Updates on uterine papillary serous carcinoma

Abstract

Uterine papillary serous carcinoma (UPSC) is a biologically aggressive subtype of endometrial cancer. Although much less common than its endometrioid carcinoma counterpart, UPSC accounts for a disproportionate number of endometrial cancer-related recurrences and subsequent deaths. Women most often present with postmenopausal vaginal bleeding. In women diagnosed with metastatic disease, ascites, omental implants or a pelvic mass may be present. Local and distant recurrences occur frequently, with extrapelvic relapses being observed most commonly. Although few prospective trials exist, several retrospective series have demonstrated that optimal cytoreduction and adjuvant platinum/taxane-based chemotherapy with or without radiotherapy appears to improve survival. In addition, another approach to the management of UPSC may lie in targeted therapy. This article reviews the recent literature concerning the epidemiology, molecular pathogenesis and management of UPSC.

Keywords::

• endometrial cancer
• platin/taxane-based chemotherapy
• radiotherapy
• surgical staging
• targeted therapy
• uterine papillary serous carcinoma

Medscape: Continuing Medical Education Online

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Learning objectives

Upon completion of this activity, participants should be able to:

• • Describe the prevalence and mortality of uterine papillary serous carcinoma (UPSC) among endometrial cancers

• • Identify characteristics of women at risk for UPSC

• • Describe presenting clinical features of UPSC

• • Identify prognostic factors for UPSC

• • Describe optimal management strategies for UPSC

Financial & competing interests disclosure

EDITOR

Elisa Manzotti, Editorial Director, Future Science Group, London, UK.

Disclosure:Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Désirée Lie, MD, MSEd, Clinical Professor, Department of Family Medicine, University of California, Irvine; Director, Division of Faculty Development, UCI Medical Center, Irvine, California.

Disclosure:Désirée Lie, MD, MSEd, has disclosed no relevant financial relationships.

AUTHORS

Amanda Nickles Fader, MD, Section of Gynecologic Oncology, Greater Baltimore Medical Center/The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD, USA

David Boruta, MD, Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA

Alexander B Olawaiye, MD, Department of Obstetrics and Gynecology, Magee-Women’s Hospital/University of Pittsburgh, Pittsburgh, PA, USA

Paola A Gehrig, MD, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, NC, USADisclosure:The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Figure 1. Proposed uterine papillary serous carcinoma management algorithm.

BSO: Bilateral salpingo-oophorectomy; CT: Computed tomography; PA: Pelvic angle; TH: Total hysterectomy; UPSC: Uterine papillary serous carcinoma.

Reproduced with permission from [79].

Endometrial cancer is the most common gynecologic malignancy in women in the USA [1]. In 2008, approximately 40,100 new cases were diagnosed and 7470 deaths occurred. Endometrial cancer is classified as type I or II, based on the dualistic classification proposed by Bokhman in 1983 [2]. Type I malignancies are primarily of low-grade endometrioid histology, present in early stages and are the most common subtype of endometrial cancer. By contrast, type II malignancies are of serous or clear-cell histologies, present in more advanced stages and have a poorer prognosis than their type I counterparts. Death rates for endometrial cancer have gradually risen over the last decade [3]. Although the reasons for this are multifactorial, findings from a recent Surveillance, Epidemiology, and End Results (SEER) database study of more than 45,000 endometrial cancer patients suggest that the increase in mortality may be related to an increased rate of advanced-stage cancers and high-risk histologies, including uterine papillary serous carcinoma (UPSC) [3].

