Sentinel node biopsy for diagnosis of lymph node involvement in endometrial cancer.

BACKGROUND: Pelvic lymphadenectomy provides prognostic information for those diagnosed with endometrial (womb) cancer and provides information that may influence decisions regarding adjuvant treatment. However, studies have not shown a therapeutic benefit, and lymphadenectomy causes significant morbidity. The technique of sentinel lymph node biopsy (SLNB), allows the first draining node from a cancer to be identified and examined histologically for involvement with cancer cells. SLNB is commonly used in other cancers, including breast and vulval cancer. Different tracers, including colloid labelled with radioactive technetium-99, blue dyes, e.g. patent or methylene blue, and near infra-red fluorescent dyes, e.g. indocyanine green (ICG), have been used singly or in combination for detection of sentinel lymph nodes (SLN). OBJECTIVES: To assess the diagnostic accuracy of sentinel lymph node biopsy (SLNB) in the identification of pelvic lymph node involvement in women with endometrial cancer, presumed to be at an early stage prior to surgery, including consideration of the detection rate. SEARCH METHODS: We searched MEDLINE (1946 to July 2019), Embase (1974 to July 2019) and the relevant Cochrane trial registers. SELECTION CRITERIA: We included studies that evaluated the diagnostic accuracy of tracers for SLN assessment (involving the identification of a SLN plus histological examination) against a reference standard of histological examination of removed pelvic +/- para-aortic lymph nodes following systematic pelvic +/- para-aortic lymphadenectomy (PLND/PPALND) in women with endometrial cancer, where there were sufficient data for the construction of two-by-two tables. DATA COLLECTION AND ANALYSIS: Two review authors (a combination of HN, JM, NW, RG, and WH) independently screened titles and abstracts for relevance, classified studies for inclusion/exclusion and extracted data. We assessed the methodological quality of studies using the QUADAS-2 tool. We calculated the detection rate as the arithmetic mean of the total number of SLNs detected out of the total number of women included in the included studies with the woman as the unit of analysis, used univariate meta-analytical methods to estimate pooled sensitivity estimates, and summarised the results using GRADE. MAIN RESULTS: The search revealed 6259 unique records after removal of duplicates. After screening 232 studies in full text, we found 73 potentially includable records (for 52 studies), although we were only able to extract 2x2 table data for 33 studies, including 2237 women (46 records) for inclusion in the review, despite writing to trial authors for additional information. We found 11 studies that analysed results for blue dye alone, four studies for technetium-99m alone, 12 studies that used a combination of blue dye and technetium-99m, nine studies that used indocyanine green (ICG) and near infra-red immunofluorescence, and one study that used a combination of ICG and technetium-99m. Overall, the methodological reporting in most of the studies was poor, which resulted in a very large proportion of 'unclear risk of bias' ratings. Overall, the mean SLN detection rate was 86.9% (95% CI 82.9% to 90.8%; 2237 women; 33 studies; moderate-certainty evidence). In studies that reported bilateral detection the mean rate was 65.4% (95% CI 57.8% to 73.0%) . When considered according to which tracer was used, the SLN detection rate ranged from 77.8% (95% CI 70.0% to 85.6%) for blue dye alone (559 women; 11 studies; low-certainty evidence) to 100% for ICG and technetium-99m (32 women; 1 study; very low-certainty evidence). The rates of positive lymph nodes ranged from 5.2% to 34.4% with a mean of 20.1% (95% CI 17.7% to 22.3%). The pooled sensitivity of SLNB was 91.8% (95% CI 86.5% to 95.1%; total 2237 women, of whom 409 had SLN involvement; moderate-certainty evidence). The sensitivity for of SLNB for the different tracers were: blue dye alone 95.2% (95% CI 77.2% to 99.2%; 559 women; 11 studies; low-certainty evidence); Technetium-99m alone 90.5% (95% CI 67.7% to 97.7%; 257 women; 4 studies; low-certainty evidence); technetium-99m and blue dye 91.9% (95% CI 74.4% to 97.8%; 548 women; 12 studies; low-certainty evidence); ICG alone 92.5% (95% CI 81.8% to 97.1%; 953 women; 9 studies; moderate-certainty evidence); ICG and blue dye 90.5% (95% CI 63.2.6% to 98.1%; 215 women; 2 studies; low-certainty evidence); and ICG and technetium-99m 100% (95% CI 63% to 100%; 32 women; 1 study; very low-certainty evidence). Meta-regression analyses found that the sensitivities did not differ between the different tracers used, between studies with a majority of women with FIGO stage 1A versus 1B or above; between studies assessing the pelvic lymph node basin alone versus the pelvic and para-aortic lymph node basin; or between studies that used subserosal alone versus subserosal and cervical injection. It should be noted that a false-positive result cannot occur, as the histological examination of the SLN is unchanged by the results from any additional nodes removed at systematic lymphadenectomy. AUTHORS' CONCLUSIONS: The diagnostic test accuracy for SLNB using either ICG alone or a combination of a dye (blue or ICG) and technetium-99m is probably good, with high sensitivity, where a SLN could be detected. Detection rates with ICG or a combination of dye (ICG or blue) and technetium-99m may be higher. The value of a SLNB approach in a treatment pathway, over adjuvant treatment decisions based on uterine factors and molecular profiling, requires examination in a high-quality intervention study.

