4. Early detection and diagnosis of endometrial cancer – Endometrial Cancer
4.1 Early detection/diagnosis in asymptomatic women
4.1.1 Asymptomatic women without increased risk
The available data do not show that screening of asymptomatic women at no increased risk for endometrial cancer with transvaginal ultrasound reduces endometrial cancer-specific mortality.
- Consensus
- Strong consensus
Transvaginal ultrasonography in asymptomatic women without increased risk of endometrial cancer for the purpose of early detection of endometrial cancer shall not be performed.
- Consensus
- Consent
Background
When considering diagnostic procedures for clinical suspicion of the presence of endometrial carcinoma, these should be distinguished from procedures for possible early detection – also in the context of a screening procedure. The question of the value of a sonographic examination was analyzed via an external literature search [146], which is also freely available on the Internet, e.g., on the pages of the Oncology Guidelines Program (http://www.leitlinienprogramm-onkologie.de/home/) and the pages of the AWMF ([147]). Only one relevant study was identified. This study, published as a congressional abstract by Woolas et al. [148], examined a sub-collective of 3,646 asymptomatic women with an intact uterus, who were screened annually with transvaginal ultrasound as part of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) [149].
The screening program ran for eight years and women had an average of 5.5 screening examinations (total number: 19,866). In 250 women, the thickness of the endometrium on at least one examination was ≥10 mm. Endometrial carcinoma was found in 7.2% (18/250) of these women and severe atypical hyperplasia in 0.4% (1/250). Among women with an endometrial thickness <10 mm, endometrial carcinoma was found in 0.1% (5/3,396) and simple atypical hyperplasia in 0.4% (2/3,396) at further follow-up. Two of these seven pathologies were found in the interval, although the authors do not describe whether these were hyperplasias and/or carcinomas. The disease-specific mortality due to endometrial carcinoma was 0% (0/3,646).
From the same study group, the diagnostic value of transvaginal measurements of endometrial thickness were also determined in a sub-collective from the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) [149].
In the intervention arm of the study (n= 48230), measurement of endometrial thickness at the thickest point in the sagittal plane from anterior to posterior was performed by specially qualified colleagues as part of the transvaginal examinations of the adnexa. Follow-up data were collected through national health registries and mail surveys.
After exclusion of women after hysterectomy or lack of documentation of endometrial thickness, 36,867 cases were available for analysis. Of these, 136 women were diagnosed with endometrial carcinoma or atypical endometrial hyperplasia within one year of transvaginal sonography. The authors calculated a value of 5.15 mm as the ideal cut-off for endometrial thickness to detect carcinoma or hyperplasia. This gave a sensitivity of 80.5% and a specificity of 86.2%; that is, 20% of endometrial carcinomas present were not detected with ultrasound.
A cut-off value of 5 mm showed a sensitivity of 80.5% as well as a specificity of 85.7%. For a cut-off of 10 mm, corresponding values were 54.1% and 97.2%. The combination of endometrial thickness of ≥5 mm and abnormal structure on ultrasound was associated with a sensitivity of 85.3% and a specificity of 80.4%.
When restricted to the 96 cases of carcinoma and hyperplasia diagnosed without history of postmenopausal bleeding, the authors calculated a sensitivity of 77.1% and a specificity of 85.5% [150].
In a meta-analysis performed by Breijer et al. [151] of 32 studies published until 2011 on the diagnostic value of transvaginal sonography for the early detection of endometrial carcinoma or atypical endometrial hyperplasia, in a total cohort of 11,100 asymptomatic postmenopausal women, an incidence of 0.62% (95%CI, 0.42–0.82%) for endometrial carcinoma and of 0.59% (95%-CI, 0.22–0.96%) for atypical hyperplasia was found. For a threshold of ≥5mm, endometrial carcinomas with a threshold of ≥5mm endometrial thickness were detected in the analyzed data pool with a sensitivity of 0.83 and a specificity of 0.72.
Alcázar et al. [152] performed a meta-analysis to test the hypothesis put forward by Smith-Bindman et al. [153] that asymptomatic postmenopausal women with an endometrial thickness ≥11mm are at comparable risk for endometrial carcinoma to women with postmenopausal bleeding and an endometrial thickness ≥ 5mm. Based on 4751 screened asymptomatic postmenopausal women from 9 studies, a relative risk of 2.59 (95%-CI:1.66-4.05, P <.001) for endometrial carcinoma was calculated for an endometrial thickness ≥11mm [152].
Sonographic screening by measuring endometrial thickness is not recommended given the low incidence of endometrial carcinoma in asymptomatic women, inadequate discriminatory power between benign and malignant findings and lack of evidence of a reduction in mortality in screened collectives.
However, there is evidence of a significantly increased risk of endometrial cancer in asymptomatic postmenopausal women with endometrial thickness ≥11mm. Histologic evaluation should be considered in women who have such findings on vaginal ultrasonography and cannot be explained by hormone replacement therapy or tamoxifen administration, especially if other morphological evidence of endometrial carcinoma [154] is present in an ultrasound.
4.1.2 Asymptomatic women at increased risk
Available data do not show that screening of asymptomatic women at increased risk for endometrial cancer (such as Lynch syndrome, obesity, diabetes mellitus, hormone replacement therapy, metabolic syndrome, PCO syndrome) with transvaginal ultrasound reduces endometrial cancer-specific mortality.
- Consensus
- Strong consensus
Available data do not show that screening with endometrial biopsy, Pipelle, Tao Brush, tumor marker, fractional curretage or hysteroscopy of asymptomatic women at increased risk for endometrial cancer (such as Lynch syndrome, obesity, diabetes mellitus, hormone replacement therapy, metabolic syndrome, PCO syndrome) reduces endometrial cancer-specific mortality.
Evidence tables (1)
4.1.2 EvT 4.4Transvaginal ultrasonography in asymptomatic women at increased risk for endometrial cancer (such as Lynch syndrome, obesity, diabetes mellitus, hormone replacement therapy, metabolic syndrome, PCO syndrome) for the purpose of early detection of endometrial cancer shall not be performed.
- Consensus
- Strong consensus
Background
Performing screening measures in sub-populations at increased risk for endometrial cancer such as obesity, diabetes mellitus, ongoing hormone replacement therapy, tamoxifen therapy, and known hyperplasia in previously performedcurrettages does not result in a clinically relevant improvement in accuracy in asymptomatic women. In the above-mentioned case-control study by Jacobs et al. [149], 25% of the collective had specific risk factors for endometrial cancer. Multivariate data analysis revealed irrelevant improved sensitivities and specificities in the sub-collective with specific risk factors.
An external literature review was performed to evaluate the utility of transvaginal ultrasound screening in patients with Lynch syndrome [157]. Of seven included screening studies, no study performed relevant comparisons for evaluating the benefit of screening with transvaginal ultrasound. According to the external literature analysis [157], tthe studies on Lynch syndrome are already conceptually poorly suited for the evaluation of a benefit of transvaginal ultrasound as screening, since a whole series of tests was used for screening.
A robust assessment of the benefit of screening is not possible based on the available evidence. There is currently no survival benefit of regular screening of patients with Lynch syndrome.
In the study by Manchanda et al. [155] with a prospective cohort study, 41 Lynch patients were followed up with transvaginal sonography, ambulatory hysteroscopy, and Pipelle biopsies according to a strict protocol. Four carcinomas and ten non-critical pathologies were detected. Thereby, in this relatively small group of affected patients, ambulatory hysteroscopy showed a NPV of 100%. Pipelle allowed differentiation between benign changes and carcinomas.
In the comparative review by Helder-Woolderink et al. [156], two screening methods were tested against each other. Annual transvaginal ultrasonography with CA-125 over a five-year period and in a second study, also five years long, with additional endometrial biopsy. Here, adding endometrial biopsy showed no benefit in screening this high-risk population.
In the case of a familial burden in Lynch syndrome (HNPCC), a structured algorithm for early detection of endometrial cancer can be offered to mutation carriers according to the recommendations of the German and the international HNPCC consortium. An improvement in overall survival by this screening has not been shown (see Chapter “Hereditary Endometrial Carcinoma”; [158]).
4.1.3 Asymptomatic women on tamoxifen therapy
In asymptomatic patients on tamoxifen therapy, transvaginal ultrasound examination for early detection of endometrial carcinoma shall not be performed. This also applies to prolonged therapy over 10 years.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 3
- Consensus
- Consent
- References
- [159] [160] [161] [162] [163] [33] [164]
Change note
In asymptomatic patients on tamoxifen therapy, transvaginal ultrasonography should not be performed for early detection of endometrial carcinoma.Background
Tamoxifen is a selective estrogen receptor modulator and is widely used in breast cancer therapy. However, in the study by Gao et al. [165], transvaginal sonography in 97 patients showed a specificity of only 63.6% with a sensitivity of only 81.1%. The positive predictive value was only 72.9% and the negative predictive value was 73.7%. This underlines the fact that transvaginal ultrasonography is very poorly able to reliably detect pathological changes of the endometrium during the follow-up of tamoxifen therapy.
In the work of Bertelli et al. [166], a study of 164 asymptomatic patients underwent transvaginal sonography. In this study, although 54% of postmenopausal patients had sonographic thickness greater than 5 mm, this imaging did not correlate with pathologic changes in the mucosa.
This unfavorable predictive value of transvaginal sonography during tamoxifen therapy was also confirmed in the study by Gerber et al. [167]. In 247 tamoxifen-treated patients (20 to 30 mg/day for >2 years) and 98 patients in the control group, transvaginal sonography was performed every six months for five years. In patients with more than 10 mm of endometrial thickness, the examination was then performed every three months. Endometrial thickness was 3.5 ±1.1 mm before treatment and increased to 9.2 ± 5.1 mm after three years (p < 0.0001), and this increase was significant compared to the control group. Fifty-two patients with thickened and/or suspicious endometrium underwent histologic evaluation with hysteroscopy and curettage. Twenty-eight patients showed atrophy, polyps were found in nine patients, hyperplasia in four patients, and endometrial carcinoma in one patient. Four perforation lesions occurred [167].
In another review by Fung-Kee-Fung et al. [168], all patients with endometrial cancer also showed vaginal bleeding as a clinical sign of severe endometrial pathology. Over six years, 304 women were enrolled in the study. At baseline, all patients received an endometrial biopsy. Over this period, 1,061 ultrasounds were performed. Thirty-two percent of the ultrasounds described abnormal findings. Eighty percent of these abnormal findings resulted in histologic evidence of a polyp, and six endometrial carcinomas were detected; all of these patients also had irregular vaginal bleeding. For a cut-off of 9 mm, sensitivity was 63.3%, specificity was 60.4%, PPV was 43.3%, and NPV was 77.5%. The PPV for endometrial cancer was 1.4% [168].
In a longitudinal cohort study from 2007 to 2012 of 151 patients on tamoxifen therapy, Saccardi et al. [169] showed that there was no case of endometrial carcinoma in the absence of atypical bleeding, regardless of endometrial thickness or duration of tamoxifen therapy.
4.1.4 Postmenopausal hormone replacement therapy (HRT)
Postmenopause, endometrial thickness is influenced by the use of hormone replacement therapy (HRT), as is the risk for the occurrence of endometrial cancer. The type of HRT is also important for sonographic assessment of endometrial thickness. In the study by Van den Bosch et al. [170] with a total of 238 women, the average endometrial thickness under continuous combined estrogen-progestin HRT was 3.5 ± 1.6 mm, whereas the endometrial thickness under tibolone use was 4.1 ± 1.9 mm and under sequential HRT use was 5.5 ± 2.5 mm [170]. Thus, endometrial thickness under sequential HRT is significantly thicker by 1.4 mm than under tibolone or continuous HRT (p = 0.0001). Thus, if the cut-off values of patients without HRT are used for patients taking HRT, there is a lower diagnostic specificity for the detection of endometrial carcinoma, especially in patients taking sequential HRT.
4.2 Work up for abnormal premenopausal uterine bleeding
The risk of endometrial cancer or atypical endometrial hyperplasia in premenopausal women with abnormal uterine bleeding is less than 1.5%.
- Level of evidence
- 2
- Consensus
- Strong consensus
- References
- [171]
Evidence tables (1)
4.2 EvT 4.7In women with premenopausal abnormal uterine bleeding, pathologic findings that do not pertain to this Guideline (e.g., disturbed early pregnancy, cervical pathology, fibroids) should first be excluded clinically and sonographically. In women with endometrial findings without sonographic malignancy criteria and without risk factors (suspicious cytology, obesity, Lynch syndrome, diabetes, polyps), conservative therapy should be attempted initially unless the bleeding is hemodynamically relevant. If conservative therapy fails, hysteroscopy/curettage should be performed.
- Consensus
- Consent
Change note
In women with premenopausal abnormal uterine bleeding with unremarkable clinical examination (no miscarriage, no cervical carcinoma), without sonographic malignancy criteria and without risk factors (suspicious cytology, obesity, Lynch syndrome, diabetes, polyps), conservative therapy should be attempted first, unless the bleeding is hemodynamically relevant. If conservative therapy fails, hysteroscopy/abrasio should be performed.For the reliable diagnosis of endometrial carcinoma, hysteroscopy in combination with fractionated curettage is the gold standard.
Evidence tables (1)
4.2 EvT 4.9Diagnostic procedures such as Pipelle and Tao Brush in the symptomatic patient have shown comparable positive and negative predictive values in the diagnosis of endometrial cancer as curettage plus hysteroscopy in smaller series. However, larger comparative studies are lacking.
- Level of evidence
- 3
- Consensus
- Strong consensus
- References
- [175]
Evidence tables (1)
4.2 EvT 4.10There is currently no nationwide, quality-assured availability of procedures such as Pipelle and Tao Brush in Germany.
- Consensus
- Strong consensus
Background
Pennant et al. [176] analyzed data from 65 studies of 29,095 premenopausal women with abnormal uterine bleeding who had undergone histologic evaluation in a systematic review. The risk of endometrial cancer was 0.33% (95%-CI 0.23–0.58%). The risk of endometrial carcinoma or atypical endometrial hyperplasia was 1.31% (95%-CI 0.96–1.8). If increased/prolonged menstrual bleeding (menorrhagia) was present, the risk of endometrial cancer was 0.11% (95%-CI 0.04–0.32), and if intermenstrual bleeding (metrorrhagia )was present, it was 0.52% (95 CI 0.23–1.16%). The authors concluded that premenopausal women with abnormal uterine bleeding should first receive medical treatment. Only if this does not work should further workup be done [176].
Van den Bosch et al. [177] found endometrial cancer in only 1.2% of cases and atypical hyperplasia in 0.7% in 1373 premenopausal patients with atypical uterine bleeding. The most frequent diagnoses in this collective were functional bleeding, intracavitary fibroids or benign endometrial polyps. Endometrial thickness measured sonographically was not useful for differential diagnosis between benign and malignant findings in premenopause because of lack of discriminatory power. The authors recommend careful sonographic evaluation of the morphology of the uterine wall and endometrium using the IETA (International Endometrial Tumor Analysis) criteria [178]. Smoothly circumscribed findings, presentation of a noninterrupted midline echo, typical triple layering of the endometrium and color Doppler sonographic exclusion of atypical vascular patterns are considered benign criteria.
A FIGO classification is available [1] for the cause of abnormal premenopausal hemorrhage (AUB) (ICD-10 N92.4) [179].
Pathophysiologically, atypical premenopausal bleeding according to the PALM-COIEN classification of FIGO is in most cases based on benign changes or functional causes.
Depending on the cause of bleeding, a number of drug treatments are available for both acute hemodynamically ineffective bleeding and chronic bleeding disorders, in addition to surgical treatment of benign conditions (e.g., uterus myomatosus or adenomyosis uteri). Only AUB-M (malignancy and hyperplasia) and AUB-E (endometrial pathology) fall within the scope of this Guideline. In particular, the patient's body mass index is important for the exclusion of AUB-M and AUB-E, respectively.
In the work of Wise et al. [180] 916 patients were retrospectively evaluated. 5% of the patients had complex hyperplasia or endometrial carcinoma. This showed that women with a BMI ≥30 kg/m2 had a fourfold higher risk of atypical hyperplasia or carcinoma (95%-CI 1.36–11.74). Also nulliparity (OR = 3.08; 95%-CI 1.43–6.64) and severe anemia (OR = 2.23; 95%-CI 1.14–4.35) were associated with increased incidence of endometrial pathology. Age, diabetes mellitus or menstrual history had no influence [180].
A retrospective cohort study shows a possible clinical benefit of determinations of tumor markers such as HE4, CA 125 or CA 19-9 in risk stratification of women with atypical uterine bleeding [181].
In Li's meta-analysis, the pooled sensitivity for HE4 was 0.65 (0.56-0.73) with a specificity of 0.91 (0.84-0.95) [182]
Data are insufficient to recommend the use of tumor markers for the early diagnosis of endometrial cancer.
The leading symptom of endometrial carcinoma is atypical vaginal bleeding. Since in premenopause in almost 99% of cases the bleeding is due to benign causes, the histological workup can be limited to risk groups with increased risk (obesity, suspicious cytology, Lynch syndrome, etc.) or to cases with suspicious sonography (very high endometrium > 2cm, inhomogeneous internal pattern, suspected invasion).
