Endometrial cancer is one of the most common gynecologic malignancies, accounting for about 6% of all cancers in women. Since patients present with symptoms at an early stage, most of them can be diagnosed by endometrial biopsy, and it should be said that most endometrial cancers can be diagnosed and treated at an early stage. Although some studies have reported that cytology of the cervix can be used to screen for endometrial cancer, it is not considered to be a valid and reliable screening method.
Studies have found that long-term, inappropriate estrogen use is often associated with an increased incidence of endometrial cancer, in contrast to the addition of progestin to estrogen use, which can significantly prevent the increased risk of endometrial cancer due to long-term estrogen use. It is well established that postoperative treatment with triamcinolone acetonide in patients with breast cancer can significantly increase the incidence of endometrial cancer, probably due to the estrogenic effect of triamcinolone on the endometrium. Therefore, regular gynecological examinations, especially monitoring of endometrial thickness by vaginal ultrasound, are needed during the treatment with triamcinolone, especially if the patient has abnormal vaginal bleeding.
At present, it is believed that the factors closely related to the prognosis of endometrial cancer include cell differentiation, muscle layer infiltration, lymph node metastasis, lymphovascular space involvement, hormone receptors, etc. However, the growth and the mode of spread are largely dependent on cell differentiation, and they are interrelated. In contrast, poorly differentiated tumors are more likely to have myometrial infiltration, more likely to have lymph node involvement and lymph vascular space involvement, usually with no detectable hormone receptor expression, and more likely to have distant metastases. In an early study, the chance of lymph node metastasis usually does not exceed 5% if the tumor is grade 1 and involves only the endometrium without any evidence of intra-abdominal metastasis; the chance of pelvic lymph node metastasis is 5%-9% if the tumor is grade 2 or 3 with less than 1/2 the depth of myometrial infiltration and no clear evidence of intra-abdominal metastasis. The chance of metastasis in the pelvic lymph nodes is 5-9% and in the para-aortic lymph nodes is 4%; if the cell differentiation is grade 3, with deep myeloid infiltration and with/without intra-abdominal lesions, the chance of metastasis in the pelvic lymph nodes is 20-60% and in the para-aortic lymph nodes is 10-30%. It should also be noted that most of the previous studies were based on univariate analysis, while multifactorial analysis revealed that the most important prognostic factor was cell differentiation.
However, there is insufficient evidence to predict the prognostic impact of patients who present with positive peritoneal cytology without clear evidence of ectopic metastasis, and there is a lack of definitive information on how to treat this condition. However, this condition at least predicts that tumor metastasis has begun.
I. Pathological types of endometrial cancer
The most common pathological type of endometrial cancer is endometrioid carcinoma, which includes ciliated, secretory and papillary endometrial adenocarcinoma, and also includes traditional endometrial carcinoma with squamous epithelial differentiation, i.e. endometrial adenosquamous carcinoma and endometrial adenosquamous carcinoma in the past, which accounts for about 75% to 80% of endometrial carcinoma.
In recent years, with the progress in the field of obstetrics and gynecology pathology and the advancement of examination means, especially due to the deeper understanding, it is gradually found that there are some special types of endometrial carcinoma in addition to the above pathological types, and the clinical biological behaviors of these special types are very different from the traditional endometrial carcinoma, i.e. endometrioid carcinoma, such as the former is well differentiated, has shallow or less myometrial infiltration, is less likely to invade the lymphovascular space, and For example, the former type has good differentiation, shallow or little myometrial infiltration, less likely to invade the lymphovascular space, more progesterone receptor expression, sensitive to hormone and chemotherapy, and easily confined to the uterus, and has a better prognosis; whereas these special types are more poorly differentiated, highly prone to myometrial infiltration, and early lymphatic metastasis, even if the lesions are confined to the uterus only, or even confined within endometrial polyps. This type is highly susceptible to lymphovascular interstitial involvement and has a poor prognosis due to the lack of progesterone receptors and insensitivity to hormones, and is usually referred to as non-endometrioid carcinoma.
