Identifying safe diagnostic algorithms for sentinel lymph node mapping in high-risk endometrial cancer: The SENTIREC-endo study.

INTRODUCTION: It is unclear if sentinel node (SLN) mapping can replace pelvic- (PLD) and paraaortic lymphadenectomy (PALD) for high-risk endometrial cancer (EC). A diagnostically safe surgical algorithm, taking failed mapping cases into account, is not defined. We aimed to investigate the diagnostic accuracy of SLN mapping algorithms in women with exclusively high-risk EC. METHODS: We undertook a prospective national diagnostic cohort study of SLN mapping in women with high-risk EC from March 2017 to January 2023. The power calculation was based on the negative predictive value (NPV). Women underwent SLN mapping, PLD and PALD besides removal of suspicious and any FDG/PET-positive lymph nodes. Accuracy analyses were performed for five algorithms. RESULTS: 170/216 included women underwent SLN mapping, PLD and PALD and were included in accuracy analyses. 42/170 (24.7%) had nodal metastasis. The algorithm SLN and PLD in case of failed mapping, demonstrated a sensitivity of 86% (95% CI 74-100) and an NPV of 96% (95% CI 91-100). The sensitivity increased to 93% (95% CI 83-100) and the NPV to 98% (95% CI 94-100) if PLD was combined with removal of any PET-positive lymph nodes. Equivalent results were obtained if PLD and PALD were performed in non-mapping cases; sensitivity 93% (95% CI 83-100) and NPV 98% (95% CI 95-100). CONCLUSION: SLN-mapping is a safe staging procedure in women with high-risk EC if strictly adhering to a surgical algorithm including removal of any PET-positive lymph nodes independent of location and PLD or PLD and PALD in case of failed mapping.

Assessment of recurrence rate and risk factors of relapse in stage in IA vulvar carcinoma.

OBJECTIVE: To evaluate recurrence rates and risk factors of relapse in stage IA vulvar squamous cell carcinoma (VSCC) patients. MATERIAL AND METHODS: Population-based prospectively collected data on stage IA VSCC was retrieved through the Danish Gynecological Cancer Database (DGCD) during 2011-2017. A central pathology review was performed on tumors from women with recurrent disease. RESULTS: 62 women diagnosed and treated for stage IA VSCC were identified. Nine (14.5%) of the included cases relapsed within the observation period. The recurrences were in the vulva, groins or both in 5 (8.1%), 3 (4.8%) and 1 (1.6%) of the women, respectively. At central pathology review, including all recurrent cases (n = 9), 5 out of 21 reviewed patients were upstaged to stage IB due to depth of invasion >1 mm and two were downstaged to Carcinoma in situ. Two of the upstaged women developed an isolated groin recurrence and one an isolated vulvar relapse. After exclusion of the seven cases the overall recurrence rate decreased to 10.9% (n = 6). Among these cases (n = 55) resection margin <8 mm and tumor size were associated with cancer recurrence. CONCLUSION: Pathological assessment of stage IA VSCC (depth of invasion ≤1 mm) may be difficult. This may result in under-staging, which impact the choice of treatment and possibly the prognosis. This suggests a need for further clarification of the FIGO measurement and may require a more radical approach when it comes to treatment and groin exploration in stage IA VSCC. Resection margins <8 mm and tumor size were associated with relapse of the disease.

Use of hypnotics among women diagnosed with cervical cancer - A population-based cohort study.

OBJECTIVE: Previous studies suggest that sleeping problems are frequent after cervical cancer. However, the evidence on the use of hypnotics is sparse. We investigated if women diagnosed with cervical cancer have an increased risk of using hypnotics and identified risk factors for prolonged use. METHODS: In this nationwide register-based cohort study, 4264 women diagnosed with cervical cancer from 1997 to 2013 and 36,632 cancer-free women were followed in registers until 2016. Prolonged use of hypnotics was defined as more than three prescriptions with no more than three months in between. Data were analysed using Cox proportional hazards regression models and multistate Markov models separately for women with localized and advanced cervical cancer. RESULTS: The rate of first use of hypnotics was substantially increased during the first year after cervical cancer diagnosis compared to cancer-free women (HRlocalized 4.4, 95% CI 3.9-5.1; HRadvanced 8.9, 95% CI 7.5-10.6) and remained markedly increased for up to five years after diagnosis. Dependent on stage of disease and age, 1.4 to 4.7 excess women per 100 with cervical cancer were prolonged users of hypnotics compared to cancer-free women one year after diagnosis. Risk factors for prolonged use of hypnotics were higher age, short education, previous use of antidepressants or anxiolytics, and advanced disease. CONCLUSIONS: Women diagnosed with cervical cancer are at increased risk of prolonged use of hypnotics. For the majority, treatment with hypnotics is initiated within the first year after cancer diagnosis, but the rate of first use is increased for up to five years.

