Endometrial large cell neuroendocrine carcinoma: A case report and literature review

The case patient was a 48-year-old woman who presented with reports of irregular vaginal bleeding for more than 1 month. Her pelvic ultrasound examination showed the mixed echo group from the uterine cavity to the cervical canal of 9.1 × 4.9 × 3.7 cm 3 ( Fig. 1 A and B). Her gynecological examination revealed a dark-red mass protruding from the cervical canal to the vagina of an approximate size 5 × 5 × 4 cm 3 , irregular in shape, with erosion and necrosis on the surface, easy to bleed on touch. The pathological examination revealed the presence of fibrous tissues, necrotic cells, and a small number of atypical cells. Immunohistochemical examination revealed the following results: Syn (+), CgA (−), CX (epithelial-), CK7 (−), P40 (−), CK5/6 (−), P63 (−), CD10 (−), P16 (partial +), S-100 (−), HMB45 (−), MelanA (−), and LCA (−). The CT revealed that the volume of the uterus was increased, with an uneven density and soft tissue mass (7.7 × 6.8 × 5.5 cm 3 ) protruding from the uterine cavity to the cervical area ( Fig. 1 C and D). Enhanced scanning revealed slight non-uniform enhancement. No abnormalities were identified in gynecological tumor markers. Fig. 1 Pelvic ultrasound (A and B) and CT (C and D) showing a soft tissue mass protruding from the uterine cavity to the cervical area. Pelvic ultrasound (A and B) and CT (C and D) showing a soft tissue mass protruding from the uterine cavity to the cervical area.

Feng Yang collected case information and follow up, all authors contributed to the writing and editing of this study.

Feng Yang: Writing – original draft, Formal analysis. Shoujun Liang: Data curation. Chuanzhong Liu: Investigation. Yeping Wei: Methodology. Liying Zhang: Writing – review & editing, Conceptualization.

Written informed consent was obtained from the patients and family meals, and the study was approved by Self-financing project of Guangxi Zhuang Autonomous Region Health and Family Planning Commission (Z2016288).

The diffuse neuroendocrine system (DNES) is another system that is independent of the somatic nervous system and the autonomic nervous system. It is also called the amine-precursor uptake and decarboxylation (APUD) system. Hormone-like endocrine cells and neuroendocrine carcinoma (NEC) are malignant tumors derived from APUD cells. The WHO (2020) classification of female reproductive system tumors ( Höhn et al., 2021 ) specifies large-cell type into high-level NEC. NEC are rare in female reproductive organs, especially in the endometrium. Endometrial LCNEC is very rare with an incidence of <60 cases worldwide ( Table 1 ). Table 1 Published reports of LCNEC Number Date Author Geographical location Age Symptoms Pathology IHC staining Tumor Size (cm) FIGO Stage Surgical Treatment Adjuvant Therapy Outcome(months) 1 2017 Aya Kobayashi Japan 52 Abdominal pain LCNEC Syn,CgA,CD56 NA IIIC TAH,BSO,LND RT,irinotecan,cisplatin DOD10 2 2017 Harunobu Matusmoto Japan 51 Uterine enlargement LCNEC + ECa Syn,CgA,CD56,Ki-67 3 IIIA TAH,BSO,LND Irinotecan, cisplatin NED20 3 2008 Lorena Posligua USA 59 Abnornal pap smear LCNEC + ECa+serous component Syn,NSE,CD56,CD57,p53,p16 12.5 IIIB