Paraneoplastic neurologic manifestations of neuroendocrine tumors.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors arising from the transformation of neuroendocrine cells in several organs, most notably the gastro-entero-pancreatic system and respiratory tract. The classification was recently revised in the 5th Edition of the WHO Classification of Endocrine and Neuroendocrine Tumors. NENs can rarely spread to the central or peripheral nervous systems. Neurologic involvement is determined by the rare development of paraneoplastic syndromes, which are remote effects of cancer. Mechanisms depend on immunologic response to a tumor, leading to the immune attack on the nervous system or the production of biologically active ("functioning") substances, which can determine humoral (endocrine) effects with neurologic manifestations. Paraneoplastic neurologic syndromes (PNS) are immunologically mediated and frequently detected in small cell lung cancer but rarely seen in other forms of NEN. PNS and Merkel cell carcinoma is increasingly reported, especially with Lambert Eaton myasthenic syndrome. Endocrine manifestations are found in a wide spectrum of NENs. They can develop at any stage of the diseases and determine neurologic manifestations. Patient outcomes are influenced by tumor prognosis, neurologic complications, and the severity of endocrine effects.

Ectopic ACTH syndrome in the course of ACTH-secreting pancreatic neuroendocrine tumour in a patient with a pituitary lesion - diagnostic challenges and individual approach.

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Fulminant ectopic Cushing's syndrome caused by metastatic small intestine neuroendocrine tumour - a case report and review of the literature.

Cushing's syndrome (CS) secondary to adrenocorticotropic hormone (ACTH) producing tumours is a severe condition with a challenging diagnosis. Ectopic ACTH-secretion often involves neuroendocrine tumours (NET) in the respiratory tract. ACTH-secreting small intestine neuro-endocrine tumours (siNET) are extremely rare entities barely reported in literature. This review is illustrated by the case of a 75-year old woman with fulminant ectopic CS caused by a ACTH-secreting metastatic siNET. Severe hypokalemia, fluid retention and refractory hypertension were the presenting symptoms. Basal and dynamic laboratory studies were diagnostic for ACTH-dependent CS. Extensive imaging studies of the pituitary and thorax-abdomen areas were normal, while [68Ga]Ga-DOTATATE PET-CT revealed increased small intestine uptake in the left iliac fossa. The hypercortisolism was well controlled with somatostatin analogues, after which a debulking resection of the tumour was performed. Pathological investigation confirmed a well-differentiated NET with sporadic ACTH immunostaining and post-operative treatment with somatostatin analogues was continued with favourable disease control.

[Ectopic acromegaly due to bronchial neuroendocrine tumors: the first description in Russia of three clinical cases].

 Acromegaly is a neuroendocrine disorder caused by excessive production of growth hormone (GH). In the majority of cases the cause of acromegaly is a pituitary tumor producing GH. Cases of ectopic acromegaly are much rarer. Ectopic acromegaly occurs in cases of tumors which produce growth hormone-releasing hormone (GHRH) or extrapituitary tumors which produce GH. The main sources of excessive GHRH production are neuroendocrine tumors (NETs) of the lung or pancreas. Treatment of ectopic acromegaly consists of surgical removal of the source of GHRH hyperproduction and in cases where surgery is not an option, somatostatin analogues, pegvisomant, chemotherapy, immunotherapy or radiation therapy are used.In this article three cases of ectopic acromegaly due to GHRH-producing lung NETs are presented, each of them being notable for a number of features. In the first two cases, clinical symptoms were mild, besides in the second case ectopic acromegaly was accompanied by primary hyperparathyroidism. In the third case ectopic acromegaly was accompanied by pituitary macroadenoma, and after surgical removal of the lung NET remission of acromegaly was not achieved. In all three cases, lung NETs were detected incidentally on radiologic chest screening for other conditions.

The global leadership into malnutrition criteria reveals a high percentage of malnutrition which influences overall survival in patients with gastroenteropancreatic neuroendocrine tumours.