Although UPSC represents less than 10% of all endometrial cancers, it accounts for up to 39% of all endometrial cancer-related deaths [4,5]. It is characterized by a high-grade, complex histology and is biologically more aggressive than endometrioid adenocarcinoma. Type I and II endometrial cancers appear to have different patterns of molecular alterations that underlie their pathogenesis and clinical outcomes. While endometrioid carcinoma tends to have alterations in the tumor-suppressor gene, PTEN, these are uncommon in UPSC, with p53 mutations and HER2/neu expression occurring more commonly in this tumor subtype [2,6]. UPSC in both early-stage (stage I/II with disease confined to the uterus) and advanced disease states (stage III/IV with metastases present outside of the uterus) behaves aggressively. UPSC has a tendency to invade the lymphatic and vascular spaces, metastasize to lymph nodes and microscopically involve other intraperitoneal structures, despite minimal or no invasion present within the uterus. These tumor characteristics lead to high recurrence rates and a poor prognosis for patients [5].

Epidemiology & diagnosis

In 1982, Hendrickson et al. first recognized UPSC as a distinct subtype of endometrial cancer, describing it as histologically similar to serous epithelial ovarian carcinoma [7]. Since then, several investigators have demonstrated that UPSC has a distinct microscopic appearance, epidemiology and clinical behavior compared with other endometrial cancer subtypes [8–10]. While type I carcinomas typically arise in relatively younger women with obesity and unopposed hyperestrogenism (endogenous or exogenous), type II carcinomas, such as UPSC, often arise in thinner, older women, and demonstrate no hormonal risk factors [11,12]. Although obesity is traditionally considered a risk factor for type I carcinomas, recent studies suggest that obesity is a risk factor for the development of all endometrial carcinomas, including the type II histologies [12].

Uterine papillary serous carcinoma also appears to occur more commonly in African–American women than women of other ethnicities and may contribute to the racial disparity observed in survival from endometrial cancer [15–17]. In an ancillary study by the Gynecologic Oncology Group (GOG), a cooperative research network, Maxwell et al., found the incidence of UPSC to be 16 versus 39% in White and Black women, respectively [16]. Furthermore, survival in African–American women was significantly worse, despite delivery of similar treatments to all women in the study. This disparity, however, was demonstrated regardless of histologic type, suggesting that other factors may contribute to the poorer survival of African–American women with endometrial cancer. Table 1 summarizes the clinical and epidemiologic differences of women with type I endometrioid adenocarcinomas versus type II UPSC cancers.

The most common presenting symptom in women diagnosed with UPSC is postmenopausal vaginal bleeding. Endometrial biopsy is highly sensitive for the detection of high-grade endometrial carcinomas. Huang et al. found Pipelle biopsy to be more than 99% sensitive in this setting [18]. However, it was less accurate at predicting specifically UPSC amongst other high-grade endometrial carcinomas. Of 67 women with a final postoperative diagnosis of UPSC, 17 were initially diagnosed with endometrioid adenocarcinoma on endometrial biopsy. This may be because UPSC is often diagnosed concurrently with other high-grade carcinomas, including those of endometrioid and clear-cell histology.

Pelvic ultrasound is also a useful tool in the evaluation of postmenopausal or abnormal vaginal bleeding, but caution must be exercised when interpreting a thin endometrial stripe in women with persistent symptoms or other ultrasonographic abnormalities. While large prospective series have demonstrated that women with an endometrial stripe thickness of 5 mm or thinner are unlikely to have an endometrial malignancy [19], this is more likely to be true for type I carcinomas. Wang et al. published a series of 52 women with type II endometrial carcinomas (of whom 24 had UPSC) who underwent preoperative ultrasound testing and found that the endometrial stripe measured at least 5 mm in 35% and less than 4 mm in 17% of cases [19]. Therefore, persistent symptoms in a patient, despite reassuring imaging, should warrant a histologic diagnosis.