TAH,BSO,omentectomy,LND RT,unspecfied chemo NED92 4 2012 Natsuko Makihara Japan 73 Abnornal distension LCNEC Syn,CgA,NSE,p53 NA IVB Refused surgery Refused chemo DOD1 5 2012 Natsuko Makihara Japan 73 PMB LCNEC Syn,CgA,CD56,p53 NA IIIC TAH,BSO,omentectomy,LND Irinotecan, cisplatin AWD13 6 2018 Jumpei Ogura Japan 52 AUB LCNEC Syn,CgA,CD56,Ki67 16.9 IIIC none none DOD1 7 2007 Nicholas J.Mulvany Australia 50 PMB LCNEC Syn,NSE 2.2 IIIC TAH,BSO,omentectomy,LND RT,carboplatin,etoposide AWD12 8 2007 Nicholas J.Mulvany Australia 80 PMB LCNEC + ECa NSE,cytokeratin,AE1/AE3 4.5 IC TAH,BSO,LND RT DOD5 9 2007 Nicholas J.Mulvany Australia 77 PMB LCNEC + ECa Syn,NSE,CD56 7.5 IIB TAH,BSO RT DOD23 10 2007 Nicholas J.Mulvany Australia 79 PMB LCNEC + ECa NSE,cytokeratin,AE1/AE3,CD56 1.5 IIIA TAH,BSO,omental and peritoneal biopsies RT AWD2 11 2007 Nicholas J.Mulvany Australia 88 PMB LCNEC + ECa + squamous differentiation NSE,cytokeratin,AE1/AE3,CD56 5 IIIC TAH,BSO,LND Paclitaxel, carboplatin AWD1 12 2016 Kyoko Ono Japan 41 AUB LCNEC + ECa Syn,CgA,CD56,CK7 10 II TAH Paclitaxel, carboplatin AWD24 13 2017 Antonio Ieni Italy 78 Colonic obstruction LCNEC + poorly dfferentiated adenocarcinoma Syn,CgA,CD56,Ki67,ER,PR,EMA,MLH1,MSH2,MSH6 21 IVB Suboptimal debulking,TAH,BSO,small bowel resection,removal of sigmoid colon and portion of rectum Unspecied chemo AWD3 14 2018 Yi-An Tu Taiwan 51 PMB LCNEC Syn,cytokeratin,p53,CD56 NA IVB TAH,BSO,omentectomy,Suboptimal debulking Etoposide,cisplatin DOD3 15 2011 Shohreh Shahabi USA 59 PMB LCNEC Syn,NSE,CgA,CD56 7 IIIC TAH,BSO,LND,optimal debulking RT,irinotecan,cisplatin DOD12 16 2019 Courtney Jenny USA 56 PMB and pelvic pain LCNEC + ECa Syn,cytokeratin 16 IVB TAH,BSO Planned etoposide and cisplatin DOD2 17 2010 Tadashi Terada Japan 40 AUB LCNEC + sarcomatous Syn, cytokeratin, CD56,vimentin, CA125, CD34, ER, PR, p53, Ki-67, KIT, and PDGFRA 3 IB TAH,BSO,omentectomy,LND Unspecied chemo AWD3 18 2008 Jorge Albores-Saavedra Mexico 42 AUB LCNEC Syn,CgA,P16 4.5 IC TAH Platinum-based combination chemo NED9 19 2011 Kedar K Deodhar India 70 PMB and mild abdominal pain LCNEC Syn, CgA, CD56, cytokeratin,EMA,CD10, MIC-2, vimentin, smooth muscle actin 3.5 IVB TAH,BSO,omentectomy Etoposide, cisplatin NED6 20 2013 My-Linh T. Nguyen USA 71 PMB LCNEC Syn,CgA,CD56,p53,p16,PR 19.5 IVB TAH,BSO,LND,omentectomy Planned etoposide,cisplatin,and octreotide DOD1 21 2004 Erhan Turkey 52 PMB LCNEC Syn,NSE NA IC TAH,BSO Etoposide and cisplatin DOD7 22 2012 Wyatt Unger USA 62 PMB LCNEC + ECa Syn,CD56,p53,IMP-3 6 NA TAH,BSO,LND,omentectomy NA NA 23 2014 Lan-xia Liu China 87 PMB LCNEC + ECa Syn,CD56,CgA，CK7，AE1/AE3，EMA，p16，p53，EＲ，PＲ 10.5 IIIA TAH,BSO NA NA 24 2014 Lan-xia Liu China 44 AUB LCNEC Syn,NSE,CD56,CK7,p53 6 IIIC1 TAH,BSO,LND NA NA 25 2018 Yong-feng Ding China 58 PMB LCNEC + SCNEC + ECa Syn,NSE,CgA,CD56,CD10，CK，EMA 0.9 IIIC TAH,BSO,LND Paclitaxel, carboplatin NED21 26 2016 Cady E. Pocrnich USA 54 NA LCNEC CgA 0.8 IA TAH,BSO RT NED96 27 2016 Cady E. Pocrnich USA 65 Bleeding LCNEC + SCNEC + ECa Syn,CgA,CD56,PanCK,CK18,p16,Pax-8,MLH1,PMS2,MSH2,MSH6 4.5 IA TAH,BSO,LND RT DOD9 28 2016 Cady E. Pocrnich USA 84 Bleeding LCNEC + ECa CD56,PanCK,CK18,p16,Pax-8,MSH2,MSH6 2.8 IB TAH,BSO,LND RT NED118 29 2016 Cady