Vaginal melanoma in Denmark from 1980 to 2018: A population-based study based on genetic profile and survival.

OBJECTIVE: To investigate the clinical, pathological, and genetic characteristics of patients with vaginal melanoma in a nationwide setting. MATERIALS/METHODS: All patients diagnosed with vaginal melanoma from 1980 to 2018 were collected by searching the digital archives of the Danish Registry of Pathology (Patobank). Patient specimens were examined, the histological diagnoses were validated, and targeted next-generation sequencing (NGS) of known frequent hot spots in 163 genes was performed. RESULTS: Fifty-two patients were included. The incidence for primary melanoma of the vagina in the Danish population (5.5 million people) was calculated to be 0.24 cases/million/year from 1980 to 2018. For all patients, the median OS was 17.5 months (95% CI: 13.0-24.0), and the 5-year OS was 19.4% (95% CI: 10.9-34.3). We identified frequent mutations in ATRX (7/25 cases) and TP53 (7/25 cases). Mutations found in TP53 were associated with a significant decrease in OS (p = 0.043), whereas mutations in the ATRX gene alone did not show a significant impact on OS (p = 0.3649). Patients who harbored co-mutations in both ATRX and TP53 showed a significant reduction in OS (p = 0.0081), with a median OS of 9.5 months compared to 20 months in those without the co-mutation. CONCLUSIONS: Vaginal melanoma is a rare disease with a poor prognosis presumably due to vague symptoms and the anatomical location of the disease. Co-mutations in ATRX and TP53 and mutations in TP53 alone were associated with a poor prognosis, and these genes are potentially interesting targets for future therapy.

SENTIREC - The sentinel node mapping in women with cervical cancer study - Patient-reported early lymphedema and its impact on quality of life.

OBJECTIVE: To evaluate patient-reported incidence and severity of early lymphedema and its impact on quality of life (QoL) after sentinel lymph node (SLN) mapping only and after SLN and pelvic lymphadenectomy (PL) in women undergoing surgery for early-stage cervical cancer. METHODS: In a national prospective multicenter study, we included women with early-stage cervical cancer from March 2017-January 2021 to undergo radical surgery including SLN mapping. Women with tumors >20 mm underwent completion PL. The incidence and severity of early lymphedema and its influence on QoL were evaluated using validated patient-reported outcome measures before surgery and three months postoperative. We investigated changes over time using linear regression. RESULTS: Two hundred of 245 (81.6%) included women completed questionnaires at baseline and three months postoperatively. The incidence of early lymphedema was 5.6% (95% CI 2.1-11.8%) and 32.3% (95% CI 22.9-42.7%) in women who underwent SLN mapping only and SLN + PL, respectively. Lymphedema symptoms in the legs, genitals, and groins increased in both groups postoperatively but three times more in women who underwent PL. Lymphedema symptoms after SLN + PL significantly impaired physical performance (p = 0.001) and appearance (p = 0.007). Reporting lymphedema was significantly associated with impaired body image, physical-, role-, and social functioning, and a high level of fatigue. CONCLUSIONS: SLN mapping alone carries a low risk of lymphedema in women undergoing surgery for early-stage cervical cancer. In contrast, completion PL is associated with a high incidence of early lymphedema. Reporting lymphedema is associated with significant impairment of several physical, psychological, and social aspects of QoL.

From FIGO-2009 to FIGO-2018 in women with early-stage cervical cancer; Does the revised staging reflect risk groups?

OBJECTIVES: We aimed to evaluate if the revised staging according to FIGO-2018 in early-stage cervical cancer correctly predicts the risk for nodal metastases. METHODS: We reallocated 245 women with early-stage cervical cancer from FIGO-2009 to FIGO-2018 stages using data from a national, prospective cohort study on sentinel lymph node (SLN) mapping. We used univariate and multivariate binary regression models to investigate the association between FIGO-2018 stages, tumor characteristics, and nodal metastases. RESULTS: Stage migration occurred in 54.7% (134/245) (95% CI 48.2-61.0), due to tumor size or depth of invasion (71.6%, 96/134) and nodal metastases (28.4%, 38/134). Imaging preoperatively upstaged 7.3% (18/245); seven had nodal metastatic disease on final pathology. Upstaging occurred in 49.8% (122/245) (95% CI 43.4-56.2%) and downstaging to FIGO-2018 IA stages in 4.9% (12/245) (95% CI 2.6-8.4). The tumor size ranged from 3.0-19.0 mm in women with FIGO-2018 IA tumor characteristics, and none of the 14 women had nodal metastases. In multivariate analysis, risk factors significantly associated with nodal metastases were FIGO-2018 ≥ IB2 (RR 5.01, 95% CI 2.30-10.93, p < 0.001), proportionate depth of invasion >2/3 (RR 1.88, 95% CI 1.05-3.35, p = 0.033), and lymphovascular space invasion (RR 5.56, 95% CI 2.92-10.62, p < 0.001). CONCLUSIONS: The FIGO-2018 revised staging system causes stage migration for a large proportion of women with early-stage cervical cancer. Women who were downstaged to FIGO-2018 IA stages did not have nodal metastatic disease. The attention on depth of invasion rather than horizontal dimension seems to correctly reflect the risk of nodal metastases.