In general, the first surgical work-up is a uterine endoscopy, usually performed on an outpatient basis, with histology obtained. Several days to weeks elapse before final surgical treatment. There are few data on the influence of this waiting time on the prognosis of the carcinoma. Matsuo et all. [183] studied 435 patients with endometrioid adenocarcinoma with a waiting time between 1–177 days for definitive surgical treatment. No difference in overall survival was found between the groups.
No studies were identified for non-endometrioid carcinoma [183]. In the systematic quantitative review by Clark et al. [184] over 56 studies with a total of 26,346 women, LR of 60.9 (CI 51.2–72.5), the importance of hysteroscopy as a diagnostic tool is outlined, but due to the relatively poor LR of 0.15 (CI 0.13–0.18) for a negative (unremarkable) result, significantly limits the diagnostic power in terms of distinguishing between certainly malignant and benign. In a retrospective cohort study by Svirsky et al. [185], among 639 patients with abnormal uterine bleeding, curettage alone could reliably detect a cause in only 8.4% of cases.
“Blind” endometrial biopsy is not considered effective for the definite exclusion of endometrial carcinoma because focal lesions, if any, are not detected. The agreement between grading on the abradate with grading on the hysterectomy specimen was investigated by Leitao et al. [186]. Out of 1,423 patients, 490 were ultimately included in the analysis. There was 85% agreement in grading between the abradate and hysterectomy specimen. Huang et al. [187] found an agreement of 93.8% to 97% for well-differentiated carcinomas and 99.2% to 100% for poorly differentiated carcinomas for 360 patients.
With regard to clear identification of malignant disease, the question arises as to whether hysteroscopy alone provides reliable identification of malignant changes. In the review by Deckardt et al. [188], 1,286 patients with vaginal bleeding were studied. In this study, two of 29 patients with endometrial carcinoma were found to have a sonographic thickness of less than 5 mm, and endometrial carcinoma was missed during hysteroscopy in ten patients. However, in this case the surgeon could only answer yes or no to the question about carcinoma [188]. In the work of Dueholm et al. [189], using a scoring system with surface changes, necrosis and papillary changes, a sensitivity of 89% and a specificity of 92% were achieved with a score above 3, but the agreement of the evaluation was not convincing (kappa = 0.56 (0.42–0.71) [189]. In cases of clinical suspicion of endometrial carcinoma, hysteroscopy, even with the use of scoring systems, has not been able to reliably differentiate between premalignant and malignant changes.
Two procedures for endometrial sampling without a need for anesthesia are offered. The first is the Pipelle, in which tissue sampling is performed within the uterine cavity by means of a vacuum. This is created by manually pulling back the inner piston of the Pipelle. The other is the Tao Brush. Here, a wide brush, similar to a Pap smear, is inserted into the cavum uteri and evaluable tissue is obtained with multiple rotations. In the study by Guido et al. [190], 65 patients with confirmed endometrial cancer were examined, and a sensitivity of 83% ±5% (54/65) was found. 127 patients were examined in the study by Tanriverdi et al. [191] first by Pipelle and then by classical method. The agreement was 79% (100/129).
In the study by Del Priore et al. [192], 101 patients (mean age 58 years, range 35–86) received either Tao brush biopsy or Pipelle sampling. 21 carcinomas were detected, sensitivity was 86%, PPV 100% NPV 98%. In the study by Fakhar et al. [193], 100 patients were examined with Pipelle followed by normal scraping. Two endometrial carcinomas were found and for these, Pipelle examination showed sensitivity, specificity, PPV and NPV of 100% in diagnosing endometrial carcinoma.
In the study by Abdelazim et al. [194], 220 patients underwent a Tao Brush procedure prior to actual classical dilation and curettage. Tao Brush demonstrated a sensitivity, specificity, PPV, and NPV of 100% for the detection or exclusion of endometrial cancer. In the work of Sanam and Majid [195], 130 patients who came for examination with vaginal bleeding were analyzed. Initially, Pipelle application was performed, followed by classical dilatation and curettage. The agreement in diagnosis was 100%. In the work of Wu et al., first 200 [196], then in the further study another 633 Tao breast examinations were evaluated [197]. The sensitivity was 100% and the specificity 96% for carcinomas.
In the comparative study by Williams et al. [198] with 200 patients, the Tao Brush showed better material yield than the Pipelle (p < 0.001). In women without delivery, both procedures were equally likely to be unfeasible (p < 0.001). Postmenopausal women were more likely to obtain inadequate samples with the Pipelle (p < 0.001). Patients preferred Tao Brush (p < 0.001). Also in the review paper by Critchley et al. [199], it is clear that among minimally invasive diagnostic procedures, Tao Brush achieves a comparable status to hysteroscopy.
In the work of Al-Azemi et al. [200] the changes of the endometrial mucosa under Tamoxifen were controlled by Pipelle. Among 50 patients controlled over a maximum of 69 months using the Pipelle method, no carcinoma was detected, but endometrial hyperplasia with and without atypia was detected. Surgical workup could thus be more targeted.
In the meta-analysis by Narice, a comparable quality between the use of Pipelle and a simple D/C is described from the data of more than 7300 documented records. Thus, this simple procedure is assigned a place in the outpatient workup for abnormal uterine bleeding in the premenopausal patient. In this analysis, Pipelle is superior to all other outpatient procedures [201].
Of all the outpatient endometrial biopsy procedures, Tao Brush shows the best results, followed by Pipelle. There is too little conclusive data for the SAP-1 and Li Brush procedures and other methods. However, the two main methods have some significant limitations. The Pipelle captures only a small portion of the endometrial surface and can detect focal changes only “randomly”. For both the Pipelle and the Tao Brush, there is also a high rate of unsuccessful attempts of up to 22% in nulliparae. Furthermore, there is currently insufficient experience in clinical routine with these outpatient diagnostic procedures in Germany.
In any case, cytological workup is part of the workup of premenopausal or postmenopausal atypical uterine bleeding. In the meta-analysis by Verdoodt [202] special attention is paid to the detection of atypical glandular cells in HPV-negative patients. Here, patients over 50 years of age showed a risk of 18% for non-HPV-related carcinoma. Therefore, histological clarification should be performed in any case in these cases.
4.2.1 Algorithm for work-up in abnormal premenopausal uterine bleeding.
4.3 Work-up for postmenopausal bleeding (PMB)
A woman with first-time postmenopausal bleeding and endometrial thickness ≤ 3 mm (double) should initially have a sonographic and clinical follow-up in three months.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 1
- Consensus
- Consent
- References
- [203]
Evidence tables (1)
4.3 EvT 4.12Persistence or recurrence of clinical symptoms or increase in endometrial thickness shall lead to histologic evaluation.
- Consensus
- Strong consensus
Background
Endometrial cancer presents with postmenopausal vaginal bleeding (ICD-10 N95.0) as an early symptom [1]. This is also the case in patients at risk. Thus, again, approximately 75% of endometrial carcinomas can be diagnosed at FIGO I stage. The importance of bleeding is also confirmed in Clarke's meta-analysis. Here, the pooled prevalence for bleeding as a symptom of existing endometrial cancer (all stages and histologies) was 91% (CI 87%-93%). However, that not all bleeding meant endometrial carcinoma was reflected in the likewise pooled prevalence for endometrial carcinoma in the presence of existing bleeding. This was only 9% (CI 8%-11%) [204].
Data from 2,896 patients are analyzed in the systematic review by Timmermans et al. [205]. It is shown that an endometrial thickness of less than 3 mm almost excludes endometrial pathology with a sensitivity of 98%.
With a prevalence of endometrial carcinoma in postmenopausal bleeding of approximately 10% (pretest probability), EC can thus be largely excluded.
In contrast, Clarke's meta-analysis clearly shows that in the evaluation of any endometrial mucosal elevation, the pooled risk for endometrial carcinoma increases to 19% [204]. However, it should be noted that in patients with a polyp, the risk of endometrial carcinoma is only 3%. In the experimental analysis of the data, for an endometrial mucosal thickness of 5 mm, a PPV of 7.4% is shown, and for a thickness of 10 mm, PPV is 14.3%. However, the data apply only to endometrioid carcinomas.
Transvaginal sonography can detect intracavitary lesions. In the meta-analysis by Bittencourt, the sensitivity for 2D contrast sonography to detect a polyp was 93% (95%-CI 89-96%) with a specificity of 81% (95%-CI 76%-86%) [206]. According to the meta-analysis by Nieuwenhuis, 3D saline contrast sonography has no significant advantages for the detection of a polyp compared to the 2D technique, sensitivity was higher with the 3D technique at 96.3% (95%-CI 79.4%-99.4%), but specificity was comparable and statistically the differences were not significant [207]. Vroom's meta-analysis showed a sensitivity of 85.1% (95%-CI 66.9-100%) and a specificity of 84.5% (95%-CI 68.1-100%) for saline contrast sonography [208].
4.3.1 Algorithm for work-up of bleeding in peri or postmenopausal women
4.4 Imaging diagnostics
4.4.1 General imaging
In endometrial cancer, surgical staging with histopathological examination is the reference method for local spread diagnosis.
For distant metastases outside the usual surgical area, imaging is the primary diagnostic method.
- Consensus
- Strong consensus
Background
In endometrial carcinoma, surgical staging with histopathological examination is the reference method for local spread diagnosis. Imaging is complementary to this. Depending on the individual clinical indication, imaging may be useful to obtain an overview of the surgical site preoperatively, to plan the further procedure and to additionally clarify tumor-specific focal findings if necessary.
In some patients, complete surgical staging including lymphadenectomy is not possible or not planned.
In this case, imaging provides non-invasive diagnostic information about the local extent of endometrial carcinoma, infiltration of adjacent organs and metastases. For distant metastases outside the usual surgical area, cross-sectional imaging is the primary diagnostic method.
4.4.2 Basic imaging diagnostics
4.4.2.1 Chest X-ray
In the primary diagnosis of endometrial carcinoma, chest X-ray in 2 planes is recommended by the ICNL and ACR Guidelines [209], [210]. As a baseline examination, its primary purpose is to assess preoperative cardiopulmonary status while allowing for the evaluation of rare pulmonary metastasis. The preoperative chest x-ray further serves as a baseline finding for possible follow-up examinations.
In initial manifestation of endometrial carcinoma, pulmonary distant metastases, although rare overall, result in FIGO stage IV. In a retrospective multicenter study, Amkreutz et al. [211] reported that pulmonary metastases of endometrial carcinoma were found in 1.3% (7 of 541) patients on chest x-rays. All affected patients had high-risk subtypes (serous, clear cell, or high grade endometrioid), and the incidence of pulmonary metastases was 4.1% for these subtypes. No pulmonary metastases were found on chest x-rays in patients with low-risk endometrial carcinoma subtypes. 243 other patients had not received chest imaging at primary diagnosis. The authors concluded that patients with low-risk endometrial carcinoma subtypes may not require chest x-rays for metastasis detection. In patients with high-risk subtypes, pulmonary metastases are present in approximately 4% of patients according to the study by Amkreutz et al. [211], and their detection may be therapeutically relevant.
4.4.2.2 Abdominal sonography
Abdominal ultrasonography is a basic examination, especially for the evaluation of the internal organs, including a possible pre-existing urinary transport disorder. However, due to bowel gas layering, assessment of the lesser pelvis and retroperitoneum is limited. In accordance with the ACR Guideline [210], transabdominal sonography is not considered appropriate for staging endometrial cancer.
4.4.2.3 Transvaginal sonography
In histologically-confirmed primary endometrial carcinoma, transvaginal sonography should be performed to assess myometrial infiltration and cervical infiltration.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 3
- Consensus
- Strong consensus
- References
- [212]
Evidence tables (1)
4.4.2.3 EvT 4.15Preoperative imaging by transvaginal sonography is used for documentation and surgical planning, even though the final locoregional staging is surgical-histologic.
- Consensus
- Strong consensus
Background
In primary endometrial cancer, transvaginal sonography (TVS) is a clinically established basic examination. It is used for preoperative assessment of myometrial infiltration and possible cervical and parametrial infiltration.
In the prospective study (74 patients) by Savelli et al. [213] TVS and MRI showed similar diagnostic accuracies in preoperative staging for endometrial cancer for the assessment of myometrial infiltration and cervical infiltration. The authors discuss that expert-performed TVS shows good accuracy in local staging of endometrial carcinoma, and therefore MRI should be offered only when TVS has poor image quality for cost reasons [213]. However, due to the limited field of examination, TVS does not allow a comprehensive assessment of locoregional lymph nodes. In addition to Savelli et al. [213], the Dutch Guideline [209] discusses other studies on TVS, and the overall conclusion is that MRI in particular is recommended for primary EC when there is a clinical indication for imaging. In this regard, the meta-analysis by Alcázar [152] no statistically significant difference is shown between the detection rate of deep myometrial infiltration via TVS or an MRI examination. For the detection of cervical stromal infiltration, the meta-analysis by [214], for TVS a pooled sensitivity of 63% (95%-CI 51%-74%) and a specificity of 91% (95%-CI 87-94%) is calculated. This means that approximately the same values are achieved as for MRI.
4.4.3 Cross-sectional imaging for local spread diagnostics
In primary endometrial carcinoma, MRI should be performed for preoperative evaluation of myometrial infiltration and cervical involvement if transvaginal sonography is not informative.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 3
- Consensus
- Strong consensus
- References
- [212]
Evidence tables (1)
4.4.3 EvT 4.17If needed for non-invasive assessment of locoregional lymph nodes, e.g., imaging diagnostics to determine spread prior to primary radiotherapy or planning surgical approach for advanced carcinoma disease (cT3), this should be done by cross-sectional imaging (CT/MRI).
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 3
- Consensus
- Strong consensus
- References
- [215] [216] [217] [218] [219] [220]
Evidence tables (1)
4.4.3 EvT 4.18In the case of primary radiotherapy, locoregional diagnostics to determine spread should be performed by MRI if possible. If MRI is not possible, CT should be performed as an alternative.
- Consensus
- Strong consensus
Background
Cross-sectional imaging for local spread diagnosis in primary endometrial carcinoma can simultaneously assess myometrial infiltration (< 50% versus ≥ 50%), cervical stromal infiltration and locoregional lymph node metastases. MRI, CT and PET-CT are available as methods. In comparison to sonography, air and bone are not obstacles. Furthermore, cross-sectional imaging is performed slice-by-slice and is also available, for example, intraoperatively as imaging material. In the following, scientific results on cross-sectional imaging in local spread diagnosis of primary endometrial carcinoma are presented.
4.4.3.1 Myometrial infiltration
To assess myometrial infiltration, current ACR and ICNL guidelines recommend MRI when imaging is clinically indicated [219], [217]. This MRI should meet certain minimum requirements as detailed by the European Society of Urogenital Radiology (ESUR). Thus, the use of antiperistaltic drugs (20 mg butylscopolamine i.m./i.v. or 1 mg glucagon i.v.) is recommended in the absence of contraindications. MRI should include a combination of native high-resolution T2-weighted sequences without fat saturation in at least sagittal and axial-oblique slices perpendicular to the uterine corpus (slice thickness ≤ 4 mm), further diffusion-weighted images with at least 2 b-values of 0 and 800-1000 s/mm2 in at least 1 plane (same plane perpendicular to the uterine corpus as T2w), and contrast-enhanced T1-weighted sequences 2 min 30 sec after contrast administration. Radiological findings should include the following: Thickness of endometrium and tumor size, depth of myometrial infiltration, cervical stromal infiltration, infiltration of uterine serosa, extension to adnexa, vaginal/parametrial infiltration, urinary bladder/rectum infiltration, lymph node status, infiltration of distant organs, presence of peritoneal carcinomatosis, and associated benign changes [221].
Image-based assessment of myometrial infiltration may also provide complementary information in the context of surgical planning. A prospective study by Haldorsen et al. [222] (55 patients) reported that MRI-based perfusion parameters of endometrial carcinoma correlated with histologic subtype (p < 0.03) and overall survival (p < 0.05), suggesting that preoperative MRI can be used for risk stratification.
In a meta-analysis of 50 studies (3,720 patients), Luomaranta et al. [223] evaluated the diagnostic accuracy of MRI for differentiating FIGO stage IA versus IB (< 50% versus ≥ 50% myometrial infiltration) and found a pooled sensitivity of 80.7% (95%–CI 76.8–84.1%) and specificity of 88.5% (95%–CI 85.3–91.1%). Similar diagnostic accuracies were reported in three other meta-analyses [224], [225], [226]. According to Luomaranta et al. [223], dynamic contrast-enhanced sequences are slightly more accurate than non-dynamic contrast-enhanced sequences. According to Andreano et al. [225], dynamic contrast-enhanced sequences and diffusion-weighted sequences have similar diagnostic accuracies without significant differences. If the administration of gadolinium-containing contrast agent is contraindicated in individual cases, the depth of myometrial infiltration can at least be assessed with diffusion-weighted sequences.
If pelvic MRI is not possible when there is a clinical question about myometrial infiltration (e.g. pacing), then imaging alternatives exist. In a meta-analysis, Kinkel et al. [224] found a high Q* value of 0.91 for contrast-enhanced MRI (9 studies, 332 patients). For comparison, the Q* value for transvaginal sonography was 0.85 (14 studies, 514 patients) [224]. For single-line detector CT, the Q* value was 0.79 (6 studies, 203 patients) [224]. A small prospective study (29 patients) with 16-line CT reported a high diagnostic accuracy of 95%, but recommended further studies [227]. The current ACR Guideline also recommends that the role of computed tomography be further evaluated [210]. For the evaluation of myometrial infiltration, Antonsen et al. [216] found similar diagnostic accuracy for PET-CT as for MRI in a prospective multicenter study in a direct comparison of methods (111 patients), so PET-CT can also be used for this question. The role of PET-MRI [228] in the assessment of myometrial infiltration should be investigated in further studies.
