Prediction of recurrence risk in endometrial cancer with multimodal deep learning.

Predicting distant recurrence of endometrial cancer (EC) is crucial for personalized adjuvant treatment. The current gold standard of combined pathological and molecular profiling is costly, hampering implementation. Here we developed HECTOR (histopathology-based endometrial cancer tailored outcome risk), a multimodal deep learning prognostic model using hematoxylin and eosin-stained, whole-slide images and tumor stage as input, on 2,072 patients from eight EC cohorts including the PORTEC-1/-2/-3 randomized trials. HECTOR demonstrated C-indices in internal (n = 353) and two external (n = 160 and n = 151) test sets of 0.789, 0.828 and 0.815, respectively, outperforming the current gold standard, and identified patients with markedly different outcomes (10-year distant recurrence-free probabilities of 97.0%, 77.7% and 58.1% for HECTOR low-, intermediate- and high-risk groups, respectively, by Kaplan-Meier analysis). HECTOR also predicted adjuvant chemotherapy benefit better than current methods. Morphological and genomic feature extraction identified correlates of HECTOR risk groups, some with therapeutic potential. HECTOR improves on the current gold standard and may help delivery of personalized treatment in EC.

QPOLE: A Quick, Simple, and Cheap Alternative for POLE Sequencing in Endometrial Cancer by Multiplex Genotyping Quantitative Polymerase Chain Reaction.

PURPOSE: Detection of 11 pathogenic variants in the POLE gene in endometrial cancer (EC) is critically important to identify women with a good prognosis and reduce overtreatment. Currently, POLE status is determined by DNA sequencing, which can be expensive, relatively time-consuming, and unavailable in hospitals without specialized equipment and personnel. This may hamper the implementation of POLE-testing in clinical practice. To overcome this, we developed and validated a rapid, low-cost POLE hotspot test by a quantitative polymerase chain reaction (qPCR) assay, QPOLE. MATERIALS AND METHODS: Primer and fluorescence-labeled 5'-nuclease probe sequences of the 11 established pathogenic POLE mutations were designed. Three assays, QPOLE-frequent for the most common mutations and QPOLE-rare-1 and QPOLE-rare-2 for the rare variants, were developed and optimized using DNA extracted from formalin-fixed paraffin-embedded tumor tissues. The simplicity of the design enables POLE status assessment within 4-6 hours after DNA isolation. An interlaboratory external validation study was performed to determine the practical feasibility of this assay. RESULTS: Cutoffs for POLE wild-type, POLE-mutant, equivocal, and failed results were predefined on the basis of a subset of POLE mutants and POLE wild-types for the internal and external validation. For equivocal cases, additional DNA sequencing is recommended. Performance in 282 EC cases, of which 99 were POLE-mutated, demonstrated an overall accuracy of 98.6% (95% CI, 97.2 to 99.9), a sensitivity of 95.2% (95% CI, 90.7 to 99.8), and a specificity of 100%. After DNA sequencing of 8.8% equivocal cases, the final sensitivity and specificity were 96.0% (95% CI, 92.1 to 99.8) and 100%. External validation confirmed feasibility and accuracy. CONCLUSION: QPOLE is a qPCR assay that is a quick, simple, and reliable alternative for DNA sequencing. QPOLE detects all pathogenic variants in the exonuclease domain of the POLE gene. QPOLE will make low-cost POLE-testing available for all women with EC around the globe.

Preoperative predictors of inguinal lymph node metastases in vulvar cancer - A nationwide study.

BACKGROUND: A combination of tumour size, differentiation grade and location may identify a group of vulvar squamous cell cancer (VSCC) patients with a very low risk of inguinal lymph node metastasis. We aim to examine these findings in a large national cohort of VSCC patients. MATERIALS AND METHODS: Population based prospective data on VSCC patients treated with vulvectomy and primary groin surgery was obtained from the Danish Gynaecological Cancer Database. Univariate chi-square and multivariate logistic regression analysis were used. Statistical tests were 2-sided. P-values of <0.05 were considered statistically significant. RESULTS: In all, 388 VSCC patients were identified. Of these 264 (63.3%) were node negative and 121 (36.7%) node positive. Increasing tumour size (diameter ≤ 2 cm vs. > 2 to 4 cm), grade (1 vs. 2-3) and location of tumour to clitoris were all associated with a significantly increased risk of inguinal lymph node metastasis OR 2.81(95% CI 1.52-5.20), OR 3.19 (95% CI 1.77-5.74) and OR 2.74 (95% CI 1.56-5.20), respectively. Previous vulvar disease was not associated with lymph node metastasis. No lymph node metastasis was demonstrated in patients with grade 1 tumours, tumour size less than 2 cm and located outside the clitoris area (n = 51). CONCLUSIONS: VSCC patients with grade 1 tumours, ≤ 2 cm and without clitoral involvement have a very low risk of inguinal lymph node metastasis. These patients may be spared inguinal lymph node staging to decrease operating time and peri- and postoperative morbidity in the future. However, studies validating our findings are needed.

