Cytology of the vulva: feasibility and preliminary results of a new brush.

OBJECTIVE: Taking a biopsy is a standard procedure to make the correct diagnosis in patients with suspicious premalignant vulvar lesions. The use of a less invasive diagnostic tool as triage instrument to determine whether biopsy is necessary may improve patient comfort especially in patients with chronic vulvar disorders that may warrant consecutive biopsies. This study was conducted to investigate whether vulvar brush cytology is feasible and may be used to detect (pre)malignant vulvar lesions. METHODS: A pilot study was performed with patients having clinically normal vulvar skin, lichen sclerosus (LS), usual or differentiated vulvar intraepithelial neoplasia or squamous cell carcinoma. A total of 65 smears were taken with the use of a vulvar brush and biopsies were performed for histopathological analysis. RESULTS: Out of 65 smears, 17 (26%) were discarded because of poor cellularity. A total of 28 of 29 (97%) smears with a histological proven (pre)malignancy had a smear classified as 'suspicious' or 'uncertain'. Cytology classified 11 smears as 'non-suspicious', of which 10 (91%) were indeed normal skin or LS. The accuracy, based on the presence of a lesion, for (pre)malignant lesions with the use of the brush showed a sensitivity of 97% and a negative predictive value of 88%. CONCLUSION: Vulvar brush cytology is feasible and may be a first step in the development of a triage instrument to determine whether subsequent biopsy of a clinically (pre)malignant lesion is necessary.

Detection of integrated human papillomavirus by human papillomavirus types 16 and 18 in situ hybridization: a valuable diagnostic tool in diagnosing cervical carcinoma?

Human papillomavirus (HPV) infection is an important factor in cervical carcinogenesis. We describe 3 cases of patients with difficulties in diagnosing either a primary or recurrent cervical carcinoma. These cases illustrate that detection of integrated HPV is helpful in diagnosing cervical carcinoma.

"Owl's eye" cells in a cervical smear of a transplant recipient: don't forget to inform the referring physician.

Cytomegalovirus (CMV) infected cells in cervical smears are a rare finding but may have severe consequences. We describe the presence of characteristic "owl eye" cells in a conventional cervical smear. Medical history revealed a liver transplantation from a CMV seropositive donor 1 yr earlier. The patient experienced a delayed primary CMV infection 6 mo after transplantation. The current CMV infection was considered to be either a persisting manifestation of that primary infection or a reactivation. Since the patient experienced no clinical symptoms, it was decided to "wait and see". Infections with cytomegalovirus in immunocompromised patients may present with aspecific symptoms, but may lead to severe organ-threatening disease such as acute or chronic transplantation loss in transplant recipients. Although in the present case no serious consequences occurred, we stress that it is important to recognize these cells and report this finding promptly to the referring physician to prevent possible severe morbidity.

A substantial part of the fallopian tube is left after standard prophylactic bilateral salpingo-oophorectomy.

Women with a deleterious germline mutation in BRCA1 or BRCA2 are candidates for bilateral salpingo-oophorectomy (BSO). To address the need for adjustment of the current BSO procedure, we investigated the length and the nature of the fallopian tube epithelium that is not removed by BSO. Fourteen consecutive hysterectomy specimens were collected. Complete cross-sections with a 3-mm interval were made of the tubal lumen from the outside of the uterus at the cutoff point of the current BSO procedure to the uterine cavity and examined for the presence or absence of tubal type (ciliated) epithelium and subepithelial endometrial stroma. The fallopian tube remnant had a median length of 12 mm (range 6-15 mm). Tubal type (ciliated) epithelium was shown to be present in all uteri in the first cross-section containing 100% endometrial stroma, as well as in the uterine cavity of all but two of the hysterectomy specimens. A substantial part of the fallopian tube remains in situ after prophylactic BSO and is covered with tubal type ciliated epithelium. More research is necessary to investigate the role of this remnant part of the tube for BRCA carriers.

Normal appearing endometrial cells in cervical smears of asymptomatic postmenopausal women have predictive value for significant endometrial pathology.

The objective of this study was to determine whether postmenopausal asymptomatic women with normal endometrial cells in their smear are at higher risk for endometrial pathology compared with women without these cells. Histologic follow-up outcome and otherwise cytologic follow-up of 29,144 asymptomatic postmenopausal women was determined. Presence of normal endometrial cells, age, use of hormones, and reported elevated maturation index were assessed. The effect of each variable on outcome as well as the combined effect were evaluated. Prevalence rate of (pre)malignant uterine disease was significantly higher when normal endometrial cells were found in the cervical smear (6.5%) as compared to smears without these cells (0.2%), resulting in a relative risk of 40.2 (95% CI 9.4-172.2). Neither age nor hormone use or elevated maturation index showed significant impact on the outcome. Asymptomatic postmenopausal women with normal endometrial cells in their smear are at significant higher risk for (pre)cancerous endometrial lesion than women without these cells. These cases should be reported to the physician with an explicit comment that normal endometrial cells in a smear of a postmenopausal woman is an abnormal finding, possibly associated with significant endometrial pathology. It raises the question whether further gynecological examination would be more appropriate.

Vulvar squamous cell carcinoma is a multifactorial disease following two separate and independent pathways.

Two separate pathways leading to vulvar carcinoma have been suggested. First, a human papillomavirus (HPV)-dependent pathway, in which premalignant stages of vulvar cancer are the classic vulvar intraepithelial neoplasia (VIN) lesions. Second, an HPV-independent pathway, associated with differentiated VIN III lesions and/or lichen sclerosus. To obtain insight into the mechanisms underlying these pathways, we determined the relationship between HPV DNA and the expression of p14(ARF) and p16(INK4A) in non- and (pre)malignant vulvar lesions. Seventy-three archival samples of non- and (pre)neoplastic vulvar lesions were selected and tested for hr-HPV DNA using a broad-spectrum HPV detection/genotyping assay (SPF(10)-LiPA) and the expression of p14(ARF) and p16(INK4A). The prevalence of HPV increased with the severity of the classic VIN lesions; in VIN I no hr-HPV was detected, in VIN II 43%, and in VIN III 71% of the samples were hr-HPV-positive. Roughly the same was true for the expression of p14(ARF) and p16(INK4A). The simultaneous expression of p14(ARF) and p16(INK4A) was highly associated with the presence of hr-HPV DNA. Hr-HPV was detected in only a single case of the differentiated VIN III lesions, whereas no expression of p14(ARF) was found and 16(INK4A) was present in only two cases. All 16 samples of vulvar cancer were hr-HPV DNA- negative, although in respectively 63% and 25%, p14(ARF) and p16(INK4A) was expressed. No relation was found between hr-HPV and the expression of p14(ARF) and p16(INK4A) in the 20 nonneoplastic vulvar lesions. Our results provide further evidence that vulvar squamous cell carcinoma is a multifactorial disease that develops from two different pathways. First, an HPV-dependent pathway with a remarkable resemblance to CIN lesions and cervical carcinoma and second, an HPV-independent pathway in which differentiated VIN III lesions that are hr-HPV-negative may be precursors.