INTRODUCTION — Uterine cancer is the most common gynecologic malignancy in resource-abundant countries and is the second most common in resource-limited countries (cervical cancer is more common). (See "Endometrial carcinoma: Epidemiology, risk factors, and prevention", section on 'Epidemiology'.)
Adenocarcinoma of the endometrium (lining of the uterus) is the most common histologic site and type of uterine cancer. Endometrial cancer is often classified into two subtypes (type 1 and type 2), which reflect general characteristics of its clinicopathological spectrum. Type 2 neoplasms are generally associated with more aggressive clinical behavior than type 1 tumors. While they comprise 10 to 20 percent of endometrial carcinomas, they account for 40 percent of deaths from the disease [1-3].
Information specific to type 2 endometrial carcinomas (eg, serous and clear cell histologies) is reviewed here. An overview of endometrial carcinoma can be found separately (see "Overview of endometrial carcinoma"). Related content is discussed in separate topics, including:
●Histopathology and pathogenesis (see "Endometrial cancer: Pathology and classification")
●Epidemiology and risk factors (see "Endometrial carcinoma: Epidemiology, risk factors, and prevention")
●Clinical features, diagnosis, and screening for high-risk patients (see "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening")
●Staging and surgical treatment (see "Endometrial carcinoma: Staging and surgical treatment")
●Adjuvant therapy (see "Overview of endometrial carcinoma", section on 'Adjuvant therapy')
HISTOLOGY AND PATHOGENESIS — Among endometrial carcinomas, there are two main histologic categories, which differ in incidence, responsiveness to estrogens, and prognosis (figure 1) [1,2]:
●Type 1 tumors include tumors of endometrioid histology that are grade 1 or 2; these comprise approximately 80 percent of endometrial carcinomas. These tumors typically have a favorable prognosis, are estrogen-responsive, and may be preceded by an intraepithelial neoplasm (atypical and/or complex endometrial hyperplasia). (See "Endometrial hyperplasia: Clinical features, diagnosis, and differential diagnosis".)
●Type 2 tumors include clear cell and serous endometrial carcinomas and account for 10 to 20 percent of endometrial carcinomas.
●Grade 3 endometrioid tumors represent a diverse subset of endometrial carcinoma, have a poor prognosis, and are not clearly associated with either type 1 or type 2 tumors. This is discussed in more detail elsewhere. (See "Endometrial cancer: Pathology and classification".)
Precursor lesion — It has been proposed that uterine serous carcinoma (USC) develops from "endometrial intraepithelial carcinoma" (EIC), a lesion related to malignant transformation of the endometrial surface epithelium (such as a benign endometrial polyp), against a background of endometrial atrophy [4,5]. However, EIC has been found in association with extrauterine serous carcinoma, with both sites having identical clones of p53 mutations [6]. This finding has led some to suggest that EIC represents an early form of USC rather than its true precursor [7]. A relatively new entity, "endometrial glandular dysplasia," which histologically bridges benign endometrium and EIC, may be the putative precursor lesion to USC [8].
A putative precursor lesion for endometrial clear cell carcinoma characterized by nuclear atypia has also been described [9].
Histology — Most endometrioid cancers are well-differentiated endometrioid adenocarcinomas, which are characterized by proliferation of back-to-back endometrial glands without intervening stroma. By contrast, USC has a complex papillary architecture that resembles serous carcinoma of the ovary; psammoma bodies are present in 60 percent [10,11]. Marked nuclear atypia is always present, and all USC is considered high grade.
Clear cell cancers are characterized by tubulocystic, papillary, or solid patterns; psammoma bodies are present in up to 10 percent of cases, most often in the papillary variant [12,13]. The cells may be clear because of the presence of glycogen. Myometrial invasion occurs in approximately 80 percent of cases. At least from the standpoint of gene expression, they appear more similar to clear cell cancers arising in other organs (eg, the kidney) than to other uterine cancers, including those of the serous variety [14]. Nevertheless, they are treated similar to serous cancers. (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma".)
USC and clear cell carcinomas may be a component of mixed-histology tumors that have endometrioid or sarcomatous elements. If 10 percent or more of the tumor has a serous component, it is classified as USC; cases in which the serous component consists of more than 10 percent but less than 90 percent of the cancer are classified as mixed serous cancers.
Earlier studies suggested little difference in survival when patients with pure USC cancers were compared with those with mixed USC [15-18]. However, a multi-institutional series comparing 58 patients with mixed USC with 50 patients with pure uterine papillary serous carcinomas found the two most important prognostic factors for progression-free and overall survival were stage and pure USC histology [19]. Patients with pure USC histology had a 2.9-fold greater risk for recurrence and a 2.6-fold higher risk of death compared with those with mixed USC [19].