Diagnostic Accuracy in Assessment of Depth of Myometrial Invasion in Low-grade Endometrioid Carcinoma: A 2 Center Comparative Study by MRI and Intraoperative Assessment.

The role of lymphadenectomy in endometrial carcinomas is controversial, especially in low-grade endometrioid carcinomas. In many institutions, lymphadenectomy in the latter neoplasms is undertaken only when there is deep myometrial invasion, defined as invasion involving 50% or more of the myometrium (FIGO stage IB). There has been considerable debate as to the best modality to detect deep myometrial invasion. In Europe, preoperative magnetic resonance imaging (MRI) is the most commonly used modality while in North America, intraoperative assessment (IOA) is undertaken in most, but not all, institutions. The aim of this study was to compare the diagnostic accuracy of these 2 modalities in identifying deep myometrial invasion in low-grade endometrioid carcinomas. Two patient cohorts were studied from Belfast, UK (n=253) and Boston, USA (n=276). With respect to detecting deep myometrial invasion, MRI had a sensitivity of 72.84%, positive predictive value of 75.64% and a positive likelihood ratio of 6.59 (95% confidence interval; 4.23-10.28). IOA had a sensitivity of 78.26%, positive predictive value of 80% and a positive likelihood ratio of 20.00 (95% confidence interval; 10.35-38.63). The superior positive likelihood ratio suggests that IOA is better than MRI in determining deep myometrial invasion and the nonoverlapping 95% confidence intervals suggest this is a significant finding. However, there are significant resource implications associated with IOA and preoperative MRI carries other advantages that are discussed herein.

Early catheter removal following laparoscopic radical hysterectomy for cervical cancer: assessment of a new bladder care protocol.

Evidence to support prolonged catheterisation after radical hysterectomy is lacking. We sought to assess feasibility of a new protocol of early post-operative catheter removal following laparoscopic radical hysterectomy for cervical cancer. A retrospective review of post-operative bladder care in patients who underwent laparoscopic radical hysterectomy for cervical cancer was carried out. The post-operative bladder care protocol recommended catheter removal after 24-72 hours. Three consecutive post-void residual scans of less than 150 millilitres (ml) were considered evidence of normal voiding function. First line management of voiding dysfunction was clean intermittent self-catheterisation (CISC). Ninety-eight patients underwent laparoscopic radical hysterectomy for cervical cancer of whom 78 patients had catheter removal 24-72 hours post-operatively. The incidence of post-operative voiding dysfunction in this group was 44%, of whom 88% were managed with CISC and 82% regained normal voiding function. Average hospital stay was 4.2 days. The overall rate of long-term voiding dysfunction was 6%. Early catheter removal after laparoscopic radical hysterectomy appears to be both feasible and effective and compliments the ethos of enhanced patient recovery.

