Volume 102 ·  Issue 14 ·  2022

Neuroendocrine neoplasms (NENs) originate from neuroendocrine cells diffusely distributed throughout the body. NENs are liable to be misdiagnosed and missed clinically, which brings great difficulties to clinical diagnosis and treatment, and seriously affects their prognosis. This article will introduce the difficulties and hot spots in the diagnosis and treatment of NENs from the aspects of laboratory and pathological examinations, anatomical and functional imaging examinations, including endoscopy, peptide receptor radionuclide therapy, somatostatin analogue and immune checkpoint inhibitor therapy. It aims to provide more ideas for the early diagnosis and early treatment of NENs, standardized diagnosis and treatment of high-grade NENs in the middle and late stages, and to provide more strategies for clinical multidisciplinary experts towards the management of focused dilemmas in NENs.

Gastrointestinal pancreas (GEP) is the most common site of neuroendocrine neoplasms (NENs). In 2019, the World Health Organization (WHO) classification for GEP NET was updated to include a new category of well-differentiated high-grade (Ki 67>20%) GEP-NET G3, distinct from high-grade poorly differentiated neuroendocrine carcinoma (NEC). As a new category, NET G3 are considered a molecularly, radiologically, and prognostically distinct entity compared to NEC and NET G1/G2. The management of NET G3 remains a challenge awaiting future trials taking into consideration the unique characteristics of this new category. The latest NCCN clinical guidelines of neuroendocrine and adrenal tumors firstly gave the recommendation of diagnosis and treatment of G3 NET separately from NEC and G1/G2 NET. Hereon,we aim to summarize the management of G3 NET in combination with the new NCCN guidelines and the current evidences.

Imaging evaluation of pancreatic neuroendocrine neoplasms is developing with the updating of pathological grading. Tumor size, blood perfusion and apparent diffusion coefficient(ADC)value are the most commonly used imaging indicators for the evaluation of the malignancy of pancreatic neuroendocrine neoplasms, as well as other imaging characteristics representing the tumor invasiveness. Dual-probe imaging with SSR-PET and FDG-PET can further improve the accuracy of diagnosis and classification of pancreatic neuroendocrine neoplasms, and provide further information for the tumor treatment and prognosis. Quantitative analysis including texture analysis and radiomics is also a new topic in the research of pancreatic neuroendocrine neoplasms. The combination of morphology, functional imaging and quantitative analysis may contribute to the non-invasive evaluation of the malignancy of pancreatic neuroendocrine neoplasms.

Surgical resection is the optimal choice to achieve a better long-term survival for patients with neuroendocrine liver metastases(NELM). With the deeper understanding of neuroendocrine neoplasms and the establishment of a comprehensive diagnosis and treatment system, the concept of surgery for NELM is continually being updated. This article shares our experience and clinical practice of surgical resection for patients with NELM, and makes a brief review about the current status and controversy of surgical resection with NELM.

In the 5th edition of WHO Classification of Digestive System Tumours, the classification and designation of gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) were updated, and G3 was redefined. Therefore, the differential diagnosis between well-differentiated neuroendocrine tumour G3(NETG3) and poorly differentiated neuroendocrine carcinomas (NEC) is both important and difficult, which has important clinical treatment and prognostic significance. Based on the latest WHO and 2020 Chinese consensus on pathological diagnosis of GEP-NEN, this paper proposed a comprehensive analysis on the differential diagnosis of gastrointestinal pancreatic neuroendocrine tumor from four aspects, including tumor morphological differentiation、tumor proliferative activity, gene change and disease progression. However, even with the above four diagnostic tools, there are still some difficulties and challenges in the work of pathological diagnosis. This paper briefly expounds and discusses them together, in order to improve the clinical application value.

To determinate the value of tumor growth rate (TGR) in evaluating the efficacy of early drug treatment for neuroendocrine neoplasm (NEN).

Patients with NEN who treated at Chinese Academy of Medical Sciences Cancer Hospital from January 2010 to December 2018 were retrospectively enrolled. A total of 30 patients (16 males and 14 females, aged from 26 to 73 (53±11) years) were enrolled. The sum of largest diameter of target lesions and the interval time were measured, TGR of 3 months after the first treatment was calculated using a formula. Intraclass correlation coefficient (ICC) were used to test the repeatability of TGR. Receiver operating characteristic curve (ROC) analysis was used to determine the optimal cut-off values of TGR for predicting progression-free survival (PFS). Overall patients and SD patients assessed by RECIST were grouped by the optimal cut-off values of TGR. Kaplan-Meier method was used to estimate PFS rates and plot patient survival curves of patients at different group of TGR. Cox risk proportional hazard model was used to assess the effect of TGR on the prognosis.