Among the specific types of non-endometrioid carcinoma, Uterine Papillary Serous Carcinoma (UPSC) is more common, accounting for about 10% of all endometrial carcinomas. In terms of pathomorphology, it resembles plasmacytoid papillary carcinoma occurring in the ovaries and oviducts, with very pronounced nuclear heterogeneity and a large number of nuclear divisions. The clinical biology is very aggressive, and metastases to the intra-abdominal cavity or more distant sites can occur in 50% to 75% of cases when the lesion is limited to the endometrium or endometrial polyps. In a study of UPSC confined to the endometrium, it was found that 22% had cervical metastases, 5% had tubal metastases, 10% had ovarian surface metastases, and 25% had peritoneal and greater omental metastases. The disease is more likely to recur, with a recurrence rate of 31% to 50% in stage I patients, a mean recurrence time of 38 months, and 46% of recurrence sites in the abdominal cavity. The prognosis of this disease is poor, and the 5-year survival rate of patients with stage I and II disease is reported to be 35% to 50%, while the 5-year survival rate of stage III and IV patients is 0-15%.
In addition, endometrial clear cell carcinoma is the second most common of this particular type, accounting for about 2% to 5% of endometrial carcinoma. The prognosis is significantly worse than endometrioid carcinoma, and even worse than UPSC.
Endometrial squamous epithelial carcinoma is rare and less frequently reported, accounting for nearly 1% of endometrial carcinoma.
II. Staging system of endometrial cancer
The staging system of endometrial cancer promulgated by the International Federation of Gynecology and Obstetrics (FIGO) in 1971 is the clinical staging system, which is based on the results of clinical examination and adjuvant examination, especially the segmental scraping. This staging system is rarely used nowadays. However, it is still applicable for those cases that are not suitable for surgery.
The staging system widely used in China and abroad is the surgical-pathological staging system for endometrial cancer recommended by the Cancer Committee of FIGO in October 1988, as shown in the table below.
Surgical-pathological staging of endometrial cancer
Stage Tumor extent
Stage I
I a (G1,2,3) Lesion confined to the endometrium
I b (G1,2,3) lesion infiltrates <1/2 of the myometrium
I c (G1,2,3) lesion infiltrates >1/2 myometrium
Stage II
IIa (G1,2,3) lesion infiltrates only to the cervical glands
IIb (G1,2,3) lesion infiltrates the interstitial layer of the cervix
Stage III
IIIa (G1,2,3) lesion invades the plasma membrane and/or adnexa and/or has positive abdominal cytology
IIIb (G1,2,3) Vaginal metastasis
IIIc (G1,2,3) Metastasis to the pelvis and/or para-aortic lymph nodes
Stage IV
IVa (G1,2,3) lesion involving the bladder and/or intestinal mucosa
IVb (G1,2,3) Distant metastases including extra-abdominal and/or inguinal lymph nodes
Note: Histopathological grading is based on the following criteria.
G1: non-squamous or non-mulberry solid growth type ≤ 5%.
G2: non-squamous or non-mulberry solid growth type of 6% to 50%.
G3: non-squamous or non-mulberry solid growth type >50%.
The Cancer Committee of FIGO has a few notes on the new staging: 1. Since endometrial cancer is now staged surgically, the previously used segmental scraping to distinguish stage I or II is no longer used; 2. The clinical staging adopted by FIGO in 1971 is still used for a small number of patients for whom radiotherapy is preferred, but should be noted; 3. The thickness of the muscular layer should be measured simultaneously with the depth of cancer infiltration. It should also be noted about pathological grading: 1. The nucleus is obviously atypical, and the pathological grading should be increased by one level; 2. The grading of the nucleus is more important for plasmacytoma, clear cell carcinoma and squamous cell carcinoma; 3. Adenocarcinoma with squamous epithelialization is graded according to the grading of the nucleus in the glandular component.
Surgical treatment of endometrial cancer
Surgery is the fundamental treatment of endometrial cancer and is the preferred treatment. Since endometrial cancer is divided into endometrioid and non-endometrioid carcinoma in terms of pathology, and their biological behaviors are completely different, different surgical methods are currently advocated for different types of endometrial cancer.
(A) Surgical approach to endometrioid carcinoma
The aim of surgery is to perform a comprehensive surgical-pathological staging and to remove both the uterus and the lesions that are likely to metastasize or have metastasized.
There are three options for surgical treatment.
1.Comprehensive staging surgery: It is the most widely used surgical procedure at home and abroad, and the scope of surgery includes total hysterectomy, double adnexal resection, cytological examination of pelvic and abdominal flushing fluid, pelvic and para-aortic lymph node resection (or biopsy). Since endometrial cancer is slow-growing and can be confined to the uterus for a considerable period of time, if there is no myometrial infiltration or if the depth of myometrial infiltration does not reach 1/2 of the myometrium and the histological grade is G1, the chance of lymph node metastasis in such cases is <5%, and many colleagues believe that lymph node dissection is not possible when there are no surgical conditions or when the patient's condition does not allow it. Many authors believe that in young, well-differentiated histologic patients without deep muscle infiltration, a well-informed attempt to preserve one or both ovaries can be made. However, if the tumor is found to have extended beyond the uterus or is cytologically positive at the time of surgery, the omentum should also be resected at the same time.
