Sentinel lymph node (SLN) isolated tumor cells (ITCs) in otherwise stage I/II endometrioid endometrial cancer: To treat or not to treat?

OBJECTIVES: To assess associations between treatment and recurrence-free survival (RFS) among patients with isolated tumor cells (ITCs) in sentinel lymph nodes (SLN) and otherwise stage I/II endometrioid endometrial cancer (EC). METHODS: A multi-institutional retrospective study of patients with SLN ITCs (<200 cells and < 0.2 mm) was performed. Only patients with otherwise stage I/II EC, endometrioid histology, and no evidence of micro-or macrometastases were included. Univariate and multivariable Cox proportional hazard models were used to evaluate associations between treatment, tumor characteristics, and RFS. RESULTS: 175 patients were included. Median follow up time was 31 months. 39% stage IB and 12% stage II disease. 76 (43%) received no adjuvant therapy or vaginal brachytherapy only (NAT/VBT), 21 (12%) had external beam radiation (EBRT), and 78 (45%) received chemotherapy +/- radiation. Patients who received chemotherapy more often had tumors with deep myoinvasion, lymphovascular space invasion (LVSI), and higher grade. Nine (5.1%) patients recurred; 5 distant, 3 retroperitoneal, and 1 vaginal. Extra-vaginal recurrences were similar in patients with or without chemotherapy (5.2% vs 3.8%, p = 0.68). After controlling for stage, LVSI and grade, chemotherapy and EBRT were not associated with RFS (HR = 0.63, 95%CI 0.11-3.52, and HR = 0.90, 95%CI 0.22-3.61, respectively). Type of lymph node dissection and ITC detection method were not associated with RFS. CONCLUSIONS: Risk of retroperitoneal and/or distant recurrence is low (4.6%) for patients with stage I/II endometrioid EC and ITCs in SLNs regardless of treatment. Our preliminary data suggests that adjuvant therapy may not be significantly associated with RFS. However, longer follow-up time and a larger sample size are needed before definitive recommendations regarding adjuvant therapy for patients with EC and only ITCs in SLN can be made.

Can MRI help assess aggressiveness of endometrial cancer?

AIM: To identify potential magnetic resonance imaging (MRI) biomarkers to predict the aggressiveness of endometrial cancer. MATERIALS AND METHODS: Seventy-one patients with endometrial cancer who underwent MRI staging were analysed retrospectively. The signal intensity (SI) of the tumours was assessed on sagittal T2-weighted imaging (WI) and sagittal T1WI sequences). The depth of myometrial invasion, tumour grade and subtype, lymphovascular invasion, and microsatellite stability status were assessed histopathologically, and these findings were compared with MRI findings using logistic regression. The log-rank test was used to assess differences in survival among groups defined by different MRI measurements. RESULTS: Tumours with qualitative higher signal than that of normal myometrium on the late T1WI DCE image sequences were more likely to have lymphovascular space invasion (p<0.001). Tumours that had a higher SI tumour ratio (T1 post-contrast arterial/T1 precontrast) had a higher chance of being microsatellite stable (odds ratio 2.36). The SI ratio of the tumour to the myometrium showed that lower T2 tumour/T2 myometrial ratio correlated with ≥50% depth of myometrial invasion as determined by imaging (p=0.006). Endometrial tumours showing a SI of >209 on delayed T1WI sequences had longer recurrence-free survival than those with tumours showing a SI ≤209 (p=0.014). Tumour subtype and grade were not associated with MRI findings. CONCLUSION: The SI of endometrial cancer on MRI may be used to predict the aggressiveness of the tumour and microsatellite stability status. Further studies are needed to confirm these findings.

Quality of life after radical trachelectomy for early-stage cervical cancer: A 5-year prospective evaluation.

OBJECTIVES: To longitudinally assess quality of life (QOL) in women undergoing radical trachelectomy for early-stage cervical cancer. METHODS: We prospectively enrolled patients with stage IA1-IB1 cervical cancer prior to undergoing radical trachelectomy to complete validated QOL instruments. These instruments included the General Health-Related QOL (SF-12), Functional Assessment of Cancer Therapy-Cervix (FACT-Cx), MD Anderson Symptom Inventory (MDASI), Female Sexual Functioning Index (FSFI), and Satisfaction with Decision scale (SWD). Instruments were filled out at baseline, postoperatively at 6weeks, 6months, 1year, and annually thereafter for 4years. RESULTS: Thirty-nine patients enrolled in the study, and 32 patients were evaluable. The scores for FSFI-arousal (p=0.0002), lubrication (p<0.0001), orgasm (p=0.006), pain (p=0.01), satisfaction (p=0.03) and total score (p=0.004) showed a significant decline at 6weeks then returned to baseline levels by 6 months. The scores for FACT-Cx functional well-being (p=0.02) and physical well-being (p<0.0001), SF-12 bodily pain (p<0.0001), physical functioning (p<0.0001), role physical (p<0.0001), role emotional (p=0.03), social functioning (p=0.002), and MDASI total (p=0.04) showed significantly worsened symptoms at 6weeks then returned to baseline by 6months. The scores for FACT-Cx emotional well-being showed significant worsening of symptoms that persisted at 6-weeks (p=0.004), 6months (p=0.007), 1year (p=0.001), 2years (p=0.002), and 4 years (p=0.03). There was no difference in SWD. CONCLUSIONS: Several quality of life assessments decline immediately postoperatively after radical trachelectomy, however, return to baseline thereafter. The long-term emotional impact of this surgery highlights a need for perioperative counseling in these patients.