The optimal cut-off value of TGR was -5.8(%/m), the area under the curve was 0.921 (95%CI: 0.824-0.999, P<0.001). Interobserver ICC was 0.955 (95%CI: 0.907-0.978,P<0.001). Multivariate Cox analysis showed that compared with the patients with TGR<-5.8, the patients with TGR ≥-5.8 had a higher risk of progression in either overall population (HR: 10.906, 95%CI: 1.953-60.898, P=0.006) or the SD population (HR: 14.354, 95%CI: 1.602-128.627, P=0.017); TGR ≥-5.8 was an independent risk factor affecting the prognosis of NEN.

TGR can evaluate the efficacy of NEN′s early anti-tumor drug treatment, and associate with prognosis.

To explore the prognosis of Chinese patients with metastatic pancreatic neuroendocrine tumor (PanNET) treated with conversion therapy and surgical resection.

The pathological data and prognostic information was retrospectively collected of patients with metastatic PanNET treated in Fudan University Shanghai cancer center from January 2010 to May 2021, and propensity score matching was used to analyze the prognosis difference between conversion treatment followed surgery and direct surgery.

There were 58 males and 43 females in 101 patients with metastatic PanNET. The age raged from 18 to 74 years, with a median age of 51 years. A total of 88 patients received primary tumor with liver metastases resection, 1 receied of primary tumor resection and 12 received primary tumor resection and combined organs or extrahepatic metastases. Multivariate analysis showed that R2(HR=1.943,95%CI:1.262-2.990,P=0.003)resection and G3(HR=1.876,95%CI:1.001-3.516,P=0.05) were independent risk factors for postoperative progression of metastatic patients. There were 63 patients (62.4%) who had received direct surgery, and 38 patients (37.6%) who had received preoperative conversion therapy. The conversion therapy had a higher proportion of T3/T4 stage (68.1% vs 39.7%, P=0.007), resection with combined organs/extrahepatic metastasis (26.3% vs 9.5%, P=0.005) and R2 resection (71.1% vs 42.9%, P=0.005). The median progression-free survival (mPFS) between conversion therapy and direct surgery had no statistically significant, but after the propensity score matching the mPFS of the conversion therapy group was significantly longer than direct surgery group (HR=0.442,95%CI:0.207-0.943,P=0.027).

Conversion therapy for partially metastatic PanNET is better than that of direct surgery. Radical resection and grade are independent prognostic factors for metastatic PanNET after resection.

To compare the clinical features of multiple endocrine adenoma type 1 (MEN-1) associated pancreatic neuroendocrine neoplasms (pNENs) as well as sporadic pNENs.

The clinical data of 28 sporadic pNENs patients and 10 MEN-1-related pNENs patients admitted to the First Affiliated Hospital of Nanjing Medical University from January 2010 to June 2021 were collected. Meanwhile, by searching PubMed database and reviewing the clinical data of 20 foreign patients with MEN-1-related pNENs which were reported at the same time.Compare and analyze the similarities and differences between MEN1-associated pNENs and sporadic pNENs in clinical features, such as family history, blood tests, pathological diagnostic indicators, tumor grade, stage and metastasis, treatment and prognosis and so on.

A total of 58 pNENs patients were included, and there were 30 MEN1-related pNENs patients and 28 sporadic pNENs patients. Eighteen patients (60%) had a family history of MEN1-related pNENs, and the mean age of onset was (35.3±13.0)years. There were no patients (0) with family history of sporadic pNENs, and the mean age of onset was(55.3±13.4)years. In contrast, the differences in family history, age of onset and NSE were statistically significant(all P<0.05).Among the pathological diagnostic indicators, there were 19 patients (63.3%) with Grade G2 of MEN1-related pNENs, and 25 patients (83.3%) with somatostatin receptor 2(SSTR2) negative. In sporadic pNENs, there were 16 patients (57.1%) with Grade G2 and 9 patients (32.1%) with SSTR2 negative. The differences in pathological grade, immunohistochemistry (Chromogranin A, CD56, and somatostatin receptor 2, SSTR2) between the two groups were statistically significant(all P<0.05). In terms of tumor staging and metastasis, 21 patients with MEN-1-related pNENs had metastasis (70%) and 20 patients with stage Ⅰ and Ⅱ AJCC (71%) in all. Eight patients with sporadic pNENs had metastasis (26.7%) and 8 patients were with stage Ⅰ and Ⅱ AJCC (28.6%). By contrast, the differences in total metastasis rate, AJCC stage and distant metastasis between the two groups were statistically significant(all P<0.05). In terms of treatment and prognosis, there was no statistical significance in the differences between surgical treatment and prognosis (P>0.05), and the difference was also not statistically significant in survival rate between them (P>0.05).

