Metastatic Neuroendocrine Tumors Research Articles

Fluorescence-guided surgery using methylene blue to improve identification of metastatic small intestinal neuroendocrine tumours.

Fluorescence-guided surgery using methylene blue to improve identification of metastatic small intestinal neuroendocrine tumours.

Update on C-Cell Neuroendocrine Neoplasm: Prognostic and Predictive Histopathologic and Molecular Features of Medullary Thyroid Carcinoma.

Medullary thyroid carcinoma (MTC) is a C-cell-derived epithelial neuroendocrine neoplasm. With the exception of rare examples, most are well-differentiated epithelial neuroendocrine neoplasms (also known as neuroendocrine tumors in the taxonomy of the International Agency for Research on Cancer [IARC] of the World Health Organization [WHO]). This review provides an overview and recent evidence-based data on the molecular genetics, disease risk stratification based on clinicopathologic variables including molecular profiling and histopathologic variables, and targeted molecular therapies in patients with advanced MTC. While MTC is not the only neuroendocrine neoplasm in the thyroid gland, other neuroendocrine neoplasms in the thyroid include intrathyroidal thymic neuroendocrine neoplasms, intrathyroidal parathyroid neoplasms, and primary thyroid paragangliomas as well as metastatic neuroendocrine neoplasms. Therefore, the first responsibility of a pathologist is to distinguish MTC from other mimics using appropriate biomarkers. The second responsibility includes meticulous assessment of the status of angioinvasion (defined as tumor cells invading through a vessel wall and forming tumor-fibrin complexes, or intravascular tumor cells admixed with fibrin/thrombus), tumor necrosis, proliferative rate (mitotic count and Ki67 labeling index), and tumorgrade (low- or high-grade) along with the tumor stage and the resection margins. Given the morphologic and proliferative heterogeneity in these neoplasms, an exhaustive sampling is strongly recommended. Routine molecular testing for pathogenic germline RET variants is typically performed in all patients with a diagnosis of MTC; however, multifocal C-cell hyperplasia in association with at least a single focus of MTC and/or multifocal C-cell neoplasia are morphological harbingers of germline RET alterations. It is of interest to assess the status of pathogenic molecular alterations involving genes other than RET like theMET variants in MTC families with no pathogenic germline RET variants. Furthermore, the status of somatic RET alterations should be determined in all advanced/progressive or metastatic diseases, especially when selective RET inhibitor therapy (e.g., selpercatinib or pralsetinib) is considered. While the role of routine SSTR2/5 immunohistochemistry remains to be further clarified, evidence suggests that patients with somatostatin receptor (SSTR)-avid metastatic disease may also benefit from the option of 177Lu-DOTATATE peptide radionuclide receptor therapy. Finally, the authors of this review make a call to support the nomenclature change of MTC to C-cell neuroendocrine neoplasm to align this entity with the IARC/WHO taxonomy since MTCs represent epithelial neuroendocrine neoplasms of endoderm-derived C-cells.

Treatment efficacy in a metastatic small intestinal neuroendocrine tumour grade 2 cohort.

Small intestinal neuroendocrine tumours (Si-NET) are often studied as a uniform group. Proliferation index Ki-67 influences prognosis and determines tumour grade. We hypothesized that Si-NET grade 2 (G2) tumours, which have a higher Ki-67 than G1 tumours, might benefit less from established treatments for metastatic disease. We conducted a retrospective cohort study of 212 patients with metastatic Si-NET G2 treated in two Swedish hospitals during 20 years (2000-2019). Median cancer-specific survival on first-line somatostatin analogues (SSA) was 77 months. Median progression-free survival (PFS) was 12.4 months when SSA was given as monotherapy and 19 months for all patients receiving first-line SSA. PFS after SSA dose escalation was 6 months in patients with radiological progression. Treatment efficacies of SSA and peptide receptor radionuclide treatment (PRRT) were studied separately in patients with Ki-67 of 3-5%, 5-10% and 10-20%. For SSA, PFS was significantly shorter at higher Ki-67 levels (31, 18 and 10 months, respectively), while there was only a minor difference in PFS for PRRT (29, 25 and 25 months). Median PFS for sequential treatment with interferon-alpha (IFNα), everolimus and chemotherapy was 6, 5 and 9 months. IFNα seemed to be effective in tumours with low somatostatin-receptor expression. In conclusion, established treatments appeared effective in Si-NET G2, despite their higher proliferation index compared to G1 tumours. However, efficacy of SSA but not PRRT was reduced at higher Ki-67 levels. SSA dose escalation provided limited disease stabilization.