Patients with neuroendocrine tumours located in the gastroenteropancreatic tract (GEP-NETs) and treatment with somatostatin analogues (SSA's) are at risk of malnutrition which has been reported previously evaluating weight loss or body mass index (BMI) only. The global leadership into malnutrition (GLIM) criteria include weight loss, BMI, and sarcopenia, for diagnosing malnutrition. These GLIM criteria have not been assessed in patients with GEP-NETs on SSA. The effect of malnutrition on overall survival has not been explored before. The aim of this study is to describe the presence of malnutrition in patients with GEP-NET on SSA based on the GLIM criteria and associate this with overall survival. Cross-sectional study screening all patients with GEP-NETs on SSA's for malnutrition using the GLIM criteria. Body composition analysis for sarcopenia diagnosis were performed. Bloods including vitamins, minerals, and lipid profile were collected. Overall survival since the date of nutrition screening was calculated. Uni- and multivariate Cox regression analysis were performed to identify malnutrition as risk factor for overall survival. A total of 118 patients, 47% male, with median age 67 years (IQR 56.8-75.0) were included. Overall, malnutrition was present in 88 patients (75%); based on low BMI in 26 (22%) patients, based on weight loss in 35 (30%) patients, and based on sarcopenia in 83 (70%) patients. Vitamin deficiencies were present for vitamin D in 64 patients (54%), and vitamin A in 29 patients (25%). The presence of malnutrition demonstrated a significantly worse overall survival (p-value = .01). In multivariate analysis meeting 2 or 3 GLIM criteria was significantly associated with worse overall survival (HR 2.16 95% CI 1.34-3.48, p-value = .002). Weight loss was the most important risk factor out of the 3 GLIM criteria (HR 3.5 95% CI 1.14-10.85, p-value = .03) for worse overall survival. A high percentage (75%) of patients with GEP-NETs using a SSA meet the GLIM criteria for malnutrition. Meeting more than 1 GLIM criterium, especially if there is weight loss these are risk factors for worse overall survival.

U-Shaped relationship of insulin-like growth factor I and incidence of nonalcoholic fatty liver in patients with pituitary neuroendocrine tumors: a cohort study.

Context: Although the role of insulin-like growth factor I (IGF-1) in nonalcoholic fatty liver disease (NAFLD) has garnered attention in recent years, few studies have examined both reduced and elevated levels of IGF-1. Objective: The aim of this study was to examine the potential relationship between IGF-1 levels and the risk of new-onset NAFLD in patients with pituitary neuroendocrine tumors (PitNET). Methods: We employed multivariable Cox regression models and two-piecewise regression models to assess the association between IGF-1 and new-onset NAFLD. Hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were calculated to quantify this association. Furthermore, a dose-response correlation between lgIGF-1 and the development of NAFLD was plotted. Additionally, we also performed subgroup analysis and a series sensitivity analysis. Results: A total of 3,291 PitNET patients were enrolled in the present study, and the median duration of follow-up was 65 months. Patients with either reduced or elevated levels of IGF-1 at baseline were found to be at a higher risk of NAFLD compared to PitNET patients with normal IGF-1(log-rank test, P < 0.001). In the adjusted Cox regression analysis model (model IV), compared with participants with normal IGF-1, the HRs of those with elevated and reduced IGF-1 were 2.33 (95% CI 1.75, 3.11) and 2.2 (95% CI 1.78, 2.7). Furthermore, in non-adjusted or adjusted models, our study revealed a U-shaped relationship between lgIGF-1 and the risk of NAFLD. Moreover, the results from subgroup and sensitivity analyses were consistent with the main results. Conclusions: There was a U-shaped trend between IGF-1 and new-onset NAFLD in patients with PitNET. Further evaluation of our discoveries is warranted.

Pituitary neuroendocrine tumor: A neuropsychological comparison with intra-axial tumor.

OBJECTIVE: Despite pituitary neuroendocrine tumor (PitNET) being extra-axial tumors without direct damage to brain tissue, patients with PitNET exhibit neuropsychological impairments. However, it remains unclear whether there are neuropsychological differences between PitNET and intra-axial tumors that directly destroy the brain parenchyma. This prospective study aims to clarify this distinction to inform decision-making for intracranial tumors of diverse origins. METHODS: A total of 146 patients with PitNET, 74 patients with glioma representing intra-axial tumors, and 52 age-, sex-, and education-matched healthy controls were recruited. All patients received standard treatment and postoperative rehabilitation. Clinical data were meticulously collected, and neuropsychological tests were administered to all participants both before and 3 months after surgery. RESULTS: Both PitNET and glioma patients experience the dual burden of cognitive and affective deficits. However, the feature of these deficits differs substantially. In PitNET patients, the deficits are relatively mild and focal, whereas in glioma patients, they are severe and extensive. Specifically, PitNET patients exhibit deficits in memory, anxiety, and negative affect. In contrast, glioma patients display deficits in executive function, attention, anxiety, positive/negative affect, and empathy. Notably, except for persistent memory deficits, the majority of neuropsychological scores declines in PitNET patients are restorable and can reach improvement within a short period after standard surgical therapy and perioperative management. Conversely, glioma patients not only fail to show improvements but also demonstrate worsening in terms of general cognition and memory postoperatively. INTERPRETATION: As an extra-axial tumor, PitNET may exhibit distinctive cognitive and affective functioning compared to intra-axial tumors, highlighting the need for specific treatment approaches for PitNET patients.

Recurrent Cushing's Disease Caused by a TPIT-Lineage Densely Granulated Corticotroph Pituitary Neuroendocrine Tumor: A Case Report.

