Hedwig P. van de Nieuwenhof

Vulvar squamous cell carcinoma development after diagnosis of VIN increases with age

OBJECTIVE The purpose of the present study is to investigate the trends in incidence of both usual (u) and differentiated (d) vulvar intraepithelial neoplasia (VIN) separately, their malignant potential and the relation with other HPV related anogenital lesions in the Netherlands during a 14-year-period. METHODS The incidences of both types of VIN and vulvar SCC were retrieved from the Nationwide Netherlands Database of Histo- and Cytopathology. Population data were retrieved from the Database of Statistics Netherlands. RESULTS In the study period, the incidence of uVIN and dVIN increased, while the incidence of vulvar SCC remained stable. The overall percentage of uVIN patients that were later diagnosed with vulvar SCC was 5.7%, which was significantly lower than the percentage for dVIN patients (32.8%). In addition to this 5.6-fold increased conversion rate, the time of progression from dVIN to SCC development was significantly shorter than that of uVIN (p=0.005). Percentage of uVIN patients that were later diagnosed with SCC significantly increased with age (p=0.005), whereas the time to SCC significantly shortened with age (p=0.05). Forty-one percent of uVIN patients had a past, concomitant or future HPV-associated lesion of the lower genital tract, which is in contrast to the 3% for dVIN patients. CONCLUSIONS An increase in diagnoses of both uVIN and dVIN has not led to an increase in vulvar SCC incidence. The malignant potential of dVIN is higher than that for uVIN. For uVIN the malignant potential increases with age.

The effect of vulvar lichen sclerosus on quality of life and sexual functioning

Lichen sclerosus (LS) is a chronic skin disorder mostly seen on the female anogenital skin. The aim of this study was to evaluate the quality of life (QoL) and sexuality in female patients with LS and to compare their scores with healthy controls. In addition, we wanted to find factors associated with impaired sexual functioning in patients with LS.  Members of the Dutch LS foundation and support group were asked to fill in three questionnaires: the Dermatology Quality of Life Index, Female Sexual Function Index (FSFI) and Female Sexual Distress Scale (FSDS). 215 of 368 patients returned their questionnaire (58.4%). Their scores were compared to a control group which consisted of 61 women of similar age (p = 0.472) without a skin disorder.  Of all domains of QoL, LS interfered most with sexual functioning. Patients significantly scored lower on all subscales of the FSFI (desire (p = 0.016), arousal (p < 0.001), lubrication (p < 0.001), orgasm (p < 0.001), satisfaction (p < 0.001) and pain (p < 0.001), indicating worse sexual functioning. These problems with sexual functioning brought about significant sexual distress (p < 0.001). Patients who experienced more influence on their QoL had more sexual difficulties, leading to more sexual distress independent of their age.

Does experience in colposcopy improve identification of high grade abnormalities

OBJECTIVE This study investigates whether experience in colposcopy improves identification of high grade abnormalities. The sensitivity and positive predictive value (PPV) of colposcopy in identifying high grade intra-epithelial lesions (HSIL) performed by relatively inexperienced as compared to experienced colposcopists are evaluated. STUDY DESIGN Of 18,421 colposcopies performed at the Royal Womens Hospital, Melbourne, Australia, between 1999 and 2004 by 5 senior and 11 junior colposcopists, the colposcopic impression was correlated with the histopathology result of the biopsy taken at 6020 colposcopies, with respect to the experience of the colposcopist. RESULTS Colposcopy had a 60% sensitivity and 60% PPV in identifying HSIL in this study. In case of a high-grade referral smear the sensitivity and PPV in identifying HSIL were, respectively 76% and 73%, compared with 26% and 48% in case of a low-grade referral smear, no difference in overall colposcopic performance between experienced and inexperienced colposcopists was observed. However, the sensitivity of identifying HSIL was significantly higher with inexperienced colposcopists, and the PPV was significantly higher with experienced colposcopists. CONCLUSION In this study experience did not improve colposcopic performance, but differences in colposcopic strategy between the two groups were noted. The rather low overall sensitivity and PPV of colposcopy in identifying HSIL, especially in case of a low-grade referral smear, indicate that the role of colposcopy in the detection and treatment of cervical abnormalities is to assess size, site, and extent of an abnormality, rather than to assess the severity of this abnormality. Histology must remain the gold standard for treatment.

