Course Of Neuroendocrine Tumors Research Articles

Current aspects of diagnosis and treatment of patients with neuroendocrine tumors

The article presents modern possibilities and existing problematic aspects of the choice of therapeutic and diagnostic tactics in patients with neuroendocrine tumors of the gastrointestinal tract and pancreas are presented. The asymptomatic course of neuroendocrine tumors of the gastrointestinal tract and pancreas was established in 18.5% and 24.6% of cases, respectively. Carcinoid syndrome was detected in 12.9%. The sensitivity rates of chromogranin A and neuron-specific enolase in the diagnosis of tumors were 54% and 13%, respectively. The levels of cancer-embryonic antigen in G-1/G-2 and G-3 tumors were 5 ng/ml and 8.9 ng/ml, respectively (p 0.001). A pathognomonic sign of neuroendocrine tumors of the small intestine is a mesentery tumor conglomerate, and the sensitivity rates of computed tomography and positron emission tomography with 68Ga to detect this sign were 92.3% and 92.9%, respectively (p 0.05). The computed tomographic density of neuroendocrine pancreatic tumors G-1/G-2 in the arterial phase was 112.1 40.2 HU and that of G-3 tumors was 54.0 10.4 HU (p = 0.025). Surgical treatment was performed in 259 (79.7%) patients. Postoperative complications that developed in localized and locally distributed neuroendocrine tumors of the gastrointestinal tract and of the pancreas were found in 3.5% and 8.8%, and in 58.1% and 40% of the cases, respectively, and those of generalized tumors were noted in 20%. The tumor-specific 5-year survival rates of patients with localized neuroendocrine tumors of the gastrointestinal tract and pancreas were 92.5% and 94.4%, those with locally distributed tumors had 66.8% and 77.8%, and those with generalized tumors had 51.8% and 47.1%, respectively. In patients with generalized tumors, the 5-year survival rates after cytoreduction and removal of the primary tumor were 88.2% and 64.6%, respectively (p = 0.097), and the rate after drug therapy was 28.8% (p 0.001). The prognosis of the 5-year survival of patients is determined by the degree of malignancy and tumor localization, treatment method, and patient age. In general, neuroendocrine tumors are a heterogeneous group of neoplasms that require a multidisciplinary approach to diagnosis and choice of therapeutic strategies.

Managing carcinoid heart disease in patients with neuroendocrine tumors

Carcinoid heart disease is a complex clinical entity frequently complicating the course of neuroendocrine tumors and carcinoid syndrome and is associated with significant morbidity and mortality. Although the pathogenesis of carcinoid heart disease remains poorly understood, it appears that the exposure to excessive circulating levels of serotonin contribute a key role, triggering a cascade of events that ultimately results in the development of plaque-like material on the endocardial surfaces of the valve leaflets. The occurrence of carcinoid heart disease may initially run an asymptomatic period, followed by the development of symptoms of congestive cardiac failure. The diagnosis of carcinoid heart disease is suspected by raised biomarkers, such as serum NT-pro-BNP and confirmed by imaging modalities, with echocardiogram being the gold standard to date. Carcinoid heart disease treatment remains challenging as in addition to cardiac dysfunction, tumor burden needs to be tackled with, hence requiring a multidisciplinary approach. Therapy comprises watchful waiting during the first initial stages of the disease; medications for heart failure; optimal control of serotonin secretion from the NET with pharmacotherapy, interventional means or even surgical techniques; and, in selected patients, cardiac valve replacement. The current review summarizes the literature on the diagnosis and management of carcinoid heart disease.

Clonal Hematopoiesis in Patients with Neuroendocrine Tumors Receiving Peptide Receptor Radionuclide Therapy (PRRT)

