Fig 2 - uploaded by Aaron I Vinik
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This figure illustrates how somatostatin binds to specific receptors on malignant cells when linked with a spacer (DOTA) and TOC or NOC. It can be combined with Gallium 68 for use as a sensitive and quantifiable tracer for scanning with many advantages over the octreoscan. It can be combined with Ytrium 90 or Lutetium 177 for peptide receptor radiotherapy with a 3-to 9-mm kill range depending on whether it is a hard or soft beta emitter.
Source publication
Objective
To review the current state of pancreatic neuroendocrine tumors (PNETS)
Methods
The literature published between 2005 and 2014 in PUBMED, Medline, Google Scholar, Cochrane reports, and ClinicalTrials.gov was examined for relevance to the topic.
Results
PNETS have an incidence < 1 per 100,000 individuals and may functionally secrete biol...
Similar publications
Despite the rarity of the disease, there has been significant recent progress in the management of pancreatic neuroendocrine tumors (PNETs). Arterial phase imaging and somatostatin scintigraphy are important parts of the diagnostic and staging work-up of PNETs. The slow growth rate of PNETs can make observation a reasonable initial option in low vo...
Citations
... pNETs may be divided into functioning and non-functioning. Non-functioning pNETs produce nonspecific peptides, such as chromogranin A, but also may secrete low quantity of hormones, most commonly pancreatic polypeptide and calcitonin [100]. Non-functioning pNETs are more dominant as PIs than functioning pNETs [5]. ...
Pancreatic incidentalomas (PIs) represent a clinical entity increasingly recognized due to advances in and easier access to imaging techniques. By definition, PIs should be detected during abdominal imaging performed for indications other than a pancreatic disease. They range from small cysts to invasive cancer. The incidental diagnosis of pancreatic cancer can contribute to early diagnosis and treatment. On the other hand, inadequate management of PIs may result in overtreatment and unneeded morbidity. Therefore, there is a strong need to evaluate the nature and clinical features of individual PIs. In this review, we summarize the major characteristics related to PIs and present suggestions for their management.
... There has been a particular increase in the incidence of nonfunctional NETs, and most patients present with metastatic disease (1). The majority of NETs are indolent and asymptomatic at early stages, but medical intervention is necessary to control many symptoms derived from tumor volume and hormone secretion at advanced stages (2). NETs are generally heterogeneous, but in rare cases nonfunctional NETs change their phenotype into functional tumors (3,4). ...
Background: Neuroendocrine tumors (NETs) are rare, but their worldwide incidence is gradually increasing. NETs are generally heterogeneous; however, in rare cases, they have been shown to change their phenotype (i.e., nonfunctional to functional or one functional phenotype to the addition of another functional phenotype). Here, we present two cases of liver metastatic NETs with phenotype transformation at the advanced stage that led to life-threatening events.
Case presentation: A 73-year-old woman had a small intestinal nonfunctional NET with liver metastasis. After uncontrollable liver metastasis at the advanced stage, she developed duodenal perforation with hypergastremia. The patient was treated with octreotide and proton pump inhibitors and underwent endoscopic closure for duodenal perforation, but her general condition gradually deteriorated, and she died 2 weeks after duodenal perforation. Another patient, a 50-year-old man, had a functional NET (gastrinoma) with liver metastasis and duodenal ulcer. After uncontrollable liver metastasis at the advanced stage, he developed hypoglycemia. Although octoreotide and diazoxide were administrated for hyperalimentation, his hypoglycemia was uncontrollable, and he died after 4 months owing to general deterioration.
Conclusion: The present cases show that advanced NETs with treatment-uncontrollable liver metastasis can transform their phenotype, specifically from a nonfunctional NET into a functional NET, and from one functional NET into the addition of another functional NET. These experiences suggest that the presence of treatment-resistant liver metastasis might be a hallmark of the potential to gain novel functions.