Sentinel lymph node mapping in early-stage cervical cancer - A national prospective multicenter study (SENTIREC trial).

OBJECTIVES: Sentinel lymph node (SLN) mapping may replace staging radical pelvic lymphadenectomy in women with early-stage cervical cancer. In a national multicenter setting, we evaluated SLN mapping in women with early-stage cervical cancer and investigated the accuracy of SLN mapping and FDG-PET/CT in tumors >20 mm. METHODS: We prospectively included women with early-stage cervical cancer from March 2017-January 2021 to undergo SLN mapping. Women with tumors >20 mm underwent completion pelvic lymphadenectomy and removal of FDG-PET/CT positive nodes. We determined SLN detection rates, incidence of nodal disease, sensitivity and negative predictive value (NPV) of SLN mapping, and the sensitivity, specificity, NPV, and positive predictive value (PPV) of FDG-PET/CT. RESULTS: We included 245 women, and 38 (15.5%) had nodal metastasis. The SLN detection rate was 96.3% (236/245), with 82.0% (201/245) bilateral detection. In a stratified analysis of 103 women with tumors >20 mm, 27 (26.2%) had nodal metastases. The sensitivity of SLN mapping adhering to the algorithm was 96.3% (95% CI 81.0-99.9%) and the NPV 98.7% (95% CI 93.0-100%). For FDG-PET/CT imaging the sensitivity was 14.8% (95% CI 4.2-33.7%), the specificity 85.5% (95% CI 75.6-92.5%), the NPV 73.9% (95% CI 63.4-82.7%), and the PPV 26.7% (95% CI 7.8-55.1%). CONCLUSIONS: SLN mapping seems to be an adequate staging procedure in early-stage cervical cancer tumors ≤20 mm. In tumors >20 mm, SLN mapping is highly sensitive but demands full adherence to the SLN algorithm. We recommend completion pelvic lymphadenectomy in tumors >20 mm until the oncological safety is established. FDG-PET/CT for nodal staging of women with early-stage cervical cancer seems limited.

Increased risk for depression persists for years among women treated for gynecological cancers - a register-based cohort study with up to 19 years of follow-up.

OBJECTIVE: Little is known about long-term risk of depression in women treated for gynecological cancers. We aim to investigate risk for depression among these women compared to women without a history of cancer. METHODS: We followed 16,833 women diagnosed with gynecological cancers between 1998 and 2013 and 138,888 reference women in nationwide registers for up to 19 years. Women with a history of severe psychiatric disorders, and those who had redeemed a prescription for antidepressants three years before study entry were excluded from analyses. Regression analyses were applied to compare the risk for antidepressant use among patients compared to reference women, and to investigate associations between socio-demographic as well as clinical risk factors and use of antidepressants. RESULTS: We found an increased risk for antidepressant use among women treated for ovarian (HR 4.14, 95% CI 3.74-4.59), endometrial (HR 2.19, 95% CI 1.97-2.45), and cervical cancer (HR 3.14, 95% CI 2.74-3.61) one year after diagnosis. This increased risk persisted years after diagnosis in all three groups, with the longest (up to eight years) found for ovarian cancer. Advanced disease was strongly associated with antidepressant use followed by short education, and comorbidity. CONCLUSIONS: Women diagnosed with gynecological cancer have an increased risk for depression compared to reference women. The risk remains increased for years after diagnosis throughout and beyond standard oncological follow-up care. Advanced disease, short education, and comorbidity are factors associated with antidepressant use in this patient group.

Quality of life, urogynecological morbidity, and lymphedema after radical vaginal trachelectomy for early-stage cervical cancer.

