The American Cancer Society’s Oncology in Practice: clinical management (2018)
Edited by American Cancer Society
Большинство рака тела матки — эндометриальные карциномы, на которые обращено основное внимание этой главы. Более редкие карциномы этой области, включая эндометриальные стромальные неоплазмы, карциносаркомы, и лейомиосаркомы, также включены.
Заболеваемость и смертность
Worldwide, the uterine corpus is the second most common site of malignancy in the female reproductive system. In developed countries, uterine corpus cancer occurs more frequently than any other female reproductive malignancy; among women in these countries, only one reproductive system cancer (ovarian) causes more deaths . In the United States, approximately 61,380 women are diagnosed with cancer of the uterine corpus and approximately 10,920 die from this disease each year. . Endometrial adenocarcinomas (and their subtypes) comprise approximately 90.6% of uterine corpus cancers; other types of carcinoma (such as squamous and “not otherwise specified”) represent another 1.5% .
Этиология и факторы риска
Существует два патогенетических типа эндометриального рака . I тип, составляющий 75-85% случаев, наблюдается у молодых, перименопаузальных женщин с историей избыточного эндогенного или экзогенного эстрогена относительно прогестерона. У этих женщин классически считается, что опухоли начинаются с гиперпластического эндометрия и прогрессируют в карциному. Эти «эстроген-зависимые» опухоли имеют тенденцию к лучшей дифференцировке и имеют более благоприятный прогноз, чем опухоли, которые не связаны с избытком эстрогена.
Type I cancers are associated with factors including menopausal hormone therapy with estrogen only (without progestin), obesity, nulliparity, early menarche, and late menopause. Type II endometrial carcinoma occurs in women without excess estrogenic stimulation of the endometrium. These spontaneously occurring cancers are not as commonly associated pathologically with endometrial hyperplasia, but usually arise in a background of atrophic endometrium. They are less differentiated and associated with poorer prognosis than estrogen-dependent tumors. These “estrogen-independent” tumors tend to occur in older, postmenopausal, thinner women and are present disproportionately in African American women [5, 6]. Molecular genetic studies show that these two tumor types evolve via distinct pathogenetic pathways [7–9].
The most frequent genetic alterations of endometrioid (type I) carcinomas are microsatellite instability and mutations in PTEN, PIK3CA, K-RASs, and CTNNBI (β-catenin), whereas nonendometrioid (type II, predominantly serous and clear cell) tumors often exhibit p53 mutations, HER2/neu amplification, and chromosomal instability. Approximately 80% of newly diagnosed endometrial carcinomas in the Western world are endometrioid in type . Any factor that increases exposure to unopposed estrogen (e.g., estrogen-replacement therapy, obesity, anovulatory cycles, estrogen-secreting tumors) increases the risk of these tumors, whereas factors that decrease exposure to estrogens or increase progesterone levels (e.g., oral contraceptives or smoking) tend to be protective . Several risk factors for the development of endometrial cancer have been identified (Table 20.1) [12–14].
The average age of women with endometrioid cancers is approximately 62 years, about 70% of these cancers are confined to the corpus at the time of diagnosis, and the 5-year survival is approximately 83% . By contrast, the average age of women with nonendometrioid cancers is 67 years, at least half of the cancers have already spread beyond the corpus at the time of diagnosis, and the 5-year survival is approximately 62% for clear cell carcinomas and 53% for papillary serous cancers . Endometrial cancer may occasionally develop after radiation treatment for cervical cancer .
Таблица 20.1. Факторы риска для эндометриального рака.
|Неспособность к деторождению||2–3|
|избыточный вес 21-50 фунтов||3|
|избыточный вес > 50 фунтов||10|
|Unopposed эстрогенная терапия||1.5–8|
|Атипичная эндометриальная гиперплазия||29|
|Синдром Линча (Lynch)||20|
Эндометриальная гиперплазия и интраэпителиальная неоплазия
Classic teaching has been that endometrial hyperplasia represents a spectrum of morphologic and biologic alterations of the endometrial glands and stroma displaying a variety of cytological and architectural alterations. Endometrial hyperplasias are important clinically because they may cause abnormal bleeding, be associated with estrogen-producing ovarian tumors, result from hormonal therapy, and precede or occur simultaneously with endometrial cancer [12, 17].
The World Health Organization (WHO) in 1994 established a widely implemented classification scheme for endometrial hyperplasia, with four categories based on architectural derangement and cytological atypia . In 2014, the WHO revised this classification, recommending only two categories – endometrial hyperplasia without atypia and atypical hyperplasia/endometrial intraepithelial neoplasia [10, 18]. Features of endometrial hyperplasia without atypia include proliferation glands with variable size and irregular shape, formed by cells without significant nuclear atypia. Approximately 1–3% of these lesions progress to endometrial carcinoma. In contrast, in atypical hyperplasia/endometrial intraepithelial neoplasia, cells with significant atypia (large nuclei of variable size and shape that have lost polarity, increased nuclear-to-cytoplasmic ratios, prominent nucleoli, and irregularly clumped chromatin) form very crowded glands with highly irregular shape, including some back-to-back glands without intervening stroma. Women with atypical hyperplasia/endometrial intraepithelial neoplasia face a 25–43% risk of being diagnosed with endometrial carcinoma following immediate hysterectomy or within the following year [10, 19].
For women who have completed childbearing, definitive treatment for hyperplastic lesions with atypia is hysterectomy with consideration of removal of both fallopian tubes and ovaries. This allows intraand postoperative evaluation and treatment of concurrent adenocarcinoma. Younger patients with endometrial cancer and hyperplastic changes of the endometrium tend to have disorders such as polycystic ovarian syndrome, chronic anovulation, and infertility, indicative of exposure to intrinsic estrogen excess . Lesions in this age group are usually well differentiated and of endometrioid subtype with the potential to regress with progestational therapy .
Patients who have multiple medical comorbidities and who are at high risk for surgical complications are another group in whom nonsurgical management may be indicated.
Although, progestational therapy can successfully treat disease while preserving fertility for women with atypical hyperplasia and well-differentiated presumed stage I endometrial cancer, there is no consensus on the treatment protocol. Women must be counseled that failure to identify recurrence or extension of disease during progestational treatment may lead to a delay in definitive surgery and ultimately a compromised prognosis  as well as the low likelihood of achieving a live birth upon completion of successful treatment. Imaging (transvaginal ultrasound and pelvic magnetic resonance imaging (MRI)) should be performed in an effort to exclude women with more advanced-stage disease. Continuous progestin therapy with megestrol acetate (40–160 mg per day) or the levonorgestrel intrauterine contraceptive device are probably the most reliable treatments for reversing complex or atypical hyperplasia. The main side effects of systemic treatment are weight gain, edema, thromboembolism, and occasionally hypertension. Short interval endometrial sampling (every 3–6 months) should be performed to evaluate treatment response. Once having achieved a complete response, surveillance should continue as these women are at high risk for disease recurrence.
Скрининг эндометриального рака в общей популяции
Screening asymptomatic women for endometrial cancer should not be undertaken because of the lack of an appropriate, costeffective and acceptable test that reduces mortality [23–25].
Studies and recommendations for the routine screening of women taking tamoxifen with transvaginal ultrasonography or endometrial biopsy are conflicting but generally screening is not considered clinically useful in the absence of symptoms [24, 25]. The American Cancer Society (ACS) considers evidence insufficient to recommend screening for endometrial cancer in women at average risk or at increased risk because of a history of unopposed estrogen therapy, tamoxifen therapy, late menopause, nulliparity, infertility or failure to ovulate, obesity, diabetes, or hypertension. However, the ACS recommends that women at average and increased risk should be informed about endometrial cancer symptoms such as unexpected bleeding and spotting at the onset of menopause and should be strongly encouraged to report these symptoms promptly to their physicians . Screening for endometrial cancer or its precursors may be justified for certain high-risk women, such as members of families with Lynch syndrome [24, 25].
