Metastatic Well-differentiated Neuroendocrine Tumors Research Articles

Impact of primary tumor resection in the management of metastatic well-differentiated neuroendocrine tumors of the small bowel and pancreas.

Patients with gastroenteropancreatic (GEP) neuroendocrine tumors (NET) often present with advanced disease. Primary tumor resection (PTR) in the setting of unresectable metastatic disease is controversial. Most studies evaluating the impact of PTR on overall survival (OS) have been performed using large population-based databases, with limited treatment related data. This study aims to determine whether PTR improves OS and progression-free survival (PFS) in patients with metastatic well-differentiated GEP-NET. This is a retrospective single-institution study of patients with metastatic well-differentiated GEP-NET between 1978 and 2021. The primary outcome was OS. The secondary outcome was PFS. Chi-squared tests and Cox regression were used to perform univariate and multivariate analyses (MVA). OS and PFS were estimated using the Kaplan-Meier method and log-rank test. Between 1978 and 2021, 505 patients presented with metastatic NET, 151 of whom had well-differentiated GEP-NET. PTR was performed in 31 PNET and 77 SBNET patients. PTR was associated with improved median OS for PNET (136 vs. 61 months, p = .003) and SBNET (not reached vs. 79 months, p<.001). On MVA, only higher grade (HR 3.70, 95%CI 1.49-9.17) and PTR (HR 0.21, 95%CI 0.08-0.53) influenced OS. PTR resulted in longer median PFS for patients with SBNET (46 vs. 28 months, p = .03) and a trend toward longer median PFS for patients with PNET (20 vs. 13 months, p = .07). In patients with metastatic well-differentiated GEP-NET, PTR is associated with improved OS and may be associated with improved PFS and should be considered in a multidisciplinary setting. Future prospective studies are needed to validate these findings.

Long-term clinical outcomes of [177Lu]Lu-DOTATATE in patients with metastatic neuroendocrine tumors

The incidence of gastroenteropancreatic neuroendocrine tumors has been rising and these tumors are usually only diagnosed at a metastatic stage. Present first line treatments include somatostatin analogs, targeted therapies and peptide receptor radionuclide therapy. The Lutetium-177 [177Lu] based radiotracer [177Lu]Lu-DOTATATE has only been approved as first-line treatment of metastatic midgut NETs however its efficacy as a third line or above treatment in patients with non ileal primaries has not been tested. In our study, we identified 25 patients with histologically confirmed well-differentiated metastatic neuroendocrine tumors and administered [177Lu]Lu-DOTATATE as a second line, third line and fourth line treatment. Our study demonstrated a notable response in patients with non-ileal primaries and heavily pretreated disease, warranting further studies for additional cycles of treatment.

Multidisciplinary Approach for the Management of Metastatic Poorly Differentiated Neuroendocrine Carcinoma of the Pancreas: A Case Report of an Exceptional Responder.

Poorly differentiated pancreatic neuroendocrine carcinomas (pNECs) are rare, highly aggressive neoplasms. Frequently metastatic at diagnosis, prognosis is poor with median overall survival estimated to be less than 1 year. Although multidisciplinary management, including systemic medications and locoregional therapies aimed at reducing and preventing symptoms caused by mass effect, is the mainstay of treatment for patients with metastatic well-differentiated pancreatic neuroendocrine tumors, rapid progression, organ dysfunction, and poor performance status often preclude initiation of even single-modality palliative chemotherapy for patients with metastatic pNEC, limiting the use of and recommendation for multidisciplinary management.We describe the case of a 51-year-old male patient diagnosed with pNEC metastatic to liver and lymph nodes presenting with impending cholestatic liver failure for whom we were able to successfully initiate and dose-escalate cytotoxic chemotherapy with excellent radiographic response. After multidisciplinary review of his case, the patient underwent pancreaticoduodenectomy and hepatic wedge biopsies, with pathology demonstrating a pathologic complete response to chemotherapy in both the pancreas and liver. Surveillance scans at 2 years from initial diagnosis and 1 year from surgery remain without evidence of locoregional or distant recurrence, highlighting the importance and utility of multidisciplinary management in select cases.

