Definition
Endometrial cancer is the most common malignancy of the female genital tract. The endometrium is the mucous membrane lining the uterine cavity, from which this carcinoma originates. It predominantly affects postmenopausal women, with peak incidence between 50 and 70 years of age, and is generally considered an estrogen-dependent neoplasm.
It is a relatively common disease: among all female malignancies it ranks fourth in incidence and affects approximately 6% of women over their lifetime. In 80% of cases the tumor has an endometrioid histotype, the form generally associated with a more favorable prognosis.
A condition that may precede disease development is atypical endometrial hyperplasia, characterized by abnormal proliferation of the uterine mucosal cells. In approximately 30% of cases this alteration may progress to endometrial carcinoma.
Risk Factors
The main risk factors include advanced age, nulliparity, early menarche, and late menopause — conditions that result in prolonged endometrial exposure to estrogen. Other recognized factors are obesity, genetic predisposition, and the use of estrogen-only hormone replacement therapy.
Estrogens exert many beneficial effects on the body; however, when administered without a progestogen, they can increase the risk of endometrial proliferation. Current hormone replacement therapies are therefore generally combined estrogen-progestogen formulations, as progesterone exerts a protective effect on the endometrium.
An additional risk factor is the use of tamoxifen, a drug employed in the hormonal treatment of breast cancer. Tamoxifen has a pro-estrogenic effect on the endometrium, which is why patients taking this medication require careful periodic gynecologic monitoring.
Symptoms
The most common symptom is abnormal vaginal bleeding. In postmenopausal women it presents as bleeding that should not occur after the definitive cessation of menstrual cycles. In premenopausal women it may present as intermenstrual bleeding or heavier-than-normal menstrual flow.
Approximately 1–14% of women with postmenopausal vaginal bleeding receive a diagnosis of endometrial carcinoma. For this reason, any bleeding after menopause — even if slight, or pink, red, or brown in color — requires prompt gynecologic evaluation.
Warning sign: any vaginal bleeding after menopause, even minimal, must be evaluated by a specialist. Early diagnosis is the most important favorable prognostic factor.
Diagnosis
The diagnostic workup begins with a gynecologic examination and thorough physical assessment. The physician then performs a transvaginal ultrasound, which allows evaluation of endometrial thickness and identification of any abnormalities within the uterine cavity.
If the ultrasound reveals suspicious findings, the patient undergoes an endometrial biopsy, generally performed by hysteroscopy — a minimally invasive procedure that enables direct visualization of the uterine cavity and targeted tissue sampling.
If the biopsy confirms a malignant lesion, blood tests, magnetic resonance imaging (MRI), or computed tomography (CT) may be requested. Together with intraoperative findings, these allow definition of the FIGO staging of the disease, classified from stage I through stage IVB.
Treatment
The standard treatment is primarily surgical and generally consists of total hysterectomy with bilateral salpingo-oophorectomy — removal of the uterus, fallopian tubes, and ovaries. Depending on the stage and pathologic risk factors, adjuvant therapy may be indicated, which can include radiotherapy and, in some cases, chemotherapy or systemic treatments.
The NCCN Guidelines for Uterine Neoplasms recommend molecular classification of all endometrial carcinomas, regardless of histotype, to complement morphologic assessment and guide treatment decisions. This recommendation is no longer optional: molecular profiling is an integral part of the standard diagnostic workup at international referral centers.
Origin and Basis of the Classification
The molecular classification derives from the 2013 TCGA project, made clinically applicable through the surrogate algorithms ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer) and TransPORTEC, accessible in any laboratory with IHC and basic molecular biology capabilities.
Molecular Diagnostic Algorithm — NCCN v2.2026
or MSI testing
or MSI-H
aberrant
mutated
Adapted from: NCCN Guidelines® Uterine Neoplasms v2.2026, ENDO-A-3, Figure 1. Hierarchical classification: when multiple alterations co-occur, the subgroup with the best prognosis prevails.
The Four Molecular Subgroups
|
POLE-mutated
Excellent prognosis
|
Disease-specific mortality near zero in localized tumors, regardless of grade and stage. Ideal candidate for de-escalation or omission of adjuvant therapy. |
|
dMMR/MSI-H
Intermediate prognosis
|
Mismatch repair deficiency / microsatellite instability-high. Very high immunogenicity with favorable response to anti-PD-1 immunotherapy. Frequently associated with Lynch syndrome. |
|
NSMP
Intermediate prognosis
|
No specific molecular profile (p53 wild-type, MMR-proficient, POLE non-mutated). Prognosis strongly dependent on stage and grade. Heterogeneous residual group requiring integration with traditional clinical factors. |
|
p53 aberrant
Unfavorable prognosis
|
Approximately 20% of cases but responsible for 50–70% of disease-specific mortality. Includes most serous and G3 tumors, as well as high-risk endometrioid carcinomas with TP53 mutation. |
The diagnostic algorithm follows a validated hierarchical order: POLE sequencing → IHC for MMR or MSI testing → IHC for p53. Cases with multiple molecular alterations are classified into the subgroup with the best prognosis.