For clear cell carcinomas, some pathologists require ≥50 percent clear cell features to classify a tumor as a clear cell carcinoma [20], while others use the benchmark of at least 25 percent clear cell component [21,22]. Patients with pure clear cell cancers and mixed clear cell cancers with endometrioid components have the same survival as those whose clear cell cancers contain less histologically favorable components [21].
Biologic behavior — Both USC and clear cell tumors have a higher propensity for lymphovascular invasion, and intraperitoneal as well as extra-abdominal spread, than endometrioid cancers [10,17,20,23-26]. At the time of presentation, approximately 60 to 70 percent of patients with USC will have disease spread outside of the uterus [17,25].
Lymph node metastasis and extrauterine disease spread are extremely rare with endometrioid cancers that are noninvasive; by contrast, they frequently occur with noninvasive USC (ie, EIC). Furthermore, while tumor grade and depth of myometrial invasion are not predictive of extrauterine spread for USC, the incidence of extrauterine spread in endometrioid cancer correlates with both tumor grade and depth of myometrial invasion (table 1).
In one study, lymph node metastases were found in 36 percent of patients with USC and no myometrial invasion, compared with 50 and 46 percent of those with inner one-half and outer one-half invasion, respectively [27]. The corresponding rates of intraperitoneal disease for these three groups were 43, 37, and 35 percent, respectively. Even having as little as 10 percent of the tumor composed of USC places the patient at the same risk for metastasis [28].
Molecular pathogenesis — Type 1 and type 2 uterine tumors also appear to have a different pattern of molecular alterations that underlie pathogenesis and/or progression [29]. Alterations in the tumor suppressor gene PTEN, microsatellite instability, and K-ras alterations have been associated with the early development of type 1 tumors, while these alterations are uncommon in type 2 cancers. On the other hand, p53 mutations appear to be important in the early pathogenesis of USC. Moreover, human epidermal growth factor receptor 2 (HER2) overexpression/amplification has been associated with type 2 tumors. Whole exome sequencing of 76 USC specimens revealed somatic mutations in TP53 (81.6 percent), PIK3CA (23.7 percent), FBXW7 (19.7 percent), and PPP2R1A (18.4 percent), and DNA copy number analysis identified amplification of CCNE1 as the most common genetic alteration in USC [30]. These issues are addressed in detail elsewhere.
There are conflicting data regarding whether USC is one of the spectrum of cancers in patients with BRCA1 or 2 gene mutations. In a large pooled series after a median follow-up of nine years, three incident cases of endometrioid-type uterine cancer were identified in 438 BRCA1 mutation carriers, and two endometrioid-type uterine cancers were identified among 390 BRCA2 mutation carriers compared with 1.04 expected (standardized incidence ratio [SIR] 2.87, 95% CI 0.59-8.43) and 0.99 expected (SIR 2.01, 95% CI 0.24-7.30; p = 0.52), and 160 patients had used tamoxifen. There were no USC identified [31]. Inheritance of these mutations is more common in Jewish patients, particularly those of Ashkenazi descent. In one report, 4 of 20 Jewish patients with USC had BRCA1 germline mutations [32]. In another study, three BRCA1 and three BRCA2 germline mutations were identified among 22 Jewish patients with USC [33]. In a review from Israeli medical centers, 14 of 60 patients with USC had an inherited BRCA gene mutation. Patients with BRCA gene mutations tended to present with more advanced disease, but the disease-specific survival was similar to that of noncarriers [34].
General principles of the histopathology of endometrial carcinoma are discussed in detail separately. (See "Endometrial cancer: Pathology and classification".)
EPIDEMIOLOGY AND RISK FACTORS — Type 2 endometrial neoplasms account for 10 to 20 percent of endometrial carcinomas [1,2]. Since they are less common, there are fewer epidemiologic data about them than type 1 carcinomas. General information about the epidemiology of endometrial carcinomas is discussed separately. (See "Endometrial carcinoma: Epidemiology, risk factors, and prevention", section on 'Epidemiology'.)
Type 2 endometrial carcinomas tend to present at an advanced stage. Approximately 70 percent of patients with uterine serous cancer (USC) and 50 percent with clear cell cancers present with stage III or IV disease [17,35,36].
Type 2 endometrial carcinomas have traditionally been thought to differ from type 1 tumors in several ways. Some of these are well established, but others are controversial [3,37]:
●The average age at diagnosis is older for type 2 disease in most studies [2,38]. However, a prospective study of over one million Norwegian females followed for an average of 25 years, which included 992 type 2 carcinomas, revealed no difference in age at diagnosis of type 1 and type 2 cancers (mean age, 65 years both groups) [39]. By comparison, the average age at diagnosis of all uterine cancer in the United States is 62 years old [40].
●Obesity is a known risk factor for type 1 endometrial carcinomas and was not thought to be associated with type 2 [3]. However, there is evidence that obesity is a risk factor for all endometrial carcinomas [39,41]. As an example, in the Norwegian cohort study cited above, obesity was associated with an increased risk of either type of tumor, but the risk was more pronounced for type 1 [39].