Acute Disseminated Intravascular Coagulation Precipitated by 177Lu-Dotatate in Metastatic Midgut Neuroendocrine Tumor: A Case Report.

Acute Disseminated Intravascular Coagulation Precipitated by 177Lu-Dotatate in Metastatic Midgut Neuroendocrine Tumor: A Case Report.

Liver transplantation in gastroenteropancreatic neuroendocrine tumors.

Neuroendocrine tumors are part of a heterogeneous group of tumors located in organs such as the gastrointestinal tract (GIT), lungs, thymus, thyroid, and adrenal glands. The most prevalent sites are the small intestine, cecal appendix, and pancreas. More than 50% of these tumors are associated with metastases at the time of diagnosis. Neuroendocrine tumors are classified according to the degree of cell differentiation and the histopathological proliferation index of the lesion. Neuroendocrine tumors can be well differentiated or poorly differentiated. G3 tumors are characterized by Ki-67 expression greater than 20% and can be either well differentiated (G3 NET) or poorly differentiated (G3 NEC). Neuroendocrine carcinoma (NEC G3) is subdivided into small-cell and large-cell types. When neuroendocrine tumors present clinical and compressive symptoms, carcinoid syndrome is evident. Carcinoid syndrome occurs when the tumor produces neuroendocrine mediators that cannot be metabolized by the liver due to either the size of the tumor or their secretion by the liver itself. Several therapeutic strategies have been described for the treatment of metastatic neuroendocrine tumors, including curative or palliative surgical approaches, peptide receptor radionuclide therapy, percutaneous therapy, systemic chemotherapy, and radiotherapy. Liver surgery is the only approach that can offer a cure for metastatic patients. Liver metastases must be completely resected, and in this context, orthotopic liver transplantation has gained prominence for yielding very promising outcomes in selected cases. The aim of this study is to review the literature on OLT as a form of treatment with curative intent for patients with gastroenteropancreatic neuroendocrine tumors with liver metastasis.

Liver-directed therapy of neuroendocrine liver metastases.

647 Background: While there have been major advances in the care of neuroendocrine tumors (NETs), there is still no widely adopted therapeutic sequencing in metastatic NETs. The roles and benefits of locoregional treatments need reassessment, in order to define a modern therapeutic algorithm. We examined contemporary short-term outcomes of liver-directed therapy for metastatic NETs. Methods: We conducted a population-based retrospective cohort study of patients with metastatic NETs (2000-2019) undergoing liver embolization (LE) or liver resection (LR). Outcomes were 30-day major morbidity (Clavien-Dindo grade 3-5) and/or re-admission (composite) and length of hospital stay. Modified Poisson regression accounting for clustering at the hospital level examined factors associated with outcomes in both treatment groups. Results: Overall, 1,224 LEs and 502 LRs were performed for 5,159 patients with metastatic NETs. Median length of hospital stay was 1 day (IQR 1-4) for liver embolization and 7 days (IQR 5-9) for liver resection. 30-day major morbidity and re-admission occurred after 213 LEs (17.4%) including 40 (3.3%) deaths, and 138 LRs (27.5%) including 11 (2.2%) deaths. There were 25 (2%) LEs followed by infectious complications. Factors independently associated with increased risk after LE were prior LE treatment (adjusted relative risk- aRR 0.62; 95%CI 0.44-0.88), rural residence (aRR 0.43; 95%CI 0.20-0.91) and high comorbidity burden (aRR 1.85; 95%CI 1.34-2.54). The only factor independently associated with increased risk after LR was metachronous metastases (RR 0.60; 95%CI 0.37-0.98). Conclusions: In this contemporary cohort, LE was associated with mortality similar to that of LR. Prior LE, rural residence, comorbidities, and metachronous metastatic diagnosis were associated with higher risk of major morbidity and re-admission. This information is important when discussing the use of and choice of liver-directed therapies in the multi-disciplinary management of metastatic NETs. Further characterization of long-term outcomes and patient-reported outcomes will further support decision-making, counselling, and patient preparation.