Molecular biology & precursor lesions

The molecular profiles of UPSC and endometrioid adenocarcinoma are vastly different. cDNA microarray analyses of endometrial carcinomas of different histologic types have established different gene expression profiles when UPSC is compared with endometrioid and clear-cell adenocarcinomas of the endometrium [6,21,22]. Further understanding and characterization of these profiles may help to explain differences in their biological behavior, which, in turn, may help to identify potential therapeutic targets. Endometrioid adenocarcinoma frequently displays inactivation of the PTEN tumor-suppressor gene, as well as defects in DNA-mismatch repair, leading to microsatellite instability and mutations in β-catenin and K-ras[23]. Alternatively, UPSC is frequently characterized by mutations in the tumor-suppressor gene p53 and amplification of the HER2/neu gene [23,24]. Of all UPSC specimens, 90% will exhibit abnormal p53 staining. However, recent studies have demonstrated that up to 7% of high-grade endometrioid adenocarcinomas of the endometrium also exhibit abnormal p53 expression and that this expression is independently correlated with poorer survival outcomes for patients [24]. Therefore, it is unclear at this point whether the histology or aberrant expression of specific genes (or both) drives the clinical behavior of these higher risk tumors.

Another gene associated with UPSC is HER2/neu. Several small studies have demonstrated that HER2, also known as c-erbB2 or HER2/neu, is frequently overexpressed in UPSC tumors (16–62%) and may contribute to transformation and tumorigenesis [25,26]. Some studies have associated HER2/neu overexpression with advanced-stage disease and poorer progression-free and overall survival outcomes, making HER2/neu a possible candidate marker of worse overall prognosis in UPSC [27–29]. In addition to serving as a candidate marker of worse prognosis, HER2/neu may also serve as a potential therapeutic target. Other molecular alterations noted in UPSC tumors include overexpression of the claudin 3/4 genes (epithelial receptors for the Clostridium perfringens enterotoxin) and the oncoprotein, Bcl-2 (Table 1)[6,23].

The precursor of type I endometrioid adenocarcinomas is commonly estrogen-stimulated, atypical endometrial hyperplasia. Precursor lesions for UPSC have only recently been identified. Sherman et al. were the first to propose a precursor lesion for UPSC, known as endometrial intraepithelial carcinoma (EIC) [10]. EIC is characterized by a thin layer of malignant-appearing cells present in surface endometrium, resembling cells of invasive serous carcinoma. Another study provided further evidence for such a relationship, establishing the presence of EIC in 98% of uteri with UPSC compared with only 6% with endometrioid adenocarcinoma [11]. Although ‘precursor’ lesions, they appear to have the potential for metastatic spread. Recent series have demonstrated the presence of extrauterine UPSC in numerous women with EIC [10,11]. This suggests that EIC may represent an ‘early’ form of UPSC as opposed to a precancerous lesion.

A lesion known as endometrial glandulardysplasia may be a precursor to EIC. These microscropic areas in the endometrium are noted for their enlarged nuclei and mild cytologic atypia, and stain positive for p53 and an antibody against Ki-67 (MIB-1), a nuclear proliferation marker [30,31]. Glandular dysplasia has been noted in the endometrial biopsy specimens of women several months to years before the appearance of EIC or UPSC.

Treatment

Surgery

Type I endometrial carcinomas are commonly diagnosed at an early stage and have a favorable prognosis, often with surgical treatment alone. Conversely, type II carcinomas, such as UPSC are more likely to present with metastatic disease at diagnosis [32–35]. In a International Federation of Gynecology and Obstetrics (FIGO) Annual Report, stage II–IV disease was noted at presentation in 46% of women with UPSC compared with 21% of women with endometrioid adenocarcinoma [32]. The initial management for the majority of women with UPSC is an exploratory laparotomy (or laparoscopy) and comprehensive surgical staging. This includes a total hysterectomy, bilateral salpingo-oophorectomy, pelvic washings, pelvic and para-aortic lymphadenectomy and omentectomy. However, Gehrig and colleagues concluded that omental sampling does not need to be performed in the routine surgical staging of UPSC as the sensitivity of a visually negative omentum was 0.89 (p < 0.0001) in their retrospective study of 65 UPSC patients [36].