Currently, full staging surgery can be performed using the classic open surgical approach and laparoscopic surgery, which is now widely used both nationally and internationally. The advantage of the former is that adequate exposure, in addition to obtaining a better field of vision, also allows touching and timely management of special conditions found during surgery, especially for surgical complications; while the main advantage of the latter is that it is less invasive and the patient recovers quickly after surgery, and it is entirely possible to replace open surgery in the near future.
2.Subextensive hysterectomy or extended total hysterectomy: Due to the high recurrence rate of vaginal stump after conventional hysterectomy, an attempt is made to extend the operation, which does not include pelvic lymphadenectomy, during which the uterine artery is cut and ligated on the outside of the ureter, and then the ureter is freed downward for a 5-6 cm long section and the bladder is further pushed downward, so that while the uterus is removed, a part of the parametrial tissue and about 2.5 cm of the bladder may be removed. A portion of the parametrial tissue and about 2 cm long section of the vaginal vault may be removed at the same time as the uterus is removed. This procedure, compared with conventional hysterectomy, only slightly prolongs the operative time, increases little in operational difficulty and trauma, and very few ureteral fistulas are formed postoperatively, helping to reduce the postoperative recurrence rate.
3.Extensive hysterectomy: The operation includes the uterus, all parametrial tissues, a 3- to 4-cm-long upper vaginal segment and pelvic lymph nodes. This surgery is generally used for cases with poorly differentiated cells, deeper myometrial infiltration or cancer that has invaded the cervical canal and outside the uterus.
At present, the above three procedures are mainly used for patients with endometrial cancer, but the latter two procedures have been applied for at least thirty years in the treatment of endometrial cancer, instead, it is hoped that surgery can be used to achieve the purpose of radical cure. Later on, with the development of radiation technology and the wide application of chemotherapy, the treatment of endometrial cancer has gradually developed in the direction of adopting a comprehensive treatment approach. In other words, the current treatment for endometrioid carcinoma is to perform a comprehensive surgical staging first, and then decide whether to give adjuvant treatment, i.e. chemotherapy and/or radiotherapy, according to the pathological results, i.e. the presence of high-risk factors.
(ii) Surgical approach for non-endometrioid carcinoma
Non-endometrioid carcinoma is separated from endometrial carcinoma because its biological behavior is very similar to that of ovarian epithelial carcinoma, and many studies have found that the treatment of ovarian carcinoma is significantly better than the traditional treatment of endometrial carcinoma.
The current surgical procedures for non-endometrioid carcinoma include total hysterectomy, omentectomy, pelvic and para-aortic lymph node dissection, appendectomy, and of course cytologic examination of ascites or pelvic and abdominal fluids, and tumor cytoreduction similar to ovarian cancer if the tumor is significantly beyond the uterus. Of course, chemotherapy after surgery is also very important, and most of the chemotherapy regimens for ovarian epithelial cancer are required.
If the tumor is mainly confined to the uterus and there is no obvious intra-abdominal metastasis, the surgery can be done through laparoscopy: however, if there is already obvious intra-abdominal metastasis, caesarean section is more advisable, especially if there is a large omental cake.
IV. Radiation therapy for endometrial cancer
Radiation therapy is one of the main means of endometrial cancer treatment, and there are mainly two methods of intracavitary and extracorporeal irradiation, and the difference between preoperative and postoperative radiotherapy. And for those patients who cannot be operated for some reasons, they can also be treated by radiotherapy alone.
The combination of surgery and radiation can be preoperative intrauterine irradiation, postoperative intravaginal irradiation, preoperative extracorporeal irradiation and postoperative extracorporeal irradiation. Currently, because of the use of surgical pathological staging for endometrial cancer, which means that most patients require surgical staging, preoperative radiotherapy is decreasing, and more widely used is postoperative adjuvant radiotherapy for those patients with poor prognostic factors. Although radiotherapy plays a pivotal role in the treatment of endometrial cancer, it still leaves us with some unexplained problems. One of the most representative problems is that radiotherapy can significantly reduce local recurrence after surgery, but cannot improve the survival of endometrial cancer patients; in addition, radiotherapy cannot prevent distant recurrence after surgery, and some even suggest that although radiotherapy can significantly reduce local recurrence, it makes distant recurrence increase. Therefore, more and more scholars propose the treatment concept of comprehensive treatment.
