Current insights into the aetiology, pathobiology, and management of local disease recurrence in squamous cell carcinoma of the vulva.

Squamous cell carcinoma of the vulva is predominantly a disease of the elderly, where the mainstay of treatment is radical surgery. Local vulval recurrence (LVR) is a significant problem for these patients, and the rates of recurrence have not improved over the last three decades. Disappointingly, we still lack an understanding of how LVRs develop, and the best approach to prevent and manage the condition. This review discusses recent insights into the key prognostic factors that influence the risk of recurrence, focusing on the role of tumour-adjacent non-neoplastic epithelial disorders, which are thought to play a causative role. TWEETABLE ABSTRACT: A review that discusses the key prognostic factors that influence local recurrence in vulval cancer.

Adjacent Lichen Sclerosis predicts local recurrence and second field tumour in women with vulvar squamous cell carcinoma.

OBJECTIVE: In this study, we investigated if the presence of histologically abnormal epithelium adjacent to the primary tumour influenced the frequency, timing, and topography of local vulvar recurrences (LVR) following treatment for squamous cell carcinoma of the vulva (VSCC). METHODS: The study population comprised a cohort of 201 consecutive cases with incident VSCC. LVR were categorised as local relapses (LR) if they occurred <2cm from the tumour margins, and as second field tumours (SFT) when ≥2cm from these margins. Univariable and multivariable competing risk modelling was performed to identify the prognostic factors associated with local disease recurrence. RESULTS: The characterization of the epithelium adjacent to the invasive component was possible for 199 (99.0%) patients. Of these, 171 (85.9%) were found to have intraepithelial abnormalities found adjacent to the surgical specimen. Multivariable analyses revealed that, following adjustment, Lichen Sclerosis (LS) was associated with an increase in the incidence of LVR, LR and SFT (SHRs: 3.4, 2.7 and 4.4, respectively). Although the incidence of LR and SFT in women with LS associated VSCC was similar, the peak incidence of SFT occurred more than two years before that of LR. CONCLUSIONS: Women with VSCC arising in a field of LS may continue to have an increased risk of developing LR and SFT for many years after resection of their primary tumour. Our study suggests that these women should be followed up more regularly so that LVR can be detected earlier; unless a more robust surveillance programme or chemopreventative treatments become available.

The role of regional anaesthesia in the surgical management of vulval malignancy.

Abstract Surgical excision is the management of choice in vulval cancer however, the patient population are typically elderly and comorbid, for whom general anaesthesia (GA) carries considerable risk. The outcome of 107 procedures were reviewed in order investigate the postoperative complication rates associated with general and regional anaesthesia for the surgical management of vulval cancer. GA was used in 78 (72.9%) cases; 27 (22.9%) had a regional anaesthetic (spinal/epidural/ileoinguinal) and two women had a GA following a failed spinal anaesthetic. Women having a regional anaesthetic were significantly older (p = 0.0198), had a higher ACE (p = 0.0001) and ASA score (p < 0.0001) than those having a GA. There was an association between GA and grade II+ complications, compared with regional techniques (odds ratio, OR 2.72) but this was not significant due to the small number of events. Regional anaesthetic techniques are safe, well-tolerated alternatives to GA for the surgical management of vulval cancer, especially in an elderly and comorbid population.

The use of sentinel node sampling in vulval cancer.

Between March 2007 and December 2009, 38 patients underwent sentinel lymph node biopsy (SLNB) sampling, along with vulvectomy, in their management of vulval cancer. A review has been conducted to establish the reliability and accuracy of the new procedure compared with the traditional total inguinofemoral lymphadenectomy. We also aimed to establish both the short- and long-term morbidities of both total inguinofemoral lymphadenectomy and SLNB and to assess the duration of hospital stay in both groups. Our data have shown a reduced short- and long-term morbidity and reduced length of hospital stay for the SLNB procedure. We conclude that it is a reliable and safe procedure, however it should only be conducted in cancer centres.

Impact of improving outcome guidance in gynaecological cancer on squamous cell carcinoma of the vulva in the West Midlands, UK.

This study aimed to assess the benefits and outcomes of squamous cell carcinoma (SCC) of the vulva managed in a cancer centre post-centralisation of cancer care in the UK. A retrospective study was performed to evaluate the demography and management outcomes of SCC of the vulva in a regional gynaecological cancer centre. The results were then compared with the Rhodes et al. (1998) population-based study. Over the years, disease demography remained largely unchanged. However, centralisation of cancer care has resulted in significant changes in the pattern of care. The number of cases managed has increased by 1.7 times and the permutation of surgeries have reduced from 15 to 4. There is also a significant increased in the number of lymphadenectomies performed (p = 0.003). These changes were accompanied by improvement in 5-year cause-specific survival (p = 0.055).

