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.

Combination bleomycin, ifosfamide, and cisplatin chemotherapy in cervical cancer.

We report a phase II study of bleomycin, ifosfamide, and cisplatin (BIP) in cervical cancer. Our aims were to assess response rate, toxicity, and survival in women treated with this combination. Among 49 patients, 34 objective responses (69%) were seen, with 10 complete responses (20%). Toxic effects were assessed in 186 treatment cycles. All patients had alopecia and nausea and vomiting. Other effects included myelosuppression, infection, reduction in renal function, and disturbance of consciousness. These data indicate that BIP is highly active against advanced and recurrent cervical cancer.

Early serum CA125 response and outcome in epithelial ovarian cancer.

The prognostic value of serum CA125 levels before and after two courses of chemotherapy was assessed in 50 patients with advanced epithelial ovarian cancer. Patients with serum CA125 values below 35 U/ml after two courses were significantly more likely to achieve complete remission and had a significantly longer median survival. In multivariate analysis, serum CA125 levels after two courses were the most important independent prognostic factor: it was possible to predict survival status at 12 months with an overall accuracy of 93%. Serum CA125 can be used to evaluate quantitatively chemotherapeutic response and at an early stage classify patients into good and poor risk groups. Such an approach would facilitate the selection of appropriate therapy and could reduce toxicity.

Glycoprotein patterns in normal and malignant cervical tissue.

Glycoproteins from normal and malignant human cervix were studied using an organ culture system and compared by gel electrophoresis and autoradiography. Five glycoproteins of 178 kDa, 95 kDa, 93 kDa, 82 kDa and 38 kDa and 1 glycolipid (46 kDa) were detected more frequently in squamous carcinomas. Certain glycoproteins were shown to be oncofoetal and some had affinity for Concanavalin A (Con A). The 82 kDa glycoprotein was present in 16/17 squamous carcinomas but in only 1/13 normal cervices. This band represented a glycoprotein containing glucosamine, mannose, small quantities of methionine and no fucose. These preliminary results suggest that these glycoproteins and in particular the 82-kDa glycoprotein are worthy of further investigation and characterisation.

Residual disease after cone biopsy: completeness of excision and follow-up cytology as predictive factors.

Residual disease was identified in the hysterectomy specimen in 19 of 65 patients (29%) previously found to have cervical intraepithelial neoplasia and in four of 19 (21%) found to have early stromal invasion on histologic examination of a cone biopsy. Residual disease was found in six of 34 cases (18%) of cervical intraepithelial neoplasia and zero of 12 cases of early stromal invasion after complete excision, and in 13 of 31 cases (42%) of cervical intraepithelial neoplasia and four of seven cases (57%) of early stromal invasion after incomplete excision by cone biopsy. Sixteen of 28 women (57%) with abnormal cytology after cone biopsy were found to have residual disease at the time of hysterectomy. In contrast, no residual disease was found in 35 patients who had no evidence of cytologic abnormality after the initial treatment. The finding of abnormal cytology after cone biopsy is shown to be a more useful prognostic indicator than histologic examination of excision margins. Therefore, we believe that a policy of expectant management, based on regular cytologic examination, is justified when histologic assessment has shown the lesion to extend to the line of excision.

Neoadjuvant (cytoreductive) chemotherapy combined with intervention debulking surgery in advanced, unresected epithelial ovarian cancer.

Thirty-six patients with epithelial ovarian cancer, incompletely resected at primary laparotomy, were treated with one of two intensive cis-platinum-based combination chemotherapy regimens. The intention was to perform further surgical debulking (intervention debulking surgery) after three cycles in patients responding to treatment. Intervention debulking surgery was carried out in 28 of 36 patients (78%) at a median interval of 12.7 weeks from primary diagnosis. Omentectomy and total abdominal hysterectomy were the most commonly performed procedures at intervention debulking. As a result of such surgery, 16 of the 28 women (57%) were left with no macroscopic residual disease, five (18%) had less than 1 cm, four (14%) less than 2 cm residuum, and three (11%) remained with more extensive disease. Post-intervention debulking surgical complications were few, with a median postoperative hospital stay of 10 days and a median interval of 21 days from debulking surgery to resumption of chemotherapy. Neoadjuvant (cytoreductive) chemotherapy combined with early secondary surgical debulking is feasible, with little severe morbidity, and can leave a high proportion of patients free of macroscopic disease. The effect of such a program on patient survival is now being tested in a randomized study.

