Endometrial neuroendocrine carcinoma frequently associated with mismatch repair deficiency

Endometrial neuroendocrine carcinoma frequently associated with mismatch repair deficiency | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Endometrial neuroendocrine carcinoma frequently associated with mismatch repair deficiency Feng Zhou, Mengfei Xu, Qin Chen, Xiaofei Zhang, Hao Chen, Wenxin Zheng This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-25180/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Endometrial neuroendocrine carcinoma (NEC) is a uncommon histologic subtype of endometrial cancer. It is currently unclear if the endometrial NEC has any particular relationship with mismatch repair (MMR) protein expression patterns. Here we report 3 endometrial NEC cases showing loss of MMR expression. Case presentation: The cancers had two components with one poorly differentiated or NEC component, accounting for 60–90% of the neoplasms and the other of well differentiated glandular component. The NEC cells mainly showed solid sheets and organoid patterns, whereas insular, trabecular and rosette/pseudorosette patterns were also found. The NEC component was composed of cells with large, polygonal, vesicular nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm. In all cases, the NEC component was diffusely positive for p16 and at least 2 of the 3 neuroendocrine markers (CGA, SYN, CD56) reactive in > 10% of the cancer cells. Loss of MMR protein expression was found in all three cases with loss of MLH1 in cases 1 and 2 and loss of MSH2 and MSH 6 in case 3. No PMS2 loss was found. In addition, aberrant TP53 and SMARCB1 (INI1) expression was found in case 3 only. All patients underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy, and two of them received postoperative chemotherapy and/or radiation therapy. The patients remained alive with no disease for 51, 17 and 6 months, respectively. Conclusion: Endometrial NEC is frequently associated with MMR deficiency, some of which may have a better prognosis than we expect. Pathology Neuroendocrine carcinoma Endometrioid carcinoma MMR deficiency Figures Figure 1 Background As recommended by the World Health Organization (WHO), the terminology for gastro-entero-pancreatic neuroendocrine tumors (NET) is applicable to nueroendocrine carcinoma (NEC) arising from the female genital tract [ 1 ]. NETs are classified as poorly-differentiated NEC and well-differentiated NET based on the tumor nuclear grade. Low-grade NET is extremely rare with only occasional reports in the English literature [ 2 , 3 ]. Meanwhile, NEC with very high grade is also rare. It is well known that NECs such as small or the large cell NEC behave aggressively and patients with such cancers have a poor prognosis [ 4 ]. There are approximately 100 cases of NEC arising from the endometrium have been reported in the past [ 4 ]. However, there were few studies addressed the relationship between the endometrial NEC and the abnormality of mismatch repair (MMR) protein expression in these cancers. We herein delineated 3 cases of the endometrial NEC with MMR deficiency. Material And Methods Tissue samples All three cases were retrieved from the archives of the Department of Pathology, the Women’s Hospital, School of Medicine, Zhejiang University, China, in the last 5 years. We obtained clinicopathologic information from hospital informatics system. This study was approved by the ethics committee of above institution. Large cell NEC is diagnosed based on World Health Organization (WHO) criteria: 1) large cells with prominent nucleoli and abundant cytoplasm, 2) a neuroendocrine growth pattern (organoid, insular, trabecular, rosette/pseudo-rosette), and 3) > 10% of tumor cells reactive to at least one NET markers including chromogranin (CGA), synaptophysin (SYN) and CD56 [ 1 ]. Hematoxylin and Eosin (H&E) and immunohistochemistry (IHC) slides were reviewed by 3 gynecologic pathologists (FZ, XZ, and WZ) and the pathologic diagnosis of the cases was confirmed by consensus. Immunohistochemical analysis Additional 4-µm paraffin sections were stained with a panel of antibodies using the 2-step Envision method according to the manufacturer’s instructions and visualized with 3-diaminobenzidine tetrachloride (Sigma, St Louis, MO) as described previously (add a reference here). The sources and dilutions of the antibodies used in this study are detailed in Table 1. All primary antibodies and the detection kit were products of Dako Corporation (Glostrup, Denmark). The omission of primary antibodies with the same class non-specific IgG was used as the negative control. The IHC stained slides were scored as follows: negative (no cells stained), focally positive (≤ 10% cells stained), patchy positive (11–49% cells stained) and diffusely positive (≥ 50% of cells stained). Results Clinical findings The main clinical findings of these cases are summarized in Table 2. Briefly, median age was 56 years (range, 54-59 years), and all patients presented with postmenopausal or perimenopausal vaginal bleeding/discharge. All patients denied familial history of endometrial or colon cancer. No any other history of malignancies were identified from patients’ relatives. The diagnosis was made on endometrial biopsy and was followed by total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH-BSO) and staging procedures. The tumors showed the FIGO stage as follows: case 1 with stage IIB, case 2 with stage IB, and case 3 with stage IIIC at the time of diagnosis. Patients of case 1 and 3 received both postoperative chemotherapy and radiation therapy, while case 2 received adjuvant radiation only. Pathological findings The main pathological findings of these cases are given in Table 2. Macroscopically, all tumors formed large, polypoid, intracavitary masses, ranging from 3 to 4.5 cm. The tumors were largely located in the uterine funds with no low uterine segment location was noted. The cut surface was soft, fleshy, and necrotic. Microscopically, the tumors showed a dominant NEC component ranging from 60-90% of the total tumor volumes of the cases. Small amount of well-differentiated endometrioid carcinoma with focal areas of squamous differentiation were identified in case 3 only. Increased tumor-infiltrating lymphocytes at the tumor invading front or periphery were found in all 3 cases (Fig. A). Extensive geographic necrosis was present. The NEC components mostly showed solid sheets with organoid growth patterns, whereas insular, trabecular and rosette/pseudorosette patterns were found in about 30% cancerous areas in average (Fig. B-D). The NEC components were composed of cells with large, polygonal, vesicular nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm. The mitotic count was >20 per 10 high-power fields for each case. Lymphovascular space invasion was evident in case 1 and 3, but not found in case 2. Three para-aortic lymph nodes showed NEC metastasis by morphology in case 3. No nodal metastasis was seen in cases 1 and 2. The immunostaining results of the tumors are given in Table 3. All NEC components of the cases were positive for p16 and at least 2 out of 3 neuroendocrine markers (CGA, SYN and CD56) with >10% of the tumor cells. SYN was the most commonly expressed biomarker (20% in case 1, 15% in case 2, 80% in case 3), followed by CGA (15% in case 2, 70% in case 3), and CD56 (20% in case 1, 80% in case 3). In case 3, there was strong and diffuse expression of all three neuroendocrine markers. The well-differentiated adenocarcinoma components were all positive for estrogen receptors, with only focally positive for CGA. p53 immunoreaction was aberrant (mutational type) in case 3 and wild type in the other two. Notably, p53 overexpression was exclusively limited to the NEC component. Loss of SMARCB1 (INI1) expression was found only in case 3, but loss of SMARCA4 (BRG1) or ARID1A expression was not found in any case. In terms of MMR biomarkers, MLH1 was lost in case 1 and 2, MSH2 and MSH6 was lost in case 3. No PMS2 loss was found in all cases. Representative pictures of the IHC staining results are shown in Figures E-I. Based on the above findings, diagnosis of primary endometrial large cell neuroendocrine carcinoma (LCNEC) was made for all three cases. Follow-up Follow-up information was available for all patients. The three patients remained alive with no disease for 51, 17 and 6 months, respectively. Discussion LCNEC arising from the endometrium are rarer than those arising from the cervix and ovaries [4-14]. Based on published reports in English, the neoplasms are either “pure” LCNEC or admixed with other histologic components [5-16]. Among other histologic components of endometrial LCNEC, endometrioid carcinoma is the most common histologic type, followed by serous carcinoma. Based on prior reports and the findings of our cases, the most common clinical symptoms