E. Pocrnich USA 66 Bleeding LCNEC + ECa Syn,PanCK,CK18,p16,MSH6 7.5 IB TAH,BSO,LND RT+Unspecied chemo NED37 30 2016 Cady E. Pocrnich USA 55 Bleeding LCNEC + ECa Syn,CgA 4.5 IB TAH,BSO NA NA 31 2016 Cady E. Pocrnich USA 47 Bleeding LCNEC + ECa Syn,CgA,PanCK,CK18,TTF-1, MLH1, PMS2,MSH2,MSH6 6 II TAH,BSO,LND RT+Unspecied chemo DOD15 32 2016 Cady E. Pocrnich USA 51 Bleeding LCNEC + ECa Syn,CgA,PanCK,CK18,p16,CD117,MLH1,PMS2,MSH2,MSH6 7 II TAH,BSO,LND,omental biopsy RT+Unspecied chemo AWD11 33 2016 Cady E. Pocrnich USA 68 Bleeding LCNEC + SCNEC + ECa Syn,CgA,CD56,p16,MSH2,MSH6 6 IIIA TAH,BSO RT+Unspecied chemo NED24 34 2016 Cady E. Pocrnich USA 69 Bleeding LCNEC CgA NA IIIA TAH,BSO,LND RT+Unspecied chemo NED5 35 2016 Cady E. Pocrnich USA 54 Bleeding LCNEC + ECa Syn,CgA,PanCK,CK18,p16,CD117,MLH1,PMS2,MSH2,MSH6 2.7 IIIB TAH,BSO,LND RT+Unspecied chemo NED134 36 2016 Cady E. Pocrnich USA 68 Bleeding LCNEC + SCNEC + ECa Syn,PanCK,CK18,p16,Pax-8, MLH1, PMS2,MSH2,MSH6 7.5 IIIB TAH,BSO,LND,appendectomy RT+Unspecied chemo DOD13 37 2016 Cady E. Pocrnich USA 52 Bleeding LCNEC CgA,PanCK,CK18,p16,CD117,MLH1,PMS2,MSH2 5.5 IIIC1 TAH,BSO,LND RT+Unspecied chemo NED66 38 2016 Cady E. Pocrnich USA 55 Bleeding LCNEC Syn,CD56,PanCK,CK18,p16,MLH1,PMS2 Entire uterus IIIC2 TAH,BSO,LND None DOD6 39 2016 Cady E. Pocrnich USA 63 NA LCNEC Syn,CgA,CD56,PanCK,CK18,p16,Pax-8,MSH2,MSH6 9 IIIC2 TAH,BSO,LND,omental biopsy NA NA 40 2016 Cady E. Pocrnich USA 87 Bleeding LCNEC + SCNEC + ECa Syn 4 IVB TAH,BSO,omental biopsy Unspecied chemo DOD21 41 2016 Cady E. Pocrnich USA 59 Dizziness(brain metastasis) LCNEC + ECa Syn,CgA,PanCK,CK18,p16,MLH1,PMS2,MSH2,MSH6 NA IVB TAH,BSO,LND RT+Unspecied chemo DOD12 42 2016 Cady E. Pocrnich USA 55 Bleeding,abdominal pain LCNEC + SCNEC + ECa Syn,CgA,CD56,PanCK,CK18,p16,MLH1,PMS2,MSH2,MSH6 Entire uterus IVB TAH,BSO,appendectomy and soft tissue biopsy NA DOD3 43 2016 Cady E. Pocrnich USA 37 Bleeding LCNEC + SCNEC Syn,CgA 6.2 IVB TAH,BSO,omental and peritoneal biopsies Unspecied chemo DOD2 44 2016 Cady E. Pocrnich USA 80 Dyspnea(lung metastasis) LCNEC Syn,CgA,PanCK,CK18,p16,CD117,MLH1,PMS2,MSH2,MSH6 NA IVB TAH,BSO, peritoneal biopsies None DOD3 45 2016 Cady E. Pocrnich USA 55 Bleeding LCNEC Syn,PanCK,CK18,p16,Pax-8,MSH2,MSH6 12 IVB TAH,BSO,LND,omental biopsies Unspecied chemo DOD9 46 2018 Lucinda Calheiros Guimarãesa Brazil 75 Bleeding LCNEC + ECa + melanocytic differentiation Syn, CgA, cytokeratin (AE1/AE3) P16, CD56, and Melan-A 7.5 IIIA TAH,BSO RT+ Cisplatin and cyclophosphamide chemo NED8 47 2019 Ruijiao Hu China 54 AUB LCNEC + SCNEC + serous carcinoma Syn,CgA,P16, P53 , CK , Villin, and Ki-67 3 IIIC2 TAH,BSO,LND Cisplatin and etoposide chemo NA 48 2020 Liesel Elisabeth Hardy Australia 47 Abdominal pain, distension, decreased appetite and loss of weight LCNEC + high-grade serous adenocarcinoma Syn,CgA,cytokeratins MNF116, CAM 5.2, EMAPAX8, ER, PR, CD99 and p16 13 IVB Modified posterior exenteration, partial posterior vaginectomy, omentectomy and Hartmanns procedure with suboptimal debulking RT,cisplatin and paclitaxel chemo,tamoxifen NED92 49 2020 Glorimar Rivera China 48 Increasing abdominal pain and girth LCNEC + low-grade endometrial stromal sarcoma Syn,CKs, chromogranin, PAX8, and Ki-67 7 NA