Prognostic relevance of the molecular classification in high-grade endometrial cancer for patients staged by lymphadenectomy and without adjuvant treatment.

INTRODUCTION: The clinical role of the molecular endometrial cancer (EC) classification has not been fully explored in patients staged with lymphadenectomy or without adjuvant treatment, conditions that could potentially moderate the prognostic value of the classification. We aimed to evaluate the clinical outcome of the molecular subgroups in patients with high-grade EC staged by lymphadenectomy and those without adjuvant treatment. METHODS: DNA-sequencing for the detection of pathogenic POLE-exonuclease domain mutations and immunohistochemistry for mismatch repair (MMR) proteins and p53 expression were performed on 412 high-grade EC from the Danish Gynaecological Cancer Database (2005-2012) to classify them as POLE-ultramutated (POLEmut), MMR-deficient (MMRd), p53-mutant (p53abn), or no specific molecular profile (NSMP). Patients with stage IV or residual disease after surgery were excluded. Kaplan-Meier method, log-rank test and Cox proportional hazard models were used for analysis. RESULTS: Molecular analysis was successful in 367 EC; 251 patients had undergone lymphadenectomy. Five-year recurrence rates in this subgroup of patients was 36.7% for women with p53abn EC, 0.0% for POLEmut EC, 13.4% for MMRd EC and 42.9% for NSMP EC (p < 0.001). Similar results were observed among stage IA-IB patients. Among patients without adjuvant treatment (n = 264), none with POLEmut EC (n = 26) had a recurrence. CONCLUSION: The molecular EC classification has strong prognostic value, independent of clinicopathological factors, also among high-grade EC patients staged by lymphadenectomy and those without adjuvant treatment. The unfavourable prognosis of early-stage p53abn EC is not due to undetected lymph node metastasis, and the indolent behaviour of POLEmut EC is independent of adjuvant treatment.

Substantial Lymphovascular Space Invasion Is an Adverse Prognostic Factor in High-Risk Endometrial Cancer.

Approximately 15% of patients with endometrial cancer present with high-risk disease (HREC). Moreover, assessing the extent of lymphovascular space invasion (LVSI) may provide prognostic insight among patients with HREC. The aim of this study was to determine whether the extent of LVSI can serve as a prognostic factor in HREC. All cases of ESMO-ESGO-ESTRO 2016 classified HREC in the Danish Gynecological Cancer Database (DGCD) diagnosed from 2005 to 2012 were reviewed for the presence and extent of LVSI (categorized using a 3-tiered definition). We used the Kaplan-Meier analysis to calculate actuarial survival rates, both adjusted and unadjusted Cox regression analyses were used to calculate the proportional hazard ratio (HR). A total of 376 patients were included in our analysis. Among 305 patients with stage I/II HREC, 8.2% and 6.2% had focal or substantial LVSI, respectively, compared with 12.7% and 38.0% of 71 patients with stage III/IV HREC, respectively. Moreover, the estimated 5-yr recurrence-free survival rate was significantly lower among patients with substantial LVSI compared with patients with no LVSI for both stage I/II (HR: 2.8; P=0.011) and stage III/IV (HR: 2.9; P=0.003) patients. Similarly, overall survival was significantly lower among patients with substantial LVSI for both stage I/II (HR: 3.1; P<0.001) and stage III/IV (HR: 3.2; P=0.020) patients. In patients with HREC, substantial LVSI is an independent adverse prognostic factor for lymph node and distant metastases, leading to reduced survival. Thus, the extent of LVSI should be incorporated into routine pathology reports in order to guide the appropriate choice of adjuvant treatment.

Defining Substantial Lymphovascular Space Invasion in Endometrial Cancer.