Наблюдение и предотвращение рака у индивидуумов с высоким риском
Women with Lynch syndrome (previously referred to as hereditary nonpolyposis colorectal cancer syndrome, or HNPCC), a cancer susceptibility syndrome with germline mutations in one of the DNA mismatch repair genes MLH1, MSH2, MSH6, PMS2, EPCAM, have a 30–60% age-specific cumulative risk by age 70 for endometrial and colon cancer [13, 26, 27]. The majority of studies have focused on the increased incidence of endometrial cancer associated with Lynch syndrome, a highly penetrant disorder (32–42%) that is responsible for 2–4% of all endometrial cancers [13, 28–30]. With regard to endometrial cancer, the disorder is characterized by early age (average age of diagnosis is 49 years). Lynch syndrome mutation carriers are at increased risk for neoplastic lesions in a variety of organs, including the colon, uterus, ovaries, stomach, urinary tract, small bowel, pancreas, gallbladder, prostate, and skin [26, 31, 32]. In a study of 10,283 patients from 537 Lynch syndrome families, the cumulative incidence of all Lynch syndrome cancers was 54% by age 70 years . The lifetime risk of endometrial cancer is 32–42% and the lifetime risk of ovarian cancer is 10–12%, although there are differences in specific risks dependent upon the specific affected gene [13, 33, 34].
Although these data appear to support the use of endometrial cancer surveillance strategies for women with Lynch syndrome, a specific algorithm is not defined [33, 35, 36]. The ACS recommends that women at very high risk for endometrial cancer because of (i) known Lynch syndrome genetic mutation carrier status, (ii) substantial likelihood of being a mutation carrier (i.e., a mutation is known to be present in the family), or (iii) absence of genetic testing results in families with suspected autosomal dominant predisposition to colon cancer should consider beginning annual testing for early endometrial cancer detection at age 35 years .
Approximately 90% of women with endometrial carcinoma have abnormal uterine bleeding as their only presenting symptom [37, 38]. Some women experience pelvic pressure or discomfort indicative of uterine enlargement or extrauterine disease spread. Bleeding may not be noted because of cervical stenosis, especially in older patients, and may be associated with hematometra or pyometra, causing a purulent vaginal discharge; this finding is often associated with a poor prognosis . Fewer than 5% of women diagnosed with endometrial cancer are asymptomatic . In the absence of symptoms, endometrial cancer is detected in some patients as the result of investigation of abnormal Pap test results, discovery of cancer in a uterus removed for some other reason, or evaluation of an abnormal finding on pelvic ultrasonography examination or computed tomography (CT) scan obtained for an unrelated reason. Women who are found to have malignant cells on Pap test are more likely to have more advanced stage disease and non-endometrioid histologies .
Abnormal perimenopausal and postmenopausal vaginal bleeding should always be properly investigated, no matter how minimal or nonpersistent. Causes may be nongenital, genital extrauterine, or uterine . Nongenital tract sites should be considered based on the history or examination, including testing for blood in the urine and stool. Invasive tumors of the cervix, vagina, and vulva are usually evident on examination, and any tumors discovered should be biopsied. Traumatic bleeding from an atrophic vagina may account for up to 15% of all causes of postmenopausal vaginal bleeding. This diagnosis can be considered if inspection reveals a thin, friable vaginal wall, but the possibility of a uterine source of bleeding must first be eliminated. Possible uterine causes of perimenopausal or postmenopausal bleeding include endometrial atrophy, endometritis, endometrial polyps, estrogen therapy, endometrial hyperplasia, and carcinoma or sarcoma [42–44]. It is important to recognize that the workup of abnormal uterine bleeding should include endometrial biopsy even in premenopausal patients, as 5% of newly diagnosed endometrial cancers are in women under the age of 40.
Physical examination seldom reveals any evidence of endometrial carcinoma. Abdominal examination is usually unremarkable, except in advanced cases in which ascites or hepatic or omental metastases may be palpable.
Office endometrial aspiration biopsy is the accepted first step in evaluating a woman with abnormal uterine bleeding or suspected endometrial pathology . The diagnostic accuracy of office-based endometrial biopsy is 90–92% when compared with subsequent findings at hysterectomy . The narrow plastic cannulas are relatively inexpensive, often can be used without a tenaculum, cause less uterine cramping (resulting in increased patient acceptance), and are successful in obtaining adequate tissue samples in more than 95% of cases. A Pap test is an unreliable diagnostic test because only about 30% of women with endometrial cancer have abnormal conventional Pap test results .
Hysteroscopy and dilatation and curettage should be reserved for situations in which cervical stenosis or patient tolerance does not permit adequate evaluation by aspiration biopsy, bleeding recurs after a negative endometrial biopsy, or the specimen obtained is inadequate to explain the abnormal bleeding [48–50].
Transvaginal ultrasonography may be a useful adjunct to endometrial biopsy for evaluation of abnormal uterine bleeding and for selecting women for additional testing . The finding of an endometrial thickness greater than 3–5 mm, a polyploidy endometrial mass, or a collection of fluid within the uterus requires further evaluation [51–53].
Гистологическая классификация карциномы, происходящая из эндометрия, и относительная частота каждого типа показаны в Таблице 20.2.
These tumors are composed of glands that resemble normal endometrial glands; they have pseudostratified columnar cells, little or no intracytoplasmic mucin, and smooth intraluminal surfaces. As tumors become less differentiated, they contain more solid areas, less glandular formation, and more cytologic atypia. The well-differentiated lesions may be difficult to separate from atypical hyperplasia. Tumors are grouped into three grades. The histologic grade is based primarily upon an evaluation of the tumor architecture, and modified by nuclear atypia. About 15–25% of endometrioid carcinomas have areas of squamous differentiation.
In these endometrial carcinomas, more than one-half of the tumor is composed of cells with intracytoplasmic mucin [55–57]. Most of these tumors have a well-differentiated glandular architecture. Their behavior is similar to that of common endometrioid carcinomas and the prognosis is good. It is important to distinguish mucinous carcinoma of the endometrium as an entity from endocervical adenocarcinoma.
Таблица 20.2. Гистологическая классификация эндометриальных карцином.
|Папиллярная или ворсинчато-железистая|
|Со сквамозной дифференцировкой|
The morphology of these endometrial carcinomas resembles serous carcinoma of the ovary and fallopian tube [58, 59]. Most often, these tumors are composed of papillae having broad fibrovascular stalks lined by highly atypical cells with tufted stratification. Psammoma bodies may be observed in 30% of cases.
Serous carcinomas, also referred to as uterine papillary serous carcinomas, are considered high-risk lesions. Compared to endometrioid type tumors, serous carcinomas are more likely to present with metastatic disease at first diagnosis and have a less favorable prognosis accounting for up to one-half of the deaths from endometrial carcinoma . They are commonly admixed with other histologic patterns, but even tumors with a small proportion of serous features remain at high risk of recurrence . Serous carcinomas are often associated with lymphvascular space and deep myometrial invasion. The presence of lymph node metastases, positive peritoneal cytology, and intraperitoneal tumor does not necessarily correlate with increasing myometrial invasion; suggesting that surgical staging should be performed regardless of traditional endometrioid risk factors . Even when these tumors appear to be confined to the endometrium or endometrial polyps without myometrial or lymphvascular invasion, they behave more aggressively than endometrioid carcinomas and have a propensity to spread intra-abdominally, simulating the behavior of ovarian carcinoma .
The cells of clear cell carcinoma have highly atypical nuclei and abundant clear or eosinophilic cytoplasm. The cells often have a hobnail shape with apical rather than basal nuclei, and can be arranged in papillary, tubulocystic, glandular, and solid patterns. Clear cell carcinoma characteristically occurs in older women and like serous carcinoma is considered aggressive, with overall survival rates varying from 33 to 64% [63–65].
Squamous cell carcinoma of the endometrium is rare, although other types of endometrial carcinoma may contain foci of squamous differentiation. To establish primary origin of squamous cell carcinoma within the endometrium, there must be no connection with or spread from cervical squamous epithelium. This tumor has a poor prognosis, with an estimated 36% survival rate in patients with clinical stage I disease .
Carcinosarcoma is a morphologically heterogeneous malignancy with some foci displaying the histological appearance of carcinoma and others having the histological characteristics of a sarcoma. The carcinomatous element typically shows glandular histology, whereas the sarcomatous element may be homologous (resembling an endometrial stromal sarcoma), or heterologous (resembling sarcomas with differentiation toward tissues foreign to the uterus, such as rhabdomyosarcoma, chondrosarcoma, osteosarcoma, or liposarcoma). These tumors have historically been classified with uterine sarcomas and in the 2014 WHO classification are in a category of mixed epithelial and mesenchymal tumors that is distinct from carcinomas and sarcomas. However, recent biological and clinical evidence supports the view that carcinomas are high-grade carcinomas with sarcomatous metaplasia. For these reasons, carcinosarcomas are staged in the FIGO system as endometrial carcinomas, and their treatment is similar to that of type II endometrial carcinomas such as serous and clear cell carcinomas [67–69].