There are no significant differences between MEN1-related pNENs and sporadic pNENs in terms of treatment, prognosis, and survival rate, but there are significant differences in clinical features, pathological features and the staging and grading of tumors. The rate of tumor grade, stage and metastasis of sporadic pNENs is higher.

To investigate the clinical manifestations, imaging, pathological and molecular features of bronchopulmonary large-cell neuroendocrine carcinoma (LCNEC).

The clinical data of 216 LCNEC patients in the First Affiliated Hospital of Zhengzhou University from 2011 to 2021 were analyzed retrospectively. The clinical manifestations, tumor location and size, characteristics of CT images, immunohistochemical and molecular pathological features were analyzed and compared with 115 cases of mixed small cell carcinoma (M-SCLC) diagnosed in the same period.

Among the 216 LCNEC patients, there were 190 males and 26 females, with a median age of 65 years. The first symptoms of the patients were mainly cough (106 cases, 49.1%) and bloody sputum (48 cases, 22.2%). The median tumor length were 4.7cm, including 55 cases of nodular type (25.5%) and 161 cases of mass-forming type (74.5%). CT imaging results showed that LCNEC lesions had soft tissue density, and the proportion of slight enhancement lesions was significantly lower than that in M-SCLC group (52.3% vs 74.8%, P<0.001). In contrast, the proportion of necrosis (87.0% vs 58.3%, P<0.001) and calcification (26.9% vs 2.6%, P<0.001) in LCNEC patients was significantly higher than that in M-SCLC group. Immunohistochemical results showed that the positive rate of CK in LCNEC was significantly higher than that in M-SCLC (99.0 % vs 90.5%, P<0.05), while the positive rate of TTF-1 was significantly lower than that in M-SCLC (51.6% vs 67.0%, P<0.05). In LCNEC group, the proportion of patients with Ki-67 positive index between 50% and 80% was significantly higher than that of M-SCLC (41.2% vs 25.2%), while the proportion between 80% and 100% was lower than that of M-SCLC (51.9% vs 72.2%). There was no significant difference in the positive rates of CD56 (91.7% vs 94.6%, P=0.336), Syn (83.8% vs 84.7%, P=0.838) and CgA (54.8% vs 50.0%, P=0.632) in both tumor types. Molecular pathology results showed that frequent mutatios were TP53 (54.5%), RB1 (36.4%), KEAP1 (18.2%), MYC(18.2%), and PTEN (14.3%), and the rate of tumor mutation burden which is more than 25 mutation/Mb was 27.3%.

LCNEC lacks specific clinical manifestations. CT imaging is powerful in distinguishing LCNEC from M-SCLC. LCNEC contains a specific mutation spectrum. Pathology combined with immunohistochemical staining is still the gold standard for LCNEC diagnosis, and the differentiation from M-SCLC mainly depends on cell size and nuclear chromatin pattern with light microscopy.

To study the alterations of p16 gene and its expression in insulinoma and to correlate the findings with clinicopathological characteristics.

Expression of p16 protein was detected in 72 insulinomas and 49 para-tumoral or normal pancreatic tissues by immunohistochemical staining. Genomic DNA was isolated from 32 tumor tissue and 17 paired pancreatic tissues and bisulfite-modified. Promoter methylation status of p16 gene was detected in 32 tumor tissue and 17 paired pancreatic tissues by methylation specific PCR. The findings were correlated with the clinicopathological features.

There were 30 males and 42 females in all 72 patients, aged (46.5±14.0) years. Loss or reduced expression of p16 protein was found in 42 of 72 insulinomas (58.3%) while loss or reduced expression of p16 was seen in only 34.7% (17/49) of para-tumoral or normal pancreatic tissues (χ²=6.52, P=0.011). Promoter methylation of p16 gene was found in 13 of 32 insulinomas (40.6%) and only 2 of 17 (11.8%) para-tumoral tissues (χ²=4.35, P=0.037). The expression of p16 protein in insulinoma was not associated with clinicopathological features such as gender, age, tumor size and tumor grade.