Lymphovascular space invasion (LVSI) occurs in a minority of endometrial cancer (EC) cases, and the extent of LVSI is an important risk factor for recurrence and/or metastases. Our aim was to improve the reproducibility of measuring clinically meaningful LVSI by performing a quantitative analysis of the correlation between LVSI and the risk of pelvic lymph node recurrence in EC. EC samples from PORTEC-1 and PORTEC-2 trials were retrieved and used to collect quantitative data, including the number of LVSI-positive vessels per H&E-stained slide. Using a predefined threshold for clinical relevance, the risk of pelvic lymph node recurrence risk was calculated (Kaplan-Meier method, with Cox regression) using a stepwise adjustment for the number of LVSI-positive vessels. This analysis was then repeated in the Danish Gynecological Cancer Database (DGCD) cohort. Among patients in PORTEC-1 and PORTEC-2 trials who did not receive external beam radiotherapy, the 5-yr pelvic lymph node recurrence risk was 3.3%, 6.7% (P=0.51), and 26.3% (P<0.001), respectively when 0, 1 to 3, or ≥4 vessels had LVSI involvement; similar results were obtained for the DGCD cohort. Furthermore, both the average number of tumor cells in the largest embolus and the number of LVSI-positive H&E slides differed significantly between focal LVSI and substantial LVSI. On the basis of these results, we propose a numeric threshold (≥4 LVSI-involved vessels in at least one H&E slide) for defining clinically relevant LVSI in EC, thereby adding supportive data to the semiquantitative approach. This will help guide gynecologic pathologists to differentiate between focal and substantial LVSI, especially in borderline cases.

The 10-year results after national introduction of pelvic lymph node staging in Danish intermediate-risk endometrial cancer patients not given postoperative radiotherapy.

The 10-year results after national introduction of pelvic lymph node staging in Danish intermediate-risk endometrial cancer patients not given postoperative radiotherapy. Gitte Ørtoft; Claus Høgdall; Estrid S Hansen; Margit Dueholm. OBJECTIVE: To prepare for the national introduction of sentinel node staging, we evaluated the consequences of the previous national decision to introduce lymph node staging in intermediate-risk endometrial cancer patients (grade 1/2 with > 50% or grade 3 with < 50% myometrial invasion) by determining the number of patients upstaged by lymphadenectomy and whether upstaging affected the survival and recurrence patterns of non-staged patients and patients with and without lymph node metastases. STUDY DESIGN: In a national cohort study, 2005-12, 1294 stage I-IV patients who should have been offered lymphadenectomy were progressively registered. The number of patients upstaged by lymphadenectomy, 10-year survivals were evaluated by Kaplan-Meier analysis and adjusted Cox regression. RESULTS: This study demonstrates that it takes time to introduce lymphadenectomy at a national level, as indicated by the increasing number of cases staged per year, from 12% in 2005 to 74% in 2012. Pelvic lymphadenectomy was performed in 43.8% (567/1294) and lymph node metastases were found in 13.6% (77/567). As 54 patients had further dissemination outside the uterine body, only 23 patients (6%) were upstaged from stage I to IIIC. Compared to lymph node-negative patients, the 77 patients with lymph node metastasis had significantly lower overall, (55% versus 68%), disease-specific (64% versus 86%), and progression-free survival (51% versus 77%), mainly due to non-local recurrences including a high number of paraaortic recurrences. In 873 final stage I intermediate-risk patients, 10-year survival and recurrence rates were not significantly lower in non-staged as compared to lymph node-negative patients (overall survival 62% versus 70%: disease-specific survival: 90% versus 90%, progression-free survival: 81% vs 83%), probably due to the low number of patients upstaged from stage I to stage IIIC. CONCLUSION: Lymph node metastases were present in 13.6% of patients with intermediate-risk who underwent pelvic lympadenectomy, and these patients had a lower 10-year survival than lymph node-negative patients. Because lymphadenectomy upstaged only 6% from stage I to stage IIIC, survival and recurrence rates were not significantly compromised in non-staged as compared to lymph node-negative intermediate-risk stage I patients. Sentinel node staging has now been implemented in Danish intermediate-risk endometrial cancer patients.

Preoperative prediction of high-risk endometrial cancer by expert and non-expert transvaginal ultrasonography, magnetic resonance imaging, and endometrial histology.