V. Chemotherapy for endometrial cancer
At present, it should be said that chemotherapy is not necessary for most patients with endometrial cancer. Chemotherapy is mainly applied to those with special pathological types, poorly differentiated tumor tissues, negative expression of estrogen and progesterone receptors, or certain patients with advanced stage or recurrence.
For chemotherapy of endometrioid carcinoma, single drug therapy has been rarely used, and more combination chemotherapy is used. Although the combination regimens and doses used have not been standardized, among the most commonly used agents are adriamycin (ADM), cyclophosphamide (CTX), cisplatin (DDP), or carboplatin (CARBO). The most commonly used chemotherapy regimen is PAC and can achieve an efficiency rate of 50% to 60%. Endometrial cancer with high-risk factors is more prone to extra-pelvic recurrence, while the value of postoperative radiation therapy is more limited. Burke et al. conducted a prospective study on 62 patients with high-risk factors, and gave PAC (DDP 50 mg/m2, ADM 50 mg/m2, CTX 500 mg/m2) chemotherapy after surgery, one course every 4 weeks for 6 courses, and found that chemotherapy, although Burke et al. also attempted a prospective study of 33 advanced and/or relapsed cases with carboplatin (360 mg/m2) every 4 weeks, of which 13 achieved complete remission, and noted that carboplatin could be used for palliative treatment in advanced or relapsed cases and was well tolerated. In addition, there are some studies that have attempted chemotherapy using paclitaxel/carboplatin with some efficacy. The exact number of courses of chemotherapy that should be given for endometrial cancer is determined according to the patient’s condition, systemic status and whether or not radiotherapy is given after surgery, and generally 3-6 courses of therapy can be applied. In advanced stage patients, the combination chemotherapy regimen is more often applied together with progestin drugs, but it is still difficult to answer whether this combination is better than chemotherapy alone.
For patients with non-endometrioid carcinoma, it should be said that postoperative chemotherapy is very necessary and is the most important treatment measure after surgery, and the chemotherapy regimen is mainly adopted similar to that for ovarian cancer.
(iv) Progestin therapy.
Hormonal drugs used in the treatment of endometrial cancer. Since the 1950s, synthetic high-efficiency progestin drugs have been introduced one after another, and they were applied to the treatment of endometrial cancer in the early 1960s, and achieved relatively obvious efficacy, and regular endometrial pathological examination revealed that many cases responded well to the extent that they could not be diagnosed as cancer morphologically. The tumor tissue usually undergoes a process of differentiation, maturation, atrophy and finally disappears.
The clinical application of progestin is mainly in the following cases.
1. precancerous lesions of endometrial cancer, i.e. atypical hyperplasia of the endometrium; 2. those who are not suitable for standard surgical treatment; 3. advanced cases; 4. recurrent cases.
As for the specific medication, there are different views on benevolence and wisdom. However, two principles need to be met when using the drugs. First, the dose should be large, the daily dosage must often reach more than ten times the conventional contraceptive dose; second, the duration of use should be long. There is no unanimous opinion as to how high the dose should be and how long it should be applied.
After treatment, many advanced or recurrent cases of endometrial cancer have completely disappeared from the lungs, bones or abdominal cavity, and the disease continues to remit, even surviving for many years without signs of recurrence. Current studies have shown that: about 70% of cases can obtain improvement of subjective symptoms, 30%-35% of patients have obvious objective effect, 20% have sustained remission or even cured; histological changes begin to occur after one week of drug administration, and in all effective cases, obvious therapeutic effects should appear in about 4-6 weeks; those with well differentiated and slow-growing cancer tissues generally have better efficacy; metastatic lesions in the lung and bone are generally more effective than those in the pelvis. The therapeutic effect is generally better than that of pelvic or abdominal recurrence.
Although progestogen therapy for endometrial cancer is widely used, it is difficult to say that it has reached maturity. It is difficult to evaluate objectively because it is mostly used in advanced or recurrent cases and is mostly adjuvant, with many confounding factors. Studies have shown that the presence or absence of receptors is directly related to the effect of progestogen therapy. It is generally believed that progesterone therapy responds well if the receptor is positive, while it responds poorly if the receptor is negative.