were postmenopausal or peri-menopausal vaginal bleeding and/or abnormal vaginal discharge [5-16]. In current cases, the patients presented within the average age range and exhibited typical clinical presentations of the endometrial LCNEC. When the tumor is poorly differentiated with morphologic suggestion of neuroendocrine differentiation, the IHC with neuroendocrine markers are deemed as the most useful method for diagnosing NEC. The most common markers used in this setting include SYN, CGA, and CD56. In our study, at least 2 out of 3 neuroendocrine markers are positive in at least 10% of the tumor cells. SYN was the most commonly expressed neuroendocrine marker, followed by CGA and CD56. However, neuroendocrine markers, especially positive CD56 expression is relatively common in endometrial cancers even without classic neuroendocrine histology [17]. Combined with morphological features, we would like to emphasize that at least 2 NE marker should be reactive in >10% of tumor cells as the diagnostic criteria of NEC. In many situations, the endometrial NECs occur in association with a more typical form of endometrioid carcinoma [4]. The adenocarcinoma components were also low-grade endometrioid carcinoma in our cases. Hence, compared with the conventional adenocarcinoma components, the NEC was dominant in all these cases. It has been indicated that NEC originates from NE cells of the endometrium and may result from “divergent differentiation” [5]. Yasuoka et al. [18] found that both cervical adenocarcinoma and NEC showed identical clonality by using an X-chromosome clonality assay. Such observation suggests that the NEC may arise from the adenocarcinoma through a “dedifferentiation process”. Moreover, the overt continuity between the two components and focally positive expression of NE markers in adenocarcinoma component in one of our cases is of supportive of this hypothesis. In addition, loss of INI1 (one of those dedifferentiation markers) expression was found in both components (case 3) suggest that “dedifferentiation” from endometrioid carcinoma to form NEC may represent part of the mechanisms for the development of these cancers. Differential diagnoses of endometrial NEC are extensive [4, 16]. One of the major differential diagnoses of the endometrial LCNEC is the dedifferentiated endometrial carcinoma [16]. Both of them share many histologic and immunophenotypic features including loss of MMR protein expression as well as positive for neuroendocrine markers [17, 19]. However, 3 cases presented here do not represent dedifferentiated carcinoma. This is mainly because of the following reasons. 1) the high-grade looking area of the cases morphologically show features of NEC without evidence of undifferentiated carcinoma such as sheet-like growth patterns; 2) immunophenotypically, the cancer cells are positive for at least 2 neuroendocrine markers; and 3) Among the three commonly used dedifferentiation markers (INI1, BRG1, and ARID1A), only INI1 was lost of expression in only one of the 3 cases we studied. The dedifferentiation markers of INI1, BRG1, and ARID1A belong to switch/sucrose non-fermenting protein complex. Loss of such protein complex expression has been widely applied for the diagnosis of dedifferentiated carcinomas [14, 20, 21]. Rosa-Rosa et al. [20] studied 10 dedifferentiated carcinomas, they found that 9 of 10 showed loss of ARID1A expression. Another study found that 15 of 30 (50%) of the dedifferentiated carcinomas showed either loss of BRG1 or INI1 or loss of both biomarkers [21]. In our cases, as mentioned earlier, there was only loss of INI1 expression in case 3, but both BRG1 and ARID1A expression were intact. All the three patients aged < 60 years old, the tumor showed increased tumor-infiltrating lymphocytes at the tumor invading front or periphery, the tumor in case 1 located at the lower uterine segment. Such morphologic findings may raise a suspicion of Lynch syndrome [21]. MMR protein panel (MLH1, PMS2, MSH2 and MSH6) IHC was implemented to screening for Lynch syndrome. Interestingly, abnormal MMR protein expression were found in all 3 cases. MLH1 was lost in case 1 and 2, MSH2 and MSH6 was lost in case 3. Only PMS2 was intact in all cases. However, germ line mutational analysis was not performed due to limitations of genetic counselling, accessibility of next generation sequencing analysis. Upon reviewing the literature, we found a few studies addressing abnormal MMR protein expression in endometrial NEC [12, 14, 23]. Combined loss of MLH1 and PMS2 is usually more common. One study by Pocrnich et al. [12] reported 6 of 18 endometrial NEC cases showing MLH1/PMS2 loss. In contrast, isolated MSH6 or MSH2/MSH6 loss is relatively rare in endometrial NECs. The same study by Pocrnich et al showed only 1 of 18 endometrial NECs with MSH2/MSH6 loss [12]. There is also isolated PMS2 loss found in 2 out of 4 endometrial NECs [14]. Compared to all those reported series, loss of MMR protein expression can be found in endometrial NECs. But it is rare for us to find all 3 cases with loss of the expression. It is quite uncommon that single MLH1 loss without loss of PMS2 in 2 of the 3 cases we show in this study. Although NEC usually exhibits aggressive behavior, our patients are alive with no disease for 51, 17 and 6 months, respectively. Interestingly, case 3 (FIGO Stage IIIC) with para-aortic lymph nodes metastasis and case 2 (FIGO Stage IB) didn’t receive either adjuvant chemotherapy or radiation therapy, though the follow-up time remains short. It is currently unclear what are the underlying reasons for patients with endometrial NECs having not very poor prognosis. Based on the findings from our cases and data presented elsewhere, we believe that loss of MMR protein expression in the tumor cells may illicit more immune responses due to incompetent repair those damaged DNA in the tumor cells. Such enhanced immune responses may contribute to a better prognosis compared to those NECs without MMR protein loss. Our observations were based on a relatively small number of follow-up samples, additional and systematic studies to address this issue are needed. In summary, endometrial NEC frequently associated with MMR deficiency, some of which may have a better prognosis than we expect. It is important to emphasize that at least 2 NE markers should be reactive in >10% of tumor cells for the diagnosis of NEC in addition to morphologic support. Declarations Ethics approval and consent to participate This study was approved by the ethics committee of the Women's Hospital, School of Medicine Zhejiang University, and the patient provided written informed consent to participate in the study. Consent for publication We obtained written informed consent of the patient for the publication of the case report and accompanying images. Availability of data and material The datasets during and/or analysed during the current study available from the corresponding author on reasonable request. Competing interests The authors state they have no competing interests. Funding This work was supported by the program for National Natural Science Foundation of China (No.81701502). Authors ’ contributions All authors made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; ZF and XM involved in drafting the manuscript and revising it critically for important intellectual content; ZF gave final approval to the version to be published. All authors read and approved the final manuscript. Acknowledgements Not applicable References Kurman RJ, Carcangiu ML,Herrington CS, Young RH. WHO Classification of Tumours of Female Reproductive Organs. Fourth Edition, Volume 6. IARC Press, Lyons, 2014. Gonzalez-Bosquet E, Gonzalez-Bosquet J, García Jiménez A, Gil A, Xercavins J. Carcinoid tumor of the uterine corpus. A case report. J Reprod Med, 1998;43:844–846. Chetty R, Clark SP, Bhathal PS. Carcinoid tumour of the uterine corpus. Virchows Arch A Pathol Anat Histopathol, 1993;422:93–95. Howitt BE, Kelly P, McCluggage WG. Pathology of Neuroendocrine Tumours of the Female Genital Tract. Curr Oncol Rep, 2017;19:59. 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Small cell carcinomas and large cell neuroendocrine carcinomas of the endometrium and cervix: polypoid tumors and those arising in polyps may have a favorable prognosis. Int J Gynecol Pathol, 2008; 27:333–339. Mulvany NJ, Allen DG. Combined large cell neuroendocrine and endometrioid carcinoma of the endometrium. Int J Gynecol Pathol, 2008; 27:49–57. Deodhar KK, Kerkar RA, Suryawanshi P, Menon H, Menon S. Large cell neuroendocrine carcinoma of the endometrium: an extremely uncommon diagnosis, but worth the efforts. J Cancer Res Ther, 2011;7: 211–213. Pocrnich CE, Ramalingam P, Euscher ED, Malpica A. Neuroendocrine carcinoma of the endometrium a clinicopathologic study of 25 cases. Am J Surg Pathol, 2016; 40:577–586. Ono K, Yokota NR, Yoshioka E, Noguchi A, Washimi K, Kawachi K, et al. Metastatic large cell neuroendocrine carcinoma of the lung arising from the uterus: a pitfall in lung cancer diagnosis. Pathol Res Pract, 2016;212(7):654–657. 