●Patients with type 2 tumors are more likely to be parous than nulliparous [42,43].
●Type 2 tumors have a different racial distribution than type 1 carcinomas. Among patients with endometrial carcinoma, Black patients are more likely than White patients to have type 2 tumors [37,44]. This may contribute to the poorer overall prognosis for Black patients compared with White patients with endometrial carcinoma [45,46].
The relationship between breast cancer and USC is uncertain, but it appears that a personal history of breast cancer is associated with a risk of developing USC [37,47,48]. As an example, in a case-control study of patients with endometrial carcinoma, patients with serous histology were more likely than those with endometrioid histology to have a personal history of breast cancer (19 versus 3 percent) [48]. This risk does not appear to be dependent upon use of tamoxifen. In addition, there have been some reports that the BRCA1 mutation carriers are at an increased risk of USC [3]. (See 'Molecular pathogenesis' above.)
Unlike other clear cell carcinomas (eg, of the ovary), endometriosis does not appear to be a risk factor for the development of clear cell carcinoma of the uterus [49].
CLINICAL FEATURES — Abnormal uterine bleeding is the most common clinical presentation for type 2 endometrial carcinomas, just as with type 1 tumors. Likewise, some patients present with endometrial cells on cervical cytology. The clinical presentation and prediagnostic evaluation of endometrial carcinoma are discussed in detail separately. (See "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening".)
Tumor markers — If a type 2 uterine cancer is suspected or diagnosed on an endometrial biopsy, a serum CA 125 level should be ordered as retrospective studies have consistently reported that elevated levels of CA 125 are associated with advanced stage, poorly differentiated endometrioid adenocarcinomas; uterine serous cancers; and uterine clear cell cancers [37,50-54]. Knowing in advance a patient may have an advanced-stage uterine cancer can influence the surgery to be performed and determine the need for a gynecologic oncologist to perform that surgery. Elevations of CA 125 are associated with positive pelvic node involvement, positive peritoneal washings, and the presence of lymphovascular invasion [55]. However, the prognostic effect of an elevated CA 125 on progression-free survival remains controversial [55,56]. While a correlation between elevated CA 125 preoperatively and lymph node metastases was noted, it was not associated with development of recurrent disease.
DIAGNOSIS — Endometrial carcinoma is a histologic diagnosis made based upon histologic evaluation of endometrial sampling, curettage, or a hysterectomy specimen. This is the same for both type 1 and type 2 tumors.
An office endometrial biopsy is a sensitive test for type 2 endometrial carcinomas. However, the correct histology may not be identified in all cases. As an example, in one study, among 67 patients with a final postoperative diagnosis of uterine serous carcinoma (USC), 17 were reported as endometrioid histology based upon evaluation of the initial endometrial biopsy [57]. This may be due to the fact that USC is often found mixed with other high-grade endometrial carcinomas (grade 3 endometrioid or clear cell). There were few cases of a false-positive diagnosis of USC (2 of 234 patients with a postoperative diagnosis of endometrioid tumors had a biopsy result of USC).
Diagnostic methods for endometrial carcinoma are discussed in detail separately. (See "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening", section on 'Diagnosis'.)
STAGING AND SURGICAL TREATMENT — Type 2 endometrial carcinomas are surgically staged in the same manner as type 1 tumors (table 2). Staging of endometrial cancer is discussed in detail separately. (See "Endometrial carcinoma: Staging and surgical treatment".)
Type 2 neoplasms are more likely to present at an advanced stage; as noted above, 50 to 70 percent of patients present with stage III or IV disease [17,35,36].
Optimal cytoreduction is an important component of surgical treatment [36,58-64]. The strongest predictor of overall survival is the amount of residual disease following surgery [36,58-63]. As an example, in a retrospective review of 70 patients with stage IIIC or IV uterine serous carcinoma, median survival was significantly longer after optimal cytoreduction with no visible residual disease as compared with optimal cytoreduction with macroscopic residual disease and suboptimal cytoreduction (51 versus 14 and 12 months, respectively) [58]. Outcomes in the group with residual disease were not substantially improved by the use of postoperative chemotherapy.
ADJUVANT TREATMENT — Type 2 endometrial carcinomas are high-risk disease. Treatment of high-risk disease is discussed in detail separately. (See "Adjuvant treatment of high-risk endometrial cancers".)