In type I cancers, factors such as myometrial invasion, primary tumor size and lymphvascular space invasion within the uterus increase the risk of metastatic disease, as well as of recurrent disease after initial treatment [37]. However, predication of performance of selective surgical staging based upon such variables is not reliable for assessing metastatic disease or recurrence in UPSC. Numerous studies have demonstrated that, after comprehensive staging, metastatic UPSC is commonly encountered despite the absence of these features. In a series of 52 surgically staged women with UPSC, Goff et al. noted similar incidence of lymph node and intraperitoneal metastases in women with either no myometrial invasion or deep invasion (36 vs 40% and 43 vs 35%, respectively) [36,37]. Several retrospective series demonstrated that women whose tumors lack myometrial invasion may still have high rates of coincident extrauterine disease at the time of comprehensive surgical staging (ranging from 37 to 63%) [36–42]. The prognostic significance of thorough surgical staging was emphasized in one such study by the finding of 94% overall survival in women with tumors limited to their uteri [40]. Furthermore, a recent clinicopathologic study identified no reliable patient or tumor factors that predicted the risk of relapse in stage I–II UPSC patients [39]. Patients with UPSC confined to their uterine specimens were still at a significant risk for recurrence (21% overall) and poor survival outcomes regardless of the presence of LVSI, tumor size or percentage of UPSC histology in the uterine specimens. UPSC often coexists with at least one other (typically high-grade) subtype of uterine cancer. However, this study suggests that any percentage of UPSC in a mixed-histology specimen confers a risk for recurrence similar to that in a pure UPSC tumor and that traditional uterine features used to predict prognosis in patients with early-stage endometrioid adenocarcinoma may not be relevant in women with UPSC. Therefore, in the absence of obvious metastatic disease, all UPSC patients should be comprehensively surgically staged.

Unfortunately, a large percentage of women with UPSC present with extrauterine disease at diagnosis. Multiple studies have documented an inverse correlation between survival and the volume of residual disease remaining after cytoreductive surgery in the setting of serous ovarian carcinoma [50–52]. A number of retrospective studies suggest that cytoreductive surgery confers a survival benefit in women with metastatic UPSC as well [49,51–55]. In a report of 70 women with stage IIIc or IV UPSC by Thomas et al., optimal cytoreduction (defined as no gross residual disease of >1 cm in diameter) was achieved in 60% of women, with no visible residual disease achieved in 37% [55]. A significant difference in median time to recurrence (9 vs 6 months; p = 0.04) and median survival (20 vs 12 months; p = 0.02) was observed between optimally and suboptimally cytoreduced patients.

Chemotherapy & radiotherapy

Owing to poor results with surgery alone, both radiotherapy (RT) and chemotherapy have been investigated postoperatively in women with both early- and advanced-stage disease in an effort to improve outcomes. However, the benefit of these modalities, as well as the optimal treatment for each disease stage, remains unclear. RT is often utilized to achieve local disease control or to treat locoregional recurrences, while chemotherapy is used to treat systemic or metastatic disease. In women with stage I endometrioid adenocarcinoma, 5-year survival is approximately 80–90%, but only 50–80% of women with stage I UPSC experience similar survival rates [4,56–59]. Furthermore, in women with UPSC, disease relapse commonly occurs outside the pelvis, limiting the ability of RT as a single modality to be delivered with curative intent.

Early-stage disease

For early-stage disease, the frequency of distant recurrence, along with treatment failures within the radiation fields, has led to increasing use of adjuvant chemotherapy [56–62]. Retrospective studies by Huh, Kelly, Dietrich, Havrilesky and others have all demonstrated that patients treated with platinum-based chemotherapies have improved outcomes compared with early-stage patients undergoing observation after surgery or RT alone [56–64]. Dietrich et al. reported their use of platinum-based adjuvant chemotherapy in 29 women with stage I UPSC [61]. Treatment consisted of carboplatin (AUC 6) and paclitaxel (135–175 mg/m²) in 21 women. All of the patients were alive without evidence of disease 10–138 months after treatment. One vaginal recurrence after three cycles of adjuvant chemotherapy was successfully treated with chemoradiation.