The tumor typically grows as a large, soft, polypoid mass that can fill and distend the uterine cavity; necrosis and hemorrhage are prominent features. The myometrium is invaded to various degrees in almost all cases. The most frequent areas of spread are the pelvis, lymph nodes, peritoneal cavity, lungs, and liver. This metastatic pattern suggests that these neoplasms spread by local extension and regional lymph node metastasis in a manner similar to that of endometrial adenocarcinoma. In a significant number of patients, lymph node metastases and positive peritoneal cytology are found with early-stage carcinosarcoma .
Одновременные опухоли эндометрия и яичника
Synchronous endometrial and ovarian cancers are the most frequent synchronous genital malignancies, with a reported incidence of 1.4–3.8% [71, 72]. Most commonly, both the ovarian and endometrial tumors are well-differentiated endometrioid adenocarcinomas of low stage, resulting in an excellent prognosis. Patients are often premenopausal and present with abnormal uterine bleeding. The ovarian cancer usually is discovered as an incidental finding and is diagnosed at an earlier stage because of the symptomatic endometrial tumor, leading to a more favorable outcome.
After establishing the diagnosis of endometrial carcinoma, the next step is to evaluate the patient thoroughly to determine the best and safest approach to management of the disease. A complete history and physical examination are of utmost importance. Patients with endometrial carcinoma are often elderly and obese with a variety of medical problems, such as diabetes mellitus and hypertension, which complicate surgical management. Any abnormal symptoms, such as bladder or intestinal symptoms, should be evaluated. On physical examination, attention should be directed to enlarged or suspicious lymph nodes, including the inguinal area, abdominal masses, and possible areas of cancer spread within the pelvis. Evidence of distant metastasis or locally advanced disease in the pelvis, such as gross cervical involvement or parametrial spread, may alter the treatment approach. The vaginal introitus and suburetheral area, and the entire vagina and cervix, should be carefully inspected and palpated. Bimanual rectovaginal examination should be performed specifically to evaluate the uterus for size and mobility, the adnexa for masses, the parametria for induration, and the cul-de-sac for nodularity.
Chest imaging should be performed to exclude pulmonary metastasis and to evaluate the cardiorespiratory status of the patient, and complete blood and platelet counts should be done. Other preoperative studies may include electrocardiography and serum chemistries (including renal and liver function tests). Studies such as cystoscopy, colonoscopy, and barium enema are not indicated unless dictated by patient symptoms, physical findings, or other laboratory tests . CT scanning of the abdomen and pelvis may be considered in patients with type II uterine cancer to determine if minimally invasive surgery (MIS) is appropriate. Stage IV disease is usually clinically evident based on patient symptomatology and clinical examination. Ultrasonography and MRI can be used to assess myometrial invasion preoperatively with a fairly high degree of accuracy . This information may be of use in planning the surgical procedure with regard to whether lymph node sampling should be undertaken.
Serum CA-125 levels are elevated in most patients with advanced or metastatic endometrial cancer . Preoperative measurement of serum CA-125 may help determine the extent of surgical staging and, if elevated, may be useful as a tumor marker in assessing response to subsequent therapy [76–78].
Clinical staging, according to the 1971 FIGO system, should be performed only in patients who are deemed not to be surgical candidates because of their poor medical condition or the degree of disease spread . The current FIGO staging is surgical, as discussed below, and has supplanted the old clinical system. With improvements in preoperative and postoperative care, anesthesia administration, and surgical techniques, almost all patients are medically suitable for operative therapy. A small percentage of patients will not be candidates for surgical staging because of gross cervical involvement, parametrial spread, invasion of the bladder or rectum, or distant metastasis.
Surgical staging for endometrial cancer, consists of hysterectomy, removal of the adnexal structures, peritoneal cytology, and lymph node sampling where appropriate (Table 20.3) [80, 81]. Surgical staging not only identifies most patients with extrauterine disease, but also identifies patients with uterine risk factors for recurrence, including large tumor size, deep myometrial invasion, lymphvascular space invasion, and cervical extension, thereby allowing for a more informed approach to postoperative adjuvant therapy. Lymph node dissections as part of surgical staging is not required in patients assessed intraoperatively to be at low risk for lymph node metastasis (<2 cm, grade 1–2 tumors with superficial myometrial invasion), whereas systematic lymph node dissection should be performed in most other patients with endometrial cancer (Table 20.4) .
Таблица 20.3. Стадийность эндометриального рака.
|Stage I||Tumor confined to the corpus uteri|
|IA||No or less than half myometrial invasion|
|IB||Invasion equal to or more than half of the myometrium|
|Stage II||Tumor invades cervical stroma, but does not extend beyond the uterus 2|
|Stage III||Local and/or regional spread of the tumor|
|IIIA||Tumor invades the serosa of the corpus uteri and/or adnexae 3|
|IIIB||Vaginal and/or parametrial involvement 3|
|IIIC||Metastases to pelvic and/or para-aortic lymph nodes 3|
|IIIC1||Positive pelvic nodes|
|IIIC2||Positive para-aortic lymph nodes with or without positive pelvic lymph nodes|
|Stage IV||Tumor invades bladder and/or bowel mucosa, and/or distant metastases|
|IVA||Tumor invasion of bladder and/or bowel mucosa|
|IVB||Distant metastases, including intra-abdominal metastases and/or inguinal lymph nodes|
Для всех стадий — Либо G1, G2, G3.
2 Endocervical glandular involvement only should be considered as Stage I and no longer as Stage II.
3 Positive cytology should be reported separately without changing the stage.
Table 20.4. Surgically staged endometrial cancer: actuarial 5-year survival rate (%) by histologic grade and stage (1988 staging criteria).
Таблица 20.5. Хирургическо-патологические находки на клинической стадии эндометриального рака.
|Surgical-pathologic findings||Percentage of patients|
|Other (papillary serous, clear cell)||4|
|Positive peritoneal cytology||12|
|Lymphvascular space invasion||15|
|Pelvic lymph node metastasis||9|
|Aortic lymph node metastasis||6|
|Other extrauterine metastasis||6|
Although disease stage is the most significant variable affecting survival, a number of other individual prognostic factors for disease recurrence or survival are known.
In general, younger women with endometrial cancer have a better prognosis than older women. Increased risk for recurrence in older patients is related to a higher incidence of grade 3 tumors or unfavorable histologic subtypes; however, increasing patient age has been shown to be independently associated with disease recurrence. In one study, for every 1-year increase in age, the estimated rate of recurrence increased 7% .
Неэндометриоидные гистологические подтипы несут высокий риск рецидива и отдаленной диссеминации [83, 84].
Histologic grade of the endometrial tumor is strongly associated with prognosis (Table 20.5) [85–87]. In one study, recurrence developed in 7.7% of grade 1 tumors, 10.5% of grade 2 tumors, and 36.1% of grade 3 tumors. Patients with grade 3 tumors were more than five times more likely to have a recurrence than were patients with grades 1 and 2 tumors. The 5-year disease-free survival rates for patients with grades 1 and 2 tumors were 92% and 86%, respectively, compared with 64% for patients with grade 3 tumors .
Объем опухоли — достоверный прогностический фактор для метастазирования в лимфатические узлы и выживаемости пациентов с эндометриальным раком [88, 89]. One report determined tumor size in 142 patients with clinical stage I endometrial cancer and found lymph node metastasis in 4% of patients with tumors 2 cm or smaller, in 15% of patients with tumors larger than 2 cm, and in 35% of patients with tumors involving the entire uterine cavity . Tumor size better defined an intermediate risk group for lymph node metastasis (i.e., with grade 2 tumors with less than 50% myometrial invasion). Overall, these patients had a 10% risk for lymph node metastasis, but there were no nodal metastases associated with tumors 2 cm or smaller, compared with 18% when tumors were larger than 2 cm. Five-year survival rates were 98% for patients with tumors 2 cm or smaller, 84% for patients with tumors larger than 2 cm, and 64% for patients with tumors involving the whole uterine cavity [89, 91].
Статус гормональных рецепторов
Patients whose carcinomas are positive for estrogen receptor and/or progesterone receptors have longer survival times than patients whose carcinomas lack these receptors. Even patients with metastases have an improved prognosis with receptorpositive tumors [92–94]. Progesterone receptor levels appear to be stronger predictors of survival than estrogen receptor levels, and the higher absolute levels of the receptors the better the prognosis.