It should be noted that the cost of PET-CT is covered by health insurance only upon request – and only if CT and MRI do not provide sufficient clarity.
4.4.3.2 Cervical stromal infiltration
When cervical stromal infiltration is suspected, current NCCN, ICNL, and ACR guidelines concur in recommending MRI, e.g. when chemotherapy and/or radiotherapy are primarily planned [229], [209], [210]. This MRI should include the same sequences as used to assess myometrial infiltration. If necessary, additional T2-weighted images axial and perpendicular to the cervical axis may be helpful [221].
Compared with FIGO stage I, the diagnosis of cervical stromal infiltration leads to upgrading to FIGO stage II and, if necessary, changes the surgical strategy. Similarly, FIGO stage II has a higher incidence of recurrence and lower disease-specific and overall survival than FIGO stage I. Preoperative imaging may support this stage differentiation.
In a meta-analysis (10 studies, 318 patients) by Kinkel et al. [224], the sensitivity of MRI for assessing cervical infiltration ranged from 66% to 100% and the specificity ranged from 92% to 100%. A meta-analysis by Luomaranta et al. [223] included 12 studies (1,153 patients) and found a pooled sensitivity of 57.0% (95%–CI 45.9–67.4%) and specificity of 94.8% (92.1–96.6%) for MRI. In this meta-analysis, a positive predictive value of 68.7% (60.5–75.8%) and a high negative predictive value of 90.5% (87.7–92.8%) were reported for MRI [223].
If pelvic MRI is not possible when there is a clinical question of cervical stromal infiltration (e.g. contraindication due to pacing), then transvaginal sonography is an imaging alternative [210]. Antonsen et al. [216] reported no significant differences between MRI, PET-CT and endovaginal sonography in a prospective multicenter study comparing methods directly (111 patients) (accuracy: PET-CT = 82.7%; MRI = 82.3%; sonography = 77.9%). The role of contrast-enhanced multidetector CT for this issue is under investigation [227], as is the role of PET-MRI [228].
4.4.4 Pelvic and para-aortic lymph node metastases
Diagnosis of pelvic or para-aortic lymph node metastases leads to FIGO stage III and requires appropriate lymphadenectomy if operable. When lymph node metastases are diagnosed, recurrences are more frequent and disease-specific and overall survival are lower than in early endometrial cancer.
A meta-analysis by Selman et al. [218] found a pooled sensitivity of 72% (95% CI 55–85%) and specificity of 97% (93–99%) for the evaluation of pelvic and para-aortic lymph node metastases for MRI with good study quality according to QUADAS-2 assessment. A meta-analysis by Luomaranta et al. [230] found a lower pooled sensitivity of 43.5% (95% CI 31.7–56.1%) with, however, high between-study heterogeneity (range for sensitivity: 0.17–0.71%; I-squared 91%) and unclear study quality, whereas the specificity of 95.9% (92.9–97.6%) was also high. According to the ESUR recommendation, MRI for lymph node assessment should include an axial T2-weighted sequence and, for G3 endometrioid as well as non-endometrioid carcinomas, an additional axial DWI from the renal hili to the symphysis.
For CT (studies through 2000; most likely single-line CT), pooled sensitivity was 45% (95%-CI 28–64%) and specificity was 88% (78–94%) [228]. A meta-analysis by Chang et al. [231] on PET-CT included 7 studies (243 patients) and found a pooled sensitivity of 63.0% (95%–CI 48.7–75.7%) and specificity of 94.7% (90.4–97.4%). A meta-analysis by Kakhki et al. [215] included 8 studies of PET-CT (332 patients) and found a similar pooled sensitivity of 68.7% (95%–CI 57.7–78.2%) and specificity of 92.7% (90.0–94.9%). In a prospective multicenter study by Antonsen et al. [232], an accuracy of 90.5% for PET-CT and 90.2% for MRI was reported for the detection of locoregional lymph node metastases in a direct comparison of methods, so that PET-CT and MRI can be considered equivalent for this question. With transvaginal sonography, a comprehensive assessment of the locoregional lymph nodes is not possible due to the limited field of examination.
4.4.5 Imaging for distant metastases
If there is a reasonable suspicion of distant metastasis, possible distant metastases should be evaluated by cross-sectional imaging (and skeletal scintigraphy, if necessary) and histologic confirmation, if necessary, for treatment planning.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 3
- Consensus
- Strong consensus
- References
- [217] [215] [219]
Evidence tables (1)
4.4.5 EvT 4.20Background
Imaging allows the diagnosis and accurate localization of distant metastases. At initial manifestation of endometrial carcinoma, the risk of distant metastases is low for low-grade subtypes, whereas it is increased for high-grade subtypes, as shown, for example, by Amkreutz et al. [211] for lung metastases. Distant metastases can occur in the lung, liver, skeleton and non-regional lymph nodes, among other regions. The diagnosis of distant metastases leads to FIGO stage IV.
If distant metastases are suspected, the ICNL, NCCN, and ACR guidelines recommend cross-sectional imaging before primary chemotherapy and/or radiotherapy or to plan surgical approach [209], [229], [210].
For the evaluation of distant metastases, recommendations are provided by the ACR Guideline. MRI with native and contrast-enhanced sequences is well suited in the abdomen and pelvis, whereas it is not established for the detection of pulmonary metastases. Contrast-enhanced CT is suitable for thorax, abdomen and pelvis [210]. A meta-analysis by Kakhki et al. [233] (16 studies, 807 patients) found a very high pooled sensitivity of 95.7% (95%-CI 85.5–99.5%) and specificity of 95.4% (92.7–97.3%) for the assessment of distant metastases for PET-CT, making it very suitable for the question of distant metastases.
Table 4: Meta-analyses on the diagnostic accuracy of cross-sectional imaging in the initial diagnosis of primary endometrial carcinoma
| Question | Studies | Patients | Sensitivity, pooled* | Specificity, pooled* | Source |
| Myometrial infiltration | |||||
| MRI | 50 | 3720 | 80.7% (76.8–84.1%) | 88.5% (85.3–91.1%) | [230] |
| MRI with CM | 9 | 332 | 78.6–100% | 71.4–100% | [224] |
| MRI with CM | 9 | 442 | 86% (80–93%) | 82% (74–90%) | [225] |
| MRI with DWI | 9 | 442 | 86% (80–93%) | 86% (78–94%) | [225] |
| MRI with DWI | 7 | 320 | 90% (81–95%) | 89% (79–94%) | [226] |
| CT | 6 | 203 | 40–100% | 75–100% | [224] |
| Cervical stromal infiltration | |||||
| MRI | 12 | 1153 | 57.0% (45.9–67.4%) | 94.8% (92.1–96.6%) | [230] |
| MRI with CA | 10 | 318 | 66–100% | 92–100% | [224] |
| Pelvic/para-aortic lymph node metastases | |||||
| MRI | 4 | 211 | 72% (55–85%) | 97% (93–99%) | [228] |
| MRI | 10 | 862 | 43.5% (31.7–56.1%) | 95.9% (92.9–97.6%) | [230] |
| CT | 5 | 279 | 45% (28–64%) | 88% (78–94%) | [228] |
| PET or PET-CT | 7 | 243 | 63.0% (48.7–75.7%) | 94.7% (90.4–97.4%) | [220] |
| PET-CT | 8 | 332 | 63.0 % (48.7–75.7 %) | 92.7 % (90.0–94.9 %) | [215] |
| Distant metastases | |||||
| PET or PET-CT | 16 | 807 | 63.0% (48.7–75.7%) | 95.4% (92.7–97.3%) | [215] |
| * = 95% confidence intervals in parentheses; CM= contrast medium; DWI = diffusion-weighted sequence | |||||
4.5 Pathology
4.5.1 Pathogenesis of endometrial cancer
Histopathological diagnosis of endometrial carcinoma results from the combination of histomorphological and immunohistochemical parameters and, if necessary, supplementary molecular pathological findings.
- Consensus
- Strong consensus
A dualistic pathogenesis model based on clinical and pathological criteria distinguishing 2 different types (type 1 and type 2) of endometrial cancer (EC) still has educational significance [234]. However, due to insufficient correlation between histomorphology and underlying pathogenetically significant alterations, the binary model is increasingly replaced by an immunohistochemical or molecular classification [235], [236], [237], [238], [239].
The morphological prototype of type 1 EC is endometrioid carcinoma and that of type 2 EC is serous carcinoma [235], [240], [241]; see the following table). Due to a partial overlap of the two types and new molecular data, a molecular classification based on the TCGA project is preferred [235], [237].
Table 5: Binary/dualistic model of endometrial cancer
|
|
Type 1 carcinoma |
Type 2 carcinoma |
|
Age |
55 – 65 years |
> 65 years |
|
Clinical constellation |
Obesity, hypertension, diabetes mellitus (metabolic syndrome) |
No special features |
|
Hyperestrogenism |
Mostly |
Absent in most cases |
|
Stage |
Mostly FIGO I |
Mostly > FIGO II |
|
Prognosis |
Favorable |
Unfavorable |
|
Hereditary background |
Lynch syndrome, Cowden syndrome |
poss. BRCA? |
|
Endometrial hyperplasia |
Mostly |
None |
|
Histologic subtype |
Endometrioid |
Serous, clear cell |
|
Molecular alteration |
PTEN, ARID-1A, MSI |
TP53, HER2, PIK3CA |
|
Molecular type |
NSMP, MMR deficient, POLE mutated |
TP53 mutated (serous-like) |
4.5.2 Precursor lesions of endometrial cancer
Non-atypical endometrial hyperplasia is classified as a high-risk lesion rather than a precancerous lesion [246], [247]. With a 14- to 45-fold increased risk, atypical endometrial hyperplasia is considered an obligate precancerous lesion for endometrioid EC [246], [248], [247], [249].
The term endometrioid intraepithelial neoplasia (EIN) is listed as a synonym in the WHO classification [235] and has identical biological characteristics to atypical hyperplasia [247], [250]. Hysterectomized patients with atypical endometrial hyperplasia/EIN show concordant endometrioid EC in 15-50% in the subsequent hysterectomy specimen [248], [250], [251], [252].
Table 6: WHO classification of endometrial hyperplasia (nomenclature)
|
Description |
Glandular-cystic hyperplasia |
Low/moderate grade adenomatous hyperplasia |
High grade adenomatous hyperplasia |
|
WHO 1994 / 2003 |
Simple hyperplasia without atypia |
Complex hyperplasia without atypia |
Atypical hyperplasia |
|
WHO 2014 and WHO 2020 |
Non-atypical hyperplasia |
Atypical hyperplasia, syn. endometrial intraepithelial neoplasia (EIN) |
|
Serous intraepithelial carcinoma (SEIC) is not considered a precancerous lesion, but a superficial serous carcinoma [235], [241]. It may be associated with minimal invasion [253] and may occur in endometrial polyps [254]. Extrauterine spread is prognostically crucial. Clinical, pathological, and immunohistochemical data suggest overlap with primary tubal carcinoma [254].
The terminology and morphologic diagnosis of endometrial hyperplasia shall be based on the current edition of the WHO classification.
- Consensus
- Strong consensus
4.5.3 Tumor typing of endometrial cancer
Exact tumor typing is therapeutically and prognostically relevant [255], [235]. In doubt, additional immunohistochemical examinations are recommended [256], [257][258], [259], [260], [261], [262], [263]. The vast majority of EC (~80%) are endometrioid carcinomas, followed by serous (3-10%), and clear cell (2-3%) EC, and carcinosarcoma (2%); [257] [263], [264], [235]. Undifferentiated or dedifferentiated EC is even rarer at < 1%; remaining intestinal-type mucinous EC, squamous cell carcinoma and mesonephric-like EC are rarities [235], [265] [266]. Endometrioid carcinomas may frequently have squamous as well as mucinous areas, but these differentiation patterns are without clinical relevance [235].
Mixed EC is defined by WHO as a carcinoma consisting of at least 2 distinct histologic types that can be differentiated from each other [235], one of which is either serous or clear cell differentiated. A quantitative threshold as in the 2014 WHO classification of 5% is not applicable [235], [263].
Mixed carcinomas of the endometrium have two or more histologic subtypes according to the WHO classification (2020), with one of these components being either serous or clear cell.
- Consensus
- Strong consensus
Change note
Mixed carcinoma of the endometrium according to WHO classification two or more histological subtypes, one of these components being either serous or clear cell.Carcinosarcomas (synonym: malignant mixed Müllerian tumors, MMMT) typically consist of a highly malignant epithelial and a mesenchymal component each [267], [268], [258]. The mesenchymal component is designated as either homologous (structures found in the uterus, such as smooth muscle) or heterologous (structures not found in the uterus, such as cartilage and bone). Carcinosarcomas are classified as EC with epithelial-mesenchymal transformation based on clinicopathologic and molecular parameters [269], [268], [270] and classified as EC in the TNM system [235], [271]
Molecular pathologically, carcinosarcomas (malignant Müllerian mixed tumors, MMMT) are assigned to carcinomas. Histological evaluation of carcinosarcomas shall be performed according to the current WHO classification. FIGO and TNM classification shall be analogous to that for endometrial carcinoma.
- Consensus
- Strong consensus
4.5.4 Histological grading in endometrial cancer
Histopathologic grading of endometrioid carcinomas is performed according to FIGO criteria based on the presence of solid non-squamous portions.
- G1: < 5% solid portions
- G2: 6–50% solid portions
- G3: > 50% solid portions
Based on prognostic studies (including [244]), according to the International Society of Gynecologic Pathologists (ISGyP; [239]), and the current WHO classification [235], based on prognostic studies [244], G1 and G2-EC are grouped as FIGO low grade and G3-EC as FIGO high-grade [255]. For adequate documentation in cancer centers, it is recommended to note both grading types in the report of findings.
Detection of high-grade cellular atypia results in upgrading by one grade each [264], [257], [238]. In case of high-grade atypia, serous EC should be excluded by immunohistochemistry [261], [258]. Due to their biological behavior, serous and clear cell carcinomas are not graded according to WHO, but are by definition classified as G3, as are carcinosarcomas and de- or undifferentiated EC. In the medium term, it can be assumed that histomorphologic grading will be supplemented or possibly replaced by molecular risk assessment [238] [272], [273], [245]. Grading of neuroendocrine tumors is based on the classification of neuroendocrine tumors of the gastrointestinal tract [235].
Endometrioid carcinomas are graded according to FIGO. According to WHO, a two-stage grading “low grade” (G1 or G2) and “high grade” (G3) should be preferred. Serous, clear cell, de- or undifferentiated endometrial carcinomas as well as carcinosarcomas are by definition high-grade carcinomas.
- Consensus
- Strong consensus
4.5.5 Determination of the invasion depth
The depth of invasion is measured from the adjacent non-cancerous endometrium to the deepest point of tumor infiltration. For exophytic growing tumors, an imaginary line from the endometrium closest to the tumor through the tumor serves as the starting point for the measurement [274], [275]; see the following figure).
If the carcinoma originated in an endometriosis/adenomyosis, the depth of invasion is measured from the boundary of the adenomyosis to the deepest point of infiltration.
Determining the depth of invasion can be problematic because there is no sharp boundary between endometrium and myometrium [276], [277]. Infiltrative growth is present when tumor glands have direct contact with the surrounding myometrium, in some cases there is little peritumoral desmoplasia and surrounding endometrial stroma is absent. Van Gieson staining to demonstrate desmoplasia and CD10 immunohistochemistry to demonstrate endometrial stroma may be helpful in cases of doubt [277].
Ingrowth of carcinoma into pre-existing endometriosis may mimic myometrial infiltration and has no prognostic significance. The following findings favor the diagnosis of co-involvement of endometriosis [276], [278], [274]:
- Evidence of benign endometrial glands in the immediate vicinity of tumor associations,
- Evidence of benign glands between tumor glands,
- Absence of peritumoral desmoplasia,
- Absence of peritumoral inflammation,
- Round contour of the lesion with sharp border to the surrounding myometrium.
Usually, the anterior and posterior uterine walls have the same thickness [279], so that, if necessary, the opposite wall thickness in each case can be used as a reference value of myometrial thickness to determine the depth of invasion.
4.5.6 Definition of TNM-relevant parameters
The definition of the parameters below is identical to the guidelines in vulvar, vaginal and cervical carcinoma.
Perineural sheath infiltration (Pn category) is defined as the detection of tumor cells in perineural clefts, regardless of their extent and whether or not the nerve itself is infiltrated [280], [281]. Periganglionic infiltration can be classified as Pn1.
Lymphatic vessel infiltration (L category) is defined by the detection of tumor cells lying singly or in groups within cavities that are clearly lined by endothelium (L1; [282], [283]. According to the TNM, detection of tumor cells within cleft spaces without clear endothelial lining is classified as L0 (no lymphovascular infiltration) [284]; these are usually shrinkage-related fixation artifacts. Furthermore, lymphovascular pseudoinvasion should be differentiated as a morphologic pattern of the MELF invasion pattern [282], [275]) and when laparoscopic and robotic-assisted surgical procedures are used [283], [285]. Routine use of immunohistochemistry to detect endothelia (e.g. D2-40/podoplanin) is not indicated outside of studies [282], [284], [286]. Despite different definitions, quantification of lymphatic vessel infiltration is prognostically relevant in different stages and histologic types of EC [287], [288], [289], [290], [291], [292]. Lymphatic vessel infiltration should be indicated in the report of findings and classified as follows ([282], [275]):
- No lymphatic vessel infiltration (L0),
- Focal lymphatic vessel infiltration (L1): involvement of < 3 lymphatic vessels in overview magnification,
- Extensive (syn. “substantial”) lymphatic vessel infiltration (L1): involvement of ≥ 3 lymphatic vessels in overview magnification.