Background. Clonal hematopoiesis (CH) prevalence increases with age. Elderly (>70 years) healthy individuals have a 10% incidence of CH. Cancer cohorts are at increased risk of harboring CH mutations (~25%). Specific tumor types such as thyroid, ovarian, and bladder, have previously been shown to be at the highest risk of CH due to increased exposure to radionuclide and chemo-radiotherapies. Radionuclide therapies in particular are associated with a high incidence of subsequent myeloid disorders. Exposure to peptide receptor radionuclide therapy (PRRT, Lu 177 dotatate) leads to an increased risk (~2-5%) of therapy related myeloid neoplasms (MNs). It is not known if baseline CH architecture of neuroendocrine tumors (NETs) contributes to the increased risk or the protracted course of NETs or exposure to leukemogenic therapies. With a broader view to understand emergence of therapy induced myeloid neoplasms in various malignancies, we aimed to characterize baseline rates of CH in patients (pts) with NETs and assess clonal evolution in serial blood samples procured prior to and after exposure to PRRT. Methods. The NET Biobank housed at Roswell Park Comprehensive Cancer Center contains banked serial samples for pts receiving PRRT since its FDA approval in 2018. In this retrospective analysis, we identified pre-PRRT blood samples from 13 pts with NET treated at our institute from 2018-19. Serial samples (post PRRT exposure) were available for 6 of 13 pts. Genomic DNA collected from pts before and after PRRT treatment initiation was analyzed for CH mutations using a custom panel targeting 93 genes. A VAF cut off of 1% was used to define putative CH mutations. Relationships among clinical, laboratory and mutational variables were examined using chi-square test, at a significance level of 0.05. Results. Pt characteristics (n=13) are shown in Table 1. Median age was 58 years. 70% were men. Only 1/13 pt had prior chemotherapy exposure, and 3/13 had prior RT exposure. The primary location of NETs was small bowel (46%) followed by pancreas (23%) and others (cecal, rectal or unknown - 31%). All pts had stage IV disease. Over half (54%) harbored CH mutations, despite their relatively young age. This prevalence is much higher than previously reported CH prevalence of 25.1% in pts with other solid tumors.1TET2 (25%) was the most commonly mutated gene, followed by ASXL1 (12.5%), CHEK (12.5%), PPM1D (12.5%) and TP53 (12.5%) which together accounted for 50% of all mutations. Other mutations (DNMT3A, JAK2, DDX41, SRCAP) were less common (Figure 1). DNMT3A mutations (usually most prevalent mutation in cancer cohorts) were uncommon in this cohort and did not occur in the R882 AML/MDS hotspot, previously described in CH. Frameshift mutations and truncations comprised 53.3% of all mutations, and these mutations had higher mean VAFs (6.14%) than single nucleotide variants (1.93%; p = 0.001). This may suggest that frameshift mutations and truncations provide survival advantage to the affected clone. Mutations were more common in smokers than in non-smokers (100% vs 40%, p = 0.067). As expected, mutations were more common in individuals age 61 and above (75% harbored 1 or more mutation) vs only 20% mutation occurrence was noted in age 60 or below (p=0.05). Conclusion. CH with a distinct mutation profile occurs in NET patients, and in higher prevalence (54%) than observed in other solid tumors (25%). High baseline prevalence of putative CH mutations in NET patients may be an important contributor to heightened risk of MN development after PRRT exposure. Ongoing serial sample evaluation will provide further insights into clonal evolution of the above detected CH mutations after exposure to PRRT. The results regarding clonal evolution may have implications in predicting risk of MN associated with PRRT therapy and influence treatment selection in pts planned for PRRT. References Coombs CC, Zehir A, Devlin SM, et al. Therapy-Related Clonal Hematopoiesis in Patients with Non-hematologic Cancers Is Common and Associated with Adverse Clinical Outcomes. Cell Stem Cell. 2017;21(3):374-382.e374. Acknowledgement: Data and samples for this study were provided by the Data Bank and BioRepository (DBBR), which is funded by the National Cancer Institute (P30 CA016056) and is a Roswell Park Cancer Institute Cancer Center Support Grant shared resource. Disclosures Iyer: Advanced Accelerator Applications: Consultancy. Guzman:SeqRx: Honoraria; Cellectis: Research Funding. Wang:Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy; Genentech: Consultancy; Stemline: Speakers Bureau; PTC Therapeutics: Consultancy; Astellas: Consultancy; Macrogenics: Consultancy; Pfizer: Speakers Bureau; Bristol Meyers Squibb (Celgene): Consultancy.

Distinct clinical course of neuroendocrine tumors presenting ectopic ACTH tissue expression and secretion

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Bone metastases in neuroendocrine tumors.

Neuroendocrine tumors arise from various cells that form a part of the endocrine system and account for a small number of cases encountered by oncologists in clinical practice. The clinical incidence of these tumors used to be low, and newer imaging modalities have now begun to be used for detecting bone metastases at an earlier stage. Bone metastases arising from neuroendocrine tumors are a well-recognized complication. Their presence carries along a poor prognosis. Clinical symptoms are similar to those encountered in other forms of cancer that are complicated by bone metastasis. Over the last decade or so, the clinical detection, diagnostic methods and treatment strategies have changed dramatically, and new treatments are emerging slowly. The indolent course of neuroendocrine tumors and the development of bone metastasis have limited our current knowledge on how to best prevent and manage the condition. Current information available from clinical studies is marred by paucity and small sample sizes, making further clinical trials an absolute necessity. In this review, we discuss the current status in the diagnosis and management of bone metastases arising from neuroendocrine tumors (Fig. 3, Ref. 28).