ASO Author Reflections: Morbidity and Outcomes of Primary Tumor Management in Patients with Widely Metastatic Well-Differentiated Small Bowel Neuroendocrine Tumors.

ASO Author Reflections: Morbidity and Outcomes of Primary Tumor Management in Patients with Widely Metastatic Well-Differentiated Small Bowel Neuroendocrine Tumors.

A pilot study of pembrolizumab and embolization or 90Y radioembolization for patients with metastatic well-differentiated neuroendocrine tumors

A pilot study of pembrolizumab and embolization or 90Y radioembolization for patients with metastatic well-differentiated neuroendocrine tumors

A pilot study of pembrolizumab and peptide receptor radionuclide therapy for patients with metastatic well-differentiated neuroendocrine tumors

A pilot study of pembrolizumab and peptide receptor radionuclide therapy for patients with metastatic well-differentiated neuroendocrine tumors

Morbidity and Outcomes of Primary Tumor Management in Patients with Widely Metastatic Well-Differentiated Small Bowel Neuroendocrine Tumors.

The benefit of primary tumor resection in distant metastatic small bowel neuroendocrine tumors (SBNETs) is controversial, with treatment-based morbidity not well-defined. We aimed to determine the impact of primary tumor resection on development of disease-specific complications in patients with metastatic well-differentiated SBNETs. A retrospective analysis was performed of patients diagnosed with metastatic well-differentiated jejunal/ileal SBNETs at a single tertiary care cancer center from 1980 to 2016. Outcomes were compared on the basis of treatment selected at diagnosis between patients who underwent initial medical treatment or primary tumor resection. Among 180 patients, 71 underwent medical management and 109 primary tumor resection. Median follow-up was 116 months. Median event-free survival did not differ between treatment approaches (log-rank p = 0.2). In patients medically managed first, 16/71 (23%) required surgery due to obstruction, perforation, or bleeding. These same complications led to resection at presentation in 31/109 (28%) surgically treated patients. Development of an obstruction from the primary tumor was not associated with disease progression/recurrence (HR 1.14, 95% CI 0.75-1.75) with all patients recovering postoperatively. Ongoing tumor progression requiring secondary laparotomy was associated with worse mortality (HR 7.51, 95% CI 3.3-16.9; p < 0.001) and occurred in 20/109 (18%) primary tumor resection and 7/16 (44%) initially medically treated patients. Rates of event-free survival among patients with metastatic SBNETs do not differ on the basis of primary tumor management. The development of an obstruction from the primary tumor was not associated with worse outcomes with all patients salvaged. Regardless of initial treatment selected, patients with metastatic SBNET should be closely followed for early signs of primary tumor complications.

Systemic Therapy for Tumor Control in Metastatic Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline.

To develop recommendations for systemic therapy for well-differentiated grade 1 (G1) to grade 3 (G3) metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). ASCO convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice. Eight randomized controlled trials met the inclusion criteria for the systematic review. Somatostatin analogs (SSAs) are recommended as first-line systemic therapy for most patients with G1-grade 2 (G2) metastatic well-differentiated GI-NETs. Observation is an option for patients with low-volume or slow-growing disease without symptoms. After progression on SSAs, peptide receptor radionuclide therapy (PRRT) is recommended as systematic therapy for patients with somatostatin receptor (SSTR)-positive tumors. Everolimus is an alternative second-line therapy, particularly in nonfunctioning NETs and patients with SSTR-negative tumors. SSAs are standard first-line therapy for SSTR-positive pancreatic (pan)NETs. Rarely, observation may be appropriate for asymptomatic patients until progression. Second-line systemic options for panNETs include PRRT (for SSTR-positive tumors), cytotoxic chemotherapy, everolimus, or sunitinib. For SSTR-negative tumors, first-line therapy options are chemotherapy, everolimus, or sunitinib. There are insufficient data to recommend particular sequencing of therapies. Patients with G1-G2 high-volume disease, relatively high Ki-67 index, and/or symptoms related to tumor growth may benefit from early cytotoxic chemotherapy. For G3 GEP-NETs, systemic options for G1-G2 may be considered, although cytotoxic chemotherapy is likely the most effective option for patients with tumor-related symptoms, and SSAs are relatively ineffective. Qualifying statements are provided to assist with treatment choice. Multidisciplinary team management is recommended, along with shared decision making with patients, incorporating their values and preferences, potential benefits and harms, and other characteristics and circumstances, such as comorbidities, performance status, geographic location, and access to care.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.