PROGNOSIS — Type 2 endometrial carcinomas have been associated with a poorer outcome than type 1 tumors in most, but not all studies [17,22,23,27,65-69], although at least one study from the Gynecologic Oncology Group suggested the association between tumor type and prognosis was weak for patients with advanced/recurrent endometrial cancer. As an example, in a study of 4180 patients with high-risk endometrial carcinoma subtypes reported to the Surveillance, Epidemiology and End Results (SEER) United States National Cancer Database between 1988 and 2001, uterine serous carcinoma (USC) and clear cell carcinoma accounted for 10 and 3 percent of all endometrial carcinomas, respectively [67]. However, they were responsible for 39 and 8 percent of all deaths. The five-year disease-specific survival rates for USC and clear cell were 55 and 68 percent, respectively. These statistics were confirmed in 2000 to 2015 SEER data, which were corrected for hysterectomy and estimated separately by race, ethnicity, and region in the United States, and histologic subtype (table 3) [69]. The overall combined five-year survival rate for USC and clear cell cancer was 57.5 percent; the corresponding value for endometrioid cancers was 91.8 percent.
Even among patients with completely surgically staged, node-negative, stage I USC, the five-year overall survival rate is approximately 70 percent [66]. Patients with clear cell carcinoma have a similar prognosis; five-year overall survival is estimated at 62.5 percent [69].
HER2 amplification — Overexpression or amplification of HER2 (erbB-2, the epidermal growth factor receptor 2 gene) has been identified in a number of studies as a poor prognostic sign for type 2 endometrial carcinomas [70-75]. This was illustrated in a series of 30 patients undergoing treatment for stage IA to IV USC (25 with stage III or IV disease) at a single institution over a seven-year period [70]. Amplification of the HER2 gene, as detected by fluorescence in situ hybridization (FISH), was observed in 14 patients (47 percent), with more tumors arising from Black American patients (67 percent) compared with those arising in White American patients (33 percent). At four years, disease-specific survival rates were 17 and 84 percent for those with FISH-positive and FISH-negative tumors, respectively.
For patients with advanced-stage, previously untreated USC whose tumors overexpress HER2, the addition of the anti-HER2-antibody trastuzumab to carboplatin and paclitaxel prolongs both progression-free and overall survival [76,77]. (See "Treatment of metastatic endometrial cancer", section on 'HER2-overexpressing tumors'.)
POSTTREATMENT SURVEILLANCE — Clear cell carcinomas are more likely than either endometrioid cancers or uterine serous carcinomas to recur with distant spread (eg, to the lungs and bones) [21]. The recurrence pattern of serous endometrial cancer is similar to epithelial ovarian cancer.
Posttreatment surveillance protocols are the same for type 2 as type 1 endometrial carcinomas. This topic is discussed separately. (See "Overview of endometrial carcinoma", section on 'Post-treatment surveillance'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Uterine cancer".)
SUMMARY AND RECOMMENDATIONS
●Histopathology – Adenocarcinoma of the endometrium (lining of the uterus) is the most common histologic site and type of uterine cancer. There are two main histologic categories of endometrial carcinoma (figure 1): type 1 (endometrioid grade 1 and 2) and type 2 (eg, serous, clear cell). Grade 3 endometrioid tumors represent a diverse subset of endometrial carcinoma and are not clearly associated with either type 1 or type 2 tumors. (See 'Histology and pathogenesis' above and "Endometrial cancer: Pathology and classification".)
●Biologic behavior – Type 2 neoplasms are generally associated with more aggressive clinical behavior than type 1 tumors. Approximately 70 percent of patients with uterine serous carcinoma (USC) and 50 percent with clear cell cancers present with stage III or IV disease. While they comprise 10 to 20 percent of endometrial carcinomas, type 2 tumors account for 40 percent of deaths from the disease. (See 'Biologic behavior' above.)
●Patient characteristics – Patients with type 2 endometrial carcinoma have different characteristics than those with type 1 tumors. They tend to be older at diagnosis, nonobese, and parous. A personal history of breast cancer appears to be a risk factor for USC. (See 'Epidemiology and risk factors' above.)
●Diagnosis – Endometrial carcinoma is a histologic diagnosis made based upon histologic evaluation of endometrial sampling, curettage, or a hysterectomy specimen. (See 'Diagnosis' above.)
●Staging – Type 2 endometrial carcinomas are surgically staged in the same manner as type 1 tumors (table 2). However, an omentectomy is routinely performed in patients with USC and clear cell cancers, though not for grade 3 endometrioid endometrial cancers. Surgical staging is performed for all type 2 tumors because of the high risk of nodal and extrauterine metastasis. Optimal cytoreduction is an important component of surgical treatment. (See 'Staging and surgical treatment' above.)
●Prognosis
•Type 2 endometrial carcinomas have been associated with a poorer outcome than type 1 tumors in some studies (table 3), but the evidence is uncertain. (See 'Prognosis' above.)
•Overexpression or amplification of HER2 (erbB-2, the epidermal growth factor receptor 2 gene) has been identified in a number of studies as a poor prognostic sign for type 2 endometrial carcinomas. (See 'HER2 amplification' above.)