OBJECTIVE: To identify women with high-risk endometrial cancers using expert and non-expert transvaginal ultrasonography (TVS) and MRI. STUDY DESIGN: Myometrial involvement was prospectively evaluated in patients with atypical hyperplasia or endometrial cancer on ultrasound by non-experts at first visit (non-expert-TVS: n = 266) and experts (expert-TVS: n = 188) at second visit. MRI (n = 175) was performed when high-risk cancer was suspected on non-expert-TVS. Preoperatively, high-risk cancer was defined as myometrial involvement ≥50 %, or preoperative unfavorable tumor histology (grade 3 endometrioid, non-endometrioid tumors, or tumor in cervical biopsies) obtained by endometrial sampling or hysteroscopic biopsies. Preoperative evaluations were compared with final histopathology obtained at surgery, high-risk cancer being defined as unfavorable tumor histology or patients with FIGO stage ≥1b. RESULTS: Preoperative unfavorable tumor histology was seen in 64 women and correctly identified 63 of 128 high-risk cancers. Preoperative diagnosis of unfavorable tumor histology or myometrial involvement ≥50 %, i.e. judged high-risk, had an area under the curve (AUC), sensitivity, and specificity of 79.5 %, 93.8 %, 65.2 % on non-expert-TVS; 85.5 %, 84.4 %, 86.5 % on expert-TVS, and 85.4 %, 89.6 %, 81.2 % on MRI. AUC values were not significantly different between MRI and expert-TVS, but lower on non-expert-TVS (p < 0.02). However, sensitivity was highest on non-expert-TVS, where a low cutpoint for myometrial involvement was used (included potentially deep and difficult evaluations) in contrast to an exact cutpoint of myometrial involvement ≥50 % used on expert-TVS and MRI. The highest AUC, 88.6 %, was seen when MRI was performed in patients with myometrial involvement ≥50 %, determined on non-expert TVS. Sensitivity was reduced to 85.9 %, while specificity increased to 91.3 %. Thus, MRI was needed for risk classification in only 104 (39 %) patients. CONCLUSION: Diagnostically, expert-TVS and MRI were comparable and superior to non-expert-TVS. However, non-expert-TVS classified all patients with unclear myometrial involvement ≥50 %, and thereby only misdiagnosed 6.2 % of high-risk cases. Non-expert-TVS combined with MRI when myometrial involvement was ≥50 % on non-expert-TVS was a simple and effective method comparable with expert imaging to identify low- and high-risk cancer and select patients for SLND. Addition of MRI to the diagnostic regimen was needed in only 39 % of our patients.

Predictive value of the new ESGO-ESTRO-ESP endometrial cancer risk classification on survival and recurrence in the Danish population.

OBJECTIVE: To compare the performance of the new ESGO-ESTRO-ESP (European Society of Gynecological Oncology-European Society for Radiotherapy & Oncology-European Society for Pathology) 2020 risk classification system with the previous 2016 risk classification in predicting survival and patterns of recurrence in the Danish endometrial cancer population. METHODS: This Danish national cohort study included 4516 patients with endometrial cancer treated between 2005 and 2012. Five-year Kaplan-Meier adjusted and unadjusted survival estimates and actuarial recurrence rates were calculated for the previous and the new classification systems. RESULTS: In the 2020 risk classification system, 81.0% of patients were allocated to low, intermediate, or high-intermediate risk compared with 69.1% in the 2016 risk classification system, mainly due to reclassification of 44.5% of patients previously classified as high risk to either intermediate or especially high-intermediate risk. The survival of the 2020 high-risk group was significantly lower, and the recurrence rate, especially the non-local recurrence rate, was significantly higher than in the 2016 high risk group (2020/2016, overall survival 59%/66%; disease specific 69%/76%; recurrence 40.5%/32.3%, non-local 34.5%/25.8%). Survival and recurrence rates in the other risk groups and the decline in overall and disease-specific survival rates from the low risk to the higher risk groups were similar in patients classified according to the 2016 and 2020 systems. CONCLUSION: The new ESGO-ESTRO-ESP 2020 risk classification system allocated fewer patients to the high risk group than the previous risk classification system. The main differences were lower overall and disease-specific survival and a higher recurrence rate in the 2020 high risk group. The introduction of the new 2020 risk classification will potentially result in fewer patients at high risk and allocation to the new high risk group will predict lower survival, potentially allowing more specific selection for postoperative adjuvant therapy.

Prognostic impact of histological review of high-grade endometrial carcinomas in a large Danish cohort.