Prognostic value of total tumor volume with 68Ga DOTATOC PET/CT in predicting response to 177-Lu-DOTATOC treatment in metastatic well-differentiated neuroendocrine tumors (NETs).

e16248 Background: PET/CT with somatostatin analogues (68 Ga DOTATOC) is essential for decision-making prior to treatment with [177Lu–Dota0–Tyr3]–Octreotate (177Lu-DOTATOC), there are biological characteristics in this type of neoplasms that allow predicting the response to therapy, the tumor burden is one of the most important variables, however its estimation with conventional imaging tools is limited, currently there are reconstruction algorithms based on artificial intelligence that allow estimating the tumor burden using molecular imaging studies with 68 Ga DOTATOC, aim of this work is to determine the value of the total tumor load with this radiotracer as a predictor of overall survival in patients treated with 177Lu DOTATOC. Methods: 45 patients (11 men and 34 women) with an average age of 57.2 (range 47.2 to 66.5) with histopathological and immunohistochemical diagnosis of well-differentiated neuroendocrine tumors (NETs) in the period from 2015 to 2021 who received therapy with (177Lu-DOTATOC) and who had a baseline 68Ga DOTATOC PET to calculate total tumor volume (TVV) and semiquantitative uptake values were retrospectively included. Results: The mean follow-up was 29.3 +/- 6 months. Using ROC curves, a cut-off point of 100 cm3 was determined to differentiate responding and non-responding patients. The difference in the overall survival curves between both groups was statistically significant (470 days vs. 180 days) with p=0.07. The main sites of origin of the primary tumor were pancreas (n=24), lung (n=11), small intestine (n=7) and liver (n=3). The mean tumor volume was 305.8 cm3 (+/- 272). The organs with the highest uptake values were pancreas with SUVmax of 27.9 (range 10.1-42.4), rectum with SUVmax 26.5 (10.7-42.3) and liver with SUVmax of 22.1 (14.4-31.7), these uptake values did not have any type of relation to patient survival. Regarding therapy with 177 Lu DOTATOC, 8 received 14.8 Gbq (400mCi), 12; 22.2 GBq (600mCi) and 25; 29.6 GBq (800 mCi), no serious adverse effect or kidney function impairment was demonstrated after 177Lu DOTATOC therapy. No grade 3 or 4 haematological toxicity was identified. Conclusions: PET/CT with 68 Ga-DOTATOC is routinely used in the management of patients with neuroendocrine tumors and also allows categorizing patients according to their tumor volume to predict overall survival in patients treated with 177 Lu-DOTATOC, thus in such a way that it could be considered as an easily accessible and widely available prognostic imaging biomarker.

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

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

Observational Study in a Real-World Setting of Targeted Therapy in the Systemic Treatment of Progressive Unresectable or Metastatic Well-Differentiated Pancreatic Neuroendocrine Tumors (pNETs) in France: OPALINE Study.