Anaesthetic choice in the colposcopy clinic: a retrospective analysis of routinely collected data.

OBJECTIVES: Current guidelines recommend that less than 20% of treatments in colposcopy clinics should be under general anaesthetic. The objective of this study was to increase the evidence base for guidelines by establishing the proportion of women receiving general anaesthesia for treatment, determining the predictors of and reasons recorded for general anaesthetic use. DESIGN: Retrospective analysis of routinely collected data. SETTING: NHS Trust in the West Midlands. PARTICIPANTS: Colposcopy patients; January 2003 to March 2005. METHODS: Logistic regression of factors associated with general anaesthetic choice. MAIN OUTCOME MEASURES: Proportion of women treated under general anaesthesia, factors associated with anaesthetic choice and reasons recorded for general anaesthetic use. RESULTS: About 5.4% (204/3777) of new appointments for colposcopy received treatment under general anaesthetic. Of women requiring treatment, 20% (204/1003) received general anaesthetic. General anaesthetic was more likely to be used when the woman required loop excision (OR = 3.63, 95% CI 2.11-6.24) and less likely when directed biopsy was performed (OR = 0.11, 95% CI 0.01-0.80), when the patient appointment date was after introduction of new guidelines (OR = 0.37, 95% CI 0.24-0.56) or when the assessment visit was with a nonconsultant status doctor rather than nurse or consultant (OR = 0.70, 95% CI 0.50-0.97). General anaesthetic use varied between colposcopists ranging from 0 to 16.5% of new patients seen. Woman's choice was the most commonly specified reason for the use of general anaesthetic. CONCLUSIONS: The proportion of colposcopy patients treated under general anaesthetic is 20%, within guideline limits. Substantial variation in general anaesthetic rates between colposcopists was observed, and further investigation is required to discover the reason for this.

Topical tacrolimus in the management of lichen sclerosus.

The effective management of vulval lichen sclerosus (LS) currently depends upon the use of topical steroids and emollients. There are concerns with regard to the long-term toxicity of potent steroids and therefore is a need to consider effective alternatives. Immunomodulatory macrolactams offer an alternative to steroids in the management of some other inflammatory skin disorders and it would seem reasonable therefore to assess their activity in LS. This pilot study of 16 histologically confirmed cases of LS suggests that macrolactams have a positive pharmacological effect.

Accuracy of magnetic resonance imaging of inguinofemoral lymph nodes in vulval cancer.

Inguinofemoral lymphadenectomy contributes to the high morbidity related to surgical treatment of vulval cancer. The objective of this study was to assess the accuracy of magnetic resonance imaging (MRI) in predicting inguinofemoral lymph nodes metastasis in women with vulval cancer. We reviewed the clinical, MRI, surgical, and pathologic findings of 59 women with vulval cancer who were treated at our institution from January 2000 to June 2004. Histology was available for 39 women who had undergone inguinofemoral lymphadenectomy. Clinical and MRI findings were compared with histology result to assess test accuracy. MRI had a positive likelihood ratio (LR+) of 4.8 (95% confidence interval of 2.7-8.6) and negative likelihood ratio (LR-) of 0.17 (0.06-0.49). It had a sensitivity of 85.7% (63.7-97), specificity of 82.1% (69.6-91.1), positive predictive value (PPV) of 64.3% (44.1-81.4), and negative predictive value (NPV) of 93.9% (83.1-98.7). Clinical examination had an LR+ of 6.1 (1.8-21.6) and LR- of 0.69 (0.5-0.96). It had a sensitivity of 35% (15.3-59.4), specificity of 94.3% (84.3-98.8), PPV of 70% (34.7-93.3), and NPV of 79.4% (67.3-88.5). Kappa statistics for interobserver and intraobserver agreement were 0.9091 and 0.8475, respectively. MRI assessment was accurate in predicting negative nodal status that is clinically useful in identifying women who can be spared inguinofemoral lymphadenectomy. It is noninvasive and is superior to clinical assessment. In clinical practice, this should encourage toward nodal sparing surgery, thus lowering surgical-related patient morbidity.

A systematic review of the accuracy of diagnostic tests for inguinal lymph node status in vulvar cancer.