Quantification of lymphatic vessel infiltration should be included in the histopathologic report of findings.
Focal lymphatic vessel infiltration is defined as involvement of < 3 lymphatic vessels and extensive (“substantial”) lymphatic vessel infiltration as an involvement of ≥ 3 lymphatic vessels.
- Consensus
- Strong consensus
Lymphatic vessel infiltration is best assessed at 25-40x magnification.
There is good interobserver correlation for both the detection of lymphatic vessel infiltration and its quantification [286].
Venous invasion (V category) distinguishes between macroscopically visible (V2) and histologically confirmed venous infiltration (V1; [293], [284]. Microscopic V1 category is defined in the TNM as the detection of tumor cells within the vein lumen and/or the detection of tumor cells infiltrating the vein wall [284].
4.5.7 Additional immunohistochemical tests
4.5.7.1 HER2 analysis in serous EC
HER2 status is currently of practical relevance only in serous EC [235]. Regarding overall survival, patients with FIGO stage III/IV or recurrence of serous endometrial carcinoma benefit from a combination of chemotherapy and HER-2 inhibition with prolongation of overall survival by about 5 months [294], making HER2 a potential therapeutic target [294], [295], [296]. In accordance with ISGyP recommendations, HER-2 expression is determined by analogy to gastric carcinoma with analysis of a latero-basal staining pattern [296], [297], [298] with re-evaluation of immunohistochemically doubtful cases by an in situ method [297]:
- IHC score 3+: > 30 of tumor cells with strong complete or basolateral/lateral membrane staining,
- IHC score 2+: < 30 with strong complete or basolateral/lateral membrane staining OR weak to moderate complete staining in > 10% of tumor cells (in situ testing required),
- IHC score 1+: very weak incomplete membrane staining of any percentage OR weak complete membrane staining in < 10% of tumor cells,
- IHC score 0: no positive tumor cells.
25 to 30% of serous EC show immunohistochemical Her2 overexpression or gene amplification [295], [296], [299] with a concordance rate of both methods of 75% [295]. There is good interobserver correlation of HER-2 determination in immunohistochemistry [297]. The concordance rate between curettage and hysterectomy is reported to be 84% [298], [297] and the discordance rate between primary tumor and metastasis is 55% [297]. ISGyP recommends that HER2 status be determined at the initial diagnosis of serous EC. Due to the above-mentioned discordance rate, HER-2 status should be re-evaluated at recurrence or (distant) metastasis.
Because of a potential therapeutic consequence, HER2 status should be determined in serous endometrial carcinoma.
- Consensus
- Strong consensus
4.5.8 Frozen section examination in endometrial carcinoma, malignant mixed Müllerian tumor and atypical endometrial hyperplasia
If pT1b and/or pT2 are clinically suspected, intraoperative histologic examination (frozen section) can be performed for verification.
- Consensus
- Strong consensus
Myometrial infiltration depth or endocervical stromal infiltration shall be assessed macroscopically and microscopically.
- Consensus
- Strong consensus
Frozen section examination shall not be performed primarily to assess histopathologic grading and to determine histologic tumor type.
- Consensus
- Strong consensus
The tubes and ovaries shall be assessed macroscopically during the intraoperative frozen section examination, and findings suspicious for tumor should be examined histologically.
- Consensus
- Strong consensus
Background
Intraoperative frozen section assessment may be requested by clinicians for evaluation of local tumor spread and any necessary modification of the immediate surgical approach. This applies, for example, to cases in which FIGO stage IB or II lymphonodectomy is planned in the same session rather than a two-stage approach after final workup of the hysterectomy specimen.
Of importance are determination of myometrial invasion depth [302], [278], [303], [240] and cervical stromal infiltration. Both parameters are relevant for staging and prognosis [304], [284], [305], [240].
Macroscopic assessment of the depth of invasion during frozen section examination alone shows a concordance with final histology of about 80%, which increases to more than 90% with microscopic assessment [306], [307], [308], [252].
The inadequate macroscopic assessment of depth of invasion is especially true for endometrioid EC with a MELF (microcystic, elongated, fragmented glands) [309]; or a minimal-deviation growth pattern ([310]), both parameters cannot be assessed on curettage material. The same applies to serous adenocarcinomas with a glandular growth pattern [311], in which the diagnosis was not made on the curettage material. Therefore, after opening the uterus, the myometrial depth of invasion should be assessed macroscopically and verified histologically, especially for tumors > 2-3cm [312], [313].
The concordance rate between intraoperative frozen section examination and final findings regarding depth of invasion, tumor size, grading and histologic subtype is greater than 95% [314], [302], [252]. During frozen section examination, the endocervical stroma should be assessed macroscopically and, if tumor infiltration is suspected, microscopically [313], [315], [316], [317], [318], [252].
Assessment of grading of endometrioid adenocarcinomas has an insufficient sensitivity of 40% [312], [313] and, like assessment of histologic tumor type, should not be the sole question of frozen section examination. If an endometrioid adenocarcinoma is unequivocally upgraded during frozen section examination as an incidental finding or if a type II carcinoma is detected in endometrioid adenocarcinoma previously diagnosed atdilatation and curettage this should be reported to the surgeon. [302].
Serous (type II) carcinomas of the endometrium and MMMT are so-called high-grade carcinomas of the uterus, so frozen section examination has no intraoperative consequences [319], [312].
Diagnostic certainty for low-grade carcinomas is significantly worse than for high-grade carcinomas [320][321]. This is also true for intraoperative frozen section examination of uteri with atypical endometrial hyperplasia [322], [323].
There is a discrepancy between intraoperative assessment of lymph nodes and final workup in endometrial carcinoma between 7–13% [324], [325].
During the frozen section examination, it seems reasonable to evaluate the adnexa macroscopically, incising the ovaries along their short axis.[240] and histologically assessing any tumor-suspicious findings on the tube or ovary.
If there are any intraoperative consequences, a frozen section examination of the sentinel lymph node (SLN) should be performed. There is no standard protocol for workup [307], [240], [282], but this should be done according to the recommendations of the AWMF Guidelines on vulvar and cervical carcinoma (S3 Guideline for Cervical Carcinoma (awmf.org)):
- All removed SLN should be examined
- Complete examination of the SLN
- Macroscopic workup as for SLN without frozen section examination (see below)
- Preparation of step sections (approx. 3) from the freezing block during frozen sectioning
- Work-up of the paraffin-embedded tissue as described below
4.5.9 Work-up of the tissue
The tissue of a (fractionated) curettage or an endometrial biopsy shall be fully embedded.
- Consensus
- Strong consensus
The report of findings from a (fractionated) curettage or an endometrial biopsy shall comment on the presence and type of endometrial hyperplasia.
If carcinoma is present, the histological tumor type shall be indicated according to the current WHO classification.
If tumor tissue is detected in the cervical fraction of a fractionated curettage, a specific statement shall be made on the presence or absence of endocervical stromal infiltration.
- Consensus
- Strong consensus
Change note
The report of findings from a (fractionated) abrasion or an endometrial biopsy should comment on the evidence and type of endometrial hyperplasia. If carcinoma is present, the histological tumor type should be indicated, taking into account the current WHO classification. If tumor tissue is detected in the cervical fraction of a fractionated abrasion, a specific statement should be made on the detection or absence of endocervical stromal infiltration.The report of findings of a hysterectomy specimen in endometrial carcinoma shall include the following information:
- Histological type according to WHO (in case of mixed tumors components in %)
- Grading
- Staging (pT)
- Evidence/absence of lymphatic or blood vessel invasion (L and V status).
- Detection/absence of perineural sheath infiltrates (Pn status)
- Metric indication of depth of invasion in relation to myometrial thickness in cm/mm
- Three-dimensional tumor size in cm/mm
- Metric measurement of the minimum distance to the vaginal resection margin if vaginal infiltration is present
- R classification (UICC)
- Consensus
- Strong consensus
Change note
The report of findings of a hysterectomy specimen in endometrial carcinoma should include the following information: Histologic type according to WHO for mixed carcinomas with indication of the respective percentage of total tumor Grading Evidence/absence of lymphatic or blood vessel invasion (L- and V-status) Evidence/absence of perineural sheath infiltrates (Pn-status) Staging (pTNM) metric indication of depth of invasion in relation to myometrial thickness in mm three-dimensional tumor size in cm if vaginal infiltration is present metric indication of minimum distance to vaginal resection margin R-Classification (UICC)Table 7: The new (revised 2020) FIGO/TNM classification of endometrial cancer.
|
TNM category |
FIGO stages |
Definition |
|
TX |
|
Primary tumor cannot be assessed |
|
T0 |
|
No evidence of primary tumor |
|
T1 |
I¹ |
Tumor limited to corpus uteri |
|
T1a |
IA¹ |
Tumor confinded to endometrium or infiltrates less than half of myometrium |
|
T1b |
IB |
Tumor infiltrates half or more of the myometrium |
|
T2 |
II |
Tumor infiltrates the cervical stroma but does not spread beyond the uterus |
|
T3 and/or N1or N2 |
III |
Local and/or regional spread as described below: |
|
T3a |
IIIA |
Tumor invades serosa and/or adnexa (direct spread or metastases) |
|
T3b |
IIIB |
Vaginal or parametrial involvement (direct spread or metastases) |
|
N1 |
IIIC1 |
Metastases in pelvic lymph nodes² |
|
N2 |
IIIIC2 |
Metastases in para-aortic lymph nodes with or without metastases in pelvic lymph nodes |
|
T4 |
IVA |
Tumor infiltrates bladder and/or rectal mucosa³ |
|
M1 |
IVB |
Distant metastases, including intra-abdominal metastases (excluding metastases to vagina, pelvic serosa, or adnexa, including metastases to inguinal and intra-abdominal lymph nodes other than para-aortic and/or pelvic lymph nodes) |
|
¹ Assessment of endocervical glands alone should be classified as stage I. Source: [293] |
||
4.5.9.1 Dilatation and Curettage/endometrial biopsies
The tissue removed by curettage or biopsy should be embedded completely (cervical or corpus fraction separately) [326].
The false-negative rate of fractionated curettage regarding the detection of atypical endometrial hyperplasia or endometrioid EC is about 10% [327], [328]. In the majority of cases, the cause is lack of representativeness of the material obtained during curettage [329], [326], [330].
There is no uniform histopathological definition of inadequate material of an endometrial biopsy or curettage [331], [329], [326].
Histopathological definition of an inadequate curettage or endometrial biopsy in the postmenopausal period
Approximately 3% of all endometrial biopsies/curettages are diagnostically inadequate [326]. The preparation of serial sections does not increase the diagnostic certainty in this case [326]. Regardless of the representativeness of the tissue sent after a curettage, the risk of atypical endometrial hyperplasia or endometrioid EC in a subsequent hysterectomy is 0.74% [326].
When tumor tissue is detected in the cervical fraction, a statement should be mades whether infiltration of the endocervical stroma is present or whether the tumor tissue is isolated due to dislocation from the cavum uteri [332], [333], [277].
4.5.9.2 Preparations after simple and radical hysterectomy for endometrial carcinoma
The pathology report of findings must comment on the size, weight and nature of the specimen with particular reference to the serosal characteristics [334], [274], [277], [240].
The macroscopic description of the endometrial carcinoma or MMMT should include the exact anatomic location (isthmus or corpus uteri, anterior or posterior wall or uterine roof), three-dimensional metric tumor extent, growth type (e.g. polypoid, sessile, diffusely infiltrating) and relationship to the endocervix [334], [274], [240].
In addition, there should be an indication of the presence or absence or length of the resected vaginal cuff [334], [274]. The distal vaginal resection margin should be completely assessed circular (preferably after separation into posterior and anterior vaginal cuff) [277].
According to the recommendations of the ICCR and ISGyP [274], [240], [303], the morphological workup of the hysterectomy specimen should be done in such a way that all the information required in the following list can be collected [334], [274], [277], [240].
The recommendation is to embed one paraffin block per 2 cm of greatest tumor extension in pure endometrioid and serous carcinomas and at least one block per cm of greatest tumor extension in rare carcinoma types, mixed carcinomas and in carcinosarcoma [334], [274], [277]. In the diagnosis or differential diagnosis of a de- or undifferentiated endometrial carcinoma, a more extensive embedding may be necessary.
If no macroscopically visible tumor is found in the hysterectomy specimen, embedding of three blocks each of non-tumorous endometrium from the anterior and posterior wall is recommended [335]. If no carcinoma is detectable histologically either (so-called vanishing endometrial cancer; [336]), complete embedding of the endometrium is recommended [240], whereby several samples of the endo-myometrial junction can be embedded in one block [277].
In endometrial carcinoma, there are also different patterns of invasion into the myometrium [244], [240]. In addition to the classic invasion pattern with infiltration of grouped glands with varying degrees of peritumoral desmoplasia and inflammatory response, there are carcinomas with growth similar to adenoma malignum [337] and the so-called MELF pattern (microcystic, elongated, fragmented glands) [338], [339]. The latter two are considered to have a less favorable prognosis, and the MELF pattern is considered to have a higher rate of lymphatic vessel invasion as well as (occult) lymph node metastases [337], [309], [340], [341], [240], [282]. Therefore, reporting a specific invasion pattern in the histology report is recommended.
Lymphatic vessel invasions are frequently seen in serous EC, as well as in about 10-15% of endometrioid carcinomas. Results from the PORTEC-2 study have supported their prognostic relevance [342]. For definition of lymphatic vessel invasion and its quantification, see Chapter “Definition of TNM-relevant parameters”.
Involvement of the adnexa may be macroscopically occult, especially in serous EC [333], [332], but is relevant for staging and prognosis. Therefore, macroscopically inconspicuous ovaries should be fully embedded with the immediately adjacent hilar/meso tissue [277], [240], lamination along the short axis of the ovary is recommended as this allows more tissue to be histologically assessed [276], [261], [240]. When working up the tubes, it is recommended to follow the SEE-FIM protocol [343], the so-called SEE-FIM-like protocol (see following figure); [240], [303], [344].
Legend to figure “Processing of the tubes in EC according to the SEE-FIM-like protocol”
*Amputation of the fimbria-bearing distal part with lamination in 0.2 to 0.3cm intervals, complete embedding
**Removal of approximately 3 transverse sections of the tube with inclusion of the portion near the uterus
Processing of the tubes should be based on the SEE-FIM-like protocol.
- Consensus
- Strong consensus
Change note
The ovaries in endometrial carcinoma should be embedded completely, with acquisition of the hilus ovarii. The work-up of the tubes should follow the SEE-FIM protocol.Involvement of the tubes in EC can have different morphologic appearances [282], [345], [346], [347], [348]. In any case of tubal involvement, primary carcinoma originating from the tube should be excluded.
Tumor cells lying freely in the tubal lumen
Cells lying freely in the tubal lumen are seen especially after laparoscopic or robotic hysterectomies [345], [346] and in serous EC [347], but are rare at 2.5% [349]. This may be associated with a higher rate of positive peritoneal cytology and extrauterine spread (especially in serous EC) [347], [349], but has no prognostic significance [349]. Detection of tumor cells lying freely in the tubal lumen should be mentioned in the pathology report, but upstaging is not performed [282].
Metastasis to the tubal mucosa
If tumor cells are detected within the tubal epithelium, a coexistent serous in situ carcinoma of the tube (STIC) may need to be excluded by immunohistochemistry [261], [348], [348]. If there is involvement of the tubal mucosa by EC, upstaging is the result [282].
Involvement of the tubal wall with or without lymphatic vessel intrusions
If there is evidence of lymphatic vessel intrusions in the tubal wall without involvement of the tubal mucosa by a STIC and/or invasive carcinoma, but especially if there are lymphatic vessel intrusions in the mesosalpinx, this is involvement by the EC [282]. Whether this finding is to be evaluated only as L1 or leads to an upstaging is not clarified in the TNM classification [293].
4.5.9.3 Sectioning in patients with risk-reducing hysterectomy with BSO for Lynch syndrome (RRHS)
Patients with risk-reducing hysterectomy with BSO (RRHS) show occult endometrial hyperplasia in 17-25% of cases [350], [351], occult EC in up to 12.5% [352], and ovarian cancer in approximately 4% [353].
Since occult endometrial hyperplasia and EC can occur circumscribed [350], [352], the following procedure is recommended in the absence of tumor at sectioning [353], [351], [350]:
- Representative embedding of the endo- and ectocervix
- Complete work-up of the isthmus endometrium (in the absence of TM detection, otherwise “more targeted sampling”, i.e. > 1 tumor block/ 2cm of greatest tumor extension)
- Complete work-up of the corpus endometrium (in the absence of TM detection, otherwise “more targeted sampling”)
- Complete workup of the distal portion of the tube/fimbrial funnel (so-called SEE-FIM-like protocol; ; [351], [240],
- Representative embedding of ovarian tissue (complete embedding if necessary).
