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.

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.

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.

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.

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.

Structured Hysteroscopic Evaluation of Endometrium in Women With Postmenopausal Bleeding.

STUDY OBJECTIVE: To evaluate visual pattern parameters obtained with hysteroscopy for the prediction of endometrial cancer, to evaluate observer variation of these parameters, and to present a scoring system of the parameters for the prediction of malignancy compared with subjective evaluation. DESIGN: A prospective controlled study (Canadian Task Force classification II-1). SETTING: A university clinic. PATIENTS: One hundred forty-nine consecutive women with postmenopausal bleeding and an endometrium thickness ≥ 5 mm. Sixty-one (41%) had endometrial cancer. Forty-six of 149 women were referred based on suspected malignancy. INTERVENTIONS: Endometrial pattern characteristics for endometrial cancer were evaluated in hysteroscopic video clips. The reference standard was pathologic evaluation of resectoscopic samples or hysterectomy. Using multivariate logistic regression, image parameters were correlated with the presence of endometrial cancer. A scoring system of visual parameters for the prediction of malignancy was compared with subjective evaluation of malignancy. MEASUREMENTS AND MAIN RESULTS: A score for lesion surface, necrosis, and vessels had an area under the curve (AUC) of 0.89, 0.89, and 0.87, respectively. A hysteroscopic cancer (HYCA) scoring system based on unsmooth lesion surface, papillary projections, surface necrosis, "candy floss" necrosis, white hyperintense spots, irregular branching vessels, and irregular distribution of irregular vessels was able to predict cancer (AUC = 0.964) with higher accuracy than subjective evaluation (AUC = 0.859, p < .01). At a score value ≥ 3, sensitivity was 89% and specificity was 92% with moderate agreement between observers (kappa = 0.56 [0.42-0.71]). CONCLUSION: A systematic pattern evaluation of optimal parameters by a HYCA scoring system based on systematically defined terms may increase accuracy in the diagnosis of endometrial cancer and should be further elaborated and external validity tested in unselected women with postmenopausal bleeding.

Reproducibility of Endometrial Pathologic Findings Obtained on Hysteroscopy, Transvaginal Sonography, and Gel Infusion Sonography in Women With Postmenopausal Bleeding.

STUDY OBJECTIVE: To evaluate and compare interobserver variation in endometrial pattern recognition with hysteroscopy (HY) and transvaginal sonography (TVS) and gel infusion sonography (GIS) with regard to the diagnosis of endometrial pathology. DESIGN: Prospective study (Canadian Task Force II-1). SETTING: University clinic. PATIENTS: One hundred twenty-two consecutive women with postmenopausal bleeding and an endometrium thickness ≥ 5 mm. INTERVENTION: Two observers using HY and 2 others using TVS and GIS evaluated the endometrial pattern in recorded video clips. Interobserver agreement regarding findings obtained with TVS, GIS, and HY for a diagnosis of cancer, hyperplasia, polyps, and no endometrial pathology was expressed by κ coefficients and compared. MEASUREMENT AND MAIN RESULTS: Interobserver agreement (κ) was as follows: identification of normal endometrium: HY (.74), TVS (.68), and GIS (.48); diagnosis of cancer: HY (.56), TVS (.59), and GIS (.34); classification in all categories of endometrial pathology: HY (.70), TVS (.47), and GIS (.41) (p < .05 HY vs GIS). The presence of additional endometrial polyps decreased agreement on HY in patients with hyperplasia or cancer. Observer agreement was poor regarding the diagnosis of hyperplasia by all techniques. CONCLUSION: Observer agreement regarding both HY and TVS was reliable for the diagnosis of a normal endometrium but poor with HY, TVS, and especially GIS for a diagnosis of cancer. In patients with hyperplasia or cancer, agreement between observers was especially low in the presence of additional polyps when HY was used. These findings call attention to the need for systematic methods to improve reliability in endometrial pattern recognition.

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.

Omitting adjuvant radiotherapy in endometrial cancer increases the rate of locoregional recurrences but has no effect on long-term survival: the Danish Endometrial Cancer Study.

OBJECTIVES: In 2 prospective nationwide studies, the Danish Endometrial Cancer Study demonstrated that postoperative radiotherapy (RT) could be omitted in low- and intermediate-risk stage I patients without loss of survival when evaluated after 5 years. In the present study, we evaluated the consequence of this decision on the long-term risk of recurrence and death. STUDY DESIGN: From 1998 to 1999, 1166 patients newly diagnosed with uterine carcinoma were included. Of these, 586 were low-risk, 231 intermediate-risk, and 78 high-risk stage I. Low- and intermediate-risk patients received standard primary surgery (hysterectomy and bilateral salpingo-oophorectomy), and no postoperative RT was given. Long-term recurrence and survival rates were estimated. RESULTS: After 14 years, 6.3% of low-risk and 22% of intermediate-risk patients had relapsed compared with 32% of high-risk patients. Recurrences were dominated by locoregional relapse in the low and intermediate risk, whereas non-locoregional relapses were prominent in high risk. After locoregional relapse, 1.5% of low and 4.3% of intermediate risk experienced a second relapse dominated by non-locoregional relapses. After curative-intended treatment of vaginal recurrence in the low- and intermediate-risk patients, 100% had complete remission after the first vaginal recurrence, whereas only 74% was cured after the first or the second recurrence. The increased recurrence rate, however, does not seem to affect survival because the survival rate did not change compared to earlier Danish population-based data. CONCLUSIONS: We conclude that omitting RT in early stage endometrial cancer increase local recurrences, but without affecting long-term survival.