OBJECTIVE: To determine the accuracy of minimally and non-invasive tests to assess the groin node status in squamous cell vulvar cancer. METHODS: A systematic review of published research from 1979 to 2004 that compares the results of tests to determine groin node status with histology at inguinofemoral lymphadenectomy was made. Studies included in the review were those that compared the index test to the standard surgical intervention of inguinofemoral lymphadenectomy and allowed the construction of two-by-two tables. From these tables, sensitivity, specificity, and the likelihood ratios (with 95% confidence intervals) were reported and, where feasible, meta-analysis was used to pool results for each test separately. Sentinel node biopsy using technetium-99m-labelled nanocolloid ((99m)Tc) had a pooled sensitivity and negative LR of 97% (91-100 95% CI) and 0.12 (0.053-0.28 95% CI), respectively, and was the most accurate test reviewed. CONCLUSION: Five diagnostic tests were identified in a total of 29 studies (961 groins). Although the studies were small and the design often poor, this represents the best summary of the data to date. Sentinel node identification using (99m)Tc appeared to be the most promising test for accurately excluding lymph node metastases in squamous cell vulvar cancer and potentially reducing the radicality of surgery. Its efficacy as a tool in reducing the need for radical surgery and associated patient morbidity without reducing survival needs further assessment probably in a randomised control trial.

Is radical hysterectomy for early stage cervical cancer an outdated operation?

Radical hysterectomy and pelvic lymphadenectomy is the standard surgical treatment for early stage cervical cancer. This operation is well recognised as having a higher morbidity and mortality rate than a simple hysterectomy. We studied the histology results of 131 patients who had standard surgery for cervical cancer to ascertain if a radical hysterectomy was required for adequate treatment. Of 110 (84%) patients with negative pelvic lymphadenopathy, only 9 (8%) had positive parametrial histology and all required adjuvant therapy independent of their parametrial histology. This study confirms that a less radical hysterectomy and pelvic lymphadenectomy provides adequate treatment and allows us to consider a more conservative, minimal access approach to the management of these patients.

Adenocarcinoma in situ of the cervix-controversies in diagnosis and treatment.

Adenocarcinoma in situ (AIS) of the uterine cervix is a rare condition. Pap smear screening is unsatisfactory, and the disease has no morphologic reliable colposcopic features. Diagnosis is often made by chance during the treatment of squamous pre-invasive disease, which commonly coexists with AIS. Although the entire endocervical canal can be the site of disease, most lesions lie within 1 cm of the squamocolumnar junction. Skip lesions are rare, making fertility-sparing surgery a possibility under certain conditions. Recurrent disease occurs in 14% of cases when cone margins are free of disease and rise to more than 50% if the margins are involved. The method of conization is immaterial provided a large enough specimen is taken and that the endocervical margins can be evaluated by the pathologist. Follow-up of conservatively managed women is not defined; however, we recommend that regular endocervical cytology be performed in addition to conventional cytology and colposcopy.

Management guidelines for women with normal colposcopy after low grade cervical abnormalities: population study.

OBJECTIVES: To develop an evidence based protocol for the follow up of women with low grade cervical abnormalities for whom treatment is not immediately indicated. DESIGN: Population outcome study. SETTING: Colposcopy clinic of an inner city teaching hospital. PARTICIPANTS: 566 women with low grade cytological abnormalities who were not treated at a first visit to the colposcopy clinic, followed up for a total of 881 years. MAIN OUTCOME MEASURES: Resolution of abnormalities, persistence of disease, and treated disease. RESULTS: Abnormalities resolved in 306 (54.1%) women, whereas 138 (24.4%) had persistent disease and 122 (21.5%) were subsequently treated. Colposcopic opinion, smear test results, age, smoking history, and number of pregnancies were all significantly related to outcome. Logistic regression analysis produced a model that correctly identified 70% of women whose abnormalities resolved. Only 23 of 295 women (7.8%) with a normal cervix on colposcopy and a smear without dyskaryosis at a first visit were treated by the end of the observation period. CONCLUSIONS: Women referred with low grade cytological abnormalities who have a normal cervix on colposcopy and a negative or borderline repeat smear test result may be discharged from the colposcopy clinic. We propose a follow up protocol that could safely avoid unnecessary visits to a clinic.

Response of vulvar lichen sclerosus and squamous cell hyperplasia to graduated topical steroids.

OBJECTIVE: To determine whether symptomatic remission could be obtained equally effectively in patients with vulvar lichen sclerosus, squamous cell hyperplasia or mixed disease in response to a standardized course of graduated topical steroids. STUDY DESIGN: A retrospective analysis of 137 patients with biopsy-proven lichen sclerosus (84), squamous cell hyperplasia (42) or mixed disease (11) treated between 1990 and 1997 with a standard, three-month regimen of graduated topical steroids was carried out. Presence or absence of symptoms and side effects of treatment were recorded three and six months following induction of the initial graduated topical steroid regimen. RESULTS: On completion of the graduated topical steroid course, 59% of patients were asymptomatic (P = .035), and at six months, 58% were asymptomatic (P = .11). Remission of symptoms was more easily achieved in patients with lichen sclerosus as compared to patients with squamous cell hyperplasia and mixed disease at both three and six months (P = .09 at three and P = .035 at six). Four cases of local reactions to the steroids were recorded, as were two cases of vulvar malignancy. CONCLUSION: Symptomatic remission was significantly easier to achieve in patients with vulvar lichen sclerosus as compared to those with squamous cell hyperplasia following treatment with graduated topical steroids.

