Prognostic factors and predictive models for patients with lung large cell neuroendocrine carcinoma: Based on SEER database.

BACKGROUND: Lung Large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive, high-grade neuroendocrine carcinoma with a poor prognosis, mainly seen in elderly men. To date, we have found no studies on predictive models for LCNEC. METHODS: We extracted data from the Surveillance, Epidemiology, and End Results (SEER) database of confirmed LCNEC from 2010 to 2018. Univariate and multivariate Cox proportional risk regression analyses were used to identify independent risk factors, and then we constructed a novel nomogram and assessed the predictive effectiveness by receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). RESULTS: A total of 2546 patients with LCNEC were included, excluding those diagnosed with autopsy or death certificate, tumor, lymph node, metastasis (TNM) stage, tumor grade deficiency, etc., and finally, a total of 743 cases were included in the study. After univariate and multivariate analyses, we concluded that the independent risk factors were N stage, intrapulmonary metastasis, bone metastasis, brain metastasis, and surgical intervention. The results of ROC curves, calibration curves, and DCA in the training and validation groups confirmed that the nomogram could accurately predict the prognosis. CONCLUSIONS: The nomogram obtained from our study is expected to be a useful tool for personalized prognostic prediction of LCNEC patients, which may help in clinical decision-making.

Gastroenteropancreatic neuroendocrine carcinoma in children and adolescents: a population-based study.

PURPOSE: Gastroenteropancreatic Neuroendocrine Carcinoma (GEP-NEC) in children is an exceptionally rare and aggressive form of cancer. We aimed to conduct a population-based cohort study to predict overall survival (OS) in pediatric patients with GEP-NEC. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was employed to identify all pediatric patients with GEP-NEC diagnosed between 2000 and 2019. To create survival curves based on various criteria, Kaplane-Meier estimations were utilized. The log-rank test was used to compare survival curves. The variables associated with OS were determined using Cox proportional-hazards regression. Furthermore, we developed a nomogram to predict overall survival in pediatric GEP-NEC patients. RESULTS: A total of 103 pediatric GEP-NEC patients were identified. The tumors primarily affected females (62.2%). The majority of GEP-NEC was found in the appendix (63.1%), followed by the pancreas (23.3%) and the intestinal tract (13.6%). The highest rates of localized stage (76.9%) and surgery (98.5%) were found in the NEC of appendix origin. However, pancreatic origins had the largest proportion of distant disease (66.7%) but the lowest percentage of surgery (37.5%). Overall 1-year, 3-year, and 5-year survival rates for all patients were 94.4%, 85.4%, and 85.4%, respectively. Tumors of pancreatic origin had the worst survival compared with those of the appendix and intestinal tract. The Cox proportional hazard regression revealed that only site was an important independent predictor of survival. CONCLUSIONS: Our study revealed that only the primary site was found to be the most important predictor of the OS in pediatric GEP-NEC. It's important to work closely with a multidisciplinary team, including oncologists, surgeons, and other specialists, to determine the most appropriate treatment plan for pediatric GEP-NEC.

Epidemiology and survival outcomes of colorectal mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinoma.

BACKGROUND: Mixed neuroendocrine-non-neuroendocrine neoplasms are a rare subtype of neuroendocrine neoplasm consisting of ≥30% each of neuroendocrine and non-neuroendocrine differentiation. Neuroendocrine carcinomas are poorly differentiated neuroendocrine tumors. The epidemiology and prognosis of colorectal mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas are not clearly defined in the literature. We sought to examine the presentation, patterns of care, and outcomes of patients with mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas. METHODS: We identified patients diagnosed with stage I-III colorectal (excluding appendix) mixed neuroendocrine-non-neuroendocrine neoplasms or neuroendocrine carcinomas with only one-lifetime cancer diagnosis who underwent surgical resection between 2010 and 2018 from the National Cancer Database. We performed bidirectional selection to identify variables to include in a multivariable Cox proportional hazards model. RESULTS: We identified 189 patients with a diagnosis of stage I to III colorectal mixed neuroendocrine-non-neuroendocrine neoplasms, 66% of whom had poorly differentiated tumors and 482 with neuroendocrine carcinomas. Among patients with stage III disease, 68% of patients with mixed neuroendocrine-non-neuroendocrine neoplasms and 54% of patients with neuroendocrine carcinomas received adjuvant chemotherapy. The median survival for the overall patients with mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas cohorts were 38 and 42 months, respectively (P = .22), and the median survival for patients with mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas with stage III disease were 30 and 25 months, respectively (P = .27). In multivariable analysis, fewer number of positive nodes and receipt of adjuvant chemotherapy were independently associated with decreased risk of mortality for patients with mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas. CONCLUSION: Adjuvant chemotherapy is associated with improved survival in stage III mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas. Future studies are warranted to identify subsets of patients benefiting most from adjuvant therapy.