Loss or reduced expression of p16 protein was found in insulinomas, and associated with p16 gene promoter methylation.

The clinical data of 14 patients with neuroendocrine tumors who received Peptide Receptor Radionuclide Therapy (PRRT) from December 2018 to May 2021 were retrospectively analyzed. Among them, 2 patients demonstrated proprogressive disease, 2 patients had partial response, and 10 patients had stable disease. Grade 1-2 myelosuppression occurred in 5 patients. and 1 patient became grade 3 myelosuppression，which recovered to grade 2 after symptomatic treatment. No grade 2 or higher treatment-related renal toxicity was observed in any of the patients. PRRT is efficacy and no significant side effects for unresectable metastatic neuroendocrine tumors.

Bidirectionally differentiated carcinoma is a rare tumor characterized by the expression of both exocrine and neuroendocrine markers in tumor cells, which can occur in various organs of the digestive system. Pathology and immunohistochemistry are the gold standard for diagnosis. This paper reports the diagnosis and treatment of a highly aggressive advanced bidirectional differentiated carcinoma of the colon in order to improve the understanding of this rare disease.

Neuroendocrine tumors (NENs) are a rare class of heterogeneous tumors of peptidergic neurons and neuroendocrine cells that originate in the human body and can occur anywhere in the body. The incidence of NENs has continued to rise worldwide for nearly 40 years. This paper reviews and analyzes the prevalence of NENs in the world, and summarizes the epidemiological characteristics of NENs in different populations, regions and different onset sites, in order to improve the understanding of NENs among clinical medical staff and help the further prevention and control of NENs.

In the past 30 years, the incidence of neuroendocrine tumors has increased rapidly by nearly 6 times, and due to the relatively long survival period of patients, the number of patients has surged, bringing a great burden to patients, families and society. However, the diagnosis and treatment standards of neuroendocrine tumors have gradually been paid attention to in the past 10 years, and there are still serious insufficient clinical understanding of them, and the effect of drug treatment is still not ideal. Therefore, this paper mainly reviews the clinical research of biological therapy, targeted therapy, radionuclide therapy and chemotherapy of poorly differentiated neuroendocrine tumors, hoping to provide some clinical guidance for the standardized treatment of such patients.

Non-invasive exhaled breath examination applied to a variety of diseases is becoming more and more popular, which provides faster results support for doctors' diagnosis and treatment. Exhaled breath can be examined for a variety of indicators, including hydrogen and methane. Hydrogen and methane are produced in the intestine, transported to the lungs through the blood, and expelled from the body in the form of exhalation. Besides reflecting the intestinal microbial genealogy, it can also reflect the state of multiple organs. This paper briefly describes the mechanism of hydrogen and methane in exhaled breath and the current status of clinical research, so as to provide new thinking for the diagnosis and treatment of hydrogen and methane in exhaled breath.

Gastric neuroendocrine tumors (G-NENs) are a rare class of gastric tumors whose incidence has increased nearly 15-fold over the past 40 years. The WHO in 2010 classified G-NENs into well-differentiated gastric neuroendocrine tumors (G-NET) and poorly differentiated gastric neuroendocrine carcinomas (G-NEC), with significant differences in prognosis. There is significant heterogeneity in G-NENs, and there is still no effective model or marker to predict the prognosis of G-NENs patients. Through analysis of the SEER database (1973-2016), the study found that the age-adjusted incidence of G-NENs increased from 0.309/100,000 in 1975 to 6.149/100,000 in 2016. The study then used data from G-NENs patients in the SEER database to perform regression analysis on G-NET and G-NEC, respectively, and constructed nomograms to predict survival. Finally, the study collected clinical data from G-NENs patients from 8 hospitals in Jiangsu Province, China, verifying the validity of the nomogram. Multivariate analysis in the study revealed independent prognostic factors for both G-NEC and G-NET, including age, distant metastasis, and surgical intervention (P<0.05）。 Furthermore, T, N stage, and pathological grade were significantly associated with survival in patients with G-NEC, while tumor size was a predictor of G-NET prognosis (P<0.05）。 The C-index of the G-NEC and G-NET nomograms was 0.840 and 0.718, respectively, higher than the AJCC staging system in version 8 (0.773 and 0.599). The simultaneous study observed good discrimination of nomograms in the validation cohort (C-index: G-NEC vs. AJCC stage 0.743 vs. 0.714; G-NET vs. AJCC stage 0.945 vs. 0.927). The survival rates predicted by nomograms in the training and validation sets are very close to the actual survival rates.