- Инвазия в миометрий
Because access to the lymphatic system increases as cancer invades into the outer one-half of the myometrium, increasing depth of invasion is associated with increasing likelihood of extrauterine spread, including lymph node metastasis and recurrence [87, 95, 96]. Of patients without demonstrable myometrial invasion, only 1% had pelvic lymph node metastasis, compared with patients with outer one-third myometrial invasion of whom 25% had pelvic and 17% had aortic lymph node metastases. Deep myometrial invasion is the strongest predictor of hematogenous recurrence . Patients with noninvasive or superficially invasive tumors have an 80–90% 5-year survival rate, whereas those with deeply invasive tumors have a 60% survival rate [98, 99].
- Инвазия в лимфоваскулярные пространства
Lymphvascular space invasion (LVSI) appears to be an independent risk factor for recurrence and death from all types of endometrial cancer [100, 101]. LVSI was demonstrated to be a strong predictor of lymphatic dissemination and lymphatic recurrence . Another study reported an 83% 5-year survival rate for patients without demonstrable LVSI, compared with a 64.5% survival rate for those in whom LVSI was present .
Isthmus and cervix extension
The location of the tumor within the uterus is important. Involvement of the uterine isthmus, cervix or both is associated with an increased risk for extrauterine disease, lymph node metastasis, and recurrence. Cervical stromal invasion (stage II) is a strong predictor of lymphatic dissemination and lymphatic recurrence, especially for pelvic lymph nodes . One study reported that if the fundus of the uterus alone was involved with tumor, there was a 13% recurrence rate, whereas if the lower uterine segment or cervix was involved with occult tumor, there was a 44% recurrence rate . A subsequent Gynecological Oncology Group (GOG) study found that tumor involvement of the isthmus or cervix without evidence of extrauterine disease was associated recurrence rate of a 16% and a relative risk of 1.6 .
Reports regarding the prognostic relevance of positive peritoneal cytology have been inconsistent, due at least in part to differences in use of multivariate analyses. Patients with positive peritoneal cytology as the only site of extrauterine disease (i.e., no adnexal or uterine serosal invasion) and without poor prognosticators (i.e., myometrial invasion more than 50%, nonendometrioid histologic subtype, grade 3, LVSI, cervical invasion) have very favorable outcomes with an absence of extra-abdominal recurrences . These patients have an associated 5-year survival of 98– 100% even when not treated with adjuvant therapy [104–106]. On the other hand, patients with positive cytology in addition to poor prognostic factors demonstrate a high rate (47%) of distant extra-abdominal failure and may potentially benefit from systemic chemotherapy. Positive peritoneal cytology seems to have an adverse effect on survival only if the endometrial cancer has spread to the adnexa, peritoneum, or lymph nodes, not if the disease is otherwise confined to the uterus [105, 107, 108]. These considerations led to the omission of cytology as a factor impacting stage in the FIGO 2009 staging criteria.
Adnexal or uterine serosal involvement (stage IIIA)
Most patients with stage IIIA disease have other poor prognostic factors that place them at high risk for recurrence. One series described treatment of all patients with serosal or adnexal invasion (or both) with whole-abdomen radiotherapy. Failures were observed outside the abdomen in 100% of patients with full thickness myometrial invasion or uterine serosal invasion, and in 20–25% of cases in the presence of isolated adnexal invasion [85, 109]. These patients may benefit from postoperative systemic chemotherapy.
Метастаз в лимфатические узлы
Lymph node metastasis is a very important prognostic factor in clinical early-stage endometrial cancer. Of patients with clinical stage I disease, about 10% will have pelvic and 6% will have paraaortic lymph node metastases. Patients with lymph node metastases have almost a sixfold higher likelihood of developing recurrent cancer than patients without lymph node metastasis. One study reported a recurrence rate of 48% among patients with positive pelvic nodes, including 45% with positive pelvic nodes and 64% with positive aortic nodes, compared to 8% for patients with negative nodes. The 5-year disease-free survival rate for patients with lymph node metastases was 54% compared to 90% for patients without lymph metastases . The GOG found that 58% of patients with para-aortic lymph node metastasis developed progressive or recurrent cancer, and only 36% of these patients were alive at 5 years, compared to 85% of patients without para-aortic node involvement . One series examined patients with lymph node metastases in addition to other extrauterine sites of disease (vagina, uterine serosa, positive peritoneal cytology, adnexal invasion). The recurrence rates were 67% (41% extranodal) for those with lymphatic dissemination versus 32% (5% extranodal) for those with other sites of extrauterine disease spread .
Extrauterine metastasis, excluding peritoneal cytology and lymph node metastasis, occurs in about 4–6% of patients with clinical stage I endometrial cancer. Gross intraperitoneal spread is highly associated with lymph node metastases; one study noted that 51% of patients with intraperitoneal tumor had positive lymph nodes, whereas only 7% of patients without gross peritoneal spread had positive nodes . Extrauterine spread other than lymph node metastasis is significantly associated with tumor recurrence. Another study found that 50% of patients with extrauterine disease developed recurrence, compared with 11% of patients without extrauterine disease. The 5-year disease-free survival rate for patients with nonlymphatic extrauterine disease was 50%, compared with 88% in other patients . Predictors of peritoneal relapse include stage IV disease, or stage II or III disease with two or more of the following risk factors: cervical invasion, positive peritoneal cytology, positive lymph nodes, and nonendometrioid histology .
The most common current protocol for surgical management of endometrial cancer includes peritoneal cytology, hysterectomy, bilateral salpingo-oophorectomy, and surgical staging. In patients with nonendometrioid cancer, omentectomy and peritoneal biopsies may be performed. The need to perform lymph node sampling or lymphadenectomy is based on the type and grade of endometrial cancer, the tumor size and extent of myometrial invasion, and the presence of extrauterine disease determined during the surgery (see Surgical Staging). The decision to administer postoperative radiation, chemotherapy, or both is predicated on the final results of pathologic examination of the surgical specimen and cytology  (Figure 20.1).
- Вагинальная гистерэктомия
Vaginal hysterectomy may be considered for selected patients who are extremely obese and have a poor medical status or for patients with extensive uterovaginal prolapse. Vaginal hysterectomy with bilateral salpingo-oophorectomy may be considered adequate treatment for patients with low-risk tumors (endometrioid histology, grade 1 or 2, <50% myometrial invasion, and tumor diameter <2 cm). Vaginal hysterectomy is particularly suitable for patients who are at low risk for extrauterine spread of disease (i.e., those with clinical stage I, well-differentiated tumors). In one report, a 94% survival rate was observed among 56 patients with clinical stage I (mostly grade 1) endometrial carcinoma treated by vaginal hysterectomy, with or without postoperative radiotherapy (mostly brachytherapy) . Vaginal hysterectomy is preferable to radiation therapy alone, but should be reserved for specific patients.
Минимально инвазивная хирургия: лапароскопическая или роботизированная
Advances in endoscopic technologies and power sources have allowed application of laparoscopic/robotic approaches to the management of endometrial cancer [114–116]. A large prospective study by GOG randomized patients to laparoscopy versus laparotomy for primary treatment of endometrial cancer . Consistent with early reports, patients randomized to laparoscopy had shorter hospital stays (52% more than 2 days vs 94% in the laparotomy group), less blood loss, and fewer postoperative complications (14% vs 21%). The rate of intraoperative complications was similar, and the operative time was longer in the laparoscopy cohort. There was no difference in lymph node counts, and stage distribution was identical between groups. A follow-up quality-of-life investigation of the same cohorts revealed better physical functioning, better body image, less pain and its interference with quality of life, and an earlier resumption of normal activities and return to work over the 6-week recovery period in the laparoscopic group . Of concern was the 24% rate of conversion in the laparoscopic cohort; only 4% were converted because of advanced disease. Furthermore, the conversion rate increased dramatically with body mass index. This implied a limitation of the surgical technique in obese patients. Recent longitudinal data from this study demonstrated that laparoscopic staging was associated with a 3-year recurrence rate of 11.4% compared with 10.2% with laparotomy and did not adversely affect overall survival or recurrence patterns .
Рисунок 20.1. Лечение пациентов с эндометриальной карциномой. Факторы риска: возраст> 60 лет, степень злокачественности 2/3, инвазия в лимфоваскулярные пространства, инвазия в наружную половину миометрия, гистологический подтип серозная или светлоклеточная.
Robotic-assisted surgery has gained popularity for endometrial cancer treatment. Improved instrumentation and visualization allow MIS to be performed by surgeons with less laparoscopic experience, and in patients, particularly obese patients, who otherwise might not be candidates for MIS . In 2010, a systematic review summarized most of the comparative studies on endometrial cancer at that time. The perioperative outcomes were similar for robotic and laparoscopic procedures with decreased blood loss and shorter hospital stays but longer operative times compared with laparotomy. The proportion of MIS cases converted to laparotomy were lower in the robotic group compared with laparoscopy (4.9% vs 9.9%; P = 0.06), but all approaches had equivalent rates of cuff dehiscence, vascular complications, and bowel or bladder injuries .