Management of postconization cervical stenosis by laser vaporization.

In 18 patients with symptomatic cervical stenosis after conization, laser vaporization of the stenotic segment was performed. Total relief of symptoms was achieved in 12 patients and partial relief in four. In seven cases there was no evidence of stenosis at follow-up, and in a further nine cases the degree of stenosis was less. In seven cases it was possible to visualize the squamocolumnar junction at follow-up. This had not been possible in any cases before the procedure. Vaporization using the carbon dioxide laser provides a useful conservative management technique for postconization stenosis.

Second-look laparotomy in the management of epithelial ovarian carcinoma: an evaluation of fifty cases.

Fifty patients with ovarian cancer had a second-look laparotomy performed after chemotherapy. Complete histologic response was confirmed in 12 patients, microscopic disease was found in 12 patients, and macroscopic disease was found in 26 patients. Fifteen patients with macroscopic disease had total tumor clearance at second look. Surgical response to chemotherapy was found to correlate well with disease volume at the onset of chemotherapy. The operation is a safe, accurate technique for assessing the ovarian cancer patient. The findings and outcome probably depend upon the timing of the procedure. Any survival benefit from the operation remains to be proved.

High-dose intravenous metoclopramide and intermittent intramuscular prochlorperazine and diazepam in the management of emesis induced by cis-dichlorodiammineplatinum.

Intravenous metoclopramide and IM prochlorperazine and diazepam were compared in the management of vomiting occurring during treatment with cis-dichlorodiammineplatinum (cis-platinum). A total of 104 cycles in 30 patients were evaluated. Twenty-two patients took part in a cross-over study in which emetic profiles for each patient managed with each anti-emetic schedule were compared. In all, 44 cycles of treatment in 22 patients were evaluated as part of a cross-over study. No significant difference in emetic control was observed between the two anti-emetic regimens. The side-effects observed using IV metoclopramide included extrapyramidal phenomena (19%) and flushing attacks (16%).

The potential for adjuvant therapy in early-stage cervical cancer.

Adjuvant therapy may potentially improve prognosis in women with early-stage cervical cancer who are at high risk of relapse after primary therapy. Patients with lymph node involvement at surgery are at high risk of recurrence and may benefit from adjuvant therapy, but many patients are treated with radical radiotherapy. At present there is no method of accurately identifying patients at high risk of recurrence in the latter group. A retrospective analysis of 141 surgically managed cases with stage I/II a cervical cancer is presented. The study aims were to characterize patients at high risk of relapse, identify independent prognostic variables predicting for relapse and, using these variables, develop a model, that would accurately predict high-risk patients. Univariate analysis identified depth of invasion, substage, lymph node involvement, lymphatic and blood vessel invasion and tumour differentiation as significant prognostic variables. After stratification for depth of invasion, which did not conform to the proportional hazards assumption implicit in the Cox model, Cox regression analysis showed substage, lymphatic and vascular invasion and histological tumour type to be independent prognostic variables. Using these variables, classification models were constructed that would be applicable to patients treated with either surgery or radiotherapy. Applying the models to 110 cases with greater than 18 months follow-up, 11/18 (61%) and 11/19 cases (58%) predicted as being at high risk of relapse have developed recurrence. Highly active chemotherapy is now available for this disease. We have demonstrated that combined bleomycin, ifosfamide and cisplatin (BIP) is one of the most active regimens in this disease. BIP produces cytoreduction in around 70% of patients with recurrent and primary advanced disease. Responses are achieved rapidly and acute radiotherapy toxicity is not enhanced by giving chemotherapy prior to radical local radiotherapy. A multicentre, prospective randomized trial testing the role of BIP as adjuvant therapy in patients with positive nodes at radical hysterectomy is now in progress. A complementary study testing the role of adjuvant chemotherapy in high-risk patients treated with radical radiotherapy is in preparation.