Does Cervical Screening in Young Women Aged 20-25 Years Lead to Unnecessary and Harmful Interventions?

BACKGROUND: Cervical human papillomavirus (HPV) infection among young women (20-25 years of age) is common and normally transient. There are growing concerns that referral to a colposcopy clinic may lead to unnecessary treatment with an increased risk of obstetric complications. Therefore, the purpose of this study was to determine the level of intervention for cervical abnormalities in this age group of the Northern Ireland population. MATERIALS AND METHODS: A review of all serial new patients under 25 years of age, who were referred to colposcopy clinics in Northern Ireland between January 1, 2009 to June 30, 2009 formed the basis of this study. RESULTS: During the study period, a total of 4,767 women under 25 years of age were screened. Two-hundred-and- thirty-four (4.9%) cases were referred to the colposcopy clinics. The cervical cytology results were: high-grade abnormality in 35%, and low-grade abnormality in 31% of these cases. One-hundred-and-seventy-eight (76%) of the referred women received at least one treatment. One-hundred-and-twenty-one of 234 (51.5%) women underwent an excisional treatment with histology showing the presence of high-grade abnormalities (CIN2-3) in 52%, CIN1 in 28%, and Koilocytosis or normal tissue in 20% of this sub-group of cases. CONCLUSIONS: Screening women under the age of 25 years cause unnecessary referral for colposcopy. This may also result in considerable anxiety and psychosexual morbidity. It leads to an over-treatment with a potential of negative impact on the future pregnancy outcomes (including pre-term delivery, low birth weight, and pre-term premature rupture of membranes).

Multifocal FIGO stage 1A1 cervical squamous carcinomas have an extremely good prognosis equivalent to unifocal lesions.

Early invasive squamous carcinomas of the cervix are sometimes multifocal. There are few guidelines regarding how to measure multifocal carcinomas and options include measuring from the edge of 1 invasive focus to the edge of the furthest invasive focus, adding the maximum horizontal dimension of each invasive focus together or regarding multiple foci as representing distinct small areas of invasion and if clearly separate measure them individually. For tumors with a shallow depth of invasion (<3 mm), this has implications for staging and management because if the maximum horizontal dimension is taken from the edge of 1 invasive focus to the edge of the furthest invasive focus, this could represent a International Federation of Gynaecology and Obstetrics (FIGO) 1B1 carcinoma, whereas alternatively these could be regarded as separate foci of 1A1 disease. It has been our practice to regard such lesions as representing multiple foci of invasion (multifocal FIGO 1A1 carcinomas) if clearly separate, arbitrarily defined by us as a minimum of 2 mm between each separate focus of invasion. In this study, we have obtained follow-up in a series of "multifocal 1A1 cervical squamous carcinomas" treated by local excisional methods (large loop excision of transformation zone or cone biopsy) with margins clear of premalignant and malignant disease. The study included 22 cases, 11 of which (50%) would have been regarded as FIGO stage 1B1 if the horizontal dimension had been measured from the edge of 1 invasive focus to the edge of the furthest invasive focus. In none of the cases was there evidence of recurrence of premalignant or malignant disease during follow-up (9-91 mo; mean and median 48 and 45.5 mo, respectively). Although limited by a relatively small number of cases, our results support the hypothesis that with regard to tumor staging and management, it is best to consider multifocal lesions as representing separate individual foci of invasion, to measure each focus separately, and to determine the FIGO stage on the basis of the highest FIGO stage of an individual focus.

Diagnostic accuracy of magnetic resonance imaging in endometrial cancer.