TAH,BSO Cisplatin and etoposide chemo DOD12 50 2021 Kotaro Inoue Japan 65 Bleeding LCNEC + SCNEC + ECa Syn,CgA,CD56 5.5 IIIB TAH,BSO,LND,omentectomy Cisplatin and irinotecan chemo NED3 51 2021 Ran Du China 73 Bleeding LCNEC Syn, CgA,cytokeratin (AE1/AE3), CD56, P16, and Ki-67 5.1 IIIC TAH,BSO Paclitaxel liposome and lobaplatin chemo NED15 52 2021 Utku Akgor Turkey 70 Bleeding LCNEC Syn, CgA, CD56, and Ki-67 6.5 IVB TAH,BSO,LND,omentectomy None DOD2 53 2023 Wing Yu Sharon Siu China 55 Bleeding LCNEC + ECa CD56 ,vimentin, p53 ,ki67 (90%), and PMS2 (-) 8.5 II TAH,BSO,LND,omentectomy Cisplatin and etoposide chemo NED5 54 2020 Present case China 48 Bleeding LCNEC Syn,vimentin,desmin,Ki67 9 IIIC TAH,BSO,LND RT+irinotecan and cisplatin chemo DOD19 1. AUB:abnormal uterine bleeding, 2. PMB:post menopausal bleeding, 3. LCNEC:large cell neuroendocrine cancer, 4. SCNEC:small cell neuroendocrine cancer, 5. ECa: endometrial cancer, 6. IHC: immunohistochemical, 7. Syn:synaptophysin, 8. NSE: neural-specific enolase, 9. CgA:chromogranin A, 10. TAH:total abdominal hysterectomy, 11. BSO:bilateralsalpingo-oophorectomy, 12. LND:lymphnodedissection, 13. RT: radiothrephy, 14. DOD:dead of disease, 15. NED:no evidence of disease, 16. AWD:alive with disease, 17. NA: not available. Published reports of LCNEC 1. AUB:abnormal uterine bleeding, 2. PMB:post menopausal bleeding, 3. LCNEC:large cell neuroendocrine cancer, 4. SCNEC:small cell neuroendocrine cancer, 5. ECa: endometrial cancer, 6. IHC: immunohistochemical, 7. Syn:synaptophysin, 8. NSE: neural-specific enolase, 9. CgA:chromogranin A, 10. TAH:total abdominal hysterectomy, 11. BSO:bilateralsalpingo-oophorectomy, 12. LND:lymphnodedissection, 13. RT: radiothrephy, 14. DOD:dead of disease, 15. NED:no evidence of disease, 16. AWD:alive with disease, 17. NA: not available. Most endometrial NEC have been reported in postmenopausal women and occasionally reported in perimenopausal or reproductive-age women. The most common clinical symptoms are abnormal vaginal bleeding and abdominal pain. Cases of paraneoplastic syndromes such as membranous glomerulonephritis, retinopathy, and Cushing's syndrome have also been reported. Some patients show no obvious clinical symptoms on physical examination. Endometrial LCNEC has no specific and sensitive tumor markers, and ultrasound outcomes are not obvious. CT and MRI are significant for preoperative evaluation, albeit the imaging performance is not specific. The diagnosis of NEC must rely on the outcomes of histopathology and immunohistochemical staining. WHO proposes that LCNEC should include the following characteristics: (1) polygonal cells with abundant cytoplasm and obvious nucleoli; (2) a neuroendocrine growth pattern of the tumor; and (3) >10% of the tumor cells expressed one or more neuroendocrine markers, such as CgA, Syn, and CD56 ( Pocrnich et al., 2016 ). Endometrial LCNEC can exist alone or occur with other tumors. Jenny et al. (2019 ) reviewed 20 cases of endometrial LCNECs, of which 8 were accompanied with endometrioid adenocarcinoma. Of these 8 cases, 1 also presented with serous components, 1 with squamous differentiation, 1 with sarcoma, and 1 with poorly differentiated adenocarcinoma. Guimarãesa reported an