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Tables Antibody Clones Dilutions Souses p16 16P04/JC2 1:100 Zeta p53 DO-7 1:600 Thermo ER 1D5 1:300 Thermo PR 1A6 1:500 Thermo CGA SP12 1:500 Thermo SYN SP11 1:200 Thermo CD56 123C3 1:400 Thermo MLH1 ES05 1:50 Leica PSM2 A16-4 1:100 Epitomics MSH2 25D12 1:100 Leica MSH6 EP49 1:400 Epitomics INI1 25/BAF47 1/100 BD Biosciences BRG1 EPR3912 1:50 Abcam ARID1A HPA005456 1:400 Sigma Ki67 MIB-1 1:400 Dako Table 1 Antibody clones, sources, and dilutions Case 1 Case 2 Case 3 Age (yr) 54 59 55 History of pregnancy G2P2 G2P2 G2P1 History of cancer NO NO NO Familial history of cancer NO NO NO Clinical presentation Irregular menstruation Postmenopausal vaginal bleeding Postmenopausal vaginal bleeding and discharge Serum tumor biomarkers Normal CEA, CA125 and CA153 Normal CEA, CA125 and CA153 CA125:50.1 U/mL, Normal CEA and CA153 Imaging findings A mass in the LUS and cervix canal A mass in the endometrium A mass in the endometrium FIGO Stage IIB IB IIIC Tumor size 4 × 3 × 1.5 cm 3 4.5×4.4×1.8cm 3 3 × 2.5 × 1 cm 3 Pathological findings LCNEC (90%) + EC G1 (10%) LCNEC (60%) + EC G1 (40%) LCNEC (70%) + EC G1 (30%) Mitotic count >20/10HPF >20/10HPF >20/10HPF MI 50% >50% Cervical interstitial infiltration YES NO NO LVSI YES NO YES Treatment TAH-BSO+RT+CTX TAH-BSO TAH-BSO+CTX Follow-up Ned at 51 mo Ned at 17 mo Ned at 6 mo Abbreviations: G, gravidity; P, parity; LCNEC, large cell neuroendocrine carcinoma; EC, endometrioid carcinoma; HPF, high power field; MI, myometrial invasion; ned, no evidence of disease; TAH-BSO, total abdominal hysterectomy and bilateral salpingo-oophorectomy; RT, radiation therapy; CTX, chemotherapy; mo, month. Table 2 Clinical findings and pathological results of the tumours Case 1 Case 2 Case 3 LCNEC EC LCNEC EC LCNEC EC P16 + (D) + (P) + (P) + (F) + (D) + (P) P53 + (P) + (F) + (F) + (F) + (D) + (F) ER - + (D) + (D) + (D) - + (P) PR - + (D) + (D) + (P) - - CGA - + (F) + (P) + (F) + (D) + (F) SYN + (D) - + (P) - + (D) - CD56 + (P) - - - + (D) + (F) MLH1 Lost Lost Lost Lost + (R) + (R) PSM2 + (R) + (R) + (R) + (R) + (R) + (R) MSH2 + (R) + (R) + (R) + (R) Lost Lost MSH6 + (R) + (R) + (R) + (R) Lost Lost INI 1 + (intact) + (intact) + (intact) + (intact) Lost Lost BRG1 + (intact) + (intact) + (intact) + (intact) + (intact) + (intact) ARID1A + (intact) + (intact) + (intact) + (intact) + (intact) + (intact) Ki67 + (D) + (P) + (D) + (P) + (D) + (D) Abbreviations: D, diffuse (≥50% labeling); F, focal (≤10% labeling); -, nagative; P, patch (11-49% labeling); +, positive; R, retained nuclear staining. Table 3 Immunostaining results of the tumours Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-25180","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research","associatedPublications":[],"authors":[{"id":519115,"identity":"f00482bd-1a48-4fd2-b643-1cf7982dace0","order_by":1,"name":"Feng Zhou","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA20lEQVRIiWNgGAWjYBAC9gYgwQgk+BkYEoBMZsJaeA5AtUg2kKzF4ACYT4wWidzDL37usEncfP7AMwmGCuvEBvazBwhoyUuz7D2TlrjtwIE0CYYz6YkNPHkJeLXYS+SYGTO2Hc7ddrAhTQLISGyQ4DEgYAtYy//czc0MQC3/iNNi/Jix7UDuBjaQlgZitPC8MWPsbUuun3GGIdki4Vi6cRtPDgEt7DnGH3622Rnz959JvPGhxlq2n/0Mfi1AwCYB1Z0Ajkw2QuqBgPkDhGY/QITiUTAKRsEoGIkAAMNfRLBmW8jSAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-2402-4774","institution":"Zhejiang University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Feng","middleName":"","lastName":"Zhou","suffix":""},{"id":519116,"identity":"623fcc37-2ed8-494f-93a8-402384251045","order_by":2,"name":"Mengfei Xu","email":"","orcid":"","institution":"Zhejiang University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mengfei","middleName":"","lastName":"Xu","suffix":""},{"id":519117,"identity":"604fc7d9-da70-411c-bf4a-31cf4a98b26f","order_by":3,"name":"Qin Chen","email":"","orcid":"","institution":"Zhejiang University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Qin","middleName":"","lastName":"Chen","suffix":""},{"id":519118,"identity":"19cc824f-e87e-40f0-8d55-37c7cac4541f","order_by":4,"name":"Xiaofei Zhang","email":"","orcid":"","institution":"Zhejiang University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaofei","middleName":"","lastName":"Zhang","suffix":""},{"id":519119,"identity":"70a7ea2c-a452-4cc6-851c-5aa1152467a7","order_by":5,"name":"Hao Chen","email":"","orcid":"","institution":"University of Texas Southwestern Medical Center at Dallas","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hao","middleName":"","lastName":"Chen","suffix":""},{"id":519120,"identity":"6f30e337-1b33-4c45-adf5-d3f78f2341d1","order_by":6,"name":"Wenxin Zheng","email":"","orcid":"","institution":"University of Texas Southwestern Medical Center at Dallas","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wenxin","middleName":"","lastName":"Zheng","suffix":""}],"badges":[],"createdAt":"2020-04-24 11:13:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-25180/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-25180/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":997894,"identity":"33f05640-1bfd-4018-bab8-8c3e54603d8e","added_by":"auto","created_at":"2020-04-29 23:51:48","extension":"tif","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":11372411,"visible":true,"origin":"","legend":"A-I. Case 3: Well-differentiated EC with local squamous differentiation and increased tumor-infiltrating lymphocytes (A, 10×). LCNEC arranged in solid sheets and organoid with necrosis (B, 10×), trabecular (C, 20×) and rosette/pseudorosette (D, 40×). The immunochemical photograph of LCNEC: CGA (E, 20×), SYN (F, 20×), CD56 (G, 20×), MSH2 (H, 20×), MSH6 (I, 20×).","description":"","filename":"FIG.tif","url":"https://assets-eu.researchsquare.com/files/rs-25180/v1/FIG.tif"},{"id":13500950,"identity":"e15ead3a-6ec0-44af-9c1d-f4ad9d15570c","added_by":"auto","created_at":"2021-09-16 23:08:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":7365093,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-25180/v1/41770db5-ee54-45ab-9787-5f1fdcf81990.pdf"}],"financialInterests":"","formattedTitle":"Endometrial neuroendocrine carcinoma frequently associated with mismatch repair deficiency","fulltext":[{"header":"Background","content":" \u003cp\u003eAs recommended by the World Health Organization (WHO), the terminology for gastro-entero-pancreatic neuroendocrine tumors (NET) is applicable to nueroendocrine carcinoma (NEC) arising from the female genital tract [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. NETs are classified as poorly-differentiated NEC and well-differentiated NET based on the tumor nuclear grade. Low-grade NET is extremely rare with only occasional reports in the English literature [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Meanwhile, NEC with very high grade is also rare. It is well known that NECs such as small or the large cell NEC behave aggressively and patients with such cancers have a poor prognosis [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. There are approximately 100 cases of NEC arising from the endometrium have been reported in the past [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, there were few studies addressed the relationship between the endometrial NEC and the abnormality of mismatch repair (MMR) protein expression in these cancers. We herein delineated 3 cases of the endometrial NEC with MMR deficiency.\u003c/p\u003e "},{"header":"Material And Methods","content":" \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eTissue samples\u003c/h2\u003e \u003cp\u003eAll three cases were retrieved from the archives of the Department of Pathology, the Women\u0026rsquo;s Hospital, School of Medicine, Zhejiang University, China, in the last 5\u0026nbsp;years. We obtained clinicopathologic information from hospital informatics system. This study was approved by the ethics committee of above institution. Large cell NEC is diagnosed based on World Health Organization (WHO) criteria: 1) large cells with prominent nucleoli and abundant cytoplasm, 2) a neuroendocrine growth pattern (organoid, insular, trabecular, rosette/pseudo-rosette), and 3)\u0026thinsp;\u0026gt;\u0026thinsp;10% of tumor cells reactive to at least one NET markers including chromogranin (CGA), synaptophysin (SYN) and CD56 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Hematoxylin and Eosin (H\u0026amp;E) and immunohistochemistry (IHC) slides were reviewed by 3 gynecologic pathologists (FZ, XZ, and WZ) and the pathologic diagnosis of the cases was confirmed by consensus.