4.5.10 MMR/MSI analysis of endometrial hyperplasia/EIN
Compared to endometrial carcinomas, associated endometrial hyperplasias (CAH/EIN) show concordant loss of mismatch-repair proteins (MMR) in immunohistochemistry. Combined loss of MLH-1/PMS-2 predominates, followed by combined loss of MSH-2/MSH-6 as well as MSH-6 loss alone. Isolated loss of PMS-2 is rare. Loss of MLH-1 is caused by promoter methylation in more than 95% of cases [354], [355].
Using sequentially collected endometrial biopsies, it has been shown that mismatch-repair protein loss in non-neoplastic endometrium can precede invasive (MMR-deficient) EC by between 7 months and up to 12 years [356], [357]. In unselected endometrial hyperplasias, immunohistochemical loss of mismatch-repair proteins was observed in 4.5%, predominantly due to methylation of the MLH-1 promoter [358]. In analogy to the detection of Lynch syndrome in patients with EC, approximately 3% of all atypical endometrial hyperplasias with loss of MMR proteins originate from patients with Lynch syndrome. Routine immunohistochemistry of MMR proteins is not currently required in atypical endometrial hyperplasia. However, this should be performed in patients with suspected Lynch syndrome or Lynch syndrome in the family history.
Routine immunohistochemical analysis of MMR proteins shall not be performed in the setting of endometrial hyperplasia.
- Consensus
- Strong consensus
4.5.11 Significance of the immunohistochemical determination of MMR proteins.
Immunohistochemical analysis of MMR proteins in EC has four main goals (see figure below):
- Classification of the individual tumor within the molecular classification [238], [273], [235]
- Resulting prognosis estimation (Wortmann et al., [359]
- Identification of patients at risk for Lynch syndrome [360], [361], [273]
- Potential therapeutic implications: Response to immune checkpoint inhibitor therapy [362], [363]
- Response to adjuvant radiotherapy [364]; in contrast, poor response to progestin therapy [365]
4.5.12 Technical aspects of the immunohistochemical determination of MSI proteins
In analogy to the S3 Guideline for colorectal carcinomas [366], there is widespread consensus in the recommendations of ESMO and ISGyP regarding the preferential use of immunohistochemistry to determine MSI status or the MMR proteins [361], [236], [273], [367], [237]. This can be complemented by molecular analyses (methylation assay, MSI-PCR) if needed.
With respect to ESMO and ISGyP, the use of all four antibodies (MLH-1, PMS-2, MSH-2, MSH-6) is recommended [237], [273], [361]. In contrast to colorectal carcinoma, there are only a few studies in endometrial carcinoma regarding the comparison of two versus four immune markers of mismatch-repair proteins [368], [369], iin which a total of 1,100 patients were analyzed. Both studies conclude that two MSI markers (PMS-2 and MSH-6) are equally effective as four markers (MLH-1, PMS-2, MSH-2, and MSH-6). However, only two MSI markers should be used only if reliable staining results and a safe interpretation in the respective institution are ensured when all four markers have been evaluated in advance [369]. Various studies as well as the German Society of Pathology (DGP) point out that the use of two MMR antibodies is possible as a more cost-effective alternative [370], [368], [369], [371], [372]. In any case, however, sequential addition of the remaining markers should always be possible if, among other things, in the respective case the staining is negative or only focally or patchily positive for one of the two initial markers (MSH-6 or PMS-2) or if the nuclear staining is weak [237], [361], [273].
Interpreting the immunohistochemical staining results with respect to MSI testing, there is a complete interobserver agreement of 90.4% corresponding to a kappa value of 0.92 [373]. These results were confirmed in a systematic review [374].
There is a concordance of more than 95% between immunohistochemical and molecular pathological analysis of MSI status [368], [375], so that, not least for economic reasons, a combination of both methods is generally not necessary [273], [370], but may be useful in individual cases with unclear test results [273].
In the case of MLH-1 failure, molecular pathology in the context of Lynch diagnostics should exclude MLH-1 promoter methylation [361].
Molecular testing of tumor tissue alone is not recommended, as a not insignificant proportion of MSH-6-deficient tumors may not be detected [361], [367], [370].
The procedure of MSI analysis is summarized algorithmically below (see figure).
Heterogeneous expression of MLH-1 and PMS-2 is rare and mostly due to methylation of the MLH-1 promoter in sporadic EC [376].
MSI analysis in endometrial carcinoma shall be primarily immunohistochemical.
The primary use of two antibodies (MSH-6 and PMS-2) is possible, with addition of the respective partner antibody (MSH2 or MLH1) in case of negative results.
Immunohistochemical analysis of MMR proteins shall be supplemented by molecular pathological methods (MLH-1 promoter methylation, MSI-PCR) according to the indication.
The exclusive use of molecular pathological methods shall not be performed.
Combined analysis by immunohistochemistry and molecular pathology shall not be performed routinely.
- Consensus
- Strong consensus
4.5.13 Timing of MMR/MSI determination
Immunohistochemical determination of MMR proteins is critically influenced by pre-analytics, the most significant parameter of which is tissue fixation [377], [236], [378], https://www.thebagp.org/download/bagp-bgcs-nice-mmr-pathway/. In standard care, the tumor tissue of the hysterectomy specimen often shows autolysis-related changes and insufficient fixation [277]. Therefore, the ESMO as well as the British Association of Gynaecological Pathologists (BAGP) recommends the determination of the MMR or MSI status on the biopsy or curettage material [236], https://www.thebagp.org/download/bagp-bgcs-nice-mmr-pathway/ because the fixation is better [370] and the result is already available for the pre-therapeutic tumor board. Repeating the examination on the surgical specimen may be useful if it shows tumor heterogeneity not visible on the biopsy or curettage material . If only a small amount of tumor tissue can be obtained by curettage the examination should be performed exclusively on the surgical specimen.
Every newly diagnosed endometrial cancer shall be screened for MMR defect/MSI regardless of age and histological subtype.
MMR/MSI analysis thus also serves to identify patients who shall be offered human genetic counseling.
4.5.14 Hereditary endometrial cancer
Most hereditary EC occur in context with Lynch syndrome [367] [381] and Cowden syndrome [382], and less frequently in BRCA mutation carriers [383], [384].
About 3-5% of all EC are Lynch-associated [367], [385]. Previous data show that about one-third of all patients have no corresponding family history and EC is the “sentinel carcinoma” for Lynch syndrome, which is diagnosed after the age of 50 in about two-thirds of cases [386], [385], [387].
In particular, endometrioid EC mayshow morphological criteria suggestive of Lynch association [261], [388], [360] however, HE morphology is not a sufficient predictor [387] [360]. Therefore, immunohistochemical analysis of MMR proteins is indicated in every case of newly diagnosed EC regardless of patient age and histologic subtype [360], [273], [389], [390]. MMR immunohistochemical analysis in endometrial cancer is used to identify patients at risk who should subsequently be offered human genetic workup ([370], see Fig. 6).
EC in association with BRCA germline mutations (mostly BRCA-1; [384]) show mostly serous and more rarely G3 endometrioid histology, each with aberrant p53 expression and/or HRD [383]. Therefore, it seems reasonable to recommend appropriate human genetic counseling to patients with a conspicuous family history [390].
4.5.15 Molecular classification of endometrial carcinoma
Based on the results of The Cancer Genome Atlas (TCGA) project [391], a morpho-molecular classification of EC has been developed in recent years [380], [392], [393], [394], [395]. This morpho-molecular classification is prognostically relevant [380], [396], [397], [398], and is increasingly implemented in therapeutic decisions [380][399] [359], [238], [364], [400]. Therefore, depending on resources, its use is recommended by WHO as well as ISGyP and other professional societies (ESGO, ESTRO, ESP) [235], [273], [237]). The most essential characteristics are included in "The new FIGO/TNM classification" and "Clinicopathological characteristics" [238], [273], [391], [392], [396], [380], [359], [383], [300], [401]. The diagnostic algorithm is summarized in Figure 7.
Molecular typing of EC is currently used only for endometrioid carcinoma, and data are very limited for the rarer histologic subtypes [235], [402], [394], [403], [404].
Molecular typing of EC should include at least immunohistochemical examination of MMR proteins and p53. POLE mutational analysis is required for complete classification, but there is currently no evidence for its practical relevance for low grade (G1-2), low stage (stage I/pT1) EC.
Risk stratification according to ESGO/ESTRO/ESP recommendation is presented in the table “Binary/dualistic model of endometrial cancer” in Chapter 4.5.
In all histologically diagnosed primary EC, immunohistochemical determination of p53 as well as MMR proteins shall be performed.
In G3 or in intermediate, high intermediate, and high-risk EC, mutational analysis of the exonuclease domain of POLE shall be performed.
Molecular classification (P53 and MMR deficiency) shall be performed preoperatively, i.e., on the curettage material or endometrial biopsy.
- Consensus
- Strong consensus
POLE mutation analysis can alternatively be performed postoperatively.
- Consensus
- Strong consensus
Table 8: Clinicopathologic characteristics of each molecular type of endometrial carcinoma
|
|
POLE mutant |
MMR deficient |
No special molecular profile |
P53 abnormal |
|
Frequency |
9% |
28% |
50% |
12% |
|
Age |
Young women |
All ages |
All ages |
|
|
Associated with obesity |
No |
No |
Yes |
No |
|
Related to hyperestrogenism |
No |
No |
Yes |
No |
|
Hereditary component |
Rare |
10% (Lynch) |
Rare |
BRCA possible |
|
Precursor lesion |
Atypical hyperplasia/EIN |
Atypical hyperplasia/EIN |
Atypical hyperplasia/EIN |
None |
|
Molecular alterations |
POLE mutations |
Microsatellite instability |
Heterogeneous |
P53 mutations |
|
Number of mutations |
Very high (ultramutated) |
High (hypermutated) |
Moderate |
Low |
|
Histology |
Often endometrioid G3, TIL/PER |
Endometrioid low/high grade, un-/dedifferentiated, TIL/PER |
Endometrioid low grade |
Serous, carcinosarcoma, endometrioid high grade |
|
Diagnostics |
POLE Mutation analysis |
MMR Immunohistochemistry |
Diagnosis of exclusion |
P53 immunohistochemistry |
|
Immunohistochemistry |
P53 wild type*, MMR normal* |
P53 wild type*, MMR deficient |
P53 wild type, MMR normal |
P53 abnormal, MMR normal |
|
Tumor stage |
Often low |
Wide range |
Often low |
Usually high, metastases frequent (lymph nodes, organ) |
|
LVSI |
Frequent |
Frequent |
Variable |
Frequent |
|
Prognosis |
Very good |
Good |
Good |
Poor |
|
* In multiple classifiers, additional p53 may be abnormal or MMR deficient. Abbreviations: TIL = tumor infiltrating lymphocytes, PER = peritumoral inflammation. Sources: [383], [409], [359], [238], [380], [273], [396], [395], [392], [300] |
||||
Table 9: Risk stratification of endometrial carcinoma according to ESGO/ESTRO/ESP depending on molecular classification
|
Risk group |
Molecular classification unknown |
Molecular classification known 1,2 |
|
Low |
Stage IA endometrioid + low-grade³ + LVSI negative or focal |
Stage I-II POLE-mut endometrioid carcinoma, without residual tumor Stage IA MMR-d/NSMP endometrioid carcinoma, low-grade, LVI negative or focal |
|
Intermediate |
Stage IB endometrioid + low-grade* + LVI negative or focal stage IA endometrioid + high-grade* + LVI negative or focal stage IA non-endometrioid (serous, clear cell, undifferentiated carcinoma, carcinosarcoma, mixed) without myometrial infiltration |
Stage IB MMR-d/NSMP endometrioid carcinoma, low-grade, LVI negative or focal Stage IA MMR-d/NSMP endometrioid carcinoma, high-grade, LVI negative or focal Stage IA p53-abn and/or non-endometrioid (serous, clear cell, undifferentiated carcinoma, carcinosarcoma, mixed), without myometrial infiltration |
|
High-intermediate |
Stage I endometrioid + significant LVI regardless of grading and depth of invasion Stage IB endometrioid high-grade* regardless of LVI status |
Stage I MMR-d/NSMP endometrioid carcinoma, substantial LVI, independent of grading and depth of invasion Stage IB MMR-d/NSMP endometrioid Stage II MMR-d/NSMP endometrioid carcinoma |
|
High |
Stage III-IVA without residual tumor Stage I-IVA non-endometrioid (serous, clear cell, undifferentiated carcinoma, carcinosarcoma, mixed) with myometrial infiltration, without residual tumor |
Stage III-IVA MMR-d/NSMP endometrioid carcinoma without residual tumor Stage I-IVA p53-abn endometrioid carcinoma with myometrial infiltration, without residual tumor Stage I-IVA MMR-d/NSMPserous or undifferentiated carcinoma or carcinosarcoma with myometrial infiltration, without residual tumor |
|
Advanced metastatic |
Stage III-IVA with residual tumor Stage IVB |
Stage III-IVA with residual tumor, independent of molecular type Stage IVB, independent of molecular type |
|
¹ For POLE-mutated stage III-IVA endometrial cancer and for MMR-deficient or NSMP clear cell endometrial cancer with myometrial infiltration, there are insufficient data to assign these patients to a prognostic risk group with respect to molecular classification. Prospective enrollment of these tumors is recommended. ² See text for „multiple classifier“ (example: patients with POLE mutation and p53 aberration should be classified as POLE mutated). ³ According to WHO, two-stage grading of endometrioid carcinomas is used; G1 and G2 carcinomas are considered low-grade, G3 carcinomas are considered high-grade (WHO 2020, Casey & Singh 2021). LVI = lymphatic vessel infiltration, MMR-d= MMR deficient (corresponds to microsatellite instability), NSMP = no special molecular profile (molecular pathologically complete EC without POLE mutation and MMR deficiency and with p53 wild type), POLE-mut = polymerase E mutated. Source: [237] |
||
Currently, there is no immunohistochemical surrogate marker for the POLE mutation; therefore a molecular pathological analysis by Sanger sequencing or NGS including exomes 9 to 14 [392], [359] is necessary in any case. To what extent fluorescence-based SNaPshot analysis is possible as an alternative method [273] cannot be answered at present [410].
p53 immunohistochemistry is an accepted surrogate marker for a p53 mutation in gynecopathology [411], [238], including EC [412], which is also recommended by the WHO [235], and is an integral part of the molecular classification [380], [392]. At the same time, p53 immunohistochemistry is also used for correct morphological typing [393], [261], [258]. The interpretation of immunohistochemistry was developed in correlation with sequencing [413], [244], recent data are oriented to high-grade serous ovarian cancer [414]. A comparison of immunohistochemistry between local and central pathology showed a concordance rate of more than 95% [412]. The same is true for the comparison of curettage material versus hysterectomy with a concordance rate of about 90% [415], [412] and the comparison of p53 immunohistochemistry and mutation analysis with 92.3% [416].
Diffuse/extended aberrant p53 expression is rare at 2–15% in G1 endometrioid (FIGO low grade) EC, but more common at 10-15% in G3 (FIGO high grade) endometrioid tumors [238]. Diffuse steroid hormone receptor expression and PTEN loss indicate endometrioid morphology. According to the ESMO/ESGO/ESTRO/ESP risk stratification (Table 3; [237]), these tumors are intermediate risk.
Endometrioid EC with aberrant p53 expression has a comparably unfavorable prognosis as serous EC [398].
A distinctive feature of EC is the so-called subclonal aberrant p53 expression, which is defined as an abrupt strong nuclear p53 expression (> 75% of tumor cell nuclei) in a circumscribed tumor area occupying > 10% of the total tumor [238], [359]. It is an expression of intratumoral heterogeneity with temporary mutation in the course of tumor progression and not a so-called founder mutation [414], [238], which has no prognostic significance at the current state of knowledge [238]. Important is an exact calibration of the immunohistochemistry in the respective institute using a “low-expressor”-positive control (e.g. tonsil; [414]) and the use of optimally fixed tissue [411], [415]. The classification into the respective molecular subgroup should be done according to the predominant change.
Intratumor molecular heterogeneity is rare [417] and occurs in EC with multiple classifiers. It is not due to founder mutations but is an expression of tumor progression through epigenetic alterations [411]. Molecular subclassification is based on the predominant molecular alteration [411], [417].
If a molecular subclassification of EC is not possible, or if the results of this subclassification are inconclusive, the addition of NOS (not otherwise classified; e.g., well-differentiated endometrioid EC NOS) may be used in addition to the histological subtype [238]. EC with NSMP (no special molecular profile), in which a complete molecular examination has been performed but no classification into the category POLE-mutated, p53-aberrant or MSI-deficient, must be clearly distinguished from this. Because of the heterogeneity of this molecular group [404], [359], attempts were made to further stratify these tumors [397], [418], [419], [420], [421]. Nuclear beta-catenin reactivity correlates with a CTTNB exon 3 mutation [419], and also appears to be associated with a less favorable prognosis [418], [419], [421]. Similarly, immunohistochemical L1CAM positivity in NSMP-EC is prognostically unfavorable [422]. However, there is insufficient data to include CTTNB and L1CAM in the WHO or ESGO/ESTRO/ESP classification [237], [405]. In the present Guideline, the determination of L1CAM is listed with a recommendation grade of 0. It may be useful, for example, when considering fertility-preserving therapy of early EC.
Regarding a possible change in molecular subtype in the context of tumor progression or metastasis, few data are available. Preliminary results suggest that the molecular subtype remains stable and that only p53-aberrant (serous) EC may result in a therapeutically relevant HRD [301].
