One day after a round of checkups, my colleagues were talking about a patient. One by one, I asked my own doctor: How thick can you “tolerate” endometrial thickness in a postmenopausal woman with no symptoms (no vaginal bleeding, fluid flow, increased leukorrhea, abdominal pain and bloating, etc.)? In other words, is there a cut-off value for the thickness of the endometrium on transvaginal ultrasound, below which it is safe and above which clinical intervention is needed? If so, what should this cut-off value be? Answers vary, but generally only a thickness of 5 to 6 mm can be “tolerated”, and some people cannot even tolerate 5 mm and let the patient scrape beyond 4 mm. Why? We all say that the current medical environment is harsh and the doctor-patient relationship is tense, so if we miss a case of endometrial lesion, won’t it cause a lot of trouble for us? Since diagnostic curettage or even hysteroscopy is “not that much of a hassle”, what is wrong with a little over-diagnosis? This is indeed a difficult question to answer. It is also difficult to decide from the medical and evidence-based nature of the practice, leaving aside the bubble of socially undesirable factors. In an expert discussion at King’s College Hospital, 52% voted to recommend routine ultrasound screening of endometrial thickness in postmenopausal asymptomatic women, and 48% voted against doing so. There was a wide range of opinions about the cut-off values for endometrial thickness, ranging from 5 mm, 6 mm, 8 mm and 10 mm and 11 mm. I sat in my office and thought for a long time. Perhaps we need to address the following questions one by one. What is the incidence of endometrial cancer in all age groups? What is the rate of endometrial malignancy in postmenopausal women with vaginal bleeding? What is the incidence of endometrial malignancy in postmenopausal women with no vaginal bleeding? What is the most reasonable threshold for women without vaginal bleeding after menopause? What is the most common pathology of the endometrium in postmenopausal women without vaginal bleeding? What is the effect of hormone therapy on postmenopausal endometrial thickness? What is the significance of active intervention for “endometrial thickening” in postmenopausal women without vaginal bleeding? 1. What is the incidence of endometrial cancer in all age groups? Endometrial cancer is the most common malignancy of the female reproductive tract, with a lifetime risk of 2.7% (1/37). There are an estimated 54,870 new cases of uterine tumors (including endometrial cancer) and 10,170 deaths per year in the United States. Before age 49, the risk was 0.3%, and in the age groups 50-59, 60-69, and >70 years, the risk of endometrial cancer was 0.6%, 0.9%, and 1.3%, respectively. Overall, the 5-year survival rate for endometrial cancer has reached 83%, without differentiating between races [2]. 2, What is the percentage of women with postmenopausal vaginal bleeding who develop endometrial malignancy? This situation has been confirmed by a large number of studies, and the general rate of endometrial malignancy and precancerous lesions in postmenopausal women with vaginal bleeding is between 8% and 10%. Transvaginal ultrasound (TVS) is known to be the most accurate and convenient tool to assess the thickness of the endometrium. Within the parameters of diagnostics, the thickness of the endothelium found by TVS correlates with the risk of malignancy, the thicker the endothelial thickness, the higher the rate of malignancy [3]. In the case of a single bleeding episode, with an endothelial thickness less than or equal to 4 mm on TVS, the risk of malignancy is generally considered to be close to 0 (0.07%) and can continue to be observed and monitored. However, in cases of recurrent or persistent bleeding, regardless of the thickness of the lining, evaluation should be performed. Hysteroscopy is the best tool for examination and evaluation. 3. What is the rate of endometrial malignancy in women with no vaginal bleeding after menopause? Cohort studies have found that among postmenopausal women without vaginal bleeding, the risk of malignancy may still be related to the thickness of the endometrium, but does not exceed the risk in the general population. A pooled study found that the incidence of endometrial cancer in postmenopausal women without vaginal bleeding was less than 0.25%, regardless of endometrial thickness [5], and in a prospective study in 2000, hysteroscopy in women with an endometrial thickness of ≤ 4 mm who had been menopausal for more than one year resulted in the detection of one adenocarcinoma in 199 asymptomatic women, with a rate of malignancy of 0.5% [6]. This figure is similar to other retrospective or observational studies. In another prospective study in 2009, the authors defined an endothelial thickness ≥6 mm as thickening and found a total of 3 cases of atypical hyperplasia (1%) and 12 cases of endothelial adenocarcinoma (3%) in a total of 304 patients (mean age 64.8 years, mean endothelial thickness 12 mm) [7]. In this study, the incidence of cancer was 3% (4/127), 2% (2/98), 5% (2/43) and 11% (4/36) for endothelial thicknesses of 6-10 mm, 11-15 mm, 16-20 mm and > 20 mm, respectively. All three cases of atypical hyperplasia occurred in patients with an endothelial thickness > 15 mm (4%). This result is confusing because the incidence of malignancy was similar in patients with different endothelial thicknesses, except in the case of endothelial thicknesses > 20 mm, and was also exceptionally high, similar to that of postmenopausal vaginal bleeding. The selection bias of the study is of concern, with an overall older age and more than 65% of patients having at least one risk factor for endometrial cancer (BMI > 30, obesity or diabetes). In a retrospective Canadian study in 2014, of 194 postmenopausal women with endometrial thickness > 4 mm and no vaginal bleeding, 109 underwent endometrial biopsy and none were found to have atypical hyperplasia or carcinoma. Of the 93 patients with hysteroscopically detected endometrial polyps, 73 underwent enderectomy, one had endometrial cancer (preoperative endometrial thickness of 24 mm), and one had atypical hyperplasia (preoperative endometrial thickness of 17 mm). In a prospective study in 2014, 4 cases of endometrial cancer (1.4%) and 3 cases of atypical hyperplasia (1.1%) were identified in 268 postmenopausal asymptomatic women with an endometrial thickness > 4 mm. For patients with an endometrial thickness < 10 mm, no case of atypical hyperplasia or malignancy was found [8]. 