OBJECTIVE: Radical vaginal trachelectomy (RVT) offers a possibility for future childbearing for young women with early-stage cervical cancer. However, the literature on quality of life and self-reported morbidity in patients undergoing RVT is scarce. The aim of this study was to prospectively assess quality of life after RVT with focus on urogynecological morbidity and lymphedema. Furthermore, the aim of this study was to compare results with those in women treated with radical abdominal hysterectomy (RAH) and with age-matched control women from the general population. METHODS AND MATERIALS: Eighteen patients with early-stage cervical cancer operated with RVT were prospectively included and assessed preoperatively, 3, 6, and 12 months postoperatively using validated questionnaires. Thirty-two patients treated with RAH were included consecutively and assessed once at 12 months postsurgery, whereas an age-matched control group of 30 healthy women was assessed once. RESULTS: Fifty percent of the RVT group and 41% of the RAH reported any grade of incomplete bladder emptying problems at 1 year postsurgery assessment. Eleven percent of the RVT patients and 12.5% of the RAH patients reported severe lymphedema of the legs as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Cervical Cancer Module. The Global Health Status scores of the RVT patients improved over time but were significantly lower than in the healthy controls during the entire observation time (P = 0.029). CONCLUSIONS: Patients treated with RVT for early-stage cervical cancer had persistent bladder emptying problems and lymphedema comparable to those experienced by patients treated with RAH and significantly higher than those reported by healthy control women.

Sentinel lymph node mapping for endometrial and cervical cancer in Denmark.

INTRODUCTION: This was a surgical pilot study to systematically introduce the technique of sentinel lymph node (SLN) mapping in women with early-stage stage cervical cancer (CC) and endometrial cancer (EC) in Denmark. The study aimed to facilitate structured surgical training to ensure surgeon proficiency in SLN mapping. The study precedes two national prospective studies on the oncological safety and correct patient selection for SLN mapping in CC and EC. METHODS: The study was conducted at four gynaecological cancer centres at Odense and Aarhus University Hospital, Rigshospitalet and Herlev Hospital, between September 2016 and August 2019. All centres went through a protocolled introduction to the surgical technique, pelvic lymphatic drainage, pathological ultra-staging and data entry. A criterion of a total (uni- and bilateral) SLN detection of > 80%, based on 30 SLN mappings was set. RESULTS: The four centres performed 140 (range: 30-46) procedures. The total SLN detection rate was 91.3% with bilateral SLN detection in 68.8% and unilateral SLN detection in 22.5% of cases. The cumulated total SLN detection rate at three centres was above the pre-set 80% criterion from the beginning of inclusion, whereas one centre reached the criterion after 20 procedures. CONCLUSIONS: In this study, all centres demonstrated international-level SLN detection rates within 30 procedures. Hence, all centres met the study criterion regarding surgeon proficiency and were eligible for the national studies. FUNDING: Eva and Henry Frænkels Fond, Frimodt-Heineke Fonden, Kong Christian X Fond. TRIAL REGISTRATION: The study was approved by the Danish Data Protection Agency (R. no.15/52037). The SENTIREC studies including this pilot study are registered with clinicaltrials.gov (NCT02825355 and NCT02820506).

Gynaecological cancer leads to long-term sick leave and permanently reduced working ability years after diagnosis.

PURPOSE: The aim of the study was to investigate overall patterns in labour market affiliation, risk for permanently reduced work ability and prevalence of long-term sickness absence among women diagnosed with gynaecological cancer. METHODS: We followed 8451 women diagnosed with ovarian, endometrial or cervical cancer, and 72,311 women with no history of cancer in nationwide registers for up to 19 years (mean 7.5 years). We computed hazards ratios for permanently reduced working ability and annual proportions of long-term sick leave. RESULTS: Patterns of labour market affiliation varied by cancer diagnosis and stage. The hazard of permanently reduced working ability was increased for survivors of all three cancers but most pronounced for women diagnosed with advanced ovarian cancer. The highest hazard ratios were found 2-5 years after diagnosis, and they persisted for years in all groups and throughout the follow-up period of 19 years in women diagnosed with advanced cervical cancer. In the subgroups of women who continued to be potentially active on the labour market, long-term sick leave was more prevalent among cancer survivors than women with no history of cancer up to 10 years after diagnosis. CONCLUSIONS: Women diagnosed with localised as well as advanced gynaecological cancer are at prolonged risk for permanently reduced working ability and long-term sick leave. IMPLICATIONS FOR CANCER SURVIVORS: Gynaecological cancer can have long-term as well as permanent consequences for working ability, and survivors who remain active on the labour market might have to take more sick leave even years after cancer diagnosis than other women at their age.

[Workup, treatment and follow-up of vulva cancer].

This review summarises the current guidelines for vulva cancer in Denmark. Vulva cancer is a rare disease. The diagnosis is often delayed, which results in large tumours and regional spread. The most important prognostic factor is inguinal lymph node metastases. Staging and treatment is centralised to two hospitals. Primary treatment is wide local excision combined with removal of either inguinal sentinel nodes or lymphadenectomy. Treatment is associated with considerable morbidity, and supportive care is often necessary. Local curable recurrences are common. Relapses in the groin are associated with a poor prognosis. Thus, long term follow-up is essential. *) On behalf of Dansk Gynækologisk Cancer Gruppe for vulvacancer.