Clinical outcome and therapeutic impact on neuroendocrine neoplasms of the breast: a national cancer database study.

PURPOSE: Neuroendocrine neoplasms (NENs) of the breast are rare and not well-studied. NEN are subcategorized as well-differentiated neuroendocrine tumor (NET) and poorly differentiated neuroendocrine carcinoma (NEC). The objectives of the current study were to review the clinicopathologic features of NENs, therapeutic efficacy of current systemic therapy and clinical outcomes of NEN of the breast. METHODS: Between 2004 and 2015, 420 NET, 205 NEC, 146 Adenocarcinoma with NE differentiation (ACNED) and 1,479,520 of invasive carcinoma, not otherwise specified (IC-NOS) of the breast were identified in the National Caner Database. Overall survival was compared among groups using Kaplan-Meier method and Log-rank test. Multivariate analyses were performed to identify prognostic factors. RESULTS: After adjusting for other prognostic factors, both NET and NEC of the breast showed significantly worse OS than IC-NOS (HR (95% CI) = 1.41 (1.17, 1.72), p = 0.005 and HR (95% CI) = 2.11 (1.67, 2.67), p < 0.001, respectively). Both NET and NEC benefited from endocrine therapy if the tumors were hormonal receptor positive (median OS for treated with vs without: 125 vs 57 months in NET, not reached vs 29 months in NEC). NEC also benefited from chemotherapy (median OS for treated with vs without: 42 vs 34 months), but not NET. CONCLUSION: NEN is a unique pathologic and clinical entity, which has worse clinical outcome compared to IC-NOS of the breast. Current therapeutics used in the treatment of IC-NOS improve, but do not fully mitigate, the poorer prognosis of NEN patients. More effective therapy for patients with this unique tumor type are needed.

Differences in clinical characteristics and prognosis between breast neuroendocrine carcinoma and breast invasive ductal carcinoma: A multicentre population-based study from China.

AIM: We constructed a multicentre cohort in China to analyse the differences in clinical characteristics, treatment strategies and prognoses between breast neuroendocrine carcinoma (NEC) and invasive ductal carcinoma (IDC) of the breast. METHODS: All patients with early-stage breast cancer who attended three hospitals in Beijing from 2000 to 2018 were included in the study. We used propensity score matching to make a 1:3 match between NEC and IDC. RESULTS: After propensity score matching, 153 patients with IDC and 51 patients with NEC were analysed. Multivariate Cox regression showed that compared to patients with IDC, patients with NEC had a worse disease-free survival (HR = 2.94, 95% CI: 1.69-5.12, p < 0.001). CONCLUSION: NEC patients have a worse disease-free survival than IDC patients.

Risk factors, survival analysis, and nomograms for distant metastasis in patients with primary pulmonary large cell neuroendocrine carcinoma: A population-based study.

Introduction: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rapidly progressive and easily metastatic high-grade lung cancer, with a poor prognosis when distant metastasis (DM) occurs. The aim of our study was to explore risk factors associated with DM in LCNEC patients and to perform survival analysis and to develop a novel nomogram-based predictive model for screening risk populations in clinical practice. Methods: The study cohort was derived from the Surveillance, Epidemiology, and End Results database, from which we selected patients with LCNEC between 2004 to 2015 and formed a diagnostic cohort (n = 959) and a prognostic cohort (n = 272). The risk and prognostic factors of DM were screened by univariate and multivariate analyses using logistic and Cox regressions, respectively. Then, we established diagnostic and prognostic nomograms using the data in the training group and validated the accuracy of the nomograms in the validation group. The diagnostic nomogram was evaluated using receiver operating characteristic curves, decision curve analysis curves, and the GiViTI calibration belt. The prognostic nomogram was evaluated using receiver operating characteristic curves, the concordance index, the calibration curve, and decision curve analysis curves. In addition, high- and low-risk groups were classified according to the prognostic monogram formula, and Kaplan-Meier survival analysis was performed. Results: In the diagnostic cohort, LCNEC close to bronchus, with higher tumor size, and with higher N stage indicated higher likelihood of DM. In the prognostic cohort (patients with LCNEC and DM), men with higher N stage, no surgery, and no chemotherapy had poorer overall survival. Patients in the high-risk group had significantly lower median overall survival than the low-risk group. Conclusion: Two novel established nomograms performed well in predicting DM in patients with LCNEC and in evaluating their prognosis. These nomograms could be used in clinical practice for screening of risk populations and treatment planning.

