Version May 2024
INTRODUCTION — Endometrioid adenocarcinoma is the most common type of endometrial carcinoma. Nonendometrioid subtypes, including serous and clear cell carcinomas, are less common than endometrioid tumors, but account for almost half of endometrial cancer deaths.
Information specific to serous and clear cell endometrial carcinomas is reviewed here. Related content is discussed in detail separately:
●Overview of endometrial carcinoma (see "Overview of resectable endometrial carcinoma")
●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 "Adjuvant treatment of intermediate-risk endometrial cancer" and "Adjuvant treatment of high-risk endometrial cancers")
CLASSIFICATION — The 2023 International Federation of Gynecology and Obstetrics (FIGO) staging system classifies serous and clear cell endometrial cancers as "aggressive" tumors, along with grade 3 endometrioid tumors and mixed, undifferentiated, mesonephric-like, and gastrointestinal-type mucinous carcinomas [1]. By contrast, endometrioid tumors that are grade 1 or 2 and nongastrointestinal-type mucinous tumors represent less aggressive histologies and are termed "nonaggressive" in the 2023 FIGO staging system. These two categories differ in incidence, responsiveness to hormones, and clinical behavior and impact surgical and postoperative treatment [1,2]. (See "Overview of resectable endometrial carcinoma", section on 'Histopathology' and "Endometrial cancer: Pathology and classification", section on 'FIGO categorization'.)
Other classification systems (eg, type I and type II; World Health Organization [WHO] categorization of tumors of the uterine corpus) are described separately. (See "Endometrial cancer: Pathology and classification", section on 'Traditional classification system' and "Endometrial cancer: Pathology and classification", section on 'WHO categorization'.)
This topic will utilize the 2023 FIGO staging system except when describing studies that used older staging systems.
PATHOGENESIS
Precursor lesions — Uterine serous carcinomas are thought to develop from endometrial intraepithelial carcinomas (EIC; also referred to as hyperplasia with atypia), a lesion related to malignant transformation of the endometrial surface epithelium (such as a benign endometrial polyp) against a background of endometrial atrophy [3,4]. They may also be associated with extrauterine serous carcinoma, with both sites having identical clones of p53 mutations [5]. This finding has led some to suggest that EIC represents an early form of uterine serous carcinoma rather than its true precursor [6]. Endometrial glandular dysplasia, which histologically bridges benign endometrium and EIC, may be the putative precursor lesion to uterine serous carcinoma [7].
A putative precursor lesion for endometrial clear cell carcinoma characterized by nuclear atypia has also been described [8].
Molecular pathogenesis — Uterine serous and clear cell tumors also appear to have a different pattern of molecular alterations that underlie pathogenesis and/or progression [9]. While alterations in the tumor suppressor gene PTEN, microsatellite instability (MSI), and K-ras alterations have been associated with the early development of endometrioid tumors, these alterations are uncommon in uterine serous and clear cell cancers. Rather, p53 mutations appear to be important in the early pathogenesis of uterine serous carcinomas. Moreover, human epidermal growth factor receptor 2 (HER2) overexpression/amplification has also been associated with serous and clear cell carcinomas. Other somatic mutations that have been described in patients with uterine serous carcinomas include PIK3CA, FBXW7, PPP2R1A, and amplification of CCNE1 [10]. These issues are discussed in detail separately. (See 'Prognosis' below and "Endometrial cancer: Pathology and classification", section on 'Integration of molecular subtypes'.)
There are conflicting data regarding whether uterine serous carcinomas are one of the spectrums of cancers in patients with BRCA1 or 2 gene mutations. In a multicentre, prospective cohort study including 828 BRCA mutation carriers (160 of whom used tamoxifen), five incident cases of endometrioid-type uterine cancer were identified compared with 2.04 expected (standardized incidence ratio 2.45; 95% CI 0.80-5.72) during a median follow-up of nine years; there were no uterine serous cancers identified [11]. By contrast, uterine serous carcinomas appear to be more common in patients with BRCA mutations of Jewish ancestry, particularly those of Ashkenazi descent. In one report including 27 patients with uterine serous carcinomas, 74 percent were of Jewish Ashkenazi origin, and of these patients, four (20 percent) had BRCA1 germline mutations [12]. In another retrospective study of 22 patients on Jewish ancestry with uterine serous carcinomas, BRCA germline mutations were identified in six (27 percent) patients [13]. In a review from Israeli medical centers, 14 of 60 patients (23 percent) with uterine serous carcinomas had an inherited BRCA gene mutation [14]. Patients with BRCA gene mutations tended to present with more advanced disease, but the disease-specific survival was similar to that of noncarriers.