Preoperative staging of endometrial cancer using TVS, MRI, and hysteroscopy.

OBJECTIVES: To evaluate the accuracy of different preoperative modalities for staging of endometrial cancer to restrict extensive surgery to patients at high risk of metastatic disease. SETTING: Aarhus University Hospital. POPULATION: 156 women referred in 2006-2011 because of atypical endometrial hyperplasia (G0) or endometrial cancer. METHODS: Patients were offered preoperative transvaginal ultrasonography (TVS), magnetic resonance imaging (MRI), and hysteroscopic-directed biopsies from the uterine tumor and cervix. Final pathology of the removed uterus was the reference standard. Patients were divided into low risk (<50% myometrial invasion, and grades 0, 1, 2, and no cervical invasion) or high risk (all others). MAIN OUTCOME MEASURES: Accuracy, sensitivity, specificity, positive/negative predictive value. RESULTS: Patients were aged 32-88 years, with a mean body mass index of 29. At final pathology 81% had cancer and 19% G0 or no residual tumor; 54% were high risk. Hysteroscopy-directed biopsies had a higher accuracy (92%) than endometrial biopsy (58%) for differentiating G0 from cancer (p < 0.001); grade 3 tumor identification had similar accuracy (93 vs. 92%). Deep myometrial invasion was estimated with higher accuracy by MRI (82%) than TVS (74%) (p < 0.02). For cervical involvement, hysteroscopy-directed biopsies had higher accuracy (94%) than MRI (84%,) and TVS (80%) (p < 0.02). Accuracy for identifying high-risk women was highest (83%) using a combination of MRI and hysteroscopic-directed biopsies, compared with TVS and endometrial biopsy (72%) (p < 0.05). CONCLUSION: Preoperative staging with MRI and hysteroscopy-directed biopsy can identify eight of 10 women with high risk of lymph node metastases and spare eight of 10 low-risk women extended surgery.

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.

Survival after stage IA endometrial cancer; can follow-up be altered? A prospective nationwide Danish survey.

OBJECTIVE: To present Danish national survival data on women with early stage endometrial cancer and use these data to discuss the relevance of postoperative follow-up. DESIGN: Prospective study. SETTING: Danish Endometrial Cancer Study (DEMCA). POPULATION: Five hundred and seventy-one FIGO stage IA (1988 classification) endometrial cancer patients prospectively included between 1986 and 1999. All patients had total abdominal hysterectomy and bilateral salpingo-oophorectomy without adjuvant therapy. METHODS: The patient and the disease characteristics were drawn from the DEMCA database with cross-references to the national death registry and the national pathology database. Statistical methods included Kaplan-Meier, log-rank and Cox regression analysis. MAIN OUTCOME MEASURES: Survival rates in relation to histopathology. RESULTS: The five year overall survival rate was 88.9% and five year disease-specific survival was 97.3%. Patients with low- (91.8%) and high-risk histopathology (8.2%) were compared. The age-adjusted overall and disease-specific survival differed significantly between women with low- and high-risk histopathology (p = 0.039 and p = 0.004, respectively). The disease-specific survival adjusted for age between patients with well-differentiated endometrioid tumors differed from those with moderately differentiated tumors (p = 0.008, hazard ratio = 3.75, 95% confidence interval 1.41-10.00). Recurrence data were available on 464 patients. Twenty-three (3.9%) experienced recurrence. Of these recurrences, 15 of 23 (65%) were vaginal. Death from recurrence was observed in nine of 23 (39%) patients, and five of these nine had vaginal recurrences. CONCLUSIONS: Women with FIGO stage IA endometrial cancer have a very high disease-specific five year survival. Survival was related to histopathology. Follow-up at a highly specialized tertiary care center for patients with an extremely good prognosis may be questioned.

Survival of Danish patients with endometrial cancer in the intermediate-risk group not given postoperative radiotherapy: the Danish Endometrial Cancer Study (DEMCA).

OBJECTIVES: In a prospective study during the years 1986 to 1988, the Danish Endometrial Cancer Group (DEMCA) demonstrated that postoperative radiotherapy was unnecessary for low-risk patients with stage I disease. In the present study, we evaluated in a population-based study if radiotherapy could also be omitted for intermediate-risk patients with stage I disease without loss of survival. STUDY DESIGN: From 1998 to 1999, 1166 patients newly diagnosed with carcinoma of the uterus were included in this prospective nationwide study. Of these, 232 were intermediate-risk patients with stage I disease. All intermediate-risk patients received standard primary surgery (hysterectomy, bilateral salpingo-oophorectomy, and peritoneal washings), and no postoperative radiotherapy was given. Survival analyses were performed using Kaplan-Meier survival estimates. The results were compared to the 1986-1988 DEMCA data. RESULTS: The 5-year overall survival (OS) rate for the entire population was 77% (stages I-IV). The patients with stage I disease were divided into low-, intermediate-, and high-risk; the OS rates were 91%, 78%, and 62%, and the endometrial cancer-specific survival rates were 97%, 87%, and 72%, respectively. Using patients' age, tumor grade, myometrial invasion, we divided the intermediate-risk group into "high risk" intermediate and "low-risk" intermediate with OS rates of 70% and 90% and cancer-specific survival of 81% and 96%, respectively. The OS rate (78%) of the intermediate-risk group after radiation had been omitted was comparable to the OS rate (79%) of the intermediate-risk group in the earlier DEMCA (1986-1988) study where postoperative radiation was still the standard of care. CONCLUSION: We conclude that in a population-based study, radiotherapy can be omitted for intermediate-risk patients with stage I endometrial cancer without loss of survival.

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.