Incidence and relative survival of pancreatic adenocarcinoma and pancreatic neuroendocrine neoplasms in Germany, 2009-2018. An in-depth analysis of two population-based cancer registries.

BACKGROUND: Pancreatic neuroendocrine neoplasms are categorized as neuroendocrine tumors and neuroendocrine carcinomas. Until now, cancer registry reporting of pancreatic cancers does not include a stratification by these two subgroups. We studied the incidence and survival of pancreatic cancer with a special focus on pancreatic neuroendocrine neoplasms. METHODS: We analyzed data from the population-based cancer registries of North Rhine-Westphalia (NRW) and Saarland (SL), Germany, of the years 2009-2018. We included primary malignant pancreatic tumors and report morphology-specific age-standardized (World Standard population) incidence rates for ages 0-79 years and age-standardized relative survival (period approach, ICSS standard). All analyses were restricted to non-death certificate only cases. RESULTS: We analyzed 23,037 patients with a newly diagnosed primary pancreatic cancer. Among morphologically specified cancers, adenocarcinoma (92 %) and neuroendocrine neoplasms (7 %) were the most common morphologies. The age-standardized incidence rates of adenocarcinoma, neuroendocrine tumors and neuroendocrine carcinomas were 4.0-5.5 (in NRW and SL), 0.1-0.3, and 0.1-0.3 per 100,000 person-years, respectively. Neuroendocrine tumors had the highest age-standardized 5-year relative survival with 75.5 % (standard error, SE 2.3) in NRW and 90.6 % (SE 10.2) in SL followed by neuroendocrine carcinomas (NRW: 30.0 %, SE 3.1; SL: 32.3 %, SE 8.7) and adenocarcinomas (NRW: 11.3 %, SE 0.4; SL: 10.2 %, SE 1.5). DISCUSSION: The distinction between neuroendocrine tumors and neuroendocrine carcinomas by the WHO divides neuroendocrine neoplasms into two prognostically clearly distinct subgroups that should be separately analyzed in terms of survival. The first year after diagnosis of pancreatic cancer is the most critical year in terms of survival.

Clinical characteristics, prognostic factors, and survival trends in esophageal neuroendocrine carcinomas: A population-based study.

BACKGROUND: Esophageal neuroendocrine carcinoma (ENEC) is an extremely rare type of malignancy. Clinical data of ENEC are limited to case reports and case series. More information is needed on its clinical feature, management, and prognosis. METHODS: This study collected information of ENEC patients diagnosed pathologically from 2010 to 2018. Data including demographic information, clinical features, and survival trends were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Statistical analyses were performed with STATA/SE 15.1, SPSS 25.0, and GraphPad Prism 8. RESULTS: A total of 283 ENEC patients were included in this study. The small-cell and large-cell subtypes of ENEC possess similar clinical features. The lower third of the esophagus (58%) was the most common location of ENEC. At the time of diagnosis, most ENEC patients were AJCC 7th stage IV (48.1%). Metastasis occurred in more than half of the ENEC patients (53.4%), and the most common metastatic site was the liver (37.1%). Compared with poorly differentiated esophageal squamous cell carcinoma (ESCC), another aggressive malignancy of the esophagus sometimes confused with ENEC because of similar histological features, our study showed differences in tumor location and metastatic rate, but similar poor survival rates. Multivariate survival analysis showed that ENEC located at the middle third of esophagus (p = 0.013), "Brain metastasis" (p = 0.019), and "Liver metastasis" (p < 0.001) were independent predictors of worse outcomes. "Surgery" (p = 0.003), and "Chemotherapy" (p < 0.001) were associated with better survival. CONCLUSION: A significant proportion of patients with newly diagnosed ENEC presented with metastatic disease. Predictors of poor survival included tumor location, brain metastasis, and liver metastasis. ENEC and poorly differentiated ESCC share certain histological features, but differ in tumor location and metastatic rate. Yet, no standard treatment strategy has been established, but surgery and chemotherapy were related to better outcomes.