Лучевая терапия как первичное лечение
Primary surgery followed by individualized radiation therapy is the most widely accepted treatment for early-stage endometrial cancers. However, about 5–15% of endometrial cancer patients have severe medical conditions that render them unsuitable for surgery . Several series show that radiotherapy is effective treatment for patients with inoperable endometrial cancer [123–125]. Although radiation alone can produce excellent survival and local control, it should be considered for definitive treatment only if the operative risk is estimated to exceed the 10–15% risk for uterine recurrence that is expected with radiation treatment alone.
Паттерны метастатической диссеминации: импликации для послеоперационного болезнь-базисного адьювантного лечения
Approximately one of every three women who dies of endometrial cancer was considered to have early locoregional disease at primary diagnosis. Most treatment failures and the accompanying compromised longevity probably result from failure to recognize sites of occult extrauterine dissemination at primary diagnosis. Traditional postoperative therapy (modality-based) for high-risk endometrial cancer is external-beam radiotherapy that is frequently supplemented with vaginal brachytherapy . This approach improves local control but not survival in early-stage disease [127–129].
Understanding the different pathways of metastatic dissemination of endometrial cancer and their predictive factors allows the development of an individualized model for target-based therapeutic approaches to the predicted site(s) of failure. The natural history of epithelial corpus cancer includes four potential routes of metastasis: (i) contiguous extension (mainly to the vagina), (ii) hematogenous dissemination, (iii) lymphatic embolization, and (iv) exfoliation with intraperitoneal spread. Independent pathologic risk factors predictive of the four routes of metastatic spread are:
1) Contiguous extension: histologic grade 3 and lymphovascular space invasion are proven predictors of vaginal relapse in stage I endometrial cancer .
2) Hematogenous: deep myometrial invasion is the strongest predictor of hematogenous recurrence (>50% for all stages and >66% for stage I) [97, 131].
3) Lymphatic: lymphatic failure (defined in this study as a relapse occurring on the pelvic sidewall, para-aortic area, or other node-bearing area) is more likely to occur when cervical stromal involvement or positive lymph nodes are present at initial surgery .
4) Peritoneal: predictors of peritoneal relapse are: (i) stage IV disease or (ii) stage II or III disease with two or more of the following risk factors: cervical invasion, positive peritoneal cytology, lymph node metastasis, and nonendometrioid histology .
Patients with the risk factors previously discussed account for 35% of all the overall population with endometrial cancer, but 89% of the observed hematogenous, lymphatic, and peritoneal relapses. Importantly, 46% of the patients considered at risk subsequently experience a recurrence in one or more of the three sites, compared with only 2% of patients not judged to be at risk based on these criteria (P <0.001). The identification of subgroups of patients at risk for the different patterns of recurrence would allow postoperative treatment targeted to the predicted areas of tumor dissemination. Patients at risk for hematogenous or peritoneal recurrence would potentially benefit from systemic cytotoxic treatment, whereas patients at risk for lymphatic or vaginal recurrence would potentially benefit from radiation treatment directed to areas at risk.
Patients with grade 1 and 2 lesions, with no or minimal myometrial invasion, and without any of the above risk factors have an excellent prognosis (disease-free 5-year survival rate approaching 100%) and require no postoperative therapy [85, 132, 133].
Vaginal brachytherapy (VBT) is an attractive alternative to external radiation therapy (ERT). High-dose rate (HDR) VBT is well tolerated with low rates of severe or chronic complications. Vaginal control rates with more convenient, bettertolerated HDR VBT are comparable to control rates with lengthier low-dose rate (LDR) VBT. The standard HDR VBT dosing of 21 Gy to 5 mm depth in three fractions provides local control rates of 98–100% [134, 135]. Retrospective data suggest that the vaginal relapse rate after VBT averages 4–5% and this is similar to the 5-year vaginal failure rate of 3.5% reported among the highest-risk patients who received ERT in PORTEC-1 [129, 132, 133, 136–138].
PORTEC-2 randomized patients with apparent uterineconfined endometrial cancer at high risk for recurrence (>60 years of age with grade 1 or 2, stage IB and grade 3, stage IA; or any age, any grade IIA with <50% myometrial invasion) to pelvic ERT (46 Gy, in 23 fractions) versus VBT (21 Gy in three HDR fractions or 30 Gy LDR, to a depth of 0.5 cm). At 3 years, there was no difference in vaginal failure rates (0.9% for VBT, 2% for pelvic ERT; P = 0.97). There was a higher rate of nonvaginal pelvic relapse in the brachytherapy group (3.6%) compared to the ERT group (0.7%). However, the absolute difference was small and there was no difference in overall survival . The difference between nonvaginal pelvic recurrence may be a reflection of unrecognized lymph node metastases at the time of initial surgery treated with ERT. One concern regarding PORTEC-2 is that there was not a surgery-only control in the study. However, the highest risk endometrial cancer subgroup in PORTEC-1 (patients >60 years of age with grade 3 or deeply invasive grade 1 or 2, all stage I) was similar to the cohort included in PORTEC-2 and the locoregional recurrence rate in patients who did not receive adjuvant ERT in PORTEC-1 was 18% . Grade 3 histology and LVSI are proven predictors of vaginal relapse in stage I endometrial cancer. Patients with these risk factors are the most likely group to benefit from VBT . Although vaginal recurrences can be successfully treated and controlled in up to 80% of cases, the addition of VBT to the initial surgical intervention can significantly reduce the risk of such recurrences .
Внешнее облучение таза
Radiation therapy traditionally was suggested to patients who were deemed to have an intermediate or high risk of recurrence, according to grade and depth of myometrial invasion. Several retrospective studies and large, randomized trials did not show an overall survival benefit for intermediateand high-risk patients with stage I endometrial cancer (or occult IIA endometrial cancer according to the 1988 FIGO staging) who received adjuvant pelvic radiotherapy.
The PORTEC trial tested the role of postoperative pelvic radiation therapy for presumed stage I endometrial cancer. Eligibility criteria were stage IB, grades 1 to 2, and stage IA, grades 2 to 3; patients with stage IA, grade 3, were only 10% of the study population, and lymph node biopsies and peritoneal cytology were not required. Local-regional recurrences developed in 14% of the surgery group, compared with 4% of the postoperative pelvic radiation group. The 5-year survival rates were not different between the two groups (85% vs 81%, respectively) . These results were confirmed by GOG99, a prospective, randomized investigation of surgery alone (including lymphadenectomy) versus surgery plus adjuvant pelvic radiation in intermediate-risk endometrial cancer (stages IA to IIB occult). After 2 years, the cumulative recurrence rate was 12% in the group with no postoperative treatment compared with 3% in the group that received pelvic radiation. The pelvic failure rate was 8.9% in the surgery-alone group compared with 1.6% in the postoperative pelvic radiation group. Overall survival rates were not significantly improved, however (92% vs 86%, respectively) . The ASTEC/EN.5 trial provided further confirmation that external-beam radiation therapy in patients at intermediate to high risk of recurrence had no significant effect on overall survival .
Postoperative whole-pelvis ERT usually involves the delivery of 4,500–5,040 cGy in 180 cGy daily fractions over 5–6 weeks to a field encompassing the upper one-half of the vagina inferiorly, the lower border of the L4 vertebral body superiorly, and 1 cm lateral to the margins of the bony pelvis. The dose of radiation at the surface of the vaginal apex usually is boosted to 6,000 to 7,000 cGy by a variety of techniques. The most frequently reported side effects are gastrointestinal, usually abdominal cramps and diarrhea, although more serious complications such as bleeding, proctitis, bowel obstruction, and fistula can occur and may require surgical correction. The urinary system may be affected in the form of hematuria, cystitis, or fistula. The overall complication rate ranges from 25 to 40%; and the rate of serious complications requiring surgical intervention is about 1.5–3%.
External-beam pelvic radiation does not appear to impact survival in patients with high-risk stage I endometrial cancer. Patients with extrauterine pelvic disease, including adnexal spread, parametrial involvement, and pelvic lymph node metastases, in the absence of extrapelvic disease, are most likely to benefit from postoperative pelvic radiation.