EPIDEMIOLOGY AND RISK FACTORS — Serous and clear cell carcinomas, along with other nonendometrioid histologies, account for 10 to 20 percent of endometrial carcinomas [2,15]. Since they are less common than endometrioid carcinomas, there are fewer epidemiologic data about them.
Risk factors for serous and clear cell endometrial carcinomas, in addition to other "aggressive" tumors (see 'Classification' above), have also traditionally been thought to differ from endometrioid tumors in several ways; some of these are well established, but others are controversial [16,17]:
●The average age at diagnosis is older in most studies [2,18]. However, in a prospective study including over 9227 females from Norway with a cancer of the uterine corpus and followed for an average of 25 years, those with type II (992 patients) compared with type I carcinomas had a similar age at diagnosis (mean age, 65 years in both groups) [19]. By comparison, the average age at diagnosis of all uterine cancers in the United States is 62 years old [20].
●Patients tend to have a lower body mass index (BMI) than those with endometrioid endometrial carcinoma [17]. However, there is evidence that obesity is a risk factor for all endometrial carcinomas [19,21]. As an example, in the cohort study including patients from Norway cited above, obesity was associated with an increased risk of either type of tumor, but the risk was more pronounced for type I [19].
●Patients are more likely to be parous than nulliparous [22,23].
●Black patients are more likely than White patients to have aggressive histologies [16,24,25], which may contribute to the poorer overall prognosis for Black patients compared with White patients with endometrial carcinoma [26,27]. Race-based biases, socioeconomic factors, and disparities in access to care likely contribute to this disparity rather than race itself. This is also discussed in detail separately. (See "Overview of resectable endometrial carcinoma", section on 'Other factors'.)
●A personal history of breast cancer appears to be associated with a risk of developing uterine clear cell carcinoma, but this relationship is uncertain [16,28,29]. 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) [29]. 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 uterine serous carcinoma [17]. (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 [30].
General information about the epidemiology of endometrial carcinomas is discussed separately. (See "Endometrial carcinoma: Epidemiology, risk factors, and prevention", section on 'Epidemiology'.)
CLINICAL PRESENTATION — As with endometrioid tumors, abnormal uterine bleeding is the most common clinical presentation for patients with serous and clear cell tumors. Likewise, some patients present with endometrial cells on cervical cytology. This is discussed in detail separately. (See "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening", section on 'Clinical presentation'.)
DIAGNOSTIC EVALUATION
Tissue sampling — As with other types of endometrial carcinoma, serous and clear cell endometrial cancer is a histologic diagnosis made based on histologic evaluation of endometrial sampling, curettage, or a hysterectomy specimen. (See "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening", section on 'Diagnosis'.)
An office endometrial biopsy is a sensitive test for aggressive endometrial carcinomas. However, the correct histology may not be identified in all cases. As an example, in one study including 67 patients with a final postoperative diagnosis of uterine serous carcinoma, 25 percent were initially reported as endometrioid histology based on endometrial biopsy [31]. There were also a few cases (2 of 234 patients) of a false-positive diagnosis of uterine serous carcinoma. These findings may reflect that uterine serous carcinomas can be of mixed histology, as discussed below. (See 'Histologic diagnosis' below.)
Dilation and curettage, with or without hysteroscopy, may be performed in those who cannot tolerate an office biopsy, in whom the office procedure is unsuccessful, or those at very high risk of endometrial cancer.
Histologic diagnosis — The histology of serous and clear cell carcinomas is presented here; the histology of endometrioid tumors is presented separately. (See "Endometrial cancer: Pathology and classification", section on 'Endometrioid carcinoma'.)