THE PROGNOSIS OF THE DIFFERENT ESOPHAGEAL NEUROENDOCRINE CARCINOMA SUBTYPES: A POPULATION-BASED STUDY.

BACKGROUND: Neuroendocrine neoplasms are extremely rare and account for 0.4% to 2% of all malignant esophageal neoplasms. The burden of the neuroendocrine histological type on the patients' prognosis and survival is poorly debated. This study aimed to compare the survival rates of primary neuroendocrine neoplasms compared with adenocarcinoma and squamous cell carcinoma of the esophagus. METHODS: This is a retrospective cohort from the Surveillance, Epidemiology, and End Results Program database. Overall survival and cancer-specific survival were evaluated with Kaplan-Meier curves and logrank tests. Proportional Cox regression models were used to evaluate variables related to overall survival. RESULTS: After eligibility criteria, 66,528 patients were selected. The mean follow-up was 22.6 months (SD 35.6). Adenocarcinoma was predominant (62%), followed by squamous cell carcinoma (36%). Large cell carcinoma, small cell carcinoma, and mixed adenoneuroendocrine carcinoma each account for less than 1% each. On the long-term overall survival analysis, esophageal adenocarcinoma showed a better prognosis than all the other histologic types (P-value for logrank test <0.001). With adenocarcinoma as a reference, HR was 1.32 for large cell carcinoma (95%CI 1.2 to 1.45) and 1.37 for small cell carcinoma (95%CI 1.23 to 1.53). The HR was 1.22 for squamous cell carcinoma (95%CI: 1.2 to 1.24); and 1.3 for adenoneuroendocrine carcinoma (95%CI 1.01 to 1.66). For multivariate Cox regression analysis, besides age and stage, the neuroendocrine subtypes large cell carcinoma and small cell carcinoma were considered independent prognostic variables. CONCLUSION: In the esophagus, large cell carcinoma and small cell carcinoma show poorer long-term survival rates than squamous cell carcinoma and adenocarcinoma.

Epidemiology of neuroendocrine neoplasmas in Japan: based on analysis of hospital-based cancer registry data, 2009†-†2015.

PURPOSE: Neuroendocrine neoplasms are rare disease and could originate from throughout the body, however, there have been little epidemiological studies in Japan, especially the organ distribution. This study was to examine the epidemiological information of neuroendocrine neoplasms in the Japanese population using data from a hospital-based cancer registry. METHODS: Using data from the national database of hospital-based cancer registries, we examined the organ distribution, the stage and initial treatment of neuroendocrine neoplasms newly diagnosed and treated in designated and non-designated cancer care hospitals between 2009 and 2015. In the present study, neuroendocrine neoplasms consisted of neuroendocrine tumors and carcinoma. RESULTS: A total of 33,215 (17,485 neuroendocrine carcinomas and 15,730 neuroendocrine tumors) cases were diagnosed. The majority in neuroendocrine carcinoma occur in lung (31.1%) followed in decreasing frequency by stomach (12.9%), pancreas (7.5%), rectum (6.7%) and esophagus (5.8%). On the other hand, the half of neuroendocrine tumor originated rectum (50.9%) and followed by pancreas (13.9%), duodenum (9.0%), lung/bronchus (8.9%), and stomach (8.7%). Neuroendocrine carcinoma presented at more advanced stage and higher age than neuroendocrine tumors.　Most cases of neuroendocrine tumors were treated surgically, while half of neuroendocrine carcinomas were treated with non-surgical therapy consisting of chemotherapy with or without radiotherapy. CONCLUSIONS: Our results demonstrated that neuroendocrine neoplasms could originate from various organs and the site distribution was different between neuroendocrine carcinoma and tumor. The national database of hospital-based cancer registries in Japan is a valuable source for evaluating the organ distribution of the rare systemic disease.

Epidemiological analysis of lung and mediastinal neuroendocrine neoplasms in Japan based on the national database.