4.5.16 Multiple molecular alterations (multiple classifier)
3-5% of all EC are “multiple classifier”, i.e. they have more than one molecular subtype (TCGA 2013, [359], [238]. In particular, this concerns EC with POLEmut or MSI, in the following constellations:
- POLEmut and MSI
- POLEmut and p53mut
- MSI and p53mut
- POLEmut, MSI and p53mut
However, these multiple molecular alterations appear to be without practical significance. POLE-mutated EC with immunohistochemically aberrant p53 expression (p53mut) behave like POLE-mutated EC with p53 wild type [359]. The same is true for MSI EC and aberrant p53 expression, MSI EC, EC with POLEmut, MSI and aberrant p53 expression and EC with POLEmut and MSI [359]. Multiple classifier EC are approximately 75% G3 carcinomas with endometrioid histology or FIGO stage I [359]. The impact of POLE mutation on tumor biologic behavior and the existence of “multiple classifier”-EC underscores the importance of POLE mutation analysis for molecular classification of EC [273], [238]. Although the data is limited, this is a rapidly developing new field of knowledge.
4.5.17 Curettage material versus hysterectomy specimen
There is a high concordance between studies on curettage material and hysterectomy specimen of 90-95% and molecular classification overall [415], [412], [424], [396], [394]. Therefore, risk stratification is in principle possible on the curettage material [239]. A repetition of the examination on the hysterectomy specimen is useful only if an additional tumor component is detected [417]. An indispensable prerequisite for adequate molecular classification is the use of optimally fixed tissue [414], [361]. This is usually more likely to be fulfilled on the curettage material than on the hysterectomy specimen.
Molecular typing of endometrial carcinoma shall be performed on optimally fixed tissue, i.e. preferably on the curettage material. Due to a high concordance rate betweencurettage and hysterectomy specimens, a repeat determination on the surgical specimen shall not be performed if no additional tumor component is detectable on the hysterectomy specimen.
- Consensus
- Strong consensus
4.5.18 PD-L1 expression
MMR-deficient and POLE-mutated EC are ultra- and hypermutated tumors, respectively [238], [401], the same applies to the so-called multiple classifier [359]. In analogy to other tumor entities [425] MMR-deficient and POLE-mutated EC show an increased neoantigen expression with consecutive increased immunogenicity due to their genetic instability. Morphologically, some of these EC have numerous intra- and peritumoral lymphocytes (see table “ESGO/ESTRO/ESP – Risk stratification of endometrial carcinoma depending on the presence of molecular pathological test results”); [409], [238], [273]. Increased immunogenicity is also associated with increased PD-L1 expression [426], [427]. A possible relationship with methylation of the MLH1 promoter is unclear here [426], [427].
4.5.19 Workup and reporting of omentectomy specimens in endometrial carcinoma
At least oneparaffin block shall be examined from omentectomy specimens with macroscopic tumor infiltration in endometrial carcinoma.
In the case of macroscopically absent tumor infiltration, four to six paraffin blocks (embedding of several specimens in one block is possible) shall be examined.
Any additional abnormal findings (e.g., intraomental lymph nodes) shall be described macroscopically and examined histologically.
- Consensus
- Strong consensus
Change note
As part of the pathological workup of an omentectomy specimen in endometrial carcinoma, at least one representative kerosene block should be examined in the case of macroscopic tumor infiltration. In the absence of macroscopic tumor infiltration, four to six kerosene blocks (embedding of multiple specimens in one block is possible) should be examined. Any additional abnormal findings (e.g., intraomental lymph nodes) should be described macroscopically and examined histologically.Omentectomy is a standard surgical treatment for type II carcinoma and is performed in individual cases of endometrioid (type I) carcinoma and MMMT.
There are currently no uniform guidelines for the workup of omentectomy specimens in endometrial carcinoma, including recent recommendations from the College of American Pathologists Tumor Extent [334] and the International Collaboration on Cancer Reporting [274]. Therefore, the following points are based on results of studies in ovarian cancer [428], [429], [430].
Attention should be paid to the following points during macroscopic evaluation and tissue sampling [431]; CAP 2015, [277]:
- Three-dimensional size of the omental resectate in cm.
- Indication of the three-dimensional size of a tumor infiltration in cm,
- Lamellation in slices approximately 0.5 cm thick,
- Description of the number and size of intraomental lymph nodes (with workup as described in the lymphonodectomy section).
- Description and embedding of focal findings,
- In case of macroscopic tumor infiltration, embedding of 1 (to 2) paraffin blocks,
- In the absence of macroscopic tumor infiltration, embedding of 4 to 6 paraffin blocks (embedding of several specimens in one block is possible).
The histopathological report of findings should include the following information [431], CAP 2015, [277]:
- Maximum extent of tumor infiltration in cm
- Indication of the histological type in case of tumor infiltration
- Number and status of intraomental lymph nodes
- Indication of any non-malignant findings (e.g., inflammatory changes, adipose tissue necrosis, mesothelial hyperplasia).
To document the diligence of the workup, it seems useful to indicate the number of examined samples or paraffin blocks in case of negative tumor detection (e.g., 7 samples in 5 blocks examined omental tissue without malignancy with 2 lymph nodes without metastases (0/2) as well as 1 cm older adipose tissue necrosis). The result of peritoneal cytology is not staging relevant [293], but correlates with (occult) involvement of the omentum [432], [433].
4.5.20 Processing and reporting of lymphonodectomy specimens in endometrial cancer
For lymphonodectomy specimens as part of surgical therapy for endometrial cancer, all removed lymph nodes shall be completely embedded and examined histologically.
- Consensus
- Strong consensus
Lymph nodes up to approximately 0.2 cm maximum extent should be embedded in toto, and larger lymph nodes shall be bisected or lamellated along their short axis and also embedded completely.
- Consensus
- Strong consensus
Change note
Lymph nodes up to approximately 0.3 cm maximum extent should be embedded in toto, and larger lymph nodes should be bisected or lamellated along their long axis and also completely embedded.The report of findings of lymphonodectomy specimens in endometrial carcinoma shall include the following information:
- Indication of the number of affected lymph nodes in relation to the number of removed lymph nodes in assignment to the sampling location (pelvic, para-aortic),
- Indication of the extent of the largest lymph node metastasis in mm/cm,
- Indication of absence/evidence of capsular rupture of lymph node metastasis(s),
- Indication of evidence of isolated tumor cells in the lymph node and evidence of lymphatic vessel invasion in the perinodal adipose tissue and/or lymph node capsule.
- Consensus
- Strong consensus
Background
The workup and reporting of lymphonodectomy specimens in endometrial carcinoma does not differ from the Guideline for cervical carcinoma (S3 guideline cervical carcinoma(awmf.org); [434], [344]. The same applies to the definition of isolated tumor cells and micro- versus macrometastases [344].
Ultrastaging with preparation of staged sections and/or additional immunohistochemical studies may increase the number of patients with isolated tumor cells or micrometastases in EC [435]. Ultrastaging with sequential sectioning and/or additional immunohistochemistry may increase the number of patients with isolated tumor cells or micrometastases in EC [435]. However, ultrastaging of negative non-sentinel lymph nodes is not recommended [240], [282], [344].
The distinction between micro- and macrometastases is not staging relevant in endometrial cancer. Studies suggest that detection of isolated tumor cells (ITC) or micrometastases (pN1mic) may be prognostically significant [436], [437], [438]. However, not all studies separate ITC and micrometastases in their definition according to UICC [438], or both parameters are combined in the evaluation. According to the recommendations in the TNM, ITC and micrometastases and their differentiation should be noted in the histology report and included in the staging.
Isolated tumor cells in the sentinel LC (< 0.2mm) (pN0 (i+) are per se not an indication for adjuvant radiotherapy and/or chemotherapy. This is recommended only in case of corresponding additional risks (e.g. p53 mutation, type II EC, LVSI).
- Consensus
- Strong consensus
For micrometastases (> 0.2 mm, < 2mm) (pN1(mi)), adjuvant radiotherapy and/or chemotherapy should be given.
- Consensus
- Strong consensus
More positive sentinel nodes are detected by ultrastaging, especially in low and intermediate risk endometrial carcinomas [437], [439], [440]. In a good half of the cases of positive sentinel nodes, these are based on isolated tumor cells (ITC) or micrometastases [437], [439], [440], whose relevance for prognosis is at least unclear, possibly even irrelevant [437], [440]. Therefore, the generous performance of sentinel node biopsy with ultrastaging may also lead to unnecessary upstaging and initiation of adjuvant therapies that only increase morbidity without improving prognosis [437], [440]. Micrometastases (> 0.2 mm to ≤ 2 mm, pN1 (mi)) are considered by most experts to be metastatic disease indicating adjuvant therapy [436], [237].
In a retrospective study, when patients with micometastases were considered as nodal positive and received adjuvant therapywere shown to have the same PFS y as nodal-negative EC patients [436]. Whether this was due to a therapeutic effect or to the lack of relevance of the micrometastases cannot be clarified by this study.
Very few data are currently available on the possible prognostic significance of extracapsular spread in endometrial carcinoma [441]. Nevertheless, all AWMF guidelines as well as the ICCR recommend to mention extracapsular spread as standard in the report of findings [442].
Parametranous (mesometranous) lymph nodes belong to the regional lymph nodes in endometrial carcinoma [281] and should be subsumized under pelvic lymph nodes. Lymph node metastases of this location are classified as pN1 rather than pT3b. Intraomental lymph nodes also belong to the regional lymph nodes.
4.5.21 Workup of sentinel lymph nodes in EC
Sentinel lymph nodes in endometrial carcinoma shall be lamellated parallel to their short axis and fully embedded and examined in sequential sections.
Sentinel lymph nodes that are negative in the hematoxylin-eosin stain shall additionally be examined by immunohistochemistry (so-called ultrastaging).
- Consensus
- Strong consensus
Change note
The sentinel lymph nodes harvested in studies of endometrial carcinoma are to be fully embedded and examined in staged sections. In addition, immunohistochemical examinations should be performed on sentinel lymph nodes that are negative in HE morphology (so-called ultrastaging).Background
With regard to the histopathological examination of sentinel lymph nodes, there is currently no uniform protocol [240], [282], [443], yet ultrastaging of sentinel lymph nodes should always be performed [444], [445], [240], [282], [344], [435], [446], [237]. The workup of sentinel lymph nodes in endometrial carcinoma is based on the S3 Guideline for Cervical Carcinoma and the S2k Guideline for Vulvar Carcinoma, as well as the recommendations of the Society of Gynecologic Oncology (SGO) for EC [447].
In this approach, the sentinel lymph nodes should be lamellated along their short axis into approximately 0.2-cm-thick slices and completely embedded [240], [344], [448], [307]. At least three sequential sections should be made, each approximately 200 µm apart, and HE-stained (S3 Guideline for Cervical Carcinoma and S2k Guideline for Vulvar Carcinoma). If no tumor cells can be detected in the HE-stained section preparations, an immunohistochemical examination with a pan-cytokeratin antibody (e.g., AE1/AE3) should be performed [444], [445], [240], [282], [344], [446].
In case of intraoperative frozen section examination [307],[237], macroscopic workup is performed as described. The complete lymph node(s) are used for frozen sectioning. Three sequential sections should be made from the frozen blocks.
4.5.22 Morphological prognostic factors
The WHO classification, ISGyP and ESGO/ESTRO/ESP consensus recommend that prognostic assessment of EC be performed morpho-molecularly [235], [282], [237]. This consists of a combination of morphological, immunohistochemical and molecular pathological parameters [282], [238], [449], [237].
Established prognostic factors are tumor stage, evidence of lymph node metastases, histologic tumor type according to WHO, grading in endometrioid EC and molecular classification [282], [238], [449], [237], [239].
Grading in endometrioid EC follows the recommendations of FIGO, with G1 and G2-EC classified as low grade and G3-EC as high grade according to WHO (see above, [235], [282], [237].
Myometrial depth of invasion and endocervical stromal involvement are staging-relevant and prognosis-associated for FIGO and TNM. Involvement of endocervical glands is not staging-relevant in the FIGO or TNM classification and is subsumed in stage FIGO I/pT1. However, it is recommended to mention this finding in the pathology report.
Peritoneal cytology status is no longer staging relevant but should be mentioned in the histopathology report [282], [240].
The histological tumor type according to WHO is an integral part of the findings report [303], [282], [237], [238]. However, the exclusive importance of histological type is increasingly modified by molecular classification [238], [258], [261].
Mixed EC consist of ≥2 histologic types, one of which must be serous or clear cell, without regard to quantity.
Carcinosarcomas (MMMT) with heterologous mesenchymal component, higher tumor stage and large tumors appear to be prognostically unfavorable [267], [450]. The majority of carcinosarcomas are molecular p53 mutated tumors [404].
In endometrioid EC, tumor size apparently has prognostic relevance [451].
Incompletely resected tumors (R1 or R2 situation) have a significantly higher local recurrence rate [452]; [453]. Therefore, incomplete tumor resection can be classified as a prognostically relevant factor.
The so-called MELF-pattern (microcystic, elongated and fragmented glands) as an invasion pattern in EC has prognostic significance due to a higher frequency of occult lymphatic vessel invasion, lymph node metastases as well as the association with epithelial-mesenchymal transition [454], [455]. To what extent tumor budding known from colorectal carcinoma is prognostically relevant [456], cannot be assessed at present.
In a study of more than 25,000 patients with stages FIGO IA/T1a and IB/T1b, lymh vascular space invasion (LVSI) showed a 4- to 10-fold increased risk of lymph node metastases [341]. Among LVSI-positive EC, the extent of LVSI is prognostically relevant [289], [286].
In many studies, venous infiltration is not explicitly evaluated or infiltration into small veins/venules is subsumed under vascular invasion or involvement of the lymphovascular space. Studies on the significance of venous infiltration are lacking [457], [453].
Perineural sheath infiltration is a parameter that has been insufficiently studied in endometrial carcinoma [457], [453].
Immunohistochemical detection of steroid hormone receptors correlates with endometrioid EC [239], [261]. Therefore, their prognostic significance should be considered unclear [458].
Regarding the significance of nomograms for prognostic assessment without or with inclusion of molecular data, there is currently insufficient evidence [459], [460], [461].
Other molecular markers outside of TCGA-based subclassification are currently not considered important in EC [239], [273].
Morphologic prognostic factors and the need to report them in the histopathologic report are summarized in the following table.
Table 10: Summary of standard*, risk, and prognostic factors and their treatment relevance in endometrial cancer and malignant mixed Müllerian tumor (MMMT; carcinosarcoma)
|
Name |
Standard factor |
Risk/Predictive factor |
Therapeutic relevance |
|
Tumor stage |
yes |
yes |
yes |
|
Myometrial invasion depth |
yes |
yes |
yes |
|
Lymph node status |
yes |
yes |
yes |
|
Histological tumor type according to WHO |
yes |
yes |
yes |
|
Size of lymph node metastases |
yes |
unclear |
no |
|
Number of metastatically affected lymph nodes |
yes |
unclear |
no |
|
Extracapsular spread of lymph node metastases |
yes |
unclear |
no |
|
Status of peritoneal cytology |
yes |
unclear |
no |
|
Perineural sheath infiltration (Pn status) |
yes |
unclear |
no |
|
Lymphatic vessel infiltration (L-status) |
yes |
yes |
yes |
|
Extent of lymphatic vessel infiltration |
yes |
yes |
unclear |
|
Vein invasion (V status) |
yes |
unclear |
no |
|
Resection margins (residual tumor status; R classification) |
yes |
yes |
yes |
|
Grading |
yes |
yes |
yes |
|
Tumor localization in the uterus |
yes |
unclear 1 |
no |
|
Three-dimensional tumor size in cm |
yes |
unclear 2 |
no |
|
Associated endometrial hyperplasia |
no |
no |
no |
|
Invasion pattern |
yes |
unclear 3 |
no 4 |
|
Hormone receptor status |
no |
unclear |
no |
|
L1CAM |
no |
yes / unclear |
unclear |
|
Molecular classification |
complete molecular classification desirable |
yes |
yes |
|
Molecular markers (except POLE, MMR, p53) |
no |
no |
no |
|
Nomograms |
no |
no |
no |
| *The term standard factor describes parameters that are essential for the histopathological report or examination procedures that should be used routinely. 1 Tumor localization in the isthmus uteri may indicate a Lynch association. There may possibly be an increased risk of cervical infiltration based on topographic/anatomic proximity alone, to be assessed sonographically/radiologically. 2 Tumor size probably has prognostic significance in endometrioid EC. Molecular data are not included. 3,4 The MELF pattern is associated with a higher rate of (occult) lymphatic vessel invasion and consecutive higher number of lymph node metastases. |
|||
Evidence tables
4.1.2 EvT 4.4
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Manchanda 2012 |
Prospektive Kohortenstudie LoE 3 |
41 Frauen mit Lynch-Syndrom (aus 69 gescreenten Frauen mit Lynch-Syndrom) im Alter > 30 Jahre: 4 Endometrium-karzinome wurden entdeckt. Drop-out-Rate: n = 6. Medianes Follow-up: 22 Monate.