The aim of this study was to investigate the outcome of histological subtype review of high-grade endometrial carcinoma (EC) and its prognostic impact in a large well-documented Danish nationwide cohort. From the Danish Gynecological Cancer Database (DGCD) 2005-2012 cohort, we included 425 patients with an original diagnosis of high-grade EC, independent of histologic subtype. Of these, at least one hematoxylin and eosin (H&E)-stained slide from 396 cases (93.2%) was available for review. The histologic subtype was reviewed by specialized gynecopathologists blinded to the original diagnosis and clinical outcome. Interobserver variability between original and revised histologic subtypes was analyzed using simple Kappa statistics. Hazard ratios (HR), recurrence-free survival (RFS), and overall survival were calculated for original and revised subtypes, respectively. Overall histologic subtype agreement was moderate (kappa = 0.42) with the highest agreement for endometrioid-type EC (EEC; 75.5%) and serous-type EC (SEC; 63.8%). For clear cell carcinoma and un-/dedifferentiated EC, agreement was significantly lower: 30.1% and 33.3% respectively. Of the 396 reviewed cases, only two (0.5%) were re-classified as low-grade EEC upon revision. Interestingly, GR3 EEC had better RFS than SEC with stronger significance after revision (HR 2.36 (95% CI 1.43-3.89), p = 0.001), compared to original diagnosis (HR 1.74 (95% CI 1.07-2.81), p = 0.024). In conclusion, this study confirmed that pathology review results in substantial shift in histological subtype in high-grade EC. After review, a stronger prognostic benefit for GR3 EEC as compared to other histological subtypes was observed. This work supports maintaining a low threshold for pathology revision of high-grade EC in clinical practice.

Trends in hysterectomy-corrected uterine cancer mortality rates during 2002 to 2015: mortality of nonendometrioid cancer on the rise?

Corpus uteri cancer is the most common gynecological malignancy in most developed countries. The disease is typically diagnosed at an early stage, is of endometrioid histologic subtype, and has a fairly good prognosis. Here, we describe hysterectomy-corrected mortality rates of corpus uteri cancer, overall and stratified by age, stage and histologic subtype. Using data from nationwide Danish registries, we calculated uncorrected and hysterectomy-corrected age-standardized mortality rates of corpus uteri cancer among women ≥35 years during 2002 to 2015. Individual-level hysterectomy status was obtained from national registries; hysterectomy-corrected mortality rates were calculated by subtracting posthysterectomy person-years from the denominator, unless hysterectomy was performed due to corpus uteri cancer. Correction for hysterectomy resulted in a 25.5% higher mortality rate (12.3/100000 person-years vs 9.8/100000 person-years). Mortality rates were highest in women aged 70+, irrespective of year of death, histologic subtype and stage. A significant decline was observed in overall hysterectomy-corrected mortality rates from 2002 to 2015, particularly among women aged 70+. Mortality rates of endometrioid cancer declined significantly over time (annual percent change [APC]: -2.32, 95% CI -3.9, -0.7, P = .01), whereas rates of nonendometrioid cancer increased (APC: 5.90, 95% CI: 3.0, 8.9, P < .001). With respect to stage, mortality rates increased significantly over time for FIGOI-IIa (APC: 6.18 [95% CI: 1.9, 10.7] P = .01) but remained unchanged for FIGO IIb-IV. In conclusion, increasing mortality rates of nonendometrioid cancer paralleled the previously observed rise in incidence rates of this histologic subtype. Given the poor prognosis of nonendometrioid cancer, more studies are needed to clarify the underlying reason for these findings.

Survival and recurrence in stage II endometrial cancers in relation to uterine risk stratification after introduction of lymph node resection and omission of postoperative radiotherapy: a Danish Gynecological Cancer Group Study.

OBJECTIVE: To evaluate survival and recurrence in stage II endometrial cancer in relation to uterine risk stratification. Outcome for stage II was compared before and after the introduction of lymph node (LN) resection and omission of all postoperative radiotherapy. METHODS: The cohort consisted of 4,380 endometrial carcinoma patients radically operated (no visual tumor, all distant metastasis removed) (2005-2012) including 461 stage II. Adjusted Cox regression was used to compare survival and actuarial recurrence rates. RESULTS: Uterine risk factors (low-, intermediate-, and high-) were the strongest predictors of survival and recurrence in stage II. Stage II low-risk having a prognosis comparable to low-risk stage I (grade 1-2, <50% myometrial invasion), whereas cervical invasion significantly increased the risk of recurrence and decreased cancer-specific survival in intermediate- and high-risk compared to the corresponding stage I risk groups. In 355 cases of 708 with cervical stromal invasion, LN-resection showed 27.9% with LN metastasis and upstaged 18.1% from stage II to IIIC resulting in longer survival and lower recurrence in LN-resected compared to non-LN resected stage II. Radical as compared to simple hysterectomy did not alter survival. Treatment with external beam radiotherapy decreased local recurrence without affecting survival. CONCLUSION: Uterine risk groups are the strongest predictors for survival and recurrence in stage II patients and should be considered when advising adjuvant therapy. LN-resected stage II had increased survival and decreased recurrence. Omitting radiotherapy increase vaginal recurrence without affecting survival.