pancreatic neuroendocrine tumor (PanNET) is heterogeneous and can be divided into hereditary and sporadic. Among them, hereditary PanNET is mostly a component of genetic syndromes. The most common genetic syndrome is multiple endocrine neoplasia 1 (MEN1). The characteristic clinical manifestations of MEN1 are parathyroid adenoma, PanNET and pituitary tumors, in addition to thymic tumors. The molecular basis of MEN1 onset is MEN1 mutation. In sporadic PanNET, MEN1 mutation is also the most common gene change. Whole exon sequencing shows that the proportion of MEN1 mutation in sporadic PanNET reaches 44%. Moreover, MEN1 mutations appeared early in the evolution of PanNET. Therefore, MEN1 is one of the most important genes in the development of PanNET. However, targeted therapies for MEN1 are not ideal.

High-grade gastrointestinal pancreatic neuroendocrine neoplasm (HG-GEP-NEN) is a rare but poorly prognostic type of tumor, and it is an understudied type of tumor. Including well-differentiated neuroendocrine tumors (NET G3) and poorly differentiated intraneurocarcinomas (NEC). NET G3 has a better prognosis than NEC, but is less sensitive to platinum-based chemotherapy than NEC. The treatment of HG GEP-NEC refers to the treatment of small cell lung cancer. At present, there is a general lack of molecular markers for the classification, treatment, and prognosis of HG GEP-NEN. Following pathological reevaluation, the study analyzed tumor DNA and matched blood samples from 181 patients with HG-GEP-NEN, including 152 NEC and 29 NET G3. Based on the sequencing of 360 cancer-related genes, mutations and copy number changes were assessed. The high-frequency mutant genes in NEC were TP53 (64%), APC (28%), KRAS (22%) and BRAF (20%). Only 14% of RB1 was mutated, but 34% of the copy number changes affected RB1. Other high-frequency copy number deletions were ARID1A (35%), ESR1 (25%), and ATM (31%), of which the two genes that showed high-frequency copy number amplification/increase were MYC (51%) and KDM5A (45%). While the similarity of these molecular features to small cell lung cancer (SCLC) is limited, potentially targeted alterations were found in 66% of NEC samples. Mutations and copy number changes vary depending on the primary tumor site, with BRAF mutations mainly seen in the colon (49%) and FBXW7 mutations mainly seen in rectal cancer (25%). Eight out of 152 NEC (5.3%) were microsatellite instability (MSI). High frequency mutations in NET G3 were common in MEN1 (21%), ATRX (17%), DAXX (14%), SETD2 (14%), and TP53 (14%). In addition, the study also found that the molecular differences of HG-GEP-NEN are related to morphological differentiation and origin site. In summary, its molecular level similarities with small cell lung cancer are limited, but the high proportion of targeted changes suggest that there is great potential for individualized treatment.

Peptide receptor radionuclide therapy (PRRT) is an effective treatment for locally advanced or metastatic neuroendocrine tumors (NEN). Although studies have shown that complete or more than 90% tumor reduction therapy can prolong the survival of patients with advanced neuroendocrine tumors, the need for resection of the primary lesion remains controversial. The study compared the effect of pre-resection of primary tumor on patient survival after PRRT treatment. Progression-free survival (PFS) and overall survival (OS) were compared by retrospectively analyzing data from 889 patients with advanced neuroendocrine tumors (G1-G3, stage IV) who received at least one cycle of PRRT (including 486 patients with primary tumors resected before PRRT in Group 1 and 403 patients with unresected primary tumors in Group 2). The median OS in group 1 was 134.0 months [95%CI: 118 to 147 months], compared to 67.0 months (95%CI: 60-80 months,HR=2.79，P<0.001）。 In addition, the median PFS in group 1 after the first PRRT was 18.0 months (95%CI: 15 to 20 months), compared to 14.0 (95%) in group 2CI: 15-18 months,HR=1.21，P=0.012）。 Most of the primary lesions were located in the pancreas (n=335； 38%) and small intestine (n=284； 32%) of patients had primary tumor resection prior to PRRT treatment. In primary gastrointestinal pancreatic and bronchial and pulmonary neuroendocrine, surgical resection of the primary lesions can provide significant survival benefits after PRRT for patients with advanced metastases.