Small Intestine Venous Ischemia, an Uncommon Carcinoid Tumour Complication.

Neuroendocrine tumors metastatic to the liver: How to select patients for liver transplantation?

Introduction: Merkel cell carcinoma (MCC) is a rare neuroendocrine skin carcinoma with documented metastases to the liver, lungs, and gastrointestinal (GI) tract. Colonic metastases are rare but seen with recurrent or primary cutaneous lesions. Described is a patient who presented with bowel obstruction with a hepatic flexure MCC of unknown primary (MCCUP). Case Description/Methods: A 69-year-old female with a history of breast, lung, and anal cancer presented to the emergency department with abdominal pain and distension. Computed tomography of her abdomen demonstrated dilated loops of small bowel and a partial obstruction with transition point in the hepatic flexure. Colonoscopy demonstrated a 4 cm mass at the hepatic flexure obstructing the lumen. Biopsy revealed a high-grade neuroendocrine carcinoma. A right colectomy and histopathology confirmed small cell neuroendocrine carcinoma involving the colonic wall into the pericolic adipose tissue with nodal involvement. It was positive on cytokeratin CAM 5.2, synaptophysin, and Merkel cell polyomavirus (MCPvY) and negative on CDX-2 and TTF-1, excluding primary bowel or lung small cell carcinomas, respectively. Dermatologic evaluation did not reveal a primary cutaneous lesion. Genetic testing was unremarkable. Discussion: This is the first case of MCCUP presenting with colonic obstruction; prior described cases of MCC metastatic to the colon were recurrent disease or from primary skin lesions. Because MCC is rare, has non-specific symptoms, and may lack a primary lesion, MCCUP must be distinguished from other small round blue cell malignancies more commonly found in the GI tract. Thus, neuroendocrine, keratin and MCPyV ancillary staining are critical to distinguish MCC from B-cell lymphoma, small cell carcinoma of bowel or lung primary, and other metastatic dermal malignancies. MCPyV testing in the absence of prior diagnosis is uncommon but vital to the workup of neuroendocrine carcinomas when CDX-2 and TTF-1 are negative as MCPyV positive lymph nodes predict worse outcomes such as disease-free survival. In this patient immunosuppression and prior radiation increased the risk of MCC, and even suggest that this might be a colonic primary. Rarely, MCC and MCCUP are root causes of neuroendocrine carcinomas of the GI tract. In immunocompromised patients, biopsy and pathologic staining are necessary to distinguish insidious malignancies. MCPyV analysis is helpful for diagnosing MCCUP and informing its prognosis.

Neuroendocrine tumours (NETs) are a group of diverse neoplasms arising from cells of neuroendocrine origin. Newer classification and staging systems have been adapted and guidelines published to help to establish a more standardised approach. The estimated incidence of 5.25/100,000 in 2004 is expected to reach to 8/100,000. Although NETs may occur at any age, it is more common after the age of 50. NETs may be associated with familial genetic neuroendocrine tumour syndromes such as multiple endocrine neoplasia (MEN) syndromes (MEN-1 and MEN-2), neurofibromatosis type 1, von Hippel-Lindau (VHL) disease, tuberous sclerosis and Carney complex. NETs are usually slow-growing tumours. They can arise from many organs but commonly from GI tract and pancreas, lung, thymus and other endocrine organs. NETs may synthesise and secrete peptides and/or amines. About 67 % of NETs are located in the GI system; these NETS are sometimes also called carcinoids or GI NETs. Carcinoids secrete numerous peptides, including serotonin (5-HT) and tachykinins. About 10 % GI NETs metastasize to liver and release 5-HT into the blood resulting in carcinoid syndrome characterised by cutaneous flushing, diarrhoea and abdominal pain. Pancreatic NETs comprise the second common group of NETs. These tumours may be functional (~40 %) or non-functional (~60 %). Functional pancreatic NETs are usually defined by the predominant, clinically relevant hormone secretion such as insulin, gastrin, glucagon and vasoactive intestinal peptide (VIP). NETs are graded based on mitotic count and Ki-67 index. Grading should be combined with organ-specific TNM staging system. NETs usually express somatostatin receptors; therefore, somatostatin expression can be used both diagnostically and therapeutically. Somatostatin receptor imaging (111In-DTPA-octreotide or preferably 68Ga-DOTATATE) can be used for initial staging, follow-up and selecting patients for peptide receptor radionuclide therapy (PRRT). Surgery is the only potentially curative treatment modality. Surgery should be considered for patients with early-stage disease, in patients with locoregional and resectable metastatic disease and in some selected symptomatic patients. Somatostatin analogues, interferon and systemic combination chemotherapy are the options for neuroendocrine carcinoma or advanced, inoperable, metastatic disease.