Recurrence and survival rates in node negative patients after sentinel node biopsy for early-stage vulva cancer - A nationwide study.

OBJECTIVE: The sentinel node (SN) procedure is adopted in selected patients with early-stage vulva cancer (VC) in Denmark. Due to the low incidence of VC, large population-based studies on the safety of SN outside multicenter clinical trials are lacking. The current study evaluated the risk of recurrence and survival in SN- negative VC patients. METHODS: Nationwide data was collected and registered prospectively in the Danish Gynecologic Cancer Database from January 2011 to July 2017. Patients with clinically stage IB-II unifocal vulva squamous cell carcinoma, tumor <4 cm and no clinically suspicious groin nodes or distant metastases, who underwent SN-procedure, were included. RESULTS: The SN-procedure was performed in 286 patients, of these 190 (66.4%) patients were SN-negative. Twenty-three of the 190 SN-negative patients (12.1%) had one or more recurrences during a median follow-up of 30 months (range 1-83). Four patients (2.1%) had an isolated groin recurrence identified from 5 to 17 months after primary surgery. Fourteen patients (7.4%) experienced a local recurrence in vulva, 1 patient (0.5%) had a recurrence in the vulva and the groin and 4 patients (2.1%) had distant recurrences. The 3-year overall (OS) and disease-specific survival (DSS) for SN-negative patients was 84% and 93%, respectively. The 3-year OS for patients with recurrent disease was 58%. CONCLUSIONS: This is the largest prospective nationwide study on SN-procedure in vulva cancer. The study confirms the safety of the SN-procedure in selected early-stage VC patients with a low isolated groin recurrence rate and a good DSS.

Lymph-vascular space invasion (LVSI) as a strong and independent predictor for non-locoregional recurrences in endometrial cancer: a Danish Gynecological Cancer Group Study.

OBJECTIVE: To evaluate the effect of lymph-vascular space invasion (LVSI) on location of recurrences in Danish patients with endometrial cancer. METHODS: This national cohort study (2005-2012) included 4,380 radically operated patients (no visual tumor, all distant metastasis removed). LVSI status was recorded in 3,377 (77.1%). In stage I patients, 2.6% received adjuvant radiotherapy and 1.4% adjuvant chemotherapy. Adjusted Cox regression was used to compare actuarial recurrence rates. RESULTS: LVSI was present in 18.7% of 3,377 patients with known LVSI status. Of these, 7.6% stage I patients with LVSI experienced an isolated locoregional and 19.4% a non-locoregional recurrence. Compared to no LVSI, 5-year recurrence rate was higher (25.5% vs. 8.5%) in patients with LVSI and the frequency of distant recurrences was strikingly higher (stage I: 15.2% vs. 2.7%), the effect being similar across International Federation of Gynecology and Obstetrics stages and histological types. In intermediate-risk stage I patients with LVSI, 8.0% experienced an isolated locoregional recurrence compared to 20.1% with non-locoregional recurrence, giving these patients a seriously adverse risk of survival. A separate analysis in patients with recurrences demonstrated that those with LVSI had significantly more distant recurrences (55.4% vs. 29.9%) and fewer isolated vaginal recurrences (24.3% vs. 42.8%) than patients with no LVSI. CONCLUSION: LVSI is a strong independent risk factor for the development of non-locoregional recurrences even in intermediate-risk stage I endometrial cancer. The non-locoregional recurrence pattern suggests a future focus for optimization of postoperative treatment in these patients.

Location of recurrences in high-risk stage Iendometrial cancer patients not given postoperative radiotherapy: A Danish gynecological cancer group study.