Beyond Traditional Histologic Classification
The classical histologic classification (type I vs type II) shows significant interobserver variability, particularly in distinguishing endometrioid G3 carcinoma from serous carcinoma. Molecular classification ensures markedly superior reproducibility among pathologists, laboratories, and between biopsy specimen and definitive surgical specimen.
Concrete Therapeutic Implications
| De-escalation (POLE-mutated) | Possible omission of adjuvant radiotherapy and chemotherapy without increased risk of recurrence, regardless of morphologic stage and grade (PORTEC-4a data). |
| Immunotherapy (dMMR/MSI-H) | Pembrolizumab and dostarlimab FDA/EMA-approved for advanced/recurrent dMMR disease. Pembrolizumab also approved in combination with chemotherapy as first-line treatment. |
| Pembrolizumab + lenvatinib (pMMR/MSS) | For NSMP and p53 aberrant MSS tumors in advanced or recurrent disease — MSI-agnostic combination. |
| Trastuzumab (p53 aberrant HER2+) | In combination with chemotherapy — benefit demonstrated in the GOG-3031/ENGOT-en9 (AdvanTHER) trial. |
| Chemoradiation (p53 aberrant) | The 10-year analysis of the PORTEC-3 trial demonstrated that the benefit of chemoradiation versus radiotherapy alone is concentrated almost exclusively in the p53 aberrant subgroup. |
Integration into International Guidelines
The NCCN also recommends: HER2 testing for all p53 aberrant carcinomas; ER/PR testing in stages III–IV; consideration of testing for NTRK, RET fusions and TMB in metastatic/recurrent disease. Since 2020 the WHO has incorporated the molecular classification. The 2023 FIGO staging and the ESGO/ESTRO/ESP 2025 guidelines incorporate the molecular data as a mandatory variable in risk stratification.
NCCN Uterine Neoplasms v2.2026 · Crosbie EJ et al. Lancet 2022;399:1412-28 · Post CCB et al. Lancet Oncol 2025 (PORTEC-3) · van den Heerik ASVM et al. Lancet Oncol 2026 (PORTEC-4a) · Lu KH, Broaddus RR. N Engl J Med 2020;383:2053-64
Surgery is now performed using minimally invasive techniques — laparoscopy or Da Vinci robotic surgery — which provide three-dimensional visualization of the operative field, greater surgical precision, reduced complications, and shorter hospital stays.
Prognosis is strongly correlated with the stage of disease at diagnosis. Thanks to the early warning symptom, approximately 90% of patients are diagnosed at stage I, a condition associated with very high cure rates.
SLN Algorithm for Surgical Staging — NCCN v2.2026
Source: NCCN Guidelines® Uterine Neoplasms v2.2026, ENDO-C-5, Figure 4. Reproduced in descriptive form for educational purposes. LND = lymph node dissection; SLN = sentinel lymph node.
The NCCN recommends sentinel lymph node (SLN) mapping as the preferred approach for lymph node assessment in the surgical staging of endometrial carcinoma apparently confined to the uterus. This recommendation reflects converging clinical evidence documenting its superiority over systematic lymphadenectomy in terms of diagnostic accuracy and morbidity profile.
Diagnostic Accuracy — FIRES Trial Data
The FIRES (Fluorescence Imaging for Robotic Endometrial Sentinel lymph node biopsy) trial is the pivotal prospective multicenter study for this indication. Conducted on 385 patients with clinical stage I endometrial carcinoma, it demonstrated:
- Successful mapping rate: 86% (bilateral mapping in approximately 77% of cases)
- Sensitivity of 97.2% (95% CI: 85.0–100) for the detection of lymph node metastases
- Negative predictive value of 99.6% (95% CI: 97.9–100)
- False-negative rate: only 2.8%
The trial concluded that SLN biopsy can safely replace systematic lymphadenectomy in the surgical staging of endometrial carcinoma. These results have been confirmed in large-scale population studies: a SEER database analysis of over 83,000 women documented that SLN use increased from 0.2% in 2005 to 29.7% in 2018, with no negative impact on cancer-specific survival compared with systematic lymphadenectomy, for both endometrioid and non-endometrioid histologies.