... The most critical diagnostic criterion is the detection of an inappropriately elevated plasma insulin level under conditions of hypoglycemia. The diagnosis of insulinoma therefore requires confirmation of the presence of hypoglycemia with evidence of inappropriate insulin secretion and the identification of a pancreatic mass by medical imaging or angiography (Vinik, 2014). ...
Delayed diagnosis of insulinoma remains an intractable clinical challenge because the symptoms are in most cases misattributed to other disorders. In this study, a 64-year-old man presented with intermittent seizure episodes after being misdiagnosed with epilepsy and receiving anti-epileptic drugs for 4 years. During this period, the patient continued to suffer from repeated seizures. A starvation test, pancreatic enhancement CT, MRI scan, and pathological examination clinically diagnosed insulinoma, and the symptoms improved following surgical removal of the tumor. The appearance of unusual manifestations and insulinoma imaging makes it difficult to accurately diagnose the condition. This case emphasizes the need for careful reassessment of all atypical and refractory seizures for neurologists.
... Pancreatic polypeptide (PP)-secreting tumors occur with a similar frequency to gastrinomas and insulinomas, and are confined to the head of the pancreas. However, PP has little bioactivity and hence elevated levels result in few if any symptoms (15). Calcitonin-producing PNETs are exceedingly rare and very few cases of their co-occurrence with MEN1 have been reported (1,6,7,13,16,17). ...
Objective: To present a patient with MEN1 Syndrome recently diagnosed with a calcitonin secreting pancreatic neuroendocrine tumor.
Methods: Clinical and diagnostic evaluation, along with intervention is presented. The relevant literature is reviewed.
Results: A 52 year-old Caucasian man with a history of known MEN1 who had a right parathyroidectomy 10 years prior to admission, completion parathyroidectomy and total thyroidectomy for C cell hyperplasia three years prior, and removal of a pituitary adenoma four years prior. He was asymptomatic but had persistently elevated serum calcitonin levels. Venous sampling and PET-CT indicated several lesions in the pancreas as the most likely cause of ectopic calcitonin secretion. The patient underwent pylorus-sparing pancreaticoduodenectomy (Whipple procedure). Several high grade neuroendocrine lesions of the pancreas were noted, with lymphatic invasion and spread to peri-pancreatic lymph nodes. Postoperatively the patient's calcitonin levels returned to normal range.
Conclusions: Calcitonin-secreting pancreatic neuroendocrine tumors are a relatively rare entity, even more rare in familial syndromes such as MEN1. Due to the clinically silent nature of these lesions they are often discovered incidentally, and late in their clinical course. More data are needed in order to establish a consensus on ideal management. Calcitonin elevation even in MEN 1 may herald malignancy, therefore demanding an aggressive approach to evaluation and treatment
... The incidence rate of pNENs is quite low, making them rare tumors, and they account for only 1%-4% of all pancreatic neoplasms. Nevertheless, their incidence rate has increased rapidly in recent years to about 1/100 000 per year [3][4][5]. This phenomenon may be partially explained by the improved radiographic techniques and physicians' increased knowledge about pNENs [6,7]. ...
The incidence rate of pancreatic neuroendocrine neoplasms (pNENs) has increased rapidly in recent years. However, the clinicopathological characteristics of pNENs are poorly understood. Medical records of patients who underwent surgery and were confirmed as pNENs by pathological examination from January 2003 to February 2015 in Qilu Hospital were reviewed retrospectively. A total of 100 patients, 36 males and 64 females, were included with a mean operation age of 46.26 + 13.41 years. Among the 100 cases, 76 had insulinomas and 24 had non-functional pNENs. Tumor size ranged from 0.5 cm to 9 cm, and the mean size was 2.20 + 1.40 cm. The percentages of TNM stages I, II, III, and IV tumors were 89.0%, 8.0%, 0.0%, and 3.0%, respectively. Based on the WHO classification, pNENs were classified into three grades: G1, G2, and G3. G1, G2, and G3 tumors were confirmed in 72.9%, 23.7%, and 3.4% patients, respectively. The positive rates of CgA and Syn immunohistochemical staining were 94.5% (69/73) and 100% (74/74), respectively. Compared with insulinoma, non-functional pNENs have larger tumor sizes, more advanced TNM staging, a higher Ki-67 index, and a higher rate of liver metastasis (P < 0.05). In conclusion, pNENs are heterogeneous tumors with varying clinical manifestations, diverse tumor biological characteristics, and different prognoses. Non-functional pNENs present a more aggressive behavioral model and have poorer prognosis than functional pNENs.