Fader et al. reported on the largest series of both stage I and II UPSC patients in the literature and demonstrated a significant improvement in recurrence rates, progression-free and overall survival in patients treated with carboplatin/paclitaxel-based regimens [57,65]. Specifically, for stage I patients, all patients treated with carboplatin/paclitaxel with or without RT had a lower risk of recurrence (9.2%) compared with patients treated with radiation alone (24.2%; p = 0.04) and observed patients after surgery (30.2%, p = 0.004). On multiple logistic regression, the adjuvant treatment strategy (p = 0.036) and substage (p = 0.003) were significantly associated with recurrence. The 5-year progression-free (p = 0.009) and overall survival rates (p = 0.012) were, again, highest in chemotherapy-treated patients when compared with RT-treated patients and those observed after surgery.

It is unclear whether all early-stage patients require adjuvant treatment. Studies by Hui et al. and Kelly et al. attempted to stratify their consideration of observation of women with surgical stage IA UPSC to those without residual disease in the uterine specimen or with disease confined to a polyp, respectively [42,64]. In these series, no recurrences were noted in 12 patients with stage IA disease without residual UPSC or in 22 patients with disease confined to a polyp who were observed following surgery. In their series of 74 stage I UPSC patients, Kelly et al. also noted a 43% recurrence rate in stage IA patients with residual uterine disease who were observed after surgery [64]. The authors proposed that concomitant platinum-based chemotherapy and vaginal-cuff radiation should be offered to all women with stage I UPSC, except for women with stage IA disease with no residual cancer present in the hysterectomy specimen. Therefore, patients with disease confined to a polyp or without residual uterine disease should be counseled that the risk of recurrence is quite low but not negligible, and that relapses may be aggressive and not curable. Therefore, there may be justification for considering postoperative adjuvant therapy, even in women whose disease is confined to an endometrial polyp.

Advanced-stage disease

Not surprisingly, recurrence rates in women diagnosed with advanced-stage UPSC are much higher than for early-stage disease, with rates of 50–90% reported in published studies [8–12]. These recurrences are often extrapelvic and largely unsalvageable, and they highlight the need for effective systemic therapy in the treatment of this disease. GOG report number 33 demonstrated that para-aortic nodal disease was more common in patients with UPSC tumors [66], and GOG report number 94 demonstrated that, in stage III/IV UPSC patients treated with whole-abdominal radiation, the majority of failures were multisite and extrapelvic (with distant failures not being uncommon) [67]. These cooperative group findings indicate that, while RT is beneficial in providing local-disease control, RT alone has a limited role in the management of UPSC.

It has been suggested that UPSC tumors more closely resemble ovarian cancers than endometrial cancers. The high rates of intra-abdominal disease spread and intra-abdominal failures reported support this concept and have led to the use of ovarian cancer-based chemotherapy regimens as treatment in women with advanced UPSC. As more effective chemotherapeutic agents have been identified in endometrial cancer, combination regimens have demonstrated improved responses, and, at least in populations with advanced disease, chemotherapy (e.g., doxorubicin, cisplatin and cyclophosphamide) has shown superiority to radiation alone in a randomized Phase III study (GOG report number 122) [67]. Chemotherapy, either alone or in combination with RT, has been evaluated in the management of advanced-staged endometrial cancer [67–69]. As UPSC is a rare tumor subtype, it is often grouped with more common endometrial tumor subtypes (i.e., endometrioid adenocarcinoma) in prospective treatment studies. However, studies suggest that UPSC patients tend to fare worse and may exhibit more heterogeneity of response to chemotherapy than their counterparts with less-aggressive subtypes. Therefore, there is a need to study UPSC as its own clinical entity.