endometrial LCNEC with foci of melanocytic differentiation ( Guimarães et al., 2018 ). Siu reported an endometrial LCNEC concomitant with Lynch syndrome ( Siu et al., 2023 ). In addition, Albores-Saavedra ( Albores-Saavedra et al., 2008 ) reported a case of endometrial LCNEC with partial sarcomatosis. Several cases of mixed growth of large- and small-cell NEC have been reported worldwide ( Pocrnich et al., 2016 , Inoue et al., 2021 ). This present patient was a perimenopausal woman, with abnormal vaginal bleeding as the main symptom. Ultrasound and CT outcomes strongly indicated endometrial cancer. The final immunohistochemistry result was Syn (+), which supported the diagnosis of LCNEC. Presently, endometrial LCNEC does not have a unified treatment plan. Courtney ( Jenny et al., 2019 ) reviewed 20 patients and found that, except for 2 patients who did not undergo surgery and 1 patient with only the uterus removed, the remaining opted for surgical resection of the whole uterus and double attachment. Of them 10 underwent with lymph node dissection, 6 underwent omentum resection, 7 underwent etoposide and platinum chemotherapy, 3 underwent irinotecan and cisplatin therapy, 2 underwent paclitaxel and carboplatin therapy, and 5 underwent adjuvant radiotherapy after the surgery. Pocrnich et al. (2016 ) analyzed 20 cases of endometrial LCNEC patients treated at the University of Texas Anderson Cancer Center from 1994 to 2014. All patients underwent surgical resection of the whole uterus and bilateral salpingo-oophorectomy, 13 underwent lymph node dissection, 5 underwent large omentum biopsy, 2 underwent appendectomy, 9 underwent adjuvant radiotherapy and chemotherapy, 3 received radiotherapy alone, and another 3 received chemotherapy only. Neoadjuvant chemotherapy was found to be beneficial against cervical small cell neuroendocrine cancer ( Lee et al., 2008 ), although there exists no literature report for endometrial LCNEC. The patient in this case report was a perimenopausal woman diagnosed with endometrial LCNEC before surgery. Therefore, she underwent hysterectomy, salpingectomy, oophorectomy, pelvic lymph nodes, and para-aortic lymph node dissection. She received radiotherapy and cisplatin chemotherapy after the surgery. Endometrial LCNEC has a poor prognosis, and early lymphatic or blood-way metastasis may occur ( Dongol et al., 2014 ). Of the 54 patients, 38 had been diagnosed at least at stage III. The current patients are diagnosed at stage IIIC. Even early patients relapsed quickly after the treatment. The 5-year survival rate of high-grade neuroendocrine cancer was 14–39% ( Höhn et al., 2021 ), and the prognosis was related to the tumor diameter (4 cm), FIGO stage, vascular invasion, parauterine involvement, depth of invasion, and other tumor types ( Peng et al., 2012 ). Albores-Saavedra ( Albores-Saavedra et al., 2008 ) believed that the stage and polypoid characteristics of the disease were the best indicators for predicting the disease. The disease-free survival time of all patients was 9 months to 7 years (average 47 months). In summary, endometrial LCNEC is a highly malignant tumor that mostly affects postmenopausal women and occasionally affects perimenopausal or reproductive-age