Neuroendocrine tumors of the vagina

The paper covers the most important topographic-anatomic and histological characteristics of the vagina, gives general information on the epidemiology of primary vaginal cancer (VC), on the rules of its staging, describes the frequently encountered morphological types of this tumor, and indicates the properties and features of the course of neuroendocrine tumors (NETs), including the most common manifestations of carcinoid syndrome and the symptoms of tumor hypersecretion of a number of biologically active substances. It also indicates the most common sites of NETs, the rules of their classification according to the grade and mitotic activity of tumor cells, as well as major methods for biochemical and radiological diagnosis. The immunohistochemical NET markers that can diagnose VC, their physiological role, sensitivity, and specificity, as well as the possibility of determining them in the body’s biological environments in order to increase physicians’ awareness are described in detail and the main aspects of tumor immunohistochemical staining are denoted. The role of circulating tumor cells as a promising method to specify the extent of NETs is defined. The paper gives epidemiological information on the development of vaginal NET and summarizes the available data by their clinical course and treatment results. It provides current guidelines on the required treatment volume and specifies the role of surgical intervention and the necessary volume if the intervention is expedient. It sets forth the up-to-date guidelines for chemotherapy for small cell tumors, as well as VC, which includes the specific features of managing patients with tumor recurrences depending on the time of their development.

Clinical Course of Neuroendocrine Tumors With Different Origins (the Pancreas, Gastrointestinal Tract, and Lung)

Neuroendocrine tumor originates from several sites. This study was conducted to reveal the differences in clinical course of neuroendocrine tumors by the origin. We reviewed data of patients diagnosed with neuroendocrine tumor between January 1996 and July 2007. A total of 371 patients were enrolled [pancreas 60, gastrointestinal (GI) tract 210, lung 35, other sites 46, unknown primary sites 20]. The primary tumor site correlated with the stage (P=0.000) and grade (P=0.000). At diagnosis, metastasis was observed in 28.3%, 6.7%, and 2.9% of the cases in pancreatic, GI, and pulmonary neuroendocrine tumors, respectively. Grade 3 neuroendocrine tumor was observed in 7.7%, 0.5%, and 0.0% in pancreatic, GI, and pulmonary neuroendocrine tumors. Overall survival was 116.0 months (95% confidence interval, 86.9-145.1). Overall survival was 116.0 months in pancreatic neuroendocrine tumor, not reached in GI neuroendocrine tumor and 120.0 months in pulmonary neuroendocrine tumor (P=0.024). The recurrence rate was 18.0%. It was 20.9%, 11.9%, and 2.9% in pancreatic, GI, and pulmonary neuroendocrine tumors (P=0.062). In multivariate analysis, stage, grade, and age were prognostic for overall survival (OS). Stage, grade, and sex were prognostic for disease-free survival. Neuroendocrine tumors from the pancreas, GI tract, and lung showed different clinical characteristics.

Neuroendocrine metastases of the liver.

Neuroendocrine liver metastases are rare, yet they represent an entity that has attracted much attention lately. The protracted course of neuroendocrine tumors and the hormone origin of their typical incapacitating symptoms constitute a logical basis for well founded and bespoke treatment. Demonstration of the liver secondaries is best done by ultrasonography (US) and contrast-enhanced computed tomography (CT), which on the whole have replaced the invasive angiography techniques. By use of histochemical and molecular biologic methods the exact nature of the tumor can be typified in tissue samples obtained percutaneously, laparoscopically, or surgically. Localization of nonpalpable metastases of the liver is best done by intraoperative US. Surgical removal of liver metastases is curative in some cases and is usually effective in relieving the symptoms. Also, palliative debulking or cytoreductive surgery is often worthwhile as it offers a chance of prolonged survival and symptom relief. Similar benefits are achieved by ischemic therapy preferably by temporary dearterialization, which in our department is done on an outpatient basis using a specially designed (externally controlled) occluder applied during a single laparotomy that includes debulking when appropriate as well as cholecystectomy. Hormonal therapy with somatostatin analogs may be used as a single treatment or in combination with ischemic therapy. It has an ensured symptom-reducing effect, whereas its influence on tumor growth is unsettled. Lately similar effects have been ascribed to human leukocyte interferon. In conclusion the specific characteristics of neuroendocrine tumors and the available treatment arsenal favor an active treatment approach in patients who have developed liver metastases.