INTRODUCTION: Recurrent Cushing's disease (recurrent CD) is an uncommon and intricate clinical form of Cushing's syndrome. However, the connection between the pathological types of ACTH-secreting PitNETs and the clinical signs of recurrent CD remains uncertain. CASE DESCRIPTION: A 64-year-old woman, previously diagnosed with renal carcinoma, was admitted to our hospital due to recent weight gain. Previous endocrine tests indicated fluctuating hypercortisolemia and a recurrent pituitary tumor over the past six years. She underwent two transsphenoidal hypophysectomies, and histopathological analysis of the tumor revealed it as a densely granulated corticotroph tumor (DGCT), a subtype of TPIT-lineage PitNET, accompanied by tumor apoplexy. CONCLUSION: This case highlights the connection between recurrent CD and the pathological subtypes of TPIT-lineage DGCT-PitNETs.

Two cases of pancreatic neuroendocrine tumors with ectopic ACTH syndrome during their disease course.

Pancreatic neuroendocrine tumors (PanNETs) are rare malignant tumors that occur in the pancreas. They are divided into functioning and non-functioning tumors based on the presence or absence of their specific hormonal hyper-expression symptoms. Adrenocorticotropic hormone (ACTH)-producing PanNETs are rare, functional tumors, and their clinical characteristics and outcomes have not been well reported.Here, we report the cases of two patients with PanNETs who presented with ectopic ACTH syndrome (EAS) during the course of their disease. Case 1 involved a non-functioning PanNET at the time of surgery. During treatment for recurrent liver metastases, the patient presented with EAS and tumor-associated hypercalcemia, probably due to ACTH and parathyroid hormone-related peptide (PTHrP) production from the liver tumor. Case 2 was a gastrinoma, and similar to Case 1, this patient presented with EAS during the treatment of recurrent liver metastases.It is not uncommon for patients with PanNETs to have multiple hormones and develop secondary hormone secretion during their disease course, although tumor phenotypes differ between primary and metastatic sites. In patients with functioning PanNETs, symptom control with anti-hormonal therapy is essential, in addition to anti-tumor therapy, especially for EAS, which is an endocrine emergency disease that requires prompt diagnosis and treatment.

Neuroendocrine tumors' patients treated with somatostatin analogue could complicate with emergency cholecystectomy.

BACKGROUND: Gastro-entero-pancreatic neuroendocrine tumors are gradually seeing their incidence increase, probably due to their low-rate mortality. Surgery and subsequent medical therapy through octeotride and somatostatin analogues is the recommended approach for hypersecretive hormonal forms, showing an effective control of symptoms and improved survival outcomes. AIM: The present study aims to evaluate the occurrence of gallbladder lithiasis, and its complications, in patients underwent upfront surgery for neuroendocrine tumors and subsequent long-term administration of somatostatin analogues. MATERIAL OF STUDY: We included four adults affected by neuroendocrine (gastric, appendiceal and ileal) tumors and without previous evidence of gallbladder stones, who needed an emergency cholecystectomy after long-term somatostatin treatment. RESULTS: The patients showed complicated conditions sustained by cholelithiasis, such as acute cholecystitis, gangrenous cholecystitis, or intestinal occlusion, which required emergency surgery. DISCUSSIONS: Somatostatin analogues may influence the cascade of enzymes that guarantee the gallbladder motility, and consequently cause the precipitation of cholesterol and calcium bilirubinate crystals. Therefore, higher and sustained levels of somatostatin may result in higher rates of gallstone development. CONCLUSIONS: The prophylactic cholecystectomy, during upfront surgery for neuroendocrine tumors, might prevent an emergency cholecystectomy for gallstones complications. KEY WORDS: Gallbladder stones, Neuroendocrine tumors, Somatostatine analogues.

Characteristics and treatment options of glucagonomas: a national study from the French Group of Endocrine Tumors and ENDOCAN-RENATEN network.