●Serous carcinomas – Uterine serous carcinomas have a complex papillary architecture that resembles serous carcinoma of the ovary (picture 1); psammoma bodies are present in 60 percent of cases [32,33]. Marked nuclear atypia is always present, and all uterine serous carcinomas are considered high grade.
●Clear cell carcinomas – Clear cell cancers are characterized by tubulocystic, papillary, or solid patterns (picture 2); psammoma bodies are present in up to 32 percent of cases, most often in the papillary variant [34,35]. The cells may be clear because of the presence of glycogen. Myometrial invasion occurs in approximately 80 percent of cases. While clear cell cancers 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 [36], they are nevertheless treated similar to serous cancers.
●Mixed-histology tumors – Uterine serous 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 uterine serous carcinoma; 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. For clear cell carcinomas, some pathologists require ≥50 percent clear cell features to classify a tumor as a clear cell carcinoma [37], while others use the benchmark of at least 25 percent clear cell component [38,39].
Role of tumor markers — If a serous or clear cell uterine cancer is suspected or diagnosed on an endometrial specimen, a serum cancer antigen (CA) 125 level should be ordered.
Retrospective studies have consistently reported that elevated levels of CA 125 are associated with uterine serous and clear cell cancers, as well as advanced stage, poorly differentiated endometrioid adenocarcinomas [16,40-44]. Elevations of CA 125 are also associated with positive pelvic node involvement, positive peritoneal washings, and the presence of lymphovascular invasion [45]. Thus, knowing a patient may have an advanced-stage uterine cancer may influence the surgery to be performed and determine the need for a gynecologic oncologist to perform that surgery. (See 'Surgical staging' below.)
However, the prognostic effect of an elevated CA 125 on progression-free survival remains controversial and elevated serum CA 125 levels may not be associated with disease recurrence [42,45].
Limited role of transvaginal ultrasound — While transvaginal ultrasound (TVUS) may initially be used to evaluate the endometrium in some patients, endometrial thickness does not reliably exclude serous and clear cell cancers [46]. TVUS, however, may be used to assess for other pelvic pathology (eg, adnexal mass).
Use of TVUS to evaluate the endometrium is discussed separately. (See "Overview of the evaluation of the endometrium for malignant or premalignant disease", section on 'Transvaginal ultrasound'.)
MANAGEMENT
Surgical staging — As with other endometrial cancers, serous and clear cell endometrial carcinomas are surgically staged (table 1 and table 2). Staging of endometrial cancer is discussed in detail separately. (See "Endometrial carcinoma: Staging and surgical treatment".)
Unlike with some endometrioid tumors, omentectomy and pelvic washings are often performed when staging uterine serous or clear cell cancers.
●Omentectomy – The omentum appears to be the most common intra-abdominal site for metastatic disease in such patients. In a cohort study of 40 patients with surgically staged, histologically pure, serous cancers with invasion limited to the endometrium or without stromal invasion, extrauterine intra-abdominal cancers were found in 18 (45 percent) patients [47]. Of these 18 patients, 78 percent had disease of the omentum: 10 patients had gross evidence of tumor deposits (ranging from 0.5 cm to bulky lesions), and an additional four patients had microscopic disease despite a normally appearing omentum.
●Pelvic washings – We perform pelvic washings in patients with serous and clear cell histologies as the presence of cancer cells in the peritoneal cavity is a poor prognostic factor for such patients. However, this practice is controversial, and pelvic washings are not part of the International Federation of Gynecology and Obstetrics (FIGO) endometrial cancer staging system, which is largely based on data from studies of endometrioid endometrial cancers [1]. (See "Endometrial carcinoma: Staging and surgical treatment", section on 'Staging system'.)
While malignant cells in peritoneal washings are found in approximately 5 percent of patients with early stage endometrioid endometrial cancers, higher rates have been reported in those with nonendometrioid endometrial cancers [48,49]. In a retrospective study of data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database, peritoneal cytology was positive in 214 of 1508 (14 percent) patients with uterine serous cancers confined to the endometrium and in 30 of 278 (10.8 percent) of patient with uterine clear cell cancers confined to the endometrium [48].