... The diagnostic strategy includes localization of the tumor (abdominal CT or MRI, somatostatin receptor scintigraphy) and laboratory tests, in order to confirm the functional or non-functional status. Therapeutic management includes surgery as first choice therapy in resectable tumors, somatostatin analogue or specific molecular targeted therapy,systemic chemotherapy and liver-directed therapies (radiofrequency ablation, hepatic artery embolization) in patients with a metastatic disease [7,8]. In our patient's case, the first choice of treatment was the surgical excision of the pancreatic tumor, followed by treatment with somatostatin analogues and medical therapy for liver metastases, noting that the patient had diffuse bilobed involvement with associated bone metastases. ...
Background: Non-functional neuroendocrine tumors of the pancreas (NF-pNETs) are a varied group of extremely rare malignancies. The majority of patients already have liver metastases at the diagnosis moment, thus, treatment options are restricted, and the survival rate is reserved.
Case report: We presented the case of 59-year-old patient, diagnosed with non-functional well-differentiated pancreatic neuroendocrine tumor grade II (NET G2) with the presence of chromogranin A, synaptophysin and somatostatin receptor 2, together with liver and bone metastases. Patient underwent a surgical excision of the pancreatic tumor, started long-acting somatostatin analogues (octreotide), interferon therapy for liver metastases and local radiotherapy for bone metastases. After one year, the patient developed diabetes, needing insulin therapy. At approximately three years after the diagnosis, the patient was still living, had a good quality of life, and was free of local recurrence of the tumor or other metastases.
Conclusion: Our case report presented a rare case of metastatic non-functional well-differentiated pancreatic neuroendocrine tumor, involving a multidisciplinary therapeutic approach in order to obtain a good long-term survival.
... 5,8,10 A vast majority of the patients with P-NET are asymptomatic with nonfunctional neoplasms. [6][7][8][9][10][11][12] Many contemporary series have reported that a majority of P-NETs have been discovered incidentally on crosssectional imaging. Of these incidentally detected tumors, a significant number are small (<2 cm), low-grade nonfunctional neoplasms without any lymph node metastasis. ...
... The risk of mortality, as well as regional nodal and distant metastases, has been found to be associated with tumor grade and size. 3,7,[11][12][13][14] The true risk for regional nodal metastasis and the benefits from surgical extirpation of low-grade P-NET are difficult to interpret as most studies lump the high-and low-grade P-NETs into a single tumor type and disregard their biologic differences. 7,8,[15][16][17][18][19] The natural history of high-grade P-NET differs significantly from their low-grade counterparts; high-grade neoplasms have a higher risk of regional nodal disease, distant metastases, and mortality regardless of the size. ...
... 8,19 However, other studies that included only low-grade P-NET have reported that observation plays a key role when the tumor size is under 2 cm. 6,8,11,[20][21][22][23] Based on these findings and other data, the European Neuroendocrine Tumor Society recommended that observation should be considered for low-grade P-NETs that are <2 cm in size. 5 To better understand the natural history, risk for nodal metastases, and the benefits of surgery versus observation for P-NET, we analyzed a large cancer registry. ...