IntroductionApproval of sunitinib and everolimus for the treatment of progressive, unresectable or metastatic well-differentiated pancreatic neuroendocrine tumors (pNETs) was obtained in France in 2011 and 2012, respectively. OPALINE was set up as an observational study to evaluate the efficacy of sunitinib and everolimus compared to usual pNET treatments of chemotherapies and somatostatin analogues that had been previously recommended by the health authorities.MethodsThe OPALINE study assessed the efficacy of everolimus and sunitinib in terms of survival, disease progression and tolerance. Patients (N = 144) were enrolled from May 2015 to September 2017, and their disease characteristics were analyzed from diagnosis to 2 years post-enrollment.ResultsAt inclusion most patients had comorbidities, and about 95% presented metastases. Patients received on average 3.2 lines of treatment from diagnosis to inclusion and two lines throughout the 2-year follow-up. Seventy-nine patients (59.0%) received at least one targeted therapy (TT) during their care path. For these patients, the overall survival (OS) was approximatively 176.5 months (95% CI: 97.2-not evaluable), with a 2-year survival rate estimated at 93.6% (SD 2.6%). Similar survival rates were observed whether the TTs were prescribed sooner or later in the treatment path. The main reasons for discontinuation of TTs were disease progression (54 patients) and adverse events (26 patients). Most patients receiving TTs did not change their dose during the follow-up reflecting the good treatment tolerability over time. No new safety alert was reported for everolimus and sunitinib during this study.ConclusionGiven their good tolerance and positive impact on estimated OS, the two TTs have an important role to play in the care path of patients with pNETs.ClinicalTrials.gov National Clinical Trial NumberNCT02264665.

Self-Administration of Long-Acting Somatostatin Analogues in NET Patients-Does It Affect the Clinical Outcome?

Background and Objectives: Long-acting somatostatin analogues (SSA) (octreotide LAR and lanreotide Autogel) are recommended as first line treatment of locally advanced or metastatic well-differentiated neuroendocrine tumors (NETs) with a good expression of somatostatin receptor (SSTR). Both of these SSAs are usually administered via injections repeated every 4 weeks. The purpose of the study was to compare the route of SSA administration (injection performed by professional medical staff and self-administration of the drug) with progression-free survival. Materials and methods: 88 patients in 2019 and 96 patients in 2020 with locally advanced or metastatic well-differentiated NETs were included in the study. All patients had a good expression of SSTR type 2 and had been treated for at least 3 months with a stable dose of long-acting somatostatin analogue every 4 weeks. All of them had received training on drug self-injections from professional NET nurses at the beginning of the COVID-19 epidemic. Results: The rate of NET progression in the study group in 2020 was higher than in 2019 29.1% vs. 18.1% (28 vs. 16 cases), p = 0.081. Conclusions: The method of administration of long-acting SSA injection performed by professional medical staff vs. self-injection of the drug may significantly affect the risk of NET progression. The unequivocal confirmation of such a relationship requires further observation.

Role of Resection of the Primary in Metastatic Well-Differentiated Neuroendocrine Tumors.

Resection of the primary (RP) in metastatic neuroendocrine tumor (NET) is controversial. The aim was to evaluate survival outcomes for RP in metastatic NET patients. Data were obtained from US hospitals at the National Cancer Database between 2004 and 2014. χ2, analysis of variance tests, univariate, and multivariate cox proportional hazards models were evaluated. Kaplan-Meier curves and log-rank tests conducted to compare the survival difference of patient characteristics. A total of 2361 patients were identified. The mean age was 62.1 years (standard deviation, 13 years), male-to-female ratio 1:1; 33% were small intestine, 26.3% pancreas, and 24.4% lung; 69.6% were well-differentiated; and 42.5% underwent RP. The 5-year overall survival (OS) was significantly improved for patients who underwent RP in small intestine (5-year OS, 63.9% vs 44.2%), lung (5-year OS, 65.4% vs 20.2%), and pancreas tumors (5-year OS, 75.6% vs 30.6%). On multivariate analysis, RP (hazard ratio, 0.46; 95% confidence interval, 0.29-0.73; P < 0.001), female, year of diagnosis 2010-2014, margin, Charlson-Deyo score less than 2, and age less than 51 years, were associated with better OS. Resection of the primary in metastatic well-differentiated NET is associated with improved OS compared with no RP.

Progress in diagnosing and treating gastroenteropancreatic neoplasms

<p indent=0mm>Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a group of highly heterogeneous malignancies originating from the diffuse neuroendocrine system, and their incidence has gradually increased in the past <sc>30 years.</sc> The results of molecular biological studies indicate that NENs of different grades and primary sites have distinct molecular characteristics and are responsible for the heterogeneity of clinical manifestations. Surgery remains the method to cure localized GEP-NENs, and prospective clinical study results support no adjuvant therapy. Treating advanced GEP-NENs requires multidisciplinary collaboration, including symptom and tumor proliferation control. Systemic treatment options for patients with metastatic well-differentiated neuroendocrine tumors (NETs) have expanded considerably. However, treating advanced poorly-differentiated neuroendocrine carcinomas (NECs) lacks prospective randomized controlled study outcomes. Platinum-based chemotherapy is the preferred first-line treatment, and the role of immune checkpoint inhibitors still needs to be confirmed by further studies. The present report reviews the recent research progress in GEP-NENs.

