Efficacy of Endometrial Cancer Follow-up Protocols: Time to Change?

OBJECTIVE: The aim of the present study was to analyze relapse rates and patterns in patients with endometrial cancer with the aim of evaluating the effectiveness of current follow-up procedures in terms of patient survival, as well as the convenience of modifying the surveillance strategy. METHODS: Retrospective descriptive study including all patients diagnosed with endometrial cancer relapse at the Department of Gynecology and Obstetrics of the Complejo Hospitalario Insular-Materno Infantil de Canarias, between 2005 and 2014. RESULTS: Recurrence was observed in 81 patients (10.04% of the sample); 66.7% of them suffered relapse within 2 years and 80.2% within 3 years after the termination of the primary treatment; 41.9% showed distant metastases while the rest corresponded to local-regional (40.7%) or ganglionar (17.4%) relapse; 42% of these were symptomatic; 14 patients showed more than 1 site of relapse. Relapse was detected mainly through symptoms and physical examination findings (54.3%), followed by elevated serum marker levels (29.6%), computed tomography (CT) images (9.9%) and abnormal vaginal cytology findings (6.2%). No differences in global survival were found between patients with symptomatic or asymptomatic relapse. CONCLUSION: Taking into account that the recurrence rate of endometrial cancer is low, that relapse occurs mainly within the first 3 years post-treatment and that symptom evaluation and physical examination are the most effective follow-up methods, we postulate that a modification of the current model of hospital follow-up should be considered.

Efficacy of endometrial cancer follow-up protocols: time to change?

Abstract Objective The aim of the present study was to analyze relapse rates and patterns in patients with endometrial cancer with the aim of evaluating the effectiveness of current follow-up procedures in terms of patient survival, as well as the convenience of modifying the surveillance strategy. Methods Retrospective descriptive study including all patients diagnosed with endometrial cancer relapse at the Department of Gynecology and Obstetrics of the Complejo Hospitalario Insular-Materno Infantil de Canarias, between 2005 and 2014. Results Recurrence was observed in 81 patients (10.04% of the sample); 66.7% of them suffered relapse within 2 years and 80.2% within 3 years after the termination of the primary treatment; 41.9% showed distant metastases while the rest corresponded to local-regional (40.7%) or ganglionar (17.4%) relapse; 42% of these were symptomatic; 14 patients showed more than 1 site of relapse. Relapse was detected mainly through symptoms and physical examination findings (54.3%), followed by elevated serummarker levels (29.6%), computed tomography (CT) images (9.9%) and abnormal vaginal cytology findings (6.2%). No differences in global survival were found between patients with symptomatic or asymptomatic relapse. Conclusion Taking into account that the recurrence rate of endometrial cancer is low, that relapse occurs mainly within the first 3 years post-treatment and that symptom evaluation and physical examination are the most effective follow-up methods, we postulate that a modification of the current model of hospital follow-up should be considered.

Does iatrogenic tumor rupture during surgery have prognostic implications for the outcome of uterine sarcomas?