Chronic venulectasias secondary to persistent flushing in the setting of a metastatic well-differentiated neuroendocrine tumor

Neuroendocrine tumors (NETs) are rare, slow-growing neoplasms characterized by their ability to store and secrete different peptides and neuroamines. 1 Some of these substances cause specific clinical syndromes, 2 whereas other may have elevated plasma or urine levels that are not associated with specific syndromes or symptom complexes Unfortunately, there is no Bideal neuroendocrine tumor marker,[ 3 but according to the presentation, the sensitivity and specificity of each marker vary, and it is generally possible to choose those of greatest value for each clinical syndrome. The biochemical markers are those hormones or amines secreted by the neuroendocrine cells from which these tumors are derived. Some of these are not specific to any tumor, but are produced and secreted by most NETs, whereas other biochemical markers are more specific to the type of tumor and where their quantification can lead to the suspicion or confirmation of the presence of such a tumor. The annual incidence of NETs has risen to 40 to 50 cases per million, perhaps because of better diagnosis and the availability of highly specific and sensitive ways to measure these tumors’ products, improved immunohistochemistry, and enhanced techniques for tumor detection. Thus, the perceived increase in incidence may not be a real change in the incidence of the disease. There are a number of impediments to the diagnosis of these tumors. They are rare, comprising less than 2% of gastrointestinal (GI) malignancies, and are therefore not high on the list of causes of specific symptom complexes. Symptoms themselves are often nonspecific and do not lend themselves readily to identifying the specific underlying tumor. In addition, the manifestations are protean and mimic a variety of disorders. Tumors may be found incidentally on laparoscopy for abdominal pain or during the surgical removal of an appendix or even during a computerized tomographic scan of the abdomen for unexplained symptoms. Lung carcinoids may present with hemoptysis or asthma-like symptoms, and midgut carcinoids may be confused with irritable bowel syndrome (IBS). The natural history of this disease is invariably attended by a long history of vague abdominal symptoms, a series of visits to a primary care practitioner, and referral to a gastroenterologist, often with a misdiagnosis of IBS. These symptoms persist with a median latency to correct diagnosis of 9.2 years by which time the tumor has metastasized, causing symptoms such as flushing and diarrhea and progressing on its slow but relentless course until the patient dies. Clearly, a greater index of suspicion and a carcinoid tumor profile screen are warranted for all patients presenting with Btraditional IBS symptoms.[ Midgut carcinoids are associated with mesenteric fibrosis, which can compress mesenteric vessels and cause bowel ischemia and malabsorption, which may be found in the absence of an abdominal mass. The diagnosis of metastases to the liver is generally more obvious but often still takes place only after a delay of many years. Even then, an incorrect diagnosis is not uncommon. Unless biopsy material is examined for the secretory peptides chromogranin, synaptophysin, or neuron-specific enolase (NSE), tumors may be labeled erroneously as adenocarcinoma, with a negative impact on physician’s attitudes regarding management and underestimation of prospects for survival. 4 The common symptomatic manifestations of patients with carcinoid tumors are illustrated in Tables 1 and 2. Flushing

Introduction:Neuroendocrine tumors (NETs) occur more often in lungs, gastrointestinal tract, or pancreas. Data about terminology and grading of NETs in rare locations are scarce and variable, and they have been reported mainly as case reports.Materials and Methods:We here describe our experience with NETs in unusual locations. We have reviewed all NETs diagnosed in our institution and summarized their clinicopathological features. We have also reviewed the literature and discussed the main characteristics of NETs in each site.Results:Two hundred and forty-three primary NETs were diagnosed. About 55.2% of patients were men and the mean age was 62 years. About 90.7% of NETs were located in lungs, gastrointestinal tract, or pancreas, and 50.8% of them were low-grade tumors. We identified 13 NETs in rare locations: breast, ovary, endometrium, vulva, uterine cervix, extrahepatic biliary tract, kidney, sinonasal tract, and thymus. Three additional tumors were diagnosed by the senior author in other institution. Patients were asymptomatic or presented with nonspecific symptoms. All NETs were treated with surgery and 31% of patients received adjuvant therapy. There were 10 Grade 3 (62.5%), 2 Grade 2 (12.5%), and 4 Grade 1 (25%) tumors. Mean follow-up was 72 months. About 60% of G3 tumors recurred or progressed. G2 tumors were located in breast, and both patients are stable. About 50% of G1 tumors recurred or progressed (both renal NETs).Conclusions:NETs in rare locations are heterogeneous, and their behavior does not seem to correlate absolutely with tumor grade. More studies are needed to clarify the role of proliferation rate in these tumors.