Optical Genome Mapping: a Novel Approach to Identifying Structural Variants in Metastatic Neuroendocrine Tumors

Optical Genome Mapping: a Novel Approach to Identifying Structural Variants in Metastatic Neuroendocrine Tumors

Surgery for metastatic pancreatic neuroendocrine tumors: a narrative review.

Pancreatic neuroendocrine tumors (PanNETs) are derived from the islet cells of the pancreas and have been increasing in incidence. Most of these tumors are nonfunctional although some can secrete hormones and lead to hormone-specific clinical syndromes. Surgery is the mainstay of treatment for localized tumors, however, surgical resection is controversial in metastatic PanNETs. This narrative review seeks to summarize the current literature surrounding surgery, specifically in the controversial area of metastatic PanNETs, review current treatment paradigms, and understand the benefits of surgery in this group of patients. Authors searched PubMed using the terms "surgery pancreatic neuroendocrine tumor", "metastatic neuroendocrine tumor", and "liver debulking neuroendocrine tumor" from January 1990 to June 2022. Only English language publications were considered. There is no consensus among the leading specialty organizations regarding surgery for metastatic PanNETs. When considering surgery for metastatic PanNETs, tumor grade and morphology, location of the primary tumor, extra-hepatic or extra-abdominal disease, as well as liver tumor burden and metastatic distribution should be considered. Because the liver is the most common site of metastasis and liver failure is the most common cause of death in patients with hepatic metastases, attention is centered here on debulking and other ablative techniques. Liver transplantation is rarely used for hepatic metastases but could be beneficial in a small subset of patients. Retrospective studies have demonstrated improvement in survival and symptoms after surgery for metastatic disease, but the lack of prospective randomized control trials significantly limits analysis of surgical benefits in patients with metastatic PanNETs. Surgery is the standard of care for localized PanNETs, while it remains controversial in metastatic disease. Many studies have shown a survival and symptomatic benefit to surgery and liver debulking in select groups of patients. However, most of the studies on which recommendations are based in this population are retrospective in nature and are subject to selection bias. This presents an opportunity for future investigation.

Liver Directed Therapy is Associated with Improved Survival in Metastatic Gastroenteropancreatic Neuroendocrine Neoplasms with Concurrent Bone Metastasis

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

Real-world outcomes in patients with gastroenteropancreatic neuroendocrine tumors receiving somatostatin analogue: Data from a public hospital in Brazil.

650 Background: Neuroendocrine tumors are rare malignant neoplasms derived from endocrine cells and known for their heterogeneous behavior and histopathological characteristics; however, largely associated with a favorable clinical outcome. Somatostatin analogues (SSA) were initially used to control the symptoms of secretory neuroendocrine tumors, and later, they were considered effective as a first-line systemic treatment in unresectable or metastatic neuroendocrine tumors of the gastroenteropancreatic tract (NET-GEP). Randomized clinical trials are performed in controlled environments, with strict inclusion and exclusion criteria, and therefore, real-world studies can add to efficacy and safety data in the general population. Methods: To evaluate, in the real world scenario of a tertiary hospital of the public health system, the efficacy and toxicities of first-line treatment with somatostatin analogue in patients diagnosed with unresectable or metastatic NET-GEP, to find real-world progression free survival (rwPFS) and real-world overall survival (rwOS), in addition to the toxicity profile in our population and possible subgroups that benefit from first-line treatment, through the analysis of variables. Results: 29 patients met the study inclusion criteria, which were diagnosed in the period from 2009 to 2017. The median wrSLP and wrSG were 4.4 (95% CI 3.2 – 5.6) and 8.2 years (CI 95% 6.2 – 10.2), respectively. In an adjusted analysis of rwSLP, the HR for patients with hindgut tumors compared to midgut tumors was 4.41 with p 0.05, indicating that these patients had a 4x increased risk for disease progression (p 0 .05). In the adjusted analysis of wrSG, a trend towards a more favorable evolution was observed in the group of patients with well-differentiated tumors, with p 0.05. Assessment of toxicities revealed grade 2 and grade 3 adverse events in 34.48% of patients. Abdominal pain was the most incident toxicity, occurring in 17.24%, followed by headache (13.79%) and diarrhea (10.34%). Conclusions: Treatment with SSA was effective in our sample, with rwPFS and rwOS data above those found in randomized clinical trials. The toxicities were easily manageable and caused no documented harm to patients.