OBJECTIVE: Tumor rupture during surgery is a risk factor for recurrence of sarcomas in other locations. However, the independent impact of rupture on prognosis is uncertain in uterine sarcomas. The aim of this study was to evaluate whether uterine rupture impacts outcomes in patients with uterine sarcoma. METHODS: A retrospective analysis was carried out of all consecutive patients with uterine sarcoma managed at the Department of Gynecology and Obstetrics of the Complejo Hospitalario Universitario Insular-Materno Infantil of the Canary Islands, Spain between January 1990 and December 2016. Inclusion criteria included all patients with histologically proven uterine sarcoma. Exclusion criteria included patients with endometrial carcinoma (non-sarcomatous) and carcinosarcomas. During this period, 1981 patients were diagnosed with a uterine malignancy; 1799 were excluded because of a diagnosis of endometrial carcinoma and 85 patients were excluded for a diagnosis of carcinosarcoma. Thus, the final sample included 97 patients with uterine sarcoma (4.9%). These included leiomyosarcoma, endometrial stromal sarcoma, adenosarcoma, and liposarcoma. Surgical resection was the primary treatment, including open, laparoscopic and vaginal surgery. Survival rates were analyzed using the Kaplan-Meier method. RESULTS: The median age was 52 years (range 25-90); 49.5% (48) were pre-menopausal. Distribution per histological type was: 46.4% (45) leiomyosarcoma, 23.7% (23) high-grade endometrial stromal sarcoma, 17.5% (17) low-grade endometrial stromal sarcoma, 11.3% (11) adenosarcoma, and 1% (1) liposarcoma. Uterine leiomyoma was the most frequent pre-operatively suspected diagnosis (49.5%). Iatrogenic rupture of the tumor during surgery occurred in 25.3% of cases (23). International Federation of Gynecology and Obstetrics stages I-II and III-IV were identified in 74.2% (72) and 25.8% (25) of patients, respectively. The median tumor size was 8 cm (range 2-40). The recurrence rate was 47.8% (11) for patients with intra-operative tumor rupture and 25% (17) for patients without uterine rupture (p=0.03). Disease-free survival rates at 1, 2, and 5 years for patients with uterine rupture were 72.7%, 55.4%, and 13.9%, respectively, with a median time of 39 months (95% CI 2.9 to 75). For those patients without uterine rupture, disease-free survival rates at 1, 2, and 5 years were 84.8%, 76.1%, and 71.3%, respectively, with a mean time of 208.6 months (95% CI 169 to 248.3) (p=0.01). Multivariate analysis showed that stage, histological type, and iatrogenic tumor rupture during surgery were all independent prognostic factors for overall survival (OR 7.9, 95% CI 1.6 to 38.2, p=0.01); OR 5.3, 95% CI 2.1 to 13, p<0.0001; and OR 2.6, 95% CI 1.1 to 6.5, respectively, p=0.03). CONCLUSION: Considering that uterine sarcomas, especially leiomyosarcomas, often occur in pre-menopausal women as bulky tumors requiring laparotomy and that they are rarely diagnosed pre-operatively, efforts should be made to avoid iatrogenic uterine rupture during surgery as it impairs patient survival.

Microsatellite instability and ploidy status define three categories with distinctive prognostic impact in endometrioid endometrial cancer.

Microsatellite instability (MSI) and aneuploidy are inversely related phenomena. We tested whether ploidy status influences the clinical impact of MSI in endometrioid endometrial cancer (EEC). We analyzed 167 EECs for MSI and ploidy. Tumors were classified in three categories according to MSI and ploidy status. Associations with clinicopathological and molecular variables, survival, and treatment response were assessed. All MSI tumors (23%) were scored as diploid, and 14% of microsatellite stable (MSS) tumors presented aneuploidy. MSI tumors associated with older age at diagnosis, non-obesity, high histological grade, and advanced surgical stage. MSS-aneuploid tumors also associated with higher grade and advanced stage. In multivariate survival analysis MSI did not influence disease-free survival (DFS) or cancer-specific survival (CSS). However, when just diploid tumors were considered for the analysis, MSI significantly contributed to worse DFS and CSS, and the same was observed for aneuploidy when MSS tumors were analyzed alone. In diploid tumors, a differential response to postoperative radiotherapy (RT) was observed according to MSI, since it predicted poor DFS and CSS in the multivariate analysis. We conclude that ploidy status influences the clinical impact of MSI in EEC. Among diploid tumors those with MSI have poor clinical outcome and respond worse to RT.

Follow-up after LLETZ: a study of 682 cases of CIN 2-CIN 3 in a single institution.

OBJECTIVE: To evaluate the importance of resection margins in the risk of persistent/recurrent lesions and to investigate other factors such as detection of high-risk HPV, which could potentially predict persistent/recurrent disease before patients engage in follow-up. STUDY DESIGN: 682 women with a histologically confirmed diagnosis of CIN 2-3 treated by loop electrosurgical excision procedure (LEEP) were included, between January 2000 and December 2006. Age, high-risk HPV detection determined by Hybrid Capture II and cone margins were evaluated as possible predictors of persistent/recurrent disease. RESULTS: The mean age at diagnosis was 37.8 years (range 18-73). The mean follow-up period was 39.9 months (SD 25.8). 6.6% of patients (45/682) were lost to follow-up. 64.7% of patients (441/682) had clear margins in the specimen and 20.1% of patients had positive surgical margins (137/682). In 8.6% of patients (59/682) the resection margins were uncertain. Positive endocervical sweep was found in 10.8% of cases (73/682). Residual/recurrent disease was demonstrated by colposcopy-guided biopsy in 13.9% of patients (88/637); 77.3% (68/88) of them developed CIN 1 while only 22.7% (20/88) developed high-grade premalignant lesions or carcinomas during the follow-up. We found significant differences in the frequency of persistent/recurrent disease depending on the status of margins: 24.8% of cases with positive margins vs 11.1% of cases with negative margins (p<0.0001). Multivariate analysis showed that only post-treatment high-risk HPV detection and status of the cone margins were significantly predictive of persistent/recurrent disease (OR 4.1, 95%CI 2.4-7.3, p<0.0001 and OR 2.7, 95%CI 1.5-4.7, p=0.001; respectively). CONCLUSION: The combination of histological examination of resection margins plus post-treatment tests for HPV detection would help to classify LEEP-treated patients into categories at different risk of recurrence.