High levels of p53 expression correlate with DNA aneuploidy in (pre)malignancies of the vulva

The molecular pathogenesis of human papilloma virus-unrelated vulvar squamous cell carcinoma is not well known. Whether malignant progression of lichen sclerosus and differentiated vulvar intraepithelial neoplasia to vulvar squamous cell carcinoma could be accompanied by altered DNA content has not been studied extensively. DNA content in isolated nuclei of microdissected normal vulvar epithelium (n = 2), lichen sclerosus (n = 9), differentiated vulvar intraepithelial neoplasia (n = 13), and squamous cell carcinoma (n = 17) from 22 patients was measured via DNA image cytometry. For additional analysis, 6 differentiated vulvar intraepithelial neoplasia lesions were selected, bringing the number of patients to 28. p53 expression was determined by immunohistochemistry on consecutive tissue sections. Thirty-eight percent (5/13) of differentiated vulvar intraepithelial neoplasia lesions and 65% (11/17) of squamous cell carcinomas were DNA aneuploid or tetraploid. In lesions that contained differentiated vulvar intraepithelial neoplasia and adjacent squamous cell carcinoma, the ploidy status of differentiated vulvar intraepithelial neoplasia did not exceed that of squamous cell carcinoma. We observed a strong correlation between high p53 expression and DNA aneuploidy. This relation was also present at the level of a single nucleus, measured by sequential image cytometry of p53 immunohistochemistry followed by DNA image cytometry on formalin-fixed tissue sections. Similarly, we found p53-positive nonproliferating cells with increased DNA content in the superficial compartment of 6 additional solitary differentiated vulvar intraepithelial neoplasia lesions that were not associated with squamous cell carcinoma, indicating ascending aneuploid cells from the basal compartment. DNA ploidy measurements suggest that differentiated vulvar intraepithelial neoplasia has a higher malignant potential than lichen sclerosus and thus is a more likely precursor of squamous cell carcinoma. Furthermore, high p53 expression correlates with increased DNA content and aneuploidy; but it requires further research to unveil a possible causal relation.

A patient with lichen sclerosus, Langerhans cell histiocytosis, and invasive squamous cell carcinoma of the vulva

We report a patient with vulvar lichen sclerosus, Langerhans cell histiocytosis (LCH), and later vulvar cancer. In LCH, high amounts of non functional Langerhans cells are present in the affected tissue, making it possible that LCH may have contributed to vulvar cancer development in this patient.

Specific intraepithelial localization of mast cells in differentiated vulvar intraepithelial neoplasia and its possible contribution to vulvar squamous cell carcinoma development

van de Nieuwenhof H P, Hebeda K M, Bulten J, Otte‐Holler I, Massuger L F A G, de Hullu J A & van Kempen L C L T
(2010) Histopathology 57, 351–362
Specific intraepithelial localization of mast cells in differentiated vulvar intraepithelial neoplasia and its possible contribution to vulvar squamous cell carcinoma development

Never forget medication as a cause: vaginal ulceration caused by nicorandil

A patient was referred to our vulvar outpatient clinic because of a vaginal ulceration that persisted for 3 years and that had been unresponsive to any prescribed therapy. After a possible association was found with nicorandil therapy, this medication was stopped. Thereafter, the ulceration fully healed within 6 months.

The prognostic value of blood and lymph vessel parameters in lichen sclerosus for vulvar squamous cell carcinoma development: an immunohistochemical and electron microscopy study

OBJECTIVE The objective of the study was to quantify vessel type and density in lichen sclerosus (LS) to find a marker for its malignant potential. STUDY DESIGN Quantitative analysis was performed on paraffin-embedded tissue samples of 28 patients with LS (7 adjacent to vulvar squamous cell carcinoma, 21 solitary) and immunohistochemical staining for CD34 (vascular and lymphangiogenic lymph endothelial cells), D2-40 (lymphatic-specific marker), and alpha-SMA (pericyte marker). Electron microscopy was performed on fresh tissue. RESULTS No significant differences in vessel density or other vessel parameters could be demonstrated between the 2 groups. In hyalinized lesions, vessel diameter, and alpha-SMA positivity was reduced compared with nonhyalinized lesions. Electron microscopy revealed detachment of pericytes from vascular endothelial cells and increased thickening of basement membrane, whereas endothelial cell function did not appear strongly impaired. CONCLUSION Malignant potential of LS cannot be predicted by vessel characteristics. Hyalinization in LS is associated with pericyte detachment from the basal lamina of vascular endothelial cells.