Prevalence of Sarcopenia and Impact on Survival in Patients with Metastatic Gastroenteropancreatic Neuroendocrine Tumours.

Sarcopenia in patients with cancer is associated with adverse outcomes such as shorter survival. However, there exists little evidence regarding the prevalence of sarcopenia in patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEP-NETs). Patients with a histologically confirmed newly diagnosed metastatic GEP-NET between 2006 and 2018, CT scan, and anthropometric data at diagnosis were included in this study. CT scans were analysed for the presence of sarcopenia and correlated with overall survival (OS). In total, 183 patients, 87 male (48%), with a median age of 62 years (IQR 52-68 years), were included. In 44 patients (24%), there was a pancreas NET, and in 136 patients, there was a small bowel NET (74%). Sarcopenia was present in 128 patients (69%) and unrelated to BMI (median 25.1). There were significant survival differences between patients with pancreatic and small bowel NETs at 86 vs. 141 months, respectively (p = 0.04). For patients with pancreatic NETs, the presence of sarcopenia was independently associated with shorter OS (HR 3.79 95% CI 1.1-13.03, p-value 0.035). A high prevalence of sarcopenia at the time of diagnosis of a metastatic GEP-NET was seen and associated with worse OS in patients with pancreatic NETs. Further research should focus on how to reverse sarcopenia and its impact on OS and/or quality of life.

Where Are We Now with Liver Transplantation in Neuroendocrine Neoplasms? The Place of Liver Transplantation for Grades 1 and 2 Well-Differentiated Unresectable Liver Metastatic Neuroendocrine Tumours

This review outlines the role of liver transplantation in selected patients with unresectable neuroendocrine tumour liver metastases. It discusses the international consensus on eligibility criteria and outlines the efforts taking place in the UK and Ireland to develop effective national liver transplant programmes for neuroendocrine tumour patients. In the early history of liver transplantation, indications included cancer metastases to the liver as well as primaries of liver origin. Often, liver transplantation was a salvage procedure. The early results were disappointing, including in patients with neuroendocrine tumours. These data discouraged the widespread adoption of liver transplantation for neuroendocrine tumour liver metastases (NET LM). A few centres persisted in performing liver transplantation for patients with NET LM and in determining parameters predictive of good outcomes. Their work has provided evidence for benefit of liver transplantation in a selected group of patients with NET LM. Liver transplantation for NET LM is now accepted as a valid indication by many professional bodies, including the European Neuroendocrine Tumour Society (ENETS) and the United Network for Organ Sharing (UNOS). It is nevertheless rarely utilised. The UK and the Republic of Ireland are commencing a pilot programme of liver transplantation in selected patients. This programme will help develop the expertise and infrastructure to make liver transplantation for NET LM a routine procedure.

Standardized Uptake Values on SPECT/CT: A Promising Alternative Tool for Treatment Evaluation and Prognosis of Metastatic Neuroendocrine Tumours.

(1) Background: The aim of our study was to assess the feasibility of 99mTcEDDA/HYNIC-TOC SPECT/CT quantitative analysis in evaluating treatment response and disease progression in patients with NETs. (2) Methods: This prospective monocentric study evaluated 35 SPECT/CT examinations performed on 14 patients with neuroendocrine tumours who underwent a baseline and at least one follow-up 99mTcEDDA/HYNIC-TOC scan as part of their clinical management. The examination protocol included a whole-body scan acquired 2 h after the radiotracer’s administration, with the SPECT/CT performed 4 h post-injection. Images were analyzed by two experienced physicians and patients were classified into response categories based on their changes in SUV values. (3) Results: We evaluated 14 baseline studies and 21 follow-up scans, accounting for 123 lesions. A statistically positive correlation has been found between the SUVmax and SUVpeak values in tumoral lesions (p < 0.05). No correlation has been found between the SUV values and the ki67 proliferation index. Finally, 64.29% patients were classified as SD at the end of the study, with only 14.29% of patients exhibiting PD and 21.43% patients with PR. (4) Conclusions: The quantitative analysis of 99mTcEDDA/HYNIC-TOC SPECT/CT data in patients with neuroendocrine tumours could represent an alternative to 68Ga-DOTA-peptides PET/CT for the monitoring and prognosis of NETs.