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eImmunohistochemical analysis\u003c/h2\u003e \u003cp\u003eAdditional 4-\u0026micro;m paraffin sections were stained with a panel of antibodies using the 2-step Envision method according to the manufacturer\u0026rsquo;s instructions and visualized with 3-diaminobenzidine tetrachloride (Sigma, St Louis, MO) as described previously (add a reference here). The sources and dilutions of the antibodies used in this study are detailed in Table\u0026nbsp;1. All primary antibodies and the detection kit were products of Dako Corporation (Glostrup, Denmark). The omission of primary antibodies with the same class non-specific IgG was used as the negative control. The IHC stained slides were scored as follows: negative (no cells stained), focally positive (\u0026le;\u0026thinsp;10% cells stained), patchy positive (11\u0026ndash;49% cells stained) and diffusely positive (\u0026ge;\u0026thinsp;50% of cells stained).\u003c/p\u003e \u003c/div\u003e "},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eClinical findings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe main clinical findings of these cases are summarized in Table 2. Briefly, median age was 56 years (range, 54-59 years), and all patients presented with postmenopausal or perimenopausal vaginal bleeding/discharge. All patients denied familial history of endometrial or colon cancer. No any other history of malignancies were identified from patients\u0026rsquo; relatives. The diagnosis was made on endometrial biopsy and was followed by total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH-BSO) and staging procedures. The tumors showed the FIGO stage as follows:\u0026nbsp; case 1 with stage IIB, case 2 with stage IB, and case 3 with stage IIIC at the time of diagnosis. Patients of case 1 and 3 received both postoperative chemotherapy and radiation therapy, while case 2 received adjuvant radiation only.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePathological findings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe main pathological findings of these cases are given in Table 2. Macroscopically, all tumors formed large, polypoid, intracavitary masses, ranging from 3 to 4.5 cm. The tumors were largely located in the uterine funds with no low uterine segment location was noted. The cut surface was soft, fleshy, and necrotic. Microscopically, the tumors showed a dominant NEC component ranging from 60-90% of the total tumor volumes of the cases. Small amount of well-differentiated endometrioid carcinoma with focal areas of squamous differentiation were identified in case 3 only. Increased tumor-infiltrating lymphocytes at the tumor invading front or periphery were found in all 3 cases (Fig. A). Extensive geographic necrosis was present. The NEC components mostly showed solid\u0026nbsp;sheets with organoid growth patterns, whereas insular, trabecular and rosette/pseudorosette patterns were found in about 30% cancerous areas in average (Fig. B-D). The NEC components were composed of cells with large, polygonal, vesicular nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm. The mitotic count was \u0026gt;20 per 10 high-power fields for each case. Lymphovascular space invasion was evident in case 1 and 3, but not found in case 2. Three para-aortic lymph nodes showed NEC metastasis by morphology in case 3. No nodal metastasis was seen in cases 1 and 2.\u003c/p\u003e\n\u003cp\u003eThe immunostaining results of the tumors are given in Table 3. All NEC components of the cases were positive for p16 and at least 2 out of 3 neuroendocrine markers (CGA, SYN and CD56) with \u0026gt;10% of the tumor cells. SYN was the most commonly expressed biomarker (20% in case 1, 15% in case 2, 80% in case 3), followed by CGA (15% in case 2, 70% in case 3), and CD56 (20% in case 1, 80% in case 3). In case 3, there was strong and diffuse expression of all three neuroendocrine markers. The well-differentiated adenocarcinoma components were all positive for estrogen receptors, with only focally positive for CGA. p53 immunoreaction was aberrant (mutational type) in case 3 and wild type in the other two. Notably, p53 overexpression was exclusively limited to the NEC component. Loss of SMARCB1 (INI1) expression was found only in case 3, but loss of SMARCA4 (BRG1) or ARID1A expression was not found in any case. In terms of MMR biomarkers, MLH1 was lost in case 1 and 2, MSH2 and MSH6 was lost in case 3. No PMS2 loss was found in all cases. Representative pictures of the IHC staining results are shown in Figures E-I.\u003c/p\u003e\n\u003cp\u003eBased on the above findings, diagnosis of primary endometrial large cell neuroendocrine carcinoma (LCNEC) was made for all three cases.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-up\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFollow-up information was available for all patients. The three patients remained alive with no disease for 51, 17 and 6 months, respectively.\u003c/p\u003e"},{"header":"Discussion","content":"\n\u003cp\u003eLCNEC arising from the endometrium are rarer than those arising from the cervix and ovaries [4-14]. Based on published reports in English, the neoplasms are either \u0026ldquo;pure\u0026rdquo; LCNEC or admixed with other histologic components [5-16]. Among other histologic components of endometrial LCNEC, endometrioid carcinoma is the most common histologic type, followed by serous carcinoma. Based on prior reports and the findings of our cases, the most common clinical symptoms were postmenopausal or peri-menopausal vaginal bleeding and/or abnormal vaginal discharge [5-16]. In current cases, the patients presented within the average age range and exhibited typical clinical presentations of the endometrial LCNEC.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; When the tumor is poorly differentiated with morphologic suggestion of neuroendocrine differentiation, the IHC with neuroendocrine markers are deemed\u0026nbsp;as\u0026nbsp;the most useful method for diagnosing NEC. The most common markers used in this setting include SYN, CGA, and CD56. In our study, at least 2 out of 3 neuroendocrine markers are positive in at least 10% of the tumor cells. SYN was the most commonly expressed neuroendocrine marker, followed by CGA and CD56. However, neuroendocrine markers, especially positive CD56 expression is relatively common in endometrial cancers even without classic neuroendocrine histology [17]. Combined with morphological features, we would like to emphasize that at least 2 NE marker should be reactive in \u0026gt;10% of tumor cells as the diagnostic criteria of NEC.\u003c/p\u003e\n\u003cp\u003eIn many situations, the endometrial NECs occur in association with a more typical form of endometrioid carcinoma [4]. The adenocarcinoma components were also low-grade endometrioid carcinoma in our cases. Hence, compared with the conventional adenocarcinoma components, the NEC was dominant in all these cases. It has been indicated that NEC originates from NE cells of the endometrium and may result from \u0026ldquo;divergent differentiation\u0026rdquo; [5]. Yasuoka et al. [18] found that both cervical adenocarcinoma and NEC showed identical clonality by using an X-chromosome clonality assay. Such observation suggests that the NEC may arise from the adenocarcinoma through a \u0026ldquo;dedifferentiation process\u0026rdquo;. Moreover, the overt continuity between the two components and focally positive expression of NE markers in adenocarcinoma component in one of our cases is of supportive of this hypothesis. In addition, loss of INI1 (one of those dedifferentiation markers) expression was found in both components (case 3) suggest that \u0026ldquo;dedifferentiation\u0026rdquo; from endometrioid carcinoma to form NEC may represent part of the mechanisms for the development of these cancers.\u003c/p\u003e\n\u003cp\u003eDifferential diagnoses of endometrial NEC are extensive [4, 16]. One of the major differential diagnoses of the endometrial LCNEC is the dedifferentiated\u0026nbsp;endometrial carcinoma [16]. Both of them share many histologic and immunophenotypic features including loss of MMR protein expression as well as positive for neuroendocrine markers [17, 19]. However, 3 cases presented here do not represent dedifferentiated carcinoma. This is mainly because of the following reasons. 1) the high-grade looking area of the cases morphologically show features of NEC without evidence of undifferentiated carcinoma such as sheet-like growth patterns; 2) immunophenotypically, the cancer cells are positive for at least 2 neuroendocrine markers; and 3) Among the three commonly used dedifferentiation markers (INI1, BRG1, and ARID1A), only INI1 was lost of expression in only one of the 3 cases we studied. The dedifferentiation markers of INI1, BRG1, and ARID1A belong to switch/sucrose non-fermenting protein complex. Loss of such protein complex expression has been widely applied for the diagnosis of dedifferentiated carcinomas [14, 20, 21]. Rosa-Rosa et al.