Involvement of Neutrophils in Metastatic Evolution of Pancreatic Neuroendocrine Tumors.

Simple SummaryThe neutrophil-to-lymphocytes (NLR) reflects the systemic inflammation. Based on a cohort of 144 patients treated for localized or metastatic well-differentiated pancreatic neuroendocrine tumors (pNET), we identified the NLR ≥ 4 to be associated with worse overall survival. Using MCP-Counter on a publicly available pNET RNA-sequencing dataset, we inferred the tumor microenvironment composition of 83 primary pNET and 30 liver metastasis. The neutrophils scores were statistically higher in liver metastasis relative to primary pancreatic tumors (p = 0.005). Gene set enrichment analysis further revealed activation of complement pathway signature in liver metastasis. Through combination of the neutrophil and complement pathway genes, we found that pNET can be classified into two clusters: Neu-Comp1 and Neu-Comp2. Notably, the Neu-Compt1 cluster was enriched in neutrophils and complement pathway signatures and was associated with liver metastasis. These data offer new insights into the role of inflammatory factors in the metastatic progression of the pNET.Well-differentiated pancreatic neuroendocrine tumors (pNET) have an unpredictable natural history. The identification of both blood and tumor immune features associated with patients’ outcomes remains limited. Herein, we evaluated the best prognostic value of the neutrophils-to-lymphocyte ratio (NLR) in a cohort of 144 pNETs. The NLR ≥ 4 was associated with worse overall survival in both univariate analysis (HR = 3.53, CI95% = 1.50–8.31, p = 0.004) and multivariate analysis (HR = 2.57, CI95% = 1.061–6.216, p = 0.036). The presence of synchronous liver metastasis was identified as a prognostic factor in multivariate analysis (HR = 3.35, CI95% = 1.411–7.973, p = 0.006). Interestingly, the absolute tumor-associated neutrophils count was higher in liver metastasis as compared to their paired primary tumor (p = 0.048). Deconvolution of immune cells from the transcriptome of 83 primary tumors and 30 liver metastases reveals enrichment for neutrophils in metastasis relative to primary tumors (p = 0.005), and this was associated with upregulation of the complement pathway (NES = 1.84, p < 0.0001). Combining neutrophils signature and complement pathway genes, unsupervised clustering identified two pNETs subgroups, namely Neu-Comp1 and Neu-Comp2. Characterized by neutrophils infiltration and activation of the complement pathway, Neu-Comp1 was highly enriched for metastatic liver samples as compared to Neu-Comp2 (p < 0.0001). These data suggest the possible link between liver metastasis, complement pathway activation, and neutrophils infiltration in well-differentiated pNET and open avenues for targeting complement pathways in these tumors.

Metastatic well-differentiated pancreatic neuroendocrine tumors to the liver: a narrative review of systemic and surgical management

Abstract Pancreatic neuroendocrine tumors (PNETs) are a rare group of neoplasms originating from the endocrine pancreas. PNETs are classified as functional or non-functional tumors. PNETs are more often diagnosed at a higher stage with distant metastases or advanced locoregional disease. The majority of individuals with hepatic metastases will ultimately die of liver failure; therefore, the treatment of liver tumor burden is critical to providing a survival impact. While surgical resection remains the only chance of cure for disease confined to the pancreas or for locoregional disease, the treatment of advanced or metastatic PNETs is more complex and often requires a multimodal approach. This review focuses on treatment options for well and moderately differentiated PNETs with metastatic disease to the liver. These include surgery, liver-directed therapies including ablative and intra-arterial therapies, and systemic therapies such as somatostatin analogues, targeted therapies, chemotherapy, and peptide receptor radionuclide therapy. Developing an individualized treatment strategy requires careful assessment of liver tumor burden and predicted biological behavior. Aggressive surgical resection of hepatic metastases secondary to PNET primary tumors is associated with improved survival in multiple retrospective studies. General goals of treatment for metastatic disease include prolonging overall survival and progression free survival, improving quality of life, and control of symptoms.