BACKGROUND: Neuroendocrine neoplasms (NENs) are rare and can originate from any body part. However, there are only few epidemiological studies, especially on lung and mediastinal NENs. This study investigated the epidemiological trends and differences between lung and mediastinal NENs in Japan. METHODS: Patients with lung and mediastinal NENs were identified in a national hospital-based cancer registry between 2009 and 2015 in Japan. NENs were subclassified into neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). NECs were further subdivided into large neuroendocrine carcinomas (LCNECs) and small cell carcinomas (SCCs). We examined the patient characteristics: sex, age, histology, year of diagnosis, diagnostic opportunity, and initial treatment. RESULTS: We identified 48,433 patients with 47,888 lung (98.9%) and 545 mediastinal (1.1%) NENs. The commonest subtype of lung NENs was SCCs (87%), followed by LCNECs (10%) and NETs (3%). In the mediastinum, SCCs were also the commonest (48%), followed by NETs (38%) and LCNECs (14%). The number of lung NEN annually increased; however, that of mediastinal NENs did not change over time. The mean age of patients with lung NETs was lower than that of patients with lung LCNECs and SCCs (NETs, 62 ± 14 years; LCNECs, 70 ± 9 years; SCCs, 71 ± 9 years; p < .001). The lung and mediastinal NENs were mainly detected based on symptoms, except for lung NETs. Surgical intervention, including multimodal therapy, was performed for 89.3% of lung NETs (surgery alone: 83.6%), while only 15.6% of lung NECs were treated with surgery. For the mediastinum, 75.9% of NETs were treated with surgery, with 27.1% of cases treated with surgery plus multimodal therapy. Surgery was performed more frequently for mediastinal NECs (37%) than for lung NECs (15.6%). CONCLUSIONS: This study highlights differences in trends of lung and mediastinal NENs. This study's findings support the importance of epidemiological evaluations based on the primary sites and histological subtypes.

Risk Patterns of Distant Metastases in Follicular, Papillary and Medullary Thyroid Cancer.

This study of 542 patients with follicular thyroid cancer, 366 patients with the follicular variant and 1452 patients with the classical variant of papillary thyroid cancer, and 819 patients with sporadic medullary thyroid cancer operated at a tertiary referral center aimed to determine risk patterns of distant metastasis for each tumor entity, which are ill-defined. On multivariable logistic regression analyses, lymph node metastasis consistently emerged as an independent risk factor of distant metastasis, yielding odds ratios (ORs) of 2.4 and 2.8 for follicular thyroid cancer and the follicular variant of papillary thyroid cancer, and ORs of 5.9 and 6.4 for the classical variant of papillary thyroid cancer and sporadic medullary thyroid cancer. Another independent risk factor consistently associated with distant metastasis, most strongly in follicular thyroid cancer and the follicular variant of papillary thyroid cancer (OR 3.5 and 4.0), was patient age >60 years. Altogether, 2 distinct risk patterns of distant metastasis were identified, which were modulated by other cancer type-dependent risk factors: one with lymph node metastasis as leading component (classical variant of papillary thyroid cancer and sporadic medullary thyroid cancer), and another one with age as leading component (follicular thyroid cancer and the follicular variant of papillary thyroid cancer). Distant metastasis was exceptional in node-negative patients with sporadic medullary thyroid cancer (1.7%) and the classical variant of papillary thyroid cancer (1.4%), and infrequent in node-negative patients with the follicular variant of papillary thyroid cancer (4.4%). These findings delineate windows of opportunity for early surgical intervention before distant metastasis has occurred.

Neuroendocrine Carcinoma as an Independent Prognostic Factor for Patients With Prostate Cancer: A Population-Based Study.

Background: Neuroendocrine carcinoma (NEC) is a rare and highly malignant variation of prostate adenocarcinoma. We aimed to investigate the prognostic value of NEC in prostate cancer. Methods: A total of 530440 patients of prostate cancer, including neuroendocrine prostate cancer (NEPC) and adenocarcinoma from 2004 to 2018 were obtained from the national Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM), multivariable Cox proportional hazard model, Kaplan-Meier method and subgroup analysis were performed in our study. Results: NEPC patients were inclined to be older at diagnosis (Median age, 69(61-77) vs. 65(59-72), P< 0.001) and had higher rates of muscle invasive disease (30.9% vs. 9.2%, P < 0.001), lymph node metastasis (32.2% vs. 2.2%, P < 0.001), and distal metastasis (45.7% vs. 3.6%, P < 0.001) compared with prostate adenocarcinoma patients. However, the proportion of NEPC patients with PSA levels higher than 4.0 ng/mL was significantly less than adenocarcinoma patients (47.3% vs. 72.9%, P<0.001). NEPC patients had a lower rate of receiving surgery treatment (28.8% vs. 43.9%, P<0.001), but they had an obviously higher rate of receiving chemotherapy (57.9% vs. 1.0%, P<0.001). A Cox regression analysis demonstrated that the NEPC patients faced a remarkably worse OS (HR = 2.78, 95% CI = 2.34-3.31, P < 0.001) and CSS (HR = 3.07, 95% CI = 2.55-3.71, P < 0.001) compared with adenocarcinoma patients after PSM. Subgroup analyses further suggested that NEPC patients obtained significantly poorer prognosis across nearly all subgroups. Conclusion: The prognosis of NEPC was worse than that of adenocarcinoma among patients with prostate cancer. The histological subtype of NEC is an independent prognostic factor for patients with prostate cancer.