OBJECTIVE: Glucagonoma is a very rare functional pancreatic neuroendocrine tumor (PanNET). We aimed to provide data on the diagnosis, prognosis, and management of patients with glucagonoma. DESIGN AND METHODS: In this retrospective national cohort, we included all patients with glucagonoma, defined by at least 1 major criterion (necrolytic migratory erythema [NME] and/or recent-onset diabetes, and/or weight loss ≥ 5 kg) associated with either glucagonemia > 2 × upper limit of normal or positive glucagon immunostaining. Antisecretory efficacy was defined as partial/complete resolution of glucagonoma symptoms. Antitumor efficacy was assessed according to the time to next treatment (TTNT). RESULTS: Thirty-eight patients were included with median age 58.7 yo, primary PanNET located in the tail (68.4%), synchronous metastases (63.2%). Median Ki-67 index was 3%. Most frequent glucagonoma symptoms at diagnosis were NME (86.8%), weight loss (68.4%), and diabetes (50%). Surgery of the primary PanNET was performed in 76.3% of cases, mainly with curative intent (61.5%). After surgery, complete resolution of NME was seen in 93.8% (n = 15/16). The secretory response rates were 85.7%, 85.7%, 75%, and 60% with surgery of metastases (n = 6/7), chemotherapy (n = 6/7), liver-directed therapy (n = 6/8), and somatostatin analogs (n = 6/10), respectively. All lines combined, longer TTNT was reported with chemotherapy (20.2 months). Median overall survival (OS) was 17.3 years. The Ki-67 index > 3% was associated with shorter OS (hazard ratio 5.27, 95% CI [1.11-24.96], P = .036). CONCLUSION: Patients with glucagonoma had prolonged survival, even in the presence of metastases at diagnosis. Curative-intent surgery should always be considered. Chemotherapy, peptide receptor radionuclide therapy, or liver-directed therapy seems to provide both substantial antitumor and antisecretory efficacies.

Carcinoid heart disease: a potentially fatal complication of carcinoid syndrome.

Carcinoid heart disease is a unique and serious cardiac complication of the neuroendocrine tumour that affects the right side of the heart, especially the tricuspid and pulmonic valves, eventually causing right heart failure. We present a middle-aged man with a history of well-differentiated neuroendocrine tumours of the small intestine with extensive metastases to the liver, mesentery and spine who is receiving monthly octreotide therapy. He presented with generalised fatigue, severe ascites and worsening dyspnoea. Both the transthoracic echocardiography and transoesophageal echocardiography revealed severe tricuspid and pulmonic regurgitations. He was considered a poor surgical candidate, underwent transcatheter pulmonic valve replacement with two bioprosthetic valve-in-valve implantations and was discharged in a stable condition.

The association between jaundice and poorly differentiated pancreatic neuroendocrine neoplasms (Ki67 index > 55.0%).

BACKGROUND: Jaundice occurs in some pancreatic disease. However, its occurrences and role in pancreatic neuroendocrine neoplasms (PNENs) has not been well studied. In this study we showed the association between jaundice and the risk of high grade and poorly differentiated PNENs. METHODS: Ninety-three patients with head-neck PNENs were included. Poorly differentiated pancreatic neuroendocrine neoplasms were defined by a ki67 index > 55.0%. Logistic regression was used to show the association between demographic information, clinical signs and symptoms and the risk of poorly differentiated tumors. A nomogram model was developed to predict poorly differentiated tumor. RESULTS: Eight of 93 PNEN patients (8.6%) had jaundice. The age and ki67 index in patients with jaundice were significantly higher than those patients without jaundice. All jaundice occurred in patients with grade 3 PNENs. Mutivariable regression analysis showed that age (odds ratio(OR) = 1.10, 95% confidence interval (CI):1.02-1.19), tumor size (OR = 1.42, 95%CI:1.01-2.00) and jaundice (OR = 14.98, 95%CI: 1.22-184.09) were associated with the risk of poorly differentiated PNENs. The age and size combination showed a good performance in predicting poorly differentiated PNENs (area under the curve (AUC) = 0.81, 95% CI: 0.71-0.90). The addition of jaundice further improved the age- and size-based model (AUC = 0.86, 95% CI: 0.78-0.91). A nomogram was developed based on age, tumor size and jaundice. CONCLUSION: Our data showed that jaundice was associated with the risk of high grade PNENs and poorly differentiated PNENs.

Update on Current Evidence for the Diagnosis and Management of Nonfunctioning Pituitary Neuroendocrine Tumors.

Pituitary neuroendocrine tumors (PitNETs) are the third most frequently diagnosed intracranial tumors, with nonfunctioning PitNETs (nfPitNETs) accounting for 30% of all pituitary tumors and representing the most common type of macroPitNETs. NfPitNETs are usually benign tumors with no evidence of hormone oversecretion except for hyperprolactinemia secondary to pituitary stalk compression. Due to this, they do not typically present with clinical syndromes like acromegaly, Cushing's disease or hyperthyroidism and instead are identified incidentally on imaging or from symptoms of mass effects (headache, vision changes, apoplexy). With the lack of effective medical interventions, first-line treatment is transsphenoidal surgical resection, however, nfPitNETs often have supra- or parasellar extension, and total resection of the tumor is often not possible, resulting in residual tumor regrowth or reoccurrence. While functional PitNETs can be easily followed for recurrence using hormonal biomarkers, there is no similar parameter to predict recurrence in nfPitNETs, hence delaying early recognition and timely management. Therefore, there is a need to identify prognostic biomarkers that can be used for patient surveillance and as therapeutic targets. This review focuses on summarizing the current evidence on nfPitNETs, with a special focus on potential new biomarkers and therapeutics.