Loss of p27 Associated with Risk for Endometrial Carcinoma Arising in the Setting of Obesity.

Endometrial carcinoma (EC) exhibits the strongest association with obesity of all cancers. Growth of these tumors is driven by PI3K/AKT activation, and opposed by tumor suppressors, including the tuberous sclerosis complex 2 (TSC-2) and p27, with inactivation of TSC2 and loss or cytoplasmic mislocalization of p27 both being linked to PI3K/AKT activation. However, little is known about the involvement of p27 in the development of EC arising in the setting of obesity, especially its role early in disease progression. Using a panel of EC cell lines, in vitro studies using PI3K inhibitors provided evidence that p27 rescue contributes to the efficacy of interventions that inhibit endometrial cell growth. In "at risk" obese patients, and in an animal model of obesity-associated EC (Tsc2-deficient Eker rats), p27 was moderately-to-severely reduced in both "normal" endometrial glands as well as in endometrial complex atypical hyperplasia (obese women), and endometrial hyperplasia (obese rats). In obese Eker rats, an energy balance intervention; caloric restriction from 2-4 months of age, reduced weight, increased adiponectin and lowered leptin to produce a favorable leptin:adiponectin ratio, and reduced circulating insulin levels. Caloric restriction also increased p27 levels, relocalized this tumor suppressor to the nucleus, and significantly decreased hyperplasia incidence. Thus, dietary and pharmacologic interventions that inhibit growth and decrease risk for development of endometrial lesions are associated with increased expression and nuclear (re)localization of p27. These data suggest that p27 levels and localization may be useful as a biomarker, and possible determinant, of risk for EC arising in the setting of obesity.

Loss of phosphatase and tensin homologue deleted on chromosome 10 and phosphorylation of mammalian target of rapamycin are associated with progesterone refractory endometrial hyperplasia.

The objective of our study was to evaluate the phosphatase and tensin homologue deleted on chromosome 10 (PTEN), p27, and mammalian target of rapamycin (mTOR) expressions in women with progesterone-responsive and refractory endometrial hyperplasia (EH) samples and to determine if these markers could be associated with response or used as potential targets for treatment. Thirty-eight matched pre- and posttreatment pairs of paraffin-embedded endometrial biopsies were obtained from patients with EH. Immunohistochemical analysis for PTEN, p27, and phospho-mTOR were performed on all samples. Median age at diagnosis was 49 years (20-79 years). Median treatment interval was 3 months (1-12 months). Sixteen patients (42.1%) had complete resolution of their hyperplasia (responders), and 22 (57.9%) had persistent hyperplasia (nonresponders) after treatment with progesterone. In the pretreatment samples, no markers were found to predict nonresponders. In posttreatment samples, loss of PTEN expression with phospho-mTOR expression was observed in more nonresponders than responders (40.9% vs 6.3%; P= 0.03). Phospho-mTOR overexpression was found in 63.6% of nonresponders. We found that persistent hyperplasia refractory to progesterone therapy was associated both with the loss of PTEN and with the loss of phosphorylation of mTOR. In select cases of non-responsive progesterone refractory EH, a rational target for treatment may involve the mTOR pathway.

Correlation of cyclin D1 and cyclin D3 overexpression with the loss of PTEN expression in endometrial carcinoma.

Cyclins D1 and D3 play key roles in cell cycle progression. The downregulation of cyclin D3 was associated with phosphatase and tensin homolog deleted on chromosome ten-(PTEN)-induced cell cycle arrest. We attempted to determine whether cyclin D1 and D3 overexpression is correlated with PTEN inactivation in endometrioid endometrial cancer (EEC). The expression of PTEN, cyclin D1, and cyclin D3 were determined by immunohistochemical analysis in 105 EEC specimens. Forty-three percent of the EEC demonstrated loss of PTEN expression. Cyclin D3 was overexpressed in only 18% of the EEC specimens and was not associated with tumor grade. Cyclin D1 was overexpressed in 64% of the specimens and was more common in moderate or high-grade tumors (P = 0.002 and P = 0.02, respectively). The overexpression of cyclin D3 was not correlated with loss of PTEN in the EEC. The overexpression of cyclin D1 was much higher in grade 1 tumors with negative PTEN than tumors with positive PTEN expression (67% vs 26%). The overexpression of cyclin D3 was neither frequent nor correlated with the loss of PTEN expression. The overexpression of cyclin D1 was higher in the low-grade tumors with negative PTEN expression than tumors with positive PTEN expression. Overexpression of cyclin D1 is frequent in moderate or high-grade EECs and likely results from multiple mechanisms.