Early second surgery in ovarian cancer--improving the potential for cure or another unnecessary operation?

The presence and amount of residual disease after primary surgery is a major adverse prognostic factor in epithelial ovarian cancer [EOC]. Rapid initial cytoreduction employing second surgery early in the primary chemotherapeutic management of patients with gross residual disease has been advocated as a means of improving outcome. To evaluate the prognostic value of such an approach we have reviewed the outcome of 24 patients with gross residual disease, who were debulked to less than 2 cm residuum at a second operation, performed after three cycles of cis-platinum-based chemotherapy (a median of 14 weeks from the initial laparotomy), and compared this with an historical series of 195 patients with residual disease (70 patients with less than 2 cm residuum) who received cis-platinum but no early secondary surgery. In the control series, stage and residual disease status were important prognostic factors. There was no significant difference in patient or disease characteristics between those patients in the early second surgery group and control patients with greater than 2 cm disease (n = 125). Initially the survival curve for the early second surgery group was similar to the less than 2 cm disease group, but at about 18 months, there was a rapid deterioration until the survival parallels that of the patients with bulky disease at presentation. Early secondary surgery did not significantly prolong survival in patients with greater than 2 cm of residual disease.

Survival after negative second-look laparotomy.

Complete pathological responses, as defined by multiple negative intraperitoneal biopsies at second-look laparotomy, were recorded in 22 of 120 patients with epithelial ovarian cancer. Patients had been previously treated with either high-dose single agent cisplatinum (19) or total abdominal and pelvic irradiation (3). Nine of 21 (43%) evaluable patients developed recurrent disease after 'negative' second-look laparotomy. The median time to relapse was 15 months (3-19) and the median survival after relapse, 4 months (1-6). One patient remains alive with evidence of disease.

Survival following intestinal obstruction in ovarian cancer.

A retrospective survey of 38 ovarian cancer patients who developed radiologically confirmed intestinal obstruction was performed. Twenty-six patients underwent surgery. In the surgical treatment group, obstruction was not due to recurrent disease in six cases. The median survival for the group as a whole was 56 days. Patients in the operative group survived significantly longer than those in the non-operative group. There was an operative mortality of 15% and major postoperative morbidity was seen in 42%. Neither the site of the obstruction nor the type of operation influenced survival. No postoperative chemotherapy responses were seen in previously treated patients.

Cervical cytologic abnormalities and negative colposcopy: histologic assessment.

Colposcopic assessment may be normal in the presence of severe or persistent minor cytologic abnormality. To assess the significance of negative satisfactory colposcopy in patients with abnormal cervical smears, a retrospective review was carried out on 1170 patients who had undergone out-patient loop diathermy excision for abnormal cervical cytology. Of these, 69 patients were treated for abnormal cervical cytology, despite normal colposcopic findings. Cytologic abnormalities ranged from persistent borderline changes to severe dyskariosis. Histologic assessment of the excision specimens revealed cervical intraepithalial neoplasia (CIN) in 43 (62.3%) cases, of which high-grade CIN accounted for 24 (34.8%) cases. There was good correlation between cytologic and histologic diagnosis. Simple regression analysis showed r = 0.46, P < 0.0001. The cytologic abnormality was highly predictive of the corresponding histologic diagnosis. This analysis has shown that significant intraepithelial lesions may exist despite negative colposcopic examination and highlights the need for histologic evaluation in such cases. In these circumstances, loop cone biopsy permits accurate definition of lesion severity, avoids potential undertreatment of significant lesions and causes less morbidity than conventional cone biopsy.