Облучение расширенных полей
Patients with histologically proven para-aortic node metastases and no other evidence of disease spread outside the pelvis should be treated with extended-field radiation. The entire pelvis, common iliac lymph nodes, and para-aortic lymph nodes are included within the radiation field. The para-aortic radiation dose is limited to 4,500–5,000 cGy. Extended-field radiotherapy appears to improve survival in patients with endometrial cancer who have positive para-aortic lymph nodes [129, 142].
Five-year survival rates of 47% and 43% are reported for patients with surgically confirmed isolated para-aortic lymph node metastases and for those with para-aortic and pelvic lymph node metastases, respectively, using postoperative extendedfield radiation. Severe enteric morbidity is uncommon (2%, in one report) . In a GOG study, 37 of 48 patients with positive para-aortic nodes received postoperative para-aortic radiation, 36% of whom remained tumor free at 5 years . A comparison of patients with positive para-aortic nodes treated with megestrol acetate alone versus extended-field radiation showed that survival rate in patients receiving extended-field radiation was significantly better: 53% vs 12.5%, respectively. In another study of 18 patients with positive para-aortic nodes, 5-year survival rates were 67% for those with microscopic nodal disease and 17% with gross nodal disease .
Облучение всего живота
Whole-abdomen radiation therapy was occasionally used for patients with stage III–IV endometrial cancer or for patients who had stage I–II carcinomas, such as serous, that have a propensity for upper-abdominal recurrence [145–147]. Since the publication of GOG122, demonstrating the superiority of chemotherapy over whole-abdominal radiotherapy in advanced endometrial cancer, the utilization of whole-abdominal radiotherapy in advanced endometrial cancer has been uncommon (see Chemotherapy section) .
Because most endometrial cancers have both estrogen and progesterone receptors and progestins have been used successfully to treat metastatic endometrial cancer, postoperative adjuvant progestin therapy attempted to reduce the risk of recurrence. This therapy seemed attractive because it provides systemic treatment and has few side effects. Unfortunately, several large randomized, placebo-controlled studies failed to identify a benefit for adjuvant progestin therapy [149, 150].
In cases of advanced disease, chemotherapy is now standard treatment. The GOG 122 trial compared whole-abdominal radiotherapy versus systemic chemotherapy in patients with stage III or IV disease who underwent maximal surgical resection of disease to less than 2 cm. Patients who received chemotherapy had a 13% improvement in 2-year progression-free survival (50% vs 46%) and an 11% improvement in overall 2-year survival (70% vs 59%) compared to patients treated with wholeabdomen radiation . However, toxicity was more prevalent with chemotherapy. Despite this improvement with chemotherapy, the proportion of patients with pelvic failure was 18%, suggesting the need for local control. GOG 177 randomized 263 women with advanced or recurrent endometrial cancer to paclitaxel, doxorubicin, and cisplatin (TAP) vs doxorubicin and cisplatin (AP). Despite an increase in toxicity, there was an increase in response rates in patients receiving the three-agent chemotherapy TAP (57% vs 34%, P <0.001) and increased median overall survival (15.3 months for TAP vs 12.3 months for AP, P = 0.037). In a study comparing TAP to the popular two drug regimen, carboplatin and paclitaxel, interim analysis suggested comparable progression-free (14 months vs 14 months, respectively) and overall survival (38 months vs 32 months, respectively) [151, 152].
Other GOG studies and the PORTEC-3 trial are investigating the combination of chemotherapy and radiotherapy in advanced or high-risk endometrial cancer. Results of these trials await maturation. GOG 249 is comparing whole pelvic ERT with or without vaginal cuff boost versus vaginal cuff brachytherapy followed by three cycles of paclitaxel and carboplatin in patients with uterine-confined endometrial cancer at high risk for recurrence. GOG 258 is comparing chemoradiation followed by chemotherapy versus chemotherapy alone in advanced endometrial cancer. PORTEC-3 is investigating overall survival and failure-free survival of patients with high-risk and advanced stage endometrial carcinoma treated after surgery with chemoradiation followed by chemotherapy versus pelvic radiation alone.
Клиническая стадия II
Endometrial cancer involving the cervix either contiguously or by lymphatic spread has a poorer prognosis than disease confined to the corpus [153–155]. Preoperative assessment of cervical involvement is difficult. Endocervical curettage has relatively high false-positive (50–80%) and false-negative rates. Histologic proof of cancer infiltration of the cervix or presence of obvious tumor on the cervix is the only reliable method to diagnose cervical involvement, although ultrasonography, hysteroscopy, or MRI may show cervical invasion.
The relatively small number of true stage II cases in reported series and the lack of randomized, prospective studies preclude formulation of a definitive treatment plan. Three areas must be addressed in any treatment plan:
1) For optimal results, the uterus should be removed in all patients.
2) Because the incidence of pelvic lymph node metastases is about 36% in stage II endometrial cancer, any treatment protocol should include treatment of these lymph nodes.
3) Because the incidence of disease spread outside the pelvis to the para-aortic lymph nodes, adnexal structures, and upper abdomen is higher than in stage I disease, attention should be directed to evaluating and treating extrapelvic disease.
Two approaches had been used in the past for treatment of clinical stage II disease:
1) Radical hysterectomy, bilateral salpingo-oophorectomy, and pelvic and para-aortic lymphadenectomy.
2) Combined radiation and surgery (external pelvic radiation and intracavitary radium or cesium followed in 6 weeks by total abdominal hysterectomy and bilateral salpingooophorectomy).
The method of management of clinical stage II endometrial cancer that has gained favor is an initial surgical approach followed by radiation. This method is based on the difficulty in establishing the preoperative diagnosis of cervical involvement in the absence of a gross cervical tumor, the evidence that radiation is equally effective when given after hysterectomy, and the high incidence of extrapelvic disease when the cervix is involved. An extrafascial hysterectomy or modified radical hysterectomy, bilateral salpingo-oophorectomy, peritoneal washings for cytology, and resection of grossly enlarged lymph nodes are performed. These procedures are followed by appropriate pelvic or extended-field external and intravaginal radiation, depending on the results of surgical staging. Excellent results are reported using this treatment scheme [69, 156].
Клинические стадии III и IV
Clinical stage III disease accounts for about 7–10% of all endometrial carcinomas [157, 158]. Patients usually have clinical evidence of disease spread to the parametria, pelvic sidewall, or adnexal structures; less frequently, there is spread to the vagina or pelvic peritoneum. Treatment for stage III endometrial carcinoma must be individualized, but initial operative evaluation and treatment should be considered because of the high risk for occult lymph node metastases and intraperitoneal spread when disease is known to extend outside of the uterus into the pelvis. In the presence of an adnexal mass, the initial impetus for surgery is to determine the nature of the mass. Surgery is performed to determine the extent of disease and to remove the bulk of the disease if possible. This procedure should include peritoneal washings for cytologic examination, paraaortic and pelvic lymphadenectomy, biopsy or excision of any suspicious areas within the peritoneal cavity, and omentectomy and peritoneal biopsies. Except in patients with bulky parametrial disease, hysterectomy and bilateral salpingooophorectomy should be performed. The goal of surgery is eradication of all macroscopic disease because this finding is one of major prognostic importance in the management of patients with clinical stage III disease. Despite the small number of patients included in the studies examining cytoreduction, it appears that optimal cytoreduction may be associated with improved survival . Postoperative therapy can be tailored to the extent of disease.
Results of therapy depend on the extent and nature of disease. A 5-year survival rate of 54% is reported for all patients with stage III disease; however, the survival is 80% when only adnexal metastases are present, compared with 15% when other extrauterine pelvic structures are involved . Patients with surgical-pathologic stage III disease have a much better survival rate (40–54%) than those with clinical stage III disease (16–36%) [158, 161]. Patients who are treated with combined surgery and radiation fare better than patients who receive radiation therapy alone .
Stage IV endometrial adenocarcinoma, in which tumor invades the bladder or rectum or extends outside the pelvis, makes up about 3% of cases . Treatment of stage IV disease is patient dependent but usually involves a combination of surgery, radiation therapy, and systemic hormonal therapy or chemotherapy. One objective of surgery and radiation therapy is to achieve local disease control in the pelvis to provide palliative relief of bleeding, discharge, and complications involving the bladder and rectum. In one report, control of pelvic disease was achieved in 28% patients with stage IV disease treated with radiation alone or in combination with surgery, progestins, or both . Several reports have noted a positive impact of cytoreductive surgery on survival, the median survival being about three times greater with optimal cytoreduction (18– 34 months vs 8–11 months, respectively) [163–165]. Pelvic exenteration may be considered in the very rare patient in whom disease is limited to the bladder, rectum, or both .