Treatment with somatostatin analogues and PRRT in metastatic middle ear adenoma with neuroendocrine features.

SummaryMiddle ear adenomas with neuroendocrine features (ANEF) are rare, with an estimated 150 reported cases. They usually pursue an indolent clinical course. Four reported cases of middle ear ANEF with distant metastases were treated with surgery, external beam radiation therapy (EBRT) and chemotherapy. To date, no successful systemic treatment for malignant behaviour of this rare tumour has been reported. Long-acting somatostatin analogues (SSAs) and peptide receptor radionuclide therapy (PRRT) have been used in well-differentiated metastatic neuroendocrine tumours (NETs), but their use has never been described in cases of metastatic middle ear ANEF. We report two patients with grade 1 middle ear ANEF treated with surgery and EBRT. They had stable disease for several years, until clinical symptoms appeared and extensive metastases were detected on 68Ga-DOTA0-Tyr3-octreotate (DOTATATE) PET/CT. Treatment with long-acting SSA was started, with stable disease for 1 year. Afterwards, despite undergoing local treatments, both patients presented progressive disease. Due to high-uptake metastases at 68Ga-DOTATATE PET/CT, both cases underwent four cycles of PRRT with 177Lu-DOTATATE, which secured disease control and improvement of quality of life in both. Similar to other well-differentiated NETs, SSA and PRRT could constitute efficacious therapeutic options in metastatic middle ear ANEF. Its neuroendocrine differentiation, potential to metastasize and somatostatin receptor type 2 expression prompt consideration and management of this disease as a neuroendocrine neoplasm.Learning pointsOur cases oppose the 2017 WHO classification of middle ear adenoma with neuroendocrine features as a benign disease.This entity warrants long-term follow-up, as local recurrence or persistence of disease is reported in up to 18% of surgically treated patients.PET/CT scan with 68Ga-labelled somatostatin analogues (SSA) can be used for staging of metastatic middle ear adenoma with neuroendocrine features.Unlabelled SSA and peptide receptor radionuclide therapy (PRRT) with radiolabelled SSA can be the first systemic therapeutic options for patients with advanced middle ear adenoma with neuroendocrine features.

Temozolomide and capecitabine (CAPTEM) is effective in metastatic well-differentiated gastrointestinal neuroendocrine tumors.

366 Background: The study aimed to evaluate patients' outcomes and prognosis with metastatic gastrointestinal neuroendocrine tumors (mgNET) who treated temozolomide and capecitabine (CAPTEM). Methods: The data of forty-three patients were retrospectively evaluated. Clinicopathological features and treatment approaches were recorded. Kaplan-Meier analysis was used for overall survival (OS) and progression-free survival (PFS). Prognostic factors were assessed with Cox-regression analysis. Results: Median age was 59 (27-85) years. The number of male and female patients was 23 (%53.5) and 20 (%46.5), respectively. Pancreas (%51.2) was the most common site of the tumor. The number of patients with well- and poorly-differentiated mgNET was 38 (%88.4) and 5 (%11.6), respectively. The most common metastatic sites were liver (%62.8), lymph node (%58.1), and bone (%18.6). Eleven (%25.6) of the patients previously had undergone surgery, and some patients received radiotherapy (%9.5), chemotherapy (%19), and nuclear therapy (%9.3). Also, patients received octreotide (%86) or lanreotide (%14) with CAPTEM. In patients with well-differentiated mgNET, median PFS was 17.4 months, and disease control ratio %79.4 (%3-complete response, %38.2-partial response, and %38.2-stable response). No response observed in patients with poorly differianted mgNET, and the median PFS was calculated as 4.5 months. Grade 1-2 toxicity was observed in 34 (%79.1) of the patients, and grade 3-4 toxicity in 8 (%18.6). Four (%9.5) patients discontinued therapy for the toxicity. The most common toxicities were anemia (%37.2), thrombocytopenia (%25.6), and fatigue (%16.3). At a median follow-up of 33.8 (2.9-172.73) months, the ratio of five-years OS was %61. In multivariate analysis; gender (p=0.008), age (p=0.007), and Ki-67 levels (p=0.011) were a statistically significant for OS. However, the site of the tumor (p=0.186), number of metastatic sites (p=0.255), and type of somatostatin receptor ligand (p=0.903) were not. Conclusions: In the study, we showed that CAPTEM + somatostatin receptor ligands (octreotide or lanreotide) were effective and well-tolerated in patients with well-differentiated mgNET. But, it was not effective in patients with poorly-differentiated mgNET. Male gender, aged over 60 years, and tumor with a high level of Ki-67 were negative prognostic factors.