Malignant cells in peritoneal washings have been associated with decreased survival. In the retrospective study of SEER data discussed above, the five-year overall survival was lower for those with positive compared with negative cytology (uterine serous: 60 versus 77 percent; clear cell: 56 versus 80 percent) [48]. However, this study had limitations including being retrospective, lacking a central pathology review, possible lead-time bias and a lack of knowledge as to why some patients received adjuvant therapy and others did not. Other studies containing small numbers of patients have reported similar results; adjuvant therapy was administered to most patients in these studies [50-52]. In one retrospective study of 68 patients with stage I and II uterine serous cancer for whom their institutional policy was to not administer adjuvant therapy, those with positive compared with negative pelvic cytology had worse five-year disease-free (hazard ratio [HR] 4.2, 95% CI 1.6-11.5) and overall (HR 4.96, 95% CI 1.3-18.3) survival [53].
Optimal cytoreduction is an important component of surgical treatment [54-61]. The strongest predictor of overall survival is the amount of residual disease following surgery [54-60]. In a retrospective review of 70 patients with stage IIIC or IV uterine serous carcinoma, those with optimal cytoreduction with no visible residual disease compared with optimal cytoreduction with macroscopic residual disease and suboptimal cytoreduction had improved rates of survival (median survival: 51 versus 14 and 12 months, respectively) [55]. Outcomes in the group with residual disease were not substantially improved by the use of postoperative chemotherapy.
Adjuvant therapy — Serous and clear cell endometrial carcinomas are considered high-risk disease and patients with such cancers should be offered adjuvant chemotherapy. (See "Adjuvant treatment of high-risk endometrial cancers".)
PROGNOSIS
Natural history — Serous and clear cell endometrial carcinomas have been associated with a poorer outcome than endometrioid tumors in most, but not all studies [39,62-70]. They also have a higher propensity for intraperitoneal and extra-abdominal spread, as well as lymphovascular invasion [62,63,71-75]. At the time of presentation, approximately 50 to 70 percent of patients with uterine serous carcinomas will have disease spread outside of the uterus [54,62,75,76]. Even having as little as 10 percent of the tumor composed of uterine serous carcinoma places the patient at increased risk of metastasis [77].
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 and clear cell carcinomas accounted for 10 and 3 percent of all endometrial carcinomas, but were responsible for 39 and 8 percent of all deaths, respectively [67]. The five-year disease-specific survival rates for serous 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 serous and clear cell cancers was 57.5 percent; the corresponding value for endometrioid cancers was 91.8 percent. Even among patients with surgically staged, node-negative, stage I uterine serous carcinoma, 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].
Prognostic factors
●Pure serous histologies – Earlier studies suggested little difference in survival when patients with pure serous cancers were compared with those with mixed serous cancers [62,78-80]. However, in a multi-institutional series comparing 58 patients with mixed uterine serous carcinomas with 50 patients with pure uterine papillary serous carcinomas, the two most important prognostic factors for progression-free and overall survival were stage and pure serous histology [81]. Patients with pure compared with mixed uterine serous histology had a 2.9-fold greater risk for recurrence and a 2.6-fold higher risk of death [81].
By contrast, patients with pure clear cell and mixed clear cell cancers with endometrioid components have similar survival as those whose clear cell cancers containing less histologically favorable components [38].
●Tumor grade and depth of invasion – While the incidence of extrauterine spread in endometrioid cancer correlates with both tumor grade and depth of myometrial invasion, tumor grade and depth of myometrial invasion are not predictive of extrauterine spread for uterine serous carcinomas (table 4). In one cohort study including patients with uterine serous carcinoma, patients with no myometrial involvement compared with inner one-half or outer one-half myometrial invasion had lymph node metastases in 36, 50, and 46 percent of cases, respectively [64]. The corresponding rates of intraperitoneal disease for these three groups were 43, 37, and 35 percent, respectively.