Recommended Technique: ICG and Cervical Injection
Indocyanine green (ICG) is the preferred tracer in NCCN guidelines and major international scientific societies due to its superiority over traditional tracers (methylene blue, technetium-99m) in bilateral detection. The validated technique involves cervical injection at the 3 and 9 o'clock positions, with a superficial component (1–3 mm) and an optional deep component (1–2 cm) into the cervical stroma. The most common pelvic SLN location is medial to the external iliac, ventral to the hypogastric, or in the upper obturator region. Robotic surgery with an integrated fluorescence system (e.g., Firefly) enables real-time identification of nodes with ICG uptake, significantly facilitating the procedure compared with traditional laparoscopy.
SLN Algorithm — Key Points for Clinical Practice
Successful SLN mapping depends on rigorous adherence to the algorithm, which includes three fundamental principles:
- Excision of all identified SLNs with pathologic ultrastaging; removal of any macroscopically suspicious node, regardless of tracer uptake.
- In case of failed mapping on a hemipelvis, mandatory side-specific lymph node dissection — this point is essential to maintain the low false-negative rate documented in the trials.
- Para-aortic lymphadenectomy at surgeon's discretion, to be considered in cases of positive pelvic nodes or high-risk tumor characteristics.
Pathologic Ultrastaging and Clinical Significance of Micrometastases
The enhanced pathologic ultrastaging protocol involves serial sectioning with H&E staining on multiple serial sections, with or without immunohistochemistry for cytokeratins (AE1/AE3 or CAM5.2). Compared with standard histologic examination, ultrastaging has been shown to significantly increase the detection of lymph node metastases — particularly micrometastases and isolated tumor cells — which would have remained unidentified and unsampled with systematic lymphadenectomy. Isolated tumor cells (ITC, ≤0.2 mm) are classified as pN0(i+): according to NCCN guidelines they should not upstage patients, but their detection should be considered in multidisciplinary discussion of adjuvant therapy, as data on their prognostic relevance are still evolving. Micrometastases (0.2–2 mm) are classified as pN1(mi) and are considered in staging definition and adjuvant therapy indications.
Applicability to High-Risk Histologies
A relevant clinical debate concerns the applicability of SLN mapping to high-risk histologies (serous carcinoma, clear cell carcinoma, carcinosarcoma, endometrioid G3 carcinoma with deep myometrial invasion). A meta-analysis of 9 prospective studies on 429 patients with high-grade tumors confirmed a sensitivity of 92% (95% CI: 84–96) with a false-negative rate of 8% — comparable to that documented for low-grade endometrioid carcinoma and other tumor sites where SLN biopsy is established practice (breast, vulva). NCCN guidelines indicate that SLN mapping can also be used in these histologies, while recommending individual assessment and rigorous adherence to the SLN algorithm.
Morbidity Reduction — Comparison with Systematic Lymphadenectomy
Traditional systematic pelvic lymphadenectomy was associated with lower-extremity lymphedema in over 30% of patients, along with significantly longer operative times, greater blood loss, and risk of vascular and nerve injury. The SLN strategy substantially reduces these complications while maintaining diagnostic accuracy. Head-to-head comparative studies have documented reductions in operative time, intraoperative blood loss, and hospital stay duration. This morbidity reduction is particularly relevant in the typical endometrial cancer population, which frequently includes elderly, obese patients with cardiovascular and metabolic comorbidities, in whom extensive lymphadenectomy carries significant additional risks.
International Consensus
A systematic comparison of major international guidelines — NCCN, SGO, ESGO, BGCS, JSGO — demonstrated broad consensus (5 of 5) that SLN mapping is an appropriate alternative to pelvic lymphadenectomy for endometrial carcinoma confined to the uterus, with agreement on the superiority of ICG and on the need for complete lymphadenectomy in case of mapping failure. SLN use is expected to increase further with the growing adoption of robotic surgery equipped with integrated fluorescence systems.
Key sources: NCCN Uterine Neoplasms v2.2026 · Rossi EC et al. Lancet Oncol 2017;18:384-92 (FIRES Trial) · Marchocki Z et al. Am J Obstet Gynecol 2021;225:367.e1-39 · Matsuo K et al. Obstet Gynecol 2022;139:809-20 · Dick A et al. Int J Gynaecol Obstet 2023;160:220-25 · Bodurtha Smith AJ et al. Am J Obstet Gynecol 2017;216:459-476.e10 · Glaser GE et al. Curr Opin Obstet Gynecol 2025
Prevention
Currently no specific screening programs exist for endometrial cancer. Prevention is primarily based on reducing modifiable risk factors. Obesity is one of the most significant factors: adipose tissue promotes peripheral estrogen production, increasing the proliferative stimulus on the endometrium.