In terms of the relevant studies on advanced-stage endometrial cancer – many of which included UPSC patients – there are several reports that help guide management. Burke et al. reported on 62 patients with high-risk endometrial cancer (21% with UPSC or CC histologies) treated with cisplatin, adriamycin and cyclophosphamide following surgical staging [68]. The 3-year survival was 82% in patients without extrauterine disease. Levenback et al. described 20 patients with all stages of UPSC treated with the same regimen and reported a 5-year survival of 23% [69]. Paclitaxel has demonstrated significant activity in endometrial cancer patients with advanced or recurrent disease in two GOG Phase II studies (GOG 86-O, 129-C) [70,71], specifically, in the treatment of UPSC [70]. The combination of cisplatin and adriamycin versus paclitaxel (Taxol^®), doxorubicin (Adriamycin^®) and cisplatin (Platinol-AQ^®), collectively known as TAP, was then studied in GOG report number 177, a Phase III trial of primary, advanced-stage endometrial cancer patients with superior progression-free and overall survival outcomes noted in the TAP cohort [73]. TAP is currently being compared with paclitaxel/carboplatin in GOG-209, a Phase III equivalence study, in the same cohort of patients.

A recent Phase II pilot study of pelvic RT ‘sandwiched’ between platinum/taxane-based therapy in stage I–IV UPSC patients demonstrated that this regimen had excellent antitumor activity and a favorable toxicity profile, but the majority of patients with advanced disease experienced disease recurrence during the 3-year study period [74]. Furthermore, two recent Phase III studies from the Japanese GOG and Nordic Society Gynecological Oncology (NSGO)/European Organisation for Research and Treatment of Cancer (EORTC), respectively, demonstrated that patients with high-risk, early-stage endometrial cancers treated with chemoradiation had improved progression-free and overall survival when compared with patients treated with RT alone. Patients with UPSC were included in these trials [75,76]. Finally, a UPSC management algorithm that takes into account and summarizes all the available literature on UPSC treatment is illustrated in Figure 1.

Treatment horizons

Targeted therapies

In addition to platinum/taxane-based chemotherapy, another reasonable approach to the treatment of UPSC may lie in targeted therapy. Several small studies have demonstrated that HER2/neu is frequently overexpressed in UPSC tumors and may contribute to transformation and tumorigenesis [24–28]. In most cases, HER2 protein overexpression has been thought to result from gene amplification and has been correlated with poor clinical outcome in patients with breast cancer. A Phase III trial of treatment with an anti-HER2/neu monoclonal antibody (trastuzumab) demonstrated a high concordance between HER2/neu expression by immunohistochemistry and gene amplification by FISH [77]. However, concordance between these molecular diagnostic tests has not been as strong in studies of other solid tumors (i.e., prostate and ovarian cancer) that may express HER2/neu. In 26 UPSC samples evaluated by Santin et al., 62% exhibited HER2/neu overexpression [25]. Protein overexpression and gene amplification were found to correlate in nine out of nine (100%) of the 3+ positive tumors but in only two out of seven (29%) of the 2+ positive tumors. There are small, retrospective studies suggesting that UPSC patients that overexpress HER2 have poorer outcomes [24–29]. In the largest reported series of UPSC patients, HER2/neu was overexpressed in 47% of patients but rates of 26–62% positivity have been observed depending on the disease stage [27]. Although gene amplification and protein expression of HER2/neu are often correlated, it remains unclear whether protein overexpression or gene amplification (or both) predict poor outcome, high-stage disease or response. Further studies are needed in this regard.