Serum Calcitonin-Negative Medullary Thyroid Carcinoma: A Case Series of 19 Patients in a Single Center.

Introduction: Medullary thyroid carcinoma (MTC) is a rare cancer that accounts for 5% of thyroid cancers. Serum calcitonin is a good biomarker for MTC, which is used for diagnosis, prognosis, and monitoring of recurrence. Calcitonin-negative MTC (CNMTC) is rare but confounds diagnostic and prognostic directions. This study introduces 19 cases of CNMTC in a single center. Method: From 2002 March to 2020 July, more than 76,500 patients had undergone thyroid surgery due to thyroid cancer at the Severance Hospital, and a total of 320 patients were diagnosed with MTC (0.4%). Serum calcitonin levels were obtained from every patient who was suspected with MTC. These patients had undergone either bilateral total thyroidectomy or unilateral thyroidectomy with central compartment lymph node dissection, and additional modified radical lymph node dissection if lateral lymph node metastasis was positive. Postoperative monitoring and out-patient clinic follow-up were performed with obtaining the serum calcitonin levels. Result: Nineteen patients tested negative for calcitonin preoperatively (6%). The mean preoperative calcitonin level was 5.1pg/mL if undetectable level is regarded as 0pg/mL. Only two patients were males, and the female bias was significant (p = 0.017). No one except two patients with modified radical neck dissection showed central compartment lymph node metastasis. Every patient's postoperative calcitonin level remained low. The median follow-up period was 71 months. There was no recurrence and only one fatality, and the overall survival rate was 95%. Conclusion: Since incidence of CNMTC is not negligible, MTC should not be ruled out in the diagnostic phase even if serum calcitonin is negative in preoperative examination. We presented 19 cases of CNMTC whose prognosis in general were favorable. Markers of serum and immunohistochemical samples other than calcitonin should be actively examined.

The Clinicopathological Features and Overall Survival of Patients With Gastric Neuroendocrine Carcinoma.

OBJECTIVES: Gastric neuroendocrine carcinoma (GNEC) is a class of rare histological subtypes in gastric cancer (GC). This retrospective case-control study aimed to explore the clinicopathological features and overall survival (OS) of patients with GNEC. METHODS: A large population of GNEC and intestinal-type GC (IGC) patients were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. The 1:1 propensity score matching (PSM) analysis was initiated to adjust the confounders between GNEC and IGC cohorts. Kaplan-Meier (KM) plots with log-rank tests were used to compare the survival differences in GNEC versus IGC. Additionally, Cox proportional hazard regression models were adopted to characterize the prognostic factors relevant to OS of the GNEC patients. RESULTS: An entity of 4596 patients were collected, including 3943 (85.8%) IGC patients and 653 (14.2%) GNEC patients. The PSM analysis well-balanced all confounders in GNEC versus IGC (all P > .05). The KM plots showed that GNEC had significantly superior OS to IGC both before and after PSM analysis. Before PSM, the median OS was 52 (33.6-70.4) months in GNEC versus 32 (29.3-34.7) months in IGC (P = .0015). After PSM, the median OS was 26 (18.3-33.7) months in GNEC versus 21 (17.7-24.3) months in IGC (P = .0039). Stratified analysis indicated that GNEC had superior survivals to IGC in early stage patients and those who received surgery. In Cox regression analysis, age ≥ 60, tumor size > 50 mm, stage II-IV, T2, and N3 were independent risk factors for the GNEC patients (hazard ratio [HR]>1, P < .05). By contrast, year 2010 to 2015, female, and surgery were independent protective factors for these patients (HR < 1, P < .05). CONCLUSIONS: GNEC has unique clinicopathological features quite different from IGC and may have a superior survival to IGC in early stage patients. The prognostic factors identified here may assist the clinicians to more individually treat these patients.