OBJECTIVES: To study recurrence rates in Danish high-risk stage I endometrial cancers not given radiotherapy in accordance with the decision of the Danish Gynecological Cancer Group. METHODS: This prospective national cohort study includes all 4707 endometrial carcinomas diagnosed from 2005 to 2012. Of these, 623 patients had grade 3 endometroid adenocarcinoma with >50% myometrial invasion or serous/clear/undifferentiated carcinoma (with any depth of invasion). In 305 patients with high-risk stage I on final pathology, 14.1% received adjuvant external beam radiotherapy and 9.6% adjuvant chemotherapy. No patients received brachytherapy. 5-year Kaplan-Meier survival estimates and actuarial recurrence rates were calculated, and adjusted Cox regression analysis used for comparison. Recurrence rates were compared with historical Danish population data (DEMCA 98-99). RESULTS: For non-irradiated patients, 5-year overall survival, cancer-specific survival, and progression-free survival rates in high-risk stage I patients were 65%, 78%, and 73%, respectively. For non-irradiated patients, isolated local recurrences were uncommon (vaginal 3.1%, pelvic 0.4%). Death was mainly due to a high occurrence of non-local recurrences, with 8.8% experiencing a first recurrence in the abdominal cavity (outside the field where radiation traditionally have been given) and 13.0% a distant metastasis outside the abdominal cavity. Grade 3 tumors with >50% myometrial invasion seem to be characterized by a different pattern of recurrences, with significantly more isolated vaginal recurrences (7.9% vs 2.2%) and fewer total number of abdominal recurrences (7.9% vs 15.3%) as compared with unfavorable tumor types. CONCLUSION: Isolated vaginal and pelvic recurrences were rare (3-5%) in patients with a final pathologic diagnosis of high-risk stage I endometrial cancer even after the Danish Gynecological Cancer Group decided to omit all types of postoperative radiotherapy and introduce lymph node staging.

The effect of introducing pelvic lymphadenectomy on survival and recurrence rates in Danish endometrial cancer patients at high risk: a Danish Gynecological Cancer Group study.

OBJECTIVES: To evaluate the rate of survival and recurrence related to the introduction of pelvic lymphadenectomy in Danish high-risk endometrial cancer patients. STUDY DESIGN: Data on 713 high-risk patients defined as grade 3 with >50% myometrial invasion or serous/clear/undifferentiated carcinomas stage I-IV endometrial cancer patients diagnosed from 2005 to 2012 were retrieved from the Danish Gynecological Cancer Database. Of these, 305 were high-risk stage I. Five year Kaplan-Meier survival estimates and actuarial recurrence rates were calculated, and adjusted Cox used for comparison. Findings were compared with earlier Danish results. RESULTS: Lymphadenectomy in 390 radically operated high-risk patients resulted in upstaging of 31 patients from stage I to IIIC and 19 patients from stage II to IIIC corresponding to 12.8%. Upstaging from stage I to IIIC had a cancer-specific survival of 77%, almost comparable to lymph node-negative high-risk stage I patients (81%). Lymphadenectomy patients had a significant higher overall survival as compared with non-lymph node resected for all patients, but not for stage I patients. Lymphadenectomy, however, did not significantly affect cancer-specific survival, progression-free survival, recurrence rate or risk of local, distant, or lymph node recurrence. When the survival of high-risk stage I patients was compared with earlier Danish results, a small improvement in overall survival (7%) and cancer-specificsurvival (8%) was demonstrated. CONCLUSION: Only a small number of high-risk patients were upstaged from stage I to III due to lymphadenectomy. These patients showed a surprisingly good survival possibly due to correct stage identification and subsequent relevant adjuvant therapy. However, even though introduction of lymphadenectomy in the Danish high-risk population seems to increase overall survival, no significant change in cancer-specific survival, progression-free survival or recurrence patterns was demonstrated.

Ultrasound Scoring of Endometrial Pattern for Fast-track Identification or Exclusion of Endometrial Cancer in Women with Postmenopausal Bleeding.