●Molecular factors – Prognosis can be further informed by molecular factors, including POLE/ultramutated (POLEmut), mismatch repair-deficient tumors (MMRd)/microsatellite instability, and somatic copy-number alterations, including TP53 mutations (p53abn) (table 1 and table 2) [1]. In general, patients with POLEmut tumors appear to have excellent disease-free survival, while patients with p53 mutated (p53abn) tumors appear to experience worse outcomes. Patients with tumors expressing POLEmut or MMRd and a secondary p53 abnormality should not be classified as p53abn as they retain the favorable prognosis of POLEmut or MMRd tumors. This is discussed in detail separately. (See "Endometrial cancer: Pathology and classification", section on 'Integration of molecular subtypes'.)
Overexpression or amplification of HER2 (erbB-2, the epidermal growth factor receptor 2 gene) has also been identified in a number of studies as a poor prognostic sign for serous and clear cell carcinomas [82-87]. In a series of 30 patients undergoing treatment for uterine serous carcinoma (the majority with stage III or IV disease) at a single institution over a seven-year period, amplification of the HER2 gene (as detected by fluorescence in situ hybridization [FISH]) was observed in almost half (47 percent) of patients [82]. At four years, disease-specific survival rates for those with FISH-positive and FISH-negative tumors were 17 and 84 percent, respectively. Management of patients with advanced-stage, previously untreated uterine serous tumors with overexpression of HER2 is discussed separately. (See "Initial treatment of metastatic endometrial cancer", section on 'HER2-overexpressing serous 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) [38]. The recurrence pattern of serous endometrial cancer is similar to epithelial ovarian cancer.
Posttreatment surveillance protocols are the same for other types of endometrial carcinomas. This topic is discussed separately. (See "Overview of resectable endometrial carcinoma", section on 'Post-treatment considerations'.)
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 – Endometrioid adenocarcinoma is the most common type of uterine cancer. Nonendometrioid subtypes, including serous and clear cell carcinomas (picture 1 and picture 2), are less common than endometrioid tumors, and are classified by the International Federation of Gynecology and Obstetrics (FIGO) staging system as "aggressive" tumors, along with grade 3 endometrioid tumors, mixed, undifferentiated, mesonephric-like, and gastrointestinal-type mucinous carcinomas. (See 'Introduction' above and 'Classification' above.)
●Patient characteristics – Patients with serous and clear cell endometrial carcinomas have different characteristics than those with endometrioid tumors. They tend to be older at diagnosis, have a lower body mass index (BMI), and parous. A personal history of breast cancer also appears to be a risk factor for uterine serous carcinoma. (See 'Epidemiology and risk factors' above.)
●Diagnosis
•Endometrial carcinoma is a histologic diagnosis made based on histologic evaluation of endometrial sampling, curettage, or a hysterectomy specimen. (See 'Diagnostic evaluation' above and "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening", section on 'Diagnosis'.)
•In patients with suspected or confirmed serous or clear cell uterine cancer, cancer antigen (CA) 125 levels are obtained preoperatively. Elevations of CA 125 are associated with positive pelvic node involvement, positive peritoneal washings, and the presence of lymphovascular invasion; 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. (See 'Role of tumor markers' above.)
●Management
•Surgical staging – Serous and clear cell endometrial carcinomas are surgically staged in the same manner as endometrioid tumors (table 1 and table 2). However, as these tumors are at high risk of nodal and extrauterine metastasis, omentectomy and pelvic washings are also often performed. Optimal cytoreduction is an important component of surgical treatment. (See 'Surgical staging' above.)
•Adjuvant therapy – Serous and clear cell endometrial carcinomas are considered high-risk disease and patients with such cancers should be offered adjuvant chemotherapy. This is discussed separately. (See "Adjuvant treatment of high-risk endometrial cancers".)
●Prognosis
•Serous and clear cell endometrial carcinomas have been associated with poorer outcomes than endometrioid tumors in some studies (table 3), but the evidence is uncertain. They also have a higher propensity for intraperitoneal and extra-abdominal spread, as well as lymphovascular invasion. (See 'Natural history' above.)
•Some molecular factors, such as TP53 mutations (p53abn) and overexpression or amplification of HER2 (erbB-2, the epidermal growth factor receptor 2 gene) are associated with poor prognosis. By contrast, POLE/ultramutated (POLEmut) is associated with an excellent prognosis. (See 'Prognostic factors' above.)
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