Наблюдение после лечения
History and physical examination remain the most effective methods of follow-up in patients treated for endometrial cancer [167–169]. Patients should be examined every 3–6 months during the first 2 or 3 years and every 6–12 months thereafter. Physical examination should include a speculum and pelvic examination. Serum CA-125 determinations are considered an optional component of follow-up. Vaginal bleeding is a common symptom consistent with local recurrence; other common symptoms include abdominal and/or pelvic pain, changes in bowel or bladder habits, lethargy, and weight loss. These or related symptoms are reported by 41–83% of patients and more than 80% of recurrences are detected by a combination of physical examination and symptoms. Very few asymptomatic recurrences are detected by vaginal cytology (0–7%) and fewer than 20% of asymptomatic recurrences are detected by annual chest X-ray. Because of the low rates of detection of these screening modalities, many gynecologic oncologists have challenged their use . The most recent National Comprehensive Cancer Network (NCCN) guideline does not specify vaginal cytology and recommends imaging only as clinically indicated. In addition to examinations and tests as surveillance for recurrent disease, the NCCN recommends patient education regarding symptoms of recurrence and health promotion (weight control, nutrition, physical activity, tobacco cessation), and consideration of genetic counseling .
About 15% of patients treated for early (stage I–II) endometrial cancer develop recurrent disease [127, 171]. In contrast, recurrent disease is detected in up to 50% of patients with advanced (stage III–IV) endometrial cancer . More than 50% of the recurrences develop within 2 years, and about 75% occur within 3 years of initial treatment. The distribution of recurrences is dependent in large part on the type of primary therapy: surgery alone versus surgery plus local or regional radiotherapy. In a GOG study of 390 patients with surgical stage I disease, vaginal and pelvic recurrences were noted to comprise 53% of all recurrences in the group treated with surgery alone, whereas only 30% of recurrences were vaginal or pelvic in the group treated with combined surgery and radiotherapy. Therefore, after combined surgery and radiotherapy (vaginal or external beam), 70% or more of patients with treatment failures have distant metastases, and most of these patients do not have evidence of local or pelvic recurrence . The most common sites of extrapelvic metastases are lung, abdomen, lymph nodes (aortic, supraclavicular, inguinal), liver, brain, and bone. Patients with isolated vaginal recurrences fare better than those with pelvic recurrences, who in turn have a better chance of cure than those with distant metastases . Patients who initially have welldifferentiated tumors or who develop recurrent cancer more than 3 years after the primary therapy also tend to have an improved prognosis.
Progestins are recommended as initial treatment for all patients with recurrent low-grade endometrioid tumors with hormone receptor-positive tumors. Radiation therapy, surgery or both should be used whenever feasible for treatment of localized recurrent cancer such as vaginal, pelvic, bone, and peripheral lymph node disease; however, these patients should also be given long-term progestin therapy unless they are known to have a progesterone-receptor-negative tumor. Patients with nonlocalized recurrent tumors, especially if progesterone receptors are known to be positive, are candidates for progestin therapy, either megestrol acetate, 80 mg twice daily, or medroxyprogesterone acetate, 50–100 mg three times daily. These commonly used progestins have response rates ranging from 15 to 25% . Higher response rates are observed in patients with well-differentiated tumors and a longer disease-free interval. Progestin therapy should be continued for at least 2–3 months before assessing response. If a response is obtained, the progestin should be continued for as long as the disease is static or in remission. In the presence of a relative contraindication to highdose progestin therapy (e.g., prior or current thromboembolic disease, severe heart disease, or inability of the patient to tolerate progestin therapy), tamoxifen, 20 mg twice daily, is recommended. Aromatase inhibitors have been used in metastatic or recurrent disease. Failure to respond to hormonal therapy is an indication for initiation of chemotherapy .
Radiotherapy is the best treatment option for patients with isolated local-regional recurrences [174, 175]. The best local control and subsequent cure are usually achieved by a combination of ERT followed by VBT boost to deliver a total tumor dose of at least 6,000 cGy. Women with low-volume disease limited to the pelvis (most of which is contained in the vagina) have the best outcome. Retrospective studies showed complete remission rates after salvage therapy for isolated vaginal relapse to be 40–80% in previously unirradiated patients, compared to 10–25% in those who had previously been irradiated . Conversely, for those patients who undergo radiation for pelvic extension of their disease, lower survival rates (0–26%) are reported. Factors associated with improved survival and control of pelvic disease in patients with locally recurrent endometrial cancer include initial low-grade and endometriod histology, younger age at recurrence, recurrent tumor size 2 cm or less, time from initial treatment to recurrence of more than 1 year, vaginal versus pelvic disease, and use of VBT.
Chemotherapy with a platinum agent and a taxane has become the standard adjuvant treatment setting for advanced endometrial cancer . Individually, the response rates of platinum agents and paclitaxel range from 20 to 36% . In one retrospective study, the overall response rate to combination carboplatin and paclitaxel in patients with either advanced or recurrent endometrial cancer was 43%, but only 5% achieved a complete response . There are no randomized control trials comparing carboplatin and paclitaxel in the recurrent setting; however, GOG 209 demonstrated carboplatin and paclitaxel to be not inferior to the combination of paclitaxel, doxorubicin, and cisplatin . There are no effective single agents for disease recurrence after treatment with first-line platinum/taxane combinations . Molecularly targeted therapies such as mTOR inhibitors and antiangiogenic agents including bevacizumab are in clinical trials.
A small subset of patients with isolated recurrent endometrial cancer may benefit from surgical intervention. A search for distant recurrences prior to treatment is obligatory as such patients are best treated with chemotherapy. In one small series, upper abdominal disease was found at laparotomy in three (37.5%) of eight patients with presumed localized pelvic recurrence. Presence of subclinical extrapelvic metastases was associated with large pelvic tumor size (>2 cm) and elevated serum CA-125 . Isolated vaginal recurrence in patients who have not received prior pelvic radiation is best treated with external radiation plus some type of brachytherapy.
Treatment of patients with pelvic recurrence (generally located on the pelvic sidewall secondary to lymphatic failure) is more complex. Although one study  showed no survivors among patients with pelvic recurrences, there is some evidence that a multimodality approach consisting of radiotherapy followed by radical surgical resection and intraoperative radiotherapy may cure some patients, albeit with a higher complication rate . Of 36 patients with isolated central pelvic recurrence who underwent pelvic exenteration for recurrent endometrial carcinoma, 75% died of their cancer within 1 year of operation, and only 14% were alive after 5 years .
Эстрогенная заместительная терапия после лечения
Most endometrial cancers are associated with excess estrogen exposure, calling into question the appropriateness of estrogen therapy for women with a history of endometrial cancer following hysterectomy and bilateral salpingo-oophorectomy. Several nonrandomized and cohort retrospective studies have reported that estrogen therapy appears safe with no documented increase in the risk of recurrence following surgical treatment for endometrial carcinoma [181–183]. However, these are small retrospective nonrandomized studies. Some investigations reported higher intercurrent death rates, such as from myocardial infarction, in the group in which estrogen was withheld [181, 184]. A randomized, double-blind, placebo-controlled study designed to determine whether estrogen therapy increased rates of disease recurrence in women with stage I or II endometrial cancer closed early because of a fall-off in accrual after the findings of the Women’s Health Initiative were made public in 2002. Although the safety of estrogen therapy in patients with endometrial cancer was not verified with level 1 evidence, this investigation provided sufficient reassurance to justify the practice of offering estrogen therapy to patients with low-grade, FIGO 2009 stage IA disease in the absence of other contraindications. The American College of Obstetricians and Gynecologists issued a committee opinion recommending that providers should take into consideration prognostic indicators, such as depth of invasion, grade, and stage when deciding to administer estrogen therapy to these patients . Similarly, the NCCN guideline also considers estrogen as a reasonable option for symptomatic women with low risk of recurrence, but notes the importance of individualizing decisions after detailed discussion with the patient . For women who decline systemic estrogen therapy, symptoms of vaginal dryness and dyspareunia may be judiciously treated with topical estrogen alone. Symptomatic relief of hot flashes can be achieved by prescribing progestins or nonhormonal agents such as clonidine and venlafaxine.
Uterine sarcomas constitute approximately 7.7% of uterine malignancies [3, 186]. There is an increased incidence of uterine sarcomas after radiation therapy to the pelvis for either carcinoma of the cervix or a benign condition. The relative risk of uterine sarcoma after pelvic radiotherapy is estimated to be 5.38, with an interval of 10–20 years . Uterine sarcomas are, in general, the most malignant group of uterine tumors and differ from endometrial cancer with regard to diagnosis, clinical behavior, pattern of spread, and management.