e16208 Background: Neuroendocrine neoplasms (NENs) are a group of biologically and clinically heterogenous malignancies of different anatomic sites, the majority of which lie within the gastrointestinal (GI) tract. Prior literature has reported on the association between NENs and other primary malignancies (OPM), but these studies are limited by small sample sizes. We aim to further analyze the association of NENs and OPM on a larger scale using a population-based cancer registry. Methods: Primary malignancies with NEN features were identified from the Surveillance Epidemiology and Ends Results registry between 1975-2017. The histology/behavior of NEN included carcinoid tumor, neuroendocrine carcinoma (NEC), pancreatic endocrine tumor, atypical carcinoid tumor, and other (insulinoma, glucagonoma, gastrinoma, VIPoma, somatostatinoma and enterochromaffin cell carcinoid). First NEN observation from each patient was examined. Patients with NEN were grouped into 3 categories: NEN only, NEN first followed by OPM, and non-NEN first followed by NEN based on sequence number of primary cancer. Secondary malignancy sites were analyzed. Distribution of NEN between GI and non-GI sites was described. Demographics were compared by NEN sequence groups and between GI and non-GI sites. Results: 45,896 patients with NEN were analyzed (77.9% Caucasian, 47.0% male, median age 62.0 yrs). 65.7% of NENs were observed in GI sites. Within the GI tract, 31.3% were small intestine, 25.1% rectum, 16.6% pancreatobiliary, and < 11% in other GI locations. Age at NEN diagnosis was younger in those with GI NENs (median 60.0 vs 65.0, p < 0.001). 71.2% of patients had NEN only, 10.4% had NEN first followed by OPM, and 18.4% had a non-NEN primary followed by NEN. Mean age was 58.9 for NEN primary only, 61.0 for NEN primary first and 68.3 for non-NEN primary first (p < 0.0001). More Caucasian patients had non-NEN primary first (82.3%) compared to NEN primary only (76.9%) and NEN primary first (75.5%). There were no gender differences amongst the three groups. Carcinoid tumor histology was more prevalent in NEN primary first (78.6%) compared to NEN primary only (67.3%) and non-NEN primary first (66.6%), while NEC histology was more prevalent in NEN only (27.4%) and non-NEN first (29.3%) compared to NEN first. Among patients with NEN first followed by a second primary malignancy (SPM), 23.6% of females had a secondary breast malignancy and 28.9% of males had a secondary prostate malignancy. Conclusions: 28.8% of patients with NENs were found to have OPM, either preceding or following their NEN diagnosis. Of those with a SPM following NEN, breast and prostate were the most common sites for women and men, respectively. It is imperative that patients with NEN undergo age-appropriate cancer screening to help identify any concurrent malignancies. Further research is warranted to identify the timeframe in which they occur in relation to the NEN.

More than 60% of neuroendocrine tumours, also called carcinoids, are localised within the gastrointestinal tract. Small bowel neuroendocrine tumours have been diagnosed with increasing frequency over the past 35 years,...

Update on the Management of Neuroendocrine Hepatic Metastases

IntroductionThe occurrence of Neuroendocrine Carcinoma (NEC) of the colon is <2% of all colon cancers. Squamous Cell Carcinoma (SCC) is even more unusual and has an occurrence in the colon as low as 0.1% of colon cancers. Coupled together mixed NEC-SCC, is nearly unheard of. SCC of the gastrointestinal tract is usually found in the esophagus and rectum, rarely are there squamous cells even present in the colon. Presentation of caseA 62-year-old female presented with abdominal pain and a palpable mass in the left lower quadrant. CT scan revealed a poly-lobulated mass in the left abdomen attached to the left colon. A left hemicolectomy was performed. There were no distant metastases at the time of diagnosis. Microscopic examination revealed NEC mixed with SCC demonstrated by keratin pearl formation. DiscussionNEC and SCC individually are unusual in the colon but together are extraordinarily rare. Histologically, the NEC in this case demonstrated squamous cell differentiation with keratin pearl formation. The median survival in studies of patients with colonic NEC is 5–10 months due to the aggressive behavior and lymph node metastases, which were present in this case. There is insufficient literature addressing ideal adjuvant therapy after resection of mixed NEC and SCC of the colon. ConclusionWe present the first case of primary colon mixed NEC and SCC which presented as abdominal pain. There is a current absence of ideal therapy recommendations in the medical literature following resection of mixed NEC and SCC of the colon.