|
Jährliche ambulante Hysteroskopie und Endometrium-biopsie (= OHES: outpatient hysteroscopy and endometrial sampling). |
Transvaginaler Ultraschall (TVS). |
Endometrium-Screening bei Lynch-Syndrom-Patientinnen: Bewertung der Leistung von OHES verglichen mit transvaginalem Ultraschall allein. |
Bei Lynch-Syndrom-Patientinnen bietet das jährliche Endometrium-Screening per Endometriumbiopsie eine hohe diagnostische Genauigkeit für die Detektion von Endometrium-karzinom/atypischen Endometriumhyper-plasien. Aber: 2 von 4 Endometrium-karzinomen wären durch transvaginalen Ultraschall übersehen worden. Effektschätzer: OHES hatte die gleiche Spezifität wie TVS, aber eine höhere positive Likelihood-Rate und eine niedrigere negative Likelihood-Rate, aber die Konsequenz ist unklar: OEHS versus alleinige TVS: Spezifität 89,9 % versus 84,75 %, Sensitivität 100 % versus 50 %, PPV 40 % versus 18,18 %, NPV 100 % versus 96,15 %, PLR 9,8 versus 3,28 und NLR 0 versus 0,59 (CI siehe Studie). Inzidenz/Jahr: Endometrium-karzinom: 3,57 % (95 % CI: 0,09–18,35) (erwartet 1 %), Polypen ca. 10 %, jegliche endometriale Pathologie ca. 21 %. Cut-off der Endometrium-Dicke: 5 mm. |
Verdacht auf Lead Time Bias; kleines Kollektiv. |
|
Helder-Woolderink 2013
|
Prospektive Kohortenstudie LoE 4 |
75 Frauen über 30 Jahre mit Lynch-Syndrom oder einem Verwandten 1. Grades mit Lynch-Syndrom (aus 98 gescreenten Frauen); 300 Frauenjahre. Screening-Zeitraum I (2003–2007): n = 44: Standard-screening. Screening-Zeitraum II (2008–2012): n = 63: Standard-screening + Pipelle/Hysteros-kopie und Abrasio gemäß neuer niederländischer Leitlinie (2011). |
Transvaginaler Ultraschall und Messung des CA- 125-Serums; ergänzend Pipelle/Hystero-skopie und Abrasio bei beschwerdefreien Patientinnen (gemäß niederländischer Leitlinie 2011). |
Transvaginaler Ultraschall und Messung des CA-125-Serums bei beschwerdefreien Patientinnen. |
Detektion von Endometriumkarzinomen und Endometrium-karzinom-Vorstufen bei Frauen mit Lynch-Syndrom. |
1 Endometrium-karzinom und 5 Hyperplasien in Zeitraum I; kein Endometrium-karzinom und 2 Hyperplasien in Zeitraum II: Pipelle/Hysteroskopie und Abrasio ergänzend zum jährlichen transvaginalen Ultraschall einzusetzen bietet keinen zusätzlichen Nutzen in der Früherkennung des Endometrium-karzinoms und seinen Vorstufen bei Frauen mit Lynch-Syndrom. |
------------------------------ |
4.1.3 EvT 4.6
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Saccardi 2013 |
Langzeit-Beobachtungsstudie (Kohortenstudie mit konsekutivem Einschluss) LoE 3 |
151 (aus 455) Frauen unter Tamoxifen-Einnahme (Mammakarzinom-Therapie), deren Endometrium mittels Hysteroskopie und histologischer Untersuchung überwacht wurde. (Durchschnittsalter der Kohorte: 58,31 ± 10,86 Jahre.)
|
Hysteroskopie; histologische Untersuchungen; transvaginaler Ultraschall. |
Keine. |
1. Vergleich histologische Befunde und Indikation zur Hysteroskopie. 2. Korrelation von Behandlungsdauer, Endometriumdicke und Histologie; Korrelation zwischen Endometrium-dicke und Endometrium-hyperplasie. |
Low-risk-Patientinnen benötigen keine gesonderte Endometriumüberwachung unter Tamoxifeneinnahme. Keine signifikante Korrelation zwischen Tamoxifen-Behandlungsdauer und histologischer Diagnose für Atypie. Detektion atypischer Endometriumhyperplasien: Hysteroskopie: Sensitivität 83,3 %; Spezifität 99 %; PPV 83,3 %; NPV 99 %. Es wurde keine signifikante Korrelation von Endometriumdicke > 5 mm ohne Blutungen und atypischer Endometriumhyper-plasie gefunden. Ultraschall mit einem 5-mm-Cut-off: Sensitivität 100 %; Spezifität 15 %; PPV 4 %; NPV 100 %. Ultraschall mit einem 10-mm-Cut-off: Sensitivität 84 %; Spezifität 69 %; PPV 10 %; NPV 99 %. |
Brustkrebspatientinnen. |
|
Gao 2011 |
Vergleichsstudie LoE 3 |
97 post-menopausale Frauen mit Mammakarzinom unter Tamoxifenein-nahme für ≥ 6 Monate (20 mg pro Tag). |
Gynäkologische Untersuchung; Pap-Test; transvaginaler Ultraschall (TVS) und diagnostische Hysteroskopie.
|
Die anschließenden histologischen Befunde der Pathologen. |
Hysteroskopie und TVS zur diagnostischen Genauigkeit. |
Es wurde kein Endometriumkarzinom gefunden. 53 Frauen (54,6 %) hatten Endometriumpolypen (histopatho-logische Ergebnisse). Positiv unter TVS: 59 Frauen (60,8 %), davon hatten 43 Polypen, 4 Hyperplasien und 12 eine Atrophie. Negativ unter TVS: 30 Frauen (39,2 %), davon hatten 10 Polypen, 3 Hyperplasien und 25 eine Atrophie. Effektschätzer: TVS zeigte eine Spezifität von 63,6 %; eine Sensitivität von 81,8 %; der PPV lag bei 72,9 %; der NPV bei 73,7 %. Diagnostische Hysteroskopie zeigte eine Spezifität von 100 %; eine Sensitivität von 98,1 %; der PPV lag bei 100 %; der NPV bei 97,8 %. Bei Mammakarzinom-Patientinnen unter Tamoxifentherapie ist TVS allein nicht ausreichend, um endometriale Veränderungen zu entdecke (zudem hohe Rate an falsch-positiven Ergebnissen). Daher = TVS + diagnostische Hysteroskopie. |
-- |
|
Bertelli 2000 |
Vergleichsstudie LoE 3–4 |
41 post-menopausale Frauen mit Mammakarzinom unter Tamoxifeneinnahme (20 mg pro Tag), welche asymptomatische Endometrium-veränderungen hatten: Diese zeigten sich unter transvaginalem Ultraschall (TVS). |
TVS + Hydrosono-graphie. |
Die anschließenden histologischen Befunde der Pathologen. |
Hydrosonographie zur diagnostischen Genauigkeit, um die Anzahl unnötiger Biopsien zu senken. Cut-off der endometrialen Dicke: 8 mm. |
Kein Endometriumkarzinom; 3 einfache Hyperplasien. Nur 21,9 % (n = 9) der Patientinnen hatten normale Hydrosono-graphie-Ergebnisse und konnten die Biopsie umgehen. Positive Befunde bei 65,8 % (n = 27), nicht erfolgreich bei 12,2 % (n = 5), gutartige Polypen bei 36,6 % (n = 15) und Atrophie bei 34,1 % (n = 14). Mammakarzinom-Patientinnen mit Tamoxifen-assoziierten asymptomatischen Endometrium-veränderungen haben kaum Vorteil von einer Hydrosonographie. |
Kleines Patientinnenkollektiv. |
|
Gerber 2000 |
Prospektive Langzeit-/ LoE 3 |
401 postmeno-pausale Frauen mit Mammakarzinom und intaktem Uterus nach Mammakarzinom-OP. Screeningzeitraum: etwa 24 Monate. Interventionsarm: Vor Tamoxifen-einnahme n = 247; Drop-out n = 33. Kontrollarm: n = 98 ohne Tamoxifen-einnahme; Drop-out n = 23.
|
Tamoxifen: 20–30 mg pro Tag für ≥ 2 Jahre.
Transvaginaler Ultraschall (TVS). |
Kein Tamoxifen. Transvaginaler Ultraschall (TVS). |
Diagnostische Genauigkeit von TVS. |
Die durchschnittliche Endometriumdicke vor Tamoxifeneinnahme betrug 3,5 ± 1,1 mm. Effektschätzer: Nach 3 Jahren unter Tamoxifen war diese signifikant erhöht (im Vergleich zu Kontrollen) = 9,2 ± 5,1 mm (p < 0,0001). 28 Patientinnen zeigten eine Atrophie, Polypen fanden sich bei neun Patientinnen, eine Hyperplasie bei vier Patientinnen und ein Endometriumkarzinom bei einer Patientin. Es kam zu vier Perforations-verletzungen Bei Patientinnen unter Tamoxifeneinnhame erbrachte der TVS eine hohe Rate an falsch-positiven Ergebnissen, auch mit einem Cut-off der Endometriumdicke von 10 mm. |
------------------------------ |
|
Fung-Kee-Fung 2003 |
Prospektive Längsschnittstudie |
304 Frauen mit Mammakarzinom unter Tamoxifenein-nahme (durchschnittlicher Einnahmezeitraum: 48,2 Monate). 72 % der Frauen waren postmeno-pausal. |
Tamoxifen + TVS mit Farbdoppler. 1.061 Ultraschall-untersuchungen über einen Zeitraum von 6 Jahren wurden durchgeführt. |
Die anschließenden histologischen Befunde der Pathologen. |
Diagnostische Genauigkeit von TVS + Farbdoppler. |
32 % der Ultraschallergebnisse zeigten singnifikante uterine Veränderungen, davon waren 80 % gutartige Polypen. Effektschätzer: Bei einem Cut-off der Endometriumdicke von mehr als 9 mm lag die Sensitivität des transvaginalen Ultraschalls + Farbdoppler bei 63,3 %; die Spezifität bei 60,4 %; der PPV bei 43,3 % und der NPV bei 77,5 %. OR: 3,9 (95 % CI 1,26–12,65), p = 0,018. Bei einem Cut-off von 9 mm lag der PPV nur bei 1,4 %. Routinescreening mit TVS ist nicht sinnvoll bei asymptomatischen Frauen unter Tamoxifeneinahme. |
----------------------------- |
Fleming 2018
| Fleming, C. A. et al. Meta-analysis of the cumulative risk of endometrial malignancy and systematic review of endometrial surveillance in extended tamoxifen therapy. Br J Surg. 105. 1098-1106. 2018 | ||||
|---|---|---|---|---|
| Evidence level/Study Types | P - I - C | Outcomes/Results | Literature References | |
| Evidence level: 2 Study type: Systematic review and meta-analysis (4 studies) To identify the risk of endometrial malignancy in the setting of extended tamoxifen therapy. Databases: Cochrane Library, PubMed and MEDLINE. Search period: Inception March 2016. Inclusion Criteria: Inclusion criteria comprised English-language studies, and those that reported outcomes related to endometrial abnormalities and pathologically confirmed malignancy. Publications reporting on the same series of patients were identified and only the most recent data were included. Exclusion Criteria: Studies describing ‘one-off’ endometrial screening in a cross-sectional design were excluded. Studies that did not report on endometrial malignancy rates were excluded. |
Population: Unclear definition: likely patients receiving tamoxifen. Intervention: Exposure to extended tamoxifen treatment. Comparison: Exposure to standard tamoxifen treatment. |
Primary: Breast cancer local recurrence, Disease specific mortality, overall mortality, endometrial malignancy incidence. Secondary: - Results: Study overview: 4 RCTs reported on endometrial risk in extended tamoxifen therapy.In total, these trials included 21 361 patients, of whom 7652 (35⋅8 per cent) received extended therapy. All studies scored highly on quality assessment. Results: The cumulative risk of endometrial malignancy increased twofold from 1⋅5 to 3⋅2 per cent with extended therapy compared with the standard 5 years of tamoxifen (RR 2⋅29, 95 percent c.i. 1⋅60 to 3⋅28; P <0⋅001). 4 studies analysed the value of endometrial screening in 5-year cohorts. Endometrial cancer rates of up to 2 per cent were reported, which is higher than rates in the large extended tamoxifen trials. Author's Conclusion: "Extended adjuvant tamoxifen is associated with an increase in endometrial cancer. No clear benefit has been shown for routine endometrial surveillance in asymptomatic patients on tamoxifen therapy." |
4 studies included: ATLAS, aTTom, Scottish, NSABP B-14. |
|
| Methodical Notes | ||||
| Funding Sources: not reported. COI: The authors declare no conflict of interest. Study Quality: Themethodological quality of included RCTs was assessed using the Cochrane Collaboration’s tool for assessing RCT risk of bias. The Newcastle–Ottawa quality assessment scale for non-randomized cohort studies was applied to determine the quality of each eligible study objectively. "All studies scored highly on quality assessment." but the scores are not reported. Heterogeneity: The degree of heterogeneity between studies was expressed as the I2 statistic. An I2 value of 0 per cent corresponds to no heterogeneity, 25–49 per cent represents low heterogeneity, 50–74 per cent moderate heterogeneity and 75 per cent or more indicates high heterogeneity between included studies. Publication Bias: Not investigated, but not feasible for the number of included studies. Notes: Oxofrd level of evidence: 1 Systematic review and meta-analysis of randomized trials. Downgrade to evidence level 2 Unclear definition of study population. High heterogeneity in some analysis but not for the outcome of interest (Combined analysis of endometrial risk was subject to low to moderate heterogeneity (I2 =41 per cent)). All scores of study quality were high, but are not reported in the article. |
||||
4.2 EvT 4.7
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Pennant 2017 |
Systematischer Literatur-Review (65 prospektive oder retrospektive Studien; Studien, die separate Daten zur Menorrhagie erheben: n = 24. Studien, die separate Daten zur intermenstruellen Blutung erheben: n = 20.) Systematische Übersichtsarbeit von Erhebungen, die auf die lokalen Umstände übertragen werden können. LoE 2 |
Prämenopausale Frauen mit abnormer uteriner Blutung. Das Alter lag in den meisten Studien durchschnittl. zwischen 40 und 50 Jahren. Summarische Angaben nur in den Einzelstudien. |
Systematische Literatursuche in PubMed, Embase und Cochrane, jeweils von Gründungs-beginn der betreffenden Datenbank bis August 2015. |
Keine. |
Endometriumkarzinom oder atypische Hyperplasie. |
Prämenopausale Frauen mit abnormer uteriner Blutung benötigen selten eine Endometriumbiopsie. Effektschätzer: Risiko für Endometrium-karzinom lag bei 0,33 % (95 % CI: 0,23–0,48 %; n = 29.059; 97 Fälle). Risiko für Endometriumkarzinom oder atypische Hyperplasie lag bei 1,3 % (95 % CI: 0,96–1,80; n = 15.772; 207 Fälle). Geringeres Risiko bei Frauen mit Menorrhagie (0,11 %; 95 % CI: 0,04–0,32 %; n = 8.352; 9 Fälle). Risiko für Endometrium-karzinome oder atypische Hyperplasien bei prämenopausalen Frauen ist gering. Tritt hier abnorme uterine Blutung auf, sollte diese zuerst medikamentös behandelt werden. Greift das nicht oder kommen inter-menstruelle Blutungen und/oder älteres Alter als Risikofaktoren hinzu, ist dies ein Indikator für weiteres Vorgehen. |
Methodische Limitation: Die hier analysierten Studien haben hauptsächlich Frauen eingeschlossen, die sich bereits in der weiterführenden Behandlung (Endometrium-biopsie, Dilatation, Kürettage) befanden. Eingeschlossene Studien nur online zugänglich unter: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5297977/. Keine Angaben zu Publication Bias. |
4.2 EvT 4.9
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Huang 2007 |
Retrospektive monozentrische Kohortenstudie LoE 3 |
360 Endometrium-karzinom-Fälle insgesamt (Drop-out-Rate: n = 14). Pipelle: n = 235. Kürettage: n = 93. |
Präoperative Abrasio mittels Pipelle und Kürettage; Gefrierschnitt (n = 278). Vergleich Pipelle versus Kürettage. |
Die anschließenden histologischen Befunde der Pathologen (nach Hysterektomie). |
Diagnose von High-grade-Endometriumkarzinomen. |
Präoperative Endometriumbiopsie eignet sich zur Diagnostik von High-grade-Endometrium-karzinomen, inklusive nicht-endometrioiden Tumoren. Effektschätzer: Sensitivität für Low-grade-Endometrium-karzinome 93,8 % und für High-grade-Endometrium-karzinome 99,2 % bzw. 100 %. Kürettage sensitiver als Pipelle (96,4 % versus 97,8 %). Endometriumbiopsie und Gefrierschnitt kommen zu vergleichbaren Ergebnissen, gemessen an den finalen histopathologischen Befunden (p = 0,39). |
Präoperative und postoperative Einteilung korreliert. |
|
Leitao 2008 |
Retrospektive monozentrische Kohortenstudie (konsekutiver Einschluss) LoE 3 |
490 Fälle von Endometrium-karzinom FIGO G1 („FIGO grade 1 endometrial adenocarcinoma“) von 1.423 überprüften Fällen (konsekutiv). |
Präoperative Abrasio. |
Die anschließenden histologischen Befunde der Pathologen (Hysterektomie). |
Genauigkeit der präoperativen Abrasio als Diagnosewerkzeug bei Endometriumkarzinom FIGO G1 und der intraoperativen Myometriuminvasion |
Die präoperative Diagnose korreliert in 85 % der Fälle. Allen Patientinnen, bei denen es möglich ist, soll ein operatives Staging angeboten werden, auch mit FIGO I. Effektschätzer: Bei 71 von 482 zu bewertenden Fällen lag der FIGO-Grad höher (14,7 %). In 6 Fällen wurden seröse oder klarzellige Histologien diagnostiziert (1,2 %). High-risk-Karzinome wurden in 86 Fällen gefunden (18,5 %). Wurde Gefrierschnitt von Myometrium-invasion durchgeführt, war dies mit der Diagnose High-risk-Karzinom (p < 0, 001) assoziiert. 9 Fälle von Lymphknoten-metastasen (4,4 %) bei 205 Patientinnen mit Lymphknoten-bewertung. |
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|
Clark 2002 |
Systematischer Review und Metaanalyse von 11 Studien LoE 3 |
Frauen mit abnormaler uteriner Blutung. Genaue Angaben zu Interventions-/
|
Ambulante Endometriumbiopsie.