Классификация и стадийность
The two most common histologic types of uterine sarcoma are leiomyosarcoma (1.9% of uterine corpus cancers) and endometrial stromal sarcoma (1.3% of uterine corpus cancers). Less common types, such as “uterine tumor resembling ovarian sex cord tumor” are included in the WHO classification but are not discussed in this chapter . Carcinosarcoma, also known as malignant mixed mullerian tumor or MMMT, have been classified as sarcomas in the past but are a distinct category (separate from carcinomas and sarcomas) in the current WHO classification, and are currently thought to represent high-grade carcinomas with mesenchymal metaplasia [67, 68].
Staging of uterine sarcomas is based on the FIGO system [188, 189].
Эндометриальные стромальные опухоли
Stromal tumors occur primarily in perimenopausal and postmenopausal women. There is no apparent relationship to parity, associated disease, or prior pelvic radiotherapy. The most frequent symptom is abnormal uterine bleeding; abdominal pain and pressure caused by an enlarging pelvic mass occur less often, and some patients do not have symptoms. Pelvic examination usually reveals regular or irregular uterine enlargement, sometimes associated with rubbery parametrial induration. The diagnosis may be determined by endometrial biopsy, but the usual preoperative diagnosis is uterine leiomyoma.
Endometrial stromal tumors are composed of cells with morphological and histochemical features resembling normal endometrial stroma. They are divided into three types: endometrial stromal nodule, low-grade endometrial stromal sarcoma, and high-grade endometrial stromal sarcoma. Additionally, undifferentiated uterine sarcoma is grouped in the same category as endometrial stromal sarcomas [18, 68].
Endometrial stromal nodule is an expansile, noninfiltrating, solitary lesion confined to the uterus with well-circumscribed or minimally irregular margins, no lymphatic or vascular invasion, and usually less than five mitotic figures per 10 high-power microscopic fields (5 MF/10 HPF). These tumors should be considered benign because there are no recurrences or tumorassociated deaths reported after surgery [190, 191].
Low-grade endometrial stromal sarcoma is distinguished from high-grade endometrial stromal sarcoma (and with undifferentiated uterine sarcoma) microscopically by mitotic rates of less than 10 MF/10 HPF and more protracted clinical course. The distinction between an endometrial stromal nodule and low-grade endometrial stromal sarcoma is based on prominent myometrial, lymphatic, and in some cases venous invasion. These sarcomas display slight nuclear atypia or little or no necrosis. Recurrences typically occur late, and local recurrence is more common than distant metastases [192, 193].
Optimum initial therapy for patients with low-grade endometrial stromal sarcoma consists of surgical excision of all grossly detectable tumor. Total hysterectomy should be performed. The fallopian tubes and ovaries should usually be removed as well because of the propensity for tumor extension into the parametria, broad ligaments, and adnexal structures and the possible stimulating effect of estrogen on tumor cells if the ovaries are retained. The relatively low rate of lymph node metastasis in the absences of gross lymph node involvement or extrauterine disease suggests that a lymph node sampling or lymphadenectomy is not necessary . Postoperative pelvic radiation is recommended for inadequately excised or locally recurrent pelvic disease. Recurrence occurs in almost 50% of cases at an average interval of 5 years after initial therapy. Owing to the indolent nature of the disease, cytotoxic chemotherapy is unlikely to be beneficial; however, hormonal treatment with progestins appears to have some efficacy, with reported response rates close to 50%. Prolonged survival and cure are common even after development of recurrent or metastatic disease. Five-year overall survival may exceed 90% .
High-grade endometrial stromal sarcoma and undifferentiated uterine sarcoma are highly malignant neoplasms although prognosis is poorer for the latter. Histologically, both exhibit greater than 10 MF/10 HPF, foci of necrosis, significant cytological pleomorphism, and prominent myometrial and lymphatic invasion. Undifferentiated uterine sarcomas, by definition, lack recognizable morphological or immunohistochemical evidence of smooth muscle differentiation or endometrial stromal differentiation . This tumor has a much more aggressive clinical course and poorer prognosis than low-grade endometrial stromal sarcoma [187, 191–193]. The 5-year disease-free survival is about 25%. Treatment of high-grade endometrial stromal sarcoma and undifferentiated uterine sarcoma should consist of total hysterectomy and bilateral salpingo-oophorectomy. The poor therapeutic results suggest that radiation therapy, chemotherapy, or both should be used in combination with surgery. These tumors, unlike low-grade endometrial stromal sarcoma, are not responsive to progestin therapy.
The median age for women with leiomyosarcoma is 43–53 years, and premenopausal women have a better chance of survival. This malignancy has no relationship with parity, and the incidence of associated disease is not as high as in carcinosarcoma or endometrial adenocarcinoma. African American women have a higher incidence and a poorer prognosis than women of other races. A history of prior pelvic radiation therapy can be elicited in about 4% of patients with leiomyosarcoma. The incidence of sarcomatous change in benign uterine leiomyomas is reported to be between 0.13 and 0.81%. Survival rates for patients with uterine leiomyosarcoma range from 20 to 63% (mean 47%) [3, 196–198].
Presenting symptoms, which are of short duration (mean 6 months) and not specific to the disease, include vaginal bleeding, pelvic pain or pressure, and awareness of an abdominopelvic mass. The principal finding is the presence of a pelvic mass. The diagnosis should be suspected if severe pelvic pain accompanies a pelvic tumor, especially in a postmenopausal woman. Endometrial biopsy, although not as useful as in other sarcomas, may establish the diagnosis in as many as one-third of cases when the lesion is submucosal.
The number of mitosis in the uterine smooth muscle tumors traditionally was considered the most reliable microscopic indicator of malignant behavior. Tumors with less than 5 MF/10 HPF behave in a benign fashion, and tumors with more than 10 MF/10 HPF are frankly malignant with a poor prognosis. Tumors with 5–10 MF/10 HPF, termed smooth muscle tumors of uncertain malignant potential (STUMP), are less predictable. In addition to a mitotic index greater than 10, other histologic indicators used to classify uterine smooth muscle tumors as malignant are severe cytologic atypia, infiltrating borders, and coagulative tumor necrosis. However, assessment of uterine smooth muscle neoplasms based on a single risk factor can be misleading, and the totality of histological and clinical features should be considered. For example, symplastic leiomyomas typically have prominent nuclear atypia but are clinically benign. Conversely, the deceptively low mitotic rate and minimal nuclear atypia of epithelioid leiomyosarcomas and myxoid leiomyosarcomas is discordant with their malignant behavior [68, 199]. Gross presentation of the tumor at the time of surgery is an important unfavorable prognostic indicator. Tumors with infiltrating tumor margins or extension beyond the uterus are associated with poor prognosis, whereas tumors less than 5 cm, originating within leiomyomas, or with pushing margins are associated with prolonged survival.
The pattern of tumor spread is to the myometrium, pelvic blood vessels and lymphatics, contiguous pelvic structures, abdomen and then distantly, most often the lungs. The recommended treatment is total hysterectomy; bilateral salpingooophorectomy is recommended in postmenopausal women and in women with gross extrauterine disease. Preservation of ovaries does not increase risk of recurrence. Retroperitoneal disease and lymphatic disease spread is rare in women with early-stage disease; therefore, routine lymphadenectomy or lymph node sampling is not recommended except with grossly involved nodes or other extrauterine disease [68, 194].
Adjuvant chemotherapy is indicated in patients with advanced leiomyosarcoma. In a phase III trial that included women with uterine leiomyosarcoma, carcinosarcoma, or other uterine sarcoma, doxorubicin 60 mg/m2 was compared with doxorubicin plus the addition of dacarbazine (DTIC), achieving an objective response in 16% of all women enrolled, with a response of 25% among those with uterine leiomyosarcoma . Ifosfamide as a single-agent for the treatment of leiomyosarcoma demonstrated a 17.2% response rate in a phase II trial . Combining ifosfamide with doxorubicin achieved an objective response of 30% in advanced leiomyosarcoma; the incidence of grade 3 or 4 neutropenia was 48% . Gemcitabine combined with docetaxel for treatment of metastatic leiomyosarcoma yielded an overall response rate of 53%, including patients previously treated with doxorubicin . Median time to progression was 5.6 months. Despite the high recurrence rate (50–70%) in earlystage uterine leiomyosarcoma that has been treated surgically, there is limited experimental data to suggest adjuvant postoperative chemotherapy or radiation affects overall survival; therefore, GOG is conducting a trial of gemcitabine/docetaxel followed by doxorubicin versus observation.
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