The role of surgical resection in low-grade pancreatic neuroendocrine tumors (P-NET) is unclear. The patients diagnosed with low-grade P-NET from 1988 to 2012 were identified in SEER. Five hundred and sixty-one patients met the inclusion criteria. A majority were white (82.9%), and node negative (69.9%). Univariate analysis revealed that tumor size (<2 cm 8.3%, 2-4 cm 38.5%, and >4 cm 40.3%; P < 0.0001) and surgery (30.9% vs 25.3%; P = 0.0014) were associated with the risk of lymph node metastases (LNM). In contrast, age (P = 0.8360), gender (P = 0.4903), and race (P = 0.4235) were not. Five-year disease-free survival was associated with size (<2 cm 89.4%, 2-4 cm 80.0%, and >4 cm 74.5%; P = 0.0089), LNM (72.4% vs 82.9%; P = 0.0025), and surgery (84.3% vs 47.5%; P < 0.0001). Cox regression model showed that the association with LNM (P = 0.0025) and surgery (P < 0.0001) was significant. Surgery was associated with an improved disease-free survival for tumors >2 cm (2-4 cm, 84.4% vs 26.0% at five years; P = 0.0003, and >4 cm, 80.5% vs 49.5% at five years; P < 0.0001) but not for those with tumor size <2 cm (P = 0.4525). In conclusions, low-grade P-NETs in patients with tumor size >2 cm showed an increased risk of LNM and improved survival with resection.
... Somatostatin analogs such as octreotide and lanreotide are commonly used as therapies to inhibit tumor growth and to provide symptomatic relief in functional PNETs by reducing hormone hypersecretion. 5,6 The rationale for their use is based on the high levels of somatostatin receptors (SSTR) that have been identified in neuroendocrine tumors. 7 SSTR-2a and SSTR-5 have received considerably more attention than the other somatostatin receptors, given that currently available somatostatin analogs have a high affinity to SSTR-2a and SSTR-5. ...
... 17,18 Based on this principle, somatostatin analogs, such as octreotide and lanreotide, have been used for many years for symptomatic management of functional neuroendocrine tumors. 9 The impact that somatostatin analogs have on neuroendocrine tumors relies on the expression of a range of somatostatin receptors (1)(2)(3)(4)(5), to which they have the highest affinity to SSTR-2a and a high affinity to SSTR-5. 3,7,9 There is evidence to suggest that SSTR-2a and SSTR-5 expressions also influence and downregulate pancreatic carcinogenesis, angiogenesis, and initiate apoptosis. ...
... During this period, surgical resection and systemic treatment have advanced considerably, which may have altered patient outcomes overtime. 5 Neuroendocrine tumors may demonstrate significant heterogeneity in their Ki-67 proliferative index. Currently based on the ENET/WHO guidelines the assessment of Ki-67 is based on the areas of tumor demonstrating the highest Ki-67 rates in whole stained sections. ...
Somatostatin receptors (SSTR) are commonly expressed by neuroendocrine tumors. Expression of SSTR-2a and SSTR-5 may impact symptomatic management; however, the impact on survival is unclear. The aim of this study is to correlate SSTR-2a and SSTR-5 expression in pancreatic neuroendocrine tumors (PNETs) with survival.
This study is designed to determine the prognostic significance of somatostatin receptors SSTR-2a and SSTR-5 in PNETs.
This retrospective cohort study included cases of resected PNETs between 1992 and 2014. Clinical data, histopathology, expression of SSTR and Ki-67 by immunohistochemistry, and long-term survival were analyzed.
A total of 99 cases were included in this study. The mean age was 57.8 years (18–87 years) and median tumor size was 25 mm (range 8–160 mm). SSTR-2a and SSTR-5 expression was scored as negative (n = 19, 19.2%; n = 75, 75.8%, respectively) and positive (n = 80, 80.1%; n = 24, 24.2%). The median follow-up was 49 months. SSTR-2a expression was associated with improved overall survival, with cumulative survival rates at 1, 3, and 5 years being 97.5%, 91.5%, and 82.9%, respectively. Univariate analysis demonstrated better survival in SSTR-2a positive patients (log rank P = 0.04). SSTR-5 expression was not associated with survival outcomes (log rank P = 0.94). Multivariate analysis showed that positive SSTR-2a expression is a stronger prognostic indicator for overall survival [Hazard Ratio (HR): 0.2, 95% Confidence interval (CI): 0.1–0.8] compared to high Ki-67 (HR: 0.8, 95% CI: 0.1–5.7).