Preliminary data suggest that patients with advanced-stage disease have higher rates of HER2/neu overexpression. These results raise the possibility of therapeutic strategies that target HER2, such as using the anti-HER2 monoclonal antibody trastuzumab (Herceptin^®; Genentech Corp, CA, USA). Results from two large, randomized, clinical trials for patients with HER2-positive invasive breast cancer show that those patients who received trastuzumab in combination with chemotherapy had a significant decrease in risk for breast cancer recurrence compared with patients who received the same chemotherapy without trastuzumab [77,78]. Since the approval in 1988 of two trastuzumab plus chemotherapy combinations, several such regimens have gained favor in the clinical practice community for the treatment of breast cancer. Recently, the National Comprehensive Cancer Network (NCCN) guidelines recommended trastuzumab plus paclitaxel and carboplatin as an acceptable combination regimen to treat HER2-expressing metastatic breast cancer.

A Phase II study of single-agent trastuzumab in advanced and/or recurrent endometrial cancer from the GOG has recently closed, with the results not yet available. However, of all endometrial cancer subtypes, HER2/neu appears to be most commonly expressed in UPSC. Therefore, there is scientific rationale for studying platinum/taxane-based regimens with trastuzumab in this patient population. Preclinical and clinical data suggest that taxane, trastuzumab and platinum compounds act at least additively, if not synergistically. Studies in HER2-positive breast cancer demonstrates improved efficacy of trastuzumab and paclitaxel with the addition of carboplatin. To date, trastuzumab therapy, either as monotherapy or in combination with chemotherapy, has not been well studied in UPSC.

Expert commentary

Women diagnosed with UPSC should undergo comprehensive surgical staging and an attempt at optimal cytoreduction. Platinum/taxane-based adjuvant chemotherapy should be considered in the treatment of both early- and advanced-stage patients. Careful long-term surveillance is indicated, as many of these women will recur. Clearly, there is a critical need to determine the optimal chemo- and radio-therapeutic regimens and whether targeted therapy may be beneficial in women with UPSC. As it is recognized that UPSC tumors are an uncommon subtype of endometrial adenocarcinoma, making it more difficult to conduct a large Phase III trial, one would argue that serial Phase II studies might help define a standard-of-care approach. A standard of care for patients with early- and advanced-stage UPSC should be defined.

Until a defined standard of care is acheived, accurate pathologic diagnosis, comprehensive surgical staging, optimal cytoreduction and a low threshold for initiation of adjuvant chemotherapy, preferably platinum/taxane-based or as part of a clinical trial, should be strongly considered. While there is debate regarding who should be treated and with what modalities, all would be in agreement that the optimal therapy for women with this disease remains to be defined and that it is our obligation to provide clinical trials for women with these relatively uncommon tumors.

Five-year view

The development of novel therapeutic agents with targets specific to UPSC is a promising area of research. As discussed earlier, UPSC is characterized by frequent HER2/neu gene amplification [25]. These results raise the possibility of therapeutic strategies that target HER2, such as using the anti-HER2 monoclonal antibody trastuzumab (Herceptin). Evidence-based guidelines and expert consensus have been slow to evolve in the management of UPSC owing to its relative rarity. Furthermore, the optimal approach to studying UPSC has yet to be defined. Given its relative infrequency, UPSC is usually ‘lumped’ with other endometrial cancer subtypes in large, randomized studies, such as those discussed earlier. The percentage of women with UPSC enrolled in these trials is usually low (<20% of all participants), leading to underpowered, and perhaps incorrect, conclusions being drawn regarding the efficacy of a specific therapy in this subgroup.

However, given its more-aggressive tumor biology, lethality and clinicopathologic distinction from endometrioid adenocarcinoma, it would be ideal to study UPSC independently, perhaps in serial Phase II studies. This may be facilitated through an international ‘rare cancer’ cooperative network. Alternatively, women with UPSC could be studied alongside women with other high-risk histologic subtypes of endometrial carcinoma, such as grade 3 endometrioid adenocarcinoma or clear-cell adenocarcinoma. This will allow us to determine whether molecular markers, such as p53 or the personally described histologies, drive the aggressive behavior of serous carcinomas and other high-grade tumor subtypes. p53, HER2/neu and other markers may help us prognosticate clinical outcomes for endometrial cancer patients in a more sophisticated manner than currently available techniques allow. This may not only help us to understand the relationship between tumoral molecular characteristics and patient outcomes but may also provide important information to clinicians regarding which patients may safely avoid adjuvant therapy and which patients require aggressive treatment beyond surgery.