Effects of marital status on survival of medullary thyroid cancer stratified by age.

PURPOSE: Marital status has emerged as an important influence on several cancer outcomes, but its role in medullary thyroid cancer (MTC) remains unclear. This study was to explore the effects of marital status on the prognosis of MTC patients and to determine whether its effects vary by age. PATIENTS AND METHODS: We retrospectively extracted 1344 eligible patients diagnosed with MTC between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. Based on the marital status, we divided those patients into married and unmarried groups. We compared the difference in overall survival (OS) and cancer-specific survival (CSS) between married and unmarried via the Kaplan-Meier analysis. Univariate and multivariate Cox proportional models were performed to identify the prognostic factors of OS and CSS. RESULTS: There were 1344 MTC eligible patients in a total of which 883 (65.7%) were married and 461 (34.3%) were unmarried. The comparison observed between married and unmarried patients was as follows: male (45.2% vs. 28.0%), age (≥52 years) (55.9% vs. 44.6%), White (86.7% vs. 78.7%), and undergo surgery (97.7% vs. 93.3%). Multivariate analysis revealed unmarried status as a risk factor independently associated with worse OS (HR: 2.15, 95% CI: 1.59-2.92) rate and CSS (HR: 1.70, 95% CI: 1.17-2.47) rate. In a further analysis stratified by age, there was no significant difference in OS and CSS between married and unmarried patients younger than 52 years. For the remaining group with 52 years old and higher, unmarried patients showed significantly higher risk of OS and CSS than married patients at all stages of the pathology except M1 stage. CONCLUSION: Married patients with MTC have a better prognosis than unmarried ones. Age can affect the association between marital status and the survival of MTC, and married elders may benefit more than youngers.

GLOBAL ENDOCRINOLOGY: Geographical variation in the profile of RET variants in patients with medullary thyroid cancer: a comprehensive review.

Genetic variability in humans is influenced by many factors, such as natural selection, mutations, genetic drift, and migrations. Molecular epidemiology evaluates the contribution of genetic risk factors in the etiology, diagnosis, and prevention of a particular disease. Few areas of medicine have been so clearly affected by genetic diagnosis and management as multiple neoplasia type 2 (MEN2), in which activating pathogenic variants in the RET gene results in the development of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism in nearly 98, 50, and 25% of gene carriers, respectively. Here, we aimed to collect RET genotyping data worldwide to analyze the distribution and frequency of RET variants from a global perspective. We show that the mutational spectrum of RET is observed worldwide. The codon 634 variants seem to be the most prevalent, but there are differences in the type of amino acid exchanges among countries and in the frequencies of the other RET codon variants. Most interestingly, studies using haplotype analysis or pedigree linkage have demonstrated that some pathogenic RET variants have been transmitted to offspring for centuries, explaining some local prevalence due to a founder effect. Unfortunately, after almost three decades after the causative role of the germline RET variants has been reported in hereditary MTC, comprehensive genotyping data remain limited to a few countries. The heterogeneity of RET variants justifies the need for a global effort to describe epidemiological data of families with MEN2 to further understand the genetic background and environmental circumstances that affect disease presentation.

Comparison of Survival and Patterns of Recurrence in Gastric Neuroendocrine Carcinoma, Mixed Adenoneuroendocrine Carcinoma, and Adenocarcinoma.