\u0026nbsp;[20]\u0026nbsp;studied 10 dedifferentiated carcinomas, they found that 9 of 10 showed loss of ARID1A expression. Another study found that 15 of 30 (50%) of the dedifferentiated carcinomas showed either loss of BRG1 or INI1 or loss of both biomarkers [21]. In our cases, as mentioned earlier, there was only loss of INI1 expression in case 3, but both BRG1 and ARID1A expression were intact.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp; All the three patients aged \u0026lt; 60 years old, the tumor showed increased tumor-infiltrating lymphocytes at the tumor invading front or periphery, the tumor in case 1 located at the lower uterine\u0026nbsp;segment. Such morphologic findings may raise a suspicion of Lynch syndrome [21]. MMR protein panel (MLH1, PMS2, MSH2 and MSH6)\u0026nbsp;IHC was implemented to screening for Lynch syndrome. Interestingly, abnormal MMR protein expression were found in all 3 cases. MLH1 was lost in case 1 and 2, MSH2 and MSH6 was lost in case 3. Only PMS2 was intact in all cases.\u0026nbsp; However, germ line mutational analysis was not performed due to limitations of genetic counselling, accessibility of next generation sequencing analysis. Upon reviewing the literature, we found a few studies addressing abnormal MMR protein expression in endometrial NEC [12, 14, 23]. Combined loss of MLH1 and PMS2 is usually more common. One study by Pocrnich\u0026nbsp;et\u0026nbsp;al. [12] reported 6 of 18 endometrial NEC cases showing MLH1/PMS2 loss. In contrast, isolated MSH6 or MSH2/MSH6 loss is relatively rare in endometrial NECs. The same study by Pocrnich et al showed only 1 of 18 endometrial NECs with MSH2/MSH6 loss [12]. There is also isolated PMS2 loss found in 2 out of 4 endometrial NECs [14]. Compared to all those reported series, loss of MMR protein expression can be found in endometrial NECs. But it is rare for us to find all 3 cases with loss of the expression. It is quite uncommon that single MLH1 loss without loss of PMS2 in 2 of the 3 cases we show in this study.\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp; Although NEC usually exhibits aggressive behavior, our patients are alive with no disease for 51, 17 and 6 months, respectively. Interestingly, case 3 (FIGO Stage IIIC) with para-aortic lymph nodes metastasis and case 2 (FIGO Stage IB) didn\u0026rsquo;t receive either adjuvant chemotherapy or radiation therapy, though the follow-up time remains short. It is currently unclear what are the underlying reasons for patients with endometrial NECs having not very poor prognosis. Based on the findings from our cases and data presented elsewhere, we believe that loss of MMR protein expression in the tumor cells may illicit more immune responses due to incompetent repair those damaged DNA in the tumor cells. Such enhanced immune responses may contribute to a better prognosis compared to those NECs without MMR protein loss. Our observations were based on a relatively small number of follow-up samples, additional and systematic studies to address this issue are needed.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn summary, endometrial NEC frequently associated with MMR deficiency, some of which may have a better prognosis than we expect. It is important to emphasize that at least 2 NE markers should be reactive in \u0026gt;10% of tumor cells for the diagnosis of NEC in addition to morphologic support.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the ethics committee of the Women's Hospital, School of Medicine Zhejiang University, and the patient provided written informed consent to participate in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe obtained written informed consent of the patient for the publication of the case report and accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets during and/or analysed during the current study available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors state they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the program for National Natural Science Foundation of China (No.81701502).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u003c/strong\u003e\u003cstrong\u003e\u0026rsquo;\u003c/strong\u003e\u003cstrong\u003econtributions \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; ZF and XM involved in drafting the manuscript and revising it critically for important intellectual content; ZF gave final approval to the version to be published. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKurman RJ, Carcangiu ML,Herrington CS, Young RH. WHO Classification of Tumours of Female Reproductive Organs. Fourth Edition, Volume 6. IARC Press, Lyons, 2014.\u003c/li\u003e\n\u003cli\u003eGonzalez-Bosquet E, Gonzalez-Bosquet J, Garc\u0026iacute;a Jim\u0026eacute;nez A,\u0026nbsp;Gil A,\u0026nbsp;Xercavins J. Carcinoid tumor of the uterine corpus. A case report. J Reprod Med, 1998;43:844\u0026ndash;846.\u003c/li\u003e\n\u003cli\u003eChetty R, Clark SP, Bhathal PS. Carcinoid tumour of the uterine corpus. Virchows Arch A Pathol Anat Histopathol, 1993;422:93\u0026ndash;95.\u003c/li\u003e\n\u003c/ol\u003e\n\u003col start=\"4\"\u003e\n\u003cli\u003eHowitt BE, Kelly P, McCluggage WG. Pathology of Neuroendocrine Tumours of the Female Genital Tract. Curr Oncol Rep, 2017;19:59.\u003c/li\u003e\n\u003cli\u003eMatsumoto H, Nasu K, Kai K, Nishida M, Narahara H, Nishida H. Combined large-cell neuroendocrine carcinoma and endometrioid adenocarcinoma of the endometrium: A case report and survey of related literature. J Obstet Gynaecol Res,\u0026nbsp;2016;42:206\u0026ndash;210.\u003c/li\u003e\n\u003cli\u003eShahabi S, Pellicciotta I, Hou J, Graceffa S, Huang GS, Samuelson RN, Goldberg GL. Clinical utility of chromogranin A and octreotide in large cell neuroendocrine carcinoma of the uterine corpus. Rare Tumors, 2011;3:129\u0026ndash;131.\u003c/li\u003e\n\u003cli\u003eTu YA, Chen YL, Lin MC, Chen CA, Cheng WF. Large cell neuroendocrine carcinoma of the endometrium: A case report and literature review. Taiwan J Obstet Gynecol, 2018;57:144\u0026ndash;149.\u003c/li\u003e\n\u003cli\u003eCetiner H, Kir G, Akoz I, Gurbuz A, Karateke A. Large-cell neuroendocrine carcinoma of the cervix associated with cervical-type invasive adenocarcinoma: a report of case and discussion of histogenesis. Int J Gynecol Cancer,\u0026nbsp;2006;16:438\u0026ndash;442.\u003c/li\u003e\n\u003cli\u003eAlbores-Saavedra J, Martinez-Benitez B,\u0026nbsp;Luevano E. Small cell carcinomas and large cell neuroendocrine carcinomas of the endometrium and cervix: polypoid tumors and those arising in polyps may have a favorable prognosis. Int J Gynecol Pathol, 2008;\u0026nbsp;27:333\u0026ndash;339.\u003c/li\u003e\n\u003cli\u003eMulvany NJ, Allen DG. Combined large cell neuroendocrine and endometrioid carcinoma of the endometrium. Int J Gynecol Pathol,\u0026nbsp;2008; 27:49\u0026ndash;57.\u003c/li\u003e\n\u003cli\u003eDeodhar KK,\u0026nbsp;Kerkar RA,\u0026nbsp;Suryawanshi P,\u0026nbsp;Menon H,\u0026nbsp;Menon S. Large cell neuroendocrine carcinoma of the endometrium: an extremely uncommon diagnosis, but worth the efforts. J\u0026nbsp;Cancer Res Ther,\u0026nbsp;2011;7: 211\u0026ndash;213.\u003c/li\u003e\n\u003cli\u003ePocrnich CE,\u0026nbsp;Ramalingam P, Euscher ED,\u0026nbsp;Malpica A. Neuroendocrine carcinoma of the endometrium a clinicopathologic study of 25 cases. Am J Surg Pathol, 2016;\u0026nbsp;40:577\u0026ndash;586.\u003c/li\u003e\n\u003cli\u003eOno K,\u0026nbsp;Yokota NR,\u0026nbsp;Yoshioka E,\u0026nbsp;Noguchi A,\u0026nbsp;Washimi K,\u0026nbsp;Kawachi K,\u0026nbsp;et al. Metastatic large cell neuroendocrine carcinoma of the lung arising from the uterus: a pitfall in lung cancer diagnosis. Pathol Res Pract, 2016;212(7):654\u0026ndash;657.\u003c/li\u003e\n\u003cli\u003eEspinosa I,\u0026nbsp;De Leo A,\u0026nbsp;D'Angelo E,\u0026nbsp;Rosa-Rosa JM,\u0026nbsp;Corominas M,\u0026nbsp;Gonzalez A,\u0026nbsp;Palacios J,\u0026nbsp;Prat J. Dedifferentiated endometrial carcinomas with neuroendocrine features: a clinicopathologic, immunohistochemical, and molecular genetic study. Hum Pathol,\u0026nbsp;2018;72:100\u0026ndash;106.\u003c/li\u003e\n\u003cli\u003eKobayashi A, Yahata T, Nanjo S, Mizoguchi M, Yamamoto M, Mabuchi Y, et al. Rapidly progressing large-cell neuroendocrine carcinoma arising from the uterine corpus: A case report and review of the literature. Mol Clin Oncol, 2017;6(6):881\u0026ndash;885.\u003c/li\u003e\n\u003cli\u003eNguyen ML, Han L, Minors AM, Bentley-Hibbert S, Pradhan TS, Pua TL, Tedjarati SS. Rare large cell neuroendocrine tumor of the endometrium: A case report and review of the literature. Int J Surg Case Rep, 2013;4:651\u0026ndash;655.\u003c/li\u003e\n\u003cli\u003eMoritz AW, Schlumbrecht MP, Nadji M, Pinto A. Expression of neuroendocrine markers in non-neuroendocrine endometrial carcinomas. Pathology, 2019;51(4):369-374.