Background: A neuroendocrine tumor (NET) begins in the specialized cells of the body's neuroendocrine system. Most NETs take years to develop and grow slowly. However, some NETs can be fast-growing. NETs can occur in any part of the body, including gastrointestinal (GI) tract (43%), lung (30%), pancreas (7%) and other organs. Here, we reported an analysis of genomic features in 16 GI tract, 45 lung and 13 pancreas NETs. Methods: Patients (pts) with neuroendocrine tumors were enrolled, and surgical tumor tissues or plasma samples were collected. Mutation profiling was performed by next-generation sequencing (NGS). Results: Compared with GI tract NETs patients (Age±SD, 52±11.2), lung NETs patients (Age±SD 62±8.4, P&amp;lt; 0.001) occurred in older patients, and the median age (±SD) of pancreas NETs patients was 58 (±10.8). Mutations were identified in 66 of NETs patients (89.19%), including 12 GI tract (75%), 43 lung (95.56%) and 11 pancreas (84.62%) NETs. Mutations of TP53 (43.85%, 7/16), APC (31.25%, 5/16) and KRAS (25%, 4/16) in GI tract NETs; TP53 (80%, 36/45), LRP1B (24.44%, 11/45) and EGFR (20%, 9/36) in lung NETs and MEN1 (30.77%4/13) in pancreas NETs were observed as the most commonly genetic variations in different type of NETs, which located in different signal pathways and suggested different pathogenesis. Meanwhile, there was no MEN1 mutations and only one LRP1B or EGFR mutation (6.25%, 1/16) occurring in GI tract NETs, one MEN1 mutation (2.22%, 1/44) occurring in lung NETs, and one TP53, KRAS or LRP1B mutation (7.69%, 1/12) and no APC or EGFR mutations occurring in pancreas NETs. In total, although gastrointestinal tract, lung and pancreas NETs all begin in the cells, which have traits of both hormone-producing endocrine cells and nerve cells, the mutation spectrums are very different. On the contrary, the mutations carried by NETs in different locations are related to the organ. Conclusions: In summary, genomic characterization of NETs may offer insights into tumorigenesis and identify potential therapeutic targets in this disease. Citation Format: Jinyan Ye, Weiran Wang, Danhua Wang, Tonghui Ma. Exploration of the genomic features of pan-neuroendocrine tumors in a Chinese retrospective analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2216.

Lynch syndrome (LS) is an autosomal dominant inherited disorder caused by pathogenic variants in DNA mismatch repair (MMR) genes, most commonly MLH1 and MSH2. LS significantly increases the risk of various cancers, including colorectal, endometrial, gastric, and ovarian malignancies. Neuroendocrine neoplasms (NENs) are rare tumors that arise from neuroendocrine cells, predominantly in the gastrointestinal tract, and are frequently associated with hereditary cancer syndromes such as multiple endocrine neoplasia types 1 and 2. While a definitive association between LS and NENs has not been established, isolated cases have been reported. We present the case of a 63-year-old woman with a history of colorectal cancer and a confirmed LS diagnosis, identified through genetic testing that revealed a pathogenic MLH1 variant. Years later, she developed a grade 2 non-functional neuroendocrine tumor (NET), likely of gastrointestinal origin. The patient underwent surgical resection, followed by treatment with somatostatin analogs. Due to this uncommon presentation, we conducted a literature review to explore the potential relationship between LS and NENs. Our analysis identified 13 additional cases of NENs in LS patients, encompassing NETs, neuroendocrine carcinomas (NECs), and mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs). This growing body of evidence suggests that NENs may be part of the LS tumor spectrum. Further research is needed to elucidate the underlying mechanisms and determine whether LS predisposes individuals to NENs. Enhanced surveillance in LS patients could improve early detection of rare malignancies such as NENs, ultimately expanding our understanding of LS-associated cancer risks and guiding more effective clinical management.