Importance: Gastric neuroendocrine carcinoma and mixed adenoneuroendocrine carcinoma are rare pathological types of gastric cancer, and there is a lack of multicenter studies comparing the prognosis and recurrence patterns of gastric neuroendocrine carcinoma, gastric mixed adenoneuroendocrine carcinoma, and gastric adenocarcinoma. Objective: To compare the differences in long-term survival and patterns of recurrence among gastric neuroendocrine carcinoma, gastric mixed adenoneuroendocrine carcinoma, and gastric adenocarcinoma. Design, Setting, and Participants: This cohort study included patients with resectable gastric neuroendocrine carcinoma and gastric mixed adenoneuroendocrine carcinoma at 23 hospitals in China from January 2006 to December 2016. In addition, patients with gastric adenocarcinoma were selected as controls. Propensity score-matched analysis was used to match pathological stage among the different pathological types, and disease-free survival (DFS), postrecurrence survival (PRS), and patterns of recurrence were examined. Data analysis was conducted from July 15, 2020, to October 21, 2020. Exposures: Curative resection for gastric neuroendocrine carcinoma, gastric mixed adenoneuroendocrine carcinoma, and gastric adenocarcinoma. Main Outcomes and Measures: The main outcomes were DFS and patterns of recurrence. Results: A total of 3689 patients were analyzed (median [interquartile range] age, 62 [55-69] years; 2748 [74.5%] men), including 503 patients (13.6%) with gastric neuroendocrine carcinoma, 401 patients (10.9%) with gastric mixed adenoneuroendocrine carcinoma, and 2785 patients (75.5%) with gastric adenocarcinoma. After propensity score matching, 5-year DFS was 47.6% (95% CI, 42.7%-52.5%) for patients with gastric neuroendocrine carcinoma, compared with 57.6% (95% CI, 55.1%-60.1%) with gastric adenocarcinoma (P < .001) and 51.1% (95% CI, 46.0%-56.2%) for patients with gastric mixed adenoneuroendocrine carcinoma, compared with 57.8% (95% CI, 55.1%-60.5%) patients with gastric adenocarcinoma (P = .02). Multivariable analyses found that, compared with gastric adenocarcinoma, gastric neuroendocrine carcinoma (hazard ratio [HR], 1.64; 95% CI, 1.40-1.93) and gastric mixed adenoneuroendocrine carcinoma (HR, 1.25; 95% CI, 1.05-1.49) were independent risk factors associated with worse DFS. Compared with matched patients with gastric adenocarcinoma, patients with gastric neuroendocrine carcinoma were more likely to have distant recurrence (268 patients [17.2%] vs 101 patients [23.7%]; P = .002), as were patients with gastric mixed adenoneuroendocrine carcinoma (232 patients [17.3%] vs 76 patients [22.8%]; P = .02). In multivariate analysis, gastric neuroendocrine carcinoma (HR, 2.22; 95% CI, 1.66-2.98) and gastric mixed adenoneuroendocrine carcinoma (HR, 1.70; 95% CI, 1.24-2.34) were independent risk factors associated with distant recurrence. Additionally, T3 to T4 stage (odds ratio, 2.84; 95% CI, 1.57-5.14; P = .001) and lymph node metastasis (odds ratio, 2.01; 95% CI, 1.31-3.10; P = .002) were independent risk factors associated with distant recurrence of gastric neuroendocrine carcinoma and gastric mixed adenoneuroendocrine carcinoma. Conclusions and Relevance: This cohort study found that patients with gastric neuroendocrine carcinoma or gastric mixed adenoneuroendocrine carcinoma had worse prognoses and were more prone to distant recurrence than those with gastric adenocarcinoma. Thus, different follow-up and treatment strategies should be developed to improve the long-term survival of patients with gastric neuroendocrine carcinoma or gastric mixed adenoneuroendocrine carcinoma, especially patients with tumors penetrating into the subserosa or deeper layers or with lymph node metastasis.

Sex-Based Differences in Prognosis of Patients With Gastroenteropancreatic-Neuroendocrine Neoplasms: A Population-Based Study.

OBJECTIVES: The aim of this study was to assess sex-based differences in prognosis of a contemporary cohort of gastroenteropancreatic-neuroendocrine neoplasm (GEP-NEN) patients. METHODS: Surveillance, Epidemiology, and End Results database was accessed, and cases with GEP-NENs were selected. Rates of GEP-NEN diagnosis from 1975 to 2016 for both male patients and female patients were reviewed. Survival outcomes of GEP-NEN patients diagnosed from 2010 to 2014 were determined through Kaplan-Meier estimates and multivariable Cox regression analysis. Overall survival analyses were stratified by stage and histology. RESULTS: A total of 20,836 GEP-NEN patients were diagnosed from 2010 to 2014, and they were included in the current analysis. These include 10,336 male patients and 10,500 female patients. Annual percent change for the age-adjusted rate for GEP-NENs in the United States (1975-2016) is 5.0 (95% confidence interval [CI], 4.8-5.2). When stratified by sex, annual percent change for male patients was 4.8 (95% CI, 4.6-5.1), whereas for female patients, it was 5.0 (95% CI, 4.8-5.3). Female patients have better overall survival compared with male patients among all substrata of patients (according to stage, histology, and differentiation) (P for all comparisons <0.01). CONCLUSIONS: Female sex seems to be associated with better overall survival among patients with GEP-NENs. It is unclear if this is the result of differences in noncancer mortality or is the result of inherent biological differences.