FOLFOX-bevacizumab chemotherapy in patients with metastatic neuroendocrine tumors.

Neuroendocrine tumors (NETs) are highly vascularized neoplasms. While FOLFOX chemotherapy has shown efficacy in patients with advanced NETs, its combination with antiangiogenics has been scarcely described. Here, we report the efficacy and tolerance of FOLFOX-bevacizumab in this setting. We retrospectively studied all consecutive patients with metastatic NET treated by FOLFOX-bevacizumab in two expert centers from 2013 to 2020. We assessed time to treatment failure (TTF), objective response rate (ORR) and toxicity. We explored factors associated with TTF and ORR using multivariate analyses. We included 57 patients (35.1% female, median age 61.7 years), with pancreatic (66.7%), small-intestine (14%) or lung (7%) NETs. Most patients (57.9%) had extra-hepatic metastases and G3 NETs accounted for 40.3% of cases. Patients received a median of 17 cycles of treatment, including a median of sevencycles of bevacizumab and/or 5-fluorouracile maintenance. Median TTF was 15.5months (95% CI: 9.8-21.2) and was shorter in patients age > 60 years (HR 2.56, 95% CI: 1.16-5.64), p= .020) and >1 previous systemic treatment line (HR 4.15, 95% CI: 1.96-8.78), p< .001). The ORR was 42.9% and was higher in cases of performance status at 0 (OR 5.25, 95% CI: 1.13-24.35), p= .034) and G3 NET (OR 5.39, 95% CI: 1.23-23.52), p= .025). The FOLFOX-bevacizumab combination has promising efficacy in patients with progressive metastatic NETs and notably for G3 NETs, for which optimal treatment as yet remains ill-defined. Hence, it could be a relevant alternative to alkylating-based chemotherapy in this setting and should be further explored prospectively.

Teranostika i precizna medicina u neuroendokrinim tumorima

Introduction. Neuroendocrine tumors (NETs) have increased expression of somatostatin receptors (SSTR), where subtype 2 and 5 are the most common. Overexpression of the SSTR is an outstanding molecular target for inoperable and metastatic NETs that enables a unique approach of targeted diagnosis and treatment. In addition to SSTRs, neuroendocrine tumors also express other receptors that can be suitable targets for visualization by nuclear medicine methods. Aim. This review paper is focused on the most common radiopharmaceuticals and their molecular targets that are used today based on theranostic approach in NETs. Results. In conventional nuclear medicine, the most important diagnostic radiopharmaceuticals are somatostatin analogs (SSA) labeled with 111 In and 99m Tc, however 99m Tc has advantages over 111 In based on better physical characteristics and better performance. In recent years, highly potent theranostic pairs have been created for the imaging and treatment of NETs, which can strongly bind SSTR. Derivatives of 68 Ga-labeled octreotide are recommended for diagnostics and follow-up of NENs. The great advantage of 68 Ga radiopharmaceuticals is that identical compounds can be labeled with therapeutic radionuclides 90 Y and 177 Lu. Conclusion. Peptide receptor radionuclide therapy is a systemic molecular target therapy that has proven to be safe and very effective in controlling the disease and prolonging the survival of patients with advanced and inoperable NETs. With a negligible number of adverse events, this therapy is safe and should be administered to all patients who meet the necessary criterias, primarily overexpression of the somatostatin receptor type 2.

Impact of primary tumor resection on metastatic well-differentiated pancreatic neuroendocrine tumors

Impact of primary tumor resection on metastatic well-differentiated pancreatic neuroendocrine tumors

A practical proposal on treatment sequencing of metastatic well-differentiated neuroendocrine tumours.