Double strand break repair components are frequent targets of microsatellite instability in endometrial cancer.

AIM: DNA double strand break (DSB) repair is a central cellular mechanism of the DNA damage response to maintain genomic stability. DSB components are frequently mutated in colorectal cancer with microsatellite instability (MSI). We investigated whether DSB repair is involved in endometrial cancer (EC) with MSI. METHODS: Mononucleotide microsatellite tracts of 14 genes of the DSB repair system were analysed in a series of 41 EC with MSI. Among these genes, the microcephalin 1 (MCPH1/BRIT1) has never been tested as target of MSI in tumour series. RESULTS: The most frequently mutated gene was DNAPKcs (n=14, 34%) followed by RAD50 (n=7, 17%), MRE11, ATR and BRCA1 (n=6, 15%), and by CtIP and MCPH1 (n=5, 12%). While DSB biallelic mutations were infrequent, a high proportion of tumours (n=30, 73%) presented mutations at some component of the DSB repair pathway, and almost half of them showed alterations at two or more components. Tumours with mutations in two or more genes were significantly associated with advanced grade (p=0.03) and vascular invasion (p=0.02) and marginally associated with advanced stage (p=0.07). CONCLUSIONS: Our results suggest that in EC, the DSB repair is a relatively common mutational target of MSI and might contribute to tumour progression, and also that MCHP1 may be a novel target gene of MSI.

Microsatellite instability predicts clinical outcome in radiation-treated endometrioid endometrial cancer.

PURPOSE: To elucidate whether microsatellite instability (MSI) predicts clinical outcome in radiation-treated endometrioid endometrial cancer (EEC). METHODS AND MATERIALS: A consecutive series of 93 patients with EEC treated with extrafascial hysterectomy and postoperative radiotherapy was studied. The median clinical follow-up of patients was 138 months, with a maximum of 232 months. Five quasimonomorphic mononucleotide markers (BAT-25, BAT-26, NR21, NR24, and NR27) were used for MSI classification. RESULTS: Twenty-five patients (22%) were classified as MSI. Both in the whole series and in early stages (I and II), univariate analysis showed a significant association between MSI and poorer 10-year local disease-free survival, disease-free survival, and cancer-specific survival. In multivariate analysis, MSI was excluded from the final regression model in the whole series, but in early stages MSI provided additional significant predictive information independent of traditional prognostic and predictive factors (age, stage, grade, and vascular invasion) for disease-free survival (hazard ratio [HR] 3.25, 95% confidence interval [CI] 1.01-10.49; p = 0.048) and cancer-specific survival (HR 4.20, 95% CI 1.23-14.35; p = 0.022) and was marginally significant for local disease-free survival (HR 3.54, 95% CI 0.93-13.46; p = 0.064). CONCLUSIONS: These results suggest that MSI may predict radiotherapy response in early-stage EEC.

Pure papillary serous tumors of the endometrium: a clinicopathological analysis of 61 cases from a single institution.

OBJECTIVE: The aim of this study was to evaluate the clinicopathological data and prognosis factors corresponding to patients with papillary serous carcinoma of the endometrium treated at a single institution. METHODS: Medical and anatomopathological records were reviewed in the Department of Gynecological Oncology of the Canarian University Hospital between 1989 and 2006. Only pure cases of papillary serous carcinoma of the endometrium were included. Survival rates were analyzed using the Kaplan-Meier technique. RESULTS: The study included 61 patients. Stages I, II, III, and IV were identified in 32.8%, 19.7%, 31.1%, and 8.2% of patients, respectively. Event-free survival rates after 5 and 10 years were 59% and 40%, respectively, with a median time of 83 months (95% confidence interval, 63-110). Relapse occurred in 40.5% of the patients. Overall survival rates after 5 and 10 years were 37.7% and 29%, respectively, with a median time of 55 months (95% confidence interval, 40-70). A univariate analysis showed that prognosis factors were tumor markers, stage, myometrial infiltration, lymphovascular invasion, and ganglia involvement. A multivariate analysis showed that tumor markers, stage, and myometrial infiltration had an independent influence on overall survival. CONCLUSIONS: Papillary serous carcinoma of the endometrium is a very aggressive type of endometrial carcinoma that behaves more similar to ovarian carcinoma than to endometrial carcinoma. Tumor markers at diagnosis, stage, and myometrial infiltration mainly determine prognosis at our institution.