Expression of SSTR-2a is an independent positive prognostic factor for survival in PNETs.
... Chromogranin A (CgA) is a soluble pro-hormone released by the neuroendocrine system or by cancer cells that can undergo neuroendocrine differentiation (6). Serum Cg A is the most widely accepted biomarker in pancreatic neuroendocrine tumors (PNETs) (7). ...
Background/aims:
Pancreatic cystic lesions have a broad spectrum of differential diagnosis. There is an ongoing demand to identify specific and sensitive cystic fluid markers for the differential diagnosis of pancreatic cysts. We aimed to evaluate the diagnostic value of cystic fluid chromogranin A (CgA) in the differential diagnosis of pancreatic cysts.
Materials and methods:
Patients who underwent endoscopic ultrasound (EUS)-guided aspiration for pancreatic cysts were included in the study. Cytopathological analysis and biochemical analysis, including cystic fluid carcinoembryonic antigen (CEA), amylase, Ca 19-9, and CgA, were performed.
Results:
Fifty-three patients were included in the study. The final diagnosis of patients was 14 pancreatic pseudocysts, 10 intraductal papillary mucinous neoplasms (IPMNs), 8 mucinous cystic neoplasms (MCN), 8 serous cystadenomas (SCAs), 2 cystic pancreatic neuroendocrine tumors (PNETs), and 11 others. The mean CgA levels were 50.51±130.04 ng/mL in pseudocysts, 12.38±8.59 in MCN, and 13.76±10.90 in cystic PNET. There was only one patient with a very high cystic fluid CgA (515.49 ng/mL) and was diagnosed as pseudocyst developed in chronic pancreatitis patient. Two patients with cystic PNET had normal levels of cystic fluid CgA.
Conclusion:
Cystic fluid CgA is not a useful marker for the differential diagnosis of cystic PNETs. It also has no value in the differential diagnosis of other pancreatic cysts.
... Pancreatic neuroendocrine tumors (pNETs) present with a heterogeneous clinical behavior (1). The majority of pNETs have an indolent course at early stage, but patients will eventually develop symptoms of tumor progression or hormone secretion that usually requires medical intervention (1). ...
... Pancreatic neuroendocrine tumors (pNETs) present with a heterogeneous clinical behavior (1). The majority of pNETs have an indolent course at early stage, but patients will eventually develop symptoms of tumor progression or hormone secretion that usually requires medical intervention (1). Based on their endocrine secretion, pNETs may be divided into functioning or nonfunctioning tumors. ...
Approximately 35% of the pancreatic neuroendocrine tumors (pNETs) are functional, the most common of which is an insulinoma. Rarely can initially nonfunctioning tumor undergo biological transformation to a hormone-secreting tumor with subsequent changes in the clinical picture. We present here three unique patients with long-standing pNETs who developed life-threatening hyperinsulinemic hypoglycemia along with tumor progression. In two of the patients, everolimus (Afinitor) was administered in an attempt to control both tumor growth and hypoglycemia. In two cases everolimus therapy resulted in the abolishment of hypoglycemia and induced significant tumor regression; however these beneficial responses were transient. These cases highlight the exceptional ability of pNETs to change biological behavior in parallel with disease progression. Our experience concurs with recently published studies demonstrating the utility of everolimus for the control of both hypoglycemia and tumor progression.
Nonfunctional pNET can gain new features such as insulin secretion with related morbidity.Gain of function in a previously nonfunctional pNET signifies tumor progression and is usually associated with poor prognosis.Everolimus proved to be a viable treatment for hypoglycemia in insulinoma patients and was also proven highly effective in the patients presented here.As disease progresses, the effect of everolimus on hypoglycemia wanes. We report for the first time the development of hypoglycemia during everolimus treatment.