|
Dilatation und Kürettage; Hysterektomie; Biopsie/Hyster-ektomie.
|
1. Genauigkeit von ambulanter Endometriumbiopsie zur Detektion von Endometriumkarzinomen. 2. Technische Schwächen/Fehlerquellen und Rate an mangelhaften Proben. |
Ambulante Endometriumbiopsie zeigt eine hohe diagnostische Genauigkeit, wenn eine zu bewertende Probe gewonnen werden kann. Positive Testergebnisse grenzen die Wahrscheinlichkeit für ein Vorliegen eines Endometriumkarzinoms eher ein, als negative Testergebnisse diese ausschließen. Effektschätzer: Gepoolte LR für die Detektion von Endometrium-karzinom: 66,48 (95 % CI: 30,04–147,13); für ein negatives Testergebnis ergab sich eine gepoolte LR von 0,14 (95 % CI: 0,08–0,27).
|
Posttest zur Wahrscheinlichkeit von Endometriumkarzinom: für ein positives Testergebnis 81,7 % (95 % CI: 59,7 %–92,9 %), für ein negatives Testergebnis 0,9 % (95 % CI: 0,4 %–2,4 %). In 9 von 11 Studien wurden die verblindeten Ergebnisse nicht dargelegt; teilweise arbiträrer Einschluss der Patienten (zu 64 %), was auf methodische Mängel der eingeschlossenen Studien schließen lässt. Hauptanteil der Studien ist methodisch LoE 3 und schlechter; methodische Details nicht erwähnt, etwa zur Failure-Rate: 7–22 %, die besagen würde, dass jede 5. bis 12. Endo-metriumbiopsie mangelhaft war. Angaben zu Publication Bias vorhanden. |
4.2 EvT 4.10
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Al-Azemi 2004 |
Prospektive Kohortenstudie (Vergleichsstudie) LoE 3 |
80 postmenopausale, asymptomatische Frauen mit Mammakarzinom, bei allen wurden die Endometriumbiopsien per Pipelle durchgeführt. Interventionsarm: Kontrollarm: n = 30. |
Tamoxifengabe von 20 mg/täglich über einen Zeitraum von 5 –60 Mon. bei östrogen-rezeptorpositivem Status. |
Keine Tamoxifengabe (östrogenrezeptor-negativer Status). |
Einfluss der demografischen Eigenschaften; der Risikofaktoren für Endometriumkarzinom; der histologischen Befunde und der Dauer der Tamoxifengabe. |
Signifikant größere Prävalenz von Endometriumver-änderungen in der Interventionsgruppe: 76 versus 33 %, p < 0,001. Alle Veränderungen waren unterteilt worden in proliferative: 54 versus 26,7 %, p = 0,02 und hyperplastische: 22 versus 6,6 %, p = nicht signifikant. Der Einfluss ist zeitabhängig. |
Brustkrebspatientinnen; kleines Kollektiv. |
4.3 EvT 4.12
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Timmermans 2010 |
Metaanalyse von 3 früheren Metaanalysen (13 randomisiert-kontrollierte Studien) zur diagnostischen Genauigkeit LoE 1 |
2.896 Frauen mit postmenopausaler Blutung, davon 259 Endometrium-karzinom-Fälle. |
Kombinierte metaanalytische Berechnungen (ROC4 und AUC5) und systematische Literaturrecherche in MEDLINE von Januar 2000 bis Dezember 2006 (s. Appendix 1). Intervention: Daten per transvaginalem Ultraschall gewonnen. |
Metaanalyse von Smith-Bindman et al. (1998).
In den randomisiert-kontrollierten Studien: Kürettage und Dilatation. |
Diagnostische Genauigkeit der endometrialen Dicke zur Detektion von Endometriumkarzinomen. |
Frühere Metaanalysen haben die Dicke des Endometriums zur diagnostischen Genauigkeit evtl. überbewertet: Smith-Bindman et al. : Cut-off von 5 mm (n = 35). Gupta et al. : Cut-off von ≤ 5 mm (n = 57). Tabor et al. : Cut-off n.a., da dieser als nicht sinnvoll zur diagnostischen Genauigkeit angesehen wird, aufgrund zu hoher falsch-positiver Rate (n = 48). Timmermans et al. geben hier nun einen Cut-off an von 3 mm endometrialer Dicke bei PMB3, um Endometrium-karzinome auszuschließen. Effektschätzer: (fußend auf individuellen Patientinnen-Daten): ROC4 zur endometrialen Dicke für die Detektion von Endometrium-karzinom pro Studie ergab einen AUC5-Wert von 0,68 und 0,93 (p < 0,01). Gepoolte Daten: ROC4-Kurve mit einem AUC von 0,82 (95 % CI:, 0,80– 0,85). |
Random-effects-Modell wurde berechnet (p < 0,01). Keine Angaben zu Publication Bias. |
4.4.2.3 EvT 4.15
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Savelli 2008 |
Prospektive Kohortenstudie LoE 3 |
74 (aus 88) Frauen mit Endometrium-karzinom vor Staging-Operation (Hysterektomie; Adnexexstirpation und pelvine Lymph-adenektomie). Staging gemäß FIGO 1988. |
Transvaginaler Ultraschall (TVU) versus Magnetresonanz-tomografie (MRT). |
Histologische Diagnose als Goldstandard. |
Detektion der myometranen Invasion. |
Wenn der transvaginale Ultraschall von erfahrenen Untersuchern durchgeführt wird, zeigt er eine gute Genauigkeit im lokalen Staging des Endometrium-karzinoms. MRT dagegen ist mit hohen Kosten verbunden und sollte daher nur bei denjenigen Patientinnen angewandt werden, bei denen mit TVU keine brauchbaren Bildergebnisse erreicht werden konnten. Effektschätzer: Beide Verfahren zeigen eine gleichwertige Effektivität in der diagnostischen Testgüte. TVU: Sensitivität: 84 %, Spezifität: 83 %, PPV: 79 %, NPV: 88 %, diagnostische Gesamtgenauigkeit: 84 %. MRT: Sensitivität: 84 %, Spezifität: 81 %, PPV: 77 %, NPV: 87 %, diagnostische Genauigkeit: 82 %. |
------------------------------ |
4.4.3 EvT 4.17
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Savelli 2008 |
Prospektive Kohortenstudie LoE 3 |
74 (aus 88) Frauen mit Endometrium-karzinom vor Staging-Operation (Hysterektomie; Adnexexstirpation und pelvine Lymph-adenektomie). Staging gemäß FIGO 1988. |
Transvaginaler Ultraschall (TVU) versus Magnetresonanz-tomografie (MRT). |
Histologische Diagnose als Goldstandard. |
Detektion der myometranen Invasion. |
Wenn der transvaginale Ultraschall von erfahrenen Untersuchern durchgeführt wird, zeigt er eine gute Genauigkeit im lokalen Staging des Endometrium-karzinoms. MRT dagegen ist mit hohen Kosten verbunden und sollte daher nur bei denjenigen Patientinnen angewandt werden, bei denen mit TVU keine brauchbaren Bildergebnisse erreicht werden konnten. Effektschätzer: Beide Verfahren zeigen eine gleichwertige Effektivität in der diagnostischen Testgüte. TVU: Sensitivität: 84 %, Spezifität: 83 %, PPV: 79 %, NPV: 88 %, diagnostische Gesamtgenauigkeit: 84 %. MRT: Sensitivität: 84 %, Spezifität: 81 %, PPV: 77 %, NPV: 87 %, diagnostische Genauigkeit: 82 %. |
------------------------------ |
4.4.3 EvT 4.18
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Selman 2008 |
Systematischer Review von Tests zur diagnostischen Genauigkeit (MRT = 4 Studien; CT = 5 Studien; Sentinel-Lymphknoten-biopsie = 8 Studien). LoE 3 |
Frauen mit einem primären Endometrium-karzinom. Summarische Angaben: siehe Effektschätzer. |
MRT; CT; Sentinel-Lymphknoten-biopsie. |
Die anschließenden histologischen Befunde (der Lymphknoten) der Pathologen. |
Lymphknotenmetastasen: ja/nein. |
Das MRT ist die genaueste diagnostische Methode, um den Lymphknotenstatus der Patientin mit einem frühen Endometrium-karzinom vorherzusagen. Effektschätzer: MRT: 4 Studien; 211 Patientinnen; Sensitivität 72 % (95 % CI: 55–58 %); Spezifität 97 % (95 % CI: 93–99 %). CT: 5 Studien; 279 Patientinnen; Sensitivität 45 % (95 % CI: 28–64 %); Spezifität 88 % (95 % CI: 78–94 %). Sentinel-Lymphknoten-biopsie: 8 Studien; 116 Patientinnen; Sensitivität 79 % (95 % CI: 58–91 %); Spezifität 96 % (95 % CI: 89–99 %). |
Die methodische Qualität der Originalstudien war heterogen (nach QUADAS2). Keine Angaben zu Verblindung. Random-effects-Modell wurde berechnet. Keine Angaben zu Publication Bias. |
|
Chang 2012 |
Systematischer Review und Metaanalyse von 7 Studien LoE 3 |
243 Frauen insgesamt. Genaue Angaben zu Interventions-/ |
Bildgebende Verfahren: FDG-PET oder PET-CT. |
Die anschließenden histologischen Befunde der Pathologen. |
Diagnostik von Lymphknotenmetastasen. |
Hoher positiver Wert der Likelihood Ratio (LR) zeigt, dass ein positives FDG-PET-oder PET-CT-Ergebnis pelvine und/oder paraaortale Lymphknoten-metastasen bei Patientinnen mit unbehandeltem Endometrium-karzinom detektieren kann. Dies könnte bei der Patientenauswahl zur Lymphadenek-tomie unterstützen. Effektschätzer: Sensitivität: 63, 0 % (95 % CI: 48,7–75,7 %); Spezifität 94,7 % (95 % CI: 90,4–97,4 %); positive LR 10,5 (95 % CI: 5,6–19,4); negative LR 0,40 (95 % CI: 0,28–0,56). |
Moderate Qualität der eingeschlos-senen Studien (nach QUADAS2). Für die Metaanalyse wurde kein Random-effects-Modell verwendet und ein möglicher Publication Bias wurde nicht untersucht. |
|
Kakhki 2013 |
Systematischer Review von 16 Studien (LoE 2: 5 Studien; LoE 3: 9 Studien; LoE 4: 4 Studien) und Metaanalyse LoE 3 |
Genaue Angaben zu Interventions-/ Kontrollarmen: sind in den Einzelstudien zu finden. |
Bildgebende Verfahren: PET oder PET-CT. |
Die anschließenden histologischen Befunde der Pathologen. |
Diagnostik des Endometriumkarzinoms und dessen Primärläsionen: Primärläsion: ja/nein. Lymphknotenmetastasen: ja/nein. Fernmetastasen: ja/nein.
|
Für das lokoregionäre Staging ist die Sensitivität begrenzt und die Spezifität hoch. Für die Beurteilung von Fernmetastasen ist PET bzw. PET-CT bei hoher Sensitivität und Spezifität gut geeignet. Effektschätzer: Primärlesion (PET oder PET-CT): 16 Studien; 807 Patientinnen; Sensitivität 81,8 % (95 % CI: 77,9–85,3 %); Spezifität 89,8 % (95 % CI: 79,2–96,2 %). Lymphknoten-Metastasen (PET oder PET-CT): 16 Studien; 807 Patientinnen; Sensitivität 72,3 % (95 % CI: 63,8–79,8 %); Spezifität 92,9 % (95 % CI: 90,6–94,8 %). Lymphknoten-Metastasen (PET-CT): 8 Studien; 332 Patientinnen; Sensitivität 68,7 % (95 % CI: 57,7–78,2 %); Spezifität 92,7 % (95 % CI: 90,0–94,9 %). Fernmetastasen (PET oder PET-CT): 16 Studien; 807 Patientinnen; Sensitivität 95,7 % (95 % CI: 85,5–99,5 %); Spezifität 95,4 % (95 % CI: 92,7–97,3 %). Partiell verblindet. Heterogenität: Sensivität: 0–85 % Spezifität: 31–57 %. |
Metaananalyse nach der PRISMA-Guideline. Qualität ist insgesamt gut, es sind jedoch 13 Studien mit einem LoE zwischen 3 und 4 eingeschlossen worden. Ein möglicher Publication Bias ist zu berücksichtigen. Random-effects-Modell: DerSimonian/Laird-Methode.
|
|
Antonsen 2012 |
Retrospektive Kohortenstudie (Datenbankanalyse aller Fälle mit AEH in Dänemark = Vollerhebung) LoE 1 |
778 Frauen mit präoperativer Diagnose atypische Endometrium-hyperplasie (AEH). |
Präoperative endometriale Histologie, gewonnen per Pipelle, Dilatation und Kürettage oder Hysteroskopie: bewertet und eingestuft (Staging) von einem lokalen Pathologen. |
Die postoperative Diagnose wurde aufgrund der histologischen Befunde der Hysterektomien, durchgeführt von den Pathologen verschiedener Kliniken, gestellt.
|
1. Outcome: Übereinstimmung prä- und postoperative Diagnose atypische endometriale Hyperplasie. 2. Outcome: Korrelation der o.g. Endpunkte mit Alter, BMI und Menopause. |
In 59 % der Fälle liegt bei präoperativer Diagnose atypische endometriale Hyperplasie ein invasives Endometrium-karzinom vor. 60 % der Frauen mit Diagnose atypische endometriale Hyperplasie hatten ein Endometrium-karzinom, 20 % davon sogar FIGO IB; da bei IB die Lymphadenek-tomie erfolgen sollte, ist die Therapie besser in onkologischen Zentren aufgehoben. Effektschätzer: Krebs korreliert signifikant mit Alter (p < 0,0001) und Menopause (p < 0,001). 80 % der postmenopausalen Frauen hatten ein höheres postoperatives Krebsrisiko, verglichen mit der prämenopausalen Gruppe (OR 2,8). Kein signifikanter Unterschied bestand in Korrelation zu BMI (p = 0,25). |
Die Aussage „besser in Zentren aufgehoben“ ist nicht evidenz-basiert. |
4.4.5 EvT 4.20
|
Referenz |
Studientyp/ |
Untersuchte Population |
Intervention |
Kontrolle |
Untersuchte Endpunkte |
Hauptergebnisse |
Methodische Bemerkungen |
|
Kakhki 2013 |
Systematischer Review von 16 Studien (LoE 2: 5 Studien; LoE 3: 9 Studien; LoE 4: 4 Studien) und Metaanalyse LoE 3 |
Genaue Angaben zu Interventions-/ Kontrollarmen: sind in den Einzelstudien zu finden. |
Bildgebende Verfahren: PET oder PET-CT. |
Die anschließenden histologischen Befunde der Pathologen. |
Diagnostik des Endometriumkarzinoms und dessen Primärläsionen: Primärläsion: ja/nein. Lymphknotenmetastasen: ja/nein. Fernmetastasen: ja/nein.
|
Für das lokoregionäre Staging ist die Sensitivität begrenzt und die Spezifität hoch. Für die Beurteilung von Fernmetastasen ist PET bzw. PET-CT bei hoher Sensitivität und Spezifität gut geeignet. Effektschätzer: Primärlesion (PET oder PET-CT): 16 Studien; 807 Patientinnen; Sensitivität 81,8 % (95 % CI: 77,9–85,3 %); Spezifität 89,8 % (95 % CI: 79,2–96,2 %). Lymphknoten-Metastasen (PET oder PET-CT): 16 Studien; 807 Patientinnen; Sensitivität 72,3 % (95 % CI: 63,8–79,8 %); Spezifität 92,9 % (95 % CI: 90,6–94,8 %). Lymphknoten-Metastasen (PET-CT): 8 Studien; 332 Patientinnen; Sensitivität 68,7 % (95 % CI: 57,7–78,2 %); Spezifität 92,7 % (95 % CI: 90,0–94,9 %). Fernmetastasen (PET oder PET-CT): 16 Studien; 807 Patientinnen; Sensitivität 95,7 % (95 % CI: 85,5–99,5 %); Spezifität 95,4 % (95 % CI: 92,7–97,3 %). Partiell verblindet. Heterogenität: Sensivität: 0–85 % Spezifität: 31–57 %. |
Metaananalyse nach der PRISMA-Guideline. Qualität ist insgesamt gut, es sind jedoch 13 Studien mit einem LoE zwischen 3 und 4 eingeschlossen worden. Ein möglicher Publication Bias ist zu berücksichtigen. Random-effects-Modell: DerSimonian/Laird-Methode.
|
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