Table 1. Contrasting features of endometrioid adenocarcinoma versus uterine papillary serous carcinoma.

Feature	EEC	UPSC
Demographic risk factors	Younger age Unopposed estrogen • Obesity (endogenous) • Unopposed oral estrogen (exogenous)	Older age Thin Race?
Clinicopathologic risk factors predictive or metastatic disease or recurrence	Myometrial invasion Lymphovascular space involvement Tumor size Tumor grade Lymph node involvement	None; all can recur in the absence of ‘risk factors’
Histologic grade	Low Intermediate High	High
Stage at presentation (incidence [%])	I (73%) II (11%) III (13%) IV (3%)	I (54%) II (8) III (22%) IV (16%)
Patterns of recurrence	Locoregional	Extrapelvic
Molecular alterations: PTEN ER/PR p53 HER-2/neu overexpressed Claudin 3/4 overexpressed Bcl-2	80% mutated Positive Mutations rare 10–30% NA NA	Mutations rare Negative 90% mutated 45% Yes Yes

EEC: Endometrioid endometrial carcinoma; ER: Estrogen receptor; MSI: Microsatellite instability; NA: Not applicable; PR: Progesterone receptor; UPSC: Uterine papillary serous carcinoma.

Data from [10–39].

Key issues

• • Although uterine papillary serous carcinoma (UPSC) comprises less than 10% of all endometrial carcinoma cases, it accounts for a disproportionately high number of endometrial cancer-related deaths and affects African–American women more frequently than non-Hispanic White women.

• • UPSC differs from the more common endometrioid subtype of endometrial cancer, in both its molecular and clinicopathologic profiles.

• • UPSC may present with symptomatic postmenopausal vaginal bleeding and is also rarely detected by cervical cytology. It can be diagnosed using office endometrial biopsy.

• • UPSC is histologically aggressive: extrauterine disease is common and can be identified with comprehensive surgical staging, and extrapelvic relapses after surgical staging are also common in women with both early- and advanced-stage disease.

• • Optimal surgical cytoreduction and treatment with platinum/taxane-based chemotherapy appears to confer a survival benefit.

• • Randomized prospective trials addressing questions pertaining to the management of UPSC are lacking.

• • Targeted therapies, such as anti-HER2/neu agents, should be investigated for the treatment of UPSC.

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Updates on uterine papillary serous carcinoma

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1. Compared with type I endometrial cancers, mortality from uterine papillary serous carcinoma (UPSC) malignancies is likely to be best described by which of the following?

• □ A Similar

• □ B Double

• □ C Triple

• □ D Quadruple

2. Which of the following best describes the profile of a woman at risk for UPSC?

• □ A 50-year-old, white, thin woman

• □ B 65-year-old, black, thin woman

• □ C 65-year-old, white, obese woman

• □ D 50-year-old, black, obese woman

3. Which of the following is the most common clinical presentation of UPSC?

• □ A Abdominal mass

• □ B Abdominal pain

• □ C Postmenopausal vaginal bleeding

• □ D Chronic anemia

4. Which of the following is considered the most reliable prognostic indicator for future relapse in patients with stage I–II UPSC?

• □ A Tumor size

• □ B Confinement to uterus

• □ C Lymph node involvement

• □ D None of the above

5. A 60-year-old woman presents with stage IA UPSC confirmed by endometrial biopsy and laparotomy, with residual uterine disease. Which of the following is the optimal initial therapy for this patient?

• □ A Cytoreductive surgery

• □ B Radiation therapy and chemotherapy

• □ C Cytoreduction and chemotherapy

• □ D Cytoreduction and radiation therapy