\u003c/li\u003e\n\u003cli\u003eYasuoka H, Tsujimoto M, Ueda M, Kodama R, Iwahashi Y, Inagaki M, et al. Monoclonality of composite large-cell neuroendocrine carcinoma and invasive intestinal-type mucinous adenocarcinoma of the cervix: a case study. Int J Gynecol Pathol, 2013;32(4):416\u0026ndash;420.\u003c/li\u003e\n\u003cli\u003eTaraif SH, Deavers MT, Malpica A,Silva EG. The significance of neuroendocrine expression in undifferentiated carcinoma of the endometrium. Int J Gynecol Pathol, 2009;28: 142\u0026ndash;147.\u003c/li\u003e\n\u003cli\u003eRosa-Rosa JM,\u0026nbsp;Leskel\u0026auml; S,\u0026nbsp;Crist\u0026oacute;bal-Lana E,\u0026nbsp;Sant\u0026oacute;n A,\u0026nbsp;L\u0026oacute;pez-Garc\u0026iacute;a M\u0026Aacute;,\u0026nbsp;Mu\u0026ntilde;oz G,\u0026nbsp;et al. Molecular genetic heterogeneity in undifferentiated endometrial carcinomas. Mod Pathol,\u0026nbsp;2016, 29:\u0026nbsp;1390\u0026ndash;1398.\u003c/li\u003e\n\u003cli\u003eKarnezis AN, Hoang LN, Coatham M, Ravn S, Almadani N, Tessier-Cloutier B. Loss of switch/sucrose non-fermenting complex protein expression is associated with dedifferentiation in endometrial carcinomas. Mod Pathol, 2016;29(3):302\u0026ndash;14.\u003c/li\u003e\n\u003cli\u003eWang Y, Wang Y, Li J, Cragun J, Hatch K, Chambers SK, Zheng W. Lynch\u0026nbsp;syndrome\u0026nbsp;related\u0026nbsp;endometrial\u0026nbsp;cancer:\u0026nbsp;clinical\u0026nbsp;significance\u0026nbsp;beyond\u0026nbsp;the\u0026nbsp;endometrium. J Hematol Oncol, 2013; 6:22.\u0026nbsp;\u003c/li\u003e\n\u003cli\u003eChougule A,\u0026nbsp;Garg R,\u0026nbsp;Jain V. Paranuclear dot-like pancytokeratin positivity and\u0026nbsp;MLH1/PMS2 loss in large cell neuroendocrine carcinoma of the\u0026nbsp;endometrium. Pathology,\u0026nbsp;2016;48(7):736\u0026ndash;739.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003ctable style=\"width: 4.8e+2pt;border: none;border-collapse:collapse;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:111.65pt;border-top:solid black 1.0pt;border-left: none;border-bottom:solid black 1.0pt;border-right:none;background:white;padding:.75pt .75pt .75pt .75pt;height:12.6pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10px; color: rgb(0, 0, 0); font-family: Verdana, Geneva, sans-serif;\"\u003eAntibody\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.45pt;border-top:solid black 1.0pt;border-left: none;border-bottom:solid black 1.0pt;border-right:none;background:white;padding:.75pt .75pt .75pt 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style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e1/100\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:132.2pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eBD Biosciences\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:111.65pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eBRG1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.45pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eEPR3912\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd 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0);\"\u003eAbcam\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:111.65pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eARID1A\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.45pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: 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Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eSigma\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:111.65pt;border:none;border-bottom:solid windowtext 1.0pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eKi67\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.45pt;border:none;border-bottom:solid windowtext 1.0pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eMIB-1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:122.05pt;border:none;border-bottom:solid windowtext 1.0pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e1:400\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:132.2pt;border:none;border-bottom:solid windowtext 1.0pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eDako\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:left;line-height:150%;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"line-height:150%;\"\u003eTable 1 Antibody clones, sources, and dilutions\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"border: none;border-collapse:collapse;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:111.65pt;border-top:solid black 1.0pt;border-left: none;border-bottom:solid black 1.0pt;border-right:none;background:white;padding:.75pt .75pt .75pt .75pt;height:12.6pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.45pt;border-top:solid black 1.0pt;border-left: none;border-bottom:solid black 1.0pt;border-right:none;background:white;padding:.75pt .75pt .75pt .75pt;height:12.6pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eCase 1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:122.05pt;border-top:solid black 1.0pt;border-left: none;border-bottom:solid black 1.0pt;border-right:none;background:white;padding:.75pt .75pt .75pt .75pt;height:12.6pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eCase 2\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:132.2pt;border-top:solid black 1.0pt;border-left: none;border-bottom:solid black 1.0pt;border-right:none;background:white;padding:.75pt .75pt .75pt .75pt;height:12.6pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eCase 3\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:111.65pt;border:none;background:white;padding:.75pt .75pt .75pt .75pt;height:13.35pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eAge (yr)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.45pt;border:none;background:white;padding:.75pt .75pt .75pt .75pt;height:13.35pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e54\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:122.05pt;border:none;background:white;padding:.75pt .75pt .75pt .75pt;height:13.35pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e59\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:132.2pt;border:none;background:white;padding:.75pt .75pt .75pt .75pt;height:13.35pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e55\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:111.65pt;background:white;padding:.75pt .75pt .75pt .75pt;height:15.15pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eHistory of pregnancy\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.45pt;background:white;padding:.75pt .75pt .75pt .75pt;height:15.15pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eG2P2\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:122.05pt;background:white;padding:.75pt .75pt .75pt .75pt;height:15.15pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eG2P2\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:132.2pt;background:white;padding:.75pt .75pt .75pt .75pt;height:15.15pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eG2P1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:111.65pt;background:white;padding:.75pt .75pt .75pt .75pt;height:20.7pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eHistory of cancer\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.45pt;background:white;padding:.75pt .75pt .75pt .75pt;height:20.7pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eNO\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:122.05pt;background:white;padding:.75pt .75pt .75pt .75pt;height:20.7pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eNO\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:132.2pt;background:white;padding:.75pt .75pt .75pt .75pt;height:20.7pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u0026nbsp;NO\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:111.65pt;background:white;padding:.75pt .75pt .75pt .75pt;height:21.45pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eFamilial history of cancer\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.45pt;background:white;padding:.75pt .75pt .75pt .75pt;height:21.45pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eNO\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:122.05pt;background:white;padding:.75pt .75pt .75pt .75pt;height:21.45pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eNO\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:132.2pt;background:white;padding:.75pt .75pt .75pt .75pt;height:21.45pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u0026nbsp;NO\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:111.65pt;background:white;padding:.75pt .75pt .75pt .75pt;height:14.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eClinical presentation\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.45pt;background:white;padding:.75pt .75pt .75pt .75pt;height:14.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eIrregular menstruation\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:122.05pt;background:white;padding:.75pt .75pt .75pt .75pt;height:14.