Liver metastases from pituitary carcinomas mimicking visceral well-differentiated neuroendocrine tumors: a series of four cases

BackgroundPathologists frequently encounter neuroendocrine tumors (NETs) presenting as multiple liver masses in routine practice. Most often, these are well-differentiated tumors with characteristic histologic features. In contrast, pituitary carcinoma is very rare, and there is limited data on its natural history and pathologic characterization.MethodsThe aim of this study was to describe clinical characteristics, histomorphology, immunophenotype and follow-up of pituitary carcinoma involving the liver and mimicking well-differentiated NETs of visceral origin. We selected a group of well-differentiated NETs of the pancreas to use as immunophenotypic controls. We identified 4 patients (age range, 51 to 73) with pituitary corticotroph carcinoma with liver metastases. Three patients presented with Cushing syndrome.ResultsAll cases histologically resembled well-differentiated NETs of visceral origin with Ki-67 proliferation indices of 5–42% and expression of T-PIT; metastatic tumors were not immunoreactive with CDX2, Islet 1 or TTF-1.ConclusionsFrequently, these cases display adrenocorticotropic hormone (ACTH) secretion and pituitary-specific transcription factor immunohistochemistry may be used as a reliable marker to distinguish metastatic pituitary carcinoma from NETs of visceral origin in addition to delineating a corticotroph carcinoma from somatotroph, lactotroph, thyrotroph, and gonadotroph lineage. Although rare, the differential diagnosis of pituitary carcinoma should be considered in metastatic well-differentiated NETs in which the site of origin is uncertain. In summary, pituitary corticotroph carcinoma can metastasize to the liver and mimic well-differentiated NET.

Neoadjuvant Capecitabine/Temozolomide for Locally Advanced or Metastatic Pancreatic Neuroendocrine Tumors.

The combination chemotherapy regimen capecitabine/temozolomide (CAPTEM) is efficacious for metastatic well-differentiated pancreatic neuroendocrine tumors (PNETs), but its role in the neoadjuvant setting has not been established. The outcomes of all patients with locally advanced or resectable metastatic PNETs who were treated with neoadjuvant CAPTEM between 2009 and 2017 at 2 high-volume institutions were retrospectively reviewed. Thirty patients with locally advanced PNET (n = 10) or pancreatic neuroendocrine hepatic metastases (n = 20) received neoadjuvant CAPTEM. Thirteen patients (43%) exhibited partial radiographic response (PR), 16 (54%) had stable disease, and 1 (3%) developed progressive disease. Twenty-six (87%) patients underwent resection (pancreatectomy [n = 12], combined pancreatectomy and liver resection [n = 8], or major hepatectomy alone [n = 6]); 3 (18%) declined surgery despite radiographic PR, and 1 (3%) underwent aborted pancreatoduodenectomy. Median primary tumor size was 5.5 cm, and median Ki-67 index was 3.5%. Rates of PR were similar across tumor grades (P = 0.24). At median follow-up of 49 months, median progression-free survival was 28.2 months and 5-year overall survival was 63%. Neoadjuvant CAPTEM is associated with favorable radiographic objective response rates for locally advanced or metastatic PNET and may facilitate selection of patients appropriate for surgical resection.