OBJECTIVES: The objectives of this study were to investigate the accuracy of magnetic resonance imaging (MRI) in predicting the depth of myometrial invasion in the preoperative assessment of women with endometrial cancer and to quantify the impact of MRI as an adjunct to predicting patients requiring full surgical staging. METHODS: This was a diagnostic accuracy study of prospective cases in conjunction with STARD guidelines using collected data from a tumor board within a cancer network. Consecutive series of all endometrial cancers in Northern Ireland over a 21-month period was discussed at the Gynaecological Oncology Multidisciplinary Team/tumor board meeting. This study concerns 183 women who met all the inclusion criteria. Main outcome measure was the correlation between the depth of myometrial invasion suggested by preoperative MRI study and the subsequent histopathological findings following examination of the hysterectomy specimen. Secondary end point was how MRI changed management of women who required surgery to be performed at a central cancer center. RESULTS: For the detection of outer-half myometrial invasion, overall sensitivity of MRI was 0.73 (95% confidence interval [CI], 0.59-0.83), and specificity was 0.83 (95% CI, 0.76-0.89). The positive predictive value was 0.63 (95% CI, 0.50-0.74), and negative predictive value was 0.89 (95% CI, 0.82-0.93). Positive likelihood ratio was 4.35 (95% CI, 2.87-6.61), and negative likelihood ratio was 0.33 (95% CI, 0.21-0.52). Magnetic resonance imaging improved the sensitivity and negative predictive value of endometrial biopsy alone in predicting women with endometrial cancer who require full surgical staging (0.73 vs 0.65 and 0.80 vs 0.78, respectively). CONCLUSIONS: Preoperative pelvic MRI is a moderately sensitive and specific method of identifying invasion to the outer half of myometrium in endometrial cancer. Addition of MRI to preoperative assessment leads to improved preoperative assessment, triage, and treatment.

Do FIGO stage IA and small (≤2 cm) IB1 cervical adenocarcinomas have a good prognosis and warrant less radical surgery?

OBJECTIVES: There is a controversy regarding the optimal management of small cervical adenocarcinomas, and more radical surgery is often undertaken compared to similar size squamous carcinomas. We wished to determine the risk of parametrial involvement and metastatic disease and the outcome in International Federation of Gynecology and Obstetrics (FIGO) stage IA and small (≤2 cm) stage IB1 cervical adenocarcinomas. METHODS: All women with a diagnosis of International Federation of Gynecology and Obstetrics stages IA1, IA2, or IB1 cervical adenocarcinoma with a maximum tumor size of 2 cm were identified between 1999 and 2010 in Northern Ireland. A single pathologist reviewed all pathology prospectively at a cancer center tumor board. RESULTS: A total of 74 women were identified (mean age, 39 years; range, 25-72 years). In total, 36 women had stage IA1, 9 women had stage IA2, and 29 women had stage IB1 cervical adenocarcinomas. Surgical treatment ranged from local excision (cone or large loop excision of transformation zone) to radical hysterectomy and pelvic lymph node dissection; adjuvant therapy was not administered in any case. No parametrial involvement was seen in the 36 women who underwent parametrial resection. No lymph node metastasis was identified in the 45 women who underwent pelvic lymph node dissection. Lymphovascular space invasion was identified in 6 cases. No tumor recurrence or metastasis was noted during a mean follow-up of 35 months. CONCLUSIONS: The optimal management of women with IA or small IB1 cervical adenocarcinoma is controversial, and radical surgery is often undertaken. Our data suggest that there is an extremely low risk of parametrial and lymph node involvement with tumors 2 cm or smaller and a low recurrence rate. Less radical surgery may be warranted for small cervical adenocarcinomas, and this should be addressed by future studies.

Postirradiation primary vaginal angiosarcoma with widespread intra-abdominal metastasis.

We report a primary vaginal angiosarcoma with widespread intra-abdominal metastasis occurring in a 73-yr-old woman 13 yr after vaginal brachytherapy for an endometrial carcinoma. This is an extremely rare phenomenon with only 7 previously reported cases of vaginal angiosarcoma, 5 of which were associated with earlier irradiation. All of the earlier reported cases have been localized to the pelvis without metastatic disease.

