dabei ist der Radiochemotherapie eine höhere Erfolgsrate zuzuordnen.
The lymphatic drainage of the vulva and the distal third of the vagina is directed to the groin lymph nodes, whereas the drainage
in the proximal two-thirds of the vagina is to the pelvic lymph nodes. Because of the significant rate of complications, indications
for treating the groin lymph nodes must be strict. In tumors exceeding an infiltration depth of 1mm and more, a significant
rate of metastases should be suspected. If the indication is there, a complete inguinofemoral groin lymph node dissection
must be performed (for sentinel node biopsy, see the separate chapter). In strictly laterally located T1 tumors and tumor-free
ipsilateral nodes, a contralateral lymphonodectomy is not necessary. In cases with advanced groin metastases, surgery or radiation
therapy is indicated. If grossly enlarged metastatic lymph nodes are found, a combined debulking therapy followed by radiation
should be considered. In cases with an increased risk of recurrence, additional radiation therapy is mandatory; alternatively,
radiochemotherapy can be given.
Der Onkologe 01/2009; 15(1):40-47. · 0.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The incidence of human papillomavirus (HPV)-induced vulvar cancer in young women is increasing and often presents as microinvasive or early invasive tumors in a grade 3 vulvar intraepithelial neoplasia. So far, the risk of lymph node metastases in early invasive vulvar carcinoma (depth of invasion 1.1-2.0 mm) is reported to be less than 8%. We present 2 cases of young women with early invasive vulvar cancers (depth of invasion 1.5 and 2.0 mm) induced by HPV 16 and 42. In both cases, the cancers are located between the clitoris and urethra and are each accompanied by one groin macro-metastatic lymph node. This case report highlights the necessity for complete inguinofemoral lymphadenectomy and/or adequate radiation therapy of the groin in early invasive tumors in young women to prevent cancer recurrence in the groin. Additionally, the indication for a sentinel node procedure in these specific cases requires particular caution.
Gynecologic and Obstetric Investigation 11/2008; 67(1):42-5. · 1.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the diagnostic accuracy of the sentinel node procedure in patients with vulvar cancer, a multicenter study was launched in Germany in 2003 involving 7 oncology centers.
Between 2003 and 2006, 127 women with primary T1-T3 vulvar cancer were entered in the study and treated with sentinel node removal after application of (99m)Technetium labeled nanocolloid and/or blue dye. Subsequently, in all women a complete inguinofemoral lymphadenectomy and the adequate vulvar operation were performed. Sentinel lymph nodes were examined by routine pathologic examination (H&E), followed by step-sectioning and immunhistochemistry if negative.
The sentinel node procedure was successful in 125 out of 127 cases, in 2 cases no sentinel nodes were detected. 21 patients received unilateral lymphadenectomy, 103 women were operated on both groins. In 39 women out of 127, positive lymph nodes in one or both groins were identified (30.7%). In 36 women, the sentinel nodes were also positive (sensitivity 92.3%). We had three cases with a false negative sentinel node (false negative rate: 7.7%), all of these women presenting with tumors in midline position. One tumor was a T1 tumor (10 mm), 2 tumors being classified as T2 (40 and 56 mm, respectively). In one additional case (18 mm T1 tumor, midline position), the sentinel was positive in the right groin, but false negative on the left side.
This study shows that identification of SLN in squamous cell cancer of the vulva is feasible, however not highly accurate depending on tumor localization and size. The false negative rate seems to be acceptable if the procedure is restricted to stage 1 tumors with clinically negative lymph node status. Tumors situated in or close to the midline seem to be less suitable for this procedure. Implementation of SLNB into clinical practice should be performed with care and only by experienced teams as to avoid preventable groin relapses.
[Show abstract][Hide abstract] ABSTRACT: To characterize the changes in incidence, age of disease onset, tumor site and patients characteristics in women with invasive vulvar cancer in a German University Hospital unit over a 28-year period.
The clinical records for women treated for invasive vulvar cancer from 01/1980 until 06/2007 were analyzed. We performed a retrospective analysis for three 9-year periods: 1/1980 to 02/1989; 3/1989 to 04/1998 and 05/1998 to 06/2007. For each cohort, the number of cases treated, age of disease onset, tumor site and further characteristics were extracted and statistically evaluated.
A total of 224 patients with vulvar cancer were identified between 1/1980 and 6/2007. The number and mean age changed significantly over time: between 1/1980 and 02/1989 53 women with a mean age of 65.6 years were treated for invasive vulvar cancer, between 03/1989 and 04/1998 this number increased to 69 women with a mean age of 63.9 years and in the last period, 102 women with a mean age of 57.0 years were treated for vulvar cancer. The total increase was 192%. In the first period 11% of the women were aged 50 years or less compared with over 41% in the third period (p=0.001). Two-third of the tumors women aged<50 years were HPV-positive. Significant changes in the tumor site were observed; from labial position to the region between clitoris and urethra: 37% in the last period compared with 19% in the first period (p>0.05).
Although in the literature the incidence of invasive cancer has been reported to be stable or only minimally increased, the results of this study show that the number of patients presenting with invasive vulvar cancer has doubled within the last three decades at one university hospital unit in Germany, with a nearly 4-time increase in younger patients (+372%) due to HPV high risk infection. The tumor localization changed significantly from the labia to the area between the clitoris and urethra. Assuming that these limited data reflect the general trend in the incidence of HPV-induced vulvar cancer, widely-implemented prophylactic quadrivalent HPV vaccination, which has been proven to be highly effective against anogenital disease, could make an important contribution to the reduction of the risk of vulvar carcinomas in younger women.