Introduction: Neuroendocrine tumours (NETs) are rare tumours, with the Gastrointestinal (GI) tract and the lung as the most common sites with indolent course. Endoscopists play a pivotal role in the diagnosis of GI-NETS because the majority of patients with NETs are asymptomatic and NETs are discovered during screening examinations. Since GI-NETs are less common than other cancers, their natural history, diagnosis, and treatment may not be completely understood. Aim: To estimate the prevalence and to characterize the clinical, endoscopic, and histological features of incidentally detected GI NETs in nodular/polypoidal/ulcerated lesions on GI endoscopy. Materials and Methods: This record-based retrospective study was conducted at the Department of Medical Gastroenterology of a tertiary care facility. The data belonged to the period between January 2018 to December 2020. Data belonged to the patients that underwent Oesophago- gastro duodenoscopy (OGD)/ Colonoscopy and were found to have nodular/ polypoidal lesions. Records on serum chromogranin, serum gastrin and radiological tests such as Ultrasonography(USG) or Computed Tomography (CT) scan were recorded. The histopathological with immunohistochemistry staining report was used to diagnose NETs. Continuous variables were analysed for normality by the Kolmogorov Smirnov test. Results: A total of 59 eligible patients were studied. The prevalence of GI NET tumours in 2018 was 17 (0. 32%), 19 (0. 33%) in 2019, and 23 (0. 41%) in 2020 with an overall rate of 59 (0. 36%) for all the three years. Total male participants were 35 (59.32%), and the mean age of the patients was 56.13 ±12.44 years. Majority had abdominal pain (32, 54.24%) and 35(59.32%) had tumours in the duodenum, 15 (25.42 %) in the stomach. The most common site was duodenum 35 (59.32%). As per World Health Organisation (WHO) NET, most tumours were Grade I (50, 45.76%). Majority of tumours had Synaptophysin (57, 96.61%), Chromogranin (49, 83.05%), and a Ki67 (Kiel-clone no.67) index≤ 2 (49, 83.05%), while 27 (84. 75 %) tumours were of size of &lt;1 cm. Conclusion: GI-NETs are uncommon, and their biology, histopathology, and clinical behavior are distinct. Typically, they are slow-growing tumours, but their growth rate can fluctuate depending on the location, size, and grade of the tumour

374 Background: Neuroendocrine tumors (NETs) are comprised of a group of biologically and clinically heterogenous malignancies arising from a variety of anatomic sites, the majority of which lie within the gastrointestinal tract. Prior literature has reported on the association between NETs and other primary malignancies (OPM), most of which also end up being within the gastrointestinal tract, but these studies are limited by small sample sizes. We aim to further analyze the association of NETs and OPM on a larger scale using a population-based cancer registry. Methods: Malignant primary cancer with NET features were identified from the Surveillance Epidemiology and Ends Results (SEER) registry between 1975 and 2017. The histology/behavior of NET included carcinoid tumor, neuroendocrine carcinoma, pancreatic endocrine tumor, atypical carcinoid tumor, and other including insulinoma, glucagonoma, gastrinoma, VIPoma, somatostatinoma and enterochromaffin cell carcinoid. First NET observation from each patient was examined. Patients with NET were grouped into three categories: only one primary cancer with NET, first primary cancer with NET and first primary cancer without NET based on sequence number of primary cancer recorded in SEER. Distribution of NET between gastrointestinal (GI) and non-GI sites was described. Demographics were compared by NET sequence group and between GI and non-GI sites. Results: 45,896 patients with NET were analyzed (77.9% Caucasian, 47.0% male, median age 62.0 years). More than half (65.7%) of the NETs were observed in GI sites. Within the GI tract, 31.3% were in the small intestine, 25.1% in the rectum, 16.6% in pancreatobiliary, and &lt; 11% in other GI locations. Age at NET diagnosis was younger in those with GI NETs (median 60.0 vs 65.0, p &lt; 0.001 ). 71.2% of NET found in only cancer diagnosis, 10.4% of NET in first followed by a second primary malignancy, and 18.4% in a non-NET primary followed by NET. Mean age was 58.9 for NET primary only, 61.0 for NET primary first and 68.3 for non-NET primary first (p &lt; 0.0001). More Caucasian patients had non-NET primary first (82.3%) compared to NET primary only (76.9%) and NET primary first (75.5%). No gender differences were observed amongst the three groups. Carcinoid tumor histology was more prevalent in NET primary first (78.6%) compared to NET primary only (67.3%) and non-NET primary first (66.6%), while neuroendocrine carcinoma histology was more prevalent in NET only (27.4%) and non-NET first (29.3%) compared to NET first. Conclusions: 28.8% of patients with NETs were found to have OPM, either preceding or following their NET diagnosis. It is imperative that patients with NET undergo age-appropriate cancer screening to help identify any concurrent malignancies. Further research is warranted to identify the location of such additional malignancies and the timeframe in which they occur in relation to the NET.

Next-Generation Sequencing Identified a Novel Crizotinib-Sensitive PLB1-ALK Rearrangement in Lung Large-Cell Neuroendocrine Carcinoma