The diagnostic accuracy of magnetic resonance imaging in detecting cervical involvement in endometrial cancer.

OBJECTIVES: The objective of this study was to determine the diagnostic accuracy of magnetic resonance imaging (MRI) in detecting cervical involvement by endometrial cancer. METHODS: A retrospective accuracy study of 135 consecutive women who underwent preoperative MRI and surgery for endometrial cancer at a single gynaecological cancer centre between 1st February 2003 and 30th November 2004. RESULTS: For the detection of any cervical involvement by MRI, the sensitivity was 72%, specificity 93.2%, positive predictive value (PPV) 89.8%, negative predictive value (NPV) 80.2%, positive likelihood ratio (+LR) 10.7 and negative likelihood ratio (-LR) 0.3. When cervical stromal invasion was considered alone, the sensitivity was 84.4%, specificity 87.4%, PPV 67.5%, NPV 94.7%, +LR 6.7 and -LR 0.18. CONCLUSION: We believe that MRI is able to accurately predict cervical involvement in endometrial cancer and allows a decision to be made on the type of hysterectomy to be offered.

Properties of SEPT9 isoforms and the requirement for GTP binding.

Members of the evolutionarily conserved septin family of genes are emerging as key components of several cellular processes including membrane trafficking, cytokinesis, and cell-cycle control events. SEPT9 has been shown to have a complex genomic architecture, such that up to 15 different isoforms are possible by the shuffling of five alternate amino termini and three alternate carboxy termini. Genomic and transcriptional alterations of SEPT9 have been associated with neoplasia. The present study has used a Sept9-specific antibody to determine the pattern of isoform expression in a range of tumour cell lines. Western blot analysis indicated considerable variation in the relative amounts and isoform content of Sept9. Immunofluorescence studies showed a range of patterns of cytoplasmic localization ranging from mainly particulate to mainly filamentous. Expression constructs were also generated for each amino terminal isoform to investigate the patterns of localization of individual isoforms and the effects on cells of ectopic expression. The present study shows that the epsilon isoform appears filamentous in this overexpression system while the remaining isoforms are particulate and cytoplasmic. Transient transfection of individual constructs into tumour cell lines results in cell-cycle perturbation with a G2/M arrest and dramatic growth suppression, which was greatest in cell lines with the lowest amounts of endogenous Sept9. Similar phenotypic observations were made with GTP-binding mutants of all five N-terminal variants of Sept9. However, dramatic differences were observed in the kinetics of accumulation of wild-type versus mutant septin protein in transfected cells. In conclusion, the present study shows that the expression patterns of Sept9 protein are very varied in a panel of tumour cell lines and the functional studies are consistent with a model of septin function as a component of a molecular scaffold that contributes to diverse cellular functions. Alterations in the levels of Sept9 protein by overexpression of individual isoforms can clearly perturb cellular behaviour and may thus provide a mechanistic explanation for observations of deranged septin expression in neoplasia.

Altered expression of the septin gene, SEPT9, in ovarian neoplasia.

The septin family of genes has been implicated in a variety of cellular processes including cytokinesis, membrane transport and fusion, exocytosis, and apoptosis. One member of the septin family maps to chromosome 17q25.3, a region commonly deleted in sporadic ovarian and breast tumours, and has also been identified as a fusion partner of MLL in acute myeloid leukaemias. The present study demonstrates that the pattern of expression of multiple splice variants of this septin gene is altered in ovarian tumours and cell lines. In particular, expression of the zeta transcript is detectable in the majority of tumours and cell lines, but not in a range of non-malignant adult and fetal tissues. Zeta expression is accompanied by loss of the ubiquitous beta transcript. Somatic mutations of the gene were not detected in ovarian tumours, but it was demonstrated that beta expression in tumour cell lines can be reactivated by 5-azacytidine treatment, suggesting a role for methylation in the control of expression of this gene.