STUDY OBJECTIVE: To evaluate the risk of endometrial cancer (REC) scoring system for the prediction of high and low probability of endometrial cancer (EC) in women with postmenopausal bleeding (PMB). DESIGN: A prospective study (Canadian Task Force classification II-1). SETTING: An academic hospital. PATIENTS: Nine hundred fifty consecutive patients with PMB underwent transvaginal ultrasonography (TVS) and REC scoring between November 2013 and December 2015. INTERVENTIONS: Obstetrics and gynecology residents supervised by trained physicians scored endometrial patterns according to the previously established REC scoring system. The reference standard was endometrial samples, endometrial thickness (ET, 4-4.9 mm), operative hysteroscopy or hysterectomy (ET ≥5 mm), and 1-year follow-up in all patients presenting with ET <4 mm. Diagnostic performance for the prediction of probability of malignancy was assessed using the REC scoring system. MEASUREMENTS AND MAIN RESULTS: The area under the receiver operating characteristic curve of the TVS REC scoring system was 97% (95% confidence interval [CI], 95%-98%) for the prediction of malignancy. In 656 patients with ET ≥4 mm, REC scoring effectively predicted a high probability of malignancy with sensitivity (95% confidence interval) of 92% (95% CI, 87%-95%) and specificity of 94% (95% CI, 91%-96%). An REC score of 0 was present in 206 (32%) patients with ET ≥4 mm and was associated with a low negative likelihood ratio of 0.026 for EC. There were only 7 patients with EC/atypical hyperplasia among these 206 patients. CONCLUSION: The REC scoring system identified or ruled out most ECs, clearly showing that more specific image analysis at first-line TVS can accelerate the diagnosis of EC in patients with PMB and may allow for improved selection of second-line strategies in patients with ET ≥4 mm.

Assessment of myometrial invasion in endometrial cancer using three-dimensional ultrasound and magnetic resonance imaging.

INTRODUCTION: Preoperative knowledge of myometrial invasion in endometrial cancer is important for surgical planning. This study aimed to assess the diagnostic efficiency of two-dimensional (2D) and three-dimensional (3D) transvaginal ultrasonography (TVS) with and without saline infusion (SIS) and magnetic resonance imaging (MRI) for assessment of myometrial invasion in endometrial cancer. MATERIAL AND METHODS: 110 women with atypical endometrial hyperplasia or endometrial adenocarcinoma underwent preoperative 2D- and 3D-TVS with and without SIS and MRI. Offline 3D-TVS measurement was performed of the minimal tumor-free margin in relation to myometrial thickness expressed as deep (≥ 50%) myometrial invasion and subjective impression of cervix involvement. The quality of images was also evaluated. Diagnostic efficiencies were calculated for myometrial and cervical involvement for each method. The pathologist's final diagnosis served as the reference standard. RESULTS: For myometrial involvement, MRI showed greater accuracy than 3D-TVS or 2D-TVS (83, 71 and 75%, respectively). The efficiency of 3D-TVS was not superior to 2D-TVS and did not improve with SIS. The sensitivities of 2D-TVS and 3D-TVS were similar to that of MRI, and the efficiency of 3D-TVS improved when volumes of inadequate quality (39%) were excluded. For evaluating cervical involvement, the accuracy of 3D-TVS was 85%, comparable to the results of 2D-TVS (80%) and MRI (85%). The results did not improve when saline was added. CONCLUSION: 3D-TVS or 3D-SIS was not more efficient than 2D-TVS or MRI for assessment of myometrial invasion in endometrial cancer. 3D-TVS assessment without 2D-TVS was impeded by difficulties in obtaining 3D-TVS volumes of sufficient quality.

PAPP-A proteolytic activity enhances IGF bioactivity in ascites from women with ovarian carcinoma.

Pregnancy-associated plasma protein-A (PAPP-A) stimulates insulin-like growth factor (IGF) action through proteolysis of IGF-binding protein (IGFBP)-4. In experimental animals, PAPP-A accelerates ovarian tumor growth by this mechanism. To investigate the effect of PAPP-A in humans, we compared serum and ascites from 22 women with ovarian carcinoma. We found that ascites contained 46-fold higher PAPP-A levels as compared to serum (P < 0.001). The majority (80%) of PAPP-A was enzymatically active. This is supported by the finding that ascites contained more cleaved than intact IGFBP-4 (P < 0.03). Ascites was more potent than serum in activating the IGF-I receptor (IGF-IR) in vitro (+31%, P < 0.05); in 8 of 22 patients by more than two-fold. In contrast, ascites contained similar levels of immunoreactive IGF-I, and lower levels of IGF-II (P < 0.001). Immunohistochemistry demonstrated the presence of IGF-IR in all but one tumor, whereas all tumors expressed PAPP-A, IGFBP-4, IGF-I and IGF-II. Addition of recombinant PAPP-A to ascites increased the cleavage of IGFBP-4 and enhanced IGF-IR activation (P < 0.05). In conclusion, human ovarian tumors express PAPP-A, IGFBP-4 and IGFs and these proteins are also present in ascites. We suggest that both soluble PAPP-A in ascites and tissue-associated PAPP-A serve to increase IGF bioactivity and, thereby, to stimulate IGF-IR-mediated tumor growth.