A study of the follow up patterns of women treated for CIN 2 and 3 before and after the introduction of the 1992 guidelines.

OBJECTIVE: To analyse the five year cytology follow up data after discharge on women treated for histologically proven cervical intraepithelial neoplasia (CIN) 2 and 3. To assess whether the introduction of the 1992 Guidelines for Clinical Practice and Programme Management affected follow up patterns. To identify who was lost to follow up and for what reasons. DESIGN: A retrospective cohort study of cervical cytological follow up data from 186 women treated for CIN 2 and 3. SETTING: Primary care services, West Midlands, United Kingdom. POPULATION: One hundred and eighty-six women with CIN 2 or 3 treated with large loop excision of the transformation zone at the City Hospital, Birmingham, in whom the first follow up smear at six months was normal. The women were divided into two groups: Group 1 consisted of women treated before the introduction of the Guidelines (1988-1990), and Group 2 consisted of women treated at the time of the introduction of the Guidelines in 1992. INTERVENTION: Introduction of the 1992 Guidelines for Clinical Practice and Programme Management. MAIN OUTCOME MEASURES: To determine the number of follow up smears each woman had over a five year period, to determine the number of women who had the recommended number of follow up smears, and to identify the number of women lost to follow up. RESULTS: The median (interquartile range) number of smears in Group 1 was five (four to six) and in Group 2 was four (four to five). A similar proportion of women in both groups subsequently had abnormal smears (15% and 13.6%). Only one woman required further treatment. 22% of women in Group 1 and 10.2% of women in Group 2 had the correct number of smears to fulfil the 1992 Guidelines. There were 21 women (11.3%) who only had one smear following discharge from the clinic in the five year follow up period. CONCLUSIONS: The data from both cohorts shows follow up to be poor, and the introduction of the 1992 Guidelines has yet to result in an improvement in follow up patterns. The absence of a national cervical cytology database means that surveys of cytology follow up data will continue to be difficult due to the problems of data collection from numerous health authorities and the mobility of women in this age group.

Lichen sclerosus of the vulva. Long-term steroid maintenance therapy.

OBJECTIVE: To assess the efficacy of graduated topical steroids for long-term maintenance therapy for vulvar lichen sclerosus. STUDY DESIGN: A prospective observational study was performed in the Gynaecological Oncology Department, City Hospital, Birmingham, U.K. Fifty-four patients were recruited for the study. The diagnosis was confirmed with histopathologic examination. After confirmation of the diagnosis, patients were started on a diminishing regimen of topical steroid. RESULTS: Of the 54 patients in the study, 51 responded to the steroid regimen, and three did not. CONCLUSION: The graduated topical steroid regimen has a high response rate and takes a relatively short time to achieve, justifying the use of graduated topical steroids for this condition. Graduated dose reduction allows the majority of patients to remain in asymptomatic remission and minimize steroid exposure.

Histologic and immunologic associations of an HPV16 variant in LoSIL smears.

BACKGROUND: Human papillomavirus type 16 variants have been described and may have different biologic activities: this has implications for the design of HPV vaccines. OBJECTIVES: The aim of this study was to see if the HPV16 variant E-G 131 can be detected in women with preinvasive disease and to consider the histological and immunological implications of such infection. DESIGN: A prospective observational cross-sectional study on a cohort of women with minor cervical cytological abnormalities was performed. METHODS: Samples were tested for HPV DNA by polymerase chain reaction and restriction enzyme digestion. Blood samples were tested for antibodies to HPV16 virus-like particles (VLP) and to determine class I HLA types. Women found to have abnormal colposcopy were treated by large-loop excision of the transformation zone on a see-and-treat basis. RESULTS: Two hundred forty-one women were included in the study. Infection with the variant was detected in 20. 9% of cases and was not associated with any specific HLA type. These cases were more likely to have high-grade CIN than those with wild-type HPV16 or no HPV16 (chi2 = 18.85, P < 0.001). There were significant differences in seropositivity to HPV16 virus-like particles between the three groups (chi2 = 32.43, P < 0.001). CONCLUSIONS: The E-G 131 variant may have increased oncogenic potential by evading host immune responses, but its identification is only weakly predictive of high-grade disease in stepwise logistic regression. The lack of seropositivity to HPV16 VLP has implications for the design of prophylactic vaccines based on VLP to HPV16.