| BackgroundLarge cell neuroendocrine carcinoma(LCNEC)of the ovary,a rare tumor of the female genital tract that is often accompanied by other epithelial and germ cell tumors,is an extremely malignant tumor with an aggressive lethal outcome.However,there are also some rare diseases entities related to the histology of pure large cell neuroendocrine carcinoma.When the H&E stained slides were observed under the microscope,the predominant pattern of lesions comprised mostly of trabecular and rosette-like formations,surrounded by connective tissues at the periphery.Pleomorphic hyper-chromatic tumor cells were arranged in rosette-like patterns,and frequently showed a high mitotic rate and a tendency of neuroendocrine differentiation.The tumor cells had large,moderate amounts of cytoplasm and round to oval nuclei,occasionally with conspicuous nucleoli,granular or coarse chromatin.Additionally,assessment of neuroendocrine differentiation through immunohistochemical analysis,such as positive immunostaining for chromogranin A(CgA),synaptophysin(Syn)or Neural Cell Adhesion Molecule(NCAM,also the cluster of differentiation CD56),is required to confirm the diagnosis of LCNEC.The initial symptoms presented by LCNEC of the ovary are identical to that of epithelial ovarian cancer(EOC),such as presence of an abdominal mass,pain or distention.However,the prognosis of ovarian LCNEC is recognized to be extremely poor even at stage Ⅰ despite extensive surgery and adjuvant chemotherapy.There is no consensus on the optimal chemotherapy regimen and the prognostic factors for the rare type of tumor.ObjectiveThe objective of the present study is to present screened cases of ovarian LCNEC in Qilu hospital,Shandong University.Among a large number of Chinese and foreign literature,we perform an analysis to summarize the clinicopathological features and prognostic factors of ovarian LCNEC patients that have been previously reported.MethodsThe clinical data of all patients with ovarian LCNEC treated in Qilu Hospital,Shandong University from Jan 1,2000 to Oct 31,2019 were collected.Eligible studies were searched for online and 59 cases were found to have been reported between Jan 1,1990 and Oct 31,2019 in the PubMed database,ClinicalTrials.gov,China National Knowledge Infrastructure(CNKI)database and Wanfang Med Online.We extracted individual patient data(IPD),including age,brief history,clinical manifestations,preoperative serum tumor marker level,preoperative imaging examination,tumor size,surgical approach,intraoperative and postoperative pathology,histological grade,surgical-pathological stage,adjuvant therapy,follow-up status and follow-up time.Statistical analysis was performed using the SPSS 20.0 statistical software.We performed chi-square test in statistical inference of categorical datasets and Mann-whitney U test to compare two independent groups.Survival curves were compared using Kaplan-Meier method.Multivariate Cox proportional hazards regression model analysis were performed to calculate hazard ratio(HR).For all statistical tests,the differences were considered as statistically significant when the p value was<0.05.Results1.From January 2000 to October 2019,a total of 3 ovarian LCNEC cases were admitted to Qilu Hospital,Shandong University.To date,only 59 ovarian LCNEC cases have been reported in the literature worldwide.2.These 62 patients were aged from 18 to 80 years and the average age of onset was 52.5 years.67.74%patients were of a middle and old age.Episode age is not a prognostic factor(P=0.994).3.This report displayed the diameter of LCNEC transformation in ovary measuring 3.5-40.0cm,with the average diameter of 14.4cm.Patients of 10cm or more in diameter accounted for 76.36%,tumor diameter is not a prognostic factor(P=0.500).4.The most common initial symptom presented by LCNEC of the ovary is abnormal sick feeling,such as presence of an abdominal pain,anorexia,nausea or distention,which accounted for 56.67%.22.0%patients presented palpable abdominal mass in conventional gynecological examination or ultrasonography,but no self-conscious symptom.5.Prognosis of ovarian LCNEC patients is poor even if early diagnosis is made.It reveals that 51.6%of patients were alive a year later,38.0%at two years and 28.5 percent at three years.6.There were 83.87%patients with elevated CA125 and the estimated value range of CA125 is 35.42 to 4681 U/ml.There was no significant difference in serum CA125 level between stage Ⅰ(early stage)and stage Ⅱ,Ⅲ,Ⅳ(advanced stage)(P=0.899).The abnormal rate of CA125 was 83.33%in early stage patients,84.21%in advanced stage,and the abnormal rate of two groups have no obvious difference(P=0.658).The level of serum CA125 in patients with different pathological patterns were not significantly different(P=0.539).7.Stage Ⅰ,Ⅱ,Ⅲ and Ⅳ accounted for 37.70%,8.20%,37.70%and 19.67%of all patients,and there were 62.30%patients in advanced stage.The median survival time for early stage patients was 17 months,compared to 10 months for those who were in advanced stage.No statistically significant difference in the two groups(P=0.749).8.There were 25.81%patients with pure ovarian LCNEC,74.19%cases with mixed ovarian LCNEC,such as epithelial ovarian tumor(62.90%),teratoma(11.29%)and ovarian malignant brenner tumor.There was no statistically significant difference in pathological patterns within the two groups(P=0.432).9.Total abdominal hysterectomy(P=0.097),omentectomy(P=0.308)and pelvic lymphadenectomy(P=0.760)can not improve prognosis in patients with ovarian LCNEC.Para-aortic lymphadenoectomy’s risk of death was 5.893 times greater for those with not having the procedure.Unfortunately,such a small series like this does not afford for a firm correlation between para-aortic lymphadenoectomy and increased risk of death(P=0.081).10.84.75%patients undergo postoperative chemotherapy,and the median survival time for patients in chemotherapy was 20 months,compared to 10 months for those who did not.Because of differences in outcome measures and follow-up times among the included trials,there was no significant difference in the two groups(P=0.142).There are mainly two types of subsequent therapy:first-line chmotherapeutic regimens of paclitaxel plus carboplatin and platinum-etoposide chemotherapy regimen,aimed at neuroendocrine components.The two regimens of chemotherapy had no significant influence on the outcome of ovarian LCNEC(P=0.931).ConclusionOvarian LCNEC is uncommon and is defined as an extremely malignant type of tumor.As a disease whose prevalence is related with advancing age,it brings about adverse effects even if early diagnosis is made.The majority of women are diagnosed with advanced stage disease.The main symptoms of the patients were abdominal pain,bloating and inappetence.To date,imaging features alone do not allow this diagnosis to be made,and the serum tumor markers of ovarian LCNEC have no certain characteristics.Therefore,it is highly recommended that LCNEC is differentiated from other ovarian tumors using histological features and immunohistochemical specificity.By tracing positive immunostaining for CgA,Syn,NCAM or NSE,we can confirm the diagnosis of LCNEC.Routine imaging examinations for retroperitoneal lymph node metastases,linked with clinical treatment guidelines can contribute to better health care.Multiple literature indicates that most patients undergo platinum-based postoperative chemotherapy,including first-line chemotherapeutic regimens of paclitaxel plus carboplatin and platinum-etoposide chemotherapy regimen.While there is still no convictive peroration on the prognosis as a result of the use of platinum-based chemotherapy.Due to the rarity of ovarian LCNEC and undisciplined follow-up,the effect of chemotherapy on long term survival has not been reported. |
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