The relationship between microsatellite instability and PTEN gene mutations in endometrial cancer.

Microsatellite instability (MSI) and mutations in the PTEN gene are among the molecular alterations involved in endometrial carcinogenesis. There is conflicting information regarding to their role in this type of tumor. For this reason, we have studied both molecular lesions in a large population-based series of 205 patients with sporadic endometrial cancer. MSI was found in 41 (20.0%) of the tumors and PTEN mutations were found in 74 (36.1%). There were differences in genotype between tumors with and without MSI. Tumors with MSI showed both a higher frequency of PTEN mutations (58.5% vs. 30.4%) (p=0.002, Fisher's exact test) and a higher number of insertions or deletions (I/D) of one nucleotide within the mononucleotide tracts of the PTEN gene (45.8% vs. 11.4% out of all I/D, p=0.005). Conversely, G:C to A:T transitions in CpG dinucleotides were found mostly in microsatellite stable tumors (57.7% vs. 18.2% out of all single-base substitutions, p=0.037). Overall, 67.6% of tumors with mutated PTEN exhibited multiple mutations or allelic imbalance (AI). Multiple PTEN mutations in the same tumor were more frequent in tumors with MSI (60% vs. 25.7%); by contrast the presence of AI accompanying PTEN mutation was higher in microsatellite stable tumors (74.3% vs. 40%) (p=0.028). In addition, patients with both genetic alterations were diagnosed at more advanced stage of progression (54.2% for MSI vs. 20.0% for MSS, p=0.006), and exhibited a worse prognosis (hazard ratio [95% confidence interval]: 3.0 [1.1-13.1], p=0.034, log-rank test) than patients with only the PTEN gene mutated. Our data suggest that the DNA mismatch repair system status influences: (i) both the frequency and the mutational spectrum of PTEN; (ii) the nature of one of the hits that inactivate this tumor-suppressor gene; and (iii) the clinical condition and behavior of the patients.

Alleles with short CAG and GGN repeats in the androgen receptor gene are associated with benign endometrial cancer.

The human androgen receptor (AR) gene possesses 2 trinucleotide repeats of CAG and GGN in exon 1. The CAG repeat corresponds to a polyglutamine tract in the N-terminal region of the receptor, that affects its transcriptional efficiency. The GGN repeat codifies for a polyglycine tract, and affects the amount of the AR protein transcribed. The endometrium contains ARs and the androgens have antiproliferative properties in cultured endometrial cancer (EC) cells. Larger CAG repeats of the AR gene give rise to a weaker transcriptional activity and have been found to be associated with endometrial carcinogenesis. The possible involvement of CAG and GGN tracts in the progression of EC is unknown. To study that possibility, we have genotyped both CAG and GGN polymorphisms of the AR gene in tumor tissue genomic DNA from a series of 204 consecutive patients with EC, and analyzed the results with regard to the pathological features and clinical outcome of patients. We classified the alleles as S (short median). The genotype with both S-CAG repeat alleles (SS-CAG) was more common in patients diagnosed at an early stage (41.6% SS-CAG vs 22.6% SL- and LL-CAG together, p = 0.048) and in tumors that did not invade the vascular space (43.0% SS-CAG vs 26.4% SL- and LL-CAG together, p = 0.034). The genotype with SS-GGN alleles was more common in well-differentiated tumors (41.2% SS-GGN vs 25.2% LS- and LL-GGN together, p = 0.017) and in endometrioid histological subtype tumors (35.3% SS-GGN vs 13.0% SL- and LL-GGN together, p = 0.034). When the genotypes of both repeats coexisting in each tumor specimen were taken into consideration, the relationship between the SS-CAG genotype and early stage remained only in the presence of the SS-GGN genotype (43.9% vs 0%, p = 0.01). No other associations were observed. In univariate survival analysis, patients with short alleles of both repeats (SS-CAG and SS-GGN genotypes simultaneously) had a lower risk of cancer-specific death (p = 0.032, mean follow-up: 63 months). Our data suggests that short CAG or GGN repeats of the AR gene are associated with a more benign condition of traditional prognostic variables in EC.