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

Highlights • Patient Presentation: 48-year-old woman with irregular vaginal bleeding, presenting a polypoid mass protruding from cervical canal.• Diagnostic Findings: Ultrasound and CT scan revealed uterine mass with necrosis, and immunohistochemistry showed characteristics of LCNEC.• Treatment and Outcome: Underwent laparoscopic hysterectomy, radiotherapy, and cisplatin chemotherapy, but died of tumor recurrence.• Pathological Examination: Revealed tumor infiltration into the muscular layer, with metastases observed in the ovary and abdominal lymph nodes.• Prognosis: Diagnosed with stage IIIc endometrial LCNEC, ultimately leading to fatal outcome despite treatment efforts.


Introduction
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.

Case summary
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. 1A 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. 1C and D).Enhanced scanning revealed slight non-uniform enhancement.No abnormalities were identified in gynecological tumor markers.

Management
On August 29, 2019, the patient received laparoscopic hysterectomy, salpingectomy, oophorectomy, pelvic lymph node dissection, and paraaortic 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. 3A 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.

Etiology
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).

Clinical manifestations
Most endometrial NEC have been reported in postmenopausal women and occasionally reported in perimenopausal or reproductiveage 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.

Diagnosis
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.

Treatment
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.

Prognosis
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.

Ethics approval and consent to participate
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

Fig. 1 .
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.

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Table 1
Published reports of LCNEC