According to the neuroendocrine tumour (NET) characteristics, 3 to 7 different treatment options are available, corresponding to 6 to 5,040 theoretical different sequences. Even though each patient is unique and despite a large heterogeneity in NET characteristics, the present review aims to discuss the main sequences and addresses how one can propose the best sequence to treat metastatic NET (mNET) on a case-by-case basis. Each treatment must be discussed during dedicated multi-disciplinary meetings, and inclusions in clinical trials should be favoured. After a thorough characterization of patients and their mNET, and taking into account the availability of drugs, the first-line treatment should be chosen according to the treatment aim. The latter is determined based on three main topics (efficacy, safety, and patient preferences) that do not necessarily converge and must be defined a priori. At baseline, physicians should design an a priori full therapeutic sequence, which may evolve at each step depending on the response to previous treatment, the occurrence of chronic toxicities, and the patients' perception of the prior treatment. To improve knowledge in terms of effectiveness and risk of cumulative toxicities regarding the different sequences, real-world data using long follow-up durations are necessary; such issues will not be resolved by randomized clinical trials.

A Case of Metastatic Hepatic Neuroendocrine Tumor from the Lung Diagnosed by Thyroid Transcription Factor (TTF) -1 Immunostaining

A Case of Metastatic Hepatic Neuroendocrine Tumor from the Lung Diagnosed by Thyroid Transcription Factor (TTF) -1 Immunostaining

Opsoclonus-myoclonus syndrome associated with pancreatic neuroendocrine tumor: a case report

BackgroundOpsoclonus-myoclonus syndrome (OMS) is a rare, immune-mediated neurological disorder. In adults, the pathogenesis can be idiopathic, post-infectious or paraneoplastic, the latter etiology belonging to the ever-expanding group of defined paraneoplastic neurological syndromes (PNS). In contrast to other phenotypes of PNS, OMS cannot be ascribed to a single pathogenic autoantibody. Here, we report the first detailed case of paraneoplastic, antibody-negative OMS occurring in association with a pancreatic neuroendocrine tumor (pNET).Case presentationA 33-year-old female presented with a two-week history of severe ataxia of stance and gait, dysarthria, head tremor, myoclonus of the extremities and opsoclonus. Her past medical history was notable for a metastatic pancreatic neuroendocrine tumor, and she was subsequently diagnosed with paraneoplastic opsoclonus-myoclonus syndrome. Further workup did not reveal a paraneoplastic autoantibody. She responded well to plasmapheresis, as she was refractory to the first-line therapy with corticosteroids.ConclusionsThis case expands current knowledge on tumors associated with paraneoplastic opsoclonus-myoclonus syndrome and the age group in which it can occur. It further adds evidence to the effectiveness of plasmapheresis in severe cases of opsoclonus-myoclonus syndrome with a lack of response to first-line therapy.

Values of debulking surgery for unresectable well-differentiated metastatic pancreatic neuroendocrine tumors: a comparative study.

The value of debulking surgery for unresectable well-differentiated metastatic pancreatic neuroendocrine tumor (m-PNET) remains poorly defined. This study aimed to evaluate the outcomes of m-PNET following debulking surgery in our institute. Patients with well-differentiated m-PNET in our hospital between February 2014 and March 2022 were collected. Clinicopathological and long-term outcomes of patients treated with radical resection, debulking surgery, and conservative therapy were compared retrospectively. Fifty-three patients with well-differentiated m-PNET were reviewed, including 47 patients with unresectable m-PNET (debulking surgery, 25; conservative therapy, 22) and 6 patients with resectable m-PNET (radical resection). Patients undergoing debulking surgery had a post-operative Clavien-Dindo ≥ III complication rate of 16.0% without mortality. The 5-year overall survival (OS) rate of patients treated with debulking surgery was significantly higher than that of those treated with conservative therapy alone (87.5% vs 37.8%, log-rank P = 0.022). Besides, the 5-year OS rate of patients treated with debulking surgery was comparable to that of patients with resectable m-PNET undergoing radical resection (87.5% vs 100%, log-rank P = 0.724). Patients with unresectable well-differentiated m-PNET who underwent resection had better long-term outcomes than those who received conservative therapy alone. The 5-year OS of patients undergoing debulking surgery and radical resection were comparable. Debulking surgery could be considered for patients with unresectable well-differentiated m-PNET if no contraindication exists.