Maintaining a healthy lifestyle — with weight management and regular physical activity — can help reduce the risk of developing this malignancy. For patients on tamoxifen therapy, periodic gynecologic surveillance is recommended.
Frequently Asked Questions
The most significant clinical sign is postmenopausal vaginal bleeding, present in over 90% of patients with endometrial carcinoma. A meta-analysis of over 40,000 women demonstrated that postmenopausal bleeding is present in 91% of cases of endometrial cancer.
However, among all women presenting with this symptom, only approximately 9% receive a cancer diagnosis, as the cause is benign in most cases (endometrial atrophy, polyps, or hyperplasia). Other symptoms, associated with more advanced disease, may include pelvic pain, abdominal distension, early satiety, and changes in bowel or urinary habits.
Ref.: [1, 2, 3]
Yes. Endometrial cancer can be treated with robotic surgery using the Da Vinci system, which is now one of the most widely used minimally invasive approaches. According to international guidelines, for disease apparently confined to the uterus, the standard of care is minimally invasive surgery, performed either laparoscopically or robotically.
Numerous clinical studies demonstrate that this approach is associated with fewer surgical complications, reduced surgical site infections, less blood loss, and shorter hospital stays, without compromising long-term oncologic outcomes.
Ref.: [4, 9, 10, 11, 12, 13]
Indocyanine green (ICG) is currently the preferred tracer for sentinel lymph node mapping in endometrial cancer. The key advantages include:
- High diagnostic accuracy: sensitivity of 97.2% and negative predictive value of 99.6% in the FIRES trial
- Greater bilateral detection rate compared with traditional tracers
- Reduced surgical morbidity, avoiding complete lymphadenectomy and the risk of lymphedema
- Capability for pathologic ultrastaging with detection of micrometastases or isolated tumor cells
- Identification of atypical lymphatic drainage patterns not captured by standard lymph node dissection
Ref.: [5, 6, 8]
Robotic surgery represents an evolution of traditional laparoscopy. The robotic system provides the surgeon with three-dimensional high-definition vision, articulated instruments with greater freedom of movement, and improved ergonomics. Scientific evidence shows that robotic surgery may be associated with:
- Reduced intraoperative complications
- Lower conversion rate to laparotomy
- Less blood loss
- Reduction of certain postoperative complications such as paralytic ileus
Long-term oncologic outcomes are comparable or potentially superior. Initial costs of robotic technology remain higher than traditional laparoscopy, but cost-effectiveness analyses tend to be favorable in adequate-volume settings.
Ref.: [9, 10, 11, 12, 13, 16]
Robotic surgery generally allows a faster recovery compared with traditional open surgery. Studies report:
- Mean hospital stay of approximately 1.6 days after robotic surgery versus approximately 5 days after open surgery
- Return to normal daily activities in approximately 4 weeks, versus approximately 7 weeks after laparotomy
- Better quality-of-life and patient satisfaction scores
In selected high-volume centers, same-day discharge may be possible.
Ref.: [9, 12, 16, 18, 19, 20]
No. Endometrial thickening does not necessarily indicate the presence of cancer. In postmenopausal women with bleeding, an endometrial thickness ≤4 mm on transvaginal ultrasound has a negative predictive value exceeding 99% for excluding endometrial carcinoma.
In asymptomatic women with incidental endometrial thickening, the most common cause is endometrial polyps or other benign conditions. The risk of malignancy increases when thickness exceeds ≥10 mm and should be assessed in the context of individual risk factors.
Ref.: [21, 22, 23, 24, 25]
The prognosis for early-stage endometrial carcinoma is very favorable. Approximately 70% of patients are diagnosed at stage I, with a 5-year survival rate of approximately 95%. In detail:
- Stage IA, grade 1–2: 5-year survival up to 97%
- Stage I overall: approximately 95%
- Stage II: approximately 70%
- Stage III: approximately 70%
- Stage IV: approximately 19%
Early recognition of the main symptom — postmenopausal bleeding — enables timely diagnosis and high probabilities of definitive cure.
Ref.: [2, 7, 26, 27]
For information on gynecologic examination, symptom assessment, and the initial diagnostic pathway for abnormal bleeding, visit the portal dedicated to clinical gynecology.
iltuoginecologo.it → Clinical Gynecology
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