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003ePostmenopausal\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003evaginal bleeding\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:132.2pt;background:white;padding:.75pt .75pt .75pt .75pt;height:14.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003ePostmenopausal vaginal\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003ebleeding and discharge\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:111.65pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eSerum tumor biomarkers\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.45pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eNormal CEA, CA125\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eand CA153\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:122.05pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eNormal CEA, CA125\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eand CA153\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:132.2pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eCA125:50.1 U/mL,\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eNormal CEA and CA153\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:111.65pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eImaging findings\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.45pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eA mass in the LUS\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eand cervix canal\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:122.05pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eA mass in\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003ethe endometrium\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:132.2pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eA mass in\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003ethe endometrium\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:111.65pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eFIGO Stage\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.45pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eIIB\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:122.05pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eIB\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:132.2pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eIIIC\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:111.65pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eTumor size\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.45pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e4 \u0026times; 3 \u0026times; 1.5 cm\u003csup\u003e3\u003c/sup\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:122.05pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e4.5\u0026times;4.4\u0026times;1.8cm\u003csup\u003e3\u003c/sup\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:132.2pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e3 \u0026times; 2.5 \u0026times; 1 cm\u003csup\u003e3\u003c/sup\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:111.65pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003ePathological findings\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.45pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eLCNEC (90%) +\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eEC G1 (10%)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:122.05pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eLCNEC (60%) +\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eEC G1 (40%)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:132.2pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eLCNEC (70%) +\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eEC G1 (30%)\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:111.65pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eMitotic count\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.45pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u0026gt;20/10HPF\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:122.05pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u0026gt;20/10HPF\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:132.2pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u0026gt;20/10HPF\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:111.65pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eMI\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.45pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u0026lt;50%\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:122.05pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u0026gt;50%\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:132.2pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u0026gt;50%\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:111.65pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eCervical\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003einterstitial infiltration\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.45pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eYES\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:122.05pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eNO\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:132.2pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eNO\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:111.65pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eLVSI\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.45pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eYES\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:122.05pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eNO\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:132.2pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eYES\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:111.65pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eTreatment\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.45pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eTAH-BSO+RT+CTX\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:122.05pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eTAH-BSO\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:132.2pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eTAH-BSO+CTX\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:111.65pt;border:none;border-bottom:solid windowtext 1.0pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eFollow-up\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.45pt;border:none;border-bottom:solid windowtext 1.0pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eNed at 51 mo\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:122.05pt;border:none;border-bottom:solid windowtext 1.0pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eNed at 17 mo\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:132.2pt;border:none;border-bottom:solid windowtext 1.0pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eNed at 6 mo\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" style=\"width:479.35pt;border:none;border-bottom:solid windowtext 1.0pt;background:white;padding:.75pt .75pt .75pt .75pt;height:12.6pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eAbbreviations: G,\u0026nbsp;gravidity; P,\u0026nbsp;parity;\u0026nbsp;LCNEC, large cell neuroendocrine carcinoma; EC, endometrioid carcinoma; HPF, high\u0026nbsp;power\u0026nbsp;field; MI, myometrial invasion; ned, no evidence of disease; TAH-BSO, total abdominal hysterectomy and bilateral salpingo-oophorectomy; RT, radiation therapy; CTX, chemotherapy; mo, month.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:left;line-height:150%;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"line-height:150%;\"\u003eTable 2 Clinical findings and pathological results of the tumours\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"width: 4.8e+2pt;border: none;border-collapse:collapse;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width:111.65pt;border-top:solid black 1.0pt;border-left:none;border-bottom:solid black 1.0pt;border-right:none;background:white;padding:.75pt .75pt .75pt .75pt;height:8.3pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width:113.45pt;border-top:solid black 1.0pt;border-left:none;border-bottom:solid black 1.0pt;border-right:none;background:white;padding:.75pt .75pt .75pt .75pt;height:8.3pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eCase 1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width:122.05pt;border-top:solid black 1.0pt;border-left:none;border-bottom:solid black 1.0pt;border-right:none;background:white;padding:.75pt .75pt .75pt .75pt;height:8.3pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eCase 2\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width:132.2pt;border-top:solid black 1.0pt;border-left:none;border-bottom:solid black 1.0pt;border-right:none;background:white;padding:.75pt .75pt .75pt .75pt;height:8.3pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eCase 3\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:56.7pt;border:none;border-bottom:solid black 1.0pt;background:white;padding:.75pt .75pt .75pt .75pt;height:8.3pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eLCNEC\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.75pt;border-top:solid black 1.0pt;border-left: none;border-bottom:solid black 1.0pt;border-right:none;background:white;padding:.75pt .75pt .75pt .75pt;height:8.3pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eEC\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.0pt;border:none;border-bottom:solid black 1.0pt;background:white;padding:.75pt .75pt .75pt .75pt;height:8.3pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eLCNEC\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.05pt;border:none;border-bottom:solid black 1.0pt;background:white;padding:.75pt .75pt .75pt .75pt;height:8.3pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eEC\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.1pt;border:none;border-bottom:solid black 1.0pt;background:white;padding:.75pt .75pt .75pt .75pt;height:8.3pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eLCNEC\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.1pt;border:none;border-bottom:solid black 1.0pt;background:white;padding:.75pt .75pt .75pt .75pt;height:8.3pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eEC\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:111.65pt;border:none;background:white;padding:.75pt .75pt .75pt .75pt;height:13.35pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eP16\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;border:none;background:white;padding:.75pt .75pt .75pt .75pt;height:13.35pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e+ (D)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.75pt;border:none;background:white;padding:.75pt .75pt .75pt .75pt;height:13.35pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e+ (P)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.0pt;border:none;background:white;padding:.75pt .75pt .75pt .75pt;height:13.35pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e+ (P)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.05pt;border:none;background:white;padding:.75pt .75pt .75pt .75pt;height:13.35pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e+ (F)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.1pt;border:none;background:white;padding:.75pt .75pt .75pt .75pt;height:13.35pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e+ (D)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.1pt;border:none;background:white;padding:.75pt .75pt .75pt .75pt;height:13.35pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e+ (P)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:111.65pt;background:white;padding:.75pt .75pt .75pt .75pt;height:15.15pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eP53\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;background:white;padding:.75pt .75pt .75pt .75pt;height:15.15pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e+ (P)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.75pt;background:white;padding:.75pt .75pt .75pt .75pt;height:15.15pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e+ (F)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.0pt;background:white;padding:.75pt .75pt .75pt .75pt;height:15.15pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e+ (F)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.05pt;background:white;padding:.75pt .75pt .75pt .75pt;height:15.15pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e+ (F)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.1pt;background:white;padding:.75pt .75pt .75pt .75pt;height:15.15pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e+ (D)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.1pt;background:white;padding:.75pt .75pt .75pt .75pt;height:15.15pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e+ (F)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:111.65pt;background:white;padding:.75pt .75pt .75pt .75pt;height:20.7pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eER\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.7pt;background:white;padding:.75pt .75pt .75pt .75pt;height:20.7pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.75pt;background:white;padding:.75pt .75pt .75pt .75pt;height:20.7pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 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style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e+ (P)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.0pt;border:none;border-bottom:solid windowtext 1.0pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e+ (D)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.05pt;border:none;border-bottom:solid windowtext 1.0pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e+ (P)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.1pt;border:none;border-bottom:solid windowtext 1.0pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e+ (D)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.1pt;border:none;border-bottom:solid windowtext 1.0pt;background:white;padding:.75pt .75pt .75pt .75pt;height:11.1pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;vertical-align:middle;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e+ (D)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" style=\"width:479.35pt;border:none;border-bottom:solid windowtext 1.0pt;background:white;padding:.75pt .75pt .75pt .75pt;height:12.6pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eAbbreviations: D, diffuse (\u0026ge;50% labeling); F, focal (\u0026le;10% labeling); -, nagative; P, patch (11-49% labeling); +, positive; R, retained nuclear staining.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;'\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin-right:0in;margin-left:0in;font-size:14px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:.0001pt;text-align:justify;'\u003e\u003cspan style=\"color: rgb(0, 0, 0); font-size: 10px; font-family: Verdana, Geneva, sans-serif;\"\u003eTable 3 Immunostaining results of the tumours\u003c/span\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Neuroendocrine carcinoma, Endometrioid carcinoma, MMR deficiency","lastPublishedDoi":"10.21203/rs.3.rs-25180/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-25180/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Endometrial neuroendocrine carcinoma (NEC) is a uncommon histologic subtype of endometrial cancer. It is currently unclear if the endometrial NEC has any particular relationship with mismatch repair (MMR) protein expression patterns. Here we report 3 endometrial NEC cases showing loss of MMR expression.\u003c/p\u003e\u003cp\u003eCase presentation: The cancers had two components with one poorly differentiated or NEC component, accounting for 60–90% of the neoplasms and the other of well differentiated glandular component. The NEC cells mainly showed solid sheets and organoid patterns, whereas insular, trabecular and rosette/pseudorosette patterns were also found. The NEC component was composed of cells with large, polygonal, vesicular nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm. In all cases, the NEC component was diffusely positive for p16 and at least 2 of the 3 neuroendocrine markers (CGA, SYN, CD56) reactive in \u0026gt; 10% of the cancer cells. Loss of MMR protein expression was found in all three cases with loss of MLH1 in cases 1 and 2 and loss of MSH2 and MSH 6 in case 3. No PMS2 loss was found. In addition, aberrant \u003cem\u003eTP53\u003c/em\u003e and SMARCB1 (INI1) expression was found in case 3 only. All patients underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy, and two of them received postoperative chemotherapy and/or radiation therapy. The patients remained alive with no disease for 51, 17 and 6 months, respectively.\u003c/p\u003e\u003cp\u003eConclusion: Endometrial NEC is frequently associated with MMR deficiency, some of which may have a better prognosis than we expect.\u003c/p\u003e","manuscriptTitle":"Endometrial neuroendocrine carcinoma frequently associated with mismatch repair deficiency","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-04-29 23:51:46","doi":"10.21203/rs.3.rs-25180/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5281ca63-7ca6-43cc-9759-b8a681ac2cb0","owner":[],"postedDate":"April 29th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":91509,"name":"Pathology"}],"tags":[],"updatedAt":"2020-06-10T20:12:35+00:00","versionOfRecord":[],"versionCreatedAt":"2020-04-29 23:51:46","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-25180","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-25180","identity":"rs-25180","version":["v1"]},"buildId":"ehx78VzkSd0WSzXnipQa-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}