4. Which cut-off value is most reasonable to set for postmenopausal women without vaginal bleeding? In other words, does a cut-off value of ≥ 5 mm still apply to those women who are asymptomatic after menopause? The evidence for this is both sparse and low, but the authors generally do not recommend 5 mm as a cut-off value. In a 2004 pooled analysis, the authors designed a model of endometrial cancer risk based on the published literature. (1) Assuming that 15% of postmenopausal endometrial carcinomas occur in women without vaginal bleeding, in this case: the risk of endometrial cancer is 6.7% if the endometrial thickness found by TVS is > 11 mm and 0.002% if the endometrial thickness is ≤ 11 mm. (2) Assuming that only 5% of postmenopausal endometrial carcinomas occur in women without vaginal bleeding, the risk of cancer in women with endometrial thickness > 11 mm is only 2.2%. (3) Assuming that 20% of postmenopausal endometrial carcinomas occur in women without vaginal bleeding, the risk of cancer in women with endometrial thickness > 11 mm is also only 8.9%. In this model, the risk of malignancy associated with endometrial thickening increases with age. Using a cut-off of 11 mm, the risk of malignancy for endo-thickness at age 50 was 4.1%, increasing to 9.3% at age 79. Other clinical factors had no significant effect on the sensitivity analysis of endothelial thickness. The table below shows the risk of endothelial cancer corresponding to different cut-off values given by the authors, and the figure below shows the cancer risk corresponding to changes in each parameter, using 11 mm as the cut-off value. On the basis of prospective studies, some authors have found that there is no ideal cut-off value for endometrial thickness that can be used to perform interventions for intrauterine pathology. The use of an endometrial thickness >5 mm as a cut-off value is quite unreasonable and leads to a large number of hysteroscopic operations with negative histopathology. If endometrial thickness ≥ 8 mm is used as a cut-off value, it may be the most appropriate for the diagnosis of all intrauterine pathologies. In contrast, the risk of malignancy in asymptomatic women with an endometrial thickness < 10 mm is 0 [8]. 5, What are the most common endometrial pathologies in postmenopausal women without vaginal bleeding? Atrophic endothelium and endothelial polyps are the most common histologic pathologies. For endothelial thickness < 5 mm, the endothelial pathology finding rate is 10%, with endothelial polyps being the most common (84%, 16/19) [6]. For endothelial thickness > 6 mm, endothelial polyps were also the most common (74.3%, 226/304) [7]. Analyzed from this perspective, the high incidence of endometrial polyps may make aggressive intervention in asymptomatic postmenopausal women inappropriate. in a prospective study in 2014, atrophic endometrium was the most common histological finding in women with an endometrial thickness > 4 mm (56.8%) and endometrial polyps in 34.4%. 6. What is the effect of hormone therapy on postmenopausal endometrial thickness? What kind of endometrial thickness is abnormal with hormone supplementation (especially estrogen therapy) and hormonal interventions such as tamoxifen application after breast cancer? This question is more difficult to answer because there are very few studies. Trying to come up with a cut-off value on these limited studies is not really doable at this point. Current guidelines are recommending to warn the users of these drugs about the possible increased risk of endometrial cancer and that they should be concerned about the associated symptoms, especially in the case of irregular and postmenopausal bleeding [9, 10]. Routine screening and testing is not necessary [9]. Tamoxifen application increases the risk of endometrial cancer by 2-3 times, and long-term application of unantagonized estrogen supplementation increases the risk of endometrial cancer by 10-20 times [11]. Therefore, it needs to be emphasized that in postmenopausal women with a uterus, estrogen supplementation therapy should always be supplemented with progestin antagonism. 7. What is the significance of active intervention for “endometrial thickening” in postmenopausal women without vaginal bleeding? This is the most difficult question to answer. Undoubtedly, early diagnosis and treatment of endometrial cancer is of great value for the survival of cancer patients. But when it comes to epidemiological analysis in the general population and health policy regarding cancer screening and prevention strategies, there are more factors to consider. Current guidelines do not even advocate routine endometrial cancer screening for people at average or even increased risk (unantagonized estrogen therapy, tamoxifen therapy, late menopause, childlessness, infertility or abnormal ovulation, obesity, diabetes or hypertension). In these populations, intervention is warranted if vaginal bleeding occurs in the postmenopausal period; it is Lynch syndrome, genetic mutations and associated family history that are the most important risk factors [10]. On the other hand, the issue of comorbidities of overly aggressive interventions should be taken into account, but unfortunately, relevant studies are extremely rare. The incidence of uterine perforation has been reported to be 0.3% [7]. Further, although endometrial biopsy is the gold standard for the diagnosis of endometrial cancer, its sensitivity as a universal screening tool is questionable [12]. It is of concern that, to date, there are also no randomized controlled studies analyzing the outcomes of early cancer screening among asymptomatic postmenopausal women using death and cancer-related severe prevalence as the primary clinical study endpoints. Large-scale, universal interventions would certainly improve the detection of early lesions, but there are no definitive data on the prevalence of related interventions, mortality rates, or their health economics analysis. Finally, my question is: How many people, who die with endometrial cancer, do not die from this disease?