women. The most common clinical symptom is abnormal vaginal bleeding with giant polypoid mass often accompanied by deep infiltration of the uterine muscle wall. Histologically, it can be simple LCNEC, mixed NEC of the large and small cells, or with accompanying endometrioid adenocarcinoma, sarcoma, or serous carcinoma. The tumor cells expressed one or more neuroendocrine markers such as CgA, Syn, and CD56. Presently, there exists no unified treatment plan. Most of the cases were in the advanced stage at the time of detection, often with poor prognosis.

On August 29, 2019, the patient received laparoscopic hysterectomy, salpingectomy, oophorectomy, pelvic lymph node dissection, and para-aortic lymph node dissection. The anatomy of the uterus revealed a polypoid mass in the uterine cavity of an approximate size 9 × 5 × 5 cm 3 ( Fig. 2 ). The pathological results revealed the following: malignant tumor, infiltration to the whole muscular layer, no tumor tissues in the cervix, vaginal wall incisal margin, vaginal fornix, and left and right ligaments. The tumors were observed in the right ovary and the right abdominal aortic lymph node, with a similar morphology to that of the uterine fundus. Immunohistochemistry examination revealed the following: Syn (+), Vim (less +), S100 (−), CK (−), α-inhibin (−), CD99 (−), Calretinin (−), CD10 (−), Desmin (Less +), CgA (−), CD138 (−), CD38 (−), ER (−), PR (−), WT1 (−), HMB45 (−), Ki67 (+, 40%), MyoD1 (−), and Myogenin (−), which were consistent with the results of LCNEC. With reference to the FIGO staging criteria, the patient was diagnosed with endometrial LCNEC stage IIIc. After surgery, she underwent external pelvic irradiation using conformal intensity modulated radiation therapy with dose of 200Gy/25f, and single-agent cisplatin (60mg dosage) chemotherapy concurrently with radiotherapy weekly. On November 13, the patient received chemotherapy with etoposide and cisplatin once, after which the patient declined the chemotherapy. On February 2020, she experienced abdominal distension without any obvious inducement accompanied with bloating and was re-admitted to the hospital. Her CT revealed multiple recurrences of tumors in the distal sigmoid colon, rectum, anterior sacrum, diaphragm, peritoneum, abdominal cavity, and lymph nodes ( Fig. 3 A and B). Considering the tumor was uncontrolled, the patient refuses to continue the treatment and started oral herbal medication, and died of the disease in March 2021. Fig. 2 Intrauterine masses in the removd uterus. Fig. 3 CT (A and B) showing multiorgan metastases after treatment. Intrauterine masses in the removd uterus. CT (A and B) showing multiorgan metastases after treatment.

Endometrial large cell neuroendocrine carcinoma (LCNEC) is a highly malignant tumor, and due to its low incidence, the clinical understanding of the biological behavior, treatment, and prognosis is poor, warranting accumulation of more clinical experience. We have analyzed and reported a case of endometrial LCNEC and reviewed the relevant literature to improve the comprehension of this disease and facilitate the development of precise clinical diagnosis and treatment.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.